The Journal of Family Practice

A 38-year-old man sought care in the emergency department for an acute, pruritic, generalized cutaneous eruption that manifested in the intertriginous areas of the inner thighs, antecubital fossae, and axilla (FIGURE 1A). He reported associated chills, a 15-pound weight gain, and swelling of his inner thighs. Two weeks before presentation, he had received azithromycin for an upper respiratory tract infection. He was unsure if the rash developed prior to or after taking the medication. He was not taking any other medications and had no history of skin conditions.

On examination, the patient was afebrile and had bilateral thigh edema. Skin examination revealed background erythema with morbilliform papules, plaques, and patches on the bilateral flanks, back, buttocks, arms, legs, and central neck. Pinpoint pustules were present in the intertriginous sites and on the low back and buttocks. The laboratory evaluation revealed leukocytosis (11.0 × 10⁹ cells/L), increased levels of neutrophils and eosinophils, and an elevated C-reactive protein level (12.8 mg/L). The remaining laboratory results were unremarkable. The patient was referred to Dermatology.

An examination by the dermatologist 3 days later revealed small areas of annular desquamation with a few pinpoint pustules, mostly located on the inner thighs and buttocks (FIGURE 1B). Skin biopsies were taken from the anterior hip region. The histopathology revealed subacute dermatitis with mixed dermal inflammatory cells, including neutrophils and eosinophils, and discrete subcorneal spongiform pustules.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The acute rash with minute pustules and associated leukocytosis with neutrophilia and eosinophilia led to an early diagnosis of AGEP, which may have been triggered by azithromycin—the patient’s only recent medication. AGEP is a severe cutaneous eruption that may be associated with systemic involvement. Medications are usually implicated, and patients often seek urgent evaluation.

The development of pustules on an erythematous base in intertriginous areas should raise suspicion for acute generalized exanthematous pustulosis—particularly in patients taking medication.

AGEP typically begins as an acute eruption in the intertriginous sites of the axilla, groin, and neck, but often becomes more generalized.^1,2 The diagnosis is strongly suggested by the condition’s key features: fever (97% of cases) and leukocytosis (87%) with neutrophilia (91%) and eosinophilia (30%); leukocytosis peaks 4 days after pustulosis occurs and lasts for about 12 days.¹ Although common, fever is not always documented in patients with AGEP. ³ (Our patient was a case in point.) While not a key characteristic of AGEP, our patient’s weight gain was likely explained by the severe edema secondary to his inflammatory skin eruption.

Medications are implicated, but pathophysiology is unknown

In approximately 90% of AGEP cases, medications such as antibiotics and calcium channel blockers are implicated; however, the lack of such an association does not preclude the diagnosis.^1,4 In cases of drug reactions, the eruption typically develops 1 to 2 days after a medication is begun, and the pustules typically resolve in fewer than 15 days.⁵ In 17% of patients, systemic involvement can occur and can include the liver, kidneys, bone marrow, and lungs.⁶ A physical exam, review of systems, and a laboratory evaluation can help rule out systemic involvement and guide additional testing.

AGEP has an incidence of 1 to 5 cases per million people per year, affecting women slightly more frequently than men.⁷ While the pathophysiology is not well understood, AGEP and its differential diagnoses are categorized as T cell-related inflammatory responses.^4,7

Distinguishing AGEP from some look-alikes

There are at least 4 severe cutaneous eruptions that might be confused with AGEP, all of which may be associated with fever. They include: drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome; Stevens-Johnson syndrome (SJS); toxic epidermal necrolysis (TEN); and pustular psoriasis.^8-10 The clinical features that may help differentiate these conditions from AGEP include timeline, mucocutaneous features, organ system involvement, and histopathologic findings.^4,8

DRESS occurs 2 to 6 weeks after drug exposure, rather than a few days, as is seen with AGEP. It often involves morbilliform erythema and facial edema with substantial eosinophilia and possible nephritis, pneumonitis, myocarditis, and thyroiditis.⁹ Unlike AGEP, DRESS does not have a predilection for intertriginous anatomic locations.

SJS and TEN occur 1 to 3 weeks after drug exposure. These conditions manifest with the development of bullae, atypical targetoid lesions, painful dusky erythema, epidermal necrosis, and mucosal involvement at multiple sites. Tubular nephritis, tracheobronchial necrosis, and multisystem organ failure can occur, with reported mortality rates of 5% to 35%.^8,11

Pustular psoriasis is frequently confused with AGEP. However, AGEP usually develops fewer than 2 days after drug exposure, with pustules that begin in intertriginous sites, and there is associated neutrophilia and possible organ involvement.^1,8 Patients who have AGEP typically do not have a history of psoriasis, while patients with pustular psoriasis often do.⁷ A history of drug reaction is uncommon with pustular psoriasis (although rapid tapering of systemic corticosteroids in patients with psoriasis can trigger the development of pustular psoriasis), whereas a previous history of drug reaction is common in AGEP.^3,7

Patients who have acute generalized exanthematous pustulosis are not likely to have a history of psoriasis.

Discontinue medication, treat with corticosteroids

Patients who have AGEP, including those with systemic involvement, generally improve after the offending drug is discontinued and treatment with topical corticosteroids is initiated.⁶ A brief course of systemic corticosteroids can also be considered for patients with severe skin involvement or systemic involvement.³

Our patient was prescribed topical corticosteroid wet dressing treatments twice daily for 2 weeks. At the 2-week follow-up visit, the rash had completely cleared, and only minimal residual erythema was noted (FIGURE 2). The patient was instructed to avoid azithromycin.

CORRESPONDENCE
David A. Wetter, MD, Department of Dermatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905; [email protected].

A 38-year-old man sought care in the emergency department for an acute, pruritic, generalized cutaneous eruption that manifested in the intertriginous areas of the inner thighs, antecubital fossae, and axilla (FIGURE 1A). He reported associated chills, a 15-pound weight gain, and swelling of his inner thighs. Two weeks before presentation, he had received azithromycin for an upper respiratory tract infection. He was unsure if the rash developed prior to or after taking the medication. He was not taking any other medications and had no history of skin conditions.

On examination, the patient was afebrile and had bilateral thigh edema. Skin examination revealed background erythema with morbilliform papules, plaques, and patches on the bilateral flanks, back, buttocks, arms, legs, and central neck. Pinpoint pustules were present in the intertriginous sites and on the low back and buttocks. The laboratory evaluation revealed leukocytosis (11.0 × 10⁹ cells/L), increased levels of neutrophils and eosinophils, and an elevated C-reactive protein level (12.8 mg/L). The remaining laboratory results were unremarkable. The patient was referred to Dermatology.

An examination by the dermatologist 3 days later revealed small areas of annular desquamation with a few pinpoint pustules, mostly located on the inner thighs and buttocks (FIGURE 1B). Skin biopsies were taken from the anterior hip region. The histopathology revealed subacute dermatitis with mixed dermal inflammatory cells, including neutrophils and eosinophils, and discrete subcorneal spongiform pustules.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The acute rash with minute pustules and associated leukocytosis with neutrophilia and eosinophilia led to an early diagnosis of AGEP, which may have been triggered by azithromycin—the patient’s only recent medication. AGEP is a severe cutaneous eruption that may be associated with systemic involvement. Medications are usually implicated, and patients often seek urgent evaluation.

The development of pustules on an erythematous base in intertriginous areas should raise suspicion for acute generalized exanthematous pustulosis—particularly in patients taking medication.

AGEP typically begins as an acute eruption in the intertriginous sites of the axilla, groin, and neck, but often becomes more generalized.^1,2 The diagnosis is strongly suggested by the condition’s key features: fever (97% of cases) and leukocytosis (87%) with neutrophilia (91%) and eosinophilia (30%); leukocytosis peaks 4 days after pustulosis occurs and lasts for about 12 days.¹ Although common, fever is not always documented in patients with AGEP. ³ (Our patient was a case in point.) While not a key characteristic of AGEP, our patient’s weight gain was likely explained by the severe edema secondary to his inflammatory skin eruption.

Medications are implicated, but pathophysiology is unknown

In approximately 90% of AGEP cases, medications such as antibiotics and calcium channel blockers are implicated; however, the lack of such an association does not preclude the diagnosis.^1,4 In cases of drug reactions, the eruption typically develops 1 to 2 days after a medication is begun, and the pustules typically resolve in fewer than 15 days.⁵ In 17% of patients, systemic involvement can occur and can include the liver, kidneys, bone marrow, and lungs.⁶ A physical exam, review of systems, and a laboratory evaluation can help rule out systemic involvement and guide additional testing.

AGEP has an incidence of 1 to 5 cases per million people per year, affecting women slightly more frequently than men.⁷ While the pathophysiology is not well understood, AGEP and its differential diagnoses are categorized as T cell-related inflammatory responses.^4,7

Distinguishing AGEP from some look-alikes

There are at least 4 severe cutaneous eruptions that might be confused with AGEP, all of which may be associated with fever. They include: drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome; Stevens-Johnson syndrome (SJS); toxic epidermal necrolysis (TEN); and pustular psoriasis.^8-10 The clinical features that may help differentiate these conditions from AGEP include timeline, mucocutaneous features, organ system involvement, and histopathologic findings.^4,8

DRESS occurs 2 to 6 weeks after drug exposure, rather than a few days, as is seen with AGEP. It often involves morbilliform erythema and facial edema with substantial eosinophilia and possible nephritis, pneumonitis, myocarditis, and thyroiditis.⁹ Unlike AGEP, DRESS does not have a predilection for intertriginous anatomic locations.

SJS and TEN occur 1 to 3 weeks after drug exposure. These conditions manifest with the development of bullae, atypical targetoid lesions, painful dusky erythema, epidermal necrosis, and mucosal involvement at multiple sites. Tubular nephritis, tracheobronchial necrosis, and multisystem organ failure can occur, with reported mortality rates of 5% to 35%.^8,11

Pustular psoriasis is frequently confused with AGEP. However, AGEP usually develops fewer than 2 days after drug exposure, with pustules that begin in intertriginous sites, and there is associated neutrophilia and possible organ involvement.^1,8 Patients who have AGEP typically do not have a history of psoriasis, while patients with pustular psoriasis often do.⁷ A history of drug reaction is uncommon with pustular psoriasis (although rapid tapering of systemic corticosteroids in patients with psoriasis can trigger the development of pustular psoriasis), whereas a previous history of drug reaction is common in AGEP.^3,7

Patients who have acute generalized exanthematous pustulosis are not likely to have a history of psoriasis.

Discontinue medication, treat with corticosteroids

Patients who have AGEP, including those with systemic involvement, generally improve after the offending drug is discontinued and treatment with topical corticosteroids is initiated.⁶ A brief course of systemic corticosteroids can also be considered for patients with severe skin involvement or systemic involvement.³

Our patient was prescribed topical corticosteroid wet dressing treatments twice daily for 2 weeks. At the 2-week follow-up visit, the rash had completely cleared, and only minimal residual erythema was noted (FIGURE 2). The patient was instructed to avoid azithromycin.

CORRESPONDENCE
David A. Wetter, MD, Department of Dermatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905; [email protected].

A 38-year-old man sought care in the emergency department for an acute, pruritic, generalized cutaneous eruption that manifested in the intertriginous areas of the inner thighs, antecubital fossae, and axilla (FIGURE 1A). He reported associated chills, a 15-pound weight gain, and swelling of his inner thighs. Two weeks before presentation, he had received azithromycin for an upper respiratory tract infection. He was unsure if the rash developed prior to or after taking the medication. He was not taking any other medications and had no history of skin conditions.

On examination, the patient was afebrile and had bilateral thigh edema. Skin examination revealed background erythema with morbilliform papules, plaques, and patches on the bilateral flanks, back, buttocks, arms, legs, and central neck. Pinpoint pustules were present in the intertriginous sites and on the low back and buttocks. The laboratory evaluation revealed leukocytosis (11.0 × 10⁹ cells/L), increased levels of neutrophils and eosinophils, and an elevated C-reactive protein level (12.8 mg/L). The remaining laboratory results were unremarkable. The patient was referred to Dermatology.

An examination by the dermatologist 3 days later revealed small areas of annular desquamation with a few pinpoint pustules, mostly located on the inner thighs and buttocks (FIGURE 1B). Skin biopsies were taken from the anterior hip region. The histopathology revealed subacute dermatitis with mixed dermal inflammatory cells, including neutrophils and eosinophils, and discrete subcorneal spongiform pustules.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The acute rash with minute pustules and associated leukocytosis with neutrophilia and eosinophilia led to an early diagnosis of AGEP, which may have been triggered by azithromycin—the patient’s only recent medication. AGEP is a severe cutaneous eruption that may be associated with systemic involvement. Medications are usually implicated, and patients often seek urgent evaluation.

The development of pustules on an erythematous base in intertriginous areas should raise suspicion for acute generalized exanthematous pustulosis—particularly in patients taking medication.

AGEP typically begins as an acute eruption in the intertriginous sites of the axilla, groin, and neck, but often becomes more generalized.^1,2 The diagnosis is strongly suggested by the condition’s key features: fever (97% of cases) and leukocytosis (87%) with neutrophilia (91%) and eosinophilia (30%); leukocytosis peaks 4 days after pustulosis occurs and lasts for about 12 days.¹ Although common, fever is not always documented in patients with AGEP. ³ (Our patient was a case in point.) While not a key characteristic of AGEP, our patient’s weight gain was likely explained by the severe edema secondary to his inflammatory skin eruption.

Medications are implicated, but pathophysiology is unknown

In approximately 90% of AGEP cases, medications such as antibiotics and calcium channel blockers are implicated; however, the lack of such an association does not preclude the diagnosis.^1,4 In cases of drug reactions, the eruption typically develops 1 to 2 days after a medication is begun, and the pustules typically resolve in fewer than 15 days.⁵ In 17% of patients, systemic involvement can occur and can include the liver, kidneys, bone marrow, and lungs.⁶ A physical exam, review of systems, and a laboratory evaluation can help rule out systemic involvement and guide additional testing.

