Controversy 1

To cool or not to cool before and/or after normothermic EVLP

An impressive wealth of documentation has been generated over recent decades to back the universal routine of cooling donor organs for preservation during transport and storage prior to EVLP or their transplantation.

Beltzer(1) established in the late 80s that a reduction of organ storage temp from 37 °C to ca 4 °C reduces metabolic activity ca 12- fold, which gave the transplant team the necessary time to retrieve, transport, assess and implant the organ without significant metabolic injury.

Based on this reasoning most donor organs retrieved for transplantation, including marginal organs scheduled for later warm EVLP, are currently preserved at ca 4 -8 °C. More recently, some advocates of warm mobile machine preservation and perfusion of lungs during transportation to the receiving hospital have questioned whether cooling for transport before warm EVLP is justified. This cold vs warm preservation controversy has also recently spilled over to include the storage/preservation time after warm EVLP (before the organ is transplanted).

The following recent experimental and clinical publications throw some light on this controversy:
a) Is a period of static cold preservation BEFORE warm EVLP beneficial or detrimental?
b) Regarding cooling AFTER warm EVLP. How long is acceptable?

Clinical studies

The only comparative clinical study of lung transplant outcomes in relation to the duration of both pre-EVLP and post-EVLP cold preservation was presented at the April 2015 ISHLT annual congress by Arango –Tomas et al2.

Findings were based on deeper analysis of data from the recent US multicenter NOVEL study on use of STEEN Solution™ and the XPS™ to re-evaluate rejected “marginal” human lungs for transplantation.

The authors found, in a comparative study of 42 patients receiving EVLP-treated marginal lungs versus 42 control patients receiving standard “accepted” lungs, that:

  • Extension of cold ischemia AFTER warm EVLP beyond 5 hours adversely affects clinical outcomes in terms of a significantly greater risk for PGD and one-year mortality!
  • However, NO negative effects were associated with longer (> 5 hours) cold ischemic times BEFORE EVLP!

A detailed breakdown of the post-EVLP cooling data is presented below: Note in particular that no cases of PGD 3 at 72 hours were reported in patients receiving lungs stored cold for less than 5 hours AFTER EVLP, and that 1 year mortality in these patients was only 3 %.

Figure 1
Caveats include the short follow-up only 2.3 years) and that mortality was based on death from all causes!

Animal studies

a) Is a period of static cold preservation BEFORE warm EVLP beneficial or detrimental?
Mulloy DP et al 20123, designed a well-controlled study on DCD pig lungs to elucidate this issue. Their results clearly demonstrated the added benefit of 4 hour of static cold preservation time before warm EVLP in comparison to control lungs subjected directly to warm EVLP without preceding cold ischemia. Gaseous exchange (P/F ratios) during EVLP and until transplantation, for example, improved significantly in the group subjected to static cold preservation before warm EVLP (delayed EVLP) compared to those subjected to immediate warm EVLP (I-EVLP) and cold static preservation alone (CSP), (fig 2). Similar results were seen for other functional parameters, and for pro-inflammatory cytokine expression in BAL at the end of 4 hours of reperfusion (fig 3).

 

b) Animal data on cooling AFTER warm EVLP? How long is acceptable?
Although well controlled human clinical data on 42 vs 42 lung recipients (see Arango above) indicate that post-EVLP cooling should not exceed 5 hours, a recent animal study on 5 vs 5 pig lungs (Hsin et al, 2015(4)) would seem to contradict these clinical results. Hsin et al indicates that a cold storage period of up to 10 hours AFTER warm EVLP may be acceptable, at least under the narrow experimental conditions dictated by their study protocol. This discrepancy as to how long cold preservation after warm EVLP is acceptable is thus somewhat controversial. Both studies seem to be well controlled, although until further reliable evidence is available, the human clinical data would seem to be more persuasive. A couple of Hsin´s results are illustrated in figs 4, 5 and 6. The differences in P/F ratios between the 2 EVLP groups and control may appear dramatic, but of course the control regime (24 hours of cold ischemia without EVLP) was particularly harsh.

(Note: Short CIT = 2 hours of cold ischemia AFTER EVLP before transplant, long CIT = 10 hours ditto. Control = 24 hours of cold ischemic preservation without EVLP)

Fig 4

Fig 5

Fig 6

c) What is the optimal temperature for lung preservation AFTER warm EVLP?

All three studies above (Arango, Mulloy & Hsin) explore the optimal duration of cold preservation before or after warm EVLP.

However, a recent interesting study from Leuven (Stanzi A et al, 2014(5)) looked at the role of differences in preservation temperature AFTER warm-EVLP. The authors monitored post-transplant outcomes after preservation of pig lungs following warm EVLP at either room temp. (25 ⁰C) or cooled on ice. Surprisingly, they reported no major differences in outcomes 6 hours after transplant, suggesting that post-EVLP preservation at room temp (25 ⁰C) may be as effective as conventional cold (4-8 ⁰C) preservation.