Tag Archives: sepsis

Sepsis Biomarkers: What’s New?

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

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

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

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

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


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

Type A Type B1

Associated with disease

Type B2

Drugs and Toxins

Type B3

Associated with inborn errors of metabolism

Tissue Hypoperfusion


Anaerobic muscular activity


Reduced tissue oxygen delivery







Thiamine deficiency




Hepatic or renal failure


Short bowel syndrome







Lactate-based dialysate fluid



Alcohols: Methanol, Ethylene Glycol







Anti-retroviral agents

Pyruvate carboxylase deficiency


Glucose-6-phosphatase deficiency


Fructose-1,6-bisphosphatase deficiencies


Oxidative phosphorylation enzyme defects


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


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

What about cryptic shock?

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

What to do with the intermediate lactate level…

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

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


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


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



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

Antibiotic Stewardship

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

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


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

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

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

ProHOSP and PRORATA trial PCT Use41,48

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

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


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

Cardiac Causes Noncardiac Causes
Acute and Chronic Heart Failure

Acute Inflammatory Myocarditis Endocarditis/Pericarditis

Aortic Dissection

Aortic Valve Disease

Apical Ballooning Syndrome

Bradyarrhythmia, Heart Block

Intervention (endomyocardial biopsy, surgery)


Direct Myocardial Trauma

Hypertrophic Cardiomyopathy


Acute Noncardiac Critical Illness

Acute Pulmonary Edema

Acute PE

Cardiotoxic Drugs

Stroke, Subarachnoid hemorrhage

Chronic Obstructive Pulmonary Disease

Chronic renal failure

Extensive Burns

Infiltrative Disease (amyloidosis)

Rhabdomyolysis with Myocyte Necrosis


Severe Pulmonary Hypertension

Strenuous Exercise/Extreme Exertion

Risk Stratification

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

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


Novel Biomarkers

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

Endothelial Markers

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

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

Proadrenomedullin (ProADM)

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

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

Acute-Phase Reactants

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

Cardiac Biomarkers

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


Key Points:

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


References/Further Reading

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

The Controversies of Corticosteroids in Sepsis

Author: Brit Long, MD (@long_brit, EM Attending Physician at SAUSHEC, USAF) // Edited by: Jamie Santistevan, MD (@Jamie_Rae_EMdoc, Admin and Quality Fellow at UW, Madison, WI) and Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW Medical Center / Parkland Memorial Hospital) 

A 54-year-old male with a history of recent antibiotic therapy is currently being managed for pneumonia with IV antibiotics including cefepime, levofloxacin, and vancomycin. Despite 6L of IV fluids and norepinephrine at 20 micrograms/minute IV infusion, his blood pressure remains at 70/42, with a heart rate of 112. Bedside US reveals a hyperdynamic heart and IVC 2 cm in size. His electrolytes reveal a sodium of 135 and potassium of 4.9. What could you be missing? Should you start corticosteroids? What about the side effects?

Sepsis is a condition emergency providers manage daily, with over 750,000 septic patients seen in the emergency department (ED) per year.1-4 Septic shock is severe, with mortality ranging from 20% to 70%.1-4

Sepsis management requires rapid diagnosis, early administration of intravenous (IV) fluids with broad-spectrum antimicrobials, and source control. Early Goal-Directed Therapy (EGDT) first brought these elements to the forefront of emergency medicine,5 with further modifications in the ProCESS, ARISE, and ProMISe trials.6-9 Specific components of sepsis management remain essential including fluid resuscitation, broad-spectrum antimicrobials, and vasopressors.6-9

The Controversy

The systemic response of sepsis includes pro-inflammatory pathways and cytokines. Corticosteroids can act to attenuate these inflammatory molecules, suggesting a possible role for corticosteroid use.3,10 Vasomotor tone may decrease in septic shock, and corticosteroids can improve vascular function and organ perfusion.3,10

Septic shock can be associated with relative adrenal insufficiency, in which a patient’s endogenous cortisol levels are not sufficient to maintain hemodynamic status. Studies demonstrate conflicting results with steroid use in these patients. The role of corticosteroid therapy in patients with vasopressor-resistant septic shock remains controversial, specifically whether corticosteroids reduce mortality or reduce time of shock and vasopressor need. Despite recent meta-analyses, no clear guidance exists on corticosteroid indications and which patients truly benefit.11-17

Sepsis and the Hypothalamic–Pituitary–Adrenal (HPA) Axis

Sepsis has many effects on the body, including the HPA axis. The hypothalamus is responsible for stimuli integration and secretion of corticotropin-releasing hormone (CRH) during times of stress.10,11,16,17 This secretion of CRH results in initiation of adrenal corticotropin hormone (ACTH) synthesis in the anterior pituitary. ACTH results in cortisol production from the adrenals, with the entire system regulated through feedback. Severe sepsis and septic shock result in decreased albumin and corticosteroid binding proteins, which decrease total cortisol.16,17

Normal serum cortisol levels vary based on stress and time of day, ranging from 5 to 24 mcg/dL. Levels may reach 50 mcg/dL during periods of peak stress.16-21 Critical illness affects cortisol through multiple mechanisms.17,20-23

Physiologic Stress and Cortisol Effects
– Reduced cortisol breakdown, resulting in increased levels and decreased production.

– Increased cortisol due to decreased breakdown in the setting of renal dysfunction.

– Cortisol binding globulin and albumin decrease, increasing free cortisol.

– Cytokines with inflammatory effects increase steroid receptor affinity, decrease steroid inactivation, and increase peripheral production of cortisol.

Relative adrenal insufficiency is based on several factors. First, stress results in cortisol increase, and as stress increases, cortisol level increases. The incidence of relative adrenal malfunction can approach 50% in severe sepsis and septic shock, due to impaired glucocorticoid and vasopressin production and dysregulated cortisol response.11-17 Medications such as etomidate, antifungals, and chronic steroid use act to decrease intrinsic corticosteroid production and affect protein binding.24,25

Septic Shock and Steroids

Steroids have been utilized in the treatment of septic shock for over 50 years.26-33 From the 1950s to the 1980s, high-dose steroids such as methylprednisolone 30 mg/kg or dexamethasone 3-6 mg/kg were used to treat patients in septic shock.30-33 Schumer et al. compared high dose corticosteroids versus normal saline, finding patients in the normal saline group experienced higher mortality.28 However, the mid-1980s ushered in several trials that did not demonstrate improved mortality in high-dose steroids.34-36 Cronin et al. found increased rate of morbidity and mortality in the high-dose steroid groups.37 Specific subpopulations in these studies experienced harm with high-dose steroids, bringing to a close this therapy.

In the 1990s, physiologic-dose steroids for patients in septic shock demonstrated trends towards improved mortality. Two of the most commonly quoted studies include the Annane and CORTICUS trials. Annane et al. randomized 300 patients with septic shock within 8 hours of diagnosis to hydrocortisone 50 mg IV every 6 hours with fludrocortisone 50 micrograms for 7 days versus placebo.38 All patients underwent a 250 microgram IV ACTH stimulation to evaluate for adrenal dysfunction, which the investigators defined as < 9 microgram/dL increase in total cortisol at 60 minutes. The primary endpoint included 28-day survival for the ACTH nonresponders, with secondary outcomes of total mortality, length of vasopressor requirements, and adverse events from steroid treatment. Low-dose steroid therapy was associated with improved mortality (28-day mortality 53% in steroid group versus 63%), which is based on an adjusted analysis, with no change in adverse events between groups. However, analysis of the complete data set suggests no mortality benefit for steroids. The 28-day mortality rate was not significantly decreased in ACTH stimulation test nonresponders.38 Median time to vasopressor withdrawal was decreased in the steroid group (7 versus 10 days). Oppert et al. suggested improved shock reversal and decreased cytokines in patients treated with hydrocortisone 50 mg IV, followed by 0.18 mg/kg/hr IV infusion.39

These studies were followed by meta-analyses suggesting reduced mortality with physiologically dosed steroids, which found improved hemodynamic effects with corticosteroids at physiologic-doses.40-42 The CORTICUS trial released in 2008 slowed the momentum of support for low-dose steroids.43 This study was a multicenter, prospective, double-blind trial of patients randomized to receive hydrocortisone 50 mg IV every 6 hours versus placebo. Patients were included only if they experienced hypotension for > 1 hour, with primary outcome 28-day mortality in ACTH nonresponders. Investigators in this study found no difference between hydrocortisone and placebo groups in 28-day mortality (39% versus 36%, respectively).43 Similar to Annane et al., the CORTICUS trial found reduced time to shock reversal with hydrocortisone, but higher rates of hyperglycemia, hypernatremia, and superinfection were found in the steroid group.38,43,44

Study Patients Included Definition of shock Intervention Outcome Secondary Outcome
Annane 300 adults with onset of shock within 8 hours, higher illness severity (SAPS II score)


All had short corticotropin test

Sepsis with SBP < 90 mm Hg despite fluid replacement, >5ug/kg dopamine or current treatment with epinephrine/ norepinephrine, lactate > 2 mmol/L, need for mechanical ventilation, within 3 hours of onset Hydrocortisone 50 mg IV every 6 hours for 1 week with fludrocortisone 50 mcg once daily for 1 week vs. placebo Improved 28-day survival distribution from randomization in nonresponder short corticotropin test: median time to death 12 vs 24 days,

hazard ratio 0.67; 95% C.I. 0.47-0.95, P=0.02, NNT 7 (95% C.I. 4-49)


No statistical difference mortality in ACTH responders, 53% vs. 61% P=0.96, or all patients, 61% vs. 55%

Median time to vasopressor withdrawal in nonresponders: 7 days in treated group, 10 days in placebo group
CORTICUS 499 adults with onset of shock within 72 hours, lower illness severity Sepsis and shock defined by SBP < 90 mm Hg despite 1 hour of fluid resuscitation or need for vasopressors, organ dysfunction attributable to shock Hydrocortisone 50 mg IV every 6 hr, tapering from day 6 to day 12 vs. placebo No change in 28-day mortality in nonresponders: 39.2% in hydrocortisone vs. 36.1% in placebo group, not statistically different.



No difference in 28-day mortality in short corticotropin responders or all patients.


Reduction in time to shock reversal with hydrocortisone. 3.3 days vs. 5.8 days


Nonsignificant increase in superinfections in hydrocortisone group: 33% vs. 26% (95% CI 0.96-1.68)

 Shock Attenuation

Corticosteroids may not decrease mortality at physiologic doses, but they do possess important effects. Patients with septic shock given corticosteroids demonstrate decreased need for vasopressors, which has the potential benefit of improving peripheral vascular recovery and organ function.11-15,38,42 Sligl et al. in 2009 found no statistical difference in mortality (42.2% [369 of 875 patients] vs. 38.4% [384 of 1001]; RR, 1.00; 95% CI, 0.84-1.18), but did find a change in incidence of shock reversal at 7 days in the steroid versus placebo groups (64.9% [314 of 484 patients] vs. 47.5% [228 of 480]; RR, 1.41; 95% CI, 1.22-1.64) and no increase in superinfection.14 Wang et al. in a 2014 meta-analysis found low dose hydrocortisone therapy decreased shock at 7 and 28 days, with no change in mortality.45 Faster time to shock reversal but no mortality benefit has been observed in another meta-analysis.46

Steroid Adverse Events

Corticosteroids affect multiple organ systems, and excess amounts are associated with adverse events including hyperglycemia, secondary infection from immunosuppression, delayed healing, skin breakdown, and muscle weakness.14,43,46-48 The CORTICUS trial suggested an increase in infection, with relative risk 1.27 (95% CI 0.96-1.68).43 However, this risk is not statistically different among the groups. Other meta-analyses do not suggest any increase in superinfection with corticosteroids.43

Elevated blood sugar is common, specifically as the dose of steroids increases.47,48 Episodes of hyperglycemia may cause harm, but treating hyperglycemia with insulin increases risk of hypoglycemia. Other issues with steroids include decreased skin integrity and delayed healing, though these are seen in high-doses. ICU patients may experience increased risk of critical illness myoneuropathy, prolonged weakness, increased length of stay, and prolonged mechanical ventilation.47,48

Many of these risks are not significant with physiologic-dose steroids, and they are more relevant to critical care physicians, rather than the ED.

What about evaluating adrenal function?

A great deal of controversy surrounds measuring adrenal function. Cortisol levels drastically change hour to hour due to corticosteroid-binding protein levels and activity, albumin production, and cortisol production during illness.21,49-52 Total cortisol levels are usually measured, though only free cortisol is active. Thus, total cortisol levels are difficult to interpret.49-52 Literature repeatedly demonstrates random serum cortisol is not beneficial due to wide range of baseline levels. Free cortisol may accurately reflect HPA axis activity, but studies do not support correlation of plasma levels with true tissue levels.

Evaluating adrenal function classically entails drawing baseline cortisol levels, administration of cosyntropin (or corticotropin), and reassessment of cortisol at 30 and 60 minutes. Low dose stimulation test uses cosyntropin 1 microgram IV, while high dose uses 250 micrograms IV. However, patients undergoing high dose testing demonstrate response even if they possess adrenal insufficiency due to the high dose of cosyntropin.50 Studies suggest the low dose testing may be more sensitive in diagnosing adrenal insufficiency, though sensitivities for diagnosing adrenal insufficiency approximate 50%. Patients with less than 9 mcg/dL response have greater mortality, along with those with higher baseline levels (34 mcg/dL).56,57

However, testing adrenal function via ACTH stimulation tests in critically ill patients is not reliable. Some patients demonstrate cortisol response > 9 mcg/dL with no cosyntropin administration, questioning this threshold.50,57-61 Many laboratories use immunoassay tests that are not available in many institutions and take days to result, along with poor correlation with gold standard mass spectrometry. At this time, these tests are not reliable for ED use and are even questionable for the ICU.57-60

Steroid Considerations in the ED

The Surviving Sepsis Guidelines advise consideration of corticosteroids for septic shock refractory to fluids and vasopressors.2 They do not recommend the use of corticotropin testing.2 Steroids can improve hemodynamic status, but literature does not support mortality benefit.11-15,38,40,43 Steroids can be used to reduce duration of septic shock in fluid and vasopressor-resistant hypotension.11-15,38,43 However, steroids are associated with side effects including hyperglycemia, myopathy, and electrolyte derangements.47,48

In septic shock, rapid diagnosis and management is integral with antimicrobials, source control, and IV fluid resuscitation. Vasopressors should be used when fluids do not increase MAP above 65 mm Hg.2,10 If the patient does not respond to these treatments, providers should evaluate for steroid indications including patient chronic baseline steroid use, chronic adrenal insufficiency, and refractory hypotension. Patients responsive to fluids and/or vasopressors receive little benefit, if any, from steroids. Contraindications should be considered including potential risk of worsening myopathy, DKA, HIV, TB, recent surgery or open wounds, and active peptic ulcer disease. If these are present, steroids should be avoided if possible. Other considerations include patient physiologic reserve (presence of other comorbidities, response to treatment, and exposure to other adrenal-suppressing agents such as etomidate).

