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Sepsis Biomarkers: What’s New?

Author: Brit Long, MD (@long_brit, EM Attending Physician at SAUSHEC, USAF) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital)

A 43-year-old female presents with cough, congestion, wheezing, fever, and myalgias. She has a history of hypertension and recurrent UTI. She tried to overcome her symptoms with acetaminophen and oral fluids, but her symptoms have worsened. Her vital signs include RR 23, HR 102, BP 102/63, T 101.2, and Saturation 94% on RA. She has right-sided crackles on exam and appears ill, with dry mucosa. You start one liter of LR, while ordering CBC, renal panel, lactate, urinalysis, and chest Xray. Her chest Xray and urinalysis are negative, but after 1L LR, she still appears ill. The lactate returns at 4.2, and you start IV antibiotics with concern for septic shock. Your medical student on shift asks about using procalcitonin to rule out a bacterial cause of sepsis. You know about lactate, but are there other markers you can use in sepsis?

Sepsis is common in the ED and a major cause of morbidity and mortality. The body’s response to an infectious source in sepsis often results in dysregulated immune response, and current diagnosis relies on physiologic criteria and suspicion for a source of infection with laboratory and imaging studies. The host response triggered by the infection can be measured using several biomarkers.1-4

Biomarkers are defined by laboratory assessments used to detect and characterize disease, and they may be used to improve clinical decision-making. Through the years, complete blood cell count (CBC), troponin, creatine kinase (CK), lactate, C-reactive protein (CRP), ESR, and myoglobin have been advocated as biomarkers for a long list of conditions. However, what do biomarkers offer in sepsis? Some argue these biomarkers lack sufficient sensitivity outside of history and exam, while others state these markers can drastically improve medical decision making. In sepsis, diagnosis may not be easy, and a reliable biomarker may be able to improve early diagnosis, risk stratification, assessment of resuscitation, and evaluation.4-8

The post will evaluate several key biomarkers including lactate, procalcitonin, troponin, and novel lab assessments.


Lactate can be used in sepsis for resuscitation and severity stratification. It is normally produced in tissues due to pyruvate and NADH metabolism. There are several causes of lactate elevation, and not all are due to shock. Excess beta activity, inflammatory mediators, and liver disease may increase lactate.8-13  The table below demonstrates types and sources of lactate production.

Type A Type B1

Associated with disease

Type B2

Drugs and Toxins

Type B3

Associated with inborn errors of metabolism

Tissue Hypoperfusion


Anaerobic muscular activity


Reduced tissue oxygen delivery







Thiamine deficiency




Hepatic or renal failure


Short bowel syndrome







Lactate-based dialysate fluid



Alcohols: Methanol, Ethylene Glycol







Anti-retroviral agents

Pyruvate carboxylase deficiency


Glucose-6-phosphatase deficiency


Fructose-1,6-bisphosphatase deficiencies


Oxidative phosphorylation enzyme defects


The Surviving Sepsis Campaign recommends lactate for screening.1 Point of care (POC) lactate can be used for this screen, with specificity of 82% for lactate > 2 mmol/L. However, POC lactate has sensitivity of 30-40%, thus physicians must consider the clinical picture and patient appearance.11-16 Arterial blood is not required for this screening, and a venous blood gas (VBG) is fast and easily obtainable. As long as analysis occurs within 15 minutes of sampling, no effect from tourniquet or room temperature is observed.16,17 Lactate is not as reliable if the sample is run over 30 minutes from the time the sample is obtained.


As lactate elevates, mortality increases. In patients with lactate greater than 2.1 mml/L, mortality approximates 14-16%. If lactate reaches 20 mmol/L, mortality approximates 40% or higher.20 Lactate is an independent marker for mortality, no matter the patient’s hemodynamic status. Lactate greater than 4 mmol/L meets criteria for septic shock, and levels greater than 2 mmol/L are associated with increased mortality and morbidity.1,21-26

What about cryptic shock?

Cryptic shock is defined by sepsis in the patient with normal vital signs. A patient who is hemodynamically stable but with elevated lactate is at increased risk for mortality, as end organ damage occurs soon after lactate production. Thus, lactate serves as an early marker for shock and provides valuable diagnostic information. 9,11,20,21

What to do with the intermediate lactate level…

Lactate > 4 is associated with high mortality, but intermediate levels are as well (2.0-3.9 mmol/L).1,20-26 In fact, levels in this range meets Centers for Medicare and Medicaid Services (CMS) criteria for severe sepsis following SSC guidelines.Importantly, mortality can reach 16.4% for patients in this range, and ¼ of these patients with an intermediate level progress to clinical shock.22 Lactate levels greater than 2 warrant close monitoring and aggressive treatment with IV fluids and antimicrobials. The table below provides recommendations based on lactate level.

Lactate Level CMS Measure Resuscitation Recommendation
< 2 mmol/L None Lactate levels may be negative in over half of patients with sepsis. Clinical gestalt takes precedence over markers.
2-4 mmol/L Severe Sepsis Resuscitation with intravenous fluids, antimicrobials and reassessment of lactate within 60 minutes.
> 4 mmol/L Septic Shock Aggressive resuscitation warranted regardless of vital signs.


Lactate clearance is an important target in sepsis resuscitation. Many target a clearance of 10%, as early lactate clearance is associated with improved outcomes. Arnold et al. found 10% clearance to strongly predict improved outcomes.28 Delayed or no clearance is associated with high mortality, some studies showing 60% mortality rates.28-21 Lactate can be substituted for ScvO2, which requires invasive, specialized equipment.4,28-31


Lactate does not always elevate in sepsis, as 45% of patients with vasopressor-dependent septic shock demonstrate a lactate level of 2.4 mmol/L.32 Hernandez et al. suggested 34% of patients with septic shock did not have elevated lactate, though patients with no lactate elevation had a mortality of 7.7%, while those with lactate elevation 42.9% mortality.33 Lactate should not be used in isolation for assessing presence of shock or as a marker for clinical improvement. Rather, other measures such as mental status, heart rate, urine output, blood pressure, and distal perfusion in combination with lactate is advised.5-7,11



A great deal of literature has evaluated procalcitonin, a calcitonin propeptide produced by the thyroid, GI tract, and lungs with bacterial infection. This biomarker is released in the setting of toxins and proinflammatory mediators, while viral infections inhibit PCT through interferon-gamma production. These levels increase by 3 hours and peak at 6-22 hours, and with infection resolution, levels fall by 50% per day.5-7,34-40 This biomarker can be specific for bacterial infection, decreases with infection control, and is not impaired in the setting of immunosuppressive states (such as steroid use or neutropenia). However, other states including surgery, paraneoplastic states, autoimmune diseases, prolonged shock states, chronic parasitic diseases (such as malaria), certain immunomodulatory medications, and major trauma can increase PCT levels.34-37

Antibiotic Stewardship

Most of the literature evaluating PCT has been published in ICU studies for lower respiratory tract infections (LRTI) and sepsis. The literature suggests algorithms guided by PCT may be able to reduce antibiotic exposure and treatment cost, though with little to no effect on outcomes.37-49

In COPD and bronchitis, it can be difficult to differentiate viral versus bacterial infection. PCT may hold promise in assisting in this differentiation. The ProResp trial randomized patients to two arms, one guided by PCT and the other not.40 If PCT levels were greater than 0.25 mcg/L, antibiotics were given. Ultimately, the group based on PCT demonstrated less antibiotic use (44% in the PCT group, versus 83%), but no difference in length of stay or mortality.40 The ProHOSP trial was a similar trial with the same cutoff. This trial found similar results to the ProResp trial.41


PCT may be useful in sepsis diagnosis, but ultimately, the clinical context and picture must be considered.43-47 Source of infection, illness severity, and likelihood of bacterial infection should take precedence over a lab marker such as PCT, which may not return while the patient is in the ED. If concerned for sepsis, antimicrobials and resuscitation should be started.

 PCT can identify culture positive sepsis and may help in prognostication. Bacterial load may also correlate with level of PCT.34-47 PCT levels of < 0.25 mcg/L indicate that bacterial infection is unlikely, with levels greater than 0.25-0.50 mcg/L indicating bacterial source.38,45-49 However, sensitivity in one meta-analysis was 77%, with specificity of 79%.45

The PRORATA trial evaluated ICU patients admitted with sepsis.48 In this trial, antibiotic use was guided by PCT levels of 0.5 mcg/L. Similar to the prior studies discussed, decreased antibiotic use was found, but the all-important patient mortality benefit was not found. This level of 0.5 mcg/L was recommended as the cutoff for bacterial sepsis diagnosis in a 2015 meta-analysis.49  The following table depicts the PCT levels used in two key studies.

ProHOSP and PRORATA trial PCT Use41,48

Antibiotic Use PCT Level
< 0.1 mcg/L 0.1-0.25 mcg/L 0.25-0.5mcg/L 0.5-1mcg/L > 1.0 mcg/L
ProHOSP antibiotic use (respiratory infection only) No No Yes Yes Yes
PRORATA antibiotic use (sepsis patients in ICU) No No No Yes Yes

Ultimately, PCT should not influence provider decision to diagnose, resuscitate, and manage patients with criteria for sepsis.50,51 This lab may assist ICU providers, specifically when to discontinue antimicrobial therapy. Levels of 0.5 mcg/L strongly suggest bacterial sepsis. Providers in the ICU may be able to trend PCT levels in regards to decision of when to discontinue antimicrobials.  If the clinical picture suggests bacterial source, severe local infection (osteomyelitis, endocarditis, etc.), patient hemodynamic instability, PCT greater than 0.5 mcg/L, or no change in PCT level while on therapy, antimicrobial therapy should continue.37-49


Yep, that’s right, troponin. Troponin is most commonly used to diagnose acute MI, with the AHA stating elevation above the 99th percentile in healthy population meets criteria for ACS.50,51 Troponin can also be used to risk stratify patients entered into the HEART pathway, and high sensitivity troponin can increase sensitivity.50-54 Cardiac troponin consists of two forms: I and T (these are regulatory proteins). Injury of cardiac tissue results in these proteins entering the bloodstream. However, troponin can elevate in multiple settings, shown below.55-59

Cardiac Causes Noncardiac Causes
Acute and Chronic Heart Failure

Acute Inflammatory Myocarditis Endocarditis/Pericarditis

Aortic Dissection

Aortic Valve Disease

Apical Ballooning Syndrome

Bradyarrhythmia, Heart Block

Intervention (endomyocardial biopsy, surgery)