AGEP has an incidence of 1 to 5 cases per million people per year, affecting women slightly more frequently than men.⁷ While the pathophysiology is not well understood, AGEP and its differential diagnoses are categorized as T cell-related inflammatory responses.^4,7

Distinguishing AGEP from some look-alikes

There are at least 4 severe cutaneous eruptions that might be confused with AGEP, all of which may be associated with fever. They include: drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome; Stevens-Johnson syndrome (SJS); toxic epidermal necrolysis (TEN); and pustular psoriasis.^8-10 The clinical features that may help differentiate these conditions from AGEP include timeline, mucocutaneous features, organ system involvement, and histopathologic findings.^4,8

DRESS occurs 2 to 6 weeks after drug exposure, rather than a few days, as is seen with AGEP. It often involves morbilliform erythema and facial edema with substantial eosinophilia and possible nephritis, pneumonitis, myocarditis, and thyroiditis.⁹ Unlike AGEP, DRESS does not have a predilection for intertriginous anatomic locations.

SJS and TEN occur 1 to 3 weeks after drug exposure. These conditions manifest with the development of bullae, atypical targetoid lesions, painful dusky erythema, epidermal necrosis, and mucosal involvement at multiple sites. Tubular nephritis, tracheobronchial necrosis, and multisystem organ failure can occur, with reported mortality rates of 5% to 35%.^8,11

Pustular psoriasis is frequently confused with AGEP. However, AGEP usually develops fewer than 2 days after drug exposure, with pustules that begin in intertriginous sites, and there is associated neutrophilia and possible organ involvement.^1,8 Patients who have AGEP typically do not have a history of psoriasis, while patients with pustular psoriasis often do.⁷ A history of drug reaction is uncommon with pustular psoriasis (although rapid tapering of systemic corticosteroids in patients with psoriasis can trigger the development of pustular psoriasis), whereas a previous history of drug reaction is common in AGEP.^3,7

Patients who have acute generalized exanthematous pustulosis are not likely to have a history of psoriasis.

Discontinue medication, treat with corticosteroids

Patients who have AGEP, including those with systemic involvement, generally improve after the offending drug is discontinued and treatment with topical corticosteroids is initiated.⁶ A brief course of systemic corticosteroids can also be considered for patients with severe skin involvement or systemic involvement.³

Our patient was prescribed topical corticosteroid wet dressing treatments twice daily for 2 weeks. At the 2-week follow-up visit, the rash had completely cleared, and only minimal residual erythema was noted (FIGURE 2). The patient was instructed to avoid azithromycin.

CORRESPONDENCE
David A. Wetter, MD, Department of Dermatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905; [email protected].

ILLUSTRATIVE CASE

A 30-year-old G1P0 woman presents to your office for routine obstetric care at 18 weeks’ gestation. Her pregnancy has been uncomplicated, but her prenatal lab evaluation is notable for blood type A-negative. She wants to know if she really needs the anti-D immune globulin injection.

Rhesus (Rh)D-negative women carrying an RhD-positive fetus are at risk of developing anti-D antibodies, placing the fetus at risk for HDFN (hemolytic disease of the fetus and newborn). If undiagnosed and/or untreated, HDFN carries significant risk of perinatal morbidity and mortality.²

With routine postnatal anti-D immunoglobulin prophylaxis of RhD-negative women who delivered an RhD-positive child (which began around 1970), the risk of maternal alloimmunization was reduced from 16% to 1.12%-1.3%.^3-5 The risk was further reduced to approximately 0.28% with the addition of consistent prophylaxis at 28 weeks’ gestation.⁴ As a result, the current standard of care is to administer anti-D immunoglobulin at 28 weeks’ gestation, within 72 hours of delivery of an RhD-positive fetus, and after events with risk of fetal-to-maternal transfusion (eg, spontaneous, threatened, or induced abortion; invasive prenatal diagnostic procedures such as amniocentesis; blunt abdominal trauma; external cephalic version; second or third trimester antepartum bleeding).⁶

The problem of unnecessary Tx. However, under this current practice, many RhD-negative women are receiving anti-D immunoglobulin unnecessarily. This is because the fetus’s RhD status is not routinely known during the prenatal period.

Enter cell-free DNA testing. Cell-free DNA testing analyzes fragments of fetal DNA found in maternal blood. The use of cell-free DNA testing at 10 to 13 weeks’ gestation to screen for fetal chromosomal abnormalities is reliable (91%-99% sensitivity for trisomies 21, 18, and 13⁷) and becoming increasingly more common.

A notable meta-analysis. A 2017 meta-analysis of 30 studies of cell-free DNA testing of RhD status in the first and second trimester calculated a sensitivity of 99.3% (95% confidence interval [CI], 98.2-99.7) and a specificity of 98.4% (95% CI, 96.4-99.3).⁷ Denmark, the Netherlands, Sweden, France, and Finland are using this method routinely. As of this writing, the American College of Obstetricians and Gynecologists (ACOG) has not recommended the use of cell-free DNA RhD testing in the United States, but they do note that as the cost of the assay declines, this method may become preferred.⁸ The National Institute for Health and Care Excellence in England recommends its use as long as its cost remains below a set threshold.⁹

This study evaluated the accuracy of using cell-free DNA testing at 27 weeks’ gestation to determine fetal RhD status compared with serologic typing of cord blood at delivery.

Cell-free DNA test gets high marks in Netherlands trial

This large observational cohort trial from the Netherlands examined the accuracy of identifying RhD-positive fetuses using cell-free DNA isolates in maternal plasma. Over the 15-month study period, fetal RhD testing was conducted during Week 27 of gestation, and results were compared with those obtained using neonatal cord blood at birth. If the fetal RhD test was positive, providers administered 200 mcg anti-D immunoglobulin during the 30th week of gestation and within 48 hours of birth. If fetal RhD was negative, providers were told immunoglobulin was unnecessary.

Fetal RhD testing at 27 weeks’ gestation appears highly accurate and could reduce the unnecessary use of anti-D immunoglobulin when the fetal RhD is negative.

More than 32,000 RhD-negative women were screened. The cell-free DNA test showed fetal RhD-positive results 62% of the time and RhD-negative results in the remainder. Cord blood samples were available for 25,789 pregnancies (80%).

Sensitivity, specificity. The sensitivity for identifying fetal RhD was 99% and the specificity was 98%. Both negative and positive predictive values were 99%. Overall, there were 225 false-positive results and 9 false-negative results. In the 9 false negatives, 6 were due to a lack of fetal DNA in the sample and 3 were due to technical error (defined as an operator ignoring a failure of the robot pipetting the plasma or other technical failures).

The false-negative rate (0.03%) was lower than the predetermined estimated false-negative rate of cord blood serology (0.25%). In 22 of the supposed false positives, follow-up serology or molecular testing found an RhD gene was actually present, meaning the results of the neonatal cord blood serology in these cases were falsely negative. If you recalculate with these data in mind, the false-negative rate for fetal DNA testing was actually less than half that of typical serologic determination.

WHAT’S NEW

An accurate test with the potential to reduce unnecessary Tx

Fetal RhD testing at 27 weeks’ gestation appears to be highly accurate and could reduce the unnecessary use of anti-D immunoglobulin when the fetal RhD is negative.

Different results with different ethnicities?

Dutch participants are not necessarily reflective of the US population. Known variation in the rate of fetal RhD positivity among RhD-negative pregnant women by race and ethnicity could mean that the number of women able to forego anti-D-immunoglobulin prophylaxis would be different in the United States from that in other countries.

Also, in this study, polymerase chain reaction (PCR) for 2 RhD sequences was run in triplicate, and a computer-based algorithm was used to automatically score samples to provide results. For safe implementation, the cell-free fetal RhD DNA testing process would need to follow similar methods.

CHALLENGES TO IMPLEMENTATION

Test cost and availability are big unknowns

Cost and availability of the test may be barriers, but there is currently too little information on either subject in the United States to make a determination. A 2013 study indicated that the use of cell-free DNA testing to determine fetal RhD status was then approximately $682.¹⁰

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 30-year-old G1P0 woman presents to your office for routine obstetric care at 18 weeks’ gestation. Her pregnancy has been uncomplicated, but her prenatal lab evaluation is notable for blood type A-negative. She wants to know if she really needs the anti-D immune globulin injection.

Rhesus (Rh)D-negative women carrying an RhD-positive fetus are at risk of developing anti-D antibodies, placing the fetus at risk for HDFN (hemolytic disease of the fetus and newborn). If undiagnosed and/or untreated, HDFN carries significant risk of perinatal morbidity and mortality.²

With routine postnatal anti-D immunoglobulin prophylaxis of RhD-negative women who delivered an RhD-positive child (which began around 1970), the risk of maternal alloimmunization was reduced from 16% to 1.12%-1.3%.^3-5 The risk was further reduced to approximately 0.28% with the addition of consistent prophylaxis at 28 weeks’ gestation.⁴ As a result, the current standard of care is to administer anti-D immunoglobulin at 28 weeks’ gestation, within 72 hours of delivery of an RhD-positive fetus, and after events with risk of fetal-to-maternal transfusion (eg, spontaneous, threatened, or induced abortion; invasive prenatal diagnostic procedures such as amniocentesis; blunt abdominal trauma; external cephalic version; second or third trimester antepartum bleeding).⁶

The problem of unnecessary Tx. However, under this current practice, many RhD-negative women are receiving anti-D immunoglobulin unnecessarily. This is because the fetus’s RhD status is not routinely known during the prenatal period.

Enter cell-free DNA testing. Cell-free DNA testing analyzes fragments of fetal DNA found in maternal blood. The use of cell-free DNA testing at 10 to 13 weeks’ gestation to screen for fetal chromosomal abnormalities is reliable (91%-99% sensitivity for trisomies 21, 18, and 13⁷) and becoming increasingly more common.

A notable meta-analysis. A 2017 meta-analysis of 30 studies of cell-free DNA testing of RhD status in the first and second trimester calculated a sensitivity of 99.3% (95% confidence interval [CI], 98.2-99.7) and a specificity of 98.4% (95% CI, 96.4-99.3).⁷ Denmark, the Netherlands, Sweden, France, and Finland are using this method routinely. As of this writing, the American College of Obstetricians and Gynecologists (ACOG) has not recommended the use of cell-free DNA RhD testing in the United States, but they do note that as the cost of the assay declines, this method may become preferred.⁸ The National Institute for Health and Care Excellence in England recommends its use as long as its cost remains below a set threshold.⁹

This study evaluated the accuracy of using cell-free DNA testing at 27 weeks’ gestation to determine fetal RhD status compared with serologic typing of cord blood at delivery.

Cell-free DNA test gets high marks in Netherlands trial

This large observational cohort trial from the Netherlands examined the accuracy of identifying RhD-positive fetuses using cell-free DNA isolates in maternal plasma. Over the 15-month study period, fetal RhD testing was conducted during Week 27 of gestation, and results were compared with those obtained using neonatal cord blood at birth. If the fetal RhD test was positive, providers administered 200 mcg anti-D immunoglobulin during the 30th week of gestation and within 48 hours of birth. If fetal RhD was negative, providers were told immunoglobulin was unnecessary.

Fetal RhD testing at 27 weeks’ gestation appears highly accurate and could reduce the unnecessary use of anti-D immunoglobulin when the fetal RhD is negative.

More than 32,000 RhD-negative women were screened. The cell-free DNA test showed fetal RhD-positive results 62% of the time and RhD-negative results in the remainder. Cord blood samples were available for 25,789 pregnancies (80%).

Sensitivity, specificity. The sensitivity for identifying fetal RhD was 99% and the specificity was 98%. Both negative and positive predictive values were 99%. Overall, there were 225 false-positive results and 9 false-negative results. In the 9 false negatives, 6 were due to a lack of fetal DNA in the sample and 3 were due to technical error (defined as an operator ignoring a failure of the robot pipetting the plasma or other technical failures).

The false-negative rate (0.03%) was lower than the predetermined estimated false-negative rate of cord blood serology (0.25%). In 22 of the supposed false positives, follow-up serology or molecular testing found an RhD gene was actually present, meaning the results of the neonatal cord blood serology in these cases were falsely negative. If you recalculate with these data in mind, the false-negative rate for fetal DNA testing was actually less than half that of typical serologic determination.

WHAT’S NEW

An accurate test with the potential to reduce unnecessary Tx

Fetal RhD testing at 27 weeks’ gestation appears to be highly accurate and could reduce the unnecessary use of anti-D immunoglobulin when the fetal RhD is negative.

Different results with different ethnicities?

Dutch participants are not necessarily reflective of the US population. Known variation in the rate of fetal RhD positivity among RhD-negative pregnant women by race and ethnicity could mean that the number of women able to forego anti-D-immunoglobulin prophylaxis would be different in the United States from that in other countries.

Also, in this study, polymerase chain reaction (PCR) for 2 RhD sequences was run in triplicate, and a computer-based algorithm was used to automatically score samples to provide results. For safe implementation, the cell-free fetal RhD DNA testing process would need to follow similar methods.

CHALLENGES TO IMPLEMENTATION

Test cost and availability are big unknowns

Cost and availability of the test may be barriers, but there is currently too little information on either subject in the United States to make a determination. A 2013 study indicated that the use of cell-free DNA testing to determine fetal RhD status was then approximately $682.¹⁰

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 30-year-old G1P0 woman presents to your office for routine obstetric care at 18 weeks’ gestation. Her pregnancy has been uncomplicated, but her prenatal lab evaluation is notable for blood type A-negative. She wants to know if she really needs the anti-D immune globulin injection.

Rhesus (Rh)D-negative women carrying an RhD-positive fetus are at risk of developing anti-D antibodies, placing the fetus at risk for HDFN (hemolytic disease of the fetus and newborn). If undiagnosed and/or untreated, HDFN carries significant risk of perinatal morbidity and mortality.²

With routine postnatal anti-D immunoglobulin prophylaxis of RhD-negative women who delivered an RhD-positive child (which began around 1970), the risk of maternal alloimmunization was reduced from 16% to 1.12%-1.3%.^3-5 The risk was further reduced to approximately 0.28% with the addition of consistent prophylaxis at 28 weeks’ gestation.⁴ As a result, the current standard of care is to administer anti-D immunoglobulin at 28 weeks’ gestation, within 72 hours of delivery of an RhD-positive fetus, and after events with risk of fetal-to-maternal transfusion (eg, spontaneous, threatened, or induced abortion; invasive prenatal diagnostic procedures such as amniocentesis; blunt abdominal trauma; external cephalic version; second or third trimester antepartum bleeding).⁶

The problem of unnecessary Tx. However, under this current practice, many RhD-negative women are receiving anti-D immunoglobulin unnecessarily. This is because the fetus’s RhD status is not routinely known during the prenatal period.

