Choudhury

A Randomized Trial Comparing Terlipressin and Noradrenaline in Patients With Cirrhosis and Septic Shock

Choudhury. Liver International 2016, published on-line doi:10.1111/liv.13252

Clinical Question

  • In patients with cirrhosis and septic shock does terlipressin in comparison with noradrenaline improve haemodynamic parameters?

Design

  • Randomised controlled trial
    • Randomised in 1:1 ratio
    • Block randomisation with fixed block size of 6
    • Sequentially numbered opaque sealed envelopes – not documented if any checks were completed to ensure allocation concealment was maintained
  • Non-blinded
  • Consecutive recruitment
  • Non-inferiority trial
  • Sample size calculation: 82 patients required to determine a non-inferiority limit of 15% from a baseline of 40% haemodynamic improvement in the noradrenaline group, with a two sided alpha of 0.05 and a power of 90%
  • Intention to treat analysis used for primary outcome
  • A per-protocol analysis was also performed

Setting

  • Single liver intensive care unit, India
  • Data collected March 2013 – September 2014

Population

  • Inclusion criteria: Decompensated cirrhosis with septic shock, that did not respond to fluids
    • Decompensated cirrhosis – not defined
    • Septic shock
      • 2+ SIRS criteria
      • Proven/suspected infection
      • Vasopressor required to maintain MAP ≥65mmHg despite 2 hours of fluid resuscitation
        • 15ml/kg normal saline over 30min followed by 5% albumin at 50ml/hr for 6 hours.
  • Exclusion criteria: age <18 years, valvular heart disease, coronary artery disease, acute mesenteric ischaemia, peripheral vascular disease, pregnancy, chronic kidney disease, uncontrolled or refractory variceal bleed, immunosuppressive drugs
  • 511 patients screened of whom 84 randomised
  • Comparing baseline characteristics of intervention vs. control group
    • Age: 47 vs. 48
    • Alcoholic liver disease: 64% vs. 52%
    • Source of sepsis – significant difference
      • Spontaneous bacterial peritonitis: 50% vs. 26.2%, p=0.04
      • Pneumonia: 21.4% vs. 47.6%, p=0.02
    • MELD score: 32 vs. 32
    • Lactate: 3 vs. 3

Intervention

  • Terlipressin
    • Titrated and infused at a rate of 1.3-5.2ug/min (2-8mg over 24)

Control

  • Noradrenaline
    • Titrated and infused at a rate of 7.5-60ug/min

For all patients

  • Standard medical therapy included IV fluids and antibiotics
  • 20% albumin given at 1.5gm/kg on 1st day followed by 1mg/kg for next 2 days, except those anuric or on renal replacement therapy
  • Target MAP ≥65mmHg
  • If unable achieve MAP at highest dose of study drug, salvage therapy initiated
    • Combination of noradrenaline at 7.5-30μg/min and terlipressin at 1.3μg-2.6ug/min.
    • Hydrocortisone 50mg every 6 hours
  • Adrenaline or phenylephrine used as per clinical need
  • Slow low-efficient dialysis was done in cases with acidosis, worsening azotemia or anuria. Continuous renal replacement therapy not available during study period

Outcome

  • Primary outcome:
    • Achieve and maintain MAP >65 for initial 48 hours – significantly greater in terlipressin group
      • 92.9% vs. 69.1%, p=0.005
      • Number needed to treat: 5
      • Fragility index: 5
  • Secondary outcomes – comparing terlipressin vs. noradrenaline groups
    • Survival
      • 48 hours – significantly higher in terlipressin group
        • 95.2% vs. 71.4%, p=0.003
      • 28 days – no significant difference
        • 26.2% vs. 14.3%, p=0.17
    • Target MAP achieved at 6 hours – no significant difference
      • 90.5% vs. 78.6%, p=0.003
    • Shock reversal at 48 hours (able to stop vasopressors) – significantly higher in terlipressin group
      • 33.1% vs. 11.9%, p<0.02
    • Need for salvage therapy – significantly higher in terlipressin group
      • 54.7% vs. 33.3%, p=0.03
    • Adverse events
      • Overall –  no significant difference
        • 40.5% vs. 21.4%, p=0.06
      • Peripheral cyanosis – significantly higher in terlipressin group
        • 29% vs. 0%, p=0.05
    • Assessment of microcirculation during first 48 hours – trend towards improvement with terlipressin
      • Central venous oxygen saturation, p=0.07
      • VBG-ABG pCO2 difference, p=0.07
      • Lactate clearance, p=0.08
    • Length of ICU stay – no significant difference
      • 6 vs. 5 days, p=0.99
    • New onset variceal bleeding – significantly lower in terlipressin group
      • 0% vs. 9.5%, p=0.01
    • Per-protocol analysis (patients who could be maintained on monotherapy till the outcome)
      • Success of therapy at 48 hours – no significant difference
        • 100% vs. 82%, p=0.07
      • 48 hour survival – no significant difference
        • 100% vs. 89%, p=0.26
      • 28 day survival – significantly higher in terlipressin group
        • 47% vs. 11%, p=0.002

Authors’ Conclusions

  • Terlipressin is as effective as noradrenaline as a vasopressor in patients with cirrhosis and septic shock and has an early survival benefit

Strengths

  • Randomised controlled trial
  • Intention to treat and per-protocol analysis performed
  • Study protocol published on clinicaltrials.gov

Weaknesses

  • Single centre
  • Non-blinded
  • Number of baseline differences
  • Large number of patients excluded limiting external validity
  • Primary outcome was not a patient orientated outcome
  • Dose of albumin recorded in gm/kg on day 1 and mg/kg on day 2. This is likely to be a typographical error

The Bottom Line

  • In patients with cirrhosis and septic shock, this single centre non-blinded RCT demonstrated that terlipressin in comparison with noradrenaline improved haemodynamics and had a mortality benefit. Due to a number of methodological flaws and baseline differences I would want further evidence before this becomes standard practice.

External Links

Metadata

Summary author: @davidslessor

Summary date: 5th March 2017

Peer-review editor: @avkwong

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