Emergency Medicine

ANSWER
The radiograph shows multiple stacked dilated loops of small bowel. The colon does not appear distended. (A nasogastric tube is also present, and there are degenerative changes in the spine.) Such a finding is typically associated with at least a partial small bowel obstruction, since no definite air fluid levels are noted.

The patient was admitted and made npo. Nasogastric decompression was started, and general surgery consultation was obtained.

ANSWER
The radiograph shows multiple stacked dilated loops of small bowel. The colon does not appear distended. (A nasogastric tube is also present, and there are degenerative changes in the spine.) Such a finding is typically associated with at least a partial small bowel obstruction, since no definite air fluid levels are noted.

The patient was admitted and made npo. Nasogastric decompression was started, and general surgery consultation was obtained.

ANSWER
The radiograph shows multiple stacked dilated loops of small bowel. The colon does not appear distended. (A nasogastric tube is also present, and there are degenerative changes in the spine.) Such a finding is typically associated with at least a partial small bowel obstruction, since no definite air fluid levels are noted.

The patient was admitted and made npo. Nasogastric decompression was started, and general surgery consultation was obtained.

A 54-year-old white man presents to the emergency department with burning pain in his left upper arm for the past 2 to 3 days. His medical history includes seizure disorder, for which he takes levetiracetam (Keppra); hypertension, for which he takes metoprolol succinate (Toprol); and in the remote past, a gunshot wound to the head that left his right arm with residual contracture and weakness.

He says he is homeless, has been “allergic to the sun for a while,” and has had dark-colored urine and intermittent abdominal pain. He states that he does not use illicit substances but that he drinks 6 to 12 beers per night and smokes 1 pack of cigarettes per day.

Initial vital signs:

• Temperature 37.7°C (99.9°F)
• Blood pressure 217/114 mm Hg
• Heart rate 82 bpm
• Respiratory rate 18 per minute
• Capillary oxygen saturation 98% while breathing room air.

On examination, his right arm is significantly weak and contracted. His left arm has decreased sensation to pinprick and light touch from elbow to fingers. His face and both arms show hyperpigmentation alternating with atrophic scarring, which also affects his lips. There is no overt mucosal involvement. His hands and forearms have a sclerotic texture and patchy hair loss. Several small bullae are present on the dorsum of the left forearm and hand. There is a 6-inch, irregular, open lesion on the left forearm and a 1-inch lesion on the left hand (Figure 1).

Initial laboratory studies show:

• Chemistries and complete blood cell count within normal limits
• Platelet count 305 × 10⁹/L (reference range 150–350)
• Orange-colored urine
• Hepatitis C virus (HCV) antibody positive (new finding)
• Human immunodeficiency virus antibody, hepatitis B surface antigen, and antinuclear antibody negative
• Phenytoin and urine drug screen negative
• Aspartate aminotransferase 70 U/L (reference range 5–34)
• Alanine aminotransferase 73 U/L (reference range 0–55)
• Prothrombin time 10.8 seconds (reference range 8.3–13.0), international normalized ratio 0.98 (reference range 0.8–1.2)
• Iron studies within normal limits.

The patient is admitted to the hospital and is started on cefazolin and clindamycin. Urine is collected for a porphyrin screen, and punch-biopsy samples from the forearms are sent for study. Ultrasonography shows splenomegaly, as well as increased echogenicity of the liver without structural abnormalities. Blood and urine cultures, drawn upon admission, are negative by discharge.

Pathologic study of the punch-biopsy specimens (Figure 2) shows the formation of subepidermal vesicles with extensive reticular and dermal fibrosis.

DIAGNOSIS: PORPHYRIA CUTANEA TARDA

Because of the patient’s history, examination, and pathology results, he was preliminarily diagnosed with porphyria cutanea tarda (PCT).^1,2 The diagnosis was confirmed after he was discharged when his urine uroporphyrin level was found to be 157.5 μmol/mol of creatinine (reference range < 4) and his urine heptacarboxylporphyrin level was 118.0 μmol/mol of creatinine (reference range < 2).

This patient’s clinical presentation is classic for sporadic (ie, type 1) PCT. Sporadic PCT is an acquired deficiency of uroporphyrinogen decarboxylase, an enzyme that catalyzes the fifth step in heme metabolism.³ The deficiency of this enzyme is exclusively hepatic and is strongly associated with chronic hepatitis C infection. Mutations of the hemochromatosis gene (HFE), human immunodeficiency virus infection, alcohol use, and smoking are also risk factors.⁴ The prevalence in the United States is about 1:25,000; nearly 80% of cases are sporadic (type 1), and 20% are familial (type 2).⁵

Manifestations of PCT include photosensitive dermatitis, facial hypertrichosis, and orange urine.³ The photosensitivity dermatitis heals slowly and leads to sclerosis and hyperpigmentation.

Repeated phlebotomy is the first-line treatment, and hydroxychloroquine (Plaquenil) is the second-line treatment.⁶ Patients with PCT and hepatitis C should be considered for antiviral therapy according to standard guidelines. Treatment of hepatitis C may reduce the symptoms of PCT, even without a sustained viral response. However, not enough evidence exists to make treatment recommendations for this group.⁷

Because we were uncertain that the patient would return for follow-up, we did not start phlebotomy or treatment for hepatitis C. However, we did prescribe hydroxychloroquine 100 mg three times a week and instructed him to cover his skin when outside and to use effective sunblock. An outpatient visit was scheduled prior to discharge. Unfortunately, the patient was lost to follow-up.

Acknowledgment: The authors would like to personally thank Dr. Karen DeSouza from the University of Tennessee, Graduate School of Medicine, Department of Pathology, for her clinical expertise and kind advice.

A 54-year-old white man presents to the emergency department with burning pain in his left upper arm for the past 2 to 3 days. His medical history includes seizure disorder, for which he takes levetiracetam (Keppra); hypertension, for which he takes metoprolol succinate (Toprol); and in the remote past, a gunshot wound to the head that left his right arm with residual contracture and weakness.

He says he is homeless, has been “allergic to the sun for a while,” and has had dark-colored urine and intermittent abdominal pain. He states that he does not use illicit substances but that he drinks 6 to 12 beers per night and smokes 1 pack of cigarettes per day.

Initial vital signs:

• Temperature 37.7°C (99.9°F)
• Blood pressure 217/114 mm Hg
• Heart rate 82 bpm
• Respiratory rate 18 per minute
• Capillary oxygen saturation 98% while breathing room air.

On examination, his right arm is significantly weak and contracted. His left arm has decreased sensation to pinprick and light touch from elbow to fingers. His face and both arms show hyperpigmentation alternating with atrophic scarring, which also affects his lips. There is no overt mucosal involvement. His hands and forearms have a sclerotic texture and patchy hair loss. Several small bullae are present on the dorsum of the left forearm and hand. There is a 6-inch, irregular, open lesion on the left forearm and a 1-inch lesion on the left hand (Figure 1).

Initial laboratory studies show:

• Chemistries and complete blood cell count within normal limits
• Platelet count 305 × 10⁹/L (reference range 150–350)
• Orange-colored urine
• Hepatitis C virus (HCV) antibody positive (new finding)
• Human immunodeficiency virus antibody, hepatitis B surface antigen, and antinuclear antibody negative
• Phenytoin and urine drug screen negative
• Aspartate aminotransferase 70 U/L (reference range 5–34)
• Alanine aminotransferase 73 U/L (reference range 0–55)
• Prothrombin time 10.8 seconds (reference range 8.3–13.0), international normalized ratio 0.98 (reference range 0.8–1.2)
• Iron studies within normal limits.

The patient is admitted to the hospital and is started on cefazolin and clindamycin. Urine is collected for a porphyrin screen, and punch-biopsy samples from the forearms are sent for study. Ultrasonography shows splenomegaly, as well as increased echogenicity of the liver without structural abnormalities. Blood and urine cultures, drawn upon admission, are negative by discharge.

Pathologic study of the punch-biopsy specimens (Figure 2) shows the formation of subepidermal vesicles with extensive reticular and dermal fibrosis.

DIAGNOSIS: PORPHYRIA CUTANEA TARDA

Because of the patient’s history, examination, and pathology results, he was preliminarily diagnosed with porphyria cutanea tarda (PCT).^1,2 The diagnosis was confirmed after he was discharged when his urine uroporphyrin level was found to be 157.5 μmol/mol of creatinine (reference range < 4) and his urine heptacarboxylporphyrin level was 118.0 μmol/mol of creatinine (reference range < 2).

This patient’s clinical presentation is classic for sporadic (ie, type 1) PCT. Sporadic PCT is an acquired deficiency of uroporphyrinogen decarboxylase, an enzyme that catalyzes the fifth step in heme metabolism.³ The deficiency of this enzyme is exclusively hepatic and is strongly associated with chronic hepatitis C infection. Mutations of the hemochromatosis gene (HFE), human immunodeficiency virus infection, alcohol use, and smoking are also risk factors.⁴ The prevalence in the United States is about 1:25,000; nearly 80% of cases are sporadic (type 1), and 20% are familial (type 2).⁵

Manifestations of PCT include photosensitive dermatitis, facial hypertrichosis, and orange urine.³ The photosensitivity dermatitis heals slowly and leads to sclerosis and hyperpigmentation.

Repeated phlebotomy is the first-line treatment, and hydroxychloroquine (Plaquenil) is the second-line treatment.⁶ Patients with PCT and hepatitis C should be considered for antiviral therapy according to standard guidelines. Treatment of hepatitis C may reduce the symptoms of PCT, even without a sustained viral response. However, not enough evidence exists to make treatment recommendations for this group.⁷

Because we were uncertain that the patient would return for follow-up, we did not start phlebotomy or treatment for hepatitis C. However, we did prescribe hydroxychloroquine 100 mg three times a week and instructed him to cover his skin when outside and to use effective sunblock. An outpatient visit was scheduled prior to discharge. Unfortunately, the patient was lost to follow-up.

Acknowledgment: The authors would like to personally thank Dr. Karen DeSouza from the University of Tennessee, Graduate School of Medicine, Department of Pathology, for her clinical expertise and kind advice.

A 54-year-old white man presents to the emergency department with burning pain in his left upper arm for the past 2 to 3 days. His medical history includes seizure disorder, for which he takes levetiracetam (Keppra); hypertension, for which he takes metoprolol succinate (Toprol); and in the remote past, a gunshot wound to the head that left his right arm with residual contracture and weakness.

He says he is homeless, has been “allergic to the sun for a while,” and has had dark-colored urine and intermittent abdominal pain. He states that he does not use illicit substances but that he drinks 6 to 12 beers per night and smokes 1 pack of cigarettes per day.

Initial vital signs:

• Temperature 37.7°C (99.9°F)
• Blood pressure 217/114 mm Hg
• Heart rate 82 bpm
• Respiratory rate 18 per minute
• Capillary oxygen saturation 98% while breathing room air.

On examination, his right arm is significantly weak and contracted. His left arm has decreased sensation to pinprick and light touch from elbow to fingers. His face and both arms show hyperpigmentation alternating with atrophic scarring, which also affects his lips. There is no overt mucosal involvement. His hands and forearms have a sclerotic texture and patchy hair loss. Several small bullae are present on the dorsum of the left forearm and hand. There is a 6-inch, irregular, open lesion on the left forearm and a 1-inch lesion on the left hand (Figure 1).

Initial laboratory studies show:

• Chemistries and complete blood cell count within normal limits
• Platelet count 305 × 10⁹/L (reference range 150–350)
• Orange-colored urine
• Hepatitis C virus (HCV) antibody positive (new finding)
• Human immunodeficiency virus antibody, hepatitis B surface antigen, and antinuclear antibody negative
• Phenytoin and urine drug screen negative
• Aspartate aminotransferase 70 U/L (reference range 5–34)
• Alanine aminotransferase 73 U/L (reference range 0–55)
• Prothrombin time 10.8 seconds (reference range 8.3–13.0), international normalized ratio 0.98 (reference range 0.8–1.2)
• Iron studies within normal limits.

The patient is admitted to the hospital and is started on cefazolin and clindamycin. Urine is collected for a porphyrin screen, and punch-biopsy samples from the forearms are sent for study. Ultrasonography shows splenomegaly, as well as increased echogenicity of the liver without structural abnormalities. Blood and urine cultures, drawn upon admission, are negative by discharge.

Pathologic study of the punch-biopsy specimens (Figure 2) shows the formation of subepidermal vesicles with extensive reticular and dermal fibrosis.

DIAGNOSIS: PORPHYRIA CUTANEA TARDA

Because of the patient’s history, examination, and pathology results, he was preliminarily diagnosed with porphyria cutanea tarda (PCT).^1,2 The diagnosis was confirmed after he was discharged when his urine uroporphyrin level was found to be 157.5 μmol/mol of creatinine (reference range < 4) and his urine heptacarboxylporphyrin level was 118.0 μmol/mol of creatinine (reference range < 2).

This patient’s clinical presentation is classic for sporadic (ie, type 1) PCT. Sporadic PCT is an acquired deficiency of uroporphyrinogen decarboxylase, an enzyme that catalyzes the fifth step in heme metabolism.³ The deficiency of this enzyme is exclusively hepatic and is strongly associated with chronic hepatitis C infection. Mutations of the hemochromatosis gene (HFE), human immunodeficiency virus infection, alcohol use, and smoking are also risk factors.⁴ The prevalence in the United States is about 1:25,000; nearly 80% of cases are sporadic (type 1), and 20% are familial (type 2).⁵

Manifestations of PCT include photosensitive dermatitis, facial hypertrichosis, and orange urine.³ The photosensitivity dermatitis heals slowly and leads to sclerosis and hyperpigmentation.

Repeated phlebotomy is the first-line treatment, and hydroxychloroquine (Plaquenil) is the second-line treatment.⁶ Patients with PCT and hepatitis C should be considered for antiviral therapy according to standard guidelines. Treatment of hepatitis C may reduce the symptoms of PCT, even without a sustained viral response. However, not enough evidence exists to make treatment recommendations for this group.⁷

Because we were uncertain that the patient would return for follow-up, we did not start phlebotomy or treatment for hepatitis C. However, we did prescribe hydroxychloroquine 100 mg three times a week and instructed him to cover his skin when outside and to use effective sunblock. An outpatient visit was scheduled prior to discharge. Unfortunately, the patient was lost to follow-up.

Acknowledgment: The authors would like to personally thank Dr. Karen DeSouza from the University of Tennessee, Graduate School of Medicine, Department of Pathology, for her clinical expertise and kind advice.

ANSWER
The radiograph demonstrates a fairly large (4 x 6 cm) right paratracheal mass of unclear etiology. This type of finding warrants further evaluation with contrasted CT.

Fortunately for this patient, a subsequent study demonstrated a slightly enlarged thyroid gland. This correlated with the radiographic
finding.       

ANSWER
The radiograph demonstrates a fairly large (4 x 6 cm) right paratracheal mass of unclear etiology. This type of finding warrants further evaluation with contrasted CT.

Fortunately for this patient, a subsequent study demonstrated a slightly enlarged thyroid gland. This correlated with the radiographic
finding.       

ANSWER
The radiograph demonstrates a fairly large (4 x 6 cm) right paratracheal mass of unclear etiology. This type of finding warrants further evaluation with contrasted CT.

Fortunately for this patient, a subsequent study demonstrated a slightly enlarged thyroid gland. This correlated with the radiographic
finding.       

A 62-year-old African-American woman presented for evaluation of a bluish discoloration of the hard palate and nail beds, noticeable for several months. In addition, she had complaints of fatigue and arthralgia. She reported that she had been taking hydroxychloroquine 400 mg/d and quinacrine 100 mg/d for several years for the treatment of systemic lupus erythematosus (SLE). Her medical history was also significant for dry mouth syndrome treated with pilocarpine.

The patient’s vital signs included a temperature of 97°F;
respiratory rate, 15 breaths/min; pulse, 72 beats/min; and blood pressure, 130/80 mm Hg. Height was 62 in, weight was 189 lb, and BMI was 34.56. A bluish gray color was noted in the subungual areas of her nails (see Figure 1). There were several circumferential areas of skin hyperpigmentation resulting from healed lupus skin lesions on her arms. Nailfold capillaroscopy revealed several dilated blood vessels. The sclerae appeared dry, but no erythema or inflammation was noted.

Examination of the mouth revealed a bluish discoloration of the hard palate (see Figure 2) and decreased salivary pool. Respiratory, cardiovascular, and abdominal examination findings were normal. Musculoskeletal examination was unremarkable for acute joint tenderness or synovitis. Crepitation and bony changes were noted in the left knee, without effusion or decreased range of motion.

Laboratory studies were ordered, and the results are listed in the table.

DISCUSSION
Hyperpigmentation of the oral mucosa can be associated with a number of conditions, including adrenal insufficiency, Peutz-Jeghers syndrome, hemochromatosis, polyostotic fibrous dysplasia, hyperparathyroidism, neurofibromatosis, and bronchogenic malignancy.^1,2 Other causes of oral hyperpigmentation include physiologic pigmentary or postinflammatory changes, oral melanoacanthosis, blue nevus, and melanoma.^2,3 While these diagnoses should be considered when encountering a mucosal lesion, they were unlikely in this patient because of the color changes in her nail beds.

Systemic skin and mucous membrane discoloration can also occur with the use of certain drugs and other substances, including chemotherapeutic agents, benzodiazepines, hormones, carotenoids, phenolphthalein, heavy metal salts, and several antimicrobial agents.¹ In dark-skinned individuals, hyperpigmentation of the oral mucosa can be caused by a physiologic deposition of melanin.⁴

Pigmentary Changes
The use of antimalarial drugs, such as quinacrine, chloroquine, and hydroxychloroquine, has long been associated with pigmentary changes to the palatal mucosa and subungual areas.^1,3 These drugs can stimulate melanin production and cause hemosiderin deposition, resulting in pigmentary changes.⁵ Skin discoloration is believed to be the result of the formation of a melanin-drug complex in areas with an elevated affinity for melanin.¹ Besides malaria, these drugs are commonly used to treat SLE and discoid lupus erythematosus, rheumatoid arthritis, and other rheumatologic conditions.⁵

The diagnosis of drug-induced hyperpigmentation is generally clinical, supported by the patient’s history—which often includes the use of antimalarial drugs—and presentation.¹ If a clear cause cannot be determined by clinical evaluation, then a biopsy to confirm a drug-induced cause may be necessary.² A classic study by Tuffanelli et al reported that the onset of hyperpigmentation related to antimalarial drug therapy may not occur until 4 to 70 months after initiation of treatment.⁶ Once the offending drug is discontinued, pigmentation changes slowly fade but often do not completely resolve,⁷ and patients should be advised of this.

