Septic shock - are we aggressive enough?

The current approach to sepsis management centres around the rapid administration of antibiotics and IV crystalloid. The Surviving Sepsis Campaign^​[1]​ recommends at least 30ml/kg of IV fluid, followed by vasopressors and/or inotropes according to the patient's physiological response. This statement is classified as: "Strong recommendation; low quality of evidence", which essentially means it is opinion rather than evidence-based. (This combination, often seen in guidelines, of strong recommendation and weak evidence always disheartens me.)

In practice, giving this 30ml/kg (3 litres in a 100kg patient) often results in delays of several hours. We administer IV fluids, check an X-ray, give more IV fluids, wait for blood tests, give more IV fluids, discuss the case with our anaesthetic colleagues, give more IV fluids... I'm exaggerating, of course, but it seems sad that we are usually quick to give the antibiotics but sometimes slow to restore the blood pressure.

Could early vasopressors be the answer?

Septic shock is a form of 'distributive' shock, because excessive vasodilation impairs the distribution of blood flow to vital organs. It follows that the solution lies in reversing this vasodilation, increasing the blood pressure so that tissue perfusion is restored. Vasopressors like noradrenaline (norepinephrine in the USA) accomplish this by causing vasoconstriction, and are frequently utilized for this purpose on the intensive care unit. This year saw the publication of the very first randomized controlled trial to investigate the effect of early norepinephrine on septic shock. It's a great study, and it comes all the way from Thailand...

The paper

Permpikul C, Tongyoo S, Viarasilpa T, et al. Early use of norepinephrine in septic shock resuscitation (CENSER). A randomized trial. Am J Respir Crit Care Med. 2019 May;199(9):1097-1105^​[2]​

This is a randomized, double-blind, placebo-controlled trial, conducted at Siriraj Hospital in Bangkok, Thailand from 2013 to 2017. A total of 310 patients with sepsis and hypotension (MAP <65mmHg) were randomised to receive early noradrenaline infusion (at a rate of 0.05ug/kg/min) or placebo. The infusion was given via a central or peripheral line and was continued for 24 hours. Both groups also received antibiotics and IV fluids as per the Surviving Sepsis Campaign of 2012. If a patient was still hypotensive (MAP <65mmHg) after 30ml/kg of crystalloid, open label vasopressors were permitted.

Results

The primary outcome was shock control at 6 hours. This was defined as sustained MAP >65mmHg (for at least 15min) with signs of adequate tissue perfusion (urine output >0.5ml/kg/hr for 2 consecutive hours or decrease in serum lactate by more than 10% from initial level). This outcome was met in 76.1% of treatment cases and only 48.4% of control (placebo) cases. The mean time to resolution of shock was 4:45 hours (treatment) vs 6:02 hours (control).

The following secondary outcomes were interesting, although not statistically significant (treatment vs control):

Mortality at 28 days: 15.5% vs 21.9%
Pulmonary oedema: 14.4% vs 27.7%
Need for open label vasopressor: 67.7% vs 80%

Limitations

This is a single centre study and it's fairly small. It wasn't powered to detect a significant difference in mortality, which would have been a more patient-centred primary outcome than shooting for a number on a monitor. That being said, the restoration of normal physiology is generally a sensible goal during resuscitation - the less time our patients spend in a state of hypo-perfusion the better for them.

Giving vasopressors peripherally

Only 44.5% of the patients had central lines inserted. This means that this study contains within it a small safety trial of peripheral vasopressor use. Out of the 88 cases of peripheral noradrenaline infusion, there was only one case of skin necrosis. However, this complication also occured in one patient in the placebo arm.

Those interested in the topic of peripheral vasopressors can find lots of interesting material on First10EM, REBEL EM, and in a post-hoc analysis study^​[3]​ published just last month.

The bottom line

This study found that administering an early infusion of noradrenaline to patients in septic shock restored normal blood pressure faster and more reliably than placebo.

Where do we go from here?

It is often said that a single study isn't enough evidence to change practice, and this is a prudent axiom. These results are encouraging though, and the physiology behind them makes sense. We need multi-centre trials of course, as well as studies to explore the optimal dosing, timing and method of administration of vasopressors in septic shock.

Those receiving noradrenaline infusion in this study still took nearly 5 hours to achieve a physiological blood pressure, which isn't exactly super-fast. Was the infusion rate too low, should there be an escalating protocol, should bolus doses be used? Several experts now advocate for 'push-dose pressors' as a stop-gap while an infusion is being prepared. Good reviews of this concept can be found on EMCrit and emDocs.

More FOAMed on this...

The Bottom Line - CENSER: early use of norepinephrine in septic shock resuscitation
First10EM - CENSER: early norepinephrine in septic shock
REBEL EM - The CENSER trial: early norepinephrine in septic shock

References

1. 
   
   
   

   Rhodes A, Evans L, Alhazzani W, Levy M, Antonelli M, Ferrer R, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med [Internet] 2017;45(3):486–552. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28098591

   
   
   
   


2. 
   
   
   

   Permpikul C, Tongyoo S, Viarasilpa T, Trainarongsakul T, Chakorn T, Udompanturak S. Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER). A Randomized Trial. Am J Respir Crit Care Med [Internet] 2019;199(9):1097–105. Available from: https://www.ncbi.nlm.nih.gov/pubmed/30704260

   
   
   
   


3. 
   
   
   

   Delaney A, Finnis M, Bellomo R, Udy A, Jones D, Keijzers G, et al. Initiation of vasopressor infusions via peripheral            versus            central access in patients with early septic shock: A retrospective cohort study. Emergency Medicine Australasia [Internet] 2019;Available from: http://dx.doi.org/10.1111/1742-6723.13394