Direct Myocardial Trauma

Hypertrophic Cardiomyopathy


Acute Noncardiac Critical Illness

Acute Pulmonary Edema

Acute PE

Cardiotoxic Drugs

Stroke, Subarachnoid hemorrhage

Chronic Obstructive Pulmonary Disease

Chronic renal failure

Extensive Burns

Infiltrative Disease (amyloidosis)

Rhabdomyolysis with Myocyte Necrosis


Severe Pulmonary Hypertension

Strenuous Exercise/Extreme Exertion

Risk Stratification

Troponin elevation is associated in worse patient outcomes, particularly mortality, as well as increased length of stay. In sepsis, anywhere from 36-85% of patients may demonstrate troponin elevation. 58-68  This elevation is associated with septic shock and mortality, with almost two times the risk of death.58-64,69 Troponin elevation may be due to several factors including demand ischemia, direct myocardial endotoxin damage, cytokine and oxygen free radical damage, and poor cardiac oxygen supply due to microcirculatory dysfunction. 57,60,61,63,65,69 LV diastolic and RV systolic dysfunction are also associated with increased troponin and mortality.64

Troponin elevation in sepsis allows for prognostication and predicts a patient who is sicker. Resuscitation is essential with elevated troponin in sepsis. However, troponin’s role in resuscitation, the assay used, and the cut-off level need to be determined. If an elevation occurs, an ECG should be obtained, along with bedside echo to evaluate for wall motion abnormalities. Sepsis cardiomyopathy can cause diffuse hypokinesis, but focal wall abnormalities require emergent cardiology consultation.56-61


Novel Biomarkers

Sepsis has a complex pathophysiology, which results in a multitude of biomarkers released. These biomarkers are currently under study, and we will discuss several here.5-8

Endothelial Markers

Sepsis results in endothelial changes, associated with modifications in hemostatic balance, change in microcirculation, leukocyte trafficking, vascular permeability, and inflammation.

Measuring this endothelial dysfunction may allow earlier diagnosis of sepsis, as well as prognostication. These include vascular cell adhesion molecule (VCAM-1), soluble intercellular adhesion molecule (ICAM-1), sE-selectin, plasminogen activator inhibitor (PAI-1), and soluble fms-like tyrosine kinase (sFlt-1).5-8,70-73

Proadrenomedullin (ProADM)

This is a precursor for adrenomedullin, a calcitonin peptide. It likely functions in a similar fashion as PCT in the setting of acute cytokine release with bacterial infection. This peptide works as a vasodilator, though it has immune modulating and metabolic effects as well, and it is elevated in renal failure, heart disease, and cancer. ProADM may be able to risk stratify patients with sepsis and pneumonia into different categories based on level.73-79

One study evaluated an algorithm utilizing CURB-65 and ProADM levels.79 CURB-65 is a validated prognostic score for community-acquired pneumonia that consists of BUN > 19 mg/dL (>7 mmol/L), respiratory rate > 30, systolic blood pressure < 90 mm Hg or diastolic blood pressure  < 60 mm Hg, and age > 65 years.80 The algorithm combining CURB-65 and ProADM did not change patient outcome, though it did decrease patient length of stay.79 This marker could assist in prognostication and early discharge, but further study in the ED is needed.

Acute-Phase Reactants

Cytokines are released in response to inflammation, especially sepsis. There are multiple markers including IL-6, IL-8, IL-10, sTREM01, suPAR, CD-64 index, Lipopolysaccharide-binding protein (LBP), ICAM-1, and pentraxins. The greater the elevation in these markers, the worse the prognosis. However, these require further study before regular use can be recommended.8,81

Cardiac Biomarkers

Commonly utilized for heart failure and coronary disease, NT-proBNP and BNP may be associated with worse outcomes in sepsis. Higher levels can predict longer hospital stay and mortality. Obtaining these biomarkers may help predict cardiac dysfunction in sepsis and the need for inotropic medications, though these require further study.67,82-86 Providers must remember that NT-proBNP and BNP lack specificity, as valvular heart disease, Afib, PE, COPD, and hyperthyroidism can elevated these markers, while obesity may decrease levels. 81-85


Key Points:

  • Biomarkers cannot replace the bedside clinician, but they may assist clinical decision making, risk stratification, and prognostication. Lactate has the best evidence in sepsis.
  • Lactate is useful for assessing severity, screening, and resuscitation. However, it is not always elevated in sepsis. Venous POC levels are recommended.
  • Procalcitonin is a marker of bacterial versus viral It is not associated with mortality benefit, but may reduce antibiotic usage. PCT requires further study in the ED.
  • Troponin can be elevated in many conditions and is associated with worse prognosis in sepsis. Sepsis cardiomyopathy is more common than many providers realize.
  • Biomarkers on the horizon include endothelial activators, acute-phase reactants, BNP/NT-proBNP, and proadrenomedullin.


References/Further Reading

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  11. Shapiro NI, Schuetz P, Yano K, et al. The association of endothelial cell signaling, severity of illness, and organ dysfunction in sepsis. Critical Care 2010; 14:R182.
  12. Becker KL, Nylen ES, White JC, Muller B, Snider RH, Jr. Procalcitonin and the calcitonin gene family of peptides in inflammation, infection, and sepsis: a journey from calcitonin back to its precursors. J Clin Endocrinol Metab 2004;89(4):1512–25.
  13. Elsasser TH, Kahl S. Adrenomedullin has multiple roles in disease stress: development and remission of the inflammatory response. Microsc Res Tech 2002;57(2):120–9.
  14. Struck J, Tao C, Morgenthaler NG, Bergmann A. Identification of an Adrenomedullin precursor fragment in plasma of sepsis patients. Peptides 2004;25(8):1369–72.
  15. Christ-Crain M, Morgenthaler NG, Struck J, Harbarth S, Bergmann A, Muller B. Mid-regional pro-adrenomedullin as a prognostic marker in sepsis: an observational study. Crit Care 2005;9(6):R816–24.
  16. Christ-Crain M, Morgenthaler NG, Stolz D, Muller C, Bingisser R, Harbarth S, et al. Pro-adrenomedullin to predict severity and outcome in community-acquired pneumonia [ISRCTN04176397]. Crit Care 2006;10(3):R96.
  17. Schuetz P, Wolbers M, Christ-Crain M, Thomann R, Falconnier C, Widmer I, et al. Prohormones for prediction of adverse medical outcome in community-acquired pneumonia and lower respiratory tract infections. Crit Care 2010;14(3) R106.
  18. Albrich WC, Dusemund F, Ruegger K, Christ-Crain M, Zimmerli W, Bregenzer T, et al. Enhancement of CURB65 score with proadrenomedullin (CURB65–A) for outcome prediction in lower respiratory tract infections: derivation of a clinical algorithm. BMC infectious diseases 2011;11:112.
  19. Lim WS, van der Eerden MM, Laing R, Boersma WG, Karalus N, Town GI, Lewis SA, Macfarlane JT. Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax 2003 May;58(5):377-82.
  20. Reinhart K, Bauer M, Riedemann NC, Hartog CS. New Approaches to Sepsis: Molecular Diagnostics and Biomarkers. Clin Microbiol Rev October 2012;25(4):609-634.
  21. Castillo JR, Zagler A, Carrillo-Jimenez R, Hennekens CH. Brain natriuretic peptide: a potential marker for mortality in septic shock. Int J Infect Dis 2004;8:271–4.
  22. Turner KL, Moore LJ, Todd SR, Sucher JF, Jones SA, McKinley BA, et al. Identification of cardiac dysfunction in sepsis with B-type 
natriuretic peptide. J Am Coll Surg 2011;213:139–46.
  23. Varpula M, Pulkki K, Karlsson S, Ruokonen E, Pettilä V; FINNSEPSIS Study Group. Predictive value of N-terminal pro-brain natriuretic peptide in severe sepsis and septic shock. Crit Care Med 2007;35:1277–83.
  24. Post F, Weilemann LS, Messow CM, Sinning C, Munzel T. B-type natriuretic peptide as a marker for sepsis-induced myocardial depression in intensive care patients. Crit Care Med Lab Med 2008;46:748–63.
  25. Hur M, Kim H, Lee S, Cristofano F, Magrini L, Marino R, Gori CS, Bongiovanni C, et al. Diagnostic and prognostic utilities of multimarkers approach using procalcitonin, B-type natriuretic peptide, and neutrophil gelatinase-associated lipocalin in critically ill patients with suspected sepsis. BMC Infect Dis 2014 Apr 24;14:224.

Acute Valvular Emergencies: Pearls and Pitfalls

Authors: Jessica Zack, MD (EM Chief Resident at SAUSHEC, USAF) and Brit Long, MD (@long_brit, EM Attending Physician at SAUSHEC, USAF) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital)

A 64-year-old male presents with sudden onset subjective fever/chills, dyspnea, weakness, and mild hemoptysis that began 2 hours prior to arrival. His VS include HR 104, BP 103/62, RR 24, O2 Sat 84% on RA, and T 99.6. On exam, you note bilateral rales R > L, a 4/6 diastolic murmur consistent with his known history of aortic regurgitation, and JVD without peripheral edema. His EKG is only significant for sinus tachycardia. You send labs that include a BNP and troponin and order a stat portable CXR which is pictured below. You subsequently order a CT scan of the chest and start him on NIPPV. You are initially considering PE, ACS, multi-lobar pneumonia, and acute heart failure syndrome … but is there something else you’re missing?


The prevalence of valvular heart disease in the United States is estimated to be about 2.5% and increases in prevalence with age.1 Though patients with clinically evident valvular heart disease have a 3.2-fold increase risk for stroke and 2.5-fold increase risk for death,2 most valvular heart disease encountered in the emergency department is chronic and does not require emergency stabilization.3 This is vastly different than the rare patient presenting with an acute valvular emergency. Symptoms of an acute valvular emergency may include dyspnea, tachycardia, pulmonary edema, and rapid development of cardiogenic shock. Many of these symptoms are seen with various other diagnoses, and the biggest pitfall clinicians may experience is leaving acute valvular emergency off the differential for patients presenting with acute dyspnea.