Regimens for corticosteroids include hydrocortisone 100 mg IV every 8 hours or 50 mg IV every 6 hours. Another option is 100 mg IV bolus followed by infusion of 0.18 mg/kg/hr IV. These regimens have not been compared directly. Fludrocortisone is not advised at this time, as the COIITSS study demonstrated increased risk of infection with fludrocortisone in conjunction with corticosteroids.61 The ADRENAL study is currently underway, comparing low-dose corticosteroids in ICU septic shock, with primary outcome of mortality at 90 days.62


– Sepsis management requires early recognition, fluid resuscitation, source control, broad spectrum antimicrobials, and vasopressors for those not responsive to IV fluids.

– Patients with septic shock unresponsive to fluid and vasopressor resuscitation warrant further management and consideration of other disease states.

– The pathophysiology of sepsis may include loss of vasomotor tone and relative adrenal insufficiency.

– High-dose corticosteroids may result in patient harm, but physiologic, or low-dose, corticosteroids may be used to decrease the need for vasopressors.

– Most current meta-analyses do not demonstrate a mortality benefit with steroids. The Surviving Sepsis Guidelines advise consideration of corticosteroids in patients with vasopressor and fluid resistant septic shock.

– Corticosteroids may decrease need for vasopressors and improve perfusion.


References/Further Reading

  1. Elixhauser A, Friedman B, Stranges E. Septicemia in U.S. Hospitals, 2009. Agency for Healthcare Research and Quality, Rockville, MD. http://www.hcup-us.ahrq.gov/reports/statbriefs/sb122.pdf
  2. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013;41:580–637.
  3. Russell JA. Management of sepsis. N Engl J Med 2006;355:699–713.
  4. Dombrovskiy VY, Martin AA, Sunderram J, Paz HL. Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003. Crit Care Med 2007;35: 1244-1250.
  5. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368–77.
  6. Process Investigators. Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;370(18):1683–93.
  7. ARISE Investigators, Anzics Clinical Trials Group. Peake SL, Delaney A, Bailey M, Bellomo R, Cameron PA, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014;371(16):1496–506. doi: 10.1056/NEJMoa1404380.
  8. Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015;372(14):1301–11.
  9. Nguyen HB, Jaehne AK, Jayaprakash N, et al. Early goal-directed therapy in severe sepsis and septic shock: insights and comparisons to ProCESS, ProMISe, and ARISE. Critical Care. 2016;20:160.
  10. Remick DG. Pathophysiology of Sepsis. Am J Pathol. 2007 May;170(5): 1435-1444.
  11. Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review. JAMA 2009; 301:2362.
  12. Minneci PC, Deans KJ, Eichacker PQ, Natanson C. The effects of steroids during sepsis depend on dose and severity of illness: an updated meta-analysis. Clin Microbiol Infect 2009; 15:308.
  13. Minneci PC, Deans KJ, Natanson C. Corticosteroid therapy for severe sepsis and septic shock. JAMA 2009; 302:1643; author reply 1644.
  14. Sligl WI, Milner DA Jr, Sundar S, et al. Safety and efficacy of corticosteroids for the treatment of septic shock: A systematic review and meta-analysis. Clin Infect Dis 2009; 49:93.
  15. Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids for treating sepsis. Cochrane Database Syst Rev 2015; :CD002243.
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  24. Mesotten D, Vanhorebeek I, Van den Berghe G. The altered adrenal axis and treatment with glucocorticoids during critical illness. Nat Clin Pract Endocrinol Metab 2008;4:496–505.
  25. Marik PE, Pastores SM, Annane D, Meduri GU, Sprung CL, Arlt W, Keh D, Briegel J, Beishuizen A, Dimopoulou I, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med 2008;36:1937–1949.
  26. Balk RA. Steroids for septic shock: back from the dead? (Pro). Chest 2003;123:490S–499S.
  27. McGee S, Hirschmann J. Use of corticosteroids in treating infectious diseases. Arch Intern Med 2008;168:1034–1046.
  28. Schumer W. Steroids in the treatment of clinical septic shock. Ann Surg 1976; 184:333.
  29. Shine KI, Kuhn M, Young LS, Tillisch JH. Aspects of the management of shock. Ann Intern Med 1980; 93:723.
  30. Spink WW. ACTH and adrenocorticosteroids as therapeutic adjuncts in infectious diseases. N Engl J Med 1957; 257:1031.
  31. Wagner HN Jr, Bennett IL Jr, Lasagna L, et al. The effect of hydrocortisone upon the course of pneumococcal pneumonia treated with penicillin. Bull Johns Hopkins Hosp 1956; 98:197.
  32. Kass EH. Adrenocorticosteroids and the management of infectious diseases. AMA Arch Intern Med 1958; 102:1.
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  34. Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med 1987;317: 653–658.
  35. Veterans Administration Systemic Sepsis Cooperative Study Group. Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. N Engl J Med 1987;317:659–665.
  36. Sprung CL, Caralis PV, Marcial EH, Pierce M, Gelbard MA, Long WM, Duncan RC, Tendler MD, Karpf M. The effects of high-dose corticosteroids in patients with septic shock: a prospective, controlled study. N Engl J Med 1984;311:1137–1143.
  37. Cronin L, Cook DJ, Carlet J, Heyland DK, King D, Lansang MA, Fisher CJ Jr. Corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature. Crit Care Med 1995;23:1430– 1439.
  38. Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troche G, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisones on mortality in patients with septic shock. JAMA 2002;288:862–871.
  39. Oppert M, Schindler R, Husung C, Offermann K, Graf KJ, Boenisch O, Barckow D, Frei U, Eckardt KU. Low-dose hydrocortisone improves shock reversal and reduces cytokine levels in early hyperdynamic septic shock. Crit Care Med 2005;33:2457–2464.
  40. Moran JL, Graham PL, Rockliff S, Bersten AD. Updating the evidence for the role of corticosteroids in severe sepsis and septic shock: a Bayesian meta-analytic perspective. Crit Care 2010;14:R134.
  41. Minneci PC, Deans KJ, Banks SM, Eichacker PQ, Natanson C. Meta-analysis: the effect of steroids on survival and shock during sepsis depends on the dose. Ann Intern Med 2004;141:47–56.
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  43. Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, Weiss Y, Benbenishty J, Kalenka A, Forst H, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008;358:111–124.
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  46. Sherwin RL, Garcia AJ, Bilkovski R. Do low-dose corticosteroids improve mortality or shock reversal in patients with septic shock? A systematic review and position statement prepared for the American Academy of Emergency Medicine. J Emerg Med. 2012 Jul;43(1):7-12.
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  53. Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free cortisol in critically ill patients. N Engl J Med 2004; 350:1629.
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Unstable Sepsis: Airway First? Not Always

Author: Jennifer Robertson, MD, MSEd // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital)


A 50 year-old male presents to the emergency department (ED) with a five day history of worsening abdominal pain. He states this has never occurred before, but he thinks he has a known ventral hernia.  He really has no other complaints other than the pain. Upon arrival, he appears diaphoretic and a little confused but is otherwise answering questions appropriately.  The patient’s brother states that his brother is “always” sweaty and that the diaphoresis is nothing unusual. The patient denies any significant past medical history, including no history of diabetes, immunosuppression or chronic steroid use.

Initial vital signs (VS):

Heart rate (HR) 100 beats per minute (bpm), normal temperature, normal blood pressure, an oxygen saturation (SpO2) of 99% on room air (RA) and a respiratory rate of 24 breaths per minute.

Initial examination:

The patient is an obese male who appears ill and diaphoretic. He is somewhat tachypneic but is able to answer questions in full sentences. He has clear breath sounds and remains slightly tachycardic. His abdominal exam appears grossly abnormal, including marked distention and firmness. There is focal enlargement of his abdomen in the right lower quadrant and he has overlying erythema and warmth of this site. His genitourinary exam is normal.

Initial interventions:

An initial concern was for an incarcerated hernia, possibly bowel necrosis. Two large bore peripheral intravenous (IV) lines were placed and an initial crystalloid bolus was administered. Broad spectrum antibiotics were given immediately due to concern for early sepsis. Labs were ordered and pending.  An electrocardiogram (ECG) was obtained showing sinus tachycardia without any acute abnormalities. The patient was deemed hemodynamically stable enough to go to computed tomography (CT) scan for imaging.

Sepsis: General Review

Extensive research, peer reviewed articles and online sites have studied, reviewed and evaluated sepsis and its dangers. The current article is not intended to cover sepsis or its definitions, however the following excellent articles can be reviewed on emdocs.net for an extensive review:










In general, sepsis can be a continuum from a very mild infection to fulminant septic shock. As a medical student and resident, one may have been taught that the airway always takes priority in any unstable patient, especially in altered patients who cannot protect their airways and those with primary airway or pulmonary diseases. However, immediately intubating a patient with sepsis may not be the right thing to do, especially if he or she is hemodynamically unstable. It should be mentioned that with the exception of the need for pre-oxygenation (see #2 below), this review is not about the patient who requires immediate intubation. Importantly, one should never wait until a patient’s physiologic reserve is completely gone and thus, if any planned resuscitation fails, then intubation should not be delayed (1).

Case Continuation

The patient returns from the CT scanner and the read is pending. The nurse taking care of the patient notifies you that the cardiac monitor demonstrates an irregularly irregular rhythm at 180 beats per minute.

 Repeat examination:

HR 180 (irregular)

Blood pressure 90/50 mmHg

RR 40 breaths per minute

Patient more confused, remains diaphoretic

Repeat ECG: atrial fibrillation with rapid ventricular response (RVR), rate 180

The nurse asks what to do next…

Issues to Consider Prior to Intubation

There are two main issues to consider prior to intubating an unstable patient who requires an urgent but not immediate airway. These issues include (1) hemodynamic instability such as severe tachycardia, bradycardia and hypotension and (2) hypoxia that does not respond to standard oxygen therapy.

(1) Hemodynamic instability

Studies have shown that tracheal intubation is not a benign event. The simple act of intubating can cause hemodynamic changes that can affect post-intubation outcomes (2). In addition, the process of intubation typically requires induction agents and positive pressure ventilation, which can also significantly contribute to the hemodynamic changes seen during and after intubation (2, 3, 4, 5). In addition, repeat laryngoscopy attempts also can be detrimental (6).  Not only can hemodynamic instability occur with intubation in normal, healthy patients, but it most definitely occurs in the critically ill emergency department (ED) patient and usually to a greater extent (2). The hemodynamic changes that result from laryngoscopy and tracheal intubation are complicated and multifactorial (8). However, research has demonstrated airway manipulation is a potent stimulator of the sympathetic and parasympathetic nervous systems, with initial increases in heart rate and blood pressure due to transient catecholamine release (3). Endogenous epinephrine has a very short half-life, however, and post-intubation hypotension (typically described as ≤ 90 mm Hg systolic) is thought to be due to rapid attenuation of this sympathetic tone (2). In addition, the addition of positive end expiratory pressure (PEEP) can further decrease cardiac preload by decreasing venous return (2). This is especially a problem in those patients who have diminished cardiac reserve, are hypovolemic, or septic (2).  Extreme bradycardia and hypotension can also occur due to repetitive laryngoscopy and can also be worsened in those patients who have concomitant hypoxemia (2, 6).

While the hemodynamic changes during intubation can be considered “normal” physiologically, it is not a benign process (8). In fact, post-intubation hypotension (and really any hypotension in the ED) is associated with increased morbidity, prolonged patient stays, cardiac arrest and death (8-14). In addition, other studies have demonstrated that lower blood pressures and elevated shock indices (such as seen in sepsis) prior to intubation are associated with post-intubation hypotension and poorer outcomes (8, 10, 15, 16). Thus, hemodynamic resuscitation prior to intubation should be considered in the unstable (but not crash airway) patient (1, 12).

Case Continued

Upon re-examination, the patient remains diaphoretic and altered. Laboratory tests started to return and demonstrated a leukocytosis and a lactate level of 4.0. Surprisingly, the serum bicarbonate level was only mildly decreased. The CT read was still pending. Clinically, the patient was septic and likely from an intra-abdominal pathology. The decision was made to intubate and start a central line, however, given the new onset atrial fibrillation with RVR and low blood pressures, it was decided to first attempt synchronized cardioversion to see if conversion to sinus rhythm would allow for increased cardiac output and blood pressure prior to intubation. Using a small dose of ketamine for comfort and pain relief, the patient was cardioverted twice without success.  He was finishing his second liter of crystalloid, remained hypotensive and tachycardic, and the nurse started to look concerned…


A few strategies to avoid hypotension and maximize cardiac preload and afterload prior, during and after intubating an urgent airway (1, 2, 17):

(a) Maximize fluid status

(b) Consider using push dose vasopressors such as phenylephrine or epinephrine. The dose of push dose phenylephrine is 50-200 micrograms (mcg) every two to five minutes. The dose of push dose epinephrine is 5-20 mcg every two to five minutes.  A good review of dosing can be seen at http://emcrit.org/wp-content/uploads/push-dose-pressors.pdf (18).

