Discussion
In contrast to our hypothesis, we found no postreperfusion syndrome and cardiac performance was not impaired in terms of systolic or diastolic function despite increased cytokine levels throughout the course of liver transplantation. Moreover, haemodynamic and echocardiographic parameters reflected the physiological haemodynamic changes due to clamping and unclamping of the vena cava and the consecutive measures like volume loading or administration of catecholamines.
Haemodynamic instability after reperfusion of the liver graft is a major concern in liver transplantation and correlated to poor outcome [
6]. In the last two decades many causal factors have been investigated, but none of them has proven the primarily responsible. Even the amount of catecholamines used for liver transplantation was analysed, but no significant correlation with cytokine release was found [
21]. The aim of the present study was to evaluate cardiac performance during liver transplantation and the reperfusion period via TEE and to assess the simultaneous cytokine release. We found decreased filling pressures, cardiac output and a compensatory increase of SVR after clamping. The reverse was documented after unclamping. The significant decrease of SVR after unclamping and reperfusion may be interpreted as a cytokine induced effect, also seen after cardiopulmonary bypass [
22]. MAP was maintained and CO increased in terms of a compensatory hyperdynamic state. Transoesophageal echocardiographic parameters proceeded similarly. There was no sign of systolic or diastolic dysfunction at any time during the transplantation. However, we are aware of the fact that FAC or EF rather reflect the adaptation to the loading conditions of the heart than inotropy. However, s’, being is less load dependent than FAC or EF, was relatively stable over the course of the transplantation and confirmed our conclusion. Unfortunately, we did not keep track of the acceleration time of s’, which might have been a less load dependent echocardiographic assessment of systolic function. The variations in transmitral flow, flow propagation velocity and early and late peak diastolic velocity of the mitral annulus were all compatible with the relevant volume variations during the clamping of the vena cava and immediately after the reperfusion of the liver. They varied according to the haemodynamic parameters and recovered at the end of the procedure.
Two cytokines are considered major cardiac depressants: IL-6 [
23] and TNF-α [
24] and therefore especially interesting to answer the question raised in this study. TNF-α was below the detection level in all of our patients.
In comparison to former liver transplantation trials we also have assessed markers that act on the various different inflammatory cells (neutrophils, macrophages, T-cells) and expanded our search pattern of inflammatory mediators to determine also molecules, not having been evaluated before. Although not significant for all parameters, there was an increase in cytokine levels during liver transplantation.
Most recently, Bezinover and collegues suggested an association between plasma cyclic guanosine monophosphate levels and haemodynamic instability during liver transplantation [
3]. Similar to their previous study [
21] they compared again the amount of catecholamines used to the levels of cGMP. However, choosing the amount of catecholamines as an indicator of haemodynamic stability may be misleading. Many other factors may contribute to catecholamine use during liver transplantation: patients often have a more or less pronounced hyperdynamic circulation with splanchnic vasodilation and a collateral circulation [
25] advanced cirrhosis may lead to cardiomyopathy [
26]. In addition the recipient may suffer from cardiovascular comorbidities. The preoperative coagulation profile may influence the amount and pace of blood loss, which might also impact on the haemodynamic situation, and catecholamine use of the recipient. Also the skills and experience of the surgeon, which have a proven impact on outcome in advanced bariatric surgery [
27], the hospital’s standard operating procedures for haemodynamic management and the individual experience and skills of the anaesthetist, might all impact on the use of catecholamines in liver transplant patients. The results of this study have to be interpreted in the background of the low caseload and all factors mentioned above. Furthermore, the considerably varying occurrence of PRS in the literature underlines this statement. The incidence reported ranges from 8 % to 50 % [
6,
8]. However, at our institution we have a detailed protocol for the anaesthetic management of liver transplantation and a specially trained team of consultants for liver and lung transplantation. In addition, one or the other of only two surgical team leaders was involved in all cases. This may have counteracted to individual differences and possibly strengthened the relevance of our results.
As mentioned above, there was no PRS and no impaired cardiac function during the whole procedure, while the level of most proinflammartory cytokines increased significantly (with exception of TNF-α, TGF-β and CD40L). The increase was similar to earlier studies, where either coincidental haemodynamic impairment was found [
28] or not present [
21]. Increased cytokines without impact on cardiac function are also regularly seen after cardiopulmonary bypass in cardiac surgery [
22].
A possible explanation for not observing PRS in our study population might be a rather low MELD-score, a good preoperative cardiac function as well as the good quality of donor organs. Cardiac output seems to adapt pretty well in response to stress in patients with a low MELD score, but even at this early stage of the disease, heart mass and the enddiastolic volume increase with higher scores [
29]. As the disease progresses, the changes in structure and function aggravate [
30]. In most patients, diastolic dysfunction seems to progress along with the progress of the disease [
31], whereas systolic dysfunction only develops in a subset of patients [
32].
