A randomized trial of normothermic preservation in liver transplantation

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Nasralla D, et al. "A randomized trial of normothermic preservation in liver transplantation". Nature. 2018. 557(7703):50-56.
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Clinical Question

In there a significant difference in the rates of graft injury, organ, discard, and preservation time, bile duct complications, and overall survival of the patient in donor livers maintained by normothermic machine perfusion in comparison to conventional cold storage?

Bottom Line

Using normothermic machine perfusion to maintain donor livers when compared to conventional cold storage was associated with a 50% decrease in graft injury, a 50% decrease in organ discard, and a 54% increase in mean organ preservation time. There was no difference in bile duct complications, graft survival, or overall mortality of the patient.

Major Points

Liver transplantation is presently accepted as the treatment for end-stage liver failure. Rates of liver disease are steadily increasing, and have surpassed the amount of viable livers available. There have been increases in the total number of organ donors, but there has been no change in number of livers transplanted annually, which is likely due to the advanced age, and comorbidities in most organ donors [1].

Presently, livers are preserved for transplant using static cold storage (SCS), in which a specific preservation fluid is flushed through the liver, which is then stored in an icebox. This method has been the mainstay in liver preservation for 30 years. This method does slow metabolism, but anaerobic activity persists, leading to ischemia and reperfusion injuries [2]. Recently there has been interest in maintaining donor livers at physiological temperatures using perfusion (normothermic machine perfusion, NMP). In NMP the liver is perfused with oxygenated blood, as well as nutrients and drugs at body temperature in order to maintain physiologic conditions [3][4][5][6].

In this RCT 220 patients undergoing liver transplantation were randomized to receive SCS or NMP. These patients were followed for 1 year to assess for prevalence of post-reperfusion syndrome, early allograft dysfunction, graft failure, primary-non function, and mortality. Rates of organ discard, length of hospitalization/ICU stay, and need for dialysis were also measured.

Guidelines

As of December 2018, no guidelines have been published that reflect the results of this trial.

Design

  • Multinational, open-label, two-arm, parallel, RCT
  • N=220
    • SCS (n=100)
    • NMP (n=120)
  • Setting: 7 centers in the UK, and 1 centre in each Belgium, Spain, and Germany
  • Enrollment: June 26 2014 to March 8 2016
  • Mean follow-up: 1 year
  • Analysis: Intention-to-treat
  • Primary outcome: Peak AST (clinically accepted biomarker for primary non function, graft survival and patient survival)

Population

Inclusion Criteria

  • Donor:
    • At least 16 years of age
    • Whole liver
    • Cardiovascular death (DCD) or brain death (DBD)
  • Recipient:
    • At least 18 years of age
    • Listed only for liver transplantation

Exclusion Criteria

  • Patient in fulminant liver failure
  • Donor a prisoner

Baseline Characteristics

From NMP recipient group

  • n=121
  • Female: 28.9%
  • Donor type
    • DBD: 71.9%
    • DCD: 28.1%
  • Mean age: 55
  • Cause of liver failure
    • Alcohol: 29.8%
    • Autoimmune hepatits: 1.7%
    • Hepatitis B: 2.5%
    • Hepatits C: 3.3%
    • Hepatocellular carcinoma on background of cirrhosis: 12.4%
    • Non alcoholic steatohepatitis: 9.1%
    • Primary biliary cirrhosis: 8.3%
    • Primary sclerosis cholangitis: 14.9%
    • Other: 18.1%
  • Mean BMI: 26.18%
  • Missing BMI (n): 0
  • Retransplant: 9.9%
  • Mean MELD score: 13
  • MELD score by location
    • UK: 13
    • Germany: 17
    • Spain:16
    • Belgium: 19
  • Mean eGFR: 87.36
  • Missing eGFR (n): 4
  • Mean ET-Donor risk index: 1.70
  • Missing ET-Donor risk index (n): 13

Interventions

  • Static cold storage group
    • Preserved, transported, and transplanted based on local standard practices
  • Normothermic machine perfusion group
    • OrganOx metra normothermic liver perfusion device was used, used for a maximum of 24 hours
    • OrganOx device and researcher were transported to the donor site
    • The device was primed with 500 mL of gelofusine, and 3 units of donor matched packed red blood cells
    • The OrganOx device was the appropriately attached to the donor liver
    • Antibiotics were then given
    • Heparin, insulin, prostacyclin, bile salts, and fat free parenteral nutrition were continuously infused throughout the perfusion process
    • The OrganOx machine measured and titrated PO2, PCO2, temperature, mean arterial pressure, inferior vena cava pressure, glucose, and typical blood flow rate

Outcomes

Comparisons are NMP vs. SCS.

