Extramammary Paget disease (EMPD) is a malignant epithelial tumor that most commonly affects the anogenital region and less frequently arises in the axillae. Most cases occur in locations where apocrine glands predominate.¹ Few cases of EMPD arising in nonapocrine-bearing regions, or ectopic EMPD, have been reported.² We describe a case of primary ectopic EMPD with an infiltrative growth pattern arising on the back of a 67-year-old Thai man.

Case Report

A 67-year-old Thai man presented to the dermatology clinic for evaluation of a persistent rash on the right lower back of approximately 30 years’ duration. He reported that the eruption had started out as a small coin-shaped area but had slowly increased in size. Over the last 2 years, the area had grown more rapidly and became pruritic. His medical history was remarkable for hypertension treated with losartan, but he was otherwise healthy. He had no history of cancer or gastrointestinal tract or genitourinary symptoms, and he had no recent fever, weight loss, or night sweats.

On physical examination a well-demarcated, asymmetric, erythematous to brown plaque was noted on the right lower back. The plaque was surfaced by scale and contained a central hyperkeratotic papule (Figure 1). The skin examination was otherwise unremarkable. The patient had no lymphadenopathy.

Two punch biopsies were performed. On low power, acanthosis and hyperkeratosis of the epidermis were noted. The epidermis contained a proliferation of large (tumor) cells with pleomorphic nuclei, prominent nucleoli, and abundant pale to clear cytoplasm. The cells were present singularly as well as in clusters and were most prominent along the basal layer but many were also seen extending to more superficial levels of the epidermis (Figure 2A). In one biopsy, the tumor cells were found in the dermis with an infiltrative growth pattern (Figure 2B). Immunohistochemistry (IHC) studies for cytokeratin 7 (Figure 3A and 3B) and carcinoembryonic antigen (Figure 3C) labeled the tumor cells. An IHC study for gross cystic disease fluid protein 15 labeled some of the tumor cells. Immunohistochemistry studies for S-100, human melanoma black 45 (HMB-45), p16, and renal cell carcinoma did not label the tumor cells. An IHC study for MIB-1 labeled many of the tumor cells, indicating a notably increased mitotic index. The patient was diagnosed with ectopic EMPD. He underwent an endoscopy, colonoscopy, and cystoscopy, all of which were normal.

Comment

Extramammary Paget disease is a malignant tumor typically found in apocrine-rich areas of the skin, particularly the anogenital skin. It is categorized as primary or secondary EMPD. Primary EMPD arises as an intraepithelial adenocarcinoma, with the Toker cell as the cell of origin.³ Secondary EMPD represents a cutaneous extension of an underlying malignancy (eg, colorectal, urothelial, prostatic, gynecologic).⁴

Ectopic EMPD arises in nonapocrine-bearing areas, specifically the nongerminative milk line. A review of the literature using Google Scholar and the search term ectopic extramammary Paget disease showed that there have been at least 30 cases of ectopic EMPD reported. Older men are more commonly affected, with a mean age at diagnosis of approximately 68 years. Although the tumor is most commonly seen on the trunk, cases on the head, arms, and legs have been reported.⁵

This tumor is most frequently seen in Asian individuals, as in our patient, with a ratio of approximately 3:1.⁵ Interestingly, triple or quadruple EMPD was reported in 68 Japanese patients but rarely has been reported outside of Japan.⁶ It is thought that some germinative apocrine-differentiating cells might preferentially exist on the trunk of Asians, leading to an increased incidence of EMPD in this population⁵; however, the exact reason for this racial preference is not completely understood, and more studies are needed to investigate this association.

Diagnosis of ectopic EMPD is made histologically. Tumor cells have abundant pale cytoplasm and large pleomorphic nuclei with prominent nucleoli. The cells are arranged in small groups or singly within the basal regions of the epidermis. In longstanding lesions, the entire thickness of the epidermis may be involved. Uncommonly, the tumor cells may invade the dermis, such as in our patient. On immunohistochemistry, the tumor cells stain positive for carcinoembryonic antigen, epithelial membrane antigen, and low-molecular-weight cytokeratins (eg, cytokeratin 7). Many of the tumor cells also express gross cystic disease fluid protein 15, which helps exclude cutaneous invasion of secondary EMPD.^7-9 Cases of primary cutaneous apocrine carcinoma can have similar histologic and immunohistochemical findings to invasive EMPD, which further supports the possible apocrine derivation of Paget disease. In our patient, we considered the diagnosis of primary cutaneous apocrine adenocarcinoma with epidermotropism; however, we favored the diagnosis of ectopic EMPD with dermal invasion given the extensive epidermal-only involvement seen in one of the biopsies, which would be unusual for primary cutaneous apocrine adenocarcinoma.

Our patient had no identified underlying malignancy upon further workup; however, many cases of EMPD have been associated with an underlying malignancy.^9-15 Several authors have reported a range of underlying malignancies associated with EMPD, with the incidence ranging from 11% to 45%.^9-15 The location of the underlying internal malignancy appears to be closely related to the location of the EMPD.¹¹ It is recommended that a thorough workup for internal malignancies be performed, including a full skin examination, lymph node examination, colonoscopy, cystoscopy, and gynecologic/prostate examination, among others.

No known differences in the prognosis or associated underlying malignancies between ectopic and ordinary EMPD have been reported; however, it has been noted that EMPD with invasion into the dermis does correlate with a more aggressive course and worse prognosis.⁸ Treatment includes surgical removal by Mohs micrographic surgery or wide local excision. Long-term follow-up is required since recurrences can be frequent.^11-15

Extramammary Paget disease (EMPD) is a malignant epithelial tumor that most commonly affects the anogenital region and less frequently arises in the axillae. Most cases occur in locations where apocrine glands predominate.¹ Few cases of EMPD arising in nonapocrine-bearing regions, or ectopic EMPD, have been reported.² We describe a case of primary ectopic EMPD with an infiltrative growth pattern arising on the back of a 67-year-old Thai man.

Case Report

A 67-year-old Thai man presented to the dermatology clinic for evaluation of a persistent rash on the right lower back of approximately 30 years’ duration. He reported that the eruption had started out as a small coin-shaped area but had slowly increased in size. Over the last 2 years, the area had grown more rapidly and became pruritic. His medical history was remarkable for hypertension treated with losartan, but he was otherwise healthy. He had no history of cancer or gastrointestinal tract or genitourinary symptoms, and he had no recent fever, weight loss, or night sweats.

On physical examination a well-demarcated, asymmetric, erythematous to brown plaque was noted on the right lower back. The plaque was surfaced by scale and contained a central hyperkeratotic papule (Figure 1). The skin examination was otherwise unremarkable. The patient had no lymphadenopathy.

Two punch biopsies were performed. On low power, acanthosis and hyperkeratosis of the epidermis were noted. The epidermis contained a proliferation of large (tumor) cells with pleomorphic nuclei, prominent nucleoli, and abundant pale to clear cytoplasm. The cells were present singularly as well as in clusters and were most prominent along the basal layer but many were also seen extending to more superficial levels of the epidermis (Figure 2A). In one biopsy, the tumor cells were found in the dermis with an infiltrative growth pattern (Figure 2B). Immunohistochemistry (IHC) studies for cytokeratin 7 (Figure 3A and 3B) and carcinoembryonic antigen (Figure 3C) labeled the tumor cells. An IHC study for gross cystic disease fluid protein 15 labeled some of the tumor cells. Immunohistochemistry studies for S-100, human melanoma black 45 (HMB-45), p16, and renal cell carcinoma did not label the tumor cells. An IHC study for MIB-1 labeled many of the tumor cells, indicating a notably increased mitotic index. The patient was diagnosed with ectopic EMPD. He underwent an endoscopy, colonoscopy, and cystoscopy, all of which were normal.

Comment

Extramammary Paget disease is a malignant tumor typically found in apocrine-rich areas of the skin, particularly the anogenital skin. It is categorized as primary or secondary EMPD. Primary EMPD arises as an intraepithelial adenocarcinoma, with the Toker cell as the cell of origin.³ Secondary EMPD represents a cutaneous extension of an underlying malignancy (eg, colorectal, urothelial, prostatic, gynecologic).⁴

Ectopic EMPD arises in nonapocrine-bearing areas, specifically the nongerminative milk line. A review of the literature using Google Scholar and the search term ectopic extramammary Paget disease showed that there have been at least 30 cases of ectopic EMPD reported. Older men are more commonly affected, with a mean age at diagnosis of approximately 68 years. Although the tumor is most commonly seen on the trunk, cases on the head, arms, and legs have been reported.⁵

This tumor is most frequently seen in Asian individuals, as in our patient, with a ratio of approximately 3:1.⁵ Interestingly, triple or quadruple EMPD was reported in 68 Japanese patients but rarely has been reported outside of Japan.⁶ It is thought that some germinative apocrine-differentiating cells might preferentially exist on the trunk of Asians, leading to an increased incidence of EMPD in this population⁵; however, the exact reason for this racial preference is not completely understood, and more studies are needed to investigate this association.

Diagnosis of ectopic EMPD is made histologically. Tumor cells have abundant pale cytoplasm and large pleomorphic nuclei with prominent nucleoli. The cells are arranged in small groups or singly within the basal regions of the epidermis. In longstanding lesions, the entire thickness of the epidermis may be involved. Uncommonly, the tumor cells may invade the dermis, such as in our patient. On immunohistochemistry, the tumor cells stain positive for carcinoembryonic antigen, epithelial membrane antigen, and low-molecular-weight cytokeratins (eg, cytokeratin 7). Many of the tumor cells also express gross cystic disease fluid protein 15, which helps exclude cutaneous invasion of secondary EMPD.^7-9 Cases of primary cutaneous apocrine carcinoma can have similar histologic and immunohistochemical findings to invasive EMPD, which further supports the possible apocrine derivation of Paget disease. In our patient, we considered the diagnosis of primary cutaneous apocrine adenocarcinoma with epidermotropism; however, we favored the diagnosis of ectopic EMPD with dermal invasion given the extensive epidermal-only involvement seen in one of the biopsies, which would be unusual for primary cutaneous apocrine adenocarcinoma.

Our patient had no identified underlying malignancy upon further workup; however, many cases of EMPD have been associated with an underlying malignancy.^9-15 Several authors have reported a range of underlying malignancies associated with EMPD, with the incidence ranging from 11% to 45%.^9-15 The location of the underlying internal malignancy appears to be closely related to the location of the EMPD.¹¹ It is recommended that a thorough workup for internal malignancies be performed, including a full skin examination, lymph node examination, colonoscopy, cystoscopy, and gynecologic/prostate examination, among others.

No known differences in the prognosis or associated underlying malignancies between ectopic and ordinary EMPD have been reported; however, it has been noted that EMPD with invasion into the dermis does correlate with a more aggressive course and worse prognosis.⁸ Treatment includes surgical removal by Mohs micrographic surgery or wide local excision. Long-term follow-up is required since recurrences can be frequent.^11-15

Extramammary Paget disease (EMPD) is a malignant epithelial tumor that most commonly affects the anogenital region and less frequently arises in the axillae. Most cases occur in locations where apocrine glands predominate.¹ Few cases of EMPD arising in nonapocrine-bearing regions, or ectopic EMPD, have been reported.² We describe a case of primary ectopic EMPD with an infiltrative growth pattern arising on the back of a 67-year-old Thai man.

Case Report

A 67-year-old Thai man presented to the dermatology clinic for evaluation of a persistent rash on the right lower back of approximately 30 years’ duration. He reported that the eruption had started out as a small coin-shaped area but had slowly increased in size. Over the last 2 years, the area had grown more rapidly and became pruritic. His medical history was remarkable for hypertension treated with losartan, but he was otherwise healthy. He had no history of cancer or gastrointestinal tract or genitourinary symptoms, and he had no recent fever, weight loss, or night sweats.

On physical examination a well-demarcated, asymmetric, erythematous to brown plaque was noted on the right lower back. The plaque was surfaced by scale and contained a central hyperkeratotic papule (Figure 1). The skin examination was otherwise unremarkable. The patient had no lymphadenopathy.

Two punch biopsies were performed. On low power, acanthosis and hyperkeratosis of the epidermis were noted. The epidermis contained a proliferation of large (tumor) cells with pleomorphic nuclei, prominent nucleoli, and abundant pale to clear cytoplasm. The cells were present singularly as well as in clusters and were most prominent along the basal layer but many were also seen extending to more superficial levels of the epidermis (Figure 2A). In one biopsy, the tumor cells were found in the dermis with an infiltrative growth pattern (Figure 2B). Immunohistochemistry (IHC) studies for cytokeratin 7 (Figure 3A and 3B) and carcinoembryonic antigen (Figure 3C) labeled the tumor cells. An IHC study for gross cystic disease fluid protein 15 labeled some of the tumor cells. Immunohistochemistry studies for S-100, human melanoma black 45 (HMB-45), p16, and renal cell carcinoma did not label the tumor cells. An IHC study for MIB-1 labeled many of the tumor cells, indicating a notably increased mitotic index. The patient was diagnosed with ectopic EMPD. He underwent an endoscopy, colonoscopy, and cystoscopy, all of which were normal.

Comment

Extramammary Paget disease is a malignant tumor typically found in apocrine-rich areas of the skin, particularly the anogenital skin. It is categorized as primary or secondary EMPD. Primary EMPD arises as an intraepithelial adenocarcinoma, with the Toker cell as the cell of origin.³ Secondary EMPD represents a cutaneous extension of an underlying malignancy (eg, colorectal, urothelial, prostatic, gynecologic).⁴

Ectopic EMPD arises in nonapocrine-bearing areas, specifically the nongerminative milk line. A review of the literature using Google Scholar and the search term ectopic extramammary Paget disease showed that there have been at least 30 cases of ectopic EMPD reported. Older men are more commonly affected, with a mean age at diagnosis of approximately 68 years. Although the tumor is most commonly seen on the trunk, cases on the head, arms, and legs have been reported.⁵

This tumor is most frequently seen in Asian individuals, as in our patient, with a ratio of approximately 3:1.⁵ Interestingly, triple or quadruple EMPD was reported in 68 Japanese patients but rarely has been reported outside of Japan.⁶ It is thought that some germinative apocrine-differentiating cells might preferentially exist on the trunk of Asians, leading to an increased incidence of EMPD in this population⁵; however, the exact reason for this racial preference is not completely understood, and more studies are needed to investigate this association.

Diagnosis of ectopic EMPD is made histologically. Tumor cells have abundant pale cytoplasm and large pleomorphic nuclei with prominent nucleoli. The cells are arranged in small groups or singly within the basal regions of the epidermis. In longstanding lesions, the entire thickness of the epidermis may be involved. Uncommonly, the tumor cells may invade the dermis, such as in our patient. On immunohistochemistry, the tumor cells stain positive for carcinoembryonic antigen, epithelial membrane antigen, and low-molecular-weight cytokeratins (eg, cytokeratin 7). Many of the tumor cells also express gross cystic disease fluid protein 15, which helps exclude cutaneous invasion of secondary EMPD.^7-9 Cases of primary cutaneous apocrine carcinoma can have similar histologic and immunohistochemical findings to invasive EMPD, which further supports the possible apocrine derivation of Paget disease. In our patient, we considered the diagnosis of primary cutaneous apocrine adenocarcinoma with epidermotropism; however, we favored the diagnosis of ectopic EMPD with dermal invasion given the extensive epidermal-only involvement seen in one of the biopsies, which would be unusual for primary cutaneous apocrine adenocarcinoma.

Our patient had no identified underlying malignancy upon further workup; however, many cases of EMPD have been associated with an underlying malignancy.^9-15 Several authors have reported a range of underlying malignancies associated with EMPD, with the incidence ranging from 11% to 45%.^9-15 The location of the underlying internal malignancy appears to be closely related to the location of the EMPD.¹¹ It is recommended that a thorough workup for internal malignancies be performed, including a full skin examination, lymph node examination, colonoscopy, cystoscopy, and gynecologic/prostate examination, among others.

No known differences in the prognosis or associated underlying malignancies between ectopic and ordinary EMPD have been reported; however, it has been noted that EMPD with invasion into the dermis does correlate with a more aggressive course and worse prognosis.⁸ Treatment includes surgical removal by Mohs micrographic surgery or wide local excision. Long-term follow-up is required since recurrences can be frequent.^11-15

The Diagnosis: Erythrasma

Erythrasma usually involves intertriginous areas (eg, axillae, groin, inframammary area). Patients present with well-demarcated, minimally scaly, red-brown patches. The interdigital web space of the toes also can be involved with macerated white plaques, often with coexistent dermatophyte infection. Corynebacterium minutissimum, the bacteria responsible for erythrasma, produces coproporphyrin type III, which emits coral red fluorescence under Wood lamp examination.¹ Bathing may result in removal of the porphyrin and result in a false-negative finding. Potassium hydroxide preparation of skin scrapings can show chains of bacilli. Biopsy appears relatively normal at low power but reveals compact orthokeratosis with coccobacilli and filamentous organisms in the superficial stratum corneum (quiz image). When not obvious on hematoxylin and eosin-stained sections, the organisms are Gram-positive and also are seen with periodic acid-Schiff (PAS) and methenamine silver stains. Unlike fungal hyphae, these organisms are thinner and nonrefractile. Inflammation typically is minimal. Due to the subtle histologic findings at low power, erythrasma is considered one of the invisible dermatoses.² The differential diagnosis of these inconspicuous dermatoses that appear normal at first glance can be approached in a stepwise fashion starting in the stratum corneum, followed by the granular layer, basal layer, dermal papillae, dermal inflammatory cells, dermal connective tissue, and eccrine glands, and should consider each of the following diagnoses: candidiasis, dermatophytosis, ichthyosis vulgaris, vitiligo, macular amyloid, urticaria, telangiectasia macularis eruptiva perstans, connective tissue nevus, and argyria.² 

Candidiasis, most commonly caused by Candida albicans, usually involves the oral cavity (eg, thrush, median rhomboid glossitis, angular cheilitis), intertriginous zones, nail fold (paronychia), genital areas (eg, vulvovaginitis, balanitis), and diaper area.³ The web space between the third and fourth fingers (erosio interdigitalis blastomycetica) can be involved in patients whose hands are frequently in water. Intertriginous candidiasis presents with bright red, sometimes erosive patches with satellite lesions. Spores and mycelia (filamentous forms) are noted on potassium hydroxide preparation of skin scrapings. Histologically, the epidermis often is acanthotic, mildly spongiotic, and contains groups of neutrophils in the superficial layers. The mnemonic device for diseases with clusters of neutrophils in the stratum corneum is PTICSS (psoriasis, tinea, impetigo, candida, seborrheic dermatitis, syphilis).² Yeast, pseudohyphae, and even true hyphae can be seen in the stratum corneum with hematoxylin and eosin-stained sections and PAS. The filamentous forms tend to be vertically oriented in relation to the skin surface (Figure 1) compared to dermatophyte hyphae that tend to be parallel to the surface.²

Pitted keratolysis is a superficial bacterial infection involving the soles of the feet. The classic clinical findings are shallow 1- to 2-mm pits in clusters that can coalesce on pressure-bearing areas. Hyperhidrosis, malodor, and maceration commonly are associated. Microscopic examination reveals clusters of small cocci and filamentous bacteria located in the dell or pit of a thick compact orthokeratotic stratum corneum of acral skin with no notable inflammatory infiltrate (Figure 2).² Special stains such as Gram, methenamine silver, or PAS can assist in visualization of the organisms. Pitted keratolysis is caused by Dermatophilus congolensis and Kytococcus sedentarius (formerly Micrococcus sedentarius), which produce keratinolytic enzymes causing the defect in the stratum corneum.³

Tinea cruris, also known as jock itch and ringworm of the groin, presents with advancing pruritic, circinate, erythematous, scaling patches with central clearing on the inner thighs and crural folds. Similar to tinea pedis, Trichophyton rubrum is the most common dermatophyte to cause tinea cruris.⁴ Potassium hydroxide preparation of skin scrapings from the advancing border show fungal hyphae that cross the keratin cell borders. The histopathology of dermatophyte infections can be subtle and resemble normal skin before close inspection of the stratum corneum, which can show compact orthokeratosis, neutrophils, or "sandwich sign" where hyphae are sandwiched between an upper basket weave layer and a lower compact cornified layer (orthokeratotic or parakeratotic)(Figure 3).¹ The presence of these patterns in the stratum corneum should result in performance of PAS to highlight obscure hyphae.

Tinea versicolor, also called pityriasis versicolor, usually presents with hypopigmented or less commonly hyperpigmented circular patches that coalesce on the upper trunk and shoulders. There is a fine fluffy scale that is most notable after scraping the skin for a potassium hydroxide preparation, which shows "spaghetti and meatballs" (hyphae and spores). Tinea versicolor typically is caused by the mycelial phase of the lipophilic yeast Malassezia globosae.³ Histologically, there are yeast and short septate hyphae scattered in a loose basket weave hyperkeratotic stratum corneum with minimal or no inflammation (Figure 4). On occasion, PAS is required for identification.

The Diagnosis: Erythrasma

Erythrasma usually involves intertriginous areas (eg, axillae, groin, inframammary area). Patients present with well-demarcated, minimally scaly, red-brown patches. The interdigital web space of the toes also can be involved with macerated white plaques, often with coexistent dermatophyte infection. Corynebacterium minutissimum, the bacteria responsible for erythrasma, produces coproporphyrin type III, which emits coral red fluorescence under Wood lamp examination.¹ Bathing may result in removal of the porphyrin and result in a false-negative finding. Potassium hydroxide preparation of skin scrapings can show chains of bacilli. Biopsy appears relatively normal at low power but reveals compact orthokeratosis with coccobacilli and filamentous organisms in the superficial stratum corneum (quiz image). When not obvious on hematoxylin and eosin-stained sections, the organisms are Gram-positive and also are seen with periodic acid-Schiff (PAS) and methenamine silver stains. Unlike fungal hyphae, these organisms are thinner and nonrefractile. Inflammation typically is minimal. Due to the subtle histologic findings at low power, erythrasma is considered one of the invisible dermatoses.² The differential diagnosis of these inconspicuous dermatoses that appear normal at first glance can be approached in a stepwise fashion starting in the stratum corneum, followed by the granular layer, basal layer, dermal papillae, dermal inflammatory cells, dermal connective tissue, and eccrine glands, and should consider each of the following diagnoses: candidiasis, dermatophytosis, ichthyosis vulgaris, vitiligo, macular amyloid, urticaria, telangiectasia macularis eruptiva perstans, connective tissue nevus, and argyria.² 

Candidiasis, most commonly caused by Candida albicans, usually involves the oral cavity (eg, thrush, median rhomboid glossitis, angular cheilitis), intertriginous zones, nail fold (paronychia), genital areas (eg, vulvovaginitis, balanitis), and diaper area.³ The web space between the third and fourth fingers (erosio interdigitalis blastomycetica) can be involved in patients whose hands are frequently in water. Intertriginous candidiasis presents with bright red, sometimes erosive patches with satellite lesions. Spores and mycelia (filamentous forms) are noted on potassium hydroxide preparation of skin scrapings. Histologically, the epidermis often is acanthotic, mildly spongiotic, and contains groups of neutrophils in the superficial layers. The mnemonic device for diseases with clusters of neutrophils in the stratum corneum is PTICSS (psoriasis, tinea, impetigo, candida, seborrheic dermatitis, syphilis).² Yeast, pseudohyphae, and even true hyphae can be seen in the stratum corneum with hematoxylin and eosin-stained sections and PAS. The filamentous forms tend to be vertically oriented in relation to the skin surface (Figure 1) compared to dermatophyte hyphae that tend to be parallel to the surface.²

Pitted keratolysis is a superficial bacterial infection involving the soles of the feet. The classic clinical findings are shallow 1- to 2-mm pits in clusters that can coalesce on pressure-bearing areas. Hyperhidrosis, malodor, and maceration commonly are associated. Microscopic examination reveals clusters of small cocci and filamentous bacteria located in the dell or pit of a thick compact orthokeratotic stratum corneum of acral skin with no notable inflammatory infiltrate (Figure 2).² Special stains such as Gram, methenamine silver, or PAS can assist in visualization of the organisms. Pitted keratolysis is caused by Dermatophilus congolensis and Kytococcus sedentarius (formerly Micrococcus sedentarius), which produce keratinolytic enzymes causing the defect in the stratum corneum.³

Tinea cruris, also known as jock itch and ringworm of the groin, presents with advancing pruritic, circinate, erythematous, scaling patches with central clearing on the inner thighs and crural folds. Similar to tinea pedis, Trichophyton rubrum is the most common dermatophyte to cause tinea cruris.⁴ Potassium hydroxide preparation of skin scrapings from the advancing border show fungal hyphae that cross the keratin cell borders. The histopathology of dermatophyte infections can be subtle and resemble normal skin before close inspection of the stratum corneum, which can show compact orthokeratosis, neutrophils, or "sandwich sign" where hyphae are sandwiched between an upper basket weave layer and a lower compact cornified layer (orthokeratotic or parakeratotic)(Figure 3).¹ The presence of these patterns in the stratum corneum should result in performance of PAS to highlight obscure hyphae.

Tinea versicolor, also called pityriasis versicolor, usually presents with hypopigmented or less commonly hyperpigmented circular patches that coalesce on the upper trunk and shoulders. There is a fine fluffy scale that is most notable after scraping the skin for a potassium hydroxide preparation, which shows "spaghetti and meatballs" (hyphae and spores). Tinea versicolor typically is caused by the mycelial phase of the lipophilic yeast Malassezia globosae.³ Histologically, there are yeast and short septate hyphae scattered in a loose basket weave hyperkeratotic stratum corneum with minimal or no inflammation (Figure 4). On occasion, PAS is required for identification.

The Diagnosis: Erythrasma

Erythrasma usually involves intertriginous areas (eg, axillae, groin, inframammary area). Patients present with well-demarcated, minimally scaly, red-brown patches. The interdigital web space of the toes also can be involved with macerated white plaques, often with coexistent dermatophyte infection. Corynebacterium minutissimum, the bacteria responsible for erythrasma, produces coproporphyrin type III, which emits coral red fluorescence under Wood lamp examination.¹ Bathing may result in removal of the porphyrin and result in a false-negative finding. Potassium hydroxide preparation of skin scrapings can show chains of bacilli. Biopsy appears relatively normal at low power but reveals compact orthokeratosis with coccobacilli and filamentous organisms in the superficial stratum corneum (quiz image). When not obvious on hematoxylin and eosin-stained sections, the organisms are Gram-positive and also are seen with periodic acid-Schiff (PAS) and methenamine silver stains. Unlike fungal hyphae, these organisms are thinner and nonrefractile. Inflammation typically is minimal. Due to the subtle histologic findings at low power, erythrasma is considered one of the invisible dermatoses.² The differential diagnosis of these inconspicuous dermatoses that appear normal at first glance can be approached in a stepwise fashion starting in the stratum corneum, followed by the granular layer, basal layer, dermal papillae, dermal inflammatory cells, dermal connective tissue, and eccrine glands, and should consider each of the following diagnoses: candidiasis, dermatophytosis, ichthyosis vulgaris, vitiligo, macular amyloid, urticaria, telangiectasia macularis eruptiva perstans, connective tissue nevus, and argyria.² 

Candidiasis, most commonly caused by Candida albicans, usually involves the oral cavity (eg, thrush, median rhomboid glossitis, angular cheilitis), intertriginous zones, nail fold (paronychia), genital areas (eg, vulvovaginitis, balanitis), and diaper area.³ The web space between the third and fourth fingers (erosio interdigitalis blastomycetica) can be involved in patients whose hands are frequently in water. Intertriginous candidiasis presents with bright red, sometimes erosive patches with satellite lesions. Spores and mycelia (filamentous forms) are noted on potassium hydroxide preparation of skin scrapings. Histologically, the epidermis often is acanthotic, mildly spongiotic, and contains groups of neutrophils in the superficial layers. The mnemonic device for diseases with clusters of neutrophils in the stratum corneum is PTICSS (psoriasis, tinea, impetigo, candida, seborrheic dermatitis, syphilis).² Yeast, pseudohyphae, and even true hyphae can be seen in the stratum corneum with hematoxylin and eosin-stained sections and PAS. The filamentous forms tend to be vertically oriented in relation to the skin surface (Figure 1) compared to dermatophyte hyphae that tend to be parallel to the surface.²

Pitted keratolysis is a superficial bacterial infection involving the soles of the feet. The classic clinical findings are shallow 1- to 2-mm pits in clusters that can coalesce on pressure-bearing areas. Hyperhidrosis, malodor, and maceration commonly are associated. Microscopic examination reveals clusters of small cocci and filamentous bacteria located in the dell or pit of a thick compact orthokeratotic stratum corneum of acral skin with no notable inflammatory infiltrate (Figure 2).² Special stains such as Gram, methenamine silver, or PAS can assist in visualization of the organisms. Pitted keratolysis is caused by Dermatophilus congolensis and Kytococcus sedentarius (formerly Micrococcus sedentarius), which produce keratinolytic enzymes causing the defect in the stratum corneum.³

Tinea cruris, also known as jock itch and ringworm of the groin, presents with advancing pruritic, circinate, erythematous, scaling patches with central clearing on the inner thighs and crural folds. Similar to tinea pedis, Trichophyton rubrum is the most common dermatophyte to cause tinea cruris.⁴ Potassium hydroxide preparation of skin scrapings from the advancing border show fungal hyphae that cross the keratin cell borders. The histopathology of dermatophyte infections can be subtle and resemble normal skin before close inspection of the stratum corneum, which can show compact orthokeratosis, neutrophils, or "sandwich sign" where hyphae are sandwiched between an upper basket weave layer and a lower compact cornified layer (orthokeratotic or parakeratotic)(Figure 3).¹ The presence of these patterns in the stratum corneum should result in performance of PAS to highlight obscure hyphae.

Tinea versicolor, also called pityriasis versicolor, usually presents with hypopigmented or less commonly hyperpigmented circular patches that coalesce on the upper trunk and shoulders. There is a fine fluffy scale that is most notable after scraping the skin for a potassium hydroxide preparation, which shows "spaghetti and meatballs" (hyphae and spores). Tinea versicolor typically is caused by the mycelial phase of the lipophilic yeast Malassezia globosae.³ Histologically, there are yeast and short septate hyphae scattered in a loose basket weave hyperkeratotic stratum corneum with minimal or no inflammation (Figure 4). On occasion, PAS is required for identification.

From the University of Texas Southwestern, Department of Internal Medicine, Dallas, TX.

Abstract

• Objective: To define intestinal failure and associated diseases that often lead to diarrhea and high-output states, and to provide a literature review on the current evidence and practice guidelines for the management of these conditions in the context of a clinical case.
• Methods: Database search on dietary and medical interventions as well as major societal guidelines for the management of intestinal failure and associated conditions.
• Results: Although major societal guidelines exist, the guidelines vary greatly amongst various specialties and are not supported by strong evidence from large randomized controlled trials. The majority of the guidelines recommend consideration of several drug classes, but do not specify medications within the drug class, optimal dose, frequency, mode of administration, and how long to trial a regimen before considering it a failure and adding additional medical therapies.
• Conclusions: Intestinal failure and high-output states affect a very heterogenous population with high morbidity and mortality. This subset of patients should be managed using a multidisciplinary approach involving surgery, gastroenterology, dietetics, internal medicine and ancillary services that include but are not limited to ostomy nurses and home health care. Implementation of a standardized protocol in the electronic medical record including both medical and nutritional therapies may be useful to help optimize efficacy of medications, aid in nutrient absorption, decrease cost, reduce hospital length of stay, and decrease hospital readmissions.

Key words: short bowel syndrome; high-output ostomy; entero-cutaneous fistula; diarrhea; malnutrition.

Intestinal failure includes but is not limited to short bowel syndrome (SBS), high-output enterostomy, and high-output related to entero-cutaneous fistulas (ECF). These conditions are unfortunate complications after major abdominal surgery requiring extensive intestinal resection leading to structural SBS. Absorption of macronutrients and micronutrients is most dependent on the length and specific segment of remaining intact small intestine [1]. The normal small intestine length varies greatly but ranges from 300 to 800 cm, while in those with structural SBS the typical length is 200 cm or less [2,3]. Certain malabsorptive enteropathies and severe intestinal dysmotility conditions may manifest as functional SBS as well. Factors that influence whether an individual will develop functional SBS despite having sufficient small intestinal absorptive area include the degree of jejunal absorptive efficacy and the ability to overcompensate with enough oral caloric intake despite high fecal energy losses, also known as hyperphagia [4].

Pathophysiology

Maintenance of normal bodily functions and homeostasis is dependent on sufficient intestinal absorption of essential macronutrients, micronutrients, and fluids. The hallmark of intestinal failure is based on the presence of decreased small bowel absorptive surface area and subsequent increased losses of key solutes and fluids [1]. Intestinal failure is a broad term that is comprised of 3 distinct phenotypes. The 3 functional classifications of intestinal failure include the following:

• Type 1. Acute intestinal failure is generally self-limiting, occurs after abdominal surgery, and typically lasts less than 28 days.
• Type 2. Subacute intestinal failure frequently occurs in septic, stressed, or metabolically unstable patients and may last up to several months.
• Type 3. Chronic intestinal failure occurs due to a chronic condition that generally requires indefinite parenteral nutrition (PN) [1,3,4].

SBS and enterostomy formation are often associated with excessive diarrhea, such that it is the most common etiology for postoperative readmissions. The definition of “high-output” varies amongst studies, but output is generally considered to be abnormally high if it is greater than 500 mL per 24 hours in ECFs and greater than 1500 mL per 24 hours for enterostomies. There is significant variability from patient to patient, as output largely depends on length of remaining bowel [2,4].

Epidemiology

SBS, high-output enterostomy, and high-output from ECFs comprise a wide spectrum of underlying disease states, including but not limited to inflammatory bowel disease, post-surgical fistula formation, intestinal ischemia, intestinal atresia, radiation enteritis, abdominal trauma, and intussusception [5]. Due to the absence of a United States registry of patients with intestinal failure, the prevalence of these conditions is difficult to ascertain. Most estimations are made using registries for patients on total parenteral nutrition (TPN). The Crohns and Colitis Foundation of America estimates 10,000 to 20,000 people suffer from SBS in the United States. This heterogenous patient population has significant morbidity and mortality for dehydration related to these high-output states. While these conditions are considered rare, they are relatively costly to the health care system. These patients are commonly managed by numerous medical and surgical services, including internal medicine, gastroenterology, surgery, dietitians, wound care nurses, and home health agencies. Management strategies differ amongst these specialties and between professional societies, which makes treatment strategies highly variable and perplexing to providers taking care of this patient population. Furthermore, most of the published guidelines are based on expert opinion and lack high-quality clinical evidence from randomized controlled trials (RCTs). Effectively treating SBS and reducing excess enterostomy output leads to reduced rates of dehydration, electrolyte imbalances, initiation of PN, weight loss and ultimately a reduction in malnutrition. Developing hospital-wide management protocols in the electronic medical record for this heterogenous condition may lead to less complications, fewer hospitalizations, and an improved quality of life for these patients.

Case Study

Initial Presentation

A 72-year-old man with history of rectal adenocarcinoma stage T4bN2 status post low anterior resection (LAR) with diverting loop ileostomy and neoadjuvant chemoradiation presented to the hospital with a 3-day history of nausea, vomiting, fatigue, and productive cough.

Additional History

On further questioning, the patient also reported odynophagia and dysphagia related to thrush. Because of his decreased oral intake, he stopped taking his usual insulin regimen prior to admission. His cancer treatment course was notable for a LAR with diverting loop ileostomy which was performed 5 months prior. He had also completed 3 out of 8 cycles of capecitabine and oxaliplatin-based therapy 2 weeks prior to this presentation.

Physical Examination

Significant physical examination findings included dry mucous membranes, oropharyngeal candidiasis, tachycardia, clear lungs, hypoactive bowel sounds, nontender, non-distended abdomen, and a right lower abdominal ileostomy bag with semi-formed stool.

Laboratory test results were pertinent for diabetic ketoacidosis (DKA) with an anion gap of 33, lactic acidosis, acute kidney injury (creatinine 2.7 mg/dL from a baseline of 1.0) and blood glucose of 1059 mg/dL. Remainder of complete blood count and complete metabolic panel were unremarkable.

Hospital Course

The patient was treated for oropharyngeal candidiasis with fluconazole, started on an insulin drip and given intravenous fluids (IVFs) with subsequent resolution of DKA. Once the DKA resolved, his diet was advanced to a mechanical soft, moderate calorie, consistent carbohydrate diet (2000 calories allowed daily with all foods chopped, pureed or cooked, and all meals containing nearly equal amounts of carbohydrates). He was also given Boost supplementation 3 times per day, and daily weights were recorded while assessing for fluid losses. However, during his hospital course the patient developed increasing ileostomy output ranging from 2.7 to 6.5 L per day that only improved when he stopped eating by mouth (NPO).

What conditions should be evaluated prior to starting therapy for high-output enterostomy/diarrhea from either functional or structural SBS?

Prior to starting anti-diarrheal and anti-secretory therapy, infectious and metabolic etiologies for high-enterostomy output should be ruled out. Depending on the patient’s risk factors (eg, recent sick contacts, travel) and whether they are immunocompetent versus immunosuppressed, infectious studies should be obtained. In this patient, Clostridium difficile, stool culture, Giardia antigen, stool ova and parasites were all negative. Additional metabolic labs including thyroid-stimulating hormone, fecal elastase, and fecal fat were obtained and were all within normal limits. In this particular scenario, fecal fat was obtained while he was NPO. Testing for fat malabsorption and pancreatic insufficiency in a patient that is consuming less than 100 grams of fat per day can result in a false-negative outcome, however, and was not an appropriate test in this patient.

Hospital Course Continued

Once infectious etiologies were ruled out, the patient was started on anti-diarrheal medication consisting of loperamide 2 mg every 6 hours and oral pantoprazole 40 mg once per day. The primary internal medicine team speculated that the Boost supplementation may be contributing to the diarrhea because of its hyperosmolar concentration and wanted to discontinue it, but because the patient had protein-calorie malnutrition the dietician recommended continuing Boost supplementation. The primary internal medicine team also encouraged the patient to drink Gatorade with each meal with the approval from the dietician.

What are key dietary recommendations to help reduce high-output enterostomy/diarrhea?

Dietary recommendations are often quite variable depending on the intestinal anatomy (specifically, whether the colon is intact or absent), comorbidities such as renal disease, and severity of fluid and nutrient loses. This patient has the majority of his colon remaining; however, fluid and nutrients are being diverted away from his colon because he has a loop ileostomy. To reduce enterostomy output, it is generally recommended that liquids be consumed separately from solids, and that oral rehydration solutions (ORS) should replace most hyperosmolar and hypoosmolar liquids. Although these recommendations are commonly used, there is sparse data to suggest separating liquids from solids in a medically stable patient with SBS is indeed necessary [6]. In our patient, however, because he has not yet reached medical stability, it would be reasonable to separate the consumption of liquids from solids. The solid component of a SBS diet should consist mainly of protein and carbohydrates, with limited intake of simple sugars and sugar alcohols. If the colon remains intact, it is particularly important to limit fats to less than 30% of the daily caloric intake, to consume a low-oxalate diet, supplement with oral calcium to reduce the risk of calcium-oxalate nephrolithiasis, and increase dietary fiber intake as tolerated. Soluble fiber is fermented by colonic bacteria into short-chain fatty acids (SCFAs) and serve as an additional energy source [7,8]. Medium-chain triglycerides (MCTs) are good sources of fat because the body is able to absorb them into the bloodstream without the use of intestinal lymphatics, which may be damaged or absent in those with intestinal failure. For this particular patient, he would have benefitted from initiation of ORS and counseled to sip on it throughout the day while limiting liquid consumption during meals. He should have also been advised to limit plain Gatorade and Boost as they are both hyperosmolar liquid formulations and can worsen diarrhea. If the patient was unable to tolerate the taste of standard ORS formulations, or the hospital did not have any ORS on formulary, sugar, salt and water at specific amounts may be added to create a homemade ORS. In summary, this patient would have likely tolerated protein in solid form better than liquid protein supplementation.

