Niemann

Screen Shot 2016-03-09 at 22.17.33

Therapeutic Hypothermia in Deceased Organ Donors and Kidney-Graft Function

Niemann NEJM;2015;,373(5)405-14; DOI: 10.1056/NEJMoa1501969

Clinical Question

  • In organ donors, following diagnosis of brainstem death, does therapeutic hypothermia decrease delayed graft function in kidney recipients?

Design

  • Randomised controlled trial
  • Computer generated block randomisation
  • Stratified according to oran-procurement organisation, donor status (either standard or expanded criteria, with expanded criteria donors being older and having more co-existing conditions), and whether or not the patient received hypothermia treatment before declaration of death
  • With 500 donors, 90% power to detect a 30% relative difference between two groups with type 1 error of 5%
  • Interim analyses that allowed the trial to be stopped early for either efficacy or futility

Setting

  • 2 organ procurement organisations in USA
  • March 2012 – October 2013

Population

  • Inclusion criteria: adult donors with death determined by neurological criteria
  • Exclusion criteria:
    • Death according to circulatory criteria
    • Age <18
    • Medical condition precluding donation of kidney
    • Coagulopathy
    • Haemodynamic instability
    • End-stage renal disease +/or dialysis at time of current hospitilisation
    • During 1st six months of study, donors excluded if anticipated to donate thoracic organs
  • 394 donors ( 788 kidneys) enrolled, of whom 566 kidney recipients had complete outcome data
    • 68 patients excluded as did not have kidneys transplanted, 11 had dual-kidney recipients; data on delayed-graft function incomplete for 6 kidneys

Comparing hypothermia vs. normothermia groups

  • Characteristics of organ donors
    • Age 45 vs. 45, P=0.82
    • GFR at enrolment 89.2 vs. 89, P=0.8
    • Kidney donor profile index (estimate of graft failure) score 51% vs. 53%, P=0.53
    • Temperature prior to organ recovery 34.6C vs. 36.8C, P<0.001
    • Method of temperature control
      • Blanket 74.7% vs. 53.3%
      • None 8.7% vs. 33.6%
      • Ice packs 4.7% vs. 1.3%
      • Arctic sun 3.3% vs. 0%
      • Fan 2.7% vs. 2.6%
      • Bair hugger 0% vs. 5.9%
      • Other/unknown 6% vs. 3.3%
    • Target temperature reached in 4 hours: 81.3% vs. 98%, P<0.001
  • Characteristics or organ recipients
    • Age 52 vs 53, P=0.14
    • Warm ischaemic time 34min vs. 38min, P=0.11
    • Cold ischaemic time (time from when organ cooled with cold perfusion solution after organ recovery surgery until tissue reaches physiological temperature during the implantation procedure)13.9hrs vs. 15.6hrs, P=0.02

Intervention

  • Mild hypothermia (Target 34 – 35C)

Control

  • Normothermia (Target 36.5 – 37.5C)

Treatment common to both groups

  • In both intervention and control groups allowed to spontaneously reach target temperature or temperature managed with forced air systems or passive-cooling device, according to system that was available at that facility.

Outcome

  • Trial terminated early on basis of interim analysis
  • Comparing hypothermia vs. normothermia groups
    • Primary outcome: Delayed graft function (the recipient’s requirement for dialysis during the 1st week post-transplantation) – significantly lower in hypothermia group
      • 28.2%  vs 39.2%, P=0.008
    • Primary efficacy analysis (multivariate model that took into account organ procurement agency, donor type (standard criteria or expanded criteria), creatinine level, donor age, and cold-ischaemic time)
      • Hypothermia vs. Normothermia: Odds Ratio of delayed graft function 0.62 (95% C.I. 0.43-0.92, P=0.02)
    • Secondary outcomes:
      • No significant difference in:
        • Number of organs donated
        • Number of adverse events
    • Sub-group analysis:
      • Expanded criteria donors (older patients with more pre-existing disease)
        • Rate of delayed graft function significantly lower in hypothermia group
      • Standard criteria donors
        • Rate of delayed graft function – no significant difference

Authors’ Conclusions

  • In organ donors the use of mild hypothermia decreased the rate of delayed graft function

Strengths

  • Randomised controlled trial
  • Multi-centre
  • Adjusted analysis performed to account for factors that are known to influence risk of poor graft function
  • Performed research in an ethically challenging population

Weaknesses

  • Non-blinded
  • Data on longterm graft function not yet available. It would have been more useful if the primary outcome was a longer term outcome rather than the requirement for dialysis in the first week
  • Information on outcome of other organs that were donated not stated
  • No set criteria for when dialysis was performed
  • The study randomised 394 patients (~788 kidneys) but only had data on 566 transplanted kidneys. This is a loss of 28% (n=222). Whilst mostly unavoidable (medical issues, withdrawal of consent, not transplanted, 2.7% data incomplete) their analysis is consequently not intention-to-treat and so may bias toward a positive outcome.

The Bottom Line

  • In organ donors, following death by neurological criteria, the use of therapeutic hypothermia vs. normothermia, significantly decreased the recipient’s requirement for dialysis during the 1st week post-transplant. This benefit was more marked for patients at a higher risk of graft failure. Further studies are required to confirm this finding,  to demonstrate the longterm outcomes, and to investigate the outcomes for other organs that are transplanted.

External Links

Metadata

Summary author: @davidslessor
Summary date: 8th August 2015
Peer-review editor: @duncanchambler

Leave a Reply