Emergency Medicine

To the Editor: I read with keen interest the high-quality review of the pathogenesis, diagnosis, and management of alcoholic hepatitis by Dugum et al.¹ They clearly emphasized the high morbidity and mortality rates associated with this condition.

An important consideration for healthcare practitioners is that the presentation of alcoholic hepatitis can mimic an infectious process, eg, presenting with fever and an elevated white blood cell count. Indeed, clinicians should be vigilant and should routinely evaluate for an underlying infection in patients with suspected alcoholic hepatitis, because patients with liver disease are immunocompromised and several problems can potentially coexist in any given patient.

Therefore, clinicians should focus on the clinical history and examination (vital signs, mental status examination, presence of ascites) and should screen for common coinfections such as urinary tract infection and pneumonia with a white blood cell count with differential and other tests. Of particular importance, patients with ascites should undergo diagnostic abdominal paracentesis,² and empiric antimicrobial therapy for spontaneous bacterial peritonitis should be considered on a case-by-case basis.³

To the Editor: I read with keen interest the high-quality review of the pathogenesis, diagnosis, and management of alcoholic hepatitis by Dugum et al.¹ They clearly emphasized the high morbidity and mortality rates associated with this condition.

An important consideration for healthcare practitioners is that the presentation of alcoholic hepatitis can mimic an infectious process, eg, presenting with fever and an elevated white blood cell count. Indeed, clinicians should be vigilant and should routinely evaluate for an underlying infection in patients with suspected alcoholic hepatitis, because patients with liver disease are immunocompromised and several problems can potentially coexist in any given patient.

Therefore, clinicians should focus on the clinical history and examination (vital signs, mental status examination, presence of ascites) and should screen for common coinfections such as urinary tract infection and pneumonia with a white blood cell count with differential and other tests. Of particular importance, patients with ascites should undergo diagnostic abdominal paracentesis,² and empiric antimicrobial therapy for spontaneous bacterial peritonitis should be considered on a case-by-case basis.³

To the Editor: I read with keen interest the high-quality review of the pathogenesis, diagnosis, and management of alcoholic hepatitis by Dugum et al.¹ They clearly emphasized the high morbidity and mortality rates associated with this condition.

An important consideration for healthcare practitioners is that the presentation of alcoholic hepatitis can mimic an infectious process, eg, presenting with fever and an elevated white blood cell count. Indeed, clinicians should be vigilant and should routinely evaluate for an underlying infection in patients with suspected alcoholic hepatitis, because patients with liver disease are immunocompromised and several problems can potentially coexist in any given patient.

Therefore, clinicians should focus on the clinical history and examination (vital signs, mental status examination, presence of ascites) and should screen for common coinfections such as urinary tract infection and pneumonia with a white blood cell count with differential and other tests. Of particular importance, patients with ascites should undergo diagnostic abdominal paracentesis,² and empiric antimicrobial therapy for spontaneous bacterial peritonitis should be considered on a case-by-case basis.³

In Reply: We thank Dr. Mirrakhimov for his interest in our article¹ and for his comments on the importance of infection evaluation and treatment in patients with alcoholic hepatitis. We agree with the points he has raised and emphasized several of them in our article. We highlighted the need to evaluate for infections in these patients, as about a quarter of them are infected at the time of presentation.²

Importantly, patients with alcoholic hepatitis frequently have systemic inflammatory response syndrome criteria, which can be related to the overall inflammatory state of the disease itself or can reflect an active bacterial infection. Therefore, clinical monitoring for symptoms and signs of infection is crucial, and screening for infections is warranted on admission as well as repeatedly during the hospital stay for patients who experience clinical deterioration.³ Obtaining blood and urine cultures and performing paracentesis in patients with ascites to evaluate for bacterial peritonitis are required. Indeed, infections are a leading cause of death in patients with severe alcoholic hepatitis, both directly and indirectly by predisposing to multiorgan failure.⁴

Another factor to consider is the increased susceptibility to infection in these patients treated with corticosteroids. A study by Louvet et al² showed that nonresponse to corticosteroids is the main factor contributing to the development of infection during treatment with corticosteroids, suggesting that infection is likely a consequence of the absence of improvement in liver function. More recently, results of the Steroids or Pentoxifylline for Alcoholic Hepatitis trial (which evaluated the treatment effect of prednisolone and pentoxifylline in the management of severe alcoholic hepatitis) showed that despite the higher rates of infections in patients treated with prednisolone, the mortality rates attributed to infections were similar across the treatment groups, regardless of whether prednisolone was administered.⁴

Finally, it is important to emphasize that criteria to initiate empiric antibiotics in patients with alcoholic hepatitis are currently lacking, and the decision to start antibiotics empirically in patients without a clear infection is largely based on the clinician’s assessment.

In Reply: We thank Dr. Mirrakhimov for his interest in our article¹ and for his comments on the importance of infection evaluation and treatment in patients with alcoholic hepatitis. We agree with the points he has raised and emphasized several of them in our article. We highlighted the need to evaluate for infections in these patients, as about a quarter of them are infected at the time of presentation.²

Importantly, patients with alcoholic hepatitis frequently have systemic inflammatory response syndrome criteria, which can be related to the overall inflammatory state of the disease itself or can reflect an active bacterial infection. Therefore, clinical monitoring for symptoms and signs of infection is crucial, and screening for infections is warranted on admission as well as repeatedly during the hospital stay for patients who experience clinical deterioration.³ Obtaining blood and urine cultures and performing paracentesis in patients with ascites to evaluate for bacterial peritonitis are required. Indeed, infections are a leading cause of death in patients with severe alcoholic hepatitis, both directly and indirectly by predisposing to multiorgan failure.⁴

Another factor to consider is the increased susceptibility to infection in these patients treated with corticosteroids. A study by Louvet et al² showed that nonresponse to corticosteroids is the main factor contributing to the development of infection during treatment with corticosteroids, suggesting that infection is likely a consequence of the absence of improvement in liver function. More recently, results of the Steroids or Pentoxifylline for Alcoholic Hepatitis trial (which evaluated the treatment effect of prednisolone and pentoxifylline in the management of severe alcoholic hepatitis) showed that despite the higher rates of infections in patients treated with prednisolone, the mortality rates attributed to infections were similar across the treatment groups, regardless of whether prednisolone was administered.⁴

Finally, it is important to emphasize that criteria to initiate empiric antibiotics in patients with alcoholic hepatitis are currently lacking, and the decision to start antibiotics empirically in patients without a clear infection is largely based on the clinician’s assessment.

In Reply: We thank Dr. Mirrakhimov for his interest in our article¹ and for his comments on the importance of infection evaluation and treatment in patients with alcoholic hepatitis. We agree with the points he has raised and emphasized several of them in our article. We highlighted the need to evaluate for infections in these patients, as about a quarter of them are infected at the time of presentation.²

Importantly, patients with alcoholic hepatitis frequently have systemic inflammatory response syndrome criteria, which can be related to the overall inflammatory state of the disease itself or can reflect an active bacterial infection. Therefore, clinical monitoring for symptoms and signs of infection is crucial, and screening for infections is warranted on admission as well as repeatedly during the hospital stay for patients who experience clinical deterioration.³ Obtaining blood and urine cultures and performing paracentesis in patients with ascites to evaluate for bacterial peritonitis are required. Indeed, infections are a leading cause of death in patients with severe alcoholic hepatitis, both directly and indirectly by predisposing to multiorgan failure.⁴

Another factor to consider is the increased susceptibility to infection in these patients treated with corticosteroids. A study by Louvet et al² showed that nonresponse to corticosteroids is the main factor contributing to the development of infection during treatment with corticosteroids, suggesting that infection is likely a consequence of the absence of improvement in liver function. More recently, results of the Steroids or Pentoxifylline for Alcoholic Hepatitis trial (which evaluated the treatment effect of prednisolone and pentoxifylline in the management of severe alcoholic hepatitis) showed that despite the higher rates of infections in patients treated with prednisolone, the mortality rates attributed to infections were similar across the treatment groups, regardless of whether prednisolone was administered.⁴

Finally, it is important to emphasize that criteria to initiate empiric antibiotics in patients with alcoholic hepatitis are currently lacking, and the decision to start antibiotics empirically in patients without a clear infection is largely based on the clinician’s assessment.

Case

A previously healthy 4-month-old girl was brought into the ED for concerns of alcohol ingestion. Reportedly, the infant’s father reconstituted 4 ounces of powdered formula using what he thought was water from an unmarked bottle in his refrigerator. He later realized that the bottle contained rum, although he still let the child finish the 4 ounces of formula in the hopes that she would vomit—which did not occur.

Upon arrival to the ED, the infant’s vital signs were: blood pressure, 100/61 mm Hg; heart rate, 155 beats/minute; respiratory rate, 36 breaths/minute; and temperature, normal. Oxygen saturation was 98% on room air. A rapid bedside blood glucose test was 89 mg/dL. The infant’s physical examination was unremarkable. She appeared active but hungry, had a strong cry, and had a developmentally appropriate gross neurological examination.

How does ethanol exposure in children typically occur?

Recent reports from the American Association of Poison Control Centers’ National Poison Data System demonstrate that ethanol exposures comprise 1% to 3% of total exposures in children aged ≤5 years.

The most common sources are ethanol-containing beverages, mouthwash, and cologne/perfume.¹ Ethanol can also be found as a solvent for certain pediatric liquid medications (eg, ranitidine) or in flavor extracts (eg, vanilla extract, orange extract). Any clear alcohol (eg, vodka, gin, rum) stored in an accessible site, such as a refrigerator, may be mistaken for water. In many reports, a caregiver unintentionally used the alcohol to reconstitute formula; however, intentional provision of alcohol to toddlers, usually as a sedative, is a recurring concern.²

What are the clinical concerns in children with ethanol intoxication?

Under usual conditions, a normal serum glucose concentration is maintained from ingested carbohydrates and via glycogenolysis of hepatic glycogen stores. Such glycogen reserves can sustain normal blood glucose concentrations for several hours in adults but for a shorter period in children. Once glycogen is depleted, as is common after an overnight fast, glucose can be generated through gluconeogenesis.

However, in the presence of ethanol (Figure), the excessive reducing potential (ie, NADH) that results from ethanol metabolism shunts pyruvate away from the gluconeogenic pathway (toward lactate), inhibiting glucose production. Unlike adults, children and infants, who have relatively low glycogen reserves, are at significant risk for hypoglycemia following ethanol exposure. This represents the largest contributor to morbidity and mortality of children with ethanol intoxication.³ Patients with hypoglycemia can have a highly variable clinical presentation including agitation, seizures, focality, or coma.⁴

Case Continuation

Intravenous (IV) access was obtained, and the patient was placed on a dextrose-containing fluid at 1.5 times the maintenance flow rate. Pertinent laboratory studies revealed a serum glucose level of 90 mg/dL, normal electrolyte panel, and an initial blood alcohol concentration of 337 mg/dL (approximately 30 minutes postingestion).

How do children with ethanol intoxication present?

While there is some variation in clinical effects among nontolerant adults, acute ethanol intoxication with a serum concentration >250 mg/dL is frequently associated with stupor, respiratory depression, and hypotension. A concentration >400 mg/dL may be associated with coma or apnea. Although similar clinical effects are expected in adolescents and children, infants often have counterintuitive clinical findings.

To date, eight cases of significant infant ethanol exposure exist in the literature (age range, 29 days to 9 months; ethanol concentration, 183-524 mg/dL). Respiratory depression was absent in all cases.^5-9 In all but two cases, the neurological examination revealed only subtle decreases in interaction or tone. The remaining two children were described as obtunded and flaccid (ethanol levels, 405 mg/dL and 524 mg/dL, respectively) and were intubated for airway protection despite normal respiratory rates.^7,10

The incongruence between the clinical findings (both the neurological examination and respiratory effects) and the ethanol concentration is difficult to explain. It may be due to age-related neurological immaturity or a limited ability to perform the required detailed neurological examinations in children. In particular, the relatively preserved level of consciousness, despite an otherwise coma-inducing ethanol concentration, is unique to infants. Accordingly, there should be a low threshold to check ethanol concentrations in infants presenting with apparent life-threatening events, altered mental status, decreased tone, or unexplained hypoglycemia or hypothermia.

What is the estimated time to sobriety in infants?

Ethanol is eliminated via a hepatic enzymatic oxidation pathway that becomes saturated at low serum levels. In nontolerant adults, this results in a zero-order kinetic elimination pattern with an ethanol elimination rate of approximately 20 mg/dL per hour. Anecdotally, it had been thought that children clear ethanol at roughly double this rate via unclear mechanisms. However, a review of published kinetic data suggests the actual rate of clearance may not differ substantially from adults (range, 19-34 mg/dL per hour).^5-7,10,11

Case Conclusion

The patient was transferred to a tertiary care pediatric hospital for continued management, where the markedly elevated serum ethanol concentration was confirmed.  She was maintained on a dextrose-containing IV fluid and observed overnight without development of any complications. Serial serum ethanol concentrations were performed and complete clearance was achieved approximately 20 hours postingestion, suggesting a metabolic rate of 16 mg/dL per hour. The infant was discharged home with supervision by child protective services.

Dr Boroughf is a toxicology fellow, department of emergency medicine, Albert Einstein Medical Center, Philadelphia, Pennsylvania. 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. Dr Henretig is an attending toxicologist, department of emergency medicine, Children’s Hospital of Philadelphia, Pennsylvania.

Case

A previously healthy 4-month-old girl was brought into the ED for concerns of alcohol ingestion. Reportedly, the infant’s father reconstituted 4 ounces of powdered formula using what he thought was water from an unmarked bottle in his refrigerator. He later realized that the bottle contained rum, although he still let the child finish the 4 ounces of formula in the hopes that she would vomit—which did not occur.

Upon arrival to the ED, the infant’s vital signs were: blood pressure, 100/61 mm Hg; heart rate, 155 beats/minute; respiratory rate, 36 breaths/minute; and temperature, normal. Oxygen saturation was 98% on room air. A rapid bedside blood glucose test was 89 mg/dL. The infant’s physical examination was unremarkable. She appeared active but hungry, had a strong cry, and had a developmentally appropriate gross neurological examination.

How does ethanol exposure in children typically occur?

Recent reports from the American Association of Poison Control Centers’ National Poison Data System demonstrate that ethanol exposures comprise 1% to 3% of total exposures in children aged ≤5 years.

The most common sources are ethanol-containing beverages, mouthwash, and cologne/perfume.¹ Ethanol can also be found as a solvent for certain pediatric liquid medications (eg, ranitidine) or in flavor extracts (eg, vanilla extract, orange extract). Any clear alcohol (eg, vodka, gin, rum) stored in an accessible site, such as a refrigerator, may be mistaken for water. In many reports, a caregiver unintentionally used the alcohol to reconstitute formula; however, intentional provision of alcohol to toddlers, usually as a sedative, is a recurring concern.²

What are the clinical concerns in children with ethanol intoxication?

Under usual conditions, a normal serum glucose concentration is maintained from ingested carbohydrates and via glycogenolysis of hepatic glycogen stores. Such glycogen reserves can sustain normal blood glucose concentrations for several hours in adults but for a shorter period in children. Once glycogen is depleted, as is common after an overnight fast, glucose can be generated through gluconeogenesis.

However, in the presence of ethanol (Figure), the excessive reducing potential (ie, NADH) that results from ethanol metabolism shunts pyruvate away from the gluconeogenic pathway (toward lactate), inhibiting glucose production. Unlike adults, children and infants, who have relatively low glycogen reserves, are at significant risk for hypoglycemia following ethanol exposure. This represents the largest contributor to morbidity and mortality of children with ethanol intoxication.³ Patients with hypoglycemia can have a highly variable clinical presentation including agitation, seizures, focality, or coma.⁴

Case Continuation

Intravenous (IV) access was obtained, and the patient was placed on a dextrose-containing fluid at 1.5 times the maintenance flow rate. Pertinent laboratory studies revealed a serum glucose level of 90 mg/dL, normal electrolyte panel, and an initial blood alcohol concentration of 337 mg/dL (approximately 30 minutes postingestion).

How do children with ethanol intoxication present?

While there is some variation in clinical effects among nontolerant adults, acute ethanol intoxication with a serum concentration >250 mg/dL is frequently associated with stupor, respiratory depression, and hypotension. A concentration >400 mg/dL may be associated with coma or apnea. Although similar clinical effects are expected in adolescents and children, infants often have counterintuitive clinical findings.

To date, eight cases of significant infant ethanol exposure exist in the literature (age range, 29 days to 9 months; ethanol concentration, 183-524 mg/dL). Respiratory depression was absent in all cases.^5-9 In all but two cases, the neurological examination revealed only subtle decreases in interaction or tone. The remaining two children were described as obtunded and flaccid (ethanol levels, 405 mg/dL and 524 mg/dL, respectively) and were intubated for airway protection despite normal respiratory rates.^7,10

The incongruence between the clinical findings (both the neurological examination and respiratory effects) and the ethanol concentration is difficult to explain. It may be due to age-related neurological immaturity or a limited ability to perform the required detailed neurological examinations in children. In particular, the relatively preserved level of consciousness, despite an otherwise coma-inducing ethanol concentration, is unique to infants. Accordingly, there should be a low threshold to check ethanol concentrations in infants presenting with apparent life-threatening events, altered mental status, decreased tone, or unexplained hypoglycemia or hypothermia.

What is the estimated time to sobriety in infants?

Ethanol is eliminated via a hepatic enzymatic oxidation pathway that becomes saturated at low serum levels. In nontolerant adults, this results in a zero-order kinetic elimination pattern with an ethanol elimination rate of approximately 20 mg/dL per hour. Anecdotally, it had been thought that children clear ethanol at roughly double this rate via unclear mechanisms. However, a review of published kinetic data suggests the actual rate of clearance may not differ substantially from adults (range, 19-34 mg/dL per hour).^5-7,10,11

Case Conclusion

The patient was transferred to a tertiary care pediatric hospital for continued management, where the markedly elevated serum ethanol concentration was confirmed.  She was maintained on a dextrose-containing IV fluid and observed overnight without development of any complications. Serial serum ethanol concentrations were performed and complete clearance was achieved approximately 20 hours postingestion, suggesting a metabolic rate of 16 mg/dL per hour. The infant was discharged home with supervision by child protective services.

Dr Boroughf is a toxicology fellow, department of emergency medicine, Albert Einstein Medical Center, Philadelphia, Pennsylvania. 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. Dr Henretig is an attending toxicologist, department of emergency medicine, Children’s Hospital of Philadelphia, Pennsylvania.

Case

A previously healthy 4-month-old girl was brought into the ED for concerns of alcohol ingestion. Reportedly, the infant’s father reconstituted 4 ounces of powdered formula using what he thought was water from an unmarked bottle in his refrigerator. He later realized that the bottle contained rum, although he still let the child finish the 4 ounces of formula in the hopes that she would vomit—which did not occur.

Upon arrival to the ED, the infant’s vital signs were: blood pressure, 100/61 mm Hg; heart rate, 155 beats/minute; respiratory rate, 36 breaths/minute; and temperature, normal. Oxygen saturation was 98% on room air. A rapid bedside blood glucose test was 89 mg/dL. The infant’s physical examination was unremarkable. She appeared active but hungry, had a strong cry, and had a developmentally appropriate gross neurological examination.

How does ethanol exposure in children typically occur?

Recent reports from the American Association of Poison Control Centers’ National Poison Data System demonstrate that ethanol exposures comprise 1% to 3% of total exposures in children aged ≤5 years.

The most common sources are ethanol-containing beverages, mouthwash, and cologne/perfume.¹ Ethanol can also be found as a solvent for certain pediatric liquid medications (eg, ranitidine) or in flavor extracts (eg, vanilla extract, orange extract). Any clear alcohol (eg, vodka, gin, rum) stored in an accessible site, such as a refrigerator, may be mistaken for water. In many reports, a caregiver unintentionally used the alcohol to reconstitute formula; however, intentional provision of alcohol to toddlers, usually as a sedative, is a recurring concern.²

What are the clinical concerns in children with ethanol intoxication?

Under usual conditions, a normal serum glucose concentration is maintained from ingested carbohydrates and via glycogenolysis of hepatic glycogen stores. Such glycogen reserves can sustain normal blood glucose concentrations for several hours in adults but for a shorter period in children. Once glycogen is depleted, as is common after an overnight fast, glucose can be generated through gluconeogenesis.

However, in the presence of ethanol (Figure), the excessive reducing potential (ie, NADH) that results from ethanol metabolism shunts pyruvate away from the gluconeogenic pathway (toward lactate), inhibiting glucose production. Unlike adults, children and infants, who have relatively low glycogen reserves, are at significant risk for hypoglycemia following ethanol exposure. This represents the largest contributor to morbidity and mortality of children with ethanol intoxication.³ Patients with hypoglycemia can have a highly variable clinical presentation including agitation, seizures, focality, or coma.⁴

Case Continuation

Intravenous (IV) access was obtained, and the patient was placed on a dextrose-containing fluid at 1.5 times the maintenance flow rate. Pertinent laboratory studies revealed a serum glucose level of 90 mg/dL, normal electrolyte panel, and an initial blood alcohol concentration of 337 mg/dL (approximately 30 minutes postingestion).

How do children with ethanol intoxication present?

While there is some variation in clinical effects among nontolerant adults, acute ethanol intoxication with a serum concentration >250 mg/dL is frequently associated with stupor, respiratory depression, and hypotension. A concentration >400 mg/dL may be associated with coma or apnea. Although similar clinical effects are expected in adolescents and children, infants often have counterintuitive clinical findings.

To date, eight cases of significant infant ethanol exposure exist in the literature (age range, 29 days to 9 months; ethanol concentration, 183-524 mg/dL). Respiratory depression was absent in all cases.^5-9 In all but two cases, the neurological examination revealed only subtle decreases in interaction or tone. The remaining two children were described as obtunded and flaccid (ethanol levels, 405 mg/dL and 524 mg/dL, respectively) and were intubated for airway protection despite normal respiratory rates.^7,10

The incongruence between the clinical findings (both the neurological examination and respiratory effects) and the ethanol concentration is difficult to explain. It may be due to age-related neurological immaturity or a limited ability to perform the required detailed neurological examinations in children. In particular, the relatively preserved level of consciousness, despite an otherwise coma-inducing ethanol concentration, is unique to infants. Accordingly, there should be a low threshold to check ethanol concentrations in infants presenting with apparent life-threatening events, altered mental status, decreased tone, or unexplained hypoglycemia or hypothermia.

What is the estimated time to sobriety in infants?

Ethanol is eliminated via a hepatic enzymatic oxidation pathway that becomes saturated at low serum levels. In nontolerant adults, this results in a zero-order kinetic elimination pattern with an ethanol elimination rate of approximately 20 mg/dL per hour. Anecdotally, it had been thought that children clear ethanol at roughly double this rate via unclear mechanisms. However, a review of published kinetic data suggests the actual rate of clearance may not differ substantially from adults (range, 19-34 mg/dL per hour).^5-7,10,11

Case Conclusion

The patient was transferred to a tertiary care pediatric hospital for continued management, where the markedly elevated serum ethanol concentration was confirmed.  She was maintained on a dextrose-containing IV fluid and observed overnight without development of any complications. Serial serum ethanol concentrations were performed and complete clearance was achieved approximately 20 hours postingestion, suggesting a metabolic rate of 16 mg/dL per hour. The infant was discharged home with supervision by child protective services.