Ocular Retinopathy
While pigmentary changes associated with antimalarial drugs are benign,³ a rare but serious adverse effect of antimalarials is retinal toxicity. Ocular retinopathy related to chloroquine and hydroxychloroquine therapy has been well documented and may result in irreversible vision loss.^8,9 The most recent recommendations from the American Academy of Ophthalmology suggest a baseline eye examination at initiation of antimalarial treatment and annual examinations starting after five years of therapy because the risk for toxicity relates to the cumulative dose.⁸ More frequent ophthalmologic evaluations are recommended for individuals at higher risk, such as those with preexisting retinal or macular disease.⁹

Outcome for the case patient >>

OUTCOME FOR THE CASE PATIENT
A biopsy of the roof of the patient’s mouth confirmed that the palatal hyperpigmentation was caused by her antimalarial medications. Since the patient displayed no evidence of active lupus skin lesions and laboratory results indicated that her SLE was inactive, one of the drugs, quinacrine, was discontinued.

The patient was referred for an ophthalmologic evaluation. No evidence of retinal toxicity was found.

Follow-up evaluations at two months and six months revealed no significant improvement in the discoloration of the patient’s oral mucosa or nail beds. At the six-month visit, her dosage of hydroxychloroquine was reevaluated.

The patient’s hydroxychloroquine dosage was determined based on 7.3 mg/kg/d. In the case of an overweight patient, especially one of shorter-than-average stature, hydroxychloroquine dosing should be based on ideal body weight to minimize the risk for overdosage; in general, a maximum dosage of 6.5 mg/kg/d is recommended.^8,9 As a result, the patient’s dosage was decreased to 300 mg/d.

At her nine-month follow-up evaluation, the discoloration to the patient’s oral mucosa had faded but had not resolved completely (see Figure 3). No significant change was noted in the subungual discoloration. The patient had experienced no exacerbations of lupus-related symptoms since her medication adjustments.

CONCLUSION
Although this patient’s hyperpigmentation was benign, staying alert to this potential adverse effect of antimalarial drugs is important in making a diagnosis. As with many skin lesions, if the clinical evaluation does not provide a clear cause, a biopsy may be needed. For anyone taking antimalarial drugs, regular ophthalmologic evaluations are recommended to facilitate early detection of the rare adverse effect of retinal toxicity. Nevertheless, with careful monitoring, antimalarial drugs are safe and effective for the treatment of inflammatory conditions such as SLE and rheumatoid arthritis.

REFERENCES
1. Kleinegger CL, Hammond HL, Finkelstein MW. Oral mucosal hyperpigmentation secondary to antimalarial drug therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000;90(2):189-194.

2. Gondak R-O, da Silva-Jorge R, Jorge J, et al. Oral pigmented lesions: clinicopathologic features and review of the literature. Med Oral Pathol Oral Cir Bucal. 2012;17(6):e919-e924.

3. Lerman MA, Karimbux N, Guze KA, Woo SB. Pigmentation of the hard palate. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;
107:8-12.

4. Kalampalikis A, Goetze S, Elsner P. Isolated hyperpigmentation of the oral mucosa due to hydroxychloroquine. J Dtsch Dermatol Ges. 2012; 10(12):921-922.

5. de Andrade BA, Fonseca FP, Pires FR, et al. Hard palate hyperpigmentation secondary to chronic chloroquine therapy: report of five cases.
J Cutan Pathol. 2013;40(9):833-838.

6. Tuffanelli D, Abraham RK, Dubois EI. Pigmentation from antimalarial therapy: its possible relationship to the ocular lesions. Arch Derm. 1963; 88:419-426.

7. Melikoglu MA, Melikoglu M, Gurbuz U, et al. Hydroxychloroquine-induced hyperpigmentation: a case report. J Clin Pharm Ther. 2008; 33(6):699-701. 

8. Marmor MF, Kellner U, Lai YY, et al; American Academy of Ophthalmology. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology. 2011;118(2):
415-422.

9. Screening for hydroxychloroquine retinopathy. Position statement, American College of Rheumatology. www.rheumatology.org/Practice/Clinical/Position/Position_Statements/. Accessed July 17, 2014.

A 62-year-old African-American woman presented for evaluation of a bluish discoloration of the hard palate and nail beds, noticeable for several months. In addition, she had complaints of fatigue and arthralgia. She reported that she had been taking hydroxychloroquine 400 mg/d and quinacrine 100 mg/d for several years for the treatment of systemic lupus erythematosus (SLE). Her medical history was also significant for dry mouth syndrome treated with pilocarpine.

The patient’s vital signs included a temperature of 97°F;
respiratory rate, 15 breaths/min; pulse, 72 beats/min; and blood pressure, 130/80 mm Hg. Height was 62 in, weight was 189 lb, and BMI was 34.56. A bluish gray color was noted in the subungual areas of her nails (see Figure 1). There were several circumferential areas of skin hyperpigmentation resulting from healed lupus skin lesions on her arms. Nailfold capillaroscopy revealed several dilated blood vessels. The sclerae appeared dry, but no erythema or inflammation was noted.

Examination of the mouth revealed a bluish discoloration of the hard palate (see Figure 2) and decreased salivary pool. Respiratory, cardiovascular, and abdominal examination findings were normal. Musculoskeletal examination was unremarkable for acute joint tenderness or synovitis. Crepitation and bony changes were noted in the left knee, without effusion or decreased range of motion.

Laboratory studies were ordered, and the results are listed in the table.

DISCUSSION
Hyperpigmentation of the oral mucosa can be associated with a number of conditions, including adrenal insufficiency, Peutz-Jeghers syndrome, hemochromatosis, polyostotic fibrous dysplasia, hyperparathyroidism, neurofibromatosis, and bronchogenic malignancy.^1,2 Other causes of oral hyperpigmentation include physiologic pigmentary or postinflammatory changes, oral melanoacanthosis, blue nevus, and melanoma.^2,3 While these diagnoses should be considered when encountering a mucosal lesion, they were unlikely in this patient because of the color changes in her nail beds.

Systemic skin and mucous membrane discoloration can also occur with the use of certain drugs and other substances, including chemotherapeutic agents, benzodiazepines, hormones, carotenoids, phenolphthalein, heavy metal salts, and several antimicrobial agents.¹ In dark-skinned individuals, hyperpigmentation of the oral mucosa can be caused by a physiologic deposition of melanin.⁴

Pigmentary Changes
The use of antimalarial drugs, such as quinacrine, chloroquine, and hydroxychloroquine, has long been associated with pigmentary changes to the palatal mucosa and subungual areas.^1,3 These drugs can stimulate melanin production and cause hemosiderin deposition, resulting in pigmentary changes.⁵ Skin discoloration is believed to be the result of the formation of a melanin-drug complex in areas with an elevated affinity for melanin.¹ Besides malaria, these drugs are commonly used to treat SLE and discoid lupus erythematosus, rheumatoid arthritis, and other rheumatologic conditions.⁵

The diagnosis of drug-induced hyperpigmentation is generally clinical, supported by the patient’s history—which often includes the use of antimalarial drugs—and presentation.¹ If a clear cause cannot be determined by clinical evaluation, then a biopsy to confirm a drug-induced cause may be necessary.² A classic study by Tuffanelli et al reported that the onset of hyperpigmentation related to antimalarial drug therapy may not occur until 4 to 70 months after initiation of treatment.⁶ Once the offending drug is discontinued, pigmentation changes slowly fade but often do not completely resolve,⁷ and patients should be advised of this.

Ocular Retinopathy
While pigmentary changes associated with antimalarial drugs are benign,³ a rare but serious adverse effect of antimalarials is retinal toxicity. Ocular retinopathy related to chloroquine and hydroxychloroquine therapy has been well documented and may result in irreversible vision loss.^8,9 The most recent recommendations from the American Academy of Ophthalmology suggest a baseline eye examination at initiation of antimalarial treatment and annual examinations starting after five years of therapy because the risk for toxicity relates to the cumulative dose.⁸ More frequent ophthalmologic evaluations are recommended for individuals at higher risk, such as those with preexisting retinal or macular disease.⁹

Outcome for the case patient >>

OUTCOME FOR THE CASE PATIENT
A biopsy of the roof of the patient’s mouth confirmed that the palatal hyperpigmentation was caused by her antimalarial medications. Since the patient displayed no evidence of active lupus skin lesions and laboratory results indicated that her SLE was inactive, one of the drugs, quinacrine, was discontinued.

The patient was referred for an ophthalmologic evaluation. No evidence of retinal toxicity was found.

Follow-up evaluations at two months and six months revealed no significant improvement in the discoloration of the patient’s oral mucosa or nail beds. At the six-month visit, her dosage of hydroxychloroquine was reevaluated.

The patient’s hydroxychloroquine dosage was determined based on 7.3 mg/kg/d. In the case of an overweight patient, especially one of shorter-than-average stature, hydroxychloroquine dosing should be based on ideal body weight to minimize the risk for overdosage; in general, a maximum dosage of 6.5 mg/kg/d is recommended.^8,9 As a result, the patient’s dosage was decreased to 300 mg/d.

At her nine-month follow-up evaluation, the discoloration to the patient’s oral mucosa had faded but had not resolved completely (see Figure 3). No significant change was noted in the subungual discoloration. The patient had experienced no exacerbations of lupus-related symptoms since her medication adjustments.

CONCLUSION
Although this patient’s hyperpigmentation was benign, staying alert to this potential adverse effect of antimalarial drugs is important in making a diagnosis. As with many skin lesions, if the clinical evaluation does not provide a clear cause, a biopsy may be needed. For anyone taking antimalarial drugs, regular ophthalmologic evaluations are recommended to facilitate early detection of the rare adverse effect of retinal toxicity. Nevertheless, with careful monitoring, antimalarial drugs are safe and effective for the treatment of inflammatory conditions such as SLE and rheumatoid arthritis.

REFERENCES
1. Kleinegger CL, Hammond HL, Finkelstein MW. Oral mucosal hyperpigmentation secondary to antimalarial drug therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000;90(2):189-194.

2. Gondak R-O, da Silva-Jorge R, Jorge J, et al. Oral pigmented lesions: clinicopathologic features and review of the literature. Med Oral Pathol Oral Cir Bucal. 2012;17(6):e919-e924.

3. Lerman MA, Karimbux N, Guze KA, Woo SB. Pigmentation of the hard palate. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;
107:8-12.

4. Kalampalikis A, Goetze S, Elsner P. Isolated hyperpigmentation of the oral mucosa due to hydroxychloroquine. J Dtsch Dermatol Ges. 2012; 10(12):921-922.

5. de Andrade BA, Fonseca FP, Pires FR, et al. Hard palate hyperpigmentation secondary to chronic chloroquine therapy: report of five cases.
J Cutan Pathol. 2013;40(9):833-838.

6. Tuffanelli D, Abraham RK, Dubois EI. Pigmentation from antimalarial therapy: its possible relationship to the ocular lesions. Arch Derm. 1963; 88:419-426.

7. Melikoglu MA, Melikoglu M, Gurbuz U, et al. Hydroxychloroquine-induced hyperpigmentation: a case report. J Clin Pharm Ther. 2008; 33(6):699-701. 

8. Marmor MF, Kellner U, Lai YY, et al; American Academy of Ophthalmology. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology. 2011;118(2):
415-422.

9. Screening for hydroxychloroquine retinopathy. Position statement, American College of Rheumatology. www.rheumatology.org/Practice/Clinical/Position/Position_Statements/. Accessed July 17, 2014.

A 62-year-old African-American woman presented for evaluation of a bluish discoloration of the hard palate and nail beds, noticeable for several months. In addition, she had complaints of fatigue and arthralgia. She reported that she had been taking hydroxychloroquine 400 mg/d and quinacrine 100 mg/d for several years for the treatment of systemic lupus erythematosus (SLE). Her medical history was also significant for dry mouth syndrome treated with pilocarpine.

The patient’s vital signs included a temperature of 97°F;
respiratory rate, 15 breaths/min; pulse, 72 beats/min; and blood pressure, 130/80 mm Hg. Height was 62 in, weight was 189 lb, and BMI was 34.56. A bluish gray color was noted in the subungual areas of her nails (see Figure 1). There were several circumferential areas of skin hyperpigmentation resulting from healed lupus skin lesions on her arms. Nailfold capillaroscopy revealed several dilated blood vessels. The sclerae appeared dry, but no erythema or inflammation was noted.

Examination of the mouth revealed a bluish discoloration of the hard palate (see Figure 2) and decreased salivary pool. Respiratory, cardiovascular, and abdominal examination findings were normal. Musculoskeletal examination was unremarkable for acute joint tenderness or synovitis. Crepitation and bony changes were noted in the left knee, without effusion or decreased range of motion.

Laboratory studies were ordered, and the results are listed in the table.

DISCUSSION
Hyperpigmentation of the oral mucosa can be associated with a number of conditions, including adrenal insufficiency, Peutz-Jeghers syndrome, hemochromatosis, polyostotic fibrous dysplasia, hyperparathyroidism, neurofibromatosis, and bronchogenic malignancy.^1,2 Other causes of oral hyperpigmentation include physiologic pigmentary or postinflammatory changes, oral melanoacanthosis, blue nevus, and melanoma.^2,3 While these diagnoses should be considered when encountering a mucosal lesion, they were unlikely in this patient because of the color changes in her nail beds.

Systemic skin and mucous membrane discoloration can also occur with the use of certain drugs and other substances, including chemotherapeutic agents, benzodiazepines, hormones, carotenoids, phenolphthalein, heavy metal salts, and several antimicrobial agents.¹ In dark-skinned individuals, hyperpigmentation of the oral mucosa can be caused by a physiologic deposition of melanin.⁴

Pigmentary Changes
The use of antimalarial drugs, such as quinacrine, chloroquine, and hydroxychloroquine, has long been associated with pigmentary changes to the palatal mucosa and subungual areas.^1,3 These drugs can stimulate melanin production and cause hemosiderin deposition, resulting in pigmentary changes.⁵ Skin discoloration is believed to be the result of the formation of a melanin-drug complex in areas with an elevated affinity for melanin.¹ Besides malaria, these drugs are commonly used to treat SLE and discoid lupus erythematosus, rheumatoid arthritis, and other rheumatologic conditions.⁵

The diagnosis of drug-induced hyperpigmentation is generally clinical, supported by the patient’s history—which often includes the use of antimalarial drugs—and presentation.¹ If a clear cause cannot be determined by clinical evaluation, then a biopsy to confirm a drug-induced cause may be necessary.² A classic study by Tuffanelli et al reported that the onset of hyperpigmentation related to antimalarial drug therapy may not occur until 4 to 70 months after initiation of treatment.⁶ Once the offending drug is discontinued, pigmentation changes slowly fade but often do not completely resolve,⁷ and patients should be advised of this.

Ocular Retinopathy
While pigmentary changes associated with antimalarial drugs are benign,³ a rare but serious adverse effect of antimalarials is retinal toxicity. Ocular retinopathy related to chloroquine and hydroxychloroquine therapy has been well documented and may result in irreversible vision loss.^8,9 The most recent recommendations from the American Academy of Ophthalmology suggest a baseline eye examination at initiation of antimalarial treatment and annual examinations starting after five years of therapy because the risk for toxicity relates to the cumulative dose.⁸ More frequent ophthalmologic evaluations are recommended for individuals at higher risk, such as those with preexisting retinal or macular disease.⁹

Outcome for the case patient >>

OUTCOME FOR THE CASE PATIENT
A biopsy of the roof of the patient’s mouth confirmed that the palatal hyperpigmentation was caused by her antimalarial medications. Since the patient displayed no evidence of active lupus skin lesions and laboratory results indicated that her SLE was inactive, one of the drugs, quinacrine, was discontinued.

The patient was referred for an ophthalmologic evaluation. No evidence of retinal toxicity was found.

Follow-up evaluations at two months and six months revealed no significant improvement in the discoloration of the patient’s oral mucosa or nail beds. At the six-month visit, her dosage of hydroxychloroquine was reevaluated.

The patient’s hydroxychloroquine dosage was determined based on 7.3 mg/kg/d. In the case of an overweight patient, especially one of shorter-than-average stature, hydroxychloroquine dosing should be based on ideal body weight to minimize the risk for overdosage; in general, a maximum dosage of 6.5 mg/kg/d is recommended.^8,9 As a result, the patient’s dosage was decreased to 300 mg/d.

At her nine-month follow-up evaluation, the discoloration to the patient’s oral mucosa had faded but had not resolved completely (see Figure 3). No significant change was noted in the subungual discoloration. The patient had experienced no exacerbations of lupus-related symptoms since her medication adjustments.

CONCLUSION
Although this patient’s hyperpigmentation was benign, staying alert to this potential adverse effect of antimalarial drugs is important in making a diagnosis. As with many skin lesions, if the clinical evaluation does not provide a clear cause, a biopsy may be needed. For anyone taking antimalarial drugs, regular ophthalmologic evaluations are recommended to facilitate early detection of the rare adverse effect of retinal toxicity. Nevertheless, with careful monitoring, antimalarial drugs are safe and effective for the treatment of inflammatory conditions such as SLE and rheumatoid arthritis.

REFERENCES
1. Kleinegger CL, Hammond HL, Finkelstein MW. Oral mucosal hyperpigmentation secondary to antimalarial drug therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000;90(2):189-194.

2. Gondak R-O, da Silva-Jorge R, Jorge J, et al. Oral pigmented lesions: clinicopathologic features and review of the literature. Med Oral Pathol Oral Cir Bucal. 2012;17(6):e919-e924.

3. Lerman MA, Karimbux N, Guze KA, Woo SB. Pigmentation of the hard palate. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;
107:8-12.

