Emergency Medicine

Middle East respiratory syndrome (MERS) is a potentially lethal illness caused by the Middle East respiratory syndrome coronavirus (MERS-CoV). The virus was first reported in 2012, when it was isolated from the sputum of a previously healthy man in Saudi Arabia who presented with acute pneumonia and subsequent renal failure with a fatal outcome.¹ Retrospective studies subsequently identified an earlier outbreak that year involving 13 patients in Jordan, and since then cases have been reported in 25 countries across the Arabian Peninsula and in Asia, Europe, Africa, and the United States, with over 1,000 confirmed cases and 450 related deaths.^2,3

At the time of this writing, two cases of MERS have been reported in the United States, both in May 2014. Both reported cases involved patients who had traveled from Saudi Arabia, and which did not result in secondary cases.⁴ Beginning in May 2015, the Republic of Korea had experienced the largest known outbreak of MERS outside the Arabian Peninsula, with over 100 cases.⁵

THE VIRUS

MERS-CoV is classified as a coronavirus, which is a family of single-stranded RNA viruses. In 2003, a previously unknown coronavirus (SARS-CoV) caused a global outbreak of pneumonia that resulted in approximately 800 deaths.⁶ The MERS-CoV virus attaches to dipeptidyl peptidase 4 to enter cells, and this receptor is believed to be critical for pathogenesis, as infection does not occur in its absence.⁷

The source and mode of transmission to humans is not completely defined. Early reports suggested that MERS-CoV originated in bats, as RNA sequences related to MERS-CoV have been found in several bat species, but the virus itself has not been isolated from bats.⁸ Camels have been found to have a high rate of anti-MERS-CoV antibodies and to have the virus in nose swabs, and evidence for camel-to-human transmission has been presented.^9–11 However, the precise role of camels and other animals as reservoirs or vectors of infection is still under investigation.

The incubation period from exposure to the development of clinical disease is estimated at 5 to 14 days.

Sustained transmission is thought unlikely, but viral adaptation remains a threat

For MERS-CoV, the basic reproduction ratio (R0), which measures the average number of secondary cases from each infected person, is estimated¹² to be less than 0.7. In diseases in which the R0 is less than 1.0, infections occur in isolated clusters as limited chains of transmission, and thus the sustained transmission of MERS-CoV resulting in a large epidemic is thought to be unlikely. As a comparison, the median R0 value for seasonal influenza is estimated¹³ at 1.28. “Superspreading” may result in limited outbreaks of secondary cases; however, the continued epidemic spread of infection is thought to be unlikely.¹⁴ Nevertheless, viral adaptation with increased transmissibility remains a concern and a potential threat.

CLINICAL PRESENTATION

MERS most commonly presents as a respiratory illness, although asymptomatic infection occurs. The percentage of patients who experience asymptomatic infection is unknown. A recent survey of 255 patients with laboratory-confirmed MERS-CoV found that 64 (25.1%) were reported as asymptomatic at time of specimen collection. However, when 33 (52%) of those patients were interviewed, 26 (79%) reported at least one symptom that was consistent with a viral respiratory illness.¹⁵

For symptomatic patients, the initial complaints are nonspecific, beginning with fever, cough, sore throat, chills, and myalgia. Patients experiencing severe infection progress to dyspnea and pneumonia, with requirements for ventilatory support, vasopressors, and renal replacement therapy.¹⁶ Gastrointestinal symptoms such as vomiting and diarrhea have been reported in about one-third of patients.¹⁷

In a study of 47 patients with MERS-CoV, most of whom had underlying medical illnesses, 42 (89%) required intensive care and 34 (72%) required mechanical ventilation.¹⁷ The case-fatality rate in this study was 60%, but other studies have reported rates closer to 30%.¹⁵

Laboratory findings in patients with MERS-CoV infection usually include leukopenia and thrombocytopenia. Severely ill patients may have evidence of acute kidney injury.

Radiographic findings of MERS are those of viral pneumonitis and acute respiratory distress syndrome. Computed tomographic findings include ground-glass opacities, with peripheral lower-lobe preference.¹⁸

DIAGNOSIS

As MERS is a respiratory illness, sampling of respiratory secretions provides the highest yield for diagnosis. A study of 112 patients with MERS-CoV reported that polymerase chain reaction (PCR) testing of tracheal aspirates and bronchoalveolar lavage samples yielded significantly higher MERS-CoV loads than nasopharyngeal swab samples and sputum samples.¹⁹ However, upper respiratory tract testing is less invasive, and a positive nasopharyngeal swab result may obviate the need for further testing.

Unfortunately, treatment for MERS is primarily supportiveThe US Centers for Disease Control and Prevention (CDC) recommends collecting multiple specimens from different sites at different times after the onset of symptoms in order to increase the diagnostic yield. Specifically, it recommends testing a lower respiratory specimen (eg, sputum, bronchoalveolar lavage fluid, tracheal aspirate), a nasopharyngeal and oropharyngeal swab, and serum, using the CDC MERS-CoV rRT-PCR assay. In addition, for patients whose symptoms began more than 14 days earlier, the CDC also recommends testing a serum specimen with the CDC MERS-CoV serologic assay. As these guidelines are updated frequently, clinicians are advised to check the CDC website for the most up-to-date information (www.cdc.gov/coronavirus/mers/guidelines-clinical-specimens.html).²⁰ The identification of MERS-CoV by virus isolation in cell culture is not recommended and, if pursued, must be performed in a biosafety level 3 facility. (Level 3 is the second-highest level of biosafety. The highest, level 4, is reserved for extremely dangerous agents such as Ebola virus).²⁰

Given the nonspecific clinical presentation of MERS-CoV, clinicians may consider testing for other respiratory pathogens. A recent review of 54 travelers to California from MERS-CoV-affected areas found that while none tested positive for MERS-CoV, 32 (62%) of 52 travelers had other respiratory viruses.²¹ When testing for alternative pathogens, clinicians should order molecular or antigen-based detection methods.

TREATMENT

Unfortunately, treatment for MERS is primarily supportive.

Ribavirin and interferon alfa-2b demonstrated activity in an animal model, but the regimen was ineffective when given a median of 19 (range 10–22) days after admission in 5 critically ill patients who subsequently died.²² A retrospective analysis comparing 20 patients with severe MERS-CoV who received ribavirin and interferon alfa-2a with 24 patients who did not reported that while survival was improved at 14 days, the mortality rates were similar at 28 days.²³

A systematic review of treatments used for severe acute respiratory syndrome (SARS) reported that most studies investigating steroid use were inconclusive and some showed possible harm, suggesting that systemic steroids should be avoided in coronavirus infections.²⁴

PREVENTION

Healthcare-associated outbreaks of MERS are well described, and thus recognition of potential cases and prompt institution of appropriate infection control measures are critical.^15,25

Healthcare providers should ask patients about recent travel history and ascertain if they meet the CDC criteria for a “patient under investigation” (PUI), ie, if they have both clinical features and an epidemiologic risk of MERS (Table 1). However, these recommendations for identification will assuredly change as the outbreak matures, and healthcare providers should refer to the CDC website for the most up-to-date information.

Once a PUI is identified, standard, contact, and airborne precautions are advised. These measures include performing hand hygiene and donning personal protective equipment, including gloves, gowns, eye protection, and respiratory protection (ie, a respirator) that is at least as protective as a fit-tested National Institute for Occupational Safety and Health-certified N95 filtering face-piece respirator. In addition, a patient with possible MERS should be placed in an airborne infection isolation room.

Traveler’s advice

The CDC does not currently recommend that Americans change their travel plans because of MERS. Clinicians performing pretravel evaluations should advise patients of current information on MERS. Patients at risk for MERS who develop a respiratory illness within 14 days of return should seek medical attention and inform healthcare providers of their travel history.

SUMMARY

Recent experience with SARS, Ebola virus disease, and now MERS-CoV highlights the impact of global air travel as a vector for the rapid worldwide dissemination of communicable diseases. Healthcare providers should elicit a travel history in all patients presenting with a febrile illness, as an infection acquired in one continent may not become manifest until the patient presents in another.

The scope of the current MERS-CoV outbreak is still evolving, with concerns that viral evolution could result in a SARS-like outbreak, as experienced almost a decade ago.

Healthcare providers are advised to screen patients at risk for MERS-CoV for respiratory symptoms, and to institute appropriate infection control measures. Through recognition and isolation, healthcare providers are at the front line in limiting the spread of this potentially lethal virus.

Middle East respiratory syndrome (MERS) is a potentially lethal illness caused by the Middle East respiratory syndrome coronavirus (MERS-CoV). The virus was first reported in 2012, when it was isolated from the sputum of a previously healthy man in Saudi Arabia who presented with acute pneumonia and subsequent renal failure with a fatal outcome.¹ Retrospective studies subsequently identified an earlier outbreak that year involving 13 patients in Jordan, and since then cases have been reported in 25 countries across the Arabian Peninsula and in Asia, Europe, Africa, and the United States, with over 1,000 confirmed cases and 450 related deaths.^2,3

At the time of this writing, two cases of MERS have been reported in the United States, both in May 2014. Both reported cases involved patients who had traveled from Saudi Arabia, and which did not result in secondary cases.⁴ Beginning in May 2015, the Republic of Korea had experienced the largest known outbreak of MERS outside the Arabian Peninsula, with over 100 cases.⁵

THE VIRUS

MERS-CoV is classified as a coronavirus, which is a family of single-stranded RNA viruses. In 2003, a previously unknown coronavirus (SARS-CoV) caused a global outbreak of pneumonia that resulted in approximately 800 deaths.⁶ The MERS-CoV virus attaches to dipeptidyl peptidase 4 to enter cells, and this receptor is believed to be critical for pathogenesis, as infection does not occur in its absence.⁷

The source and mode of transmission to humans is not completely defined. Early reports suggested that MERS-CoV originated in bats, as RNA sequences related to MERS-CoV have been found in several bat species, but the virus itself has not been isolated from bats.⁸ Camels have been found to have a high rate of anti-MERS-CoV antibodies and to have the virus in nose swabs, and evidence for camel-to-human transmission has been presented.^9–11 However, the precise role of camels and other animals as reservoirs or vectors of infection is still under investigation.

The incubation period from exposure to the development of clinical disease is estimated at 5 to 14 days.

Sustained transmission is thought unlikely, but viral adaptation remains a threat

For MERS-CoV, the basic reproduction ratio (R0), which measures the average number of secondary cases from each infected person, is estimated¹² to be less than 0.7. In diseases in which the R0 is less than 1.0, infections occur in isolated clusters as limited chains of transmission, and thus the sustained transmission of MERS-CoV resulting in a large epidemic is thought to be unlikely. As a comparison, the median R0 value for seasonal influenza is estimated¹³ at 1.28. “Superspreading” may result in limited outbreaks of secondary cases; however, the continued epidemic spread of infection is thought to be unlikely.¹⁴ Nevertheless, viral adaptation with increased transmissibility remains a concern and a potential threat.

CLINICAL PRESENTATION

MERS most commonly presents as a respiratory illness, although asymptomatic infection occurs. The percentage of patients who experience asymptomatic infection is unknown. A recent survey of 255 patients with laboratory-confirmed MERS-CoV found that 64 (25.1%) were reported as asymptomatic at time of specimen collection. However, when 33 (52%) of those patients were interviewed, 26 (79%) reported at least one symptom that was consistent with a viral respiratory illness.¹⁵

For symptomatic patients, the initial complaints are nonspecific, beginning with fever, cough, sore throat, chills, and myalgia. Patients experiencing severe infection progress to dyspnea and pneumonia, with requirements for ventilatory support, vasopressors, and renal replacement therapy.¹⁶ Gastrointestinal symptoms such as vomiting and diarrhea have been reported in about one-third of patients.¹⁷

In a study of 47 patients with MERS-CoV, most of whom had underlying medical illnesses, 42 (89%) required intensive care and 34 (72%) required mechanical ventilation.¹⁷ The case-fatality rate in this study was 60%, but other studies have reported rates closer to 30%.¹⁵

Laboratory findings in patients with MERS-CoV infection usually include leukopenia and thrombocytopenia. Severely ill patients may have evidence of acute kidney injury.

Radiographic findings of MERS are those of viral pneumonitis and acute respiratory distress syndrome. Computed tomographic findings include ground-glass opacities, with peripheral lower-lobe preference.¹⁸

DIAGNOSIS

As MERS is a respiratory illness, sampling of respiratory secretions provides the highest yield for diagnosis. A study of 112 patients with MERS-CoV reported that polymerase chain reaction (PCR) testing of tracheal aspirates and bronchoalveolar lavage samples yielded significantly higher MERS-CoV loads than nasopharyngeal swab samples and sputum samples.¹⁹ However, upper respiratory tract testing is less invasive, and a positive nasopharyngeal swab result may obviate the need for further testing.

