You are asked to review a 47-year-old male in the Emergency Department with hypotension that has not responded to rapid infusion of 2 litres intravenous crystalloid. On examination his temperature is 40°C, he is warm peripherally with a respiratory rate of 24 breaths per minute, an arterial oxygen saturation of 98% on room air, a heart rate of 140 beats per minute, and a blood pressure of 80/40 mmHg with an arterial lactate concentration of 6 mmol/L.
Describe the steps for the initial haemodynamic management of this patient, including a brief discussion of the underlying evidence for each step.

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College Answer

Step 1

Initial fluid resuscitation

  • Give more volume 1000 – 2000 ml or 20 ml/kg up to minimum 30 ml/kg in total
  • Evidence:
    • Surviving sepsis guidelines recommendation
    • Rivers et al EGDT study although ProCESS (NEJM May 2014) showed no outcome benefit from protocolised care in septic shock
    • Usual care in ICU based upon physiological reasoning with relative volume depletion due to vasodilation in sepsis
  • Avoid starch
  • Evidence:
    • 6S and CHEST studies
  • Probably just use crystalloid (0.9% NaCl or Hartmanns)
  • Evidence:
    • SAFE – no difference with albumin or crystalloid
  • Consider 4% albumin
  • Evidence:
    • SSG recommendation for refractory hypotension in sepsis
  • Blood transfusion if bleeding/low haemoglobin
  • Evidence:
    • Rivers EGDT recommend target haematocrit 30%
    • SSG aim for haemoglobin 70-90 g/L
    • TRICC and Patient Blood Management Guidelines recommend transfusion trigger at Hb <70 g/L

Step 2

Assess response and need for more fluid

  • Monitoring:
  • Clinical reassessment after fluid bolus; HR, BP, peripheral perfusion, urine output
    Lactate clearance
  • Evidence:
    • SSG recommends ongoing fluid resuscitation according to response using dynamic or static variables
    • Jones et al JAMA 2010 lactate clearance had no additional benefit in addition to ScvO2 for guiding resuscitation in sepsis
  • Arterial line and target MAP >? 60 mmHg ? 65 mmHg
  • Evidence:
    • Asfar et al NEJM Mar 2014 no outcome benefit in 65-75 mmHg MAP v 80-85 mmHg MAP except higher MAP with pre-existing hypertension had less renal replacement therapy but more atrial fib
  • CVC and target CVP >8-12 mmHg
  • Evidence:
    • Convention but no good evidence (Marik meta-analyses 2008 and 2013)
    • EGDT/SSG recommends CVP >8-12 but very controversial regarding use of static pressure measurements to determine fluid responsiveness.
  • Use of dynamic measure of fluid responsiveness
    E.g. Passive leg raising, PPV, echo
  • Evidence:
    • Many small physiological studies but no large RCTs with patient oriented outcomes to guide practice
  • ScvO2 or SvO2
  • Evidence:
    • ScvO2 in SSG / supported by RCT evidence. SvO2 requires PAC and not commonly used in this particular scenario
  • PAC and PAOP
  • Evidence:
    • PAC-Man study and Connors SUPPORT study JAMA 1996 - PA catheters do not improve / may worsen outcome

Step 3
Commence vasopressors

  • If hypotensive and not responsive to further filling will need vasopressor, probably noradrenaline
    as first line, but adrenaline probably acceptable
  • Evidence:
    • SSG/ EGDT study
    • CAT study showed no real difference in outcomes with adrenaline v noradrenaline

Step 4
Consider adequacy of cardiac output

  • Consider Echo, ScvO2, SvO2, PiCCO or other measure of cardiac output
  • If low consider inotrope as well as vasopressor - either dobutamine or adrenaline
  • Evidence:
    • Low cardiac output (absolute or relative) is common in sepsis, inotropic support recommended in SSG and in the EGDT resuscitation algorithm
    • PAC-Man and SUPPORT study

Step 5
Refractory hypotension

  • Consider vasopressin 0.03 u/min
  • Evidence:
    • VASST study NEJM 2008 did not demonstrate an improvement in outcome with additional
      vasopressin in patients receiving low dose noradrenaline.
    • Not recommended as first line vasopressor
  • If hypotensive following fluid resuscitation and vasopressors, consider hydrocortisone 200mg daily.
  • Evidence:
    • Very mixed evidence to use of steroids (Annane JAMA 2002 - Pro) and CORTICUS NEJM 2008 - No support for hydrocortisone). Erring to no benefit. Awaiting results of ADRENAL ANZICS CTG study

Additional Examiners’ Comments: Candidates omitted resuscitation end-points and assessment of fluid responsiveness. Some candidates did not describe the management of septic shock

Discussion

This college answer was used as the foundation of an evidence-based summary (Resuscitation of the Septic Shock patient) which can be found in the Required Reading section. One can do little to improve on the model answer, as it is succinct yet comprehensive. The summary merely expands upon it with references.

In brief:

Step 1: Fluid resuscitation and antibiotics

Step 2: Assess need for further fluid resuscitation

The college examiners made much of the candidates' failure to suggest resuscitation endpoints and fluid responsiveness assessment methods.