(c) Cardiovert any unstable rhythms

(d) Consider using induction and sedative agents that work best for each patient’s hemodynamic status. This article is not intended to be a review of pharmacologic agents. A nice medication review can be seen at http://www.emdocs.net/8751-2/ (19).

(e) Avoid too much PEEP after intubating if possible

Case Resolution

After a failed cardioversion, the patient’s blood pressure continued to decline. Three doses of push dose phenylephrine were given while the patient was prepared for intubation. His blood pressure rose and his heart rate declined with the phenylephrine, but he did remain in atrial fibrillation. The patient was given an induction dose of ketamine and intubated on the first pass without any complications. The patient’s CT read finally returned, demonstrating a ruptured bowel with pneumoperitoneum. A central line was placed and the patient was transferred to a higher level of care and he was extubated by day ten of hospitalization.

(2) Hypoxia

While the patient did not sustain hypoxia and had a normal PO2 on his initial and subsequent arterial blood gas (ABG) measurements, many patients do. On occasion, patients with an urgent, but not crash, need for an airway may not be able to sustain oxygen saturations above 90% on high levels of supplemental oxygen. In this case, ED providers may be eager to intubate the patient to “increase oxygen levels”. However, it is not the intubation that helps this but likely the positive pressure that is provided after intubation and during the patient’s therapy on the ventilator (17).

The goal of pre-oxygenation is to get the oxygen saturation as high as possible in order to allow for enough time for intubation and prevent severe hypoxemia during the procedure (17). If patients are intubated prior to adequate pre-oxygenation, they are at risk for a rapid decline in oxygen levels. This is even more pronounced in the obese and critically ill patients (20, 21). The oxygen-hemoglobin dissociation curve demonstrates this physiology.


Severe hypoxemia is a risk factor for cardiac arrest and thus, it is imperative that patients, even those whose oxygen saturations do not reach above 90% on supplemental oxygen, receive adequate pre-oxygenation prior to intubation (7, 17, 22). Patients with poor alveolar oxygenation whose oxygen saturations do not rise with simple supplemental oxygen may be undergoing a number of possible pathologies such as dead space where there is normal ventilation but no perfusion, a shunt, and a low venous oxygen saturation (17).  Examples include a septal cardiac defect (anatomic shunt), pneumonia or pulmonary edema (physiologic shunt), a pulmonary embolism (dead space), and shock states (poor venous oxygen saturation) (17).

In order to properly pre-oxygenate the above types of patients, it may be necessary to incorporate other techniques prior to intubation. It is imperative that emergency physicians understand this need to take the time to properly pre-oxygenate and not to “jump to intubation” when a patient does not respond to simple supplemental oxygen therapy and a standard bag valve mask.  Techniques to consider include: (1) Non-invasive positive pressure ventilation (NIPPV) and the use of PEEP valves, (2) Apneic oxygenation and (3) Delayed sequence intubation (17, 21, 22).

(1) NIPPV – In a patient whose oxygen saturation does not improve with standard pre-oxygenation techniques, such as a patient with shunting, may require positive pressure ventilation. In this case, positive pressure ventilation has been shown to improve the efficiency of gas exchange, recruit more alveoli, increase lung volumes and increase the amount of time it takes for desaturation to occur (17, 21). In order to achieve this, a standard continuous positive airway pressure (CPAP) machine can be utilized, maintaining a PEEP of 5 to 15 cm H20 (17). Another strategy is to use the ventilator for this and the 2010 article by Dr. Weingart can be reviewed for the proper ventilator settings for pre-oxygenation (17). If a patient cannot tolerate the positive pressure mask, then a technique called delayed sequence intubation can be used as mentioned below (17, 23).

Another noteworthy topic is the use of the BVM. Standard BVMs do not provide any PEEP. Therefore, if there is a shunt and the patient’s oxygenation is not improving with the BVM, a tool called a PEEP valve can also be used (17). It is imperative that the mask seal is tight, otherwise the PEEP valve will not be useful (17).

(2) Apneic Oxygenation – The very act of rapid sequence intubation does entail a period of apnea while the tube is being placed. It is thought that placing supplemental oxygen via nasal cannula may be helpful to supply additional oxygen while the patient is apneic. It has been demonstrated that alveoli continue to take up some oxygen, even without active breathing (22). While carbon dioxide does increase during this time, the patient still may be oxygenated during the apneic period with the idea of “apneic oxygenation” (17, 22). Of note, once the patient is paralyzed, it is important to make sure that the tongue and posterior pharynx is not occluding the airway and a head tilt with chin lift is adequate for most patients. A nasal or oral airway may be required as well (22).

(3) Delayed sequence intubation – For the difficult patient who requires pre-oxygenation, a simple facemask may not work, as it may be pulled off due to agitation or confusion. In addition, the added hypoxia and hypercapnia may add to any agitation, causing patients to become even more uncooperative (17). One proposed way to get around this agitation is with a concept called “delayed sequence intubation” (DSI). Several articles have been written by Dr. Weingart and his articles are listed below for review. However, in short, DSI consists of administering a sedative agent that does not cause spontaneous respirations to decline, such as ketamine at a dose of 1-1.5 mg/kg slow intravenous push (17). After giving the medication, the patient becomes calmer, allowing proper preoxygenation to occur (17, 23). After the patient is adequately preoxygenated, then standard rapid sequence intubation can occur. This procedure was recently researched by Dr. Weingart in 2015 with promising results (23). The same concepts of needing PPV may be required in those patients who demonstrate shunt physiology.

Conclusions: Tracheal intubation is more complicated than a simple airway tube, especially in the critically ill and septic patients. While some patients require an immediate airway, many patients should be critically assessed prior to intubation. Proper pre-oxygenation should always occur and hemodynamic resuscitation should be considered in order to avoid post-intubation hypotension and increased morbidity and mortality.

References / Further Reading

  1. Manthous CA. Avoiding circulatory complications during endotracheal intubation and initiation of positive pressure ventilation. J Emerg Med 2010; 38 (5): 622-31.
  2. Mort TC. Complications of emergency tracheal intubation: hemodynamic alterations-Part I. J Intensive Care Med 2007; 22 (3): 157-65.
  3. Shribman AJ, Smith JG, Achola KJ. Cardiovascular and catecholamine responses to laryngoscopy with and without tracheal intubation. Br J Anaesth 1987; 59 (3): 295-99.
  4. Bucx MJL, Van Geel RTM, Scheck PAE, et al. Cardiovascular effects of forces applied during laryngoscopy.Anaesthesia 1992; 47 (12): 1029-33.
  5. Schwab TM, Greaves TH. Cardiac arrest as a possible sequela of critical airway management and intubation. Am J Emerg Med 1998; 16 (6): 609-12.
  6. Mort TC. Emergency tracheal intubation: complications associated with repeated laryngoscopic attempts. Anesth Analg 2004; 99 (2): 607-13.
  7. Mort TC. The incidence and risk factors for cardiac arrest during emergency tracheal intubation: a justification for incorporating the ASA Guidelines in the remote location. J Clin Anesth 2005; 16 (7): 508-16.
  8. Heffner AC, Swords DS, Nussbaum ML, et al. Predictors of the complication of post-intubation hypotension during emergency airway management. J Crit Care 2012; 27 (6): 587-93.
  9. Heffner AC, Swords DS, Kline JA. The frequency and significant of post-intubation hypotension during emergency airway management. J Crit Care 2012; 27 (4): 417-e9.
  10. Schwartz DE, Matthay MA, Cohen NH. Death and other complications of emergency airway management in critically ill adults. A prospective investigation of 297 tracheal intubations. Anesthesiology 1995; 82 (2): 367-76.
  11. Heffner AC, Swords DS, Neale MN, et al. Incidence and factors associated with cardiac arrest complicating emergency airway management. Resuscitation 2013; 84 (11): 1500-04.
  12. Kim WY, Kwak MK, Ko BS, et al. Factors associated with the occurrence of cardiac arrest after emergency tracheal intubation in the emergency department. PLOS One 2014; 9 (11): e112779.
  13. Jones AE, Yiannibas V, Johnson C, et al. Emergency department hypotension predicts sudden unexpected in-hospital mortality: a prospective cohort study.”CHEST 2006; 130 (4): 941-46.
  14. Merz TM, Etter R, Mende L, et al. Risk assessment in the first fifteen minutes: a prospective cohort study of a simple physiological scoring system in the emergency department. Crit Care 2011; 15 (1): 1.
  15. Green RS, Edwards J, Sabri E, et al. Evaluation of the incidence, risk factors and impact on patient outcomes of post-intubation hemodynamic instability. CJEM 2012; 14 (2): 74-82.
  16. Lin CC, Chen KF, Shih CP, et al. The prognostic factors of hypotension after rapid sequence intubation. Am J Emerg Med 2008; 26 (8): 845-51.
  17. Weingart SD. Preoxygenation, reoxygenation, and delayed sequence intubation in the emergency department. J Emerg Med 2011; 40 (6): 661-67.
  18. http://emcrit.org/wp-content/uploads/push-dose-pressors.pdf.
  19. http://www.emdocs.net/8751-2/
  20. Dargin J, Medzon R. Emergency department management of the airway in obese adults. Ann Emerg Med 2010; 56 (2): 95-104.
  21. Baillard C, Fosse JP, Sebbane M, et al. Noninvasive ventilation improves preoxygenation before intubation of hypoxic patients. Am J Respir CritCareMed 2006; 174 (2): 171-77.
  22. Weingart SD, Levitan RM. Preoxygenation and prevention of desaturation during emergency airway management. Ann Emerg Med 2012; 59 (3): 165-75.
  23. Weingart SD, Trueger S, Wong N, et al. Delayed sequence intubation: a prospective observational study. Ann Emerg Med 2015; 65 (4): 349-55.

Occult Sepsis in Traumatic Injuries

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

It is 7pm, and several trauma patients are already being treated in the emergency department (ED). This includes one male patient who was transported to the ED by emergency medical services (EMS) from the site of a bad motor vehicle crash (MVC). He required orotracheal intubation, two units each of packed red blood cells (PRBC), two units of fresh frozen plasma (FFP), and a right-sided chest tube. Unfortunately, he also had a positive FAST (Focused Assessment with Sonography for Trauma) with continued hypotension. Thus, the patient was transported to the operating room (OR) for definitive repair of his injuries.

Suddenly, the radio alerts again. EMS is bringing in another patient who was the driver in a head-on collision. The 54-year-old male patient is tachycardic, has a blood pressure (BP of 92/54 mm Hg, an oxygen saturation of 92% on 2 liters (L) nasal cannula (NC) oxygen (O2), and a respiratory rate (RR) of 22 breaths/minute (min).  The patient arrives in the ED with repeat vital signs (VS) showing a BP 110/56 after one L of normal saline (NS), a heart rate (HR) 101, RR 22/min, and an O2 saturation of 94% on 2L NC. He is protecting his airway, has a Glasgow Coma Scale (GCS) of 12, has symmetric rise and fall of his chest with equal breath sounds, and has warm skin with palpable distal pulses. His rapid glucose level (D-stick) is 192, and his FAST with lung windows (E-FAST) is negative for acute injury.  The cardiac window demonstrates hyperkinesis. A nurse shouts out that his temperature is 101° Fahrenheit (F). The patient’s venous blood gas (VBG) demonstrates normal electrolytes but an abnormal lactic acid of 4.2 and a base excess of (-) 10.

Two large peripheral intravenous lines are placed and the patient is put on supplemental O2 by facemask. However, the patient remains febrile, tachycardic and tachypneic. His mental status is also not appropriate. Is something else going on with this patient?


Emergency physicians are well acquainted with trauma. Trauma is the predominant cause of mortality in patients ages 1 year to 44 years, and it is the third leading cause of death overall. The major causes of death include head injury, chest injury, and vascular injury. Interestingly, 90% of patients survive the initial trauma, but ongoing morbidity occurs due to traumatic brain injuries, chronic pain, and/or extremity injuries.1,2

However, despite the obvious causes of morbidity from trauma, some trauma patients may also be septic. Obviously we are drawn to the initial stabilization with Airway-Breathing-Circulation-Disability-Exposure-FAST-Glucose.  Unfortunately, many patients with trauma also demonstrate SIRS (systemic inflammatory response) criteria, which creates a diagnostic challenge. What steps can be taken in order to prevent missing sepsis in trauma?

SIRS and Sepsis


SIRS and sepsis are common clinical entities, but there are distinct differences because there must be infection for sepsis to occur, while SIRS can occur without an underlying infection.

The definition of SIRS includes: HR > 90 beats per minute (bpm), RR > 20/min or arterial carbon dioxide tension (PaCO2) < 32 mmHg, temperature < 36oCelcius (C) or > 38oC, and a white blood cell (WBC) count < 4 x 109 cells/L or > 12 x 109 cells/L or > 10% bands. Two or more of these equals SIRS, and two or more with a source of infection equals sepsis.1,2 Unfortunately these criteria are non-specific, and the criteria alone do not provide a diagnosis or predict outcome.3,4 As you can see, traumatic injury often meets SIRS criteria. The updated Sepsis 3.0 definition will be discussed later in the post.

The diagnostic challenge is present because sepsis is defined using SIRS criteria, but it is not always initially known which patients are simply SIRS without infection, while others have actual sepsis.  This post will evaluate two aspects of sepsis in trauma: sepsis with initial trauma and sepsis after multiple trauma.

Together, sepsis and trauma are deadly. Patients with acute trauma are often in extremis, and many will meet SIRS criteria. However, a source of infection is necessary to diagnose true sepsis and this can be difficult due to other clinical findings. For example, an infiltrate on chest x-ray could be lobar pneumonia or a pulmonary contusion. Sepsis hinges on suspected infection and unfortunately, is a subjective diagnosis.