Dr Boroughf is a toxicology fellow, department of emergency medicine, Albert Einstein Medical Center, Philadelphia, Pennsylvania. 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. Dr Henretig is an attending toxicologist, department of emergency medicine, Children’s Hospital of Philadelphia, Pennsylvania.

Nevertheless, careful attention to the ST-T and QRS-complex configurations often allows diagnosis of the cause of ST elevation (Figure 1, Table 1). This paper discusses the differential diagnosis of ST elevation.

MEASURED AT THE J POINT OR LATER

ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION

A diagnosis of STEMI that mandates emergency reperfusion requires ST elevation equaling or exceeding the following cut-points, in at least two contiguous leads (using the standardization of 1.0 mV = 10 mm)^4,5:

• 1 mm in all standard leads other than V₂ and V₃
• 2.5 mm in leads V₂ and V₃ in men younger than age 40, 2 mm in leads V₂ and V₃ in men age 40 and older, and 1.5 mm in these leads in women
• 0.5 mm in the posterior chest leads V₇ to V₉; ST elevation is attenuated in the posterior leads because of their greater distance from the heart, explaining the lower cut-point.⁶

While ST elevation that falls below these cut-points may be a normal variant, any ST elevation or depression (≥ 0.5 mm) may be abnormal and may necessitate further evaluation for ischemia, particularly when the clinical setting or the ST morphology suggests ischemia or when other signs of ischemia such as T-wave abnormalities, Q waves, or reciprocal ST-segment changes are also present on the electrocardiogram.

Conversely, ST elevation that exceeds these cut-points may not represent STEMI. In an analysis of patients with chest pain manifesting ST elevation, only 15% were eventually diagnosed with STEMI.⁷ In addition to size, careful attention to the morphology of the ST segment and the associated features is critical (Figure 1).

Other features of STEMI

Four other features characteristic of STEMI may be present (Figures 2 and 3):

• Concomitant T-wave abnormalities (wide, ample, or inverted T waves)
• Q waves
• ST depression in the reciprocal leads. Reciprocal ST depression is seen in all inferior STEMIs and in 70% of anterior STEMIs.^11,12 Diffuse ST elevation mimicking pericarditis may be seen with midvessel occlusion of a left anterior descending artery that wraps around the apex and supplies part of the inferior wall.

• 

  ST or T-wave amplitude may approximate or exceed the QRS amplitude in at least one lead.^3,13,14 This finding is characteristic of STEMI, in which the QRS “shrinks” as the infarcted area becomes electrically neutral, whereas the ST-T segments become ample.^3,13 In fact, early STEMI may be characterized by a small R wave that seems to be “pulled up” by the elevated ST segment. A small or absent R wave along with an ample, convex ST segment that fuses with the T wave and exceeds the height of the remaining R wave is called “tombstoning” (Figure 3). Tombstoning is most commonly seen with anterior infarction and implies more extensive myocardial damage and a worse prognosis than STEMI without tombstoning.¹⁵

Note that ST elevation may not be acute STEMI but an old STEMI with a chronically dysfunctional myocardium (dyskinetic or aneurysmal myocardium). In fact, an old STEMI may manifest as a chronic, persistent ST elevation along with Q waves, and T waves may be inverted or upright, but not ample.¹⁴ A history of an old MI, old electrocardiograms, if available, and quick bedside echocardiography may allow the diagnosis. In the case of an old dyskinetic infarct, echocardiography shows a thin, bright (scarred), and possibly aneurysmal myocardium, whereas in acute STEMI, the myocardium is neither thin nor scarred yet. If the patient does not report a history of MI, if the T wave is ample (> 75% the size of QRS), or if the patient presents with atypical ongoing angina, presume it is acute STEMI.

EARLY REPOLARIZATION

Early repolarization is a normal variant of ST elevation that equals or exceeds 1 mm (measured at the J point). It is highly prevalent in people under age 40 and remains prevalent in middle-aged people.

Two distinct and sometimes coexistent forms of early repolarization have been described: (1) ST elevation in the anterior leads V₁ to V₃,^16–19 and (2) ST elevation in the lateral leads (V₄ to V₆, I, aVL) or inferior leads.^18–22 The prevalence of the first form—ie, ST elevation of 1 mm or more in any of the leads V₁ through V₃—is 60% to 90% in men  age 45 and younger, 20% to 40% in men over age 45, and about 10% in women of any age.¹⁶ Thus, this form of early repolarization is called “normal male pattern.”

Even early repolarization that involves the lateral or inferior leads is common, with a prevalence of about 15% in people ages 30 to 40 and about 5% to 10% in those 40 to 65.^20–23 It is two to four times more prevalent in men and three times more prevalent in African Americans. It is also highly prevalent in athletes younger than 25 (about 30% to 40%).²²

• The ST segment is concave upward, and the J point is well demarcated and may be notched or slurred (Figure 1).
• ST elevation is usually no more than 3 mm.
• ST elevation may be limited to the anterior leads or, in many instances, may extend to the inferior or lateral leads. Early repolarization is very rarely limited to the limb leads, and involvement of some precordial leads is the rule.^18,19 The ST segment is depressed in lead aVR in 50% of patients.^18,19

• 

  The T wave is usually ample and may be more than 10 mm tall in the precordial leads in one-third of patients,¹⁷ but as opposed to the ample T wave of STEMI, it is not broad and remains smaller than the QRS complex. The ample T wave distinguishes early repolarization from pericarditis, and explains the low ST-T ratio in lead V₆. In up to 10% of young black men, the T wave has a terminal inversion in leads V₃ to V₅, and occasionally in V₁ and V₂, mimicking infarction (Figure 5).²⁴
• The QRS complex tends to have prominent precordial voltage, in sharp contrast to STEMI, in which QRS shrinking occurs.^3,17,22

The early repolarization pattern may be intermittent, may vary among serial electrocardiograms, may decrease with a rise in sympathetic tone, as observed during exercise, and may increase with a rise in vagal tone.^18,19,25,26  Although it is usually a benign finding, the early repolarization pattern in leads other than V₁ to V₃ has been associated with an increased risk of sudden death, particularly when the ST elevation is horizontal-descending rather than upsloping and, possibly, when early repolarization involves the inferior leads with a J point that is notched or elevated 2 mm or more.^20,22

PERICARDITIS

Transient PR depression greater than 1 mm is often seen, particularly in leads II, aVF, and V₄ to V₆, and represents atrial subepicardial injury. PR depression in those leads is always associated with PR elevation in lead aVR and sometimes V₁. PR changes often coexist with ST changes but may be isolated and may precede ST changes.³⁰ PR depression is characteristic of pericarditis but may be seen in early repolarization, where it is less marked than in pericarditis (< 0.8 mm) and implies early repolarization of the atrial tissue,³¹ and in MI, where it implies atrial infarction with atrial injury pattern.

Classically, it is said that in pericarditis, unlike in STEMI, the T wave does not invert until the ST elevation subsides. In reality, up to 40% of patients develop a notched or biphasic positive-negative T wave before full return of the ST segment to the baseline.^27,32 And if T-wave inversion antedates pericarditis, concomitant ST elevation and T-wave inversion may be seen once pericarditis develops. However, the T wave inverts less deeply and less completely than in STEMI, and the corrected QT interval remains normal even when the T wave inverts.

Three criteria distinguish pericarditis from early repolarization (but not from STEMI):

• PR depression greater than 1 mm
• ST-segment depression in lead V₁
• A ratio of ST-segment height to T-wave height of at least 25% in lead V₆, V₅, V₄, or I. This feature distinguishes pericarditis from early repolarization with a high sensitivity and specificity. In pericarditis, the T waves have normal or reduced amplitude, and the ST-T ratio is therefore high,³³ whereas in early repolarization the T waves are tall, so the ST-T ratio is less than 25%.

Widespread ST elevation may be seen with both pericarditis and early repolarization. ST elevation limited to the anterior leads is more likely to be early repolarization than pericarditis.

LEFT BUNDLE BRANCH BLOCK

The following findings imply MI:

• 

  ST elevation or depression that is concordant with the QRS complex. Moreover, since ST deviation is mandatory with left bundle branch block, a “normal-looking” ST segment implies ischemia.
• Inverted T waves concordant with the QRS in more than one lead, or biphasic T waves in more than one lead (eg, V₁ to V₃). Across the precordial leads, T waves may transition from positive to negative one lead earlier or later than the QRS and ST transition. Therefore, even in the absence of ischemia, the T wave may be inverted in lead V₃, in which the QRS is deeply negative and the ST is still elevated (negative T-wave concordance in one lead). Also, the T wave may be upright in leads V₅, V₆, and I where QRS is upright and the ST segment is depressed (positive T-wave concordance does not imply ischemia).

• 

  In addition to concordance, a discordant ST segment or T wave that is very large may imply ischemia. For example, a discordant ST segment or T wave that is larger than the QRS height implies ischemia. A discordant ST elevation greater than 5 mm has been suggested by Sgarbossa et al³⁵ as a diagnostic feature of STEMI; however, this feature is seen in 10% of control patients with left bundle branch block and no STEMI, and it is thus poorly specific and also poorly sensitive, frequently missing STEMI.^35–37 Smith et al³⁶ have suggested that a discordant ST elevation of at least 25% of the S-wave depth is a far more sensitive and accurate feature but one that may still be found in up to 10% of control patients.³⁶

LEFT VENTRICULAR HYPERTROPHY

In left ventricular hypertrophy, a deep S wave is seen in leads V₁ to V₃, with ST elevation and T waves that are discordant with the QRS complex. Rarely, ST elevation may be straight or convex. The following findings imply MI:

• ST elevation or depression that is concordant with the QRS.
• Inverted T waves that are concordant with the QRS in more than one lead, or biphasic T waves in more than one lead (eg, V₁ to V₃).
• A discordant ST segment or a T wave that is very large may imply ischemia. In left ventricular hypertrophy, ST elevation is usually less than 2.5 mm in leads V₁ to V₃ and is rarely seen in the inferior leads, where it would be less than 1 mm.³⁴ When ST elevation is seen in leads V₁ to V₃ in left ventricular hypertrophy, an ST magnitude of 25% or more of the total QRS voltage has a 91% specificity for STEMI.³⁴

On another note, right ventricular hypertrophy and right bundle branch block may lead to ST-segment depression and T-wave inversion, but not to ST elevation. Thus, ST elevation occurring with right ventricular hypertrophy or right bundle branch block implies STEMI. While only left bundle branch block poses a diagnostic challenge, both types of bundle branch block, if secondary to STEMI, represent equally high-risk categories.³⁸

PREEXCITATION

HYPERKALEMIA

OTHER CAUSES OF ST-SEGMENT ELEVATION

Takotsubo cardiomyopathy

Takotsubo cardiomyopathy mimics all electrocardiographic features of anteroapical STEMI. ST elevation may extend to the inferior leads but cannot be isolated in the inferior leads.³⁹ As in apical STEMI, reciprocal ST depression is uncommon. Within 24 to 48 hours, ST elevation evolves into deep anterior T-wave inversion and a prolonged QT interval. Transient Q waves may be seen.

Myocarditis

Myocarditis may have one of two electrocardiographic patterns: a pericarditis pattern, or a typical STEMI pattern with Q waves sometimes localized to one area.⁴⁰

Atrial flutter waves

Large pulmonary embolism

A large pulmonary embolism may be associated with T-wave inversion in the anterior leads or the inferior leads, or both, reflective of cor pulmonale. Less commonly, ST elevation in the anterior or inferior leads is seen. In fact, changes of both anterior and inferior ischemia should always suggest a pulmonary embolism.^41,42

Brugada syndrome

Hyperkalemia, Brugada syndrome, and sometimes pulmonary embolism are characterized by an ST elevation that slopes downward (Figures 11 and 13), which contrasts with the upsloping, convex ST elevation of STEMI.

Nevertheless, careful attention to the ST-T and QRS-complex configurations often allows diagnosis of the cause of ST elevation (Figure 1, Table 1). This paper discusses the differential diagnosis of ST elevation.

MEASURED AT THE J POINT OR LATER

ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION

A diagnosis of STEMI that mandates emergency reperfusion requires ST elevation equaling or exceeding the following cut-points, in at least two contiguous leads (using the standardization of 1.0 mV = 10 mm)^4,5:

• 1 mm in all standard leads other than V₂ and V₃
• 2.5 mm in leads V₂ and V₃ in men younger than age 40, 2 mm in leads V₂ and V₃ in men age 40 and older, and 1.5 mm in these leads in women
• 0.5 mm in the posterior chest leads V₇ to V₉; ST elevation is attenuated in the posterior leads because of their greater distance from the heart, explaining the lower cut-point.⁶

While ST elevation that falls below these cut-points may be a normal variant, any ST elevation or depression (≥ 0.5 mm) may be abnormal and may necessitate further evaluation for ischemia, particularly when the clinical setting or the ST morphology suggests ischemia or when other signs of ischemia such as T-wave abnormalities, Q waves, or reciprocal ST-segment changes are also present on the electrocardiogram.

Conversely, ST elevation that exceeds these cut-points may not represent STEMI. In an analysis of patients with chest pain manifesting ST elevation, only 15% were eventually diagnosed with STEMI.⁷ In addition to size, careful attention to the morphology of the ST segment and the associated features is critical (Figure 1).

Other features of STEMI

Four other features characteristic of STEMI may be present (Figures 2 and 3):

• Concomitant T-wave abnormalities (wide, ample, or inverted T waves)
• Q waves
• ST depression in the reciprocal leads. Reciprocal ST depression is seen in all inferior STEMIs and in 70% of anterior STEMIs.^11,12 Diffuse ST elevation mimicking pericarditis may be seen with midvessel occlusion of a left anterior descending artery that wraps around the apex and supplies part of the inferior wall.

• 

  ST or T-wave amplitude may approximate or exceed the QRS amplitude in at least one lead.^3,13,14 This finding is characteristic of STEMI, in which the QRS “shrinks” as the infarcted area becomes electrically neutral, whereas the ST-T segments become ample.^3,13 In fact, early STEMI may be characterized by a small R wave that seems to be “pulled up” by the elevated ST segment. A small or absent R wave along with an ample, convex ST segment that fuses with the T wave and exceeds the height of the remaining R wave is called “tombstoning” (Figure 3). Tombstoning is most commonly seen with anterior infarction and implies more extensive myocardial damage and a worse prognosis than STEMI without tombstoning.¹⁵

Note that ST elevation may not be acute STEMI but an old STEMI with a chronically dysfunctional myocardium (dyskinetic or aneurysmal myocardium). In fact, an old STEMI may manifest as a chronic, persistent ST elevation along with Q waves, and T waves may be inverted or upright, but not ample.¹⁴ A history of an old MI, old electrocardiograms, if available, and quick bedside echocardiography may allow the diagnosis. In the case of an old dyskinetic infarct, echocardiography shows a thin, bright (scarred), and possibly aneurysmal myocardium, whereas in acute STEMI, the myocardium is neither thin nor scarred yet. If the patient does not report a history of MI, if the T wave is ample (> 75% the size of QRS), or if the patient presents with atypical ongoing angina, presume it is acute STEMI.

EARLY REPOLARIZATION

Early repolarization is a normal variant of ST elevation that equals or exceeds 1 mm (measured at the J point). It is highly prevalent in people under age 40 and remains prevalent in middle-aged people.

Two distinct and sometimes coexistent forms of early repolarization have been described: (1) ST elevation in the anterior leads V₁ to V₃,^16–19 and (2) ST elevation in the lateral leads (V₄ to V₆, I, aVL) or inferior leads.^18–22 The prevalence of the first form—ie, ST elevation of 1 mm or more in any of the leads V₁ through V₃—is 60% to 90% in men  age 45 and younger, 20% to 40% in men over age 45, and about 10% in women of any age.¹⁶ Thus, this form of early repolarization is called “normal male pattern.”

Even early repolarization that involves the lateral or inferior leads is common, with a prevalence of about 15% in people ages 30 to 40 and about 5% to 10% in those 40 to 65.^20–23 It is two to four times more prevalent in men and three times more prevalent in African Americans. It is also highly prevalent in athletes younger than 25 (about 30% to 40%).²²

• The ST segment is concave upward, and the J point is well demarcated and may be notched or slurred (Figure 1).
• ST elevation is usually no more than 3 mm.
• ST elevation may be limited to the anterior leads or, in many instances, may extend to the inferior or lateral leads. Early repolarization is very rarely limited to the limb leads, and involvement of some precordial leads is the rule.^18,19 The ST segment is depressed in lead aVR in 50% of patients.^18,19

• 

  The T wave is usually ample and may be more than 10 mm tall in the precordial leads in one-third of patients,¹⁷ but as opposed to the ample T wave of STEMI, it is not broad and remains smaller than the QRS complex. The ample T wave distinguishes early repolarization from pericarditis, and explains the low ST-T ratio in lead V₆. In up to 10% of young black men, the T wave has a terminal inversion in leads V₃ to V₅, and occasionally in V₁ and V₂, mimicking infarction (Figure 5).²⁴
• The QRS complex tends to have prominent precordial voltage, in sharp contrast to STEMI, in which QRS shrinking occurs.^3,17,22

The early repolarization pattern may be intermittent, may vary among serial electrocardiograms, may decrease with a rise in sympathetic tone, as observed during exercise, and may increase with a rise in vagal tone.^18,19,25,26  Although it is usually a benign finding, the early repolarization pattern in leads other than V₁ to V₃ has been associated with an increased risk of sudden death, particularly when the ST elevation is horizontal-descending rather than upsloping and, possibly, when early repolarization involves the inferior leads with a J point that is notched or elevated 2 mm or more.^20,22

PERICARDITIS

Transient PR depression greater than 1 mm is often seen, particularly in leads II, aVF, and V₄ to V₆, and represents atrial subepicardial injury. PR depression in those leads is always associated with PR elevation in lead aVR and sometimes V₁. PR changes often coexist with ST changes but may be isolated and may precede ST changes.³⁰ PR depression is characteristic of pericarditis but may be seen in early repolarization, where it is less marked than in pericarditis (< 0.8 mm) and implies early repolarization of the atrial tissue,³¹ and in MI, where it implies atrial infarction with atrial injury pattern.

Classically, it is said that in pericarditis, unlike in STEMI, the T wave does not invert until the ST elevation subsides. In reality, up to 40% of patients develop a notched or biphasic positive-negative T wave before full return of the ST segment to the baseline.^27,32 And if T-wave inversion antedates pericarditis, concomitant ST elevation and T-wave inversion may be seen once pericarditis develops. However, the T wave inverts less deeply and less completely than in STEMI, and the corrected QT interval remains normal even when the T wave inverts.

Three criteria distinguish pericarditis from early repolarization (but not from STEMI):

• PR depression greater than 1 mm
• ST-segment depression in lead V₁
• A ratio of ST-segment height to T-wave height of at least 25% in lead V₆, V₅, V₄, or I. This feature distinguishes pericarditis from early repolarization with a high sensitivity and specificity. In pericarditis, the T waves have normal or reduced amplitude, and the ST-T ratio is therefore high,³³ whereas in early repolarization the T waves are tall, so the ST-T ratio is less than 25%.

Widespread ST elevation may be seen with both pericarditis and early repolarization. ST elevation limited to the anterior leads is more likely to be early repolarization than pericarditis.

LEFT BUNDLE BRANCH BLOCK

The following findings imply MI:

• 

  ST elevation or depression that is concordant with the QRS complex. Moreover, since ST deviation is mandatory with left bundle branch block, a “normal-looking” ST segment implies ischemia.
• Inverted T waves concordant with the QRS in more than one lead, or biphasic T waves in more than one lead (eg, V₁ to V₃). Across the precordial leads, T waves may transition from positive to negative one lead earlier or later than the QRS and ST transition. Therefore, even in the absence of ischemia, the T wave may be inverted in lead V₃, in which the QRS is deeply negative and the ST is still elevated (negative T-wave concordance in one lead). Also, the T wave may be upright in leads V₅, V₆, and I where QRS is upright and the ST segment is depressed (positive T-wave concordance does not imply ischemia).

• 

  In addition to concordance, a discordant ST segment or T wave that is very large may imply ischemia. For example, a discordant ST segment or T wave that is larger than the QRS height implies ischemia. A discordant ST elevation greater than 5 mm has been suggested by Sgarbossa et al³⁵ as a diagnostic feature of STEMI; however, this feature is seen in 10% of control patients with left bundle branch block and no STEMI, and it is thus poorly specific and also poorly sensitive, frequently missing STEMI.^35–37 Smith et al³⁶ have suggested that a discordant ST elevation of at least 25% of the S-wave depth is a far more sensitive and accurate feature but one that may still be found in up to 10% of control patients.³⁶

LEFT VENTRICULAR HYPERTROPHY

In left ventricular hypertrophy, a deep S wave is seen in leads V₁ to V₃, with ST elevation and T waves that are discordant with the QRS complex. Rarely, ST elevation may be straight or convex. The following findings imply MI:

• ST elevation or depression that is concordant with the QRS.
• Inverted T waves that are concordant with the QRS in more than one lead, or biphasic T waves in more than one lead (eg, V₁ to V₃).
• A discordant ST segment or a T wave that is very large may imply ischemia. In left ventricular hypertrophy, ST elevation is usually less than 2.5 mm in leads V₁ to V₃ and is rarely seen in the inferior leads, where it would be less than 1 mm.³⁴ When ST elevation is seen in leads V₁ to V₃ in left ventricular hypertrophy, an ST magnitude of 25% or more of the total QRS voltage has a 91% specificity for STEMI.³⁴

On another note, right ventricular hypertrophy and right bundle branch block may lead to ST-segment depression and T-wave inversion, but not to ST elevation. Thus, ST elevation occurring with right ventricular hypertrophy or right bundle branch block implies STEMI. While only left bundle branch block poses a diagnostic challenge, both types of bundle branch block, if secondary to STEMI, represent equally high-risk categories.³⁸

PREEXCITATION

HYPERKALEMIA

OTHER CAUSES OF ST-SEGMENT ELEVATION

Takotsubo cardiomyopathy

Takotsubo cardiomyopathy mimics all electrocardiographic features of anteroapical STEMI. ST elevation may extend to the inferior leads but cannot be isolated in the inferior leads.³⁹ As in apical STEMI, reciprocal ST depression is uncommon. Within 24 to 48 hours, ST elevation evolves into deep anterior T-wave inversion and a prolonged QT interval. Transient Q waves may be seen.

Myocarditis

Myocarditis may have one of two electrocardiographic patterns: a pericarditis pattern, or a typical STEMI pattern with Q waves sometimes localized to one area.⁴⁰

Atrial flutter waves

Large pulmonary embolism

A large pulmonary embolism may be associated with T-wave inversion in the anterior leads or the inferior leads, or both, reflective of cor pulmonale. Less commonly, ST elevation in the anterior or inferior leads is seen. In fact, changes of both anterior and inferior ischemia should always suggest a pulmonary embolism.^41,42

Brugada syndrome

Hyperkalemia, Brugada syndrome, and sometimes pulmonary embolism are characterized by an ST elevation that slopes downward (Figures 11 and 13), which contrasts with the upsloping, convex ST elevation of STEMI.

Nevertheless, careful attention to the ST-T and QRS-complex configurations often allows diagnosis of the cause of ST elevation (Figure 1, Table 1). This paper discusses the differential diagnosis of ST elevation.