4. Kalampalikis A, Goetze S, Elsner P. Isolated hyperpigmentation of the oral mucosa due to hydroxychloroquine. J Dtsch Dermatol Ges. 2012; 10(12):921-922.

5. de Andrade BA, Fonseca FP, Pires FR, et al. Hard palate hyperpigmentation secondary to chronic chloroquine therapy: report of five cases.
J Cutan Pathol. 2013;40(9):833-838.

6. Tuffanelli D, Abraham RK, Dubois EI. Pigmentation from antimalarial therapy: its possible relationship to the ocular lesions. Arch Derm. 1963; 88:419-426.

7. Melikoglu MA, Melikoglu M, Gurbuz U, et al. Hydroxychloroquine-induced hyperpigmentation: a case report. J Clin Pharm Ther. 2008; 33(6):699-701. 

8. Marmor MF, Kellner U, Lai YY, et al; American Academy of Ophthalmology. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology. 2011;118(2):
415-422.

9. Screening for hydroxychloroquine retinopathy. Position statement, American College of Rheumatology. www.rheumatology.org/Practice/Clinical/Position/Position_Statements/. Accessed July 17, 2014.

ANSWER
There are degenerative changes present. Bilateral hip prostheses are noted. Within the coccyx, there is bone remodeling and angulation that are likely chronic and related to remote trauma or injury (arrow). Below this, some cortical lucency (circled) is noted, most likely consistent with an acute fracture. The patient was prescribed a nonsteroidal medication and a mild narcotic pain medication. 

ANSWER
There are degenerative changes present. Bilateral hip prostheses are noted. Within the coccyx, there is bone remodeling and angulation that are likely chronic and related to remote trauma or injury (arrow). Below this, some cortical lucency (circled) is noted, most likely consistent with an acute fracture. The patient was prescribed a nonsteroidal medication and a mild narcotic pain medication. 

ANSWER
There are degenerative changes present. Bilateral hip prostheses are noted. Within the coccyx, there is bone remodeling and angulation that are likely chronic and related to remote trauma or injury (arrow). Below this, some cortical lucency (circled) is noted, most likely consistent with an acute fracture. The patient was prescribed a nonsteroidal medication and a mild narcotic pain medication. 

From the Children’s Hospital & Research Center Oakland, Oakland, CA.

Abstract

• Objective: To determine whether a quality improvement (QI) initiative would result in more timely assessment and treatment of acute sickle cell–related pain for pediatric patients with sickle cell disease (SCD) treated in the emergency department (ED).
• Methods: We created and implemented a protocol for SCD pain management in the ED with the goals of improving (1) mean time from triage to first analgesic dose; (2) percentage of patients that received their first analgesic dose within 30 minutes of triage, and (3) percentage of patients who had pain assessment performed within 30 minutes of triage and who were re-assessed within 30 minutes after the first analgesic dose.
• Results: Significant improvements were achieved between baseline (55 patient visits) and post order set implementation (165 visits) in time from triage to administration of first analgesic (decreased from 89.9 ± 50.5 to 35.2 ± 22.8 minutes, P < 0.001); percentage of patient visits receiving pain medications within 30 minutes of triage (from 7% to 53%, P < 0.001); percentage of patient visits assessed within 30 minutes of triage (from 64% to 99.4%, P < 0.001); and percentage of patient visits re-assessed within 30 minutes of initial analgesic (from 54% to 86%, P < 0.001).
• Conclusions: Implementation of a QI initiative in the ED led to expeditious care for pediatric patients with SCD presenting with pain. A QI framework provided us with unique challenges but also invaluable lessons as we address our objective of decreasing the quality gap in SCD medical care.

Pain is the leading cause of emergency department (ED) visits for patients with sickle cell disease (SCD) [1]. In the United States, 78% of the nearly 200,000 annual ED visits for SCD are for a complaint of pain [1]. Guidelines for the management of sickle cell vaso-occlusive pain episodes (VOE) suggest prompt initiation of parenteral opioids, use of effective opioid doses, and repeat opioid doses at frequent intervals [2–4]. Adherence to guidelines is poor. Both pediatric and adult patients with SCD experience delays in the initiation of analgesics and are routinely undertreated with respect to opioid dosing [5–8]. Even after controlling for race, the delays in time to analgesic administration experienced by patients with SCD exceed the delays encountered by patients who present to the ED with other types of pain [5,9]. These disparities warrant efforts designed to improve the delivery of quality care to patients with SCD.

Barriers to rapid and appropriate care of VOE in the ED are multifactorial and include systems-based limitations, such as acuity of the ED census, staffing limitations (eg, nurse-to-patient ratios), and facility limitations (eg, room availability) [6]. Provider-based limitations may include lack of awareness of available guidelines [10]. Biases and misunderstandings amongst providers about sickle cell pain and adequate medication dosing may also play a role [11–13]. These provider biases often lead to undertreatment of the pain, which in turn can lead to pseudoaddiction (drug-seeking behavior due to inadequate treatment) and a cycle of increased ED and inpatient utilization [14,15].

Patient-specific barriers to effective ED management of pain are equally complex. Previous negative experiences in the ED can lead patients and families to delay seeking care or avoid the ED altogether despite severe VOE pain [16]. Patients report frustration with the lack of consideration that they receive for their reports of pain, perceived insensitivity of hospital staff, inadequate analgesic administration, staff preoccupation with concerns of drug addiction, and an overall lack of respect and trust [17–19]. Patients also perceive a lack of knowledge of SCD and its treatments on the part of ED staff [7]. Other barriers to effective management are technical in nature, such as difficulty in establishing timely intravenous (IV) access.

Gaps and variations in quality of care contribute to poor outcomes for patients with SCD [20,21]. To help address these inequities, the Working to Improve Sickle Cell Healthcare (WISCH) project began in 2010 to improve care and outcomes for patients with SCD. WISCH is a collaborative quality improvement (QI) project funded by the Health Resources and Services Administration (HRSA) that has the goal to use improvement science to improve outcomes for patients with SCD across the life course (Ed note: see Editorial by Oyeku et al in this issue). As one of the HRSA-WISCH grantee networks, we undertook a QI project designed to decrease the quality gap in SCD medical care by creating and implementing a protocol for ED pain management for pediatric patients. Goals of the project were to improve the timely and appropriate assessment and treatment of acute VOE in the ED.

Methods

Setting

This ED QI initiative was implemented at Children’s Hospital & Research Center Oakland, an urban free-standing pediatric hospital that serves a demographically diverse population. The hospital ED sees over 45,000 visits per year, with 250 visits per year for VOE. Residents in pediatrics, family medicine, and emergency medicine staff the ED. All attending physicians are subspecialists in pediatric emergency medicine. Study procedures were approved by the hospital’s institutional review board.

Intervention

A multidisciplinary team consisting of ED staff and sickle cell center staff drafted a nursing-driven protocol for the assessment and management of acute pain associated with VOE, incorporating elements from a protocol in use by another WISCH collaborative member. The protocol called for the immediate triage and assessment of all patients with SCD who presented with moderate to severe pain suggestive of VOE. Moderate to severe pain was defined as a pain score of ≥ 5 on a numeric scale of 0 to 10, where 0 = no pain and 10 = the worst pain imaginable. Exclusion criteria included a chief complaint of pain not considered secondary to VOE (eg, trauma, fracture). Patients were also excluded if they had been transferred from another facility. The protocol called for IV pain medication to be administered within 10 minutes of the patient being roomed, with re-evaluation at 20-minute intervals and re-dosing of pain medication based on the patient’s subsequent pain rating.

Measures

We selected performance measures from the bank developed by the WISCH team to track improvement and evaluate progress. These performance measures included (1) mean time from triage to first analgesic dose, (2) percentage of patients that received their first dose of analgesic within 30 minutes of triage, (3) percentage of patients who had a pain assessment performed within 30 minutes of triage, and (4) percentage of patients re-assessed within 30 minutes after the first dose of analgesic had been administered. Our aims were to have 80% of patients assessed and given pain medications within 30 minutes of triage, and to have 80% of patients re-assessed within 30 minutes after having received their first dose of an analgesic, within 12 months of implementing our intervention.

Data Collection and Analysis

The WISCH project coordinator reviewed records of visits to the ED for a baseline period of 6 months and post-order set implementaton. Demographic data (age, gender), clinical data (hemoglobin type), pain scores, utilization data (number of ED visits during the study period), and data pertaining to the metrics chosen from the WISCH measurement bank were extracted from each eligible patient’s ED chart after the visit was completed. If patients were admitted, their length of hospitalization was extracted from their inpatient medical record.

All biostatistical analyses were conducted using Stata 9.2 (StataCorp, College Station, TX). Descriptive statistics computed at 2 time-points (pre and post order set implementation) were utilized to examine means, standard deviations and percentages. The 2 time-points were initially compared at the visit level of measurement, using Student’s t tests corrected for unequal variances where necessary for continuous variables and chi-square analyses for categorical variables, to evaluate if there was an improvement in timely triage, assessment, and treatment of acute VOE pain for all ED visits pre and post order set implementation. To account for trends and possible correlations across the months post order set implementation, we ran a mixed linear model with repeated measures over time to compare visits during all months post order set implementation with the baseline months, for metric 1, time from triage to first pain medication. If significant differences were found, we used Dunnett’s method of multiple comparisons to determine which months differed from baseline. For metrics 2 through 4, we ran linear models with a binary outcome, a logit link function and using general estimating equations to determine trends and to account for correlations over time.

Secondary analyses were conducted to evaluate whether mean pain scores were significantly different over the course of the ED visit for the 78 unique patients seen post order set implementation. A multivariable mixed linear model, for the outcome of the third pain score, was used to assess the associations with prior scores and to control for potential covariates (age, gender, number of ED visits, hemoglobin type) that were determined in advance. A statistical significance level of 0.05 was used for all tests.

Results

Baseline data were collected from December 2011 to May 2012. The protocol was implemented in July 2012 and was utilized during 165 ED visits (91% of eligible visits) through April 2013. There were no statistically significant differences in demographic or clinical characteristics between the 55 patients whose charts were reviewed prior to implementing the order set and the 78 unique patients treated thereafter. Pre order set implementation, the mean age was 14.6 ± 6.4 years; 60% were female and the primary diagnosis was HgbSS disease (61.8% of diagnoses). Post order set implementation, the mean age was 16.0 ± 8.0 years; 51.3% were female and the primary diagnosis was HgbSS disease (61.5% of diagnoses). The mean number of visits was 1.5 visits per patient with a range of 1–8 visits, both pre and post order set implementation. Thirty-one patients had ED visits at both time periods.

It can be seen in Figure 2 that staff performance on 3 of the 4 metrics (with the exception of initial analgesic within 30 minutes of triage) began to improve prior to implementing the order set. The mean length of ED stays decreased by 30 minutes, from a mean of 5.2 hours down to 4.7 hours (P < 0.05, Table). There was no significant change in the percentage of patients admitted to the inpatient unit.

We performed secondary analyses to determine if performance on our first metric, mean time from triage to first analgesic dose, was associated with any improvement on the third pain assessment for the patients enrolled post order set implementation. Looking at the first ED visit during the study period for the 78 unique patients, we found significant decreases in mean pain scores from the first to the second, from the second to the third, and from the first to the third assessment (P < 0.01). The mean pain scores were 8.3 ± 1.8, 5.9 ± 2.8, and 5.1 ± 3.0 on initial, second and third assessments, respectively. A multivariable model controlling for gender, hemoglobin type, number of ED visits and time to first pain medication showed that only the score at the second pain assessment (β = 0.88 ± 0.08, P < 0.001) was a significant predictor of the score at the third pain assessment.

Discussion

We demonstrated that a QI initiative to improve acute pain management resulted in more timely assessment and treatment of pain in pediatric patients with SCD. Significant improvements from baseline were achieved and sustained over a 10-month period in all 4 targeted metrics. We consistently exceeded our goal of having 80% of patients assessed within 30 minutes of triage, and our mean time to first pain medication (35.2 ± 22.8 minutes) came close to our goal of 30 minutes from triage. While we also achieved our goal to have 80% of patients re-assessed within 30 minutes after having received their first dose of an analgesic, we fell short in the percent who received their initial pain medication within 30 minutes of triage (52.7% versus goal of 80%). Although the length of stay in the ED decreased, no change was observed in the percentage of patients who required admission to the inpatient unit. A secondary analysis showed that mean pain scores significantly decreased over the course of the ED visit, from severe to moderate intensity.

The improvements that we observed began prior to implementation of the order set. We recognize that simply raising awareness and educating staff about the importance of timely and appropriate assessment and treatment of acute sickle cell related pain in the ED might be a potential confounder of our results. However, changes were sustained for 10 months post order set implementation and beyond, with no evidence that the performance on the target metrics is drifting back to baseline levels. Education and awareness-raising alone rarely result in sustained application of clinical practice guidelines [22]. We collaborated with NICHQ and other HRSA-WISCH grantees to systematically implement improvement science to ensure that the changes that we observed were indeed improvements and would be sustained [23] by first changing the system of care in the ED by introducing a standard order set [24,25]. We put a system into place to track use of the order set and to work with providers almost immediately if deviations were observed, to understand and overcome any barriers to the order set implementation. Systems in the ED and in the sickle cell center were aligned with the hospital’s QI initiatives [23].

Another strategy that we used to insure that the changes we observed would be sustained was to create a multidisciplinary team to build knowledge, skills, and new practices, including learning from other WISCH grantees and the NICHQ coordinating center [23]. We modified and adapted the intervention to our specific context [25]; although the outline of the order set was influenced by our WISCH colleagues, the final order set was structured to be consistent with other protocols within our institution. Finally, we included consumer input in the design of the project from the outset.

A previous study of a multi-institutional QI initiative aimed at improving acute SCD pain management for adult patients in the ED was unable to demonstrate an improvement in time to administration of initial analgesic [26]. Our study with pediatric patients was able to demonstrate a clinically meaningful decrease in the time to administration of first parenteral analgesic. The factors that account for the discrepant findings between these studies are likely multifactorial. Age (ie, pediatric vs. adult patients) may have played a role given that IV access may become increasingly difficult as patients with SCD age [26]. Education for providers should include the importance of alternative methods of administration of opioids, including subcutaneous and intranasal routes, to avoid delays when IV access is difficult. It is possible that negative provider attitudes converge with the documented increase in patient visits during the young adult years [27]. This may set up a challenging feedback loop wherein these vulnerable young adults are faced with greater stigma and consequently receive lower quality care, even when there is an attempt to carry out a standardized protocol.

We did not find that the QI intervention resulted in decreased admissions to the inpatient unit, with 68% of visits resulting in admission. In a recent pediatric SCD study, hospital admissions for pain control accounted for 78% of all admissions and 70% of readmissions within 30 days [28]. The investigators found that use of a SCD analgesic protocol including patient-controlled analgesia (PCA) improved quality of care as well as hospital readmission rates within 30 days (from 28% to 11%). Our ED QI protocol focused on only the first 90 minutes of the visit for pain. Our team has discussed the potential for starting the PCA in the ED and we should build on our success to focus on specific care that patients receive beyond their initial presentation. Further, we introduced pain action planning into outpatient care and need to continue to improve positive patient self-management strategies to ensure more seamless transition of pain management between home, ED, and inpatient settings.

Several valuable lessons were learned over the course of the ED QI initiative. Previous researchers [28] have emphasized the importance of coupling provider education with standardized order sets in efforts to improve the care of patients with SCD. Although we did not offer monthly formal education to our providers, the immediate follow-up when there were protocol deviations most likely served as teaching moments. These teaching moments also surfaced when some ED and hematology providers expressed concerns about the risk for oversedation with the rapid reassessment of pain and re-dosing of pain medications. Although rare, some parents also expressed that their child was being treated too vigorously with opioids. Our project highlighted the element of stigma that still accompanies the use of opioids for SCD pain management.

The project could not have been undertaken were it not for a small but determined multidisciplinary team of individuals who were personally invested in seeing the project come to fruition. The identification of physician and nurse champions who were enthusiastic about the project, invested in its conduct, and committed to its success was a cornerstone of the project’s success. These champions played an essential role in engaging staff interest in the project and oversaw the practicalities of implementing a new protocol in the ED. A spirit of collaboration, teamwork, and good communication between all involved parties was also critical. At the same time, we incorporated input from the treating ED and hematology clinicians using PDSA cycles as we were refining our protocol. We believe that our process enhanced buy-in from participating providers and clarified any issues that needed to be addressed in our setting, resulting in accelerated and sustained quality improvement.

Limitations

Although protocol-driven interventions are designed to provide a certain degree of uniformity of care, the protocol was not designed nor utilized in such a way that it superseded the best medical judgment of the treating clinicians. Deviations from the protocol were permissible when they were felt to be in the patient’s best interest. The study did not control for confounding variables such as disease severity, how long the patient had been in pain prior to coming to the ED, nor did we assess therapeutic interventions the patient had utilized at home prior to seeking out care in the ED. All of these factors could affect how well a patient might respond to treatment. We believe that sharing baseline data and monthly progress via run charts (graphs of data over time) with ED and sickle cell center staff and with consumer representatives enhanced the pace and focus of the project [23]. We had a dedicated person managing our data in real time through our HRSA funding, thus the project might not be generalizable to other institutions that do not have such staffing or access to the technology to allow project progress to be closely monitored by stakeholders.

Future Directions

With the goal of further reducing the time to administration of first analgesic dose in the ED setting, intranasal fentanyl will be utilized in our ED as the initial drug of choice for patients who do not object to or have a contraindication to its use. Collection of data from patients and family members is being undertaken to assess consumer satisfaction with the ED QI initiative. Recognizing that the ED management of acute pain addresses only one aspect of sickle cell pain, we are looking at ways to more comprehensively address pain. Individualized outpatient pain management plans are being created and patients and families are being encouraged and empowered to become active partners with their sickle cell providers in their own care. Although our initial efforts have focused on our pediatric patients, an additional aim of our project is to broaden the scope of our ED QI initiative to include community hospitals in the region that serve adult patients with SCD.

Conclusion

Implementation of a QI initiative in the ED has led to expeditious care for pediatric patients with SCD presenting with VOE. A multidisciplinary approach, ongoing staff education, and commitment to the initiative have been necessary to sustain the improvements. Our success can provide a template for other QI initiatives in the ED that translate to improved patient care for other diseases. A QI framework provided us with unique challenges but also invaluable lessons as we addressed our objective to improve outcomes for patients with SCD across the life course.

