Background

The number of lung transplantations has increased over the past 30 years. Adults who underwent primary lung transplantation (LTx) between 1990 and 2012 had a median survival of 5.7 years, with unadjusted survival rates of 88% at 3 months and 80% at 1 year [1]. The development of primary graft dysfunction (PGD) during the first 3 days is approximately 30% and PGD has been associated with significantly longer hospital length of stay, duration of mechanical ventilation, and 90-day mortality [2]. After standardization of the definition of PGD in 2005 by the International Society for Heart and Lung Transplantation (ISHLT), risk factors for grade 3 PGD were: receipt of an organ from a donor with any smoking history, elevated FiO2 during reperfusion, preoperative diagnosis of sarcoidosis, use of cardiopulmonary bypass, single LTx, large-volume blood transfusion, elevated pulmonary arterial pressures, and an overweight or obese recipient [3,4]. A systematic review and meta-analysis found that, in addition, recipient female gender, African-American race, and preoperative diagnosis of idiopathic pulmonary fibrosis were also associated with PGD [5].

For several solid transplant organs, such as heart, liver, kidney and pancreas, donor hypernatremia has been found to be associated with reduced graft survival. Post-transplant edema of the hypernatremic graft in a recipient with normal sodium levels has been proposed as one of the pathogenic mechanisms [6–9]. However, it is not known if donor hypernatremia is also associated with poor outcomes in lung transplant recipients.

In cohorts of critically ill patients, it has been shown that hypernatremia at intensive care unit (ICU) admission or hypernatremia acquired during ICU stay was associated with increased risk of mortality that was independent of age and severity of disease [10–12]. However, for patients presenting with a respiratory diagnosis, this was not found to be the case, suggesting that the general adverse effects of hypernatremia are overcome by lung protective effects in patients with lung injury [13]. The lung is different from other solid organs because of the small interstitial space and because its main function of gas exchange is a passive function. Alveolar fluid clearance through the osmotic gradient between sodium and chloride is crucial for the reabsorption of alveolar edema in cases of increased alveolar permeability.

We hypothesized that donor lungs from hypernatremic donors might display higher rates of PGD due to the difference in osmolality between hypernatremic donor and normonatremic recipients. We therefore studied the relation of donor hypernatremia with the duration of postoperative mechanical ventilation, the occurrence of severe PGD following lung transplantation, and mortality.

Material and Methods

STATISTICAL ANALYSIS:

Demographic data on categorical variables are shown as absolute numbers as well as percentages. Unless otherwise indicated, values are expressed as means ±SD. The unpaired Student’s t-test, and the Kruskal-Wallis and Fisher’s exact tests (all 2-tailed) were used to compare the 3 groups. Kaplan-Meier curves for graft survival were constructed and compared with the log-rank test. Graft failure was defined as re-transplantation or death. Risk factors for PGD were used in Cox regression analysis to determine predictors for survival. A value of P<0.05 was considered to be statistically significant. IBM SPSS software version 23 was used.

Results

There were 474 recipients included in this study, with a mean ±SD age of 48±12 years; 48% of recipients were men. Of these, 69 recipients (15%) were admitted to the ICU pre-transplantation, and 28 recipients (6%) were mechanically ventilated pre-transplantation; 386 recipients (81%) underwent bilateral LTx.

Donor age was mean ±SD of 43±14 years. Donor serum sodium levels were available for all donors and ranged from 123–182 mmol/L, with a mean of 147±8 mmol/L.

There were no significant differences in demographic donor- and recipient-related variables among recipients with normal, moderate, and severe donor sodium levels (Table 1). Outcomes between the 3 groups were similar (Table 2). The change of preservation solution from Euro-Collins to Perfadex showed no relation with outcome parameters. For all patients, the time on mechanical ventilation was 8±20 days, grade 3 PGD at any moment occurred in 28% of patients, length of stay in the ICU was 12±18 days, length of stay in hospital was 42±28 days. There were 17 patients (3.6%) who had a re-transplantation. Overall, the 10-year mortality was 38%. Kaplan-Meier time-to-event curves for the 3 groups were not different for patient or graft survival (Figures 1, 2). Results from the Cox regression analysis are presented in Tables 3 and 4. In this model, hypernatremia was added to the available risk factors for (graft) survival, including the use of cardiopulmonary bypass, single LTx, body mass index (BMI) <22 kg/m2, number of transfused red blood cells in the first 24 hours postoperatively, and any donor smoking history. In this multivariate analysis, the only significant predictor for patient and graft survival was the number of red blood cells transfused in the first 24 hours (P=0.007 and P=0.009, respectively).