MEASURED AT THE J POINT OR LATER

ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION

A diagnosis of STEMI that mandates emergency reperfusion requires ST elevation equaling or exceeding the following cut-points, in at least two contiguous leads (using the standardization of 1.0 mV = 10 mm)^4,5:

• 1 mm in all standard leads other than V₂ and V₃
• 2.5 mm in leads V₂ and V₃ in men younger than age 40, 2 mm in leads V₂ and V₃ in men age 40 and older, and 1.5 mm in these leads in women
• 0.5 mm in the posterior chest leads V₇ to V₉; ST elevation is attenuated in the posterior leads because of their greater distance from the heart, explaining the lower cut-point.⁶

While ST elevation that falls below these cut-points may be a normal variant, any ST elevation or depression (≥ 0.5 mm) may be abnormal and may necessitate further evaluation for ischemia, particularly when the clinical setting or the ST morphology suggests ischemia or when other signs of ischemia such as T-wave abnormalities, Q waves, or reciprocal ST-segment changes are also present on the electrocardiogram.

Conversely, ST elevation that exceeds these cut-points may not represent STEMI. In an analysis of patients with chest pain manifesting ST elevation, only 15% were eventually diagnosed with STEMI.⁷ In addition to size, careful attention to the morphology of the ST segment and the associated features is critical (Figure 1).

Other features of STEMI

Four other features characteristic of STEMI may be present (Figures 2 and 3):

• Concomitant T-wave abnormalities (wide, ample, or inverted T waves)
• Q waves
• ST depression in the reciprocal leads. Reciprocal ST depression is seen in all inferior STEMIs and in 70% of anterior STEMIs.^11,12 Diffuse ST elevation mimicking pericarditis may be seen with midvessel occlusion of a left anterior descending artery that wraps around the apex and supplies part of the inferior wall.

• 

  ST or T-wave amplitude may approximate or exceed the QRS amplitude in at least one lead.^3,13,14 This finding is characteristic of STEMI, in which the QRS “shrinks” as the infarcted area becomes electrically neutral, whereas the ST-T segments become ample.^3,13 In fact, early STEMI may be characterized by a small R wave that seems to be “pulled up” by the elevated ST segment. A small or absent R wave along with an ample, convex ST segment that fuses with the T wave and exceeds the height of the remaining R wave is called “tombstoning” (Figure 3). Tombstoning is most commonly seen with anterior infarction and implies more extensive myocardial damage and a worse prognosis than STEMI without tombstoning.¹⁵

Note that ST elevation may not be acute STEMI but an old STEMI with a chronically dysfunctional myocardium (dyskinetic or aneurysmal myocardium). In fact, an old STEMI may manifest as a chronic, persistent ST elevation along with Q waves, and T waves may be inverted or upright, but not ample.¹⁴ A history of an old MI, old electrocardiograms, if available, and quick bedside echocardiography may allow the diagnosis. In the case of an old dyskinetic infarct, echocardiography shows a thin, bright (scarred), and possibly aneurysmal myocardium, whereas in acute STEMI, the myocardium is neither thin nor scarred yet. If the patient does not report a history of MI, if the T wave is ample (> 75% the size of QRS), or if the patient presents with atypical ongoing angina, presume it is acute STEMI.

EARLY REPOLARIZATION

Early repolarization is a normal variant of ST elevation that equals or exceeds 1 mm (measured at the J point). It is highly prevalent in people under age 40 and remains prevalent in middle-aged people.

Two distinct and sometimes coexistent forms of early repolarization have been described: (1) ST elevation in the anterior leads V₁ to V₃,^16–19 and (2) ST elevation in the lateral leads (V₄ to V₆, I, aVL) or inferior leads.^18–22 The prevalence of the first form—ie, ST elevation of 1 mm or more in any of the leads V₁ through V₃—is 60% to 90% in men  age 45 and younger, 20% to 40% in men over age 45, and about 10% in women of any age.¹⁶ Thus, this form of early repolarization is called “normal male pattern.”

Even early repolarization that involves the lateral or inferior leads is common, with a prevalence of about 15% in people ages 30 to 40 and about 5% to 10% in those 40 to 65.^20–23 It is two to four times more prevalent in men and three times more prevalent in African Americans. It is also highly prevalent in athletes younger than 25 (about 30% to 40%).²²

• The ST segment is concave upward, and the J point is well demarcated and may be notched or slurred (Figure 1).
• ST elevation is usually no more than 3 mm.
• ST elevation may be limited to the anterior leads or, in many instances, may extend to the inferior or lateral leads. Early repolarization is very rarely limited to the limb leads, and involvement of some precordial leads is the rule.^18,19 The ST segment is depressed in lead aVR in 50% of patients.^18,19

• 

  The T wave is usually ample and may be more than 10 mm tall in the precordial leads in one-third of patients,¹⁷ but as opposed to the ample T wave of STEMI, it is not broad and remains smaller than the QRS complex. The ample T wave distinguishes early repolarization from pericarditis, and explains the low ST-T ratio in lead V₆. In up to 10% of young black men, the T wave has a terminal inversion in leads V₃ to V₅, and occasionally in V₁ and V₂, mimicking infarction (Figure 5).²⁴
• The QRS complex tends to have prominent precordial voltage, in sharp contrast to STEMI, in which QRS shrinking occurs.^3,17,22

The early repolarization pattern may be intermittent, may vary among serial electrocardiograms, may decrease with a rise in sympathetic tone, as observed during exercise, and may increase with a rise in vagal tone.^18,19,25,26  Although it is usually a benign finding, the early repolarization pattern in leads other than V₁ to V₃ has been associated with an increased risk of sudden death, particularly when the ST elevation is horizontal-descending rather than upsloping and, possibly, when early repolarization involves the inferior leads with a J point that is notched or elevated 2 mm or more.^20,22

PERICARDITIS

Transient PR depression greater than 1 mm is often seen, particularly in leads II, aVF, and V₄ to V₆, and represents atrial subepicardial injury. PR depression in those leads is always associated with PR elevation in lead aVR and sometimes V₁. PR changes often coexist with ST changes but may be isolated and may precede ST changes.³⁰ PR depression is characteristic of pericarditis but may be seen in early repolarization, where it is less marked than in pericarditis (< 0.8 mm) and implies early repolarization of the atrial tissue,³¹ and in MI, where it implies atrial infarction with atrial injury pattern.

Classically, it is said that in pericarditis, unlike in STEMI, the T wave does not invert until the ST elevation subsides. In reality, up to 40% of patients develop a notched or biphasic positive-negative T wave before full return of the ST segment to the baseline.^27,32 And if T-wave inversion antedates pericarditis, concomitant ST elevation and T-wave inversion may be seen once pericarditis develops. However, the T wave inverts less deeply and less completely than in STEMI, and the corrected QT interval remains normal even when the T wave inverts.

Three criteria distinguish pericarditis from early repolarization (but not from STEMI):

• PR depression greater than 1 mm
• ST-segment depression in lead V₁
• A ratio of ST-segment height to T-wave height of at least 25% in lead V₆, V₅, V₄, or I. This feature distinguishes pericarditis from early repolarization with a high sensitivity and specificity. In pericarditis, the T waves have normal or reduced amplitude, and the ST-T ratio is therefore high,³³ whereas in early repolarization the T waves are tall, so the ST-T ratio is less than 25%.

Widespread ST elevation may be seen with both pericarditis and early repolarization. ST elevation limited to the anterior leads is more likely to be early repolarization than pericarditis.

LEFT BUNDLE BRANCH BLOCK

The following findings imply MI:

• 

  ST elevation or depression that is concordant with the QRS complex. Moreover, since ST deviation is mandatory with left bundle branch block, a “normal-looking” ST segment implies ischemia.
• Inverted T waves concordant with the QRS in more than one lead, or biphasic T waves in more than one lead (eg, V₁ to V₃). Across the precordial leads, T waves may transition from positive to negative one lead earlier or later than the QRS and ST transition. Therefore, even in the absence of ischemia, the T wave may be inverted in lead V₃, in which the QRS is deeply negative and the ST is still elevated (negative T-wave concordance in one lead). Also, the T wave may be upright in leads V₅, V₆, and I where QRS is upright and the ST segment is depressed (positive T-wave concordance does not imply ischemia).

• 

  In addition to concordance, a discordant ST segment or T wave that is very large may imply ischemia. For example, a discordant ST segment or T wave that is larger than the QRS height implies ischemia. A discordant ST elevation greater than 5 mm has been suggested by Sgarbossa et al³⁵ as a diagnostic feature of STEMI; however, this feature is seen in 10% of control patients with left bundle branch block and no STEMI, and it is thus poorly specific and also poorly sensitive, frequently missing STEMI.^35–37 Smith et al³⁶ have suggested that a discordant ST elevation of at least 25% of the S-wave depth is a far more sensitive and accurate feature but one that may still be found in up to 10% of control patients.³⁶

LEFT VENTRICULAR HYPERTROPHY

In left ventricular hypertrophy, a deep S wave is seen in leads V₁ to V₃, with ST elevation and T waves that are discordant with the QRS complex. Rarely, ST elevation may be straight or convex. The following findings imply MI:

• ST elevation or depression that is concordant with the QRS.
• Inverted T waves that are concordant with the QRS in more than one lead, or biphasic T waves in more than one lead (eg, V₁ to V₃).
• A discordant ST segment or a T wave that is very large may imply ischemia. In left ventricular hypertrophy, ST elevation is usually less than 2.5 mm in leads V₁ to V₃ and is rarely seen in the inferior leads, where it would be less than 1 mm.³⁴ When ST elevation is seen in leads V₁ to V₃ in left ventricular hypertrophy, an ST magnitude of 25% or more of the total QRS voltage has a 91% specificity for STEMI.³⁴

On another note, right ventricular hypertrophy and right bundle branch block may lead to ST-segment depression and T-wave inversion, but not to ST elevation. Thus, ST elevation occurring with right ventricular hypertrophy or right bundle branch block implies STEMI. While only left bundle branch block poses a diagnostic challenge, both types of bundle branch block, if secondary to STEMI, represent equally high-risk categories.³⁸

PREEXCITATION

HYPERKALEMIA

OTHER CAUSES OF ST-SEGMENT ELEVATION

Takotsubo cardiomyopathy

Takotsubo cardiomyopathy mimics all electrocardiographic features of anteroapical STEMI. ST elevation may extend to the inferior leads but cannot be isolated in the inferior leads.³⁹ As in apical STEMI, reciprocal ST depression is uncommon. Within 24 to 48 hours, ST elevation evolves into deep anterior T-wave inversion and a prolonged QT interval. Transient Q waves may be seen.

Myocarditis

Myocarditis may have one of two electrocardiographic patterns: a pericarditis pattern, or a typical STEMI pattern with Q waves sometimes localized to one area.⁴⁰

Atrial flutter waves

Large pulmonary embolism

A large pulmonary embolism may be associated with T-wave inversion in the anterior leads or the inferior leads, or both, reflective of cor pulmonale. Less commonly, ST elevation in the anterior or inferior leads is seen. In fact, changes of both anterior and inferior ischemia should always suggest a pulmonary embolism.^41,42

Brugada syndrome

Hyperkalemia, Brugada syndrome, and sometimes pulmonary embolism are characterized by an ST elevation that slopes downward (Figures 11 and 13), which contrasts with the upsloping, convex ST elevation of STEMI.

A 40-year-old man with end-stage renal disease on intermittent hemodialysis presented to the emergency department with a 1-week history of pain affecting his left lower back, left flank, and left lower abdomen, diagnosed as zoster prodrome.

Of note, both corneas were cloudy, most severely in the limbus (Figure 1). His visual acuity and findings on funduscopic examination were normal.

CORNEAL OPACITY

The finding of corneal opacity should prompt an immediate ophthalmologic evaluation by the internist as well as an ophthalmologist. The initial examination should include visual acuity testing; gross examination with the naked eye; penlight examination of the pupil, conjunctiva, and anterior chamber; funduscopic examination to at least confirm a red reflex; and fluorescein examination of the cornea. Fluorescein testing is done last, as the dye may interfere with the other initial tests.¹

A number of causes of opacity

A number of conditions can cause corneal opacity. Several genetic conditions can cause developmental anomalies of the cornea, leading to corneal defects present at birth.² Causes of secondary corneal opacity in early infancy include infections such as herpes, iatrogenic injury during amniocentesis or forceps delivery, and infantile congenital glaucoma.²

Later in life, causes of corneal opacity include cataract, glaucoma, chemical exposure, foreign body injury, irradiation, infection (eg, syphilis, herpes, chlamydia), endophthalmitis, and metabolic genetic disorders such as Fabry disease, trisomy 18 syndrome, and lecithin-cholesterol acyltransferase (LCAT) deficiency.³

LCAT DEFICIENCY

LCAT is a key protein in reverse transport of cholesterol from the systemic circulation to the liver for excretion into the bile. Its deficiency results in low serum concentrations of high-density lipoprotein cholesterol (HDL-C).⁴ About 80 different mutations in the LCAT gene have been linked to LCAT deficiency.⁵

LCAT deficiency varies in severity. Patients with complete deficiency can have nearly undetectable levels of HDL-C, eruptive xanthoma, hepatosplenomegaly, and premature coronary artery disease (ie, by age 40).5,6 Features of coronary atherosclerosis can be lacking in patients with partial deficiency.

Regardless of the degree of LCAT deficiency, most patients have corneal opacification that is most severe near the limbus (thus, the term “fish eye syndrome”) and anemia.⁷ Although corneal opacification presents early in life and persists, it does not seem to affect vision.⁵ The anemia is associated with enhanced fractional clearance of red blood cells secondary to hypersplenism.⁸

LCAT deficiency and the kidneys

LCAT deficiency has its most devastating effect on the kidney. Renal disease begins early in life with mild proteinuria and microscopic hematuria. With increasing age, renal function deteriorates and proteinuria and hematuria worsen.⁹

Renal biopsy study may reveal foam cells in the glomerular tufts, arterioles with thickened intima and narrowed lumens, and subendothelial deposits of lipids in the renal arteries and arterioles.¹⁰ Some studies have suggested that kidney disease is most likely initiated by lipid deposition or cellular uptake of lipoproteins in the glomerular basement membrane, mesangium, and capillary subendothelium.

Treatment

There are few treatment options for patients with LCAT deficiency. Control of hypertension, if present, may halt or slow renal deterioration.⁵ Many patients eventually require dialysis, and some undergo renal transplantation, but the renal disease can recur.

OUR PATIENT

Our patient had a known diagnosis of LCAT deficiency. Five years before this presentation at our emergency department, he developed malignant hypertension, followed shortly by renal disease. Over the next 4 years, his kidney function deteriorated, culminating in the need for dialysis; his corneal opacities manifested and gradually worsened; and after extensive studies including kidney biopsies, he was finally diagnosed with LCAT deficiency.

He also exhibited a chronically low level of HDL-C (2 to 5 mg/dL) and significant coronary artery disease. Although unrelated, his zoster pain was treated with renally dosed acyclovir and gabapentin. He never demonstrated the characteristic rash, and his pain improved significantly within 5 days of treatment.

A 40-year-old man with end-stage renal disease on intermittent hemodialysis presented to the emergency department with a 1-week history of pain affecting his left lower back, left flank, and left lower abdomen, diagnosed as zoster prodrome.

Of note, both corneas were cloudy, most severely in the limbus (Figure 1). His visual acuity and findings on funduscopic examination were normal.

CORNEAL OPACITY

The finding of corneal opacity should prompt an immediate ophthalmologic evaluation by the internist as well as an ophthalmologist. The initial examination should include visual acuity testing; gross examination with the naked eye; penlight examination of the pupil, conjunctiva, and anterior chamber; funduscopic examination to at least confirm a red reflex; and fluorescein examination of the cornea. Fluorescein testing is done last, as the dye may interfere with the other initial tests.¹

A number of causes of opacity

A number of conditions can cause corneal opacity. Several genetic conditions can cause developmental anomalies of the cornea, leading to corneal defects present at birth.² Causes of secondary corneal opacity in early infancy include infections such as herpes, iatrogenic injury during amniocentesis or forceps delivery, and infantile congenital glaucoma.²

Later in life, causes of corneal opacity include cataract, glaucoma, chemical exposure, foreign body injury, irradiation, infection (eg, syphilis, herpes, chlamydia), endophthalmitis, and metabolic genetic disorders such as Fabry disease, trisomy 18 syndrome, and lecithin-cholesterol acyltransferase (LCAT) deficiency.³

LCAT DEFICIENCY

LCAT is a key protein in reverse transport of cholesterol from the systemic circulation to the liver for excretion into the bile. Its deficiency results in low serum concentrations of high-density lipoprotein cholesterol (HDL-C).⁴ About 80 different mutations in the LCAT gene have been linked to LCAT deficiency.⁵

LCAT deficiency varies in severity. Patients with complete deficiency can have nearly undetectable levels of HDL-C, eruptive xanthoma, hepatosplenomegaly, and premature coronary artery disease (ie, by age 40).5,6 Features of coronary atherosclerosis can be lacking in patients with partial deficiency.

Regardless of the degree of LCAT deficiency, most patients have corneal opacification that is most severe near the limbus (thus, the term “fish eye syndrome”) and anemia.⁷ Although corneal opacification presents early in life and persists, it does not seem to affect vision.⁵ The anemia is associated with enhanced fractional clearance of red blood cells secondary to hypersplenism.⁸

LCAT deficiency and the kidneys

LCAT deficiency has its most devastating effect on the kidney. Renal disease begins early in life with mild proteinuria and microscopic hematuria. With increasing age, renal function deteriorates and proteinuria and hematuria worsen.⁹

Renal biopsy study may reveal foam cells in the glomerular tufts, arterioles with thickened intima and narrowed lumens, and subendothelial deposits of lipids in the renal arteries and arterioles.¹⁰ Some studies have suggested that kidney disease is most likely initiated by lipid deposition or cellular uptake of lipoproteins in the glomerular basement membrane, mesangium, and capillary subendothelium.

Treatment

There are few treatment options for patients with LCAT deficiency. Control of hypertension, if present, may halt or slow renal deterioration.⁵ Many patients eventually require dialysis, and some undergo renal transplantation, but the renal disease can recur.

OUR PATIENT

Our patient had a known diagnosis of LCAT deficiency. Five years before this presentation at our emergency department, he developed malignant hypertension, followed shortly by renal disease. Over the next 4 years, his kidney function deteriorated, culminating in the need for dialysis; his corneal opacities manifested and gradually worsened; and after extensive studies including kidney biopsies, he was finally diagnosed with LCAT deficiency.

He also exhibited a chronically low level of HDL-C (2 to 5 mg/dL) and significant coronary artery disease. Although unrelated, his zoster pain was treated with renally dosed acyclovir and gabapentin. He never demonstrated the characteristic rash, and his pain improved significantly within 5 days of treatment.

A 40-year-old man with end-stage renal disease on intermittent hemodialysis presented to the emergency department with a 1-week history of pain affecting his left lower back, left flank, and left lower abdomen, diagnosed as zoster prodrome.

Of note, both corneas were cloudy, most severely in the limbus (Figure 1). His visual acuity and findings on funduscopic examination were normal.

CORNEAL OPACITY

The finding of corneal opacity should prompt an immediate ophthalmologic evaluation by the internist as well as an ophthalmologist. The initial examination should include visual acuity testing; gross examination with the naked eye; penlight examination of the pupil, conjunctiva, and anterior chamber; funduscopic examination to at least confirm a red reflex; and fluorescein examination of the cornea. Fluorescein testing is done last, as the dye may interfere with the other initial tests.¹

A number of causes of opacity

A number of conditions can cause corneal opacity. Several genetic conditions can cause developmental anomalies of the cornea, leading to corneal defects present at birth.² Causes of secondary corneal opacity in early infancy include infections such as herpes, iatrogenic injury during amniocentesis or forceps delivery, and infantile congenital glaucoma.²

Later in life, causes of corneal opacity include cataract, glaucoma, chemical exposure, foreign body injury, irradiation, infection (eg, syphilis, herpes, chlamydia), endophthalmitis, and metabolic genetic disorders such as Fabry disease, trisomy 18 syndrome, and lecithin-cholesterol acyltransferase (LCAT) deficiency.³

LCAT DEFICIENCY

LCAT is a key protein in reverse transport of cholesterol from the systemic circulation to the liver for excretion into the bile. Its deficiency results in low serum concentrations of high-density lipoprotein cholesterol (HDL-C).⁴ About 80 different mutations in the LCAT gene have been linked to LCAT deficiency.⁵

LCAT deficiency varies in severity. Patients with complete deficiency can have nearly undetectable levels of HDL-C, eruptive xanthoma, hepatosplenomegaly, and premature coronary artery disease (ie, by age 40).5,6 Features of coronary atherosclerosis can be lacking in patients with partial deficiency.

Regardless of the degree of LCAT deficiency, most patients have corneal opacification that is most severe near the limbus (thus, the term “fish eye syndrome”) and anemia.⁷ Although corneal opacification presents early in life and persists, it does not seem to affect vision.⁵ The anemia is associated with enhanced fractional clearance of red blood cells secondary to hypersplenism.⁸

LCAT deficiency and the kidneys

LCAT deficiency has its most devastating effect on the kidney. Renal disease begins early in life with mild proteinuria and microscopic hematuria. With increasing age, renal function deteriorates and proteinuria and hematuria worsen.⁹

Renal biopsy study may reveal foam cells in the glomerular tufts, arterioles with thickened intima and narrowed lumens, and subendothelial deposits of lipids in the renal arteries and arterioles.¹⁰ Some studies have suggested that kidney disease is most likely initiated by lipid deposition or cellular uptake of lipoproteins in the glomerular basement membrane, mesangium, and capillary subendothelium.

Treatment

There are few treatment options for patients with LCAT deficiency. Control of hypertension, if present, may halt or slow renal deterioration.⁵ Many patients eventually require dialysis, and some undergo renal transplantation, but the renal disease can recur.

OUR PATIENT

Our patient had a known diagnosis of LCAT deficiency. Five years before this presentation at our emergency department, he developed malignant hypertension, followed shortly by renal disease. Over the next 4 years, his kidney function deteriorated, culminating in the need for dialysis; his corneal opacities manifested and gradually worsened; and after extensive studies including kidney biopsies, he was finally diagnosed with LCAT deficiency.

He also exhibited a chronically low level of HDL-C (2 to 5 mg/dL) and significant coronary artery disease. Although unrelated, his zoster pain was treated with renally dosed acyclovir and gabapentin. He never demonstrated the characteristic rash, and his pain improved significantly within 5 days of treatment.

From the Department of Medicine, University of Pennsylvania, and the Department of Emergency Medicine, Thomas Jefferson University Hospital, Philadelphia, PA.

Abstract

• Objective: To detail strategies to improve sepsis recognition and the quality of care provided to the septic patient.
• Methods: Review of the literature.
• Results: Severe sepsis affects nearly 3 million individuals each year in the United States, and cost estimates for these hospitalizations exceed $24 billion. Effective management is predicated on timely recognition. In this review, we detail strategies to improve early identification of potentially septic patients as well as the quality of care provided to the septic patient in the emergency department (ED). The strategies discussed are based upon an understanding of the signs and symptoms of sepsis and the clinical risk factors associated with sepsis, which can be used to design novel strategies to screen patients for sepsis and risk stratify patients at risk for clinical deterioration.
• Conclusion: ED structures and processes can be used to increase adherence with sepsis management guidelines to improve patient outcomes.