Enter cell-free DNA testing. Cell-free DNA testing analyzes fragments of fetal DNA found in maternal blood. The use of cell-free DNA testing at 10 to 13 weeks’ gestation to screen for fetal chromosomal abnormalities is reliable (91%-99% sensitivity for trisomies 21, 18, and 13⁷) and becoming increasingly more common.

A notable meta-analysis. A 2017 meta-analysis of 30 studies of cell-free DNA testing of RhD status in the first and second trimester calculated a sensitivity of 99.3% (95% confidence interval [CI], 98.2-99.7) and a specificity of 98.4% (95% CI, 96.4-99.3).⁷ Denmark, the Netherlands, Sweden, France, and Finland are using this method routinely. As of this writing, the American College of Obstetricians and Gynecologists (ACOG) has not recommended the use of cell-free DNA RhD testing in the United States, but they do note that as the cost of the assay declines, this method may become preferred.⁸ The National Institute for Health and Care Excellence in England recommends its use as long as its cost remains below a set threshold.⁹

This study evaluated the accuracy of using cell-free DNA testing at 27 weeks’ gestation to determine fetal RhD status compared with serologic typing of cord blood at delivery.

Cell-free DNA test gets high marks in Netherlands trial

This large observational cohort trial from the Netherlands examined the accuracy of identifying RhD-positive fetuses using cell-free DNA isolates in maternal plasma. Over the 15-month study period, fetal RhD testing was conducted during Week 27 of gestation, and results were compared with those obtained using neonatal cord blood at birth. If the fetal RhD test was positive, providers administered 200 mcg anti-D immunoglobulin during the 30th week of gestation and within 48 hours of birth. If fetal RhD was negative, providers were told immunoglobulin was unnecessary.

Fetal RhD testing at 27 weeks’ gestation appears highly accurate and could reduce the unnecessary use of anti-D immunoglobulin when the fetal RhD is negative.

More than 32,000 RhD-negative women were screened. The cell-free DNA test showed fetal RhD-positive results 62% of the time and RhD-negative results in the remainder. Cord blood samples were available for 25,789 pregnancies (80%).

Sensitivity, specificity. The sensitivity for identifying fetal RhD was 99% and the specificity was 98%. Both negative and positive predictive values were 99%. Overall, there were 225 false-positive results and 9 false-negative results. In the 9 false negatives, 6 were due to a lack of fetal DNA in the sample and 3 were due to technical error (defined as an operator ignoring a failure of the robot pipetting the plasma or other technical failures).

The false-negative rate (0.03%) was lower than the predetermined estimated false-negative rate of cord blood serology (0.25%). In 22 of the supposed false positives, follow-up serology or molecular testing found an RhD gene was actually present, meaning the results of the neonatal cord blood serology in these cases were falsely negative. If you recalculate with these data in mind, the false-negative rate for fetal DNA testing was actually less than half that of typical serologic determination.

WHAT’S NEW

An accurate test with the potential to reduce unnecessary Tx

Fetal RhD testing at 27 weeks’ gestation appears to be highly accurate and could reduce the unnecessary use of anti-D immunoglobulin when the fetal RhD is negative.

Different results with different ethnicities?

Dutch participants are not necessarily reflective of the US population. Known variation in the rate of fetal RhD positivity among RhD-negative pregnant women by race and ethnicity could mean that the number of women able to forego anti-D-immunoglobulin prophylaxis would be different in the United States from that in other countries.

Also, in this study, polymerase chain reaction (PCR) for 2 RhD sequences was run in triplicate, and a computer-based algorithm was used to automatically score samples to provide results. For safe implementation, the cell-free fetal RhD DNA testing process would need to follow similar methods.

CHALLENGES TO IMPLEMENTATION

Test cost and availability are big unknowns

Cost and availability of the test may be barriers, but there is currently too little information on either subject in the United States to make a determination. A 2013 study indicated that the use of cell-free DNA testing to determine fetal RhD status was then approximately $682.¹⁰

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

THE CASE

A 40-year-old man was referred to the emergency department (ED) with critical anemia after routine blood work at an outside clinic showed a hemoglobin level of 3.5 g/dL. On presentation, he reported symptoms of fatigue, shortness of breath, bilateral leg swelling, dizziness (characterized as light-headedness), and frequent heartburn. He said that the symptoms began 5 weeks earlier, after he was exposed to a relative with hand, foot, and mouth disease.

Additionally, the patient reported an intentional 14-lb weight loss over the 6 months prior to presentation. He denied fever, rash, chest pain, loss of consciousness, headache, abdominal pain, hematemesis, melena, and hematochezia. His medical history was significant for peptic ulcer disease (diagnosed and treated at age 8). He did not recall the specifics, and he denied any related chronic symptoms or complications. His family history (paternal) was significant for colon cancer.

The physical exam revealed conjunctival pallor, skin pallor, jaundice, +1 bilateral lower extremity edema, tachycardia, and tachypnea. Stool Hemoccult was negative. On repeat complete blood count (performed in the ED), hemoglobin was found to be 3.1 g/dL with a mean corpuscular volume of 47 fL.

THE DIAGNOSIS

The patient was admitted to the family medicine service and received 4 units of packed red blood cells, which increased his hemoglobin to the target goal of >7 g/dL. A colonoscopy and an esophagogastroduodenoscopy (EGD) were performed (FIGURE 1A-1C), with results suggestive of diverticulosis, probable Barrett’s mucosa, esophageal ulcer, huge hiatal hernia (at least one-half of the stomach was in the chest), and Cameron ulcers. Esophageal biopsies showed cardiac mucosa with chronic inflammation. Esophageal ulcer biopsies revealed Barrett’s esophagus without dysplasia. Duodenal biopsies displayed normal mucosa.

DISCUSSION

A Cameron ulcer is a gastric lesion that is typically linear and found in hiatal hernias. These ulcers are often localized to areas where the herniated stomach is narrowed by the surrounding diaphragm, but they can extend onto the lesser curvature.¹ They are found in approximately 5% of patients with hiatal hernias (and an even higher percentage when the hernias are >5 cm^1,2).³ Because physical agitation of the ulcer-containing hernia occurs when the patient breathes, these ulcers can be the source of otherwise unexplained chronic iron-deficiency anemia in this patient population.³ While some patients present with typical symptoms of anemia or gastrointestinal bleeding, such as fatigue, pallor, hematemesis, and melena, others have a much subtler clinical picture or may be asymptomatic altogether.⁴

Although rare, Cameron ulcers must be considered in the differential diagnosis of patients with chronic anemia of unknown origin. The potential for these lesions to result in chronic blood loss, which could over time manifest as severe anemia or hypovolemic shock, makes proper diagnosis and prompt treatment especially important.^4,5

In our patient’s case, his severe anemia was likely the result of a combination of the esophageal and Cameron ulcers evidenced on EGD, rather than any single ulcer. In our review of the literature, we found no reports of any patients with anemia and Cameron ulcers who presented with hemoglobin levels as low as our patient had.

Multiple EGDs may be needed to properly diagnose Cameron ulcers, as they can be difficult to identify. Once a patient receives the diagnosis, he or she will typically be put on a daily proton pump inhibitor (PPI) regimen, such as omeprazole 20 mg bid. However, since many patients with Cameron ulcers also have acid-related problems (as was true in this case), a multifactorial acid suppression approach may be warranted.¹ This may include recommending lifestyle modifications (eg, eating small meals, avoiding foods that provoke symptoms, or losing weight) and prescribing medications in addition to a PPI, such as an H2 blocker (eg, 300 mg qid, before meals and at bedtime).

In addition, iron sulfate (325 mg/d, in this case) and blood transfusions may be required to treat the anemia. In refractory cases, endoscopic or surgical interventions, such as hemoclipping, Nissen fundoplication, or laparoscopic gastropexy, may need to be performed.²

Our patient was given a prescription for ferrous sulfate 325 mg/d and omeprazole 20 mg bid. His symptoms improved with treatment, and he was discharged on Day 5; his hemoglobin remained >7 g/dL.

THE TAKEAWAY

The association between chronic iron deficiency anemia and Cameron ulcers has been established but is commonly overlooked in patients presenting with unexplained anemia or an undiagnosed hiatal hernia. This is likely due to their rarity as a cause of anemia, in general.

Furthermore, the lesions can be missed on EGD; multiple EGDs may be needed to make the diagnosis. Once diagnosed, Cameron ulcers typically respond well to twice daily PPI treatment. Patients with refractory, recurrent, or severe lesions, or large, symptomatic hiatal hernias should be referred for surgical assessment.

CORRESPONDENCE
Megan Yee, 801 Broadward Avenue NW, Grand Rapids, MI 49504; [email protected].

THE CASE

A 40-year-old man was referred to the emergency department (ED) with critical anemia after routine blood work at an outside clinic showed a hemoglobin level of 3.5 g/dL. On presentation, he reported symptoms of fatigue, shortness of breath, bilateral leg swelling, dizziness (characterized as light-headedness), and frequent heartburn. He said that the symptoms began 5 weeks earlier, after he was exposed to a relative with hand, foot, and mouth disease.

Additionally, the patient reported an intentional 14-lb weight loss over the 6 months prior to presentation. He denied fever, rash, chest pain, loss of consciousness, headache, abdominal pain, hematemesis, melena, and hematochezia. His medical history was significant for peptic ulcer disease (diagnosed and treated at age 8). He did not recall the specifics, and he denied any related chronic symptoms or complications. His family history (paternal) was significant for colon cancer.

The physical exam revealed conjunctival pallor, skin pallor, jaundice, +1 bilateral lower extremity edema, tachycardia, and tachypnea. Stool Hemoccult was negative. On repeat complete blood count (performed in the ED), hemoglobin was found to be 3.1 g/dL with a mean corpuscular volume of 47 fL.

THE DIAGNOSIS

The patient was admitted to the family medicine service and received 4 units of packed red blood cells, which increased his hemoglobin to the target goal of >7 g/dL. A colonoscopy and an esophagogastroduodenoscopy (EGD) were performed (FIGURE 1A-1C), with results suggestive of diverticulosis, probable Barrett’s mucosa, esophageal ulcer, huge hiatal hernia (at least one-half of the stomach was in the chest), and Cameron ulcers. Esophageal biopsies showed cardiac mucosa with chronic inflammation. Esophageal ulcer biopsies revealed Barrett’s esophagus without dysplasia. Duodenal biopsies displayed normal mucosa.

DISCUSSION

A Cameron ulcer is a gastric lesion that is typically linear and found in hiatal hernias. These ulcers are often localized to areas where the herniated stomach is narrowed by the surrounding diaphragm, but they can extend onto the lesser curvature.¹ They are found in approximately 5% of patients with hiatal hernias (and an even higher percentage when the hernias are >5 cm^1,2).³ Because physical agitation of the ulcer-containing hernia occurs when the patient breathes, these ulcers can be the source of otherwise unexplained chronic iron-deficiency anemia in this patient population.³ While some patients present with typical symptoms of anemia or gastrointestinal bleeding, such as fatigue, pallor, hematemesis, and melena, others have a much subtler clinical picture or may be asymptomatic altogether.⁴

Although rare, Cameron ulcers must be considered in the differential diagnosis of patients with chronic anemia of unknown origin. The potential for these lesions to result in chronic blood loss, which could over time manifest as severe anemia or hypovolemic shock, makes proper diagnosis and prompt treatment especially important.^4,5

In our patient’s case, his severe anemia was likely the result of a combination of the esophageal and Cameron ulcers evidenced on EGD, rather than any single ulcer. In our review of the literature, we found no reports of any patients with anemia and Cameron ulcers who presented with hemoglobin levels as low as our patient had.

Multiple EGDs may be needed to properly diagnose Cameron ulcers, as they can be difficult to identify. Once a patient receives the diagnosis, he or she will typically be put on a daily proton pump inhibitor (PPI) regimen, such as omeprazole 20 mg bid. However, since many patients with Cameron ulcers also have acid-related problems (as was true in this case), a multifactorial acid suppression approach may be warranted.¹ This may include recommending lifestyle modifications (eg, eating small meals, avoiding foods that provoke symptoms, or losing weight) and prescribing medications in addition to a PPI, such as an H2 blocker (eg, 300 mg qid, before meals and at bedtime).

In addition, iron sulfate (325 mg/d, in this case) and blood transfusions may be required to treat the anemia. In refractory cases, endoscopic or surgical interventions, such as hemoclipping, Nissen fundoplication, or laparoscopic gastropexy, may need to be performed.²

Our patient was given a prescription for ferrous sulfate 325 mg/d and omeprazole 20 mg bid. His symptoms improved with treatment, and he was discharged on Day 5; his hemoglobin remained >7 g/dL.

THE TAKEAWAY

The association between chronic iron deficiency anemia and Cameron ulcers has been established but is commonly overlooked in patients presenting with unexplained anemia or an undiagnosed hiatal hernia. This is likely due to their rarity as a cause of anemia, in general.

Furthermore, the lesions can be missed on EGD; multiple EGDs may be needed to make the diagnosis. Once diagnosed, Cameron ulcers typically respond well to twice daily PPI treatment. Patients with refractory, recurrent, or severe lesions, or large, symptomatic hiatal hernias should be referred for surgical assessment.

CORRESPONDENCE
Megan Yee, 801 Broadward Avenue NW, Grand Rapids, MI 49504; [email protected].

THE CASE

A 40-year-old man was referred to the emergency department (ED) with critical anemia after routine blood work at an outside clinic showed a hemoglobin level of 3.5 g/dL. On presentation, he reported symptoms of fatigue, shortness of breath, bilateral leg swelling, dizziness (characterized as light-headedness), and frequent heartburn. He said that the symptoms began 5 weeks earlier, after he was exposed to a relative with hand, foot, and mouth disease.