Unfortunately, treatment for MERS is primarily supportiveThe US Centers for Disease Control and Prevention (CDC) recommends collecting multiple specimens from different sites at different times after the onset of symptoms in order to increase the diagnostic yield. Specifically, it recommends testing a lower respiratory specimen (eg, sputum, bronchoalveolar lavage fluid, tracheal aspirate), a nasopharyngeal and oropharyngeal swab, and serum, using the CDC MERS-CoV rRT-PCR assay. In addition, for patients whose symptoms began more than 14 days earlier, the CDC also recommends testing a serum specimen with the CDC MERS-CoV serologic assay. As these guidelines are updated frequently, clinicians are advised to check the CDC website for the most up-to-date information (www.cdc.gov/coronavirus/mers/guidelines-clinical-specimens.html).²⁰ The identification of MERS-CoV by virus isolation in cell culture is not recommended and, if pursued, must be performed in a biosafety level 3 facility. (Level 3 is the second-highest level of biosafety. The highest, level 4, is reserved for extremely dangerous agents such as Ebola virus).²⁰

Given the nonspecific clinical presentation of MERS-CoV, clinicians may consider testing for other respiratory pathogens. A recent review of 54 travelers to California from MERS-CoV-affected areas found that while none tested positive for MERS-CoV, 32 (62%) of 52 travelers had other respiratory viruses.²¹ When testing for alternative pathogens, clinicians should order molecular or antigen-based detection methods.

TREATMENT

Unfortunately, treatment for MERS is primarily supportive.

Ribavirin and interferon alfa-2b demonstrated activity in an animal model, but the regimen was ineffective when given a median of 19 (range 10–22) days after admission in 5 critically ill patients who subsequently died.²² A retrospective analysis comparing 20 patients with severe MERS-CoV who received ribavirin and interferon alfa-2a with 24 patients who did not reported that while survival was improved at 14 days, the mortality rates were similar at 28 days.²³

A systematic review of treatments used for severe acute respiratory syndrome (SARS) reported that most studies investigating steroid use were inconclusive and some showed possible harm, suggesting that systemic steroids should be avoided in coronavirus infections.²⁴

PREVENTION

Healthcare-associated outbreaks of MERS are well described, and thus recognition of potential cases and prompt institution of appropriate infection control measures are critical.^15,25

Healthcare providers should ask patients about recent travel history and ascertain if they meet the CDC criteria for a “patient under investigation” (PUI), ie, if they have both clinical features and an epidemiologic risk of MERS (Table 1). However, these recommendations for identification will assuredly change as the outbreak matures, and healthcare providers should refer to the CDC website for the most up-to-date information.

Once a PUI is identified, standard, contact, and airborne precautions are advised. These measures include performing hand hygiene and donning personal protective equipment, including gloves, gowns, eye protection, and respiratory protection (ie, a respirator) that is at least as protective as a fit-tested National Institute for Occupational Safety and Health-certified N95 filtering face-piece respirator. In addition, a patient with possible MERS should be placed in an airborne infection isolation room.

Traveler’s advice

The CDC does not currently recommend that Americans change their travel plans because of MERS. Clinicians performing pretravel evaluations should advise patients of current information on MERS. Patients at risk for MERS who develop a respiratory illness within 14 days of return should seek medical attention and inform healthcare providers of their travel history.

SUMMARY

Recent experience with SARS, Ebola virus disease, and now MERS-CoV highlights the impact of global air travel as a vector for the rapid worldwide dissemination of communicable diseases. Healthcare providers should elicit a travel history in all patients presenting with a febrile illness, as an infection acquired in one continent may not become manifest until the patient presents in another.

The scope of the current MERS-CoV outbreak is still evolving, with concerns that viral evolution could result in a SARS-like outbreak, as experienced almost a decade ago.

Healthcare providers are advised to screen patients at risk for MERS-CoV for respiratory symptoms, and to institute appropriate infection control measures. Through recognition and isolation, healthcare providers are at the front line in limiting the spread of this potentially lethal virus.

Middle East respiratory syndrome (MERS) is a potentially lethal illness caused by the Middle East respiratory syndrome coronavirus (MERS-CoV). The virus was first reported in 2012, when it was isolated from the sputum of a previously healthy man in Saudi Arabia who presented with acute pneumonia and subsequent renal failure with a fatal outcome.¹ Retrospective studies subsequently identified an earlier outbreak that year involving 13 patients in Jordan, and since then cases have been reported in 25 countries across the Arabian Peninsula and in Asia, Europe, Africa, and the United States, with over 1,000 confirmed cases and 450 related deaths.^2,3

At the time of this writing, two cases of MERS have been reported in the United States, both in May 2014. Both reported cases involved patients who had traveled from Saudi Arabia, and which did not result in secondary cases.⁴ Beginning in May 2015, the Republic of Korea had experienced the largest known outbreak of MERS outside the Arabian Peninsula, with over 100 cases.⁵

THE VIRUS

MERS-CoV is classified as a coronavirus, which is a family of single-stranded RNA viruses. In 2003, a previously unknown coronavirus (SARS-CoV) caused a global outbreak of pneumonia that resulted in approximately 800 deaths.⁶ The MERS-CoV virus attaches to dipeptidyl peptidase 4 to enter cells, and this receptor is believed to be critical for pathogenesis, as infection does not occur in its absence.⁷

The source and mode of transmission to humans is not completely defined. Early reports suggested that MERS-CoV originated in bats, as RNA sequences related to MERS-CoV have been found in several bat species, but the virus itself has not been isolated from bats.⁸ Camels have been found to have a high rate of anti-MERS-CoV antibodies and to have the virus in nose swabs, and evidence for camel-to-human transmission has been presented.^9–11 However, the precise role of camels and other animals as reservoirs or vectors of infection is still under investigation.

The incubation period from exposure to the development of clinical disease is estimated at 5 to 14 days.

Sustained transmission is thought unlikely, but viral adaptation remains a threat

For MERS-CoV, the basic reproduction ratio (R0), which measures the average number of secondary cases from each infected person, is estimated¹² to be less than 0.7. In diseases in which the R0 is less than 1.0, infections occur in isolated clusters as limited chains of transmission, and thus the sustained transmission of MERS-CoV resulting in a large epidemic is thought to be unlikely. As a comparison, the median R0 value for seasonal influenza is estimated¹³ at 1.28. “Superspreading” may result in limited outbreaks of secondary cases; however, the continued epidemic spread of infection is thought to be unlikely.¹⁴ Nevertheless, viral adaptation with increased transmissibility remains a concern and a potential threat.

CLINICAL PRESENTATION

MERS most commonly presents as a respiratory illness, although asymptomatic infection occurs. The percentage of patients who experience asymptomatic infection is unknown. A recent survey of 255 patients with laboratory-confirmed MERS-CoV found that 64 (25.1%) were reported as asymptomatic at time of specimen collection. However, when 33 (52%) of those patients were interviewed, 26 (79%) reported at least one symptom that was consistent with a viral respiratory illness.¹⁵

For symptomatic patients, the initial complaints are nonspecific, beginning with fever, cough, sore throat, chills, and myalgia. Patients experiencing severe infection progress to dyspnea and pneumonia, with requirements for ventilatory support, vasopressors, and renal replacement therapy.¹⁶ Gastrointestinal symptoms such as vomiting and diarrhea have been reported in about one-third of patients.¹⁷

In a study of 47 patients with MERS-CoV, most of whom had underlying medical illnesses, 42 (89%) required intensive care and 34 (72%) required mechanical ventilation.¹⁷ The case-fatality rate in this study was 60%, but other studies have reported rates closer to 30%.¹⁵

Laboratory findings in patients with MERS-CoV infection usually include leukopenia and thrombocytopenia. Severely ill patients may have evidence of acute kidney injury.

Radiographic findings of MERS are those of viral pneumonitis and acute respiratory distress syndrome. Computed tomographic findings include ground-glass opacities, with peripheral lower-lobe preference.¹⁸

DIAGNOSIS

As MERS is a respiratory illness, sampling of respiratory secretions provides the highest yield for diagnosis. A study of 112 patients with MERS-CoV reported that polymerase chain reaction (PCR) testing of tracheal aspirates and bronchoalveolar lavage samples yielded significantly higher MERS-CoV loads than nasopharyngeal swab samples and sputum samples.¹⁹ However, upper respiratory tract testing is less invasive, and a positive nasopharyngeal swab result may obviate the need for further testing.

Unfortunately, treatment for MERS is primarily supportiveThe US Centers for Disease Control and Prevention (CDC) recommends collecting multiple specimens from different sites at different times after the onset of symptoms in order to increase the diagnostic yield. Specifically, it recommends testing a lower respiratory specimen (eg, sputum, bronchoalveolar lavage fluid, tracheal aspirate), a nasopharyngeal and oropharyngeal swab, and serum, using the CDC MERS-CoV rRT-PCR assay. In addition, for patients whose symptoms began more than 14 days earlier, the CDC also recommends testing a serum specimen with the CDC MERS-CoV serologic assay. As these guidelines are updated frequently, clinicians are advised to check the CDC website for the most up-to-date information (www.cdc.gov/coronavirus/mers/guidelines-clinical-specimens.html).²⁰ The identification of MERS-CoV by virus isolation in cell culture is not recommended and, if pursued, must be performed in a biosafety level 3 facility. (Level 3 is the second-highest level of biosafety. The highest, level 4, is reserved for extremely dangerous agents such as Ebola virus).²⁰

Given the nonspecific clinical presentation of MERS-CoV, clinicians may consider testing for other respiratory pathogens. A recent review of 54 travelers to California from MERS-CoV-affected areas found that while none tested positive for MERS-CoV, 32 (62%) of 52 travelers had other respiratory viruses.²¹ When testing for alternative pathogens, clinicians should order molecular or antigen-based detection methods.

TREATMENT

Unfortunately, treatment for MERS is primarily supportive.

Ribavirin and interferon alfa-2b demonstrated activity in an animal model, but the regimen was ineffective when given a median of 19 (range 10–22) days after admission in 5 critically ill patients who subsequently died.²² A retrospective analysis comparing 20 patients with severe MERS-CoV who received ribavirin and interferon alfa-2a with 24 patients who did not reported that while survival was improved at 14 days, the mortality rates were similar at 28 days.²³

A systematic review of treatments used for severe acute respiratory syndrome (SARS) reported that most studies investigating steroid use were inconclusive and some showed possible harm, suggesting that systemic steroids should be avoided in coronavirus infections.²⁴

PREVENTION

Healthcare-associated outbreaks of MERS are well described, and thus recognition of potential cases and prompt institution of appropriate infection control measures are critical.^15,25

Healthcare providers should ask patients about recent travel history and ascertain if they meet the CDC criteria for a “patient under investigation” (PUI), ie, if they have both clinical features and an epidemiologic risk of MERS (Table 1). However, these recommendations for identification will assuredly change as the outbreak matures, and healthcare providers should refer to the CDC website for the most up-to-date information.

Once a PUI is identified, standard, contact, and airborne precautions are advised. These measures include performing hand hygiene and donning personal protective equipment, including gloves, gowns, eye protection, and respiratory protection (ie, a respirator) that is at least as protective as a fit-tested National Institute for Occupational Safety and Health-certified N95 filtering face-piece respirator. In addition, a patient with possible MERS should be placed in an airborne infection isolation room.

Traveler’s advice

The CDC does not currently recommend that Americans change their travel plans because of MERS. Clinicians performing pretravel evaluations should advise patients of current information on MERS. Patients at risk for MERS who develop a respiratory illness within 14 days of return should seek medical attention and inform healthcare providers of their travel history.

SUMMARY

Recent experience with SARS, Ebola virus disease, and now MERS-CoV highlights the impact of global air travel as a vector for the rapid worldwide dissemination of communicable diseases. Healthcare providers should elicit a travel history in all patients presenting with a febrile illness, as an infection acquired in one continent may not become manifest until the patient presents in another.

The scope of the current MERS-CoV outbreak is still evolving, with concerns that viral evolution could result in a SARS-like outbreak, as experienced almost a decade ago.

Healthcare providers are advised to screen patients at risk for MERS-CoV for respiratory symptoms, and to institute appropriate infection control measures. Through recognition and isolation, healthcare providers are at the front line in limiting the spread of this potentially lethal virus.

ANSWER
The radiograph shows complete opacification of the left hemithorax. The differential includes total atelectasis of the lung, mucus plug within the left bronchus, or possible blood or fluid collection. Of note, the patient has a catheter within the left subclavian vein, the distal tip of which appears to be in an unusual location. In this case, it was determined that the displaced catheter tip, resulting in hemothorax, was the etiology. The line was removed, and urgent cardiothoracic consultation was obtained. A left chest tube was promptly placed, with a resultant 2 L of immediate output. The patient improved clinically as well.

ANSWER
The radiograph shows complete opacification of the left hemithorax. The differential includes total atelectasis of the lung, mucus plug within the left bronchus, or possible blood or fluid collection. Of note, the patient has a catheter within the left subclavian vein, the distal tip of which appears to be in an unusual location. In this case, it was determined that the displaced catheter tip, resulting in hemothorax, was the etiology. The line was removed, and urgent cardiothoracic consultation was obtained. A left chest tube was promptly placed, with a resultant 2 L of immediate output. The patient improved clinically as well.

ANSWER
The radiograph shows complete opacification of the left hemithorax. The differential includes total atelectasis of the lung, mucus plug within the left bronchus, or possible blood or fluid collection. Of note, the patient has a catheter within the left subclavian vein, the distal tip of which appears to be in an unusual location. In this case, it was determined that the displaced catheter tip, resulting in hemothorax, was the etiology. The line was removed, and urgent cardiothoracic consultation was obtained. A left chest tube was promptly placed, with a resultant 2 L of immediate output. The patient improved clinically as well.