Emergency physicians train and work to develop excellent clinical gestalt and be masters of resuscitation. The clinician at the bedside is the best diagnostic test available.  In the setting of acute trauma, there are several steps that can be followed in order to reduce the risk of missing sepsis.

  1. First, work to stabilize the patient and take care of Airway-Breathing-Circulation-Disability-Exposure-FAST/Fetus-Glucose (D-stick). Obtain laboratory and radiographic studies as indicated, but also try to determine what could be missed before automatically sending the patient to the computed tomography (CT) scanner.
  2. Do your best to obtain an accurate history. What was the cause of the trauma? If a patient, especially an elderly patient, was in a MVC, did he or she lose consciousness? Was there an arrhythmia? Was the patient weak from hypotension in the setting of a pneumonia (PNA) or urinary tract infection (UTI)? Try to understand why the trauma occurred and if there were any other issues before the trauma, such as symptoms concerning for infection such as dysuria, cough or fever. If a patient is not cooperative or is confused or intubated, try to obtain a collateral history from the patient’s family and/or from EMS.
  1. Next, ensure a complete examination is done. Never forget to look over every nook and cranny in the trauma patient (primary survey = exposure) and complete a thorough secondary examination, including the feet, back, and perianal regions. You may uncover cellulitis, necrotizing fasciitis, or even a head/ears/nose/throat (HEENT) infection. Does the patient have stigmata of drug use and new murmur (or better yet, ultrasound (US) evidence of vegetation on cardiac views)? Are there any other clinical findings consistent with endocarditis, pneumonia, a UTI, or meningitis? Also, beware of the altered patient with negative imaging. New-onset delirium can be a marker of infection, especially in older patients.5
  1. Carefully scrutinize VS of the patient. We commonly consider a systolic BP (SBP) < 90 mmHg as hypotensive. However, this may be an extremely abnormal blood pressure compared to a patient’s baseline. An older male may have a baseline BP of 170/100. In the setting of trauma, a drop of 30mmHg to a SBP of 140 mmHg is abnormal and a marker of disease.5 Pay close attention to the patient’s temperature. Any fever requires an explanation. Trauma may slightly elevate a baseline temperature, but any reading over 100.4 requires explanation and evaluation. Tachypnea is an early marker of infection in the elderly (one of the first).5,6 A trauma patient with abnormal VS, especially tachypnea and fever, in the setting of normal imaging, requires further evaluation and consideration of sepsis.

Older patients present an even greater challenge in trauma.5,6 Many of these patients will be on a beta-blocker or other hypertensive medications. Unfortunately, if you resuscitate just based on VS alone, half of trauma patients will not receive proper resuscitation. The relationship of cardiac output and blood pressure is reliable for diagnosing shock only with almost 50% of total blood loss.7

  1. Use your ultrasound. Almost every trauma patient receives an E-FAST exam. Pay close attention to the cardiac window (hyperkinesis), and consider looking at the lungs for findings consistent with pneumonia (consolidation, shred sign, bronchograms). Hypotension and loss of intravascular volume can be due to bleeding from trauma or third-spacing in sepsis. A view of the inferior vena cava (IVC) will show respiratory variation in the setting of hypovolemia/third spacing from trauma or sepsis.
  1. Use biomarkers carefully. Lactic acid and base excess are commonly used tests in resuscitation, especially in trauma. Abnormal lactic acid and base excess levels speak to hypoperfusion, which is associated with increased morbidity and mortality. These markers reflect metabolic derangement at the cellular level and will often elevate before clinically apparent end organ damage or decompensation occurs. Base excess (BE) more negative than -6 mmol/L and a lactic acid greater than 2.0 are consistent with shock, or occult shock in those patients with normal VS.8-14 If these tests are abnormal in the setting of trauma, but your other evaluations including imaging and labs are normal, strongly consider other diagnoses. Both tests are markers of end organ damage and hypoperfusion, and if abnormal, some pathology is present.

One very informative article about occult infection in sepsis found that in those trauma patients with infection, close to 70% did not normalize their lactate levels after initial resuscitation. Injury severity score and occult hypoperfusion were both predictive of infection. Thus, patients with lactic acid levels or other markers of hypoperfusion that do not normalize with trauma resuscitation warrant evaluation for infection.15

Other biomarkers for sepsis include procalcitonin (PCT) and C-reactive protein (CRP). PCT, in particular, has shown strong correlation with sepsis, though this has not been specifically evaluated in patients with trauma.16-21

  1. Can the new Sepsis 3.0 definition assist you? Both the new and older definitions of sepsis are subjective. The new definition of sepsis includes an acute increase of ≥ 2 SOFA (sepsis related organ failure assessment) points in a patient with unexplained organ dysfunction PLUS documented or suspected infection. However, every critical patient in an ED usually has some organ dysfunction.22

And just for reference, the qSOFA (quick Sepsis Related Organ Failure Assessment)   score uses SBP < 100, altered mental status, or a RR > 22. Please see http://www.emdocs.net/8419-2/, http://www.jamasepsis.com, http://rebelem.com/sepsis-3-0/, http://foamcast.org/2016/02/21/sepsis-redefined/, http://stemlynsblog.org/sepsis-16/, and http://emcrit.org/pulmcrit/problems-sepsis-3-definition/ for further thoughts on Sepsis 3.0.

Sepsis 3.0 is a marker for severity of disease and should not be used for screening of sepsis. However, the new definition may have some utility in trauma, as it can act as a trigger for providers to consider sepsis. A patient with qSOFA ≥ 2 or organ dysfunction has risk of greater mortality. The following algorithm is from the new Sepsis 3.0 definition and literature.22


Sepsis 3.0 Clinical pathway from http://www.jamasepsis.com

  1. This final step is looking at the overall clinical picture. Emergency physicians are masters of resuscitation. If anything is abnormal from the history, vital signs, exam, laboratory findings, or other studies, consider sepsis. The clinician must take into account the entire clinical picture including the history, physical exam, US, biomarkers, and vital signs. We rely on our clinical gestalt every day and with every patient. If something does not seem right with the clinical picture, consider any missing pieces and consider sepsis.

Sepsis after Multiple Trauma

Sepsis is a challenging complication after trauma. One study evaluated the incidence of sepsis in trauma over four periods, finding 14.8% in 1993-1996, 12.5% in 1997-2000, 9.4% in 2001-2004, and 9.7% in 2005-2008.  Unfortunately, in this study, patients with sepsis had mortality rates of 16.2%, 21.5%, 22.0%, and 18.2% respectively.

Post-traumatic sepsis is associated with male gender, existing co-morbidities, high injury severity score (ISS), greater number of injuries, the number of units of RBCs transfused, the number of operative procedures, and laparotomy.23

Another study found the existence of co-morbidities, male gender, lower admission GCS, and higher injury severity scores (ISS) to be associated an increased risk of sepsis. Compared to mild injury, moderate injury (ISS 15-29) had a 6-fold increased incidence of sepsis, while severe injury (ISS ≥ 30) had a 16-fold increased incidence of sepsis.  Thus, the sicker the patient, the higher risk of sepsis.24

Why would older age and co-morbidities predict sepsis? These patients have decreased cardiopulmonary function, poor nutrition, increased bleeding risk, and decreased immune function (decreased/dysfunctional antibodies, T cells, macrophages).23,24

One 2014 review demonstrated that the combination of risk factors and abnormal PCT and/or lactate should raise the suspicion for sepsis in trauma. Again, older age and presence of co-morbidities also increase risk of sepsis.25 The value of these from the 2014 study are listed below. 25 Providers may balk at the article’s preference for biomarkers. However, this study is important in that it provides important risk factors for the development of sepsis in trauma patients.


Biomarkers from He Jin, Zheng Liu, Ya Xiao, Xia Fan, Jun Yan, Huaping Liang. Ji H, Liu Z, Xiao Y, et al. Prediction of sepsis in trauma patients. July 2014;2(3):106-113.

So what do you do?

Sepsis and Trauma patients may both demonstrate positive SIRS criteria. The qSOFA score may also be positive in these patients, which raises questions regarding the use of Sepsis 3.0 to differentiate sepsis and trauma.

The best tools for diagnosis likely include the use of history, vital signs, physical examination, ultrasound, laboratory markers, and clinical gestalt.

 One recent review article published in 2015 compares the classic approaches to resuscitation in trauma and sepsis patients.26


Management priorities in trauma from Frankel HL, Magee GA, Ivatury RR. Why is sepsis resuscitation not more like trauma resuscitation? Should it be? J Trauma Acute Care Surg 2015 Oct; 79 (4): 669-77.

This diagram reflects the primary strategies for trauma management: (1) fix the problem (often bleeding source), (2) provide fluids (usually blood products), and (3) utilize appropriate tests and monitoring. The authors advocate that sepsis should be cared for similar to trauma, with targeted source control and minimizing “collateral damage,” including over-resuscitation.26

The initial management strategy of the patient in extremis for trauma and sepsis is similar. Resuscitate first and ask questions later. As discussed above, go through Airway, Breathing, Circulation, Disability/D-stick, Exposure, E-FAST exam/fetus (is the female patient pregnant?). Obtain IV access, attach monitors, and be prepared to provide supplemental O2.

Finally, when diagnosing sepsis, a potential source needs to be found. The LUCCASSS pneumonic is helpful toward assisting in a search for the source: source: lung (pneumonia), urine (cystitis/pyelonephritis), cardiac (endocarditis), CNS (meningitis, encephalitis), abdominal (abscess, cholecystitis), spine (osteomyelitis, abscess), skin (cellulitis, IV line/PICC infection), and septic arthritis.  Fortunately, an accurate history, physical examination, and appropriate laboratory tests and imaging can usually pinpoint the source of sepsis, but a systematic approach should be followed. Look for biomarkers that are not improving, and evaluate for hypotension, altered mental status, and RR ≥ 22/min. These are markers for mortality and should trigger consideration of sepsis.

References/Further Reading:

  1. Bonnie RJ, Fulco CE, Liverman CT (eds); Committee on Injury Prevention and Control, Division of Health Promotion and Disease Prevention, Institute of Medicine. Reducing the Burden of Injury: Advancing Prevention and Treatment. Washington, DC: National Academy Press, 1999.
  2. American College of Surgeons, Committee on Trauma: Resources for Optimal Care of the Injured Patient: 1999. Chicago, American College of Surgeons, 1998.
  3. Elixhauser A, Friedman B, Stranges E. Septicemia in U.S. Hospitals, 2009. Agency for Healthcare Research and Quality, Rockville, MD. http://www.hcup-us.ahrq.gov/reports/statbriefs/sb122.pdf

  4. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013;41:580–637.

  5. Caterino JM. Evaluation and management of geriatric infections in the emergency department. Emerg Med Clin N Am 2008;26:319-343.

  6. Khoujah D, Shen C. Systemic infections in the elderly patients. Critical Decisions April 2013.
  7. Wo CC, Shoemaker WC, Appel PL, Bishop MH, Kram HB, Hardin E. Unreliability of blood pressure and heart rate to evaluate cardiac output in emergency resuscitation and critical illness. Crit Care Med 1993 Feb;21(2):218-23.
  8. Ziglar MK. Application of base deficit in resuscitation of trauma patients. Int J Trauma Nurs. 2000 Jul-Sep;6(3):81-4.
  9. Porter JM, Ivatury RR. In search of the optimal end points of resuscitation in trauma patients: a review. J Trauma. 1998 May;44(5):908-14.
  10. Paladino L, Sinert R, Wallace D, Anderson T, Yadav K, Zehtabchi S.The utility of base deficit and arterial lactate in differentiating major from minor injury in trauma patients with normal vital signs. Resuscitation. 2008 Jun;77(3):363-8.
  11. Singer AJ, Taylor M, Domingo A, Ghazipura S, Khorasonchi A, Thode HC Jr, Shapiro NI. Diagnostic characteristics of a clinical screening tool in combination with measuring bedside lactate level in emergency department patients with suspected sepsis. Acad Emerg Med. 2014 Aug;21(8):853-7.
  12. Nguyen H, Rivers E, Knoblich B, et al. Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit Care Med. 2004; 32:1637–42.
  13. Arnold RC, Shapiro NI, Jones AE, et al. Multi-center study of early lactate clearance as a determinant of survival in patients with presumed sepsis. Shock. 2009;32:36–9.
  14. .Jansen TC, van Bommel J, Schoonderbeek FJ, et al. Early lactate-guided therapy in intensive care unit patients a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med. 2010;182:752–61.
  15. Ciriello V, Gudipati S, Stavrou PZ, Kanakaris NK, Bellamy MC, Giannoudis PV. Biomarkers predicting sepsis in polytrauma patients: Current evidence. Injury. 2013 Dec;44(12):1680-92.
  16. Schuetz P, Aujesky D, Mueller C, and Mueller B. Biomarker-guided personalised emergency medicine for all – hope for another hype? Swiss Med Wkly. 2015;145:w14079.
  17. Wacker C, Prkno A, Brunkhorst FM, et al. Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis. Lancet Infect Dis. 2013;13:426-435.
  18. Schuetz P, Briel M, Mueller B. Clinical outcomes associated with procalcitonin algorithms to guide antibiotic therapy in respiratory tract infections. JAMA. 2013;309(7):717–8.
  19. Schuetz P, Chiappa V, Briel M, Greenwald JL. Procalcitonin algorithms for antibiotic therapy decisions: a systematic review of randomized controlled trials and recommendations for clinical algorithms. Arch Intern Med. 2011;171(15):1322–31.
  20. Schuetz P, Muller B, Christ-Crain M, Stolz D, Tamm M, Bouadma L, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev. 2012; 9: CD007498.
  21. Freund Y, Delerme S, Goulet H, et al. Serum lactate and procalcitonin measurements in emergency room for the diagnosis and risk-stratification of patients with suspected infection. Biomarkers. 2012;17:590-596.
  22. Singer M et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315(8): 801 – 810.
  23. Wafaisade A, Lefering R, Bouillon B, et al. Epidemiology and Risk Factors of Sepsis after Multiple Trauma. Crit Care Med. 2011;39(4):621-628.
  24. Osborn TM, Tracy JK, Dunne JR, Pasquale M, Napolitano LM. Epidemiology of sepsis in patients with traumatic injury. Crit Care Med. 2004 Nov;32(11):2234-40.
  25. He Jin, Zheng Liu, Ya Xiao, Xia Fan, Jun Yan, Huaping Liang. Jin H, Liu Z, Xiao Y, et al. Prediction of sepsis in trauma patients. July 2014;2(3):106-113.
  26. Frankel HL, Magee GA, Ivatury RR.Why is sepsis resuscitation not more like trauma resuscitation? Should it be? J Trauma Acute Care Surg. 2015 Oct;79(4):669-77.