Severe sepsis affects nearly 3 million individuals each year in the United States and cost estimates for these hospitalizations exceed $24 billion [1–3]. Sepsis is a life-threatening condition characterized by a suspected or identified infection accompanied by a vigorous host inflammatory response. In severe sepsis, end-organ dysfunction manifests in myriad forms, including altered mental status, acute kidney injury, liver dysfunction, pulmonary dysfunction, and hemodynamic compromise [4,5]. This protean presentation of a deadly condition makes identification and risk stratification both challenging and essential to improving patient outcomes. The majority of patients with severe sepsis will receive their initial care within an emergency department (ED) [6,7]. It is essential that emergency medicine providers have the means to appropriately identify patients presenting with severe sepsis in a timely manner—thus facilitating life-saving measures such as early intravenous fluid resuscitation and administration of timely and appropriate antimicrobials.

In this review, we detail strategies to improve sepsis recognition and the quality of care provided to the septic patient in the ED. The strategies discussed are based upon an understanding of the signs and symptoms of sepsis and the clinical risk factors associated with sepsis, which can be used to design novel strategies to screen patients for sepsis and risk stratify patients for clinical deterioration. Then, we review suggested ED structures and processes to increase adherence with sepsis-based guidelines to improve patient outcomes. Successful implementation is predicated on hospital administrative support towards the efforts given the time and resources required and strong and committed leadership across the health care system.

Epidemiology of Severe Sepsis

Estimates of annual cases of severe sepsis vary, ranging from 1 million to 3 million cases in the United States [1–3]. In-hospital mortality for this condition ranges from 14% to 30% [5]. The incidence of severe sepsis in the United States has been increasing at a rate of 13% annually, with an estimated cost of greater than $24 billion per year [1,2]. In 2 large cohorts of hospitalized patients, it was found that sepsis contributed to 1 in every 2 to 3 deaths following inpatient admission [8]. Coincident with these increased estimates, advances in the early identification and treatment of sepsis have led to decreasing mortality rates over the past decade [1,9].

Of importance to the ED clinician, an episode of sepsis has long-term effects on cognitive and physical function, quality-of-life, and survival [10,11]. Post-discharge, approximately one-quarter of sepsis survivors will be readmitted within 30 days [12–14]. In as many as half of these instances, another life-threatening infection is the cause for readmission, making the past medical history, including a detailed accounting of recent episodes of sepsis, an important part of the initial ED evaluation [12]. Furthermore, severe sepsis survivors spend a large proportion of their time following discharge within a health care facility, and will frequently present to the ED with an acute condition from such an environment. Important factors for predicting readmission after a sepsis hospitalization include patient age, severity of illness, hospital length of stay, and the need for intensive care during the initial hospitalization [12–14].

Principles of Effective Sepsis Management

The principles of effective sepsis management begin with early identification in the pre-hospital setting, at triage, or when a patient begins to decompensate in the hospital. After the point of initial recognition, core principles include risk stratification, timely and appropriate antimicrobial administration, initial intravenous fluid boluses and ongoing resuscitation guided by physical examination and objective resuscitation end-points [4,5]. These practices have been operationalized in the care bundles of the Surviving Sepsis Campaign Guidelines [4]. Within 3 hours, the resuscitation bundle includes measuring serum lactate to risk stratify patients, obtaining blood cultures, administering broad-spectrum antibiotics, and administering 30 mL/kg crystalloid in patients with hypotension or hyperlactatemia [4]. The 6-hour bundle expands upon these initial measures and includes additional management recommendations based on resuscitation end-points.

As effective management is predicated on timely recognition, an understanding of the impact of delayed recognition is essential to provide optimal care for the severe sepsis patient in the ED. Decades of research has revealed that certain markers predict adverse outcomes, including transition to septic shock and death, as do delayed processes of care. Importantly, while early quantitative resuscitation was demonstrated to improve outcomes in a meta-analysis, there was no demonstrable benefit when resuscitation was initiated late (> 24 hours) in the course in the ICU (odds ratio of death, 1.16 [95% confidence interval, 0.60–2.22]) [15].

Strategies To Improve Recognition

Pre-Hospital Environment

From EMS to ED Triage

Borrowing the principle “time equals tissue” from a variety of time sensitive conditions (eg, myocardial infarction management [“time equals muscle”] and stroke care [“time equals brain”]), clinicians and researchers have realized that expedited recognition of severe sepsis patients begins at the time of initial contact with the health care system. For severe sepsis patients, clinicians need to think “time equals organ function.” Given the frequency with which sepsis patients arrive to the ED via EMS, effective communication between EMS and ED providers could be leveraged to prepare the ED team to provide timely care for the sepsis patient via a “sepsis alert.” While confirmation of its applicability to sepsis care is required in the absence of a regionalized network of sepsis centers, the rationale is based on the experience of the effectiveness of trauma and stroke alert systems [20–22]. For patients not recognized as potentially being infected by EMS providers during transport, repeat vital signs during ED triage can be screened to identify patients exhibiting signs of the systemic inflammatory response syndrome (SIRS) [4,23]. The same principles of effective communication apply for patients being sent from medical clinics to the ED for evaluation and treatment of potential severe sepsis. For patients arriving independent of EMS, focused triage and initial vital signs are the starting point for identifying severe sepsis at the most proximal phase of entry into the health care system.

Vital Signs and SIRS Criteria in the ED

The Afferent Arm: Multimodal Screening Strategies

While institutional practice improvement initiatives to facilitate sepsis recognition and care should incorporate educational strategies, led by champions with expertise in sepsis, the complex presentation of sepsis requires multimodal approaches [29]. These multimodal approaches, beginning at the time of ED triage, should be designed to harness information technology to screen patients to improve severe sepsis recognition (the afferent arm) and to utilize structures and processes of care efficiently and effectively (the efferent arm) to guide severe sepsis management according to sepsis-care bundles espoused by guidelines (Figure) [4].

Operational processes to screen for sepsis in the ED will need to account for ED organizational flow (eg, average time from registration to triage, average time from triage to being seen by a physician, average length of stay in the ED, number of hospital beds) and hand-off practices (eg, care transition from ED team to floor or ICU team, or within ED at shift change). For ED organizations with shorter ED lengths of stay (eg, < 2 hours), screening practices at ED triage will serve as the focal point to identify cases of sepsis. Boarding, defined as caring for a patient in the ED pending transfer, is common, increasing as a result of ED closures [30,31], and associated with prolonged hospital length of stay and increased in-hospital mortality when ICU transfer is delayed [32]. Sepsis patients in particular appear to be a vulnerable group of patients. While many explanations exist to account for the relationship between delayed transfer and adverse outcomes, timely recognition and management of the septic patient could be compromised with prolonged boarding. To combat this potential effect, continual assessment during the entire ED stay may unmask an initially unclear presentation of sepsis.

One strategy to identify sepsis in ED organizations with prolonged ED lengths of stay is through the use of a track-and-trigger system, or early warning system. Traditionally, track-and-trigger systems were implemented on the hospital wards, as means to identify physiological deterioration in a timely manner to prevent clinical deterioration [33]. More recently, early warning systems have been used to identify patients with sepsis on the hospital wards and within EDs, as these systems rely on physiological parameters such as SIRS that are cardinal features of sepsis [34]. However, given the potential for alert fatigue, designing a system that operates with high accuracy is imperative.

Efforts are underway to redefine sepsis, using a simplified approach and readily available physiological variables, with the main goal of targeting those most at-risk of an adverse outcome during the hospitalization. Simultaneously, an understanding of the overt and more occult manifestations are essential to incorporate into the clinical decision-making and pattern recognition required to identify sepsis in a timely and accurate manner. In Table 2, the signs and symptoms that may serve as flags for severe sepsis are presented.

Mature early warning systems, designed to leverage the electronic medical record (EMR) by capturing vital signs, laboratory measures, (eg, elevated serum creatinine compared to a recent hospitalization) and symptoms (eg, altered mental status), are well-positioned to herald clinical deterioration (eg, cardiac arrest) with improved accuracy [35] and to be applied to sepsis specifically [34]. While sophisticated analytical strategies, such as machine learning, are being used to improve the test characteristics of these early warning systems, iterative, prospective chart review is an essential and complementary performance improvement step to refine the process. Further, chart review affords the opportunity to ensure compliance with sepsis care bundles.

Knowledge of the risk factors associated with development of sepsis is critical for the front-line emergency physician and nurse. Additionally, as many of these risk factors are associated with adverse outcomes, including unplanned ICU transfer and in-hospital mortality, which occur in as many as one out of 8 patients admitted directly to the ward, they have utility for early risk-stratification and triaging purposes in the ED. Advanced age and pre-existing comorbid conditions, particularly an oncologic diagnosis and/or chronic organ dysfunction, are major risk factors for sepsis and worse outcomes result in those who develop sepsis [2]. Further, illness severity, including an elevated serum lactate level, is associated with adverse outcomes. These factors can be incorporated into triage decisions and/or close monitoring for patients admitted to the general ward [36]. Conversely, because patients admitted to the ICU setting and subsequently stepped down through their hospitalization may experience better outcomes compared to patients admitted to the general ward who then require step-up to an ICU setting (37,38), attention to triage practices is critical.

These complementary strategies, which serve as the afferent arm of the system, summon health care providers to the bedside of a vulnerable patient. However, clinical effectiveness in the management of severe sepsis requires a robust, sophisticated, and mature efferent arm capable of delivering expert care to the now recognized septic patient.

Principles of Effective Management Post-Recognition

Risk Stratification

An elevated serum lactate level was initially described in pathological states in the mid 19th century by Johann Joseph Scherer [39] and has long been associated with increased mortality in hospitalized patients [40]. Lactate is a useful biomarker for risk stratification in a variety of patients arriving to the ED, particularly those who have been identified at high risk for sepsis. Jansen and colleagues examined the measurement of pre-hospital serum lactate at the time of paramedic on-scene assessment in a group of acutely ill patients [41]. Patients with point-of-care lactate levels of 3.5 mmol/L or greater were found to have an in-hospital mortality of 41% versus 12% for those with lactate levels less than 3.5 mmol/L. Within the population with an elevated lactate, patients with a systolic blood pressure greater than 100 mgHg experienced a mortality of nearly 30%, while it was greater than 50% in hypotensive patients with an elevated lactate, highlighting the value of both hemodynamic and serum lactate measures. Upon arrival to the ED, lactate measurements have a strong correlation with mortality. In one retrospective cohort, lactate level was linearly associated with mortality in a broad array of patients older than age 65 years [42]. An initial serum lactate level in the ED in the intermediate (2.0 – 3.9 mmol/L) or high range (≥ 4 mmol/L) has been associated with increased odds of death 2 to 5 times higher independent of organ dysfunction in severe sepsis specifically [43].

As the association between serum lactate levels and death is independent of organ dysfunction, serum lactate is a simple and reliable tool to both enhance detection and risk-stratify patients presenting to the ED with severe sepsis. Given the frequency with which hyperlactatemia is present in patients with suspected infection [43], operationalizing serum lactate measures with the initial phlebotomy draw is an important step to risk-stratify patients. This step can be coupled later with intravenous fluid resuscitation for those with marked elevations (≥ 4 mmol/L), in accord with guideline recommendations [4]. Screening of initial lactate values can be further expedited by utilizing fingerstick point-of-care lactate devices [44]. Last, while serial lactate measures can be incorporated into triage decisions, there is no clear threshold that warrants ICU admission. Rather, persistent elevations in serum lactate can be used to identify patients who require close observation regardless of their admission location.

Several scoring systems have been developed to augment sepsis risk stratification within the ED. The most prominent of these are the Predisposition Insult Response and Organ failure (PIRO), Sequential Organ Failure Assessment (SOFA), and Mortality in the Emergency Department Sepsis (MEDS) scores, and the National early warning score (NEWS) [45-48]. The MEDS score incorporates host factors including age and co-morbid illness, as well as physiologic and laboratory tests which can be obtained rapidly in an ED setting. Multiple prospective and retrospective examinations of the MEDS scoring systems have demonstrated that it performs optimally in ED patients with sepsis but not those with severe sepsis, in terms of predicting 30-day mortality [46,47]. The PIRO score more extensively incorporates predisposing co-morbidities, physiologic and laboratory parameters, and has been modified to consider presumed source of infection, leading to a stronger predictive ability for mortality in more severely ill patients. In patients presenting to the ED with severe sepsis and septic shock, a prospective observational study found the PIRO to be the best predictor of mortality, compared to SOFA and MEDS scores [45]. In a recent study by Corfield et al, sepsis patients with a higher NEWS, according to initial ED vital signs (temperature, pulse, respiratory rate, systolic blood pressure, oxyhemoglobin saturation) and consciousness level, were significantly more likely to be admitted to an ICU within 48 hours or to experience in-hospital mortality [48].

Timely and Appropriate Antibiotics

In a landmark study published by Kumar and colleagues in 2006, the relationship between timing of antibiotics and mortality was established [49]. In 2731 adult septic shock patients, mortality increased 7.6% for every hour delay in effective antimicrobial administration. A striking finding, given that the study population was limited to patients cared for in the ICU, was the fact that only 50% of patients received appropriate antibiotics within 6 hours of onset of shock and nearly one-quarter of patients did not receive antibiotics until the 15th hour. As a direct result, in-hospital mortality was observed to be 58% in this study.

Over the ensuing decade, a series of studies have demonstrated a narrowing of the quality gap in this regard, and the result has coincided with a significant improvement in survival. In 2010, Gaieski and colleagues demonstrated a significant improvement in the prompt administration of antibiotic delivery in patients presenting to an ED with severe sepsis, with the median time from shock onset (sustained hypotension or lactate ≥ 4 mmol/L) to antibiotics down to 42 minutes [50]. Importantly, consistent with the Kumar study, time to appropriate antibiotics, rather than simply initial antibiotics, remained associated with in-hospital mortality independent of initiating early goal-directed therapy. In 2011, Puskarich and colleagues revealed that time to antibiotics continued to improve and, as a result, the investigators did not identify a relationship between time from triage to antibiotics and in-hospital mortality [51]. However, when antibiotics were delayed until after shock recognition, consistent with the study by Kumar and colleagues, survival decreased. Until recently, this important observation was challenging to operationalize clinically as little was known about how to facilitate risk-stratification of those at risk to develop shock. However, Capp and colleagues recently found that deterioration to septic shock 48 hours after ED presentation occurs in approximately one out of eight patients and identified gender (female), transient hypotension, and/or hyperlactatemia upon presentation as risk factors associated with such a deterioration [52].

As an essential element of sepsis care bundles, a focus on timely use of antibiotics in patients with suspected infection, has the potential to increase the use of antibiotics in the ED in patients determined subsequently to not be infected. To combat this acknowledged downstream effect, reconsideration of the utility of empiric antibiotics 48 to 72 hours after admission is required. This step can be accomplished through the use of a sepsis care pathway and/or a formal antibiotic stewardship program.

Quantitative Resuscitation

Rivers and colleagues, in a landmark 2001 trial, examined the effectiveness of a protocolized resuscitation strategy in the most proximal phase of severe sepsis and septic shock [53]. A distinguishing characteristic between the usual care arm and the intervention in this ED-based study, in addition to whether mixed central venous oxygen saturation was measured as a resuscitation end-point, was the inclusion of an ED provider at the bedside to attend to clinical management. The intervention, aimed at achieving physiologic targets, resulted in significantly more fluid resuscitation (3.5 L vs. 5.0 L within the first 6 hours) and a significant decrease in in-hospital mortality compared to the usual care arm (46.5 vs. 30.5%). The study revolutionized the culture and practice of sepsis care, in part by shining a light on the importance of timely resuscitation at the most proximal point of contact between the patient and the healthcare system. It also highlighted the importance of integrating serum lactate measurement into the early screening and risk stratification processes for sepsis care delivery.

The 2014 randomized trial of Protocol-Based Care for Early Septic Shock (ProCESS) revisited this concept, comparing the Rivers 2001 protocol to both a current guideline-based non-invasive algorithmic protocol and what had become usual ED care in the interim [54]. The ProCESS trial, which operationalized a team of bedside providers to direct care for each of the 3 distinct arms, found no significant difference between the arms in terms of 90-day and 1-year mortality, but mortality was approximately 10% less in all arms compared with the intervention arm of the Rivers trial. Further, subjects in each of the 3 arms received in excess of 2 L intravenous fluid resuscitation pre-randomization and 4.4–5.5 L when resuscitation spanned from pre-randomization to 6 hours post-randomization. The conclusion drawn is that the commonalities between the arms—early fluid resuscitation, early antibiotics, and the option to use physiologic measures as markers of the adequacy of treatment, all guided by bedside ED providers—are the most important factors for surviving sepsis. And the result is that practitioners have refined these tools over a decade, leading to steady improvements in survival.

Consistent with the ProCESS trial, a recent Australia and New Zealand trial confirmed no significant difference in 90-day mortality between protocolized EGDT and current usual care for septic shock within an ED [55]. Consistent with ProCESS and ProMISe [56], subjects enrolled in ARISE received in excess of 2.5 L in resuscitation pre-randomization, which when paired with fluid resuscitation in the 0-6 hour post-randomization period (1.96 L in the EGDT arm and 1.71 in the usual-care arm) resulted in resuscitation in the 4.5 to 5L range during the initial resuscitation. The ARISE trial was unique in that appropriate antibiotic administration was a requirement prior to randomization, ensuring that this important driver of mortality reduction was standardized between the two arms of the trial. In summary, while the ideal fluid resuscitation amount is unknown, requires a personalized approach, and further investigation is required to effectively incorporate non-invasive measures to guide fluid responsiveness, early and aggressive resuscitation paired with early antibiotic administration are essential aspects of effective sepsis management.

The Efferent Arm: Structure And Processes To Improve Outcomes

Personnel and Staffing

Quality care for the septic patient requires immediate availability of a multidisciplinary care team, including physicians and nurses with critical care experience who can be rapidly deployed to the bedside. The location of care provision may include on-going care in the initial ED room assignment or transfer to a dedicated area for the care of the critically ill patient within the ED.

To provide optimal care in the era of overcrowding and delayed transfer to an ICU, a movement towards ED intensive care units (ED-ICUs) has emerged [57]. The models of practice range from a model based upon ED intensivists, with expertise in critical care medicine, providing care within the traditional structure of an ED, to a model wherein a portion of the ED is assigned for the care of the critically ill for extended periods of time beyond the initial resuscitation. As these models mature from resuscitation bays capable of scaling up based on need to dedicated ED-ICUs, investments in shared Unit leadership (physician and nursing), staffing (physician, critical care nursing, respiratory therapy, critical care pharmacist) and processes of care (eg, multidisciplinary rounds) in line with established ICUs will be necessary.

While attractive conceptually, large-scale implementation of this movement is unlikely to occur outside of tertiary care academic medical centers. In the many EDs across the US without ED intensivists, and confronted with limited clinician resources, flexible physician and nursing staffing models will be necessary to ensure that care provisions are in accord with established guidelines. Potential solutions to provide the resources to meet the needs of these high-intensity patients include critical care consultation and a strategy traditionally applied to the ICU, telemedicine [58]. Last, given the relationship between hospital volume and mortality in severe sepsis [59,60], timely transfer to a high-volume center for specific cases may be appropriate, although the optimal timing, case selection, and impact of transfer on outcomes warrant further examination.

Clinical Decision Support Strategies

To complement the identification and risk-stratification available by screening and scoring systems, clinical decision support systems are novel tools to improve outcomes in the era of electronic medical records (EMR). Specific to sepsis care delivery, performance improvement initiatives including audit-and-feedback practice can increase severe sepsis guideline adherence, and even modest improvements in adherence appear to lead to sustained improvements that contributed to a 25% relative risk reduction in the observed mortality rate [61,62]. Clinical decision support tools can be used to link early recognition to optimal care processes, such as the Surviving Sepsis Campaign resuscitation and management bundles. The use of prompts as strategies to ensure that bundles of care are ordered and carried out is an important aspect to operationalize during the design phase [63].

Significant preparation is required to effectively carry out the clinical decision support design strategy. For example, to ensure timely antibiotic dispensing, a number of process steps will be required, including prompt notification to a central pharmacist or preferably, an ED pharmacist with access to a local pharmacy pre-stocked with commonly used antibiotics [64]. In addition, the use of an institution-specific antibiogram within the physician computer-order entry sepsis order set, that includes site-specific recommendations (eg, pulmonary, gastrointestinal source) and susceptibility patterns, is an essential aspect of optimal sepsis processes of care. Last, the antibiogram will need to be frequently updated to include season-specific (eg, oseltamivir administration for high-risk cases during influenza season) recommendations to ensure that providers are prompted with the most up-to-date clinical information.

Audit and Feedback and Continuous Performance Improvement

The multimodal approach required to translate knowledge (eg, guidelines) into sepsis care implemented at the bedside is an iterative process. An ED armed with a robust track-and-trigger system and an effective efferent arm, including sophisticated clinical decision support strategies, will require frequent auditing in the plan-do-study-act model of quality improvement to yield clinical effectiveness [61,62,65]. Auditing, paired with feedback to frontline providers, is essential to refine and improve the complex process required to provide expert care to the septic patient [29,65]. Sustained success in optimizing sepsis care delivery is the goal, yet significant work is required to determine the best strategies to achieve this endpoint.

Conclusion

Severe sepsis affects millions of individuals each year in the United States. Delays in recognition result in increased morbidity and mortality, at a tremendous cost to the patient and society. By designing strategies to identify sepsis in a timely, efficient, and effective manner, and by implementing ED structures and processes to increase adherence with sepsis-based guidelines, improved patient-centered outcomes can be realized.

Corresponding author: Mark E. Mikkelsen, MD, MSCE, Gates 05.042, 3400 Spruce St., Philadelphia, PA 19104, [email protected].

Financial disclosures: None.

Author contributions: conception and design, JHM, MEM; analysis and interpretation of data, DFG; drafting of article, JHM, DFG, MEM; critical revision of the article, JHM, MEM.

From the Department of Medicine, University of Pennsylvania, and the Department of Emergency Medicine, Thomas Jefferson University Hospital, Philadelphia, PA.

Abstract

• Objective: To detail strategies to improve sepsis recognition and the quality of care provided to the septic patient.
• Methods: Review of the literature.
• Results: Severe sepsis affects nearly 3 million individuals each year in the United States, and cost estimates for these hospitalizations exceed $24 billion. Effective management is predicated on timely recognition. In this review, we detail strategies to improve early identification of potentially septic patients as well as the quality of care provided to the septic patient in the emergency department (ED). The strategies discussed are based upon an understanding of the signs and symptoms of sepsis and the clinical risk factors associated with sepsis, which can be used to design novel strategies to screen patients for sepsis and risk stratify patients at risk for clinical deterioration.
• Conclusion: ED structures and processes can be used to increase adherence with sepsis management guidelines to improve patient outcomes.

Severe sepsis affects nearly 3 million individuals each year in the United States and cost estimates for these hospitalizations exceed $24 billion [1–3]. Sepsis is a life-threatening condition characterized by a suspected or identified infection accompanied by a vigorous host inflammatory response. In severe sepsis, end-organ dysfunction manifests in myriad forms, including altered mental status, acute kidney injury, liver dysfunction, pulmonary dysfunction, and hemodynamic compromise [4,5]. This protean presentation of a deadly condition makes identification and risk stratification both challenging and essential to improving patient outcomes. The majority of patients with severe sepsis will receive their initial care within an emergency department (ED) [6,7]. It is essential that emergency medicine providers have the means to appropriately identify patients presenting with severe sepsis in a timely manner—thus facilitating life-saving measures such as early intravenous fluid resuscitation and administration of timely and appropriate antimicrobials.