Valvular emergencies can be broken down by type of valve: native or prosthetic.  Native valve emergencies are almost always the result of regurgitation, while acute prosthetic valve dysfunction may be the result of either regurgitation or stenosis.4  

Valvular Structure and Function:

The heart is composed of four valves: the mitral and tricuspid valves (atrioventricular valves) and the pulmonic and aortic valves (semilunar valves). These valves all open and close passively in response to changes in pressure and volume. The right side of the heart functions similarly to left except that these valves experience much lower pressures. Since most native valve emergencies involve the mitral and aortic valves, we will focus our discussion here.  Inscreen-shot-2017-01-04-at-8-23-01-pm a normally functioning heart, the aortic valve is open during ventricular systole. This allows blood to flow from the left ventricle into systemic circulation. Once the aortic root pressure supersedes that of the left ventricle, the three cusps of the aortic valve fold in, and valve closure occurs. This marks the beginning of ventricular diastole. During this phase of the cardiac cycle, the mitral valve opens allowing flow from the left atrium to the left ventricle. Filling of the left ventricle is completed after the atrial “kick” which provides 10-40 % of the left ventricular end-diastolic volume.5 This is followed by closure of the mitral valve, and the cycle begins again with ventricular contraction. The anterior and posterior leaflets of the mitral valve are supported by the papillary muscles and chordae tendinae during ventricular contraction and aid in the prevention of reverse flow in the left atrium.6


Acute Aortic Regurgitation

Pathophysiology:  Acute aortic insufficiency is typically the result of either acute aortic dissection or endocarditis.7 It has also been reported in the case of blunt chest trauma.8 In acute aortic regurgitation (AR), the left ventricle (LV) pathologically fills during ventricular diastole preventing forward flow from the left atrium (LA). This greatly reduces stroke volume and causes a compensatory tachycardia to maintain cardiac output. In the acute setting, this regurgitation is met by a relatively stiff LV and causes increased LV pressure. The increased pressure in the LV stifles flow from the left atrium (LA) and may cause pulmonary congestion.  In severe AR, increased LV pressure may cause early closure of the mitral valve prior to atrial systole and exacerbate pulmonary congestion as the atria contracts against a closed valve.9,10 When AR is severe enough, the decreased cardiac output leads to progressive hypotension, peripheral vasoconstriction, and cardiogenic shock.

History/Exam: These patients will typically present with sudden onset of dyspnea. Other significant historical features may include those associated with the underlying cause of their AR such as tearing chest pain in aortic dissection or fevers in the setting of endocarditis. Physical exam may reveal evidence of pulmonary edema and cardiogenic shock such as rales, JVD, hypotension, pallor, and diaphoresis.3,13  Don’t be fooled by the absence of the typical blowing diastolic murmur in this patient. Murmurs are created by the velocity of blood flow over the valve. This velocity is largely determined by pressure gradients. In the acute AR versus chronic AR, the LV is less compliant which lends to equalization of end diastolic pressure in the aorta and LV.10 With a decreased pressure gradient, your murmur will likely be softer and shorter. Throw in a noisy ED, tachycardia, tachypnea, and rales, and your murmur may be completely inaudible.

Treatment: Definitive treatment for severe acute AR is immediate surgical intervention. Mortality for acute type A aortic dissection is as high as 1-2% per hour for the first several hours.11 So, how do we keep them alive until the OR?

-Intubate if necessary

-Nitroprusside: Yes, their blood pressure is probably already low. Stay with me. Nitroprusside causes afterload reduction, decreased LV preload, and results in reduced regurgitant volume.12 If your patient is going downhill, consider simultaneously starting dobutamine.

-Dobutamine: This ionotropic agent helps to increase contractility and stroke volume. In combination with nitroprusside, you may be able to achieve increased forward flow and temporize the patient.4,13

-Don’t forget antibiotics in the setting of suspected endocarditis.

Treatment Pitfalls:
-Beta blockers: I know, they’re tempting. Especially if your patient is dissecting. Beta blockers are relatively contraindicated in the case of acute AR.4 Beta blockers will decrease reflex tachycardia, but that tachycardia is currently maintaining their cardiac output. Additionally, that decrease in heart rate will increase the time spent in diastole and cause more aortic regurgitation.4

-Aortic Balloon Counterpulsation: This is absolutely contraindicated.4,13 Remember, the balloon pump will inflate during diastole and definitively make the problem worse.

Acute Mitral Regurgitation

Pathophysiology: The most common cause of acute mitral regurgitation (MR) is rupture of chordae tendinae or papillary muscles from ischemia and is typically seen within the first week following a myocardial infarction.13 However, other causes include leaflet perforation from infective endocarditis, blunt chest trauma, and leaflet tethering in acute cardiomyopathies.3,4,14  In acute MR, blood flows back across the mitral valve during ventricular systole. This causes a precipitous decrease in cardiac output. Additionally, blood is flowing into an atrium with normal compliance. This often results in rapid onset of pulmonary edema. In some cases, unilateral pulmonary edema may be seen. Most commonly, this unilateral edema is isolated to the right side or right upper lobe due to the regurgitant jet, particularly from a posterior flail leaflet, being directed towards the right pulmonary vein.15,16

History/Exam: Like acute AR, acute MR frequently leads to overt cardiogenic shock. One key historical difference is that these patients typically present 2-7 days after acute MI.13  Patients with acute MR present with sudden onset of dyspnea from rapidly amassing pulmonary edema, as well as tachycardia.13  Since the atria has not had time to develop additional compliance like in chronic mitral regurgitation, expect left atrial pressures to be high. Again, without a significant pressure gradient across the valve, don’t be surprised if the typical high-pitched holosystolic murmur is absent. This is particularly true if your regurgitant jet is aimed posteriorly and you are auscultating anteriorly.

Treatment: In addition to treating any underlying ischemia if present, definitive treatment is operative management.

Similar temporizing measures as used in acute AR may be useful here, with a few differences.

-Positive pressure for respiratory failure.3

-Nitroprusside or nitrates for afterload reduction.3,4,13 Often other afterload reducing agents, such as nicardipine, are more readily available in the ED. There is little data available directly evaluating whether other afterload reducing agents have similar clinical effects as nitroprusside.

-Dobutamine for inotropic effects.3,13

-Aortic Balloon Counterpulsation: A balloon pump may provide some benefit here if surgical intervention is not readily available.4,13 This will increase forward flow, increase mean arterial pressure, decrease regurgitant volume, and decrease left ventricular filling pressures.3

-Antibiotics if endocarditis is suspected.

Critical Aortic Stenosis

Background: Aortic stenosis (AS) is most commonly caused by age-related calcific changes of a normal valve, calcification of a bicuspid aortic valve, or rheumatic heart disease.17 The difference between AS and the other native valve emergencies discussed in this article is that aortic stenosis develops over many years prior to symptoms onset.18 Even patients with severe aortic stenosis may never develop symptoms, and their estimated risk of sudden cardiac death is still 0.5%-1.0% per year.18 However, once symptom onset does occur, mortality rate rapidly increases. Seventy-five percent of patients will die within 3 years of symptom onset.19

screen-shot-2017-01-04-at-8-22-46-pmPathophysiology: Severe AS is characterized by a fixed outflow obstruction, and cardiac output is preload dependent.  Since severity increases over time, LV hypertrophy develops as a compensatory mechanism to maintain ejection fraction. Patients will often maintain a normal ejection fraction, but this is commonly associated with an overall decreased cardiac output due to decreased end diastolic volumes in the hypertrophied LV.18  LV hypertrophy itself reduces diastolic function and impairs coronary perfusion contributing to angina,19 one of the most common symptoms of AS.  Another common presenting symptom of AS is syncope during exercise. Though not completely understood, it is theorized that the high resistance across the aortic valve prevents the increase in cardiac output required to maintain normotension during exercise when peripheral vasodilation occurs.18 When the AS becomes severe enough, it can lead to severe LV dysfunction and acute heart failure.

History/Exam: The most common symptoms of severe AS are angina, syncope, and dyspnea.17,18 Since severe AS is a disease process that happens over time, you are more likely to appreciate the crescendo-decrescendo systolic ejection murmur. However, it may be absent in the critically ill patient.17 This murmur often radiates into the carotids. Additionally, you may see evidence of LV hypertrophy on EKG and cardiomegaly on CXR.  Occasionally, patients with severe AS will present with acute left ventricular dysfunction and signs and symptoms of acute heart failure such as dyspnea, pulmonary edema, JVD, and even cardiogenic shock.

Treatment: There are two types of AS patients generally encountered in the ED: patients who have the potential to be sick at any time and patients who are currently really sick.

Patients with symptomatic AS (potential to be sick):

-IV Fluids: overall, AS is preload dependent, and these patients may require IVF resuscitation to maintain cardiac output.17

-Inpatient admission for echocardiography and evaluation for surgical aortic valve replacement.17,20

Patients with severe AS and failing LV (currently really sick AS), consider the following:

-Nitroprusside:17,19 There is limited data supporting the use of nitroprusside infusion in patients with severe AS and MAP > 60mm Hg.21 In this subset of patients, there is some evidence to suggest nitroprusside will decrease afterload, improve systolic and diastolic function, and reduce myocardial ischemia.22 This newer data goes against traditional teaching that nitrates will cause decreased blood pressure and decreased coronary perfusion.21 This should be considered in patients who can be closely monitored in an ICU setting and in conjunction with cardiology and/or an intensivist.

-Ionotropic agents such as dobutamine.17

-Early consultation with cardiology: in some cases percutaneous balloon dilation may be performed as a temporizing measure in patients too ill to immediately receive aortic valve replacement.20

 Prosthetic Valve Emergencies

Acute Valve Thrombosis:  During the first three months following surgery, both mechanical and bioprosthetic valves are at the greatest risk for thrombosis and thromboembolic complications.23 However, this risk has a lifelong persistence for patients with a mechanical valve. Thrombosis of a mechanical valve can lead to acute regurgitation, acute stenosis, or both.4 In severe cases, patients will present with acute dyspnea, weakness, and cardiogenic shock. The preferred treatment for patients with acute valve thrombosis is surgery. However, there is some evidence to support the use of intravenous thrombolytics.24 This decision should be made in conjunction with a cardiologist and cardiothoracic surgeon.

Other complications: While acute thrombosis is typically seen with mechanical valves, other complications such as paravalvular regurgitation from suture failure or dehiscence from endocarditis is seen in both mechanical and bioprosthetic valves.4 Up to 6% of prosthetic valves will be complicated by endocarditis within 5 years.3 This finding is associated with an overall poor prognosis, as approximately one third of patients diagnosed with prosthetic valve endocarditis will die within one year of diagnosis.25 If there is suspicion for prosthetic valve endocarditis, blood cultures should be drawn, antibiotics started, and echocardiography and consult with cardiology should be obtained.


Case Resolution:

The patient was admitted to the MICU and was later intubated for worsening respiratory distress.  He had an echo performed and was found to have new severe mitral regurgitation with a flail posterior leaflet, in addition to his known chronic aortic regurgitation. After his echo, he was immediately taken to the operating room and underwent uncomplicated valve replacement of both mitral and aortic valves. He recovered uneventfully and was subsequently discharged home.

