Early Use of Noradrenaline in Septic Shock Resuscitation (CENSER): A Randomized Trial

Permpikul C, Tongyoo S, Viarasilpa T et al.

American Journal of Respiratory and Critical Care Medicine 2019, 199, 9:1097-1105. doi: 10.1164/rccm.201806-1034OC.

Aim of Study

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)?

Design and Location

Phase II Randomised double-blinded placebo control trial. Single centre in Bangkok

Methodology

Eligibility criteria

  • patients >18 years,
  • meeting Surviving Sepsis Campagin 2012 diagnostic criteria for sepsis,
  • with a MAP <65mmHg attributable to infection.

Exclusion criteria

  • having met septic shock criteria for >1hr prior to randomisation,
  • requiring immediate surgery,
  • advanced stage cancer,
  • burn injury,
  • trauma,
  • drug overodse,
  • seizures,
  • pregnancy,
  • active GI bleed,
  • severe asthma,
  • ACS,
  • acute pulmonary oedema,
  • arrhythmias,
  • refusal of fluid resuscitation,
  • vasopressors
  • intubation.

Participants were randomised to receive noradrenaline in 5% dextrose at 0.05mcg/kg/min or placebo (5% dextrose at the same rate) from the onset of resuscitation, through a peripheral or central line. Medical staff caring for the patient were blinded to the identity of the trial infusate; all the rest of their treatment was as directed by medical staff, including the use of open-label vasopressors. All patients received treatment for septic shock as usual including fluid resuscitation, appropriate antibiotic therapy, source control, and organ support as directed by the attending medical team. If the hemodynamic goal (MAP > 65 mm Hg) was not reached after optimal fluid (at least 30 ml/kg) and study drug infusion, open- label vasopressors were permitted when no attenuation of shock was observed.

Primary Outcome

Control of shock at 6 hrs (defined by both MAP >65mmHg on 2 consecutive BP measurements 15 minutes apart) plus evidence of organ perfusion (either urine output >0.5ml/kg/hr for 2 consecutive hours, or a >10% reduction in lactate from baseline).

Secondary Outcomes

  • 28 day mortality
  • Hospital mortality
  • Rate of respiratory failure requiring ventilation, RRT, days requiring organ support up to Day 28

Safety Outcomes

  • New onset of arrhythmias, organ ischaemic, pulmonary oedema
  • Death

Statistics

Intention to treat analysis

Continuous variables – Wilcoxon rank sum test

Categorical variables – chi squared test

Results

Well matched baseline characteristics

1* outcome:

Treatment with noradrenaline from the start resulted a greater number of patients achieving MAP target of >65mmHg plus evidence of organ perfusion (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.

2* outcomes:

No significant difference between groups in need for organ support, ICU admissions, length of ICU stay, length of hospital stay, 28 day mortality or hospital mortality

No significant difference in volume of fluid administered, use of open label vasopressors.

Adverse Events:

Treatment with noradrenaline compared to placebo group resulted in a lower incidence of cardiogenic pulmonary oedema (22/155 patients comp. 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, UGI haemorrhage, acute limb/intestinal ischaemia, skin necrosis.

Conclusions/Discussions

Early use of noradrenaline from onset of resuscitation has a beneficial effect on BP / UO / Lactate clearance but no significant effect on larger clinical outcomes. However, the trial was not powered to detect a difference in these larger clinical outcomes so we cannot conclude that it has no effect.

The benefical effect of early noradrenaline on rates of pulmonary oedema and arrhythmias are small.

Stated Limitations from the Study

Overall small number of patients: 310. This met with the power calculation required to detect the primary outcome but not any of the secondary outcomes.

Discussion from Journal Club Meeting (?Change of Practice)

  • Interesting that they infused low dose noradrenaline through central or peripheral access, whichever the patient had.
  • Fitting with local practise of starting low dose peripheral metaraminol infusions
  • Unsurprising that early use of vasopressors results in faster resolution of shock
  • Cannot make conclusions about larger clinical outcomes given lack of power to assess these.

Summary by Dr S Jones. Journal Club Meeting 04 November 2019.

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