Tag Archives: #FOAMcc

Fever in the Returning Traveler: Systematic ED Approach

Authors: Katie Lupez, MD (@KatieLupez, EM Resident Physician, Carolinas Medical Center) and Michael Runyon, MD, MPH (Professor of EM, Carolinas Medical Center) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital) and Brit Long, MD (@long_brit, EM Attending Physician, SAUSHEC)


A 21-year-old female presents with fever one week after returning from Uganda, where she participated in a college service trip to an orphanage. She has had no symptoms other than a fever for the past few days. Vitals: HR 100, BP 120/80, T 102° F, RR 15. The patient is well appearing, and the physical examination reveals no rash, clear lungs, a soft and non-distended abdomen with mild splenomegaly, and no focal neurological findings.


  • Approximately three percent of international travelers contract an illness requiring medical attention with isolated fever being most common presentation.1
  • These patients are at a high risk of misdiagnosis and delayed treatment due to the relative rarity of tropical diseases in high-income countries.
  • It is imperative that the EM physician undertakes a systematic approach to evaluating these patients.
  • We must be able to rapidly and accurately identify potentially communicable diseases, immediately initiate any indicated treatment and isolation measures, and determine the optimal patient disposition.

Initial Assessment

  • Our initial assessment should include reviewing the patient’s vital signs and overall appearance.
  • Promptly recognize life threats requiring immediate intervention, such as airway, breathing, or circulatory compromise, and resuscitate appropriately.
  • Keep a broad differential that includes tropical diseases.
  • If at all suspicious for a communicable disease, isolate the patient early and use the appropriate level of personal protective equipment to ensure your safety and that of your staff and other patients.


  • Placing the patient’s fever in perspective of an epidemiological link will help guide your differential diagnosis.
  • Begin with open-ended questions, eventually narrowing down to identify the patient’s specific chief complaint, duration of complaint, and associated symptoms.
  • The travel history should include:
    • all destinations visited
    • the day-to-day itinerary and duration of travel
    • any pre-travel vaccinations or prophylaxis (including specific drugs, doses, and dates of treatment, including any missed or delayed doses)
    • travel exposures: arthropod, bird, exotic pet, and livestock exposures, types of foods consumed, piercings/tattoos obtained, IV drug use, sexual encounters or any healthcare exposure or treatment abroad
  • A thorough evaluation of the patient’s past medical history is important to help further delineate their potential susceptibility to certain diseases.

Physical Exam

  • A detailed physical exam will help solidify your diagnosis.
  • Vital signs: note any relative bradycardia (heart rate lower than would otherwise be expected given the degree of fever) and remember recent antipyretic use can mask fever.
  • Skin: ensure that the patient is fully unclothed and examine for any evidence of bites, jaundice, pallor or rash with specific rashes to consider including petechiae and rose-colored spots.
  • HEENT: look for conjunctivitis, lymphadenopathy, and nuchal rigidity.
  • Cardiopulmonary: identify any focal crackles, diffuse wheezing, or murmurs.
  • Abdominal exam: assess for tenderness in all quadrants, identify any hepatomegaly or splenomegaly, and assess for Murphy’s sign.
  • Neuro: identify any altered mental status or focal neurologic findings.
  • Special tests: consider performing specialized tests such as the Rumpel-Leede test.
    • Rumpel-Leede (tourniquet test): This test assesses for capillary fragility that is classically suggestive of dengue, but can be associated with a wide variety of tropical diseases and has been recently associated with Chikungunya and Zika infections2. The test is performed after initially taking the patient’s blood pressure and then re-inflating the blood pressure cuff midway between the systolic and diastolic pressures, maintaining this pressure for approximately 5 minutes. After removing the cuff, the test is considered positive if you identify >10 petechiae per square inch within approximately 2 minutes of deflating the BP cuff as noted in Figure 1 below.3,4

Screen Shot 2017-03-13 at 5.29.42 PM

Figure 1.5 Rumpel-Leede Test

Diagnostic Testing

  • Use your initial assessment, HPI, and physical exam to help guide your differential diagnosis and inform your diagnostic testing.
  • In general, a CBC with diff, urinalysis/urine culture, and CMP will be the minimum work up in a returning traveler with fever.6
  • Review your CBC for platelet count and absolute eosinophil count.
  • Consider a CXR for patients with respiratory symptoms or abnormal cardiopulmonary examination findings.
  • Consider stool examination for patients with diarrhea.
  • Send blood cultures if patient’s fever remains undifferentiated or patient’s illness appears systemic.
  • Consider rapid antigen detection tests for malaria, if available.
    • Thick and thin blood smears should be sent also since in addition to identifying the presence of parasites, they can inform management by quantitating the parasitemia, and identifying the particular species. If the initial blood smear is negative, yet your suspicion remains high or the patient is immunosuppressed, send q12h smears for a total of three negative smears before ruling out malaria.
  • Order serological testing (RT-PCR, ELISA, immunoassay) of the specific diseases you are concerned about
    • It may not yield results quickly enough to impact ED decision-making, but may be important to assist admitting or outpatient team management.
  • Order a UPT in all women of childbearing potential.


  • Initiate isolation and appropriate level of personal protective equipment early.
    • Clearly communicate your concerns and the potential threat to the clinical staff treating the patient.
  • Resuscitate as needed
  • Treat identified diseases
    • Initiating early treatment can help prevent morbidity/mortality from rapidly progressing diseases such as falciparum malaria.
    • Of note, many of these tropical diseases have no definitive treatment, but are managed by supportive care alone.
  • Determine disposition
    • Disposition will greatly vary based on patient’s overall appearance, social situation, and treatment needs.
    • If you feel the patient is appropriate for outpatient management, ensure good outpatient follow up.
  • Use the resources below to identify geographical outbreaks and the clinical manifestations (i.e. during recent Ebola outbreaks in West Africa, most patients presented with fever and GI symptoms and only a minority had hemorrhagic manifestation7).
    • CDC Yellow Book8
    • GeoSentinel9
    • WHO10
  • If patient still remains undifferentiated, consider consulting your infectious disease colleagues from the ED.

 Working Through Your Differential Diagnosis

Fever and Abdominal Pain

Tropical Differential Diagnosis  Location Incubation Signs and Symptoms Diagnostic Tests Treatment
Giardiasis Worldwide 1-3 weeks Greasy stools, diarrhea Stool ova and parasites Metronidazole
Typhoid Fever Southern Asia 7-18 days Rose colored spots Blood cultures Ciprofloxacin
Cholera Africa, Southeast Asia, Caribbean 2-3 days Rice water stools Clinical, rectal swab can be sent for lab dx Aggressive rehydration, can consider doxycycline
Schistosomiasis (Katayama Fever) Africa 4-8 weeks Hematuria, diarrhea stool or urine parasites Praziquantel
Liver Fluke Clonorchiasis Asia 1 month RUQ tenderness CBC with diff, ultrasound, stool exam Praziquantel or albendazole
Fascioliasis Africa, Middle East, South America 6-12 weeks nitazoxanide/triclabendazole
Liver Abscess (Entamoeba) India, Indonesia, Thailand, Mexico 7-14 days RUQ tenderness,
watery or bloody diarrhea
RUQ U/S, stool microscopy,
PCR and serologic tests as needed
Metronidazole ± iodoquinol
ETEC, norovirus, campylobacter,
shigella, salmonella
Worldwide variable diarrhea if prolonged can consider stool examination and culture supportive care
if prolonged consider tx with ciprofloxacin

Screen Shot 2017-03-13 at 5.29.01 PM

Figure 211 Typhoid Fever Rose Colored Spots

Screen Shot 2017-03-13 at 5.29.11 PM

 Figure 312. Liver Abscess. Case courtesy of Dr Maulik S Patel, Radiopaedia.org, rID: 9335

Fever and Respiratory Symptoms

Tropical Differential Diagnosis  Location Incubation Signs and Symptoms Diagnostic Tests Treatment
MERS-CoV Arabian Peninsula 2-14 days cough specimen or serologic PCR supportive care and isolation
Tuberculosis Worldwide 1-2 week cough, hemoptysis, weight loss CXR, sputum culture (+acid fast bacilli), NAAT RIPE (rifampin, isoniazid, pyrazinamide, ethambutol)
Influenza Worldwide,
China (Avian flu)
1-3 days nonproductive cough, malaise,
vomiting/diarrhea myalgias
rapid identification test, RT-PCR, viral culture early neuraminidase inhibitor
isolation if avian flu suspected
Q fever Africa and Middle East 2-4 weeks flu like illness, cough indirect immunofluorescent assay Doxycycline

Fever and Jaundice

Tropical Differential Diagnosis  Location Incubation Signs and Symptoms Diagnostic Tests Treatment
Yellow Fever Equatorial Belt 3-6 days black emesis, relative bradycardia cbc, cmp, urinalysis, titers supportive care
Hep A Africa and Asia 2-6 weeks malaise, hepatomegaly hepatitis panel dose of monovalent hepatitis vaccine or IG
Hep B Worldwide 60-150 days Supportive care
Hep C Worldwide 6-9 weeks boceprevir and telaprevir
Hep E Africa and Asia 2-9 weeks supportive care

Fever and Arthralgia

Tropical Differential Diagnosis  Location Incubation Signs and Symptoms Diagnostic Tests Treatment
Dengue Latin America, Southeast Asia 4-8 days petechiae, retro-orbital pain, epistaxis RT-PCR, DENV immunoassay, ELISA supportive care, avoid NSAIDs risk of hemorrhage
Zika Africa, Asia, Latin America 2 weeks conjunctivitis, flu like illness clinical dx, rRT-PCR supportive care
Chikungunya Africa, Asia, Latin America 2-4 days flu like illness, maculopapular rash clinical dx, CHIKV IgM, viral culture supportive care

Fever and Hemorrhage

Tropical Differential Diagnosis  Location Incubation Signs and Symptoms Diagnostic Tests Treatment
Viral Ebola West Africa 2-21 days flu like symptoms RT-PCR supportive care and isolation
Crimean-Congo Africa/Eastern Europe 1-13 days headache, vomiting, conjunctivitis ELISA, RT-PCR supportive care, if severe ribavirin, isolation
Lassa West Africa 3-16 days severe sore throat ELISA, RT-PCR supportive care, if severe ribavirin, isolation

Fever and AMS

Tropical Differential Diagnosis  Location Incubation Signs and Symptoms Diagnostic Tests Treatment
Encephalitis Japanese Asia 5-15 days  nuchal rigidity, seizure clinical dx, LP to r/o other causes, ELISA, RT-PCR supportive care
West Nile Africa, Middle East, Europe

Undifferentiated Fever

Tropical Differential Diagnosis  Location Incubation Signs and Symptoms Diagnostic Tests Treatment
Malaria P. falciparum Worldwide, predominate species in Africa 7-30 days malaise, nausea, vomiting,
mild jaundice, body aches
Thick and thin smear,
Rapid diagnostic test (antigen detection),
(can use chloroquine in sensitive regions)
P. malaria South America, Africa, Asia
P. knowlesi Southeast Asia
P. Ovale Sub-Saharan Africa Atovaquone-proguanil + Primaquine
P. Vivax Worldwide, predominate species outside of Africa

Case Conclusion

Her UPT is negative. Her CBC reveals a mild anemia with a Hgb of 11 g/dl. The rest of her CBC with differential, CMP, and urinalysis are within normal limits. A rapid malaria test is preformed and comes back positive. You send for a thick and thin smear. Her parasitemia level is approximately 2 percent, and the reader has identified the malaria species as P. falciparum. You reference the CDC yellow book, and based on her geographical area of travel you find this is most likely an area of chloroquine resistance and therefore prescribe atovaquone-proguanil. Based on your above work up you believe she does not meet criteria for severe malaria. After assessing her social situation, you feel she is a candidate for outpatient management of her uncomplicated malaria with close primary care follow-up.