End-point of resuscitation:

Step 3: Vasopressors

  • Noradrenaline is the first choice (SSG)
  • Adrenaline is the second choice (CATSSSG)

Step 4: Assess adequacy of cardiac output

Inotrope options:

Step 5: Refractory hypotension

Step 6: Innovative therapies

References

Dellinger, R. Phillip, et al. "Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012." Intensive care medicine 39.2 (2013): 165-228.

Weinstein, Melvin P., et al. "The clinical significance of positive blood cultures: a comprehensive analysis of 500 episodes of bacteremia and fungemia in adults. I. Laboratory and epidemiologic observations." Review of infectious diseases 5.1 (1983): 35-53.

Kumar A, Roberts D, Wood KE et al "Duration of hypotension prior to initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock." Crit Care Med(2006)34:1589–1596

Myburgh, John A., et al. "Hydroxyethyl starch or saline for fluid resuscitation in intensive care." New England Journal of Medicine 367.20 (2012): 1901-1911.

Finfer, Simon, et al. "A comparison of albumin and saline for fluid resuscitation in the intensive care unit." N Engl j Med 350.22 (2004): 2247-2256.

Caironi, Pietro, et al. "Albumin replacement in patients with severe sepsis or septic shock." New England Journal of Medicine 370.15 (2014): 1412-1421.

Raghunathan, Karthik, et al. "Association between the choice of IV crystalloid and in-hospital mortality among critically ill adults with sepsis*." Critical care medicine 42.7 (2014): 1585-1591.

Holst, Lars B., et al. "Lower versus higher hemoglobin threshold for transfusion in septic shock." New England Journal of Medicine 371.15 (2014): 1381-1391.

Bourquin, Vincent, et al. "Use of high-volume haemodiafiltration in patients with refractory septic shock and acute kidney injury." Clinical Kidney Journal 6.1 (2013): 40-44.

Cornejo, Rodrigo, et al. "High-volume hemofiltration as salvage therapy in severe hyperdynamic septic shock." Intensive care medicine 32.5 (2006): 713-722.

Rivers, Emanuel, et al. "Early goal-directed therapy in the treatment of severe sepsis and septic shock." New England Journal of Medicine 345.19 (2001): 1368-1377.

Peake, Sandra L., et al. "Goal-directed resuscitation for patients with early septic shock." The New England journal of medicine 371.16 (2014): 1496.

Yealy, Donald M., et al. "A randomized trial of protocol-based care for early septic shock." The New England journal of medicine 370.18 (2014): 1683-1693.

Asfar, Pierre, et al. "High versus low blood-pressure target in patients with septic shock." New England Journal of Medicine 370.17 (2014): 1583-1593.

Marik, Paul E., and Rodrigo Cavallazzi. "Does the central venous pressure predict fluid responsiveness? An updated meta-analysis and a plea for some common sense*." Critical care medicine 41.7 (2013): 1774-1781.

An excellent resource for this topic is a paper by Marik, Paul E. "Hemodynamic parameters to guide fluid therapy." Transfusion Alternatives in Transfusion Medicine 11.3 (2010): 102-112.

Cavallaro, Fabio, et al. "Diagnostic accuracy of passive leg raising for prediction of fluid responsiveness in adults: systematic review and meta-analysis of clinical studies." Applied Physiology in Intensive Care Medicine 1. Springer Berlin Heidelberg, 2012. 225-233.

Zhang, Zhongheng, et al. "Accuracy of stroke volume variation in predicting fluid responsiveness: a systematic review and meta-analysis." Journal of anesthesia25.6 (2011): 904-916.

Biais, Matthieu, et al. "Clinical relevance of pulse pressure variations for predicting fluid responsiveness in mechanically ventilated intensive care unit patients: the grey zone approach."Critical Care 18.6 (2014): 587.

Kumar, Anand, et al. "Pulmonary artery occlusion pressure and central venous pressure fail to predict ventricular filling volume, cardiac performance, or the response to volume infusion in normal subjects." Critical care medicine 32.3 (2004): 691-699.

Marik, Paul E., et al. "Dynamic changes in arterial waveform derived variables and fluid responsiveness in mechanically ventilated patients: a systematic review of the literature*." Critical care medicine 37.9 (2009): 2642-2647.

Hanson, Josh, et al. "The reliability of the physical examination to guide fluid therapy in adults with severe falciparum malaria: an observational study."Malaria journal 12.1 (2013): 348.

Zhang, Zhongheng, et al. "Ultrasonographic Measurement of the Respiratory Variation in the Inferior Vena Cava Diameter Is Predictive of Fluid Responsiveness in Critically Ill Patients: Systematic Review and Meta-analysis." Ultrasound in medicine & biology (2014).

Monnet, Xavier, et al. "Predicting volume responsiveness by using the end-expiratory occlusion in mechanically ventilated intensive care unit patients."Critical care medicine 37.3 (2009): 951-956.

Mandeville, Justin C., and Claire L. Colebourn. "Can transthoracic echocardiography be used to predict fluid responsiveness in the critically ill patient? A systematic review." Critical care research and practice (2012). Article ID 513480, 9 pages

Jones, Alan E., et al. "Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial." Jama 303.8 (2010): 739-746.