Acknowledgments: The authors wish to thank Theresa Freitas, RN, Lisa Hale, PNP, Carolyn Hoppe, MD, Ileana Mendez, RN, Helen Mitchell, Mary Rutherford, MD, Augusta Saulys, MD and the Children’s Hospital & Research Center Oakland Emergency Medicine Department and Sickle Cell Center for their support.

Corresponding author: Marsha Treadwell, PhD, Children’s Hospital & Research Center Oakland, 747 52nd St, Oakland, CA 94609, [email protected].

Funding/support: This research was conducted as part of the National Initiative for Children’s Healthcare Quality (NICHQ) Working to Improve Sickle Cell Healthcare (WISCH) project. Further support came from a grant from the Health Resources and Services Administration Sickle Cell Disease Treatment Demonstration Project Grant No. U1EMC16492 and from NIH CTSA grant UL1 RR024131. The views expressed in this publication do not necessarily reflect the views of WISCH, NICHQ, or HRSA.

From the Children’s Hospital & Research Center Oakland, Oakland, CA.

Abstract

• Objective: To determine whether a quality improvement (QI) initiative would result in more timely assessment and treatment of acute sickle cell–related pain for pediatric patients with sickle cell disease (SCD) treated in the emergency department (ED).
• Methods: We created and implemented a protocol for SCD pain management in the ED with the goals of improving (1) mean time from triage to first analgesic dose; (2) percentage of patients that received their first analgesic dose within 30 minutes of triage, and (3) percentage of patients who had pain assessment performed within 30 minutes of triage and who were re-assessed within 30 minutes after the first analgesic dose.
• Results: Significant improvements were achieved between baseline (55 patient visits) and post order set implementation (165 visits) in time from triage to administration of first analgesic (decreased from 89.9 ± 50.5 to 35.2 ± 22.8 minutes, P < 0.001); percentage of patient visits receiving pain medications within 30 minutes of triage (from 7% to 53%, P < 0.001); percentage of patient visits assessed within 30 minutes of triage (from 64% to 99.4%, P < 0.001); and percentage of patient visits re-assessed within 30 minutes of initial analgesic (from 54% to 86%, P < 0.001).
• Conclusions: Implementation of a QI initiative in the ED led to expeditious care for pediatric patients with SCD presenting with pain. A QI framework provided us with unique challenges but also invaluable lessons as we address our objective of decreasing the quality gap in SCD medical care.

Pain is the leading cause of emergency department (ED) visits for patients with sickle cell disease (SCD) [1]. In the United States, 78% of the nearly 200,000 annual ED visits for SCD are for a complaint of pain [1]. Guidelines for the management of sickle cell vaso-occlusive pain episodes (VOE) suggest prompt initiation of parenteral opioids, use of effective opioid doses, and repeat opioid doses at frequent intervals [2–4]. Adherence to guidelines is poor. Both pediatric and adult patients with SCD experience delays in the initiation of analgesics and are routinely undertreated with respect to opioid dosing [5–8]. Even after controlling for race, the delays in time to analgesic administration experienced by patients with SCD exceed the delays encountered by patients who present to the ED with other types of pain [5,9]. These disparities warrant efforts designed to improve the delivery of quality care to patients with SCD.

Barriers to rapid and appropriate care of VOE in the ED are multifactorial and include systems-based limitations, such as acuity of the ED census, staffing limitations (eg, nurse-to-patient ratios), and facility limitations (eg, room availability) [6]. Provider-based limitations may include lack of awareness of available guidelines [10]. Biases and misunderstandings amongst providers about sickle cell pain and adequate medication dosing may also play a role [11–13]. These provider biases often lead to undertreatment of the pain, which in turn can lead to pseudoaddiction (drug-seeking behavior due to inadequate treatment) and a cycle of increased ED and inpatient utilization [14,15].

Patient-specific barriers to effective ED management of pain are equally complex. Previous negative experiences in the ED can lead patients and families to delay seeking care or avoid the ED altogether despite severe VOE pain [16]. Patients report frustration with the lack of consideration that they receive for their reports of pain, perceived insensitivity of hospital staff, inadequate analgesic administration, staff preoccupation with concerns of drug addiction, and an overall lack of respect and trust [17–19]. Patients also perceive a lack of knowledge of SCD and its treatments on the part of ED staff [7]. Other barriers to effective management are technical in nature, such as difficulty in establishing timely intravenous (IV) access.

Gaps and variations in quality of care contribute to poor outcomes for patients with SCD [20,21]. To help address these inequities, the Working to Improve Sickle Cell Healthcare (WISCH) project began in 2010 to improve care and outcomes for patients with SCD. WISCH is a collaborative quality improvement (QI) project funded by the Health Resources and Services Administration (HRSA) that has the goal to use improvement science to improve outcomes for patients with SCD across the life course (Ed note: see Editorial by Oyeku et al in this issue). As one of the HRSA-WISCH grantee networks, we undertook a QI project designed to decrease the quality gap in SCD medical care by creating and implementing a protocol for ED pain management for pediatric patients. Goals of the project were to improve the timely and appropriate assessment and treatment of acute VOE in the ED.

Methods

Setting

This ED QI initiative was implemented at Children’s Hospital & Research Center Oakland, an urban free-standing pediatric hospital that serves a demographically diverse population. The hospital ED sees over 45,000 visits per year, with 250 visits per year for VOE. Residents in pediatrics, family medicine, and emergency medicine staff the ED. All attending physicians are subspecialists in pediatric emergency medicine. Study procedures were approved by the hospital’s institutional review board.

Intervention

A multidisciplinary team consisting of ED staff and sickle cell center staff drafted a nursing-driven protocol for the assessment and management of acute pain associated with VOE, incorporating elements from a protocol in use by another WISCH collaborative member. The protocol called for the immediate triage and assessment of all patients with SCD who presented with moderate to severe pain suggestive of VOE. Moderate to severe pain was defined as a pain score of ≥ 5 on a numeric scale of 0 to 10, where 0 = no pain and 10 = the worst pain imaginable. Exclusion criteria included a chief complaint of pain not considered secondary to VOE (eg, trauma, fracture). Patients were also excluded if they had been transferred from another facility. The protocol called for IV pain medication to be administered within 10 minutes of the patient being roomed, with re-evaluation at 20-minute intervals and re-dosing of pain medication based on the patient’s subsequent pain rating.

Measures

We selected performance measures from the bank developed by the WISCH team to track improvement and evaluate progress. These performance measures included (1) mean time from triage to first analgesic dose, (2) percentage of patients that received their first dose of analgesic within 30 minutes of triage, (3) percentage of patients who had a pain assessment performed within 30 minutes of triage, and (4) percentage of patients re-assessed within 30 minutes after the first dose of analgesic had been administered. Our aims were to have 80% of patients assessed and given pain medications within 30 minutes of triage, and to have 80% of patients re-assessed within 30 minutes after having received their first dose of an analgesic, within 12 months of implementing our intervention.

Data Collection and Analysis

The WISCH project coordinator reviewed records of visits to the ED for a baseline period of 6 months and post-order set implementaton. Demographic data (age, gender), clinical data (hemoglobin type), pain scores, utilization data (number of ED visits during the study period), and data pertaining to the metrics chosen from the WISCH measurement bank were extracted from each eligible patient’s ED chart after the visit was completed. If patients were admitted, their length of hospitalization was extracted from their inpatient medical record.

All biostatistical analyses were conducted using Stata 9.2 (StataCorp, College Station, TX). Descriptive statistics computed at 2 time-points (pre and post order set implementation) were utilized to examine means, standard deviations and percentages. The 2 time-points were initially compared at the visit level of measurement, using Student’s t tests corrected for unequal variances where necessary for continuous variables and chi-square analyses for categorical variables, to evaluate if there was an improvement in timely triage, assessment, and treatment of acute VOE pain for all ED visits pre and post order set implementation. To account for trends and possible correlations across the months post order set implementation, we ran a mixed linear model with repeated measures over time to compare visits during all months post order set implementation with the baseline months, for metric 1, time from triage to first pain medication. If significant differences were found, we used Dunnett’s method of multiple comparisons to determine which months differed from baseline. For metrics 2 through 4, we ran linear models with a binary outcome, a logit link function and using general estimating equations to determine trends and to account for correlations over time.

Secondary analyses were conducted to evaluate whether mean pain scores were significantly different over the course of the ED visit for the 78 unique patients seen post order set implementation. A multivariable mixed linear model, for the outcome of the third pain score, was used to assess the associations with prior scores and to control for potential covariates (age, gender, number of ED visits, hemoglobin type) that were determined in advance. A statistical significance level of 0.05 was used for all tests.

Results

Baseline data were collected from December 2011 to May 2012. The protocol was implemented in July 2012 and was utilized during 165 ED visits (91% of eligible visits) through April 2013. There were no statistically significant differences in demographic or clinical characteristics between the 55 patients whose charts were reviewed prior to implementing the order set and the 78 unique patients treated thereafter. Pre order set implementation, the mean age was 14.6 ± 6.4 years; 60% were female and the primary diagnosis was HgbSS disease (61.8% of diagnoses). Post order set implementation, the mean age was 16.0 ± 8.0 years; 51.3% were female and the primary diagnosis was HgbSS disease (61.5% of diagnoses). The mean number of visits was 1.5 visits per patient with a range of 1–8 visits, both pre and post order set implementation. Thirty-one patients had ED visits at both time periods.

It can be seen in Figure 2 that staff performance on 3 of the 4 metrics (with the exception of initial analgesic within 30 minutes of triage) began to improve prior to implementing the order set. The mean length of ED stays decreased by 30 minutes, from a mean of 5.2 hours down to 4.7 hours (P < 0.05, Table). There was no significant change in the percentage of patients admitted to the inpatient unit.

We performed secondary analyses to determine if performance on our first metric, mean time from triage to first analgesic dose, was associated with any improvement on the third pain assessment for the patients enrolled post order set implementation. Looking at the first ED visit during the study period for the 78 unique patients, we found significant decreases in mean pain scores from the first to the second, from the second to the third, and from the first to the third assessment (P < 0.01). The mean pain scores were 8.3 ± 1.8, 5.9 ± 2.8, and 5.1 ± 3.0 on initial, second and third assessments, respectively. A multivariable model controlling for gender, hemoglobin type, number of ED visits and time to first pain medication showed that only the score at the second pain assessment (β = 0.88 ± 0.08, P < 0.001) was a significant predictor of the score at the third pain assessment.

Discussion

We demonstrated that a QI initiative to improve acute pain management resulted in more timely assessment and treatment of pain in pediatric patients with SCD. Significant improvements from baseline were achieved and sustained over a 10-month period in all 4 targeted metrics. We consistently exceeded our goal of having 80% of patients assessed within 30 minutes of triage, and our mean time to first pain medication (35.2 ± 22.8 minutes) came close to our goal of 30 minutes from triage. While we also achieved our goal to have 80% of patients re-assessed within 30 minutes after having received their first dose of an analgesic, we fell short in the percent who received their initial pain medication within 30 minutes of triage (52.7% versus goal of 80%). Although the length of stay in the ED decreased, no change was observed in the percentage of patients who required admission to the inpatient unit. A secondary analysis showed that mean pain scores significantly decreased over the course of the ED visit, from severe to moderate intensity.

The improvements that we observed began prior to implementation of the order set. We recognize that simply raising awareness and educating staff about the importance of timely and appropriate assessment and treatment of acute sickle cell related pain in the ED might be a potential confounder of our results. However, changes were sustained for 10 months post order set implementation and beyond, with no evidence that the performance on the target metrics is drifting back to baseline levels. Education and awareness-raising alone rarely result in sustained application of clinical practice guidelines [22]. We collaborated with NICHQ and other HRSA-WISCH grantees to systematically implement improvement science to ensure that the changes that we observed were indeed improvements and would be sustained [23] by first changing the system of care in the ED by introducing a standard order set [24,25]. We put a system into place to track use of the order set and to work with providers almost immediately if deviations were observed, to understand and overcome any barriers to the order set implementation. Systems in the ED and in the sickle cell center were aligned with the hospital’s QI initiatives [23].

Another strategy that we used to insure that the changes we observed would be sustained was to create a multidisciplinary team to build knowledge, skills, and new practices, including learning from other WISCH grantees and the NICHQ coordinating center [23]. We modified and adapted the intervention to our specific context [25]; although the outline of the order set was influenced by our WISCH colleagues, the final order set was structured to be consistent with other protocols within our institution. Finally, we included consumer input in the design of the project from the outset.

A previous study of a multi-institutional QI initiative aimed at improving acute SCD pain management for adult patients in the ED was unable to demonstrate an improvement in time to administration of initial analgesic [26]. Our study with pediatric patients was able to demonstrate a clinically meaningful decrease in the time to administration of first parenteral analgesic. The factors that account for the discrepant findings between these studies are likely multifactorial. Age (ie, pediatric vs. adult patients) may have played a role given that IV access may become increasingly difficult as patients with SCD age [26]. Education for providers should include the importance of alternative methods of administration of opioids, including subcutaneous and intranasal routes, to avoid delays when IV access is difficult. It is possible that negative provider attitudes converge with the documented increase in patient visits during the young adult years [27]. This may set up a challenging feedback loop wherein these vulnerable young adults are faced with greater stigma and consequently receive lower quality care, even when there is an attempt to carry out a standardized protocol.

We did not find that the QI intervention resulted in decreased admissions to the inpatient unit, with 68% of visits resulting in admission. In a recent pediatric SCD study, hospital admissions for pain control accounted for 78% of all admissions and 70% of readmissions within 30 days [28]. The investigators found that use of a SCD analgesic protocol including patient-controlled analgesia (PCA) improved quality of care as well as hospital readmission rates within 30 days (from 28% to 11%). Our ED QI protocol focused on only the first 90 minutes of the visit for pain. Our team has discussed the potential for starting the PCA in the ED and we should build on our success to focus on specific care that patients receive beyond their initial presentation. Further, we introduced pain action planning into outpatient care and need to continue to improve positive patient self-management strategies to ensure more seamless transition of pain management between home, ED, and inpatient settings.

Several valuable lessons were learned over the course of the ED QI initiative. Previous researchers [28] have emphasized the importance of coupling provider education with standardized order sets in efforts to improve the care of patients with SCD. Although we did not offer monthly formal education to our providers, the immediate follow-up when there were protocol deviations most likely served as teaching moments. These teaching moments also surfaced when some ED and hematology providers expressed concerns about the risk for oversedation with the rapid reassessment of pain and re-dosing of pain medications. Although rare, some parents also expressed that their child was being treated too vigorously with opioids. Our project highlighted the element of stigma that still accompanies the use of opioids for SCD pain management.

The project could not have been undertaken were it not for a small but determined multidisciplinary team of individuals who were personally invested in seeing the project come to fruition. The identification of physician and nurse champions who were enthusiastic about the project, invested in its conduct, and committed to its success was a cornerstone of the project’s success. These champions played an essential role in engaging staff interest in the project and oversaw the practicalities of implementing a new protocol in the ED. A spirit of collaboration, teamwork, and good communication between all involved parties was also critical. At the same time, we incorporated input from the treating ED and hematology clinicians using PDSA cycles as we were refining our protocol. We believe that our process enhanced buy-in from participating providers and clarified any issues that needed to be addressed in our setting, resulting in accelerated and sustained quality improvement.

Limitations

Although protocol-driven interventions are designed to provide a certain degree of uniformity of care, the protocol was not designed nor utilized in such a way that it superseded the best medical judgment of the treating clinicians. Deviations from the protocol were permissible when they were felt to be in the patient’s best interest. The study did not control for confounding variables such as disease severity, how long the patient had been in pain prior to coming to the ED, nor did we assess therapeutic interventions the patient had utilized at home prior to seeking out care in the ED. All of these factors could affect how well a patient might respond to treatment. We believe that sharing baseline data and monthly progress via run charts (graphs of data over time) with ED and sickle cell center staff and with consumer representatives enhanced the pace and focus of the project [23]. We had a dedicated person managing our data in real time through our HRSA funding, thus the project might not be generalizable to other institutions that do not have such staffing or access to the technology to allow project progress to be closely monitored by stakeholders.

Future Directions

With the goal of further reducing the time to administration of first analgesic dose in the ED setting, intranasal fentanyl will be utilized in our ED as the initial drug of choice for patients who do not object to or have a contraindication to its use. Collection of data from patients and family members is being undertaken to assess consumer satisfaction with the ED QI initiative. Recognizing that the ED management of acute pain addresses only one aspect of sickle cell pain, we are looking at ways to more comprehensively address pain. Individualized outpatient pain management plans are being created and patients and families are being encouraged and empowered to become active partners with their sickle cell providers in their own care. Although our initial efforts have focused on our pediatric patients, an additional aim of our project is to broaden the scope of our ED QI initiative to include community hospitals in the region that serve adult patients with SCD.

Conclusion

Implementation of a QI initiative in the ED has led to expeditious care for pediatric patients with SCD presenting with VOE. A multidisciplinary approach, ongoing staff education, and commitment to the initiative have been necessary to sustain the improvements. Our success can provide a template for other QI initiatives in the ED that translate to improved patient care for other diseases. A QI framework provided us with unique challenges but also invaluable lessons as we addressed our objective to improve outcomes for patients with SCD across the life course.

Acknowledgments: The authors wish to thank Theresa Freitas, RN, Lisa Hale, PNP, Carolyn Hoppe, MD, Ileana Mendez, RN, Helen Mitchell, Mary Rutherford, MD, Augusta Saulys, MD and the Children’s Hospital & Research Center Oakland Emergency Medicine Department and Sickle Cell Center for their support.

Corresponding author: Marsha Treadwell, PhD, Children’s Hospital & Research Center Oakland, 747 52nd St, Oakland, CA 94609, [email protected].

Funding/support: This research was conducted as part of the National Initiative for Children’s Healthcare Quality (NICHQ) Working to Improve Sickle Cell Healthcare (WISCH) project. Further support came from a grant from the Health Resources and Services Administration Sickle Cell Disease Treatment Demonstration Project Grant No. U1EMC16492 and from NIH CTSA grant UL1 RR024131. The views expressed in this publication do not necessarily reflect the views of WISCH, NICHQ, or HRSA.

