Intraoperative Changes in Hyponatremia as a Risk Factor for Prolonged Mechanical Ventilation After Living Donor Liver Transplantation

Intraoperative Changes in Hyponatremia as a Risk Factor for Prolonged Mechanical Ventilation After Living Donor Liver Transplantation C. Park, D. Kim, J. Choi, and E. Kim ABSTRACT Prolonged mechanical ventilation (PMV), a common clinical manifestation, may result in fatal outcomes after living donor liver transplantation (LDLT). Although hyponatremia contributes to neurologic alterations in association with PMV, the effects of acute changes in hyponatremia during LDLT have not been well studied. We sought to determine whether an acute change in hyponatremia during surgery might be a risk factor for PMV after LDLT. Perioperative data were retrospectively collected from 381 patients who underwent LDLT from January 2000 to December 2008. PMV was defined as the need for ⱖ24 hours of mechanical ventilation within the first postoperative week. Using multivariate logistic regression a simple comparison of perioperative variables between the PMV group and the non-PMV group yielded a predictive model to establish PMV. Thirty-seven patients (9.7%) experienced PMV after LDLT. Intraoperative changes in blood sodium were associated with postoperative PMV; however, the relationship was limited to patients with preoperative hyponatremia. Patients with PMV showed lower survival rates than those without PMV (56.3% vs 86.3%; P ⬍.001). A multivariate analysis revealed that preoperative hepatic encephalopathy, hypotension during surgery (more than 3 bowls), and intraoperative changes in hyponatremia were predictive of PMV. Among the hyponatremia change subgroups, only a severe intraoperative change (ⱖ10 mEq/L) was associated with PMV occurrence (odds ratio, 5.85; 95% confidence interval, 1.62 to 21.20, P ⫽ .007). In conclusion, a severe intraoperative change in hyponatremia was a risk factor for PMV in the immediate period after LDLT. ROLONGED MECHANICAL VENTILATION (PMV) is a clinical manifestation that frequently occurs during the intensive care period after liver transplantation. More than 10% of liver transplantation recipients require mechanical ventilator support lasting longer than 24 hours during the immediate postoperative phase.1 After organ transplantation, PMV is considered to be a sign of a poor prognosis in immunocompromised patients, due to its negative impact on blood flow to the grafted liver2 and the potential infectious episodes.3 Among the many risk factors for PMV after liver transplantation,4,5 neurologic dysfunction plays a critical role in the need for extended mechanical ventilation during the perioperative period.6,7 A patient’s neurologic status is strongly associated with acute, wide dysregulation of blood electrolytes. In particular, hyponatremia (blood sodium concentration ⬍130 mEq/L) contributes to a disruption of

P

neuronal electrophysiology; therefore, it has been widely studied in neurosurgery.8,9 During liver transplantation, the body fluid composition, including electrolytes, changes greatly from the preoperative value after a difficult intraoperative course. Due to hemorrhagic tendencies administration of large volumes of transfusions or fluids with high sodium content is required complex living donor liver transplantations (LDLT) with long surgical times for microscopic vascular anastomoses,10

From the Department of Anesthesiology and Pain Medicine, College of Medicine (C.P., J.C., E.K.), The Catholic University of Korea, Seoul, Korea. Address reprint requests to Prof. Eunsung Kim, MD, College of Medicine, 505 Banpo-4 Dong, Seocho-gu, Seoul, Korea. E-mail: [email protected]

0041-1345/10/$–see front matter doi:10.1016/j.transproceed.2010.06.039

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Transplantation Proceedings, 42, 3612–3616 (2010)

INTRAOPERATIVE CHANGES IN HYPONATREMIA

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Table 1. Comparison of Preoperative Variables Between the Group With and That Without Prolonged Mechanical Ventilation After Living Donor Liver Transplantation Non-PMV Group (n ⫽ 344)

