Description of the perioperative evolution of sodium levels and neurohormonal response in patients with cirrhotic liver disease undergoing OLT was the main objective of our study. All patients with hyponatremia were in the ChildC group. Interestingly, low plasma sodium concentration was corrected rapidly after cirrhotic liver was removed and the plasma sodium concentration remained within normal ranges 1 day, as well as 6 months after surgery. This correction was not associated with adverse outcomes within study’s observation period. Specifically, no central pontine myelinolysis was observed.
Hyponatremia in cirrhosis is primarily the result of solute-free water retention exceeding that of sodium [20]. The proposed mechanism is splanchnic arterial vasodilatation leading to reduced systemic vascular resistance and the release of various neurohormones. An arterial underfilling is sensed by baroreceptors and activates a compensatory neurohumoral response through the sympathetic nervous system, the renin-angiotensin-aldosterone system, as well as the release of arginine vasopressin. The net result of this activation is solute-free water retention, intense renal sodium retention, and hypervolemic hyponatremia. The degree of activation of these neurohumoral mechanisms correlates directly to the degree of portal hypertension [21]. Serum sodium concentration is therefore an important parameter to be considered before OLT as it might reflect the severity of the disease.
Several studies emphasize the importance of sodium levels in the assessement fot OLT priority within potential candidates. Hyponatremia < 130 mmol/L was shown to be an independent predictor of mortality after listing, as lower sodium levels at inclusion in the waiting list were associated with 3- and 12-month decreased survival [7]. A clear cutoff for the association between hyponatremia and survival after listing in not yet well defined and differ between studies: < 135 mmol/L [22], < 130 mmol/L[23], or 126 mmol/L [24] respectively. The mortality risk might also be inversely correlated to the plasma sodium concentrations [16, 25]. Consequently, several MELD-derived scores that incorporate plasma sodium concentration proposed to include hyponatremia as a priority criterion for OLT. The prevalence of hyponatremia in OLT candidates varies from 11–34%. It is 21,6% (cutoff at 130 mmol/L) or 49.4% (cutoff at 135 mmol/L) in the overall population of cirrhotic patients. In our study, hyponatremia was present in four patients (30%, cutoff at 135 mmol/L). None of the patients had a sodium concentration lower than 120 mEq/L.
The predictive effect of sodium concenratation was shown to be greater within patients with low MELD SCORE. Thus, in the same way that serial MELD scores predict mortality better than a single value, serial measurements of plasma sodium could have a better predictive value than a single measurement [16]. While awaiting OLT, hyponatremia is likely to fluctuate over time concomitantly with the complications of cirrhosis and the patient treatment [26, 27]. This fluctuation was reproduced in our study (see Fig. 2). The number of acute aggravations and the ability to recover would probably be a factor of interest at the time of OLT listing and should be futher studied. An increased risk of death is associated with a serum sodium concentration < 126 mmol/L (6.5fold increase) or < 131 mmol/L (5-fold increase) measured at any time during the waiting period for OLT [25]. In our study, a serum sodium concentration < 131 mmol/L at the time of listing was not associated with an increased risk of death at 6 monthes following OLT. The fact that sodium levels fluctuate before OLT and that hyponatremia seem to have predictive effect for postOLT increased mortality might strengthen the importance of studying the effect of serial sodium concentration measuring before OLT as they could provide a fuller picture of postOLT mortality risk.
In addition, Hyponatremia prior to OLT was associated with an increased 90-day postoperative mortality [14]. Similarly, in patients with cirrhosis, hyponatremia at time of OLT (< 130 mmol/L) was shown to increase the risk of postoperative neurologic disorders, infectious complications, and renal failure during the first month after OLT and reduced the 3-month survival rate [13]. However, the postOLT outcome highly depends on donor characteristics, cardiovascular evolution during liver replacement, and surgical complications. In our study, sodium levels were significantly lower in patients with severe liver failure before OLT. Sodium correction took place during OLT before the surgical anhepatic phase (Fig. 1), reaching similar normal values in both groups. None of the patients experienced neurological complications due to this rapid correction of sodium concentration.
Correction of hyponatremia following OLT and its outcomes seems to be a matter of debate. Few studies have focused on the fluctuations of sodium levels during and after OLT. Both, Romanovski et al. [28] and Hudcova et al. [29], have shown that rapid correction of natremia after OLT in hyponatremic patients was associated with worse outcomes and complications in the post operative period of OLT. Similarly, Park et al. [30] has found that major shift of natremia during OLT with liver donor was a risk factor for prolonged mecanical ventilation post transplantation. In contrast, the study from Brandmann et al. [31] paying particular attention to the consequences of fluctuations in sodium levels in patient with hepatic encephalopathy before OLT, showed that there was no influence on neurological outcome or length of stay in ICU. Leise and al [32] have even found that hyponatremia was not associated with worse outcomes unlike hypernatremia before OLT. In our study, natremia correction was not associated with negative outcomes and the time spent in ICU after OLT was not significantly longer in patients with hyponatremia.