Take Home Message

  • Take a thorough history and perform a complete physical examination.
  • Keep a broad differential including thinking through various tropical diseases pertinent to the patient’s travel history and examination findings.
  • Rapidly identify transmissible diseases, institute appropriate isolation, PPE, treatment, and determine the optimal patient disposition.


References / Further Reading:

  1. Ryan ET, Wilson ME, Kain KC. Illness after International Travel. N Engl J Med. 2002;347(7):505-516. doi:10.1056/NEJMra020118.
  2. Kulkarni SA, Strobelt E, Sargsyan Z. Capillary Fragility in Zika Virus Infection. Am J Med. 2017;130(2):e59. doi:10.1016/j.amjmed.2016.10.008.
  3. Clinical Assessment. Available at: https://www.cdc.gov/dengue/training/cme/ccm/page73112.html.
  4. Wang K, Lee J. Rumpel–Leede Sign. N Engl J Med. 2014;370(1):e1. doi:10.1056/NEJMicm1305270.
  5. Dengue virus infection: Clinical manifestations and diagnosis – UpToDate. Available at: https://www.uptodate.com/contents/dengue-virus-infection-clinical-manifestations-and-diagnosis?source=search_result&search=tourniquet test&selectedTitle=1~150.
  6. VanRooyen MJ, Venugopal R. Chapter 156. World Travelers. In: Tintinalli JE, Stapczynski JS, Ma OJ, et al., eds. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 7e. New York, NY: The McGraw-Hill Companies; 2011. Available at: accessmedicine.mhmedical.com/content.aspx?aid=6375223.
  7. Moole H, Chitta S, Victor D, et al. Association of clinical signs and symptoms of Ebola viral disease with case fatality: a systematic review and meta-analysis. J community Hosp Intern Med Perspect. 2015;5(4):28406. doi:10.3402/jchimp.v5.28406.
  8. 2016 Yellow Book Home | Travelers’ Health | CDC. Available at: https://wwwnc.cdc.gov/travel/page/yellowbook-home-2014.
  9. The International Society of Travel Medicine. Available at: http://www.istm.org/geosentinel.
  10. WHO | World Health Organization. WHO. 2017.
  11. Typhoid, Let’s win the war: Typhoid (Salmonella S Typhi) Fever- Causes, Symptoms, Diagnosis, Types. Available at: http://www.typhoid.co/2015/03/typhoid-symptoms-salmonella-typhi.html.
  12. Al G et. Radiopaedia Hepatic Abscess.


Maximizing ED Management of Amputations

Authors: Cara Kanter, MD (EM Resident Physician, Temple EM) and Zachary Repanshek, MD (Assistant Professor of Emergency Medicine, Lewis Katz School of Medicine; Assistant Program Director, Temple EM) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital) and Brit Long, MD (@long_brit)

A Clinical Case

A 43-year-old male with a history of IV drug use presented to the Emergency Department after being struck by a train. EMS reported 10 minutes of extraction time. The patient reported copious alcohol use prior to the incident and complained primarily of right leg pain. Physical exam was notable for GCS 13 (E4V4M5), bilateral periorbital ecchymosis with tarsal sparing, and near total amputation of the right lower extremity below the knee.


Numbers Game (1)
  • Roughly 83,000 traumatic amputations in the U.S. yearly
  • Majority of victims are men age 15-40
  • Most common mechanisms: MVC (51%), industrial accidents (19%), agricultural accidents (10%)
  • Most common sites: partial hand amputation (1+ fingers), unilateral upper extremity
Definitions (1,2)
  • Partial Amputation: bone, muscle, or tissue keeps the amputated segment connected to the body
    • More common among civilians
    • Ideal treatment = revascularization
  • Complete Amputation: no connecting tissue
    • More common in military
    • Ideal treatment = reimplantation
  • Sharp/Guillotine Amputation: Well-defined edges, minimal damage to associated anatomy
    • Best prognosis for reimplantation
  • Crush Amputation: extensive soft tissue & arterial damage
    • Reimplantation less likely to be successful
  • Avulsion Amputation: forceful overstretching & tearing of nerves & vascular tissue at many different levels from the site of separation
    • Reimplantation unlikely


Pearl #1: ED management is the same for ALL types of traumatic amputation => ALL patients are candidates for reimplantation until a surgeon says otherwise!



  • Ischemia time (2)
    • Irreversible muscle necrosis begins at 6 hours of ischemia
    • Temperature & muscle amount in tissue predict tolerable ischemia time
      • Digits: less muscle mass, tolerate more ischemia time
        • Warm ischemia time: 8-12 hours
        • Cool ischemia time: up to 24 hours
      • Limbs: more muscle mass, tolerate less ischemia time
        • Warm ischemia time: 4-6 hours
        • Cold ischemia time: 10-12 hours
      • Mechanism of Injury
        • Guillotine amputations best chance of successful reimplantation
        • Crush/Avulsion amputations have worse prognosis for limb salvage
      • Co-morbidities
        • Young, healthy patients have better chance of successful limb salvage (shocking!)
        • Worse prognosis: smoking, diabetes, PVD, rheumatologic disease
      • Handedness
      • Occupation


PEARL #2: ISCHEMIA TIME predicts success for reimplantation!


Physical Exam  
  • Primary & Secondary Survey
    • Significant traumatic amputations portend significant internal injuries that may be more immediately life-threatening
    • Control hemorrhage & proceed with ATLS resuscitation as you would any trauma
  • Assess & document a complete exam of the injured extremity
    • Neuro exam
      • Test for sensation & 2-point discrimination in each nerve distribution
    • Vascular exam
      • Capillary refill
      • Pulses via palpation and Doppler, ABIs when appropriate
      • Ribbon sign: tortuous artery in amputated segment, indicates significant vascular compromise (3)
      • Use Allen test in hand injuries
    • Soft tissue & Bone (2)
      • Assess skin, muscle, bone, tendon and nail bed integrity
      • Identify fractures
        • Exposed bone, gross deformity, tenderness, crepitus


PEARL #3: Don’t forget ABCDE => look for other injuries that may kill the patient first!


ED Management

Care of the amputated segment (1,2,4)
  • Irrigate with saline or sterile water & remove gross contamination
  • Control any bleeding with a pressure dressing
  • Wrap in moistened sterile gauze & seal in water-tight container
  • Place container on ice, in ice water bath, or in refrigerator
  • Do NOT allow limb to freeze!
Care of the stump (2,5)
  • Elevate the limb
  • Irrigate with saline & cover with damp gauze
  • Splint obvious/unstable fractures, keep as near anatomic position as possible
  • Control hemorrhage!
Tourniquet Use
  • Indications for tourniquet use (5,6)
    • Uncontrollable bleeding from a site amenable to proximal placement of a tourniquet
    • Limb amputation or mangled extremity
    • Exsanguinating wound associated with shock
    • Life-threatening hemorrhage inadequately controlled with direct pressure, elevation and other hemostatic methods
  • Pearls of tourniquet application (5)
    • Place the tourniquet as distal as possible, at least 5 cm proximal to the injury
    • Spare joints as much as possible
    • Apply directly onto exposed skin
    • Time of application should be recorded
    • Any amputated limb should be transported with the patient to the hospital


PEARL #4: Life over limb!


Other Considerations
  • Tetanus prophylaxis
  • Prophylactic antibiotics (2,7)
    • Strep & staph coverage
    • Should be given within 6 hours of trauma
      • Cefuroxime 1.5g IV q8h or Cefazolin 0.5-1.5g IV or IM q6-8h
        • Peds: 25-100mg/kg/d divided q8hr (max 6g/d)
      • MRSA coverage: Vancomycin 15-20mg/kg IV q12h
      • Clostridia coverage: Piperacillin/Tazobactam 80mg/kg IV q8h
    • Immediate surgical consultation – orthopedics, plastics, vascular, trauma! Time is limb!


PEARL #5: Traumatic amputation is a surgical emergency! Get the patient to a surgeon ASAP!


Review of the Pearls

  1. ED management is the same for ALL types of traumatic amputation => ALL patients are candidates for reimplantation until a surgeon says otherwise!
  2. ISCHEMIA TIME predicts success for reimplantation!
  3. Don’t forget ATLS => look for other injuries that may kill the patient first!
  4. Life over limb!
  5. Traumatic amputation is a surgical emergency! Get the patient to a surgeon ASAP!


Case Resolution

The patient was intubated in the trauma bay for airway protection. A CT head obtained demonstrated multiple skull fractures and an epidural hematoma without mass effect. The patient was taken to the OR with trauma surgery for a right through-knee guillotine amputation. A repeat CT head obtained immediately post-op demonstrated an expanding epidural hematoma. The patient went immediately back to the OR with neurosurgery for a hematoma evacuation. The patient was taken back to the OR a few days later with trauma surgery for a formal above-knee-amputation.


