On ICU, does IV paracetamol cause more hypotension than NG?

The true art aspires to something real and objective, therefore it can not be satisfied with an appearance of truth only – Friedrich Schiller

Kelly et al. Haemodynamic effects of parenteral vs. enteral paracetamol in critically ill patients: a randomised controlled trial. Anaesthesia. 2016, 71, 1153-1162 doi:10.1111/anae.13562

Background

  • Paracetamol is one of the most widely prescribed medications in critical care.
  • Low level evidence supports an association of hypotension with paracetamol.
  • The incidence of hypotension with parenteral (intravenous – IV) paracetamol is unknown
  • There are no randomized control trials comparing the haemodynamic effects of parenteral (IV) paracetamol with other routes of administration in the critically ill.

Study Aims

  1. To determine the incidence of prospectively defined hypotension following parenteral (IV) paracetamol in mechanically ventilated critically ill patients.
  2. To determine whether the effect of paracetamol on blood pressure independent of route of administration.
  3. To describe the pharmacokinetic profiles IV vs PO paracetamol in the critically ill.

Design and Setting

  • Single-centre, prospective, open-label, randomised, parallel-arm, active-control trial
  • Tertiary referral, University-affiliated ICU in Australia.
  • December 2009 and March 2011
  • Ethical approval from the local institutional HREC
  • Informed and delayed consent from the patient’s legal surrogate

Methods

Subjects

Inclusion criteria:

  • Adult patients (≥ 18 years) whose lungs were mechanically ventilated
  • Prescribed paracetamol for either fever or pain
  • Ability to receive either parenteral (intravenous – IV) or enteral (naso-gastric – NG) paracetamol
  • Indwelling arterial catheter to facilitate blood sampling.

Exclusion criteria:

  • Childs-Pugh C liver disease
  • Known paracetamol allergy or recent paracetamol exposure

Randomisation:

  • 1:1 receive either the IV or NG paracetamol formulation.
  • 1 g of either IV or NG paracetamol 6-hourly for 24 hrs.
  • Permuted block design with variable block sizing

Blinding:

  • Sealed opaque envelopes were used for allocation concealment.
  • Data collectors and analysers blinded only to allocation of groups.

Data collection:

Physiological and pharmacokinetic variables were collected at multiple time points over 24 hour study period following first oral or IV dose of paracetamol. This included temperature, HR, BP and pharmacokinetic indices such as maximum plasma concentration and time to maximum concentration.

Outcomes

  • Primary outcome: incidence of hypotension following administration of IV vs. NG paracetamol in the critically ill (incident rate ratio).
  • Secondary outcomes: pharmacokinetic profiles of IV and NG paracetamol in the critically ill.

Results

  • 134 patients screened: 50 patients enrolled: 25 each arm
  • The incidence rate ratio of hypotension for IV vs. NG paracetamol is 2.94 (95% CI 0.97–8.92; p = 0.06).
  • The maximum plasma concentration of the IV formulation was significantly greater than for the NG preparation (p = 0.0005) and the time to maximum concentration was shorter (p = 0.0016).

Conclusions

This study shows that there is no significant difference in the incidence of hypotension following IV paracetamol administration compared with NG paracetamol in ICU patients.  There was a trend towards an increased incidence of hypotension following IV paracetamol administration in ICU patients and this is considerably greater than previously reported by manufacturers.

Strengths

  • Focused research question with objective primary outcome.
  • No loss to follow up.
  • Sound statistical methods with intention to treat analysis.
  • CONSORT reporting criteria met, primary and secondary analyses
  • Some attempts made at reducing bias
  • ‘Real world’ environment
  • Pre-trial power calculation attempted

Weaknesses

  • The authors’ definition means that “hypotension” is not always a harmful outcome eg. a hypertensive patient in pain becoming normotensive due to pain relief after paracetamol
  • Small sample size – more than 2/3 excluded without explanation.
  • No data on how well matched groups were.
  • Not fully blinded – no report of who did what in the study protocol
  • Multiple biases: selection, reporting, measurement and detection
  • Confounders eg is BP drop solely to due paracetamol?
  • IV group had higher SBP – no comment on why?
  • Insufficient patients to offer insights into cardiac indeces eg SVR
  • Incomplete NG pharmacokinetic profile.
  • Non generalizable as single-centre study

Impact

The results of this study pose some interesting questions over the choice of prescribing route in critical care and the necessity of paracetamol prescription.

summary by Dr Christine Sathananthan

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