Hospital Course Continued

The patient continued to have greater than 5 L of output from the ileostomy per day, so the following day the primary team increased the loperamide from 2 mg every 6 hours to 4 mg every 6 hours, added 2 tabs of diphenoxylate-atropine every 8 hours, and made the patient NPO. He continued to require IVFs and frequent electrolyte repletion because of the significant ongoing gastrointestinal losses.

What is the recommended first-line medical therapy for high-output enterostomy/diarrhea?

Anti-diarrheal medications are commonly used in high-output states because they work by reducing the rate of bowel translocation thereby allowing for longer time for nutrient and fluid absorption in the small and large intestine. Loperamide in particular also improves fecal incontinence because it effects the recto-anal inhibitory reflex and increases internal anal sphincter tone [9]. Four RCTs showed that loperamide lead to a significant reduction in enterostomy output compared to placebo with enterostomy output reductions ranging from 22% to 45%; varying dosages of loperamide were used, and ranged from 6 mg per day to 16 total mg per day [10–12]. King et al compared loperamide and codeine to placebo and found that both medications led to reductions in enterostomy output with a greater reduction and better side effect profile in those that received loperamide or combination therapy with loperamide and codeine [13,14]. The majority of studies used a maximum dose of 16 mg per day of loperamide, and this is the maxium daily dose approved by the US Food and Drug Administration (FDA). Interestingly however, loperamide circulates through the enterohepatic circulation which is severely disrupted in SBS, so titrating up to a maximum dose of 32 mg per day while closely monitoring for side effects is also practiced by experts in intestinal failure [15]. It is also important to note that anti-diarrheal medications are most effective when administered 20 to 30 minutes prior to meals and not scheduled every 4 to 6 hours if the patient is eating by mouth. If intestinal transit is so rapid such that undigested anti-diarrheal tablets or capsules are visualized in the stool or stoma, medications can be crushed or opened and mixed with liquids or solids to enhance digestion and absorption.

Hospital Course Continued

The patient continued to have greater than 3 L of ileostomy output per day despite being on scheduled loperamide, diphenoxylate-atropine, and a proton pump inhibitory (PPI), although improved from greater than 5 L per day. He was subsequently started on opium tincture 6 mg every 6 hours, psyllium 3 times per day, the dose of diphenoxylate-atropine was increased from 2 tablets every 8 hours to 2 tablets every 6 hours, and he was encouraged to drink water in between meals. As mentioned previously, the introduction of dietary fiber should be carefully monitored, as this patient population is commonly intolerant of high dietary fiber intake, and hypoosmolar liquids like water should actually be minimized. Within a 48-hour time period, the surgical team recommended increasing the loperamide from 4 mg every 6 hours (16 mg total daily dose) to 12 mg every 6 hours (48 mg total daily dose), increased opium tincture from 6 mg every 6 hours (24 mg total daily dose) to 10 mg every 6 hours (40 mg total daily dose), and increased oral pantoprazole from 40 mg once per day to twice per day.

What are important considerations with regard to dose changes?

Evidence is lacking to suggest an adequate time period to monitor for response to therapy in regards to improvement in diarrheal output. In this scenario, it may have been prudent to wait 24 to 48 hours after each medication change instead of making drastic dose changes in several medications simultaneously. PPIs irreversibly inhibit gastrointestinal acid secretion as do histamine-2 receptor antagonists (H2RAs) but to a lesser degree, and thus reduce high-output enterostomy [16]. Reduction in pH related to elevated gastrin levels after intestinal resection is associated with pancreatic enzyme denaturation and downstream bile salt dysfunction, which can further lead to malabsorption [17]. Gastrin hypersecretion is most prominent within the first 6 months after intestinal resection such that the use of high- dose PPIs for reduction in gastric acid secretion are most efficacious within that time period [18,19]. Jeppesen et al demonstrated that both omeprazole 40 mg oral twice per day and ranitidine 150 mg IV once per day were effective in reducing enterostomy output, although greater reductions were seen with omeprazole [20]. Three studies using cimetidine (both oral and IV formulations) with dosages varying from 200 mg to 800 mg per day showed significant reductions in enterostomy output as well [21–23].

Hospital Course Continued

Despite the previously mentioned interventions, the patient’s ileostomy output remained greater than 3 L per day. Loperamide was increased from 12 mg every 6 hours to 16 mg every 6 hours (64 mg total daily dose) hours and opium tincture was increased from 10 mg to 16 mg every 6 hours (64 mg total daily dose). Despite these changes, no significant reduction in output was noted, so the following day, 4 grams of cholestyramine light was added twice per day.

If the patient continues to have high-output enterostomy/diarrhea, what are additional treatment options?

Bile acid binding resins like cholestyramine, colestipol, and colesevelam are occasionally used if there is a high suspicion for bile acid diarrhea. Bile salt diarrhea typically occurs because of alterations in the enterohepatic circulation of bile salts, which leads to an increased level of bile salts in the colon and stimulation of electrolyte and water secretion and watery diarrhea [24]. Optimal candidates for bile acid binding therapy are those with an intact colon and less than 100 cm of resected ileum. Patients with little to no remaining or functional ileum have a depleted bile salt pool, therefore the addition of bile acid resin binders may actually lead to worsening diarrhea secondary to bile acid deficiency and fat malabsorption. Bile-acid resin binders can also decrease oxalate absorption and precipitate oxalate stone formation in the kidneys. Caution should also be taken to ensure that these medications are administered separately from the remainder of the patient’s medications to limit medication binding.

If the patient exhibits hemodynamic stability, alpha-2 receptor agonists are occasionally used as adjunctive therapy in reducing enterostomy output, although strong evidence to support its use is lacking. The mechanism of action involves stimulation of alpha-2 adrenergic receptors on enteric neurons, which theoretically causes a reduction in gastric and colonic motility and decreases fluid secretion. Buchman et al showed that the effects of a clonidine patch versus placebo did not in fact lead to a significant reduction in enterostomy output; however, a single case report suggested that the combination of 1200 mcg of clonidine per day and somatostatin resulted in decreased enterostomy output via alpha 2-receptor inhibition of adenylate cyclase [25,26].

Hospital Course Continued

The patient’s ileostomy output remained greater than 3 L per day, so loperamide was increased from 14 mg every 6 hours to 20 mg every 6 hours (80 mg total daily dose), cholestyramine was discontinued because of metabolic derangements, and the patient was initiated on 100 mcg of subcutaneous octreotide 3 times per day. Colorectal surgery was consulted for ileostomy takedown given persistently high-output, but surgery was deferred. After a 16-day hospitalization, the patient was eventually discharged home. At the time of discharge, he was having 2–3 L of ileostomy output per day and plans for future chemotherapy were discontinued because of this.

Does hormonal therapy have a role in the management of high-output enterostomy or entero-cutaneous fistulas?

Somatostatin analogues are growth-hormone inhibiting factors that have been used in the treatment of SBS and gastrointestinal fistulas. These medications reduce intestinal and pancreatic fluid secretion, slow intestinal motility, and inhibit the secretion of several hormones including gastrin, vasoactive intestinal peptide, cholecystokinin, and other key intestinal hormones. There is conflicting evidence for the role of these medications in reducing enterostomy output when first-line treatments have failed. Several previous studies using octreotide or somatostatin showed significant reductions in enterostomy output using variable dosages [27–30]. One study using the long-acting release depot octreotide preparation in 8 TPN-dependent patients with SBS showed a significant increase in small bowel transit time, however there was no significant improvement in the following parameters: body weight, stool weight, fecal fat excretion, stool electrolyte excretion, or gastric emptying [31]. Other studies evaluating enterostomy output from gastrointestinal and pancreatic fistulas comparing combined therapy with octreotide and TPN to placebo and TPN failed to show a significant difference in output and spontaneous fistula closure within 20 days of treatment initiation [32]. Because these studies use highly variable somatostatin analogue dosages and routes of administration, the most optimal dosing and route of administration (SQ versus IV) are unknown. In patients with difficult to control blood sugars, initiation of somatostatin analogues should be cautioned since these medications can lead to blood sugar alterations [33]. Additional unintended effects include impairment in intestinal adaptation and an increased risk in gallstone formation [8].

The most recent medical advances in SBS management include gut hormones. Glucagon-like peptide 2 (GLP-2) analogues improve structural and functional intestinal adaptation following intestinal resection by decreasing gastric emptying, decreasing gastric acid secretion, increasing intestinal blood flow, and enhancing nutrient and fluid absorption. Teduglutide, a GLP-2 analog, was successful in reducing fecal energy losses and increasing intestinal wet weight absorption, and reducing the need for PN support in SBS patients [1].

Whose problem is it anyway?

Not only is there variation in management strategies among subspecialties, but recommendations amongst societies within the same subspecialty differ, and thus make management perplexing.

Gastroenterology Guidelines

Several major gastroenterology societies have published guidelines on the management of diarrhea in patients with intestinal failure. The British Society of Gastroenterology (BSG) published guidelines on the management of SBS in 2006 and recommended the following first-line therapy for diarrhea-related complications: start loperamide at 2–8 mg thirty minutes prior to meals, taken up to 4 times per day, and the addition of codeine phosphate 30–60 mg thirty minutes before meals if output remains above goal on loperamide monotherapy. Cholestyramine may be added for those with 100 cm or less of resected terminal ileum to assist with bile-salt-induced diarrhea, though no specific dosage recommendations were reported. In regards to anti-secretory medications, the BSG recommends cimetidine (400 mg oral or IV 4 times per day), ranitidine (300 mg oral twice per day), or omeprazole (40 mg oral once per day or IV twice per day) to reduce jejunostomy output particularly in patients with greater than 2 L of output per day [15,34]. If diarrhea or enterostomy output continues to remain above goal, the guidelines suggest initiating octreotide and/or growth factors (although dosing and duration of therapy is not discussed in detail), and considering evaluation for intestinal transplant once the patient develops complications related to long-term TPN.

The American Gastroenterology Association (AGA) published guidelines and a position statement in 2003 for the management of high-gastric output and fluid losses. For postoperative patients, the AGA recommends the use of PPIs and H2RAs for the first 6 months following bowel resection when hyper-gastrinemia most commonly occurs. The guidelines do not specify which PPI or H2RA is preferred or recommended dosages. For long-term management of diarrhea or excess fluid losses, the guidelines suggest using loperamide or diphenoxylate (4-16 mg per day) first, followed by codeine sulfate 15–60 mg two to three times per day or opium tincture (dosages not specified). The use of octreotide (100 mcg SQ 3 times per day, 30 minutes prior to meals) is recommended only as a last resort if IVF requirements are greater than 3 L per day [8].

Surgical Guidelines

The Cleveland Clinic published institutional guidelines for the management of intestinal failure in 2010 with updated recommendations in 2016. Dietary recommendations include the liberal use of salt, sipping on 1–2 L of ORS between meals, and a slow reintroduction of soluble fiber from foods and/or supplements as tolerated. The guidelines also suggest considering placement of a nasogastric feeding tube or percutaneous gastrostomy tube (PEG) for continuous enteral feeding in addition to oral intake to enhance nutrient absorption [35]. If dietary manipulation is inadequate and medical therapy is required, the following medications are recommended in no particular order: loperamide 4 times per day (maximum dosage of 16 mg), diphenoxylate-atropine 4 times per day (maximum dosage of 20 mg per day), codeine 4 times per day (maximum dosage 240 mg per day), paregoric 5 mL (containing 2 mg of anhydrous morphine) 4 times per day, and opium tincture 0.5 mL (10 mg/mL) 4 times per day. H2RAs and PPIs are recommended for postoperative high-output states, although no dosage recommendations or routes of administration were discussed. 

Nutrition Guidelines

Villafranca et al published a protocol for the management of high-output stomas in 2015 that was shown to be effective in reducing high-enterostomy output. The protocol recommended initial treatment with loperamide 2 mg orally up to 4 times per day. If enterostomy output did not improve, the protocol recommended increasing loperamide to 4 mg four times per day, adding omeprazole 20 mg orally or cholestyramine 4 g twice per day before lunch and dinner if fat malabsorption or steatorrhea is suspected, and lastly the addition of codeine 15–60 mg up to 4 times per day and octreotide 200 mcg per day only if symptoms had not improved after 2 weeks [37].

The American Society for Parenteral and Enteral Nutrition (ASPEN) does not have published guidelines for the management of SBS. In 2016 however, the European Society for Clinical Nutrition and Metabolism (ESPEN) published guidelines on the management of chronic intestinal failure in adults. In patients with an intact colon, ESPEN strongly recommends a diet rich in complex carbohydrates and low in fat and using H2RAs or PPIs to treat hyper-gastrinemia within the first 6 months after intestinal resection particularly in those with greater than 2 L per day of fecal output. The ESPEN guidelines do not include whether to start a PPI or H2RA first, which particular drug in each class to try, or dosage recommendations but state that IV soluble formulations should be considered in those that do not seem to respond to tablets. ESPEN does not recommend the addition of soluble fiber to enhance intestinal absorption or probiotics and glutamine to aid in intestinal rehabilitation. For diarrhea and excessive fecal fluid, the guidelines recommend 4 mg of oral loperamide 30–60 minutes prior to meals, 3 to 4 times per day, as first-line treatment in comparison to codeine phosphate or opium tincture given the risks of dependence and sedation with the latter agents. They report, however, that dosages up to 12–24 mg at one time of loperamide are used in patients with terminal ileum resection and persistently high-output enterostomy [38].

Case Conclusion

The services that were closely involved in this patient’s care were general internal medicine, general surgery, colorectal surgery, and ancillary services, including dietary and wound care. Interestingly, despite persistent high ileostomy output during the patient’s 16-day hospital admission, the gastroenterology service was never consulted. This case illustrates the importance of having a multidisciplinary approach to the care of these complicated patients to ensure that the appropriate medications are ordered based on the individual’s anatomy and that medications are ordered at appropriate dosages and timing intervals to maximize drug efficacy. It is also critical to ensure that nursing staff accurately documents all intake and output so that necessary changes can be made after adequate time is given to assess for a true response. There should be close communication between the primary medical or surgical service with the dietician to ensure the patient is counseled on appropriate dietary intake to help minimize diarrhea and fluid losses.

Conclusion

In conclusion, intestinal failure is a heterogenous group of disease states that often occurs after major intestinal resection and is commonly associated with malabsorption and high output states. High-output enterostomy and diarrhea are the most common etiologies leading to hospital re-admission following enterostomy creation or intestinal resection. These patients have high morbidity and mortality rates, and their conditions are costly to the health care system. Lack of high-quality evidence from RCTs and numerous societal guidelines without clear medication and dietary algorithms and low prevalence of these conditions makes management of these patients by general medical and surgical teams challenging. The proper management of intestinal failure and related complications requires a multidisciplinary approach with involvement from medical, surgical, and ancillary services. We propose a multidisciplinary approach with involvement from medical, surgical, and ancillary services in designed and implementing a protocol using electronic medical record based order sets to simplify and improve the management of these patients in the inpatient setting.

Corresponding author: Jake Hutto, 5323 Harry Hines Blvd, Dallas, TX 75390-9030, [email protected].

Financial disclosures: None.

From the University of Texas Southwestern, Department of Internal Medicine, Dallas, TX.

Abstract

• Objective: To define intestinal failure and associated diseases that often lead to diarrhea and high-output states, and to provide a literature review on the current evidence and practice guidelines for the management of these conditions in the context of a clinical case.
• Methods: Database search on dietary and medical interventions as well as major societal guidelines for the management of intestinal failure and associated conditions.
• Results: Although major societal guidelines exist, the guidelines vary greatly amongst various specialties and are not supported by strong evidence from large randomized controlled trials. The majority of the guidelines recommend consideration of several drug classes, but do not specify medications within the drug class, optimal dose, frequency, mode of administration, and how long to trial a regimen before considering it a failure and adding additional medical therapies.
• Conclusions: Intestinal failure and high-output states affect a very heterogenous population with high morbidity and mortality. This subset of patients should be managed using a multidisciplinary approach involving surgery, gastroenterology, dietetics, internal medicine and ancillary services that include but are not limited to ostomy nurses and home health care. Implementation of a standardized protocol in the electronic medical record including both medical and nutritional therapies may be useful to help optimize efficacy of medications, aid in nutrient absorption, decrease cost, reduce hospital length of stay, and decrease hospital readmissions.

Key words: short bowel syndrome; high-output ostomy; entero-cutaneous fistula; diarrhea; malnutrition.

Intestinal failure includes but is not limited to short bowel syndrome (SBS), high-output enterostomy, and high-output related to entero-cutaneous fistulas (ECF). These conditions are unfortunate complications after major abdominal surgery requiring extensive intestinal resection leading to structural SBS. Absorption of macronutrients and micronutrients is most dependent on the length and specific segment of remaining intact small intestine [1]. The normal small intestine length varies greatly but ranges from 300 to 800 cm, while in those with structural SBS the typical length is 200 cm or less [2,3]. Certain malabsorptive enteropathies and severe intestinal dysmotility conditions may manifest as functional SBS as well. Factors that influence whether an individual will develop functional SBS despite having sufficient small intestinal absorptive area include the degree of jejunal absorptive efficacy and the ability to overcompensate with enough oral caloric intake despite high fecal energy losses, also known as hyperphagia [4].

Pathophysiology

Maintenance of normal bodily functions and homeostasis is dependent on sufficient intestinal absorption of essential macronutrients, micronutrients, and fluids. The hallmark of intestinal failure is based on the presence of decreased small bowel absorptive surface area and subsequent increased losses of key solutes and fluids [1]. Intestinal failure is a broad term that is comprised of 3 distinct phenotypes. The 3 functional classifications of intestinal failure include the following:

• Type 1. Acute intestinal failure is generally self-limiting, occurs after abdominal surgery, and typically lasts less than 28 days.
• Type 2. Subacute intestinal failure frequently occurs in septic, stressed, or metabolically unstable patients and may last up to several months.
• Type 3. Chronic intestinal failure occurs due to a chronic condition that generally requires indefinite parenteral nutrition (PN) [1,3,4].

SBS and enterostomy formation are often associated with excessive diarrhea, such that it is the most common etiology for postoperative readmissions. The definition of “high-output” varies amongst studies, but output is generally considered to be abnormally high if it is greater than 500 mL per 24 hours in ECFs and greater than 1500 mL per 24 hours for enterostomies. There is significant variability from patient to patient, as output largely depends on length of remaining bowel [2,4].

Epidemiology

SBS, high-output enterostomy, and high-output from ECFs comprise a wide spectrum of underlying disease states, including but not limited to inflammatory bowel disease, post-surgical fistula formation, intestinal ischemia, intestinal atresia, radiation enteritis, abdominal trauma, and intussusception [5]. Due to the absence of a United States registry of patients with intestinal failure, the prevalence of these conditions is difficult to ascertain. Most estimations are made using registries for patients on total parenteral nutrition (TPN). The Crohns and Colitis Foundation of America estimates 10,000 to 20,000 people suffer from SBS in the United States. This heterogenous patient population has significant morbidity and mortality for dehydration related to these high-output states. While these conditions are considered rare, they are relatively costly to the health care system. These patients are commonly managed by numerous medical and surgical services, including internal medicine, gastroenterology, surgery, dietitians, wound care nurses, and home health agencies. Management strategies differ amongst these specialties and between professional societies, which makes treatment strategies highly variable and perplexing to providers taking care of this patient population. Furthermore, most of the published guidelines are based on expert opinion and lack high-quality clinical evidence from randomized controlled trials (RCTs). Effectively treating SBS and reducing excess enterostomy output leads to reduced rates of dehydration, electrolyte imbalances, initiation of PN, weight loss and ultimately a reduction in malnutrition. Developing hospital-wide management protocols in the electronic medical record for this heterogenous condition may lead to less complications, fewer hospitalizations, and an improved quality of life for these patients.

Case Study

Initial Presentation

A 72-year-old man with history of rectal adenocarcinoma stage T4bN2 status post low anterior resection (LAR) with diverting loop ileostomy and neoadjuvant chemoradiation presented to the hospital with a 3-day history of nausea, vomiting, fatigue, and productive cough.

Additional History

On further questioning, the patient also reported odynophagia and dysphagia related to thrush. Because of his decreased oral intake, he stopped taking his usual insulin regimen prior to admission. His cancer treatment course was notable for a LAR with diverting loop ileostomy which was performed 5 months prior. He had also completed 3 out of 8 cycles of capecitabine and oxaliplatin-based therapy 2 weeks prior to this presentation.

Physical Examination

Significant physical examination findings included dry mucous membranes, oropharyngeal candidiasis, tachycardia, clear lungs, hypoactive bowel sounds, nontender, non-distended abdomen, and a right lower abdominal ileostomy bag with semi-formed stool.

Laboratory test results were pertinent for diabetic ketoacidosis (DKA) with an anion gap of 33, lactic acidosis, acute kidney injury (creatinine 2.7 mg/dL from a baseline of 1.0) and blood glucose of 1059 mg/dL. Remainder of complete blood count and complete metabolic panel were unremarkable.

Hospital Course

The patient was treated for oropharyngeal candidiasis with fluconazole, started on an insulin drip and given intravenous fluids (IVFs) with subsequent resolution of DKA. Once the DKA resolved, his diet was advanced to a mechanical soft, moderate calorie, consistent carbohydrate diet (2000 calories allowed daily with all foods chopped, pureed or cooked, and all meals containing nearly equal amounts of carbohydrates). He was also given Boost supplementation 3 times per day, and daily weights were recorded while assessing for fluid losses. However, during his hospital course the patient developed increasing ileostomy output ranging from 2.7 to 6.5 L per day that only improved when he stopped eating by mouth (NPO).

What conditions should be evaluated prior to starting therapy for high-output enterostomy/diarrhea from either functional or structural SBS?

Prior to starting anti-diarrheal and anti-secretory therapy, infectious and metabolic etiologies for high-enterostomy output should be ruled out. Depending on the patient’s risk factors (eg, recent sick contacts, travel) and whether they are immunocompetent versus immunosuppressed, infectious studies should be obtained. In this patient, Clostridium difficile, stool culture, Giardia antigen, stool ova and parasites were all negative. Additional metabolic labs including thyroid-stimulating hormone, fecal elastase, and fecal fat were obtained and were all within normal limits. In this particular scenario, fecal fat was obtained while he was NPO. Testing for fat malabsorption and pancreatic insufficiency in a patient that is consuming less than 100 grams of fat per day can result in a false-negative outcome, however, and was not an appropriate test in this patient.

Hospital Course Continued

Once infectious etiologies were ruled out, the patient was started on anti-diarrheal medication consisting of loperamide 2 mg every 6 hours and oral pantoprazole 40 mg once per day. The primary internal medicine team speculated that the Boost supplementation may be contributing to the diarrhea because of its hyperosmolar concentration and wanted to discontinue it, but because the patient had protein-calorie malnutrition the dietician recommended continuing Boost supplementation. The primary internal medicine team also encouraged the patient to drink Gatorade with each meal with the approval from the dietician.

What are key dietary recommendations to help reduce high-output enterostomy/diarrhea?

Dietary recommendations are often quite variable depending on the intestinal anatomy (specifically, whether the colon is intact or absent), comorbidities such as renal disease, and severity of fluid and nutrient loses. This patient has the majority of his colon remaining; however, fluid and nutrients are being diverted away from his colon because he has a loop ileostomy. To reduce enterostomy output, it is generally recommended that liquids be consumed separately from solids, and that oral rehydration solutions (ORS) should replace most hyperosmolar and hypoosmolar liquids. Although these recommendations are commonly used, there is sparse data to suggest separating liquids from solids in a medically stable patient with SBS is indeed necessary [6]. In our patient, however, because he has not yet reached medical stability, it would be reasonable to separate the consumption of liquids from solids. The solid component of a SBS diet should consist mainly of protein and carbohydrates, with limited intake of simple sugars and sugar alcohols. If the colon remains intact, it is particularly important to limit fats to less than 30% of the daily caloric intake, to consume a low-oxalate diet, supplement with oral calcium to reduce the risk of calcium-oxalate nephrolithiasis, and increase dietary fiber intake as tolerated. Soluble fiber is fermented by colonic bacteria into short-chain fatty acids (SCFAs) and serve as an additional energy source [7,8]. Medium-chain triglycerides (MCTs) are good sources of fat because the body is able to absorb them into the bloodstream without the use of intestinal lymphatics, which may be damaged or absent in those with intestinal failure. For this particular patient, he would have benefitted from initiation of ORS and counseled to sip on it throughout the day while limiting liquid consumption during meals. He should have also been advised to limit plain Gatorade and Boost as they are both hyperosmolar liquid formulations and can worsen diarrhea. If the patient was unable to tolerate the taste of standard ORS formulations, or the hospital did not have any ORS on formulary, sugar, salt and water at specific amounts may be added to create a homemade ORS. In summary, this patient would have likely tolerated protein in solid form better than liquid protein supplementation.

Hospital Course Continued

The patient continued to have greater than 5 L of output from the ileostomy per day, so the following day the primary team increased the loperamide from 2 mg every 6 hours to 4 mg every 6 hours, added 2 tabs of diphenoxylate-atropine every 8 hours, and made the patient NPO. He continued to require IVFs and frequent electrolyte repletion because of the significant ongoing gastrointestinal losses.

What is the recommended first-line medical therapy for high-output enterostomy/diarrhea?

Anti-diarrheal medications are commonly used in high-output states because they work by reducing the rate of bowel translocation thereby allowing for longer time for nutrient and fluid absorption in the small and large intestine. Loperamide in particular also improves fecal incontinence because it effects the recto-anal inhibitory reflex and increases internal anal sphincter tone [9]. Four RCTs showed that loperamide lead to a significant reduction in enterostomy output compared to placebo with enterostomy output reductions ranging from 22% to 45%; varying dosages of loperamide were used, and ranged from 6 mg per day to 16 total mg per day [10–12]. King et al compared loperamide and codeine to placebo and found that both medications led to reductions in enterostomy output with a greater reduction and better side effect profile in those that received loperamide or combination therapy with loperamide and codeine [13,14]. The majority of studies used a maximum dose of 16 mg per day of loperamide, and this is the maxium daily dose approved by the US Food and Drug Administration (FDA). Interestingly however, loperamide circulates through the enterohepatic circulation which is severely disrupted in SBS, so titrating up to a maximum dose of 32 mg per day while closely monitoring for side effects is also practiced by experts in intestinal failure [15]. It is also important to note that anti-diarrheal medications are most effective when administered 20 to 30 minutes prior to meals and not scheduled every 4 to 6 hours if the patient is eating by mouth. If intestinal transit is so rapid such that undigested anti-diarrheal tablets or capsules are visualized in the stool or stoma, medications can be crushed or opened and mixed with liquids or solids to enhance digestion and absorption.

Hospital Course Continued

The patient continued to have greater than 3 L of ileostomy output per day despite being on scheduled loperamide, diphenoxylate-atropine, and a proton pump inhibitory (PPI), although improved from greater than 5 L per day. He was subsequently started on opium tincture 6 mg every 6 hours, psyllium 3 times per day, the dose of diphenoxylate-atropine was increased from 2 tablets every 8 hours to 2 tablets every 6 hours, and he was encouraged to drink water in between meals. As mentioned previously, the introduction of dietary fiber should be carefully monitored, as this patient population is commonly intolerant of high dietary fiber intake, and hypoosmolar liquids like water should actually be minimized. Within a 48-hour time period, the surgical team recommended increasing the loperamide from 4 mg every 6 hours (16 mg total daily dose) to 12 mg every 6 hours (48 mg total daily dose), increased opium tincture from 6 mg every 6 hours (24 mg total daily dose) to 10 mg every 6 hours (40 mg total daily dose), and increased oral pantoprazole from 40 mg once per day to twice per day.

What are important considerations with regard to dose changes?

Evidence is lacking to suggest an adequate time period to monitor for response to therapy in regards to improvement in diarrheal output. In this scenario, it may have been prudent to wait 24 to 48 hours after each medication change instead of making drastic dose changes in several medications simultaneously. PPIs irreversibly inhibit gastrointestinal acid secretion as do histamine-2 receptor antagonists (H2RAs) but to a lesser degree, and thus reduce high-output enterostomy [16]. Reduction in pH related to elevated gastrin levels after intestinal resection is associated with pancreatic enzyme denaturation and downstream bile salt dysfunction, which can further lead to malabsorption [17]. Gastrin hypersecretion is most prominent within the first 6 months after intestinal resection such that the use of high- dose PPIs for reduction in gastric acid secretion are most efficacious within that time period [18,19]. Jeppesen et al demonstrated that both omeprazole 40 mg oral twice per day and ranitidine 150 mg IV once per day were effective in reducing enterostomy output, although greater reductions were seen with omeprazole [20]. Three studies using cimetidine (both oral and IV formulations) with dosages varying from 200 mg to 800 mg per day showed significant reductions in enterostomy output as well [21–23].

Hospital Course Continued

Despite the previously mentioned interventions, the patient’s ileostomy output remained greater than 3 L per day. Loperamide was increased from 12 mg every 6 hours to 16 mg every 6 hours (64 mg total daily dose) hours and opium tincture was increased from 10 mg to 16 mg every 6 hours (64 mg total daily dose). Despite these changes, no significant reduction in output was noted, so the following day, 4 grams of cholestyramine light was added twice per day.

If the patient continues to have high-output enterostomy/diarrhea, what are additional treatment options?

Bile acid binding resins like cholestyramine, colestipol, and colesevelam are occasionally used if there is a high suspicion for bile acid diarrhea. Bile salt diarrhea typically occurs because of alterations in the enterohepatic circulation of bile salts, which leads to an increased level of bile salts in the colon and stimulation of electrolyte and water secretion and watery diarrhea [24]. Optimal candidates for bile acid binding therapy are those with an intact colon and less than 100 cm of resected ileum. Patients with little to no remaining or functional ileum have a depleted bile salt pool, therefore the addition of bile acid resin binders may actually lead to worsening diarrhea secondary to bile acid deficiency and fat malabsorption. Bile-acid resin binders can also decrease oxalate absorption and precipitate oxalate stone formation in the kidneys. Caution should also be taken to ensure that these medications are administered separately from the remainder of the patient’s medications to limit medication binding.

If the patient exhibits hemodynamic stability, alpha-2 receptor agonists are occasionally used as adjunctive therapy in reducing enterostomy output, although strong evidence to support its use is lacking. The mechanism of action involves stimulation of alpha-2 adrenergic receptors on enteric neurons, which theoretically causes a reduction in gastric and colonic motility and decreases fluid secretion. Buchman et al showed that the effects of a clonidine patch versus placebo did not in fact lead to a significant reduction in enterostomy output; however, a single case report suggested that the combination of 1200 mcg of clonidine per day and somatostatin resulted in decreased enterostomy output via alpha 2-receptor inhibition of adenylate cyclase [25,26].

Hospital Course Continued

The patient’s ileostomy output remained greater than 3 L per day, so loperamide was increased from 14 mg every 6 hours to 20 mg every 6 hours (80 mg total daily dose), cholestyramine was discontinued because of metabolic derangements, and the patient was initiated on 100 mcg of subcutaneous octreotide 3 times per day. Colorectal surgery was consulted for ileostomy takedown given persistently high-output, but surgery was deferred. After a 16-day hospitalization, the patient was eventually discharged home. At the time of discharge, he was having 2–3 L of ileostomy output per day and plans for future chemotherapy were discontinued because of this.

Does hormonal therapy have a role in the management of high-output enterostomy or entero-cutaneous fistulas?

Somatostatin analogues are growth-hormone inhibiting factors that have been used in the treatment of SBS and gastrointestinal fistulas. These medications reduce intestinal and pancreatic fluid secretion, slow intestinal motility, and inhibit the secretion of several hormones including gastrin, vasoactive intestinal peptide, cholecystokinin, and other key intestinal hormones. There is conflicting evidence for the role of these medications in reducing enterostomy output when first-line treatments have failed. Several previous studies using octreotide or somatostatin showed significant reductions in enterostomy output using variable dosages [27–30]. One study using the long-acting release depot octreotide preparation in 8 TPN-dependent patients with SBS showed a significant increase in small bowel transit time, however there was no significant improvement in the following parameters: body weight, stool weight, fecal fat excretion, stool electrolyte excretion, or gastric emptying [31]. Other studies evaluating enterostomy output from gastrointestinal and pancreatic fistulas comparing combined therapy with octreotide and TPN to placebo and TPN failed to show a significant difference in output and spontaneous fistula closure within 20 days of treatment initiation [32]. Because these studies use highly variable somatostatin analogue dosages and routes of administration, the most optimal dosing and route of administration (SQ versus IV) are unknown. In patients with difficult to control blood sugars, initiation of somatostatin analogues should be cautioned since these medications can lead to blood sugar alterations [33]. Additional unintended effects include impairment in intestinal adaptation and an increased risk in gallstone formation [8].

The most recent medical advances in SBS management include gut hormones. Glucagon-like peptide 2 (GLP-2) analogues improve structural and functional intestinal adaptation following intestinal resection by decreasing gastric emptying, decreasing gastric acid secretion, increasing intestinal blood flow, and enhancing nutrient and fluid absorption. Teduglutide, a GLP-2 analog, was successful in reducing fecal energy losses and increasing intestinal wet weight absorption, and reducing the need for PN support in SBS patients [1].

Whose problem is it anyway?

Not only is there variation in management strategies among subspecialties, but recommendations amongst societies within the same subspecialty differ, and thus make management perplexing.

Gastroenterology Guidelines

Several major gastroenterology societies have published guidelines on the management of diarrhea in patients with intestinal failure. The British Society of Gastroenterology (BSG) published guidelines on the management of SBS in 2006 and recommended the following first-line therapy for diarrhea-related complications: start loperamide at 2–8 mg thirty minutes prior to meals, taken up to 4 times per day, and the addition of codeine phosphate 30–60 mg thirty minutes before meals if output remains above goal on loperamide monotherapy. Cholestyramine may be added for those with 100 cm or less of resected terminal ileum to assist with bile-salt-induced diarrhea, though no specific dosage recommendations were reported. In regards to anti-secretory medications, the BSG recommends cimetidine (400 mg oral or IV 4 times per day), ranitidine (300 mg oral twice per day), or omeprazole (40 mg oral once per day or IV twice per day) to reduce jejunostomy output particularly in patients with greater than 2 L of output per day [15,34]. If diarrhea or enterostomy output continues to remain above goal, the guidelines suggest initiating octreotide and/or growth factors (although dosing and duration of therapy is not discussed in detail), and considering evaluation for intestinal transplant once the patient develops complications related to long-term TPN.

The American Gastroenterology Association (AGA) published guidelines and a position statement in 2003 for the management of high-gastric output and fluid losses. For postoperative patients, the AGA recommends the use of PPIs and H2RAs for the first 6 months following bowel resection when hyper-gastrinemia most commonly occurs. The guidelines do not specify which PPI or H2RA is preferred or recommended dosages. For long-term management of diarrhea or excess fluid losses, the guidelines suggest using loperamide or diphenoxylate (4-16 mg per day) first, followed by codeine sulfate 15–60 mg two to three times per day or opium tincture (dosages not specified). The use of octreotide (100 mcg SQ 3 times per day, 30 minutes prior to meals) is recommended only as a last resort if IVF requirements are greater than 3 L per day [8].

Surgical Guidelines

The Cleveland Clinic published institutional guidelines for the management of intestinal failure in 2010 with updated recommendations in 2016. Dietary recommendations include the liberal use of salt, sipping on 1–2 L of ORS between meals, and a slow reintroduction of soluble fiber from foods and/or supplements as tolerated. The guidelines also suggest considering placement of a nasogastric feeding tube or percutaneous gastrostomy tube (PEG) for continuous enteral feeding in addition to oral intake to enhance nutrient absorption [35]. If dietary manipulation is inadequate and medical therapy is required, the following medications are recommended in no particular order: loperamide 4 times per day (maximum dosage of 16 mg), diphenoxylate-atropine 4 times per day (maximum dosage of 20 mg per day), codeine 4 times per day (maximum dosage 240 mg per day), paregoric 5 mL (containing 2 mg of anhydrous morphine) 4 times per day, and opium tincture 0.5 mL (10 mg/mL) 4 times per day. H2RAs and PPIs are recommended for postoperative high-output states, although no dosage recommendations or routes of administration were discussed. 

Nutrition Guidelines

Villafranca et al published a protocol for the management of high-output stomas in 2015 that was shown to be effective in reducing high-enterostomy output. The protocol recommended initial treatment with loperamide 2 mg orally up to 4 times per day. If enterostomy output did not improve, the protocol recommended increasing loperamide to 4 mg four times per day, adding omeprazole 20 mg orally or cholestyramine 4 g twice per day before lunch and dinner if fat malabsorption or steatorrhea is suspected, and lastly the addition of codeine 15–60 mg up to 4 times per day and octreotide 200 mcg per day only if symptoms had not improved after 2 weeks [37].

The American Society for Parenteral and Enteral Nutrition (ASPEN) does not have published guidelines for the management of SBS. In 2016 however, the European Society for Clinical Nutrition and Metabolism (ESPEN) published guidelines on the management of chronic intestinal failure in adults. In patients with an intact colon, ESPEN strongly recommends a diet rich in complex carbohydrates and low in fat and using H2RAs or PPIs to treat hyper-gastrinemia within the first 6 months after intestinal resection particularly in those with greater than 2 L per day of fecal output. The ESPEN guidelines do not include whether to start a PPI or H2RA first, which particular drug in each class to try, or dosage recommendations but state that IV soluble formulations should be considered in those that do not seem to respond to tablets. ESPEN does not recommend the addition of soluble fiber to enhance intestinal absorption or probiotics and glutamine to aid in intestinal rehabilitation. For diarrhea and excessive fecal fluid, the guidelines recommend 4 mg of oral loperamide 30–60 minutes prior to meals, 3 to 4 times per day, as first-line treatment in comparison to codeine phosphate or opium tincture given the risks of dependence and sedation with the latter agents. They report, however, that dosages up to 12–24 mg at one time of loperamide are used in patients with terminal ileum resection and persistently high-output enterostomy [38].

Case Conclusion

The services that were closely involved in this patient’s care were general internal medicine, general surgery, colorectal surgery, and ancillary services, including dietary and wound care. Interestingly, despite persistent high ileostomy output during the patient’s 16-day hospital admission, the gastroenterology service was never consulted. This case illustrates the importance of having a multidisciplinary approach to the care of these complicated patients to ensure that the appropriate medications are ordered based on the individual’s anatomy and that medications are ordered at appropriate dosages and timing intervals to maximize drug efficacy. It is also critical to ensure that nursing staff accurately documents all intake and output so that necessary changes can be made after adequate time is given to assess for a true response. There should be close communication between the primary medical or surgical service with the dietician to ensure the patient is counseled on appropriate dietary intake to help minimize diarrhea and fluid losses.

Conclusion

In conclusion, intestinal failure is a heterogenous group of disease states that often occurs after major intestinal resection and is commonly associated with malabsorption and high output states. High-output enterostomy and diarrhea are the most common etiologies leading to hospital re-admission following enterostomy creation or intestinal resection. These patients have high morbidity and mortality rates, and their conditions are costly to the health care system. Lack of high-quality evidence from RCTs and numerous societal guidelines without clear medication and dietary algorithms and low prevalence of these conditions makes management of these patients by general medical and surgical teams challenging. The proper management of intestinal failure and related complications requires a multidisciplinary approach with involvement from medical, surgical, and ancillary services. We propose a multidisciplinary approach with involvement from medical, surgical, and ancillary services in designed and implementing a protocol using electronic medical record based order sets to simplify and improve the management of these patients in the inpatient setting.

Corresponding author: Jake Hutto, 5323 Harry Hines Blvd, Dallas, TX 75390-9030, [email protected].

Financial disclosures: None.

From the University of Texas Southwestern, Department of Internal Medicine, Dallas, TX.