References/Further Reading

  1. Meenach, Dean. “How to manage traumatic amputations and uncontrolled bleeding.” EMS In Focus. EMS1.com, 30 Apr. 2014. Web. 24 Feb. 2017
  2. Schaider, J. (2015). Amputation Traumatic/Replantation. ROSEN & BARKIN’S 5-MINUTE EMERGENCY MEDICINE CONSULT. Retrieved February 24, 2017 from http://www.r2library.com.libproxy.temple.edu/Resource/Title/1451190670/ch0001s0822
  3. Van Beek AL, Kutz JE, Zook EG. (1978). Importance of the ribbon sign, indicating unsuitability of the vessel, in replanting a finger. Plastic and Reconstructive Surgery, 61(1):32-5.
  4. Stone, C. (2005). Traumatic Amputation. CURRENT ESSENTIALS OF EMERGENCY MEDICINE. Retrieved February 24, 2017 from http://www.r2library.com.libproxy.temple.edu/Resource/Title/0071440585/ch0022s2072
  5. Lee C, Porter KM, Hodgetts TJ. (2007). Tourniquet use in the civilian prehospital setting. Emergency Medicine Journal, 24, 584-7.
  6. Rush RM, Arrington ED, & Hsu JR. (2012). Management of complex extremity injuries: Tourniquets, compartment syndrome detection, fasciotomy, and amputation care. Surgical Clinics of North America, 92(4), 987-1007.
  7. Schmitt SK. Treatment and prevention of osteomyelitis following trauma in adults. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on February 24, 2017).

Severe Transfusion Reactions and their ED-focused management

Authors: Richard Wroblewski, MD (EM Resident Physician, Temple EM) and Zachary Repanshek, MD (Assistant Professor of EM / APD, Temple EM) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital) and Brit Long, MD (@long_brit)

The decision to transfuse blood is made based on the clinical combination of hemoglobin level, concurrent comorbidities, and the overall clinical picture.  Once the decision is made, granted that our patient is stable and competent, it is our job to inform and consent the patient to receive blood.  As a clinician, we run through the list of possibilities that can occur when receiving blood: fevers, allergic reactions, infections, lung injury, and possibly death.  We explain that we try to minimize risks in every way possible; however, we must make the patient aware so that they understand the risks.  But how rare are these adverse events, and how do we manage them?

In 2011 approximately 20,933,000 units of blood product were transfused. The average patient received 2.6 units per transfusion1. Based on these numbers, almost 8,000,000 people in America received a blood transfusion in 2011.  In that year, there were 51,000 reportable reactions, and only 317 of them required increased levels of critical management: ICU care, intubation, or pressor support1.

Screen Shot 2017-02-20 at 2.58.07 PMThe graph demonstrates the likelihood of transfusion reaction as reported in The National Blood Collection and Utilization Survey Report1. One should note the pie chart represents <1% of all blood transfusions during the data year1.   Although these reactions are rare and the fact that a majority of reactions are benign in nature, it is important to recognize the acute, emergent transfusion reactions. For the purpose of consent, the prevalence of viral infections should be noted. Current screening techniques have reduced the risk of viral transmission lower than any other adverse event: HIV is 1: 1,467,000 units / Hepatitis C is 1: 1,149,000 units / and Hepatitis B is 1: 357,000 units2.

Acute Hemolytic Reactions

Acute hemolytic reaction is the most severe reaction, and in most cases, the easiest to prevent. This reaction occurs most commonly with ABO incompatibility due to human or systematic error3. The reaction often occurs within minutes of initiation, and this can help delineate this reaction from febrile-non-hemolytic reaction which typically occurs greater than 1 hour post transfusion4.

The patient will present with chills, agitation, fever, tachycardia, hypotension, abdominal and back pain, nausea, and progress to have changes in urine color, jaundice, and possibly diffuse bleeding due to coagulopathy. The symptoms often occur within minutes of transfusion initiation due to high levels of hemolysis within the body, resulting in spilling of free hemoglobin and diffuse proliferation of inflammatory cytokines5.Screen Shot 2017-02-20 at 3.00.38 PM

Treatment for all transfusion reactions begins with stopping the transfusion and calling the blood bank for further guidance and monitoring. In a serious transfusion reaction, you will want to send a set of new labs immediately to trend: type and cross, DAT (direct antiglobulin test), CBC, CMP, haptoglobin, fibrinogen levels, LDH, PT, and PTT6. These labs and their trends will help guide further treatment.

In the case of acute hemolytic reaction, fluid resuscitation should be initiated early to promote renal perfusion. The goal is to prevent kidney injury secondary to hypoperfusion and occlusive thrombi from DIC5. Therapy should be as follows:

  • IV fluids with goal urine output of 1cc/kg/hr6.
    • Furosemide 40-80mg IV can be used to augment urine output if the patient is oliguric; however, it should be stopped if there is no response or persistent hypotension within 4 hours of therapy6.
    • Continued hypotension after IV fluids should be treated with dopamine (2-5micrograms/kg/min6. Other vasopressors such as epinephrine and norepinephrine should be used with caution due to decreased renal perfusion.
    • If DIC is suspected, the use of replacement therapy should be used as follows:
    • FFP used if PT greater than 1.5
    • Cryoprecipitate if fibrinogen levels below 1g/L
    • Platelets replaced if count is below 50,000/uL6
    • Dialysis can be used to remove the immune complexes5.
    • Red Blood Cell Exchange Transfusion has been successful in a few case reports7.

Febrile Reaction

Febrile non-hemolytic transfusion reaction (FNHTR) is the most common transfusion reaction, occurring during the transfusion to 8 hours after.  Patients may also present will chills. It is due to recipient antibodies against donor leukocytes most commonly. With its similarity to acute hemolytic reaction, any fever warrants immediate discontinuation of the transfusion.  However, FNHTR is benign, with no sequelae. Acetaminophen should be provided1,3-5.

Transfusion Related Acute Lung Injury 

Transfusion Related Acute Lung Injury is currently the most common cause of transfusion related fatalities8. According to current consensus, TRALI is defined as new lung injury within 6 hours of transfusion: hypoxemia <90% and CXR with infiltrates and lack of other risk factors9.

Screen Shot 2017-02-20 at 3.01.25 PMTRALI occurs within the first 6 hours of transfusion and presents with dyspnea, tachypnea, and hypoxemia. Patients often are noted to have associated rigors, tachycardia, fever, and hypotension10. Diagnostically, a chest X-ray will be the most beneficial; however, the findings can range from a small amount of bilateral infiltrate to an entire white-out of the lungs as seen in ARDS11. Laboratory testing is not specific but can be helpful; often a leukopenia and thrombocytopenia can be seen as the lungs sequester these inflammatory cells, but these are not diagnostic for TRALI10,11.

The current theory on the pathogenesis of TRALI is based on the two-hit model. The first hit is an underlying patient factor that causes adherence of primed neutrophils in the pulmonary endothelium11,12.  At risk patients include those with sepsis, on mechanical ventilation, acute renal failure, liver disease, chronic alcoholics, patients in shock, smokers, and those with a history of blood cancer13. The second hit occurs when the blood transfusion itself causes activation of the primed neutrophils within the lungs resulting in inflammatory changes that cause acute pulmonary edema mostly due to increased capillary permeability11,12.

In general, TRALI has a favorable prognosis with mortality ranging between 5-10%14. Despite its prognosis, a significant number of patients (70-90%) require mechanical ventilation11.

Screen Shot 2017-02-28 at 6.24.28 PMFirst line treatment is to stop the transfusion and call the blood bank. Initially high flow oxygen should be administered to improve oxygenation; however, as the pulmonary edema continues, the need for mechanical ventilation becomes more likely. Due to its clinical similarity to ARDS, patients with TRALI are suggested to have restrictive tidal volume ventilation11. There has been little evidence for the use of corticosteroids and diuretics in these patients11.

Allergic Reactions

Allergic reactions occur in 1-3% of transfusions and can range from rash to anaphalyxis15. Although common, there is little evidence to show any benefit to pre-treating all patients with antihistamines, and at this time, it is not recommended16.  Patients typically develop symptoms within minutes and present with common signs of an allergic response: rash, urticaria, and itching. These symptoms can quickly progress to anaphylactic reactions with hypotension, angioedema, and respiratory distress. 

All reactions should prompt the emergency physician to stop the transfusion immediately and provide antihistamines. If only a mild reaction occurs and antihistamines provide relief, the transfusion can continue.  If symptoms appear to be more severe, epinephrine should be administered immediately. Monitoring for signs of hypotension and airway compromise may prompt further interventions6.

Transfusion Associated Circulatory Overload

Transfusion Associated Circulatory Overload can be thought of as pulmonary edema from acute heart failure secondary to blood transfusion. The reaction is associated with a significant increase in morbidity and mortality as well as length of hospital stay19.  TACO is more likely to occur in patients with a history of congestive heart failure, renal failure, hemorrhagic shock, and those receiving multiple units of blood product19. Patients typically present within 6 hours of transfusion with signs of acute pulmonary edema and heart failure: new respiratory distress, hypertension, new pulmonary edema, widened pulse pressure, and increased JVD. 

Screen Shot 2017-02-20 at 3.02.02 PMDiagnostically, TACO is very difficult to differentiate from TRALI, and the chest radiograph is similar to that seen in TRALI. The use of BNP to measure heart strain in the setting of TACO has been studied with conflicting results and may only be useful if a pre-transfusion BNP is collected21,22.

Physiologically, TACO can be thought of as volume overload due to blood transfusion. Therefore, the problem is simply a volume overload and should be treated as such.

Treatment for TACO can start before the transfusion even begins. When high risk patients are identified, preventative measures should be put in place to avoid circulatory overload:

  • Slower transfusion rates (<120cc/hr), 1 unit at a time with reassessment in between multiunit transfusions, and intravenous dose of furosemide (40mg) prior to transfusion20.

Screen Shot 2017-02-28 at 6.26.08 PMIf TACO does occur, treatment starts with stopping the transfusion and promoting oxygenation and clearance by sitting the patient upright, providing supplemental oxygen, and providing nitrates/diuretics to remove excess volume and reduce preload. In cases of significant respiratory distress, non-invasive positive pressure ventilation can be beneficial. If these methods fail, therapeutic phlebotomy can be used 6.


Introduction of bacteria to the patient during transfusion occurs with a quoted incidence between 1:38,000 for packed red blood cells and 1:2000 for platelets; however, adverse reactions from bacterial contamination remain low at 1:250,000 and 1:25,000, respectively23. Most commonly, packed red blood cells are contaminated with organisms such as Yersinia Entercolitica, Serratia, and Psuedomonas, whereas platelet transfusions are more likely to grow skin contaminants such as Staphylococcus aureus and Streptococci24.

Patients will rapidly develop high fevers, chills, rigors, tachycardia, and hypotension along with dyspnea and can progress into DIC6. These symptoms are very similar to acute hemolytic transfusion reaction and therefore must often be considered together and treated similarly. If sepsis is considered, along with testing for AHTR, blood cultures from the unit of blood being transfused and a separate culture from the patient should be sent to the lab and broad spectrum antibiotic initiated based upon most likely culprits.  These patients should have their transfusions stopped immediately, and begin fluid resuscitation along with antibiotic treatment before any results return.