Age (yrs) Male/female Body mass index (kg/m2) MELD score (points) Child-Pugh-Turcott class C Emergency Hepatorenal syndrome Hepatic encephalopathy Ischemic heart disease or cardiac arrythmia Dialysis Hyponatremia (Na⫹ ⬍130 mEq/L) Laboratory findings Hematocrit (%) Platelet (⫻109/L) Serum glutamic pyruvic transaminase (U/L) Ammonia (␮g/dL) Arterial blood bas analysis O2 index (PaO2/FiO2) PaCO2 (mm Hg)

PMV Group (n ⫽ 37)

P

49.3 ⫾ 8.5 72.4/27.6 23.7 ⫾ 3.2 18.1 ⫾ 7.7 46.6 4.9 7.0 12.5 8.5 3.5 10.4

48.4 ⫾ 11.8 59.5/40.5 23.8 ⫾ 2.9 26.2 ⫾ 10.5 75.7 27.0 24.5 48.6 19.4 21.6 24.3

NS NS NS ⬍.001 .001 ⬍.001 ⬍.001 ⬍.001 .064 ⬍.001 .027

29.66 ⫾ 4.70 64.95 ⫾ 46.96 59.8 ⫾ 127.2 120.9 ⫾ 65.8

29.28 ⫾ 5.02 59.68 ⫾ 33.06 209.3 ⫾ 410.7 165.0 ⫾ 99.9

NS NS .039 .016

458.8 ⫾ 114.1 35.3 ⫾ 5.2

431.6 ⫾ 124.0 35.0 ⫾ 6.6

NS NS

Data are expressed as mean ⫾ SD or percentage. NS, P ⬎.10. MELD: model for end-stage liver disease; NS: not significant; PMV: prolonged mechanical ventilation.

As a result, the blood sodium concentration rises tremendously in most preoperatively hyponatremic patients. This study was designed to address perioperative risk factors affecting PMV occurrence after LDLT. In particular, we sought to investigate whether intraoperative changes in hyponatremia could be independent predictors of the need for PMV during the immediate phase after LDLT. PATIENTS AND METHODS We reviewed the perioperative data of 404 patients who underwent liver transplantation from January 2000 to December 2008 after approval from our institutional review board. Data were limited to adult living donor cases. Our electronic medical recoding system and chart system were used for retrospective data collection. We divided the patients into a PMV group or a non-PMV group to compare perioperative variables. Transplantation was performed using the right hepatic lobe. Anesthesia was performed according to our routine guidelines. Blood sodium concentrations were checked by blood sampling through an arterial line at 1-hour intervals. The difference between the first and last blood sodium concentration measurement was defined as the intraoperative change in blood sodium, which was grouped by clinically recommended values for statistical analyses: mild: ⬍6.0 mEq/L-moderate: 6.0 to 9.9 mEq/L; and severe: ⱖ10.0 mEq/L.11 PMV was defined as mechanical ventilation support lasting longer than 24 hours within the first postoperative week Mechanical ventilation after reintubation or reoperation was also included in the total mechanical ventilation time. One-year survival data after LDLT were studied to evaluate the PMV prognosis. A sample size of 313 for this study was obtained according to results of a pilot study (odds ratio, 4.0; power, 0.8; type I error probability, 0.05) using the Power Analysis and Sample Size (PASS) 2008 statistic software (NCSS, Kaysville, Utah, USA).

Continuous variables were dichotomized or grouped at the median, quartile, or clinically referred values. Student t test and Pearson chi-square, or Fisher exact tests were used for univariate analyses. Kaplan-Meier analysis with a log-rank test was applied to compare the survival rates of the 2 groups. Selected potential risk factors (P ⬍.10) according to the univariate analysis were subjected to forward and backward stepwise logistic regression processes to build a PMV predictive model after LDLT. Results of the multivariate analysis were displayed as odds ratios (ORs), 95% confidence intervals (CIs), and P values. A 2-tailed P ⬍ .05 was considered significant. The sensitivity and unbiased estimate of the PMV predictive model was evaluated according to area under the receiver operating characteristic (ROC) curve. The Statistical Package for the Social Sciences 15.0 for Windows (SPSS Inc., Chicago, Ill, USA) and MEDCALC for Windows version 11.0 (MedCalc Software, Mariakerke, Belgium) were used for statistical analyses.