Primary Outcomes

Mean peak AST after 7 days NMP group
6.191 (95% CI 6.013-6.368)
Mean peak AST after 7 days SCS group
6.872 (95% CI 6.678-7.066)
Reduction in mean peak AST after 7 days in NMP vs SCS
-0.681 (95% CI -0.946 - -0.417; P<0.001)
 % Reduction in geometric mean peak AST after 7 days in NMP vs SCS
49,4% (95% CI 34.1%-61.2%; P<0.001)

Secondary Outcomes

Donor organ discard rates
11.7% vs. 24.1%, Effect -12.4% (95% CI -21.4% - -3.3%; P=0.008)
Primary non-function
0.8% vs. 0%, Effect NA (95% CI NA; P=NA)
Post reperfusion syndrome
12.4% vs. 33.0%, Effect -20.6% (95% CI -31.6% - -9.6%; P=0.0002)
Post reperfusion lactate
3.6 (2.6-4.2) vs. 4.1(3.2-5.0) (P=0.018)
Early allograft dysfunction (n)
12 vs. 29, Effect 0.263 (95% CI 0.126-0.550; P=0.0002)

Subgroup Analysis

 % Reduction in mean peak AST after 7 days in NMP vs SCS, DCD subgroup
73.3% (95% CI 53.7%-84.6%; P<0.001)
 % Reduction in mean peak AST after 7 days in NMP vs SCS, DBD subgroup
40.2% (95% CI 19.3%-55.7%; P=0.001)

Adverse Events

Total % of adverse events NMP group
55.4% (95% CI 46.1–64.4%)
Total % of adverse events SCS group
57.4% (95% CI 47.2–67.2%)
Total % of serious adverse events (Clavien–Dindo grade ≥IIIb)
16.4% vs. 22% (no statistical tests applied)

Criticisms

  • While there have been several animal and discarded organ studies on different techniques to preserve donated livers, this study represents the first living human trial on normothermic liver transplantation [7] [8] [9] [10] [11] [12] [13]. The preliminary results of these studies have been favorable to normothermic liver preservation, however further research evaluating economics and logistics will need to be completed before it is possible to determine how normothermic liver preservation will fit into the clinical practice landscape.

Funding

The authors had no conflicts of interest to declare. Funding from this study was provided by the European Commission Seventh Framework Programme.

Further Reading

  1. Annual Report on Liver Transplantation 2016/2017 (NHS Blood and Transplant, 2017). https://nhsbtdbe.blob.core.windows.net/umbraco-assets-corp/5007/annual_liver_transplantation_report_2017.pdf
  2. Todo S et al. Extended preservation of human liver grafts with UW solution. JAMA 1989. 261:711-4.
  3. Watson CJ et al. Preimplant Normothermic Liver Perfusion of a Suboptimal Liver Donated After Circulatory Death. Am. J. Transplant. 2016. 16:353-7.
  4. Mergental H et al. Transplantation of Declined Liver Allografts Following Normothermic Ex-Situ Evaluation. Am. J. Transplant. 2016. 16:3235-3245.
  5. Perera T et al. First human liver transplantation using a marginal allograft resuscitated by normothermic machine perfusion. Liver Transpl. 2016. 22:120-4.
  6. Ravikumar R et al. Liver Transplantation After Ex Vivo Normothermic Machine Preservation: A Phase 1 (First-in-Man) Clinical Trial. Am. J. Transplant. 2016. 16:1779-87.
  7. Friend PJ et al. Normothermic perfusion of the isolated liver. Transplant. Proc. 2001. 33:3436-8.
  8. Imber CJ et al. Advantages of normothermic perfusion over cold storage in liver preservation. Transplantation 2002. 73:701-9.
  9. St Peter SD et al. Extended preservation of non-heart-beating donor livers with normothermic machine perfusion. Br J Surg 2002. 89:609-16.
  10. Reddy SP et al. Preservation of porcine non-heart-beating donor livers by sequential cold storage and warm perfusion. Transplantation 2004. 77:1328-32.
  11. Reddy S et al. Non-heart-beating donor porcine livers: the adverse effect of cooling. Liver Transpl. 2005. 11:35-8.
  12. Brockmann J et al. Normothermic perfusion: a new paradigm for organ preservation. Ann. Surg. 2009. 250:1-6.
  13. op den Dries S et al. Ex vivo normothermic machine perfusion and viability testing of discarded human donor livers. Am. J. Transplant. 2013. 13:1327-35.