Resuscitation of the Septic Shock Patient

The College, in their model answer to Question 1 from the second paper of 2014, have constructed an excellent resuscitation protocol, which does not afford this author very much room for improvement.

One can merely summarise their model, and expand upon it with references. To be clear, this approach is not "Early Goal-Directed Therapy"; protocolised sepsis management may not be especially effective in reducing mortality (ProCESSARISE).

Question 1 from the second paper of 2014 follows the similar Question 1 from the first paper of 2014, which asked for a critique of the Surviving Sepsis Guidelines. In turn this followed Question 16 from the second paper of 2013, which asked the candidates to critique the Early Goal Directed Therapy protocol.

In short, over those 18 months the college seems to have focused on interrogating the candidate's understanding of sepsis and its resuscitation.

The series of steps offered below represents a summary of a summary of a summary.

  • IV access and blood cultures
  • Early (within 1 hour) antibiotics
  • Fluid resuscitation: 30ml/kg
  • Albumin - harmless (SAFE) and haemodynamic goals are achieved faster (ALBIOS)
  • Assess efficacy of fluid resuscitation: mention "haemodynamic goals" and lactate
  • Vasopressors: noradrenaline as first line
  • Septic cardiomyopathy: consider inotropes (no evidence to suggest any specific one)
  • Refractory shock: vasopressin (VASSTVANISH) and corticosteroids (CORTICUS)
  • Super-refractory shock: iCa2+, methylene blue, esmolol, angiotensin-II, bicarbonate.
  • Consider toxic shock: IV immunoglobulin and clindamycin

Each step is sufficiently complex to merit its own chapter, and so the chapter headings are offered below as internal links:

Step 1: Fluid resuscitation and antibiotics

Get started with access and antibiotics

Fluid resuscitation

A more detailed review of fluid resuscitation in sepsis can be found elsewhere.

Step 2: Assess the need for further fluid resuscitation

Monitoring and haemodynamic goals

  • Get an arterial line in there (SSG)
    • This will exclude the "artifactual shock" generated by cack-handed NIBP measurements.
  • A central line is recommended by the SSG.
  • MAP goals:
  • CVP goals:
  • Advanced haemodynamic assessment:
    • PA catheter (routine use not recommended by the SSG, on the basis of SUPPORT)
    • PiCCO (routine use not recommended by the SSG)
    • ScvO2 monitoring: recommended by the SSG, but may be pointless (ProCESS and ARISE)

Is there room for more fluid?

Is the resuscitation adequate?

Step 3: No more room for fluid; start some vasopressors

  • Noradrenaline is the first choice (SSG) ... but why?
  • Perhaps there is no good reason:
    • No better than adrenaline (CATS) though it does not muddle the use of lactate
    • No better than phenylephrine (Morelli et al, 2008) - perhaps better for the stroke volume
    • No better than vasopressin in terms of mortality (VASST)
    • As good as vasopressin at preventing renal failure (VANISH)
    • Better than dopamine (SOAP-II) -but who uses dopamine these days?...

Step 4: Assess adequacy of cardiac output

After the ProCESS and ARISE studies we can all safely forget about routinely using dobutamine to magically transform the microcirculation. However, septic cardiomyopathy is a thing. One needs to consider the use of inotropes.

Identification of patients who may benefit from inotropes

  • Patients whose (low) cardiac output is being monitored (that's difficult to argue with)
  • Patients whose resuscitation goals (as above - ScvO2, Pv-aCO2 urine output, lactate clearance) remain inadequately met in spite of adequate preload and adequate mean arterial pressure.

Which inotrope?

The options:

Step 5: Refractory hypotension

What makes the hypotension "refractory"?

  • All available evidence suggests that the patient has adequate preload and requires no further fluid
  • All available evidence suggests that the cardiac output is adequate.
  • The surrogate markers for adequacy of resuscitation suggest that it is still inadequate.
  • The blood pressure won't stay up in spite of large doses of noradrenaline.
    • What's a "large" dose?
      • For one, it is whatever dose that is required to start causing cardiac arrhythmias.
      • VASST investigators added vasopressin once noradrenaline dose reached 15μg/min.
        That equates to around 0.21 μg/kg/min for the average 70kg person.

Vasopressin for septic shock

A more detailed review of vasopressin in septic shock can be found elsewhere.

Steroids for septic shock: "relative adrenal insufficiency"

  • Recommended by the SSG - 200mg hydrocortisone per day
  • Only indicated for severe septic shock
    • There may be no mortality benefit for "mild" septic shock (CORTICUS)
    • It appears that your risk of mortality has to be over 60% before you will benefit.

A more detailed review of steroids in septic shock can be found elsewhere.

Could there be toxic shock?

The syndrome has some stereotypical features, which are described nicely in this old article from 1988.

The key signs are whole-body erythema and later, desquamation.

Step 6: Try anything

Perhaps you have run out of strategies for which there is strong evidence.

Now, time for some black magic.


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.

Gordon, Anthony C., et al. "Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial." JAMA 316.5 (2016): 509-518.

Lamontagne, François, et al. "Pooled analysis of higher versus lower blood pressure targets for vasopressor therapy septic and vasodilatory shock." Intensive care medicine(2017): 1-10.

Grassi, P., et al. "Pulse pressure variation as a predictor of fluid responsiveness in mechanically ventilated patients with spontaneous breathing activity: a pragmatic observational study." HSR proceedings in intensive care & cardiovascular anesthesia 5.2 (2013): 98.