From the Children’s Hospital & Research Center Oakland, Oakland, CA.

Abstract

• Objective: To determine whether a quality improvement (QI) initiative would result in more timely assessment and treatment of acute sickle cell–related pain for pediatric patients with sickle cell disease (SCD) treated in the emergency department (ED).
• Methods: We created and implemented a protocol for SCD pain management in the ED with the goals of improving (1) mean time from triage to first analgesic dose; (2) percentage of patients that received their first analgesic dose within 30 minutes of triage, and (3) percentage of patients who had pain assessment performed within 30 minutes of triage and who were re-assessed within 30 minutes after the first analgesic dose.
• Results: Significant improvements were achieved between baseline (55 patient visits) and post order set implementation (165 visits) in time from triage to administration of first analgesic (decreased from 89.9 ± 50.5 to 35.2 ± 22.8 minutes, P < 0.001); percentage of patient visits receiving pain medications within 30 minutes of triage (from 7% to 53%, P < 0.001); percentage of patient visits assessed within 30 minutes of triage (from 64% to 99.4%, P < 0.001); and percentage of patient visits re-assessed within 30 minutes of initial analgesic (from 54% to 86%, P < 0.001).
• Conclusions: Implementation of a QI initiative in the ED led to expeditious care for pediatric patients with SCD presenting with pain. A QI framework provided us with unique challenges but also invaluable lessons as we address our objective of decreasing the quality gap in SCD medical care.

Pain is the leading cause of emergency department (ED) visits for patients with sickle cell disease (SCD) [1]. In the United States, 78% of the nearly 200,000 annual ED visits for SCD are for a complaint of pain [1]. Guidelines for the management of sickle cell vaso-occlusive pain episodes (VOE) suggest prompt initiation of parenteral opioids, use of effective opioid doses, and repeat opioid doses at frequent intervals [2–4]. Adherence to guidelines is poor. Both pediatric and adult patients with SCD experience delays in the initiation of analgesics and are routinely undertreated with respect to opioid dosing [5–8]. Even after controlling for race, the delays in time to analgesic administration experienced by patients with SCD exceed the delays encountered by patients who present to the ED with other types of pain [5,9]. These disparities warrant efforts designed to improve the delivery of quality care to patients with SCD.

Barriers to rapid and appropriate care of VOE in the ED are multifactorial and include systems-based limitations, such as acuity of the ED census, staffing limitations (eg, nurse-to-patient ratios), and facility limitations (eg, room availability) [6]. Provider-based limitations may include lack of awareness of available guidelines [10]. Biases and misunderstandings amongst providers about sickle cell pain and adequate medication dosing may also play a role [11–13]. These provider biases often lead to undertreatment of the pain, which in turn can lead to pseudoaddiction (drug-seeking behavior due to inadequate treatment) and a cycle of increased ED and inpatient utilization [14,15].

Patient-specific barriers to effective ED management of pain are equally complex. Previous negative experiences in the ED can lead patients and families to delay seeking care or avoid the ED altogether despite severe VOE pain [16]. Patients report frustration with the lack of consideration that they receive for their reports of pain, perceived insensitivity of hospital staff, inadequate analgesic administration, staff preoccupation with concerns of drug addiction, and an overall lack of respect and trust [17–19]. Patients also perceive a lack of knowledge of SCD and its treatments on the part of ED staff [7]. Other barriers to effective management are technical in nature, such as difficulty in establishing timely intravenous (IV) access.

Gaps and variations in quality of care contribute to poor outcomes for patients with SCD [20,21]. To help address these inequities, the Working to Improve Sickle Cell Healthcare (WISCH) project began in 2010 to improve care and outcomes for patients with SCD. WISCH is a collaborative quality improvement (QI) project funded by the Health Resources and Services Administration (HRSA) that has the goal to use improvement science to improve outcomes for patients with SCD across the life course (Ed note: see Editorial by Oyeku et al in this issue). As one of the HRSA-WISCH grantee networks, we undertook a QI project designed to decrease the quality gap in SCD medical care by creating and implementing a protocol for ED pain management for pediatric patients. Goals of the project were to improve the timely and appropriate assessment and treatment of acute VOE in the ED.

Methods

Setting

This ED QI initiative was implemented at Children’s Hospital & Research Center Oakland, an urban free-standing pediatric hospital that serves a demographically diverse population. The hospital ED sees over 45,000 visits per year, with 250 visits per year for VOE. Residents in pediatrics, family medicine, and emergency medicine staff the ED. All attending physicians are subspecialists in pediatric emergency medicine. Study procedures were approved by the hospital’s institutional review board.

Intervention

A multidisciplinary team consisting of ED staff and sickle cell center staff drafted a nursing-driven protocol for the assessment and management of acute pain associated with VOE, incorporating elements from a protocol in use by another WISCH collaborative member. The protocol called for the immediate triage and assessment of all patients with SCD who presented with moderate to severe pain suggestive of VOE. Moderate to severe pain was defined as a pain score of ≥ 5 on a numeric scale of 0 to 10, where 0 = no pain and 10 = the worst pain imaginable. Exclusion criteria included a chief complaint of pain not considered secondary to VOE (eg, trauma, fracture). Patients were also excluded if they had been transferred from another facility. The protocol called for IV pain medication to be administered within 10 minutes of the patient being roomed, with re-evaluation at 20-minute intervals and re-dosing of pain medication based on the patient’s subsequent pain rating.

Measures

We selected performance measures from the bank developed by the WISCH team to track improvement and evaluate progress. These performance measures included (1) mean time from triage to first analgesic dose, (2) percentage of patients that received their first dose of analgesic within 30 minutes of triage, (3) percentage of patients who had a pain assessment performed within 30 minutes of triage, and (4) percentage of patients re-assessed within 30 minutes after the first dose of analgesic had been administered. Our aims were to have 80% of patients assessed and given pain medications within 30 minutes of triage, and to have 80% of patients re-assessed within 30 minutes after having received their first dose of an analgesic, within 12 months of implementing our intervention.

Data Collection and Analysis

The WISCH project coordinator reviewed records of visits to the ED for a baseline period of 6 months and post-order set implementaton. Demographic data (age, gender), clinical data (hemoglobin type), pain scores, utilization data (number of ED visits during the study period), and data pertaining to the metrics chosen from the WISCH measurement bank were extracted from each eligible patient’s ED chart after the visit was completed. If patients were admitted, their length of hospitalization was extracted from their inpatient medical record.

All biostatistical analyses were conducted using Stata 9.2 (StataCorp, College Station, TX). Descriptive statistics computed at 2 time-points (pre and post order set implementation) were utilized to examine means, standard deviations and percentages. The 2 time-points were initially compared at the visit level of measurement, using Student’s t tests corrected for unequal variances where necessary for continuous variables and chi-square analyses for categorical variables, to evaluate if there was an improvement in timely triage, assessment, and treatment of acute VOE pain for all ED visits pre and post order set implementation. To account for trends and possible correlations across the months post order set implementation, we ran a mixed linear model with repeated measures over time to compare visits during all months post order set implementation with the baseline months, for metric 1, time from triage to first pain medication. If significant differences were found, we used Dunnett’s method of multiple comparisons to determine which months differed from baseline. For metrics 2 through 4, we ran linear models with a binary outcome, a logit link function and using general estimating equations to determine trends and to account for correlations over time.

Secondary analyses were conducted to evaluate whether mean pain scores were significantly different over the course of the ED visit for the 78 unique patients seen post order set implementation. A multivariable mixed linear model, for the outcome of the third pain score, was used to assess the associations with prior scores and to control for potential covariates (age, gender, number of ED visits, hemoglobin type) that were determined in advance. A statistical significance level of 0.05 was used for all tests.

Results

Baseline data were collected from December 2011 to May 2012. The protocol was implemented in July 2012 and was utilized during 165 ED visits (91% of eligible visits) through April 2013. There were no statistically significant differences in demographic or clinical characteristics between the 55 patients whose charts were reviewed prior to implementing the order set and the 78 unique patients treated thereafter. Pre order set implementation, the mean age was 14.6 ± 6.4 years; 60% were female and the primary diagnosis was HgbSS disease (61.8% of diagnoses). Post order set implementation, the mean age was 16.0 ± 8.0 years; 51.3% were female and the primary diagnosis was HgbSS disease (61.5% of diagnoses). The mean number of visits was 1.5 visits per patient with a range of 1–8 visits, both pre and post order set implementation. Thirty-one patients had ED visits at both time periods.

It can be seen in Figure 2 that staff performance on 3 of the 4 metrics (with the exception of initial analgesic within 30 minutes of triage) began to improve prior to implementing the order set. The mean length of ED stays decreased by 30 minutes, from a mean of 5.2 hours down to 4.7 hours (P < 0.05, Table). There was no significant change in the percentage of patients admitted to the inpatient unit.

We performed secondary analyses to determine if performance on our first metric, mean time from triage to first analgesic dose, was associated with any improvement on the third pain assessment for the patients enrolled post order set implementation. Looking at the first ED visit during the study period for the 78 unique patients, we found significant decreases in mean pain scores from the first to the second, from the second to the third, and from the first to the third assessment (P < 0.01). The mean pain scores were 8.3 ± 1.8, 5.9 ± 2.8, and 5.1 ± 3.0 on initial, second and third assessments, respectively. A multivariable model controlling for gender, hemoglobin type, number of ED visits and time to first pain medication showed that only the score at the second pain assessment (β = 0.88 ± 0.08, P < 0.001) was a significant predictor of the score at the third pain assessment.

Discussion

We demonstrated that a QI initiative to improve acute pain management resulted in more timely assessment and treatment of pain in pediatric patients with SCD. Significant improvements from baseline were achieved and sustained over a 10-month period in all 4 targeted metrics. We consistently exceeded our goal of having 80% of patients assessed within 30 minutes of triage, and our mean time to first pain medication (35.2 ± 22.8 minutes) came close to our goal of 30 minutes from triage. While we also achieved our goal to have 80% of patients re-assessed within 30 minutes after having received their first dose of an analgesic, we fell short in the percent who received their initial pain medication within 30 minutes of triage (52.7% versus goal of 80%). Although the length of stay in the ED decreased, no change was observed in the percentage of patients who required admission to the inpatient unit. A secondary analysis showed that mean pain scores significantly decreased over the course of the ED visit, from severe to moderate intensity.

The improvements that we observed began prior to implementation of the order set. We recognize that simply raising awareness and educating staff about the importance of timely and appropriate assessment and treatment of acute sickle cell related pain in the ED might be a potential confounder of our results. However, changes were sustained for 10 months post order set implementation and beyond, with no evidence that the performance on the target metrics is drifting back to baseline levels. Education and awareness-raising alone rarely result in sustained application of clinical practice guidelines [22]. We collaborated with NICHQ and other HRSA-WISCH grantees to systematically implement improvement science to ensure that the changes that we observed were indeed improvements and would be sustained [23] by first changing the system of care in the ED by introducing a standard order set [24,25]. We put a system into place to track use of the order set and to work with providers almost immediately if deviations were observed, to understand and overcome any barriers to the order set implementation. Systems in the ED and in the sickle cell center were aligned with the hospital’s QI initiatives [23].

Another strategy that we used to insure that the changes we observed would be sustained was to create a multidisciplinary team to build knowledge, skills, and new practices, including learning from other WISCH grantees and the NICHQ coordinating center [23]. We modified and adapted the intervention to our specific context [25]; although the outline of the order set was influenced by our WISCH colleagues, the final order set was structured to be consistent with other protocols within our institution. Finally, we included consumer input in the design of the project from the outset.

A previous study of a multi-institutional QI initiative aimed at improving acute SCD pain management for adult patients in the ED was unable to demonstrate an improvement in time to administration of initial analgesic [26]. Our study with pediatric patients was able to demonstrate a clinically meaningful decrease in the time to administration of first parenteral analgesic. The factors that account for the discrepant findings between these studies are likely multifactorial. Age (ie, pediatric vs. adult patients) may have played a role given that IV access may become increasingly difficult as patients with SCD age [26]. Education for providers should include the importance of alternative methods of administration of opioids, including subcutaneous and intranasal routes, to avoid delays when IV access is difficult. It is possible that negative provider attitudes converge with the documented increase in patient visits during the young adult years [27]. This may set up a challenging feedback loop wherein these vulnerable young adults are faced with greater stigma and consequently receive lower quality care, even when there is an attempt to carry out a standardized protocol.

We did not find that the QI intervention resulted in decreased admissions to the inpatient unit, with 68% of visits resulting in admission. In a recent pediatric SCD study, hospital admissions for pain control accounted for 78% of all admissions and 70% of readmissions within 30 days [28]. The investigators found that use of a SCD analgesic protocol including patient-controlled analgesia (PCA) improved quality of care as well as hospital readmission rates within 30 days (from 28% to 11%). Our ED QI protocol focused on only the first 90 minutes of the visit for pain. Our team has discussed the potential for starting the PCA in the ED and we should build on our success to focus on specific care that patients receive beyond their initial presentation. Further, we introduced pain action planning into outpatient care and need to continue to improve positive patient self-management strategies to ensure more seamless transition of pain management between home, ED, and inpatient settings.

Several valuable lessons were learned over the course of the ED QI initiative. Previous researchers [28] have emphasized the importance of coupling provider education with standardized order sets in efforts to improve the care of patients with SCD. Although we did not offer monthly formal education to our providers, the immediate follow-up when there were protocol deviations most likely served as teaching moments. These teaching moments also surfaced when some ED and hematology providers expressed concerns about the risk for oversedation with the rapid reassessment of pain and re-dosing of pain medications. Although rare, some parents also expressed that their child was being treated too vigorously with opioids. Our project highlighted the element of stigma that still accompanies the use of opioids for SCD pain management.

The project could not have been undertaken were it not for a small but determined multidisciplinary team of individuals who were personally invested in seeing the project come to fruition. The identification of physician and nurse champions who were enthusiastic about the project, invested in its conduct, and committed to its success was a cornerstone of the project’s success. These champions played an essential role in engaging staff interest in the project and oversaw the practicalities of implementing a new protocol in the ED. A spirit of collaboration, teamwork, and good communication between all involved parties was also critical. At the same time, we incorporated input from the treating ED and hematology clinicians using PDSA cycles as we were refining our protocol. We believe that our process enhanced buy-in from participating providers and clarified any issues that needed to be addressed in our setting, resulting in accelerated and sustained quality improvement.

Limitations

Although protocol-driven interventions are designed to provide a certain degree of uniformity of care, the protocol was not designed nor utilized in such a way that it superseded the best medical judgment of the treating clinicians. Deviations from the protocol were permissible when they were felt to be in the patient’s best interest. The study did not control for confounding variables such as disease severity, how long the patient had been in pain prior to coming to the ED, nor did we assess therapeutic interventions the patient had utilized at home prior to seeking out care in the ED. All of these factors could affect how well a patient might respond to treatment. We believe that sharing baseline data and monthly progress via run charts (graphs of data over time) with ED and sickle cell center staff and with consumer representatives enhanced the pace and focus of the project [23]. We had a dedicated person managing our data in real time through our HRSA funding, thus the project might not be generalizable to other institutions that do not have such staffing or access to the technology to allow project progress to be closely monitored by stakeholders.

Future Directions

With the goal of further reducing the time to administration of first analgesic dose in the ED setting, intranasal fentanyl will be utilized in our ED as the initial drug of choice for patients who do not object to or have a contraindication to its use. Collection of data from patients and family members is being undertaken to assess consumer satisfaction with the ED QI initiative. Recognizing that the ED management of acute pain addresses only one aspect of sickle cell pain, we are looking at ways to more comprehensively address pain. Individualized outpatient pain management plans are being created and patients and families are being encouraged and empowered to become active partners with their sickle cell providers in their own care. Although our initial efforts have focused on our pediatric patients, an additional aim of our project is to broaden the scope of our ED QI initiative to include community hospitals in the region that serve adult patients with SCD.

Conclusion

Implementation of a QI initiative in the ED has led to expeditious care for pediatric patients with SCD presenting with VOE. A multidisciplinary approach, ongoing staff education, and commitment to the initiative have been necessary to sustain the improvements. Our success can provide a template for other QI initiatives in the ED that translate to improved patient care for other diseases. A QI framework provided us with unique challenges but also invaluable lessons as we addressed our objective to improve outcomes for patients with SCD across the life course.

Acknowledgments: The authors wish to thank Theresa Freitas, RN, Lisa Hale, PNP, Carolyn Hoppe, MD, Ileana Mendez, RN, Helen Mitchell, Mary Rutherford, MD, Augusta Saulys, MD and the Children’s Hospital & Research Center Oakland Emergency Medicine Department and Sickle Cell Center for their support.

Corresponding author: Marsha Treadwell, PhD, Children’s Hospital & Research Center Oakland, 747 52nd St, Oakland, CA 94609, [email protected].

Funding/support: This research was conducted as part of the National Initiative for Children’s Healthcare Quality (NICHQ) Working to Improve Sickle Cell Healthcare (WISCH) project. Further support came from a grant from the Health Resources and Services Administration Sickle Cell Disease Treatment Demonstration Project Grant No. U1EMC16492 and from NIH CTSA grant UL1 RR024131. The views expressed in this publication do not necessarily reflect the views of WISCH, NICHQ, or HRSA.

A 48-year-old man with gout, multiple sclerosis, and previously treated methicillin-resistant Staphylococcus aureus (MRSA) infection presented to the emergency room with pain and significant swelling at the site of a dog bite on his left forearm. He had been bitten 2 weeks earlier by a friend’s dog, and the bite had punctured the skin. He also had red streaking on the skin of the left arm from the wrist to the elbow, and he reported feeling “feverish” and having night sweats.

At first, the bite had seemed to improve, then swelling and pain had developed and increased. He reported this to his primary care physician, along with the information that he had previously had an anaphylactic reaction to penicillin and a cephalosporin. His physician, considering a penicillin allergy, started him on ciprofloxacin (Cipro) plus clindamycin (Cleocin). The patient took this for 5 days, but without improvement. The appearance of the red streaking on his left forearm prompted his presentation to our emergency room.