Pearls and Pitfalls: Approach to Reactions

Screen Shot 2017-02-20 at 3.02.34 PM

  • Maintaining high clinical suspicion for reaction will save lives; although rare these are serious reactions.
  • Report any reaction to the blood bank to allow for reporting and monitoring.
  • For any reaction: stop transfusion, call blood bank, and double check that the correct patient received the correct blood.
  • Most reactions with fever will require a full laboratory work-up for signs of hemolysis and infection: CMP, CBC, Haptoglobin, DAT, LDH, PT, PTT, fibrinogen, blood culture, and gram stains from patient and sample, and a type and cross.
  • Any signs of dyspnea require a chest radiograph; if there is a fever and hypotension, it is more likely to be TRALI than TACO.
  • Treatment for all is largely supportive; however, in severe reactions antibiotics can be initiated for any suspicion of septic transfusion.

This post is sponsored by www.ERdocFinder.com, a supporter of FOAM and medical education, who with their sponsorship are making FOAM material more accessible to ER physicians around the world.

Screen Shot 2017-03-05 at 9.32.20 PM

References/Further Reading:

1) United States Department of Health and Human Services.  The 2011 National Blood Collection and Utilization Survey Report.  2013. Accessed Feb 5,2017. http://www.hhs.gov/ash/bloodsafety/2011-nbcus.pdf.

2) Epstein, J. S. and Holmberg, J. A. (2010), Progress in monitoring blood safety. Transfusion, 50: 1408–1412. doi:10.1111/j.1537-2995.2010.02728.x

3) Dean L. Blood Groups and Red Cell Antigens [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2005. Chapter 3, Blood transfusions and the immune system. Available from: https://www.ncbi.nlm.nih.gov/books/NBK2265/

4) Chaffin, J. (2012 November/December) Transfusion Reactions [Audio Podcast] Retrieved from http://www.bbguy.org/pdf/2012_11_TX_RXNs.pdf

5) Strobel, E. (2008). Hemolytic Transfusion Reactions. Transfusion Medicine and Hemotherapy, 35(5), 346–353. http://doi.org/10.1159/000154811

6) Adewoyin, A., & Oyewale, O. (2015). Complications of Allogeneic Blood Transfusion: Current Approach to Diagnosis and Management. International Blood Research & Reviews, 3(4), 135-151. doi:10.9734/ibrr/2015/17874

7) Rose, S. S., George, S., Wong, S., Tenorino, G., & Kuriyan, M. (2007). Red Blood Cell Exchange Transfusion (RBCET) in the Management of Acute Hemolytic Transfusion Reaction (AHTR).. Blood, 110(11), 4021. Accessed February 05, 2017. Retrieved from http://www.bloodjournal.org/content/110/11/4021.

8) L Holness, MA Knippen, L Simmons, PA Lachenbruch. Fatalities caused by TRALI. Transfus Med Rev, 18 (2004), pp. 184–188

9) Goldman, M., Webert, K. E., Arnold, D. M., Freedman, J., Hannon, J., & Blajchman, M. A. (2005). Proceedings of a Consensus Conference: Towards an Understanding of TRALI. Transfusion Medicine Reviews, 19(1), 2-31. doi:10.1016/j.tmrv.2004.10.001

10) EA Fadeyi, MM De Los Angeles, AS Wayne, HG Klein, SF Leitman, DF Stroncek. The transfusion of neutrophil-specific antibodies causes leukopenia and a broad spectrum of pulmonary reactions. Transfusion. 2007 Mar;47(3):545-50.

11)Vlaar, A. P., & Juffermans, N. P. (2013). Transfusion-related acute lung injury: a clinical review. The Lancet, 382(9896), 984-994. doi:10.1016/s0140-6736(12)62197-7

12) CC Silliman The two-event model of transfusion-related acute lung injury Crit Care Med, 34 (2006), pp. S124–S131

13) Toy, P., Gajic, O., Bacchetti, P., Looney, M. R., Gropper, M. A., Hubmayr, R., . . . Matthay, M. A. (2011). Transfusion-related acute lung injury: incidence and risk factors. Blood, 119(7), 1757-1767. doi:10.1182/blood-2011-08-370932

14) SB Moore. Transfusion-related acute lung injury (TRALI): clinical presentation, treatment, and prognosis Crit Care Med, 34 (2006), pp. S114–S117

15) Hendrickson, J. E., & Hillyer, C. D. (2009). Noninfectious Serious Hazards of Transfusion. Anesthesia & Analgesia, 108(3), 759-769. doi:10.1213/ane.0b013e3181930a6e

16) Geiger, T. L., & Howard, S. C. (2007). Acetaminophen and Diphenhydramine Premedication for Allergic and Febrile Non-hemolytic Transfusion Reactions: Good Prophylaxis or Bad Practice? Transfusion Medicine Reviews, 21(1), 1–12. http://doi.org/10.1016/j.tmrv.2006.09.001

17) Haji, A. G., Sharma, S., Vijaykumar, D. K., & Paul, J. (2008). Transfusion related acute lung injury presenting with acute dyspnea: a case report. Journal of Medical Case Reports,2(1). doi:10.1186/1752-1947-2-336

18) Silvergleid, A.J. (2016) Approach to the patient with a suspected acute transfusion reaction. In Kleinman, S. (Ed), Uptodate.

19) Murphy, E. L., Kwaan, N., Looney, M. R., Gajic, O., Hubmayr, R. D., Gropper, M. A., … the TRALI Study Group. (2013). Risk Factors and Outcomes in Transfusion-associated Circulatory Overload. The American Journal of Medicine, 126(4), 357.e29–357.e38. http://doi.org/10.1016/j.amjmed.2012.08.019

20) Alam, A. A. (04/2013). Transfusion medicine reviews: The prevention of transfusion-associated circulatory overload. Elsevier. doi:10.1016/j.tmrv.2013.02.001

21) Li, G., Daniels, C. E., Kojicic, M., Krpata, T., Wilson, G. A., Winters, J. L., … Gajic, O. (2009). The Accuracy of Natriuretic Peptides (BNP and NT-pro-BNP) in the Differentiation between Transfusion Related Acute Lung Injury (TRALI) and Transfusion Related Circulatory Overload (TACO) in the Critically Ill. Transfusion, 49(1), 13–20. http://doi.org/10.1111/j.1537-2995.2008.01941.x

22) Zhou, L. L. (07/2005). Transfusion (philadelphia, pa.): Use of B-natriuretic peptide as a diagnostic marker in the differential diagnosis of transfusion-associated circulatory overload. Blackwell Publishing. doi:10.1111/j.1537-2995.2005.04326.x

23) Hillyer CD, Josephson CD, Blajchman MA, et al. Bacterial contamination of blood products: risks, strategies, and regulation. Hematology 2003: American Society of Hematology Educational Program Book. Washington, DC: American Society of Hematology; 2003: 575-589

24) Squires, J. E. J. (11/2011). Southern medical journal (birmingham, ala.): Risks of transfusion. Hop Wechsler. doi:10.1097/SMJ.0b013e31823213b6




EM Mindset: Tips on Becoming a Supreme Educator

Author: Benjamin H. Schnapp, MD (@schnappadap, Assistant Program Director, Assistant Professor, Department of Emergency Medicine, University of Wisconsin) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Brit Long, MD (@long_brit)

I can’t pretend to know more about how to be a great EM doc than the amazing folks who have already written for this series – the archives are filled with endless pearls of wisdom and are well worth a look (http://www.emdocs.net/category/em-mindset/).  Educating in the midst of a busy EM shift, however, requires its own dedicated mindset to be successful.  Here are some of the things I’ve learned about teaching in EM along the way.

Every great teaching shift has a beginning, middle, and end.

I sometimes find myself at a loss as to what feedback to give residents at the end of shift; the day goes by so quickly, it’s hard to remember what points I once wanted to communicate.  This is almost always because I didn’t organize my day properly from the start.  If I ask learners at the beginning of the shift what their goals are for the day, it helps organize my interactions with them.  Rather than trying to evaluate everything they do, I can zero in on one aspect of their performance, which is easier to accomplish.  The feedback conversation at the end of shift also flows naturally – it’s easy to bring up your initial conversation and immediately have specific suggestions that you know the resident is interested in.

Bring a toolbox to work.

You wouldn’t show up to build a house without the proper set of tools for the job.  Why would you show up for your next teaching shift similarly unprepared?  All sorts of great teaching tools have been developed to help you deal with any educational quandary you might come across.  Need to work on developing a learner’s differential diagnosis?  You’ve got to know about the SPIT technique.  Don’t have time for a verbose presentation right now?  Aunt Minnie may be just the thing.  “Teaching When Time Is Limited” (http://bit.ly/2kQPs9S) is a great place to learn more about these essential skills.

Smaller is better.

It’s easy to feel that if you aren’t sitting your team down for an extensive lesson on every patient that you’re not doing much teaching on shift.  However, these extended moments for teaching can be hard to come by in the ED.  Instead of looking for big teaching opportunities that may never come, think small.  One article, pearl of wisdom or even a simple fact can have a huge impact on your learner’s future practice, and there’s no risk of distraction from extraneous information.  This goes for feedback at the end of shift too – if you’ve got an important point to get across, don’t bury it in a pile of less essential feedback.

Don’t signpost.  Billboard – in neon.

Signposting refers to the practice of telling residents that you’re about to teach them before you do.  In theory, this avoids the common problem of residents underrecognizing the educational pearls you impart throughout the shift. In practice, I find even this is often insufficient.  You need glaring, unmistakable indications of ongoing education.  Grab a giant whiteboard (@amalmattu is a fan of this one).  Stick brightly colored post-its to your computer (a la @M_Lin).  Stand up and shout (I have been known to do exactly this prior to a mini-teaching session).  Find something that meshes well with your teaching style and get credit for your great work.

Eliminate mindreading.

It is fun to teach evidence-based medicine, but the world we encounter every day in the ED is highly complex. Often, great evidence to aid us in managing our patients is lacking.  In this setting, learners can see wide variations in attending practice patterns, which can be frustrating to their learning.  Why does this elderly patient who has fallen get admitted and this one goes home?  Aid learners in developing expert-level thinking by lending them some of yours.  For particularly tricky cases, I highlight my diagnostic process out loud to my learners, including what pieces of the case I am keying in on most.  Though some may worry that verbalizing their thinking may expose a lack of solid grounding for their decisions, learning to make good choices with limited information is an essential part of the job.

Hidden teachers are everywhere.