Additionally, the patient reported an intentional 14-lb weight loss over the 6 months prior to presentation. He denied fever, rash, chest pain, loss of consciousness, headache, abdominal pain, hematemesis, melena, and hematochezia. His medical history was significant for peptic ulcer disease (diagnosed and treated at age 8). He did not recall the specifics, and he denied any related chronic symptoms or complications. His family history (paternal) was significant for colon cancer.

The physical exam revealed conjunctival pallor, skin pallor, jaundice, +1 bilateral lower extremity edema, tachycardia, and tachypnea. Stool Hemoccult was negative. On repeat complete blood count (performed in the ED), hemoglobin was found to be 3.1 g/dL with a mean corpuscular volume of 47 fL.

THE DIAGNOSIS

The patient was admitted to the family medicine service and received 4 units of packed red blood cells, which increased his hemoglobin to the target goal of >7 g/dL. A colonoscopy and an esophagogastroduodenoscopy (EGD) were performed (FIGURE 1A-1C), with results suggestive of diverticulosis, probable Barrett’s mucosa, esophageal ulcer, huge hiatal hernia (at least one-half of the stomach was in the chest), and Cameron ulcers. Esophageal biopsies showed cardiac mucosa with chronic inflammation. Esophageal ulcer biopsies revealed Barrett’s esophagus without dysplasia. Duodenal biopsies displayed normal mucosa.

DISCUSSION

A Cameron ulcer is a gastric lesion that is typically linear and found in hiatal hernias. These ulcers are often localized to areas where the herniated stomach is narrowed by the surrounding diaphragm, but they can extend onto the lesser curvature.¹ They are found in approximately 5% of patients with hiatal hernias (and an even higher percentage when the hernias are >5 cm^1,2).³ Because physical agitation of the ulcer-containing hernia occurs when the patient breathes, these ulcers can be the source of otherwise unexplained chronic iron-deficiency anemia in this patient population.³ While some patients present with typical symptoms of anemia or gastrointestinal bleeding, such as fatigue, pallor, hematemesis, and melena, others have a much subtler clinical picture or may be asymptomatic altogether.⁴

Although rare, Cameron ulcers must be considered in the differential diagnosis of patients with chronic anemia of unknown origin. The potential for these lesions to result in chronic blood loss, which could over time manifest as severe anemia or hypovolemic shock, makes proper diagnosis and prompt treatment especially important.^4,5

In our patient’s case, his severe anemia was likely the result of a combination of the esophageal and Cameron ulcers evidenced on EGD, rather than any single ulcer. In our review of the literature, we found no reports of any patients with anemia and Cameron ulcers who presented with hemoglobin levels as low as our patient had.

Multiple EGDs may be needed to properly diagnose Cameron ulcers, as they can be difficult to identify. Once a patient receives the diagnosis, he or she will typically be put on a daily proton pump inhibitor (PPI) regimen, such as omeprazole 20 mg bid. However, since many patients with Cameron ulcers also have acid-related problems (as was true in this case), a multifactorial acid suppression approach may be warranted.¹ This may include recommending lifestyle modifications (eg, eating small meals, avoiding foods that provoke symptoms, or losing weight) and prescribing medications in addition to a PPI, such as an H2 blocker (eg, 300 mg qid, before meals and at bedtime).

In addition, iron sulfate (325 mg/d, in this case) and blood transfusions may be required to treat the anemia. In refractory cases, endoscopic or surgical interventions, such as hemoclipping, Nissen fundoplication, or laparoscopic gastropexy, may need to be performed.²

Our patient was given a prescription for ferrous sulfate 325 mg/d and omeprazole 20 mg bid. His symptoms improved with treatment, and he was discharged on Day 5; his hemoglobin remained >7 g/dL.

THE TAKEAWAY

The association between chronic iron deficiency anemia and Cameron ulcers has been established but is commonly overlooked in patients presenting with unexplained anemia or an undiagnosed hiatal hernia. This is likely due to their rarity as a cause of anemia, in general.

Furthermore, the lesions can be missed on EGD; multiple EGDs may be needed to make the diagnosis. Once diagnosed, Cameron ulcers typically respond well to twice daily PPI treatment. Patients with refractory, recurrent, or severe lesions, or large, symptomatic hiatal hernias should be referred for surgical assessment.

CORRESPONDENCE
Megan Yee, 801 Broadward Avenue NW, Grand Rapids, MI 49504; [email protected].

In this issue of JFP, Dr. Mendoza reminds us that “Parkinson’s disease can be a tough diagnosis to navigate.”¹ Classically, Parkinson’s disease (PD) is associated with a resting tremor, but bradykinesia is actually the hallmark of the disease. PD can also present with subtle movement disorders, as well as depression and early dementia. It is, indeed, a difficult clinical diagnosis, and consultation with an expert to confirm or deny its presence can be quite helpful.

Other conundrums. PD, however, is not the only illness whose signs and symptoms can present a challenge. Chronic and intermittent shortness of breath, for example, can be very difficult to sort out. Is the shortness of breath due to congestive heart failure, chronic obstructive pulmonary disease, asthma, or a neurologic condition such as myasthenia gravis? Or is it the result of several causes?

When asthma isn’t asthma. Because it is a common illness, physicians often diagnose asthma in patients with shortness of breath or wheezing. But a recent study suggests that as many as 30% of primary care patients with a current diagnosis of asthma do not have asthma at all.²

In the study, Canadian researchers recruited 701 adults with physician-diagnosed asthma, all of whom were taking asthma medications regularly. The researchers did baseline pulmonary function testing (including methacholine challenge testing, if needed) and monitored symptoms frequently. Then they gradually withdrew asthma medications from those who did not appear to have a definitive diagnosis of asthma. They followed these patients for one year. One-third (203 of 613) of the patients with complete follow-up data were no longer taking asthma medications one year later and had no symptoms of asthma. Twelve patients had serious alternative diagnoses such as coronary artery disease and bronchiectasis.

Reevaluate your asthma patients to be sure they have the correct Dx, and keep Parkinson's in the differential for patients with atypical symptoms.

Closer to home. In my practice, I found 2 patients with long-standing diagnoses of asthma who didn’t, in fact, have the condition at all. In both cases, my suspicion was raised by lung examination. In one case, fine bibasilar rales suggested pulmonary fibrosis, which was the correct diagnosis, and the patient is now on the lung transplant list. In the other case, a loud venous hum suggested an arteriovenous malformation. Surgery corrected the patient’s “asthma.”

I urge you to reevaluate your asthma patients to be sure they have the correct diagnosis and to keep PD in your differential for patients who present with atypical symptoms. Primary care clinicians must be expert diagnosticians, willing to question prior diagnoses.

In this issue of JFP, Dr. Mendoza reminds us that “Parkinson’s disease can be a tough diagnosis to navigate.”¹ Classically, Parkinson’s disease (PD) is associated with a resting tremor, but bradykinesia is actually the hallmark of the disease. PD can also present with subtle movement disorders, as well as depression and early dementia. It is, indeed, a difficult clinical diagnosis, and consultation with an expert to confirm or deny its presence can be quite helpful.

Other conundrums. PD, however, is not the only illness whose signs and symptoms can present a challenge. Chronic and intermittent shortness of breath, for example, can be very difficult to sort out. Is the shortness of breath due to congestive heart failure, chronic obstructive pulmonary disease, asthma, or a neurologic condition such as myasthenia gravis? Or is it the result of several causes?

When asthma isn’t asthma. Because it is a common illness, physicians often diagnose asthma in patients with shortness of breath or wheezing. But a recent study suggests that as many as 30% of primary care patients with a current diagnosis of asthma do not have asthma at all.²

In the study, Canadian researchers recruited 701 adults with physician-diagnosed asthma, all of whom were taking asthma medications regularly. The researchers did baseline pulmonary function testing (including methacholine challenge testing, if needed) and monitored symptoms frequently. Then they gradually withdrew asthma medications from those who did not appear to have a definitive diagnosis of asthma. They followed these patients for one year. One-third (203 of 613) of the patients with complete follow-up data were no longer taking asthma medications one year later and had no symptoms of asthma. Twelve patients had serious alternative diagnoses such as coronary artery disease and bronchiectasis.

Reevaluate your asthma patients to be sure they have the correct Dx, and keep Parkinson's in the differential for patients with atypical symptoms.

Closer to home. In my practice, I found 2 patients with long-standing diagnoses of asthma who didn’t, in fact, have the condition at all. In both cases, my suspicion was raised by lung examination. In one case, fine bibasilar rales suggested pulmonary fibrosis, which was the correct diagnosis, and the patient is now on the lung transplant list. In the other case, a loud venous hum suggested an arteriovenous malformation. Surgery corrected the patient’s “asthma.”

I urge you to reevaluate your asthma patients to be sure they have the correct diagnosis and to keep PD in your differential for patients who present with atypical symptoms. Primary care clinicians must be expert diagnosticians, willing to question prior diagnoses.

In this issue of JFP, Dr. Mendoza reminds us that “Parkinson’s disease can be a tough diagnosis to navigate.”¹ Classically, Parkinson’s disease (PD) is associated with a resting tremor, but bradykinesia is actually the hallmark of the disease. PD can also present with subtle movement disorders, as well as depression and early dementia. It is, indeed, a difficult clinical diagnosis, and consultation with an expert to confirm or deny its presence can be quite helpful.

Other conundrums. PD, however, is not the only illness whose signs and symptoms can present a challenge. Chronic and intermittent shortness of breath, for example, can be very difficult to sort out. Is the shortness of breath due to congestive heart failure, chronic obstructive pulmonary disease, asthma, or a neurologic condition such as myasthenia gravis? Or is it the result of several causes?

When asthma isn’t asthma. Because it is a common illness, physicians often diagnose asthma in patients with shortness of breath or wheezing. But a recent study suggests that as many as 30% of primary care patients with a current diagnosis of asthma do not have asthma at all.²

In the study, Canadian researchers recruited 701 adults with physician-diagnosed asthma, all of whom were taking asthma medications regularly. The researchers did baseline pulmonary function testing (including methacholine challenge testing, if needed) and monitored symptoms frequently. Then they gradually withdrew asthma medications from those who did not appear to have a definitive diagnosis of asthma. They followed these patients for one year. One-third (203 of 613) of the patients with complete follow-up data were no longer taking asthma medications one year later and had no symptoms of asthma. Twelve patients had serious alternative diagnoses such as coronary artery disease and bronchiectasis.

Reevaluate your asthma patients to be sure they have the correct Dx, and keep Parkinson's in the differential for patients with atypical symptoms.

Closer to home. In my practice, I found 2 patients with long-standing diagnoses of asthma who didn’t, in fact, have the condition at all. In both cases, my suspicion was raised by lung examination. In one case, fine bibasilar rales suggested pulmonary fibrosis, which was the correct diagnosis, and the patient is now on the lung transplant list. In the other case, a loud venous hum suggested an arteriovenous malformation. Surgery corrected the patient’s “asthma.”

I urge you to reevaluate your asthma patients to be sure they have the correct diagnosis and to keep PD in your differential for patients who present with atypical symptoms. Primary care clinicians must be expert diagnosticians, willing to question prior diagnoses.

EVIDENCE SUMMARY

Before the statin era, the Coronary Drug Project RCT (8341 patients) showed that niacin monotherapy in patients with definite electrocardiographic evidence of previous myocardial infarction (MI) reduced nonfatal MI to 8.9% compared with 12.2% for placebo (P=.002).¹ (See TABLE.^1-4) It also decreased long-term mortality by 11% compared with placebo (P=.0004).⁵

Adverse effects such as flushing, hyperglycemia, gastrointestinal disturbance, and elevated liver enzymes interfered with adherence to niacin treatment (66.3% of patients were adherent to treatment with niacin vs 77.8% for placebo). The study was limited by the fact that flushing essentially unblinded participants and physicians.

But adding niacin to a statin has no effect

A 2014 meta-analysis driven by the power of the large HPS2-Thrive study evaluated data from 35,301 patients primarily in secondary prevention trials.^2,3 It found that adding niacin to statins had no effect on all-cause mortality, coronary heart disease mortality, nonfatal MI, or stroke. The subset of 6 trials (N=4991) assessing niacin monotherapy did show a reduction in cardiovascular events (odds ratio [OR]=0.62; confidence interval [CI], 0.54-0.82), whereas the 5 studies (30,310 patients) involving niacin with a statin demonstrated no effect (OR=0.94; CI, 0.83-1.06).

No benefit from niacin/statin therapy despite an improved lipid profile

A 2011 RCT included 3414 patients with coronary heart disease on simvastatin who were randomized to niacin or placebo.⁴ All patients received simvastatin 40 to 80 mg ± ezetimibe 10 mg/d to achieve low-density lipoprotein (LDL) cholesterol levels of 40 to 80 mg/dL.

At 3 years, no benefit was seen in the composite CVD primary endpoint (hazard ratio=1.02; 95% CI, 0.87-1.21; P=.79) even though the niacin group had significantly increased median high-density lipoprotein (HDL) cholesterol compared with placebo and lower triglycerides and LDL cholesterol compared with baseline.

A nonsignificant trend toward increased stroke in the niacin group compared with placebo led to early termination of the study. However, multivariate analysis showed independent associations between ischemic stroke risk and age older than 65 years, history of stroke/transient ischemic attack/carotid artery disease, and elevated baseline cholesterol.⁶

Niacin combined with a statin increases the risk of adverse events

The largest RCT in the 2014 meta-analysis (HPS2-Thrive) evaluated 25,673 patients with established CVD receiving cholesterol-lowering therapy with simvastatin ± ezetimibe who were randomized to niacin or placebo for a median follow-up period of 3.9 years.³ A pre-randomization run-in phase established effective cholesterol-lowering therapy with simvastatin ± ezetimibe.

Niacin didn’t reduce the incidence of major vascular events even though, once again, it decreased LDL and increased HDL more than placebo. Niacin increased the risk of serious adverse events 56% vs 53% (risk ratio [RR]=6; 95% CI, 3-8; number needed to harm [NNH]=35; 95% CI, 25-60), such as new onset diabetes (5.7% vs 4.3%; P<.001; NNH=71) and gastrointestinal bleeding/ulceration and other gastrointestinal disorders (4.8% vs 3.8%; P<.001; NNH=100).