ORGANISMS IN DOG BITES

1. Which is the most common cause of infected dog bite?

• Pasteurella canis
• Streptococci and S aureus
• Erysipelothrix rhusiopathiae
• Capnocytophaga canimorsus
• Eikenella corrodens

Streptococci (50%) and S aureus (20% to 40%) are the organisms most commonly responsible for infected dog bites, as they are for other skin and soft-tissue infections.¹P canis is unique to dog bite infections but accounts for only 18%.²E rhusiopathiae is an unusual isolate from cat and dog bites and is more commonly isolated from the mouths of fish and aquatic mammals. C canimorsus is a normal inhabitant of the oral cavity of dogs and cats but an unusual cause of wound infection from a dog bite. It is notable for sepsis and central nervous system infections uniquely associated with veterinarians, dog owners, kennel workers, and mail carriers.³E corrodens infection is more common with human bites.⁴

THE EVALUATION BEGINS

On examination, the patient had marked edema of the left forearm and pain in the joints of the left hand. His temperature was 100.2°F (37.9°C). Because of the duration and severity of symptoms, the examining physician was concerned about septic arthritis of the wrist, and the patient was admitted to the hospital.

In the hospital, our patient was thermodynamically stable without documented fever or chills. There was no open wound to culture, and blood cultures were negative. Marked edema and joint involvement raised suspicion of erysipeloid. This “cousin” of erysipelas often involves the underlying joint, is associated with edema, and produces systemic manifestations of fever and arthralgia.

Radiography of the left forearm and hand demonstrated multiple foci of demineralization within the carpal bones and proximal radius, attributed to disuse. Magnetic resonance imaging (MRI) the next day showed multiple bone infarcts in the carpal bones and the distal radius, with synovitis and fluid in the carpal joints and without adjacent osteomyelitis. Fluid was also seen in the soft tissues in the ulnar aspect of the left wrist, and tenosynovitis involving the flexor carpi radialis tendon was noted.

Arthrocentesis of his left radiocarpal joint produced synovial fluid negative for crystals and negative on Gram stain; the fluid was also sent for culture. The patient’s tetanus immunization was current, and the dog was known to have been immunized against rabies.

ANTIBIOTICS FOR INFECTED DOG BITES

2. Which antibiotic regimen would you choose for this patient?

• Oral amoxicillin and clavulanate
• Meropenem
• Vancomycin, clindamycin, aztreonam
• Clindamycin and levofloxacin
• Clindamycin and trimethoprim-sulfamethoxazole

Oral amoxicillin and clavulanate (Augmentin) is a judicious choice for prophylactic treatment of deep bites in the early stages of infection. However, our patient’s wound was no longer in the early stages of infection, and he had a history of an adverse reaction to penicillin.

Meropenem (Merrem IV) cross-reacts minimally with penicillin allergy and is reported to be safe in patients with a history of anaphylactic reactions to penicillin,⁵ but overuse of carbapenems has led to the development of carbapenem-resistant strains of Klebsiella, Stenotrophomonas, and Acinetobacter organisms.

Given the rise of MRSA infections and the common involvement of staphylococci, streptococci, and anaerobic bacteria in complicated dog bites, the combination of vancomycin and clindamycin is a good choice, and aztreonam (Azactam) would add empiric coverage of gram-negative enteric organisms.

Levofloxacin (Levaquin) also covers gramnegative enteric organisms, but Fusobacterium canifelinum, a common anaerobe in the oral flora of dogs and cats, is intrinsically resistant to fluoroquinolones.

Clindamycin and levofloxacin would be a good step-down oral regimen. Pasteurella multocida has variable sensitivity to the commonly used agents dicloxacillin (Dynapen), cephalexin (Keflex), macrolides, and clindamycin, but it is a less likely pathogen at this late stage and could be covered with levofloxacin alone.

C canimorsus is resistant to trimethoprim-sulfamethoxazole (Bactrim) and cephalexin, but is well covered by clindamycin.⁶

CASE CONTINUED

Our patient was started on intravenous vancomycin, clindamycin, and aztreonam for coverage of dog-mouth flora. Blood cultures and cultures of synovial fluid of the left wrist were negative. Vancomycin was discontinued after 48 hours when blood cultures did not grow staphylococcal organisms, but clindamycin and aztreonam were continued for a total of 8 days to treat possible infection with anaerobic and gram-negative enteric pathogens.

To test for autonomic dysfunction, a plastic pen case drawn lightly across each forearm revealed a loss of tactile adherence (ie, areas where moist, sweaty skin impeded the movement of the pen case) on the affected forearm, a sign of underlying nerve injury. The affected forearm was sensitive to light touch, with pain out of proportion to the stimulus.

ARRIVING AT THE DIAGNOSIS

Based on the wide distribution of inflammation, autonomic dysfunction (shown by differences in temperature and sweating), radiographic evidence of demineralization, hyperesthesia, and lack of improvement in pain and swelling after two courses of antibiotics, the patient’s clinical course was determined to be consistent with complex regional pain syndrome type 1, previously referred to as reflex sympathetic dystrophy.

Symptoms of complex regional pain syndrome traditionally include pain, regional edema, joint stiffness, muscular atrophy, vasomotor disturbances (causing temperature variability and erythema), regional diaphoresis, and localized skeletal demineralization on radiography.

Complex regional pain syndrome type 1 occurs as regional pain and inflammation as an excessive sympathetic reaction to an often minor insult, without nerve injury. When the syndrome occurs in a patient with obvious partial nerve injury, it is categorized as type 2 (formerly known as causalgia). The two types are clinically indistinguishable and are not uncommon. About 10% of all patients with complex regional pain syndrome have obvious nerve injury (complex regional pain syndrome type 2). In a study of 109 patients with Colles fracture, 25% developed symptoms of complex regional pain syndrome.⁷

Complex regional pain syndrome is difficult to diagnose, as it resembles many other ailments, such as gout, infection, bone tumor, stress fracture, and arthritis. Its pathophysiology is poorly understood, but it is believed to result from a “short circuit” in the reflex arc between somatic afferent sensory fibers and autonomic sympathetic efferent fibers, and this is thought to explain the increased sympathetic stimulation.

Although the pathophysiology is likely the same in type 1 and type 2, electromyography with a nerve conduction study is a reliable way to detect nerve damage and thus distinguish between the two types of complex regional pain syndrome.⁸

Our understanding of this syndrome is evolving. A recent study using sensory testing showed that 33% of patients with type 1 had combinations of increased and decreased thresholds for the detection of thermal, vibratory, and mechanical stimuli in the distribution of discrete peripheral nerves, suggesting that the patients actually had type 2.⁹

CONFIRMING COMPLEX REGIONAL PAIN SYNDROME TYPE 1

3. Which of the following is the best way to confirm complex regional pain syndrome type 1?

• Erythrocyte sedimentation rate, C-reactive protein, and complete blood cell count
• Plain radiography of the hand and forearm
• Three-phase technetium bone scan
• The Budapest diagnostic criteria
• MRI
• Autonomic testing

Complex regional pain syndrome type 1 is a clinical diagnosis. Diagnostic studies lack sensitivity and specificity but may confirm complex regional pain syndrome type 1 or rule out other diagnoses. The Budapest diagnostic criteria¹⁰ (Table 1) may be the best way to confirm this diagnosis. The criteria are as follows: continuing pain disproportionate to an inciting event, coupled with three of four symptoms plus at least one sign from sensory, vasomotor, sudomotor, and motor-trophic categories.

Laboratory tests are not helpful because acute-phase reactants and blood counts remain normal in these patients.

Plain radiography is not sensitive in early diagnosis, but at 2 weeks it may show patchy areas of osteopenia in adjacent bones throughout the region, as well as subsequent diffuse demineralization.

Three-phase bone scanning is more sensitive than plain radiography, with 75% of patients showing regional disparities in blood flow in early sequences and increased bone uptake in the later sequences.

MRI is a sensitive early test, as it better defines focal areas of bone loss and increased T2 bone signal in adjacent bone, as well as early soft-tissue changes. Computed tomography does not show early specific changes in muscle, tendon, or bone and so is not recommended.

THE EVALUATION CONTINUES

The admitting diagnosis was septic arthritis, and our patient underwent computed tomography, which showed focal demineralization that could have represented bone infarcts or infection, confounding the diagnosis of complex regional pain syndrome.

Autonomic nerve testing can help distinguish complex regional pain syndrome from other disorders. Complex regional pain syndrome is characterized by increased sympathetic activity and results in increased sweat output. Autonomic testing includes resting sweat output, resting skin temperature, and quantitative sudomotor axon reflex testing. In one study, an increase in resting sweat output used in conjunction with quantitative sudomotor axon reflex testing predicted the diagnosis of complex regional pain syndrome with a specificity of 98%.¹¹ However, autonomic testing is limited to academic centers and is not readily available.

TREATING COMPLEX REGIONAL PAIN SYNDROME TYPE 1

4. Which is the best first-line therapy for complex regional pain syndrome type 1?

• Stellate ganglion nerve block
• Occupational therapy to splint the wrist and forearm
• Oral corticosteroids
• Physical therapy to prevent loss of joint motion
• Tricyclic antidepressant drugs (eg, amitriptyline), pregabalin, and bisphosphonates

Physical therapy should be started early in all patients, with range-of-motion exercises to prevent contracture and enhance mobility.

Stellate ganglion nerve block has been used to counter severe sympathetic hyperactivity, but it also may aggravate symptoms of complex regional pain syndrome and so remains a controversial treatment.

Immobilization and splinting should be avoided, as this will augment edema, pain, and contracture of joints.

Corticosteroids do not shorten the course or assuage symptoms and may increase edema.

Amitriptyline (Elavil) and pregabalin (Lyrica) have been used successfully to counter extended courses of allodynia and hyperalgesia. Bisphosphonates may decrease bone loss and pain and may be needed should the course be complicated by myositis ossificans, a form of dystrophic bone formation in juxtaposed tendon and muscle related to neuroactivation of fibroblasts and osteoblasts.

THE COURSE OF COMPLEX REGIONAL PAIN SYNDROME

Traditionally, type 1 was divided into three stages—an early inflammatory stage, a dystrophic stage, and a late atrophic stage.¹² Although there is no evidence to support a consistent three-stage evolution, the severity of symptoms may help determine the best approach to management.¹³

Patients initially exhibit burning or throbbing pain, diffuse aching, sensitivity to touch or cold (allodynia), localized edema, and vasomotor disturbances of variable intensity that may produce altered color and temperature. Topical capsaicin cream; a tricyclic antidepressant; an anticonvulsant such as gabapentin (Neurontin), pregabalin, or lamotrigine (Lamictal); or a nonsteroidal anti-inflammatory drug should be tried first. Some of these treatments are poorly tolerated in elderly patients. If pain persists, nasal calcitonin may be added. Trigger-point injections with an anesthetic or glucocorticoid may be tried.

The management of early complex regional pain syndrome is sometimes supplemented with systemic corticosteroids, but reviews of randomized controlled trials have failed to show efficacy.¹⁴

Later in the course, patients may suffer persistent soft-tissue edema, accompanied by thickening of the skin and periarticular soft tissues, muscle wasting, and the skin changes of brawny edema. Regional blockade of sympathetic ganglions, epidural administration of clonidine, implantable peripheral nerve stimulators, and spinal cord stimulators have all been applied by experts in pain management and may provide benefit. Progression of the syndrome may include cyanosis, mottling, increased sweating, abnormal hair growth, and diffuse swelling in nonarticular tissue.

It is always acceptable to refer to an experienced pain management specialist, and a multidisciplinary approach is recommended at the outset.¹²

OUR PATIENT’S CARE CONTINUED

Our patient’s forearm and wrist were placed in a sling to keep his left arm elevated when active. This helped control sympathetic vascular edema and throbbing pain. Physical therapy with range-of-motion exercises prevented contracture.

He was discharged home on limited oxycodone as needed, with close follow-up by his primary care physician to monitor his pain symptoms. The pain and swelling slowly improved over the next 2 months, but he suffered a fall, twisting his left wrist. This minor injury was followed by more intense pain and swelling of the forearm, hand, and wrist.

COMORBIDITIES

5. Which of the following statements about conditions associated with complex regional pain syndrome most likely applies to our patient?

• Gout is likely following minor trauma
• Minor trauma or surgical bone biopsy may reactivate complex regional pain syndrome
• Septic hip arthritis due to MRSA may have reemerged and seeded the wrist
• Patients with multiple sclerosis have a propensity for complex regional pain syndrome
• Complex regional pain syndrome type 1 begets type 2

Gout does follow minor injury, but our patient’s uric acid was well controlled on allopurinol (Zyloprim), and gout is unlikely to be causing polyarticular swelling of the hand, wrist, and forearm.

Minor trauma, sometimes inconsequential enough to have been completely forgotten, may either initiate complex regional pain syndrome or, as seen here, reactivate it. Bone changes seen on MRI sometimes trigger surgical bone biopsy, only to reactivate the dysesthesia and sympathetic vascular reaction. Surgery should be avoided. Trauma and surgery are causative rather than associative comorbidities.

Sepsis due to MRSA after total hip arthroplasty may be reactivated, especially in the setting of immunosuppressive treatment. But the diffuse bone changes seen in multiple carpal, radial, and ulnar bones suggest generalized vascular and sympathetic disarray, most consistent with complex regional pain syndrome type 1.

AN ASSOCIATION WITH MULTIPLE SCLEROSIS?

Multiple sclerosis and other central neuropathic conditions such as stroke are associated with complex regional pain syndrome type 1.^15,16

A hypothetical cause for the higher prevalence of complex regional pain syndrome in patients with multiple sclerosis may be demyelination resulting in aberrant signaling and overreaction to distal pain receptors. Demyelination of neurons within the autonomic or spinothalamic tracts potentially increases susceptibility to development of the pain syndrome.

Our patient had an apparent stimulus for the development of the syndrome, ie, the initial dog bite, and the wrist injury later may have caused peripheral nerve injury. Such injury may lead to release of vasodilatory neuropeptides including substance P from stimulated cutaneous nerves with cell bodies in the dorsal root ganglia. Excessive vasodilation and increased vascular permeability result in the affected limb becoming edematous and causing cutaneous nerves to be further activated. Stimulated cutaneous neurons normally have an inhibitory influence on sympathetic activity at the level of entry of the dorsal root ganglia in the cord. In complex regional pain syndrome, this inhibition is lost, resulting in a hyperactive somatosympathetic reflex.¹⁷ Underlying multiple sclerosis may have contributed to the loss of inhibition by the cutaneous nerves on the sympathetic system.

CASE CONCLUDED

We continued to closely follow this patient, who was on a self-directed program of physical therapy. One year after the original dog bite, the complex regional pain syndrome had completely resolved.

A 48-year-old man with gout, multiple sclerosis, and previously treated methicillin-resistant Staphylococcus aureus (MRSA) infection presented to the emergency room with pain and significant swelling at the site of a dog bite on his left forearm. He had been bitten 2 weeks earlier by a friend’s dog, and the bite had punctured the skin. He also had red streaking on the skin of the left arm from the wrist to the elbow, and he reported feeling “feverish” and having night sweats.

At first, the bite had seemed to improve, then swelling and pain had developed and increased. He reported this to his primary care physician, along with the information that he had previously had an anaphylactic reaction to penicillin and a cephalosporin. His physician, considering a penicillin allergy, started him on ciprofloxacin (Cipro) plus clindamycin (Cleocin). The patient took this for 5 days, but without improvement. The appearance of the red streaking on his left forearm prompted his presentation to our emergency room.

ORGANISMS IN DOG BITES

1. Which is the most common cause of infected dog bite?

• Pasteurella canis
• Streptococci and S aureus
• Erysipelothrix rhusiopathiae
• Capnocytophaga canimorsus
• Eikenella corrodens

Streptococci (50%) and S aureus (20% to 40%) are the organisms most commonly responsible for infected dog bites, as they are for other skin and soft-tissue infections.¹P canis is unique to dog bite infections but accounts for only 18%.²E rhusiopathiae is an unusual isolate from cat and dog bites and is more commonly isolated from the mouths of fish and aquatic mammals. C canimorsus is a normal inhabitant of the oral cavity of dogs and cats but an unusual cause of wound infection from a dog bite. It is notable for sepsis and central nervous system infections uniquely associated with veterinarians, dog owners, kennel workers, and mail carriers.³E corrodens infection is more common with human bites.⁴

THE EVALUATION BEGINS

On examination, the patient had marked edema of the left forearm and pain in the joints of the left hand. His temperature was 100.2°F (37.9°C). Because of the duration and severity of symptoms, the examining physician was concerned about septic arthritis of the wrist, and the patient was admitted to the hospital.

In the hospital, our patient was thermodynamically stable without documented fever or chills. There was no open wound to culture, and blood cultures were negative. Marked edema and joint involvement raised suspicion of erysipeloid. This “cousin” of erysipelas often involves the underlying joint, is associated with edema, and produces systemic manifestations of fever and arthralgia.

Radiography of the left forearm and hand demonstrated multiple foci of demineralization within the carpal bones and proximal radius, attributed to disuse. Magnetic resonance imaging (MRI) the next day showed multiple bone infarcts in the carpal bones and the distal radius, with synovitis and fluid in the carpal joints and without adjacent osteomyelitis. Fluid was also seen in the soft tissues in the ulnar aspect of the left wrist, and tenosynovitis involving the flexor carpi radialis tendon was noted.

Arthrocentesis of his left radiocarpal joint produced synovial fluid negative for crystals and negative on Gram stain; the fluid was also sent for culture. The patient’s tetanus immunization was current, and the dog was known to have been immunized against rabies.

ANTIBIOTICS FOR INFECTED DOG BITES

2. Which antibiotic regimen would you choose for this patient?

• Oral amoxicillin and clavulanate
• Meropenem
• Vancomycin, clindamycin, aztreonam
• Clindamycin and levofloxacin
• Clindamycin and trimethoprim-sulfamethoxazole

Oral amoxicillin and clavulanate (Augmentin) is a judicious choice for prophylactic treatment of deep bites in the early stages of infection. However, our patient’s wound was no longer in the early stages of infection, and he had a history of an adverse reaction to penicillin.