While EM docs like to think that we have the most interesting job in the department, there is a ton of important work that’s constantly being done by nurses, pharmacists, techs, social workers, and others that can offer incredibly valuable learning experiences, especially for more junior learners.  While you shouldn’t unload your learner onto another staff member for a whole shift, helping a nurse place an IV or catheter, assisting a pharmacist with dosing medications or watching a tech do a 12-lead EKG can be great opportunities for learners to get involved and learn new skills one on one from staff that will likely be thrilled for the teaching opportunity.  Don’t be afraid to utilize your resources.

Be there.

Woody Allen once said that 80 percent of life is showing up, and in many ways, the same goes for educating in the ED.  There are a million reasons not to leave your chair on shift – the chair is warm and close to your coffee, you have charts to complete, the resident doesn’t need your help, etc.  Resist this impulse and go observe your learners at work.  You’ll be surprised what knowledge gaps you find – there are senior residents out there with poor laceration repair skills!  This is also an excellent method to uncover previously hidden communication and efficiency issues that may not come to light elsewhere.  Even the most skilled learner can benefit from your experience and perspective on how to fine-tune their approach to patients and procedures.

Silence is golden.

When learners don’t know the answer to one of your questions, it can be tempting to just give it to them rather than sit in awkward silence.  Resist this urge, and embrace the awkwardness.  Some learners may need more time to think about your question, and you won’t understand the exact nature of their deficit unless you wait.  One learner might know exactly the right answer but not be confident enough to share.  Another might misunderstand the entire concept you’re inquiring about.  The next step in your teaching is completely different for these two learners, but unless you stop and wait to hear what they have to say, you’ll never know the difference.

Be humble.

The ED is a constantly humbling place.  You make thousands of decisions per shift: the best you can hope for is only getting a few of the small ones wrong.  Occasionally though, you may find yourself humbled by a bigger error.  The resident orders a CT scan that you tell them wasn’t needed and there’s a major finding.  The patient you sent home comes back septic.  Own up to these errors.  I’ll even email the resident directly to point out what happened – if the unexpected outcome was a learning experience for you, it will also be one for the resident.  Open dialogue will go a lot further for promoting trust and a positive learning environment than futilely trying to preserve an aura of invincibility.  Similarly, don’t be afraid to ask your learners for feedback on your teaching – they may have a great tip that you’ve overlooked!

You are always teaching.

There are days when all the consultants are difficult, all the dispositions are complicated, and by the way, your electronic medical record system is going to be down for the remainder of your shift.  When catastrophes (large or small) occur, teaching is often the first thing to go – who has time to sit down with the medical student when the ED is falling apart?  It’s important to remember in times like these that you are actually doing some of the most critical teaching that you’ll ever do.  As the captain of the ship, all eyes are on you for how you’ll manage the crisis.  Bad behaviors like avoidance, blaming others, or taking frustrations out on patients will quickly establish for all of your learners that these are acceptable behaviors when circumstances get difficult.  Show them instead how you lead through tough situations – even if that’s all you teach them that day.

Ultimately, I think it’s your intrinsic interest in improving as a teacher that will get you the farthest as an educator, and if you’ve made it to the end of this post, you likely have this quality in spades!  Do you have experience with any of the above techniques?  Words of wisdom of your own?  Feel free to share in the comments.

Special thanks to Dr. Abra Fant (@DrAbracadabra) and Dr. Aaron Kraut (@akraut23md) for their assistance with this piece.

Staphylococcal toxic shock syndrome: EM-focused highlights

Authors: Cameron J. Gettel, MD (EM Resident Physician, Alpert Medical School of Brown University) and Jessica L. Smith, MD (EM Attending Physician/Residency Program Director, Alpert Medical School of Brown University) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Brit Long, MD (@long_brit)


A 14 year-old female presents with fever, vomiting, diarrhea, muscle aches, and a diffuse, painless erythroderma all over her body. She is hypotensive despite IV fluid resuscitation. Further history suggests that her menstrual cycle ended yesterday.


Staphylococcus aureus colonizes the skin and mucous membranes of 30-50% of healthy adults and children1 and produces many exotoxins and enzymes that lead to inflammation. Toxic shock syndrome (TSS), caused by toxic shock syndrome toxin-1 (TSST-1),2 first came to attention in 1980 with menstrual-associated cases,3,4 and the disease is associated with a severe, life-threatening syndrome causing electrolyte disturbances, renal failure, and shock.5 Half of all cases are related to menstruation, with the remainder of cases observed in surgical/postpartum wound infections, mastitis, septorhinoplasty, osteomyelitis, burns, nasal packing, or complications from intrauterine devices.6,7 Cases of methicillin-resistant S. aureus (MRSA) have emerged as infection rates rise, but the majority of reported TSS cases are due to methicillin-sensitive S. aureus (MSSA). This post will focus primarily on staphylococcal toxic shock.


Signs and symptoms of TSS develop rapidly, described below in the clinical criteria. Definitive diagnosis requires all criteria, and a probable diagnosis is suggested if one of the confirming criteria is absent.8 The criteria below were developed for surveillance and do not exclude TSS cases if the presentation is highly suspicious. Notably, the isolation of S. aureus is not required for confirmation of staphylococcal TSS, but it is recovered from the wound/mucosa in 80-90% of those with TSS, and blood cultures are positive in only 5% of cases.9,10 For strep TSS, over 60% will have positive blood cultures.

Clinical criteria for staph TSS have been established by the United States Center for Disease Control and Prevention (CDC) and require:11

  • Fever, temperature 39°C (102.0°F)
  • Hypotension, systolic blood pressure < 90 mmHg for adults and less than 95th percentile by age for children <16 years of age
  • Rash with diffuse macular erythroderma
  • Desquamation, 1-2 weeks after onset of illness, particularly of the palms/soles
  • Multisystem involvement (3 or more systems):
    • Gastrointestinal – Vomiting or diarrhea at disease onset of illness
    • Muscular – Myalgias or creatine phosphokinase > 2 times the upper limit of normal
    • Mucous membranes – Vaginal, oropharyngeal, or conjunctival hyperemia
    • Renal – Blood urea nitrogen or serum creatinine > 2 times the upper limit of normal or pyuria (>5 white blood cell count/high power field) in the absence of a urinary tract infection
    • Hepatic – Bilirubin or transaminases > 2 times the upper limit of normal
    • Hematologic – Platelets < 100,000/microL
    • Central nervous system – Disorientation or alteration in consciousness without focal neurologic signs in the absence of fever and hypotension
  • Negative testing, if obtained of CSF and serologic testing for Rocky Mountain spotted fever, leptospirosis, measles

Persistent hypotension is caused by a decrease in systemic vascular resistance and fluid leakage from the intravascular space to the interstitial space,12 with massive cytokine release and nonpitting edema. The erythroderma of TSS often resembles a ‘painless sunburn’ that includes the palms and soles. Desquamation is a late manifestation, occurring 1-3 weeks after disease onset, and therefore is not required in the acute diagnostic approach to possible TSS. GI symptoms including diffuse vomiting and diarrhea may be present.  Staphylococcal TSS differs from streptococcal TSS in that the latter often causes severe pain and tenderness at a site of trauma, and it often requires immediate debridement.


Inspection for foreign material in the vaginal canal (tampon, contraceptive sponge, IUD) should be undertaken, with removal and subsequent culture. Source control is essential, as in all cases of sepsis. Given the extensive capillary leak, patients with TSS may require 10 to 20 liters of fluid per day, and supportive care starts in the Emergency Department with vasopressors such as norepinephrine to augment blood pressure.

All patients with suspected staph TSS require empiric antibiotics with:

  • Clindamycin 900 mg IV every 8 hours for adults, and 25-40 mg/kg/day divided in 3 doses for children
  • Vancomycin 15-20 mg/kg/dose every 8 to 12 hours, not to exceed 2 g/dose, and 40 mg/kg/day divided in 4 doses for children
  • Linezolid is another option. Similar to clindamycin, this medication reduces toxin production.

If culture results confirm:

  • Patients with MSSA TSS should receive clindamycin, as above, plus oxacillin or nafcillin 2 g IV every 4 hours for adults, and 100-150 mg/kg/day divided in 4 doses for children
  • Patients with MRSA TSS, should receive empiric regimen above including clindamycin and vancomycin, or single agent linezolid 600 mg PO/IV every 12 hours for adults, and 10 mg/kg PO/IV every 12 hours for children

TSS should be treated for a duration of 1-2 weeks, and nasal carriage eradication should be attempted with mupirocin. An additional treatment option is intravenous immune globulin. In severe cases nonresponsive to supportive care, IVIG can be considered, dosed as 1 g/kg in a single dose administered on day 1, and repeat doses of 0.5 g/kg on days 2 and 3. Corticosteroids have not been proven to show benefit in TSS cases. Mortality rate is <3% for menses-related cases of TSS, and <6% in non-menses related TSS cases.

Key Points for the ED provider

  • TSS is often a late diagnosis, and there have been many unfortunate cases, which were initially given a more benign diagnosis.
  • Systemic illness plus blanchable, diffuse rash or ‘pain out of proportion’ should clue the clinician into TSS, either from aureus or S. pyogenes.
  • Half of the cases are from tampon use, while other common precipitants include nasal packing and surgical wound infections.
  • Resuscitation efforts should be initiated by the ED provider, including source control and supportive care with IV fluids, vasopressors, and appropriate antibiotics.


References / Further Reading

1Kluytmans J, van Belkum A, Verbrugh H. Nasal carriage of Staphylococcus aureus: epidemiology, underlying mechanisms, and associated risks. Clin Microbiol Rev 1997;10:505.

2Spaulding A, Salgado-Pabon W, Kohler P, et al. Staphylococcal and streptococcal superantigen exotoxins. Clin Microbiol Rev 2013:26:422.

3Davis J, Chesney P, Wand P, LaVenture M. Toxic-shock syndrome: epidemiologic features, recurrence, risk factors, and prevention. N Engl J Med 1980;303:1429.

4Centers for Disease Control (CDC). Update: toxic-shock syndrome – United States. MMWR Morb Mortal Wkly Rep 1983;32:398.

5Lappin E, Ferguson A. Gram-positive toxic shock syndromes. Lancet Infect Dis 2009;9(5):281.

6Reingold A, Hargrett N, Dan B, et al. Nonmenstrual toxic shock syndrome: a review of 130 cases. Ann Intern Med 1982;96:871.

7Weidner V. Toxic shock. In: Tintinalli J, Cline D, Ma O, Cydulka R, Meckler G, Handel D, Thomas S., editors. Tintinalli’s Emergency Medicine. 7th ed. New York: McGraw-Hill; 2012;(cited 2017 Jan 22).

8Tofte R, Williams D. Toxic shock syndrome. Evidence of a broad clinical spectrum. JAMA 1981;246:2163.