Dr. Strangelove or How I Learned to Stop Worrying and Sit on the qSOFA: A pathophysiologic approach to qSOFA

Author: Nikolai Schnittke, MD (@nikolaischnittk, EM Resident Physician, Berbee Walsh Department of Emergency Medicine, University of Wisconsin Hospital and Clinics) // Edited by: Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit)


The last few months have seen an enormous amount of controversy in the press, in the FOAMsphere, and in our ED hallways regarding the new consensus sepsis definition1,2. The goal of this post is not to rehash the strengths and weaknesses of Sepsis 3, but rather to explore the pathophysiologic basis of the simplified clinical features of sepsis outlined in the qSOFA score, which might explain why the definition shook out the way it did. Hopefully, such an understanding will help us apply lessons learned from the derivation of Sepsis 3 to the management of these profoundly sick patients.

So what is Sepsis 3? In his “biography of cancer”, The Emperor of all Maladies, Siddhartha Mukherjee writes about how in the mid 1800s Virchow set out to “describe human diseases in simple cellular terms”3. This need for a pathophysiologic, cellular, and molecular explanation of human disease has permeated many of the advances of modern medicine, but has been curiously lacking from our understanding of sepsis. While past definitions sought to define sepsis as a clinical syndrome based on clinical features (SIRS)4, Sepsis 3 seeks to define sepsis as a pathophysiologic entity. This was predicated on research done in the past few decades yielding a considerable, albeit still elementary body of scientific study revealing sepsis to be correlated with a dysregulated metabolic5,6, immunologic7, and microvascular response to infection8, which leads to organ failure. Thus, the authors defined sepsis as “a life-threatening organ dysfunction caused by a dysregulated host response to infection”.

This cerebral definition, while scholarly and useful in our conceptualization of the essence of sepsis, seems to do little to help the clinician recognize and treat sepsis. After over two decades of consensus sepsis definitions most clinicians have grown familiar and comfortable using SIRS. The three sepsis mega-trials: PROCESS9, ARISE10, and PROMISE11 seem to have validated a simplified approach to identification and treatment of sepsis using SIRS criteria. The authors of Sepsis 3 however, argue that SIRS has unsatisfactory sensitivity and specificity (best demonstrated by the Area Under the Receiver Operating Curve or AUROC) when it comes to the identification of a life threatening disease. That point was hammered home with disturbing force by a study in the NEJM in 2015, which used a large EMR database to check the sensitivity of SIRS in detecting downstream organ failure caused by infection, and found that SIRS missed 1 out of 8 patients (12%) with severe sepsis or septic shock12.

Moreover the mortality rate for sepsis remains high despite the significant advances of the last three decades. Indeed, the sepsis mega-trials consistently demonstrated a 90 day mortality in the range of 20-30%, which while significantly better than the 46% baseline mortality rate of Dr. Rivers’ initial EGDT trial13, is a shockingly high mortality for a disease whose prevalence continues to increase14. For comparison, consider that as of 2010, 30-day mortality rate for STEMI by one estimate is down to ~4.4%15. In an attempt to translate Sepsis 3 into a clinically helpful entity, the authors then worked backwards in a statistical tour de force to define the clinical features that might correlate with mortality in sepsis.

This behemoth retrospective derivation from 1.3 million EMR charts and subsequent validation of 700 thousand charts revealed three clinical variables that were strongly correlated with mortality: RR>21, Altered mental status[1], and SBP<100. The AUROC for situations where two of these variables were present was comparable to or better than that of SIRS in both ICU and non-ICU settings2. Thus, Sepsis 3 provides not only a pathophysiologic definition of sepsis, but also the first evidence based description of its clinical features, which are predictive of mortality. The goal of this post is to explore how these two realms fit. In other words, why are these three clinical changes so predictive of mortality secondary to organ dysfunction caused by a dysregulated host response to infection?

 1. Altered mental status

Consider the following case seen recently at Janus General:

An 89 year old man is brought to the ED unresponsive to painful stimuli. His VS are: HR 72, BP 112/54, RR 24, SpO2 96% on 2L NC, FSBG 112. This is his third visit to the ED in three days. During each of these visits, neighbors called EMS, because the patient was found on the floor of his trailer. During the last two visits, he would have his eyes closed, moan occasionally, and would not respond to painful stimuli. After about 30-60 minutes he would wake up, curse out the staff, and demand to be discharged home. Because his labs, CXR, and CT head were all within normal limits, he was discharged home.

This visit is not different from the past two days, except you note that he seems to moan a bit more when your press on his abdomen, but is otherwise unresponsive to sternal rub or nasal trumpet. The patient has a history of dementia, and review of recent admissions indicate that he has a habit of becoming belligerent when admitted, cursing at staff and driving several nurses to tears with insensitive and aggressive comments.


Altered mental status has long been recognized as a feature of sepsis where it has gone by other monikers such as Sepsis Associated Encephalopathy and Sepsis Associated Delirium18. The concept of “delirium” may be particularly useful in understanding this phenomenon and our relationship to it in the ED.

The DSM-5 defines delirium as an acute change in consciousness not explained by a previous neurocognitive disorder, and thought to be due to a medical or toxicologic condition19.  As sepsis is a medical condition, the alterations in mentation, which often accompany it can be classified as a subset of a broader delirium syndrome.

The pathophysiology of the delirium syndrome is complex and involves neurotransmitter balances (the cholinergic and dopaminergic axes are strongly implicated), underlying dementia (as with any organ failure, the chronic brain failure of dementia is a strong risk factor for developing acute exacerbations of delirium), vasculopathic changes, and inflammatory changes20.  The latter two are very strongly implicated in sepsis associated delirium, and are the same pathophysiologic changes that cause inflammatory and microangiopathic organ dysfunction during sepsis21.  Thus, sepsis associated delirium is a powerful indicator of life-threatening organ dysfunction. While other organs require labwork (creatinine, troponin, liver enzymes) to evaluate for damage, the CNS is the one organ whose function is assessed at the bedside.

This seems like a no-brainer: infection is always at the top of our differential when it comes to altered mental status. However, it turns out that EPs are notoriously poor at picking up delirium when “altered mental status” is not listed as the chief complaint. Several studies place us at around 30% sensitivity in the recognition of delirium and many of these patients are discharged home with no specific plan with regard to their mental status22,23.  This, despite findings that delirium in the ED is likely an independent risk factor for mortality24. Why is it so difficult to recognize a clinical feature, which requires no additional invasive tests and has such a high predictive value for morbidity and mortality? Of course many of these patients are elderly, with dementia at baseline, and it is difficult to establish how truly different from baseline they are at the time of our evaluation. There are few things as frustrating as being on hold with a nursing home while a nurse who knows the patient’s baseline can be found. Moreover subtle changes in attention can require a full assessment such as a Confusion Assessment Method (CAM), which takes several minutes. And yet, this is perhaps the most powerful clinical lesson we can glean from the sepsis 3 derivation:

We cannot afford to miss altered mentation: a clinical state of organ dysfunction that can be assessed at the bedside.

Identifying mental status aberrations is often as simple as paying attention to this part of the clinical exam. In cases where we are not sure if a patient is altered, the following steps might be helpful in assessing altered mentation in the busy ED setting:

I) Obtain the patient’s baseline. It’s impossible to know if the patient is altered without knowing where the patient usually is. This often means contacting family and/or nursing home staff. If you do not have time on a busy shift to be on hold with the nursing home, it’s ok to delegate this step to a nurse or a tech. Do not rely on hospital admission records to establish the patient’s baseline: many of these patients are not at baseline when in the hospital.

II) Use a cognitive forcing strategy. Too often we see documented exams of intubated patients who are “AOx3”. Force yourself to think of the diagnosis of delirium by documenting the mental status appropriately in the exam. If the patient is AOx3, that’s ok, but if you didn’t ask them to tell you the date, don’t write AOx3.

III) Screening test. Han et al designed a Delirium Triage Screen (DTS) outlined in Figure 125 . This screen can be done in about 20 seconds and when compared to a 30 min psychiatrist evaluation, the sensitivity of the DTS was 98%. This quick screen performs just as well, regardless of whether it is done by a physician or a non-MD research assistant.

Screen Shot 2016-07-04 at 11.55.20 AMIV) Confirmation test. While the DTS is very sensitive, it is only ~55%  specific. In order to confirm delirium use a modified brief Confusion Assessment Method (bCAM), which has a specificity ~96% (Figure 2). This method is a bit more involved, but still takes about 1-2 minutes. Again if you don’t have time, ask the nurse/tech/med student.

Screen Shot 2016-07-04 at 11.54.59 AM

 Remember, these two tests are aids to help guide your clinical assessment. You don’t need to do this with every nursing home resident, but if you’re on the fence, it may well be worth the 2 minutes to validate your concerns. On the other hand, you might be surprised: a nursing home resident who hasn’t had to go to a meeting in twenty years might not know the date, but can still be sharp as a tack.

2. Tachypnea

This is the only carryover from SIRS, and yet it continues to get almost no clinical respect in the ED setting. Pathophysiologically, tachypnea is a respiratory regulatory response to increased metabolic stress and primary metabolic acidosis. The metabolic profile of septic patients is rather complex as it seems to be characterized by both an increased level of cellular respiration as well as mitochondrial dysfunction 26,27. The net balance of these two opposing forces appears to be an increase in the overall energy expenditure through both aerobic and anaerobic pathways26. These pathways result in net overproduction of CO2 and lactic acid, and subsequent respiratory compensation through tachypnea.

Increased energy expenditure in sepsis seems to be an early feature of the septic response and is mediated by endocrine mechanisms including increased corticosteroid and catecholamine production. As sepsis proceeds to more severe organ failure and shock, energy expenditure actually appears to decrease as a result of mitochondrial shutdown27,28. The lactate that we measure in the early risk stratification of septic patients is most likely not due to anaerobic glycolysis alone, but rather is a marker of overall increased metabolic demand and sympathetic overdrive29. Adding a lactate level did not seem to add significantly to the predictive value of qSOFA2,30. This may be because, pathophysiologically, tachypnea addresses the same metabolic processes as the lactate level.

Like altered mental status, and unlike lactate, tachypnea does not require a blood test. Instead, it requires careful measurement of the respiratory rate, an activity that takes an ENTIRE MINUTE, yet, once again gives us immediate information about the patient’s metabolic status with prognostic value comparable to the lactate level. This brings us to the second most powerful clinical lesson of Sepsis 3:

The respiratory rate is the most important vital sign when you think a patient might be sick, but can’t quite tell yet.

3. Hypotension 

This is perhaps the most straightforward clinical feature. All EPs are acutely aware of hypotension and will treat it aggressively. Even in Sepsis 3, persistent hypotension requiring vasopressors is still classified as septic shock with even worse prognostic value than the qSOFA score2,31. But what about transient hypotension? In trauma patients, we have known for some time that transient hypotension in the field is correlated with increased mortality32. More recently, transient hypotension has been correlated with increased mortality in all comers to the ED, and a small study in 2009 showed that this effect may be more pronounced in septic patients33,34.  qSOFA now solidifies sepsis as a disease state in which transient hypotension is correlated with adverse outcomes. Yet, when we admit the pneumonia patient with a presenting SBP of 80/40 who responded to IV fluids, we often hear from our medicine colleagues: “great he can go to the obs unit”. Or worse: “sounds like you fixed her, she can follow up with her PCP tomorrow”.

There are at least three pathophysiologic mechanisms which can contribute to hypotension in sepsis: distributive vasodilation, relative hypovolemia due to poor PO intake and potential insensible losses, and sepsis associated cardiomyopathy. When we talk about volume responsiveness, we are referring to the heart’s ability to improve cardiac output when we fill a relatively depleted and functionally expanded tank35. While volume responsiveness is reassuring (it means the heart can still keep up and is a defining difference between sepsis and the more deadly septic shock), it does little in and of itself to improve the process that got the tank empty and dilated enough to cause a drop in blood pressure. Moreover, the observation that a patient was volume responsive in the ED may result in downstream aggressive volume resuscitation, and delay in initiating vasopressor therapy, which can lead to worse patient outcomes. For more on the physiology and dangers of IV fluid therapy in sepsis see these two excellently researched and referenced emdocs posts36,37. Thus, transient hypotension is a marker of the life-threatening organ dysfunction of sepsis, and should be taken seriously even if the blood pressure improves with initial volume resuscitation.

 Case resolution:

The patient woke up and began to berate staff. While this appeared consistent with his recent presentation during admission for UTI, his daughter informed the ED team over the phone, that he is usually belligerent only when he has health problems, and he normally does not act this way. At this time his total bilirubin came back at 4.1, AST 156, ALT 163, alkaline phosphatase 377. Right upper quadrant ultrasound showed cholecystitis with biliary tree dilatation concerning for cholangitis. He continued to have waxing and waning mental status throughout his stay in the ED, tearing off his clothes, cursing at staff, demanding discharge, and then falling asleep. He was admitted to the ICU for IV antibiotics and ERCP in the morning.