Abstract

• Objective: To define intestinal failure and associated diseases that often lead to diarrhea and high-output states, and to provide a literature review on the current evidence and practice guidelines for the management of these conditions in the context of a clinical case.
• Methods: Database search on dietary and medical interventions as well as major societal guidelines for the management of intestinal failure and associated conditions.
• Results: Although major societal guidelines exist, the guidelines vary greatly amongst various specialties and are not supported by strong evidence from large randomized controlled trials. The majority of the guidelines recommend consideration of several drug classes, but do not specify medications within the drug class, optimal dose, frequency, mode of administration, and how long to trial a regimen before considering it a failure and adding additional medical therapies.
• Conclusions: Intestinal failure and high-output states affect a very heterogenous population with high morbidity and mortality. This subset of patients should be managed using a multidisciplinary approach involving surgery, gastroenterology, dietetics, internal medicine and ancillary services that include but are not limited to ostomy nurses and home health care. Implementation of a standardized protocol in the electronic medical record including both medical and nutritional therapies may be useful to help optimize efficacy of medications, aid in nutrient absorption, decrease cost, reduce hospital length of stay, and decrease hospital readmissions.

Key words: short bowel syndrome; high-output ostomy; entero-cutaneous fistula; diarrhea; malnutrition.

Intestinal failure includes but is not limited to short bowel syndrome (SBS), high-output enterostomy, and high-output related to entero-cutaneous fistulas (ECF). These conditions are unfortunate complications after major abdominal surgery requiring extensive intestinal resection leading to structural SBS. Absorption of macronutrients and micronutrients is most dependent on the length and specific segment of remaining intact small intestine [1]. The normal small intestine length varies greatly but ranges from 300 to 800 cm, while in those with structural SBS the typical length is 200 cm or less [2,3]. Certain malabsorptive enteropathies and severe intestinal dysmotility conditions may manifest as functional SBS as well. Factors that influence whether an individual will develop functional SBS despite having sufficient small intestinal absorptive area include the degree of jejunal absorptive efficacy and the ability to overcompensate with enough oral caloric intake despite high fecal energy losses, also known as hyperphagia [4].

Pathophysiology

Maintenance of normal bodily functions and homeostasis is dependent on sufficient intestinal absorption of essential macronutrients, micronutrients, and fluids. The hallmark of intestinal failure is based on the presence of decreased small bowel absorptive surface area and subsequent increased losses of key solutes and fluids [1]. Intestinal failure is a broad term that is comprised of 3 distinct phenotypes. The 3 functional classifications of intestinal failure include the following:

• Type 1. Acute intestinal failure is generally self-limiting, occurs after abdominal surgery, and typically lasts less than 28 days.
• Type 2. Subacute intestinal failure frequently occurs in septic, stressed, or metabolically unstable patients and may last up to several months.
• Type 3. Chronic intestinal failure occurs due to a chronic condition that generally requires indefinite parenteral nutrition (PN) [1,3,4].

SBS and enterostomy formation are often associated with excessive diarrhea, such that it is the most common etiology for postoperative readmissions. The definition of “high-output” varies amongst studies, but output is generally considered to be abnormally high if it is greater than 500 mL per 24 hours in ECFs and greater than 1500 mL per 24 hours for enterostomies. There is significant variability from patient to patient, as output largely depends on length of remaining bowel [2,4].

Epidemiology

SBS, high-output enterostomy, and high-output from ECFs comprise a wide spectrum of underlying disease states, including but not limited to inflammatory bowel disease, post-surgical fistula formation, intestinal ischemia, intestinal atresia, radiation enteritis, abdominal trauma, and intussusception [5]. Due to the absence of a United States registry of patients with intestinal failure, the prevalence of these conditions is difficult to ascertain. Most estimations are made using registries for patients on total parenteral nutrition (TPN). The Crohns and Colitis Foundation of America estimates 10,000 to 20,000 people suffer from SBS in the United States. This heterogenous patient population has significant morbidity and mortality for dehydration related to these high-output states. While these conditions are considered rare, they are relatively costly to the health care system. These patients are commonly managed by numerous medical and surgical services, including internal medicine, gastroenterology, surgery, dietitians, wound care nurses, and home health agencies. Management strategies differ amongst these specialties and between professional societies, which makes treatment strategies highly variable and perplexing to providers taking care of this patient population. Furthermore, most of the published guidelines are based on expert opinion and lack high-quality clinical evidence from randomized controlled trials (RCTs). Effectively treating SBS and reducing excess enterostomy output leads to reduced rates of dehydration, electrolyte imbalances, initiation of PN, weight loss and ultimately a reduction in malnutrition. Developing hospital-wide management protocols in the electronic medical record for this heterogenous condition may lead to less complications, fewer hospitalizations, and an improved quality of life for these patients.

Case Study

Initial Presentation

A 72-year-old man with history of rectal adenocarcinoma stage T4bN2 status post low anterior resection (LAR) with diverting loop ileostomy and neoadjuvant chemoradiation presented to the hospital with a 3-day history of nausea, vomiting, fatigue, and productive cough.

Additional History

On further questioning, the patient also reported odynophagia and dysphagia related to thrush. Because of his decreased oral intake, he stopped taking his usual insulin regimen prior to admission. His cancer treatment course was notable for a LAR with diverting loop ileostomy which was performed 5 months prior. He had also completed 3 out of 8 cycles of capecitabine and oxaliplatin-based therapy 2 weeks prior to this presentation.

Physical Examination

Significant physical examination findings included dry mucous membranes, oropharyngeal candidiasis, tachycardia, clear lungs, hypoactive bowel sounds, nontender, non-distended abdomen, and a right lower abdominal ileostomy bag with semi-formed stool.

Laboratory test results were pertinent for diabetic ketoacidosis (DKA) with an anion gap of 33, lactic acidosis, acute kidney injury (creatinine 2.7 mg/dL from a baseline of 1.0) and blood glucose of 1059 mg/dL. Remainder of complete blood count and complete metabolic panel were unremarkable.

Hospital Course

The patient was treated for oropharyngeal candidiasis with fluconazole, started on an insulin drip and given intravenous fluids (IVFs) with subsequent resolution of DKA. Once the DKA resolved, his diet was advanced to a mechanical soft, moderate calorie, consistent carbohydrate diet (2000 calories allowed daily with all foods chopped, pureed or cooked, and all meals containing nearly equal amounts of carbohydrates). He was also given Boost supplementation 3 times per day, and daily weights were recorded while assessing for fluid losses. However, during his hospital course the patient developed increasing ileostomy output ranging from 2.7 to 6.5 L per day that only improved when he stopped eating by mouth (NPO).

What conditions should be evaluated prior to starting therapy for high-output enterostomy/diarrhea from either functional or structural SBS?

Prior to starting anti-diarrheal and anti-secretory therapy, infectious and metabolic etiologies for high-enterostomy output should be ruled out. Depending on the patient’s risk factors (eg, recent sick contacts, travel) and whether they are immunocompetent versus immunosuppressed, infectious studies should be obtained. In this patient, Clostridium difficile, stool culture, Giardia antigen, stool ova and parasites were all negative. Additional metabolic labs including thyroid-stimulating hormone, fecal elastase, and fecal fat were obtained and were all within normal limits. In this particular scenario, fecal fat was obtained while he was NPO. Testing for fat malabsorption and pancreatic insufficiency in a patient that is consuming less than 100 grams of fat per day can result in a false-negative outcome, however, and was not an appropriate test in this patient.

Hospital Course Continued

Once infectious etiologies were ruled out, the patient was started on anti-diarrheal medication consisting of loperamide 2 mg every 6 hours and oral pantoprazole 40 mg once per day. The primary internal medicine team speculated that the Boost supplementation may be contributing to the diarrhea because of its hyperosmolar concentration and wanted to discontinue it, but because the patient had protein-calorie malnutrition the dietician recommended continuing Boost supplementation. The primary internal medicine team also encouraged the patient to drink Gatorade with each meal with the approval from the dietician.

What are key dietary recommendations to help reduce high-output enterostomy/diarrhea?

Dietary recommendations are often quite variable depending on the intestinal anatomy (specifically, whether the colon is intact or absent), comorbidities such as renal disease, and severity of fluid and nutrient loses. This patient has the majority of his colon remaining; however, fluid and nutrients are being diverted away from his colon because he has a loop ileostomy. To reduce enterostomy output, it is generally recommended that liquids be consumed separately from solids, and that oral rehydration solutions (ORS) should replace most hyperosmolar and hypoosmolar liquids. Although these recommendations are commonly used, there is sparse data to suggest separating liquids from solids in a medically stable patient with SBS is indeed necessary [6]. In our patient, however, because he has not yet reached medical stability, it would be reasonable to separate the consumption of liquids from solids. The solid component of a SBS diet should consist mainly of protein and carbohydrates, with limited intake of simple sugars and sugar alcohols. If the colon remains intact, it is particularly important to limit fats to less than 30% of the daily caloric intake, to consume a low-oxalate diet, supplement with oral calcium to reduce the risk of calcium-oxalate nephrolithiasis, and increase dietary fiber intake as tolerated. Soluble fiber is fermented by colonic bacteria into short-chain fatty acids (SCFAs) and serve as an additional energy source [7,8]. Medium-chain triglycerides (MCTs) are good sources of fat because the body is able to absorb them into the bloodstream without the use of intestinal lymphatics, which may be damaged or absent in those with intestinal failure. For this particular patient, he would have benefitted from initiation of ORS and counseled to sip on it throughout the day while limiting liquid consumption during meals. He should have also been advised to limit plain Gatorade and Boost as they are both hyperosmolar liquid formulations and can worsen diarrhea. If the patient was unable to tolerate the taste of standard ORS formulations, or the hospital did not have any ORS on formulary, sugar, salt and water at specific amounts may be added to create a homemade ORS. In summary, this patient would have likely tolerated protein in solid form better than liquid protein supplementation.

Hospital Course Continued

The patient continued to have greater than 5 L of output from the ileostomy per day, so the following day the primary team increased the loperamide from 2 mg every 6 hours to 4 mg every 6 hours, added 2 tabs of diphenoxylate-atropine every 8 hours, and made the patient NPO. He continued to require IVFs and frequent electrolyte repletion because of the significant ongoing gastrointestinal losses.

What is the recommended first-line medical therapy for high-output enterostomy/diarrhea?

Anti-diarrheal medications are commonly used in high-output states because they work by reducing the rate of bowel translocation thereby allowing for longer time for nutrient and fluid absorption in the small and large intestine. Loperamide in particular also improves fecal incontinence because it effects the recto-anal inhibitory reflex and increases internal anal sphincter tone [9]. Four RCTs showed that loperamide lead to a significant reduction in enterostomy output compared to placebo with enterostomy output reductions ranging from 22% to 45%; varying dosages of loperamide were used, and ranged from 6 mg per day to 16 total mg per day [10–12]. King et al compared loperamide and codeine to placebo and found that both medications led to reductions in enterostomy output with a greater reduction and better side effect profile in those that received loperamide or combination therapy with loperamide and codeine [13,14]. The majority of studies used a maximum dose of 16 mg per day of loperamide, and this is the maxium daily dose approved by the US Food and Drug Administration (FDA). Interestingly however, loperamide circulates through the enterohepatic circulation which is severely disrupted in SBS, so titrating up to a maximum dose of 32 mg per day while closely monitoring for side effects is also practiced by experts in intestinal failure [15]. It is also important to note that anti-diarrheal medications are most effective when administered 20 to 30 minutes prior to meals and not scheduled every 4 to 6 hours if the patient is eating by mouth. If intestinal transit is so rapid such that undigested anti-diarrheal tablets or capsules are visualized in the stool or stoma, medications can be crushed or opened and mixed with liquids or solids to enhance digestion and absorption.

Hospital Course Continued

The patient continued to have greater than 3 L of ileostomy output per day despite being on scheduled loperamide, diphenoxylate-atropine, and a proton pump inhibitory (PPI), although improved from greater than 5 L per day. He was subsequently started on opium tincture 6 mg every 6 hours, psyllium 3 times per day, the dose of diphenoxylate-atropine was increased from 2 tablets every 8 hours to 2 tablets every 6 hours, and he was encouraged to drink water in between meals. As mentioned previously, the introduction of dietary fiber should be carefully monitored, as this patient population is commonly intolerant of high dietary fiber intake, and hypoosmolar liquids like water should actually be minimized. Within a 48-hour time period, the surgical team recommended increasing the loperamide from 4 mg every 6 hours (16 mg total daily dose) to 12 mg every 6 hours (48 mg total daily dose), increased opium tincture from 6 mg every 6 hours (24 mg total daily dose) to 10 mg every 6 hours (40 mg total daily dose), and increased oral pantoprazole from 40 mg once per day to twice per day.

What are important considerations with regard to dose changes?

Evidence is lacking to suggest an adequate time period to monitor for response to therapy in regards to improvement in diarrheal output. In this scenario, it may have been prudent to wait 24 to 48 hours after each medication change instead of making drastic dose changes in several medications simultaneously. PPIs irreversibly inhibit gastrointestinal acid secretion as do histamine-2 receptor antagonists (H2RAs) but to a lesser degree, and thus reduce high-output enterostomy [16]. Reduction in pH related to elevated gastrin levels after intestinal resection is associated with pancreatic enzyme denaturation and downstream bile salt dysfunction, which can further lead to malabsorption [17]. Gastrin hypersecretion is most prominent within the first 6 months after intestinal resection such that the use of high- dose PPIs for reduction in gastric acid secretion are most efficacious within that time period [18,19]. Jeppesen et al demonstrated that both omeprazole 40 mg oral twice per day and ranitidine 150 mg IV once per day were effective in reducing enterostomy output, although greater reductions were seen with omeprazole [20]. Three studies using cimetidine (both oral and IV formulations) with dosages varying from 200 mg to 800 mg per day showed significant reductions in enterostomy output as well [21–23].

Hospital Course Continued

Despite the previously mentioned interventions, the patient’s ileostomy output remained greater than 3 L per day. Loperamide was increased from 12 mg every 6 hours to 16 mg every 6 hours (64 mg total daily dose) hours and opium tincture was increased from 10 mg to 16 mg every 6 hours (64 mg total daily dose). Despite these changes, no significant reduction in output was noted, so the following day, 4 grams of cholestyramine light was added twice per day.

If the patient continues to have high-output enterostomy/diarrhea, what are additional treatment options?

Bile acid binding resins like cholestyramine, colestipol, and colesevelam are occasionally used if there is a high suspicion for bile acid diarrhea. Bile salt diarrhea typically occurs because of alterations in the enterohepatic circulation of bile salts, which leads to an increased level of bile salts in the colon and stimulation of electrolyte and water secretion and watery diarrhea [24]. Optimal candidates for bile acid binding therapy are those with an intact colon and less than 100 cm of resected ileum. Patients with little to no remaining or functional ileum have a depleted bile salt pool, therefore the addition of bile acid resin binders may actually lead to worsening diarrhea secondary to bile acid deficiency and fat malabsorption. Bile-acid resin binders can also decrease oxalate absorption and precipitate oxalate stone formation in the kidneys. Caution should also be taken to ensure that these medications are administered separately from the remainder of the patient’s medications to limit medication binding.

If the patient exhibits hemodynamic stability, alpha-2 receptor agonists are occasionally used as adjunctive therapy in reducing enterostomy output, although strong evidence to support its use is lacking. The mechanism of action involves stimulation of alpha-2 adrenergic receptors on enteric neurons, which theoretically causes a reduction in gastric and colonic motility and decreases fluid secretion. Buchman et al showed that the effects of a clonidine patch versus placebo did not in fact lead to a significant reduction in enterostomy output; however, a single case report suggested that the combination of 1200 mcg of clonidine per day and somatostatin resulted in decreased enterostomy output via alpha 2-receptor inhibition of adenylate cyclase [25,26].

Hospital Course Continued

The patient’s ileostomy output remained greater than 3 L per day, so loperamide was increased from 14 mg every 6 hours to 20 mg every 6 hours (80 mg total daily dose), cholestyramine was discontinued because of metabolic derangements, and the patient was initiated on 100 mcg of subcutaneous octreotide 3 times per day. Colorectal surgery was consulted for ileostomy takedown given persistently high-output, but surgery was deferred. After a 16-day hospitalization, the patient was eventually discharged home. At the time of discharge, he was having 2–3 L of ileostomy output per day and plans for future chemotherapy were discontinued because of this.

Does hormonal therapy have a role in the management of high-output enterostomy or entero-cutaneous fistulas?

Somatostatin analogues are growth-hormone inhibiting factors that have been used in the treatment of SBS and gastrointestinal fistulas. These medications reduce intestinal and pancreatic fluid secretion, slow intestinal motility, and inhibit the secretion of several hormones including gastrin, vasoactive intestinal peptide, cholecystokinin, and other key intestinal hormones. There is conflicting evidence for the role of these medications in reducing enterostomy output when first-line treatments have failed. Several previous studies using octreotide or somatostatin showed significant reductions in enterostomy output using variable dosages [27–30]. One study using the long-acting release depot octreotide preparation in 8 TPN-dependent patients with SBS showed a significant increase in small bowel transit time, however there was no significant improvement in the following parameters: body weight, stool weight, fecal fat excretion, stool electrolyte excretion, or gastric emptying [31]. Other studies evaluating enterostomy output from gastrointestinal and pancreatic fistulas comparing combined therapy with octreotide and TPN to placebo and TPN failed to show a significant difference in output and spontaneous fistula closure within 20 days of treatment initiation [32]. Because these studies use highly variable somatostatin analogue dosages and routes of administration, the most optimal dosing and route of administration (SQ versus IV) are unknown. In patients with difficult to control blood sugars, initiation of somatostatin analogues should be cautioned since these medications can lead to blood sugar alterations [33]. Additional unintended effects include impairment in intestinal adaptation and an increased risk in gallstone formation [8].

The most recent medical advances in SBS management include gut hormones. Glucagon-like peptide 2 (GLP-2) analogues improve structural and functional intestinal adaptation following intestinal resection by decreasing gastric emptying, decreasing gastric acid secretion, increasing intestinal blood flow, and enhancing nutrient and fluid absorption. Teduglutide, a GLP-2 analog, was successful in reducing fecal energy losses and increasing intestinal wet weight absorption, and reducing the need for PN support in SBS patients [1].

Whose problem is it anyway?

Not only is there variation in management strategies among subspecialties, but recommendations amongst societies within the same subspecialty differ, and thus make management perplexing.

Gastroenterology Guidelines

Several major gastroenterology societies have published guidelines on the management of diarrhea in patients with intestinal failure. The British Society of Gastroenterology (BSG) published guidelines on the management of SBS in 2006 and recommended the following first-line therapy for diarrhea-related complications: start loperamide at 2–8 mg thirty minutes prior to meals, taken up to 4 times per day, and the addition of codeine phosphate 30–60 mg thirty minutes before meals if output remains above goal on loperamide monotherapy. Cholestyramine may be added for those with 100 cm or less of resected terminal ileum to assist with bile-salt-induced diarrhea, though no specific dosage recommendations were reported. In regards to anti-secretory medications, the BSG recommends cimetidine (400 mg oral or IV 4 times per day), ranitidine (300 mg oral twice per day), or omeprazole (40 mg oral once per day or IV twice per day) to reduce jejunostomy output particularly in patients with greater than 2 L of output per day [15,34]. If diarrhea or enterostomy output continues to remain above goal, the guidelines suggest initiating octreotide and/or growth factors (although dosing and duration of therapy is not discussed in detail), and considering evaluation for intestinal transplant once the patient develops complications related to long-term TPN.

The American Gastroenterology Association (AGA) published guidelines and a position statement in 2003 for the management of high-gastric output and fluid losses. For postoperative patients, the AGA recommends the use of PPIs and H2RAs for the first 6 months following bowel resection when hyper-gastrinemia most commonly occurs. The guidelines do not specify which PPI or H2RA is preferred or recommended dosages. For long-term management of diarrhea or excess fluid losses, the guidelines suggest using loperamide or diphenoxylate (4-16 mg per day) first, followed by codeine sulfate 15–60 mg two to three times per day or opium tincture (dosages not specified). The use of octreotide (100 mcg SQ 3 times per day, 30 minutes prior to meals) is recommended only as a last resort if IVF requirements are greater than 3 L per day [8].

Surgical Guidelines

The Cleveland Clinic published institutional guidelines for the management of intestinal failure in 2010 with updated recommendations in 2016. Dietary recommendations include the liberal use of salt, sipping on 1–2 L of ORS between meals, and a slow reintroduction of soluble fiber from foods and/or supplements as tolerated. The guidelines also suggest considering placement of a nasogastric feeding tube or percutaneous gastrostomy tube (PEG) for continuous enteral feeding in addition to oral intake to enhance nutrient absorption [35]. If dietary manipulation is inadequate and medical therapy is required, the following medications are recommended in no particular order: loperamide 4 times per day (maximum dosage of 16 mg), diphenoxylate-atropine 4 times per day (maximum dosage of 20 mg per day), codeine 4 times per day (maximum dosage 240 mg per day), paregoric 5 mL (containing 2 mg of anhydrous morphine) 4 times per day, and opium tincture 0.5 mL (10 mg/mL) 4 times per day. H2RAs and PPIs are recommended for postoperative high-output states, although no dosage recommendations or routes of administration were discussed. 

Nutrition Guidelines

Villafranca et al published a protocol for the management of high-output stomas in 2015 that was shown to be effective in reducing high-enterostomy output. The protocol recommended initial treatment with loperamide 2 mg orally up to 4 times per day. If enterostomy output did not improve, the protocol recommended increasing loperamide to 4 mg four times per day, adding omeprazole 20 mg orally or cholestyramine 4 g twice per day before lunch and dinner if fat malabsorption or steatorrhea is suspected, and lastly the addition of codeine 15–60 mg up to 4 times per day and octreotide 200 mcg per day only if symptoms had not improved after 2 weeks [37].

The American Society for Parenteral and Enteral Nutrition (ASPEN) does not have published guidelines for the management of SBS. In 2016 however, the European Society for Clinical Nutrition and Metabolism (ESPEN) published guidelines on the management of chronic intestinal failure in adults. In patients with an intact colon, ESPEN strongly recommends a diet rich in complex carbohydrates and low in fat and using H2RAs or PPIs to treat hyper-gastrinemia within the first 6 months after intestinal resection particularly in those with greater than 2 L per day of fecal output. The ESPEN guidelines do not include whether to start a PPI or H2RA first, which particular drug in each class to try, or dosage recommendations but state that IV soluble formulations should be considered in those that do not seem to respond to tablets. ESPEN does not recommend the addition of soluble fiber to enhance intestinal absorption or probiotics and glutamine to aid in intestinal rehabilitation. For diarrhea and excessive fecal fluid, the guidelines recommend 4 mg of oral loperamide 30–60 minutes prior to meals, 3 to 4 times per day, as first-line treatment in comparison to codeine phosphate or opium tincture given the risks of dependence and sedation with the latter agents. They report, however, that dosages up to 12–24 mg at one time of loperamide are used in patients with terminal ileum resection and persistently high-output enterostomy [38].

Case Conclusion

The services that were closely involved in this patient’s care were general internal medicine, general surgery, colorectal surgery, and ancillary services, including dietary and wound care. Interestingly, despite persistent high ileostomy output during the patient’s 16-day hospital admission, the gastroenterology service was never consulted. This case illustrates the importance of having a multidisciplinary approach to the care of these complicated patients to ensure that the appropriate medications are ordered based on the individual’s anatomy and that medications are ordered at appropriate dosages and timing intervals to maximize drug efficacy. It is also critical to ensure that nursing staff accurately documents all intake and output so that necessary changes can be made after adequate time is given to assess for a true response. There should be close communication between the primary medical or surgical service with the dietician to ensure the patient is counseled on appropriate dietary intake to help minimize diarrhea and fluid losses.

Conclusion

In conclusion, intestinal failure is a heterogenous group of disease states that often occurs after major intestinal resection and is commonly associated with malabsorption and high output states. High-output enterostomy and diarrhea are the most common etiologies leading to hospital re-admission following enterostomy creation or intestinal resection. These patients have high morbidity and mortality rates, and their conditions are costly to the health care system. Lack of high-quality evidence from RCTs and numerous societal guidelines without clear medication and dietary algorithms and low prevalence of these conditions makes management of these patients by general medical and surgical teams challenging. The proper management of intestinal failure and related complications requires a multidisciplinary approach with involvement from medical, surgical, and ancillary services. We propose a multidisciplinary approach with involvement from medical, surgical, and ancillary services in designed and implementing a protocol using electronic medical record based order sets to simplify and improve the management of these patients in the inpatient setting.

Corresponding author: Jake Hutto, 5323 Harry Hines Blvd, Dallas, TX 75390-9030, [email protected].

Financial disclosures: None.

Division of Infectious Diseases, Department of Internal Medicine, VA Ann Arbor Healthcare System and University of Michigan Health System, Ann Arbor, MI.

Abstract

• Objective: To review prevention of central line–associated bloodstream infection (CLABSI).
• Method: Review of the literature.
• Results: Evidence-based prevention practices include ensuring hand hygiene before the procedure, using maximal sterile barrier precautions, cleaning the skin with alcoholic chlorhexidine before central line insertion, avoiding the femoral site for insertion, and removing unneeded catheters.
• Conclusion: For continued success in CLABSI prevention, best practices should be followed and patient safety should be emphasized.

Health care–associated infections (HAIs) are a preventable cause of morbidity and mortality in the United States and internationally. A Centers for Disease Control and Prevention (CDC) report estimates that in acute care hospitals, 1 in 25 patients end up with at least one HAI during their hospital stay [1]. HAIs can also be costly; in the United States, the indirect and direct cost has been estimated to be between $96 to $147 billion dollars [2]. National initiatives to prevent these types of infections have included efforts from the Department of Health and Human Services (HHS), the Institute of Medicine (IOM), the Institute for Healthcare Improvement (IHI) and the Centers for Medicare and Medicaid Services (CMS). This work has led to particular success in preventing central line–associated bloodstream infection (CLABSI).

CLABSI can lead to considerable mortality, morbidity, and cost. An estimated 250,000 CLABSIs occur in patients yearly, and about 80,000 of those are estimated to occur in the intensive care unit (ICU) setting [3]. Since central venous catheters (CVCs), or central lines, are most often used in the ICU setting, much of the work on prevention and management of CLABSI has been within the ICU population [4,5]. The increased use of peripherally inserted central catheters (PICCs) in the non-ICU setting and recognition of CLABSI in non-ICU settings has led to new efforts to understand the best way to prevent CLABSI in the non-ICU setting [4,6]. Regardless of setting, the annual cost of these infections has been estimated to be as high as $2.3 billion [7]. One episode is estimated to cost a hospital up to $46,485 per episode with components of excess length of stay, antibiotic cost, and cost of care [8]. In this review, selected best practices in CLABSI prevention are identified and described.

Elements of CLABSI Prevention

One of the key papers in the CLABSI literature was the Keystone ICU project in Michigan [9]. This state-wide effort grew out of a successful pilot patient-safety program that was trialed at Johns Hopkins Medical Institutions to reduce CLABSI in the ICU setting. In 2003, the Agency for Healthcare Research and Quality (AHRQ) funded a study to examine the intervention in ICUs in the state of Michigan. A total of 108 ICUs from 67 individual hospitals participated in the pre-intervention/post-intervention study [9]. A combination of technical and socio-adaptive interventions to prevent CLABSI included clinician education on best practices in insertion of central lines, having a central-line cart in each ICU, an insertion checklist of best practices, empowering nursing staff to stop the procedure if best practices were not being followed, discussing removal of catheters daily, and providing feedback to units regarding rates of CLABSI [10]. Executive administration of each hospital was also involved and there were monthly phone calls for hospital teams to share successes and barriers.

In the pre-intervention phase, the median catheter- related bloodstream infection rate was 2.7 infections per 1000 catheter days for the sum of hospitals. After the interventions were put in place, the median rate of catheter related bloodstream infections was down to 0.34 at 18 months. The study showed that results from a relatively inexpensive and straightforward intervention could be effective and could last in the long term. This study led to many other single center and multicenter studies, nationally and internationally, to replicate results in efforts to decrease CLABSI in ICU populations [5]. The CDC and AHRQ have continued to partner with regional, state and national efforts to focus on CLABSI prevention.

The Bundle Approach

A number of interventions have been proven to be effective at preventing CLABSI. Combining more than one intervention can often have additive effects. This effect has been recognized in numerous quality improvement studies on CLABSI and has been termed using the “bundle” approach. 

Hand Hygiene

Poor hand hygiene by health care workers is generally thought to be the most common cause of HAIs [12]. Guidelines recommend an alcohol-based waterless product or antiseptic soap and water prior to catheter insertion [13]. The most common underlying etiology of CLABSI is through microorganisms introduced at time of insertion of catheter. This can be extraluminally mediated via skin flora of the patient, or due to lack of hand washing on the inserter’s part and can lead to CLABSI [14]. While a randomized controlled trial would be unethical, several studies have shown when targeted hand hygiene campaigns are held, CLABSI rates tend to decrease [15–17].

Maximal Barrier Precautions

The use of maximal sterile barrier precautions has been associated with less mortality, decreasing catheter colonization, incidence of HAI and cost savings [18–20]. Like most components of the bundle, maximal sterile barrier precautions have rarely been studied alone, but are often a part of a “bundle” or number of interventions [21]. Like hand hygiene, while regularly a part of many hospital’s checklist or bundle process, compliance with this key part of infection prevention can be deficient; one study noted measured maximal sterile barriers compliance to be 44% [22].

Chlorhexidine Skin Antisepsis

Chlorhexidine skin preparation decreases bacterial burden at site of insertion and is thought to reduce infection from this mechanism. Chlorhexidine-alcohol skin preparation has been proven in randomized controlled trials to outperform povidone iodine-alcohol in preventing CLABSI [23,24]. Chlorhexidine skin preparation is considered a technical element of checklists and is thought to be a straightforward and easily implementable action [25]. If a hospital supplies only alcoholic chlorhexidine and doesn’t provide povidone-iodine for skin preparation, then clinicians can be “nudged” towards performing this part of the bundle.

Optimal Catheter Site Selection

For all sites of insertion of CVC, the risk of mechanical and infectious complications depends on the skill and proficiency of operators, the clinical situation, and the availability of ultrasound to help guide placement. These factors are important in determining which anatomical site is best for each patient [26]. The femoral site has been associated with a greater risk of catheter-related infection and catheter-related thrombosis and is not recommended as the initial choice for non-emergent CVC insertion according to national guidelines [13,27]. The internal jugular vein site is associated with a lower risk of severe mechanical complications such as pneumothorax when compared to subclavian vein site [27]. The subclavian vein site is associated with a lower risk of catheter-related blood stream infection and lower rate of thrombosis, but this greatly depends on experience of operator. Experts have proposed that the subclavian site has a lower burden of colonization by bacteria than other sites and is anatomically more protected by catheter dressing; also the subcutaneous course of the central line itself is longer for the subclavian site than other sites and these reasons could contribute to the lower risk of infection [28]. The subclavian site is, however, associated with a higher risk of mechanical complications that can be serious for ICU patients. In general, the femoral vein site should be avoided in non-emergent line placement situations, particularly if the patient is an obese adult [13]. Using ultrasound as a guidance for catheter insertion has also been shown to reduce risk of CLABSI and other mechanical complications and is recommended [29,30].

Daily Review of Line Necessity

Removing unnecessary catheters as soon as possible decreases catheter dwell time and risk of infection. Few studies have concentrated on this step alone in CLABSI prevention, but the studies that have focused on catheter removal usually implement electronic reminders or multidisciplinary catheter rounds (where need for catheter is incorporated into daily rounds or discussed separately by a multidisciplinary group) [5,31].

Additional Considerations

Other basic practices that all hospitals should adopt include the above strategies and providing all inclusive catheter carts or kits, disinfecting hubs in maintenance care of catheters, covering the CVC site with sterile dressings, having recurrent educational interventions and using checklists to assure adherence to the evidence-based bundle (Table) [4,13]. As prevalence of non-ICU central lines has also grown, maintenance care is particularly important in reducing CLABSI. Maintenance bundles that highlight best practices such as aseptic technique, correct hand hygiene, chlorhexidine skin disinfection scrub, antimicrobial bandage application, and catheter hub disinfection have been used with success [32]. Specialized CVC insertion teams with trained personnel have also been recommended [4]. When these basic evidence-based practices are still unable to bring down CLABSI rates for select populations or during an outbreak, supplemental strategies can be tried to reduce CLABSI. These include antimicrobial-impregnated catheters, chlorhexidine-impregnated dressings, and chlorhexidine bathing, which is increasingly being used in the ICU setting [5,13,33].

Epidemiology/Risk Factors

At-risk Populations

ICU patients are at risk for CLABSI because of frequent use of multiple catheters, and the comorbidities and acuity of care that these patients have. ICU patients also tend to have lots of manipulation of their catheters and often these catheters are placed in emergent situations [13]. Patients in the non-ICU and outpatient setting are also at risk for CLABSI when they have a central venous catheter. Long courses of antibiotics for disease states such as osteomyelitis and endocarditis often entail central venous catheters. Recent work has shown that PICCs carry as high of a CLABSI risk as short-term CVCs in hospitalized patients [34]. Patients with end-stage renal disease, especially those undergoing maintenance hemodialysis via a tunneled dialysis catheter are particularly vulnerable to CLABSI [13,35].

Risk Factors for CLABSI

A number of studies have reviewed risk factors and epidemiology of CLABSI in the adult and pediatric population. Factors that have been associated with risk of CLABSI in more than one study include prolonged hospitalization before placement of the central line, prolonged duration of the central line, heavy microbial colonization at the site of insertion, heavy microbial colonization of the catheter hub, multiple lumens, internal jugular site catheterization, femoral vein site catheterization, neutropenia of the patient, a reduced nurse to patient ratio in the ICU setting, presence of total parenteral nutrition, and poor maintenance care of the catheter [4,13,36–40]. One study [41] that calculated a score to help predict risk of PICC-CLABSI found that previous CLABSI (within 3 months of PICC insertion) significantly increases risk of repeat CLABSI.

Conclusion

CLABSI is an important cause of morbidity, mortality and cost. There has been remarkable success in prevention of these infections in recent years due to focused efforts on patient safety. As efforts have multiplied to put into place interventions to decrease CLABSI nationally, the CDC published a Vital Signs report discussing the impact of these efforts [42]. It was estimated that over one decade, infection prevention efforts had avoided 25,000 CLABSIs in U.S. ICUs, a 58% reduction in this infection [42]. CLABSI has served as the best example of using evidence-based interventions through an infection prevention bundle or framework to reduce HAIs. Similar approaches are being used to try to reduce catheter-associated urinary tract infection, Clostridium difficile infection, surgical site infection, and ventilator-associated pneumonia, but there have been less distinct successes nationally and internationally for these other HAIs.

The literature emphasizes that there are several evidence-based measures that can prevent CLABSI. These include hand hygiene, using alcoholic chlorhexidine for skin preparation prior to insertion, maximal sterile barrier precautions, avoiding the femoral site for CVC insertion, and removing unnecessary catheters as soon as possible. Support from administration in emphasizing patient safety and HAI prevention along with following evidence-based practice could lead to long-term improvement in CLABSI prevention across hospital systems.

Corresponding author: Payal K. Patel, MD, MPH, Div of Infectious Diseases, Dept of Internal Medicine, VA Ann Arbor Healthcare System, 2215 Fuller Rd, Ann Arbor, MI 48105, [email protected].

Financial disclosures: None.

Division of Infectious Diseases, Department of Internal Medicine, VA Ann Arbor Healthcare System and University of Michigan Health System, Ann Arbor, MI.

Abstract

• Objective: To review prevention of central line–associated bloodstream infection (CLABSI).
• Method: Review of the literature.
• Results: Evidence-based prevention practices include ensuring hand hygiene before the procedure, using maximal sterile barrier precautions, cleaning the skin with alcoholic chlorhexidine before central line insertion, avoiding the femoral site for insertion, and removing unneeded catheters.
• Conclusion: For continued success in CLABSI prevention, best practices should be followed and patient safety should be emphasized.

Health care–associated infections (HAIs) are a preventable cause of morbidity and mortality in the United States and internationally. A Centers for Disease Control and Prevention (CDC) report estimates that in acute care hospitals, 1 in 25 patients end up with at least one HAI during their hospital stay [1]. HAIs can also be costly; in the United States, the indirect and direct cost has been estimated to be between $96 to $147 billion dollars [2]. National initiatives to prevent these types of infections have included efforts from the Department of Health and Human Services (HHS), the Institute of Medicine (IOM), the Institute for Healthcare Improvement (IHI) and the Centers for Medicare and Medicaid Services (CMS). This work has led to particular success in preventing central line–associated bloodstream infection (CLABSI).

CLABSI can lead to considerable mortality, morbidity, and cost. An estimated 250,000 CLABSIs occur in patients yearly, and about 80,000 of those are estimated to occur in the intensive care unit (ICU) setting [3]. Since central venous catheters (CVCs), or central lines, are most often used in the ICU setting, much of the work on prevention and management of CLABSI has been within the ICU population [4,5]. The increased use of peripherally inserted central catheters (PICCs) in the non-ICU setting and recognition of CLABSI in non-ICU settings has led to new efforts to understand the best way to prevent CLABSI in the non-ICU setting [4,6]. Regardless of setting, the annual cost of these infections has been estimated to be as high as $2.3 billion [7]. One episode is estimated to cost a hospital up to $46,485 per episode with components of excess length of stay, antibiotic cost, and cost of care [8]. In this review, selected best practices in CLABSI prevention are identified and described.

Elements of CLABSI Prevention

One of the key papers in the CLABSI literature was the Keystone ICU project in Michigan [9]. This state-wide effort grew out of a successful pilot patient-safety program that was trialed at Johns Hopkins Medical Institutions to reduce CLABSI in the ICU setting. In 2003, the Agency for Healthcare Research and Quality (AHRQ) funded a study to examine the intervention in ICUs in the state of Michigan. A total of 108 ICUs from 67 individual hospitals participated in the pre-intervention/post-intervention study [9]. A combination of technical and socio-adaptive interventions to prevent CLABSI included clinician education on best practices in insertion of central lines, having a central-line cart in each ICU, an insertion checklist of best practices, empowering nursing staff to stop the procedure if best practices were not being followed, discussing removal of catheters daily, and providing feedback to units regarding rates of CLABSI [10]. Executive administration of each hospital was also involved and there were monthly phone calls for hospital teams to share successes and barriers.

In the pre-intervention phase, the median catheter- related bloodstream infection rate was 2.7 infections per 1000 catheter days for the sum of hospitals. After the interventions were put in place, the median rate of catheter related bloodstream infections was down to 0.34 at 18 months. The study showed that results from a relatively inexpensive and straightforward intervention could be effective and could last in the long term. This study led to many other single center and multicenter studies, nationally and internationally, to replicate results in efforts to decrease CLABSI in ICU populations [5]. The CDC and AHRQ have continued to partner with regional, state and national efforts to focus on CLABSI prevention.

The Bundle Approach

A number of interventions have been proven to be effective at preventing CLABSI. Combining more than one intervention can often have additive effects. This effect has been recognized in numerous quality improvement studies on CLABSI and has been termed using the “bundle” approach. 

Hand Hygiene

Poor hand hygiene by health care workers is generally thought to be the most common cause of HAIs [12]. Guidelines recommend an alcohol-based waterless product or antiseptic soap and water prior to catheter insertion [13]. The most common underlying etiology of CLABSI is through microorganisms introduced at time of insertion of catheter. This can be extraluminally mediated via skin flora of the patient, or due to lack of hand washing on the inserter’s part and can lead to CLABSI [14]. While a randomized controlled trial would be unethical, several studies have shown when targeted hand hygiene campaigns are held, CLABSI rates tend to decrease [15–17].