In this review, we detail strategies to improve sepsis recognition and the quality of care provided to the septic patient in the ED. The strategies discussed are based upon an understanding of the signs and symptoms of sepsis and the clinical risk factors associated with sepsis, which can be used to design novel strategies to screen patients for sepsis and risk stratify patients for clinical deterioration. Then, we review suggested ED structures and processes to increase adherence with sepsis-based guidelines to improve patient outcomes. Successful implementation is predicated on hospital administrative support towards the efforts given the time and resources required and strong and committed leadership across the health care system.

Epidemiology of Severe Sepsis

Estimates of annual cases of severe sepsis vary, ranging from 1 million to 3 million cases in the United States [1–3]. In-hospital mortality for this condition ranges from 14% to 30% [5]. The incidence of severe sepsis in the United States has been increasing at a rate of 13% annually, with an estimated cost of greater than $24 billion per year [1,2]. In 2 large cohorts of hospitalized patients, it was found that sepsis contributed to 1 in every 2 to 3 deaths following inpatient admission [8]. Coincident with these increased estimates, advances in the early identification and treatment of sepsis have led to decreasing mortality rates over the past decade [1,9].

Of importance to the ED clinician, an episode of sepsis has long-term effects on cognitive and physical function, quality-of-life, and survival [10,11]. Post-discharge, approximately one-quarter of sepsis survivors will be readmitted within 30 days [12–14]. In as many as half of these instances, another life-threatening infection is the cause for readmission, making the past medical history, including a detailed accounting of recent episodes of sepsis, an important part of the initial ED evaluation [12]. Furthermore, severe sepsis survivors spend a large proportion of their time following discharge within a health care facility, and will frequently present to the ED with an acute condition from such an environment. Important factors for predicting readmission after a sepsis hospitalization include patient age, severity of illness, hospital length of stay, and the need for intensive care during the initial hospitalization [12–14].

Principles of Effective Sepsis Management

The principles of effective sepsis management begin with early identification in the pre-hospital setting, at triage, or when a patient begins to decompensate in the hospital. After the point of initial recognition, core principles include risk stratification, timely and appropriate antimicrobial administration, initial intravenous fluid boluses and ongoing resuscitation guided by physical examination and objective resuscitation end-points [4,5]. These practices have been operationalized in the care bundles of the Surviving Sepsis Campaign Guidelines [4]. Within 3 hours, the resuscitation bundle includes measuring serum lactate to risk stratify patients, obtaining blood cultures, administering broad-spectrum antibiotics, and administering 30 mL/kg crystalloid in patients with hypotension or hyperlactatemia [4]. The 6-hour bundle expands upon these initial measures and includes additional management recommendations based on resuscitation end-points.

As effective management is predicated on timely recognition, an understanding of the impact of delayed recognition is essential to provide optimal care for the severe sepsis patient in the ED. Decades of research has revealed that certain markers predict adverse outcomes, including transition to septic shock and death, as do delayed processes of care. Importantly, while early quantitative resuscitation was demonstrated to improve outcomes in a meta-analysis, there was no demonstrable benefit when resuscitation was initiated late (> 24 hours) in the course in the ICU (odds ratio of death, 1.16 [95% confidence interval, 0.60–2.22]) [15].

Strategies To Improve Recognition

Pre-Hospital Environment

From EMS to ED Triage

Borrowing the principle “time equals tissue” from a variety of time sensitive conditions (eg, myocardial infarction management [“time equals muscle”] and stroke care [“time equals brain”]), clinicians and researchers have realized that expedited recognition of severe sepsis patients begins at the time of initial contact with the health care system. For severe sepsis patients, clinicians need to think “time equals organ function.” Given the frequency with which sepsis patients arrive to the ED via EMS, effective communication between EMS and ED providers could be leveraged to prepare the ED team to provide timely care for the sepsis patient via a “sepsis alert.” While confirmation of its applicability to sepsis care is required in the absence of a regionalized network of sepsis centers, the rationale is based on the experience of the effectiveness of trauma and stroke alert systems [20–22]. For patients not recognized as potentially being infected by EMS providers during transport, repeat vital signs during ED triage can be screened to identify patients exhibiting signs of the systemic inflammatory response syndrome (SIRS) [4,23]. The same principles of effective communication apply for patients being sent from medical clinics to the ED for evaluation and treatment of potential severe sepsis. For patients arriving independent of EMS, focused triage and initial vital signs are the starting point for identifying severe sepsis at the most proximal phase of entry into the health care system.

Vital Signs and SIRS Criteria in the ED

The Afferent Arm: Multimodal Screening Strategies

While institutional practice improvement initiatives to facilitate sepsis recognition and care should incorporate educational strategies, led by champions with expertise in sepsis, the complex presentation of sepsis requires multimodal approaches [29]. These multimodal approaches, beginning at the time of ED triage, should be designed to harness information technology to screen patients to improve severe sepsis recognition (the afferent arm) and to utilize structures and processes of care efficiently and effectively (the efferent arm) to guide severe sepsis management according to sepsis-care bundles espoused by guidelines (Figure) [4].

Operational processes to screen for sepsis in the ED will need to account for ED organizational flow (eg, average time from registration to triage, average time from triage to being seen by a physician, average length of stay in the ED, number of hospital beds) and hand-off practices (eg, care transition from ED team to floor or ICU team, or within ED at shift change). For ED organizations with shorter ED lengths of stay (eg, < 2 hours), screening practices at ED triage will serve as the focal point to identify cases of sepsis. Boarding, defined as caring for a patient in the ED pending transfer, is common, increasing as a result of ED closures [30,31], and associated with prolonged hospital length of stay and increased in-hospital mortality when ICU transfer is delayed [32]. Sepsis patients in particular appear to be a vulnerable group of patients. While many explanations exist to account for the relationship between delayed transfer and adverse outcomes, timely recognition and management of the septic patient could be compromised with prolonged boarding. To combat this potential effect, continual assessment during the entire ED stay may unmask an initially unclear presentation of sepsis.

One strategy to identify sepsis in ED organizations with prolonged ED lengths of stay is through the use of a track-and-trigger system, or early warning system. Traditionally, track-and-trigger systems were implemented on the hospital wards, as means to identify physiological deterioration in a timely manner to prevent clinical deterioration [33]. More recently, early warning systems have been used to identify patients with sepsis on the hospital wards and within EDs, as these systems rely on physiological parameters such as SIRS that are cardinal features of sepsis [34]. However, given the potential for alert fatigue, designing a system that operates with high accuracy is imperative.

Efforts are underway to redefine sepsis, using a simplified approach and readily available physiological variables, with the main goal of targeting those most at-risk of an adverse outcome during the hospitalization. Simultaneously, an understanding of the overt and more occult manifestations are essential to incorporate into the clinical decision-making and pattern recognition required to identify sepsis in a timely and accurate manner. In Table 2, the signs and symptoms that may serve as flags for severe sepsis are presented.

Mature early warning systems, designed to leverage the electronic medical record (EMR) by capturing vital signs, laboratory measures, (eg, elevated serum creatinine compared to a recent hospitalization) and symptoms (eg, altered mental status), are well-positioned to herald clinical deterioration (eg, cardiac arrest) with improved accuracy [35] and to be applied to sepsis specifically [34]. While sophisticated analytical strategies, such as machine learning, are being used to improve the test characteristics of these early warning systems, iterative, prospective chart review is an essential and complementary performance improvement step to refine the process. Further, chart review affords the opportunity to ensure compliance with sepsis care bundles.

Knowledge of the risk factors associated with development of sepsis is critical for the front-line emergency physician and nurse. Additionally, as many of these risk factors are associated with adverse outcomes, including unplanned ICU transfer and in-hospital mortality, which occur in as many as one out of 8 patients admitted directly to the ward, they have utility for early risk-stratification and triaging purposes in the ED. Advanced age and pre-existing comorbid conditions, particularly an oncologic diagnosis and/or chronic organ dysfunction, are major risk factors for sepsis and worse outcomes result in those who develop sepsis [2]. Further, illness severity, including an elevated serum lactate level, is associated with adverse outcomes. These factors can be incorporated into triage decisions and/or close monitoring for patients admitted to the general ward [36]. Conversely, because patients admitted to the ICU setting and subsequently stepped down through their hospitalization may experience better outcomes compared to patients admitted to the general ward who then require step-up to an ICU setting (37,38), attention to triage practices is critical.

These complementary strategies, which serve as the afferent arm of the system, summon health care providers to the bedside of a vulnerable patient. However, clinical effectiveness in the management of severe sepsis requires a robust, sophisticated, and mature efferent arm capable of delivering expert care to the now recognized septic patient.

Principles of Effective Management Post-Recognition

Risk Stratification

An elevated serum lactate level was initially described in pathological states in the mid 19th century by Johann Joseph Scherer [39] and has long been associated with increased mortality in hospitalized patients [40]. Lactate is a useful biomarker for risk stratification in a variety of patients arriving to the ED, particularly those who have been identified at high risk for sepsis. Jansen and colleagues examined the measurement of pre-hospital serum lactate at the time of paramedic on-scene assessment in a group of acutely ill patients [41]. Patients with point-of-care lactate levels of 3.5 mmol/L or greater were found to have an in-hospital mortality of 41% versus 12% for those with lactate levels less than 3.5 mmol/L. Within the population with an elevated lactate, patients with a systolic blood pressure greater than 100 mgHg experienced a mortality of nearly 30%, while it was greater than 50% in hypotensive patients with an elevated lactate, highlighting the value of both hemodynamic and serum lactate measures. Upon arrival to the ED, lactate measurements have a strong correlation with mortality. In one retrospective cohort, lactate level was linearly associated with mortality in a broad array of patients older than age 65 years [42]. An initial serum lactate level in the ED in the intermediate (2.0 – 3.9 mmol/L) or high range (≥ 4 mmol/L) has been associated with increased odds of death 2 to 5 times higher independent of organ dysfunction in severe sepsis specifically [43].

As the association between serum lactate levels and death is independent of organ dysfunction, serum lactate is a simple and reliable tool to both enhance detection and risk-stratify patients presenting to the ED with severe sepsis. Given the frequency with which hyperlactatemia is present in patients with suspected infection [43], operationalizing serum lactate measures with the initial phlebotomy draw is an important step to risk-stratify patients. This step can be coupled later with intravenous fluid resuscitation for those with marked elevations (≥ 4 mmol/L), in accord with guideline recommendations [4]. Screening of initial lactate values can be further expedited by utilizing fingerstick point-of-care lactate devices [44]. Last, while serial lactate measures can be incorporated into triage decisions, there is no clear threshold that warrants ICU admission. Rather, persistent elevations in serum lactate can be used to identify patients who require close observation regardless of their admission location.

Several scoring systems have been developed to augment sepsis risk stratification within the ED. The most prominent of these are the Predisposition Insult Response and Organ failure (PIRO), Sequential Organ Failure Assessment (SOFA), and Mortality in the Emergency Department Sepsis (MEDS) scores, and the National early warning score (NEWS) [45-48]. The MEDS score incorporates host factors including age and co-morbid illness, as well as physiologic and laboratory tests which can be obtained rapidly in an ED setting. Multiple prospective and retrospective examinations of the MEDS scoring systems have demonstrated that it performs optimally in ED patients with sepsis but not those with severe sepsis, in terms of predicting 30-day mortality [46,47]. The PIRO score more extensively incorporates predisposing co-morbidities, physiologic and laboratory parameters, and has been modified to consider presumed source of infection, leading to a stronger predictive ability for mortality in more severely ill patients. In patients presenting to the ED with severe sepsis and septic shock, a prospective observational study found the PIRO to be the best predictor of mortality, compared to SOFA and MEDS scores [45]. In a recent study by Corfield et al, sepsis patients with a higher NEWS, according to initial ED vital signs (temperature, pulse, respiratory rate, systolic blood pressure, oxyhemoglobin saturation) and consciousness level, were significantly more likely to be admitted to an ICU within 48 hours or to experience in-hospital mortality [48].

Timely and Appropriate Antibiotics

In a landmark study published by Kumar and colleagues in 2006, the relationship between timing of antibiotics and mortality was established [49]. In 2731 adult septic shock patients, mortality increased 7.6% for every hour delay in effective antimicrobial administration. A striking finding, given that the study population was limited to patients cared for in the ICU, was the fact that only 50% of patients received appropriate antibiotics within 6 hours of onset of shock and nearly one-quarter of patients did not receive antibiotics until the 15th hour. As a direct result, in-hospital mortality was observed to be 58% in this study.

Over the ensuing decade, a series of studies have demonstrated a narrowing of the quality gap in this regard, and the result has coincided with a significant improvement in survival. In 2010, Gaieski and colleagues demonstrated a significant improvement in the prompt administration of antibiotic delivery in patients presenting to an ED with severe sepsis, with the median time from shock onset (sustained hypotension or lactate ≥ 4 mmol/L) to antibiotics down to 42 minutes [50]. Importantly, consistent with the Kumar study, time to appropriate antibiotics, rather than simply initial antibiotics, remained associated with in-hospital mortality independent of initiating early goal-directed therapy. In 2011, Puskarich and colleagues revealed that time to antibiotics continued to improve and, as a result, the investigators did not identify a relationship between time from triage to antibiotics and in-hospital mortality [51]. However, when antibiotics were delayed until after shock recognition, consistent with the study by Kumar and colleagues, survival decreased. Until recently, this important observation was challenging to operationalize clinically as little was known about how to facilitate risk-stratification of those at risk to develop shock. However, Capp and colleagues recently found that deterioration to septic shock 48 hours after ED presentation occurs in approximately one out of eight patients and identified gender (female), transient hypotension, and/or hyperlactatemia upon presentation as risk factors associated with such a deterioration [52].

As an essential element of sepsis care bundles, a focus on timely use of antibiotics in patients with suspected infection, has the potential to increase the use of antibiotics in the ED in patients determined subsequently to not be infected. To combat this acknowledged downstream effect, reconsideration of the utility of empiric antibiotics 48 to 72 hours after admission is required. This step can be accomplished through the use of a sepsis care pathway and/or a formal antibiotic stewardship program.

Quantitative Resuscitation

Rivers and colleagues, in a landmark 2001 trial, examined the effectiveness of a protocolized resuscitation strategy in the most proximal phase of severe sepsis and septic shock [53]. A distinguishing characteristic between the usual care arm and the intervention in this ED-based study, in addition to whether mixed central venous oxygen saturation was measured as a resuscitation end-point, was the inclusion of an ED provider at the bedside to attend to clinical management. The intervention, aimed at achieving physiologic targets, resulted in significantly more fluid resuscitation (3.5 L vs. 5.0 L within the first 6 hours) and a significant decrease in in-hospital mortality compared to the usual care arm (46.5 vs. 30.5%). The study revolutionized the culture and practice of sepsis care, in part by shining a light on the importance of timely resuscitation at the most proximal point of contact between the patient and the healthcare system. It also highlighted the importance of integrating serum lactate measurement into the early screening and risk stratification processes for sepsis care delivery.

The 2014 randomized trial of Protocol-Based Care for Early Septic Shock (ProCESS) revisited this concept, comparing the Rivers 2001 protocol to both a current guideline-based non-invasive algorithmic protocol and what had become usual ED care in the interim [54]. The ProCESS trial, which operationalized a team of bedside providers to direct care for each of the 3 distinct arms, found no significant difference between the arms in terms of 90-day and 1-year mortality, but mortality was approximately 10% less in all arms compared with the intervention arm of the Rivers trial. Further, subjects in each of the 3 arms received in excess of 2 L intravenous fluid resuscitation pre-randomization and 4.4–5.5 L when resuscitation spanned from pre-randomization to 6 hours post-randomization. The conclusion drawn is that the commonalities between the arms—early fluid resuscitation, early antibiotics, and the option to use physiologic measures as markers of the adequacy of treatment, all guided by bedside ED providers—are the most important factors for surviving sepsis. And the result is that practitioners have refined these tools over a decade, leading to steady improvements in survival.

Consistent with the ProCESS trial, a recent Australia and New Zealand trial confirmed no significant difference in 90-day mortality between protocolized EGDT and current usual care for septic shock within an ED [55]. Consistent with ProCESS and ProMISe [56], subjects enrolled in ARISE received in excess of 2.5 L in resuscitation pre-randomization, which when paired with fluid resuscitation in the 0-6 hour post-randomization period (1.96 L in the EGDT arm and 1.71 in the usual-care arm) resulted in resuscitation in the 4.5 to 5L range during the initial resuscitation. The ARISE trial was unique in that appropriate antibiotic administration was a requirement prior to randomization, ensuring that this important driver of mortality reduction was standardized between the two arms of the trial. In summary, while the ideal fluid resuscitation amount is unknown, requires a personalized approach, and further investigation is required to effectively incorporate non-invasive measures to guide fluid responsiveness, early and aggressive resuscitation paired with early antibiotic administration are essential aspects of effective sepsis management.

The Efferent Arm: Structure And Processes To Improve Outcomes

Personnel and Staffing

Quality care for the septic patient requires immediate availability of a multidisciplinary care team, including physicians and nurses with critical care experience who can be rapidly deployed to the bedside. The location of care provision may include on-going care in the initial ED room assignment or transfer to a dedicated area for the care of the critically ill patient within the ED.

To provide optimal care in the era of overcrowding and delayed transfer to an ICU, a movement towards ED intensive care units (ED-ICUs) has emerged [57]. The models of practice range from a model based upon ED intensivists, with expertise in critical care medicine, providing care within the traditional structure of an ED, to a model wherein a portion of the ED is assigned for the care of the critically ill for extended periods of time beyond the initial resuscitation. As these models mature from resuscitation bays capable of scaling up based on need to dedicated ED-ICUs, investments in shared Unit leadership (physician and nursing), staffing (physician, critical care nursing, respiratory therapy, critical care pharmacist) and processes of care (eg, multidisciplinary rounds) in line with established ICUs will be necessary.

While attractive conceptually, large-scale implementation of this movement is unlikely to occur outside of tertiary care academic medical centers. In the many EDs across the US without ED intensivists, and confronted with limited clinician resources, flexible physician and nursing staffing models will be necessary to ensure that care provisions are in accord with established guidelines. Potential solutions to provide the resources to meet the needs of these high-intensity patients include critical care consultation and a strategy traditionally applied to the ICU, telemedicine [58]. Last, given the relationship between hospital volume and mortality in severe sepsis [59,60], timely transfer to a high-volume center for specific cases may be appropriate, although the optimal timing, case selection, and impact of transfer on outcomes warrant further examination.

Clinical Decision Support Strategies

To complement the identification and risk-stratification available by screening and scoring systems, clinical decision support systems are novel tools to improve outcomes in the era of electronic medical records (EMR). Specific to sepsis care delivery, performance improvement initiatives including audit-and-feedback practice can increase severe sepsis guideline adherence, and even modest improvements in adherence appear to lead to sustained improvements that contributed to a 25% relative risk reduction in the observed mortality rate [61,62]. Clinical decision support tools can be used to link early recognition to optimal care processes, such as the Surviving Sepsis Campaign resuscitation and management bundles. The use of prompts as strategies to ensure that bundles of care are ordered and carried out is an important aspect to operationalize during the design phase [63].

Significant preparation is required to effectively carry out the clinical decision support design strategy. For example, to ensure timely antibiotic dispensing, a number of process steps will be required, including prompt notification to a central pharmacist or preferably, an ED pharmacist with access to a local pharmacy pre-stocked with commonly used antibiotics [64]. In addition, the use of an institution-specific antibiogram within the physician computer-order entry sepsis order set, that includes site-specific recommendations (eg, pulmonary, gastrointestinal source) and susceptibility patterns, is an essential aspect of optimal sepsis processes of care. Last, the antibiogram will need to be frequently updated to include season-specific (eg, oseltamivir administration for high-risk cases during influenza season) recommendations to ensure that providers are prompted with the most up-to-date clinical information.

Audit and Feedback and Continuous Performance Improvement

The multimodal approach required to translate knowledge (eg, guidelines) into sepsis care implemented at the bedside is an iterative process. An ED armed with a robust track-and-trigger system and an effective efferent arm, including sophisticated clinical decision support strategies, will require frequent auditing in the plan-do-study-act model of quality improvement to yield clinical effectiveness [61,62,65]. Auditing, paired with feedback to frontline providers, is essential to refine and improve the complex process required to provide expert care to the septic patient [29,65]. Sustained success in optimizing sepsis care delivery is the goal, yet significant work is required to determine the best strategies to achieve this endpoint.

Conclusion

Severe sepsis affects millions of individuals each year in the United States. Delays in recognition result in increased morbidity and mortality, at a tremendous cost to the patient and society. By designing strategies to identify sepsis in a timely, efficient, and effective manner, and by implementing ED structures and processes to increase adherence with sepsis-based guidelines, improved patient-centered outcomes can be realized.

Corresponding author: Mark E. Mikkelsen, MD, MSCE, Gates 05.042, 3400 Spruce St., Philadelphia, PA 19104, [email protected].

Financial disclosures: None.

Author contributions: conception and design, JHM, MEM; analysis and interpretation of data, DFG; drafting of article, JHM, DFG, MEM; critical revision of the article, JHM, MEM.

From the Department of Medicine, University of Pennsylvania, and the Department of Emergency Medicine, Thomas Jefferson University Hospital, Philadelphia, PA.

Abstract

• Objective: To detail strategies to improve sepsis recognition and the quality of care provided to the septic patient.
• Methods: Review of the literature.
• Results: Severe sepsis affects nearly 3 million individuals each year in the United States, and cost estimates for these hospitalizations exceed $24 billion. Effective management is predicated on timely recognition. In this review, we detail strategies to improve early identification of potentially septic patients as well as the quality of care provided to the septic patient in the emergency department (ED). The strategies discussed are based upon an understanding of the signs and symptoms of sepsis and the clinical risk factors associated with sepsis, which can be used to design novel strategies to screen patients for sepsis and risk stratify patients at risk for clinical deterioration.
• Conclusion: ED structures and processes can be used to increase adherence with sepsis management guidelines to improve patient outcomes.

Severe sepsis affects nearly 3 million individuals each year in the United States and cost estimates for these hospitalizations exceed $24 billion [1–3]. Sepsis is a life-threatening condition characterized by a suspected or identified infection accompanied by a vigorous host inflammatory response. In severe sepsis, end-organ dysfunction manifests in myriad forms, including altered mental status, acute kidney injury, liver dysfunction, pulmonary dysfunction, and hemodynamic compromise [4,5]. This protean presentation of a deadly condition makes identification and risk stratification both challenging and essential to improving patient outcomes. The majority of patients with severe sepsis will receive their initial care within an emergency department (ED) [6,7]. It is essential that emergency medicine providers have the means to appropriately identify patients presenting with severe sepsis in a timely manner—thus facilitating life-saving measures such as early intravenous fluid resuscitation and administration of timely and appropriate antimicrobials.