 Key Takeaways:

-In patients presenting with sudden onset dyspnea, always keep a valvular emergency on the differential.

-Murmurs may not be audible in the acute setting.

-Definitive management is surgery more often than not, so get consultants on board early.

-If you have a sick patient with a native valve emergency consider nitroprusside +/- dobutamine.

-If present, don’t forget to treat the underlying cause of aortic regurgitation (aortic dissection, endocarditis), mitral regurgitation (ischemia, endocarditis), or prosthetic valve emergency (endocarditis, thrombosis).


References/Further Reading

  1. Nkomo, Vuyisile T., Julius M. Gardin, Thomas N. Skelton, John S. Gottdiener, Christopher G. Scott, and Maurice Enriquez-Sarano. “Burden of Valvular Heart Diseases: A Population-based Study.” The Lancet9540 (2006): 1005-011.
  2. Petty, G. W., B. K. Khandheria, J. P. Whisnant, J. D. Sicks, W. M. O’Fallon, and D. O. Wiebers. “Predictors of Cerebrovascular Events and Death among Patients with Valvular Heart Disease: A Population-Based Study.” Stroke11 (2000): 2628-635.
  3. Alley, William D., and Simon A. Mahler. “Chapter 54: Valvular Emergencies.” Tintinalli’s Emergency Medicine: A Comprehensive Study Guide. 8th ed. N.p.: McGraw Hill, 2015.
  4. Mcclung, John Arthur. “Native and Prosthetic Valve Emergencies.” Cardiology in Review1 (2016): 14-18.
  5. Alhogbani, Tariq, Oliver Strohm, and Matthias G. Friedrich. “Evaluation of Left Atrial Contraction Contribution to Left Ventricular Filling Using Cardiovascular Magnetic Resonance.” Journal of Magnetic Resonance Imaging4 (2012): 860-64.
  6. Perpetua, Elizabeth M., Dmitry B. Levin, and Mark Reisman. “Anatomy and Function of the Normal and Diseased Mitral Apparatus.” Interventional Cardiology Clinics1 (2016): 1-16.
  7. Roberts, W. C., J. M. Ko, T. R. Moore, and W. H. Jones. “Causes of Pure Aortic Regurgitation in Patients Having Isolated Aortic Valve Replacement at a Single US Tertiary Hospital (1993 to 2005).” Circulation5 (2006): 422-29.
  8. Baek, J. H., J. H. Lee, and D. H. Lee. “Acute Aortic Valve Insufficiency following Blunt Chest Trauma.” European Journal of Trauma and Emergency Surgery5 (2010): 499-501.
  9. Eusebio, Jose, Eric K. Louie, Lonnie C. Edwards, Henry S. Loeb, and Patrick J. Scanlon. “Alterations in Transmitral Flow Dynamics in Patients with Early Mitral Valve Closure and Aortic Regurgitation.” American Heart Journal5 (1994): 941-47.
  10. Rees, J. R., E. J. Epstein, J. M. Criley, and R. S. Ross. “HAEMODYNAMIC EFFECTS OF SEVERE AORTIC REGURGITATION.” Heart3 (1964): 412-21.
  11. Hamirani, Y. S., C. A. Dietl, W. Voyles, M. Peralta, D. Begay, and V. Raizada. “Acute Aortic Regurgitation.” Circulation9 (2012): 1121-126.
  12. Miller, Richard R., Louis A. Vismara, Anthony N. Demaria, Antone F. Salel, and Dean T. Mason. “Afterload Reduction Therapy with Nitroprusside in Severe Aortic Regurgitation: Improved Cardiac Performance and Reduced Regurgitant Volume.” The American Journal of Cardiology5 (1976): 564-67.
  13. Lefebvre, Cedric, James C. O’Neill, and David Cline. Atlas of Cardiovascular Emergencies. New York: McGraw-Hill Education, 2015.
  14. Smedira, Nicholas G., Magued Zikri, James D. Thomas, Michael S. Lauer, John J. Kelleman, and Patrick M. Mccarthy. “Blunt Traumatic Rupture of a Mitral Papillary Muscle Head.” The Annals of Thoracic Surgery5 (1996): 1526-528.
  15. Shin, Jeong Hun, Seok Hwan Kim, Jinkyu Park, Young-Hyo Lim, Hwan-Cheol Park, Sung Il Choi, Jinho Shin, Kyung-Soo Kim, Soon-Gil Kim, Mun K. Hong, and Jae Ung Lee. “Unilateral Pulmonary Edema: A Rare Initial Presentation of Cardiogenic Shock Due to Acute Myocardial Infarction.” Journal of Korean Medical Science2 (2012): 211.
  16. Young, Andrew L., Charles S. Langston, Robert L. Schiffman, and Michael J. Shortsleeve. “Mitral Valve Regurgitation Causing Right Upper Love Pulmonary Edema.” Texas Heart Institute Journal1 (2001): 53-56.
  17. Chen RS, Bivens MJ, Grossman SA. Diagnosis and Management of Valvular Heart Disease in Emergency Medicine. Emergency Medicine Clinics of North America. 2011;29(4):801-810. doi:10.1016/j.emc.2011.08.001.
  18. Carabello BA. Introduction to Aortic Stenosis. Circulation Research. 2013;113(2):179-185. doi:10.1161/circresaha.113.300156
  19. Carabello BA, Paulus WJ. Aortic stenosis. The Lancet. 2009;373(9667):956-966. doi:10.1016/s0140-6736(09)60211-7.
  20. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(23):2440-2492. doi:10.1161/cir.0000000000000029.
  21. Khot UN, Novaro GM, Popović ZB, et al. Nitroprusside in Critically Ill Patients with Left Ventricular Dysfunction and Aortic Stenosis. New England Journal of Medicine. 2003;348(18):1756-1763. doi:10.1056/nejmoa022021.
  22. Popovic ZB. Effects of sodium nitroprusside in aortic stenosis associated with severe heart failure: pressure-volume loop analysis using a numerical model. AJP: Heart and Circulatory Physiology. 2004;288(1):H416-H423. doi:10.1152/ajpheart.00615.2004.
  23. Carnicelli, Anthony. “Anticoagulation for Valvular Heart Disease.” American College of Cardiology. N.p., 18 May 2015. Web. 05 Dec. 2016.
  24. Özkan, Mehmet, Cihangir Kaymaz, Cevat Kirma, Kenan Sönmez, Nihal Özdemir, Mehmet Balkanay, Cevat Yakut, and Ubeydullah Deligönül. “Intravenous Thrombolytic Treatment of Mechanical Prosthetic Valve Thrombosis: A Study Using Serial Transesophageal Echocardiography.” Journal of the American College of Cardiology7 (2000): 1881-889.
  25. Lalani, Tahaniyat. “In-Hospital and 1-Year Mortality in Patients Undergoing Early Surgery for Prosthetic Valve Endocarditis.” JAMA Internal Medicine16 (2013): 1495-503.

A Myth Revisited: Epinephrine for Cardiac Arrest

Author: Brit Long, MD (@long_brit, EM Attending Physician, SAUSHEC) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital)

 You receive a radio call from an EMS unit. They are transporting a 61-year-old male who collapsed approximately 5 minutes ago. He is currently in ventricular fibrillation, and the EMS crew is actively doing compressions. They have obtained IV access, defibrillated the patient once, given 1mg epinephrine IV, and are actively bagging the patient. The patient arrives, and you take over the resuscitation. Your partner cleanly intubates the patient while chest compressions are ongoing. The patient receives another defibrillation, and compressions resume. Should the patient receive more epinephrine? What’s the evidence behind its use?

Sudden cardiac arrest accounts for over 450,000 deaths per year in the U.S., with 15% of total deaths due to arrest.1-4 Close to half are out-of-hospital, with poor survival rate (7-9%).1-5

A prior emdocs.net post evaluated epinephrine use in cardiac arrest. Please see this at: http://www.emdocs.net/epinephrine-cardiac-arrest/. Epinephrine is a staple of the AHA Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Updated guidelines were released in 2015, building on a “Chain of Survival”: recognition and activation of emergency response system, immediate high-quality cardiopulmonary resuscitation (CPR), rapid defibrillation, basic and advanced emergency medical services, and advanced life support and post arrest care including advanced cardiac life support (ACLS) for out-of-hospital cardiac arrest (OHCA).7,8 ACLS is considered the standard of care in cardiac arrest, though some argue a lack of evidence.

For more information on the updated guidelines, see http://eccguidelines.heart.org/wp-content/uploads/2015/10/2015-AHA-Guidelines-Highlights-English.pdf, https://emergencymedicinecases.com/acls-guidelines-2015-cardiac-arrest/, https://first10em.com/2015/10/21/acls-2015/, http://rebelem.com/rebel-cast-wee-our-top-5-aha-2015-guideline-updates-for-cpr-and-ecc/.

The Myth: Epinephrine improves patient survival and neurologic outcome in cardiac arrest.

Is this important?

A class IIb recommendation from the AHA states “standard dose epinephrine may be reasonable for patients with cardiac arrest” in the 2015 updates, with doses of 1mg of 1:10,000 epinephrine every 3-5 minutes intravenously.7 Epinephrine has alpha and beta adrenergic effects, which are thought to improve coronary perfusion pressure, though the effect on cerebral perfusion is controversial (and may worsen cerebral perfusion).

The recommendation for epinephrine is based on studies in the 1960s, which found epinephrine given to asphyxiated dogs improved survival.9 The alpha-adrenergic effects improved coronary perfusion in these dogs, with some benefit in survival.