ANSWER
The radiographs demonstrate a left inferior pubic ramus fracture. The patient was referred to orthopedics for follow-up. She was given a walker and a series of home exercises for hip stretching and strengthening, as well as anti-inflammatories as needed for discomfort. She was scheduled for a four-week follow-up visit and repeat radiographs of the pelvis.

ANSWER
The radiographs demonstrate a left inferior pubic ramus fracture. The patient was referred to orthopedics for follow-up. She was given a walker and a series of home exercises for hip stretching and strengthening, as well as anti-inflammatories as needed for discomfort. She was scheduled for a four-week follow-up visit and repeat radiographs of the pelvis.

ANSWER
The radiographs demonstrate a left inferior pubic ramus fracture. The patient was referred to orthopedics for follow-up. She was given a walker and a series of home exercises for hip stretching and strengthening, as well as anti-inflammatories as needed for discomfort. She was scheduled for a four-week follow-up visit and repeat radiographs of the pelvis.

A 53-year-old woman presented to the ED after experiencing a fall. Her medical history was significant for chronic obstructive pulmonary disease, hepatitis, and a remote history of intravenous drug use, for which she had been maintained on methadone for the past 20 years. She reported that she had suffered several “fainting episodes” over the past month, and the morning prior to arrival, had sustained what she thought was a mechanical fall outside of the methadone program she attended. She complained of tenderness on her head but denied any other injuries.

The methadone program had referred the patient to the ED for evaluation, noting to the ED staff that her daily methadone dose of 185 mg had not been dispensed prior to transfer. During evaluation, the patient requested that the emergency physician (EP) provide the methadone dose since the clinic would close prior to her discharge from the ED. 

How can requests for methadone be managed in the ED?

Methadone is a long-acting oral opioid that is used for both opioid replacement therapy and pain management. When used to reduce craving in opioid-dependent patients, methadone is administered daily through federally sanctioned methadone maintenance treatment (MMT) programs. Patients who consistently adhere to the required guidelines are given “take home” doses. When used for pain management, methadone is typically administered several times daily and may be prescribed by any provider with an appropriate DEA registration.

When given for MMT, methadone saturates the µ-opioid receptors and hinders their binding and agonism by other opioids such as heroin or oxycodone. Patients in MMT programs are started on a low initial dose and slowly titrated upward as tolerance to the adverse effects (eg, sedation) develop.

How are symptomatic patients with methadone withdrawal treated?

Most methadone programs have limited hours and require that patients who miss a dose wait until the following day to return to the program. This is typically without medical consequence because the high dose dispensed by these programs maintains a therapeutic blood concentration for far longer than the expected delay. Although the half-life of methadone exhibits wide interindividual variability, it generally ranges from 12 hours to more than 40 hours.¹ Regardless, patients may feel anxious about potential opioid withdrawal, and this often leads them to access the ED for a missed dose.

The neuropsychiatric symptoms attending withdrawal may precede the objective signs of opioid withdrawal. Patients with objective signs of opioid withdrawal (eg, piloerection, vomiting, diarrhea, dilated pupils) may be sufficiently treated with supportive care alone, using antiemetics, hydration, and sometimes clonidine.

Administration of substitute opioids is problematic due to the patient’s underlying tolerance necessitating careful dose titration. Therefore, direct replacement of methadone in the ED remains controversial, and some EDs have strict policies prohibiting the administration of methadone to patients who have missed an MMT dose. Such policies, which are intended to discourage patients from using the ED as a convenience, may be appropriate given the generally benign—though uncomfortable—course of opioid withdrawal due to abstinence.

Other EDs provide replacement methadone for asymptomatic, treat-and-release patients confirmed to be enrolled in an MMT program when the time to the next dose is likely to be 24 hours or greater from the missed dose. Typically, a dose of no more than 10 mg orally or 10 mg intramuscularly (IM) is recommended, and patients should be advised that they will be receiving only a low dose to sufficient to prevent withdrawal—one that may not have the equivalent effects of the outpatient dose.

Whenever possible, a patient’s MMT program should be contacted and informed of the ED visit. For patients who display objective signs of withdrawal and who cannot be confirmed or who do not participate in an MMT program, 10 mg of methadone IM will prevent uncertainty of drug absorption in the setting of nausea or vomiting. All patients receiving oral methadone should be observed for 1 hour, and those receiving IM methadone should be observed for at least 90 minutes to assess for unexpected sedation.²

Patients encountering circumstances that prevent opioid access (eg, incarceration) and who are not in withdrawal but have gone without opioids for more than 5 days may have a loss of tolerance to their usual doses—whether the medication was obtained through an MMT program or illicitly. Harm-reduction strategies aimed at educating patients on the potential vulnerability to their familiar dosing regimens are warranted to avert inadvertent overdoses in chronic opioid users who are likely to resume illicit opoiod use.

Does this patient need syncope evaluation?

Further complicating the decision regarding ED dispensing of methadone are the effects of the drug on myocardial repolarization. Methadone affects conduction across the hERG potassium rectifier current and can prolong the QTc interval on the surface electrocardiogram (ECG), predisposing a patient to torsade de pointes (TdP). Although there is controversy regarding the role of ECG screening during the enrollment of patients in methadone maintenance clinics, doses above 60 mg, underlying myocardial disease, female sex, and electrolyte disturbances may increase the risk of QT prolongation and TdP.³

Whether there is value in obtaining a screening ECG in a patient receiving an initial dose of methadone in the ED is unclear, and this practice is controversial even among methadone clinics. However, some of the excess death in patients taking methadone may be explained by the dysrhythmogenic potential of methadone.⁴ An ECG therefore may elucidate a correctable cause in methadone patients presenting with syncope.  

Administering methadone to patients with documented QT prolongation must weigh the risk of methadone’s conduction effects against the substantial risks of illicit opioid self-administration. For some patients at-risk for TdP, it may be preferable to use buprenorphine if possible, since it does not carry the same cardiac effects as methadone.^1,5 Such therapy requires referral to a physician licensed to prescribe this medication.

How should admitted patients be managed?

While administration of methadone for withdrawal or maintenance therapy in the ED is acceptable, outpatient prescribing of methadone for these reasons is not legal, and only federally regulated clinics may engage in this practice. Hospitalized patients who are enrolled in an MMT program should have their daily methadone dose confirmed and continued—as long as the patient has not lost tolerance. Patients not participating in an MMT program can receive up to 3 days of methadone in the hospital, even if the practitioner is not registered to provide methadone.⁶ For these patients, it is recommended that the physician order a low dose of methadone and also consult with an addiction specialist to determine whether the patient should continue on MMT maintenance or undergo detoxification.

It is important to note that methadone may be prescribed for pain, but its use in the ED for this purpose is strongly discouraged, especially in patients who have never received methadone previously. For admitted patients requiring such potent opioid analgesia, consultation with a pain service or, when indicated, a palliative care/hospice specialist is warranted as the dosing intervals are different in each setting, and the risk of respiratory depression is high.

Case Conclusion

As requested by the MMT clinic, the patient was administered methadone 185 mg orally in the ED, though a dose of 10 mg would have been sufficient to prevent withdrawal. Unfortunately, the EP did not appreciate the relationship of the markedly prolonged QTc and the methadone, which should have prompted a dose reduction.

Evaluation of the patient’s electrolyte levels, which included magnesium and potassium, were normal. An ECG was repeated 24 hours later and revealed a persistent, but improved, QT interval at 505 ms. The remainder of the syncope workup was negative. Because the patient had no additional symptoms or events during her stay, she was discharged. At discharge, the EP followed up with the MMT clinic to discuss lowering the patient’s daily methadone dose, as well as close cardiology follow-up.

Dr Rao is the chief of the division of medical toxicology at New York Presbyterian Hospital/Weill Cornell Medical Center, New York. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board.

A 53-year-old woman presented to the ED after experiencing a fall. Her medical history was significant for chronic obstructive pulmonary disease, hepatitis, and a remote history of intravenous drug use, for which she had been maintained on methadone for the past 20 years. She reported that she had suffered several “fainting episodes” over the past month, and the morning prior to arrival, had sustained what she thought was a mechanical fall outside of the methadone program she attended. She complained of tenderness on her head but denied any other injuries.

The methadone program had referred the patient to the ED for evaluation, noting to the ED staff that her daily methadone dose of 185 mg had not been dispensed prior to transfer. During evaluation, the patient requested that the emergency physician (EP) provide the methadone dose since the clinic would close prior to her discharge from the ED. 

How can requests for methadone be managed in the ED?

Methadone is a long-acting oral opioid that is used for both opioid replacement therapy and pain management. When used to reduce craving in opioid-dependent patients, methadone is administered daily through federally sanctioned methadone maintenance treatment (MMT) programs. Patients who consistently adhere to the required guidelines are given “take home” doses. When used for pain management, methadone is typically administered several times daily and may be prescribed by any provider with an appropriate DEA registration.

When given for MMT, methadone saturates the µ-opioid receptors and hinders their binding and agonism by other opioids such as heroin or oxycodone. Patients in MMT programs are started on a low initial dose and slowly titrated upward as tolerance to the adverse effects (eg, sedation) develop.

How are symptomatic patients with methadone withdrawal treated?

Most methadone programs have limited hours and require that patients who miss a dose wait until the following day to return to the program. This is typically without medical consequence because the high dose dispensed by these programs maintains a therapeutic blood concentration for far longer than the expected delay. Although the half-life of methadone exhibits wide interindividual variability, it generally ranges from 12 hours to more than 40 hours.¹ Regardless, patients may feel anxious about potential opioid withdrawal, and this often leads them to access the ED for a missed dose.

The neuropsychiatric symptoms attending withdrawal may precede the objective signs of opioid withdrawal. Patients with objective signs of opioid withdrawal (eg, piloerection, vomiting, diarrhea, dilated pupils) may be sufficiently treated with supportive care alone, using antiemetics, hydration, and sometimes clonidine.

Administration of substitute opioids is problematic due to the patient’s underlying tolerance necessitating careful dose titration. Therefore, direct replacement of methadone in the ED remains controversial, and some EDs have strict policies prohibiting the administration of methadone to patients who have missed an MMT dose. Such policies, which are intended to discourage patients from using the ED as a convenience, may be appropriate given the generally benign—though uncomfortable—course of opioid withdrawal due to abstinence.

Other EDs provide replacement methadone for asymptomatic, treat-and-release patients confirmed to be enrolled in an MMT program when the time to the next dose is likely to be 24 hours or greater from the missed dose. Typically, a dose of no more than 10 mg orally or 10 mg intramuscularly (IM) is recommended, and patients should be advised that they will be receiving only a low dose to sufficient to prevent withdrawal—one that may not have the equivalent effects of the outpatient dose.

Whenever possible, a patient’s MMT program should be contacted and informed of the ED visit. For patients who display objective signs of withdrawal and who cannot be confirmed or who do not participate in an MMT program, 10 mg of methadone IM will prevent uncertainty of drug absorption in the setting of nausea or vomiting. All patients receiving oral methadone should be observed for 1 hour, and those receiving IM methadone should be observed for at least 90 minutes to assess for unexpected sedation.²

Patients encountering circumstances that prevent opioid access (eg, incarceration) and who are not in withdrawal but have gone without opioids for more than 5 days may have a loss of tolerance to their usual doses—whether the medication was obtained through an MMT program or illicitly. Harm-reduction strategies aimed at educating patients on the potential vulnerability to their familiar dosing regimens are warranted to avert inadvertent overdoses in chronic opioid users who are likely to resume illicit opoiod use.

Does this patient need syncope evaluation?

Further complicating the decision regarding ED dispensing of methadone are the effects of the drug on myocardial repolarization. Methadone affects conduction across the hERG potassium rectifier current and can prolong the QTc interval on the surface electrocardiogram (ECG), predisposing a patient to torsade de pointes (TdP). Although there is controversy regarding the role of ECG screening during the enrollment of patients in methadone maintenance clinics, doses above 60 mg, underlying myocardial disease, female sex, and electrolyte disturbances may increase the risk of QT prolongation and TdP.³

Whether there is value in obtaining a screening ECG in a patient receiving an initial dose of methadone in the ED is unclear, and this practice is controversial even among methadone clinics. However, some of the excess death in patients taking methadone may be explained by the dysrhythmogenic potential of methadone.⁴ An ECG therefore may elucidate a correctable cause in methadone patients presenting with syncope.  

Administering methadone to patients with documented QT prolongation must weigh the risk of methadone’s conduction effects against the substantial risks of illicit opioid self-administration. For some patients at-risk for TdP, it may be preferable to use buprenorphine if possible, since it does not carry the same cardiac effects as methadone.^1,5 Such therapy requires referral to a physician licensed to prescribe this medication.

How should admitted patients be managed?

While administration of methadone for withdrawal or maintenance therapy in the ED is acceptable, outpatient prescribing of methadone for these reasons is not legal, and only federally regulated clinics may engage in this practice. Hospitalized patients who are enrolled in an MMT program should have their daily methadone dose confirmed and continued—as long as the patient has not lost tolerance. Patients not participating in an MMT program can receive up to 3 days of methadone in the hospital, even if the practitioner is not registered to provide methadone.⁶ For these patients, it is recommended that the physician order a low dose of methadone and also consult with an addiction specialist to determine whether the patient should continue on MMT maintenance or undergo detoxification.