Closing thoughts

For centuries, we have defined sepsis in terms of its clinical features. Sepsis 3 takes a radically different approach: it defines the physiologic essence of sepsis and works backwards to define the clinical features of sepsis. While the resultant clinical features of qSOFA seem intuitive, they are pathophysiologically complex: a complexity that is congruent with the definition of life-threatening organ dysfunction caused by infection.

Although this consortium of critical care physicians “unanimously considered SIRS to be unhelpful”, it is difficult to abandon SIRS altogether. SIRS will continue to help us suspect significant infection and it will be a component of CMS sepsis core measures for some time, however it does not identify life-threatening organ dysfunction very specifically. In order to understand how sick a patient captured by the broad net of SIRS might be, qSOFA provides us with a tool to judge the severity of illness in these patients38. While prospective validation is needed to assess its utility in guiding clinical decision making, this tool includes several key features, which are grounded in pathophysiology. These features are frequently overlooked in the ED setting, and it’s up to us to start taking these symptoms seriously.

Finally, Sepsis 3 and qSOFA have many weaknesses spelled out elsewhere39,40. However, this is a strong attempt to bring the understanding of sepsis into the modern era of medicine. An era that demands an understanding of the underlying mechanisms of disease. As our understanding becomes more sophisticated we should be able to improve on this definition. Despite its flaws, Sepsis 3 still provides a significant improvement over older definitions, and should not be ignored just because our current “usual care” is just as good as “aggressive care” in losing a quarter of the lives affected by this life-threatening condition.

Acknowledgements: I’d like to thank Jamie Santistevan (@jamie_rae_EMdoc) and Matt Anderson (@CCInquisitivist) for their amazing and detailed comments and suggestions for this post.

[1]Note: The qSOFA derivation actually used a GCS of 13 or less as the formal criteria for AMS2, however the GCS has known problems of interobserver concordance and qSOFA has been widely interpreted by the medical community and its authors to include altered mentation in general, or GCS<15.16,17


References / Further Reading:

  1. Singer, M. et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 315, 801–810 (2016).
  2. Seymour, C. W. et al. Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 315, 762–774 (2016).
  3. Mukherjee, S. The Emperor of All Maladies: A Biography of Cancer. (Simon and Schuster, 2010).
  4. Bone, R. C. et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 101, 1644–1655 (1992).
  5. Zolfaghari, P. S., Pinto, B. B., Dyson, A. & Singer, M. The metabolic phenotype of rodent sepsis: cause for concern? Intensive Care Med Exp 1, 25 (2013).
  6. Singer, M., De Santis, V., Vitale, D. & Jeffcoate, W. Multiorgan failure is an adaptive, endocrinemediated, metabolic response to overwhelming systemic inflammation. Lancet 364, 545–548 (2004).
  7. Aziz, M., Jacob, A., Yang, W.-L., Matsuda, A. & Wang, P. Current trends in inflammatory and immunomodulatory mediators in sepsis. J. Leukoc. Biol. 93, 329–342 (2013).
  8. Trzeciak, S. et al. Early microcirculatory perfusion derangements in patients with severe sepsis and septic shock: Relationship to hemodynamics, oxygen transport, and survival. Ann. Emerg. Med. 49, 88–98.e2 (2007).
  9. ProCESS Investigators et al. A randomized trial of protocolbased care for early septic shock. N. Engl. J. Med. 370, 1683–1693 (2014).
  10. ARISE Investigators et al. Goaldirected resuscitation for patients with early septic shock. N. Engl. J. Med. 371, 1496–1506 (2014).
  11. Mouncey, P. R. et al. Protocolised Management In Sepsis (ProMISe): a multicentre randomised controlled trial of the clinical effectiveness and costeffectiveness of early, goaldirected, protocolised resuscitation for emerging septic shock. Health Technol. Assess. 19, ixxv, 1–150 (2015).
  12. Kaukonen, K.-M. et al. Systemic Inflammatory Response Syndrome Criteria in Defining Severe Sepsis. N. Engl. J. Med. 372, 1629–1638 (2015).
  13. Rivers, E. et al. Early GoalDirected Therapy in the Treatment of Severe Sepsis and Septic Shock. N. Engl. J. Med. 345, 1368–1377 (2001).
  14. ProductsData BriefsNumber 62 – June 2011. Available at: http://www.cdc.gov/nchs/data/databriefs/db62.htm. (Accessed: 28th June 2016)
  15. Puymirat, E. et al. Association of changes in clinical characteristics and management with improvement in survival among patients with STelevation myocardial infarction. JAMA 308, 998–1006 (2012).
  16. Reith, F. C. M., Van den Brande, R., Synnot, A., Gruen, R. & Maas, A. I. R. The reliability of the Glasgow Coma Scale: a systematic review. Intensive Care Med. 42, 3–15 (2016).
  17. qSOFA :: quick Sepsis Related Organ Failure Assessment. Available at: http://qsofa.org/. (Accessed: 24th June 2016)
  18. Tsuruta, R. & Oda, Y. A clinical perspective of sepsisassociated delirium. J. Intensive Care Med. 4, 18 (2016).
  19. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-5®). (American Psychiatric Pub, 2013).
  20. Inouye, S. K., Westendorp, R. G. J. & Saczynski, J. S. Delirium in elderly people. Lancet 383, 911–922 (2014).
  21. Zampieri, F. G., Marcelo, P., Machado, F. S. & Azevedo, L. C. P. Sepsisassociated encephalopathy: not just delirium. Clinics 66, 1825–1831 (2011).
  22. Han, J. H. et al. Delirium in older emergency department patients: recognition, risk factors, and psychomotor subtypes. Acad. Emerg. Med. 16, 193–200 (2009).
  23. Elie, M. et al. Prevalence and detection of delirium in elderly emergency department patients. CMAJ 163, 977–981 (2000).
  24. Han, J. H. et al. Delirium in the Emergency Department: An Independent Predictor of Death Within 6 Months. Ann. Emerg. Med. 56, 244–252.e1 (2010).
  25. Han, J. H. et al. Diagnosing delirium in older emergency department patients: validity and reliability of the delirium triage screen and the brief confusion assessment method. Ann. Emerg. Med. 62, 457–465 (2013).
  26. Chioléro, R., René, C., JeanPierre, R. & Luc, T. Energy metabolism in sepsis and injury. Nutrition 13, 45–51 (1997).
  27. Brealey, D. et al. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 360, 219–223 (2002).
  28. Kreymann, G. et al. Oxygen consumption and resting metabolic rate in sepsis, sepsis syndrome, and septic shock. Crit. Care Med. 21, 1012–1019 (1993).
  29. Marik PE, B. R. Lactate clearance as a target of therapy in sepsis: A flawed paradigm. OA Critical Care 1, (2013).
  30. EMCrit, A., Weingart, S. & Crew, T. E. WeeCliff Deutschman with Additional Thoughts on Sepsis 3.0. EMCrit (2016). Available at: http://emcrit.org/wee/weecliffdeutschmanadditionalthoughtssepsis-3-0/. (Accessed: 17th June 2016)
  31. ShankarHari, M. et al. Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 315, 775–787 (2016).
  32. Chan, L., Lisa, C., Bartfield, J. M. & Reilly, K. M. The Significance of Outofhospital Hypotension in Blunt Trauma Patients. Acad. Emerg. Med. 4, 785–788 (1997).
  33. Marion, M. & Matthew, M. Emergency department hypotension predicts sudden unexpected inhospital mortality: A prospective cohort study. J. Emerg. Med. 32, 225–226 (2007).
  34. Marchick, M. R., Kline, J. A. & Jones, A. E. The significance of nonsustained hypotension in emergency department patients with sepsis. Intensive Care Med. 35, 1261–1264 (2009).
  35. Marik, P. & Bellomo, R. A rational approach to fluid therapy in sepsis. Br. J. Anaesth. 116, 339–349 (2016).
  36. Long, B. Resuscitation in Sepsis: How Much is Too Much? – emdocs. emdocs (2015). Available at: http://www.emdocs.net/howmuchistoomuch/. (Accessed: 17th June 2016)
  37. Long, A. The Dangers of OverResuscitation in Sepsisemdocs. emdocs (2016). Available at: http://www.emdocs.net/thedangersofoverresuscitationinsepsis/. (Accessed: 17th June 2016)
  38. Moskowitz, A., Andersen, L. W., Cocchi, M. & Donnino, M. W. The Misapplication of SeverityofIllness Scores Toward Clinical Decision Making. Am. J. Respir. Crit. Care Med. (2016). doi:10.1164/rccm.201605-1005ED
  39. EMCrit, A., Farkas, J. & Crew, T. E. PulmCritTop ten problems with the new sepsis definition. EMCrit (2016). Available at: http://emcrit.org/pulmcrit/problemssepsis-3-definition/. (Accessed: 15th June 2016)
  40. Morgenstern, J. Sepsis 3.0 – No thank you. First10EM (2016). Available at: https://first10em.com/2016/02/25/sepsis-3-0/. (Accessed: 15th June 2016)

The Dangers of Over-Resuscitation in Sepsis

Authors: Adrianna Long, MD (EM Senior Resident at SAUSHEC, USA) and Brit Long, MD (@long_brit – EM Chief Resident at SAUSHEC, USAF) // Edited by: Alex Koyfman, MD (@EMHighAK – EM Attending Physician, UTSW / Parkland Memorial Hospital) and Manpreet Singh, MD (@MPrizzleER – Clinical Instructor & Ultrasound/Med-Ed Fellow / Harbor-UCLA Medical Center)

Sepsis can be life-threatening and is a commonly managed condition in the emergency department. This area is heavily researched, with studies evaluating multiple aspects of sepsis including evaluation, management, antibiotic use, intravenous and vasopressor resuscitation, and monitoring.  One specific area of research has focused on fluid resuscitation in sepsis, specifically the type and amount of intravenous fluid. With all of the new sepsis updates, what is the literature on the harms of over-resuscitation?

The evidence continues to indicate that over-aggressive fluid resuscitation in septic shock is associated with increased morbidity and mortality. While the Sepsis Campaign Guidelines indicate that a patient with sepsis and hypotension or an elevated lactate (≥4mmol/L) should be treated with a 30ml/kg dose of crystalloid fluids, there is a lack of evidence to support this recommended fluid dose.1

In previous discussions, we have addressed that IV fluid choices affect patient outcomes in septic shock, and we have shown the evidence that invasive monitoring coupled with aggressive treatments are actually harming our patients.  Please refer to these prior posts for more information:

  1. How much fluid is too much?
  2. Does fluid choice matter?

The question we now face is what is the result of over-resuscitation?

The results of the ProCESS, ARISE, PROMISE trials indicate that EGDT as defined by Rivers et al may be more invasive than what is actually necessary to provide adequate resuscitation for patients in septic shock.2-5 These trials did not address the question of potential harm with excessive fluid administration to our patients during resuscitation. The majority of the patients in these trials received approximately 1.5L to 3L of fluids in the first 6 hours of treatment, with resuscitation approaching 4L after 6 hours.

Evidence is now indicating that intravenous fluids may be harmful in patients with septic shock, as excess fluid may cause edema in the lungs, kidneys, and brain amongst other organ systems.6 All organ systems are affected with resuscitation and excess fluid, which is shown in Figure 1.


Figure 1 – Over-resuscitation effects on organ systems from Malbrain ML, Marik PE, Witters I, Cordemans C, Kirkpatrick AW, Roberts DJ, Van Regenmortel N. Fluid overload, de-resuscitation, and outcomes in critically ill or injured patients: a systematic review with suggestions for clinical practice. Anaesthesiol Intensive Ther. 2014 Nov-Dec;46(5):361-80.

A more clearly defined endpoint of resuscitation in goal directed therapy should be defined in order to prevent fluid overload.7 To date, finding this endpoint has been problematic. Multiple studies have shown that a positive fluid balance is associated with increased mortality.8-12 One study found that a negative fluid balance in patients with septic shock was associated with increased survival.13 This study consisting of 36 patients admitted to the ICU found improved outcomes in patients with a negative fluid balance in the first 3 days of admission.

The FEAST trial explored the effects of fluid treatment in septic children and showed an increased 48-hour mortality in children who received more fluids, specifically bolus fluids. This was a randomized controlled trial conducted across several sites in Africa. The patients were ages 60 days to 12 years with severe infection, fever, and impaired perfusion. Patients were randomized to treatment arms of albumin bolus (20-40ml/kg), saline bolus (20-40ml/kg), or no fluid bolus.9 Patients receiving no bolus demonstrated a 3.3% survival benefit at 48 hours over the groups receiving bolus fluids.  Of note, this study contained a high percentage of patients with malaria, anemia (1/3 of patients had a hemoglobin < 5 g/dL) and respiratory distress (80% of patients).  Few patients were included with severe hypotension, and these patients were given bolus fluids.  The mechanism of excess mortality has been attributed to refractory septic shock or cardiogenic shock in patients treated with the higher doses of fluids.14,15

The SOAP study was an observational study of adults with sepsis that showed an association between a higher cumulative fluid balance in the first 72-hours of onset of sepsis and increased mortality.11 This study of 3,147 patients found predictors of poor prognosis included age, septic shock, cancer, and positive fluid balance.

One prospective observational study of patients with septic shock questioned whether the amount of initial IV fluids and cumulative IV fluids over the initial 72-hour period was associated with a higher mortality. This study included 364 patients and showed that initial fluid volume and total cumulative 72-hour fluid volume were not associated with increased mortality, which at first glance contrasts with the evidence published from the other studies listed above.16 At three days, patients with continued shock receiving more fluids demonstrated lower mortality. However, at 72 hours, patients on average had received 7.5L, vastly decreased from other studies approaching 20L.  These other studies demonstrated worse outcome with this fluid amount compared to patients receiving less.

This illustrates the need for randomized control trials to identify the appropriate amount of fluid that should be administered to patients with septic shock. These prior trials included patients of different ages, comorbidities, illness severity, and most importantly, differing definitions of the amount of fluid.

What does excess fluid do?