9Davis J, Osterhold M, Helms C, et al. Tri-state toxic-shock syndrome study. J Infect Dis 1982;145:441.

10Reingold A, Dan BB, Shands K, Broome C. Toxic-shock syndrome not associated with menstruation. A review of 54 cases. Lancet 1982;1:1.

11Case definitions for infectious conditions under public health surveillance. Centers for Disease Control and Prevention. MMWR Recomm Rep 1997;46:1.

12Chesney P. Clinical aspects and spectrum of illness of toxic shock syndrome: overview. Rev Infect Dis 1989;11 Suppl 1:S1.

Neurotrauma Resuscitation: Pearls & Pitfalls

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 24-year-old male arrives by EMS with a GCS of 5 after a severe MVC. He was ejected from the vehicle, and EMS placed a C-collar, followed by positioning on a backboard for transport. Bilateral IV’s were placed, and 1 L NS was started. They did not intubate him in the field, as they were 4 minutes from your hospital. What are your priorities in evaluation and management of this patient? What are the pearls and pitfalls in resuscitating the sick neurotrauma patient?

Neurotrauma, particularly traumatic brain injury (TBI), is a significant cause of death around the world and the leading cause of death in patients age 1 to 45 years.1-5 Approximately 78% of patients are managed in the emergency department (ED), with males and young adults the two primary populations affected.1.2 Traumatic neurologic injury not only causes an initial primary injury, but it is associated with several secondary insults.1-6

Some pathophysiology…

Cerebral perfusion pressure (CPP) is defined by the mean arterial pressure (MAP) minus the intracranial pressure (ICP). ICP is a function of the brain parenchyma, blood, and cerebrospinal fluid.2,7-12 The key is that an increase in one requires a decrease in another.2,7-12 Once compensatory methods are exhausted, further volume leads to drastic increases in ICP. Cerebral perfusion pressure is related to ICP, and increase in ICP may decrease cerebral perfusion. The ultimate goal of resuscitation and management of the neurotrauma patient is to ensure normal ICP, while preserving cerebral blood flow and perfusion.2,8,11,12

Are there physiologic goals?

Hypotension is associated with increased morbidity and mortality. A CPP goal of 50 to 70 mm Hg should be used, with SBP of at least 100 mm Hg (ages 50-69) and 110 mm Hg for 15-49 years and > 70 years, per the Brain Trauma Foundation.2,8,11-13  Otherwise, a MAP of 70-80 mm Hg is advised.5 Avoiding cerebral hypotension is recommended, though aggressive CPP targeting is not associated with improved outcomes.13-15 Hypoxemia also results in a significant increase in mortality. Key targets of resuscitation are shown below.

Goal Physiologic Parameters5,11,12
-Pulse oximetry > 94%, less than 100% (avoid hypoxemia and hyperoxemia)

-PaCO2 35-45 mm Hg

-SBP > 100 mm Hg (ages 50-69), and > 110 mm Hg (ages 15-49, > 70 years)

-pH 7.35-7.45

-ICP < 20 mm Hg

-Glucose 80-180 mg/dL

-CPP > 60 mm Hg

-Serum Na 135-145, (Hypertonic saline goal is 145-160)

-INR < 1.4

-Platelets > 75 x 103/mm3

-Hgb > 8 mg/dL

What are several dangerous secondary injuries?

Neurotrauma begins a cascade that may cause further cell death.8,11,12 The following are significant secondary injuries, all which increase adverse outcomes. Awareness of these injuries is necessary for prevention.5,8,11-15

– Hypotension: 30% of patients, resulting in higher likelihood of poor outcome (OR 2.67).2,8,11-15

– Hypoxia: 50% of patients, resulting in higher likelihood of poor outcome (OR 2.14).2,8,11-15

– Hyperoxia: PaO2 levels above 300-470 mm Hg are associated with worse outcome.2,8,11-15

– Fever: Elevated temperature worsens morbidity by secondary brain injury aggravation.2,13

– Coagulopathy: Associated with the traumatic event and may cause worsening of the neurologic injury and death. Acute TBI may cause coagulopathy itself through tissue factor and phospholipid release.16

– Glucose: Hyper- and hypoglycemia are predictors of poor neurologic status.2,8,11-15

Pearls in Evaluation and Management

Focus on airway, breathing, circulation, disability, and exposure in the primary survey, with spinal precautions.2,11,17-20 Avoid secondary complications, and other markers of worse outcome include poor GCS motor score, pupillary dysfunction, and increased ICP. Abnormal pupillary response and altered motor function are markers for severe brain trauma, as is posturing. Decorticate posturing (arm flexion and leg extension) is due to injury above the midbrain, and decerebrate posturing (arm extension and internal rotation, wrist and finger flexion, leg internal rotation and extension) is a sign of more caudal injury involving the midbrain.11,12,17 Abnormal pupils, decreased mental status, abnormal GCS, penetrating injury, abnormal motor status, and severe injury require neuroimaging.  Severe neurotrauma requires consultation with neurosurgery.2,11,12,17  This post will focus on the hypotensive patient with neurologic injury.

ED Considerations
-Maintain spinal precautions

-Conduct primary and secondary surveys; address life-threatening injuries

-Advanced airway management may be needed for airway protection, hypoxia, and control of ventilation

-Obtain rapid IV access

-Optimize oxygenation, blood pressure, and ventilation

-Target oxygen saturation > 94%, with systolic blood pressure > 100-110 mm Hg

– Focused neuro exam: GCS, motor function, and pupillary function

-Obtain head CT noncontrast

-Any sign of worsening neurologic status warrants hyperosmolar therapy

Tiers of ICP management, per the Brain Trauma Foundation, are shown below.11,12,17 We will discuss pearls and subtleties for these therapies, but first, let’s discuss airway.

Tier Options
0 -Head of bed elevation

-Control fever, pain, and agitation

-Optimize physiologic parameters such as blood pressure and oxygen

-Target PaCO2 to 35-38 mm Hg

1 -Osmotic therapy includes mannitol, hypertonic saline, or sodium bicarbonate

-External ventricular drainage system should be placed if acute obstruction is present

2 -Propofol drip titration

-Optimize other parameters

3 -Barbiturate coma

-Surgical decompression if ICP refractory to treatment

-Therapeutic hypothermia

-Moderate hyperventilation (only if active herniation)

How should the airway be managed?

Airway protection and blood pressure support for severe neurotrauma are priorities, and first pass success is vital. Rapid sequence intubation with in-line stabilization of the cervical spine may be necessary.2,11,18-20 Preoxygenation is important to avoid desaturation, so start your NO DESAT interventions early.21,22

Intubation Considerations
-Preparation: Proper positioning, preoxygenate, and use apneic oxygenation with nasal cannula, facemask, or noninvasive positive pressure ventilation

-Elevate head of bed to improve CPP and decrease aspiration

-Premedication regimens are controversial. Fentanyl at 2-5 micrograms/kg IV or esmolol 1.5mg/kg IV may decrease catecholamine surge and control the hemodynamic response to intubation

-Induction agent may include ketamine (does not adversely affect patients with neurotrauma) and etomidate – these agents have less hemodynamics effects

-Propofol has neuroprotective effects, but hypotension may occur

-Post intubation analgesia and sedation are essential – have your drips ready to go at the time of intubation


Up to 80% of patients may experience a hypertensive response to laryngoscopy or suctioning, and lidocaine was initially thought to blunt this. However, lidocaine has not demonstrated ability to reduce ICP or improve neurologic outcome.18-20,23 Fentanyl at doses of 2-5 micrograms/kg IV prior to intubation can reduce the hyperdynamic response to intubation, as can esmolol at 1.5 mg/kg IV. However, esmolol should be avoided in patients with hypotension, hemorrhagic shock, or signs of multiple trauma.18-20,24


Traditionally, ketamine was contraindicated for induction in intubation in TBI, but literature suggests that not only is it safe, but it may be beneficial. Ketamine improves cerebral blood flow, and evidence suggests it does not raise ICP.19,25  Propofol has high lipid solubility and rapid onset of action that can reduce ICP and oxidative stress. However, it may cause hypotension.19,20,26 Etomidate may result in less hypotension and cardiac dysfunction. It can reduce ICP and maintain CPP, but it also may lower the seizure threshold and increase the risk of vomiting and myoclonic movements.19,27 The key for an induction agent is utilizing lower doses in patients with hypotension, as any agent at full dose will worsen hypotension.


Paralysis is essential to improve first pass success including succinylcholine or rocuronium. Succinylcholine allows faster time to recovery and assessment of neurologic status, as rocuronium will last longer. Ultimately, the choice of paralytic rests on the physician, as both are safe and efficacious.19,20  However, defasciculating doses of paralytics such as succinylcholine or pancuronium are not beneficial and do not reduce ICP.19,20

Post Intubation

Post intubation sedation and analgesia are an absolute must.18-20 An intubated patient with inadequate analgesia and sedation may experience increased ICP due to sympathomimetic response.24 The key is to order your post intubation meds at the same time as your paralytic and induction agent.18-20 Analgesics including fentanyl and remifentanil are fast and predictable. Morphine and hydromorphone may accumulate with prolonged infusion, though they do have longer duration of action. Sedative medications include propofol, which possesses fast onset and offset, allowing for repeat neurologic assessment.  If used keep close tabs on blood pressure. Infusion, rather than bolus doses, will mitigate the risk of decreasing BP. Benzodiazepines can be used, though they can reduce BP and respiratory status. However, they do reduce cerebral blood flow and ICP.28 Unfortunately, tolerance may develop, and reassessment is difficult due to metabolite accumulation. The new kid on the block, dexmedetomidine, is a selective alpha-2 receptor agonist with anxiolytic and sedative effects.19,29 Hypotension and bradycardia are the most common side effects, most commonly seen with bolus dosing. It may reduce ICP, though further study is needed.

Avoid hypoxia post intubation, targeting O2 saturation 94%-98%. Hyperoxia with PaO2 greater than 300-470 mm Hg is discouraged due to worse outcomes.13,18-20  Unless actively herniating, hyperventilation is not recommended. PaCO2 levels of 35 to 45 mm Hg, or end-tidal CO2 30 to 40 mm Hg, are your goals.2,11,18

What about hypotension?