In this review, we detail strategies to improve sepsis recognition and the quality of care provided to the septic patient in the ED. The strategies discussed are based upon an understanding of the signs and symptoms of sepsis and the clinical risk factors associated with sepsis, which can be used to design novel strategies to screen patients for sepsis and risk stratify patients for clinical deterioration. Then, we review suggested ED structures and processes to increase adherence with sepsis-based guidelines to improve patient outcomes. Successful implementation is predicated on hospital administrative support towards the efforts given the time and resources required and strong and committed leadership across the health care system.

Epidemiology of Severe Sepsis

Estimates of annual cases of severe sepsis vary, ranging from 1 million to 3 million cases in the United States [1–3]. In-hospital mortality for this condition ranges from 14% to 30% [5]. The incidence of severe sepsis in the United States has been increasing at a rate of 13% annually, with an estimated cost of greater than $24 billion per year [1,2]. In 2 large cohorts of hospitalized patients, it was found that sepsis contributed to 1 in every 2 to 3 deaths following inpatient admission [8]. Coincident with these increased estimates, advances in the early identification and treatment of sepsis have led to decreasing mortality rates over the past decade [1,9].

Of importance to the ED clinician, an episode of sepsis has long-term effects on cognitive and physical function, quality-of-life, and survival [10,11]. Post-discharge, approximately one-quarter of sepsis survivors will be readmitted within 30 days [12–14]. In as many as half of these instances, another life-threatening infection is the cause for readmission, making the past medical history, including a detailed accounting of recent episodes of sepsis, an important part of the initial ED evaluation [12]. Furthermore, severe sepsis survivors spend a large proportion of their time following discharge within a health care facility, and will frequently present to the ED with an acute condition from such an environment. Important factors for predicting readmission after a sepsis hospitalization include patient age, severity of illness, hospital length of stay, and the need for intensive care during the initial hospitalization [12–14].

Principles of Effective Sepsis Management

The principles of effective sepsis management begin with early identification in the pre-hospital setting, at triage, or when a patient begins to decompensate in the hospital. After the point of initial recognition, core principles include risk stratification, timely and appropriate antimicrobial administration, initial intravenous fluid boluses and ongoing resuscitation guided by physical examination and objective resuscitation end-points [4,5]. These practices have been operationalized in the care bundles of the Surviving Sepsis Campaign Guidelines [4]. Within 3 hours, the resuscitation bundle includes measuring serum lactate to risk stratify patients, obtaining blood cultures, administering broad-spectrum antibiotics, and administering 30 mL/kg crystalloid in patients with hypotension or hyperlactatemia [4]. The 6-hour bundle expands upon these initial measures and includes additional management recommendations based on resuscitation end-points.

As effective management is predicated on timely recognition, an understanding of the impact of delayed recognition is essential to provide optimal care for the severe sepsis patient in the ED. Decades of research has revealed that certain markers predict adverse outcomes, including transition to septic shock and death, as do delayed processes of care. Importantly, while early quantitative resuscitation was demonstrated to improve outcomes in a meta-analysis, there was no demonstrable benefit when resuscitation was initiated late (> 24 hours) in the course in the ICU (odds ratio of death, 1.16 [95% confidence interval, 0.60–2.22]) [15].

Strategies To Improve Recognition

Pre-Hospital Environment

From EMS to ED Triage

Borrowing the principle “time equals tissue” from a variety of time sensitive conditions (eg, myocardial infarction management [“time equals muscle”] and stroke care [“time equals brain”]), clinicians and researchers have realized that expedited recognition of severe sepsis patients begins at the time of initial contact with the health care system. For severe sepsis patients, clinicians need to think “time equals organ function.” Given the frequency with which sepsis patients arrive to the ED via EMS, effective communication between EMS and ED providers could be leveraged to prepare the ED team to provide timely care for the sepsis patient via a “sepsis alert.” While confirmation of its applicability to sepsis care is required in the absence of a regionalized network of sepsis centers, the rationale is based on the experience of the effectiveness of trauma and stroke alert systems [20–22]. For patients not recognized as potentially being infected by EMS providers during transport, repeat vital signs during ED triage can be screened to identify patients exhibiting signs of the systemic inflammatory response syndrome (SIRS) [4,23]. The same principles of effective communication apply for patients being sent from medical clinics to the ED for evaluation and treatment of potential severe sepsis. For patients arriving independent of EMS, focused triage and initial vital signs are the starting point for identifying severe sepsis at the most proximal phase of entry into the health care system.

Vital Signs and SIRS Criteria in the ED

The Afferent Arm: Multimodal Screening Strategies

While institutional practice improvement initiatives to facilitate sepsis recognition and care should incorporate educational strategies, led by champions with expertise in sepsis, the complex presentation of sepsis requires multimodal approaches [29]. These multimodal approaches, beginning at the time of ED triage, should be designed to harness information technology to screen patients to improve severe sepsis recognition (the afferent arm) and to utilize structures and processes of care efficiently and effectively (the efferent arm) to guide severe sepsis management according to sepsis-care bundles espoused by guidelines (Figure) [4].

Operational processes to screen for sepsis in the ED will need to account for ED organizational flow (eg, average time from registration to triage, average time from triage to being seen by a physician, average length of stay in the ED, number of hospital beds) and hand-off practices (eg, care transition from ED team to floor or ICU team, or within ED at shift change). For ED organizations with shorter ED lengths of stay (eg, < 2 hours), screening practices at ED triage will serve as the focal point to identify cases of sepsis. Boarding, defined as caring for a patient in the ED pending transfer, is common, increasing as a result of ED closures [30,31], and associated with prolonged hospital length of stay and increased in-hospital mortality when ICU transfer is delayed [32]. Sepsis patients in particular appear to be a vulnerable group of patients. While many explanations exist to account for the relationship between delayed transfer and adverse outcomes, timely recognition and management of the septic patient could be compromised with prolonged boarding. To combat this potential effect, continual assessment during the entire ED stay may unmask an initially unclear presentation of sepsis.

One strategy to identify sepsis in ED organizations with prolonged ED lengths of stay is through the use of a track-and-trigger system, or early warning system. Traditionally, track-and-trigger systems were implemented on the hospital wards, as means to identify physiological deterioration in a timely manner to prevent clinical deterioration [33]. More recently, early warning systems have been used to identify patients with sepsis on the hospital wards and within EDs, as these systems rely on physiological parameters such as SIRS that are cardinal features of sepsis [34]. However, given the potential for alert fatigue, designing a system that operates with high accuracy is imperative.

Efforts are underway to redefine sepsis, using a simplified approach and readily available physiological variables, with the main goal of targeting those most at-risk of an adverse outcome during the hospitalization. Simultaneously, an understanding of the overt and more occult manifestations are essential to incorporate into the clinical decision-making and pattern recognition required to identify sepsis in a timely and accurate manner. In Table 2, the signs and symptoms that may serve as flags for severe sepsis are presented.

Mature early warning systems, designed to leverage the electronic medical record (EMR) by capturing vital signs, laboratory measures, (eg, elevated serum creatinine compared to a recent hospitalization) and symptoms (eg, altered mental status), are well-positioned to herald clinical deterioration (eg, cardiac arrest) with improved accuracy [35] and to be applied to sepsis specifically [34]. While sophisticated analytical strategies, such as machine learning, are being used to improve the test characteristics of these early warning systems, iterative, prospective chart review is an essential and complementary performance improvement step to refine the process. Further, chart review affords the opportunity to ensure compliance with sepsis care bundles.

Knowledge of the risk factors associated with development of sepsis is critical for the front-line emergency physician and nurse. Additionally, as many of these risk factors are associated with adverse outcomes, including unplanned ICU transfer and in-hospital mortality, which occur in as many as one out of 8 patients admitted directly to the ward, they have utility for early risk-stratification and triaging purposes in the ED. Advanced age and pre-existing comorbid conditions, particularly an oncologic diagnosis and/or chronic organ dysfunction, are major risk factors for sepsis and worse outcomes result in those who develop sepsis [2]. Further, illness severity, including an elevated serum lactate level, is associated with adverse outcomes. These factors can be incorporated into triage decisions and/or close monitoring for patients admitted to the general ward [36]. Conversely, because patients admitted to the ICU setting and subsequently stepped down through their hospitalization may experience better outcomes compared to patients admitted to the general ward who then require step-up to an ICU setting (37,38), attention to triage practices is critical.

These complementary strategies, which serve as the afferent arm of the system, summon health care providers to the bedside of a vulnerable patient. However, clinical effectiveness in the management of severe sepsis requires a robust, sophisticated, and mature efferent arm capable of delivering expert care to the now recognized septic patient.

Principles of Effective Management Post-Recognition

Risk Stratification

An elevated serum lactate level was initially described in pathological states in the mid 19th century by Johann Joseph Scherer [39] and has long been associated with increased mortality in hospitalized patients [40]. Lactate is a useful biomarker for risk stratification in a variety of patients arriving to the ED, particularly those who have been identified at high risk for sepsis. Jansen and colleagues examined the measurement of pre-hospital serum lactate at the time of paramedic on-scene assessment in a group of acutely ill patients [41]. Patients with point-of-care lactate levels of 3.5 mmol/L or greater were found to have an in-hospital mortality of 41% versus 12% for those with lactate levels less than 3.5 mmol/L. Within the population with an elevated lactate, patients with a systolic blood pressure greater than 100 mgHg experienced a mortality of nearly 30%, while it was greater than 50% in hypotensive patients with an elevated lactate, highlighting the value of both hemodynamic and serum lactate measures. Upon arrival to the ED, lactate measurements have a strong correlation with mortality. In one retrospective cohort, lactate level was linearly associated with mortality in a broad array of patients older than age 65 years [42]. An initial serum lactate level in the ED in the intermediate (2.0 – 3.9 mmol/L) or high range (≥ 4 mmol/L) has been associated with increased odds of death 2 to 5 times higher independent of organ dysfunction in severe sepsis specifically [43].

As the association between serum lactate levels and death is independent of organ dysfunction, serum lactate is a simple and reliable tool to both enhance detection and risk-stratify patients presenting to the ED with severe sepsis. Given the frequency with which hyperlactatemia is present in patients with suspected infection [43], operationalizing serum lactate measures with the initial phlebotomy draw is an important step to risk-stratify patients. This step can be coupled later with intravenous fluid resuscitation for those with marked elevations (≥ 4 mmol/L), in accord with guideline recommendations [4]. Screening of initial lactate values can be further expedited by utilizing fingerstick point-of-care lactate devices [44]. Last, while serial lactate measures can be incorporated into triage decisions, there is no clear threshold that warrants ICU admission. Rather, persistent elevations in serum lactate can be used to identify patients who require close observation regardless of their admission location.

Several scoring systems have been developed to augment sepsis risk stratification within the ED. The most prominent of these are the Predisposition Insult Response and Organ failure (PIRO), Sequential Organ Failure Assessment (SOFA), and Mortality in the Emergency Department Sepsis (MEDS) scores, and the National early warning score (NEWS) [45-48]. The MEDS score incorporates host factors including age and co-morbid illness, as well as physiologic and laboratory tests which can be obtained rapidly in an ED setting. Multiple prospective and retrospective examinations of the MEDS scoring systems have demonstrated that it performs optimally in ED patients with sepsis but not those with severe sepsis, in terms of predicting 30-day mortality [46,47]. The PIRO score more extensively incorporates predisposing co-morbidities, physiologic and laboratory parameters, and has been modified to consider presumed source of infection, leading to a stronger predictive ability for mortality in more severely ill patients. In patients presenting to the ED with severe sepsis and septic shock, a prospective observational study found the PIRO to be the best predictor of mortality, compared to SOFA and MEDS scores [45]. In a recent study by Corfield et al, sepsis patients with a higher NEWS, according to initial ED vital signs (temperature, pulse, respiratory rate, systolic blood pressure, oxyhemoglobin saturation) and consciousness level, were significantly more likely to be admitted to an ICU within 48 hours or to experience in-hospital mortality [48].

Timely and Appropriate Antibiotics

In a landmark study published by Kumar and colleagues in 2006, the relationship between timing of antibiotics and mortality was established [49]. In 2731 adult septic shock patients, mortality increased 7.6% for every hour delay in effective antimicrobial administration. A striking finding, given that the study population was limited to patients cared for in the ICU, was the fact that only 50% of patients received appropriate antibiotics within 6 hours of onset of shock and nearly one-quarter of patients did not receive antibiotics until the 15th hour. As a direct result, in-hospital mortality was observed to be 58% in this study.

Over the ensuing decade, a series of studies have demonstrated a narrowing of the quality gap in this regard, and the result has coincided with a significant improvement in survival. In 2010, Gaieski and colleagues demonstrated a significant improvement in the prompt administration of antibiotic delivery in patients presenting to an ED with severe sepsis, with the median time from shock onset (sustained hypotension or lactate ≥ 4 mmol/L) to antibiotics down to 42 minutes [50]. Importantly, consistent with the Kumar study, time to appropriate antibiotics, rather than simply initial antibiotics, remained associated with in-hospital mortality independent of initiating early goal-directed therapy. In 2011, Puskarich and colleagues revealed that time to antibiotics continued to improve and, as a result, the investigators did not identify a relationship between time from triage to antibiotics and in-hospital mortality [51]. However, when antibiotics were delayed until after shock recognition, consistent with the study by Kumar and colleagues, survival decreased. Until recently, this important observation was challenging to operationalize clinically as little was known about how to facilitate risk-stratification of those at risk to develop shock. However, Capp and colleagues recently found that deterioration to septic shock 48 hours after ED presentation occurs in approximately one out of eight patients and identified gender (female), transient hypotension, and/or hyperlactatemia upon presentation as risk factors associated with such a deterioration [52].

As an essential element of sepsis care bundles, a focus on timely use of antibiotics in patients with suspected infection, has the potential to increase the use of antibiotics in the ED in patients determined subsequently to not be infected. To combat this acknowledged downstream effect, reconsideration of the utility of empiric antibiotics 48 to 72 hours after admission is required. This step can be accomplished through the use of a sepsis care pathway and/or a formal antibiotic stewardship program.

Quantitative Resuscitation

Rivers and colleagues, in a landmark 2001 trial, examined the effectiveness of a protocolized resuscitation strategy in the most proximal phase of severe sepsis and septic shock [53]. A distinguishing characteristic between the usual care arm and the intervention in this ED-based study, in addition to whether mixed central venous oxygen saturation was measured as a resuscitation end-point, was the inclusion of an ED provider at the bedside to attend to clinical management. The intervention, aimed at achieving physiologic targets, resulted in significantly more fluid resuscitation (3.5 L vs. 5.0 L within the first 6 hours) and a significant decrease in in-hospital mortality compared to the usual care arm (46.5 vs. 30.5%). The study revolutionized the culture and practice of sepsis care, in part by shining a light on the importance of timely resuscitation at the most proximal point of contact between the patient and the healthcare system. It also highlighted the importance of integrating serum lactate measurement into the early screening and risk stratification processes for sepsis care delivery.

The 2014 randomized trial of Protocol-Based Care for Early Septic Shock (ProCESS) revisited this concept, comparing the Rivers 2001 protocol to both a current guideline-based non-invasive algorithmic protocol and what had become usual ED care in the interim [54]. The ProCESS trial, which operationalized a team of bedside providers to direct care for each of the 3 distinct arms, found no significant difference between the arms in terms of 90-day and 1-year mortality, but mortality was approximately 10% less in all arms compared with the intervention arm of the Rivers trial. Further, subjects in each of the 3 arms received in excess of 2 L intravenous fluid resuscitation pre-randomization and 4.4–5.5 L when resuscitation spanned from pre-randomization to 6 hours post-randomization. The conclusion drawn is that the commonalities between the arms—early fluid resuscitation, early antibiotics, and the option to use physiologic measures as markers of the adequacy of treatment, all guided by bedside ED providers—are the most important factors for surviving sepsis. And the result is that practitioners have refined these tools over a decade, leading to steady improvements in survival.

Consistent with the ProCESS trial, a recent Australia and New Zealand trial confirmed no significant difference in 90-day mortality between protocolized EGDT and current usual care for septic shock within an ED [55]. Consistent with ProCESS and ProMISe [56], subjects enrolled in ARISE received in excess of 2.5 L in resuscitation pre-randomization, which when paired with fluid resuscitation in the 0-6 hour post-randomization period (1.96 L in the EGDT arm and 1.71 in the usual-care arm) resulted in resuscitation in the 4.5 to 5L range during the initial resuscitation. The ARISE trial was unique in that appropriate antibiotic administration was a requirement prior to randomization, ensuring that this important driver of mortality reduction was standardized between the two arms of the trial. In summary, while the ideal fluid resuscitation amount is unknown, requires a personalized approach, and further investigation is required to effectively incorporate non-invasive measures to guide fluid responsiveness, early and aggressive resuscitation paired with early antibiotic administration are essential aspects of effective sepsis management.

The Efferent Arm: Structure And Processes To Improve Outcomes

Personnel and Staffing

Quality care for the septic patient requires immediate availability of a multidisciplinary care team, including physicians and nurses with critical care experience who can be rapidly deployed to the bedside. The location of care provision may include on-going care in the initial ED room assignment or transfer to a dedicated area for the care of the critically ill patient within the ED.

To provide optimal care in the era of overcrowding and delayed transfer to an ICU, a movement towards ED intensive care units (ED-ICUs) has emerged [57]. The models of practice range from a model based upon ED intensivists, with expertise in critical care medicine, providing care within the traditional structure of an ED, to a model wherein a portion of the ED is assigned for the care of the critically ill for extended periods of time beyond the initial resuscitation. As these models mature from resuscitation bays capable of scaling up based on need to dedicated ED-ICUs, investments in shared Unit leadership (physician and nursing), staffing (physician, critical care nursing, respiratory therapy, critical care pharmacist) and processes of care (eg, multidisciplinary rounds) in line with established ICUs will be necessary.

While attractive conceptually, large-scale implementation of this movement is unlikely to occur outside of tertiary care academic medical centers. In the many EDs across the US without ED intensivists, and confronted with limited clinician resources, flexible physician and nursing staffing models will be necessary to ensure that care provisions are in accord with established guidelines. Potential solutions to provide the resources to meet the needs of these high-intensity patients include critical care consultation and a strategy traditionally applied to the ICU, telemedicine [58]. Last, given the relationship between hospital volume and mortality in severe sepsis [59,60], timely transfer to a high-volume center for specific cases may be appropriate, although the optimal timing, case selection, and impact of transfer on outcomes warrant further examination.

Clinical Decision Support Strategies

To complement the identification and risk-stratification available by screening and scoring systems, clinical decision support systems are novel tools to improve outcomes in the era of electronic medical records (EMR). Specific to sepsis care delivery, performance improvement initiatives including audit-and-feedback practice can increase severe sepsis guideline adherence, and even modest improvements in adherence appear to lead to sustained improvements that contributed to a 25% relative risk reduction in the observed mortality rate [61,62]. Clinical decision support tools can be used to link early recognition to optimal care processes, such as the Surviving Sepsis Campaign resuscitation and management bundles. The use of prompts as strategies to ensure that bundles of care are ordered and carried out is an important aspect to operationalize during the design phase [63].

Significant preparation is required to effectively carry out the clinical decision support design strategy. For example, to ensure timely antibiotic dispensing, a number of process steps will be required, including prompt notification to a central pharmacist or preferably, an ED pharmacist with access to a local pharmacy pre-stocked with commonly used antibiotics [64]. In addition, the use of an institution-specific antibiogram within the physician computer-order entry sepsis order set, that includes site-specific recommendations (eg, pulmonary, gastrointestinal source) and susceptibility patterns, is an essential aspect of optimal sepsis processes of care. Last, the antibiogram will need to be frequently updated to include season-specific (eg, oseltamivir administration for high-risk cases during influenza season) recommendations to ensure that providers are prompted with the most up-to-date clinical information.

Audit and Feedback and Continuous Performance Improvement

The multimodal approach required to translate knowledge (eg, guidelines) into sepsis care implemented at the bedside is an iterative process. An ED armed with a robust track-and-trigger system and an effective efferent arm, including sophisticated clinical decision support strategies, will require frequent auditing in the plan-do-study-act model of quality improvement to yield clinical effectiveness [61,62,65]. Auditing, paired with feedback to frontline providers, is essential to refine and improve the complex process required to provide expert care to the septic patient [29,65]. Sustained success in optimizing sepsis care delivery is the goal, yet significant work is required to determine the best strategies to achieve this endpoint.

Conclusion

Severe sepsis affects millions of individuals each year in the United States. Delays in recognition result in increased morbidity and mortality, at a tremendous cost to the patient and society. By designing strategies to identify sepsis in a timely, efficient, and effective manner, and by implementing ED structures and processes to increase adherence with sepsis-based guidelines, improved patient-centered outcomes can be realized.

Corresponding author: Mark E. Mikkelsen, MD, MSCE, Gates 05.042, 3400 Spruce St., Philadelphia, PA 19104, [email protected].

Financial disclosures: None.

Author contributions: conception and design, JHM, MEM; analysis and interpretation of data, DFG; drafting of article, JHM, DFG, MEM; critical revision of the article, JHM, MEM.

ANSWER
The radiograph shows a fracture dislocation of the ankle. The distal tibia is dislocated medially relative to the talus, as evidenced by the widened joint space. There is also an oblique fracture of the distal fibula.

Since the patient was experiencing neurovascular compromise, the dislocation was promptly reduced in the emergency department. Subsequently, he was taken to the operating room for open reduction and internal fixation of his fibula fracture.   

ANSWER
The radiograph shows a fracture dislocation of the ankle. The distal tibia is dislocated medially relative to the talus, as evidenced by the widened joint space. There is also an oblique fracture of the distal fibula.

Since the patient was experiencing neurovascular compromise, the dislocation was promptly reduced in the emergency department. Subsequently, he was taken to the operating room for open reduction and internal fixation of his fibula fracture.   

ANSWER
The radiograph shows a fracture dislocation of the ankle. The distal tibia is dislocated medially relative to the talus, as evidenced by the widened joint space. There is also an oblique fracture of the distal fibula.

Since the patient was experiencing neurovascular compromise, the dislocation was promptly reduced in the emergency department. Subsequently, he was taken to the operating room for open reduction and internal fixation of his fibula fracture.   

Case

An 8-month-old boy with a history of hypotonia, developmental delay, and seizure disorder refractory to multiple anticonvulsant medications, was presented to the ED with a 2-week history of intermittent fever and poor oral intake. His current medications included sodium bromide 185 mg orally twice daily for his seizure disorder.

On physical examination, the boy appeared small for his age, with diffuse hypotonia and diminished reflexes. He was able to track with his eyes but was otherwise unresponsive. No rash was present. Results of initial laboratory studies were: sodium 144 mEq/L; potassium, 4.8 mEq/L; chloride, 179 mEq/L; bicarbonate, 21 mEq/L; blood urea nitrogen, 6 mg/dL; creatinine, 0.1 mg/dL; and glucose, 63 mg/dL. His anion gap (AG) was −56.

What does the anion gap represent?

The AG is a valuable clinical calculation derived from the measured extracellular electrolytes and provides an index of acid-base status.¹ Due to the necessity of electroneutrality, the sum of positive charges (cations) in the extracellular fluid must be balanced exactly with the sum of negative charges (anions). However, to routinely measure all of the cations and anions in the serum would be time-consuming and is also unnecessary. Because most clinical laboratories commonly only measure one relevant cation (sodium) and two anions (chloride and bicarbonate), the positive and negative sums are not completely balanced. The AG therefore refers to this difference (ie, AG = Na – [Cl + HCO₃]).