Several explanations exist for why excess fluid causes harm. These include release of natriuretic peptides in the setting of hypervolemia resulting in vasodilation, disruption of the glycocalyx, loss of physiologic compensation (sympathetically mediated) leading to cardiovascular collapse, fluid overload resulting in cardiotoxicity, increased interstitial edema, impaired gas exchange, and acid-base and electrolyte disturbances.17-19 As detailed in Figure 1, all organ systems may be affected by excess fluid.

Wait, the glycocalyx?

The glycocalyx is a thin layer containing several types of protein.  The components include proteoglycans, glycoproteins, albumin, and glycosaminoglycans which form a tight network of negatively charged ions. This layer is thought to maintain vascular permeability, mediate nitric oxide production, retain vascular protective enzymes, and modulate inflammatory markers such as cytokines.  Disruption of this layer may further edema, inflammation, hypercoagulability, platelet aggregation, and sepsis syndromes including capillary leak.  Studies are underway evaluating risk factors contributing to glycocalyx damage, other mechanisms of damage, and treatments aimed towards the glycocalyx.20-22

So what should the emergency provider do?

First, recognize that resuscitation goals include obtaining adequate perfusion pressure and microcirculatory flow, while limiting extra tissue edema.  These measures can be completed using adequate fluid loading, as the patient still requires fluids for preload. Providing three to four liters of crystalloid will likely not harm the patient, but will improve perfusion pressure and microcirculatory flow. Second, infusing peripheral vasopressors, specifically norepinephrine, for patients with poor perfusion following this fluid load is recommended to provide peripheral squeeze, further increasing preload.

Measure the response through multiple measures, rather than relying on just one. Closely evaluate urine output, capillary refill, mental status, and IVC variation on bedside US in combination. Unfortunately microcirculatory endpoints are currently not feasible in the ED, but many are undergoing validation for use in the critical care setting.


The dosing of intravenous fluids in septic patients should be taken as seriously as any potentially lethal medication. It is essential for physicians to give appropriate doses of intravenous fluids while avoiding fluid overload. Patients’ fluid status must be re-evaluated after administration of fluids. Further research must be conducted to identify the appropriate dosing of intravenous fluid bolus at onset of sepsis and any patient subsets that require different treatment.

References/Further Reading

  1. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580-637.
  2. Pro CI, Yealy DM, Kellum JA, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;370(18):1683-1693.
  3. Investigators A, Group ACT, Peake SL, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014;371(16):1496-1506.
  4. Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015;372(14):1301-1311.
  5. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368-1377.
  6. Durairaj L, Schmidt GA. Fluid therapy in resuscitated sepsis: less is more. Chest. 2008;133(1):252-263.
  7. Kozek-Langenecker SA. Intravenous fluids: should we go with the flow? Crit Care. 2015;19 Suppl 3:S2.
  8. Sadaka F, Juarez M, Naydenov S, O’Brien J. Fluid resuscitation in septic shock: the effect of increasing fluid balance on mortality. J Intensive Care Med. 2014;29(4):213-217.
  9. Maitland K, Kiguli S, Opoka RO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med. 2011;364(26):2483-2495.
  10. Payen D, de Pont AC, Sakr Y, et al. A positive fluid balance is associated with a worse outcome in patients with acute renal failure. Crit Care. 2008;12(3):R74.
  11. Vincent JL, Sakr Y, Sprung CL, et al. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med. 2006;34(2):344-353.
  12. Boyd JH, Forbes J, Nakada TA, Walley KR, Russell JA. Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality. Crit Care Med. 2011;39(2):259-265.
  13. Alsous F, Khamiees M, DeGirolamo A, Amoateng-Adjepong Y, Manthous CA. Negative fluid balance predicts survival in patients with septic shock: a retrospective pilot study. Chest. 2000;117(6):1749-1754.
  14. Maitland K, George EC, Evans JA, et al. Exploring mechanisms of excess mortality with early fluid resuscitation: insights from the FEAST trial. BMC Med. 2013;11:68.
  15. Myburgh J, Finfer S. Causes of death after fluid bolus resuscitation: new insights from FEAST. BMC Med. 2013;11:67.
  16. Smith SH, Perner A. Higher vs. lower fluid volume for septic shock: clinical characteristics and outcome in unselected patients in a prospective, multicenter cohort. Crit Care. 2012;16(3):R76.
  17. Glassford NJ, Eastwood GM, Bellomo R. Physiological changes after fluid bolus therapy in sepsis: a systematic review of contemporary data. Critical care. 18(6):696. 2014.
  18. Hilton AK, Bellomo R. A critique of fluid bolus resuscitation in severe sepsis. Crit Care. 2012;16:(1)302.
  19. Malbrain ML, Marik PE, Witters I, Cordemans C, Kirkpatrick AW, Roberts DJ, Van Regenmortel N. Fluid overload, de-resuscitation, and outcomes in critically ill or injured patients: a systematic review with suggestions for clinical practice. Anaesthesiol Intensive Ther. 2014 Nov-Dec;46(5):361-80.
  20. Chappell D, Westphal M, Jacob M. The impact of the glycocalyx on microcirculatory oxygen distribution in critical illness. Curr Opin Anaesthesiol. 2009 Apr;22(2):155-62.
  21. Burke-Gaffney A, Evans TW. Lest we forget the endothelial glycocalyx in sepsis. Crit Care. 2012 Dec 12;16(2):121.
  22. Becker BF, Chappell D, Bruegger D, Annecke T, Jacob M. Therapeutic strategies targeting the endothelial glycocalyx: acute deficits, but great potential. Cardiovasc Res. 2010 Jul 15;87(2):300-10.

Blood cultures: when do they make a meaningful impact on clinical care?

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


1) A 46-year-old male that reports he is otherwise healthy except for a childhood history of asthma presents to your emergency department with a 3-day history of fever, cough productive of green sputum, and shortness of breath. He has a temperature of 101.2 degrees Fahrenheit, he is tachycardic to 122 beats per minute, his respiratory rate is 22, he is hypoxic to 89% on room air, and he has a normal blood pressure. On physical exam, he appears mildly ill and you hear some scattered wheezes and has decreased breath sounds in his right middle and lower lobes. Your workup confirms your suspicion of pneumonia, and he has had mild improvement (wheezing, fever, and heart rate improve, but he remains tachypneic and hypoxic) with your treatments. You decide to admit for IV antibiotics. The inpatient team asks for blood cultures, and you wonder if this will benefit your patient.

2) A 68-year-old Hispanic female presents to your emergency department with fatigue, fever, and rash. She reports that she does not take any medications. Her vital signs are normal. She looks well. You see the following rash:

Screen Shot 2016-04-22 at 4.32.42 AM

You diagnose her with bacterial endocarditis and admit her for IV antibiotics. You ordered two blood cultures in the emergency department to be drawn at separate venipuncture sites and wonder if you should have ordered a third.



Blood cultures are commonly ordered in the emergency department for patients with suspected infection. They are generally considered to be the most sensitive method for detection of bacteremia or fungemia1 and are generally thought to be useful in certain diagnoses and critically ill patients; however, it appears as though rising trends in obtaining blood cultures over the past decade in low-risk patients have been tied to core measures and payments (introduced by the Joint Commission on Accreditation of healthcare Organizations and Centers for Medicaid and Medicare Services).2 As a result, their utility has been a focus of controversy prompting ample research in recent years all conveying the same information: blood cultures ordered from the emergency department rarely alter patient management and can at times cause harm to patients. Not only is the harm financial, false-positive results can lead to inappropriate antimicrobial use and longer hospital stays.3


Yield of Blood Cultures

The yield of blood cultures has been evaluated in multiple studies in several different patient populations. A study published in 2006 showed a useful culture rate of 2.8% (6/218) – meaning clinical management was influenced by culture result – and suggested that blood cultures should be eliminated in immunocompetent patients with common illnesses such as urinary tract infection, community acquire pneumonia, and cellulitis.4 Another study published in 2007 showed that of 2,210 blood cultures, only 132 (6%) yielded growth, and 4 (0.18%) resulted in altered patient management.5

 For patients with pneumonia, a NNT approaching 150 has been found in regards to blood cultures affecting patient care (such as cultures causing modification of the antibiotic regimen). This is based on 0.18% and 1.6% of blood cultures actually affecting patient management.6 Another study from 2007 found a true positive rate of 3.4% and false positive rate of 7.8%.7 Of these true positive cultures, 3 out of 23 patients had management changed based on cultures. These authors recommended eliminating use of blood cultures for community-acquired pneumonia.7 In 2005, another article was published also supporting decreased use of blood cultures and concluded “blood cultures rarely altered therapy for patients presenting to the ED with pneumonia. More discriminatory blood culture use may potentially reduce resource utilization.”8

Cellulitis is a common condition and is broken into simple and complicated, which is defined by an immunocompromised state such as HIV/AIDS, chemotherapy, organ transplantation, diabetes, and vascular insufficiency. Simple cellulitis is defined by absence of these conditions. Mills et al. examined five other studies, finding blood cultures did not alter treatment in immunocompetent patients with cellulitis.9 Paolo et al. examined the yield of blood cultures and found contaminated cultures in 4% of complicated and 3% of uncomplicated cellulitis cases. A change in management occurred in 6 of 314 cases in complicated cellulitis and in 4 of 325 uncomplicated cases. True positive cultures occurred more commonly in patients with fever and diabetes.10


Are there any factors associated with true positive cultures?

Coburn et al. in JAMA 2012 conducted a meta-analysis investigating true positive blood cultures in a population of immunocompetent adults.11 Predictors of true positive cultures included shaking chills, hypotension, vasopressor use, neutrophil to lymphocyte ratio > 10, and presence of SIRS. However, risk factors including subjective fever, tachycardia alone, elevated WBC, and documented fever were not found to be sensitive. Blood cultures were recommended in patients with pyelonephritis, severe sepsis, septic shock, and meningitis. Cultures in pneumonia and cellulitis were not recommended.11

A clinical predication rule has been created and validated for use in predicting true blood cultures.12 A prospective analysis in 2008 evaluated 3,370 patients. The study found several criteria increasing the predictive value of blood cultures. The major criteria includes suspected endocarditis, temperature > 103F, and indwelling vascular catheter. Minor criteria include temperature > 101F, age > 65 years, chills, vomiting, SBP < 90 mm Hg, WBC > 18,000, band count > 5%, platelets < 150,000, and creatinine > 2 mg/dL. The negative predictive value for true positive blood culture was 99.4% in the derivation group and 99.1% in the validation group.12

A second study in 2011 evaluated multiple predictors associated with bacteremia. This study conducted in an urban ED found a 90.9% probability of a negative blood culture if the following were negative: no chemotherapy within past 6 moths, heart rate < 100, and normal or elevated electrolytes to predict a negative blood culture.13 This rule has not been validated.


When (and how) to order blood cultures in the ER

UpToDate suggests that diagnoses in which blood cultures are considered important include sepsis, meningitis, osteomyelitis, septic arthritis, endocarditis, peritonitis, pneumonia, and fever of unknown origin. 1 In general, patients who are acutely ill or have high likelihood of continuous bacteremia should have blood cultures drawn in the emergency department.11

At least two sets of blood cultures should be drawn prior to initiation of antimicrobial therapy. A single blood culture lacks sensitivity as well as precludes the ability to distinguish contaminants from true bacteremia.17 It is reasonable to obtain four blood cultures when the probability of bacteremia is high and the anticipated pathogen is likely to be a common contaminant (ex: infected internal hardware is suspected).1

An article published in 2008 demonstrated that fever at the time of blood culture collection is neither sensitive nor specific for the presence of bacteremia.18 Blood cultures therefore do not need to be rapidly drawn when a patient is noted to be febrile.

Antiseptic technique is essential. The skin should be cleaned first with an alcohol swab followed by chlorhexidine from two separate venipuncture sites.14 An IV catheter line at the time of IV insertion should not be used.15 Volume does matter when obtaining a culture, as there is a 3% increase in positive culture per milliliter blood obtained. At least 7 ml per bottle are recommended.16



1) Blood cultures are still recommended in this patient because he has evidence of sepsis on arrival to the emergency department.