Discussion

To our knowledge, this is the first report on the possible effect of donor hypernatremia on outcome after LTx. In contrast to observations for heart, pancreas, and liver transplantations [6–8], we found no adverse effect of donor hypernatremia on ventilation time, primary graft dysfunction, or mortality after LTx.

Donor hypernatremia has been associated with worse outcomes in other solid organs. In one study of 181 liver grafts, it was found that donor hypernatremia caused postoperative elevated AST and ALT levels and an increased rate of early graft loss [7]. But the aforementioned study indicated that changes in hepatocytes induced by hypernatremia were reversible and the correction attenuated liver graft injury [7]. In one study, 164 recipients had a larger intraoperative increase in serum sodium associated with worse recipient short-term outcomes. The 10% of patients with preoperative hyponatremia (<130 mmol/L) seemed to be at risk for complications because of their larger shift in sodium, which was associated with higher odds of prolonged intubation and longer ICU stay and hospital length of stay [15]. Importantly, in assessment of donor livers, a peak serum sodium >155 mmol/L is considered a marginal donor criterion [16]. In a single center retrospective study on donor sodium levels, no impact was found on the outcome after heart transplantation, however, the comparatively mild donor hypernatremia in the high-risk group (162±7 mmol/L) potentially limited their results [17]. In a much larger cohort of 4641 patients after cardiac transplantation, a clear U-shaped correlation of both high (>170 mmol/L) and low (<130 mmol/L) donor sodium levels with 1-year mortality rate was found [6]. This effect was mainly evident within the first 3 months after transplantation, suggesting that hypo- and hypernatremia affect initial graft function. In the consensus statement for PGD in heart transplantation, hypernatremia was named as a donor risk factor [18]. In a small study of 80 kidney recipients from 54 brain dead donors in Poland during 2006–2008, no relationship was observed between donor serum sodium concentration and early or 1-year renal function [9]. But there was a negative correlation between donor serum sodium concentration and recipient creatinine clearance at 2, 3, and 4 years after kidney transplantation. This suggests that high sodium concentrations in donors may initiate chronic reactions, which damage the kidney [9]. A retrospective analysis of in vivo and in vitro pancreatic islet function studies in mice was performed on islets isolated from hypernatremic (serum sodium levels ≥160 mmol/L) and control (serum sodium levels ≤155 mmol/L) human pancreatic donors. In the assessment of islet efficacy and survival, it was shown that donor hypernatremia, dependent on its duration, was associated with a significant islet loss and diminished function when transplanted. The authors proposed an additional role of elevated chloride levels in hypernatremic donors, suggesting that the influx of chloride ions may also trigger cell death and loss of islets [8]. Various other mechanisms could explain the relation between donor hypernatremia and outcome after solid organ transplantation. Donor hypernatremia might be a marker of severe injury to the host and may be related to other relevant but unspecified factors. Hypernatremia may result in retention of extra amounts of sodium by the transplanted organ leading to increased edema upon reperfusion. Although the lung is obviously very sensitive to the development of edema, the impact of the preservation phase on a “hypernatremic” lung might differ from normonatremic organs. In an animal study of LPS-induced acute lung injury, it was shown that a hyperosmolar state – in this model of hypernatremia with a maximum of 165 mmol/L – led to decreased vascular permeability and less pulmonary edema [19].

We also looked at the potential effect of different preservation solutions over the study time period. In our institution, in 2001, we changed the preservation solution from Euro-Collins, a solution with a sodium concentration of 10 mmol/L, to Perfadex, a solution with a sodium concentration of 138 mmol/L. The high sodium content of Perfadex is thought to maintain the intracellular energy levels better and avoid hyperkalemia-induced pulmonary vasoconstriction. There is no proven difference in survival between the 2 solutions but the use of Perfadex has been shown to improve the PaO2/FiO2 ratio and lower the duration of mechanical ventilation [20]. In our study, we did not find a relation of this change in policy with outcomes.

Limitations of our analysis were its retrospective nature and that it was a single center study. Although we had a large cohort, it was not as large as an international registry. The Eurotransplant report form only contains data on sodium at the day of donation, so the duration of the hypernatremia in the donor could not be determined. We chose to use the peak sodium levels on the day of procurement because hypernatremia is typically only slowly corrected in the ICU [21,22]. Also, the sodium level in the recipient was not known. Measurement of pulmonary artery pressure was not routine at our center, so these data were missing from this study. During the long study period other factors (like the use of different immunosuppression schemes) may have confounded the effect of donor hypernatremia. We also did not have complete data on the use of extended donor criteria or the lung allocation score of the recipients.

Conclusions

In conclusion, donor hypernatremia was not associated with primary graft dysfunction, duration of mechanical ventilation, or long-term survival. Thus, in contrast to other solid organs, donor hypernatremia is not a contraindication for lung transplantation.