Vallée, Fabrice, et al. "Central venous-to-arterial carbon dioxide difference: an additional target for goal-directed therapy in septic shock?." Intensive care medicine 34.12 (2008): 2218-2225.

Mallat, Jihad, et al. "Central venous-to-arterial carbon dioxide partial pressure difference in early resuscitation from septic shock: a prospective observational study." European Journal of Anaesthesiology (EJA) 31.7 (2014): 371-380.

Ospina-Tascón, G. A., et al. "0032. Relationship between microcirculatory alterations and venous-to-arterial carbon dioxide differences in patients with septic shock." Intensive Care Medicine Experimental 2.Suppl 1 (2014): O5.

Russell, James A., et al. "Vasopressin versus norepinephrine infusion in patients with septic shock."New England Journal of Medicine 358.9 (2008): 877-887.

Annane, D., et al. "Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: aárandomised trial." Lancet 370 (2007): 676-684.

Morelli, Andrea, et al. "Phenylephrine versus norepinephrine for initial hemodynamic support of patients with septic shock: a randomized, controlled trial." Critical Care 12.6 (2008): R143.

De Backer, Daniel, et al. "Comparison of dopamine and norepinephrine in the treatment of shock." New England Journal of Medicine 362.9 (2010): 779-789.

Martin, Claude, et al. "Effect of norepinephrine on the outcome of septic shock." Critical care medicine 28.8 (2000): 2758-2765.

Morelli, Andrea, et al. "Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial." JAMA 310.16 (2013): 1683-1691.

Connors, Alfred F., et al. "The effectiveness of right heart catheterization in the initial care of critically III patients." Jama 276.11 (1996): 889-897.

Vieillard-Baron, Antoine. "Septic cardiomyopathy." Annals of intensive care 1.1 (2011): 1-7.

Hunter, J. D., and M. Doddi. "Sepsis and the heart." British journal of anaesthesia 104.1 (2010): 3-11.

Barton, Phil, et al. "Hemodynamic effects of iv milrinone lactate in pediatric patients with septic shock: A prospective, double-blinded, randomized, placebo-controlled, interventional study." CHEST Journal 109.5 (1996): 1302-1312.

Morelli, Andrea, et al. "Levosimendan for resuscitating the microcirculation in patients with septic shock: a randomized controlled study." Crit Care 14.6 (2010): R232.

Orme, Robert M. L’E., et al. "An efficacy and mechanism evaluation study of Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS): protocol for a randomized controlled trial." Trials 15.1 (2014): 199.

Ducrocq, Nicolas, et al. "Comparison of equipressor doses of norepinephrine, epinephrine, and phenylephrine on septic myocardial dysfunction." Survey of Anesthesiology 56.6 (2012): 277-278.

Bihari, D., S. Prakash, and A. Bersten. "Low-dose vasopressin in addition to noradrenaline may lead to faster resolution of organ failure in patients with severe sepsis/septic shock." Anaesthesia and intensive care 42.5 (2014): 671.

Sharshar, Tarek, et al. "Circulating vasopressin levels in septic shock." Critical care medicine 31.6 (2003): 1752-1758.

Patel, Gourang P., and Robert A. Balk. "Systemic steroids in severe sepsis and septic shock." American journal of respiratory and critical care medicine185.2 (2012): 133-139.

Todd, JAMES K. "Toxic shock syndrome." Clinical microbiology reviews 1.4 (1988): 432-446.

Darenberg, Jessica, et al. "Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial." Clinical Infectious Diseases 37.3 (2003): 333-340.

Linnér, Anna, et al. "Clinical efficacy of polyspecific intravenous immunoglobulin therapy in patients with streptococcal toxic shock syndrome: a comparative observational study." Clinical Infectious Diseases 59.6 (2014): 851-857.

STEINHORN, DAVID M., MICHAEL F. SWEENEY, and LISA K. LAYMAN. "Pharmacodynamic response to ionized calcium during acute sepsis." Critical care medicine 18.8 (1990): 851-857.

DESAI, TUSAR K., et al. "A direct relationship between ionized calcium and arterial pressure among patients in an intensive care unit." Critical care medicine 16.6 (1988): 578-582.

Jang, David H., Lewis S. Nelson, and Robert S. Hoffman. "Methylene blue for distributive shock: a potential new use of an old antidote." Journal of Medical Toxicology 9.3 (2013): 242-249.

Yunge, Mauricio, and Andy Petros. "Angiotensin for septic shock unresponsive to noradrenaline." Archives of disease in childhood 82.5 (2000): 388-389.

Chawla, Lakhmir S., et al. "Intravenous angiotensin II for the treatment of high-output shock (ATHOS trial): a pilot study." Crit Care 18 (2014): 534.

Kimmoun, Antoine, and Bruno Levy. "Angiotensin II: a new approach for refractory shock management?." Critical Care 18.6 (2014): 694.

Cariou, Alain, Christophe Vinsonneau, and Jean-François Dhainaut. "Adjunctive therapies in sepsis: an evidence-based review." Critical care medicine 32.11 (2004): S562-S570.