It is important to note that methadone may be prescribed for pain, but its use in the ED for this purpose is strongly discouraged, especially in patients who have never received methadone previously. For admitted patients requiring such potent opioid analgesia, consultation with a pain service or, when indicated, a palliative care/hospice specialist is warranted as the dosing intervals are different in each setting, and the risk of respiratory depression is high.

Case Conclusion

As requested by the MMT clinic, the patient was administered methadone 185 mg orally in the ED, though a dose of 10 mg would have been sufficient to prevent withdrawal. Unfortunately, the EP did not appreciate the relationship of the markedly prolonged QTc and the methadone, which should have prompted a dose reduction.

Evaluation of the patient’s electrolyte levels, which included magnesium and potassium, were normal. An ECG was repeated 24 hours later and revealed a persistent, but improved, QT interval at 505 ms. The remainder of the syncope workup was negative. Because the patient had no additional symptoms or events during her stay, she was discharged. At discharge, the EP followed up with the MMT clinic to discuss lowering the patient’s daily methadone dose, as well as close cardiology follow-up.

Dr Rao is the chief of the division of medical toxicology at New York Presbyterian Hospital/Weill Cornell Medical Center, New York. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board.

A 53-year-old woman presented to the ED after experiencing a fall. Her medical history was significant for chronic obstructive pulmonary disease, hepatitis, and a remote history of intravenous drug use, for which she had been maintained on methadone for the past 20 years. She reported that she had suffered several “fainting episodes” over the past month, and the morning prior to arrival, had sustained what she thought was a mechanical fall outside of the methadone program she attended. She complained of tenderness on her head but denied any other injuries.

The methadone program had referred the patient to the ED for evaluation, noting to the ED staff that her daily methadone dose of 185 mg had not been dispensed prior to transfer. During evaluation, the patient requested that the emergency physician (EP) provide the methadone dose since the clinic would close prior to her discharge from the ED. 

How can requests for methadone be managed in the ED?

Methadone is a long-acting oral opioid that is used for both opioid replacement therapy and pain management. When used to reduce craving in opioid-dependent patients, methadone is administered daily through federally sanctioned methadone maintenance treatment (MMT) programs. Patients who consistently adhere to the required guidelines are given “take home” doses. When used for pain management, methadone is typically administered several times daily and may be prescribed by any provider with an appropriate DEA registration.

When given for MMT, methadone saturates the µ-opioid receptors and hinders their binding and agonism by other opioids such as heroin or oxycodone. Patients in MMT programs are started on a low initial dose and slowly titrated upward as tolerance to the adverse effects (eg, sedation) develop.

How are symptomatic patients with methadone withdrawal treated?

Most methadone programs have limited hours and require that patients who miss a dose wait until the following day to return to the program. This is typically without medical consequence because the high dose dispensed by these programs maintains a therapeutic blood concentration for far longer than the expected delay. Although the half-life of methadone exhibits wide interindividual variability, it generally ranges from 12 hours to more than 40 hours.¹ Regardless, patients may feel anxious about potential opioid withdrawal, and this often leads them to access the ED for a missed dose.

The neuropsychiatric symptoms attending withdrawal may precede the objective signs of opioid withdrawal. Patients with objective signs of opioid withdrawal (eg, piloerection, vomiting, diarrhea, dilated pupils) may be sufficiently treated with supportive care alone, using antiemetics, hydration, and sometimes clonidine.

Administration of substitute opioids is problematic due to the patient’s underlying tolerance necessitating careful dose titration. Therefore, direct replacement of methadone in the ED remains controversial, and some EDs have strict policies prohibiting the administration of methadone to patients who have missed an MMT dose. Such policies, which are intended to discourage patients from using the ED as a convenience, may be appropriate given the generally benign—though uncomfortable—course of opioid withdrawal due to abstinence.

Other EDs provide replacement methadone for asymptomatic, treat-and-release patients confirmed to be enrolled in an MMT program when the time to the next dose is likely to be 24 hours or greater from the missed dose. Typically, a dose of no more than 10 mg orally or 10 mg intramuscularly (IM) is recommended, and patients should be advised that they will be receiving only a low dose to sufficient to prevent withdrawal—one that may not have the equivalent effects of the outpatient dose.

Whenever possible, a patient’s MMT program should be contacted and informed of the ED visit. For patients who display objective signs of withdrawal and who cannot be confirmed or who do not participate in an MMT program, 10 mg of methadone IM will prevent uncertainty of drug absorption in the setting of nausea or vomiting. All patients receiving oral methadone should be observed for 1 hour, and those receiving IM methadone should be observed for at least 90 minutes to assess for unexpected sedation.²

Patients encountering circumstances that prevent opioid access (eg, incarceration) and who are not in withdrawal but have gone without opioids for more than 5 days may have a loss of tolerance to their usual doses—whether the medication was obtained through an MMT program or illicitly. Harm-reduction strategies aimed at educating patients on the potential vulnerability to their familiar dosing regimens are warranted to avert inadvertent overdoses in chronic opioid users who are likely to resume illicit opoiod use.

Does this patient need syncope evaluation?

Further complicating the decision regarding ED dispensing of methadone are the effects of the drug on myocardial repolarization. Methadone affects conduction across the hERG potassium rectifier current and can prolong the QTc interval on the surface electrocardiogram (ECG), predisposing a patient to torsade de pointes (TdP). Although there is controversy regarding the role of ECG screening during the enrollment of patients in methadone maintenance clinics, doses above 60 mg, underlying myocardial disease, female sex, and electrolyte disturbances may increase the risk of QT prolongation and TdP.³

Whether there is value in obtaining a screening ECG in a patient receiving an initial dose of methadone in the ED is unclear, and this practice is controversial even among methadone clinics. However, some of the excess death in patients taking methadone may be explained by the dysrhythmogenic potential of methadone.⁴ An ECG therefore may elucidate a correctable cause in methadone patients presenting with syncope.  

Administering methadone to patients with documented QT prolongation must weigh the risk of methadone’s conduction effects against the substantial risks of illicit opioid self-administration. For some patients at-risk for TdP, it may be preferable to use buprenorphine if possible, since it does not carry the same cardiac effects as methadone.^1,5 Such therapy requires referral to a physician licensed to prescribe this medication.

How should admitted patients be managed?

While administration of methadone for withdrawal or maintenance therapy in the ED is acceptable, outpatient prescribing of methadone for these reasons is not legal, and only federally regulated clinics may engage in this practice. Hospitalized patients who are enrolled in an MMT program should have their daily methadone dose confirmed and continued—as long as the patient has not lost tolerance. Patients not participating in an MMT program can receive up to 3 days of methadone in the hospital, even if the practitioner is not registered to provide methadone.⁶ For these patients, it is recommended that the physician order a low dose of methadone and also consult with an addiction specialist to determine whether the patient should continue on MMT maintenance or undergo detoxification.

It is important to note that methadone may be prescribed for pain, but its use in the ED for this purpose is strongly discouraged, especially in patients who have never received methadone previously. For admitted patients requiring such potent opioid analgesia, consultation with a pain service or, when indicated, a palliative care/hospice specialist is warranted as the dosing intervals are different in each setting, and the risk of respiratory depression is high.

Case Conclusion

As requested by the MMT clinic, the patient was administered methadone 185 mg orally in the ED, though a dose of 10 mg would have been sufficient to prevent withdrawal. Unfortunately, the EP did not appreciate the relationship of the markedly prolonged QTc and the methadone, which should have prompted a dose reduction.

Evaluation of the patient’s electrolyte levels, which included magnesium and potassium, were normal. An ECG was repeated 24 hours later and revealed a persistent, but improved, QT interval at 505 ms. The remainder of the syncope workup was negative. Because the patient had no additional symptoms or events during her stay, she was discharged. At discharge, the EP followed up with the MMT clinic to discuss lowering the patient’s daily methadone dose, as well as close cardiology follow-up.

Dr Rao is the chief of the division of medical toxicology at New York Presbyterian Hospital/Weill Cornell Medical Center, New York. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board.

A 57-year-old man hospitalized for treatment of multilobar pneumonia was noted to have a rapid, irregular heart rate on telemetry. He was hypoxemic and appeared to be in respiratory distress. A 12-lead electrocardiogram (ECG) demonstrated atrial fibrillation with rapid ventricular response, as well as what looked like distinct and regular P waves dissociated from the QRS complexes at a rate of about 44/min (Figure 1). What is the explanation and clinical significance of this curious finding?

What appear to be dissociated P waves actually represent respiratory artifact.^1–3 The sharp deflections mimicking P waves signify the tonic initiation of inspiratory effort; the subsequent brief periods of low-amplitude, high-frequency micro-oscillations represent surface electrical activity associated with the increased force of the accessory muscles of respiration.^1–3

Surface electromyography noninvasively measures muscle activity using electrodes placed on the skin overlying the muscle.⁴ Using simultaneously recorded mechanical respiratory waveform tracings, we have previously demonstrated that the repetitive pseudo-P waves followed by micro-oscillations have a close temporal relationship with the inspiratory phase of respiration.³ The presence of respiratory artifact indicates a high-risk state frequently necessitating ventilation support.

In addition, when present, respiratory artifact can be viewed as the “second vital sign” on the ECG, the first vital sign being the heart rate. The respiratory rate can be approximated by counting the number of respiratory artifacts in a 10-second recording and multiplying it by 6. A more accurate rate assessment is achieved by measuring 1 or more respiratory artifact cycles in millimeters and then dividing that number into 1,500 or its multiples.³ Based on these calculations, the respiratory rate in this patient was 44/min.

The presence of two atrial rhythms on the same ECG, one not disturbing the other, is consistent with the diagnosis of atrial dissociation.⁵ Atrial dissociation is a common finding in cardiac transplant recipients in whom the transplantation was performed using atrio-atrial anastomosis.⁶ Most other cases of apparent atrial dissociation described in the old cardiology and critical care literature probably represented unrecognized respiratory artifact.^7,8

An ECG from a different patient (Figure 2) demonstrates rapid respiratory artifact that raised awareness of severe respiratory failure. The respiratory rate calculated from spacing of the pseudo-P waves is 62/min, confirmed by simultaneous respirography.

A FREQUENT FINDING IN SICK HOSPITALIZED PATIENTS

Respiratory artifact is a frequent finding in sick hospitalized patients.³ Most commonly, it manifests as repetitive micro-oscillations.³ Pseudo-P waves, as in this 57-year-old patient, are less often observed; but if their origin is not recognized, the interpretation of the ECG can become puzzling.^1–3,7,8

Respiratory artifact is a marker of increased work of breathing and a strong indicator of significant cardiopulmonary compromise. Improvement in the patient’s cardiac or respiratory condition is typically associated with a decrease in the rate or complete elimination of respiratory artifact.³

Recognition of rapid respiratory artifact is less important in critical care units, where patients’ vital signs and cardiorespiratory status are carefully observed. However, in hospital settings where respiratory rate and oxygen saturation are not continuously monitored, recognizing rapid respiratory artifact can help raise awareness of the possibility of severe respiratory distress.

A 57-year-old man hospitalized for treatment of multilobar pneumonia was noted to have a rapid, irregular heart rate on telemetry. He was hypoxemic and appeared to be in respiratory distress. A 12-lead electrocardiogram (ECG) demonstrated atrial fibrillation with rapid ventricular response, as well as what looked like distinct and regular P waves dissociated from the QRS complexes at a rate of about 44/min (Figure 1). What is the explanation and clinical significance of this curious finding?

What appear to be dissociated P waves actually represent respiratory artifact.^1–3 The sharp deflections mimicking P waves signify the tonic initiation of inspiratory effort; the subsequent brief periods of low-amplitude, high-frequency micro-oscillations represent surface electrical activity associated with the increased force of the accessory muscles of respiration.^1–3

Surface electromyography noninvasively measures muscle activity using electrodes placed on the skin overlying the muscle.⁴ Using simultaneously recorded mechanical respiratory waveform tracings, we have previously demonstrated that the repetitive pseudo-P waves followed by micro-oscillations have a close temporal relationship with the inspiratory phase of respiration.³ The presence of respiratory artifact indicates a high-risk state frequently necessitating ventilation support.

In addition, when present, respiratory artifact can be viewed as the “second vital sign” on the ECG, the first vital sign being the heart rate. The respiratory rate can be approximated by counting the number of respiratory artifacts in a 10-second recording and multiplying it by 6. A more accurate rate assessment is achieved by measuring 1 or more respiratory artifact cycles in millimeters and then dividing that number into 1,500 or its multiples.³ Based on these calculations, the respiratory rate in this patient was 44/min.

The presence of two atrial rhythms on the same ECG, one not disturbing the other, is consistent with the diagnosis of atrial dissociation.⁵ Atrial dissociation is a common finding in cardiac transplant recipients in whom the transplantation was performed using atrio-atrial anastomosis.⁶ Most other cases of apparent atrial dissociation described in the old cardiology and critical care literature probably represented unrecognized respiratory artifact.^7,8

An ECG from a different patient (Figure 2) demonstrates rapid respiratory artifact that raised awareness of severe respiratory failure. The respiratory rate calculated from spacing of the pseudo-P waves is 62/min, confirmed by simultaneous respirography.