A subsequent 2014 study examined the adverse events recorded in the AIM-HIGH⁴ study and found that niacin caused more gastrointestinal disorders (7.4% vs 5.5%; P=.02; NNH=53) and infections and infestations (8.1% vs 5.8%; P=.008; NNH=43) than placebo.⁷ The overall observed rate of serious hemorrhagic adverse events was low, however, showing no significant difference between the 2 groups (3.4% vs 2.9%; P=.36).

RECOMMENDATIONS

As of November 2013, the Institute for Clinical Systems Improvement recommends against using niacin in combination with statins because of the increased risk of adverse events without a reduction in CVD outcomes. Niacin may be considered as monotherapy in patients who can’t tolerate statins or fibrates based on results of the Coronary Drug Project and other studies completed before the era of widespread statin use.⁸

Similarly, American College of Cardiology/American Heart Association guidelines state that patients who are completely statin intolerant may use nonstatin cholesterol-lowering drugs, including niacin, that have been shown to reduce CVD events in RCTs if the CVD risk-reduction benefits outweigh the potential for adverse effects.⁹

EVIDENCE SUMMARY

Before the statin era, the Coronary Drug Project RCT (8341 patients) showed that niacin monotherapy in patients with definite electrocardiographic evidence of previous myocardial infarction (MI) reduced nonfatal MI to 8.9% compared with 12.2% for placebo (P=.002).¹ (See TABLE.^1-4) It also decreased long-term mortality by 11% compared with placebo (P=.0004).⁵

Adverse effects such as flushing, hyperglycemia, gastrointestinal disturbance, and elevated liver enzymes interfered with adherence to niacin treatment (66.3% of patients were adherent to treatment with niacin vs 77.8% for placebo). The study was limited by the fact that flushing essentially unblinded participants and physicians.

But adding niacin to a statin has no effect

A 2014 meta-analysis driven by the power of the large HPS2-Thrive study evaluated data from 35,301 patients primarily in secondary prevention trials.^2,3 It found that adding niacin to statins had no effect on all-cause mortality, coronary heart disease mortality, nonfatal MI, or stroke. The subset of 6 trials (N=4991) assessing niacin monotherapy did show a reduction in cardiovascular events (odds ratio [OR]=0.62; confidence interval [CI], 0.54-0.82), whereas the 5 studies (30,310 patients) involving niacin with a statin demonstrated no effect (OR=0.94; CI, 0.83-1.06).

No benefit from niacin/statin therapy despite an improved lipid profile

A 2011 RCT included 3414 patients with coronary heart disease on simvastatin who were randomized to niacin or placebo.⁴ All patients received simvastatin 40 to 80 mg ± ezetimibe 10 mg/d to achieve low-density lipoprotein (LDL) cholesterol levels of 40 to 80 mg/dL.

At 3 years, no benefit was seen in the composite CVD primary endpoint (hazard ratio=1.02; 95% CI, 0.87-1.21; P=.79) even though the niacin group had significantly increased median high-density lipoprotein (HDL) cholesterol compared with placebo and lower triglycerides and LDL cholesterol compared with baseline.

A nonsignificant trend toward increased stroke in the niacin group compared with placebo led to early termination of the study. However, multivariate analysis showed independent associations between ischemic stroke risk and age older than 65 years, history of stroke/transient ischemic attack/carotid artery disease, and elevated baseline cholesterol.⁶

Niacin combined with a statin increases the risk of adverse events

The largest RCT in the 2014 meta-analysis (HPS2-Thrive) evaluated 25,673 patients with established CVD receiving cholesterol-lowering therapy with simvastatin ± ezetimibe who were randomized to niacin or placebo for a median follow-up period of 3.9 years.³ A pre-randomization run-in phase established effective cholesterol-lowering therapy with simvastatin ± ezetimibe.

Niacin didn’t reduce the incidence of major vascular events even though, once again, it decreased LDL and increased HDL more than placebo. Niacin increased the risk of serious adverse events 56% vs 53% (risk ratio [RR]=6; 95% CI, 3-8; number needed to harm [NNH]=35; 95% CI, 25-60), such as new onset diabetes (5.7% vs 4.3%; P<.001; NNH=71) and gastrointestinal bleeding/ulceration and other gastrointestinal disorders (4.8% vs 3.8%; P<.001; NNH=100).

A subsequent 2014 study examined the adverse events recorded in the AIM-HIGH⁴ study and found that niacin caused more gastrointestinal disorders (7.4% vs 5.5%; P=.02; NNH=53) and infections and infestations (8.1% vs 5.8%; P=.008; NNH=43) than placebo.⁷ The overall observed rate of serious hemorrhagic adverse events was low, however, showing no significant difference between the 2 groups (3.4% vs 2.9%; P=.36).

RECOMMENDATIONS

As of November 2013, the Institute for Clinical Systems Improvement recommends against using niacin in combination with statins because of the increased risk of adverse events without a reduction in CVD outcomes. Niacin may be considered as monotherapy in patients who can’t tolerate statins or fibrates based on results of the Coronary Drug Project and other studies completed before the era of widespread statin use.⁸

Similarly, American College of Cardiology/American Heart Association guidelines state that patients who are completely statin intolerant may use nonstatin cholesterol-lowering drugs, including niacin, that have been shown to reduce CVD events in RCTs if the CVD risk-reduction benefits outweigh the potential for adverse effects.⁹

EVIDENCE SUMMARY

Before the statin era, the Coronary Drug Project RCT (8341 patients) showed that niacin monotherapy in patients with definite electrocardiographic evidence of previous myocardial infarction (MI) reduced nonfatal MI to 8.9% compared with 12.2% for placebo (P=.002).¹ (See TABLE.^1-4) It also decreased long-term mortality by 11% compared with placebo (P=.0004).⁵

Adverse effects such as flushing, hyperglycemia, gastrointestinal disturbance, and elevated liver enzymes interfered with adherence to niacin treatment (66.3% of patients were adherent to treatment with niacin vs 77.8% for placebo). The study was limited by the fact that flushing essentially unblinded participants and physicians.

But adding niacin to a statin has no effect

A 2014 meta-analysis driven by the power of the large HPS2-Thrive study evaluated data from 35,301 patients primarily in secondary prevention trials.^2,3 It found that adding niacin to statins had no effect on all-cause mortality, coronary heart disease mortality, nonfatal MI, or stroke. The subset of 6 trials (N=4991) assessing niacin monotherapy did show a reduction in cardiovascular events (odds ratio [OR]=0.62; confidence interval [CI], 0.54-0.82), whereas the 5 studies (30,310 patients) involving niacin with a statin demonstrated no effect (OR=0.94; CI, 0.83-1.06).

No benefit from niacin/statin therapy despite an improved lipid profile

A 2011 RCT included 3414 patients with coronary heart disease on simvastatin who were randomized to niacin or placebo.⁴ All patients received simvastatin 40 to 80 mg ± ezetimibe 10 mg/d to achieve low-density lipoprotein (LDL) cholesterol levels of 40 to 80 mg/dL.

At 3 years, no benefit was seen in the composite CVD primary endpoint (hazard ratio=1.02; 95% CI, 0.87-1.21; P=.79) even though the niacin group had significantly increased median high-density lipoprotein (HDL) cholesterol compared with placebo and lower triglycerides and LDL cholesterol compared with baseline.

A nonsignificant trend toward increased stroke in the niacin group compared with placebo led to early termination of the study. However, multivariate analysis showed independent associations between ischemic stroke risk and age older than 65 years, history of stroke/transient ischemic attack/carotid artery disease, and elevated baseline cholesterol.⁶

Niacin combined with a statin increases the risk of adverse events

The largest RCT in the 2014 meta-analysis (HPS2-Thrive) evaluated 25,673 patients with established CVD receiving cholesterol-lowering therapy with simvastatin ± ezetimibe who were randomized to niacin or placebo for a median follow-up period of 3.9 years.³ A pre-randomization run-in phase established effective cholesterol-lowering therapy with simvastatin ± ezetimibe.

Niacin didn’t reduce the incidence of major vascular events even though, once again, it decreased LDL and increased HDL more than placebo. Niacin increased the risk of serious adverse events 56% vs 53% (risk ratio [RR]=6; 95% CI, 3-8; number needed to harm [NNH]=35; 95% CI, 25-60), such as new onset diabetes (5.7% vs 4.3%; P<.001; NNH=71) and gastrointestinal bleeding/ulceration and other gastrointestinal disorders (4.8% vs 3.8%; P<.001; NNH=100).

A subsequent 2014 study examined the adverse events recorded in the AIM-HIGH⁴ study and found that niacin caused more gastrointestinal disorders (7.4% vs 5.5%; P=.02; NNH=53) and infections and infestations (8.1% vs 5.8%; P=.008; NNH=43) than placebo.⁷ The overall observed rate of serious hemorrhagic adverse events was low, however, showing no significant difference between the 2 groups (3.4% vs 2.9%; P=.36).

RECOMMENDATIONS

As of November 2013, the Institute for Clinical Systems Improvement recommends against using niacin in combination with statins because of the increased risk of adverse events without a reduction in CVD outcomes. Niacin may be considered as monotherapy in patients who can’t tolerate statins or fibrates based on results of the Coronary Drug Project and other studies completed before the era of widespread statin use.⁸

Similarly, American College of Cardiology/American Heart Association guidelines state that patients who are completely statin intolerant may use nonstatin cholesterol-lowering drugs, including niacin, that have been shown to reduce CVD events in RCTs if the CVD risk-reduction benefits outweigh the potential for adverse effects.⁹

CASE

Patrick S, an 85-year-old man with multiple medical problems, was brought to his primary care provider after being found at home with altered mental status. His caretaker reported that Mr. S had been using extra blankets in bed and sleeping more, but he hadn’t had significant outdoor exposure. Measurement of his vital signs revealed tachycardia, tachypnea, hypotension, and a rectal temperature of 32°C (89.6°F).

How would you proceed with the care of this patient?

What is accidental hypothermia?

Accidental hypothermia is an unintentional drop in core body temperature to <35°C (<95°F). Mild hypothermia is defined as a core body temperature of 32°C to 35°C (90°F - 95°F); moderate hypothermia, 28°C to 32°C (82°F - 90°F); and severe hypothermia, <28°C (<82°F).¹

The International Commission for Mountain Emergency Medicine divides hypothermia into 5 categories, emphasizing the clinical features of each stage as a guide to treatment (TABLE 1).² These categories were adopted to help prehospital rescuers estimate the severity of hypothermia using physical symptoms. For example, most patients stop shivering at approximately 30°C (86°F)—the “moderate (HT II)” category of hypothermia—although this response varies widely from patient to patient. Notably, there are reports in the literature of survival in hypothermia with a temperature as low as 13.7°C (56.7°F) and with cardiac arrest for as long as 8 hours and 40 minutes, although these events are rare.³

Each year, approximately 700 deaths in the United States are the result of hypothermia.⁴ Between 1995 to 2004 in the United States, it is estimated that 15,574 visits were made to a health care provider or facility for hypothermia and other cold-related concerns.⁵ Based on reports in the international literature, the incidence of nonlethal hypothermia is much greater than the incidence of lethal hypothermia.⁵ Almost half of deaths from hypothermia are in people older than age 65 years; the male to female ratio is 2.5:1.¹

Variables that predispose the body to temperature dysregulation include extremes of age, comorbid conditions, intoxication, chronic cold exposure, immersion accident, mental illness, impaired shivering, and lack of acclimatization.¹ The most common causes of death associated with hypothermia are falls, drownings, and cardiovascular disease.⁴ In a 2008 study, hypothermia and other cold-related morbidity emergency department (ED) visits required more transfers of patients to a critical care unit than any other reason for visiting an ED (risk ratio, 6.73; 95% confidence interval, 1.8-25).⁵ Mortality among inpatients whose hypothermia is classified as moderate or severe reaches as high as 40%.³

More than just cold-weather exposure

Accidental hypothermia occurs when heat loss is superseded by the body’s ability to generate heat. It commonly happens in cold environments but can also occur at higher temperatures if the body’s thermoregulatory system malfunctions.

Environmental or iatrogenic factors (ie, primary hypothermia), such as wind, water immersion, wetness, aggressive fluid resuscitation, and heat stroke treatment can make people more susceptible to hypothermia. Medical conditions (ie, secondary hypothermia), such as burns, exfoliative dermatitis, severe psoriasis, hypoadrenalism, hypopituitarism, hypothyroidism, acute spinal cord transection, head trauma, stroke, tumor, pneumonia, Wernicke’s disease (encephalopathy), and sepsis can also predispose to hypothermia.¹ Drugs, such as ethanol, phenothiazines, and sedative–hypnotics may decrease the hypothermia threshold.¹ (For information on preventing hypothermia, see TABLE 2.⁶)

Humans maintain body temperature by balancing heat production and heat loss to the environment. Heat is lost through the skin and lungs by 5 different mechanisms: radiation, conduction, convection, evaporation, and respiration. Convective heat loss to cold air and conductive heat loss to water are the most common mechanisms of accidental hypothermia.⁷

Maintain a high index of suspicion for hypothermia when caring for the elderly or patients presenting with unexplained illness.

To maintain temperature homeostasis at 37°C (98.6°F) (±0.5°C [±0.9°F]), the hypothalamus receives input from central and peripheral thermal receptors and stimulates heat production through shivering, increasing the basal metabolic rate 2-fold to 5-fold.¹ The hypothalamus also increases thyroid, catecholamine, and adrenal activity to increase the body’s production of heat and raise core temperature.

Heat conservation occurs by activation of sympathetically mediated vasoconstriction, reducing conduction to the skin, where cooling is greatest. After time, temperature regulation in the body becomes overwhelmed and catecholamine levels return to a pre-hypothermic state.