Of course, electroneutrality exists in vivo, and is accomplished by the presence of unmeasured anions (UA) (eg, lactate and phosphate) and unmeasured cations (UC) (eg, potassium and calcium) not accounted for in the AG (ie, AG = UA – UC). In other words, the sum of measured plus the unmeasured anions must equal the sum of the measured plus unmeasured cations.

What causes a low or negative anion gap?

While most healthcare providers are well versed in the clinical significance of an elevated AG (eg, MUDPILES [methanol, uremia, diabetic ketoacidosis, propylene glycol or phenformin, iron or isoniazid, lactate, ethylene glycol, salicylates]), the meaning of a low or negative AG is underappreciated. There are several scenarios that could potentially yield a low or negative AG, including decreased concentration of UA, increased concentrations of nonsodium cations (UC), and overestimation of serum chloride.

Decreased Concentration of Unmeasured Anions. This most commonly occurs by two mechanisms: dilution of the extracellular fluid or hypoalbuminemia. The addition of water to the extracellular fluid will cause a proportionate dilution of all the measured electrolytes. Since the concentration of measured cations is higher than the measured anions, there is a small and relatively insignificant decrease in the AG.

Alternatively, hypoalbuminemia results in a low AG due to the change in UA; albumin is negatively charged. At physiologic pH, the overwhelming majority of serum proteins are anionic and counter-balanced by the positive charge of sodium. Albumin, the most abundant serum protein, accounts for approximately 75% of the normal AG. Hypoalbuminemic states, such as cirrhosis or nephrotic syndrome, can therefore cause low AG due to the retention of chloride to replace the lost negative charge. The albumin concentration can be corrected to calculate the AG.²

Nonsodium Cations. There are a number of clinical conditions that result in the retention of nonsodium cations. For example, the excess positively charged paraproteins associated with IgG myeloma raise the UC concentration, resulting in a low AG. Similarly, elevations of unmeasured cationic electrolytes, such as calcium and magnesium, may also result in a lower AG. Significant changes in AG, though, are caused only by profound (and often life-threatening) hypercalcemia or hypermagnesemia.

Overestimation of Serum Chloride. Overestimation of serum chloride most commonly occurs in the clinical scenario of bromide exposure. In normal physiologic conditions, chloride is the only halide present in the extracellular fluid. With intake of brominated products, chloride may be partially replaced by bromide. As there is greater renal tubular avidity for bromide, chronic ingestion of bromide results in a gradual rise in serum bromide concentrations with a proportional fall in chloride. However, and more importantly, bromide interferes with a number of laboratory techniques measuring chloride concentrations, resulting in a spuriously elevated chloride, or pseudohyperchloremia. Because the measured sodium and bicarbonate concentrations will remain unchanged, this falsely elevated chloride measurement will result in a negative AG.

What causes the falsely elevated chloride?

All of the current laboratory techniques for measurement of serum chloride concentration can potentially result in a falsely elevated value. However, the degree of pseudohyperchloremia will depend on the specific assay used for measurement. The ion-selective electrode method used by many common laboratory analyzers appears to have the greatest interference on chloride measurement in the presence of bromide. This is simply due to the molecular similarity of bromide and chloride. Conversely, the coulometry method, often used as a reference standard, has the least interference of current laboratory methods.³ This is because coulometry does not completely rely on molecular structure to measure concentration, but rather it measures the amount of energy produced or consumed in an electrolysis reaction. Iodide, another halide compound, has also been described as a cause of pseudohyperchloremia, whereas fluoride does not seem to have significant interference.⁴ 

How are patients exposed to bromide salts?

Bromide salts, specifically sodium bromide, are infrequently used to treat seizure disorders, but are generally reserved for patients with epilepsy refractory to other, less toxic anticonvulsant medications. During the era when bromide salts were more commonly used to treat epilepsy, bromide intoxication, or bromism, was frequently observed.

Bromism may manifest as a constellation of nonspecific neurological and psychiatric symptoms. These most commonly include headache, weakness, agitation, confusion, and hallucinations. In more severe cases of bromism, stupor and coma may occur.^3,5

Although bromide salts are no longer commonly prescribed, a number of products still contain brominated ingredients. Symptoms of bromide intoxication can occur with chronic use of a cough syrup containing dextromethorphan hydrobromide as well as the brominated vegetable oils found in some soft drinks.⁵ 

How is bromism treated?

The treatment of bromism involves preventing further exposure to bromide and promoting bromide excretion. Bromide has a long half-life (10-12 days), and in patients with normal renal function, it is possible to reduce this half-life to approximately 3 days with hydration and diuresis with sodium chloride.³ Alternatively, in patients with impaired renal function or severe intoxication, hemodialysis has been used effectively.⁵

Case Conclusion

The patient was admitted for observation and treated with intravenous sodium chloride. After consultation with his neurologist, he was discharged home in the care of his parents, who were advised to continue him on sodium bromide 185 mg orally twice daily since his seizures were refractory to other anticonvulsant medications.

Dr Repplinger is a medical toxicology fellow in the department of emergency medicine at New York University Langone Medical Center. 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

An 8-month-old boy with a history of hypotonia, developmental delay, and seizure disorder refractory to multiple anticonvulsant medications, was presented to the ED with a 2-week history of intermittent fever and poor oral intake. His current medications included sodium bromide 185 mg orally twice daily for his seizure disorder.

On physical examination, the boy appeared small for his age, with diffuse hypotonia and diminished reflexes. He was able to track with his eyes but was otherwise unresponsive. No rash was present. Results of initial laboratory studies were: sodium 144 mEq/L; potassium, 4.8 mEq/L; chloride, 179 mEq/L; bicarbonate, 21 mEq/L; blood urea nitrogen, 6 mg/dL; creatinine, 0.1 mg/dL; and glucose, 63 mg/dL. His anion gap (AG) was −56.

What does the anion gap represent?

The AG is a valuable clinical calculation derived from the measured extracellular electrolytes and provides an index of acid-base status.¹ Due to the necessity of electroneutrality, the sum of positive charges (cations) in the extracellular fluid must be balanced exactly with the sum of negative charges (anions). However, to routinely measure all of the cations and anions in the serum would be time-consuming and is also unnecessary. Because most clinical laboratories commonly only measure one relevant cation (sodium) and two anions (chloride and bicarbonate), the positive and negative sums are not completely balanced. The AG therefore refers to this difference (ie, AG = Na – [Cl + HCO₃]).

Of course, electroneutrality exists in vivo, and is accomplished by the presence of unmeasured anions (UA) (eg, lactate and phosphate) and unmeasured cations (UC) (eg, potassium and calcium) not accounted for in the AG (ie, AG = UA – UC). In other words, the sum of measured plus the unmeasured anions must equal the sum of the measured plus unmeasured cations.

What causes a low or negative anion gap?

While most healthcare providers are well versed in the clinical significance of an elevated AG (eg, MUDPILES [methanol, uremia, diabetic ketoacidosis, propylene glycol or phenformin, iron or isoniazid, lactate, ethylene glycol, salicylates]), the meaning of a low or negative AG is underappreciated. There are several scenarios that could potentially yield a low or negative AG, including decreased concentration of UA, increased concentrations of nonsodium cations (UC), and overestimation of serum chloride.

Decreased Concentration of Unmeasured Anions. This most commonly occurs by two mechanisms: dilution of the extracellular fluid or hypoalbuminemia. The addition of water to the extracellular fluid will cause a proportionate dilution of all the measured electrolytes. Since the concentration of measured cations is higher than the measured anions, there is a small and relatively insignificant decrease in the AG.

Alternatively, hypoalbuminemia results in a low AG due to the change in UA; albumin is negatively charged. At physiologic pH, the overwhelming majority of serum proteins are anionic and counter-balanced by the positive charge of sodium. Albumin, the most abundant serum protein, accounts for approximately 75% of the normal AG. Hypoalbuminemic states, such as cirrhosis or nephrotic syndrome, can therefore cause low AG due to the retention of chloride to replace the lost negative charge. The albumin concentration can be corrected to calculate the AG.²

Nonsodium Cations. There are a number of clinical conditions that result in the retention of nonsodium cations. For example, the excess positively charged paraproteins associated with IgG myeloma raise the UC concentration, resulting in a low AG. Similarly, elevations of unmeasured cationic electrolytes, such as calcium and magnesium, may also result in a lower AG. Significant changes in AG, though, are caused only by profound (and often life-threatening) hypercalcemia or hypermagnesemia.

Overestimation of Serum Chloride. Overestimation of serum chloride most commonly occurs in the clinical scenario of bromide exposure. In normal physiologic conditions, chloride is the only halide present in the extracellular fluid. With intake of brominated products, chloride may be partially replaced by bromide. As there is greater renal tubular avidity for bromide, chronic ingestion of bromide results in a gradual rise in serum bromide concentrations with a proportional fall in chloride. However, and more importantly, bromide interferes with a number of laboratory techniques measuring chloride concentrations, resulting in a spuriously elevated chloride, or pseudohyperchloremia. Because the measured sodium and bicarbonate concentrations will remain unchanged, this falsely elevated chloride measurement will result in a negative AG.

What causes the falsely elevated chloride?

All of the current laboratory techniques for measurement of serum chloride concentration can potentially result in a falsely elevated value. However, the degree of pseudohyperchloremia will depend on the specific assay used for measurement. The ion-selective electrode method used by many common laboratory analyzers appears to have the greatest interference on chloride measurement in the presence of bromide. This is simply due to the molecular similarity of bromide and chloride. Conversely, the coulometry method, often used as a reference standard, has the least interference of current laboratory methods.³ This is because coulometry does not completely rely on molecular structure to measure concentration, but rather it measures the amount of energy produced or consumed in an electrolysis reaction. Iodide, another halide compound, has also been described as a cause of pseudohyperchloremia, whereas fluoride does not seem to have significant interference.⁴ 

How are patients exposed to bromide salts?

Bromide salts, specifically sodium bromide, are infrequently used to treat seizure disorders, but are generally reserved for patients with epilepsy refractory to other, less toxic anticonvulsant medications. During the era when bromide salts were more commonly used to treat epilepsy, bromide intoxication, or bromism, was frequently observed.

Bromism may manifest as a constellation of nonspecific neurological and psychiatric symptoms. These most commonly include headache, weakness, agitation, confusion, and hallucinations. In more severe cases of bromism, stupor and coma may occur.^3,5

Although bromide salts are no longer commonly prescribed, a number of products still contain brominated ingredients. Symptoms of bromide intoxication can occur with chronic use of a cough syrup containing dextromethorphan hydrobromide as well as the brominated vegetable oils found in some soft drinks.⁵ 

How is bromism treated?

The treatment of bromism involves preventing further exposure to bromide and promoting bromide excretion. Bromide has a long half-life (10-12 days), and in patients with normal renal function, it is possible to reduce this half-life to approximately 3 days with hydration and diuresis with sodium chloride.³ Alternatively, in patients with impaired renal function or severe intoxication, hemodialysis has been used effectively.⁵

Case Conclusion

The patient was admitted for observation and treated with intravenous sodium chloride. After consultation with his neurologist, he was discharged home in the care of his parents, who were advised to continue him on sodium bromide 185 mg orally twice daily since his seizures were refractory to other anticonvulsant medications.

Dr Repplinger is a medical toxicology fellow in the department of emergency medicine at New York University Langone Medical Center. 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

An 8-month-old boy with a history of hypotonia, developmental delay, and seizure disorder refractory to multiple anticonvulsant medications, was presented to the ED with a 2-week history of intermittent fever and poor oral intake. His current medications included sodium bromide 185 mg orally twice daily for his seizure disorder.

On physical examination, the boy appeared small for his age, with diffuse hypotonia and diminished reflexes. He was able to track with his eyes but was otherwise unresponsive. No rash was present. Results of initial laboratory studies were: sodium 144 mEq/L; potassium, 4.8 mEq/L; chloride, 179 mEq/L; bicarbonate, 21 mEq/L; blood urea nitrogen, 6 mg/dL; creatinine, 0.1 mg/dL; and glucose, 63 mg/dL. His anion gap (AG) was −56.

What does the anion gap represent?

The AG is a valuable clinical calculation derived from the measured extracellular electrolytes and provides an index of acid-base status.¹ Due to the necessity of electroneutrality, the sum of positive charges (cations) in the extracellular fluid must be balanced exactly with the sum of negative charges (anions). However, to routinely measure all of the cations and anions in the serum would be time-consuming and is also unnecessary. Because most clinical laboratories commonly only measure one relevant cation (sodium) and two anions (chloride and bicarbonate), the positive and negative sums are not completely balanced. The AG therefore refers to this difference (ie, AG = Na – [Cl + HCO₃]).

Of course, electroneutrality exists in vivo, and is accomplished by the presence of unmeasured anions (UA) (eg, lactate and phosphate) and unmeasured cations (UC) (eg, potassium and calcium) not accounted for in the AG (ie, AG = UA – UC). In other words, the sum of measured plus the unmeasured anions must equal the sum of the measured plus unmeasured cations.

What causes a low or negative anion gap?

While most healthcare providers are well versed in the clinical significance of an elevated AG (eg, MUDPILES [methanol, uremia, diabetic ketoacidosis, propylene glycol or phenformin, iron or isoniazid, lactate, ethylene glycol, salicylates]), the meaning of a low or negative AG is underappreciated. There are several scenarios that could potentially yield a low or negative AG, including decreased concentration of UA, increased concentrations of nonsodium cations (UC), and overestimation of serum chloride.

Decreased Concentration of Unmeasured Anions. This most commonly occurs by two mechanisms: dilution of the extracellular fluid or hypoalbuminemia. The addition of water to the extracellular fluid will cause a proportionate dilution of all the measured electrolytes. Since the concentration of measured cations is higher than the measured anions, there is a small and relatively insignificant decrease in the AG.

Alternatively, hypoalbuminemia results in a low AG due to the change in UA; albumin is negatively charged. At physiologic pH, the overwhelming majority of serum proteins are anionic and counter-balanced by the positive charge of sodium. Albumin, the most abundant serum protein, accounts for approximately 75% of the normal AG. Hypoalbuminemic states, such as cirrhosis or nephrotic syndrome, can therefore cause low AG due to the retention of chloride to replace the lost negative charge. The albumin concentration can be corrected to calculate the AG.²

Nonsodium Cations. There are a number of clinical conditions that result in the retention of nonsodium cations. For example, the excess positively charged paraproteins associated with IgG myeloma raise the UC concentration, resulting in a low AG. Similarly, elevations of unmeasured cationic electrolytes, such as calcium and magnesium, may also result in a lower AG. Significant changes in AG, though, are caused only by profound (and often life-threatening) hypercalcemia or hypermagnesemia.

Overestimation of Serum Chloride. Overestimation of serum chloride most commonly occurs in the clinical scenario of bromide exposure. In normal physiologic conditions, chloride is the only halide present in the extracellular fluid. With intake of brominated products, chloride may be partially replaced by bromide. As there is greater renal tubular avidity for bromide, chronic ingestion of bromide results in a gradual rise in serum bromide concentrations with a proportional fall in chloride. However, and more importantly, bromide interferes with a number of laboratory techniques measuring chloride concentrations, resulting in a spuriously elevated chloride, or pseudohyperchloremia. Because the measured sodium and bicarbonate concentrations will remain unchanged, this falsely elevated chloride measurement will result in a negative AG.

What causes the falsely elevated chloride?

All of the current laboratory techniques for measurement of serum chloride concentration can potentially result in a falsely elevated value. However, the degree of pseudohyperchloremia will depend on the specific assay used for measurement. The ion-selective electrode method used by many common laboratory analyzers appears to have the greatest interference on chloride measurement in the presence of bromide. This is simply due to the molecular similarity of bromide and chloride. Conversely, the coulometry method, often used as a reference standard, has the least interference of current laboratory methods.³ This is because coulometry does not completely rely on molecular structure to measure concentration, but rather it measures the amount of energy produced or consumed in an electrolysis reaction. Iodide, another halide compound, has also been described as a cause of pseudohyperchloremia, whereas fluoride does not seem to have significant interference.⁴ 

How are patients exposed to bromide salts?

Bromide salts, specifically sodium bromide, are infrequently used to treat seizure disorders, but are generally reserved for patients with epilepsy refractory to other, less toxic anticonvulsant medications. During the era when bromide salts were more commonly used to treat epilepsy, bromide intoxication, or bromism, was frequently observed.

Bromism may manifest as a constellation of nonspecific neurological and psychiatric symptoms. These most commonly include headache, weakness, agitation, confusion, and hallucinations. In more severe cases of bromism, stupor and coma may occur.^3,5

Although bromide salts are no longer commonly prescribed, a number of products still contain brominated ingredients. Symptoms of bromide intoxication can occur with chronic use of a cough syrup containing dextromethorphan hydrobromide as well as the brominated vegetable oils found in some soft drinks.⁵ 

How is bromism treated?

The treatment of bromism involves preventing further exposure to bromide and promoting bromide excretion. Bromide has a long half-life (10-12 days), and in patients with normal renal function, it is possible to reduce this half-life to approximately 3 days with hydration and diuresis with sodium chloride.³ Alternatively, in patients with impaired renal function or severe intoxication, hemodialysis has been used effectively.⁵

Case Conclusion

The patient was admitted for observation and treated with intravenous sodium chloride. After consultation with his neurologist, he was discharged home in the care of his parents, who were advised to continue him on sodium bromide 185 mg orally twice daily since his seizures were refractory to other anticonvulsant medications.

Dr Repplinger is a medical toxicology fellow in the department of emergency medicine at New York University Langone Medical Center. 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.

Pericarditis is in most cases a one-time disease simply treated with anti-inflammatory drugs. It requires no extensive workup for systemic inflammatory or autoimmune disease. Further evaluation is required for patients who have recurrent pericarditis resistant to conventional therapy or pericarditis with manifestations of systemic disease.

ACUTE PERICARDITIS

Pericardial disease has different presentations: acute, recurrent, constrictive, effusive-constrictive, and pericardial effusion with or without tamponade. Acute pericarditis is the most common of these and can affect people of all ages. The typical acute manifestations are chest pain (usually pleuritic), a pericardial friction rub, and widespread ST-segment elevation on the electrocardiogram.^1,2 The chest pain tends to be sharp and long-lasting; it radiates to the trapezius ridge and increases during respiration or body movements.

Acute pericarditis usually responds to an anti-inflammatory drug such as colchicine 0.6 mg/day for 3 months, a nonsteroidal anti-inflammatory drug such as ibuprofen 600 mg three times a day for 10 days, and in advanced resistant cases, an oral corticosteroid.^3,4

Most often, pericarditis is either idiopathic or occurs after a respiratory viral illness. Much less common causes include bacterial infection, postpericardiotomy syndrome, myocardial infarction, primary or metastatic tumors, trauma, radiation, and uremia. However, pericarditis can also be part of the presentation of systemic inflammatory and autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus; hereditary periodic fever syndromes such as familial Mediterranean fever; and systemic-onset juvenile idiopathic arthritis.^1,5

Patients with recurrent pericarditis and pericarditis with manifestations of systemic disease need a thorough workup for autoimmune disease

In acute pericarditis, a complex workup is usually not justified, since the results will have limited usefulness in the clinical management of the patient. It is most often diagnosed by the presenting symptoms, auscultation, electrocardiography, echocardiography, and chest radiography, and by additional basic tests that include a complete blood cell count, complete metabolic profile, erythrocyte sedimentation rate, and C-reactive protein level. However, if pericarditis does not respond to anti-inflammatory treatment and if an autoimmune or infectious disease is suspected, further evaluation may include antinuclear antibody testing and testing for human immunodeficiency virus and tuberculosis. If the diagnosis of acute pericarditis remains uncertain, cardiac magnetic resonance imaging (MRI) may be useful.

RECURRENT PERICARDITIS

Although acute pericarditis most often has a benign course and responds well to anti-inflammatory drugs, 20% to 30% of patients who have a first attack of acute pericarditis have a recurrence, and up to 50% of patients who have one recurrence will have another.^3,4

Disease activity can be followed with serial testing of inflammatory markers—eg, erythrocyte sedimentation rate and C-reactive protein level. Echocardiography, cardiac computed tomography, and cardiac MRI can characterize active inflammation, edema, pericardial thickness, and pericardial effusion.^6–8

Recurrent pericarditis is often resistant to standard therapy and requires corticosteroids in high doses, which paradoxically can increase the risk of recurrence. Therefore, further workup for underlying autoimmune disease, systemic inflammatory disease, or infection is necessary. More potent immunosuppressive therapy may be required, not only in pericarditis associated with systemic autoimmune or inflammatory conditions, but even in idiopathic recurrent pericarditis, either to control symptoms or to mitigate the effects of corticosteroids.

SYSTEMIC INFLAMMATION

The true prevalence of pericardial disease in most systemic inflammatory and autoimmune diseases is difficult to determine from current data. But advances in serologic testing and imaging techniques have shown cardiac involvement in a number of inflammatory diseases.⁹

In one study, a serologic autoimmune workup in patients with acute pericarditis found that 2% had collagen vascular disease.⁹ Pericardial involvement is likely in systemic lupus erythematosus,¹⁰ and a postmortem study of patients with systemic sclerosis found that 72% had pericarditis.¹¹ Mixed connective tissue disease has been associated with pericarditis in 29% of cases and 56% in autopsy studies.^12,13  Pericarditis may be the initial manifestation of vasculitis—eg, Takayasu arteritis or granulomatosis with polyangiitis (formerly known as Wegener granulomatosis).

Other diseases with pericardial involvement include Still disease, Sjögren syndrome, sarcoidosis, and inflammatory bowel disease. Symptomatic pericarditis occurs in about 25% of patients with Sjögren syndrome and asymptomatic pericardial involvement in more than half. Autopsy studies reported pericardial involvement in up to 80% of patients with systemic lupus erythematosus. Cardiac tamponade occurs in fewer than 2%, and constrictive pericarditis is extremely rare.^5,9–11

RECOMMENDATIONS

Patients with a first episode of pericarditis should be treated with an anti-inflammatory medication, with no comprehensive testing for autoimmune disease. An evaluation for autoimmune and infectious disease should be carried out in patients with fever (temperature > 38°C; 100.4°F), recurrent pericarditis, recurrent large pericardial effusion or tamponade, or night sweats despite conventional medical therapy. Signs of systemic disease such as renal failure, elevated liver enzymes, or skin rash merit further evaluation.

Prospective studies using appropriate serologic testing and imaging are needed to determine the correlation between myopericardial involvement and inflammatory diseases because of increased morbidity and mortality in several of these diseases.

Pericarditis is in most cases a one-time disease simply treated with anti-inflammatory drugs. It requires no extensive workup for systemic inflammatory or autoimmune disease. Further evaluation is required for patients who have recurrent pericarditis resistant to conventional therapy or pericarditis with manifestations of systemic disease.

ACUTE PERICARDITIS

Pericardial disease has different presentations: acute, recurrent, constrictive, effusive-constrictive, and pericardial effusion with or without tamponade. Acute pericarditis is the most common of these and can affect people of all ages. The typical acute manifestations are chest pain (usually pleuritic), a pericardial friction rub, and widespread ST-segment elevation on the electrocardiogram.^1,2 The chest pain tends to be sharp and long-lasting; it radiates to the trapezius ridge and increases during respiration or body movements.