A FREQUENT FINDING IN SICK HOSPITALIZED PATIENTS

Respiratory artifact is a frequent finding in sick hospitalized patients.³ Most commonly, it manifests as repetitive micro-oscillations.³ Pseudo-P waves, as in this 57-year-old patient, are less often observed; but if their origin is not recognized, the interpretation of the ECG can become puzzling.^1–3,7,8

Respiratory artifact is a marker of increased work of breathing and a strong indicator of significant cardiopulmonary compromise. Improvement in the patient’s cardiac or respiratory condition is typically associated with a decrease in the rate or complete elimination of respiratory artifact.³

Recognition of rapid respiratory artifact is less important in critical care units, where patients’ vital signs and cardiorespiratory status are carefully observed. However, in hospital settings where respiratory rate and oxygen saturation are not continuously monitored, recognizing rapid respiratory artifact can help raise awareness of the possibility of severe respiratory distress.

A 57-year-old man hospitalized for treatment of multilobar pneumonia was noted to have a rapid, irregular heart rate on telemetry. He was hypoxemic and appeared to be in respiratory distress. A 12-lead electrocardiogram (ECG) demonstrated atrial fibrillation with rapid ventricular response, as well as what looked like distinct and regular P waves dissociated from the QRS complexes at a rate of about 44/min (Figure 1). What is the explanation and clinical significance of this curious finding?

What appear to be dissociated P waves actually represent respiratory artifact.^1–3 The sharp deflections mimicking P waves signify the tonic initiation of inspiratory effort; the subsequent brief periods of low-amplitude, high-frequency micro-oscillations represent surface electrical activity associated with the increased force of the accessory muscles of respiration.^1–3

Surface electromyography noninvasively measures muscle activity using electrodes placed on the skin overlying the muscle.⁴ Using simultaneously recorded mechanical respiratory waveform tracings, we have previously demonstrated that the repetitive pseudo-P waves followed by micro-oscillations have a close temporal relationship with the inspiratory phase of respiration.³ The presence of respiratory artifact indicates a high-risk state frequently necessitating ventilation support.

In addition, when present, respiratory artifact can be viewed as the “second vital sign” on the ECG, the first vital sign being the heart rate. The respiratory rate can be approximated by counting the number of respiratory artifacts in a 10-second recording and multiplying it by 6. A more accurate rate assessment is achieved by measuring 1 or more respiratory artifact cycles in millimeters and then dividing that number into 1,500 or its multiples.³ Based on these calculations, the respiratory rate in this patient was 44/min.

The presence of two atrial rhythms on the same ECG, one not disturbing the other, is consistent with the diagnosis of atrial dissociation.⁵ Atrial dissociation is a common finding in cardiac transplant recipients in whom the transplantation was performed using atrio-atrial anastomosis.⁶ Most other cases of apparent atrial dissociation described in the old cardiology and critical care literature probably represented unrecognized respiratory artifact.^7,8

An ECG from a different patient (Figure 2) demonstrates rapid respiratory artifact that raised awareness of severe respiratory failure. The respiratory rate calculated from spacing of the pseudo-P waves is 62/min, confirmed by simultaneous respirography.

A FREQUENT FINDING IN SICK HOSPITALIZED PATIENTS

Respiratory artifact is a frequent finding in sick hospitalized patients.³ Most commonly, it manifests as repetitive micro-oscillations.³ Pseudo-P waves, as in this 57-year-old patient, are less often observed; but if their origin is not recognized, the interpretation of the ECG can become puzzling.^1–3,7,8

Respiratory artifact is a marker of increased work of breathing and a strong indicator of significant cardiopulmonary compromise. Improvement in the patient’s cardiac or respiratory condition is typically associated with a decrease in the rate or complete elimination of respiratory artifact.³

Recognition of rapid respiratory artifact is less important in critical care units, where patients’ vital signs and cardiorespiratory status are carefully observed. However, in hospital settings where respiratory rate and oxygen saturation are not continuously monitored, recognizing rapid respiratory artifact can help raise awareness of the possibility of severe respiratory distress.

A 25-year-old Jamaican man presented to the emergency department for evaluation of a rash on his face, back, and hands (Figure 1). He recalled a puncture injury after handling garbage at work. He denied recent travel, blood transfusions, or sick contacts. He was not aware of any recent arthropod bites. All standard vaccines including a tetanus booster were up to date.

Examination revealed edema of the hands and uvula. He was discharged with diphenhydramine and a short course of a systemic corticosteroid for presumed contact dermatitis.

He returned 4 days later with new symptoms, including sore throat, fever with a temperature of 103°F (39.4°C), oropharyngeal pain, dysphagia, dysuria, and purpura on the hands, abdomen, and legs. He was admitted to the hospital.

Examination revealed bright red confluent erythema of both legs extending to the lower abdomen, with petechiae on the palms (Figure 2), soles, toes, and fingers. Several small scrotal ulcers with well-defined borders were noted. Oral examination revealed white-yellow adherent plaques on the tongue and similar small ulcers on the lower lip and soft and hard palates.

A complete blood cell count revealed absolute lymphopenia, with a white blood cell count of 0.64 × 10⁹/L (reference range 1.0–4.8) and a neutrophil percentage of 78.9% (39%–68%). Other values were within normal limits, with a red blood cell count of 5.3 × 10¹²/L (3.9–5.5) and a platelet count of 161 × 10⁹/L (150–350). Serum liver enzymes were also within normal limits.

Treatment with intravenous fluids and intramuscular penicillin G was started empirically, pending a workup for infectious disease. Tests for syphilis immunoglobulin G (IgG), streptococci, anti-streptolysin O, Epstein-Barr virus, and human immunodeficiency virus (HIV) 1 and 2 were negative. The scrotal ulcers were swabbed, and culture and direct fluorescent antibody testing for cytomegalovirus and herpes simplex virus were negative. Urine testing for gonococcal and chlamydial infection was negative.

On the fifth day of hospitalization, the patient’s condition was improving, but there was still no definitive diagnosis. Consultation with the inpatient dermatology team prompted testing for parvovirus B19 infection, based on the gloves-and-socks distribution of the purpura. Testing revealed a slightly elevated parvovirus B19 IgG titer (2.61) and a significantly elevated parvovirus B19 IgM titer (12.74), which confirmed acute parvovirus infection.

The patient’s condition improved over several days with fluid administration, and he was discharged in good condition. He returned 1 week later for a follow-up appointment, at which time only superficial desquamation was noted in the areas previously affected by purpura.

PARVOVIRUS B19: NOT ONLY IN CHILDREN

Parvovirus B19 is responsible for the common childhood viral exanthem known as fifth disease.¹ However, although much less common, the virus can also affect young adults, precipitating a dermatosis referred to as gloves-and-socks syndrome characterized by purpura on the hands and feet,^2,3 and with a higher incidence in the spring and summer.¹

Although papular-purpuric gloves-and- socks syndrome is characterized by purpura on the hands and feet, the cheeks, oral mucosa, inner thighs, buttocks, and genitalia are affected in about 50% of patients.² In one report, in two-thirds of adult patients the presentation was caused by parvovirus B19 infection,⁴ but the syndrome has also been associated with Epstein-Barr virus, cytomegalovirus, human herpesvirus types 6 and 7, hepatitis B virus, rubella virus, and varicella zoster virus.⁴

Parvovirus B19 infection is commonly associated with systemic manifestations such as fever, fatigue, and lymphadenopathy, as well as swelling of the lips, cutaneous and mucosal ulcerations, polyarthritis, and petechiae involving the hard palate, the soft palate, or both.¹

The syndrome is self-limited and resolves within 1 to 2 weeks.¹

THE DIAGNOSTIC CHALLENGE

The differential diagnosis of the syndrome’s gloves-and-socks presentation includes hand-foot-mouth disease, erythema multiforme, Henoch-Schönlein purpura, and Kawasaki disease,⁴ in addition to viral exanthems and sexually transmitted diseases. Our patient’s fever, rash, and absolute lymphopenia focused attention on possible HIV infection, which caused the patient significant anxiety while awaiting the results of HIV testing. Heightened awareness of the cutaneous presentation of parvovirus B19 infection can help avoid unnecessary hospitalization and patient anxiety.

A 25-year-old Jamaican man presented to the emergency department for evaluation of a rash on his face, back, and hands (Figure 1). He recalled a puncture injury after handling garbage at work. He denied recent travel, blood transfusions, or sick contacts. He was not aware of any recent arthropod bites. All standard vaccines including a tetanus booster were up to date.

Examination revealed edema of the hands and uvula. He was discharged with diphenhydramine and a short course of a systemic corticosteroid for presumed contact dermatitis.

He returned 4 days later with new symptoms, including sore throat, fever with a temperature of 103°F (39.4°C), oropharyngeal pain, dysphagia, dysuria, and purpura on the hands, abdomen, and legs. He was admitted to the hospital.

Examination revealed bright red confluent erythema of both legs extending to the lower abdomen, with petechiae on the palms (Figure 2), soles, toes, and fingers. Several small scrotal ulcers with well-defined borders were noted. Oral examination revealed white-yellow adherent plaques on the tongue and similar small ulcers on the lower lip and soft and hard palates.

A complete blood cell count revealed absolute lymphopenia, with a white blood cell count of 0.64 × 10⁹/L (reference range 1.0–4.8) and a neutrophil percentage of 78.9% (39%–68%). Other values were within normal limits, with a red blood cell count of 5.3 × 10¹²/L (3.9–5.5) and a platelet count of 161 × 10⁹/L (150–350). Serum liver enzymes were also within normal limits.

Treatment with intravenous fluids and intramuscular penicillin G was started empirically, pending a workup for infectious disease. Tests for syphilis immunoglobulin G (IgG), streptococci, anti-streptolysin O, Epstein-Barr virus, and human immunodeficiency virus (HIV) 1 and 2 were negative. The scrotal ulcers were swabbed, and culture and direct fluorescent antibody testing for cytomegalovirus and herpes simplex virus were negative. Urine testing for gonococcal and chlamydial infection was negative.

On the fifth day of hospitalization, the patient’s condition was improving, but there was still no definitive diagnosis. Consultation with the inpatient dermatology team prompted testing for parvovirus B19 infection, based on the gloves-and-socks distribution of the purpura. Testing revealed a slightly elevated parvovirus B19 IgG titer (2.61) and a significantly elevated parvovirus B19 IgM titer (12.74), which confirmed acute parvovirus infection.

The patient’s condition improved over several days with fluid administration, and he was discharged in good condition. He returned 1 week later for a follow-up appointment, at which time only superficial desquamation was noted in the areas previously affected by purpura.

PARVOVIRUS B19: NOT ONLY IN CHILDREN

Parvovirus B19 is responsible for the common childhood viral exanthem known as fifth disease.¹ However, although much less common, the virus can also affect young adults, precipitating a dermatosis referred to as gloves-and-socks syndrome characterized by purpura on the hands and feet,^2,3 and with a higher incidence in the spring and summer.¹

Although papular-purpuric gloves-and- socks syndrome is characterized by purpura on the hands and feet, the cheeks, oral mucosa, inner thighs, buttocks, and genitalia are affected in about 50% of patients.² In one report, in two-thirds of adult patients the presentation was caused by parvovirus B19 infection,⁴ but the syndrome has also been associated with Epstein-Barr virus, cytomegalovirus, human herpesvirus types 6 and 7, hepatitis B virus, rubella virus, and varicella zoster virus.⁴

Parvovirus B19 infection is commonly associated with systemic manifestations such as fever, fatigue, and lymphadenopathy, as well as swelling of the lips, cutaneous and mucosal ulcerations, polyarthritis, and petechiae involving the hard palate, the soft palate, or both.¹

The syndrome is self-limited and resolves within 1 to 2 weeks.¹

THE DIAGNOSTIC CHALLENGE

The differential diagnosis of the syndrome’s gloves-and-socks presentation includes hand-foot-mouth disease, erythema multiforme, Henoch-Schönlein purpura, and Kawasaki disease,⁴ in addition to viral exanthems and sexually transmitted diseases. Our patient’s fever, rash, and absolute lymphopenia focused attention on possible HIV infection, which caused the patient significant anxiety while awaiting the results of HIV testing. Heightened awareness of the cutaneous presentation of parvovirus B19 infection can help avoid unnecessary hospitalization and patient anxiety.

A 25-year-old Jamaican man presented to the emergency department for evaluation of a rash on his face, back, and hands (Figure 1). He recalled a puncture injury after handling garbage at work. He denied recent travel, blood transfusions, or sick contacts. He was not aware of any recent arthropod bites. All standard vaccines including a tetanus booster were up to date.

Examination revealed edema of the hands and uvula. He was discharged with diphenhydramine and a short course of a systemic corticosteroid for presumed contact dermatitis.

He returned 4 days later with new symptoms, including sore throat, fever with a temperature of 103°F (39.4°C), oropharyngeal pain, dysphagia, dysuria, and purpura on the hands, abdomen, and legs. He was admitted to the hospital.

Examination revealed bright red confluent erythema of both legs extending to the lower abdomen, with petechiae on the palms (Figure 2), soles, toes, and fingers. Several small scrotal ulcers with well-defined borders were noted. Oral examination revealed white-yellow adherent plaques on the tongue and similar small ulcers on the lower lip and soft and hard palates.