At 35°C (95°F), neurologic function begins to decline; at 32°C (89.6°F), metabolism, ventilation, and cardiac output decrease until shivering ceases. Changes in peripheral blood flow can create a false warming sensation, causing a person to remove clothing, a phenomenon referred to as paradoxical undressing. As hypothermia progresses, the neurologic, respiratory, and cardiac systems continue to slow until there is eventual cardiorespiratory failure.

Assessment and diagnosis

History and physical examination. A high index of suspicion for the diagnosis of hypothermia is essential, especially when caring for the elderly or patients presenting with unexplained illness. Often, symptoms of a primary condition may overshadow those reflecting hypothermia. In a multicenter survey that reviewed 428 cases of accidental hypothermia in the United States, 44% of patients had an underlying illness; 18%, coexisting infection; 19%, trauma; and 6%, overdose.³

There are no strict diagnostic criteria for hypothermia other than a core body temperature <35°C (<95°F). Standard thermometers often do not read below 34.4°C (93.2°F), so it is recommended that a rectal thermometer capable of reading low body temperatures be used for accurate measurement.

Hypothermic patients can exhibit a variety of symptoms, depending on the degree of decrease in core body temperature¹:

• A mildly hypothermic patient might present with any combination of tachypnea, tachycardia, ataxia, impaired judgment, shivering, and vasoconstriction.
• Moderate hypothermia typically manifests as a decreased heart rate, decreased blood pressure, decreased level of consciousness, decreased respiratory effort, dilated pupils, extinction of shivering, and hyporeflexia. Cardiac abnormalities, such as atrial fibrillation and junctional bradycardia, may be seen in moderate hypothermia.
• Severe hypothermia presents with apnea, coma, nonreactive pupils, oliguria, areflexia, hypotension, bradycardia, and continued cardiac abnormalities, such as ventricular arrhythmias and asystole.

Laboratory evaluation. No specific laboratory tests are needed to diagnose hypothermia. General lab tests, however, may help determine whether hypothermia is the result, or the cause, of the clinical scenario. Recommended laboratory tests for making that determination include a complete blood count (CBC), chemistry panel, arterial blood gases, fingerstick glucose, and coagulation panel.

General lab tests may help determine whether hypothermia is the result, or the cause, of the clinical scenario.

Results of lab tests may be abnormal because of the body’s decreased core body temperature. White blood cells and platelets in the CBC, for example, may be decreased due to splenic sequestration; these findings reverse with rewarming. With every 1°C (1.8°F) drop in core body temperature, hematocrit increases 2%.³ Sodium, chloride, and magnesium concentrations do not display consistent abnormalities with any core body temperature >25°C (77°F),^3,8 but potassium levels may fluctuate because of acid-base changes that occur during rewarming.¹ Creatinine and creatine kinase levels may be increased secondary to rhabdomyolysis or acute tubular necrosis.¹

Arterial blood gases typically show metabolic acidosis or respiratory alkalosis, or both.⁸ Prothrombin time and partial thromboplastin time are typically elevated in vivo, secondary to temperature-dependent enzymes in the coagulation cascade, but are reported normal in a blood specimen that is heated to 37°C (98.6°F) prior to analysis.^1,8

Both hyperglycemia and hypoglycemia can be associated with hypothermia. The lactate level can be elevated, due to hypoperfusion. Hepatic impairment may be seen secondary to decreased cardiac output. An increase in the lipase level may also occur.³

When a hypothermic patient fails to respond to rewarming, or there is no clear source of cold exposure, consider testing for other causes of the problem, including hypothyroidism and adrenal insufficiency (see “Differential diagnosis”). Hypothermia may also decrease thyroid function in people with preexisting disease.

Other laboratory studies that can be considered include fibrinogen, blood-alcohol level, urine toxicology screen, and blood and fluid cultures.³

Imaging. Imaging studies are not performed routinely in the setting of hypothermia; however:

• Chest radiography can be considered to assess for aspiration pneumonia, vascular congestion, and pulmonary edema.
• Computed tomography (CT) of the head is helpful in the setting of trauma or if mental status does not clear with rewarming.³
• Bedside ultrasonography can assess for cardiac activity, volume status, pulmonary edema, free fluid, and trauma. (See "Point-of-care ultrasound: Coming soon to primary care?" J Fam Pract. 2018;67:70-80.)

Electrocardiography. An electrocardiogram is essential to evaluate for arrhythmias. Findings associated with hypothermia are prolongation of PR, QRS, and QT intervals; ST-segment elevation, T-wave inversion; and Osborn waves (J waves), which represent a positive deflection at the termination of the QRS complex with associated J-point elevation.⁸ Osborn waves generally present when the core body temperature is <32°C (89.6°F) and become larger as the core body temperature drops further.³

Differential diagnosis. Hypothermia is most commonly caused by environmental exposure, but the differential diagnosis is broad: many medical conditions, as well as drug and alcohol intoxication, can contribute to hypothermia (TABLE 3¹).

Treatment: Usually unnecessary, sometimes crucial

Most patients with mild hypothermia recover completely with little intervention. These patients should be evaluated for cognitive irregularities and observed in the ED before discharge.⁹ Moderate and severe hypothermia patients should be assessed using pre-hospital protocols and given cardiopulmonary resuscitation (CPR) for cardiac arrest. Pre-hospital providers should rely more on symptoms in guiding their treatment response because core body temperature measurements can be difficult to obtain, and the response to a drop in core body temperature varies from patient to patient.¹⁰

Early considerations: Airway, breathing, circulation (ABC)

A first responder might have difficulty palpating the pulse of a hypothermic patient if that patient’s cardiopulmonary effort is diminished.⁹ This inability to palpate a pulse should not delay treatment unless the patient presents with lethal injury; the scene is unsafe; the chest is too stiff for CPR; do-not-resuscitate status is present; or the patient was buried in an avalanche for ≥35 minutes and the airway is filled with snow (FIGURE^3,11,12). Pulse should be checked carefully for 60 seconds. If pulses are not present, CPR should be initiated.

Prevention of further heat loss should begin promptly for hypothermic patients who retain a perfusing rhythm.¹¹ Lifesaving interventions, such as airway management, vascular access for volume replenishment, and defibrillation for ventricular tachycardia or ventricular fibrillation should be carried out according to Advanced Cardiac Life Support protocols.¹¹ Patients in respiratory distress or incapable of protecting their airway because of altered mental status should undergo endotracheal intubation. Fluid resuscitation with isotonic crystalloid fluids, warmed to 40°C (104°F) to 42°C (~107°F) and delivered through 2 large-bore, peripheral intravenous (IV) needles, can be considered.

Special care should be taken when moving a hypothermic patient. Excessive movement can lead to stimulation of the irritable hypothermic heart and cause an arrhythmia.

Medical therapy. Caution is advised because the reduced metabolism of a hypothermic patient can lead to potentially toxic accumulation of drugs peripherally. In fact, outcomes have not been positively influenced by routine use of medications, other than treatment of ventricular fibrillation with amiodarone.¹¹ Any intravenous (IV) drug should be held until the patient’s core temperature is >30°C (>86°F).¹¹

Vasopressors can be beneficial during rewarming for a patient in cardiac arrest and are a reasonable consideration.² Nitroglycerin, in conjunction with active external rewarming, can increase the overall hourly temperature gain in a moderately hypothermic patient.¹³

Rewarming. The extent of rewarming required can be predicted by the severity of hypothermia (FIGURE^3,11,12). Mildly hypothermic patients can generally be rewarmed using passive external measures. Patients with moderate hypothermia benefit from active rewarming in addition to passive measures. Intervention for severe hypothermia requires external rewarming and internal warming, with admission to the intensive care unit.

Treatment plans for severely hypothermic patients differ, depending on whether the person has a perfusing or nonperfusing cardiac rhythm. Patients who maintain a perfusing rhythm can be rewarmed using external methods (although core rewarming is used more often). Patients who do not have a perfusing rhythm require more invasive procedures.¹¹ When using any rewarming method, afterdrop phenomenon can occur: ie, vasodilation, brought on by rewarming, causes a drop in core body temperature, as cooler peripheral blood returns to the central circulation. This effect may be reduced by focused rewarming of the trunk prior to rewarming the extremities.³

With every 1°C (1.8°F) drop in core body temperature, hematocrit increases 2%.

Rewarming for mild hypothermia patients begins with passive external techniques. First, the patient is moved away from the environment for protection from further exposure. Next, wet or damaged clothing is removed, blankets or foil insulators are applied, and room temperature is maintained at ≥28°C (82°F).^3,11,13,14

If the patient’s temperature does not normalize, or if the patient presented with moderate or severe hypothermia, rewarming is continued with active external and internal measures. Active external rewarming can supplement passive measures using radiant heat from warmed blankets, air rewarming devices, and heating pads.^3,13,14 Active internal rewarming techniques rely on invasive measures to raise the core temperature. Heated crystalloid IV fluids do not treat hypothermia, but do help reduce further heat loss and can be helpful in patients in need of volume resuscitation.^3,13

Severely hypothermic patients might require more invasive active internal rewarming techniques, such as body-cavity lavage and extracorporeal methods. Body-cavity lavage can be facilitated with large volumes (10-120 L) of warm fluid at 40°C to 42°C, circulated through the thoracic or abdominal cavities to raise core body temperature 3°C to 6°C per hour.^3,13

Extracorporeal rewarming can be achieved through hemodialysis, continuous arteriovenous rewarming (CAVR), continuous veno-venous rewarming (CVVR), or cardiopulmonary bypass.^3,13 Research has shown cardiopulmonary bypass to be the most effective technique, with as high as a 7°C rise in core body temperature per hour; CVVR and CAVR are less invasive, however, and more readily available in hospitals.^3,11,13

Rewarming interventions should continue until return of spontaneous circulation and core body temperature reaches 32°C (89.6°F) to 34°C (93.2°F).¹¹ Overall, resuscitation efforts may take longer than normal due to the need for rewarming and should continue until the patient has achieved a normal temperature of 37°C (97.8°F).

In healthy, mildly hypothermic patients, full recovery is common if heat loss is minimized and the cause is treated. Moderately hypothermic patients who receive proper care can also have a favorable result. Outcomes for severe hypothermia vary with duration, comorbidities, and severity of core body temperature loss.¹⁵

Heated crystalloid IV fluids do not treat hypothermia, but do help reduce further heat loss and can be helpful in patients in need of volume resuscitation.

Immediate initiation of rewarming by pre-hospital providers improves outcomes, and higher mortality has been demonstrated with hospital admission temperatures <35°C (95°F).¹⁵ Almost 100% of primary hypothermia patients with cardiac stability who were treated using active external and minimally invasive rewarming techniques survived with an intact neurologic system.¹² Fifty percent of patients who endured cardiac arrest or who were treated with extracorporeal rewarming had an intact neurologic system. In cardiac arrest cases without significant underlying disease or trauma, and in which hypoxia did not precede hypothermia, full recovery is possible (and has been observed).¹²

CASE

Mr. S was given a diagnosis of mild to moderate hypothermia and transferred to the nearest ED for further treatment. His age had put him at increased risk of hypothermia. The work-up included laboratory testing (CBC, chemistry panel, thyroid-stimulating hormone, urinalysis, and blood cultures), electrocardiography, chest radiography, and CT of the head.

The chest radiograph showed pneumonia. Based on the results of blood culture, bacterial infection (pneumonia) was determined to be the underlying cause of hypothermia. Mr. S was started on antibiotics.

CORRESPONDENCE
Natasha J. Pyzocha, DO, Bldg 1058, 1856 Irwin Dr, Fort Carson, CO 80913; [email protected].

CASE

Patrick S, an 85-year-old man with multiple medical problems, was brought to his primary care provider after being found at home with altered mental status. His caretaker reported that Mr. S had been using extra blankets in bed and sleeping more, but he hadn’t had significant outdoor exposure. Measurement of his vital signs revealed tachycardia, tachypnea, hypotension, and a rectal temperature of 32°C (89.6°F).

How would you proceed with the care of this patient?

What is accidental hypothermia?

Accidental hypothermia is an unintentional drop in core body temperature to <35°C (<95°F). Mild hypothermia is defined as a core body temperature of 32°C to 35°C (90°F - 95°F); moderate hypothermia, 28°C to 32°C (82°F - 90°F); and severe hypothermia, <28°C (<82°F).¹

The International Commission for Mountain Emergency Medicine divides hypothermia into 5 categories, emphasizing the clinical features of each stage as a guide to treatment (TABLE 1).² These categories were adopted to help prehospital rescuers estimate the severity of hypothermia using physical symptoms. For example, most patients stop shivering at approximately 30°C (86°F)—the “moderate (HT II)” category of hypothermia—although this response varies widely from patient to patient. Notably, there are reports in the literature of survival in hypothermia with a temperature as low as 13.7°C (56.7°F) and with cardiac arrest for as long as 8 hours and 40 minutes, although these events are rare.³

Each year, approximately 700 deaths in the United States are the result of hypothermia.⁴ Between 1995 to 2004 in the United States, it is estimated that 15,574 visits were made to a health care provider or facility for hypothermia and other cold-related concerns.⁵ Based on reports in the international literature, the incidence of nonlethal hypothermia is much greater than the incidence of lethal hypothermia.⁵ Almost half of deaths from hypothermia are in people older than age 65 years; the male to female ratio is 2.5:1.¹

Variables that predispose the body to temperature dysregulation include extremes of age, comorbid conditions, intoxication, chronic cold exposure, immersion accident, mental illness, impaired shivering, and lack of acclimatization.¹ The most common causes of death associated with hypothermia are falls, drownings, and cardiovascular disease.⁴ In a 2008 study, hypothermia and other cold-related morbidity emergency department (ED) visits required more transfers of patients to a critical care unit than any other reason for visiting an ED (risk ratio, 6.73; 95% confidence interval, 1.8-25).⁵ Mortality among inpatients whose hypothermia is classified as moderate or severe reaches as high as 40%.³

More than just cold-weather exposure

Accidental hypothermia occurs when heat loss is superseded by the body’s ability to generate heat. It commonly happens in cold environments but can also occur at higher temperatures if the body’s thermoregulatory system malfunctions.