If some is good, is more better? High dose epinephrine was assumed to be better, with several studies finding increased ROSC and survival to hospital admission, but no improvement in survival to hospital discharge or neurologic recovery.10-14 Studies suggest worse survival to hospital discharge and neurologic recovery with higher doses of epinephrine.7,15-20

What about standard dose epinephrine?  Studies suggest improvement in ROSC, but worse neurologic and survival to discharge. Why? The beta agonism provided by epinephrine increases myocardial work, increases tachydysrhythmias, promotes thrombogenesis and platelet activation, and reduces microvascular perfusion (including the brain).7,15

Now down to the nuts and bolts: the evidence on epinephrine…

Table 1 shows the studies on epinephrine. A study in 2011 evaluated over 600 patients with OHCA (one of the few randomized trials).16 Improved likelihood of ROSC, 24% in the epinephrine group versus 8%, with an odds ratio (OR) of 3.4 (95% CI 2.0-5.6) was found. Patients demonstrated no improvement in survival to hospital discharge.16 Ong et al. in 2007 found no difference in survival to discharge, survival to admission, or ROSC with epinephrine versus no epinephrine.17

Nakahara et al. conducted a retrospective study comparing epinephrine versus no epinephrine for patients with ventricular fibrillation, PEA, or asystole.18 Higher overall survival with epinephrine (17.0% vs 13.4%) was found, but not neurologically intact survival.18 Hagihara et al. conducted a prospective non-randomized analysis of over 400,000 patients and found an increase in ROSC with epinephrine (adjusted odds ratio 2.36), but no increase in survival or functional outcome.19 As discussed, ROSC occurred in the epinephrine group at higher rate (18.5% vs. 5.7%), but patients receiving epinephrine had lower survival at one month and worse neurologic outcome.19

One study found those with initially shockable rhythm demonstrated worse outcomes if they receive epinephrine for prehospital ROSC, survival at one month, and neurologic outcome at one month.20 A Swedish study found patients receiving epinephrine experience lower survival, with OR 0.30 (95% CI 0.07-0.82).21

How about BLS compared with ACLS?

ACLS measures include epinephrine, as compared with BLS focusing on optimizing compressions. Stiell et al. in 2004 analyzed 1,400 patients before use of ACLS measures, followed by 4,300 patients after ACLS was implemented.22 Admission rate increased by 3.7% (10.9% to 14.6%), but survival to discharge did not change.  Survivor neurologic status worsened after ACLS implementation (78.3% versus 66.8%).22  Olasveengen et al. evaluated ACLS with and without epinephrine, finding a 40% rate of ROSC in the group receiving epinephrine, versus 25% in the group receiving no epinephrine.23 Survival to discharge and neurologic outcomes were similar, though the epinephrine group had higher hospital admission rates.23  Sanghavi et al. compared BLS and ACLS in an observational cohort study.24 BLS patients had higher survival to hospital discharge (13.1% versus 9.2%), improved survival to 90 days, and better neurologic function.24

Table 1 – Studies evaluating epinephrine16-24

Study Outcome Odds Ratio (95% CI)
Holmberg et al. Survival decrease with epinephrine Survival 0.43 (0.27-.066) for shockable, 0.30 (0.07-0.82) for non-shockable rhythms
Stiell et al. Improved ROSC, no difference in survival to discharge Survival to discharge 1.1 (0.8-1.5)
Ong et al. No difference in ROSC or survival to discharge ROSC 0.9 (0.6-4.5), survival to discharge 1.7 (0.6-4.5)
Olasveengen et al. Improved ROSC, No difference in survival to discharge Survival to discharge 1.15 (0.69-1.91)
Jacobs et al. Improved ROSC, No difference in survival to discharge ROSC 3.4 (2.0-5.6), Survival to discharge 2.2 (0.7-6.3)
Hagihara et al. Improved ROSC, Worse survival and functional outcome ROSC 2.35 (2.22-2.5), Survival 0.46 (0.42-0.51), Functional outcome 0.31-0.32 (0.26-0.38)
Nakahara et al. No difference in neurologic outcome or total survival Neurologic outcome 1.01 (0.78-1.30) for shockable and 1.57 (1.04-2.37) for nonshockable rhythms; Total survival 1.34 (1.12-1.60) for shockable and 1.72 (1.45-2.05) for nonshockable rhythms
Sanghavi et al. No epinephrine associated with improved neurologic outcome, survival to discharge, and total survival Improved neurologic outcome 23.0 (18.6-27.4) for no epinephrine, Survival to discharge 4.0 (2.3-5.7) for no epinephrine, Total survival 2.6 (1.2-4.0) for no epinephrine

The Bottom Line: Epinephrine can increase ROSC, but it does not improve survival to hospital discharge or neurological improvement and may worsen these outcomes.

How does this change practice? Epinephrine is a significant component of the AHA guidelines, despite the controversial literature. A role may exist for epinephrine, though further study is required. Studies suggest three phases (electrical, circulatory, and metabolic) are present in cardiac arrest.25 The electrical phase needs rapid defibrillation and compressions.15,25 The circulatory phase (within 10 minutes of arrest) focuses on perfusion, where epinephrine may improve cardiac perfusion. Epinephrine during the final metabolic phase (greater than 10 minutes after arrest) can impair oxygen utilization, increase oxygen demand and ischemia, cause dysrhythmia, increase clotting, and increase lactate.15,25

The timing and total dose of epinephrine can impact patient outcome.7,15,25-27 A study by Dumas et al. suggests timing of first administration and total epinephrine given impacts survival (with less epinephrine given related to improved outcome).25 This study found that 17% of patients in the group receiving epinephrine demonstrated a good outcome defined by “favorable discharge outcome coded by Cerebral Performance Category,” compared to 63% not receiving epinephrine. However, in this study patients with a shockable rhythm, patients receiving 1mg epinephrine, and patients receiving epinephrine less than 9 minutes after arrest demonstrate the best outcomes, not impacted by the total time of resuscitation. Patients receiving late or multiple doses of epinephrine have decreased neurologic survival.25

Table 2 – Epinephrine Dosing Outcomes25

Treatment Adjusted OR (95% CI)
Time to Epinephrine Dose

< 9 min

10-15 min

16-22 min

> 22 min


0.54 (0.32-0.91)

0.33 (0.20-0.56)

0.23 (0.12-0.43)

0.17 (0.09-0.34)

Total Epinephrine Dose

1 mg

2-5 mg

> 5 mg


0.48 (0.27-0.84)

0.30 (0.20-0.47)

0.23 (0.14-0.37)

Epinephrine within 10 minutes of arrest may provide the most benefit. Koscik et al. found earlier provision of epinephrine improved ROSC, from 21.5% to 48.6% (OR 3.45).26 Nakahara et al. compared early epinephrine in OHCA (within 10 minutes of arrest), finding early epinephrine was associated with survival (OR 1.73, 95% CI 1.46-2.04) and improved neurologic outcome (OR 1.39, 95% CI 1.08-1.78).27 However, there is potential harm with epinephrine within the first two minutes of arrest.27 Anderson et al. compared epinephrine before or after the second defibrillation attempt.28 Patients receiving epinephrine before the second defibrillation demonstrated decreased survival (OR 0.70), decreased functional outcome (OR 0.69), and decreased ROSC (OR 0.71). This study suggests epinephrine within the first two minutes after arrest can be harmful, and they recommend epinephrine should be given after the second defibrillation.27

Some support targeting coronary perfusion pressure (CPP), or the aortic to right atrial pressure gradient during the relaxation phase of CPR. Targeting coronary perfusion pressure is supported by several animal studies.29,30 CPP levels > 15 mm Hg demonstrate greater likelihood of ROSC.31 Epinephrine is most commonly used to maintain CPP levels with compressions. However, this needs further study and requires the use of invasive monitoring.25,31

What improves outcomes?

Components that improve outcomes include witnessed arrest, witnessed by EMS, bystander CPR, shockable rhythm (VF/VT), early defibrillation, minimal interruptions to CPR, automated external AED use, and therapeutic hypothermia in comatose cardiac arrest patients.7,15,32 Optimal chest compressions and early defibrillation if warranted are essential.7 Emergency PCI is recommended for all patients with STEMI and for hemodynamically unstable patients without ST elevation infarction if a cardiovascular lesion is suspected. Targeted temperature management between 32oC and 36oC is acceptable for comatose patients with ROSC.7 The 2015 recommendations for BLS measures are shown below. 7,32

2015 Guideline Recommendations for Compressions
-Perform compressions at rate 100-120 per minute

-Perform compressions at depth of 5-6 cm (at least 2 inches), but not more than 6 cm (2.4 in)

-Rescuers should allow full chest wall recoil and avoid leaning on the chest between compressions

-Rescuers should minimize the frequency and duration of intervals between compressions

-Audiovisual devices and compression depth analyzers can be used to optimize CPR quality

Bottom Line: The most important aspect of care in cardiac arrest is basic life support measures with compressions and early defibrillation.



– 2015 AHA Guidelines state epinephrine is reasonable to give for patients in cardiac arrest.

– Recommendations are based on studies with asphyxiated dogs in the 1960s.

High dose epinephrine is harmful and is not advised.

– Epinephrine can increase ROSC, but it may worsen neurologic outcome and survival upon discharge.

– Epinephrine may provide the greatest benefit if given within 10 minutes of arrest (though it may be harmful if given before 2 minutes).

BLS measures with optimal compressions and early defibrillation are essential!