Maximal Barrier Precautions

The use of maximal sterile barrier precautions has been associated with less mortality, decreasing catheter colonization, incidence of HAI and cost savings [18–20]. Like most components of the bundle, maximal sterile barrier precautions have rarely been studied alone, but are often a part of a “bundle” or number of interventions [21]. Like hand hygiene, while regularly a part of many hospital’s checklist or bundle process, compliance with this key part of infection prevention can be deficient; one study noted measured maximal sterile barriers compliance to be 44% [22].

Chlorhexidine Skin Antisepsis

Chlorhexidine skin preparation decreases bacterial burden at site of insertion and is thought to reduce infection from this mechanism. Chlorhexidine-alcohol skin preparation has been proven in randomized controlled trials to outperform povidone iodine-alcohol in preventing CLABSI [23,24]. Chlorhexidine skin preparation is considered a technical element of checklists and is thought to be a straightforward and easily implementable action [25]. If a hospital supplies only alcoholic chlorhexidine and doesn’t provide povidone-iodine for skin preparation, then clinicians can be “nudged” towards performing this part of the bundle.

Optimal Catheter Site Selection

For all sites of insertion of CVC, the risk of mechanical and infectious complications depends on the skill and proficiency of operators, the clinical situation, and the availability of ultrasound to help guide placement. These factors are important in determining which anatomical site is best for each patient [26]. The femoral site has been associated with a greater risk of catheter-related infection and catheter-related thrombosis and is not recommended as the initial choice for non-emergent CVC insertion according to national guidelines [13,27]. The internal jugular vein site is associated with a lower risk of severe mechanical complications such as pneumothorax when compared to subclavian vein site [27]. The subclavian vein site is associated with a lower risk of catheter-related blood stream infection and lower rate of thrombosis, but this greatly depends on experience of operator. Experts have proposed that the subclavian site has a lower burden of colonization by bacteria than other sites and is anatomically more protected by catheter dressing; also the subcutaneous course of the central line itself is longer for the subclavian site than other sites and these reasons could contribute to the lower risk of infection [28]. The subclavian site is, however, associated with a higher risk of mechanical complications that can be serious for ICU patients. In general, the femoral vein site should be avoided in non-emergent line placement situations, particularly if the patient is an obese adult [13]. Using ultrasound as a guidance for catheter insertion has also been shown to reduce risk of CLABSI and other mechanical complications and is recommended [29,30].

Daily Review of Line Necessity

Removing unnecessary catheters as soon as possible decreases catheter dwell time and risk of infection. Few studies have concentrated on this step alone in CLABSI prevention, but the studies that have focused on catheter removal usually implement electronic reminders or multidisciplinary catheter rounds (where need for catheter is incorporated into daily rounds or discussed separately by a multidisciplinary group) [5,31].

Additional Considerations

Other basic practices that all hospitals should adopt include the above strategies and providing all inclusive catheter carts or kits, disinfecting hubs in maintenance care of catheters, covering the CVC site with sterile dressings, having recurrent educational interventions and using checklists to assure adherence to the evidence-based bundle (Table) [4,13]. As prevalence of non-ICU central lines has also grown, maintenance care is particularly important in reducing CLABSI. Maintenance bundles that highlight best practices such as aseptic technique, correct hand hygiene, chlorhexidine skin disinfection scrub, antimicrobial bandage application, and catheter hub disinfection have been used with success [32]. Specialized CVC insertion teams with trained personnel have also been recommended [4]. When these basic evidence-based practices are still unable to bring down CLABSI rates for select populations or during an outbreak, supplemental strategies can be tried to reduce CLABSI. These include antimicrobial-impregnated catheters, chlorhexidine-impregnated dressings, and chlorhexidine bathing, which is increasingly being used in the ICU setting [5,13,33].

Epidemiology/Risk Factors

At-risk Populations

ICU patients are at risk for CLABSI because of frequent use of multiple catheters, and the comorbidities and acuity of care that these patients have. ICU patients also tend to have lots of manipulation of their catheters and often these catheters are placed in emergent situations [13]. Patients in the non-ICU and outpatient setting are also at risk for CLABSI when they have a central venous catheter. Long courses of antibiotics for disease states such as osteomyelitis and endocarditis often entail central venous catheters. Recent work has shown that PICCs carry as high of a CLABSI risk as short-term CVCs in hospitalized patients [34]. Patients with end-stage renal disease, especially those undergoing maintenance hemodialysis via a tunneled dialysis catheter are particularly vulnerable to CLABSI [13,35].

Risk Factors for CLABSI

A number of studies have reviewed risk factors and epidemiology of CLABSI in the adult and pediatric population. Factors that have been associated with risk of CLABSI in more than one study include prolonged hospitalization before placement of the central line, prolonged duration of the central line, heavy microbial colonization at the site of insertion, heavy microbial colonization of the catheter hub, multiple lumens, internal jugular site catheterization, femoral vein site catheterization, neutropenia of the patient, a reduced nurse to patient ratio in the ICU setting, presence of total parenteral nutrition, and poor maintenance care of the catheter [4,13,36–40]. One study [41] that calculated a score to help predict risk of PICC-CLABSI found that previous CLABSI (within 3 months of PICC insertion) significantly increases risk of repeat CLABSI.

Conclusion

CLABSI is an important cause of morbidity, mortality and cost. There has been remarkable success in prevention of these infections in recent years due to focused efforts on patient safety. As efforts have multiplied to put into place interventions to decrease CLABSI nationally, the CDC published a Vital Signs report discussing the impact of these efforts [42]. It was estimated that over one decade, infection prevention efforts had avoided 25,000 CLABSIs in U.S. ICUs, a 58% reduction in this infection [42]. CLABSI has served as the best example of using evidence-based interventions through an infection prevention bundle or framework to reduce HAIs. Similar approaches are being used to try to reduce catheter-associated urinary tract infection, Clostridium difficile infection, surgical site infection, and ventilator-associated pneumonia, but there have been less distinct successes nationally and internationally for these other HAIs.

The literature emphasizes that there are several evidence-based measures that can prevent CLABSI. These include hand hygiene, using alcoholic chlorhexidine for skin preparation prior to insertion, maximal sterile barrier precautions, avoiding the femoral site for CVC insertion, and removing unnecessary catheters as soon as possible. Support from administration in emphasizing patient safety and HAI prevention along with following evidence-based practice could lead to long-term improvement in CLABSI prevention across hospital systems.

Corresponding author: Payal K. Patel, MD, MPH, Div of Infectious Diseases, Dept of Internal Medicine, VA Ann Arbor Healthcare System, 2215 Fuller Rd, Ann Arbor, MI 48105, [email protected].

Financial disclosures: None.

Division of Infectious Diseases, Department of Internal Medicine, VA Ann Arbor Healthcare System and University of Michigan Health System, Ann Arbor, MI.

Abstract

• Objective: To review prevention of central line–associated bloodstream infection (CLABSI).
• Method: Review of the literature.
• Results: Evidence-based prevention practices include ensuring hand hygiene before the procedure, using maximal sterile barrier precautions, cleaning the skin with alcoholic chlorhexidine before central line insertion, avoiding the femoral site for insertion, and removing unneeded catheters.
• Conclusion: For continued success in CLABSI prevention, best practices should be followed and patient safety should be emphasized.

Health care–associated infections (HAIs) are a preventable cause of morbidity and mortality in the United States and internationally. A Centers for Disease Control and Prevention (CDC) report estimates that in acute care hospitals, 1 in 25 patients end up with at least one HAI during their hospital stay [1]. HAIs can also be costly; in the United States, the indirect and direct cost has been estimated to be between $96 to $147 billion dollars [2]. National initiatives to prevent these types of infections have included efforts from the Department of Health and Human Services (HHS), the Institute of Medicine (IOM), the Institute for Healthcare Improvement (IHI) and the Centers for Medicare and Medicaid Services (CMS). This work has led to particular success in preventing central line–associated bloodstream infection (CLABSI).

CLABSI can lead to considerable mortality, morbidity, and cost. An estimated 250,000 CLABSIs occur in patients yearly, and about 80,000 of those are estimated to occur in the intensive care unit (ICU) setting [3]. Since central venous catheters (CVCs), or central lines, are most often used in the ICU setting, much of the work on prevention and management of CLABSI has been within the ICU population [4,5]. The increased use of peripherally inserted central catheters (PICCs) in the non-ICU setting and recognition of CLABSI in non-ICU settings has led to new efforts to understand the best way to prevent CLABSI in the non-ICU setting [4,6]. Regardless of setting, the annual cost of these infections has been estimated to be as high as $2.3 billion [7]. One episode is estimated to cost a hospital up to $46,485 per episode with components of excess length of stay, antibiotic cost, and cost of care [8]. In this review, selected best practices in CLABSI prevention are identified and described.

Elements of CLABSI Prevention

One of the key papers in the CLABSI literature was the Keystone ICU project in Michigan [9]. This state-wide effort grew out of a successful pilot patient-safety program that was trialed at Johns Hopkins Medical Institutions to reduce CLABSI in the ICU setting. In 2003, the Agency for Healthcare Research and Quality (AHRQ) funded a study to examine the intervention in ICUs in the state of Michigan. A total of 108 ICUs from 67 individual hospitals participated in the pre-intervention/post-intervention study [9]. A combination of technical and socio-adaptive interventions to prevent CLABSI included clinician education on best practices in insertion of central lines, having a central-line cart in each ICU, an insertion checklist of best practices, empowering nursing staff to stop the procedure if best practices were not being followed, discussing removal of catheters daily, and providing feedback to units regarding rates of CLABSI [10]. Executive administration of each hospital was also involved and there were monthly phone calls for hospital teams to share successes and barriers.

In the pre-intervention phase, the median catheter- related bloodstream infection rate was 2.7 infections per 1000 catheter days for the sum of hospitals. After the interventions were put in place, the median rate of catheter related bloodstream infections was down to 0.34 at 18 months. The study showed that results from a relatively inexpensive and straightforward intervention could be effective and could last in the long term. This study led to many other single center and multicenter studies, nationally and internationally, to replicate results in efforts to decrease CLABSI in ICU populations [5]. The CDC and AHRQ have continued to partner with regional, state and national efforts to focus on CLABSI prevention.

The Bundle Approach

A number of interventions have been proven to be effective at preventing CLABSI. Combining more than one intervention can often have additive effects. This effect has been recognized in numerous quality improvement studies on CLABSI and has been termed using the “bundle” approach. 

Hand Hygiene

Poor hand hygiene by health care workers is generally thought to be the most common cause of HAIs [12]. Guidelines recommend an alcohol-based waterless product or antiseptic soap and water prior to catheter insertion [13]. The most common underlying etiology of CLABSI is through microorganisms introduced at time of insertion of catheter. This can be extraluminally mediated via skin flora of the patient, or due to lack of hand washing on the inserter’s part and can lead to CLABSI [14]. While a randomized controlled trial would be unethical, several studies have shown when targeted hand hygiene campaigns are held, CLABSI rates tend to decrease [15–17].

Maximal Barrier Precautions

The use of maximal sterile barrier precautions has been associated with less mortality, decreasing catheter colonization, incidence of HAI and cost savings [18–20]. Like most components of the bundle, maximal sterile barrier precautions have rarely been studied alone, but are often a part of a “bundle” or number of interventions [21]. Like hand hygiene, while regularly a part of many hospital’s checklist or bundle process, compliance with this key part of infection prevention can be deficient; one study noted measured maximal sterile barriers compliance to be 44% [22].

Chlorhexidine Skin Antisepsis

Chlorhexidine skin preparation decreases bacterial burden at site of insertion and is thought to reduce infection from this mechanism. Chlorhexidine-alcohol skin preparation has been proven in randomized controlled trials to outperform povidone iodine-alcohol in preventing CLABSI [23,24]. Chlorhexidine skin preparation is considered a technical element of checklists and is thought to be a straightforward and easily implementable action [25]. If a hospital supplies only alcoholic chlorhexidine and doesn’t provide povidone-iodine for skin preparation, then clinicians can be “nudged” towards performing this part of the bundle.

Optimal Catheter Site Selection

For all sites of insertion of CVC, the risk of mechanical and infectious complications depends on the skill and proficiency of operators, the clinical situation, and the availability of ultrasound to help guide placement. These factors are important in determining which anatomical site is best for each patient [26]. The femoral site has been associated with a greater risk of catheter-related infection and catheter-related thrombosis and is not recommended as the initial choice for non-emergent CVC insertion according to national guidelines [13,27]. The internal jugular vein site is associated with a lower risk of severe mechanical complications such as pneumothorax when compared to subclavian vein site [27]. The subclavian vein site is associated with a lower risk of catheter-related blood stream infection and lower rate of thrombosis, but this greatly depends on experience of operator. Experts have proposed that the subclavian site has a lower burden of colonization by bacteria than other sites and is anatomically more protected by catheter dressing; also the subcutaneous course of the central line itself is longer for the subclavian site than other sites and these reasons could contribute to the lower risk of infection [28]. The subclavian site is, however, associated with a higher risk of mechanical complications that can be serious for ICU patients. In general, the femoral vein site should be avoided in non-emergent line placement situations, particularly if the patient is an obese adult [13]. Using ultrasound as a guidance for catheter insertion has also been shown to reduce risk of CLABSI and other mechanical complications and is recommended [29,30].

Daily Review of Line Necessity

Removing unnecessary catheters as soon as possible decreases catheter dwell time and risk of infection. Few studies have concentrated on this step alone in CLABSI prevention, but the studies that have focused on catheter removal usually implement electronic reminders or multidisciplinary catheter rounds (where need for catheter is incorporated into daily rounds or discussed separately by a multidisciplinary group) [5,31].

Additional Considerations

Other basic practices that all hospitals should adopt include the above strategies and providing all inclusive catheter carts or kits, disinfecting hubs in maintenance care of catheters, covering the CVC site with sterile dressings, having recurrent educational interventions and using checklists to assure adherence to the evidence-based bundle (Table) [4,13]. As prevalence of non-ICU central lines has also grown, maintenance care is particularly important in reducing CLABSI. Maintenance bundles that highlight best practices such as aseptic technique, correct hand hygiene, chlorhexidine skin disinfection scrub, antimicrobial bandage application, and catheter hub disinfection have been used with success [32]. Specialized CVC insertion teams with trained personnel have also been recommended [4]. When these basic evidence-based practices are still unable to bring down CLABSI rates for select populations or during an outbreak, supplemental strategies can be tried to reduce CLABSI. These include antimicrobial-impregnated catheters, chlorhexidine-impregnated dressings, and chlorhexidine bathing, which is increasingly being used in the ICU setting [5,13,33].

Epidemiology/Risk Factors

At-risk Populations

ICU patients are at risk for CLABSI because of frequent use of multiple catheters, and the comorbidities and acuity of care that these patients have. ICU patients also tend to have lots of manipulation of their catheters and often these catheters are placed in emergent situations [13]. Patients in the non-ICU and outpatient setting are also at risk for CLABSI when they have a central venous catheter. Long courses of antibiotics for disease states such as osteomyelitis and endocarditis often entail central venous catheters. Recent work has shown that PICCs carry as high of a CLABSI risk as short-term CVCs in hospitalized patients [34]. Patients with end-stage renal disease, especially those undergoing maintenance hemodialysis via a tunneled dialysis catheter are particularly vulnerable to CLABSI [13,35].

Risk Factors for CLABSI

A number of studies have reviewed risk factors and epidemiology of CLABSI in the adult and pediatric population. Factors that have been associated with risk of CLABSI in more than one study include prolonged hospitalization before placement of the central line, prolonged duration of the central line, heavy microbial colonization at the site of insertion, heavy microbial colonization of the catheter hub, multiple lumens, internal jugular site catheterization, femoral vein site catheterization, neutropenia of the patient, a reduced nurse to patient ratio in the ICU setting, presence of total parenteral nutrition, and poor maintenance care of the catheter [4,13,36–40]. One study [41] that calculated a score to help predict risk of PICC-CLABSI found that previous CLABSI (within 3 months of PICC insertion) significantly increases risk of repeat CLABSI.

Conclusion

CLABSI is an important cause of morbidity, mortality and cost. There has been remarkable success in prevention of these infections in recent years due to focused efforts on patient safety. As efforts have multiplied to put into place interventions to decrease CLABSI nationally, the CDC published a Vital Signs report discussing the impact of these efforts [42]. It was estimated that over one decade, infection prevention efforts had avoided 25,000 CLABSIs in U.S. ICUs, a 58% reduction in this infection [42]. CLABSI has served as the best example of using evidence-based interventions through an infection prevention bundle or framework to reduce HAIs. Similar approaches are being used to try to reduce catheter-associated urinary tract infection, Clostridium difficile infection, surgical site infection, and ventilator-associated pneumonia, but there have been less distinct successes nationally and internationally for these other HAIs.

The literature emphasizes that there are several evidence-based measures that can prevent CLABSI. These include hand hygiene, using alcoholic chlorhexidine for skin preparation prior to insertion, maximal sterile barrier precautions, avoiding the femoral site for CVC insertion, and removing unnecessary catheters as soon as possible. Support from administration in emphasizing patient safety and HAI prevention along with following evidence-based practice could lead to long-term improvement in CLABSI prevention across hospital systems.

Corresponding author: Payal K. Patel, MD, MPH, Div of Infectious Diseases, Dept of Internal Medicine, VA Ann Arbor Healthcare System, 2215 Fuller Rd, Ann Arbor, MI 48105, [email protected].

Financial disclosures: None.

From the Center for Nursing Science & Clinical Inquiry (Dr. McCarthy), and Nutrition Care Division, (Ms. Phipps), Madigan Army Medical Center, Tacoma, WA.

Abstract

• Background: Many controversies exist in the field of nutrition support today, particularly in the critical care environment where nutrition plays a more primary rather than adjunctive role.
• Objective: To provide a brief review of current controversies regarding nutrition therapy in the ICU focusing on the choices regarding the nutrition regimen and the safe, consistent delivery of nutrition as measured by clinical outcomes.
• Methods: Selected areas of controversy are discussed detailing the strengths and weaknesses of the research behind opposing opinions.
• Results: ICU nutrition support controversies include enteral vs parenteral nutrition, use of supplmental parenteral nutrition, protein quantity and quality, and polymeric vs immune-modulating nutrients. Issues surrounding the safety of nutrition support therapy include gastric vs small bowel feeding and trophic vs full feeding. Evidence-based recommendations published by professional societies are presented.
• Conclusion: Understanding a patient’s risk for disease and predicting their response to treatment will assist clinicians with selecting those nutrition interventions that will achieve the best possible outcomes.

According to the National Library of Medicine’s translation of the Hippocratic oath, nowhere does it explicitly say “First, do no harm.” What is written is this: “I will use those dietary regimens which will benefit my patients according to my greatest ability and judgement, and I will do no harm or injustice to them” [1]. In another renowned text, one can find this observation regarding diet by a noted scholar, clinician, and the founder of modern nursing, Florence Nightingale: “Every careful observer of the sick will agree in this that thousands of patients are annually starved in the midst of plenty, from want of attention to the ways which alone make it possible for them to take food” [2,]. While Nightingale was alluding to malnutrition of hospitalized patients, it seems that her real concern may have been the iatrogenic malnutrition that inevitably accompanies hospitalization, even today [3].

From these philosophic texts, we have two ongoing controversies in modern day nutrition therapy identified: (1) what evidence do we have to support the choice of dietary regimens (ie, enteral vs parenteral therapy, timing of supplemental parenteral nutrition, standard vs high protein formula, polymeric vs immune-modulating nutrients) that best serve critically ill patients, and (2) how do we ensure that ICU patients are fed in a safe, consistent, and effective manner (gastric vs small bowel tube placement, gastric residual monitoring or not, trophic vs full feeding) as measured by clinically relevant outcomes? Many controversies exist in the field of nutrition support today [4–7] and a comprehensive discussion of all of them is beyond the scope of this paper. In this paper we will provide a brief review of current controversies focusing on those mentioned above which have only recently been challenged by new rigorous randomized clinical trials (RCTs), and in some cases, subsequent systematic reviews and meta-analyses [8–11].

The Path to Modern Day Nutrition Support Therapy

The field of nutrition support, in general, has expanded greatly over the last 4 decades, but perhaps the most notable advancements have occurred in the critical care environment where efforts have been directed at advancing our understanding of the molecular and biological effects of nutrients in maintaining homeostasis in the critically ill [6]. In recent years, specialized nutrition, delivered by the enteral or parenteral route, was finally recognized for its contribution to important clinical outcomes in the critically ill population [12]. Critical care clinicians have been educated about the advances in nutrition therapy designed to address the unique needs of a vulnerable population where survival is threatened by poor nutritional status upon admission, compromised immune function, weakened respiratory muscles with decreased ventilation capacity, and gastrointestinal (GI) dysfunction [6]. The rapid deterioration seen in these patients is exaggerated by the all too common ICU conditions of systemic inflammatory response syndrome (SIRS), sepsis, hemodynamic instability, respiratory failure, coagulation disorders, and acute kidney injury [13,14].

Beginning in the early 1990s, formulations of enteral nutrition (EN) contained active nutrients that reportedly reduced oxidative damage to cells and tissues, modulated inflammation, and improved feeding tolerance. These benefits are now referred to as the non-nutritive benefits of enteral feeding [15]. For the next 20 years, scientific publications released new results from studies examining the role of omega-3 fatty acids, antioxidant vitamins, minerals such as selenium and zinc, ribonucleotides, and conditionally essential amino acids like glutamine and arginine, in healing and recovery from critical illness. The excitement was summarized succinctly by Hegazi and Wischmeyer in 2011 when they remarked that the modern ICU clinician now has scientific data to guide specialized nutrition therapy, for example, choosing formulas supplemented with anti-inflammatory, immune-modulating, or tolerance-promoting nutrients that have the potential to enhance natural recovery processes and prevent complications [16].

The improvements in nutritional formulas were accompanied by numerous technological advances including bedside devices (electromagnetic enteral access system, real-time image-guided disposable feeding tube, smart feeding pumps with water flush technology) that quickly and safely establish access for small bowel feedings, which help minimize risk of gastric aspiration and ventilator-associated pneumonia, promote tolerance, decrease radiologic exposure, and may reduce nursing time consumed by tube placements, GI dysfunction, and patient discomfort [17–20]. Nasogastric feeding remains the most common first approach, with local practices, contraindications, and ease of placement usually determining the location of the feeding tube [5]. The advancements helped to overcome the many barriers to initiating and maintaining feedings and thus, efforts to feed critically ill patients early and effectively became more routine, along with nurse, patient, and family satisfaction. In conjunction with the innovative approaches to establishing nutrition therapy, practice guidelines published by United States, European, and Canadian nutrition societies became widely available in the past decade with graded evidence-based recommendations for who, when, what, and how to feed, and unique considerations for various critically ill populations [12,21,22]. The tireless efforts by the nutrition societies to provide much needed guidelines for clinicians were appreciated, yet there was a wide range in the grade of the recommendations, with many based on expert opinion alone. In some cases, the research conducted lacked rigor or had missing data with obvious limits to the generalizability of results. Nevertheless, for the 7 years between the publication of the old and newly revised Society of Critical Care Medicine (SCCM)/ American Society of Parenteral and Enteral Nutrition (ASPEN) Guidelines (2016), [12,23] nutrition therapy was a high-priority intervention in most ICUs. The goal was to initiate feeding within 48 hours, select an immune-modulating or other metabolic support formula, and aggressively advance the rate to 80% to 100% of goal to avoid caloric deficit, impaired intestinal integrity, nitrogen losses, and functional impairments [9,24,25]. Nutrition support evolved from adjunctive care to its rightful place in the ABCD mnemonic of early priorities of ICU care: Airway, Breathing, Circulation, Diet.

The 2016 joint publication of the SCCM/ASPEN guidelines includes primarily randomized controlled trial (RCT) data, along with some observational trial data, indexed in any major publication database through December 2013. In these guidelines there were 98 recommendations, of which only 5 were a Level 1A; most of the recommendations were categorized as “expert consensus” [12]. The results of several important clinical trials in the United States and Europe that were underway at the time have since been published and compared to the SCCM/ASPEN relevant recommendations [7]. The results have forced nutrition support clinicians to take a step back and re-examine their practice. For many seasoned clinicians who comprised the nutrition support teams of the 1980s and 1990s, it feels like a return to the basics. Until biology-driven personalized medicine is commonplace and genotype data is readily available to guide nutrition therapy for each critically ill patient, standard enteral feeding that begins slow and proceeds carefully over 5 to 7 days towards 80% of goal caloric intake under judicious monitoring of biochemical and metabolic indices may be the “best practice” today, without risk of harm [15,26]. As in all aspects of clinical care, this practice is not without controversy.

ICU Nutrition Support Controversies Today

Enteral vs Parenteral Nutrition

There is universal consensus that EN is the preferred route for nutrition therapy due to the superior physiological response and both nutritional and non-nutritional benefits [24]. Changes in gut permeability tend to occur as illness progresses and consequences include increased bacterial challenge, risk for multiple organ dysfunction syndrome, and systemic infection. It is best to intervene with nutrition early, defined as within the first 48 hours of ICU admission, while the likelihood of success and opportunity to impact the disease process is greater [12]. Early initiation of feeding provides the necessary nutrients to support gut-associated lymphoid tissue (GALT), mucosal-associated lymphoid tissue (MALT), and preserve gut integrity and microbial diversity [27]. The intestine is an effective barrier against bacteria and intraluminal toxins due to the high rate of enterocyte turnover, the mucus secreted by the goblet cells, and the large amount of protective immunological tissue; 80% of the immunoglobulins are synthesized in the GI tract [28]. Fasting states for procedures or delays in feeding longer than 3 days for any reason may contribute to disruption of intestinal integrity through atrophy and derangements in the physical structure and function of the microvilli and crypts [29]. Intestinal dysfunction leads to increased intestinal permeability and the possibility of bacterial translocation. Intestinal ischemia resulting from shock and sepsis may produce hypoxia and reperfusion injuries further affecting intestinal wall permeability [29]. In surgical patients, early enteral feeding has been found to reduce inflammation, oxidative stress, and the catabolic response to anesthesia and surgical-induced stress, help restore intestinal motility, reverse enteric mucosal atrophy, and improve wound healing [26].

We did not have sufficient data to refute the benefits of EN over PN until the paper by Harvey et al (2014), which reported no difference in mortality or infectious complications in ICU patients receiving EN or PN within 36 hours of admission and for up to 5 days [30]. This was the largest published pragmatic RCT, referred to as the CALORIES trial, which analyzed 2388 patients from 33 ICUs and resulted in controversy over what was an unchallenged approach up until this time. It was only a matter of time before other investigators would set out to confirm or negate this finding, which is what Elke and coworkers (2016) did a few years later [31]. They performed an updated systematic review and meta-analysis to evaluate the overall effect of the route of nutrition (EN versus PN) on clinical outcomes in adult critically ill patients. Similar to the Harvey et al report, they found no difference in mortality between the two routes of nutrition. However, unlike the earlier report, patients receiving EN compared to PN had a significant reduction in the number of infectious complications and ICU length of stay. No significant effect was found for hospital length of stay or days requiring mechanical ventilation. The authors suggest that EN delivery of macronutrients below predefined targets may be responsible as PN is more likely to meet or exceed these targets and overwhelm metabolic capacity in the early days of critical illness [31].

The most recent trial prompting even more discussion about early PN versus early EN in mechanically ventilated ICU patients in shock is the Reignier et al (2018) NUTRIREA-2 trial involving 2410 patients from 44 ICUs in France [32]. The investigators hypothesized that outcomes would be better with early exclusive EN compared to early exclusive PN; their hypothesis was not supported by the results, which found no difference in 28-day mortality or ICU-acquired infections. Also unexpected was the higher cumulative incidence of gastrointestinal complications including vomiting, diarrhea, bowel ischemia, and acute colonic obstruction in the EN group. The trial was stopped early after an interim analysis determined that additional enrollment was not likely to significantly change the results of the trial. Given the similarities between the CALORIES trial and this NUTRIREA-2 trial, clinicians now have mounting evidence that equivalent options for nutrition therapy exist and an appropriate selection should be made based on patient-specific indications and treatment goals. In summary, EN remains preferable to PN for the majority of adult critically ill patients due to crucial support of gut integrity, but the optimal dose or rate of delivery to favorably influence clinical outcomes in the first few days following admission remains unknown.

Use of Supplemental Parenteral Nutrition

Both the nutrition support and bench science communities have learned a great deal about PN over the 4 decades it has been in existence, with the most compelling data coming from more recent trials [31–38]. This is because it has taken many years to recover from the days of hyperalimentation or overfeeding ICU patients by providing excessive calories to meet the elevated energy demands and to reverse the hypercatabolism of critical illness. This approach contributed to the complications of hyperglycemia, hyperlipidemia, increased infectious complications, and liver steatosis, all of which gave PN a negative reputation [37]. We now have adjusted the caloric distribution and the actual formulation of PN using the recent FDA-approved lipid emulsion (Soy, Medium-chain triglycerides, Olive oil, and Fish oil; SMOF) and created protocols for administering it based on specific indications, such as loss of GI integrity or demonstrated intolerance. In general, the advances in PN have led to a safer more therapeutic formulation that has its place in critical illness. Manzanares et al [40] reported a trend toward a decrease in ventilation requirement and mortality when a fish oil–containing lipid emulsion was administered to patients who were receiving nutrition support either enterally or parenterally. The meta-analysis combined all soybean oil–sparing lipid emulsions for comparison with soybean oil and was able to show the trend for improved clinical outcomes with soybean oil–sparing lipid emulsions. The main findings of this meta-analysis were that fish oil–containing lipid emulsions may reduce infections and may be associated with a tendency toward fewer mechanical ventilation days, although not mortality, when compared with soybean oil-based strategies or administration of other alternative lipid emulsions in ICU patients [40]. Recent trial results do not change the recommendation for selecting EN first but do suggest lowering the threshold for using PN when EN alone is insufficient to meet nutrition goals. A systematic review reported no benefit of early supplemental PN over late supplemental PN and cautioned that our continued inability to explain greater infectious morbidity and unresolved organ failure limits any justification for early PN [35].

Protein Quantity and Quality

The practice of providing protein in the range of 1.2–2.0 g/kg actual body weight early in critical illness is suggested by expert consensus in the 2016 SCCM/ASPEN guidelines [12]; however, the evidence for efficacy remains controversial. It is argued that the evidence for benefit comes from observational studies, not from prospective RCTs, and that the patients at high risk are often excluded from study protocols. It has also been suggested that in patients with limited vital organ function increased protein delivery may lead to organ compromise. In a recent (2017) paper, Rooyackers et al discussed the post-hoc analyses of data from the EPANIC Trial stating the statistical correlation between protein intake and outcomes indicate that protein was associated with unfavorable outcomes, possibly by inhibiting autophagy [41].

The nutrition support community may have widely varying approaches to feeding critically ill patients but most experts agree that protein may be the most important macronutrient delivered during critical illness. There is consensus that the hypercatabolism associated with stress induces proteolysis and the loss of lean muscle mass, which may affect clinical and functional outcomes beyond the ICU stay. Using multiple assessment modalities, Puthucheary et al (2013) demonstrated a reduction in the rectus femoris muscle of 12.5% over the first week of hospitalization in the ICU and up to 17.7% by day 10. These numbers imply that sufficient protein of at least 1.2 g/kg/day should be provided to minimize these losses, even if the effect on overall outcome remains unknown [42]. Evidence is lacking for whether or not we can prevent the muscle wasting that occurs in critical illness with increased protein dosing. We also need to better identify the possible risks involved with a high-protein intake at the level of the individual patient. A secondary analysis done by Heyland et al (2013) determined that no specific dose or type of macronutrient was found to be associated with improved outcome [43]. It is clear that more large-scale RCTs of protein/amino acid interventions are needed to prove that these nutrition interventions have favorable effects on clinically important outcomes, including long-term physical function.

Polymeric vs Immune-Modulating Nutrients

The Marik and Zaloga (2008) systematic review on immunonutrition in the critically ill convinced most clinicians that while fish-oil based immunonutrition improves the outcome of medical ICU patients, diets supplemented with arginine, with or without glutamine or fish oils, do not demonstrate an advantage over standard enteral products in general ICU, trauma, or burn patients[44]. What followed these trials examining early formulations of immunonutrition was decades of well-intentioned research dedicated to elucidating the mechanism of action for individual immune-modulating nutrients for various populations, including those with acute lung injury/acute respiratory distress syndrome (ARDS) [45–47], sepsis/systemic inflammatory response syndrome [48–50], head and neck cancer [51], upper and lower GI cancer [52–55], and severe acute pancreatitis [56]. Our understanding of immunonutrition and the administration of this formulation in specific disease conditions has grown considerably yet clinicians are still asking exactly what is the role of immunonutrition and who stands to benefit the most from immune-modulating nutrition therapy. The enteral formulations currently available have a proprietary composition and dosage of individual nutrients which yield unpredictable physiologic effects. In addition, the pervasive problem of underfeeding during hospitalization prevents adequate delivery of physiologic doses of nutrients thus contributing to the widely variable research results.

Prevailing expert opinion today is that the majority of critically ill patients will benefit from nutrition support initiated early and delivered consistently; the standard polymeric formula will suffice for the majority of patients with surgical ICU patients potentially deriving benefit from immunonutrition that supports a reduction in infectious complications [57]. In the recent multiple-treatment meta-analysis performed by Mazaki et al (2015) involving 74 studies and 7572 patients, immunonutrition was ranked first for reducing the incidence of 7 complications according to the surface under the cumulative ranking curve; these were as follows: any infection, 0.86; overall complication, 0.88; mortality, 0.81; wound infection, 0.79; intra-abdominal abscess, 0.98; anastomotic leak, 0.79; and sepsis, 0.92. immunonutrition was ranked second for reducing ventilator-associated pneumonia and catheter-associated urinary tract infection (CAUTI), behind immune-modulating PN. The authors stated that immuno­nutrition was efficacious for reducing the incidence of complications in GI surgery unrelated to the timing of administration [57]. The 2014 publication of results from the MetaPlus Trial [58]challenged the published recommendations for the use of immunonutrition in the medical critically ill population. This trial used high-protein immuno­nutrition or standard formula for 301 adult critically ill patients in 14 European ICUs with diagnoses such as pneumonia or infections of the urinary tract, bloodstream, central nervous system, eye, ear, nose or throat, and the skin and soft tissue. Even with higher than average target energy intakes of 70% for the high protein immunonutrition group and 80% for the high protein standard group, there were no statistically significant differences in the primary outcome of new infections, or the secondary outcomes of days on mechanical ventilation, Sequential Organ Failure Assessment scores, or ICU and hospital length of stay. However, the 6-month mortality rate of 28% was higher in the medical subgroup [58]. Using these results, as well as existing publications of negative outcomes in medical ICU patients [44,46], the SCCM/ASPEN Guidelines Committee updated its position in 2016 to suggest that immunonutrition formulations or disease-specific formulations should no longer be used routinely in medical ICU patients, including those with acute lung injury/ARDS [12]. The Committee did suggest that these formulations should be reserved for patients with traumatic brain injury and for surgical ICU patients. The benefit for ICU postoperative patients has been linked to the synergistic effect of fish oil and arginine, which must both be present to achieve outcome benefits. A meta-analysis comprised of 35 trials was conducted by Drover et al [58], who reported that administering an arginine and fish oil-containing formula postoperatively reduced infection (RR 0.78; 95% CI, 0.64 to 0.95; P = 0.01) and hospital length of stay (WMD –2.23, 95% CI, –3.80 to –0.65; P = 0.006) but not mortality, when compared to use of a standard formula. Similar results were reported in a second meta-analysis [56], thus providing supportive evidence for the current SCCM/ASPEN recommendation to use an immune-modulating formula (containing both arginine and fish oils) in the SICU for the postoperative patient who requires EN therapy [12].

Safe, Consistent, and Effective Nutrition Support Therapy

Gastric vs Small Bowel Feeding

There is a large group of critically ill patients in whom impaired gastric emptying presents challenges to feeding; 50% of mechanically ventilated patients demonstrate delayed gastric emptying, and 80% of patients with increased intracranial pressure following head injury [60]. In one prospective RCT, Huang et al (2012) showed that severely ill patients (defined by an APACHE II score > 20) fed by the nasoduodenal route experienced significantly shortened hospital LOS, fewer complications, and improved nutrient delivery compared to similar patients fed by the nasogastric route. Less severely ill patients (APACHE II < 20) showed no differences between nasogastric and nasoduodenal feeding for the same outcomes [61]. A recent systematic review [17] pooled data from 14 trials of 1109 participants who received either gastric or small bowel feeding. Moderate quality evidence suggested that post-pyloric feeding was associated with lower rates of pneumonia compared with gastric feeding (RR 0.65, 95% CI, 0.51 to 0.84). Low-quality evidence showed an increase in the percentage of total nutrient delivered to the patient by post-pyloric feeding (mean difference 7.8%, 95% CI, 1.43 to 14.18). Overall, the authors found a 30% lower rate of pneumonia associated with post-pyloric feeding. There is insufficient evidence to show that other clinically important outcomes such as duration of mechanical ventilation, mortality, or LOS were affected by the site of feeding. The American Thoracic Society and ASPEN, as well as the Infectious Diseases Society of America, have published guidelines in support of small bowel feeding in the ICU setting due to its association with reduced incidence of health care–associated infections, specifically ventilator-associated pneumonia [62]. The experts who developed the SCCM/ASPEN and Canadian guidelines stress that critically ill patients at high risk for aspiration or feeding intolerance should be fed using small bowel access [12,21]. The reality in ICU clinical practice is that many centers will begin with gastric feeding, barring absolute contraindications, and carefully monitor the patient for signs of intolerance before moving the feeding tube tip into a post-pyloric location. This follows the general recommendation by experts saying in most critically ill patients, it is acceptable to initiate EN in the stomach [12,21]. Protocols that guide management of risk prevention and intolerance typically recommend head of bed elevation, prokinetic agents, and frequent abdominal assessments [63,64].

Once the decision is made to use a post-pyloric feeding tube for nutrition therapy, the next decision is how to safely place the tube, ensure the tip is in an acceptable small bowel location, and minimize delays in feeding. Challenges related to feeding tube insertion may preclude timely advancement to nutrition goals. Placement of feeding tubes into the post-pyloric position is often done at the bedside by trained nursing or medical staff without endoscopic or fluoroscopic guidance; however, the blind bedside approach is not without risks. Success rates of this approach vary greatly depending on the patient population and provider expertise. Placement using endoscopic or fluoroscopic guidance is a safe alternative but usually requires coordinating a transport to the radiologic suite, posing safety risks and possible feeding delays for the patient [65]. Bedside use of an electromagnetic placement device (EMPD), such as Cortrak, provides yet another alternative with reports in the literature of 98% success rates for initial placement in less than 20 minutes. In a multicenter prospective study by Powers et al (2011), only one of 194 patients enrolled had data showing a discrepancy between the original EMPD verification and the final radiograph interpretation, demonstrating a 99.5% agreement between the two readings [20]. Median placement time was 12 minutes and no patient experienced an adverse event related to tube insertion using this device. The ability to monitor the location of the feeding tube tip in real time provides a desirable safety feature for the clinician performing bedside insertions. Nurses should consider incorporating the EMPD into the unit feeding protocol, as this would reduce the time to initiation of feedings with early and accurate tube insertion. Ongoing staff education and experience with the procedure are necessary elements to achieve the high rates of success often reported in the literature [66,67]. Procedural complications from placement of nasoenteral feeding tubes by all methods can be as high as 10%, with complication rates of 1% to 3% for inadvertent placement of the feeding tube in the airway alone [65]. Radiographic confirmation of tube placement is advised prior to initiating feeding, thus eliminating any possibility of misplacement and administration of formula into the lungs.