A complete blood cell count revealed absolute lymphopenia, with a white blood cell count of 0.64 × 10⁹/L (reference range 1.0–4.8) and a neutrophil percentage of 78.9% (39%–68%). Other values were within normal limits, with a red blood cell count of 5.3 × 10¹²/L (3.9–5.5) and a platelet count of 161 × 10⁹/L (150–350). Serum liver enzymes were also within normal limits.

Treatment with intravenous fluids and intramuscular penicillin G was started empirically, pending a workup for infectious disease. Tests for syphilis immunoglobulin G (IgG), streptococci, anti-streptolysin O, Epstein-Barr virus, and human immunodeficiency virus (HIV) 1 and 2 were negative. The scrotal ulcers were swabbed, and culture and direct fluorescent antibody testing for cytomegalovirus and herpes simplex virus were negative. Urine testing for gonococcal and chlamydial infection was negative.

On the fifth day of hospitalization, the patient’s condition was improving, but there was still no definitive diagnosis. Consultation with the inpatient dermatology team prompted testing for parvovirus B19 infection, based on the gloves-and-socks distribution of the purpura. Testing revealed a slightly elevated parvovirus B19 IgG titer (2.61) and a significantly elevated parvovirus B19 IgM titer (12.74), which confirmed acute parvovirus infection.

The patient’s condition improved over several days with fluid administration, and he was discharged in good condition. He returned 1 week later for a follow-up appointment, at which time only superficial desquamation was noted in the areas previously affected by purpura.

PARVOVIRUS B19: NOT ONLY IN CHILDREN

Parvovirus B19 is responsible for the common childhood viral exanthem known as fifth disease.¹ However, although much less common, the virus can also affect young adults, precipitating a dermatosis referred to as gloves-and-socks syndrome characterized by purpura on the hands and feet,^2,3 and with a higher incidence in the spring and summer.¹

Although papular-purpuric gloves-and- socks syndrome is characterized by purpura on the hands and feet, the cheeks, oral mucosa, inner thighs, buttocks, and genitalia are affected in about 50% of patients.² In one report, in two-thirds of adult patients the presentation was caused by parvovirus B19 infection,⁴ but the syndrome has also been associated with Epstein-Barr virus, cytomegalovirus, human herpesvirus types 6 and 7, hepatitis B virus, rubella virus, and varicella zoster virus.⁴

Parvovirus B19 infection is commonly associated with systemic manifestations such as fever, fatigue, and lymphadenopathy, as well as swelling of the lips, cutaneous and mucosal ulcerations, polyarthritis, and petechiae involving the hard palate, the soft palate, or both.¹

The syndrome is self-limited and resolves within 1 to 2 weeks.¹

THE DIAGNOSTIC CHALLENGE

The differential diagnosis of the syndrome’s gloves-and-socks presentation includes hand-foot-mouth disease, erythema multiforme, Henoch-Schönlein purpura, and Kawasaki disease,⁴ in addition to viral exanthems and sexually transmitted diseases. Our patient’s fever, rash, and absolute lymphopenia focused attention on possible HIV infection, which caused the patient significant anxiety while awaiting the results of HIV testing. Heightened awareness of the cutaneous presentation of parvovirus B19 infection can help avoid unnecessary hospitalization and patient anxiety.

ANSWER
The radiograph shows that the distal femur is medially dislocated relative to the tibial plateau. In addition, the patella is laterally dislocated. No obvious fractures are evident. 

Such injuries are typically associated with significant ligament injuries, especially of the medial collateral ligament (MCL), lateral collateral ligament (LCL), and anterior cruciate ligament (ACL). Orthopedics was consulted for reduction of the dislocation, as well as further workup (including MRI of the knee).

ANSWER
The radiograph shows that the distal femur is medially dislocated relative to the tibial plateau. In addition, the patella is laterally dislocated. No obvious fractures are evident. 

Such injuries are typically associated with significant ligament injuries, especially of the medial collateral ligament (MCL), lateral collateral ligament (LCL), and anterior cruciate ligament (ACL). Orthopedics was consulted for reduction of the dislocation, as well as further workup (including MRI of the knee).

ANSWER
The radiograph shows that the distal femur is medially dislocated relative to the tibial plateau. In addition, the patella is laterally dislocated. No obvious fractures are evident. 

Such injuries are typically associated with significant ligament injuries, especially of the medial collateral ligament (MCL), lateral collateral ligament (LCL), and anterior cruciate ligament (ACL). Orthopedics was consulted for reduction of the dislocation, as well as further workup (including MRI of the knee).

Case

A 62-year-old man with a history of hypercholesterolemia and HIV infection presented to the ED for evaluation of diffuse myalgia and tea-colored urine. His medication history included lopinavir/ritonavir (Kaletra) and simvastatin. A week prior to presentation, the patient’s primary care physician had instructed him to increase his daily dose of simvastatin from 40 mg to 80 mg. The patient stated that he had taken simvastatin 80 mg daily for approximately 5 days and then, 2 days prior to presentation, had independently further increased the dose to 160 mg daily.

In the ED, the patient reported feeling fatigued. His initial vital signs were: blood pressure, 129/86 mm Hg; heart rate, 93 beats/minute; respiratory rate, 17 breaths/minute; and temperature, 98.5˚F. Oxygen saturation was 98% on room air. His physical examination was unremarkable. Initial laboratory testing revealed the following: creatine kinase (CK) 350,000 U/L; blood urea nitrogen, 27 mg/dL; creatinine, 0.7 mg/dL; aspartate aminotransferase (AST), 2,950 U/L; and alanine aminotransferase (ALT), 1,305 U/L.

What can cause tea-colored/cola-colored urine and myalgia?

Numerous medications can result in dark-colored urine. These include antimalarial drugs such as chloroquine and primaquine; antibiotics such as metronidazole or nitrofurantoin; and the muscle relaxant methocarbamol. Myalgia and tea-colored urine are the hallmarks of rhabdomyolysis. Rhabdomyolysis involves the destruction of myocytes, which can occur as a result of a long list of processes, including crush injuries, poor oxygenation or perfusion, hypermetabolic states, and direct (or indirect) toxin-mediated myocyte damage.¹ The list of toxic substances that can cause rhabdomyolysis is extensive, and statins are one of the most common drug-induced causes (Table).

Simvastatin is one of seven currently available 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (ie, statins) that are commonly used to treat hypercholesterolemia. Because simvastatin is lipophilic, it can more readily cross cell membranes than nonlipophilic statins such as pravastatin. Simvastatin, therefore, has a propensity to disrupt the cellular integrity of myocytes and hepatocytes.What is the likely cause of this patient’s rhabdomyolysis?

At doses greater than 40 mg daily, simvastatin is associated with myalgia, myositis, and rhabdomyolysis. In December 2011, the US Food and Drug Administration (FDA) released a drug safety announcement recommending the originally approved maximum daily dose of simvastatin 80 mg be limited to patients who have already tolerated that dose for at least 12 months without evidence of muscular injury. The FDA further recommended no new patients be escalated to this dose. According to the FDA, patients taking 80 mg of simvastatin daily are also at increased risk of myopathy. 

The metabolism of simvastatin, in addition to increased dosage of the drug, contributes to its potential for adverse effects. Of the seven available statins, only atorvastatin, lovastatin, and simvastatin are metabolized by the cytochrome P450 3A4 (CYP3A4). Lovastatin and simvastatin appear to have the highest potential for drug-drug interactions when coadministered with drugs that inhibit this enzyme (eg, ritonavir).² The resulting elevation in blood concentration of simvastatin increases the risk of rhabdomyolysis. Other nonlipophilic statins, such as pravastatin, which are mostly eliminated unchanged in the urine and bile, would be preferable for patients taking CYP3A4 inhibitors.

How should patients with rhabdomyolysis be monitored?

Statins interfere with the myocyte’s ability to produce adenosine triphosphate, most likely by depleting coenzyme Q—one of the complexes found in the electron transport chain of the mitochondria. Under conditions of a high-energy requirement, myocytes incapable of producing sufficient energy ultimately fail and lyse, releasing cellular contents such as CK and myoglobin.¹ The serum CK activity serves as a marker of muscle injury and should be monitored closely in patients with rhabdomyolysis. Although values above 5,000 U/L has been associated with renal injury,⁴ in healthy patients with access to hydration, renal injury is relatively uncommon with CK activities less than 50,000 U/L. Even though the prediction of renal failure is difficult, a validated nephrotoxicity prediction instrument using the patient’s age, gender, and initial laboratory data (serum creatinine, calcium, CK, phosphate, and bicarbonate) is available.⁵

Although the association between rhabdomyolysis and acute renal injury is well established, the mechanism remains unclear. Myoglobin from skeletal myocytes passes through the glomerulus without causing damage and is reabsorbed in the proximal renal tubular cell. Iron is subsequently released from the porphyrin ring and, in large concentrations, exceeds the binding capacity of the tissue ferritin. Because it is a transition metal, the free iron ion participates in oxidant stress reactions causing direct injury to the renal tubular cells.⁶ Furthermore, myoglobin also combines with renal tubular proteins, a process enhanced by an environment with lower pH, to form casts and cause renal tubular obstruction.

Patients with rhabdomyolysis may also be at risk for aminotransferase elevation, as occurred in the patient presented here. This elevation is most likely due to myocyte injury. In addition, potassium release due to myocyte destruction may cause life-threatening hyperkalemia, and phosphate liberation from these myocytes may cause hypocalcemia. Laboratory monitoring along with an electrocardiogram should be performed as required.

What is the treatment for rhabdomyolysis?

No adequate randomized controlled trials exist to guide the treatment of patients with rhabdomyolysis. As a result, recommendations for management come from retrospective observational studies, animal studies, case reports, and expert opinion.⁷

Once airway, breathing, and circulation have been addressed, patients with statin-induced rhabdomyolysis should be immediately treated with intravenous (IV) fluids to maintain renal perfusion, which helps to limit acute renal injury. Normal saline appears to be the most recommended fluid type, with a goal of maintaining a urine output of approximately 3 to 5 mL/kg/h.^4,7

Some recommendations include the use of a sodium bicarbonate infusion to raise the urine pH, which may help limit the formation of renal casts from myoglobin. The data to support the benefit of sodium bicarbonate, however, is weak.³ A 2013 systematic review indicated that sodium bicarbonate should only be used to treat severe metabolic acidosis in patients with rhabdomyolysis.⁴

In addition to sodium bicarbonate, the use of diuretics is also discouraged by current recommendations. In patients with refractory electrolyte abnormalities or renal failure, hemodialysis may be required. Before disposition of a patient, his or her medication list should be reconciled to reflect statin discontinuation. 

Case Conclusion

The patient received IV normal saline to maintain his urine output at 2 to 3 cc/kg/h. His repeat creatinine was 0.8 mg/dL and remained stable on repeat testing. His CK and AST concentrations trended down during his hospitalization. On hospital day 4, laboratory values were CK, less than 10,000 U/L; AST, 56 U/L; and ALT, 23 U/L. He had normal serum potassium levels and no dysrhythmia on electrocardiogram. His symptoms resolved on hospital day 2, and he was discharged on hospital day 4 with instructions to discontinue simvastatin.

Dr Fernandez is a senior toxicology fellow, department of emergency medicine, New York University School of Medicine. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board.

Case

A 62-year-old man with a history of hypercholesterolemia and HIV infection presented to the ED for evaluation of diffuse myalgia and tea-colored urine. His medication history included lopinavir/ritonavir (Kaletra) and simvastatin. A week prior to presentation, the patient’s primary care physician had instructed him to increase his daily dose of simvastatin from 40 mg to 80 mg. The patient stated that he had taken simvastatin 80 mg daily for approximately 5 days and then, 2 days prior to presentation, had independently further increased the dose to 160 mg daily.

In the ED, the patient reported feeling fatigued. His initial vital signs were: blood pressure, 129/86 mm Hg; heart rate, 93 beats/minute; respiratory rate, 17 breaths/minute; and temperature, 98.5˚F. Oxygen saturation was 98% on room air. His physical examination was unremarkable. Initial laboratory testing revealed the following: creatine kinase (CK) 350,000 U/L; blood urea nitrogen, 27 mg/dL; creatinine, 0.7 mg/dL; aspartate aminotransferase (AST), 2,950 U/L; and alanine aminotransferase (ALT), 1,305 U/L.

What can cause tea-colored/cola-colored urine and myalgia?

Numerous medications can result in dark-colored urine. These include antimalarial drugs such as chloroquine and primaquine; antibiotics such as metronidazole or nitrofurantoin; and the muscle relaxant methocarbamol. Myalgia and tea-colored urine are the hallmarks of rhabdomyolysis. Rhabdomyolysis involves the destruction of myocytes, which can occur as a result of a long list of processes, including crush injuries, poor oxygenation or perfusion, hypermetabolic states, and direct (or indirect) toxin-mediated myocyte damage.¹ The list of toxic substances that can cause rhabdomyolysis is extensive, and statins are one of the most common drug-induced causes (Table).

Simvastatin is one of seven currently available 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (ie, statins) that are commonly used to treat hypercholesterolemia. Because simvastatin is lipophilic, it can more readily cross cell membranes than nonlipophilic statins such as pravastatin. Simvastatin, therefore, has a propensity to disrupt the cellular integrity of myocytes and hepatocytes.What is the likely cause of this patient’s rhabdomyolysis?