Acute pericarditis usually responds to an anti-inflammatory drug such as colchicine 0.6 mg/day for 3 months, a nonsteroidal anti-inflammatory drug such as ibuprofen 600 mg three times a day for 10 days, and in advanced resistant cases, an oral corticosteroid.^3,4

Most often, pericarditis is either idiopathic or occurs after a respiratory viral illness. Much less common causes include bacterial infection, postpericardiotomy syndrome, myocardial infarction, primary or metastatic tumors, trauma, radiation, and uremia. However, pericarditis can also be part of the presentation of systemic inflammatory and autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus; hereditary periodic fever syndromes such as familial Mediterranean fever; and systemic-onset juvenile idiopathic arthritis.^1,5

Patients with recurrent pericarditis and pericarditis with manifestations of systemic disease need a thorough workup for autoimmune disease

In acute pericarditis, a complex workup is usually not justified, since the results will have limited usefulness in the clinical management of the patient. It is most often diagnosed by the presenting symptoms, auscultation, electrocardiography, echocardiography, and chest radiography, and by additional basic tests that include a complete blood cell count, complete metabolic profile, erythrocyte sedimentation rate, and C-reactive protein level. However, if pericarditis does not respond to anti-inflammatory treatment and if an autoimmune or infectious disease is suspected, further evaluation may include antinuclear antibody testing and testing for human immunodeficiency virus and tuberculosis. If the diagnosis of acute pericarditis remains uncertain, cardiac magnetic resonance imaging (MRI) may be useful.

RECURRENT PERICARDITIS

Although acute pericarditis most often has a benign course and responds well to anti-inflammatory drugs, 20% to 30% of patients who have a first attack of acute pericarditis have a recurrence, and up to 50% of patients who have one recurrence will have another.^3,4

Disease activity can be followed with serial testing of inflammatory markers—eg, erythrocyte sedimentation rate and C-reactive protein level. Echocardiography, cardiac computed tomography, and cardiac MRI can characterize active inflammation, edema, pericardial thickness, and pericardial effusion.^6–8

Recurrent pericarditis is often resistant to standard therapy and requires corticosteroids in high doses, which paradoxically can increase the risk of recurrence. Therefore, further workup for underlying autoimmune disease, systemic inflammatory disease, or infection is necessary. More potent immunosuppressive therapy may be required, not only in pericarditis associated with systemic autoimmune or inflammatory conditions, but even in idiopathic recurrent pericarditis, either to control symptoms or to mitigate the effects of corticosteroids.

SYSTEMIC INFLAMMATION

The true prevalence of pericardial disease in most systemic inflammatory and autoimmune diseases is difficult to determine from current data. But advances in serologic testing and imaging techniques have shown cardiac involvement in a number of inflammatory diseases.⁹

In one study, a serologic autoimmune workup in patients with acute pericarditis found that 2% had collagen vascular disease.⁹ Pericardial involvement is likely in systemic lupus erythematosus,¹⁰ and a postmortem study of patients with systemic sclerosis found that 72% had pericarditis.¹¹ Mixed connective tissue disease has been associated with pericarditis in 29% of cases and 56% in autopsy studies.^12,13  Pericarditis may be the initial manifestation of vasculitis—eg, Takayasu arteritis or granulomatosis with polyangiitis (formerly known as Wegener granulomatosis).

Other diseases with pericardial involvement include Still disease, Sjögren syndrome, sarcoidosis, and inflammatory bowel disease. Symptomatic pericarditis occurs in about 25% of patients with Sjögren syndrome and asymptomatic pericardial involvement in more than half. Autopsy studies reported pericardial involvement in up to 80% of patients with systemic lupus erythematosus. Cardiac tamponade occurs in fewer than 2%, and constrictive pericarditis is extremely rare.^5,9–11

RECOMMENDATIONS

Patients with a first episode of pericarditis should be treated with an anti-inflammatory medication, with no comprehensive testing for autoimmune disease. An evaluation for autoimmune and infectious disease should be carried out in patients with fever (temperature > 38°C; 100.4°F), recurrent pericarditis, recurrent large pericardial effusion or tamponade, or night sweats despite conventional medical therapy. Signs of systemic disease such as renal failure, elevated liver enzymes, or skin rash merit further evaluation.

Prospective studies using appropriate serologic testing and imaging are needed to determine the correlation between myopericardial involvement and inflammatory diseases because of increased morbidity and mortality in several of these diseases.

Pericarditis is in most cases a one-time disease simply treated with anti-inflammatory drugs. It requires no extensive workup for systemic inflammatory or autoimmune disease. Further evaluation is required for patients who have recurrent pericarditis resistant to conventional therapy or pericarditis with manifestations of systemic disease.

ACUTE PERICARDITIS

Pericardial disease has different presentations: acute, recurrent, constrictive, effusive-constrictive, and pericardial effusion with or without tamponade. Acute pericarditis is the most common of these and can affect people of all ages. The typical acute manifestations are chest pain (usually pleuritic), a pericardial friction rub, and widespread ST-segment elevation on the electrocardiogram.^1,2 The chest pain tends to be sharp and long-lasting; it radiates to the trapezius ridge and increases during respiration or body movements.

Acute pericarditis usually responds to an anti-inflammatory drug such as colchicine 0.6 mg/day for 3 months, a nonsteroidal anti-inflammatory drug such as ibuprofen 600 mg three times a day for 10 days, and in advanced resistant cases, an oral corticosteroid.^3,4

Most often, pericarditis is either idiopathic or occurs after a respiratory viral illness. Much less common causes include bacterial infection, postpericardiotomy syndrome, myocardial infarction, primary or metastatic tumors, trauma, radiation, and uremia. However, pericarditis can also be part of the presentation of systemic inflammatory and autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus; hereditary periodic fever syndromes such as familial Mediterranean fever; and systemic-onset juvenile idiopathic arthritis.^1,5

Patients with recurrent pericarditis and pericarditis with manifestations of systemic disease need a thorough workup for autoimmune disease

In acute pericarditis, a complex workup is usually not justified, since the results will have limited usefulness in the clinical management of the patient. It is most often diagnosed by the presenting symptoms, auscultation, electrocardiography, echocardiography, and chest radiography, and by additional basic tests that include a complete blood cell count, complete metabolic profile, erythrocyte sedimentation rate, and C-reactive protein level. However, if pericarditis does not respond to anti-inflammatory treatment and if an autoimmune or infectious disease is suspected, further evaluation may include antinuclear antibody testing and testing for human immunodeficiency virus and tuberculosis. If the diagnosis of acute pericarditis remains uncertain, cardiac magnetic resonance imaging (MRI) may be useful.

RECURRENT PERICARDITIS

Although acute pericarditis most often has a benign course and responds well to anti-inflammatory drugs, 20% to 30% of patients who have a first attack of acute pericarditis have a recurrence, and up to 50% of patients who have one recurrence will have another.^3,4

Disease activity can be followed with serial testing of inflammatory markers—eg, erythrocyte sedimentation rate and C-reactive protein level. Echocardiography, cardiac computed tomography, and cardiac MRI can characterize active inflammation, edema, pericardial thickness, and pericardial effusion.^6–8

Recurrent pericarditis is often resistant to standard therapy and requires corticosteroids in high doses, which paradoxically can increase the risk of recurrence. Therefore, further workup for underlying autoimmune disease, systemic inflammatory disease, or infection is necessary. More potent immunosuppressive therapy may be required, not only in pericarditis associated with systemic autoimmune or inflammatory conditions, but even in idiopathic recurrent pericarditis, either to control symptoms or to mitigate the effects of corticosteroids.

SYSTEMIC INFLAMMATION

The true prevalence of pericardial disease in most systemic inflammatory and autoimmune diseases is difficult to determine from current data. But advances in serologic testing and imaging techniques have shown cardiac involvement in a number of inflammatory diseases.⁹

In one study, a serologic autoimmune workup in patients with acute pericarditis found that 2% had collagen vascular disease.⁹ Pericardial involvement is likely in systemic lupus erythematosus,¹⁰ and a postmortem study of patients with systemic sclerosis found that 72% had pericarditis.¹¹ Mixed connective tissue disease has been associated with pericarditis in 29% of cases and 56% in autopsy studies.^12,13  Pericarditis may be the initial manifestation of vasculitis—eg, Takayasu arteritis or granulomatosis with polyangiitis (formerly known as Wegener granulomatosis).

Other diseases with pericardial involvement include Still disease, Sjögren syndrome, sarcoidosis, and inflammatory bowel disease. Symptomatic pericarditis occurs in about 25% of patients with Sjögren syndrome and asymptomatic pericardial involvement in more than half. Autopsy studies reported pericardial involvement in up to 80% of patients with systemic lupus erythematosus. Cardiac tamponade occurs in fewer than 2%, and constrictive pericarditis is extremely rare.^5,9–11

RECOMMENDATIONS

Patients with a first episode of pericarditis should be treated with an anti-inflammatory medication, with no comprehensive testing for autoimmune disease. An evaluation for autoimmune and infectious disease should be carried out in patients with fever (temperature > 38°C; 100.4°F), recurrent pericarditis, recurrent large pericardial effusion or tamponade, or night sweats despite conventional medical therapy. Signs of systemic disease such as renal failure, elevated liver enzymes, or skin rash merit further evaluation.

Prospective studies using appropriate serologic testing and imaging are needed to determine the correlation between myopericardial involvement and inflammatory diseases because of increased morbidity and mortality in several of these diseases.

A 72-year-old woman came to the emergency department because of persistent light-headedness. Her medical history included end-stage renal disease, hypertension, peripheral vascular disease, and diabetes mellitus. She said she had experienced similar symptoms before, but they had gone away.

She reported no visual changes, no loss of consciousness, and no history of seizures, syncope, chest pain, palpitations, or diaphoresis. She was not taking a beta-blocker, calcium channel blocker, or digoxin.

Her blood pressure was 75/44 mm Hg, heart rate 44 beats per minute, respiratory rate 16 breaths per minute, and oxygen saturation 97% while receiving oxygen at 3 L per minute. An electrolyte panel was normal except for an elevated creatinine level secondary to end-stage renal disease.

In view of her symptoms and bradycardia, she was admitted to the hospital. The initial electrocardiogram (Figure 1) showed an atrial rate of approximately 46 beats per minute, a ventricular rate of approximately 48 beats per minute, and a P wave in the refractory period caused by a junction impulse.

These findings pointed to atrioventricular (AV) dissociation, a term commonly applied to arrhythmias in which the atria and ventricles are rhythmically detached.

ATRIOVENTRICULAR DISSOCIATION

AV dissociation is often used interchangeably with complete heart block, but this is incorrect¹; though complete heart block is a form of AV dissociation, not all AV dissociation is complete heart block. In complete heart block, there is no rhythmic relationship between the atria and ventricles, as they beat independently with no influence on each other. On the other hand, when a “blockade” is created by the physiologic refractory period of the atria (sinus node or atrial ectopic focus) and ventricles, interference dissociation can result.² In this condition, when the ventricles are not in a refractory period, an atrial impulse may be conducted through the AV node, resulting in an atrial-driven beat. Simply put, a P wave has the potential to be conducted in AV dissociation if there is an opportunity, but in complete heart block it does not.¹

In AV dissociation, the ventricular rate is higher than the atrial rate

AV dissociation is a secondary manifestation of a primary disorder or rhythm disturbance. In general, any rhythm that competes against an atrial impulse and inhibits its conduction through the AV node can cause AV dissociation. Common examples include junctional escape or accelerated rhythms, premature ventricular beats or ventricular tachycardia, and accelerated idioventricular rhythms. It also can be caused by drugs (eg, digoxin) or an increase in vagal tone.²

In normal myocardium, the sinus node has a higher impulse rate than the subordinate pacemaker (AV node or ventricular pacemaker). Generally, the atrial rate is higher than the ventricular rate in complete heart block, whereas in AV dissociation the ventricular rate is higher than the atrial rate.³

Thus, AV dissociation can result from one of the following mechanisms⁴:

• Slowing of the dominant pacemaker (sinus or atrial pacemaker)
• Acceleration or overtaking of the sinus node (or atrial focus) by a subordinate pacemaker (eg, a junctional or ventricular pacemaker)
• A block within the AV node that prevents an impulse generated by the dominant pacemaker (sinus or atrial focus) from crossing the AV node
• A combination of these mechanisms.

Another form of AV dissociation is isorhythmic dissociation. In this subtype, atrial and ventricular impulses occur at the same rate. This type of dissociation is most commonly confused with third-degree (or complete) heart block. It may be difficult to distinguish one from the other, but at higher sinus (or atrial) rates the difference becomes obvious—properly timed P waves may be conducted through the AV node in isorhythmic dissociation.¹

The prevalence of AV dissociation is thought to be 0.48% to 0.68%,³ but it could be more common since it is underdiagnosed.⁵

Treatment should be directed at the primary disorder.⁴ The need for a pacemaker depends on the condition causing the AV dissociation. In conditions that slow the sinus node, such as increased vagal tone, patients may benefit from medications that decrease parasympathetic activity or increase adrenergic activity in the AV node (eg, isoproterenol, atropine).⁶ 

OUR PATIENT

Our patient’s electrocardiogram showed interference dissociation from competing junctional rhythms. Possibly, she had sinus node disease, explaining why the sinus node was not the dominant pacemaker. She had symptomatic hypotension, requiring dopamine for pressure support. She was started on intravenous isoproterenol, which eventually restored sinus rhythm.

During the same hospitalization, she was diagnosed with osteomyelitis of the left foot, without bacteremia. She was treated for her infection and later received a pacemaker. She was discharged to a rehabilitation facility.

TAKE-AWAY POINTS

• When an occasional impulse is conducted through the AV node, AV dissociation is most likely interference dissociation.
• AV dissociations are often confused with complete heart block.
• In AV dissociation, the ventricular rate is higher than the atrial rate.
• Complete heart block is a form of AV dissociation, but not all AV dissociation is complete heart block.
• AV dissociation can be caused by three main mechanisms or by a combination of them.
• AV dissociation is secondary to a primary rhythm disorder.
• Adrenergic drugs may help to correct the AV dissociation, but not always completely.

A 72-year-old woman came to the emergency department because of persistent light-headedness. Her medical history included end-stage renal disease, hypertension, peripheral vascular disease, and diabetes mellitus. She said she had experienced similar symptoms before, but they had gone away.

She reported no visual changes, no loss of consciousness, and no history of seizures, syncope, chest pain, palpitations, or diaphoresis. She was not taking a beta-blocker, calcium channel blocker, or digoxin.

Her blood pressure was 75/44 mm Hg, heart rate 44 beats per minute, respiratory rate 16 breaths per minute, and oxygen saturation 97% while receiving oxygen at 3 L per minute. An electrolyte panel was normal except for an elevated creatinine level secondary to end-stage renal disease.

In view of her symptoms and bradycardia, she was admitted to the hospital. The initial electrocardiogram (Figure 1) showed an atrial rate of approximately 46 beats per minute, a ventricular rate of approximately 48 beats per minute, and a P wave in the refractory period caused by a junction impulse.

These findings pointed to atrioventricular (AV) dissociation, a term commonly applied to arrhythmias in which the atria and ventricles are rhythmically detached.

ATRIOVENTRICULAR DISSOCIATION

AV dissociation is often used interchangeably with complete heart block, but this is incorrect¹; though complete heart block is a form of AV dissociation, not all AV dissociation is complete heart block. In complete heart block, there is no rhythmic relationship between the atria and ventricles, as they beat independently with no influence on each other. On the other hand, when a “blockade” is created by the physiologic refractory period of the atria (sinus node or atrial ectopic focus) and ventricles, interference dissociation can result.² In this condition, when the ventricles are not in a refractory period, an atrial impulse may be conducted through the AV node, resulting in an atrial-driven beat. Simply put, a P wave has the potential to be conducted in AV dissociation if there is an opportunity, but in complete heart block it does not.¹

In AV dissociation, the ventricular rate is higher than the atrial rate

AV dissociation is a secondary manifestation of a primary disorder or rhythm disturbance. In general, any rhythm that competes against an atrial impulse and inhibits its conduction through the AV node can cause AV dissociation. Common examples include junctional escape or accelerated rhythms, premature ventricular beats or ventricular tachycardia, and accelerated idioventricular rhythms. It also can be caused by drugs (eg, digoxin) or an increase in vagal tone.²

In normal myocardium, the sinus node has a higher impulse rate than the subordinate pacemaker (AV node or ventricular pacemaker). Generally, the atrial rate is higher than the ventricular rate in complete heart block, whereas in AV dissociation the ventricular rate is higher than the atrial rate.³

Thus, AV dissociation can result from one of the following mechanisms⁴:

• Slowing of the dominant pacemaker (sinus or atrial pacemaker)
• Acceleration or overtaking of the sinus node (or atrial focus) by a subordinate pacemaker (eg, a junctional or ventricular pacemaker)
• A block within the AV node that prevents an impulse generated by the dominant pacemaker (sinus or atrial focus) from crossing the AV node
• A combination of these mechanisms.

Another form of AV dissociation is isorhythmic dissociation. In this subtype, atrial and ventricular impulses occur at the same rate. This type of dissociation is most commonly confused with third-degree (or complete) heart block. It may be difficult to distinguish one from the other, but at higher sinus (or atrial) rates the difference becomes obvious—properly timed P waves may be conducted through the AV node in isorhythmic dissociation.¹

The prevalence of AV dissociation is thought to be 0.48% to 0.68%,³ but it could be more common since it is underdiagnosed.⁵

Treatment should be directed at the primary disorder.⁴ The need for a pacemaker depends on the condition causing the AV dissociation. In conditions that slow the sinus node, such as increased vagal tone, patients may benefit from medications that decrease parasympathetic activity or increase adrenergic activity in the AV node (eg, isoproterenol, atropine).⁶ 

OUR PATIENT

Our patient’s electrocardiogram showed interference dissociation from competing junctional rhythms. Possibly, she had sinus node disease, explaining why the sinus node was not the dominant pacemaker. She had symptomatic hypotension, requiring dopamine for pressure support. She was started on intravenous isoproterenol, which eventually restored sinus rhythm.

During the same hospitalization, she was diagnosed with osteomyelitis of the left foot, without bacteremia. She was treated for her infection and later received a pacemaker. She was discharged to a rehabilitation facility.

TAKE-AWAY POINTS

• When an occasional impulse is conducted through the AV node, AV dissociation is most likely interference dissociation.
• AV dissociations are often confused with complete heart block.
• In AV dissociation, the ventricular rate is higher than the atrial rate.
• Complete heart block is a form of AV dissociation, but not all AV dissociation is complete heart block.
• AV dissociation can be caused by three main mechanisms or by a combination of them.
• AV dissociation is secondary to a primary rhythm disorder.
• Adrenergic drugs may help to correct the AV dissociation, but not always completely.

A 72-year-old woman came to the emergency department because of persistent light-headedness. Her medical history included end-stage renal disease, hypertension, peripheral vascular disease, and diabetes mellitus. She said she had experienced similar symptoms before, but they had gone away.

She reported no visual changes, no loss of consciousness, and no history of seizures, syncope, chest pain, palpitations, or diaphoresis. She was not taking a beta-blocker, calcium channel blocker, or digoxin.

Her blood pressure was 75/44 mm Hg, heart rate 44 beats per minute, respiratory rate 16 breaths per minute, and oxygen saturation 97% while receiving oxygen at 3 L per minute. An electrolyte panel was normal except for an elevated creatinine level secondary to end-stage renal disease.

In view of her symptoms and bradycardia, she was admitted to the hospital. The initial electrocardiogram (Figure 1) showed an atrial rate of approximately 46 beats per minute, a ventricular rate of approximately 48 beats per minute, and a P wave in the refractory period caused by a junction impulse.

These findings pointed to atrioventricular (AV) dissociation, a term commonly applied to arrhythmias in which the atria and ventricles are rhythmically detached.

ATRIOVENTRICULAR DISSOCIATION

AV dissociation is often used interchangeably with complete heart block, but this is incorrect¹; though complete heart block is a form of AV dissociation, not all AV dissociation is complete heart block. In complete heart block, there is no rhythmic relationship between the atria and ventricles, as they beat independently with no influence on each other. On the other hand, when a “blockade” is created by the physiologic refractory period of the atria (sinus node or atrial ectopic focus) and ventricles, interference dissociation can result.² In this condition, when the ventricles are not in a refractory period, an atrial impulse may be conducted through the AV node, resulting in an atrial-driven beat. Simply put, a P wave has the potential to be conducted in AV dissociation if there is an opportunity, but in complete heart block it does not.¹

In AV dissociation, the ventricular rate is higher than the atrial rate

AV dissociation is a secondary manifestation of a primary disorder or rhythm disturbance. In general, any rhythm that competes against an atrial impulse and inhibits its conduction through the AV node can cause AV dissociation. Common examples include junctional escape or accelerated rhythms, premature ventricular beats or ventricular tachycardia, and accelerated idioventricular rhythms. It also can be caused by drugs (eg, digoxin) or an increase in vagal tone.²

In normal myocardium, the sinus node has a higher impulse rate than the subordinate pacemaker (AV node or ventricular pacemaker). Generally, the atrial rate is higher than the ventricular rate in complete heart block, whereas in AV dissociation the ventricular rate is higher than the atrial rate.³

Thus, AV dissociation can result from one of the following mechanisms⁴:

• Slowing of the dominant pacemaker (sinus or atrial pacemaker)
• Acceleration or overtaking of the sinus node (or atrial focus) by a subordinate pacemaker (eg, a junctional or ventricular pacemaker)
• A block within the AV node that prevents an impulse generated by the dominant pacemaker (sinus or atrial focus) from crossing the AV node
• A combination of these mechanisms.

Another form of AV dissociation is isorhythmic dissociation. In this subtype, atrial and ventricular impulses occur at the same rate. This type of dissociation is most commonly confused with third-degree (or complete) heart block. It may be difficult to distinguish one from the other, but at higher sinus (or atrial) rates the difference becomes obvious—properly timed P waves may be conducted through the AV node in isorhythmic dissociation.¹

The prevalence of AV dissociation is thought to be 0.48% to 0.68%,³ but it could be more common since it is underdiagnosed.⁵

Treatment should be directed at the primary disorder.⁴ The need for a pacemaker depends on the condition causing the AV dissociation. In conditions that slow the sinus node, such as increased vagal tone, patients may benefit from medications that decrease parasympathetic activity or increase adrenergic activity in the AV node (eg, isoproterenol, atropine).⁶ 

OUR PATIENT

Our patient’s electrocardiogram showed interference dissociation from competing junctional rhythms. Possibly, she had sinus node disease, explaining why the sinus node was not the dominant pacemaker. She had symptomatic hypotension, requiring dopamine for pressure support. She was started on intravenous isoproterenol, which eventually restored sinus rhythm.

During the same hospitalization, she was diagnosed with osteomyelitis of the left foot, without bacteremia. She was treated for her infection and later received a pacemaker. She was discharged to a rehabilitation facility.

TAKE-AWAY POINTS

• When an occasional impulse is conducted through the AV node, AV dissociation is most likely interference dissociation.
• AV dissociations are often confused with complete heart block.
• In AV dissociation, the ventricular rate is higher than the atrial rate.
• Complete heart block is a form of AV dissociation, but not all AV dissociation is complete heart block.
• AV dissociation can be caused by three main mechanisms or by a combination of them.
• AV dissociation is secondary to a primary rhythm disorder.
• Adrenergic drugs may help to correct the AV dissociation, but not always completely.