Gastric Residual Volume Monitoring

A number of factors impede the delivery of EN in the critical care setting; these include gastrointestinal intolerance, under-prescribing to meet daily requirements, frequent interruptions for procedures, and technical issues with tube placement and maintaining patency [68]. Monitoring gastric residual volumes (GRV) contributes to these factors, yet volumes do not correlate well with incidence of pneumonia [69], measures of gastric emptying, or to the incidence of regurgitation and aspiration [70,71]. However, few studies have highlighted the difficulty of obtaining an accurate GRV due to feeding tube tip location, patient position, and type of tube [69]. Several high quality studies have demonstrated that raising the cutoff value for GRV from a lower number of 50–150 mL to a higher number of 250–500 mL does not increase risk for regurgitation, aspiration, or pneumonia [70,71]. A lower cutoff value for GRV does not protect the patient from complications, often leads to inappropriate cessation, and may adversely affect outcome through reduced volume of EN infused [72]. Gastric residual volumes in the range of 200–500 mL should raise concern and lead to the implementation of measures to reduce risk of aspiration, but automatic cessation of feeding should not occur for GRV < 500 mL in the absence of other signs of intolerance [12,69]. Metheny et al (2012) conducted a survey in which more than 97% of nurses responded that they assessed intolerance by measuring GRV; the most frequently cited threshold levels for interrupting feedings were 200 mL and 250 mL [73]. While threshold levels varied widely, only 12.6% of the nurse respondents reported allowing GRV up to 500 mL before interrupting feedings. While monitoring GRV is unnecessary with small bowel feeding, the location of the feeding tube tip should be questioned if gastric contents are obtained from a small bowel tube. The use of GRV as a parameter for trending may also yield important information regarding tolerance of feeding when the patient is unable to communicate abdominal discomfort. Other objective measures to use in the assessment of tolerance include an abdominal exam with documentation of changes in bowel sounds, expanding girth, tenderness or firmness on palpation, increasing nasogastric output, and vomiting [12,68]. If there are indications of intolerance, it is appropriate to divert the tip of the feeding tube into the distal small bowel as discussed previously.

Trophic vs Full Feeding

For the patient with low nutrition risk, there is a lack of convincing data to support an aggressive approach to feeding, either EN or PN, in the first week of critical illness [7]. In recent years, results of several trials suggest early goal-directed feeding in this population may cause net harm with increased morbidity and mortality. When discussing recent controversies in critical care nutrition, one must mention the two schools of thought when it comes to full versus limited energy provision in the first week following ICU admission. Studies in animals and humans have shown a trophic effect of enteral nutrients on the integrity of the gut mucosa, a finding that has provided the rationale for instituting enteral nutrition early during critical illness [15]. However, the inability to provide enteral nutrition early may be a marker of the severity of illness (ie, patients who can be fed enterally are less ill than those who cannot) rather than a mediator of complications and poor outcomes. Compher et al (2017) stated that greater nutritional intake is associated with lower mortality and faster time to discharge alive in high-risk, chronic patients but does not seem to be significant in nutritionally low-risk patients [74]. The findings of the EPaNIC and EDEN trials raised concern that targeting goals that meet full energy needs early in critical illness does not provide benefit and may cause harm in some populations or settings [32,75]. The EDEN trial [32] left us believing that trophic feeding at 10–20 mL/hr may be just as effective as any feeding in the first few days of critical illness striving for 15% to 20% of daily goal calories. After establishing tolerance, advancing daily intake to > 50% to 65% of goal calories, and up to 80% for the highest risk patients, may be required to prevent intestinal permeability and achieve positive clinical outcomes [33].

The systematic review and meta-analysis performed by Al-Dorzi et al (2016) adds further evidence for judicious advancement of EN for critically ill patients [76]. The authors reported finding no association between the dose of caloric intake and hospital mortality. Furthermore, a lower caloric intake resulted in lower risk of bloodstream infections and the need for renal replacement therapy (in 5 of the 21 trials only). As with many other meta-analyses, the authors reported that their results are most assuredly impacted by the heterogeneity in design, feeding route, and dose prescribed and delivered [16,76,77]. Other recent trials such as Arabi et al (2015) that enrolled 894 patients with different feeding targets further confirmed that there is no difference in outcome between groups when it comes to moderate (40% to 60% of goal) vs high (70% to 100% of goal) energy intake, infection rates, or 90-day mortality. The authors summarized their findings saying feeding closer to target is associated with better outcomes compared with severe underfeeding [78]. This adds to the controversy when considering the findings of still other RCTs or meta-analyses that evaluated minimal or trophic feeding versus standard feeding rates [9,46,77]. The meta-analysis performed by Marik and Hooper concluded that there were no differences in the risk of acquired infections, hospital mortality, ICU LOS, or ventilator-free days whether patients received intentional hypocaloric or normocaloric nutrition support [9]. Similarly, there was no significant difference in overall mortality between the underfeeding and full-feeding groups (OR, 0.94; 95% CI, 0.74–1.19; I2 = 26.6%; P = 0.61) in the meta-analysis done by Choi et al (2015), although only 4 trials were included to ensure homogeneity of the population and the intervention [77]. Furthermore, the hospital LOS and ICU LOS did not differ between the 2 groups, nor did any other secondary clinical outcome, leading the authors to conclude that calorie intake of the initial EN support for ICU patients had no bearing on relevant outcomes.

Recent studies have attempted to correlate caloric intake and patient outcomes without success; achieving 100% of caloric goal has not favorably impacted morbidity and mortality. Evidence suggests that intake greater than 65% to 70% of daily caloric requirement in the first 7 to 10 days of ICU stay may be associated with poorer outcomes, particularly when parenteral nutrition is used to supplement intake to achieve the caloric target [33–35].

Conclusion

In this review we described current ICU controversies surrounding nutrition therapy and briefly discussed the data that support more than one course of action. A summary of key points covered is presented in the Table. 

Disclaimer: The views expressed in this paper are those of the authors and do not reflect the official policy of the Department of the Army, the Department of Defense, or the U.S. government.

Corresponding author: Mary S. McCarthy, PhD, RN, CNSC, 1611 Nisqually St, Steilacoom, WA 98388.

Financial disclosures: None.

From the Center for Nursing Science & Clinical Inquiry (Dr. McCarthy), and Nutrition Care Division, (Ms. Phipps), Madigan Army Medical Center, Tacoma, WA.

Abstract

• Background: Many controversies exist in the field of nutrition support today, particularly in the critical care environment where nutrition plays a more primary rather than adjunctive role.
• Objective: To provide a brief review of current controversies regarding nutrition therapy in the ICU focusing on the choices regarding the nutrition regimen and the safe, consistent delivery of nutrition as measured by clinical outcomes.
• Methods: Selected areas of controversy are discussed detailing the strengths and weaknesses of the research behind opposing opinions.
• Results: ICU nutrition support controversies include enteral vs parenteral nutrition, use of supplmental parenteral nutrition, protein quantity and quality, and polymeric vs immune-modulating nutrients. Issues surrounding the safety of nutrition support therapy include gastric vs small bowel feeding and trophic vs full feeding. Evidence-based recommendations published by professional societies are presented.
• Conclusion: Understanding a patient’s risk for disease and predicting their response to treatment will assist clinicians with selecting those nutrition interventions that will achieve the best possible outcomes.

According to the National Library of Medicine’s translation of the Hippocratic oath, nowhere does it explicitly say “First, do no harm.” What is written is this: “I will use those dietary regimens which will benefit my patients according to my greatest ability and judgement, and I will do no harm or injustice to them” [1]. In another renowned text, one can find this observation regarding diet by a noted scholar, clinician, and the founder of modern nursing, Florence Nightingale: “Every careful observer of the sick will agree in this that thousands of patients are annually starved in the midst of plenty, from want of attention to the ways which alone make it possible for them to take food” [2,]. While Nightingale was alluding to malnutrition of hospitalized patients, it seems that her real concern may have been the iatrogenic malnutrition that inevitably accompanies hospitalization, even today [3].

From these philosophic texts, we have two ongoing controversies in modern day nutrition therapy identified: (1) what evidence do we have to support the choice of dietary regimens (ie, enteral vs parenteral therapy, timing of supplemental parenteral nutrition, standard vs high protein formula, polymeric vs immune-modulating nutrients) that best serve critically ill patients, and (2) how do we ensure that ICU patients are fed in a safe, consistent, and effective manner (gastric vs small bowel tube placement, gastric residual monitoring or not, trophic vs full feeding) as measured by clinically relevant outcomes? Many controversies exist in the field of nutrition support today [4–7] and a comprehensive discussion of all of them is beyond the scope of this paper. In this paper we will provide a brief review of current controversies focusing on those mentioned above which have only recently been challenged by new rigorous randomized clinical trials (RCTs), and in some cases, subsequent systematic reviews and meta-analyses [8–11].

The Path to Modern Day Nutrition Support Therapy

The field of nutrition support, in general, has expanded greatly over the last 4 decades, but perhaps the most notable advancements have occurred in the critical care environment where efforts have been directed at advancing our understanding of the molecular and biological effects of nutrients in maintaining homeostasis in the critically ill [6]. In recent years, specialized nutrition, delivered by the enteral or parenteral route, was finally recognized for its contribution to important clinical outcomes in the critically ill population [12]. Critical care clinicians have been educated about the advances in nutrition therapy designed to address the unique needs of a vulnerable population where survival is threatened by poor nutritional status upon admission, compromised immune function, weakened respiratory muscles with decreased ventilation capacity, and gastrointestinal (GI) dysfunction [6]. The rapid deterioration seen in these patients is exaggerated by the all too common ICU conditions of systemic inflammatory response syndrome (SIRS), sepsis, hemodynamic instability, respiratory failure, coagulation disorders, and acute kidney injury [13,14].

Beginning in the early 1990s, formulations of enteral nutrition (EN) contained active nutrients that reportedly reduced oxidative damage to cells and tissues, modulated inflammation, and improved feeding tolerance. These benefits are now referred to as the non-nutritive benefits of enteral feeding [15]. For the next 20 years, scientific publications released new results from studies examining the role of omega-3 fatty acids, antioxidant vitamins, minerals such as selenium and zinc, ribonucleotides, and conditionally essential amino acids like glutamine and arginine, in healing and recovery from critical illness. The excitement was summarized succinctly by Hegazi and Wischmeyer in 2011 when they remarked that the modern ICU clinician now has scientific data to guide specialized nutrition therapy, for example, choosing formulas supplemented with anti-inflammatory, immune-modulating, or tolerance-promoting nutrients that have the potential to enhance natural recovery processes and prevent complications [16].

The improvements in nutritional formulas were accompanied by numerous technological advances including bedside devices (electromagnetic enteral access system, real-time image-guided disposable feeding tube, smart feeding pumps with water flush technology) that quickly and safely establish access for small bowel feedings, which help minimize risk of gastric aspiration and ventilator-associated pneumonia, promote tolerance, decrease radiologic exposure, and may reduce nursing time consumed by tube placements, GI dysfunction, and patient discomfort [17–20]. Nasogastric feeding remains the most common first approach, with local practices, contraindications, and ease of placement usually determining the location of the feeding tube [5]. The advancements helped to overcome the many barriers to initiating and maintaining feedings and thus, efforts to feed critically ill patients early and effectively became more routine, along with nurse, patient, and family satisfaction. In conjunction with the innovative approaches to establishing nutrition therapy, practice guidelines published by United States, European, and Canadian nutrition societies became widely available in the past decade with graded evidence-based recommendations for who, when, what, and how to feed, and unique considerations for various critically ill populations [12,21,22]. The tireless efforts by the nutrition societies to provide much needed guidelines for clinicians were appreciated, yet there was a wide range in the grade of the recommendations, with many based on expert opinion alone. In some cases, the research conducted lacked rigor or had missing data with obvious limits to the generalizability of results. Nevertheless, for the 7 years between the publication of the old and newly revised Society of Critical Care Medicine (SCCM)/ American Society of Parenteral and Enteral Nutrition (ASPEN) Guidelines (2016), [12,23] nutrition therapy was a high-priority intervention in most ICUs. The goal was to initiate feeding within 48 hours, select an immune-modulating or other metabolic support formula, and aggressively advance the rate to 80% to 100% of goal to avoid caloric deficit, impaired intestinal integrity, nitrogen losses, and functional impairments [9,24,25]. Nutrition support evolved from adjunctive care to its rightful place in the ABCD mnemonic of early priorities of ICU care: Airway, Breathing, Circulation, Diet.

The 2016 joint publication of the SCCM/ASPEN guidelines includes primarily randomized controlled trial (RCT) data, along with some observational trial data, indexed in any major publication database through December 2013. In these guidelines there were 98 recommendations, of which only 5 were a Level 1A; most of the recommendations were categorized as “expert consensus” [12]. The results of several important clinical trials in the United States and Europe that were underway at the time have since been published and compared to the SCCM/ASPEN relevant recommendations [7]. The results have forced nutrition support clinicians to take a step back and re-examine their practice. For many seasoned clinicians who comprised the nutrition support teams of the 1980s and 1990s, it feels like a return to the basics. Until biology-driven personalized medicine is commonplace and genotype data is readily available to guide nutrition therapy for each critically ill patient, standard enteral feeding that begins slow and proceeds carefully over 5 to 7 days towards 80% of goal caloric intake under judicious monitoring of biochemical and metabolic indices may be the “best practice” today, without risk of harm [15,26]. As in all aspects of clinical care, this practice is not without controversy.

ICU Nutrition Support Controversies Today

Enteral vs Parenteral Nutrition

There is universal consensus that EN is the preferred route for nutrition therapy due to the superior physiological response and both nutritional and non-nutritional benefits [24]. Changes in gut permeability tend to occur as illness progresses and consequences include increased bacterial challenge, risk for multiple organ dysfunction syndrome, and systemic infection. It is best to intervene with nutrition early, defined as within the first 48 hours of ICU admission, while the likelihood of success and opportunity to impact the disease process is greater [12]. Early initiation of feeding provides the necessary nutrients to support gut-associated lymphoid tissue (GALT), mucosal-associated lymphoid tissue (MALT), and preserve gut integrity and microbial diversity [27]. The intestine is an effective barrier against bacteria and intraluminal toxins due to the high rate of enterocyte turnover, the mucus secreted by the goblet cells, and the large amount of protective immunological tissue; 80% of the immunoglobulins are synthesized in the GI tract [28]. Fasting states for procedures or delays in feeding longer than 3 days for any reason may contribute to disruption of intestinal integrity through atrophy and derangements in the physical structure and function of the microvilli and crypts [29]. Intestinal dysfunction leads to increased intestinal permeability and the possibility of bacterial translocation. Intestinal ischemia resulting from shock and sepsis may produce hypoxia and reperfusion injuries further affecting intestinal wall permeability [29]. In surgical patients, early enteral feeding has been found to reduce inflammation, oxidative stress, and the catabolic response to anesthesia and surgical-induced stress, help restore intestinal motility, reverse enteric mucosal atrophy, and improve wound healing [26].

We did not have sufficient data to refute the benefits of EN over PN until the paper by Harvey et al (2014), which reported no difference in mortality or infectious complications in ICU patients receiving EN or PN within 36 hours of admission and for up to 5 days [30]. This was the largest published pragmatic RCT, referred to as the CALORIES trial, which analyzed 2388 patients from 33 ICUs and resulted in controversy over what was an unchallenged approach up until this time. It was only a matter of time before other investigators would set out to confirm or negate this finding, which is what Elke and coworkers (2016) did a few years later [31]. They performed an updated systematic review and meta-analysis to evaluate the overall effect of the route of nutrition (EN versus PN) on clinical outcomes in adult critically ill patients. Similar to the Harvey et al report, they found no difference in mortality between the two routes of nutrition. However, unlike the earlier report, patients receiving EN compared to PN had a significant reduction in the number of infectious complications and ICU length of stay. No significant effect was found for hospital length of stay or days requiring mechanical ventilation. The authors suggest that EN delivery of macronutrients below predefined targets may be responsible as PN is more likely to meet or exceed these targets and overwhelm metabolic capacity in the early days of critical illness [31].

The most recent trial prompting even more discussion about early PN versus early EN in mechanically ventilated ICU patients in shock is the Reignier et al (2018) NUTRIREA-2 trial involving 2410 patients from 44 ICUs in France [32]. The investigators hypothesized that outcomes would be better with early exclusive EN compared to early exclusive PN; their hypothesis was not supported by the results, which found no difference in 28-day mortality or ICU-acquired infections. Also unexpected was the higher cumulative incidence of gastrointestinal complications including vomiting, diarrhea, bowel ischemia, and acute colonic obstruction in the EN group. The trial was stopped early after an interim analysis determined that additional enrollment was not likely to significantly change the results of the trial. Given the similarities between the CALORIES trial and this NUTRIREA-2 trial, clinicians now have mounting evidence that equivalent options for nutrition therapy exist and an appropriate selection should be made based on patient-specific indications and treatment goals. In summary, EN remains preferable to PN for the majority of adult critically ill patients due to crucial support of gut integrity, but the optimal dose or rate of delivery to favorably influence clinical outcomes in the first few days following admission remains unknown.

Use of Supplemental Parenteral Nutrition

Both the nutrition support and bench science communities have learned a great deal about PN over the 4 decades it has been in existence, with the most compelling data coming from more recent trials [31–38]. This is because it has taken many years to recover from the days of hyperalimentation or overfeeding ICU patients by providing excessive calories to meet the elevated energy demands and to reverse the hypercatabolism of critical illness. This approach contributed to the complications of hyperglycemia, hyperlipidemia, increased infectious complications, and liver steatosis, all of which gave PN a negative reputation [37]. We now have adjusted the caloric distribution and the actual formulation of PN using the recent FDA-approved lipid emulsion (Soy, Medium-chain triglycerides, Olive oil, and Fish oil; SMOF) and created protocols for administering it based on specific indications, such as loss of GI integrity or demonstrated intolerance. In general, the advances in PN have led to a safer more therapeutic formulation that has its place in critical illness. Manzanares et al [40] reported a trend toward a decrease in ventilation requirement and mortality when a fish oil–containing lipid emulsion was administered to patients who were receiving nutrition support either enterally or parenterally. The meta-analysis combined all soybean oil–sparing lipid emulsions for comparison with soybean oil and was able to show the trend for improved clinical outcomes with soybean oil–sparing lipid emulsions. The main findings of this meta-analysis were that fish oil–containing lipid emulsions may reduce infections and may be associated with a tendency toward fewer mechanical ventilation days, although not mortality, when compared with soybean oil-based strategies or administration of other alternative lipid emulsions in ICU patients [40]. Recent trial results do not change the recommendation for selecting EN first but do suggest lowering the threshold for using PN when EN alone is insufficient to meet nutrition goals. A systematic review reported no benefit of early supplemental PN over late supplemental PN and cautioned that our continued inability to explain greater infectious morbidity and unresolved organ failure limits any justification for early PN [35].

Protein Quantity and Quality

The practice of providing protein in the range of 1.2–2.0 g/kg actual body weight early in critical illness is suggested by expert consensus in the 2016 SCCM/ASPEN guidelines [12]; however, the evidence for efficacy remains controversial. It is argued that the evidence for benefit comes from observational studies, not from prospective RCTs, and that the patients at high risk are often excluded from study protocols. It has also been suggested that in patients with limited vital organ function increased protein delivery may lead to organ compromise. In a recent (2017) paper, Rooyackers et al discussed the post-hoc analyses of data from the EPANIC Trial stating the statistical correlation between protein intake and outcomes indicate that protein was associated with unfavorable outcomes, possibly by inhibiting autophagy [41].

The nutrition support community may have widely varying approaches to feeding critically ill patients but most experts agree that protein may be the most important macronutrient delivered during critical illness. There is consensus that the hypercatabolism associated with stress induces proteolysis and the loss of lean muscle mass, which may affect clinical and functional outcomes beyond the ICU stay. Using multiple assessment modalities, Puthucheary et al (2013) demonstrated a reduction in the rectus femoris muscle of 12.5% over the first week of hospitalization in the ICU and up to 17.7% by day 10. These numbers imply that sufficient protein of at least 1.2 g/kg/day should be provided to minimize these losses, even if the effect on overall outcome remains unknown [42]. Evidence is lacking for whether or not we can prevent the muscle wasting that occurs in critical illness with increased protein dosing. We also need to better identify the possible risks involved with a high-protein intake at the level of the individual patient. A secondary analysis done by Heyland et al (2013) determined that no specific dose or type of macronutrient was found to be associated with improved outcome [43]. It is clear that more large-scale RCTs of protein/amino acid interventions are needed to prove that these nutrition interventions have favorable effects on clinically important outcomes, including long-term physical function.

Polymeric vs Immune-Modulating Nutrients

The Marik and Zaloga (2008) systematic review on immunonutrition in the critically ill convinced most clinicians that while fish-oil based immunonutrition improves the outcome of medical ICU patients, diets supplemented with arginine, with or without glutamine or fish oils, do not demonstrate an advantage over standard enteral products in general ICU, trauma, or burn patients[44]. What followed these trials examining early formulations of immunonutrition was decades of well-intentioned research dedicated to elucidating the mechanism of action for individual immune-modulating nutrients for various populations, including those with acute lung injury/acute respiratory distress syndrome (ARDS) [45–47], sepsis/systemic inflammatory response syndrome [48–50], head and neck cancer [51], upper and lower GI cancer [52–55], and severe acute pancreatitis [56]. Our understanding of immunonutrition and the administration of this formulation in specific disease conditions has grown considerably yet clinicians are still asking exactly what is the role of immunonutrition and who stands to benefit the most from immune-modulating nutrition therapy. The enteral formulations currently available have a proprietary composition and dosage of individual nutrients which yield unpredictable physiologic effects. In addition, the pervasive problem of underfeeding during hospitalization prevents adequate delivery of physiologic doses of nutrients thus contributing to the widely variable research results.

Prevailing expert opinion today is that the majority of critically ill patients will benefit from nutrition support initiated early and delivered consistently; the standard polymeric formula will suffice for the majority of patients with surgical ICU patients potentially deriving benefit from immunonutrition that supports a reduction in infectious complications [57]. In the recent multiple-treatment meta-analysis performed by Mazaki et al (2015) involving 74 studies and 7572 patients, immunonutrition was ranked first for reducing the incidence of 7 complications according to the surface under the cumulative ranking curve; these were as follows: any infection, 0.86; overall complication, 0.88; mortality, 0.81; wound infection, 0.79; intra-abdominal abscess, 0.98; anastomotic leak, 0.79; and sepsis, 0.92. immunonutrition was ranked second for reducing ventilator-associated pneumonia and catheter-associated urinary tract infection (CAUTI), behind immune-modulating PN. The authors stated that immuno­nutrition was efficacious for reducing the incidence of complications in GI surgery unrelated to the timing of administration [57]. The 2014 publication of results from the MetaPlus Trial [58]challenged the published recommendations for the use of immunonutrition in the medical critically ill population. This trial used high-protein immuno­nutrition or standard formula for 301 adult critically ill patients in 14 European ICUs with diagnoses such as pneumonia or infections of the urinary tract, bloodstream, central nervous system, eye, ear, nose or throat, and the skin and soft tissue. Even with higher than average target energy intakes of 70% for the high protein immunonutrition group and 80% for the high protein standard group, there were no statistically significant differences in the primary outcome of new infections, or the secondary outcomes of days on mechanical ventilation, Sequential Organ Failure Assessment scores, or ICU and hospital length of stay. However, the 6-month mortality rate of 28% was higher in the medical subgroup [58]. Using these results, as well as existing publications of negative outcomes in medical ICU patients [44,46], the SCCM/ASPEN Guidelines Committee updated its position in 2016 to suggest that immunonutrition formulations or disease-specific formulations should no longer be used routinely in medical ICU patients, including those with acute lung injury/ARDS [12]. The Committee did suggest that these formulations should be reserved for patients with traumatic brain injury and for surgical ICU patients. The benefit for ICU postoperative patients has been linked to the synergistic effect of fish oil and arginine, which must both be present to achieve outcome benefits. A meta-analysis comprised of 35 trials was conducted by Drover et al [58], who reported that administering an arginine and fish oil-containing formula postoperatively reduced infection (RR 0.78; 95% CI, 0.64 to 0.95; P = 0.01) and hospital length of stay (WMD –2.23, 95% CI, –3.80 to –0.65; P = 0.006) but not mortality, when compared to use of a standard formula. Similar results were reported in a second meta-analysis [56], thus providing supportive evidence for the current SCCM/ASPEN recommendation to use an immune-modulating formula (containing both arginine and fish oils) in the SICU for the postoperative patient who requires EN therapy [12].

Safe, Consistent, and Effective Nutrition Support Therapy

Gastric vs Small Bowel Feeding

There is a large group of critically ill patients in whom impaired gastric emptying presents challenges to feeding; 50% of mechanically ventilated patients demonstrate delayed gastric emptying, and 80% of patients with increased intracranial pressure following head injury [60]. In one prospective RCT, Huang et al (2012) showed that severely ill patients (defined by an APACHE II score > 20) fed by the nasoduodenal route experienced significantly shortened hospital LOS, fewer complications, and improved nutrient delivery compared to similar patients fed by the nasogastric route. Less severely ill patients (APACHE II < 20) showed no differences between nasogastric and nasoduodenal feeding for the same outcomes [61]. A recent systematic review [17] pooled data from 14 trials of 1109 participants who received either gastric or small bowel feeding. Moderate quality evidence suggested that post-pyloric feeding was associated with lower rates of pneumonia compared with gastric feeding (RR 0.65, 95% CI, 0.51 to 0.84). Low-quality evidence showed an increase in the percentage of total nutrient delivered to the patient by post-pyloric feeding (mean difference 7.8%, 95% CI, 1.43 to 14.18). Overall, the authors found a 30% lower rate of pneumonia associated with post-pyloric feeding. There is insufficient evidence to show that other clinically important outcomes such as duration of mechanical ventilation, mortality, or LOS were affected by the site of feeding. The American Thoracic Society and ASPEN, as well as the Infectious Diseases Society of America, have published guidelines in support of small bowel feeding in the ICU setting due to its association with reduced incidence of health care–associated infections, specifically ventilator-associated pneumonia [62]. The experts who developed the SCCM/ASPEN and Canadian guidelines stress that critically ill patients at high risk for aspiration or feeding intolerance should be fed using small bowel access [12,21]. The reality in ICU clinical practice is that many centers will begin with gastric feeding, barring absolute contraindications, and carefully monitor the patient for signs of intolerance before moving the feeding tube tip into a post-pyloric location. This follows the general recommendation by experts saying in most critically ill patients, it is acceptable to initiate EN in the stomach [12,21]. Protocols that guide management of risk prevention and intolerance typically recommend head of bed elevation, prokinetic agents, and frequent abdominal assessments [63,64].

Once the decision is made to use a post-pyloric feeding tube for nutrition therapy, the next decision is how to safely place the tube, ensure the tip is in an acceptable small bowel location, and minimize delays in feeding. Challenges related to feeding tube insertion may preclude timely advancement to nutrition goals. Placement of feeding tubes into the post-pyloric position is often done at the bedside by trained nursing or medical staff without endoscopic or fluoroscopic guidance; however, the blind bedside approach is not without risks. Success rates of this approach vary greatly depending on the patient population and provider expertise. Placement using endoscopic or fluoroscopic guidance is a safe alternative but usually requires coordinating a transport to the radiologic suite, posing safety risks and possible feeding delays for the patient [65]. Bedside use of an electromagnetic placement device (EMPD), such as Cortrak, provides yet another alternative with reports in the literature of 98% success rates for initial placement in less than 20 minutes. In a multicenter prospective study by Powers et al (2011), only one of 194 patients enrolled had data showing a discrepancy between the original EMPD verification and the final radiograph interpretation, demonstrating a 99.5% agreement between the two readings [20]. Median placement time was 12 minutes and no patient experienced an adverse event related to tube insertion using this device. The ability to monitor the location of the feeding tube tip in real time provides a desirable safety feature for the clinician performing bedside insertions. Nurses should consider incorporating the EMPD into the unit feeding protocol, as this would reduce the time to initiation of feedings with early and accurate tube insertion. Ongoing staff education and experience with the procedure are necessary elements to achieve the high rates of success often reported in the literature [66,67]. Procedural complications from placement of nasoenteral feeding tubes by all methods can be as high as 10%, with complication rates of 1% to 3% for inadvertent placement of the feeding tube in the airway alone [65]. Radiographic confirmation of tube placement is advised prior to initiating feeding, thus eliminating any possibility of misplacement and administration of formula into the lungs.

Gastric Residual Volume Monitoring

A number of factors impede the delivery of EN in the critical care setting; these include gastrointestinal intolerance, under-prescribing to meet daily requirements, frequent interruptions for procedures, and technical issues with tube placement and maintaining patency [68]. Monitoring gastric residual volumes (GRV) contributes to these factors, yet volumes do not correlate well with incidence of pneumonia [69], measures of gastric emptying, or to the incidence of regurgitation and aspiration [70,71]. However, few studies have highlighted the difficulty of obtaining an accurate GRV due to feeding tube tip location, patient position, and type of tube [69]. Several high quality studies have demonstrated that raising the cutoff value for GRV from a lower number of 50–150 mL to a higher number of 250–500 mL does not increase risk for regurgitation, aspiration, or pneumonia [70,71]. A lower cutoff value for GRV does not protect the patient from complications, often leads to inappropriate cessation, and may adversely affect outcome through reduced volume of EN infused [72]. Gastric residual volumes in the range of 200–500 mL should raise concern and lead to the implementation of measures to reduce risk of aspiration, but automatic cessation of feeding should not occur for GRV < 500 mL in the absence of other signs of intolerance [12,69]. Metheny et al (2012) conducted a survey in which more than 97% of nurses responded that they assessed intolerance by measuring GRV; the most frequently cited threshold levels for interrupting feedings were 200 mL and 250 mL [73]. While threshold levels varied widely, only 12.6% of the nurse respondents reported allowing GRV up to 500 mL before interrupting feedings. While monitoring GRV is unnecessary with small bowel feeding, the location of the feeding tube tip should be questioned if gastric contents are obtained from a small bowel tube. The use of GRV as a parameter for trending may also yield important information regarding tolerance of feeding when the patient is unable to communicate abdominal discomfort. Other objective measures to use in the assessment of tolerance include an abdominal exam with documentation of changes in bowel sounds, expanding girth, tenderness or firmness on palpation, increasing nasogastric output, and vomiting [12,68]. If there are indications of intolerance, it is appropriate to divert the tip of the feeding tube into the distal small bowel as discussed previously.

Trophic vs Full Feeding

For the patient with low nutrition risk, there is a lack of convincing data to support an aggressive approach to feeding, either EN or PN, in the first week of critical illness [7]. In recent years, results of several trials suggest early goal-directed feeding in this population may cause net harm with increased morbidity and mortality. When discussing recent controversies in critical care nutrition, one must mention the two schools of thought when it comes to full versus limited energy provision in the first week following ICU admission. Studies in animals and humans have shown a trophic effect of enteral nutrients on the integrity of the gut mucosa, a finding that has provided the rationale for instituting enteral nutrition early during critical illness [15]. However, the inability to provide enteral nutrition early may be a marker of the severity of illness (ie, patients who can be fed enterally are less ill than those who cannot) rather than a mediator of complications and poor outcomes. Compher et al (2017) stated that greater nutritional intake is associated with lower mortality and faster time to discharge alive in high-risk, chronic patients but does not seem to be significant in nutritionally low-risk patients [74]. The findings of the EPaNIC and EDEN trials raised concern that targeting goals that meet full energy needs early in critical illness does not provide benefit and may cause harm in some populations or settings [32,75]. The EDEN trial [32] left us believing that trophic feeding at 10–20 mL/hr may be just as effective as any feeding in the first few days of critical illness striving for 15% to 20% of daily goal calories. After establishing tolerance, advancing daily intake to > 50% to 65% of goal calories, and up to 80% for the highest risk patients, may be required to prevent intestinal permeability and achieve positive clinical outcomes [33].

The systematic review and meta-analysis performed by Al-Dorzi et al (2016) adds further evidence for judicious advancement of EN for critically ill patients [76]. The authors reported finding no association between the dose of caloric intake and hospital mortality. Furthermore, a lower caloric intake resulted in lower risk of bloodstream infections and the need for renal replacement therapy (in 5 of the 21 trials only). As with many other meta-analyses, the authors reported that their results are most assuredly impacted by the heterogeneity in design, feeding route, and dose prescribed and delivered [16,76,77]. Other recent trials such as Arabi et al (2015) that enrolled 894 patients with different feeding targets further confirmed that there is no difference in outcome between groups when it comes to moderate (40% to 60% of goal) vs high (70% to 100% of goal) energy intake, infection rates, or 90-day mortality. The authors summarized their findings saying feeding closer to target is associated with better outcomes compared with severe underfeeding [78]. This adds to the controversy when considering the findings of still other RCTs or meta-analyses that evaluated minimal or trophic feeding versus standard feeding rates [9,46,77]. The meta-analysis performed by Marik and Hooper concluded that there were no differences in the risk of acquired infections, hospital mortality, ICU LOS, or ventilator-free days whether patients received intentional hypocaloric or normocaloric nutrition support [9]. Similarly, there was no significant difference in overall mortality between the underfeeding and full-feeding groups (OR, 0.94; 95% CI, 0.74–1.19; I2 = 26.6%; P = 0.61) in the meta-analysis done by Choi et al (2015), although only 4 trials were included to ensure homogeneity of the population and the intervention [77]. Furthermore, the hospital LOS and ICU LOS did not differ between the 2 groups, nor did any other secondary clinical outcome, leading the authors to conclude that calorie intake of the initial EN support for ICU patients had no bearing on relevant outcomes.

Recent studies have attempted to correlate caloric intake and patient outcomes without success; achieving 100% of caloric goal has not favorably impacted morbidity and mortality. Evidence suggests that intake greater than 65% to 70% of daily caloric requirement in the first 7 to 10 days of ICU stay may be associated with poorer outcomes, particularly when parenteral nutrition is used to supplement intake to achieve the caloric target [33–35].

Conclusion

In this review we described current ICU controversies surrounding nutrition therapy and briefly discussed the data that support more than one course of action. A summary of key points covered is presented in the Table. 

Disclaimer: The views expressed in this paper are those of the authors and do not reflect the official policy of the Department of the Army, the Department of Defense, or the U.S. government.

Corresponding author: Mary S. McCarthy, PhD, RN, CNSC, 1611 Nisqually St, Steilacoom, WA 98388.

Financial disclosures: None.

From the Center for Nursing Science & Clinical Inquiry (Dr. McCarthy), and Nutrition Care Division, (Ms. Phipps), Madigan Army Medical Center, Tacoma, WA.

Abstract

• Background: Many controversies exist in the field of nutrition support today, particularly in the critical care environment where nutrition plays a more primary rather than adjunctive role.
• Objective: To provide a brief review of current controversies regarding nutrition therapy in the ICU focusing on the choices regarding the nutrition regimen and the safe, consistent delivery of nutrition as measured by clinical outcomes.
• Methods: Selected areas of controversy are discussed detailing the strengths and weaknesses of the research behind opposing opinions.
• Results: ICU nutrition support controversies include enteral vs parenteral nutrition, use of supplmental parenteral nutrition, protein quantity and quality, and polymeric vs immune-modulating nutrients. Issues surrounding the safety of nutrition support therapy include gastric vs small bowel feeding and trophic vs full feeding. Evidence-based recommendations published by professional societies are presented.
• Conclusion: Understanding a patient’s risk for disease and predicting their response to treatment will assist clinicians with selecting those nutrition interventions that will achieve the best possible outcomes.

According to the National Library of Medicine’s translation of the Hippocratic oath, nowhere does it explicitly say “First, do no harm.” What is written is this: “I will use those dietary regimens which will benefit my patients according to my greatest ability and judgement, and I will do no harm or injustice to them” [1]. In another renowned text, one can find this observation regarding diet by a noted scholar, clinician, and the founder of modern nursing, Florence Nightingale: “Every careful observer of the sick will agree in this that thousands of patients are annually starved in the midst of plenty, from want of attention to the ways which alone make it possible for them to take food” [2,]. While Nightingale was alluding to malnutrition of hospitalized patients, it seems that her real concern may have been the iatrogenic malnutrition that inevitably accompanies hospitalization, even today [3].

From these philosophic texts, we have two ongoing controversies in modern day nutrition therapy identified: (1) what evidence do we have to support the choice of dietary regimens (ie, enteral vs parenteral therapy, timing of supplemental parenteral nutrition, standard vs high protein formula, polymeric vs immune-modulating nutrients) that best serve critically ill patients, and (2) how do we ensure that ICU patients are fed in a safe, consistent, and effective manner (gastric vs small bowel tube placement, gastric residual monitoring or not, trophic vs full feeding) as measured by clinically relevant outcomes? Many controversies exist in the field of nutrition support today [4–7] and a comprehensive discussion of all of them is beyond the scope of this paper. In this paper we will provide a brief review of current controversies focusing on those mentioned above which have only recently been challenged by new rigorous randomized clinical trials (RCTs), and in some cases, subsequent systematic reviews and meta-analyses [8–11].

The Path to Modern Day Nutrition Support Therapy

The field of nutrition support, in general, has expanded greatly over the last 4 decades, but perhaps the most notable advancements have occurred in the critical care environment where efforts have been directed at advancing our understanding of the molecular and biological effects of nutrients in maintaining homeostasis in the critically ill [6]. In recent years, specialized nutrition, delivered by the enteral or parenteral route, was finally recognized for its contribution to important clinical outcomes in the critically ill population [12]. Critical care clinicians have been educated about the advances in nutrition therapy designed to address the unique needs of a vulnerable population where survival is threatened by poor nutritional status upon admission, compromised immune function, weakened respiratory muscles with decreased ventilation capacity, and gastrointestinal (GI) dysfunction [6]. The rapid deterioration seen in these patients is exaggerated by the all too common ICU conditions of systemic inflammatory response syndrome (SIRS), sepsis, hemodynamic instability, respiratory failure, coagulation disorders, and acute kidney injury [13,14].

Beginning in the early 1990s, formulations of enteral nutrition (EN) contained active nutrients that reportedly reduced oxidative damage to cells and tissues, modulated inflammation, and improved feeding tolerance. These benefits are now referred to as the non-nutritive benefits of enteral feeding [15]. For the next 20 years, scientific publications released new results from studies examining the role of omega-3 fatty acids, antioxidant vitamins, minerals such as selenium and zinc, ribonucleotides, and conditionally essential amino acids like glutamine and arginine, in healing and recovery from critical illness. The excitement was summarized succinctly by Hegazi and Wischmeyer in 2011 when they remarked that the modern ICU clinician now has scientific data to guide specialized nutrition therapy, for example, choosing formulas supplemented with anti-inflammatory, immune-modulating, or tolerance-promoting nutrients that have the potential to enhance natural recovery processes and prevent complications [16].

The improvements in nutritional formulas were accompanied by numerous technological advances including bedside devices (electromagnetic enteral access system, real-time image-guided disposable feeding tube, smart feeding pumps with water flush technology) that quickly and safely establish access for small bowel feedings, which help minimize risk of gastric aspiration and ventilator-associated pneumonia, promote tolerance, decrease radiologic exposure, and may reduce nursing time consumed by tube placements, GI dysfunction, and patient discomfort [17–20]. Nasogastric feeding remains the most common first approach, with local practices, contraindications, and ease of placement usually determining the location of the feeding tube [5]. The advancements helped to overcome the many barriers to initiating and maintaining feedings and thus, efforts to feed critically ill patients early and effectively became more routine, along with nurse, patient, and family satisfaction. In conjunction with the innovative approaches to establishing nutrition therapy, practice guidelines published by United States, European, and Canadian nutrition societies became widely available in the past decade with graded evidence-based recommendations for who, when, what, and how to feed, and unique considerations for various critically ill populations [12,21,22]. The tireless efforts by the nutrition societies to provide much needed guidelines for clinicians were appreciated, yet there was a wide range in the grade of the recommendations, with many based on expert opinion alone. In some cases, the research conducted lacked rigor or had missing data with obvious limits to the generalizability of results. Nevertheless, for the 7 years between the publication of the old and newly revised Society of Critical Care Medicine (SCCM)/ American Society of Parenteral and Enteral Nutrition (ASPEN) Guidelines (2016), [12,23] nutrition therapy was a high-priority intervention in most ICUs. The goal was to initiate feeding within 48 hours, select an immune-modulating or other metabolic support formula, and aggressively advance the rate to 80% to 100% of goal to avoid caloric deficit, impaired intestinal integrity, nitrogen losses, and functional impairments [9,24,25]. Nutrition support evolved from adjunctive care to its rightful place in the ABCD mnemonic of early priorities of ICU care: Airway, Breathing, Circulation, Diet.