At doses greater than 40 mg daily, simvastatin is associated with myalgia, myositis, and rhabdomyolysis. In December 2011, the US Food and Drug Administration (FDA) released a drug safety announcement recommending the originally approved maximum daily dose of simvastatin 80 mg be limited to patients who have already tolerated that dose for at least 12 months without evidence of muscular injury. The FDA further recommended no new patients be escalated to this dose. According to the FDA, patients taking 80 mg of simvastatin daily are also at increased risk of myopathy. 

The metabolism of simvastatin, in addition to increased dosage of the drug, contributes to its potential for adverse effects. Of the seven available statins, only atorvastatin, lovastatin, and simvastatin are metabolized by the cytochrome P450 3A4 (CYP3A4). Lovastatin and simvastatin appear to have the highest potential for drug-drug interactions when coadministered with drugs that inhibit this enzyme (eg, ritonavir).² The resulting elevation in blood concentration of simvastatin increases the risk of rhabdomyolysis. Other nonlipophilic statins, such as pravastatin, which are mostly eliminated unchanged in the urine and bile, would be preferable for patients taking CYP3A4 inhibitors.

How should patients with rhabdomyolysis be monitored?

Statins interfere with the myocyte’s ability to produce adenosine triphosphate, most likely by depleting coenzyme Q—one of the complexes found in the electron transport chain of the mitochondria. Under conditions of a high-energy requirement, myocytes incapable of producing sufficient energy ultimately fail and lyse, releasing cellular contents such as CK and myoglobin.¹ The serum CK activity serves as a marker of muscle injury and should be monitored closely in patients with rhabdomyolysis. Although values above 5,000 U/L has been associated with renal injury,⁴ in healthy patients with access to hydration, renal injury is relatively uncommon with CK activities less than 50,000 U/L. Even though the prediction of renal failure is difficult, a validated nephrotoxicity prediction instrument using the patient’s age, gender, and initial laboratory data (serum creatinine, calcium, CK, phosphate, and bicarbonate) is available.⁵

Although the association between rhabdomyolysis and acute renal injury is well established, the mechanism remains unclear. Myoglobin from skeletal myocytes passes through the glomerulus without causing damage and is reabsorbed in the proximal renal tubular cell. Iron is subsequently released from the porphyrin ring and, in large concentrations, exceeds the binding capacity of the tissue ferritin. Because it is a transition metal, the free iron ion participates in oxidant stress reactions causing direct injury to the renal tubular cells.⁶ Furthermore, myoglobin also combines with renal tubular proteins, a process enhanced by an environment with lower pH, to form casts and cause renal tubular obstruction.

Patients with rhabdomyolysis may also be at risk for aminotransferase elevation, as occurred in the patient presented here. This elevation is most likely due to myocyte injury. In addition, potassium release due to myocyte destruction may cause life-threatening hyperkalemia, and phosphate liberation from these myocytes may cause hypocalcemia. Laboratory monitoring along with an electrocardiogram should be performed as required.

What is the treatment for rhabdomyolysis?

No adequate randomized controlled trials exist to guide the treatment of patients with rhabdomyolysis. As a result, recommendations for management come from retrospective observational studies, animal studies, case reports, and expert opinion.⁷

Once airway, breathing, and circulation have been addressed, patients with statin-induced rhabdomyolysis should be immediately treated with intravenous (IV) fluids to maintain renal perfusion, which helps to limit acute renal injury. Normal saline appears to be the most recommended fluid type, with a goal of maintaining a urine output of approximately 3 to 5 mL/kg/h.^4,7

Some recommendations include the use of a sodium bicarbonate infusion to raise the urine pH, which may help limit the formation of renal casts from myoglobin. The data to support the benefit of sodium bicarbonate, however, is weak.³ A 2013 systematic review indicated that sodium bicarbonate should only be used to treat severe metabolic acidosis in patients with rhabdomyolysis.⁴

In addition to sodium bicarbonate, the use of diuretics is also discouraged by current recommendations. In patients with refractory electrolyte abnormalities or renal failure, hemodialysis may be required. Before disposition of a patient, his or her medication list should be reconciled to reflect statin discontinuation. 

Case Conclusion

The patient received IV normal saline to maintain his urine output at 2 to 3 cc/kg/h. His repeat creatinine was 0.8 mg/dL and remained stable on repeat testing. His CK and AST concentrations trended down during his hospitalization. On hospital day 4, laboratory values were CK, less than 10,000 U/L; AST, 56 U/L; and ALT, 23 U/L. He had normal serum potassium levels and no dysrhythmia on electrocardiogram. His symptoms resolved on hospital day 2, and he was discharged on hospital day 4 with instructions to discontinue simvastatin.

Dr Fernandez is a senior toxicology fellow, department of emergency medicine, New York University School of Medicine. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board.

Case

A 62-year-old man with a history of hypercholesterolemia and HIV infection presented to the ED for evaluation of diffuse myalgia and tea-colored urine. His medication history included lopinavir/ritonavir (Kaletra) and simvastatin. A week prior to presentation, the patient’s primary care physician had instructed him to increase his daily dose of simvastatin from 40 mg to 80 mg. The patient stated that he had taken simvastatin 80 mg daily for approximately 5 days and then, 2 days prior to presentation, had independently further increased the dose to 160 mg daily.

In the ED, the patient reported feeling fatigued. His initial vital signs were: blood pressure, 129/86 mm Hg; heart rate, 93 beats/minute; respiratory rate, 17 breaths/minute; and temperature, 98.5˚F. Oxygen saturation was 98% on room air. His physical examination was unremarkable. Initial laboratory testing revealed the following: creatine kinase (CK) 350,000 U/L; blood urea nitrogen, 27 mg/dL; creatinine, 0.7 mg/dL; aspartate aminotransferase (AST), 2,950 U/L; and alanine aminotransferase (ALT), 1,305 U/L.

What can cause tea-colored/cola-colored urine and myalgia?

Numerous medications can result in dark-colored urine. These include antimalarial drugs such as chloroquine and primaquine; antibiotics such as metronidazole or nitrofurantoin; and the muscle relaxant methocarbamol. Myalgia and tea-colored urine are the hallmarks of rhabdomyolysis. Rhabdomyolysis involves the destruction of myocytes, which can occur as a result of a long list of processes, including crush injuries, poor oxygenation or perfusion, hypermetabolic states, and direct (or indirect) toxin-mediated myocyte damage.¹ The list of toxic substances that can cause rhabdomyolysis is extensive, and statins are one of the most common drug-induced causes (Table).

Simvastatin is one of seven currently available 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (ie, statins) that are commonly used to treat hypercholesterolemia. Because simvastatin is lipophilic, it can more readily cross cell membranes than nonlipophilic statins such as pravastatin. Simvastatin, therefore, has a propensity to disrupt the cellular integrity of myocytes and hepatocytes.What is the likely cause of this patient’s rhabdomyolysis?

At doses greater than 40 mg daily, simvastatin is associated with myalgia, myositis, and rhabdomyolysis. In December 2011, the US Food and Drug Administration (FDA) released a drug safety announcement recommending the originally approved maximum daily dose of simvastatin 80 mg be limited to patients who have already tolerated that dose for at least 12 months without evidence of muscular injury. The FDA further recommended no new patients be escalated to this dose. According to the FDA, patients taking 80 mg of simvastatin daily are also at increased risk of myopathy. 

The metabolism of simvastatin, in addition to increased dosage of the drug, contributes to its potential for adverse effects. Of the seven available statins, only atorvastatin, lovastatin, and simvastatin are metabolized by the cytochrome P450 3A4 (CYP3A4). Lovastatin and simvastatin appear to have the highest potential for drug-drug interactions when coadministered with drugs that inhibit this enzyme (eg, ritonavir).² The resulting elevation in blood concentration of simvastatin increases the risk of rhabdomyolysis. Other nonlipophilic statins, such as pravastatin, which are mostly eliminated unchanged in the urine and bile, would be preferable for patients taking CYP3A4 inhibitors.

How should patients with rhabdomyolysis be monitored?

Statins interfere with the myocyte’s ability to produce adenosine triphosphate, most likely by depleting coenzyme Q—one of the complexes found in the electron transport chain of the mitochondria. Under conditions of a high-energy requirement, myocytes incapable of producing sufficient energy ultimately fail and lyse, releasing cellular contents such as CK and myoglobin.¹ The serum CK activity serves as a marker of muscle injury and should be monitored closely in patients with rhabdomyolysis. Although values above 5,000 U/L has been associated with renal injury,⁴ in healthy patients with access to hydration, renal injury is relatively uncommon with CK activities less than 50,000 U/L. Even though the prediction of renal failure is difficult, a validated nephrotoxicity prediction instrument using the patient’s age, gender, and initial laboratory data (serum creatinine, calcium, CK, phosphate, and bicarbonate) is available.⁵

Although the association between rhabdomyolysis and acute renal injury is well established, the mechanism remains unclear. Myoglobin from skeletal myocytes passes through the glomerulus without causing damage and is reabsorbed in the proximal renal tubular cell. Iron is subsequently released from the porphyrin ring and, in large concentrations, exceeds the binding capacity of the tissue ferritin. Because it is a transition metal, the free iron ion participates in oxidant stress reactions causing direct injury to the renal tubular cells.⁶ Furthermore, myoglobin also combines with renal tubular proteins, a process enhanced by an environment with lower pH, to form casts and cause renal tubular obstruction.

Patients with rhabdomyolysis may also be at risk for aminotransferase elevation, as occurred in the patient presented here. This elevation is most likely due to myocyte injury. In addition, potassium release due to myocyte destruction may cause life-threatening hyperkalemia, and phosphate liberation from these myocytes may cause hypocalcemia. Laboratory monitoring along with an electrocardiogram should be performed as required.

What is the treatment for rhabdomyolysis?

No adequate randomized controlled trials exist to guide the treatment of patients with rhabdomyolysis. As a result, recommendations for management come from retrospective observational studies, animal studies, case reports, and expert opinion.⁷

Once airway, breathing, and circulation have been addressed, patients with statin-induced rhabdomyolysis should be immediately treated with intravenous (IV) fluids to maintain renal perfusion, which helps to limit acute renal injury. Normal saline appears to be the most recommended fluid type, with a goal of maintaining a urine output of approximately 3 to 5 mL/kg/h.^4,7

Some recommendations include the use of a sodium bicarbonate infusion to raise the urine pH, which may help limit the formation of renal casts from myoglobin. The data to support the benefit of sodium bicarbonate, however, is weak.³ A 2013 systematic review indicated that sodium bicarbonate should only be used to treat severe metabolic acidosis in patients with rhabdomyolysis.⁴

In addition to sodium bicarbonate, the use of diuretics is also discouraged by current recommendations. In patients with refractory electrolyte abnormalities or renal failure, hemodialysis may be required. Before disposition of a patient, his or her medication list should be reconciled to reflect statin discontinuation. 

Case Conclusion

The patient received IV normal saline to maintain his urine output at 2 to 3 cc/kg/h. His repeat creatinine was 0.8 mg/dL and remained stable on repeat testing. His CK and AST concentrations trended down during his hospitalization. On hospital day 4, laboratory values were CK, less than 10,000 U/L; AST, 56 U/L; and ALT, 23 U/L. He had normal serum potassium levels and no dysrhythmia on electrocardiogram. His symptoms resolved on hospital day 2, and he was discharged on hospital day 4 with instructions to discontinue simvastatin.

Dr Fernandez is a senior toxicology fellow, department of emergency medicine, New York University School of Medicine. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board.

A 49-year-old woman with a history of depression, bipolar disorder, and chronic back pain was brought to the emergency department unresponsive after having taken an unknown quantity of amitriptyline tablets.

On arrival, she was comatose, with a score of 3 (the lowest possible score) on the 15-point Glasgow Coma Scale. Her blood pressure was 65/22 mm Hg, heart rate 121 beats per minute, respiratory rate 14 per minute, and oxygen saturation 88% on room air. The rest of the initial physical examination was normal.

She was immediately intubated, put on mechanical ventilation, and given an infusion of a 1-L bolus of normal saline and 50 mmol (1 mmol/kg) of sodium bicarbonate. Norepinephrine infusion was started. Gastric lavage was not done.

Results of initial laboratory testing showed a serum potassium of 2.9 mmol/L (reference range 3.5–5.0) and a serum magnesium of 1.6 mmol/L (1.7–2.6), which were corrected with infusion of 60 mmol of potassium chloride and 2 g of magnesium sulfate. The serum amitriptyline measurement was ordered at the time of her presentation to the emergency department.

Arterial blood gas analysis showed:

• pH 7.15 (normal range 7.35–7.45)
• Paco₂ 66 mm Hg (34–46)
• Pao₂ 229 mm Hg (85–95)
• Bicarbonate 22 mmol/L (22–26).

The initial electrocardiogram (ECG) (Figure 1) showed regular wide-complex tachycardia with no definite right or left bundle branch block morphology, no discernible P waves, a QRS duration of 198 msec, right axis deviation, and no Brugada criteria to suggest ventricular tachycardia.