2) The Duke diagnostic criteria are widely used to diagnose endocarditis and require at least 2 positive blood cultures either persistently positive for the same organism from cultures drawn more than 12 hours apart OR 3 or more separate blood cultures drawn at least 1 hour apart.11, 19



  • In general, patients who are acutely ill or have high likelihood of continuous bacteremia should have blood cultures drawn in the emergency department.
  • Blood cultures should not be taken from routinely stable, immunocompetent patients with common or typical infections such as cellulitis, orchitis, and community acquired pneumonia.12
  • Blood cultures should be obtained prior to initiation of antibiotic therapy to maximize possibility of being useful clinically
  • When you have high suspicion for endocarditis, you may order 3 blood cultures from different venipuncture sites in the ED, each drawn 1 hour apart, OR 2 blood cultures from different venipuncture sites with a third to be ordered >12 hours later by your inpatient team.11,19
  • Fever at the time of blood culture collection is neither sensitive nor specific for the presence of bacteremia.10
  • An IV catheter line at the time of IV insertion should not be used.8


References / Further Reading

  1. Doern, Gary. Blood cultures for the detection of bacteremia. UpToDate. Accessed April 1, 2016. http://www.uptodate.com/contents/blood-cultures-for-the-detection-of-bacteremia/.
  2. Makam AN, Auerbach AD, Steinman MA. Blood Culture Use in the Emergency Department in Patients Hospitalized for Community-Acquired Pneumonia. JAMA Intern Med. 2014;174(5):803-806. doi:10.1001/jamainternmed.2013.13808.
  3. Mandell  LA, Wunderink  RG, Anzueto  A,  et al; Infectious Diseases Society of America; American Thoracic Society.  Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(suppl 2):S27-S72.
  4. Mountain D, Bailey PM, O’Brien D, Jelinek GA. Blood cultures ordered in the adult emergency department are rarely useful. Eur J Emerg Med. 2006;13(2):76–9. doi:10.1097/01.mej.0000188231.45109.ec.
  5. Howie N, Gerstenmaier JF, Munro PT. Do peripheral blood cultures taken in the emergency department influence clinical management? Emerg Med J. 2007;24(3):213–4. doi: 10.1136/emj.2006.039875.
  6. Kelly AM. Clinical impact of blood cultures taken in the emergency department. J Accid Emerg Med. 1998 Jul;15(4):254-6.
  7. Benenson RS, Kepner AM, Pyle DN 2nd, Cavanaugh S. Selective use of blood cultures in emergency department pneumonia patients. J Emerg Med. 2007 Jul;33(1):1-8.
  8. Kennedy, Maura et al. Do Emergency Department Blood Cultures Change Practice in Patients With Pneumonia? Annals of Emergency Medicine. 2005. Volume 46, Issue 5, 393 – 400.
  9. Mills AM, Chen EH. Are blood cultures necessary in adults with cellulitis? Ann Emerg Med. 2005 May;45(5):548-9.
  10. Paolo WF, Poreda AR, Grant W, Scordino D, Wojcik S. J Emerg Med. 2013 Aug;45(2):163-7.
  11. Coburn B, Morris AM, Tomlinson G, Detsky AS. Does this adult patient with suspected bacteremia require blood cultures? JAMA 2012; 308:502.
  12. Shapiro NI, Wolfe RE, Wright SB, Moore R, Bates DW. Who needs a blood culture? A prospectively derived and validated prediction rule. J Emerg Med. 2008;35(3):255–64. doi: 10.1016/j.jemermed.2008.04.001
  13. Roque PJ, Oliver B, Anderson L, et al. Blood culture prediction rule in an urban emergency department. Ann Emerg Med. 2011;58(4):S290.
  14. Little JR, Murray PR, Traynor PS, Spitznagel E. A randomized trial of povidone-iodine compared with iodine tincture for venipuncture site disinfection: effects on rates of blood culture contamination. Am J Med 1999; 107:119.
  15. Norberg A, Christopher NC, Ramundo ML, et al. Contamination rates of blood cultures obtained by dedicated phlebotomy vs intravenous catheter. JAMA 2003; 289:726.
  16. Mermel LA, Maki DG. Detection of bacteremia in adults: consequences of culturing an inadequate volume of blood. Ann Intern Med. 1993 Aug 15;119(4):270-2.
  17. Mirrett S, Weinstein MP, Reimer LG, et al. Relevance of the number of positive bottles in determining clinical significance of coagulase-negative staphylococci in blood cultures. J Clin Microbiol 2001; 39:3279.
  18. Riedel S, Bourbeau P, Swartz B, et al. Timing of specimen collection for blood cultures from febrile patients with bacteremia. J Clin Microbiol 2008; 46:1381.
  19. Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Duke Endocarditis Service. Am J Med. 1994 Mar. 96(3):200-9.


Septic shock: Who should be treated with early pressors?

Author: Adrianna Long, MD (Senior EM Resident at SAUSHEC, US Army) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Brit Long, MD (EM Chief Resident at SAUSHEC, USAF)


A 74 year-old female is brought in by ambulance from a rehabilitation facility with a chief complaint of confusion and vomiting for the past day. Her husband reports that she is normally alert and oriented but has been more confused over the past day. She is in rehabilitation after a fall three weeks ago when she sustained a fracture to her left hip.

Her initial vital signs include temperature of 100.5°F, pulse of 114, blood pressure 76/34 mmHg (mean arterial pressure 48 mmHg), respiratory rate of 22, and saturating 98% on room air. Exam reveals suprapubic tenderness and right sided costovertebral angle tenderness. Laboratory values reveal leukocytosis with 18,200 WBCs, BUN/sCr of 32/1.6 and all other values within normal limits. The patient has frank pyuria with urinalysis markedly positive for nitrites, WBCs, RBCs, and bacteria.

You recognize that your patient is in septic shock due to a urinary tract infection, so you order an IV fluid bolus and initiate antibiotic therapy. With recognition that this patient already has poor renal function and a decreased MAP, when should you consider starting a vasopressor?


The true goal seems to be targeting the MAP

The current recommendations from the Surviving Sepsis Campaign are to maintain a MAP ≥ 65 mmHg (Level 1C).1 However, the current evidence does not indicate subsets of patients that may need to be treated differently (i.e. patients with chronic hypertension, patients with history of renal disease, etc.). Here are the studies available regarding MAP and septic shock:

  • A retrospective study of 274 septic shock patients indicated that one or more episodes of MAP decreased less than 60 mmHg was associated with an increased risk of death by 2.96. Further, one or more episode of MAP decreased less than 75 mmHg increased the need for renal replacement therapy.2
  • A prospective study on 10 patients with septic shock aimed to titrate norepinephrine to target a MAP of 65, 75 and 85 mmHg. There was no significant difference found in the serum lactate, UOP, skin capillary blood flow, or red blood cell velocity as the MAP increased higher than 65mmHg.3
  • Another prospective study of 28 patients with septic shock treated half of the patients with norepinephrine to target a MAP of 65 mmHg and the other half with norepinephrine to target a MAP of 85 mmHg, showing no significant difference in urine output or creatinine clearance.4
  • In 2014, a large prospective study of 776 septic shock patients targeted MAPs of 65 to 70 mmHg or 80 to 85 mmHg and found no significant difference in 28- or 90-day mortality. This study did indicate that the patients with targeted MAPs of 80 to 85 mmHg were found to have increased risk of new onset atrial fibrillation, were on vasopressors longer, and required higher doses of norepinephrine.5
  • A retrospective study of 111 patients with septic shock found a strong correlation with mortality and duration of time spent below MAP 65 mmHg.6


Should we “fill the tank” first? Or when should we initiate vasopressor therapy?

The current guidelines require that patients be treated with 30cc/kg of IV fluid before being treated with vasoactive medications, but not all patients are responsive to IV fluids and studies indicate the vitality in starting norepinephrine early.

  • A retrospective study of 2,849 septic shock patients found that mortality was lowest when vasoactive agents were begun 1-6 hours after onset.7
  • A retrospective study of 213 patients found that every hour of delayed treatment with norepinephrine was associated with 5.3% increased mortality. They also found that when norepinephrine was started within 2 hours of diagnosis of septic shock, patients were more likely to have increased MAPs, decreased serial serum lactates, and shorter duration of norepinephrine.8
  • A retrospective study in 2004 of 142 patients showed that norepinephrine started early may have some benefit.9

The basic theory behind giving IV fluids prior to vasopressors is that septic patients are often intravascularly volume depleted due to third-space losses, and there is concern that arterial constriction alone could impair perfusion. However, not all patients in septic shock are volume-depleted causing decreased perfusion. There are several factors that may lead to hypoperfusion in a septic patient to include venodilation, arterial dilation, cardiomyopathy, cor pulmonale, renal failure, in addition to dehydration/intravascular depletion. When initiating IV fluids, we are only treating one of these issues. Further, excess volume status is correlated with renal failure and increased mortality in shock patients.10 It is much more reasonable to address the patient’s physiological state especially assessing volume status prior to blindly treating with IV fluids and delaying treatment with vasopressors.


What is the problem in waiting to start vasopressors?

Renal and pulmonary injuries may be the result of delayed initiation of vasopressors, affecting morbidity and mortality. The kidneys are prone to experiencing hypoperfusion as a result of shock status.11 Renal injury is associated with septic shock and hypotension, which may be reduced with the use of norepinephrine and decrease the risk of renal failure.5,10 Also, patients who are resuscitated for septic shock often have resulting pulmonary edema, which may be the result of volume overload or the result of cytokine release with renal injury.12 Patients who suffer renal injury often have long-term sequelae as a result, including increased risk of chronic renal failure and end stage renal disease.13 The RIFLE classification for renal injury shows a clear increase in mortality with worsened renal failure.14


Can vasoactive drugs be given peripherally?

One barrier to starting vasoactive agents early is the concern for a need to have a central line for infusion of these medications. This is another reason that many providers may still prefer the fluid-first approach.

However, it has been shown that norepinephrine may be given peripherally for a limited period of time while stabilizing the patient. There is risk for extravasation, which can be minimized with appropriate protocols, use of a well-functioning proximal intravenous catheter, and a goal to obtain central venous access as quickly as possible. Intraosseous infusion of norepinephrine is also temporarily permissible with verification that the line has been placed appropriately.15

One benefit to starting vasoactive drugs peripherally is that they can be infused simultaneously with intravenous fluids to target an adequate MAP. If a patient is fluid responsive, the norepinephrine may be titrated down and potentially discontinued before central access is obtained.


More evidence is needed to make appropriate recommendations regarding the initiation of early vasopressor therapy and who would benefit.

In a patient who presents with MAPs less than 65 mmHg, it is unknown how quickly those patients should reach that target MAP to avoid renal injury. The data indicates that hypotension should be avoided to prevent hypoperfusion of the kidneys, but are there specific patients that are at higher risk for renal injury? Is there a rate at which we should be increasing MAP or a specific amount of time that the blood pressure must be corrected? The data and recommendations only indicate that we should urgently address a septic shock patient with a MAP less than 65 mmHg.

The studies that have been published regarding delay to vasopressor initiation and outcome are all retrospective and correlate time of onset with outcomes, but are all likely to have confounding variables. Subramanian et al found a trend toward increased mortality with initiation of early vasopressors, which was not significant.16 Beck et al found a correlation between early vasopressors and improved mortality.17 Waechter et al found that it may be detrimental to start vasoactive agents within the first hour after shock onset, but vasopressors started within 1-6 hours had the lowest mortality rates.7 Bai et al found an association between early norepinephrine and survival.8 Interestingly, Beck and Waechter used the same database of patients with the same research group and had differing results. Only one of these studies used norepinephrine only, while the others used a variety of vasoactive medications. This makes some question the clinical significance of these studies with regards to Emergency Department treatment because we are primarily concerned about the early use of norepinephrine.

Currently, the CENSER study is being performed, which is the first prospective randomized controlled trial to evaluate the use of early norepinephrine in septic shock with a control group of 5% dextrose water intravenous infusion. This study is not expected to finish until August 2017.18



  • Vital signs are vital! Drops in blood pressure lead to increased mortality, and blood pressure may not respond simply to fluids.
  • Vasopressors should be started early in septic shock patients, but there is controversy as to how early and what subsets of patients would benefit most due to a lack of evidence currently available.
  • Delaying norepinephrine in a septic shock patient with a low MAP while first attempting to fluid resuscitate may increase morbidity and mortality, but further studies must be conducted to confirm this.
  • A drop in MAP causes renal hypoperfusion and renal injury contributing to further complications and possibly worsening shock.
  • It is essential to assess your patient’s fluid status and weigh the risk of renal injury when considering initiation of vasopressor therapy.


 References / Further Reading

  1. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580-637.
  2. Dunser MW, Takala J, Ulmer H, et al. Arterial blood pressure during early sepsis and outcome. Intensive Care Med. 2009;35(7):1225-1233.
  3. LeDoux D, Astiz ME, Carpati CM, Rackow EC. Effects of perfusion pressure on tissue perfusion in septic shock. Crit Care Med. 2000;28(8):2729-2732.
  4. Bourgoin A, Leone M, Delmas A, Garnier F, Albanese J, Martin C. Increasing mean arterial pressure in patients with septic shock: effects on oxygen variables and renal function. Crit Care Med. 2005;33(4):780-786.
  5. Asfar P, Meziani F, Hamel JF, et al. High versus low blood-pressure target in patients with septic shock. N Engl J Med. 2014;370(17):1583-1593.
  6. Varpula M, Tallgren M, Saukkonen K, Voipio-Pulkki LM, Pettila V. Hemodynamic variables related to outcome in septic shock. Intensive Care Med. 2005;31(8):1066-1071.
  7. Waechter J, Kumar A, Lapinsky SE, et al. Interaction between fluids and vasoactive agents on mortality in septic shock: a multicenter, observational study. Crit Care Med. 2014;42(10):2158-2168.
  8. Bai X, Yu W, Ji W, et al. Early versus delayed administration of norepinephrine in patients with septic shock. Crit Care. 2014;18(5):532.
  9. Morimatsu H, Singh K, Uchino S, Bellomo R, Hart G. Early and exclusive use of norepinephrine in septic shock. Resuscitation. 2004;62(2):249-254.
  10. Bellomo R, Wan L, May C. Vasoactive drugs and acute kidney injury. Crit Care Med. 2008;36(4 Suppl):S179-186.
  11. Lehman LW, Saeed M, Moody G, Mark R. Hypotension as a Risk Factor for Acute Kidney Injury in ICU Patients. Comput Cardiol (2010). 2010;37:1095-1098.
  12. Basu RK, Wheeler D. Effects of ischemic acute kidney injury on lung water balance: nephrogenic pulmonary edema? Pulm Med. 2011;2011:414253.
  13. Chawla LS, Kimmel PL. Acute kidney injury and chronic kidney disease: an integrated clinical syndrome. Kidney Int. 2012;82(5):516-524.
  14. Ricci Z, Cruz D, Ronco C. The RIFLE criteria and mortality in acute kidney injury: A systematic review. Kidney Int. 2008;73(5):538-546.
  15. Weingart S. Podcast 107 – Peripheral Vasopressor Infusions and Extravasation. Emcrit. 2013.http://emcrit.org/podcasts/peripheral-vasopressors-extravasation/
  16. Subramanian S, Yilmaz M, Rehman A, Hubmayr RD, Afessa B, Gajic O. Liberal vs. conservative vasopressor use to maintain mean arterial blood pressure during resuscitation of septic shock: an observational study. Intensive Care Med. 2008;34(1):157-162.
  17. Beck V, Chateau D, Bryson GL, et al. Timing of vasopressor initiation and mortality in septic shock: a cohort study. Crit Care. 2014;18(3):R97.
  18. Permpikul C. Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER). https://clinicaltrials.gov/ct2/show/study/NCT01945983#contacts.