Hypotension increases mortality two-fold, specifically any SBP drop less than 90 mm Hg.2,11-15,19 The polytrauma patient with head trauma can be difficult.  These patients are often hypotensive, and permissive hypotension is not recommended. Target a SBP of at least greater than 100 mm Hg (for patients 50-69 years of age) or 110 mm Hg (for those 15-49 years and > 70 years).11 Keep in mind that ATLS states a MAP > 80 mm Hg in patients with severe TBI is reasonable.5 Start first with fluids, specifically normal saline or blood.2,11,18 Avoid hypo-osmotic fluids, which can increase cerebral edema and ICP.30  Albumin is associated with higher mortality, which was demonstrated in the SAFE trial in TBI patients.31 Literature suggests no difference between normal saline and HTS for patients with no signs of herniation.30

Wait, what’s this about neurogenic shock?

Neurogenic shock occurs with injury above T6 and is a form of distributive shock. It is caused by loss of sympathetic tone.32-35 Patients may show low HR and BP; however, hypovolemic shock must first be ruled out in the trauma patient. Spinal shock is different, with loss of sensation and motor function below the spinal cord injury. Reflexes are often depressed below the injury level.32-35

Are vasopressors needed?

A SBP of at least 100-110 mm Hg is recommended by the Brain Trauma Foundation, as hypotension increases morbidity and mortality.11 Specifically in neurogenic shock with hypotension and bradycardia, fluids and vasopressors will be needed.32,33 Loss of sympathetic tone is common within the first week of injury.6,32-35 A goal MAP of 85 mm Hg is recommended by the AANS and CNS in neurogenic shock.35  Dopamine, norepinephrine, or phenylephrine may be used.  Norepinephrine will increase afterload and inotropy, needed with the loss of sympathetic tone.  Phenylephrine will improve vascular tone and can be used in patients who are not bradycardic.6,33-35

What hyperosmolar therapies are available?

Hyperosmolar therapy is a foundation of management. These measures can reduce ICP and improve cerebral blood flow.2,12,17,18  Hyperosmolar agents should be used with signs of increased ICP, pupillary change, decrease in GCS > 2 points, or posturing.2,12,17,18   Agents include 20% mannitol 0.25-1 g/kg IV as a rapid infusion over 5 minutes or 3% NaCl 150 ml IV over 10 minutes (HTS 23.4% 30mL can be used through central line).2,11,17,18,30,36-38 We will discuss these agents further, but keep in mind that if hypotension is a concern, HTS may be a better resuscitation fluid.5,17,18  For ICP reduction, a 2015 meta-analysis finds no difference in neurologic outcome or mortality between mannitol and HTS.30

  1. Mannitol

Mannitol is administered as a 20% solution.2,30,36-38 This solution deforms RBCs and decreases blood viscosity, improving cerebral blood flow.36-38  A major consideration is autoregulation and the presence of intact Blood-Brain-Barrier, as if these are intact, ICP will decrease. If not intact, mannitol may worsen outcomes.11,18,30 Rebound increases in ICP can occur, and the solution may cause renal injury through excess diuresis. IV fluids are necessary when providing mannitol, along with Foley catheter.11,17,18

  1. HTS

HTS concentrations range from 2% to 23.4%, which also improves cerebral blood flow and reduces parenchymal water content.2,11,12,17 HTS can improve blood pressure as a volume expander. The risk of rebound ICP is less than that of mannitol.2,11,17,18,30 The most common side effect of HTS is hyperchloremic metabolic acidosis.2,18,30

What about ocular US for increased ICP?

Ultrasound can measure optic nerve sheath diameter (ONSD), which correlates closely with ICP.18,39,40 The normal optic nerve sheath is up to 5 mm in diameter, and ONSD will increase with elevated ICP. ONSD should be measured 3 mm posterior to the globe for both eyes, with an average between measurements. Values greater than 5 mm predict increased ICP, with sensitivity and specificity greater than 90%.39,40

When is surgery required?

Surgical management of TBI may be needed to repair depressed skull fracture or evacuate intracranial mass (such as blood).2,11,17,18 Decompressive craniectomy is indicated for refractory intracranial hypertension; however, decompressive craniectomy may not improve functional outcome while decreasing ICP, as shown in the DECRA trial.41-45 Ultimately, your neurosurgeon will make this decision, but they must be on board early in the patient’s management.11,45

Is hypothermia effective in neurotrauma?

Studies have not found an improvement in mortality or neurologic status with hypothermia in neurotrauma.2,11,18,46,47 However, hypothermia can reduce intracranial hypertension.46,47 Targeted management of temperature reduces cerebral metabolic rate and release of excitatory neurotransmitters, but more study is required.11,46,47

Should you reverse coagulopathy with traumatic intracerebral hemorrhage?

Coagulopathy is common, as close to 1/3 of patients with TBI display a coagulopathy, due to patient medication or release of tissue factor causing consumptive coagulopathy.11,16 Coagulation panel and TEG can be helpful, with reversal dependent on results and patient medication. Vitamin K, PCC/FFP, and novel antidotes can be utilized.11,48-50 We will not go into detail here on reversal. However, keep in mind that platelet transfusion in patients on antiplatelet medication with ICH may be harmful per the recent PATCH trial.51

What is the role of pharmacologically-induced coma?

Barbiturates can be used to reduce ICP, if refractory to other treatment, through suppression of cerebral metabolism, modification of vascular resistance, and decrease of neuronal excitotoxicity.2,18,52,53 However, barbiturates have significant side effects, as one in four experiences hypotension.2,11,53 A 2012 Cochrane Review found no change in outcomes for severe TBI with barbiturate coma.53

Corticosteroids used to be recommended, but what about today?

The CRASH trial suggests worse outcomes and increased mortality for patients with TBI given steroids.54-57 In the setting of spinal cord injury, the American Association of Neurologic Surgeons and Congress of Neurologic Surgeons do not recommend steroids.2,6,11

Should seizures be treated in neurotrauma?

Early posttraumatic seizures occur within 7 days of injury, with late seizures beyond 7 days.2,11,58,59 Seizures occur in up to 30% of TBI patients (50% of patients with penetrating injury).2,58,59 With seizures increasing ICP, any active seizure requires immediate treatment, with benzodiazepines first line. Prophylaxis on the other hand is more controversial. The presence of any risk factor including include GCS < 10, cortical contusion, any intracranial hematoma, depressed skull fracture, penetrating head injury, or seizure within 24 hours of injury requires prophuulaxis.11,58,59 Otherwise, prophylaxis is not recommended. Levetiracetam is equivalent to phenytoin for seizure reduction, and it is associated with less risk of side effect.58,59

Does tranexamic acid have a place in neurotrauma?

The CRASH-2 and MATTERs studies have suggested survival benefit within three hours of trauma for TXA.60,61 The CRASH-2 Intracranial Bleeding Study found a trend towards reduction in intracranial hemorrhage growth and lower mortality in patients with traumatic hemorrhage, with another study finding reduction in hemorrhage growth.60,62 CRASH-3 is underway, evaluating TXA in TBI specifically.63

Pitfalls in evaluation and management

Several medications have not demonstrated improvement in outcomes for TBI, including progesterone, magnesium, hyperbaric oxygen, and cyclosporine.2,11,64,65

Hyperventilation can reduce ICP for short periods.2,11,18,66,67 However, hyperventilation may result in secondary ischemia if used for prolonged periods and increases the risk of cerebral edema. Hyperventilation has demonstrated worse clinical outcomes in patients hyperventilated to PaCO2 less than 30 mm Hg for six hours up to five days.18,66,67 Mild hyperventilation can be used for acute worsening, but only for a short period, targeting PaCO2 30-35 mmHg.2,11,18

Key points

– Neurotrauma is common, as it is the leading cause of death in North America in those between ages 1 year to 45 years. Primary and secondary injuries result in severe morbidity and mortality.

– Neurotrauma includes head contusion, epidural hematoma, subdural hematoma, subarachnoid hemorrhage, diffuse axonal injury, skull fracture, and traumatic spinal cord injury.

– Cerebral perfusion pressure requires adequate cerebral blood flow.

–  Evaluation and management in the emergency department entails initial stabilization and resuscitation while assessing neurologic status.

– Targeting mean arterial pressure, oxygen levels, and neurologic status are key components. ICP management should follow a tiered approach.

Intubation of the patient with neurotrauma should be completed with several considerations.

– Hyperosmolar treatments include HTS and mannitol.