References / Further Reading

  1. Zheng ZJ, Croft JB, Giles WH, Mensah GA. Sudden cardiac death in the United States, 1989 to 1998. Circulation 2001; 104:2158.
  2. Rea TD, Pearce RM, Raghunathan TE, et al. Incidence of out-of-hospital cardiac arrest. Am J Cardiol 2004; 93:1455.
  3. Centers for Disease Control and Prevention (CDC). State-specific mortality from sudden cardiac death–United States, 1999. MMWR Morb Mortal Wkly Rep 2002; 51:123.
  4. Chugh SS, Jui J, Gunson K, et al. Current burden of sudden cardiac death: multiple source surveillance versus retrospective death certificate-based review in a large U.S. community. J Am Coll Cardio 2004;44:1268.
  5. Kuller LH. Sudden death–definition and epidemiologic considerations. Prog Cardiovasc Dis 1980; 23:1.
  6. Gillum RF. Sudden coronary death in the United States: 1980-1985. Circulation 1989; 79:756.
  7. Link MS, Berkow LC, Kudenchuk PJ, et al. Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015;132:S444-S464.
  8. Neumar RW, Otto CW, Link MS, et al. Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010;122(Suppl 3):S729-67.
  9. Callaham M. Evidence in support of a back-to-basics approach in out-of-hospital cardiopulmonary resuscitation vs. “advanced treatment.” JAMA Intern Med. 2015;175:205-206.
  10. Stiell IG, Hebert PC, Weitzman BN, et al. High-dose epinephrine in adult cardiac arrest. N Engl J Med. 1992;327:1045-1050.
  11. Brown CG, Martin DR, Pepe PE, et al. A comparison of standard-dose and high-dose epinephrine in cardiac arrest outside the hospital. The Multicenter High-Dose Epinephrine Study Group. N Engl J Med. 1992;327:1051-1055.
  12. Rivers EP, Wortsman J, Rady MY, et al. The effect of total cumulative epinephrine dose administered during human CPR on hemodynamic, oxygen transport, and utilization variables in the postresuscitation period. Chest. 1994;106:1499-1507.
  13. Behringer W, Kittler H, Sterz F, et al. Cumulative epinephrine dose during cardiopulmonary resuscitation and neurologic outcome. Ann Intern Med. 1998;129:450-456.
  14. Guegniaud PY, Mols P, Goldstein P, et al. A comparison of repeated high doses and repeated standard doses of epinephrine for cardiac arrest outside the hospital. N Engl J Med. 1998;339:1595-1601.
  15. Callaway CW. Questioning the use of epinephrine to treat cardiac arrest. JAMA. 2012;307:1198-1199.
  16. Jacobs IG, Finn JC, Jelinek GA, Oxer HF, Thompson PL. Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial. Resuscitation. 2011 Sep;82(9):1138-43.
  17. Ong ME, Tan EH, Ng FS, Panchalingham A, Lim SH, Manning PG, et al. Survival outcomes with the introduction of intravenous epinephrine in the management of out-of-hospital cardiac arrest. Ann Emerg Med. 2007 Dec;50(6):635-42.
  18. Nakahara S, Tomio J, Takahashi H, et al. Evaluation of pre-hospital administration of adrenaline (epinephrine) by emergency medical services for patients with out of hospital cardiac arrest in Japan: controlled propensity matched retrospective cohort study. The BMJ. 2013;347:f6829. doi:10.1136/bmj.f6829.
  19. Hagihara A, Hasegawa M, Abe T, Nagata T, Wakata Y, Miyazaki S. Prehospital epinephrine use and survival among patients with out-of-hospital cardiac arrest. JAMA. 2012 Mar 21;307(11):1161-8. doi: 10.1001/jama.2012.294.
  20. Goto Y, Maeda T, Goto YN. Effects of prehospital epinephrine during out-of-hospital cardiac arrest with initial non-shockable rhythm: an observational cohort study. Critical Care. 2013;17(5):R188. doi:10.1186/cc12872.
  21. Holmberg M, Holmberg S, Herlitz J. Low chance of survival among patients requiring adrenaline (epinephrine) or intubation after out-of-hospital cardiac arrest in Sweden. Resuscitation. 2002 Jul;54(1):37-45.
  22. Stiell IG, Wells GA, Field B, Spaite DW, Nesbitt LP, De Maio VJ, Nichol G, Cousineau D, Blackburn J, Munkley D, Luinstra-Toohey L, Campeau T, Dagnone E, Lyver M; Ontario Prehospital Advanced Life Support Study Group. Advanced cardiac life support in out-of-hospital cardiac arrest. N Engl J Med. 2004 Aug 12;351(7):647-56.
  23. Olasveengen TM, Sunde K, Brunborg C, Thowsen J, Steen PA, Wik L. Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial. JAMA. 2009 Nov 25;302(20):2222-9.
  24. Sanghavi P, Jena AB, Newhouse JP, Zaslavsky AM. Outcomes After Out-of-Hospital Cardiac Arrest Treated by Basic vs Advanced Life Support. JAMA Intern Med 2015;175(2):196-204.
  25. Dumas F, Bougouin W, Geri G, Lamhaut L, Bougle A, Daviaud F, et al. Is epinephrine during cardiac arrest associated with worse outcomes in resuscitated patients? J Am Coll Cardiol. 2014; 64(22):2360–7.
  26. Koscik C, Pinawin A, McGovern H, Allen D, Media DE, Ferguson T, Hopkins W, Sawyer KN, Boura J, Swor R. Rapid epinephrine administration improves early outcomes in out-of-hospital cardiac arrest. Resuscitation. 2013 Jul;84(7):915-20.
  27. Nakahara S, Tomio J, Nishida M, Morimura N, Ichikawa M, Sakamoto T. Association between timing of epinephrine administration and intact neurologic survival following out-of-hospital cardiac arrest in Japan: a population-based prospective observational study. Acad Emerg Med. 2012 Jul;19(7):782-92.
  28. Andersen LW, Kurth T, Chase M, et al. Early administration of epinephrine (adrenaline) in patients with cardiac arrest with initial shockable rhythm in hospital: propensity score matched analysis. BMJ 2016; 353:i1577.
  29. Friess SH, Sutton RM, French B, et al. Hemodynamic Directed CPR Improves Cerebral Perfusion Pressure and Brain Tissue Oxygenation. Resuscitation. 2014;85(9):1298-1303.
  30. Sutton RM, Friess SH, Naim MY, et al. Patient-centric Blood Pressure–targeted Cardiopulmonary Resuscitation Improves Survival from Cardiac Arrest. American Journal of Respiratory and Critical Care Medicine. 2014;190(11):1255-1262.
  31. Paradis NA, Martin GB, Rivers EP, et al. Coronary Perfusion Pressure and the Return of Spontaneous Circulation in Human Cardiopulmonary Resuscitation. JAMA. 1990;263(8):1106-1113.
  32. Sasson C, Rogers MA, Dahl J, Kellermann AL. Predictors of survival from out-of-hospital cardiac arrest: a systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes. 2010 Jan;3(1):63-81.

Can Giant Cell Arteritis Be Ruled Out in the ED?

Authors: Mike Butterfield, MD, MS, MPH1 and Lauren Jeang, MD2 (University of South Florida Departments of Emergency Medicine1 and Ophthalmology2) // Edited by: Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit, EM Chief Resident at SAUSHEC, USAF)


A 70-year-old woman presents to the ED for worsening left-sided headache. She has not had headaches in the past, but doesn’t have any other “red-flag” symptoms (fever, thunderclap, etc). Her vitals are normal, and she has some tenderness over the left temple. Her visual acuity, fields, and the rest of her exam are normal. The CT of her head returns without acute findings, and her lab markers are notable for an ESR of 41. The ibuprofen you give her improves the headache somewhat. By this time, it is 2am. Given her age and scalp tenderness, you have considered giant cell arteritis (GCA), but not everything in her history matches up. You are reluctant to page the ophthalmology resident on call or empirically start steroids with this muddled picture.

You wonder: Is there a good way to rule out GCA myself in the ED?

Giant cell arteritis (also: “temporal arteritis”) is the most common large vessel vasculitis, primarily affecting the cranial arteries and aorta. Risk of disease increases steadily in patients after age 50, but is very rare before then. Women are twice as likely as men to develop the disease (lifetime incidence 1% vs. 0.5%), and disease prevalence is highest among northern Europeans.1,2

GCA causes transmural vessel inflammation leading to both stenosis of the cranial arteries and mural weakening of the proximal aorta. GCA is most feared for its potential to cause monocular or binocular blindness in untreated individuals, which happens 13-50% of the time. Visual loss is often irreversible, and patients presenting with this complaint are treated in hopes of preserving vision in an unaffected eye.3,4


Clinical Signs and Symptoms

GCA is associated with an array of both local and systemic symptoms. The former include headache, jaw claudication, scalp tenderness, and vision changes, while the latter include more protean manifestations such as fever, fatigue, and weight loss. About 30% will have polymyalgia rheumatica, characterized by proximal muscle pain, weakness, and morning stiffness. On physical exam, abnormalities of the temporal artery, scalp tenderness, and synovitis may be observed.

Unfortunately, none of these classic findings accurately separates those with disease from those without it.

Smetana et al. (2002) have written the most comprehensive review on this subject for JAMA’s series, the Rational Clinical Examination. Pooling together 2680 patients with suspected GCA from 21 studies, they found that none of the 27 most commonly reported symptoms and signs had a sensitivity greater than 76% (any headache), a positive likelihood ratio greater than 4.6 (a beaded temporal artery), or a negative likelihood ratio of less than 0.53 (any temporal artery abnormality). Perhaps the most useful finding from Smetana’s review was demographic – only 2/1435 patients with positive biopsies were under the age of 50.5

The poor performance of the history and physical in predicting GCA diagnosis leads to the thorny issue of diagnosis of GCA itself.

Hunder et al. published the American College of Rheumatology’s (ACR) criteria for GCA in 1990, the most widely referenced paper on this subject. They determined that fulfilling 3 of 5 criteria – age 50+, new headache, temporal artery tenderness (or decreased pulse), ESR > 50 mm/h, or a positive biopsy – had a sensitivity of 93.5% and a specificity of 91.2% for disease.6

But the problem with the ACR criteria has been their misapplication – as Hunder and others have pointed out, the ACR criteria were meant to distinguish GCA from other vasculidities for research studies and actually perform poorly when applied in clinical practice.7–9

So regarding GCA, we as clinicians are still left with an amorphous syndrome without well-defined features that can accurately rule out disease – except for age.


Erythrocyte Sedimentation Rate (ESR) and C-Reactive Protein (CRP)

Diagnosis of GCA has been traditionally associated with an ESR. However, the literature is replete with cases in which GCA is diagnosed in patients with an ESR less than 50 or even normal. To a lesser extent, CRP has also been examined as a screening method for GCA. 10

Parikh et al. (2006) offered encouraging results in a series of 119 patients diagnosed biopsy-positive GCA. Sensitivities for GCA were 76-86% (depending on the formula used) for ESR, 97.5% for CRP (< 0.5 mg/dL), and 99.2% (118/119) for an elevation in either marker.11

Kermani et al. (2012), however, did not reproduce those findings in a subsequent large retrospective case series (n = 177). In their study, sensitivities were 84.2% for ESR, 86.4% for CRP, and 89.8% for either (96% if patients taking steroids at the time of testing were excluded). Notably, the authors used a cutoff of 8mg/L (ie 0.8mg/dL) for CRP, which is higher than that used by Parikh.12

Additionally, Hegg et al. (2011) have shown that ESR was significantly reduced in GCA patients taking anti-inflammatory medications such as statins and NSAIDS.13

All of these studies are limited by their retrospective nature, incomplete information, and focus on only biopsy-proven GCA patients. Even so, they do not support the idea that lab tests can rule out GCA.


Ultrasound and Magnetic Resonance Imaging (MRI)

Over the last 10 years, imaging studies gained importance in the diagnostic evaluation of GCA. In particular, ultrasound of the temporal arteries has been endorsed as a potential replacement for temporal artery biopsy, given its high specificity, non-invasiveness, and ability to evaluate both arteries over time.