Environmental or iatrogenic factors (ie, primary hypothermia), such as wind, water immersion, wetness, aggressive fluid resuscitation, and heat stroke treatment can make people more susceptible to hypothermia. Medical conditions (ie, secondary hypothermia), such as burns, exfoliative dermatitis, severe psoriasis, hypoadrenalism, hypopituitarism, hypothyroidism, acute spinal cord transection, head trauma, stroke, tumor, pneumonia, Wernicke’s disease (encephalopathy), and sepsis can also predispose to hypothermia.¹ Drugs, such as ethanol, phenothiazines, and sedative–hypnotics may decrease the hypothermia threshold.¹ (For information on preventing hypothermia, see TABLE 2.⁶)

Humans maintain body temperature by balancing heat production and heat loss to the environment. Heat is lost through the skin and lungs by 5 different mechanisms: radiation, conduction, convection, evaporation, and respiration. Convective heat loss to cold air and conductive heat loss to water are the most common mechanisms of accidental hypothermia.⁷

Maintain a high index of suspicion for hypothermia when caring for the elderly or patients presenting with unexplained illness.

To maintain temperature homeostasis at 37°C (98.6°F) (±0.5°C [±0.9°F]), the hypothalamus receives input from central and peripheral thermal receptors and stimulates heat production through shivering, increasing the basal metabolic rate 2-fold to 5-fold.¹ The hypothalamus also increases thyroid, catecholamine, and adrenal activity to increase the body’s production of heat and raise core temperature.

Heat conservation occurs by activation of sympathetically mediated vasoconstriction, reducing conduction to the skin, where cooling is greatest. After time, temperature regulation in the body becomes overwhelmed and catecholamine levels return to a pre-hypothermic state.

At 35°C (95°F), neurologic function begins to decline; at 32°C (89.6°F), metabolism, ventilation, and cardiac output decrease until shivering ceases. Changes in peripheral blood flow can create a false warming sensation, causing a person to remove clothing, a phenomenon referred to as paradoxical undressing. As hypothermia progresses, the neurologic, respiratory, and cardiac systems continue to slow until there is eventual cardiorespiratory failure.

Assessment and diagnosis

History and physical examination. A high index of suspicion for the diagnosis of hypothermia is essential, especially when caring for the elderly or patients presenting with unexplained illness. Often, symptoms of a primary condition may overshadow those reflecting hypothermia. In a multicenter survey that reviewed 428 cases of accidental hypothermia in the United States, 44% of patients had an underlying illness; 18%, coexisting infection; 19%, trauma; and 6%, overdose.³

There are no strict diagnostic criteria for hypothermia other than a core body temperature <35°C (<95°F). Standard thermometers often do not read below 34.4°C (93.2°F), so it is recommended that a rectal thermometer capable of reading low body temperatures be used for accurate measurement.

Hypothermic patients can exhibit a variety of symptoms, depending on the degree of decrease in core body temperature¹:

• A mildly hypothermic patient might present with any combination of tachypnea, tachycardia, ataxia, impaired judgment, shivering, and vasoconstriction.
• Moderate hypothermia typically manifests as a decreased heart rate, decreased blood pressure, decreased level of consciousness, decreased respiratory effort, dilated pupils, extinction of shivering, and hyporeflexia. Cardiac abnormalities, such as atrial fibrillation and junctional bradycardia, may be seen in moderate hypothermia.
• Severe hypothermia presents with apnea, coma, nonreactive pupils, oliguria, areflexia, hypotension, bradycardia, and continued cardiac abnormalities, such as ventricular arrhythmias and asystole.

Laboratory evaluation. No specific laboratory tests are needed to diagnose hypothermia. General lab tests, however, may help determine whether hypothermia is the result, or the cause, of the clinical scenario. Recommended laboratory tests for making that determination include a complete blood count (CBC), chemistry panel, arterial blood gases, fingerstick glucose, and coagulation panel.

General lab tests may help determine whether hypothermia is the result, or the cause, of the clinical scenario.

Results of lab tests may be abnormal because of the body’s decreased core body temperature. White blood cells and platelets in the CBC, for example, may be decreased due to splenic sequestration; these findings reverse with rewarming. With every 1°C (1.8°F) drop in core body temperature, hematocrit increases 2%.³ Sodium, chloride, and magnesium concentrations do not display consistent abnormalities with any core body temperature >25°C (77°F),^3,8 but potassium levels may fluctuate because of acid-base changes that occur during rewarming.¹ Creatinine and creatine kinase levels may be increased secondary to rhabdomyolysis or acute tubular necrosis.¹

Arterial blood gases typically show metabolic acidosis or respiratory alkalosis, or both.⁸ Prothrombin time and partial thromboplastin time are typically elevated in vivo, secondary to temperature-dependent enzymes in the coagulation cascade, but are reported normal in a blood specimen that is heated to 37°C (98.6°F) prior to analysis.^1,8

Both hyperglycemia and hypoglycemia can be associated with hypothermia. The lactate level can be elevated, due to hypoperfusion. Hepatic impairment may be seen secondary to decreased cardiac output. An increase in the lipase level may also occur.³

When a hypothermic patient fails to respond to rewarming, or there is no clear source of cold exposure, consider testing for other causes of the problem, including hypothyroidism and adrenal insufficiency (see “Differential diagnosis”). Hypothermia may also decrease thyroid function in people with preexisting disease.

Other laboratory studies that can be considered include fibrinogen, blood-alcohol level, urine toxicology screen, and blood and fluid cultures.³

Imaging. Imaging studies are not performed routinely in the setting of hypothermia; however:

• Chest radiography can be considered to assess for aspiration pneumonia, vascular congestion, and pulmonary edema.
• Computed tomography (CT) of the head is helpful in the setting of trauma or if mental status does not clear with rewarming.³
• Bedside ultrasonography can assess for cardiac activity, volume status, pulmonary edema, free fluid, and trauma. (See "Point-of-care ultrasound: Coming soon to primary care?" J Fam Pract. 2018;67:70-80.)

Electrocardiography. An electrocardiogram is essential to evaluate for arrhythmias. Findings associated with hypothermia are prolongation of PR, QRS, and QT intervals; ST-segment elevation, T-wave inversion; and Osborn waves (J waves), which represent a positive deflection at the termination of the QRS complex with associated J-point elevation.⁸ Osborn waves generally present when the core body temperature is <32°C (89.6°F) and become larger as the core body temperature drops further.³

Differential diagnosis. Hypothermia is most commonly caused by environmental exposure, but the differential diagnosis is broad: many medical conditions, as well as drug and alcohol intoxication, can contribute to hypothermia (TABLE 3¹).

Treatment: Usually unnecessary, sometimes crucial

Most patients with mild hypothermia recover completely with little intervention. These patients should be evaluated for cognitive irregularities and observed in the ED before discharge.⁹ Moderate and severe hypothermia patients should be assessed using pre-hospital protocols and given cardiopulmonary resuscitation (CPR) for cardiac arrest. Pre-hospital providers should rely more on symptoms in guiding their treatment response because core body temperature measurements can be difficult to obtain, and the response to a drop in core body temperature varies from patient to patient.¹⁰

Early considerations: Airway, breathing, circulation (ABC)

A first responder might have difficulty palpating the pulse of a hypothermic patient if that patient’s cardiopulmonary effort is diminished.⁹ This inability to palpate a pulse should not delay treatment unless the patient presents with lethal injury; the scene is unsafe; the chest is too stiff for CPR; do-not-resuscitate status is present; or the patient was buried in an avalanche for ≥35 minutes and the airway is filled with snow (FIGURE^3,11,12). Pulse should be checked carefully for 60 seconds. If pulses are not present, CPR should be initiated.

Prevention of further heat loss should begin promptly for hypothermic patients who retain a perfusing rhythm.¹¹ Lifesaving interventions, such as airway management, vascular access for volume replenishment, and defibrillation for ventricular tachycardia or ventricular fibrillation should be carried out according to Advanced Cardiac Life Support protocols.¹¹ Patients in respiratory distress or incapable of protecting their airway because of altered mental status should undergo endotracheal intubation. Fluid resuscitation with isotonic crystalloid fluids, warmed to 40°C (104°F) to 42°C (~107°F) and delivered through 2 large-bore, peripheral intravenous (IV) needles, can be considered.

Special care should be taken when moving a hypothermic patient. Excessive movement can lead to stimulation of the irritable hypothermic heart and cause an arrhythmia.

Medical therapy. Caution is advised because the reduced metabolism of a hypothermic patient can lead to potentially toxic accumulation of drugs peripherally. In fact, outcomes have not been positively influenced by routine use of medications, other than treatment of ventricular fibrillation with amiodarone.¹¹ Any intravenous (IV) drug should be held until the patient’s core temperature is >30°C (>86°F).¹¹

Vasopressors can be beneficial during rewarming for a patient in cardiac arrest and are a reasonable consideration.² Nitroglycerin, in conjunction with active external rewarming, can increase the overall hourly temperature gain in a moderately hypothermic patient.¹³

Rewarming. The extent of rewarming required can be predicted by the severity of hypothermia (FIGURE^3,11,12). Mildly hypothermic patients can generally be rewarmed using passive external measures. Patients with moderate hypothermia benefit from active rewarming in addition to passive measures. Intervention for severe hypothermia requires external rewarming and internal warming, with admission to the intensive care unit.

Treatment plans for severely hypothermic patients differ, depending on whether the person has a perfusing or nonperfusing cardiac rhythm. Patients who maintain a perfusing rhythm can be rewarmed using external methods (although core rewarming is used more often). Patients who do not have a perfusing rhythm require more invasive procedures.¹¹ When using any rewarming method, afterdrop phenomenon can occur: ie, vasodilation, brought on by rewarming, causes a drop in core body temperature, as cooler peripheral blood returns to the central circulation. This effect may be reduced by focused rewarming of the trunk prior to rewarming the extremities.³

With every 1°C (1.8°F) drop in core body temperature, hematocrit increases 2%.

Rewarming for mild hypothermia patients begins with passive external techniques. First, the patient is moved away from the environment for protection from further exposure. Next, wet or damaged clothing is removed, blankets or foil insulators are applied, and room temperature is maintained at ≥28°C (82°F).^3,11,13,14

If the patient’s temperature does not normalize, or if the patient presented with moderate or severe hypothermia, rewarming is continued with active external and internal measures. Active external rewarming can supplement passive measures using radiant heat from warmed blankets, air rewarming devices, and heating pads.^3,13,14 Active internal rewarming techniques rely on invasive measures to raise the core temperature. Heated crystalloid IV fluids do not treat hypothermia, but do help reduce further heat loss and can be helpful in patients in need of volume resuscitation.^3,13

Severely hypothermic patients might require more invasive active internal rewarming techniques, such as body-cavity lavage and extracorporeal methods. Body-cavity lavage can be facilitated with large volumes (10-120 L) of warm fluid at 40°C to 42°C, circulated through the thoracic or abdominal cavities to raise core body temperature 3°C to 6°C per hour.^3,13

Extracorporeal rewarming can be achieved through hemodialysis, continuous arteriovenous rewarming (CAVR), continuous veno-venous rewarming (CVVR), or cardiopulmonary bypass.^3,13 Research has shown cardiopulmonary bypass to be the most effective technique, with as high as a 7°C rise in core body temperature per hour; CVVR and CAVR are less invasive, however, and more readily available in hospitals.^3,11,13

Rewarming interventions should continue until return of spontaneous circulation and core body temperature reaches 32°C (89.6°F) to 34°C (93.2°F).¹¹ Overall, resuscitation efforts may take longer than normal due to the need for rewarming and should continue until the patient has achieved a normal temperature of 37°C (97.8°F).

In healthy, mildly hypothermic patients, full recovery is common if heat loss is minimized and the cause is treated. Moderately hypothermic patients who receive proper care can also have a favorable result. Outcomes for severe hypothermia vary with duration, comorbidities, and severity of core body temperature loss.¹⁵

Heated crystalloid IV fluids do not treat hypothermia, but do help reduce further heat loss and can be helpful in patients in need of volume resuscitation.

Immediate initiation of rewarming by pre-hospital providers improves outcomes, and higher mortality has been demonstrated with hospital admission temperatures <35°C (95°F).¹⁵ Almost 100% of primary hypothermia patients with cardiac stability who were treated using active external and minimally invasive rewarming techniques survived with an intact neurologic system.¹² Fifty percent of patients who endured cardiac arrest or who were treated with extracorporeal rewarming had an intact neurologic system. In cardiac arrest cases without significant underlying disease or trauma, and in which hypoxia did not precede hypothermia, full recovery is possible (and has been observed).¹²

CASE

Mr. S was given a diagnosis of mild to moderate hypothermia and transferred to the nearest ED for further treatment. His age had put him at increased risk of hypothermia. The work-up included laboratory testing (CBC, chemistry panel, thyroid-stimulating hormone, urinalysis, and blood cultures), electrocardiography, chest radiography, and CT of the head.

The chest radiograph showed pneumonia. Based on the results of blood culture, bacterial infection (pneumonia) was determined to be the underlying cause of hypothermia. Mr. S was started on antibiotics.

CORRESPONDENCE
Natasha J. Pyzocha, DO, Bldg 1058, 1856 Irwin Dr, Fort Carson, CO 80913; [email protected].

CASE

Patrick S, an 85-year-old man with multiple medical problems, was brought to his primary care provider after being found at home with altered mental status. His caretaker reported that Mr. S had been using extra blankets in bed and sleeping more, but he hadn’t had significant outdoor exposure. Measurement of his vital signs revealed tachycardia, tachypnea, hypotension, and a rectal temperature of 32°C (89.6°F).

How would you proceed with the care of this patient?

What is accidental hypothermia?

