Early Use of Noradrenaline in Septic Shock resuscitation (CENSER): A Randomized Trial
- Murine models show increased organ perfusion with increased mean arterial blood pressure
- There are retrospective studies in humans that show improvements in mortality
Does administering low-dose noradrenaline at the beginning of sepsis-induced hypotension resuscitation accelerate shock control compared to fluid resuscitation followed by noradrenaline (usual practise)?
- Randomised, double-blinded, placebo-controlled trial
- Single centre in Bangkok (tertiary teaching hospital)
- October 2013 – March 2017
- All patients >18 years meeting Surviving Sepsis Campaign 2012 diagnostic criteria for sepsis with a MAP <65mmHg attributable to infection
- Exclusion criteria attempted to exclude other causes of hypotension
- Randomisation by computer generated randomization table produced by co-author (sequential 1:1 ratio)
- Randomised to NA in 5% dextrose in water at 0.05mcg/kg/min or placebo (5% Dextrose in water) from onset of resuscitation through a peripheral or central line
- Patient & medical staff were blinded to trial infusion
- All subjects got anti-infective agent, source control and organ support as needed
- Open-label vasopressors were permitted for refractory shock after 30ml/kg of intravenous fluid
- Those needing further organ support went to ICU (for arterial-line monitoring), others went to general medical ward (no arterial-line) with nursing ratio 1:3
Primary: Control of shock at 6 hours
- MAP >65mmHg (on 2 consecutive BP measurements 15 mins apart)
- PLUS, evidence of organ perfusion: either UO >0.5ml/kg/hr for 2 consecutive hours OR >10% reduction in lactate from baseline
Secondary: 28-day mortality, hhospital mortality and rate of resp failure requiring mechanical ventilation, RRT, days requiring organ support up to Day 28
Safety: New onset arrhythmias, organ ischaemia, pulmonary oedema (till hospital d/c or death) and death
- Well matched baseline characteristics
- Primary outcome: Treatment with noradrenaline from the start resulted a greater number of patients achieving MAP target of >65mmHg plus evidence of organ perfusion by 6 hours. 118/155 patients in treatment group compared to 75/155 patients in placebo group, OR 3.4 (2.09-5.53 95%CI), p<0.001.
- Secondary outcomes: there were no significant difference between the groups in need for organ support, ICU admissions, length of ICU stay, length of hospital stay, 28-day mortality or hospital mortality
- Safety outcomes: Treatment with noradrenaline compared to placebo group resulted in a lower incidence of cardiogenic pulmonary oedema (22/155 patients vs 43/155 patients. RR 0.70 (95% CI 0.56-0.87), p=0.004. No significant difference in ARDS, new onset cardiac arrhythmias, hospital acquired infection, upper gastro-intestinal haemorrhage, acute limb/intestinal ischaemia, or skin necrosis.
- Ther was no significant difference in volume of fluid administered or use of open label vasopressors.
- Relatively small number in each group (n = 150)
- Although blinded, clinicians may have seen the effects of intervention group which would have added bias
- Half of intervention group went to general medical ward (nursed 1:3!) on NA
- Fluid resuscitation rate was not controlled (but should have equalled out between groups)
- Single centre trial in Bangkok– and may not be generalisable
- No cardiac output monitoring details
- Cannot make conclusions about secondary outcomes given lack of power to assess these
- Expectedly, early use of vasopressors results in faster resolution of shock! Early NA didn’t result in less fluid given?!
- Improves macro and micro circulation but with no significant improvement in organ function seen in this study
- Interesting that they infused low dose noradrenaline through central (43%) or peripheral access (57%)
- One case of skin necrosis in both groups and no difference in evidence of splanchnic hypoperfusion
- Fitting with local practise of starting low dose peripheral metaraminol infusions… metaraminol/phenylephrine vs NA in sepsis debate
- Less cardiogenic shock (= fluid, ? due ↑CO) & fewer arrhythmias in NA group?
- Safety data on peripheral NA – sample size too small to see issues here?
- Unlikely to change practise because of the safety concerns of peripheral noradrenaline
Summary by Dr Jason Van Schoor.