Schmidt et al.’s (1997) prospective cohort study compared 30 patients diagnosed with GCA with 82 controls. Even though 22/30 had gotten steroids within 10 days of examination, 22/30 had a positive “halo sign” on ultrasound, indicating edema in and surrounding the wall of the temporal artery, compared to 0/82 of the controls.14

Ball et al. (2010), a decade later, conducted a meta-analysis of 9 studies comparing the halo sign to temporal artery biopsy, finding the halo sign to have a weighted sensitivity and specificity of 75% and 85%. Another metaanalysis found similar results.15,16

Aschwanden et al. (2012), recognizing the technical difficulty of ultrasound examination, examined whether an abnormal “compression sign” of the temporal artery (continued visualization despite compression) might perform better than the halo sign alone. The compression sign was just as sensitive (79 vs. 80%) as the halo sign in the 43 patients with GCA, and none of the patients without GCA had either ultrasound finding.17

MRI has also shown promise in detecting GCA, albeit with less clinical investigation than ultrasound. Contrast-enhanced studies are capable of detecting signs of inflammation in the superficial cranial and other arteries.18,19

Bley et al. (2007) used a contrast-enhanced MRI protocol in 64 consecutive patients with suspected GCA, looking for abnormalities in vessel lumen diameter, wall enhancement, and wall thickening. Overall sensitivity and specificity were 80.6% and 97.0%, with improved sensitivity (85.7%) if only patients with less than 10 days of steroid treatment were included.20

Klink et al. (2014), in a larger prospective study (n = 185) using the same MRI criteria as Bley et al., estimated sensitivities and specificities between 78.4-83.3% and 85.5-90.4%, respectively. Notably, in this study only patients with an ESR >50 were included.21

In summary, imaging studies are emerging as useful, noninvasive tools for supporting and confirming diagnosis of GCA – for rheumatologists. Unfortunately, these tests do not possess sufficient sensitivity/negative predictive value beyond ESR/CRP to comfortably rule out serious disease. Neither do most ED physicians, technicians, or even radiologists likely have enough experience with these modalities to perform them with a high degree of accuracy, at least at this moment. While ED physicians have demonstrated proficiency in performing many kinds of bedside ultrasonography, evaluation of the temporal arteries is entirely new, esoteric, territory.


Clinical Bottom Line

Given its protean manifestations, the insufficient sensitivity of biomarkers, and unavailability of highly accurate imaging modalities, GCA will be difficult, if not impossible to rule out in the ED. Emergency physicians should have a low threshold for making a presumptive diagnosis of GCA and managing accordingly. One exception to this rule might be patients under 50 years old with an unconvincing presentation and another plausible reason for abnormal biomarkers (if elevated), as only about 40 cases of GCA have ever been reported in this age group.22 Another might be patients with an atypical presentation, normal ESR and CRP, who have been counseled on the risks of GCA, and have reliable follow-up (a lot of “ifs” in that statement).

For all others, consultants should be called, and if unavailable, steroid treatment should be started until follow-up. Patients without visual symptoms should be started on 40-60 mg of prednisone daily, while those with visual impairment need to start with 1 g of intravenous methylprednisolone for 3 days, according to the British Society for Rheumatology guidelines.23


References / Further Reading

  1. Lindor RA, Laughlin MJ, Sadosty AT. Elderly woman with headache. Giant cell arteritis/temporal arteritis. Ann Emerg Med 2015;65(5):614, 622.
  2. Watts RA, Lane S, Scott DGI. What is known about the epidemiology of the vasculitides? Best Pract Res Clin Rheumatol 2005;19(2):191–207.
  3. Azhar SS, Tang RA, Dorotheo EU. Giant cell arteritis: diagnosing and treating inflammatory disease in older adults. Geriatrics 2005;60(8):26–30.
  4. Danesh-Meyer H, Savino PJ, Gamble GG. Poor prognosis of visual outcome after visual loss from giant cell arteritis. Ophthalmology 2005;112(6):1098–103.
  5. Smetana GW, Shmerling RH. Does this patient have temporal arteritis? JAMA 2002;287(1):92–101.
  6. Hunder GG, Bloch DA, Michel BA, et al. The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis. Arthritis Rheum 1990;33(8):1122–8.
  7. Hunder GG. The use and misuse of classification and diagnostic criteria for complex diseases. Ann Intern Med 1998;129(5):417–8.
  8. Rao JK, Allen NB, Pincus T. Limitations of the 1990 American College of Rheumatology classification criteria in the diagnosis of vasculitis. Ann Intern Med 1998;129(5):345–52.
  9. Jhun P, Aguilera P, Shoenberger J, Bright A, Herbert M. Giant cell arteritis: read the fine print! Ann Emerg Med 2015;65(5):615–7.
  10. Ciccarelli M, Jeanmonod D, Jeanmonod R. Giant cell temporal arteritis with a normal erythrocyte sedimentation rate: report of a case. Am J Emerg Med 2009;27(2):255.e1–3.
  11. Parikh M, Miller NR, Lee AG, et al. Prevalence of a normal C-reactive protein with an elevated erythrocyte sedimentation rate in biopsy-proven giant cell arteritis. Ophthalmology 2006;113(10):1842–5.
  12. Kermani TA, Schmidt J, Crowson CS, et al. Utility of erythrocyte sedimentation rate and C-reactive protein for the diagnosis of giant cell arteritis. Semin Arthritis Rheum 2012;41(6):866–71.
  13. Hegg R, Lee AG, Tagg NT, Zimmerman MB. Statin or nonsteroidal anti-inflammatory drug use is associated with lower erythrocyte sedimentation rate in patients with giant cell arteritis. J Neuro-Ophthalmol Off J North Am Neuro-Ophthalmol Soc 2011;31(2):135–8.
  14. Schmidt WA, Kraft HE, Vorpahl K, Völker L, Gromnica-Ihle EJ. Color duplex ultrasonography in the diagnosis of temporal arteritis. N Engl J Med 1997;337(19):1336–42.
  15. Ball EL, Walsh SR, Tang TY, Gohil R, Clarke JMF. Role of ultrasonography in the diagnosis of temporal arteritis. Br J Surg 2010;97(12):1765–71.
  16. Karassa FB, Matsagas MI, Schmidt WA, Ioannidis JPA. Meta-analysis: test performance of ultrasonography for giant-cell arteritis. Ann Intern Med 2005;142(5):359–69.
  17. Aschwanden M, Daikeler T, Kesten F, et al. Temporal artery compression sign–a novel ultrasound finding for the diagnosis of giant cell arteritis. Ultraschall Med Stuttg Ger 1980 2013;34(1):47–50.
  18. Geiger J, Ness T, Uhl M, et al. Involvement of the ophthalmic artery in giant cell arteritis visualized by 3T MRI. Rheumatol Oxf Engl 2009;48(5):537–41.
  19. Khan A, Dasgupta B. Imaging in Giant Cell Arteritis. Curr Rheumatol Rep 2015;17(8):52.
  20. Bley TA, Uhl M, Carew J, et al. Diagnostic value of high-resolution MR imaging in giant cell arteritis. AJNR Am J Neuroradiol 2007;28(9):1722–7.
  21. Klink T, Geiger J, Both M, et al. Giant cell arteritis: diagnostic accuracy of MR imaging of superficial cranial arteries in initial diagnosis-results from a multicenter trial. Radiology 2014;273(3):844–52.
  22. Nesher G, Oren S, Lijovetzky G, Nesher R. Vasculitis of the temporal arteries in the young. Semin Arthritis Rheum 2009;39(2):96–107.
  23. Dasgupta B, Borg FA, Hassan N, et al. BSR and BHPR guidelines for the management of giant cell arteritis. Rheumatol Oxf Engl 2010;49(8):1594–7.


Serotonin Syndrome and Neuroleptic Malignant Syndrome: Pearls & Pitfalls

Authors: Jacob Avila, MD and Jonathan Bronner, MD (EM Attending Physicians, University of Kentucky) // Edited by: Alex Koyfman, MD (EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital, @EMHighAK) and Brit Long, MD (@long_brit, EM Chief Resident at SAUSHEC, USAF)

Your next 3 patients…

#1: 35yo M w/ fever and agitation

#2: 21yo F w/ “jitteriness” s/p a med change

#3: 40yo F from nursing home w/ “stiffness”

Serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) are two types of pathologies that often give a very confusing picture. They are both associated with psychiatric diseases and are often seen in the setting of polypharmacy,1,2 which give the provider a broad differential to work through when these patients present in the emergency department (ED).2-8 To get a better understanding of how to differentiate between the two, let’s look at each of these diseases a bit more in depth.

Why do we care about this disease? We care about this because the medical community often misses it. In a previously published survey study, as many as 85% of physicians didn’t know what SS was.9 While that number is probably much better these days, SS still often goes unrecognized. At least part of the reason why we miss this disease is due to the fact that mild cases can present with non-specific symptoms such as tremors, diarrhea, and tachycardia.4 Often when SS starts advancing from the mild into the moderate category, we may inadvertently treat the condition with more serotonergic medications, further precipitating decline.10 Most importantly, it can be deadly. Unrecognized SS can quickly deteriorate into irreparable kidney damage, respiratory failure, or DIC.8 The mortality rate of severe SS has been reported to be 2-12%.6 Work hour restrictions in the US were first established after a case of missed SS where an intern continued to give serotonergic medications for agitation in a patient with SS, likely resulting in her death.11

So now that we’re scared, how do we not miss this deadly disease? First, let us consider the mechanism for how SS occurs. While most of the total body serotonin is found in the periphery,5 what we care about is the serotonin that causes SS, namely, the serotonin produced in the central nervous system (CNS). The overall level of serotonin in the CNS doesn’t matter as much as how much of it is stuck in the neuronal synapses, causing the effects of SS.7 Serotonin in the CNS is mostly produced in the pons and upper brainstem. Once released, it will bind to post-synaptic receptors and remains viable until it is either degraded by monoamine oxidase (MAO) or removed from the synapse by reuptake pumps.5 In the CNS, serotonin functions by modulating core body temperature, wakefulness, analgesia, sexual behavior, mood, affect, perception, personality, emesis, and eating behavior (among other things).7,12 The broad effects of serotonin are mediated by multiple receptors. There are 7 types of receptors, several of which have unique receptor subclasses. As a whole, this results in around 14 distinct serotonin receptors found throughout the body, though only two are thought to be involved in the mechanism of SS: 5-HT1A and 5-HT2A. As far as SS goes, the less important one is 5-HT1A, which is thought to be responsible for myoclonus, hyperreflexia, and alterations on mental status.5,13-15 The most important receptor in SS is 5-HT2A,12,16,17 which increases heart rate, elevates blood pressure and temperature, and has a role in neuromuscular excitement.5,13,15,16 These abnormalities in vital physiologic homeostasis reflect adrenal gland stimulation of catecholamine release12,14,18 and stimulation of the hypothalamus manifesting as fever.5,13,15,16 Using this basic molecular understanding of the neurohormonal pathway, the triad associated with SS – mental status changes, increased neuromuscular tone, and autonomic instability in the setting of an individual who has taken a serotonergic medication – becomes more tangible. 3,4,7,8,17 One of the reasons this disease can be tricky do diagnose is that there is such a variable presentation. Not all patients with SS will present with the classic triad. In fact, the most commonly reported symptom (myoclonus) is only seen in 57% of patients.19