She remained hypotensive, with regular wide-complex tachycardia on the ECG. She was given an additional 1-L bolus of normal saline and 100 mmol (2 mmol/kg) of sodium bicarbonate, and within 1 minute the wide-complex tachycardia resolved to narrow-complex sinus tachycardia (Figure 2). At this point, an infusion of 150 mmol/L of sodium bicarbonate in dextrose 5% in water was started, with serial ECGs to monitor the QRS duration and serial arterial blood gas monitoring to maintain the pH between 7.45 and 7.55.

TRANSFER TO THE ICU

She was then transferred to the intensive care unit (ICU), where she remained for 2 weeks. While in the ICU, she had a single recurrence of wide-complex tachycardia that resolved immediately with an infusion of 100 mmol of sodium bicarbonate. A urine toxicology screen was negative, and the serum amitriptyline measurement, returned from the laboratory 48 hours after her initial presentation, was 594 ng/mL (reference range 100–250 ng/mL). She was eventually weaned off the norepinephrine infusion after 20 hours, the sodium bicarbonate infusion was discontinued after 4 days, and she was taken off mechanical ventilation after 10 days. Also during her ICU stay, she had seizures on day 3 and developed aspiration pneumonia.

From the ICU, she was transferred to a regular floor, where she stayed for another week and then was transferred to a rehabilitation center. This patient was known to have clinical depression and to have attempted suicide once before. She had recently been under additional psychosocial stresses, which likely prompted this second attempt.

She reportedly had no neurologic or cardiovascular sequelae after her discharge from the hospital.

AMITRIPTYLINE OVERDOSE

Amitriptyline causes a relatively high number of fatal overdoses, at 34 per 1 million prescriptions.¹ Death is usually from hypotension and ventricular arrhythmia caused by blockage of cardiac fast sodium channels leading to disturbances of cardiac conduction such as wide-complex tachycardia.

Other manifestations of amitriptyline overdose include seizures, sedation, and anticholinergic toxicity from variable blockade of gamma-aminobutyric acid receptors, histamine 1 receptors, and alpha receptors.²

In amitriptyline overdose, sinus tachycardia is the most common finding on ECG

Of the various changes on ECG described with amitriptyline overdose, sinus tachycardia is the most common. A QRS duration greater than 100 msec, right to extreme-right axis deviation with negative QRS complexes in leads I and aVL, and an R-wave amplitude greater than 3 mm in lead aVR are indications for sodium bicarbonate infusion, especially in hemodynamically unstable patients.³ Sodium bicarbonate increases the serum concentration of sodium and thereby overcomes the sodium channel blockade. It also alkalinizes the serum, favoring an electrically neutral form of amitriptyline that binds less to receptors and binds more to alpha-1-acid glycoprotein, decreasing the fraction of free drug available for toxicity.⁴

In patients with amitriptyline overdose, wide-complex tachycardia and hypotension refractory to sodium bicarbonate infusion can be treated with lidocaine, magnesium sulfate, direct-current cardioversion, and lipid resuscitation.^5,6 Treatment with class IA, IC, and III antiarrhythmics is contraindicated, as they block sodium channels and thus can worsen conduction disturbances.

A 49-year-old woman with a history of depression, bipolar disorder, and chronic back pain was brought to the emergency department unresponsive after having taken an unknown quantity of amitriptyline tablets.

On arrival, she was comatose, with a score of 3 (the lowest possible score) on the 15-point Glasgow Coma Scale. Her blood pressure was 65/22 mm Hg, heart rate 121 beats per minute, respiratory rate 14 per minute, and oxygen saturation 88% on room air. The rest of the initial physical examination was normal.

She was immediately intubated, put on mechanical ventilation, and given an infusion of a 1-L bolus of normal saline and 50 mmol (1 mmol/kg) of sodium bicarbonate. Norepinephrine infusion was started. Gastric lavage was not done.

Results of initial laboratory testing showed a serum potassium of 2.9 mmol/L (reference range 3.5–5.0) and a serum magnesium of 1.6 mmol/L (1.7–2.6), which were corrected with infusion of 60 mmol of potassium chloride and 2 g of magnesium sulfate. The serum amitriptyline measurement was ordered at the time of her presentation to the emergency department.

Arterial blood gas analysis showed:

• pH 7.15 (normal range 7.35–7.45)
• Paco₂ 66 mm Hg (34–46)
• Pao₂ 229 mm Hg (85–95)
• Bicarbonate 22 mmol/L (22–26).

The initial electrocardiogram (ECG) (Figure 1) showed regular wide-complex tachycardia with no definite right or left bundle branch block morphology, no discernible P waves, a QRS duration of 198 msec, right axis deviation, and no Brugada criteria to suggest ventricular tachycardia.

She remained hypotensive, with regular wide-complex tachycardia on the ECG. She was given an additional 1-L bolus of normal saline and 100 mmol (2 mmol/kg) of sodium bicarbonate, and within 1 minute the wide-complex tachycardia resolved to narrow-complex sinus tachycardia (Figure 2). At this point, an infusion of 150 mmol/L of sodium bicarbonate in dextrose 5% in water was started, with serial ECGs to monitor the QRS duration and serial arterial blood gas monitoring to maintain the pH between 7.45 and 7.55.

TRANSFER TO THE ICU

She was then transferred to the intensive care unit (ICU), where she remained for 2 weeks. While in the ICU, she had a single recurrence of wide-complex tachycardia that resolved immediately with an infusion of 100 mmol of sodium bicarbonate. A urine toxicology screen was negative, and the serum amitriptyline measurement, returned from the laboratory 48 hours after her initial presentation, was 594 ng/mL (reference range 100–250 ng/mL). She was eventually weaned off the norepinephrine infusion after 20 hours, the sodium bicarbonate infusion was discontinued after 4 days, and she was taken off mechanical ventilation after 10 days. Also during her ICU stay, she had seizures on day 3 and developed aspiration pneumonia.

From the ICU, she was transferred to a regular floor, where she stayed for another week and then was transferred to a rehabilitation center. This patient was known to have clinical depression and to have attempted suicide once before. She had recently been under additional psychosocial stresses, which likely prompted this second attempt.

She reportedly had no neurologic or cardiovascular sequelae after her discharge from the hospital.

AMITRIPTYLINE OVERDOSE

Amitriptyline causes a relatively high number of fatal overdoses, at 34 per 1 million prescriptions.¹ Death is usually from hypotension and ventricular arrhythmia caused by blockage of cardiac fast sodium channels leading to disturbances of cardiac conduction such as wide-complex tachycardia.

Other manifestations of amitriptyline overdose include seizures, sedation, and anticholinergic toxicity from variable blockade of gamma-aminobutyric acid receptors, histamine 1 receptors, and alpha receptors.²

In amitriptyline overdose, sinus tachycardia is the most common finding on ECG

Of the various changes on ECG described with amitriptyline overdose, sinus tachycardia is the most common. A QRS duration greater than 100 msec, right to extreme-right axis deviation with negative QRS complexes in leads I and aVL, and an R-wave amplitude greater than 3 mm in lead aVR are indications for sodium bicarbonate infusion, especially in hemodynamically unstable patients.³ Sodium bicarbonate increases the serum concentration of sodium and thereby overcomes the sodium channel blockade. It also alkalinizes the serum, favoring an electrically neutral form of amitriptyline that binds less to receptors and binds more to alpha-1-acid glycoprotein, decreasing the fraction of free drug available for toxicity.⁴

In patients with amitriptyline overdose, wide-complex tachycardia and hypotension refractory to sodium bicarbonate infusion can be treated with lidocaine, magnesium sulfate, direct-current cardioversion, and lipid resuscitation.^5,6 Treatment with class IA, IC, and III antiarrhythmics is contraindicated, as they block sodium channels and thus can worsen conduction disturbances.

A 49-year-old woman with a history of depression, bipolar disorder, and chronic back pain was brought to the emergency department unresponsive after having taken an unknown quantity of amitriptyline tablets.

On arrival, she was comatose, with a score of 3 (the lowest possible score) on the 15-point Glasgow Coma Scale. Her blood pressure was 65/22 mm Hg, heart rate 121 beats per minute, respiratory rate 14 per minute, and oxygen saturation 88% on room air. The rest of the initial physical examination was normal.

She was immediately intubated, put on mechanical ventilation, and given an infusion of a 1-L bolus of normal saline and 50 mmol (1 mmol/kg) of sodium bicarbonate. Norepinephrine infusion was started. Gastric lavage was not done.

Results of initial laboratory testing showed a serum potassium of 2.9 mmol/L (reference range 3.5–5.0) and a serum magnesium of 1.6 mmol/L (1.7–2.6), which were corrected with infusion of 60 mmol of potassium chloride and 2 g of magnesium sulfate. The serum amitriptyline measurement was ordered at the time of her presentation to the emergency department.

Arterial blood gas analysis showed:

• pH 7.15 (normal range 7.35–7.45)
• Paco₂ 66 mm Hg (34–46)
• Pao₂ 229 mm Hg (85–95)
• Bicarbonate 22 mmol/L (22–26).

The initial electrocardiogram (ECG) (Figure 1) showed regular wide-complex tachycardia with no definite right or left bundle branch block morphology, no discernible P waves, a QRS duration of 198 msec, right axis deviation, and no Brugada criteria to suggest ventricular tachycardia.

She remained hypotensive, with regular wide-complex tachycardia on the ECG. She was given an additional 1-L bolus of normal saline and 100 mmol (2 mmol/kg) of sodium bicarbonate, and within 1 minute the wide-complex tachycardia resolved to narrow-complex sinus tachycardia (Figure 2). At this point, an infusion of 150 mmol/L of sodium bicarbonate in dextrose 5% in water was started, with serial ECGs to monitor the QRS duration and serial arterial blood gas monitoring to maintain the pH between 7.45 and 7.55.

TRANSFER TO THE ICU

She was then transferred to the intensive care unit (ICU), where she remained for 2 weeks. While in the ICU, she had a single recurrence of wide-complex tachycardia that resolved immediately with an infusion of 100 mmol of sodium bicarbonate. A urine toxicology screen was negative, and the serum amitriptyline measurement, returned from the laboratory 48 hours after her initial presentation, was 594 ng/mL (reference range 100–250 ng/mL). She was eventually weaned off the norepinephrine infusion after 20 hours, the sodium bicarbonate infusion was discontinued after 4 days, and she was taken off mechanical ventilation after 10 days. Also during her ICU stay, she had seizures on day 3 and developed aspiration pneumonia.

From the ICU, she was transferred to a regular floor, where she stayed for another week and then was transferred to a rehabilitation center. This patient was known to have clinical depression and to have attempted suicide once before. She had recently been under additional psychosocial stresses, which likely prompted this second attempt.

She reportedly had no neurologic or cardiovascular sequelae after her discharge from the hospital.

AMITRIPTYLINE OVERDOSE

Amitriptyline causes a relatively high number of fatal overdoses, at 34 per 1 million prescriptions.¹ Death is usually from hypotension and ventricular arrhythmia caused by blockage of cardiac fast sodium channels leading to disturbances of cardiac conduction such as wide-complex tachycardia.

Other manifestations of amitriptyline overdose include seizures, sedation, and anticholinergic toxicity from variable blockade of gamma-aminobutyric acid receptors, histamine 1 receptors, and alpha receptors.²

In amitriptyline overdose, sinus tachycardia is the most common finding on ECG

Of the various changes on ECG described with amitriptyline overdose, sinus tachycardia is the most common. A QRS duration greater than 100 msec, right to extreme-right axis deviation with negative QRS complexes in leads I and aVL, and an R-wave amplitude greater than 3 mm in lead aVR are indications for sodium bicarbonate infusion, especially in hemodynamically unstable patients.³ Sodium bicarbonate increases the serum concentration of sodium and thereby overcomes the sodium channel blockade. It also alkalinizes the serum, favoring an electrically neutral form of amitriptyline that binds less to receptors and binds more to alpha-1-acid glycoprotein, decreasing the fraction of free drug available for toxicity.⁴

In patients with amitriptyline overdose, wide-complex tachycardia and hypotension refractory to sodium bicarbonate infusion can be treated with lidocaine, magnesium sulfate, direct-current cardioversion, and lipid resuscitation.^5,6 Treatment with class IA, IC, and III antiarrhythmics is contraindicated, as they block sodium channels and thus can worsen conduction disturbances.

ANSWER
The radiograph shows a small calcifi­cation along the medial aspect of the medial collateral ligament. This finding is known as a Pellegrini-Stieda lesion. While it certainly could represent a small avulsion fracture, the lack of joint fluid and soft-tissue swelling makes this diagnosis less likely. The patient was treated symptomatically with anti-inflammatory medications.

ANSWER
The radiograph shows a small calcifi­cation along the medial aspect of the medial collateral ligament. This finding is known as a Pellegrini-Stieda lesion. While it certainly could represent a small avulsion fracture, the lack of joint fluid and soft-tissue swelling makes this diagnosis less likely. The patient was treated symptomatically with anti-inflammatory medications.

ANSWER
The radiograph shows a small calcifi­cation along the medial aspect of the medial collateral ligament. This finding is known as a Pellegrini-Stieda lesion. While it certainly could represent a small avulsion fracture, the lack of joint fluid and soft-tissue swelling makes this diagnosis less likely. The patient was treated symptomatically with anti-inflammatory medications.