Meropenem (Merrem IV) cross-reacts minimally with penicillin allergy and is reported to be safe in patients with a history of anaphylactic reactions to penicillin,⁵ but overuse of carbapenems has led to the development of carbapenem-resistant strains of Klebsiella, Stenotrophomonas, and Acinetobacter organisms.

Given the rise of MRSA infections and the common involvement of staphylococci, streptococci, and anaerobic bacteria in complicated dog bites, the combination of vancomycin and clindamycin is a good choice, and aztreonam (Azactam) would add empiric coverage of gram-negative enteric organisms.

Levofloxacin (Levaquin) also covers gramnegative enteric organisms, but Fusobacterium canifelinum, a common anaerobe in the oral flora of dogs and cats, is intrinsically resistant to fluoroquinolones.

Clindamycin and levofloxacin would be a good step-down oral regimen. Pasteurella multocida has variable sensitivity to the commonly used agents dicloxacillin (Dynapen), cephalexin (Keflex), macrolides, and clindamycin, but it is a less likely pathogen at this late stage and could be covered with levofloxacin alone.

C canimorsus is resistant to trimethoprim-sulfamethoxazole (Bactrim) and cephalexin, but is well covered by clindamycin.⁶

CASE CONTINUED

Our patient was started on intravenous vancomycin, clindamycin, and aztreonam for coverage of dog-mouth flora. Blood cultures and cultures of synovial fluid of the left wrist were negative. Vancomycin was discontinued after 48 hours when blood cultures did not grow staphylococcal organisms, but clindamycin and aztreonam were continued for a total of 8 days to treat possible infection with anaerobic and gram-negative enteric pathogens.

To test for autonomic dysfunction, a plastic pen case drawn lightly across each forearm revealed a loss of tactile adherence (ie, areas where moist, sweaty skin impeded the movement of the pen case) on the affected forearm, a sign of underlying nerve injury. The affected forearm was sensitive to light touch, with pain out of proportion to the stimulus.

ARRIVING AT THE DIAGNOSIS

Based on the wide distribution of inflammation, autonomic dysfunction (shown by differences in temperature and sweating), radiographic evidence of demineralization, hyperesthesia, and lack of improvement in pain and swelling after two courses of antibiotics, the patient’s clinical course was determined to be consistent with complex regional pain syndrome type 1, previously referred to as reflex sympathetic dystrophy.

Symptoms of complex regional pain syndrome traditionally include pain, regional edema, joint stiffness, muscular atrophy, vasomotor disturbances (causing temperature variability and erythema), regional diaphoresis, and localized skeletal demineralization on radiography.

Complex regional pain syndrome type 1 occurs as regional pain and inflammation as an excessive sympathetic reaction to an often minor insult, without nerve injury. When the syndrome occurs in a patient with obvious partial nerve injury, it is categorized as type 2 (formerly known as causalgia). The two types are clinically indistinguishable and are not uncommon. About 10% of all patients with complex regional pain syndrome have obvious nerve injury (complex regional pain syndrome type 2). In a study of 109 patients with Colles fracture, 25% developed symptoms of complex regional pain syndrome.⁷

Complex regional pain syndrome is difficult to diagnose, as it resembles many other ailments, such as gout, infection, bone tumor, stress fracture, and arthritis. Its pathophysiology is poorly understood, but it is believed to result from a “short circuit” in the reflex arc between somatic afferent sensory fibers and autonomic sympathetic efferent fibers, and this is thought to explain the increased sympathetic stimulation.

Although the pathophysiology is likely the same in type 1 and type 2, electromyography with a nerve conduction study is a reliable way to detect nerve damage and thus distinguish between the two types of complex regional pain syndrome.⁸

Our understanding of this syndrome is evolving. A recent study using sensory testing showed that 33% of patients with type 1 had combinations of increased and decreased thresholds for the detection of thermal, vibratory, and mechanical stimuli in the distribution of discrete peripheral nerves, suggesting that the patients actually had type 2.⁹

CONFIRMING COMPLEX REGIONAL PAIN SYNDROME TYPE 1

3. Which of the following is the best way to confirm complex regional pain syndrome type 1?

• Erythrocyte sedimentation rate, C-reactive protein, and complete blood cell count
• Plain radiography of the hand and forearm
• Three-phase technetium bone scan
• The Budapest diagnostic criteria
• MRI
• Autonomic testing

Complex regional pain syndrome type 1 is a clinical diagnosis. Diagnostic studies lack sensitivity and specificity but may confirm complex regional pain syndrome type 1 or rule out other diagnoses. The Budapest diagnostic criteria¹⁰ (Table 1) may be the best way to confirm this diagnosis. The criteria are as follows: continuing pain disproportionate to an inciting event, coupled with three of four symptoms plus at least one sign from sensory, vasomotor, sudomotor, and motor-trophic categories.

Laboratory tests are not helpful because acute-phase reactants and blood counts remain normal in these patients.

Plain radiography is not sensitive in early diagnosis, but at 2 weeks it may show patchy areas of osteopenia in adjacent bones throughout the region, as well as subsequent diffuse demineralization.

Three-phase bone scanning is more sensitive than plain radiography, with 75% of patients showing regional disparities in blood flow in early sequences and increased bone uptake in the later sequences.

MRI is a sensitive early test, as it better defines focal areas of bone loss and increased T2 bone signal in adjacent bone, as well as early soft-tissue changes. Computed tomography does not show early specific changes in muscle, tendon, or bone and so is not recommended.

THE EVALUATION CONTINUES

The admitting diagnosis was septic arthritis, and our patient underwent computed tomography, which showed focal demineralization that could have represented bone infarcts or infection, confounding the diagnosis of complex regional pain syndrome.

Autonomic nerve testing can help distinguish complex regional pain syndrome from other disorders. Complex regional pain syndrome is characterized by increased sympathetic activity and results in increased sweat output. Autonomic testing includes resting sweat output, resting skin temperature, and quantitative sudomotor axon reflex testing. In one study, an increase in resting sweat output used in conjunction with quantitative sudomotor axon reflex testing predicted the diagnosis of complex regional pain syndrome with a specificity of 98%.¹¹ However, autonomic testing is limited to academic centers and is not readily available.

TREATING COMPLEX REGIONAL PAIN SYNDROME TYPE 1

4. Which is the best first-line therapy for complex regional pain syndrome type 1?

• Stellate ganglion nerve block
• Occupational therapy to splint the wrist and forearm
• Oral corticosteroids
• Physical therapy to prevent loss of joint motion
• Tricyclic antidepressant drugs (eg, amitriptyline), pregabalin, and bisphosphonates

Physical therapy should be started early in all patients, with range-of-motion exercises to prevent contracture and enhance mobility.

Stellate ganglion nerve block has been used to counter severe sympathetic hyperactivity, but it also may aggravate symptoms of complex regional pain syndrome and so remains a controversial treatment.

Immobilization and splinting should be avoided, as this will augment edema, pain, and contracture of joints.

Corticosteroids do not shorten the course or assuage symptoms and may increase edema.

Amitriptyline (Elavil) and pregabalin (Lyrica) have been used successfully to counter extended courses of allodynia and hyperalgesia. Bisphosphonates may decrease bone loss and pain and may be needed should the course be complicated by myositis ossificans, a form of dystrophic bone formation in juxtaposed tendon and muscle related to neuroactivation of fibroblasts and osteoblasts.

THE COURSE OF COMPLEX REGIONAL PAIN SYNDROME

Traditionally, type 1 was divided into three stages—an early inflammatory stage, a dystrophic stage, and a late atrophic stage.¹² Although there is no evidence to support a consistent three-stage evolution, the severity of symptoms may help determine the best approach to management.¹³

Patients initially exhibit burning or throbbing pain, diffuse aching, sensitivity to touch or cold (allodynia), localized edema, and vasomotor disturbances of variable intensity that may produce altered color and temperature. Topical capsaicin cream; a tricyclic antidepressant; an anticonvulsant such as gabapentin (Neurontin), pregabalin, or lamotrigine (Lamictal); or a nonsteroidal anti-inflammatory drug should be tried first. Some of these treatments are poorly tolerated in elderly patients. If pain persists, nasal calcitonin may be added. Trigger-point injections with an anesthetic or glucocorticoid may be tried.

The management of early complex regional pain syndrome is sometimes supplemented with systemic corticosteroids, but reviews of randomized controlled trials have failed to show efficacy.¹⁴

Later in the course, patients may suffer persistent soft-tissue edema, accompanied by thickening of the skin and periarticular soft tissues, muscle wasting, and the skin changes of brawny edema. Regional blockade of sympathetic ganglions, epidural administration of clonidine, implantable peripheral nerve stimulators, and spinal cord stimulators have all been applied by experts in pain management and may provide benefit. Progression of the syndrome may include cyanosis, mottling, increased sweating, abnormal hair growth, and diffuse swelling in nonarticular tissue.

It is always acceptable to refer to an experienced pain management specialist, and a multidisciplinary approach is recommended at the outset.¹²

OUR PATIENT’S CARE CONTINUED

Our patient’s forearm and wrist were placed in a sling to keep his left arm elevated when active. This helped control sympathetic vascular edema and throbbing pain. Physical therapy with range-of-motion exercises prevented contracture.

He was discharged home on limited oxycodone as needed, with close follow-up by his primary care physician to monitor his pain symptoms. The pain and swelling slowly improved over the next 2 months, but he suffered a fall, twisting his left wrist. This minor injury was followed by more intense pain and swelling of the forearm, hand, and wrist.

COMORBIDITIES

5. Which of the following statements about conditions associated with complex regional pain syndrome most likely applies to our patient?

• Gout is likely following minor trauma
• Minor trauma or surgical bone biopsy may reactivate complex regional pain syndrome
• Septic hip arthritis due to MRSA may have reemerged and seeded the wrist
• Patients with multiple sclerosis have a propensity for complex regional pain syndrome
• Complex regional pain syndrome type 1 begets type 2

Gout does follow minor injury, but our patient’s uric acid was well controlled on allopurinol (Zyloprim), and gout is unlikely to be causing polyarticular swelling of the hand, wrist, and forearm.

Minor trauma, sometimes inconsequential enough to have been completely forgotten, may either initiate complex regional pain syndrome or, as seen here, reactivate it. Bone changes seen on MRI sometimes trigger surgical bone biopsy, only to reactivate the dysesthesia and sympathetic vascular reaction. Surgery should be avoided. Trauma and surgery are causative rather than associative comorbidities.

Sepsis due to MRSA after total hip arthroplasty may be reactivated, especially in the setting of immunosuppressive treatment. But the diffuse bone changes seen in multiple carpal, radial, and ulnar bones suggest generalized vascular and sympathetic disarray, most consistent with complex regional pain syndrome type 1.

AN ASSOCIATION WITH MULTIPLE SCLEROSIS?

Multiple sclerosis and other central neuropathic conditions such as stroke are associated with complex regional pain syndrome type 1.^15,16

A hypothetical cause for the higher prevalence of complex regional pain syndrome in patients with multiple sclerosis may be demyelination resulting in aberrant signaling and overreaction to distal pain receptors. Demyelination of neurons within the autonomic or spinothalamic tracts potentially increases susceptibility to development of the pain syndrome.

Our patient had an apparent stimulus for the development of the syndrome, ie, the initial dog bite, and the wrist injury later may have caused peripheral nerve injury. Such injury may lead to release of vasodilatory neuropeptides including substance P from stimulated cutaneous nerves with cell bodies in the dorsal root ganglia. Excessive vasodilation and increased vascular permeability result in the affected limb becoming edematous and causing cutaneous nerves to be further activated. Stimulated cutaneous neurons normally have an inhibitory influence on sympathetic activity at the level of entry of the dorsal root ganglia in the cord. In complex regional pain syndrome, this inhibition is lost, resulting in a hyperactive somatosympathetic reflex.¹⁷ Underlying multiple sclerosis may have contributed to the loss of inhibition by the cutaneous nerves on the sympathetic system.

CASE CONCLUDED

We continued to closely follow this patient, who was on a self-directed program of physical therapy. One year after the original dog bite, the complex regional pain syndrome had completely resolved.

A 48-year-old man with gout, multiple sclerosis, and previously treated methicillin-resistant Staphylococcus aureus (MRSA) infection presented to the emergency room with pain and significant swelling at the site of a dog bite on his left forearm. He had been bitten 2 weeks earlier by a friend’s dog, and the bite had punctured the skin. He also had red streaking on the skin of the left arm from the wrist to the elbow, and he reported feeling “feverish” and having night sweats.

At first, the bite had seemed to improve, then swelling and pain had developed and increased. He reported this to his primary care physician, along with the information that he had previously had an anaphylactic reaction to penicillin and a cephalosporin. His physician, considering a penicillin allergy, started him on ciprofloxacin (Cipro) plus clindamycin (Cleocin). The patient took this for 5 days, but without improvement. The appearance of the red streaking on his left forearm prompted his presentation to our emergency room.

ORGANISMS IN DOG BITES

1. Which is the most common cause of infected dog bite?

• Pasteurella canis
• Streptococci and S aureus
• Erysipelothrix rhusiopathiae
• Capnocytophaga canimorsus
• Eikenella corrodens

Streptococci (50%) and S aureus (20% to 40%) are the organisms most commonly responsible for infected dog bites, as they are for other skin and soft-tissue infections.¹P canis is unique to dog bite infections but accounts for only 18%.²E rhusiopathiae is an unusual isolate from cat and dog bites and is more commonly isolated from the mouths of fish and aquatic mammals. C canimorsus is a normal inhabitant of the oral cavity of dogs and cats but an unusual cause of wound infection from a dog bite. It is notable for sepsis and central nervous system infections uniquely associated with veterinarians, dog owners, kennel workers, and mail carriers.³E corrodens infection is more common with human bites.⁴

THE EVALUATION BEGINS

On examination, the patient had marked edema of the left forearm and pain in the joints of the left hand. His temperature was 100.2°F (37.9°C). Because of the duration and severity of symptoms, the examining physician was concerned about septic arthritis of the wrist, and the patient was admitted to the hospital.

In the hospital, our patient was thermodynamically stable without documented fever or chills. There was no open wound to culture, and blood cultures were negative. Marked edema and joint involvement raised suspicion of erysipeloid. This “cousin” of erysipelas often involves the underlying joint, is associated with edema, and produces systemic manifestations of fever and arthralgia.

Radiography of the left forearm and hand demonstrated multiple foci of demineralization within the carpal bones and proximal radius, attributed to disuse. Magnetic resonance imaging (MRI) the next day showed multiple bone infarcts in the carpal bones and the distal radius, with synovitis and fluid in the carpal joints and without adjacent osteomyelitis. Fluid was also seen in the soft tissues in the ulnar aspect of the left wrist, and tenosynovitis involving the flexor carpi radialis tendon was noted.

Arthrocentesis of his left radiocarpal joint produced synovial fluid negative for crystals and negative on Gram stain; the fluid was also sent for culture. The patient’s tetanus immunization was current, and the dog was known to have been immunized against rabies.

ANTIBIOTICS FOR INFECTED DOG BITES

2. Which antibiotic regimen would you choose for this patient?

• Oral amoxicillin and clavulanate
• Meropenem
• Vancomycin, clindamycin, aztreonam
• Clindamycin and levofloxacin
• Clindamycin and trimethoprim-sulfamethoxazole

Oral amoxicillin and clavulanate (Augmentin) is a judicious choice for prophylactic treatment of deep bites in the early stages of infection. However, our patient’s wound was no longer in the early stages of infection, and he had a history of an adverse reaction to penicillin.

Meropenem (Merrem IV) cross-reacts minimally with penicillin allergy and is reported to be safe in patients with a history of anaphylactic reactions to penicillin,⁵ but overuse of carbapenems has led to the development of carbapenem-resistant strains of Klebsiella, Stenotrophomonas, and Acinetobacter organisms.

Given the rise of MRSA infections and the common involvement of staphylococci, streptococci, and anaerobic bacteria in complicated dog bites, the combination of vancomycin and clindamycin is a good choice, and aztreonam (Azactam) would add empiric coverage of gram-negative enteric organisms.

Levofloxacin (Levaquin) also covers gramnegative enteric organisms, but Fusobacterium canifelinum, a common anaerobe in the oral flora of dogs and cats, is intrinsically resistant to fluoroquinolones.

Clindamycin and levofloxacin would be a good step-down oral regimen. Pasteurella multocida has variable sensitivity to the commonly used agents dicloxacillin (Dynapen), cephalexin (Keflex), macrolides, and clindamycin, but it is a less likely pathogen at this late stage and could be covered with levofloxacin alone.

C canimorsus is resistant to trimethoprim-sulfamethoxazole (Bactrim) and cephalexin, but is well covered by clindamycin.⁶

CASE CONTINUED

Our patient was started on intravenous vancomycin, clindamycin, and aztreonam for coverage of dog-mouth flora. Blood cultures and cultures of synovial fluid of the left wrist were negative. Vancomycin was discontinued after 48 hours when blood cultures did not grow staphylococcal organisms, but clindamycin and aztreonam were continued for a total of 8 days to treat possible infection with anaerobic and gram-negative enteric pathogens.

To test for autonomic dysfunction, a plastic pen case drawn lightly across each forearm revealed a loss of tactile adherence (ie, areas where moist, sweaty skin impeded the movement of the pen case) on the affected forearm, a sign of underlying nerve injury. The affected forearm was sensitive to light touch, with pain out of proportion to the stimulus.

ARRIVING AT THE DIAGNOSIS

Based on the wide distribution of inflammation, autonomic dysfunction (shown by differences in temperature and sweating), radiographic evidence of demineralization, hyperesthesia, and lack of improvement in pain and swelling after two courses of antibiotics, the patient’s clinical course was determined to be consistent with complex regional pain syndrome type 1, previously referred to as reflex sympathetic dystrophy.

Symptoms of complex regional pain syndrome traditionally include pain, regional edema, joint stiffness, muscular atrophy, vasomotor disturbances (causing temperature variability and erythema), regional diaphoresis, and localized skeletal demineralization on radiography.