So now that we have an appreciation for the pathophysiology and how SS may present, how do we diagnose it? The first step is to recognize patients at higher risk of developing SS even before they’re exposed to serotonergic medications. Smokers, individuals with cardiovascular disease, and those with liver disease may develop acquired deficits in MAO activity and serotonin metabolism.7,15 Ethanol can stimulate the release of serotonin from neurons,15 and there is an increased incidence of SS in patients on dialysis who are also taking selective serotonin reuptake inhibitors (SSRI’s).12 Patients with defective CYP2C19 and CYP2D6 enzymes (either acquired or congenital) may also be at a higher risk since these enzymes are responsible for the break down of many serotonergic medications. 8,20 So which medications have been known to cause serotonin syndrome? This long list includes MAOI, TCA, SSRI, SNRI, anti-emetics, street drugs/drugs of abuse, diet pills, antibiotics, opioids (including tramadol), dextromethorphan, Benadryl, linezolid, methylphenidate, and lithium.5,13,15,21-25 These medications increase the synaptic concentration of serotonin via multiple mechanisms— by increasing the synthesis or release of serotonin, increasing receptor stimulation, inhibiting serotonin reuptake, or decreasing the breakdown of serotonin. 5,25

Approximately 60% of SS is caused by drug-drug interactions – usually paroxetine and tramadol – while 40% is triggered by a single drug. The most common individual culprits are SSRIs, with opioids coming in second. 26 After ingestion of an offending medication or medication combination, symptoms often begin within hours. 4 In fact, the majority of patients will present with SS 6 hours after administration of the provoking agent.5,27 While the gold standard for the diagnosis is an examination by a medical toxicologist,5, 28 there are methods available to help you diagnose SS at bedside. The Sternbach and Hunter criteria are the most common and most accessible for the Emergency Physician,28, 29 though the Sternbach criteria is less sensitive and specific for serotonin syndrome when compared to the newer Hunter criteria.4,30, 28 The reason for this discrepancy is that the Sternbach criteria are more likely to miss mild, early, or subacute cases of SS. 8 While the Hunter criteria may also miss mild, early or subacute cases of SS, it has been reported to have a sensitivity of 84% and a specificity of 97%.28

Sternbach Criteria
Sternbach Criteria
Hunter Criteria
Hunter Criteria

Aside from the history and physical exam, there are ancillary tests that can be helpful in diagnosis. While there is no definitive test that can diagnose SS 4,25 a basic laboratory assessment and a CT of the head are helpful in both ruling out other diseases that present similarly to SS as well as monitoring the severity of the patient’s symptoms. 8 Other diseases that should be on your differential when you suspect SS are NMS, malignant hyperthermia, anticholinergic poisoning, sympathomimetic poisoning, opioid withdrawal, CNS infection, sepsis, delirium tremens, and heat stroke. 4-8

Once you’ve arrived at a diagnosis of SS, how should the emergency physician initiate treatment? As with most acute pathologies, you must start with the ABC’s, but in a simultaneous fashion the effort to stop the serotonergic medication is of utmost importance.30 In mild cases, this is usually all that is required. When evaluating a patient in the moderate category you might need to start benzodiazepines for agitation, tachycardia, and hypertension. 4,6 When things start to look bad, you may need to give serotonin antagonists. Although there are no randomized controlled trials supporting its use in this setting,5,30 cyproheptadine – a non-selective histamine H1 receptor and serotonin receptor antagonist – is the drug of choice to treat moderate and severe cases of SS.4, 17, 23 The initial recommended dose is 12 mg, followed by 4-8 mg every 6 hours as needed.4, 5 Some sources recommend starting at 12 mg, then tapering the dose down by 2 mg every 2 hours as needed. 6 The main downsides to this drug is sedation (which may actually assist in the patient’s care) and the fact that it is only available in oral form.5 In an uncooperative, agitated patient any medication by mouth may be difficult to administer. Other options are chlorpromazine (Thorazine),31-33 which can be given IV or IM, olanzapine (Zyprexa)31-33 which can be given IM, dexmedetomidine (Precedex)34 or propofol (Diprivan),34 both of which are given IV. Care must be taken when treating with chlorpromazine, since it has potential to cause serious hypotension and lower the seizure threshold. 6,7

The main things you need to consider when weighing treatment options is the autonomic instability and increased neuromuscular tone. More specifically, the hemodynamics and the temperature of the patient. There are two theories of how the fever develops – central versus peripherally mediated. From the central perspective, serotonin acts to stimulate receptors in the hypothalamus, thus increasing the set point for the body temperature. 5,13,15,16 The peripherally mediated theory suggests that the body’s temperature increases due to the hypermetabolic state caused by increased muscular tone. 6, 7 The truth is that they probably both play a role. Regardless of etiology, fever and hemodynamic instability are of critical therapeutic importance as these are the pathways leading to patient mortality. Up to 14% of patients with SS present with hypotension19 and when the vital organs aren’t perfused, patient outcomes suffer significantly. Impaired temperature regulation can also be deadly due to the sequelae of the fever itself as well as the processes that cause the fever. Patients with uncontrolled muscle spasms spill myoglobin into their serum and suffer renal failure due to rhabdomyolysis.3 If a patient’s muscle rigidity is difficult to control, you should consider intubation and neuromuscular paralysis. If the patient does undergo rapid sequence intubation, care should be taken with the administration of succinylcholine and the potential for elevated serum potassium.3 Typically after discontinuing the offending medication, symptoms are gone within 24 hrs.5,7,27 Still, some SSRI’s have half-lives of 1-2 weeks so symptoms can persist up to 6 weeks after cessation.12

There are a few other SS-inducing medications worthy of special mention. First, not all opioids cause SS. There are two broad classes of opioids called phenanthrenes and non-phenanthrenes. The phenanthrenes are divided into those with an oxygen bridge and those without. The only one in the latter class is dextromethorphan. The phenanthrenes with an oxygen bridge include buprenorphine, codeine, oxycodone, hydrocodone, hydromorphone, morphine, naloxone, and naltrexone. Theoretically speaking, none of these narcotics should cause SS. However, despite the biochemical structure, there have been case reports of SS associated with hydromorphone, buprenorphine, naloxone, and oxycodone. Specifically, synthetic medications such as fentanyl, meperidine, methadone, and tramadol have been associated with SS. On the other hand, there have been no case reports of SS associated with hydrocodone, morphine, or codeine.1 The second class of drugs necessitating mention are triptans. You know those anti-headache medications? They’re serotonin agonists. In 2006 the FDA sent out a warning about the potential for SS when using triptans and SSRI’s or SNRI’s in combination.35 Interestingly, the evidence for this phenomenon is not entirely convincing. Triptans are selective agonists of 5-HT1B, 5-HT1D, and 5-HT1F.36 If you recall, SS is primarily mediated by 5-HT2a and 5-HT1A. Additionally, the FDA alert was based off of 29 cases of suspected SS, only 10 of which met Sternbach’s criteria. None of the 29 met the Hunter criteria.37


Neuroleptic malignant syndrome (NMS) is a disease that tends to occur in a similar population as SS and can manifest in a similar manner.38 Previously, NMS was reported to occur in 0.2%-3.2% of patients on neuroleptics,39 but due to increased awareness of the disease and decreased use of 1st generation anti-psychotics the incidence of NMS has declined to 0.01-0.02% of all patients at risk.39 However, even though the incidence is low, the mortality rate has been reported to be as high as 55%.2 There is a certain population of patients that are at higher risk for the development of NMS, and those include dehydrated patients, patients with underlying brain damage and dementia, and those on high dosages of dopaminergic medications.3 As stated previously, the administration of neuroleptics (also known as anti-psychotics) are the medications most commonly associated with NMS. First generation anti-psychotics have an odds ratio of 23.4, while 2nd generation anti-psychotics have an odds ratio of 4.8 for the development of NMS.40 One of the differences between NMS and SS is the time of onset. While SS will usually manifest within 24 hours after the offending medication is administered, only about 16% of patients who develop NMS will do so within 24 hours, and 66% will develop symptoms within the first week.41

So now that we know a little background on NMS, what are the symptoms? In order to understand the symptoms, one must consider the pathophysiology of how NMS affects the body. It is very likely that there are multiple mechanisms involved, but the most probable theory is that dopamine acts as a tonic inhibitor of the central sympathetic nervous system (SNS).42 When the dopamine is removed, the SNS becomes unopposed. The evidence behind this isn’t grade A, but the pathophysiology of the theory makes sense, and multiple studies have found elevated levels of catecholamines in both the serum and the CSF.38,41-43 NMS manifests classically as extrapyramidal symptoms, altered mental status, and autonomic dysfunction.38 The extrapyramidal symptoms appear as Parkinsonian features such as rigidity, tremor, dystonia, and akinesia, and the autonomic dysfunction manifests as tachycardia, diaphoresis, hyperthermia, and labile blood pressure. Just as in SS, getting an adequate history and a medication list is crucial. That being said, often patients in extremis and with altered mental status present without any past medical history, and we then have to rely on the physical exam. The main differentiating feature of SS and NMS are reflexes. SS will typically be hyperreflexic whereas NMS will have rigidity.

The initial treatment of NMS is identical to SS, which includes stopping the offending medication and administering supportive care, including benzodiazepines. However, if that doesn’t work, escalating care may be necessary. This is where the similarities between the treatment of SS and NMS diverge. The three main medications that are given are bromocriptine, amantadine, or dantrolene.41 The two former medications are dopamine agonists, and the latter blocks calcium release. Other options include L-dopa,3 and surprisingly, electroconvulsive therapy has successfully been used in refractory cases.3,41


Even though both NMS and SS are relatively rare clinical entities, their incidences are expected to increase due to both enhanced awareness as well as a rise in medication administration. 34 Understanding the complex presentations is a critical initial step in identification of the process. If you do suspect SS or NMS, make sure to review the patient’s medications. At the bedside you will need to remember to check reflexes, especially in the lower extremities. These initial clues, along with a few other things, such as autonomic instability, mental status changes, extrapyramidal symptoms, and increased neuromuscular tone, will help you differentiate SS from NMS or from other pathologies and begin treating your patient appropriately.


References / Further Reading

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