The 2016 joint publication of the SCCM/ASPEN guidelines includes primarily randomized controlled trial (RCT) data, along with some observational trial data, indexed in any major publication database through December 2013. In these guidelines there were 98 recommendations, of which only 5 were a Level 1A; most of the recommendations were categorized as “expert consensus” [12]. The results of several important clinical trials in the United States and Europe that were underway at the time have since been published and compared to the SCCM/ASPEN relevant recommendations [7]. The results have forced nutrition support clinicians to take a step back and re-examine their practice. For many seasoned clinicians who comprised the nutrition support teams of the 1980s and 1990s, it feels like a return to the basics. Until biology-driven personalized medicine is commonplace and genotype data is readily available to guide nutrition therapy for each critically ill patient, standard enteral feeding that begins slow and proceeds carefully over 5 to 7 days towards 80% of goal caloric intake under judicious monitoring of biochemical and metabolic indices may be the “best practice” today, without risk of harm [15,26]. As in all aspects of clinical care, this practice is not without controversy.

ICU Nutrition Support Controversies Today

Enteral vs Parenteral Nutrition

There is universal consensus that EN is the preferred route for nutrition therapy due to the superior physiological response and both nutritional and non-nutritional benefits [24]. Changes in gut permeability tend to occur as illness progresses and consequences include increased bacterial challenge, risk for multiple organ dysfunction syndrome, and systemic infection. It is best to intervene with nutrition early, defined as within the first 48 hours of ICU admission, while the likelihood of success and opportunity to impact the disease process is greater [12]. Early initiation of feeding provides the necessary nutrients to support gut-associated lymphoid tissue (GALT), mucosal-associated lymphoid tissue (MALT), and preserve gut integrity and microbial diversity [27]. The intestine is an effective barrier against bacteria and intraluminal toxins due to the high rate of enterocyte turnover, the mucus secreted by the goblet cells, and the large amount of protective immunological tissue; 80% of the immunoglobulins are synthesized in the GI tract [28]. Fasting states for procedures or delays in feeding longer than 3 days for any reason may contribute to disruption of intestinal integrity through atrophy and derangements in the physical structure and function of the microvilli and crypts [29]. Intestinal dysfunction leads to increased intestinal permeability and the possibility of bacterial translocation. Intestinal ischemia resulting from shock and sepsis may produce hypoxia and reperfusion injuries further affecting intestinal wall permeability [29]. In surgical patients, early enteral feeding has been found to reduce inflammation, oxidative stress, and the catabolic response to anesthesia and surgical-induced stress, help restore intestinal motility, reverse enteric mucosal atrophy, and improve wound healing [26].

We did not have sufficient data to refute the benefits of EN over PN until the paper by Harvey et al (2014), which reported no difference in mortality or infectious complications in ICU patients receiving EN or PN within 36 hours of admission and for up to 5 days [30]. This was the largest published pragmatic RCT, referred to as the CALORIES trial, which analyzed 2388 patients from 33 ICUs and resulted in controversy over what was an unchallenged approach up until this time. It was only a matter of time before other investigators would set out to confirm or negate this finding, which is what Elke and coworkers (2016) did a few years later [31]. They performed an updated systematic review and meta-analysis to evaluate the overall effect of the route of nutrition (EN versus PN) on clinical outcomes in adult critically ill patients. Similar to the Harvey et al report, they found no difference in mortality between the two routes of nutrition. However, unlike the earlier report, patients receiving EN compared to PN had a significant reduction in the number of infectious complications and ICU length of stay. No significant effect was found for hospital length of stay or days requiring mechanical ventilation. The authors suggest that EN delivery of macronutrients below predefined targets may be responsible as PN is more likely to meet or exceed these targets and overwhelm metabolic capacity in the early days of critical illness [31].

The most recent trial prompting even more discussion about early PN versus early EN in mechanically ventilated ICU patients in shock is the Reignier et al (2018) NUTRIREA-2 trial involving 2410 patients from 44 ICUs in France [32]. The investigators hypothesized that outcomes would be better with early exclusive EN compared to early exclusive PN; their hypothesis was not supported by the results, which found no difference in 28-day mortality or ICU-acquired infections. Also unexpected was the higher cumulative incidence of gastrointestinal complications including vomiting, diarrhea, bowel ischemia, and acute colonic obstruction in the EN group. The trial was stopped early after an interim analysis determined that additional enrollment was not likely to significantly change the results of the trial. Given the similarities between the CALORIES trial and this NUTRIREA-2 trial, clinicians now have mounting evidence that equivalent options for nutrition therapy exist and an appropriate selection should be made based on patient-specific indications and treatment goals. In summary, EN remains preferable to PN for the majority of adult critically ill patients due to crucial support of gut integrity, but the optimal dose or rate of delivery to favorably influence clinical outcomes in the first few days following admission remains unknown.

Use of Supplemental Parenteral Nutrition

Both the nutrition support and bench science communities have learned a great deal about PN over the 4 decades it has been in existence, with the most compelling data coming from more recent trials [31–38]. This is because it has taken many years to recover from the days of hyperalimentation or overfeeding ICU patients by providing excessive calories to meet the elevated energy demands and to reverse the hypercatabolism of critical illness. This approach contributed to the complications of hyperglycemia, hyperlipidemia, increased infectious complications, and liver steatosis, all of which gave PN a negative reputation [37]. We now have adjusted the caloric distribution and the actual formulation of PN using the recent FDA-approved lipid emulsion (Soy, Medium-chain triglycerides, Olive oil, and Fish oil; SMOF) and created protocols for administering it based on specific indications, such as loss of GI integrity or demonstrated intolerance. In general, the advances in PN have led to a safer more therapeutic formulation that has its place in critical illness. Manzanares et al [40] reported a trend toward a decrease in ventilation requirement and mortality when a fish oil–containing lipid emulsion was administered to patients who were receiving nutrition support either enterally or parenterally. The meta-analysis combined all soybean oil–sparing lipid emulsions for comparison with soybean oil and was able to show the trend for improved clinical outcomes with soybean oil–sparing lipid emulsions. The main findings of this meta-analysis were that fish oil–containing lipid emulsions may reduce infections and may be associated with a tendency toward fewer mechanical ventilation days, although not mortality, when compared with soybean oil-based strategies or administration of other alternative lipid emulsions in ICU patients [40]. Recent trial results do not change the recommendation for selecting EN first but do suggest lowering the threshold for using PN when EN alone is insufficient to meet nutrition goals. A systematic review reported no benefit of early supplemental PN over late supplemental PN and cautioned that our continued inability to explain greater infectious morbidity and unresolved organ failure limits any justification for early PN [35].

Protein Quantity and Quality

The practice of providing protein in the range of 1.2–2.0 g/kg actual body weight early in critical illness is suggested by expert consensus in the 2016 SCCM/ASPEN guidelines [12]; however, the evidence for efficacy remains controversial. It is argued that the evidence for benefit comes from observational studies, not from prospective RCTs, and that the patients at high risk are often excluded from study protocols. It has also been suggested that in patients with limited vital organ function increased protein delivery may lead to organ compromise. In a recent (2017) paper, Rooyackers et al discussed the post-hoc analyses of data from the EPANIC Trial stating the statistical correlation between protein intake and outcomes indicate that protein was associated with unfavorable outcomes, possibly by inhibiting autophagy [41].

The nutrition support community may have widely varying approaches to feeding critically ill patients but most experts agree that protein may be the most important macronutrient delivered during critical illness. There is consensus that the hypercatabolism associated with stress induces proteolysis and the loss of lean muscle mass, which may affect clinical and functional outcomes beyond the ICU stay. Using multiple assessment modalities, Puthucheary et al (2013) demonstrated a reduction in the rectus femoris muscle of 12.5% over the first week of hospitalization in the ICU and up to 17.7% by day 10. These numbers imply that sufficient protein of at least 1.2 g/kg/day should be provided to minimize these losses, even if the effect on overall outcome remains unknown [42]. Evidence is lacking for whether or not we can prevent the muscle wasting that occurs in critical illness with increased protein dosing. We also need to better identify the possible risks involved with a high-protein intake at the level of the individual patient. A secondary analysis done by Heyland et al (2013) determined that no specific dose or type of macronutrient was found to be associated with improved outcome [43]. It is clear that more large-scale RCTs of protein/amino acid interventions are needed to prove that these nutrition interventions have favorable effects on clinically important outcomes, including long-term physical function.

Polymeric vs Immune-Modulating Nutrients

The Marik and Zaloga (2008) systematic review on immunonutrition in the critically ill convinced most clinicians that while fish-oil based immunonutrition improves the outcome of medical ICU patients, diets supplemented with arginine, with or without glutamine or fish oils, do not demonstrate an advantage over standard enteral products in general ICU, trauma, or burn patients[44]. What followed these trials examining early formulations of immunonutrition was decades of well-intentioned research dedicated to elucidating the mechanism of action for individual immune-modulating nutrients for various populations, including those with acute lung injury/acute respiratory distress syndrome (ARDS) [45–47], sepsis/systemic inflammatory response syndrome [48–50], head and neck cancer [51], upper and lower GI cancer [52–55], and severe acute pancreatitis [56]. Our understanding of immunonutrition and the administration of this formulation in specific disease conditions has grown considerably yet clinicians are still asking exactly what is the role of immunonutrition and who stands to benefit the most from immune-modulating nutrition therapy. The enteral formulations currently available have a proprietary composition and dosage of individual nutrients which yield unpredictable physiologic effects. In addition, the pervasive problem of underfeeding during hospitalization prevents adequate delivery of physiologic doses of nutrients thus contributing to the widely variable research results.

Prevailing expert opinion today is that the majority of critically ill patients will benefit from nutrition support initiated early and delivered consistently; the standard polymeric formula will suffice for the majority of patients with surgical ICU patients potentially deriving benefit from immunonutrition that supports a reduction in infectious complications [57]. In the recent multiple-treatment meta-analysis performed by Mazaki et al (2015) involving 74 studies and 7572 patients, immunonutrition was ranked first for reducing the incidence of 7 complications according to the surface under the cumulative ranking curve; these were as follows: any infection, 0.86; overall complication, 0.88; mortality, 0.81; wound infection, 0.79; intra-abdominal abscess, 0.98; anastomotic leak, 0.79; and sepsis, 0.92. immunonutrition was ranked second for reducing ventilator-associated pneumonia and catheter-associated urinary tract infection (CAUTI), behind immune-modulating PN. The authors stated that immuno­nutrition was efficacious for reducing the incidence of complications in GI surgery unrelated to the timing of administration [57]. The 2014 publication of results from the MetaPlus Trial [58]challenged the published recommendations for the use of immunonutrition in the medical critically ill population. This trial used high-protein immuno­nutrition or standard formula for 301 adult critically ill patients in 14 European ICUs with diagnoses such as pneumonia or infections of the urinary tract, bloodstream, central nervous system, eye, ear, nose or throat, and the skin and soft tissue. Even with higher than average target energy intakes of 70% for the high protein immunonutrition group and 80% for the high protein standard group, there were no statistically significant differences in the primary outcome of new infections, or the secondary outcomes of days on mechanical ventilation, Sequential Organ Failure Assessment scores, or ICU and hospital length of stay. However, the 6-month mortality rate of 28% was higher in the medical subgroup [58]. Using these results, as well as existing publications of negative outcomes in medical ICU patients [44,46], the SCCM/ASPEN Guidelines Committee updated its position in 2016 to suggest that immunonutrition formulations or disease-specific formulations should no longer be used routinely in medical ICU patients, including those with acute lung injury/ARDS [12]. The Committee did suggest that these formulations should be reserved for patients with traumatic brain injury and for surgical ICU patients. The benefit for ICU postoperative patients has been linked to the synergistic effect of fish oil and arginine, which must both be present to achieve outcome benefits. A meta-analysis comprised of 35 trials was conducted by Drover et al [58], who reported that administering an arginine and fish oil-containing formula postoperatively reduced infection (RR 0.78; 95% CI, 0.64 to 0.95; P = 0.01) and hospital length of stay (WMD –2.23, 95% CI, –3.80 to –0.65; P = 0.006) but not mortality, when compared to use of a standard formula. Similar results were reported in a second meta-analysis [56], thus providing supportive evidence for the current SCCM/ASPEN recommendation to use an immune-modulating formula (containing both arginine and fish oils) in the SICU for the postoperative patient who requires EN therapy [12].

Safe, Consistent, and Effective Nutrition Support Therapy

Gastric vs Small Bowel Feeding

There is a large group of critically ill patients in whom impaired gastric emptying presents challenges to feeding; 50% of mechanically ventilated patients demonstrate delayed gastric emptying, and 80% of patients with increased intracranial pressure following head injury [60]. In one prospective RCT, Huang et al (2012) showed that severely ill patients (defined by an APACHE II score > 20) fed by the nasoduodenal route experienced significantly shortened hospital LOS, fewer complications, and improved nutrient delivery compared to similar patients fed by the nasogastric route. Less severely ill patients (APACHE II < 20) showed no differences between nasogastric and nasoduodenal feeding for the same outcomes [61]. A recent systematic review [17] pooled data from 14 trials of 1109 participants who received either gastric or small bowel feeding. Moderate quality evidence suggested that post-pyloric feeding was associated with lower rates of pneumonia compared with gastric feeding (RR 0.65, 95% CI, 0.51 to 0.84). Low-quality evidence showed an increase in the percentage of total nutrient delivered to the patient by post-pyloric feeding (mean difference 7.8%, 95% CI, 1.43 to 14.18). Overall, the authors found a 30% lower rate of pneumonia associated with post-pyloric feeding. There is insufficient evidence to show that other clinically important outcomes such as duration of mechanical ventilation, mortality, or LOS were affected by the site of feeding. The American Thoracic Society and ASPEN, as well as the Infectious Diseases Society of America, have published guidelines in support of small bowel feeding in the ICU setting due to its association with reduced incidence of health care–associated infections, specifically ventilator-associated pneumonia [62]. The experts who developed the SCCM/ASPEN and Canadian guidelines stress that critically ill patients at high risk for aspiration or feeding intolerance should be fed using small bowel access [12,21]. The reality in ICU clinical practice is that many centers will begin with gastric feeding, barring absolute contraindications, and carefully monitor the patient for signs of intolerance before moving the feeding tube tip into a post-pyloric location. This follows the general recommendation by experts saying in most critically ill patients, it is acceptable to initiate EN in the stomach [12,21]. Protocols that guide management of risk prevention and intolerance typically recommend head of bed elevation, prokinetic agents, and frequent abdominal assessments [63,64].

Once the decision is made to use a post-pyloric feeding tube for nutrition therapy, the next decision is how to safely place the tube, ensure the tip is in an acceptable small bowel location, and minimize delays in feeding. Challenges related to feeding tube insertion may preclude timely advancement to nutrition goals. Placement of feeding tubes into the post-pyloric position is often done at the bedside by trained nursing or medical staff without endoscopic or fluoroscopic guidance; however, the blind bedside approach is not without risks. Success rates of this approach vary greatly depending on the patient population and provider expertise. Placement using endoscopic or fluoroscopic guidance is a safe alternative but usually requires coordinating a transport to the radiologic suite, posing safety risks and possible feeding delays for the patient [65]. Bedside use of an electromagnetic placement device (EMPD), such as Cortrak, provides yet another alternative with reports in the literature of 98% success rates for initial placement in less than 20 minutes. In a multicenter prospective study by Powers et al (2011), only one of 194 patients enrolled had data showing a discrepancy between the original EMPD verification and the final radiograph interpretation, demonstrating a 99.5% agreement between the two readings [20]. Median placement time was 12 minutes and no patient experienced an adverse event related to tube insertion using this device. The ability to monitor the location of the feeding tube tip in real time provides a desirable safety feature for the clinician performing bedside insertions. Nurses should consider incorporating the EMPD into the unit feeding protocol, as this would reduce the time to initiation of feedings with early and accurate tube insertion. Ongoing staff education and experience with the procedure are necessary elements to achieve the high rates of success often reported in the literature [66,67]. Procedural complications from placement of nasoenteral feeding tubes by all methods can be as high as 10%, with complication rates of 1% to 3% for inadvertent placement of the feeding tube in the airway alone [65]. Radiographic confirmation of tube placement is advised prior to initiating feeding, thus eliminating any possibility of misplacement and administration of formula into the lungs.

Gastric Residual Volume Monitoring

A number of factors impede the delivery of EN in the critical care setting; these include gastrointestinal intolerance, under-prescribing to meet daily requirements, frequent interruptions for procedures, and technical issues with tube placement and maintaining patency [68]. Monitoring gastric residual volumes (GRV) contributes to these factors, yet volumes do not correlate well with incidence of pneumonia [69], measures of gastric emptying, or to the incidence of regurgitation and aspiration [70,71]. However, few studies have highlighted the difficulty of obtaining an accurate GRV due to feeding tube tip location, patient position, and type of tube [69]. Several high quality studies have demonstrated that raising the cutoff value for GRV from a lower number of 50–150 mL to a higher number of 250–500 mL does not increase risk for regurgitation, aspiration, or pneumonia [70,71]. A lower cutoff value for GRV does not protect the patient from complications, often leads to inappropriate cessation, and may adversely affect outcome through reduced volume of EN infused [72]. Gastric residual volumes in the range of 200–500 mL should raise concern and lead to the implementation of measures to reduce risk of aspiration, but automatic cessation of feeding should not occur for GRV < 500 mL in the absence of other signs of intolerance [12,69]. Metheny et al (2012) conducted a survey in which more than 97% of nurses responded that they assessed intolerance by measuring GRV; the most frequently cited threshold levels for interrupting feedings were 200 mL and 250 mL [73]. While threshold levels varied widely, only 12.6% of the nurse respondents reported allowing GRV up to 500 mL before interrupting feedings. While monitoring GRV is unnecessary with small bowel feeding, the location of the feeding tube tip should be questioned if gastric contents are obtained from a small bowel tube. The use of GRV as a parameter for trending may also yield important information regarding tolerance of feeding when the patient is unable to communicate abdominal discomfort. Other objective measures to use in the assessment of tolerance include an abdominal exam with documentation of changes in bowel sounds, expanding girth, tenderness or firmness on palpation, increasing nasogastric output, and vomiting [12,68]. If there are indications of intolerance, it is appropriate to divert the tip of the feeding tube into the distal small bowel as discussed previously.

Trophic vs Full Feeding

For the patient with low nutrition risk, there is a lack of convincing data to support an aggressive approach to feeding, either EN or PN, in the first week of critical illness [7]. In recent years, results of several trials suggest early goal-directed feeding in this population may cause net harm with increased morbidity and mortality. When discussing recent controversies in critical care nutrition, one must mention the two schools of thought when it comes to full versus limited energy provision in the first week following ICU admission. Studies in animals and humans have shown a trophic effect of enteral nutrients on the integrity of the gut mucosa, a finding that has provided the rationale for instituting enteral nutrition early during critical illness [15]. However, the inability to provide enteral nutrition early may be a marker of the severity of illness (ie, patients who can be fed enterally are less ill than those who cannot) rather than a mediator of complications and poor outcomes. Compher et al (2017) stated that greater nutritional intake is associated with lower mortality and faster time to discharge alive in high-risk, chronic patients but does not seem to be significant in nutritionally low-risk patients [74]. The findings of the EPaNIC and EDEN trials raised concern that targeting goals that meet full energy needs early in critical illness does not provide benefit and may cause harm in some populations or settings [32,75]. The EDEN trial [32] left us believing that trophic feeding at 10–20 mL/hr may be just as effective as any feeding in the first few days of critical illness striving for 15% to 20% of daily goal calories. After establishing tolerance, advancing daily intake to > 50% to 65% of goal calories, and up to 80% for the highest risk patients, may be required to prevent intestinal permeability and achieve positive clinical outcomes [33].

The systematic review and meta-analysis performed by Al-Dorzi et al (2016) adds further evidence for judicious advancement of EN for critically ill patients [76]. The authors reported finding no association between the dose of caloric intake and hospital mortality. Furthermore, a lower caloric intake resulted in lower risk of bloodstream infections and the need for renal replacement therapy (in 5 of the 21 trials only). As with many other meta-analyses, the authors reported that their results are most assuredly impacted by the heterogeneity in design, feeding route, and dose prescribed and delivered [16,76,77]. Other recent trials such as Arabi et al (2015) that enrolled 894 patients with different feeding targets further confirmed that there is no difference in outcome between groups when it comes to moderate (40% to 60% of goal) vs high (70% to 100% of goal) energy intake, infection rates, or 90-day mortality. The authors summarized their findings saying feeding closer to target is associated with better outcomes compared with severe underfeeding [78]. This adds to the controversy when considering the findings of still other RCTs or meta-analyses that evaluated minimal or trophic feeding versus standard feeding rates [9,46,77]. The meta-analysis performed by Marik and Hooper concluded that there were no differences in the risk of acquired infections, hospital mortality, ICU LOS, or ventilator-free days whether patients received intentional hypocaloric or normocaloric nutrition support [9]. Similarly, there was no significant difference in overall mortality between the underfeeding and full-feeding groups (OR, 0.94; 95% CI, 0.74–1.19; I2 = 26.6%; P = 0.61) in the meta-analysis done by Choi et al (2015), although only 4 trials were included to ensure homogeneity of the population and the intervention [77]. Furthermore, the hospital LOS and ICU LOS did not differ between the 2 groups, nor did any other secondary clinical outcome, leading the authors to conclude that calorie intake of the initial EN support for ICU patients had no bearing on relevant outcomes.

Recent studies have attempted to correlate caloric intake and patient outcomes without success; achieving 100% of caloric goal has not favorably impacted morbidity and mortality. Evidence suggests that intake greater than 65% to 70% of daily caloric requirement in the first 7 to 10 days of ICU stay may be associated with poorer outcomes, particularly when parenteral nutrition is used to supplement intake to achieve the caloric target [33–35].

Conclusion

In this review we described current ICU controversies surrounding nutrition therapy and briefly discussed the data that support more than one course of action. A summary of key points covered is presented in the Table. 

Disclaimer: The views expressed in this paper are those of the authors and do not reflect the official policy of the Department of the Army, the Department of Defense, or the U.S. government.

Corresponding author: Mary S. McCarthy, PhD, RN, CNSC, 1611 Nisqually St, Steilacoom, WA 98388.

Financial disclosures: None.

Study Overview

Objective. To examine the effect of nivolumab plus ipilimumab vs nivolumab monotherapy vs standard of care chemotherapy in front line metastatic non-small cell lung cancer (NSCLC).

Design. Multipart phase 3 randomized controlled trial (CheckMate 227 trial).

Setting and participants. Study patients were enrolled at multiple centers around the world. Patients were eligible for enrollment if they had biopsy-proven metastatic NSCLC and had not received prior systemic anti-cancer therapy. Exclusion criteria were patients with known ALK translocations or EGFR mutations, known autoimmune disease, current comorbidity requiring treatment with steroids or other immunosuppression at the time of randomization, or untreated central nervous system (CNS) metastasis. Patients with CNS metastasis could be enrolled if they were adequately treated and had returned to their neurologic baseline.

Intervention. At the time of randomization, patients were split into two treatment groups based on their PD-L1 percentage. Patients with PD-L1 of greater than or equal to 1% were randomly assigned in a 1:1:1 ratio to nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1mg/kg every 6 weeks, nivolumab 240 mg every 2 weeks, or standard chemotherapy based on tumor type (platinum/pemetrexed for non-squamous histology and platinum/gemcitabine for squamous). Patients with PD-L1 less than 1% were randomly assigned in a 1:1:1 ratio to nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks, nivolumab 360mg every 3 weeks, or standard chemotherapy based on tumor type. Patient’s with non-squamous histology that had stable disease or a response to chemotherapy could receive maintenance pemetrexed +/- nivolumab. Patients were followed with imaging every 6 weeks for the first year, then every 12 weeks afterwards. All treatments were continued until disease progression, unacceptable toxicity, or completion of protocol (2 years for immunotherapy).

Main outcome measures. There were 2 co-primary outcomes: Progression-free survival (PFS) of nivolumab/ipilimumab vs chemotherapy in patients selected via tumor mutational burden (TMB), and overall survival in patients selected on PD-L1 status. TMB was defined as 10 or greater mutations per megabase. In this publication, only the first primary end point is reported.

Results. Between August 2015 and November 2016, 2877 patients were enrolled and 1739 were randomized on a 1:1:1 to nivolumab plus ipilimumab, nivolumab monotherapy, or standard of care chemotherapy. Of those, 1004 (57.7%) had adequate data for TMB to be evaluated. Of those, 299 patients met the TMB cutoff for the first primary end point—139 in the nivolumab plus ipilimumab arm and 160 in the chemotherapy arm. The 1-year PFS in patients with a high TMB was 42.6% in the immunotherapy arm vs 13.2% with chemotherapy and the median PFS was 7.2 months vs 5.5 months (hazard ratio [HR] 0.58; 97.5% CI 0.41–0.81; P < 0.001). In low TMB patients, the PFS was greater for chemotherapy vs immunotherapy (3.2 vs 5.5 months). The HR for patients with high TMB was significant for all PD-L1 values and for non-squamous histology. For squamous histology, there was a benefit of 12 month PFS of 36% vs 7%, however it was not statistically significant (HR 0.63; 95% CI, 0.39–1.04). In the supplemental index, nivolumab vs chemotherapy with a TMB greater than 13 was shown to have no benefit (HR 0.95; 95% CI 0.64–1.40; P = 0.7776).

With regard to adverse events, 31.2% of the nivolumab plus ipilimumab group experienced a grade 3 or greater event vs 36.1% of the chemotherapy group and 18.9% of the nivolumab monotherapy group. Events higher in the combination immunotherapy group were rash (1.6% vs 0%), diarrhea (1.6% vs 0.7%), and hypothyroidism (0.3% vs 0%). Events higher in the chemotherapy arm were anemia (11.2% vs 1.6%), neutropenia/decreased neutrophil count (15.8% vs 0%), nausea (2.1% vs 0.5%), and vomiting (2.3% vs 0.3%).

Conclusion. Among patients with newly diagnosed metastatic NSCLC with tumor mutational burden of 10 or greater mutations per megabase, the combination of nivolumab and ipilimumab resulted in higher progression-free survival than standard chemotherapy.

Commentary

Non-small cell lung cancer is undergoing a renaissance in improved survival as a result of new targeted therapies [1]. Medications to target the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) translocations have shown clinical benefit over standard chemotherapy as initial treatment. In addition, in patients with programed death ligand 1 (PD-L1) expression of greater than 50%, pembrolizumab has showed to be superior to standard chemotherapy in the front-line setting. It is currently standard to test all non-squamous lung cancer specimens for EGFR, ALK, and PD-L1, and some argue to test squamous as well. However, through all these treatments, the prognosis of metastatic NSCLC remains poor, as only 4.7% of patients live to 5 years [2].

This study asks if we can add tumor mutational burden (TMB) as actionable information, and should we perform this test on all NSCLC specimens. The theory is that tumors with high TMB will express more foreign antigens, and thus be more responsive to immune checkpoint inhibition. Reviewing the literature, there has been varying correlation between TMB and response to immunotherapy [3]. Despite its potential use as a biomarker, no prior study has shown that using any treatment in a high TMB population conveys any benefit and thus it is not considered standard of care to test for TMB.

This article’s conclusion has several major implications. First, does dual immunotherapy have a role in NSCLC? The data in the trial shows that in high TMB patients there is a clear PFS benefit to nivolumab plus ipilimumab over chemotherapy. In addition, about 40% of patients had a durable response at 2 years follow-up. Strengths of this study are the large size, although smaller when selected for only high TMB patients. Another strength is the long follow-up with a minimum of 11.2 months, with a significant number followed for about 2 years. A weakness of this trial is that patients were randomized before their TMB status was known. In addition, only 57.7% of the randomized patients were able to be analyzed for TMB. The third arm of this study (nivolumab monotherapy), while providing the information that it is less effective in this population, does cloud the information. Finally, while a benefit in PFS was found in the TMB cohort, this does not always correlate with an OS benefit in mature data.

Second, if it does have a role, should TMB be a standard test on all NSCLC specimens? While it was borderline, there was no benefit to squamous histology. In the supplemental index it was reported that nivolumab monotherapy did not show a benefit, thus the need to offer ipilimumab depends on TMB status. Pembrolizumab is already approved in patients with PD-L1 expression greater than 50% [2]. However, in patients with PD-L1 less than 50% and no ALK or EGFR mutation, chemotherapy would be frontline treatment; with TMB testing these patients could be spared this toxic treatment. In addition, a parallel published study shows benefit to adding pembrolizumab to standard chemotherapy [4].

Another consideration is the requirements of tissue for testing TMB. This study used the Foundation One assay. This test required optimally 25 square millimeters of tissue and preferred the whole block of tissue or 10 unstained slides [5]. For patients who are diagnosed with full surgical resection this is not an issue and should not be a barrier for this therapy. However, metastatic disease patients are often diagnosed on core biopsy of a metastatic site, thus getting an accurate TMB profile (in addition to testing other actionable mutations) could be a challenge. Identifying patients who would be a candidate for this therapy prior to biopsy will be important given the tissue requirements.

Another advantage to immunotherapy vs standard chemotherapy has been favorable toxicity rates. PD-L1 inhibitor monotherapy has generally been superior to standard chemotherapy and has been a better option for frail patients. However, the addition of the CTLA-4 inhibitor ipilimumab to PD-L1 blockade has increased the toxicity profile. In this trial, the grade 3 or greater toxicity rate was similar between dual immunotherapy and chemotherapy, although with different major symptoms. In addition, patients with prior autoimmune disease or active brain metastasis were excluded from the study and thus should not be offered dual immunotherapy. A clinician will need to consider if their patient is a candidate for dual immunotherapy before considering the application of this trial.

In the future, researchers will need to compare these agents to the new standard of care. Chemotherapy as a control arm no longer is appropriate in a majority of patients. Some patients in this study were PD-L1 greater than 50% and TMB greater than 10; for them, the control should be pembrolizumab. In addition, sequencing therapy continues to be a challenge. Finally, studies in patients with other malignancies have looked at shorter courses of ipilimumab with reduced toxicity with similar benefit [6], and this could be applied to lung cancer as well.

Application for Clinical Practice

This trial adds an additional actionable target to the array of treatments for NSCLC. In patients with newly diagnosed metastatic non-squamous NSCLC with no actionable EGFR or ALK mutation and PD-L1 less than 50%, testing for TMB on tumor should be performed. If the test shows 10 or greater mutations per megabase, combination nivolumab and ipilimumab should be offered over standard chemotherapy. Special consideration of patient characteristics to determine candidacy and tolerability of this treatment should be evaluated.

— Jacob Elkon, MD, George Washington University School of Medicine, Washington, DC

Study Overview

Objective. To examine the effect of nivolumab plus ipilimumab vs nivolumab monotherapy vs standard of care chemotherapy in front line metastatic non-small cell lung cancer (NSCLC).

Design. Multipart phase 3 randomized controlled trial (CheckMate 227 trial).

Setting and participants. Study patients were enrolled at multiple centers around the world. Patients were eligible for enrollment if they had biopsy-proven metastatic NSCLC and had not received prior systemic anti-cancer therapy. Exclusion criteria were patients with known ALK translocations or EGFR mutations, known autoimmune disease, current comorbidity requiring treatment with steroids or other immunosuppression at the time of randomization, or untreated central nervous system (CNS) metastasis. Patients with CNS metastasis could be enrolled if they were adequately treated and had returned to their neurologic baseline.

Intervention. At the time of randomization, patients were split into two treatment groups based on their PD-L1 percentage. Patients with PD-L1 of greater than or equal to 1% were randomly assigned in a 1:1:1 ratio to nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1mg/kg every 6 weeks, nivolumab 240 mg every 2 weeks, or standard chemotherapy based on tumor type (platinum/pemetrexed for non-squamous histology and platinum/gemcitabine for squamous). Patients with PD-L1 less than 1% were randomly assigned in a 1:1:1 ratio to nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks, nivolumab 360mg every 3 weeks, or standard chemotherapy based on tumor type. Patient’s with non-squamous histology that had stable disease or a response to chemotherapy could receive maintenance pemetrexed +/- nivolumab. Patients were followed with imaging every 6 weeks for the first year, then every 12 weeks afterwards. All treatments were continued until disease progression, unacceptable toxicity, or completion of protocol (2 years for immunotherapy).

Main outcome measures. There were 2 co-primary outcomes: Progression-free survival (PFS) of nivolumab/ipilimumab vs chemotherapy in patients selected via tumor mutational burden (TMB), and overall survival in patients selected on PD-L1 status. TMB was defined as 10 or greater mutations per megabase. In this publication, only the first primary end point is reported.

Results. Between August 2015 and November 2016, 2877 patients were enrolled and 1739 were randomized on a 1:1:1 to nivolumab plus ipilimumab, nivolumab monotherapy, or standard of care chemotherapy. Of those, 1004 (57.7%) had adequate data for TMB to be evaluated. Of those, 299 patients met the TMB cutoff for the first primary end point—139 in the nivolumab plus ipilimumab arm and 160 in the chemotherapy arm. The 1-year PFS in patients with a high TMB was 42.6% in the immunotherapy arm vs 13.2% with chemotherapy and the median PFS was 7.2 months vs 5.5 months (hazard ratio [HR] 0.58; 97.5% CI 0.41–0.81; P < 0.001). In low TMB patients, the PFS was greater for chemotherapy vs immunotherapy (3.2 vs 5.5 months). The HR for patients with high TMB was significant for all PD-L1 values and for non-squamous histology. For squamous histology, there was a benefit of 12 month PFS of 36% vs 7%, however it was not statistically significant (HR 0.63; 95% CI, 0.39–1.04). In the supplemental index, nivolumab vs chemotherapy with a TMB greater than 13 was shown to have no benefit (HR 0.95; 95% CI 0.64–1.40; P = 0.7776).

With regard to adverse events, 31.2% of the nivolumab plus ipilimumab group experienced a grade 3 or greater event vs 36.1% of the chemotherapy group and 18.9% of the nivolumab monotherapy group. Events higher in the combination immunotherapy group were rash (1.6% vs 0%), diarrhea (1.6% vs 0.7%), and hypothyroidism (0.3% vs 0%). Events higher in the chemotherapy arm were anemia (11.2% vs 1.6%), neutropenia/decreased neutrophil count (15.8% vs 0%), nausea (2.1% vs 0.5%), and vomiting (2.3% vs 0.3%).

Conclusion. Among patients with newly diagnosed metastatic NSCLC with tumor mutational burden of 10 or greater mutations per megabase, the combination of nivolumab and ipilimumab resulted in higher progression-free survival than standard chemotherapy.

Commentary

Non-small cell lung cancer is undergoing a renaissance in improved survival as a result of new targeted therapies [1]. Medications to target the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) translocations have shown clinical benefit over standard chemotherapy as initial treatment. In addition, in patients with programed death ligand 1 (PD-L1) expression of greater than 50%, pembrolizumab has showed to be superior to standard chemotherapy in the front-line setting. It is currently standard to test all non-squamous lung cancer specimens for EGFR, ALK, and PD-L1, and some argue to test squamous as well. However, through all these treatments, the prognosis of metastatic NSCLC remains poor, as only 4.7% of patients live to 5 years [2].

This study asks if we can add tumor mutational burden (TMB) as actionable information, and should we perform this test on all NSCLC specimens. The theory is that tumors with high TMB will express more foreign antigens, and thus be more responsive to immune checkpoint inhibition. Reviewing the literature, there has been varying correlation between TMB and response to immunotherapy [3]. Despite its potential use as a biomarker, no prior study has shown that using any treatment in a high TMB population conveys any benefit and thus it is not considered standard of care to test for TMB.

This article’s conclusion has several major implications. First, does dual immunotherapy have a role in NSCLC? The data in the trial shows that in high TMB patients there is a clear PFS benefit to nivolumab plus ipilimumab over chemotherapy. In addition, about 40% of patients had a durable response at 2 years follow-up. Strengths of this study are the large size, although smaller when selected for only high TMB patients. Another strength is the long follow-up with a minimum of 11.2 months, with a significant number followed for about 2 years. A weakness of this trial is that patients were randomized before their TMB status was known. In addition, only 57.7% of the randomized patients were able to be analyzed for TMB. The third arm of this study (nivolumab monotherapy), while providing the information that it is less effective in this population, does cloud the information. Finally, while a benefit in PFS was found in the TMB cohort, this does not always correlate with an OS benefit in mature data.

Second, if it does have a role, should TMB be a standard test on all NSCLC specimens? While it was borderline, there was no benefit to squamous histology. In the supplemental index it was reported that nivolumab monotherapy did not show a benefit, thus the need to offer ipilimumab depends on TMB status. Pembrolizumab is already approved in patients with PD-L1 expression greater than 50% [2]. However, in patients with PD-L1 less than 50% and no ALK or EGFR mutation, chemotherapy would be frontline treatment; with TMB testing these patients could be spared this toxic treatment. In addition, a parallel published study shows benefit to adding pembrolizumab to standard chemotherapy [4].

Another consideration is the requirements of tissue for testing TMB. This study used the Foundation One assay. This test required optimally 25 square millimeters of tissue and preferred the whole block of tissue or 10 unstained slides [5]. For patients who are diagnosed with full surgical resection this is not an issue and should not be a barrier for this therapy. However, metastatic disease patients are often diagnosed on core biopsy of a metastatic site, thus getting an accurate TMB profile (in addition to testing other actionable mutations) could be a challenge. Identifying patients who would be a candidate for this therapy prior to biopsy will be important given the tissue requirements.

Another advantage to immunotherapy vs standard chemotherapy has been favorable toxicity rates. PD-L1 inhibitor monotherapy has generally been superior to standard chemotherapy and has been a better option for frail patients. However, the addition of the CTLA-4 inhibitor ipilimumab to PD-L1 blockade has increased the toxicity profile. In this trial, the grade 3 or greater toxicity rate was similar between dual immunotherapy and chemotherapy, although with different major symptoms. In addition, patients with prior autoimmune disease or active brain metastasis were excluded from the study and thus should not be offered dual immunotherapy. A clinician will need to consider if their patient is a candidate for dual immunotherapy before considering the application of this trial.

In the future, researchers will need to compare these agents to the new standard of care. Chemotherapy as a control arm no longer is appropriate in a majority of patients. Some patients in this study were PD-L1 greater than 50% and TMB greater than 10; for them, the control should be pembrolizumab. In addition, sequencing therapy continues to be a challenge. Finally, studies in patients with other malignancies have looked at shorter courses of ipilimumab with reduced toxicity with similar benefit [6], and this could be applied to lung cancer as well.

Application for Clinical Practice

This trial adds an additional actionable target to the array of treatments for NSCLC. In patients with newly diagnosed metastatic non-squamous NSCLC with no actionable EGFR or ALK mutation and PD-L1 less than 50%, testing for TMB on tumor should be performed. If the test shows 10 or greater mutations per megabase, combination nivolumab and ipilimumab should be offered over standard chemotherapy. Special consideration of patient characteristics to determine candidacy and tolerability of this treatment should be evaluated.

— Jacob Elkon, MD, George Washington University School of Medicine, Washington, DC

Study Overview

Objective. To examine the effect of nivolumab plus ipilimumab vs nivolumab monotherapy vs standard of care chemotherapy in front line metastatic non-small cell lung cancer (NSCLC).

Design. Multipart phase 3 randomized controlled trial (CheckMate 227 trial).

Setting and participants. Study patients were enrolled at multiple centers around the world. Patients were eligible for enrollment if they had biopsy-proven metastatic NSCLC and had not received prior systemic anti-cancer therapy. Exclusion criteria were patients with known ALK translocations or EGFR mutations, known autoimmune disease, current comorbidity requiring treatment with steroids or other immunosuppression at the time of randomization, or untreated central nervous system (CNS) metastasis. Patients with CNS metastasis could be enrolled if they were adequately treated and had returned to their neurologic baseline.