Another interesting observation of our study is that hyponatremia coexists with most complications of cirrhosis as previously reviewed by Schrier el al. [1, 4] (Fig. 4). Activation of arterial baroreceptors occurs with low cardiac output (cirrhotic cardiomyopathy or decreased preload) as well as high cardiac output (septic-like syndrome/inflammation) and exacerbation of splanchnic vasodilatation with increased portal pressure [1, 4, 33]. This unifying hypothesis further reinforces the usefulness of hyponatremia as a marker of disease severity. When serum sodium concentrations were measured over time in a single patient (Fig. 2), hyponatremia was associated with decreased preload (digestive hemorrhage) or sepsis/inflammation (bacterial peritonitis). Recurrent ascites with hyponatremia frequently remains of unknown origin. Thus, besides rare neurological disorders induced by rapid modifications of serum sodium concentration, hyponatremia is likely to be a surrogate marker of either decreased preload, aggravation of cardiomyopathy, aggravation of liver disease (increased splanchnic vasodilatation), or occurrence of a septic-like syndrome through arterial underfilling. Guidelines have been published to treat episodes of hyponatremia in cirrhotic patients [34]. However, treatment of acute complications of cirrhosis and OLT are likely to be the best therapies when hyponatremia occurs [35].
Finally, the exact mechanism of hyponatremia correction during OLT is yet to be elucidated. In our study, normalization of serum sodium concentrations within the surgical period was unrelated to the systemic vascular resistance that remain unchanged in ChildC patients during the perioperative period. Although, portal blood flow immediately increases with graft placement, correction of the splanchnic arterial vasodilatation is usually observed only within 3 to 6 months after OLT [36]. The systemic vascular resistance is unlikely to be reflected by the stimulation of arterial baroreceptors by arterial underfilling as previously shown by Rector et al. [37]. RW Schrier [1, 4] emphasizes that arterial underfilling should be assessed by the release of neurohormones. In the ANH phase of OLT, serum renin activity and concentrations of epinephrine, vasopressin, and pro-BNP increased similarly in both ChildAB and ChildC patients (Table 4) as previously described [38]. However, the unstable peroperative conditions associated with a high neurohormonal response precludes correlating the normalization of serum sodium concentration to a decrease hormone release. Eyraud et al. have already shown in 2002 [39] that, in patients with normal liver function who had major hepatic resection with portal triad clamping and occlusion of the inferior vena cava below and above the liver, the sudden drop in venous return enhances the neurohormonal response to sustain the systemic hemodynamics. After unclamping, endogen catecholamines, vasopressin, renin and atrial natriuretic peptide return to baseline values within five minutes. These observations suggest that this acute neurohmoral response, which is similarly observed in our study, do not solely explain the progressive normalization of sodium levels observed after OLT.
Interstignly, Cystatin-C values were moderately but significaly higher in the ChildC group 24 hours after OLT. This increase is consistent with recent studies showing that Cystatin-C is a more sensitive indicator for renal impairment in cirrothic patients than serum creatinine and creatinine clearance [40]. Moreover, higher values of Cystatin-C were correlated with a more severe cirrothic disease [41] and has been shown to be an independent predictor of post OLT survival [42]. Thus, Cystatin-C measurement might be of interest for early detection of kidney disease and as so, help prevent renal related complications in cirrothic patients. In addition, the sensitivity of Cystatin-C for early detection of kidney disease in cirrothic patients, its correlation with the severity of the disease and its prediction value for post OLT mortalilty could place the cystatin-C as an interesting factor in priotizing patients in the OLT waiting list and should be further studied.
Our study has significant limitations. The number of patients was limited and the number of patients with a very low natremia (only 3 ou of 27 patients had sodium levels < 130 mmol/l) even smaller, the sample size however, correlates to our institution’s annual average liver trasnplatations. Furthermore, the choice of using the Child-Pugh classification to assess severity of cirrhosis could be a matter of debate. Since the MELD score was adopted in 2002 to allocate priority to candidates, the mortality on the waiting list has decreased. The MELD score predicts the survival for patients with cirrhosis more acurately than the Child score. Interestingly, in patients with hyponatremia, the MELD-Na score might further decrease the 90-days mortality on the waiting list [14]. However, to assess the severity of cirrhosis in our study, we chose the Child-Pugh score that reflects clinical symptoms (encephalopathy and ascites) better than the MELD score, which is based on the logarithmic transformation of bilirubin, creatinine, and INR.