Accidental hypothermia is an unintentional drop in core body temperature to <35°C (<95°F). Mild hypothermia is defined as a core body temperature of 32°C to 35°C (90°F - 95°F); moderate hypothermia, 28°C to 32°C (82°F - 90°F); and severe hypothermia, <28°C (<82°F).¹

The International Commission for Mountain Emergency Medicine divides hypothermia into 5 categories, emphasizing the clinical features of each stage as a guide to treatment (TABLE 1).² These categories were adopted to help prehospital rescuers estimate the severity of hypothermia using physical symptoms. For example, most patients stop shivering at approximately 30°C (86°F)—the “moderate (HT II)” category of hypothermia—although this response varies widely from patient to patient. Notably, there are reports in the literature of survival in hypothermia with a temperature as low as 13.7°C (56.7°F) and with cardiac arrest for as long as 8 hours and 40 minutes, although these events are rare.³

Each year, approximately 700 deaths in the United States are the result of hypothermia.⁴ Between 1995 to 2004 in the United States, it is estimated that 15,574 visits were made to a health care provider or facility for hypothermia and other cold-related concerns.⁵ Based on reports in the international literature, the incidence of nonlethal hypothermia is much greater than the incidence of lethal hypothermia.⁵ Almost half of deaths from hypothermia are in people older than age 65 years; the male to female ratio is 2.5:1.¹

Variables that predispose the body to temperature dysregulation include extremes of age, comorbid conditions, intoxication, chronic cold exposure, immersion accident, mental illness, impaired shivering, and lack of acclimatization.¹ The most common causes of death associated with hypothermia are falls, drownings, and cardiovascular disease.⁴ In a 2008 study, hypothermia and other cold-related morbidity emergency department (ED) visits required more transfers of patients to a critical care unit than any other reason for visiting an ED (risk ratio, 6.73; 95% confidence interval, 1.8-25).⁵ Mortality among inpatients whose hypothermia is classified as moderate or severe reaches as high as 40%.³

More than just cold-weather exposure

Accidental hypothermia occurs when heat loss is superseded by the body’s ability to generate heat. It commonly happens in cold environments but can also occur at higher temperatures if the body’s thermoregulatory system malfunctions.

Environmental or iatrogenic factors (ie, primary hypothermia), such as wind, water immersion, wetness, aggressive fluid resuscitation, and heat stroke treatment can make people more susceptible to hypothermia. Medical conditions (ie, secondary hypothermia), such as burns, exfoliative dermatitis, severe psoriasis, hypoadrenalism, hypopituitarism, hypothyroidism, acute spinal cord transection, head trauma, stroke, tumor, pneumonia, Wernicke’s disease (encephalopathy), and sepsis can also predispose to hypothermia.¹ Drugs, such as ethanol, phenothiazines, and sedative–hypnotics may decrease the hypothermia threshold.¹ (For information on preventing hypothermia, see TABLE 2.⁶)

Humans maintain body temperature by balancing heat production and heat loss to the environment. Heat is lost through the skin and lungs by 5 different mechanisms: radiation, conduction, convection, evaporation, and respiration. Convective heat loss to cold air and conductive heat loss to water are the most common mechanisms of accidental hypothermia.⁷

Maintain a high index of suspicion for hypothermia when caring for the elderly or patients presenting with unexplained illness.

To maintain temperature homeostasis at 37°C (98.6°F) (±0.5°C [±0.9°F]), the hypothalamus receives input from central and peripheral thermal receptors and stimulates heat production through shivering, increasing the basal metabolic rate 2-fold to 5-fold.¹ The hypothalamus also increases thyroid, catecholamine, and adrenal activity to increase the body’s production of heat and raise core temperature.

Heat conservation occurs by activation of sympathetically mediated vasoconstriction, reducing conduction to the skin, where cooling is greatest. After time, temperature regulation in the body becomes overwhelmed and catecholamine levels return to a pre-hypothermic state.

At 35°C (95°F), neurologic function begins to decline; at 32°C (89.6°F), metabolism, ventilation, and cardiac output decrease until shivering ceases. Changes in peripheral blood flow can create a false warming sensation, causing a person to remove clothing, a phenomenon referred to as paradoxical undressing. As hypothermia progresses, the neurologic, respiratory, and cardiac systems continue to slow until there is eventual cardiorespiratory failure.

Assessment and diagnosis

History and physical examination. A high index of suspicion for the diagnosis of hypothermia is essential, especially when caring for the elderly or patients presenting with unexplained illness. Often, symptoms of a primary condition may overshadow those reflecting hypothermia. In a multicenter survey that reviewed 428 cases of accidental hypothermia in the United States, 44% of patients had an underlying illness; 18%, coexisting infection; 19%, trauma; and 6%, overdose.³

There are no strict diagnostic criteria for hypothermia other than a core body temperature <35°C (<95°F). Standard thermometers often do not read below 34.4°C (93.2°F), so it is recommended that a rectal thermometer capable of reading low body temperatures be used for accurate measurement.

Hypothermic patients can exhibit a variety of symptoms, depending on the degree of decrease in core body temperature¹:

• A mildly hypothermic patient might present with any combination of tachypnea, tachycardia, ataxia, impaired judgment, shivering, and vasoconstriction.
• Moderate hypothermia typically manifests as a decreased heart rate, decreased blood pressure, decreased level of consciousness, decreased respiratory effort, dilated pupils, extinction of shivering, and hyporeflexia. Cardiac abnormalities, such as atrial fibrillation and junctional bradycardia, may be seen in moderate hypothermia.
• Severe hypothermia presents with apnea, coma, nonreactive pupils, oliguria, areflexia, hypotension, bradycardia, and continued cardiac abnormalities, such as ventricular arrhythmias and asystole.

Laboratory evaluation. No specific laboratory tests are needed to diagnose hypothermia. General lab tests, however, may help determine whether hypothermia is the result, or the cause, of the clinical scenario. Recommended laboratory tests for making that determination include a complete blood count (CBC), chemistry panel, arterial blood gases, fingerstick glucose, and coagulation panel.

General lab tests may help determine whether hypothermia is the result, or the cause, of the clinical scenario.

Results of lab tests may be abnormal because of the body’s decreased core body temperature. White blood cells and platelets in the CBC, for example, may be decreased due to splenic sequestration; these findings reverse with rewarming. With every 1°C (1.8°F) drop in core body temperature, hematocrit increases 2%.³ Sodium, chloride, and magnesium concentrations do not display consistent abnormalities with any core body temperature >25°C (77°F),^3,8 but potassium levels may fluctuate because of acid-base changes that occur during rewarming.¹ Creatinine and creatine kinase levels may be increased secondary to rhabdomyolysis or acute tubular necrosis.¹

Arterial blood gases typically show metabolic acidosis or respiratory alkalosis, or both.⁸ Prothrombin time and partial thromboplastin time are typically elevated in vivo, secondary to temperature-dependent enzymes in the coagulation cascade, but are reported normal in a blood specimen that is heated to 37°C (98.6°F) prior to analysis.^1,8

Both hyperglycemia and hypoglycemia can be associated with hypothermia. The lactate level can be elevated, due to hypoperfusion. Hepatic impairment may be seen secondary to decreased cardiac output. An increase in the lipase level may also occur.³

When a hypothermic patient fails to respond to rewarming, or there is no clear source of cold exposure, consider testing for other causes of the problem, including hypothyroidism and adrenal insufficiency (see “Differential diagnosis”). Hypothermia may also decrease thyroid function in people with preexisting disease.

Other laboratory studies that can be considered include fibrinogen, blood-alcohol level, urine toxicology screen, and blood and fluid cultures.³

Imaging. Imaging studies are not performed routinely in the setting of hypothermia; however:

• Chest radiography can be considered to assess for aspiration pneumonia, vascular congestion, and pulmonary edema.
• Computed tomography (CT) of the head is helpful in the setting of trauma or if mental status does not clear with rewarming.³
• Bedside ultrasonography can assess for cardiac activity, volume status, pulmonary edema, free fluid, and trauma. (See "Point-of-care ultrasound: Coming soon to primary care?" J Fam Pract. 2018;67:70-80.)

Electrocardiography. An electrocardiogram is essential to evaluate for arrhythmias. Findings associated with hypothermia are prolongation of PR, QRS, and QT intervals; ST-segment elevation, T-wave inversion; and Osborn waves (J waves), which represent a positive deflection at the termination of the QRS complex with associated J-point elevation.⁸ Osborn waves generally present when the core body temperature is <32°C (89.6°F) and become larger as the core body temperature drops further.³

Differential diagnosis. Hypothermia is most commonly caused by environmental exposure, but the differential diagnosis is broad: many medical conditions, as well as drug and alcohol intoxication, can contribute to hypothermia (TABLE 3¹).

Treatment: Usually unnecessary, sometimes crucial

Most patients with mild hypothermia recover completely with little intervention. These patients should be evaluated for cognitive irregularities and observed in the ED before discharge.⁹ Moderate and severe hypothermia patients should be assessed using pre-hospital protocols and given cardiopulmonary resuscitation (CPR) for cardiac arrest. Pre-hospital providers should rely more on symptoms in guiding their treatment response because core body temperature measurements can be difficult to obtain, and the response to a drop in core body temperature varies from patient to patient.¹⁰

Early considerations: Airway, breathing, circulation (ABC)

A first responder might have difficulty palpating the pulse of a hypothermic patient if that patient’s cardiopulmonary effort is diminished.⁹ This inability to palpate a pulse should not delay treatment unless the patient presents with lethal injury; the scene is unsafe; the chest is too stiff for CPR; do-not-resuscitate status is present; or the patient was buried in an avalanche for ≥35 minutes and the airway is filled with snow (FIGURE^3,11,12). Pulse should be checked carefully for 60 seconds. If pulses are not present, CPR should be initiated.

Prevention of further heat loss should begin promptly for hypothermic patients who retain a perfusing rhythm.¹¹ Lifesaving interventions, such as airway management, vascular access for volume replenishment, and defibrillation for ventricular tachycardia or ventricular fibrillation should be carried out according to Advanced Cardiac Life Support protocols.¹¹ Patients in respiratory distress or incapable of protecting their airway because of altered mental status should undergo endotracheal intubation. Fluid resuscitation with isotonic crystalloid fluids, warmed to 40°C (104°F) to 42°C (~107°F) and delivered through 2 large-bore, peripheral intravenous (IV) needles, can be considered.

Special care should be taken when moving a hypothermic patient. Excessive movement can lead to stimulation of the irritable hypothermic heart and cause an arrhythmia.

Medical therapy. Caution is advised because the reduced metabolism of a hypothermic patient can lead to potentially toxic accumulation of drugs peripherally. In fact, outcomes have not been positively influenced by routine use of medications, other than treatment of ventricular fibrillation with amiodarone.¹¹ Any intravenous (IV) drug should be held until the patient’s core temperature is >30°C (>86°F).¹¹

Vasopressors can be beneficial during rewarming for a patient in cardiac arrest and are a reasonable consideration.² Nitroglycerin, in conjunction with active external rewarming, can increase the overall hourly temperature gain in a moderately hypothermic patient.¹³

Rewarming. The extent of rewarming required can be predicted by the severity of hypothermia (FIGURE^3,11,12). Mildly hypothermic patients can generally be rewarmed using passive external measures. Patients with moderate hypothermia benefit from active rewarming in addition to passive measures. Intervention for severe hypothermia requires external rewarming and internal warming, with admission to the intensive care unit.

Treatment plans for severely hypothermic patients differ, depending on whether the person has a perfusing or nonperfusing cardiac rhythm. Patients who maintain a perfusing rhythm can be rewarmed using external methods (although core rewarming is used more often). Patients who do not have a perfusing rhythm require more invasive procedures.¹¹ When using any rewarming method, afterdrop phenomenon can occur: ie, vasodilation, brought on by rewarming, causes a drop in core body temperature, as cooler peripheral blood returns to the central circulation. This effect may be reduced by focused rewarming of the trunk prior to rewarming the extremities.³

With every 1°C (1.8°F) drop in core body temperature, hematocrit increases 2%.

Rewarming for mild hypothermia patients begins with passive external techniques. First, the patient is moved away from the environment for protection from further exposure. Next, wet or damaged clothing is removed, blankets or foil insulators are applied, and room temperature is maintained at ≥28°C (82°F).^3,11,13,14

If the patient’s temperature does not normalize, or if the patient presented with moderate or severe hypothermia, rewarming is continued with active external and internal measures. Active external rewarming can supplement passive measures using radiant heat from warmed blankets, air rewarming devices, and heating pads.^3,13,14 Active internal rewarming techniques rely on invasive measures to raise the core temperature. Heated crystalloid IV fluids do not treat hypothermia, but do help reduce further heat loss and can be helpful in patients in need of volume resuscitation.^3,13

Severely hypothermic patients might require more invasive active internal rewarming techniques, such as body-cavity lavage and extracorporeal methods. Body-cavity lavage can be facilitated with large volumes (10-120 L) of warm fluid at 40°C to 42°C, circulated through the thoracic or abdominal cavities to raise core body temperature 3°C to 6°C per hour.^3,13

Extracorporeal rewarming can be achieved through hemodialysis, continuous arteriovenous rewarming (CAVR), continuous veno-venous rewarming (CVVR), or cardiopulmonary bypass.^3,13 Research has shown cardiopulmonary bypass to be the most effective technique, with as high as a 7°C rise in core body temperature per hour; CVVR and CAVR are less invasive, however, and more readily available in hospitals.^3,11,13

Rewarming interventions should continue until return of spontaneous circulation and core body temperature reaches 32°C (89.6°F) to 34°C (93.2°F).¹¹ Overall, resuscitation efforts may take longer than normal due to the need for rewarming and should continue until the patient has achieved a normal temperature of 37°C (97.8°F).

In healthy, mildly hypothermic patients, full recovery is common if heat loss is minimized and the cause is treated. Moderately hypothermic patients who receive proper care can also have a favorable result. Outcomes for severe hypothermia vary with duration, comorbidities, and severity of core body temperature loss.¹⁵

Heated crystalloid IV fluids do not treat hypothermia, but do help reduce further heat loss and can be helpful in patients in need of volume resuscitation.

Immediate initiation of rewarming by pre-hospital providers improves outcomes, and higher mortality has been demonstrated with hospital admission temperatures <35°C (95°F).¹⁵ Almost 100% of primary hypothermia patients with cardiac stability who were treated using active external and minimally invasive rewarming techniques survived with an intact neurologic system.¹² Fifty percent of patients who endured cardiac arrest or who were treated with extracorporeal rewarming had an intact neurologic system. In cardiac arrest cases without significant underlying disease or trauma, and in which hypoxia did not precede hypothermia, full recovery is possible (and has been observed).¹²

CASE