Intervention. At the time of randomization, patients were split into two treatment groups based on their PD-L1 percentage. Patients with PD-L1 of greater than or equal to 1% were randomly assigned in a 1:1:1 ratio to nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1mg/kg every 6 weeks, nivolumab 240 mg every 2 weeks, or standard chemotherapy based on tumor type (platinum/pemetrexed for non-squamous histology and platinum/gemcitabine for squamous). Patients with PD-L1 less than 1% were randomly assigned in a 1:1:1 ratio to nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks, nivolumab 360mg every 3 weeks, or standard chemotherapy based on tumor type. Patient’s with non-squamous histology that had stable disease or a response to chemotherapy could receive maintenance pemetrexed +/- nivolumab. Patients were followed with imaging every 6 weeks for the first year, then every 12 weeks afterwards. All treatments were continued until disease progression, unacceptable toxicity, or completion of protocol (2 years for immunotherapy).

Main outcome measures. There were 2 co-primary outcomes: Progression-free survival (PFS) of nivolumab/ipilimumab vs chemotherapy in patients selected via tumor mutational burden (TMB), and overall survival in patients selected on PD-L1 status. TMB was defined as 10 or greater mutations per megabase. In this publication, only the first primary end point is reported.

Results. Between August 2015 and November 2016, 2877 patients were enrolled and 1739 were randomized on a 1:1:1 to nivolumab plus ipilimumab, nivolumab monotherapy, or standard of care chemotherapy. Of those, 1004 (57.7%) had adequate data for TMB to be evaluated. Of those, 299 patients met the TMB cutoff for the first primary end point—139 in the nivolumab plus ipilimumab arm and 160 in the chemotherapy arm. The 1-year PFS in patients with a high TMB was 42.6% in the immunotherapy arm vs 13.2% with chemotherapy and the median PFS was 7.2 months vs 5.5 months (hazard ratio [HR] 0.58; 97.5% CI 0.41–0.81; P < 0.001). In low TMB patients, the PFS was greater for chemotherapy vs immunotherapy (3.2 vs 5.5 months). The HR for patients with high TMB was significant for all PD-L1 values and for non-squamous histology. For squamous histology, there was a benefit of 12 month PFS of 36% vs 7%, however it was not statistically significant (HR 0.63; 95% CI, 0.39–1.04). In the supplemental index, nivolumab vs chemotherapy with a TMB greater than 13 was shown to have no benefit (HR 0.95; 95% CI 0.64–1.40; P = 0.7776).

With regard to adverse events, 31.2% of the nivolumab plus ipilimumab group experienced a grade 3 or greater event vs 36.1% of the chemotherapy group and 18.9% of the nivolumab monotherapy group. Events higher in the combination immunotherapy group were rash (1.6% vs 0%), diarrhea (1.6% vs 0.7%), and hypothyroidism (0.3% vs 0%). Events higher in the chemotherapy arm were anemia (11.2% vs 1.6%), neutropenia/decreased neutrophil count (15.8% vs 0%), nausea (2.1% vs 0.5%), and vomiting (2.3% vs 0.3%).

Conclusion. Among patients with newly diagnosed metastatic NSCLC with tumor mutational burden of 10 or greater mutations per megabase, the combination of nivolumab and ipilimumab resulted in higher progression-free survival than standard chemotherapy.

Commentary

Non-small cell lung cancer is undergoing a renaissance in improved survival as a result of new targeted therapies [1]. Medications to target the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) translocations have shown clinical benefit over standard chemotherapy as initial treatment. In addition, in patients with programed death ligand 1 (PD-L1) expression of greater than 50%, pembrolizumab has showed to be superior to standard chemotherapy in the front-line setting. It is currently standard to test all non-squamous lung cancer specimens for EGFR, ALK, and PD-L1, and some argue to test squamous as well. However, through all these treatments, the prognosis of metastatic NSCLC remains poor, as only 4.7% of patients live to 5 years [2].

This study asks if we can add tumor mutational burden (TMB) as actionable information, and should we perform this test on all NSCLC specimens. The theory is that tumors with high TMB will express more foreign antigens, and thus be more responsive to immune checkpoint inhibition. Reviewing the literature, there has been varying correlation between TMB and response to immunotherapy [3]. Despite its potential use as a biomarker, no prior study has shown that using any treatment in a high TMB population conveys any benefit and thus it is not considered standard of care to test for TMB.

This article’s conclusion has several major implications. First, does dual immunotherapy have a role in NSCLC? The data in the trial shows that in high TMB patients there is a clear PFS benefit to nivolumab plus ipilimumab over chemotherapy. In addition, about 40% of patients had a durable response at 2 years follow-up. Strengths of this study are the large size, although smaller when selected for only high TMB patients. Another strength is the long follow-up with a minimum of 11.2 months, with a significant number followed for about 2 years. A weakness of this trial is that patients were randomized before their TMB status was known. In addition, only 57.7% of the randomized patients were able to be analyzed for TMB. The third arm of this study (nivolumab monotherapy), while providing the information that it is less effective in this population, does cloud the information. Finally, while a benefit in PFS was found in the TMB cohort, this does not always correlate with an OS benefit in mature data.

Second, if it does have a role, should TMB be a standard test on all NSCLC specimens? While it was borderline, there was no benefit to squamous histology. In the supplemental index it was reported that nivolumab monotherapy did not show a benefit, thus the need to offer ipilimumab depends on TMB status. Pembrolizumab is already approved in patients with PD-L1 expression greater than 50% [2]. However, in patients with PD-L1 less than 50% and no ALK or EGFR mutation, chemotherapy would be frontline treatment; with TMB testing these patients could be spared this toxic treatment. In addition, a parallel published study shows benefit to adding pembrolizumab to standard chemotherapy [4].

Another consideration is the requirements of tissue for testing TMB. This study used the Foundation One assay. This test required optimally 25 square millimeters of tissue and preferred the whole block of tissue or 10 unstained slides [5]. For patients who are diagnosed with full surgical resection this is not an issue and should not be a barrier for this therapy. However, metastatic disease patients are often diagnosed on core biopsy of a metastatic site, thus getting an accurate TMB profile (in addition to testing other actionable mutations) could be a challenge. Identifying patients who would be a candidate for this therapy prior to biopsy will be important given the tissue requirements.

Another advantage to immunotherapy vs standard chemotherapy has been favorable toxicity rates. PD-L1 inhibitor monotherapy has generally been superior to standard chemotherapy and has been a better option for frail patients. However, the addition of the CTLA-4 inhibitor ipilimumab to PD-L1 blockade has increased the toxicity profile. In this trial, the grade 3 or greater toxicity rate was similar between dual immunotherapy and chemotherapy, although with different major symptoms. In addition, patients with prior autoimmune disease or active brain metastasis were excluded from the study and thus should not be offered dual immunotherapy. A clinician will need to consider if their patient is a candidate for dual immunotherapy before considering the application of this trial.

In the future, researchers will need to compare these agents to the new standard of care. Chemotherapy as a control arm no longer is appropriate in a majority of patients. Some patients in this study were PD-L1 greater than 50% and TMB greater than 10; for them, the control should be pembrolizumab. In addition, sequencing therapy continues to be a challenge. Finally, studies in patients with other malignancies have looked at shorter courses of ipilimumab with reduced toxicity with similar benefit [6], and this could be applied to lung cancer as well.

Application for Clinical Practice

This trial adds an additional actionable target to the array of treatments for NSCLC. In patients with newly diagnosed metastatic non-squamous NSCLC with no actionable EGFR or ALK mutation and PD-L1 less than 50%, testing for TMB on tumor should be performed. If the test shows 10 or greater mutations per megabase, combination nivolumab and ipilimumab should be offered over standard chemotherapy. Special consideration of patient characteristics to determine candidacy and tolerability of this treatment should be evaluated.

— Jacob Elkon, MD, George Washington University School of Medicine, Washington, DC

Study Overview

Objective. To evaluate balanced crystalloids in comparison with normal saline in the intensive care unit (ICU) population.

Design. Pragmatic, un-blinded, cluster-randomized, multiple-crossover clinical trial (the SMART study).

Setting and participants. The study evaluated critically ill adults > 18 years of age, admitted and readmitted into 5 ICUs, both medical and surgical, from June 2015 to April 2017. 15,802 patients were enrolled, powered to detect a 1.9% percentage point difference in primary outcome. ICUs were randomized to use either balanced crystalloids (lactated Ringer’s [LR] or Plasma-Lyte A, depending on the provider’s preference) or normal saline during alternate calendar months. Relative contraindications to use of balanced crystalloids included traumatic brain injury and hyperkalemia. The admitting emergency rooms and operating rooms coordinated intravenous fluid (IVF) choice with their respective ICUs. An intention-to-treat analysis was conducted. In addition to primary and secondary outcome analyses, subgroup analyses based on factors including total IVF volume to day 30, vasopressor use, predicted in-hospital mortality, sepsis or traumatic brain injury diagnoses, ICU type, source of admission, and kidney function at baseline were also done. Furthermore, sensitivity analyses taking into account the total volume of crystalloid, crossover and excluding readmissions were performed.

Main outcome measures. The primary outcome was the proportion of patients that met at least 1 of the 3 criteria for a Major Adverse Kidney Event at day 30 (MAKE30) or discharge, whichever occurred earlier. MAKE30 is a composite measure consisting of death, persistent renal dysfunction (creatinine ≥ 200% baseline), or new renal replacement therapy (RRT). Patients previously on RRT were included for mortality analysis alone. In addition, secondary clinical outcomes including in-hospital mortality (prior to ICU discharge, at day 30 and day 60), ventilator-free days, vasopressor-free days, ICU-free days, days alive and RRT-free days in the first 28 days were assessed. Secondary renal outcomes such as persistent renal dysfunction, acute kidney injury (AKI) ≥ stage 2 (per Kidney Disease: Improving Global Outcomes Criteria {KDIGO}) criteria, new RRT, highest creatinine during hospitalization, creatinine at discharge and highest change in creatinine during hospitalization were also evaluated.

Results. 7942 patients were randomized to the balanced crystalloid group and 7860 to the saline group. Median age for both groups was 58 years and 57.6% patients were male. In terms of patient acuity, approximately 34% patients were on mechanical ventilation, 26% were on vasopressors, and around 14% carried a diagnosis of sepsis. At time of presentation, 17% had chronic kidney disease (CKD) ≥ stage 3 and approximately 5% were on RRT. Around 8% came in with AKI ≥ stage 2. Baseline creatinine in the both groups was 0.89 (interquartile range [IQR] 0.74–1.1). Median volumes of balanced crystalloid and saline administered was 1L (IQR 0–3.2L) and 1.02L (IQR 0–3.5L) respectively. Less than 5% in both groups received unassigned fluids. Predicted risk of in-hospital death for both groups was approximately 9%.

Significantly higher number of patients had plasma chloride ≥ 110 mmol/L and bicarbonate ≤ 20 mmol/L in the saline group (P < 0.001). In terms of primary outcome, MAKE30 rates in the balanced crystalloid vs saline groups were 14.3 vs 15.4 (marginal odds ratio {OR} 0.91, 95% confidence interval {CI} 0.84–0.99, P = 0.04) with similar results in the pre-specified sensitivity analyses. This difference was more prominent with larger volumes of infused fluids. All 3 components of composite primary outcome were improved in the crystalloid group, although none of the 3 individually achieved statistical significance.

Overall, mortality before discharge and within 30 days of admission in the balanced crystalloid group was 10.3% compared to 11.1% in the saline group (OR 0.9, CI 0.8–1.01, P = 0.06). In-hospital death before ICU discharge and at 60 days also mirrored this trend, although they did not achieve statistical significance either. Of note, in septic patients, 30-day mortality rates were 25.2 vs 29.4 in the balanced crystalloid and saline groups respectively (OR 0.8, 95% CI 0.67–0.97, P = 0.02).

With regard to renal outcomes in the balanced crystalloid vs normal saline groups, results were as follows: new RRT {2.5 vs 2.9%, P = 0.08}, new AKI development 10.7% vs 11.5% (OR 0.9, P = 0.09). In patients with a history of previous RRT or presenting with an AKI, crystalloids appeared to provide better MAKE30 outcomes, although not achieving statistical significance.

Conclusion. In the critically ill population, balanced crystalloids provide a beneficial effect over normal saline on the composite outcome of persistent renal dysfunction, new RRT and mortality at day 30.

Commentary

Unbalanced crystalloids, especially normal saline, are the most commonly used IVF for resuscitation in the critically ill. Given the data suggesting risk of kidney injury, acidosis, and effect on mortality with the use of normal saline, this study aimed to evaluate balanced crystalloids in comparison with normal saline in the ICU population.

Interest in the consequences of hyperchloremia and metabolic acidosis from supra-physiologic chloride concentrations in normal saline first stemmed from data in preclinical models, which demonstrated that chloride-induced renal inflammation adversely impacted renal function and mortality [1,2]. While in theory “balanced” solutions carry dual benefits of both an electrolyte composition that closely mirrors plasma and the presence of buffers which improve acid-base milieu, the exact repercussions on patient-centered outcomes with use of one over the other remain unknown.

An exploratory randomized control trial (RCT) evaluating biochemistry up to day 4 in normal saline vs Plasma-Lyte groups in 70 critically ill adults showed significantly higher hyperchloremia with normal saline but no difference in AKI rates between the two groups [3]. A pilot study evaluating “chloride-restrictive vs chloride liberal” strategies in 760 ICU patients involved use of Hartmann’s solution and Plasma-Lyte in place of saline for a 6-month period except in case of specific contraindications such as traumatic brain injury.  Results indicated that incidence of AKI and use of RRT significantly reduced by limiting chloride. No changes in mortality, ICU length of stay or RRT on discharge were noted [4].A large retrospective study in over 53,000 ICU patients admitted with sepsis and on vasopressors across 360 US hospitals showed that balanced fluids were associated with lower in-hospital mortality especially when higher volume of IVFs were infused. While no differences were seen in terms of AKI rates, lower risk of CKD was noted in balanced fluid groups [5].

In post-surgical populations, an observational study analyzing saline vs balanced fluids over 30,000 patients showed significantly lower mortality, renal failure, acidosis investigation/intervention rates with balanced fluids [6].Additionally, a meta-analysis assessing outcomes in peri-operative and ICU patients based on whether they received high or low chloride containing fluids was performed on over 6000 patients across 21 studies. No association with mortality was found. However, statistically significant correlations were noted between high chloride fluids and hyperchloremia, metabolic acidosis, AKI, mechanical ventilation times and blood transfusion volumes [7].

In 2015, a large RCT involving ICUs in New Zealand evaluated balanced crystalloids vs normal saline and rates of AKI in a double-blind, cluster-randomized, double-crossover trial (the SPLIT study). 2278 patients from medical and surgical ICUs were enrolled. Patients already receiving RRT were excluded. No significant difference in incidence of AKI (defined as a two-fold rise or a 0.5mg/dL increase in creatinine), new RRT or mortality was detected between the two groups [8].

Given the ambiguity and lack of consensus on outcomes, the current SMART study addresses an important gap in knowledge. Its large sample size makes it well powered, geared to detect small signals in outcomes. Inclusion of medical, surgical, and neurologic ICUs helps diversify applicability. Being a pragmatic, intention-to-treat RCT, the study design mirrors real-world clinical practice.

In terms of patient acuity, less than a third of the patients were intubated or on vasopressors. Predicted mortality rates were 9%. In addition, median volume infused was around 1 L. Given the investigators’ conclusions that the MAKE30 outcome signals were more pronounced with larger volumes of infusions, this brings into question whether more dramatic signals could have been appreciated in each of the 3 components of the primary outcome had the study population been a higher acuity group requiring larger infusion volumes.

While the composite MAKE30 outcome reflects a sense of an overarching benefit with balanced crystalloids, there was no statistically significant improvement noted in each primary component. This questions the rationale for combining the components of the MAKE30 outcome as well as how generalizable the results are. Overall, as is the case with many studies that evaluate a composite outcome, this raises concern about overestimation of the intervention’s true impact.

The study was un-blinded, raising concern for bias, and it was a single-center trial, which raises questions regarding generalizability. Un-blinding may have played a role in influencing decisions to initiate RRT earlier in the saline group. The extent to which this impacted RRT rates (one of the MAKE30 outcomes), remains unclear. Furthermore, approximately 5% of the participants received unassigned fluids, and while this is in line with the pragmatic/intention-to-treat design, the clinical repercussions remain unclear. Hyperkalemia is an exclusion criterion for balanced fluids and it is unclear whether a proportion of patients presenting with AKI-associated hyperkalemia were restricted from receiving balanced fluids. In addition, very few patients received Plasma-Lyte, confining the study’s conclusions to lactated Ringer’s alone.

Despite these pitfalls, the study addresses an extremely relevant clinical question. It urges clinicians to tailor fluid choices on a case-by-case basis and pay attention to the long-term implications of daily biochemical changes on renal outcomes, particularly in large volume resuscitation scenarios. There is a negligible cost difference between lactated Ringer’s and saline, making use of a balanced fluid economically feasible. The number needed to treat for MAKE30 based on this study is 94 patients, and changes in clinical practice extrapolated to ICUs nationwide could have an impact on renal outcomes from an epidemiologic point of view without risking financial burden at an institution level.

Applications for Clinical Practice

Overall, this trial clarifies an important gap in knowledge regarding fluid choice in the care of critically ill adults. The composite outcome of death, persistent renal dysfunction, and new RRT was significantly lower when a balanced fluid was used in comparison with saline. The ease of implementation, low financial impact, and epidemiologically significant renal outcomes supports a consideration for change in practice. However, clinicians should evaluate implementation on a case-by-case basis. More studies evaluating MAKE30 outcomes individually in specific diagnoses and clinical contexts are necessary. Moreover, data on long-term MAKE outcomes would help characterize long-term public health implications of 30-day effects.

—Divya Padmanabhan Menon, MD, Christopher L. Trautman, MD, and Neal M. Patel, MD, Mayo Clinic, Jacksonville, FL

Study Overview

Objective. To evaluate balanced crystalloids in comparison with normal saline in the intensive care unit (ICU) population.

Design. Pragmatic, un-blinded, cluster-randomized, multiple-crossover clinical trial (the SMART study).

Setting and participants. The study evaluated critically ill adults > 18 years of age, admitted and readmitted into 5 ICUs, both medical and surgical, from June 2015 to April 2017. 15,802 patients were enrolled, powered to detect a 1.9% percentage point difference in primary outcome. ICUs were randomized to use either balanced crystalloids (lactated Ringer’s [LR] or Plasma-Lyte A, depending on the provider’s preference) or normal saline during alternate calendar months. Relative contraindications to use of balanced crystalloids included traumatic brain injury and hyperkalemia. The admitting emergency rooms and operating rooms coordinated intravenous fluid (IVF) choice with their respective ICUs. An intention-to-treat analysis was conducted. In addition to primary and secondary outcome analyses, subgroup analyses based on factors including total IVF volume to day 30, vasopressor use, predicted in-hospital mortality, sepsis or traumatic brain injury diagnoses, ICU type, source of admission, and kidney function at baseline were also done. Furthermore, sensitivity analyses taking into account the total volume of crystalloid, crossover and excluding readmissions were performed.

Main outcome measures. The primary outcome was the proportion of patients that met at least 1 of the 3 criteria for a Major Adverse Kidney Event at day 30 (MAKE30) or discharge, whichever occurred earlier. MAKE30 is a composite measure consisting of death, persistent renal dysfunction (creatinine ≥ 200% baseline), or new renal replacement therapy (RRT). Patients previously on RRT were included for mortality analysis alone. In addition, secondary clinical outcomes including in-hospital mortality (prior to ICU discharge, at day 30 and day 60), ventilator-free days, vasopressor-free days, ICU-free days, days alive and RRT-free days in the first 28 days were assessed. Secondary renal outcomes such as persistent renal dysfunction, acute kidney injury (AKI) ≥ stage 2 (per Kidney Disease: Improving Global Outcomes Criteria {KDIGO}) criteria, new RRT, highest creatinine during hospitalization, creatinine at discharge and highest change in creatinine during hospitalization were also evaluated.

Results. 7942 patients were randomized to the balanced crystalloid group and 7860 to the saline group. Median age for both groups was 58 years and 57.6% patients were male. In terms of patient acuity, approximately 34% patients were on mechanical ventilation, 26% were on vasopressors, and around 14% carried a diagnosis of sepsis. At time of presentation, 17% had chronic kidney disease (CKD) ≥ stage 3 and approximately 5% were on RRT. Around 8% came in with AKI ≥ stage 2. Baseline creatinine in the both groups was 0.89 (interquartile range [IQR] 0.74–1.1). Median volumes of balanced crystalloid and saline administered was 1L (IQR 0–3.2L) and 1.02L (IQR 0–3.5L) respectively. Less than 5% in both groups received unassigned fluids. Predicted risk of in-hospital death for both groups was approximately 9%.

Significantly higher number of patients had plasma chloride ≥ 110 mmol/L and bicarbonate ≤ 20 mmol/L in the saline group (P < 0.001). In terms of primary outcome, MAKE30 rates in the balanced crystalloid vs saline groups were 14.3 vs 15.4 (marginal odds ratio {OR} 0.91, 95% confidence interval {CI} 0.84–0.99, P = 0.04) with similar results in the pre-specified sensitivity analyses. This difference was more prominent with larger volumes of infused fluids. All 3 components of composite primary outcome were improved in the crystalloid group, although none of the 3 individually achieved statistical significance.

Overall, mortality before discharge and within 30 days of admission in the balanced crystalloid group was 10.3% compared to 11.1% in the saline group (OR 0.9, CI 0.8–1.01, P = 0.06). In-hospital death before ICU discharge and at 60 days also mirrored this trend, although they did not achieve statistical significance either. Of note, in septic patients, 30-day mortality rates were 25.2 vs 29.4 in the balanced crystalloid and saline groups respectively (OR 0.8, 95% CI 0.67–0.97, P = 0.02).

With regard to renal outcomes in the balanced crystalloid vs normal saline groups, results were as follows: new RRT {2.5 vs 2.9%, P = 0.08}, new AKI development 10.7% vs 11.5% (OR 0.9, P = 0.09). In patients with a history of previous RRT or presenting with an AKI, crystalloids appeared to provide better MAKE30 outcomes, although not achieving statistical significance.

Conclusion. In the critically ill population, balanced crystalloids provide a beneficial effect over normal saline on the composite outcome of persistent renal dysfunction, new RRT and mortality at day 30.

Commentary

Unbalanced crystalloids, especially normal saline, are the most commonly used IVF for resuscitation in the critically ill. Given the data suggesting risk of kidney injury, acidosis, and effect on mortality with the use of normal saline, this study aimed to evaluate balanced crystalloids in comparison with normal saline in the ICU population.

Interest in the consequences of hyperchloremia and metabolic acidosis from supra-physiologic chloride concentrations in normal saline first stemmed from data in preclinical models, which demonstrated that chloride-induced renal inflammation adversely impacted renal function and mortality [1,2]. While in theory “balanced” solutions carry dual benefits of both an electrolyte composition that closely mirrors plasma and the presence of buffers which improve acid-base milieu, the exact repercussions on patient-centered outcomes with use of one over the other remain unknown.

An exploratory randomized control trial (RCT) evaluating biochemistry up to day 4 in normal saline vs Plasma-Lyte groups in 70 critically ill adults showed significantly higher hyperchloremia with normal saline but no difference in AKI rates between the two groups [3]. A pilot study evaluating “chloride-restrictive vs chloride liberal” strategies in 760 ICU patients involved use of Hartmann’s solution and Plasma-Lyte in place of saline for a 6-month period except in case of specific contraindications such as traumatic brain injury.  Results indicated that incidence of AKI and use of RRT significantly reduced by limiting chloride. No changes in mortality, ICU length of stay or RRT on discharge were noted [4].A large retrospective study in over 53,000 ICU patients admitted with sepsis and on vasopressors across 360 US hospitals showed that balanced fluids were associated with lower in-hospital mortality especially when higher volume of IVFs were infused. While no differences were seen in terms of AKI rates, lower risk of CKD was noted in balanced fluid groups [5].

In post-surgical populations, an observational study analyzing saline vs balanced fluids over 30,000 patients showed significantly lower mortality, renal failure, acidosis investigation/intervention rates with balanced fluids [6].Additionally, a meta-analysis assessing outcomes in peri-operative and ICU patients based on whether they received high or low chloride containing fluids was performed on over 6000 patients across 21 studies. No association with mortality was found. However, statistically significant correlations were noted between high chloride fluids and hyperchloremia, metabolic acidosis, AKI, mechanical ventilation times and blood transfusion volumes [7].

In 2015, a large RCT involving ICUs in New Zealand evaluated balanced crystalloids vs normal saline and rates of AKI in a double-blind, cluster-randomized, double-crossover trial (the SPLIT study). 2278 patients from medical and surgical ICUs were enrolled. Patients already receiving RRT were excluded. No significant difference in incidence of AKI (defined as a two-fold rise or a 0.5mg/dL increase in creatinine), new RRT or mortality was detected between the two groups [8].

Given the ambiguity and lack of consensus on outcomes, the current SMART study addresses an important gap in knowledge. Its large sample size makes it well powered, geared to detect small signals in outcomes. Inclusion of medical, surgical, and neurologic ICUs helps diversify applicability. Being a pragmatic, intention-to-treat RCT, the study design mirrors real-world clinical practice.

In terms of patient acuity, less than a third of the patients were intubated or on vasopressors. Predicted mortality rates were 9%. In addition, median volume infused was around 1 L. Given the investigators’ conclusions that the MAKE30 outcome signals were more pronounced with larger volumes of infusions, this brings into question whether more dramatic signals could have been appreciated in each of the 3 components of the primary outcome had the study population been a higher acuity group requiring larger infusion volumes.

While the composite MAKE30 outcome reflects a sense of an overarching benefit with balanced crystalloids, there was no statistically significant improvement noted in each primary component. This questions the rationale for combining the components of the MAKE30 outcome as well as how generalizable the results are. Overall, as is the case with many studies that evaluate a composite outcome, this raises concern about overestimation of the intervention’s true impact.

The study was un-blinded, raising concern for bias, and it was a single-center trial, which raises questions regarding generalizability. Un-blinding may have played a role in influencing decisions to initiate RRT earlier in the saline group. The extent to which this impacted RRT rates (one of the MAKE30 outcomes), remains unclear. Furthermore, approximately 5% of the participants received unassigned fluids, and while this is in line with the pragmatic/intention-to-treat design, the clinical repercussions remain unclear. Hyperkalemia is an exclusion criterion for balanced fluids and it is unclear whether a proportion of patients presenting with AKI-associated hyperkalemia were restricted from receiving balanced fluids. In addition, very few patients received Plasma-Lyte, confining the study’s conclusions to lactated Ringer’s alone.

Despite these pitfalls, the study addresses an extremely relevant clinical question. It urges clinicians to tailor fluid choices on a case-by-case basis and pay attention to the long-term implications of daily biochemical changes on renal outcomes, particularly in large volume resuscitation scenarios. There is a negligible cost difference between lactated Ringer’s and saline, making use of a balanced fluid economically feasible. The number needed to treat for MAKE30 based on this study is 94 patients, and changes in clinical practice extrapolated to ICUs nationwide could have an impact on renal outcomes from an epidemiologic point of view without risking financial burden at an institution level.

Applications for Clinical Practice

Overall, this trial clarifies an important gap in knowledge regarding fluid choice in the care of critically ill adults. The composite outcome of death, persistent renal dysfunction, and new RRT was significantly lower when a balanced fluid was used in comparison with saline. The ease of implementation, low financial impact, and epidemiologically significant renal outcomes supports a consideration for change in practice. However, clinicians should evaluate implementation on a case-by-case basis. More studies evaluating MAKE30 outcomes individually in specific diagnoses and clinical contexts are necessary. Moreover, data on long-term MAKE outcomes would help characterize long-term public health implications of 30-day effects.

—Divya Padmanabhan Menon, MD, Christopher L. Trautman, MD, and Neal M. Patel, MD, Mayo Clinic, Jacksonville, FL

Study Overview

Objective. To evaluate balanced crystalloids in comparison with normal saline in the intensive care unit (ICU) population.

Design. Pragmatic, un-blinded, cluster-randomized, multiple-crossover clinical trial (the SMART study).

Setting and participants. The study evaluated critically ill adults > 18 years of age, admitted and readmitted into 5 ICUs, both medical and surgical, from June 2015 to April 2017. 15,802 patients were enrolled, powered to detect a 1.9% percentage point difference in primary outcome. ICUs were randomized to use either balanced crystalloids (lactated Ringer’s [LR] or Plasma-Lyte A, depending on the provider’s preference) or normal saline during alternate calendar months. Relative contraindications to use of balanced crystalloids included traumatic brain injury and hyperkalemia. The admitting emergency rooms and operating rooms coordinated intravenous fluid (IVF) choice with their respective ICUs. An intention-to-treat analysis was conducted. In addition to primary and secondary outcome analyses, subgroup analyses based on factors including total IVF volume to day 30, vasopressor use, predicted in-hospital mortality, sepsis or traumatic brain injury diagnoses, ICU type, source of admission, and kidney function at baseline were also done. Furthermore, sensitivity analyses taking into account the total volume of crystalloid, crossover and excluding readmissions were performed.

Main outcome measures. The primary outcome was the proportion of patients that met at least 1 of the 3 criteria for a Major Adverse Kidney Event at day 30 (MAKE30) or discharge, whichever occurred earlier. MAKE30 is a composite measure consisting of death, persistent renal dysfunction (creatinine ≥ 200% baseline), or new renal replacement therapy (RRT). Patients previously on RRT were included for mortality analysis alone. In addition, secondary clinical outcomes including in-hospital mortality (prior to ICU discharge, at day 30 and day 60), ventilator-free days, vasopressor-free days, ICU-free days, days alive and RRT-free days in the first 28 days were assessed. Secondary renal outcomes such as persistent renal dysfunction, acute kidney injury (AKI) ≥ stage 2 (per Kidney Disease: Improving Global Outcomes Criteria {KDIGO}) criteria, new RRT, highest creatinine during hospitalization, creatinine at discharge and highest change in creatinine during hospitalization were also evaluated.

Results. 7942 patients were randomized to the balanced crystalloid group and 7860 to the saline group. Median age for both groups was 58 years and 57.6% patients were male. In terms of patient acuity, approximately 34% patients were on mechanical ventilation, 26% were on vasopressors, and around 14% carried a diagnosis of sepsis. At time of presentation, 17% had chronic kidney disease (CKD) ≥ stage 3 and approximately 5% were on RRT. Around 8% came in with AKI ≥ stage 2. Baseline creatinine in the both groups was 0.89 (interquartile range [IQR] 0.74–1.1). Median volumes of balanced crystalloid and saline administered was 1L (IQR 0–3.2L) and 1.02L (IQR 0–3.5L) respectively. Less than 5% in both groups received unassigned fluids. Predicted risk of in-hospital death for both groups was approximately 9%.

Significantly higher number of patients had plasma chloride ≥ 110 mmol/L and bicarbonate ≤ 20 mmol/L in the saline group (P < 0.001). In terms of primary outcome, MAKE30 rates in the balanced crystalloid vs saline groups were 14.3 vs 15.4 (marginal odds ratio {OR} 0.91, 95% confidence interval {CI} 0.84–0.99, P = 0.04) with similar results in the pre-specified sensitivity analyses. This difference was more prominent with larger volumes of infused fluids. All 3 components of composite primary outcome were improved in the crystalloid group, although none of the 3 individually achieved statistical significance.

Overall, mortality before discharge and within 30 days of admission in the balanced crystalloid group was 10.3% compared to 11.1% in the saline group (OR 0.9, CI 0.8–1.01, P = 0.06). In-hospital death before ICU discharge and at 60 days also mirrored this trend, although they did not achieve statistical significance either. Of note, in septic patients, 30-day mortality rates were 25.2 vs 29.4 in the balanced crystalloid and saline groups respectively (OR 0.8, 95% CI 0.67–0.97, P = 0.02).

With regard to renal outcomes in the balanced crystalloid vs normal saline groups, results were as follows: new RRT {2.5 vs 2.9%, P = 0.08}, new AKI development 10.7% vs 11.5% (OR 0.9, P = 0.09). In patients with a history of previous RRT or presenting with an AKI, crystalloids appeared to provide better MAKE30 outcomes, although not achieving statistical significance.

Conclusion. In the critically ill population, balanced crystalloids provide a beneficial effect over normal saline on the composite outcome of persistent renal dysfunction, new RRT and mortality at day 30.

Commentary

Unbalanced crystalloids, especially normal saline, are the most commonly used IVF for resuscitation in the critically ill. Given the data suggesting risk of kidney injury, acidosis, and effect on mortality with the use of normal saline, this study aimed to evaluate balanced crystalloids in comparison with normal saline in the ICU population.

Interest in the consequences of hyperchloremia and metabolic acidosis from supra-physiologic chloride concentrations in normal saline first stemmed from data in preclinical models, which demonstrated that chloride-induced renal inflammation adversely impacted renal function and mortality [1,2]. While in theory “balanced” solutions carry dual benefits of both an electrolyte composition that closely mirrors plasma and the presence of buffers which improve acid-base milieu, the exact repercussions on patient-centered outcomes with use of one over the other remain unknown.

An exploratory randomized control trial (RCT) evaluating biochemistry up to day 4 in normal saline vs Plasma-Lyte groups in 70 critically ill adults showed significantly higher hyperchloremia with normal saline but no difference in AKI rates between the two groups [3]. A pilot study evaluating “chloride-restrictive vs chloride liberal” strategies in 760 ICU patients involved use of Hartmann’s solution and Plasma-Lyte in place of saline for a 6-month period except in case of specific contraindications such as traumatic brain injury.  Results indicated that incidence of AKI and use of RRT significantly reduced by limiting chloride. No changes in mortality, ICU length of stay or RRT on discharge were noted [4].A large retrospective study in over 53,000 ICU patients admitted with sepsis and on vasopressors across 360 US hospitals showed that balanced fluids were associated with lower in-hospital mortality especially when higher volume of IVFs were infused. While no differences were seen in terms of AKI rates, lower risk of CKD was noted in balanced fluid groups [5].

In post-surgical populations, an observational study analyzing saline vs balanced fluids over 30,000 patients showed significantly lower mortality, renal failure, acidosis investigation/intervention rates with balanced fluids [6].Additionally, a meta-analysis assessing outcomes in peri-operative and ICU patients based on whether they received high or low chloride containing fluids was performed on over 6000 patients across 21 studies. No association with mortality was found. However, statistically significant correlations were noted between high chloride fluids and hyperchloremia, metabolic acidosis, AKI, mechanical ventilation times and blood transfusion volumes [7].

In 2015, a large RCT involving ICUs in New Zealand evaluated balanced crystalloids vs normal saline and rates of AKI in a double-blind, cluster-randomized, double-crossover trial (the SPLIT study). 2278 patients from medical and surgical ICUs were enrolled. Patients already receiving RRT were excluded. No significant difference in incidence of AKI (defined as a two-fold rise or a 0.5mg/dL increase in creatinine), new RRT or mortality was detected between the two groups [8].

Given the ambiguity and lack of consensus on outcomes, the current SMART study addresses an important gap in knowledge. Its large sample size makes it well powered, geared to detect small signals in outcomes. Inclusion of medical, surgical, and neurologic ICUs helps diversify applicability. Being a pragmatic, intention-to-treat RCT, the study design mirrors real-world clinical practice.

In terms of patient acuity, less than a third of the patients were intubated or on vasopressors. Predicted mortality rates were 9%. In addition, median volume infused was around 1 L. Given the investigators’ conclusions that the MAKE30 outcome signals were more pronounced with larger volumes of infusions, this brings into question whether more dramatic signals could have been appreciated in each of the 3 components of the primary outcome had the study population been a higher acuity group requiring larger infusion volumes.

While the composite MAKE30 outcome reflects a sense of an overarching benefit with balanced crystalloids, there was no statistically significant improvement noted in each primary component. This questions the rationale for combining the components of the MAKE30 outcome as well as how generalizable the results are. Overall, as is the case with many studies that evaluate a composite outcome, this raises concern about overestimation of the intervention’s true impact.

The study was un-blinded, raising concern for bias, and it was a single-center trial, which raises questions regarding generalizability. Un-blinding may have played a role in influencing decisions to initiate RRT earlier in the saline group. The extent to which this impacted RRT rates (one of the MAKE30 outcomes), remains unclear. Furthermore, approximately 5% of the participants received unassigned fluids, and while this is in line with the pragmatic/intention-to-treat design, the clinical repercussions remain unclear. Hyperkalemia is an exclusion criterion for balanced fluids and it is unclear whether a proportion of patients presenting with AKI-associated hyperkalemia were restricted from receiving balanced fluids. In addition, very few patients received Plasma-Lyte, confining the study’s conclusions to lactated Ringer’s alone.

Despite these pitfalls, the study addresses an extremely relevant clinical question. It urges clinicians to tailor fluid choices on a case-by-case basis and pay attention to the long-term implications of daily biochemical changes on renal outcomes, particularly in large volume resuscitation scenarios. There is a negligible cost difference between lactated Ringer’s and saline, making use of a balanced fluid economically feasible. The number needed to treat for MAKE30 based on this study is 94 patients, and changes in clinical practice extrapolated to ICUs nationwide could have an impact on renal outcomes from an epidemiologic point of view without risking financial burden at an institution level.

Applications for Clinical Practice

Overall, this trial clarifies an important gap in knowledge regarding fluid choice in the care of critically ill adults. The composite outcome of death, persistent renal dysfunction, and new RRT was significantly lower when a balanced fluid was used in comparison with saline. The ease of implementation, low financial impact, and epidemiologically significant renal outcomes supports a consideration for change in practice. However, clinicians should evaluate implementation on a case-by-case basis. More studies evaluating MAKE30 outcomes individually in specific diagnoses and clinical contexts are necessary. Moreover, data on long-term MAKE outcomes would help characterize long-term public health implications of 30-day effects.

—Divya Padmanabhan Menon, MD, Christopher L. Trautman, MD, and Neal M. Patel, MD, Mayo Clinic, Jacksonville, FL

Study Overview

Objective. To determine the prognostic impact of multivessel percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) multivessel disease presenting with cardiogenic shock.

Design. Retrospective study using the nationwide, multicenter, prospective KAMIR-NIH (Korea Acute Myocardial Infarction-National Institutes of Health) registry.

Setting and participants. Among the 13,104 patients enrolled in the KAMIR-NIH registry, 659 patients with STEMI with multivessel disease presenting with cardiogenic shock who underwent primary PCI were selected.

Main outcome measures. The primary outcome was all-cause death at 1 year. Secondary outcomes included patient-oriented composite outcome (composite of all-cause death, any myocardial infarction, and any repeat revascularization) and its individual components.

Main results. A total of 260 patients were treated with multivessel PCI and 399 patients were treated with infarct-related artery (IRA) PCI only. The risk of all-cause death was significantly lower in the multivessel PCI group (21.3% vs 31.7%; hazard ratio [HR] 0.59, 95% CI 0.43–0.82, P = 0.001). Non-IRA repeat revascularization was significantly lower in the multivessel group (6.7% vs 8.2%; HR 0.39, 95% CI 0.17–0.90, P = 0.028). In multivariate model, multivessel PCI was independently associated with reduced risk of 1-year all-cause death and patient-oriented composite outcome.

Conclusion. Among patients with STEMI and multivessel disease with cardiogenic shock, multivessel PCI was associated with significantly lower risk of all-cause death and non-IRA repeat revascularization.