References/Further Reading

  1. Faul M, Xu L, Wald MM, et al. Traumatic brain injury in the United States: emergency department visits, hospitalizations and deaths 2002–2006. Atlanta (GA): Centers for Disease Control and Prevention, National Center for Injury Prevention and Control; 2010.
  2. Wan-Tsu WC, Badjatia N. Neurotrauma. Emerg Med Clin N Am 2014;32:889-905.
  3. Rutland-Brown W, Langlois JA, Thomas KE, Xi YL. Incidence of traumatic brain injury in the United States, 2003. J Head Trauma Rehabil 2006; 21:544.
  4. Stein DM, Roddy V, Mark J, Smith WS, Weingart SD. Emergency Neurological Life Support: Traumatic Spine Injury. Neurocrit Care 2012;17:S102-S111.
  5. ATLS Subcommittee; American College of Surgeons’ Committee on Trauma; International ATLS working group. Advanced trauma life support (ATLS®): the ninth edition. J Trauma Acute Care Surg. 2013 May;74(5):1363-6.
  6. Hadley MN, Walters BC, Aarabi B, et al. Guidelines for the management of acute cervical spine and spinal cord injuries. Neurosurgery 2013;72(Suppl 2): 1–259.
  7. Oddo M, Le Roux PD. What is the etiology, pathogenesis and pathophysiology of elevated intracranial pressure? In: Neligan P, Deutschman CS, editors. The evidenced based practice of critical care. Philadelphia: Elsevier Science; 2009.
  8. Swadron SP, LeRoux P, Smith WS, Weingart SD. Emergency Neurological Life Support: Traumatic Brain Injury. Neurocrit Care 2012;17:S112–S121.
  9. Bouma GJ, Muizelaar JP. Cerebral blood flow, cerebral blood volume, and cerebrovascular reactivity after severe head injury. J Neurotrauma 1992; 9 Suppl 1:S333.
  10. Bouma GJ, Muizelaar JP, Bandoh K, Marmarou A. Blood pressure and intracranial pressure-volume dynamics in severe head injury: relationship with cerebral blood flow. J Neurosurg 1992; 77:15.
  11. Carney N, Totten AM, O’Reilly C, Ullman JS, Hawryluk GWJ, bell MJ, et al. Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery 2016;0(0):1-10.
  12. Stevens RD, Huff JS, Duckworth J, et al. Emergency neurological life support: intracranial hypertension and herniation. Neurocrit Care 2012;17(Suppl 1):S60–5.
  13. McHugh GS, Engel DC, Butcher I, et al. Prognostic value of secondary insults in traumatic brain injury: results from the IMPACT study. J Neurotrauma 2007; 24:287.
  14. Chestnut RM, Marshall LF, Klauber MR, et al. The role of secondary brain injury in determining outcome from severe head injury. J Trauma 1993;34(2):216-22.
  15. Marmarou A, Anderson RL, Ward JD, et al. Impact of ICP instability and hypotension on outcome in patients with severe head trauma. J Neurosurg 1991; 75(Suppl):S59–66.
  16. Harhangi BS, Kompanje EJ, Leebeek FW, Maas AI. Coagulation disorders after traumatic brain injury. Acta Neurochir (Wien) 2008; 150:165.]
  17. Emergency Neurological Life Support: Elevated ICP or Herniation. 2014. Available at http://enlsprotocols.org/files/ICP.pdf. Accessed 16 November 2016.
  18. Weingart S. EMCrit: Podcast 78 – Increased intra-cranial pressure (ICP) and herniation, aka brain code. Available at http://emcrit.org/podcasts/high-icp-herniation/. Accessed 16 November 2016.
  19. Bucher J, Koyfman A. Intubation of the Neurologically Injured Patient. JEM 2015;49(6):920-7.
  20. Seder DB, Riker RR, Jagoda A, Smith WS, Weingart SD. Emergency Neurological Life Support: Airway, Ventilation, and Sedation. Neurocrit Care 2010;17:S4-S20.
  21. Weingart SD, Levitan RM. Preoxygenation and prevention of desaturation during emergency airway management. Ann Emerg Med 2012;59:165–1751.
  22. Dixon BJ, Dixon JB, Carden JR, et al. Preoxygenation is more effective in the 25 degrees head-up position than in the supine position in severely obese patients: a randomized controlled study. Anesthesiology 2005;102:1110–5. discussion 1115A.
  23. Robinson N, Clancy M. In patients with head injury undergoing rapid sequence intubation, does pretreatment with intravenous lignocaine/lidocaine lead to an improved neurological outcome? A review of the literature. Emergency Medicine Journal : EMJ. 2001;18(6):453-457. doi:10.1136/emj.18.6.453
  24. Dahlgren N, Messeter K. Treatment of stress response to laryngoscopy and intubation with fentanyl. Anaesthesia 1981;36:1022–6.
  25. Cohen L, Athaide V, Wickham ME, Doyle-Waters MM, Rose NG, Hohl CM. The effect of ketamine on intracranial and cerebral perfusion pressure and health outcomes: a systematic review. Ann Emerg Med 2015;65:43–51.
  26. Rossaint J, Rossaint R, Weis J, et al. Propofol: neuroprotection in an in vitro model of traumatic brain injury. Crit Care 2009; 13:R61.
  27. Moss E, Powell D, Gibson RM, McDowall DG. Effect of etomidate on intracranial pressure and cerebral perfusion pressure. Br J Anaesth. 1979;51:347–52.
  28. Barrientos-Vega R, Mar Sanchez-Soria M, Morales-Garcia C, Robas-Gomez A, Cuena-Boy R, Ayensa-Rincon A. Prolonged sedation of critically ill patients with midazolam or propofol: impact on weaning and costs. Crit Care Med. 1997;25:33–40.
  29. Jakob SM, Ruokonen E, Grounds RM, et al. Dexmedetomidine vs. midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. JAMA. 2012;307:1151–60.
  30. Boone MD, Oren-Grinberg A, Robinson TM, Chen CC, Kasper EM. Mannitol or hypertonic saline in the setting of traumatic brain injury: What have we learned? Surgical Neurology International. 2015;6:177.
  31. The SAFE Study Investigators. A Comparison of Albumin and Saline for Fluid Resuscitation in the Intensive Care Unit. N Engl J Med 2004; 350:2247-2256.
  32. Jia X, Kowalski RG, Sciubba DM, Geocadin RG. Critical care of traumatic spinal cord injury. J Intensive Care Med 2013; 28:12.
  33. Blood pressure management after acute spinal cord injury. Neurosurgery 2002; 50:S58.
  34. Ditunno JF, Little JW, Tessler A, Burns AS. Spinal shock revisited: a four-phase model. Spinal Cord 2004; 42:383.
  35. Guidelines for the management of Acute Cervical Spine and Spinal Cord Injuries: http://www.aans.org/en/Education%20and %20Meetings/*/media/Files/Education%20and%20Meetingf/ Clinical%20Guidelines/TraumaGuidelines.ashx (2007). Accessed May 2016.
  36. Vialet R, Albanèse J, Thomachot L, et al. Isovolume hypertonic solutes (sodium chloride or mannitol) in the treatment of refractory posttraumatic intracranial hypertension: 2 mL/kg 7.5% saline is more effective than 2 mL/kg 20% mannitol. Crit Care Med 2003; 31:1683.
  37. Kassell N, Baumann K, Hitchon P, et al. The effects of high dose mannitol on cerebral blood flow in dogs with normal intracranial pressure. Stroke 1982;13(1): 59–61.
  38. Mendelow AD, Teasdale GM, Russell T, et al. Effect of mannitol on cerebral blood flow and cerebral perfusion pressure in human head injury. J Neurosurg 1985; 63(1):43–8.
  39. Sekhon MS, McBeth P, Zou J, et al. Association between optic nerve sheath diameter and mortality in patients with severe traumatic brain injury. Neurocrit Care. 2014;21(2):245-252.
  40. Hassen GW, Bruck I, Donahue J, et al. Accuracy of optic nerve sheath diameter measurement by emergency physicians using bedside ultrasound. J Emerg Med. 2015;48(4):450-457.
  41. Bullock MR, Chestnut R, Ghajar J, et al. Guidelines for the surgical management of traumatic brain injury. Neurosurgery 2006;58(Suppl)S2-1-3.
  42. Cooper DJ, Rosenfeld JV, Murray L, et al. Decompressive craniectomy in diffuse traumatic brain injury. N Engl J Med 2011;364(16):1493–502.
  43. Honeybul S, Ho KM, Lind CR. What can be learned from the DECRA study. World Neurosurg 2013;79(1):159–61.
  44. Sahuquillo J, Martinez-Ricarte F, Poca MA. Decompressive craniectomy in traumatic brain injury after the DECRA trial. Where do we stand? Curr Opin Crit Care 2013;19(2):101–6.
  45. Hutchinson PJ, Kolias AG, Timofeev IS, Corteen EA, Czosnyka M, Timothy J, et al. Trial of Decompressive Craniectomy for Traumatic Intracranial Hypertension. N Engl J Med. 2016 Sep 7. [Epub ahead of print].
  46. Sydenham E, Roberts I, Alderson P. Hypothermia for traumatic head injury. Cochrane Database Syst Rev 2009;(2):CD00104.
  47. Clifton GL, Valadka A, Zygun D, et al. Very early hypothermia induction in patients with severe brain injury (the National Acute Brain Injury Study: Hypothermia II): a randomised trial. Lancet Neurol 2011;10(2):131–9.
  48. Morgenstern LB, Hemphill JC 3rd, Anderson C, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2010; 41:2108.
  49. Eller T, Busse J, Dittrich M, et al. Dabigatran, rivaroxaban, apixaban, argatroban and fondaparinux and their effects on coagulation POC and platelet function tests. Clin Chem Lab Med 2014; 52:835.
  50. Dickneite G, Hoffman M. Reversing the new oral anticoagulants with prothrombin complex concentrates (PCCs): what is the evidence? Thromb Haemost 2014; 111:189.
  51. Baharoglu MI, Cordonnier C, Al-Shahi Salman R, de Gans K, Koopman MM, Brand A, Majoie CB. Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial. 2016 Jun 25;387(10038):2605-13.
  52. Eisenberg HM, Frankowski RF, Contant CF, et al. High-dose barbiturate control of elevated intracranial pressure in patients with severe head injury. J Neurosurg 1988;69(1):15–23.
  53. Roberts I, Sydenham E. Barbiturates for acute traumatic brain injury. Cochrane Database Syst Rev 2012;(12):CD000033.
  54. Roberts I, Yates D, Sandercock P, et al. Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-controlled trial. Lancet 2004;364(9442): 1321–8.
  55. Bracken M, Shepard M, Collins W, et al. A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. N Engl J Med 1990; 322(20):1405–11.
  56. Bracken MB, Shepard MJ, Holford TR, et al. Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. JAMA 1997;277(20):1597–604.
  57. Bracken M. Steroids for acute spinal cord injury. Cochrane Database Syst Rev 2012;(1):CD001046.
  58. Inaba K, Menaker J, Branco BC, et al. A prospective multicenter comparison of levetiracetam versus phenytoin for early posttraumatic seizure prophylaxis. J Trauma Acute Care Surg 2013;74(3):766-71 [discussion: 771-3].
  59. Torbic H, Forni A, Anger KE, et al. Use of antiepileptics for seizure prophylaxis after traumatic brain injury. Am J Heal Pharm 2013;70(9):759–66.
  60. Roberts I, Shakur H, Coats T, Hunt B, Balogun E, Barnetson L, Cook L, Kawahara T, et al. The CRASH-2 trial: a randomised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients. Health Technol Assess. 2013 Mar;17(10):1-79.
  61. Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study. 2012 Feb;147(2):113-9.
  62. Perel P, Al-Shahi Salman R, Kawahara T, Morris Z, Prieto-Merino D, Roberts I, Sandercock P, et al. CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage) intracranial bleeding study: the effect of tranexamic acid in traumatic brain injury–a nested randomised, placebo-controlled trial. Health Technol Assess. 2012;16(13):iii-xii, 1-54.
  63. Dewan Y, Komolafe EO, Mejía-Mantilla JH, Perel P, Roberts I, Shakur H. CRASH-3 – tranexamic acid for the treatment of significant traumatic brain injury: study protocol for an international randomized, double-blind, placebo-controlled trial. Trials. 2012;13:87.
  64. Wright DW, Yeatts SD, Silbergleit R, et al. Very Early Administration of Progesterone for Acute Traumatic Brain Injury. N Engl J Med 2014;371(26):2457-2466.
  65. Skolnick BE, Maas AI, Narayan RK, van der Hoop RG, et al; SYNAPSE Trial Investigators. A clinical trial of progesterone for severe traumatic brain injury. N Engl J Med 2014 Dec 25;371(26):2467-76.
  66. Coles JP, Minhas PS, Fryer TD, et al. Effect of hyperventilation on cerebral blood flow in traumatic head injury: clinical relevance and monitoring correlates. Crit Care Med 2002; 30:1950.
  67. Coles JP, Fryer TD, Coleman MR, et al. Hyperventilation following head injury: effect on ischemic burden and cerebral oxidative metabolism. Crit Care Med. 2007;35:568–78.

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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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.