Complex regional pain syndrome type 1 occurs as regional pain and inflammation as an excessive sympathetic reaction to an often minor insult, without nerve injury. When the syndrome occurs in a patient with obvious partial nerve injury, it is categorized as type 2 (formerly known as causalgia). The two types are clinically indistinguishable and are not uncommon. About 10% of all patients with complex regional pain syndrome have obvious nerve injury (complex regional pain syndrome type 2). In a study of 109 patients with Colles fracture, 25% developed symptoms of complex regional pain syndrome.⁷

Complex regional pain syndrome is difficult to diagnose, as it resembles many other ailments, such as gout, infection, bone tumor, stress fracture, and arthritis. Its pathophysiology is poorly understood, but it is believed to result from a “short circuit” in the reflex arc between somatic afferent sensory fibers and autonomic sympathetic efferent fibers, and this is thought to explain the increased sympathetic stimulation.

Although the pathophysiology is likely the same in type 1 and type 2, electromyography with a nerve conduction study is a reliable way to detect nerve damage and thus distinguish between the two types of complex regional pain syndrome.⁸

Our understanding of this syndrome is evolving. A recent study using sensory testing showed that 33% of patients with type 1 had combinations of increased and decreased thresholds for the detection of thermal, vibratory, and mechanical stimuli in the distribution of discrete peripheral nerves, suggesting that the patients actually had type 2.⁹

CONFIRMING COMPLEX REGIONAL PAIN SYNDROME TYPE 1

3. Which of the following is the best way to confirm complex regional pain syndrome type 1?

• Erythrocyte sedimentation rate, C-reactive protein, and complete blood cell count
• Plain radiography of the hand and forearm
• Three-phase technetium bone scan
• The Budapest diagnostic criteria
• MRI
• Autonomic testing

Complex regional pain syndrome type 1 is a clinical diagnosis. Diagnostic studies lack sensitivity and specificity but may confirm complex regional pain syndrome type 1 or rule out other diagnoses. The Budapest diagnostic criteria¹⁰ (Table 1) may be the best way to confirm this diagnosis. The criteria are as follows: continuing pain disproportionate to an inciting event, coupled with three of four symptoms plus at least one sign from sensory, vasomotor, sudomotor, and motor-trophic categories.

Laboratory tests are not helpful because acute-phase reactants and blood counts remain normal in these patients.

Plain radiography is not sensitive in early diagnosis, but at 2 weeks it may show patchy areas of osteopenia in adjacent bones throughout the region, as well as subsequent diffuse demineralization.

Three-phase bone scanning is more sensitive than plain radiography, with 75% of patients showing regional disparities in blood flow in early sequences and increased bone uptake in the later sequences.

MRI is a sensitive early test, as it better defines focal areas of bone loss and increased T2 bone signal in adjacent bone, as well as early soft-tissue changes. Computed tomography does not show early specific changes in muscle, tendon, or bone and so is not recommended.

THE EVALUATION CONTINUES

The admitting diagnosis was septic arthritis, and our patient underwent computed tomography, which showed focal demineralization that could have represented bone infarcts or infection, confounding the diagnosis of complex regional pain syndrome.

Autonomic nerve testing can help distinguish complex regional pain syndrome from other disorders. Complex regional pain syndrome is characterized by increased sympathetic activity and results in increased sweat output. Autonomic testing includes resting sweat output, resting skin temperature, and quantitative sudomotor axon reflex testing. In one study, an increase in resting sweat output used in conjunction with quantitative sudomotor axon reflex testing predicted the diagnosis of complex regional pain syndrome with a specificity of 98%.¹¹ However, autonomic testing is limited to academic centers and is not readily available.

TREATING COMPLEX REGIONAL PAIN SYNDROME TYPE 1

4. Which is the best first-line therapy for complex regional pain syndrome type 1?

• Stellate ganglion nerve block
• Occupational therapy to splint the wrist and forearm
• Oral corticosteroids
• Physical therapy to prevent loss of joint motion
• Tricyclic antidepressant drugs (eg, amitriptyline), pregabalin, and bisphosphonates

Physical therapy should be started early in all patients, with range-of-motion exercises to prevent contracture and enhance mobility.

Stellate ganglion nerve block has been used to counter severe sympathetic hyperactivity, but it also may aggravate symptoms of complex regional pain syndrome and so remains a controversial treatment.

Immobilization and splinting should be avoided, as this will augment edema, pain, and contracture of joints.

Corticosteroids do not shorten the course or assuage symptoms and may increase edema.

Amitriptyline (Elavil) and pregabalin (Lyrica) have been used successfully to counter extended courses of allodynia and hyperalgesia. Bisphosphonates may decrease bone loss and pain and may be needed should the course be complicated by myositis ossificans, a form of dystrophic bone formation in juxtaposed tendon and muscle related to neuroactivation of fibroblasts and osteoblasts.

THE COURSE OF COMPLEX REGIONAL PAIN SYNDROME

Traditionally, type 1 was divided into three stages—an early inflammatory stage, a dystrophic stage, and a late atrophic stage.¹² Although there is no evidence to support a consistent three-stage evolution, the severity of symptoms may help determine the best approach to management.¹³

Patients initially exhibit burning or throbbing pain, diffuse aching, sensitivity to touch or cold (allodynia), localized edema, and vasomotor disturbances of variable intensity that may produce altered color and temperature. Topical capsaicin cream; a tricyclic antidepressant; an anticonvulsant such as gabapentin (Neurontin), pregabalin, or lamotrigine (Lamictal); or a nonsteroidal anti-inflammatory drug should be tried first. Some of these treatments are poorly tolerated in elderly patients. If pain persists, nasal calcitonin may be added. Trigger-point injections with an anesthetic or glucocorticoid may be tried.

The management of early complex regional pain syndrome is sometimes supplemented with systemic corticosteroids, but reviews of randomized controlled trials have failed to show efficacy.¹⁴

Later in the course, patients may suffer persistent soft-tissue edema, accompanied by thickening of the skin and periarticular soft tissues, muscle wasting, and the skin changes of brawny edema. Regional blockade of sympathetic ganglions, epidural administration of clonidine, implantable peripheral nerve stimulators, and spinal cord stimulators have all been applied by experts in pain management and may provide benefit. Progression of the syndrome may include cyanosis, mottling, increased sweating, abnormal hair growth, and diffuse swelling in nonarticular tissue.

It is always acceptable to refer to an experienced pain management specialist, and a multidisciplinary approach is recommended at the outset.¹²

OUR PATIENT’S CARE CONTINUED

Our patient’s forearm and wrist were placed in a sling to keep his left arm elevated when active. This helped control sympathetic vascular edema and throbbing pain. Physical therapy with range-of-motion exercises prevented contracture.

He was discharged home on limited oxycodone as needed, with close follow-up by his primary care physician to monitor his pain symptoms. The pain and swelling slowly improved over the next 2 months, but he suffered a fall, twisting his left wrist. This minor injury was followed by more intense pain and swelling of the forearm, hand, and wrist.

COMORBIDITIES

5. Which of the following statements about conditions associated with complex regional pain syndrome most likely applies to our patient?

• Gout is likely following minor trauma
• Minor trauma or surgical bone biopsy may reactivate complex regional pain syndrome
• Septic hip arthritis due to MRSA may have reemerged and seeded the wrist
• Patients with multiple sclerosis have a propensity for complex regional pain syndrome
• Complex regional pain syndrome type 1 begets type 2

Gout does follow minor injury, but our patient’s uric acid was well controlled on allopurinol (Zyloprim), and gout is unlikely to be causing polyarticular swelling of the hand, wrist, and forearm.

Minor trauma, sometimes inconsequential enough to have been completely forgotten, may either initiate complex regional pain syndrome or, as seen here, reactivate it. Bone changes seen on MRI sometimes trigger surgical bone biopsy, only to reactivate the dysesthesia and sympathetic vascular reaction. Surgery should be avoided. Trauma and surgery are causative rather than associative comorbidities.

Sepsis due to MRSA after total hip arthroplasty may be reactivated, especially in the setting of immunosuppressive treatment. But the diffuse bone changes seen in multiple carpal, radial, and ulnar bones suggest generalized vascular and sympathetic disarray, most consistent with complex regional pain syndrome type 1.

AN ASSOCIATION WITH MULTIPLE SCLEROSIS?

Multiple sclerosis and other central neuropathic conditions such as stroke are associated with complex regional pain syndrome type 1.^15,16

A hypothetical cause for the higher prevalence of complex regional pain syndrome in patients with multiple sclerosis may be demyelination resulting in aberrant signaling and overreaction to distal pain receptors. Demyelination of neurons within the autonomic or spinothalamic tracts potentially increases susceptibility to development of the pain syndrome.

Our patient had an apparent stimulus for the development of the syndrome, ie, the initial dog bite, and the wrist injury later may have caused peripheral nerve injury. Such injury may lead to release of vasodilatory neuropeptides including substance P from stimulated cutaneous nerves with cell bodies in the dorsal root ganglia. Excessive vasodilation and increased vascular permeability result in the affected limb becoming edematous and causing cutaneous nerves to be further activated. Stimulated cutaneous neurons normally have an inhibitory influence on sympathetic activity at the level of entry of the dorsal root ganglia in the cord. In complex regional pain syndrome, this inhibition is lost, resulting in a hyperactive somatosympathetic reflex.¹⁷ Underlying multiple sclerosis may have contributed to the loss of inhibition by the cutaneous nerves on the sympathetic system.

CASE CONCLUDED

We continued to closely follow this patient, who was on a self-directed program of physical therapy. One year after the original dog bite, the complex regional pain syndrome had completely resolved.

Large-volume thoracentesis is defined as the drainage of more than 1 L of fluid. Inherent in this procedure is the removal of a large amount of fluid from a cavity with a rigid wall, which leads to changes in pleural pressure and to expansion of the lung. Two specific complications occur, pneumothorax and reexpansion pulmonary edema. The images submitted for the Clinical Picture article by Drs. Apter and Aronowitz in this issue of the Journal highlight these complications.

See related article

Retrospective studies have found an association between the amount of fluid drained and the incidence of pneumothorax.^1,2 Although technical issues may account for it (eg, needle injury to the lung that leads to postprocedural pneumothorax), the available evidence suggests that it has more to do with the drainage of larger volumes than the lung can expand to fill.^3,4 That is, the patient’s lung cannot expand,⁵ so drainage creates a vacuum, and air enters the pleural space³ through the lung parenchyma, or perhaps from around the drainage catheter.

In a series of patients who underwent therapeutic thoracentesis,³ 23 (8.7%) of 265 patients had pneumothorax. Interestingly, some patients had only symptoms, some had only excessively negative pressures (< 25 cm H₂O), some had both, and some had neither. Thus, there does not seem to be a reliable sign or symptom of an unexpanding lung, but pleural manometry may help increase its detection.⁶ This technique, however, is rarely used in clinical practice.

Another consequence of therapeutic thoracentesis is reexpansion pulmonary edema. This rare condition occurs only after large-volume thoracentesis or evacuation of a moderate to large pneumothorax.⁷ The pathophysiology behind this is controversial.⁸ As with pneumothorax, a large case series did not find a correlation between volume removed or pleural pressures and reexpansion pulmonary edema.⁷ Experimental data and analysis of case series^8–10 suggest that the duration of lung collapse and the speed of drainage and negative pressure applied contribute to the development of edema. Vacuum bottles are often used to speed drainage and to contain the large amount of fluid drained. These bottles have an initial negative pressure of about −723 mm Hg (personal communication with Baxter Healthcare Product information line), which may lead to rapid changes in lung volume and perhaps to higher negative pleural pressures.

Given the risks discussed above, we believe it is appropriate to avoid vacuum bottles and instead to use the syringe and one-way valve supplied in most thoracentesis kits. Further, pleural manometry to detect changes in pressure that suggest an unexpandable lung may lead to the appropriate early termination of a planned large-volume thoracentesis.³ The complications reported by Drs. Apter and Aronowitz are relatively rare and, at this point, unpredictable; therefore, generating high-quality evidence for prediction or management will be difficult. In the meantime, understanding the physiologic changes in the lung and the pleural space when draining large effusions from the chest may help avoid double trouble.

Large-volume thoracentesis is defined as the drainage of more than 1 L of fluid. Inherent in this procedure is the removal of a large amount of fluid from a cavity with a rigid wall, which leads to changes in pleural pressure and to expansion of the lung. Two specific complications occur, pneumothorax and reexpansion pulmonary edema. The images submitted for the Clinical Picture article by Drs. Apter and Aronowitz in this issue of the Journal highlight these complications.

See related article

Retrospective studies have found an association between the amount of fluid drained and the incidence of pneumothorax.^1,2 Although technical issues may account for it (eg, needle injury to the lung that leads to postprocedural pneumothorax), the available evidence suggests that it has more to do with the drainage of larger volumes than the lung can expand to fill.^3,4 That is, the patient’s lung cannot expand,⁵ so drainage creates a vacuum, and air enters the pleural space³ through the lung parenchyma, or perhaps from around the drainage catheter.

In a series of patients who underwent therapeutic thoracentesis,³ 23 (8.7%) of 265 patients had pneumothorax. Interestingly, some patients had only symptoms, some had only excessively negative pressures (< 25 cm H₂O), some had both, and some had neither. Thus, there does not seem to be a reliable sign or symptom of an unexpanding lung, but pleural manometry may help increase its detection.⁶ This technique, however, is rarely used in clinical practice.

Another consequence of therapeutic thoracentesis is reexpansion pulmonary edema. This rare condition occurs only after large-volume thoracentesis or evacuation of a moderate to large pneumothorax.⁷ The pathophysiology behind this is controversial.⁸ As with pneumothorax, a large case series did not find a correlation between volume removed or pleural pressures and reexpansion pulmonary edema.⁷ Experimental data and analysis of case series^8–10 suggest that the duration of lung collapse and the speed of drainage and negative pressure applied contribute to the development of edema. Vacuum bottles are often used to speed drainage and to contain the large amount of fluid drained. These bottles have an initial negative pressure of about −723 mm Hg (personal communication with Baxter Healthcare Product information line), which may lead to rapid changes in lung volume and perhaps to higher negative pleural pressures.

Given the risks discussed above, we believe it is appropriate to avoid vacuum bottles and instead to use the syringe and one-way valve supplied in most thoracentesis kits. Further, pleural manometry to detect changes in pressure that suggest an unexpandable lung may lead to the appropriate early termination of a planned large-volume thoracentesis.³ The complications reported by Drs. Apter and Aronowitz are relatively rare and, at this point, unpredictable; therefore, generating high-quality evidence for prediction or management will be difficult. In the meantime, understanding the physiologic changes in the lung and the pleural space when draining large effusions from the chest may help avoid double trouble.

Large-volume thoracentesis is defined as the drainage of more than 1 L of fluid. Inherent in this procedure is the removal of a large amount of fluid from a cavity with a rigid wall, which leads to changes in pleural pressure and to expansion of the lung. Two specific complications occur, pneumothorax and reexpansion pulmonary edema. The images submitted for the Clinical Picture article by Drs. Apter and Aronowitz in this issue of the Journal highlight these complications.

See related article

Retrospective studies have found an association between the amount of fluid drained and the incidence of pneumothorax.^1,2 Although technical issues may account for it (eg, needle injury to the lung that leads to postprocedural pneumothorax), the available evidence suggests that it has more to do with the drainage of larger volumes than the lung can expand to fill.^3,4 That is, the patient’s lung cannot expand,⁵ so drainage creates a vacuum, and air enters the pleural space³ through the lung parenchyma, or perhaps from around the drainage catheter.

In a series of patients who underwent therapeutic thoracentesis,³ 23 (8.7%) of 265 patients had pneumothorax. Interestingly, some patients had only symptoms, some had only excessively negative pressures (< 25 cm H₂O), some had both, and some had neither. Thus, there does not seem to be a reliable sign or symptom of an unexpanding lung, but pleural manometry may help increase its detection.⁶ This technique, however, is rarely used in clinical practice.

Another consequence of therapeutic thoracentesis is reexpansion pulmonary edema. This rare condition occurs only after large-volume thoracentesis or evacuation of a moderate to large pneumothorax.⁷ The pathophysiology behind this is controversial.⁸ As with pneumothorax, a large case series did not find a correlation between volume removed or pleural pressures and reexpansion pulmonary edema.⁷ Experimental data and analysis of case series^8–10 suggest that the duration of lung collapse and the speed of drainage and negative pressure applied contribute to the development of edema. Vacuum bottles are often used to speed drainage and to contain the large amount of fluid drained. These bottles have an initial negative pressure of about −723 mm Hg (personal communication with Baxter Healthcare Product information line), which may lead to rapid changes in lung volume and perhaps to higher negative pleural pressures.

Given the risks discussed above, we believe it is appropriate to avoid vacuum bottles and instead to use the syringe and one-way valve supplied in most thoracentesis kits. Further, pleural manometry to detect changes in pressure that suggest an unexpandable lung may lead to the appropriate early termination of a planned large-volume thoracentesis.³ The complications reported by Drs. Apter and Aronowitz are relatively rare and, at this point, unpredictable; therefore, generating high-quality evidence for prediction or management will be difficult. In the meantime, understanding the physiologic changes in the lung and the pleural space when draining large effusions from the chest may help avoid double trouble.

ANSWER
Several findings are evident from this radiograph. First, the quality is slightly diminished due to the patient’s size and artifact from the backboard. The patient’s mediastinum is somewhat widened, which is concerning for possible occult chest/vascular injury. There is some haziness within the left apical region suggestive of a hemothorax; no definite pneumothorax is seen. The left clavicle is fractured and displaced, and the left scapula is fractured as well.

ANSWER
Several findings are evident from this radiograph. First, the quality is slightly diminished due to the patient’s size and artifact from the backboard. The patient’s mediastinum is somewhat widened, which is concerning for possible occult chest/vascular injury. There is some haziness within the left apical region suggestive of a hemothorax; no definite pneumothorax is seen. The left clavicle is fractured and displaced, and the left scapula is fractured as well.

ANSWER
Several findings are evident from this radiograph. First, the quality is slightly diminished due to the patient’s size and artifact from the backboard. The patient’s mediastinum is somewhat widened, which is concerning for possible occult chest/vascular injury. There is some haziness within the left apical region suggestive of a hemothorax; no definite pneumothorax is seen. The left clavicle is fractured and displaced, and the left scapula is fractured as well.