Commentary

Historically, non-culprit vessel revascularization in the setting of acute myocardial infarction (AMI) was not routinely performed. However, recent trials have shown the benefit of non-culprit vessel revascularization in patients with hemodynamically stable AMI [1–3]. The result of these trials have led to upgrade in U.S. guideline recommendations for non-infarct-related artery PCI in hemodynamically stable patients presenting with AMI to Class IIb from Class III [4]. Whether these findings can be extended to hemodynamically unstable (cardiogenic shock) patients is controversial. Recently, results of a well-designed randomized control trial (CULPRIT-SHOCK) suggested worse outcome with immediate multivessel PCI in this population [5]. The composite endpoint of death and renal replacement therapy at 30 days was higher in the multivessel PCI at the time of primary PCI group compared to initial culprit lesion only group (55.9% vs 45.9%, P = 0.01). The composite endpoint was mainly driven by death (51.6% vs 43.3%, P = 0.03), and the rate of renal replacement therapy was numerically higher in the mutivessel PCI group (16.4% vs 11.6%, P = 0.07).

Lee et al investigated a similar clinical question using the nationwide, multicenter, prospective KAMIR-NIH registry data [6]. In this study, the primary endpoint of all cause death occurred in 53 of the 260 patients (21.3%) in the multivessel PCI group and 126 of the 399 patients (31.7%) in the IRA-only PCI group (relative risk [RR] 0.59, 95% CI 0.43–0.82, P = 0.001). Similarly, the multivessel PCI group had lower non-IRA repeat revascularization (RR 0.39, 95% CI 0.17-0.90, P = 0.028) and lower patient-oriented composite outcome (all-cause death, any myocardial infarction, or any repeat revascularization) (RR 0.58, 95% CI 0.44–0.77, P < 0.001). These results remained similar after multivariate adjustment, propensity matching, and inverse probability weighted analysis.

The discrepancy of the results of the KAMIR study compared to CULPRIT-SHOCK is likely related to the difference in the design of the two studies. First, CUPRIT-SHOCK compared multivessel revascularization during index primary PCI to culprit-only revascularization strategy with staged revascularization if necessary. There were 9.4% randomized to multivessel PCI who crossed over to IRA-only PCI and 17.4% randomized to IRA-only PCI who crossed over to multivessel PCI during the index hospitalization. In contrast, the KAMIR registry compared patients who underwent IRA-only PCI to multivessel PCI, which included those who had immediate revascularization during the primary PCI and those who had staged revascularization during the index hospitalization. Therefore, multivessel PCI is defined very differently in both studies and cannot be considered equivalent.

Second, CULPRIT-SHOCK was a prospective randomized control study and KAMIR was an observational study analyzing data from a prospectively collected large database. Although multiple statistical adjustments were performed, this observational nature of the study is subject to selection bias and other unmeasured biases such as frailty assessment.

Third, the timing of the revascularization was different between two studies. In CULPRIT-SHOCK, immediate revascularization of non-IRA was achieved in 90.6% of patients in the multivessel PCI group. On the other hand, only 60.4% of patients of multivessel PCI group in KAMIR study underwent immediate revascularization of the non-IRA and 39.6 % of patients underwent staged procedure. This leads to significant survival bias, since these 39.6% of patients survived the initial event to be able to undergo the staged procedure. Patients who had planned staged intervention but could not survive were included in the IRA-only PCI group.

Fourth, there may be difference in the severity of the patient population included in the analysis. In the CULPRIT-SHOCK trial, a significant non-IRA was defined as > 70% stenosis, and all chronic total occlusions (CTO) were attempted in the multivessel PCI group according to trial protocol. In CULPRIT-SHOCK, 23% of patient had one or more CTO lesions. In the KAMIR registry, a significant non-IRA was defined as > 50% stenosis of the non-culprit vessel and CTO vessels were not accounted for. Although CTO intervention improves angina and ejection fraction [7,8], whether CTO intervention has mortality benefit needs further investigation. In a recent EXPLORE trial, the feasibility and safety of intervention of chronic total occlusion in non-infarct-related artery in STEMI population was established [8]. However, only hemodynamically stable patients were included in the study and all CTO interventions were performed in staged fashion (5 ± 2 days after index procedure) [8]. There is a possibility of attempting CTO PCI in this acute setting caused more harm than benefit.

Finally, in order to be enrolled in the CULPRIT-SHOCK trial, patients needed to meet stringent criteria for cardiogenic shock. In KAMIR study, this data was retrospectively determined and individual components used to define cardiogenic shock were not available. This difference may have led to inclusion of more stable patients as evidenced by lower mortality rate in KAMIR study compared to CULPRIT-SHOCK (51.6% mortality for multivessel PCI in CULPRIT-SHOCK and 21.3% mortality for multivessel PCI patients in KAMIR study). CULPRIT-SHOCK trial had a high rate of mechanical ventilation (~80%), requirement of catecholamine support (~90%), and long ICU stays (median 5 days). This information is not reported in the KAMIR study.

Considering above differences in the study design, the evidence level for CULPRIT-SHOCK appears to be stronger compared to the KAMIR study, which should be considered as hypothesis-generating as all other observational studies. However, the KAMIR study is still an important study suggesting possible benefit of multivessel PCI in patients presenting with ST elevation myocardial infarction and cardiogenic shock. This leads us to an answered question whether staged multivessel intervention or less aggressive multivessel intervention (not attempting CTO) is a better option in this population.

Applications for Clinical Practice

In patients presenting with cardiogenic shock and acute myocardial infarction, culprit lesion-only intervention and staged intervention if necessary, seems to be a better strategy. However, there may be benefit in multivessel intervention in this population, depending on the timing and revascularization strategy. Further studies are needed.

—Taishi Hirai, MD, and John E.A. Blair, MD, University of Chicago Medical Center, Chicago, IL

Study Overview

Objective. To determine the prognostic impact of multivessel percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) multivessel disease presenting with cardiogenic shock.

Design. Retrospective study using the nationwide, multicenter, prospective KAMIR-NIH (Korea Acute Myocardial Infarction-National Institutes of Health) registry.

Setting and participants. Among the 13,104 patients enrolled in the KAMIR-NIH registry, 659 patients with STEMI with multivessel disease presenting with cardiogenic shock who underwent primary PCI were selected.

Main outcome measures. The primary outcome was all-cause death at 1 year. Secondary outcomes included patient-oriented composite outcome (composite of all-cause death, any myocardial infarction, and any repeat revascularization) and its individual components.

Main results. A total of 260 patients were treated with multivessel PCI and 399 patients were treated with infarct-related artery (IRA) PCI only. The risk of all-cause death was significantly lower in the multivessel PCI group (21.3% vs 31.7%; hazard ratio [HR] 0.59, 95% CI 0.43–0.82, P = 0.001). Non-IRA repeat revascularization was significantly lower in the multivessel group (6.7% vs 8.2%; HR 0.39, 95% CI 0.17–0.90, P = 0.028). In multivariate model, multivessel PCI was independently associated with reduced risk of 1-year all-cause death and patient-oriented composite outcome.

Conclusion. Among patients with STEMI and multivessel disease with cardiogenic shock, multivessel PCI was associated with significantly lower risk of all-cause death and non-IRA repeat revascularization.

Commentary

Historically, non-culprit vessel revascularization in the setting of acute myocardial infarction (AMI) was not routinely performed. However, recent trials have shown the benefit of non-culprit vessel revascularization in patients with hemodynamically stable AMI [1–3]. The result of these trials have led to upgrade in U.S. guideline recommendations for non-infarct-related artery PCI in hemodynamically stable patients presenting with AMI to Class IIb from Class III [4]. Whether these findings can be extended to hemodynamically unstable (cardiogenic shock) patients is controversial. Recently, results of a well-designed randomized control trial (CULPRIT-SHOCK) suggested worse outcome with immediate multivessel PCI in this population [5]. The composite endpoint of death and renal replacement therapy at 30 days was higher in the multivessel PCI at the time of primary PCI group compared to initial culprit lesion only group (55.9% vs 45.9%, P = 0.01). The composite endpoint was mainly driven by death (51.6% vs 43.3%, P = 0.03), and the rate of renal replacement therapy was numerically higher in the mutivessel PCI group (16.4% vs 11.6%, P = 0.07).

Lee et al investigated a similar clinical question using the nationwide, multicenter, prospective KAMIR-NIH registry data [6]. In this study, the primary endpoint of all cause death occurred in 53 of the 260 patients (21.3%) in the multivessel PCI group and 126 of the 399 patients (31.7%) in the IRA-only PCI group (relative risk [RR] 0.59, 95% CI 0.43–0.82, P = 0.001). Similarly, the multivessel PCI group had lower non-IRA repeat revascularization (RR 0.39, 95% CI 0.17-0.90, P = 0.028) and lower patient-oriented composite outcome (all-cause death, any myocardial infarction, or any repeat revascularization) (RR 0.58, 95% CI 0.44–0.77, P < 0.001). These results remained similar after multivariate adjustment, propensity matching, and inverse probability weighted analysis.

The discrepancy of the results of the KAMIR study compared to CULPRIT-SHOCK is likely related to the difference in the design of the two studies. First, CUPRIT-SHOCK compared multivessel revascularization during index primary PCI to culprit-only revascularization strategy with staged revascularization if necessary. There were 9.4% randomized to multivessel PCI who crossed over to IRA-only PCI and 17.4% randomized to IRA-only PCI who crossed over to multivessel PCI during the index hospitalization. In contrast, the KAMIR registry compared patients who underwent IRA-only PCI to multivessel PCI, which included those who had immediate revascularization during the primary PCI and those who had staged revascularization during the index hospitalization. Therefore, multivessel PCI is defined very differently in both studies and cannot be considered equivalent.

Second, CULPRIT-SHOCK was a prospective randomized control study and KAMIR was an observational study analyzing data from a prospectively collected large database. Although multiple statistical adjustments were performed, this observational nature of the study is subject to selection bias and other unmeasured biases such as frailty assessment.

Third, the timing of the revascularization was different between two studies. In CULPRIT-SHOCK, immediate revascularization of non-IRA was achieved in 90.6% of patients in the multivessel PCI group. On the other hand, only 60.4% of patients of multivessel PCI group in KAMIR study underwent immediate revascularization of the non-IRA and 39.6 % of patients underwent staged procedure. This leads to significant survival bias, since these 39.6% of patients survived the initial event to be able to undergo the staged procedure. Patients who had planned staged intervention but could not survive were included in the IRA-only PCI group.

Fourth, there may be difference in the severity of the patient population included in the analysis. In the CULPRIT-SHOCK trial, a significant non-IRA was defined as > 70% stenosis, and all chronic total occlusions (CTO) were attempted in the multivessel PCI group according to trial protocol. In CULPRIT-SHOCK, 23% of patient had one or more CTO lesions. In the KAMIR registry, a significant non-IRA was defined as > 50% stenosis of the non-culprit vessel and CTO vessels were not accounted for. Although CTO intervention improves angina and ejection fraction [7,8], whether CTO intervention has mortality benefit needs further investigation. In a recent EXPLORE trial, the feasibility and safety of intervention of chronic total occlusion in non-infarct-related artery in STEMI population was established [8]. However, only hemodynamically stable patients were included in the study and all CTO interventions were performed in staged fashion (5 ± 2 days after index procedure) [8]. There is a possibility of attempting CTO PCI in this acute setting caused more harm than benefit.

Finally, in order to be enrolled in the CULPRIT-SHOCK trial, patients needed to meet stringent criteria for cardiogenic shock. In KAMIR study, this data was retrospectively determined and individual components used to define cardiogenic shock were not available. This difference may have led to inclusion of more stable patients as evidenced by lower mortality rate in KAMIR study compared to CULPRIT-SHOCK (51.6% mortality for multivessel PCI in CULPRIT-SHOCK and 21.3% mortality for multivessel PCI patients in KAMIR study). CULPRIT-SHOCK trial had a high rate of mechanical ventilation (~80%), requirement of catecholamine support (~90%), and long ICU stays (median 5 days). This information is not reported in the KAMIR study.

Considering above differences in the study design, the evidence level for CULPRIT-SHOCK appears to be stronger compared to the KAMIR study, which should be considered as hypothesis-generating as all other observational studies. However, the KAMIR study is still an important study suggesting possible benefit of multivessel PCI in patients presenting with ST elevation myocardial infarction and cardiogenic shock. This leads us to an answered question whether staged multivessel intervention or less aggressive multivessel intervention (not attempting CTO) is a better option in this population.

Applications for Clinical Practice

In patients presenting with cardiogenic shock and acute myocardial infarction, culprit lesion-only intervention and staged intervention if necessary, seems to be a better strategy. However, there may be benefit in multivessel intervention in this population, depending on the timing and revascularization strategy. Further studies are needed.

—Taishi Hirai, MD, and John E.A. Blair, MD, University of Chicago Medical Center, Chicago, IL

Study Overview

Objective. To determine the prognostic impact of multivessel percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) multivessel disease presenting with cardiogenic shock.

Design. Retrospective study using the nationwide, multicenter, prospective KAMIR-NIH (Korea Acute Myocardial Infarction-National Institutes of Health) registry.

Setting and participants. Among the 13,104 patients enrolled in the KAMIR-NIH registry, 659 patients with STEMI with multivessel disease presenting with cardiogenic shock who underwent primary PCI were selected.

Main outcome measures. The primary outcome was all-cause death at 1 year. Secondary outcomes included patient-oriented composite outcome (composite of all-cause death, any myocardial infarction, and any repeat revascularization) and its individual components.

Main results. A total of 260 patients were treated with multivessel PCI and 399 patients were treated with infarct-related artery (IRA) PCI only. The risk of all-cause death was significantly lower in the multivessel PCI group (21.3% vs 31.7%; hazard ratio [HR] 0.59, 95% CI 0.43–0.82, P = 0.001). Non-IRA repeat revascularization was significantly lower in the multivessel group (6.7% vs 8.2%; HR 0.39, 95% CI 0.17–0.90, P = 0.028). In multivariate model, multivessel PCI was independently associated with reduced risk of 1-year all-cause death and patient-oriented composite outcome.

Conclusion. Among patients with STEMI and multivessel disease with cardiogenic shock, multivessel PCI was associated with significantly lower risk of all-cause death and non-IRA repeat revascularization.

Commentary

Historically, non-culprit vessel revascularization in the setting of acute myocardial infarction (AMI) was not routinely performed. However, recent trials have shown the benefit of non-culprit vessel revascularization in patients with hemodynamically stable AMI [1–3]. The result of these trials have led to upgrade in U.S. guideline recommendations for non-infarct-related artery PCI in hemodynamically stable patients presenting with AMI to Class IIb from Class III [4]. Whether these findings can be extended to hemodynamically unstable (cardiogenic shock) patients is controversial. Recently, results of a well-designed randomized control trial (CULPRIT-SHOCK) suggested worse outcome with immediate multivessel PCI in this population [5]. The composite endpoint of death and renal replacement therapy at 30 days was higher in the multivessel PCI at the time of primary PCI group compared to initial culprit lesion only group (55.9% vs 45.9%, P = 0.01). The composite endpoint was mainly driven by death (51.6% vs 43.3%, P = 0.03), and the rate of renal replacement therapy was numerically higher in the mutivessel PCI group (16.4% vs 11.6%, P = 0.07).

Lee et al investigated a similar clinical question using the nationwide, multicenter, prospective KAMIR-NIH registry data [6]. In this study, the primary endpoint of all cause death occurred in 53 of the 260 patients (21.3%) in the multivessel PCI group and 126 of the 399 patients (31.7%) in the IRA-only PCI group (relative risk [RR] 0.59, 95% CI 0.43–0.82, P = 0.001). Similarly, the multivessel PCI group had lower non-IRA repeat revascularization (RR 0.39, 95% CI 0.17-0.90, P = 0.028) and lower patient-oriented composite outcome (all-cause death, any myocardial infarction, or any repeat revascularization) (RR 0.58, 95% CI 0.44–0.77, P < 0.001). These results remained similar after multivariate adjustment, propensity matching, and inverse probability weighted analysis.

The discrepancy of the results of the KAMIR study compared to CULPRIT-SHOCK is likely related to the difference in the design of the two studies. First, CUPRIT-SHOCK compared multivessel revascularization during index primary PCI to culprit-only revascularization strategy with staged revascularization if necessary. There were 9.4% randomized to multivessel PCI who crossed over to IRA-only PCI and 17.4% randomized to IRA-only PCI who crossed over to multivessel PCI during the index hospitalization. In contrast, the KAMIR registry compared patients who underwent IRA-only PCI to multivessel PCI, which included those who had immediate revascularization during the primary PCI and those who had staged revascularization during the index hospitalization. Therefore, multivessel PCI is defined very differently in both studies and cannot be considered equivalent.

Second, CULPRIT-SHOCK was a prospective randomized control study and KAMIR was an observational study analyzing data from a prospectively collected large database. Although multiple statistical adjustments were performed, this observational nature of the study is subject to selection bias and other unmeasured biases such as frailty assessment.

Third, the timing of the revascularization was different between two studies. In CULPRIT-SHOCK, immediate revascularization of non-IRA was achieved in 90.6% of patients in the multivessel PCI group. On the other hand, only 60.4% of patients of multivessel PCI group in KAMIR study underwent immediate revascularization of the non-IRA and 39.6 % of patients underwent staged procedure. This leads to significant survival bias, since these 39.6% of patients survived the initial event to be able to undergo the staged procedure. Patients who had planned staged intervention but could not survive were included in the IRA-only PCI group.

Fourth, there may be difference in the severity of the patient population included in the analysis. In the CULPRIT-SHOCK trial, a significant non-IRA was defined as > 70% stenosis, and all chronic total occlusions (CTO) were attempted in the multivessel PCI group according to trial protocol. In CULPRIT-SHOCK, 23% of patient had one or more CTO lesions. In the KAMIR registry, a significant non-IRA was defined as > 50% stenosis of the non-culprit vessel and CTO vessels were not accounted for. Although CTO intervention improves angina and ejection fraction [7,8], whether CTO intervention has mortality benefit needs further investigation. In a recent EXPLORE trial, the feasibility and safety of intervention of chronic total occlusion in non-infarct-related artery in STEMI population was established [8]. However, only hemodynamically stable patients were included in the study and all CTO interventions were performed in staged fashion (5 ± 2 days after index procedure) [8]. There is a possibility of attempting CTO PCI in this acute setting caused more harm than benefit.

Finally, in order to be enrolled in the CULPRIT-SHOCK trial, patients needed to meet stringent criteria for cardiogenic shock. In KAMIR study, this data was retrospectively determined and individual components used to define cardiogenic shock were not available. This difference may have led to inclusion of more stable patients as evidenced by lower mortality rate in KAMIR study compared to CULPRIT-SHOCK (51.6% mortality for multivessel PCI in CULPRIT-SHOCK and 21.3% mortality for multivessel PCI patients in KAMIR study). CULPRIT-SHOCK trial had a high rate of mechanical ventilation (~80%), requirement of catecholamine support (~90%), and long ICU stays (median 5 days). This information is not reported in the KAMIR study.

Considering above differences in the study design, the evidence level for CULPRIT-SHOCK appears to be stronger compared to the KAMIR study, which should be considered as hypothesis-generating as all other observational studies. However, the KAMIR study is still an important study suggesting possible benefit of multivessel PCI in patients presenting with ST elevation myocardial infarction and cardiogenic shock. This leads us to an answered question whether staged multivessel intervention or less aggressive multivessel intervention (not attempting CTO) is a better option in this population.

Applications for Clinical Practice

In patients presenting with cardiogenic shock and acute myocardial infarction, culprit lesion-only intervention and staged intervention if necessary, seems to be a better strategy. However, there may be benefit in multivessel intervention in this population, depending on the timing and revascularization strategy. Further studies are needed.

—Taishi Hirai, MD, and John E.A. Blair, MD, University of Chicago Medical Center, Chicago, IL

Study Overview

Objective. To assess whether a combination of venetoclax with rituximab, compared to standard chemoimmunotherapy (bendamustine with rituximab), improves outcomes in patients with relapsed or refractory chronic lymphocytic leukemia.

Design. International, randomized, open-label, phase 3 clinical trial (MURANO).

Setting and participants. Patients were eligilble for the study if they were 18 years of age or older with a diagnosis of relapsed or refractory chronic lymphocytic leukemia that required therapy, and had received 1 to 3 previous treatments (including at least 1 chemotherapy-containing regimen), had an Eastern Cooperative Oncology Group performance status score of 0 or 1, and had adequate bone marrow, renal, and hepatic function. Patients were randomly assigned either to receive venetoclax plus rituximab or bendamustine plus rituximab. Randomization was stratified by geographic region, responsiveness to previous therapy, as well as the presence or absence of chromosome 17p deletion.

Main outcome measures. Primary outcome was investigator-assessed progression-free survival, which was defined as the time from randomization to the first occurrence of disease progression or relapse or death from any cause, whichever occurs first. Secondary efficacy endpoints included independent review committee-assessed progression-free survival (stratified by chromosome 17p deletion), independent review committee-assessed overall response rate and complete response rate, overall survival, rates of clearance of minimal residual disease, the duration of response, event-free survival, and the time to the next treatment for chronic lymphocytic leukemia.

Main results. From 31 March 2014 to 23 September 2015, a total of 389 patients were enrolled at 109 sites in 20 countries and were randomly assigned to receive venetoclax plus rituximab (n = 194), or bendamustine plus rituximab (n = 195). Median age was 65 years (range, 22–85) and a majority of the patients (73.8%) were men. Overall, the demographic and disease characteristics of the 2 groups were similar at baseline.

The median follow-up period was 23.8 months (range, 0–37.4). The median investigator-assessed progression-free survival was significantly longer in the venetoclax-rituximab group (median progression-free survival not reached, 32 events of progression or death in 194 patients) and was 17 months in the bendamustine-rituximab group (114 events in 195 patients). The 2-year rate of investigator-assessed progression-free survival was 84.9% (95% confidence interval [CI] 79.1–90.5) in the venetoclax-rituximab group and 36.3% (95% CI 28.5–44.0) in the bendamustine-rituximab group (hazard ratio for progression or death, 0.17; 95% CI 0.11 to 0.25; P < 0.001). Benefit was consistent in favor of the venetoclax-rituximab group in all prespecified subgroup analyses, with or without chromosome 17p deletion.

The rate of overall survival was higher in the venetoclax-rituximab group than in the bendamustine-rituximab group, with 24-month rates of 91.9% and 86.6%, respectively (hazard ratio 0.58, 95% CI 0.25–0.90). Assessments of minimal residual disease were available for 366 of the 389 patients (94.1%). On the basis of peripheral-blood samples, the venetoclax-rituximab group had a higher minimal residual disease compared to the bendamustine-rituximab group (121 of 194 patients [62.4%] vs. 26 of 195 patients [13.3%]). In bone marrow aspirate, higher rates of clearance of minimal residual disease was seen in the venetoclax-rituximab group (53 of 194 patients [27.3%]) as compared to the bendamustine-rituximab group (3 of 195 patients [1.5%]).

In terms of safety, the most common adverse event reported was neutropenia (60.8% of the patients in the venetoclax-rituximab group vs. 44.1% of the patients in the bendamustine-rituximab group). This contributed to the overall higher grade 3 or 4 adverse event rate in the venetoclax-rituximab group (159 of the 194 patients, or 82.0%) as compared to the bendamustine-rituximab group (132 of 188 patients, or 70.2%). The incidence of serious adverse events, as well as adverse events that resulted in death were similar in the 2 groups.

Conclusion. For patients with relapsed or refractory chronic lymphocytic leukemia, venetoclax plus rituximab resulted in significantly higher rates of progression-free survival than standard therapy with bendamustine plus rituximab.

Commentary

Despite advances in treatment, chronic lymphocytic leukemia remains incurable with conventional chemoimmunotherapy regimens, and almost all patient relapse after initial therapy. Following relapse of the disease, the goal is to provide durable progression-free survival, which may extend overall survival [1]. In a subset of chronic lymphocytic leukemia patients with deletion or mutation of TP53 loci on chromosome 17p13, their disease responds especially poorly to conventional treatment and they have a median survival of less than 3 years from the time of initiating first treatment.

Apoptosis defines a process of programmed cell death with an extrinsic and intrinsic cellular apoptotic pathway. B-cell lymphoma/leukemia 2 (BCL-2) protein is a key regulator of the intrinsic apoptotic pathway and almost all chronic lymphocytic leukemia cells elude apoptosis through overexpression of BCL-2. Venetoclax is an orally administered, highly selective, potent BCL-2 inhibitor approved by the FDA in 2016 for the treatment of chronic lymphocytic leukemia patients with 17p deletion who have received at least 1 prior therapy [3]. There has been great interest in combining venetoclax with other active agents in chronic lymphocytic leukemia such as chemotherapy, monoclonal antibodies, and B-cell receptor inhibitors. The combination of venetoclax with the CD20 antibody rituximab was found to be able to overcome micro-environment-induced resistance to venetoclax [4].

In this analysis of the phase 3 MURANO trial of venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukemia by Seymour et al, the authors demonstrated a significantly higher rate of progression-free survival with venetoclax plus rituximab than with standard chemoimmunotherapy bendamustine plus rituximab. In addition, secondary efficacy measures, including the complete response rate, the overall response rate, and overall survival were also higher in the venetoclax plus rituximab than with bendamustine plus rituximab.

There are several limitations of this study. First, this study was terminated early at the time of the data review on 6 September 2017. The independent data monitoring committee recommended that the primary analysis be conducted at that time because the prespecified statistical boundaries for early stopping were crossed for progression-free survival on the basis of stratified log-rank tests. In a letter to the editor, Alexander et al questioned the validity of results when design stages are violated. In immunotherapy trials, progression-free survival curves often separated at later time, rather than as a constant process; this violates the key assumption of proportionality of hazard functions. When the study was terminated early, post hoc confirmatory analyses and evaluations of robustness of the statistical plan could be used; however, prespecified analyses are critical to reproducibility in trials that are meant to be practice-changing [5]. Second, complete response rates were lower when responses was assessed by the independent review committee than when assessed by the investigator. While this represented a certain degree of author bias, the overall results were similar and the effect of venetoclax plus rituximab remain significantly better than bendamustine plus rituximab.

Applications for Clinical Practice

The current study demonstrated that venetoclax is safe and effective when combining with rituximab in the treating of chronic lymphocytic leukemia patients with or without 17p deletion who have received at least one prior therapy. The most common serious adverse event was neutropenia, correlated with tumor lysis syndrome. Careful monitoring, slow dose ramp-up, and adequate prophylaxis can mitigate some of the adverse effects.

—Ka Ming Gordon Ngai, MD, MPH

Study Overview

Objective. To assess whether a combination of venetoclax with rituximab, compared to standard chemoimmunotherapy (bendamustine with rituximab), improves outcomes in patients with relapsed or refractory chronic lymphocytic leukemia.

Design. International, randomized, open-label, phase 3 clinical trial (MURANO).

Setting and participants. Patients were eligilble for the study if they were 18 years of age or older with a diagnosis of relapsed or refractory chronic lymphocytic leukemia that required therapy, and had received 1 to 3 previous treatments (including at least 1 chemotherapy-containing regimen), had an Eastern Cooperative Oncology Group performance status score of 0 or 1, and had adequate bone marrow, renal, and hepatic function. Patients were randomly assigned either to receive venetoclax plus rituximab or bendamustine plus rituximab. Randomization was stratified by geographic region, responsiveness to previous therapy, as well as the presence or absence of chromosome 17p deletion.

Main outcome measures. Primary outcome was investigator-assessed progression-free survival, which was defined as the time from randomization to the first occurrence of disease progression or relapse or death from any cause, whichever occurs first. Secondary efficacy endpoints included independent review committee-assessed progression-free survival (stratified by chromosome 17p deletion), independent review committee-assessed overall response rate and complete response rate, overall survival, rates of clearance of minimal residual disease, the duration of response, event-free survival, and the time to the next treatment for chronic lymphocytic leukemia.

Main results. From 31 March 2014 to 23 September 2015, a total of 389 patients were enrolled at 109 sites in 20 countries and were randomly assigned to receive venetoclax plus rituximab (n = 194), or bendamustine plus rituximab (n = 195). Median age was 65 years (range, 22–85) and a majority of the patients (73.8%) were men. Overall, the demographic and disease characteristics of the 2 groups were similar at baseline.

The median follow-up period was 23.8 months (range, 0–37.4). The median investigator-assessed progression-free survival was significantly longer in the venetoclax-rituximab group (median progression-free survival not reached, 32 events of progression or death in 194 patients) and was 17 months in the bendamustine-rituximab group (114 events in 195 patients). The 2-year rate of investigator-assessed progression-free survival was 84.9% (95% confidence interval [CI] 79.1–90.5) in the venetoclax-rituximab group and 36.3% (95% CI 28.5–44.0) in the bendamustine-rituximab group (hazard ratio for progression or death, 0.17; 95% CI 0.11 to 0.25; P < 0.001). Benefit was consistent in favor of the venetoclax-rituximab group in all prespecified subgroup analyses, with or without chromosome 17p deletion.

The rate of overall survival was higher in the venetoclax-rituximab group than in the bendamustine-rituximab group, with 24-month rates of 91.9% and 86.6%, respectively (hazard ratio 0.58, 95% CI 0.25–0.90). Assessments of minimal residual disease were available for 366 of the 389 patients (94.1%). On the basis of peripheral-blood samples, the venetoclax-rituximab group had a higher minimal residual disease compared to the bendamustine-rituximab group (121 of 194 patients [62.4%] vs. 26 of 195 patients [13.3%]). In bone marrow aspirate, higher rates of clearance of minimal residual disease was seen in the venetoclax-rituximab group (53 of 194 patients [27.3%]) as compared to the bendamustine-rituximab group (3 of 195 patients [1.5%]).

In terms of safety, the most common adverse event reported was neutropenia (60.8% of the patients in the venetoclax-rituximab group vs. 44.1% of the patients in the bendamustine-rituximab group). This contributed to the overall higher grade 3 or 4 adverse event rate in the venetoclax-rituximab group (159 of the 194 patients, or 82.0%) as compared to the bendamustine-rituximab group (132 of 188 patients, or 70.2%). The incidence of serious adverse events, as well as adverse events that resulted in death were similar in the 2 groups.

Conclusion. For patients with relapsed or refractory chronic lymphocytic leukemia, venetoclax plus rituximab resulted in significantly higher rates of progression-free survival than standard therapy with bendamustine plus rituximab.

Commentary

Despite advances in treatment, chronic lymphocytic leukemia remains incurable with conventional chemoimmunotherapy regimens, and almost all patient relapse after initial therapy. Following relapse of the disease, the goal is to provide durable progression-free survival, which may extend overall survival [1]. In a subset of chronic lymphocytic leukemia patients with deletion or mutation of TP53 loci on chromosome 17p13, their disease responds especially poorly to conventional treatment and they have a median survival of less than 3 years from the time of initiating first treatment.

Apoptosis defines a process of programmed cell death with an extrinsic and intrinsic cellular apoptotic pathway. B-cell lymphoma/leukemia 2 (BCL-2) protein is a key regulator of the intrinsic apoptotic pathway and almost all chronic lymphocytic leukemia cells elude apoptosis through overexpression of BCL-2. Venetoclax is an orally administered, highly selective, potent BCL-2 inhibitor approved by the FDA in 2016 for the treatment of chronic lymphocytic leukemia patients with 17p deletion who have received at least 1 prior therapy [3]. There has been great interest in combining venetoclax with other active agents in chronic lymphocytic leukemia such as chemotherapy, monoclonal antibodies, and B-cell receptor inhibitors. The combination of venetoclax with the CD20 antibody rituximab was found to be able to overcome micro-environment-induced resistance to venetoclax [4].

In this analysis of the phase 3 MURANO trial of venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukemia by Seymour et al, the authors demonstrated a significantly higher rate of progression-free survival with venetoclax plus rituximab than with standard chemoimmunotherapy bendamustine plus rituximab. In addition, secondary efficacy measures, including the complete response rate, the overall response rate, and overall survival were also higher in the venetoclax plus rituximab than with bendamustine plus rituximab.

There are several limitations of this study. First, this study was terminated early at the time of the data review on 6 September 2017. The independent data monitoring committee recommended that the primary analysis be conducted at that time because the prespecified statistical boundaries for early stopping were crossed for progression-free survival on the basis of stratified log-rank tests. In a letter to the editor, Alexander et al questioned the validity of results when design stages are violated. In immunotherapy trials, progression-free survival curves often separated at later time, rather than as a constant process; this violates the key assumption of proportionality of hazard functions. When the study was terminated early, post hoc confirmatory analyses and evaluations of robustness of the statistical plan could be used; however, prespecified analyses are critical to reproducibility in trials that are meant to be practice-changing [5]. Second, complete response rates were lower when responses was assessed by the independent review committee than when assessed by the investigator. While this represented a certain degree of author bias, the overall results were similar and the effect of venetoclax plus rituximab remain significantly better than bendamustine plus rituximab.

Applications for Clinical Practice

The current study demonstrated that venetoclax is safe and effective when combining with rituximab in the treating of chronic lymphocytic leukemia patients with or without 17p deletion who have received at least one prior therapy. The most common serious adverse event was neutropenia, correlated with tumor lysis syndrome. Careful monitoring, slow dose ramp-up, and adequate prophylaxis can mitigate some of the adverse effects.

—Ka Ming Gordon Ngai, MD, MPH

Study Overview

Objective. To assess whether a combination of venetoclax with rituximab, compared to standard chemoimmunotherapy (bendamustine with rituximab), improves outcomes in patients with relapsed or refractory chronic lymphocytic leukemia.

Design. International, randomized, open-label, phase 3 clinical trial (MURANO).

Setting and participants. Patients were eligilble for the study if they were 18 years of age or older with a diagnosis of relapsed or refractory chronic lymphocytic leukemia that required therapy, and had received 1 to 3 previous treatments (including at least 1 chemotherapy-containing regimen), had an Eastern Cooperative Oncology Group performance status score of 0 or 1, and had adequate bone marrow, renal, and hepatic function. Patients were randomly assigned either to receive venetoclax plus rituximab or bendamustine plus rituximab. Randomization was stratified by geographic region, responsiveness to previous therapy, as well as the presence or absence of chromosome 17p deletion.

Main outcome measures. Primary outcome was investigator-assessed progression-free survival, which was defined as the time from randomization to the first occurrence of disease progression or relapse or death from any cause, whichever occurs first. Secondary efficacy endpoints included independent review committee-assessed progression-free survival (stratified by chromosome 17p deletion), independent review committee-assessed overall response rate and complete response rate, overall survival, rates of clearance of minimal residual disease, the duration of response, event-free survival, and the time to the next treatment for chronic lymphocytic leukemia.

Main results. From 31 March 2014 to 23 September 2015, a total of 389 patients were enrolled at 109 sites in 20 countries and were randomly assigned to receive venetoclax plus rituximab (n = 194), or bendamustine plus rituximab (n = 195). Median age was 65 years (range, 22–85) and a majority of the patients (73.8%) were men. Overall, the demographic and disease characteristics of the 2 groups were similar at baseline.

The median follow-up period was 23.8 months (range, 0–37.4). The median investigator-assessed progression-free survival was significantly longer in the venetoclax-rituximab group (median progression-free survival not reached, 32 events of progression or death in 194 patients) and was 17 months in the bendamustine-rituximab group (114 events in 195 patients). The 2-year rate of investigator-assessed progression-free survival was 84.9% (95% confidence interval [CI] 79.1–90.5) in the venetoclax-rituximab group and 36.3% (95% CI 28.5–44.0) in the bendamustine-rituximab group (hazard ratio for progression or death, 0.17; 95% CI 0.11 to 0.25; P < 0.001). Benefit was consistent in favor of the venetoclax-rituximab group in all prespecified subgroup analyses, with or without chromosome 17p deletion.

The rate of overall survival was higher in the venetoclax-rituximab group than in the bendamustine-rituximab group, with 24-month rates of 91.9% and 86.6%, respectively (hazard ratio 0.58, 95% CI 0.25–0.90). Assessments of minimal residual disease were available for 366 of the 389 patients (94.1%). On the basis of peripheral-blood samples, the venetoclax-rituximab group had a higher minimal residual disease compared to the bendamustine-rituximab group (121 of 194 patients [62.4%] vs. 26 of 195 patients [13.3%]). In bone marrow aspirate, higher rates of clearance of minimal residual disease was seen in the venetoclax-rituximab group (53 of 194 patients [27.3%]) as compared to the bendamustine-rituximab group (3 of 195 patients [1.5%]).

In terms of safety, the most common adverse event reported was neutropenia (60.8% of the patients in the venetoclax-rituximab group vs. 44.1% of the patients in the bendamustine-rituximab group). This contributed to the overall higher grade 3 or 4 adverse event rate in the venetoclax-rituximab group (159 of the 194 patients, or 82.0%) as compared to the bendamustine-rituximab group (132 of 188 patients, or 70.2%). The incidence of serious adverse events, as well as adverse events that resulted in death were similar in the 2 groups.

Conclusion. For patients with relapsed or refractory chronic lymphocytic leukemia, venetoclax plus rituximab resulted in significantly higher rates of progression-free survival than standard therapy with bendamustine plus rituximab.

Commentary

Despite advances in treatment, chronic lymphocytic leukemia remains incurable with conventional chemoimmunotherapy regimens, and almost all patient relapse after initial therapy. Following relapse of the disease, the goal is to provide durable progression-free survival, which may extend overall survival [1]. In a subset of chronic lymphocytic leukemia patients with deletion or mutation of TP53 loci on chromosome 17p13, their disease responds especially poorly to conventional treatment and they have a median survival of less than 3 years from the time of initiating first treatment.

Apoptosis defines a process of programmed cell death with an extrinsic and intrinsic cellular apoptotic pathway. B-cell lymphoma/leukemia 2 (BCL-2) protein is a key regulator of the intrinsic apoptotic pathway and almost all chronic lymphocytic leukemia cells elude apoptosis through overexpression of BCL-2. Venetoclax is an orally administered, highly selective, potent BCL-2 inhibitor approved by the FDA in 2016 for the treatment of chronic lymphocytic leukemia patients with 17p deletion who have received at least 1 prior therapy [3]. There has been great interest in combining venetoclax with other active agents in chronic lymphocytic leukemia such as chemotherapy, monoclonal antibodies, and B-cell receptor inhibitors. The combination of venetoclax with the CD20 antibody rituximab was found to be able to overcome micro-environment-induced resistance to venetoclax [4].

In this analysis of the phase 3 MURANO trial of venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukemia by Seymour et al, the authors demonstrated a significantly higher rate of progression-free survival with venetoclax plus rituximab than with standard chemoimmunotherapy bendamustine plus rituximab. In addition, secondary efficacy measures, including the complete response rate, the overall response rate, and overall survival were also higher in the venetoclax plus rituximab than with bendamustine plus rituximab.

There are several limitations of this study. First, this study was terminated early at the time of the data review on 6 September 2017. The independent data monitoring committee recommended that the primary analysis be conducted at that time because the prespecified statistical boundaries for early stopping were crossed for progression-free survival on the basis of stratified log-rank tests. In a letter to the editor, Alexander et al questioned the validity of results when design stages are violated. In immunotherapy trials, progression-free survival curves often separated at later time, rather than as a constant process; this violates the key assumption of proportionality of hazard functions. When the study was terminated early, post hoc confirmatory analyses and evaluations of robustness of the statistical plan could be used; however, prespecified analyses are critical to reproducibility in trials that are meant to be practice-changing [5]. Second, complete response rates were lower when responses was assessed by the independent review committee than when assessed by the investigator. While this represented a certain degree of author bias, the overall results were similar and the effect of venetoclax plus rituximab remain significantly better than bendamustine plus rituximab.

Applications for Clinical Practice

The current study demonstrated that venetoclax is safe and effective when combining with rituximab in the treating of chronic lymphocytic leukemia patients with or without 17p deletion who have received at least one prior therapy. The most common serious adverse event was neutropenia, correlated with tumor lysis syndrome. Careful monitoring, slow dose ramp-up, and adequate prophylaxis can mitigate some of the adverse effects.

—Ka Ming Gordon Ngai, MD, MPH