Study limitations might be, that our patients had a rather low MELD score and a good cardiac baseline function. This makes the study population more homogenous on one hand but is likely not to reflect the full spectrum of changes related to end stage liver disease, especially in patients with a high MELD score. Also the low patient number may be considered a limitation of the current study. Strength of the study is the quality of the data and detailed echocardiography data. Since only our most experienced echocardiologist performed all echoes and measurements, we can assume that the quality of the measurements is very high and an inter-investigator variation can be excluded. The quality of the grafts was considered very good and although we observed a significant increase of some cytokines. We cannot exclude that a more pronounced cytokine release could have impacted on cardiac function.
We hope that our study lays ground for a larger study, observing patients in a more advanced stage of end stage liver disease, as PRS may be more frequent in this patient population and may thus uncover whether the pathophysiology of PRS is related to cardiac function or to vasoplegia.
Competing interests
MPZ, MS, BBS, BS and DB declare no competing interests related to the current study.
DRS’s academic department is receiving grant support from the Swiss National Science Foundation, Berne, Switzerland, the Ministry of Health (Gesundheitsdirektion) of the Canton of Zurich, Switzerland for Highly Specialized Medicine, the Swiss Society of Anesthesiology and Reanimation (SGAR), Berne, Switzerland, the Swiss Foundation for Anesthesia Research, Zurich, Switzerland, Bundesprogramm Chancengleichheit, Berne, Switzerland, CSL Behring, Berne, Switzerland, Vifor SA, Villars-sur-Glâne, Switzerland.
Dr. Spahn was the chairman of the ABC Faculty and is the co-chairman of the ABC-Trauma Faculty, which both are managed by Physicians World Europe GmbH, Mannheim, Germany and sponsored by unrestricted educational grants from Novo Nordisk Health Care AG, Zurich, Switzerland, CSL Behring GmbH, Marburg, Germany and LFB Biomédicaments, Courtaboeuf Cedex, France.
In the past 5 years, Dr. Spahn has received honoraria or travel support for consulting or lecturing from the following companies: Abbott AG, Baar, Switzerland, AMGEN GmbH, Munich, Germany, AstraZeneca AG, Zug, Switzerland, Bayer (Schweiz) AG, Zürich, Switzerland, Baxter AG, Volketswil, Switzerland, Baxter S.p.A., Roma, Italy, B. Braun Melsungen AG, Melsungen, Germany, Boehringer Ingelheim (Schweiz) GmbH, Basel, Switzerland, Bristol-Myers-Squibb, Rueil-Malmaison Cedex, France and Baar, Switzerland, CSL Behring GmbH, Hattersheim am Main, Germany and Berne, Switzerland, Curacyte AG, Munich, Germany, Ethicon Biosurgery, Sommerville, New Jersey, USA, Fresenius SE, Bad Homburg v.d.H., Germany, Galenica AG, Bern, Switzerland (including Vifor SA, Villars-sur-Glâne, Switzerland),GlaxoSmithKline GmbH & Co. KG, Hamburg, Germany, Janssen-Cilag AG, Baar, Switzerland, Janssen-Cilag EMEA, Beerse, Belgium, Merck Sharp & Dohme AG, Luzern, Switzerland, Novo Nordisk A/S, Bagsvärd, Denmark, Octapharma AG, Lachen, Switzerland, Organon AG, Pfäffikon/SZ, Switzerland, Oxygen Biotherapeutics, Costa Mesa, CA, Photonics Healthcare GmbH, Munich, Germany, ratiopharm Arzneimittel Vertriebs-GmbH, Vienna, Austria, Roche Diagnostics International Ltd, Reinach, Switzerland, Roche Pharma (Schweiz) AG, Reinach, Switzerland, Schering-Plough International, Inc., Kenilworth, New Jersey, USA, Tem International GmbH, Munich, Germany, Verum Diagnostica GmbH, Munich, Germany, Vifor Pharma Deutschland GmbH, Munich, Germany, Vifor Pharma Österreich GmbH, Vienna, Austria, Vifor (International) AG, St. Gallen, Switzerland.
Authors’ contributions
MPZ and DB designed the study; MPZ, DB and BBS performed the study; MPZ, MS, BBS, BS, DRS and DB analysed the data; MPZ wrote the manuscript; MS, BBS, DRS and DB revised the manuscript. All authors read and approved the final manuscript.