RESULTS

We investigated 381 of 404 LDLT patients during the study period, excluding cadaveric donor, pediatric, and incomplete cases. The most common diagnosis for liver transplantation was liver cirrhosis due to hepatitis B virus (59.9%). The mean postoperative mechanical ventilation time was 17.1 hours. Thirty-seven patients (9.7%) were categorized into the PMV group, including, 11 (29.7%) who had undergone reoperations and 10 (27.0%) who had been reintubated. Table 1 shows a comparison of the preoperative variables. The PMV group had a more severe disease classification, as expressed by higher points in the model for end-stage liver disease (MELD) score, and a greater incidence of Child-Pugh-Turcott class C than the non-PMV

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PARK, KIM, CHOI ET AL

Table 2. Comparison of Donor and Intraoperative Variables Between the Group With and That Without Prolonged Mechanical Ventilation After Living Donor Liver Transplantation Non-PMV Group (n ⫽ 344)

PMV Group (n ⫽ 37)

Donor variables Graft macrosteatosis 6.4 16.1 (⬎20%) Graft recipient weight 1.31 ⫾ 0.21 1.38 ⫾ 0.21 ratio (%) Intraoperative variables Transfusion and fluid Packed red cell (units) 13.1 ⫾ 8.6 16.0 ⫾ 10.3 Fresh frozen plasma 10.9 ⫾ 7.8 13.6 ⫾ 10.7 (units) 0.9% normal saline (L) 4.4 ⫾ 2.2 5.2 ⫾ 2.9 Hypotension (⬍70 mm Hg, 19.8 35.1 more than 3 times) Last serum Na⫹ (mEq/L) 138.9 ⫾ 4.7 139.1 ⫾ 5.8 Last O2 index (PaO2/FiO2) 494.9 ⫾ 94.4 461.8 ⫾ 110.5 Blood sodium change Mild: ⬍6.0 mEq/L 76.6 60.0 Moderate: 6.0–9.9 16.3 25.7 mEq/L Severe: ⱖ10.0 mEq/L 7.1 14.3 Blood sodium change in hyponatremic patients Mild: ⬍6.0 mEq/L 92.9 78.4 Moderate: 6.0–9.9 4.0 8.1 mEq/L Severe: ⱖ10.0 mEq/L 3.1 13.5

P

.063 .069

.056 NS .096 .036 NS .092 .089

.004

Data are expressed as mean ⫾ SD or percentage. NS. P ⬎ .10. NS: not significant; PMV: prolonged mechanical ventilation.

group (P ⫽ .001). Approximately half of the patients in the PMV group experienced complications from hepatic encephalopathy, with correspondingly high blood ammonia levels. Renal complications, such as hepatorenal syndrome or dialysis, were also more frequent in the PMV group (P ⬍ .05). However, pulmonary manifestations upon radiologic examinations and arterial blood gas analyses were not different between the 2 groups. The prevalence of preoperative hyponatremia in the PMV group was more than double that in the non-PMV group (24.3% vs 10.4%, P ⫽ .027). The association of donor and intraoperative variables with PMV is shown in Table 2 Frequent episodes of intraoperative hypotension influenced long postoperative ventilator support (P ⬍ .05), but the volume of transfused blood or administered fluids was not associated with PMV. Oxygenation status of patients during surgery also was not associated with long postoperative mechanical ventilation. Overall blood sodium changes during surgery did not affect postoperative PMV. In contrast, intraoperative blood sodium changes in hyponatremic patients showed a significant association with PMV (P ⫽ .004). In particular, a greater than moderate change in hyponatremia (ⱖ6 mEq/L) corre-

lated with a higher incidence of PMV after surgery. No donor variables influenced the differences between the 2 groups. The multivariate analysis revealed that preoperative hepatic encephalopathy, intraoperative hypotension, and intraoperative changes in hyponatremia were risk factors predicting PMV after LDLT (Table 3). In an analysis based on the severity of the changes in intraoperative hyponatremia only a change ⬎10 mEq/L was selected as associated with PMV (OR, 5.85; 95% CI, 1.62 to 21.20, P ⫽ .007). The area under the ROC curve indicated that this model had a clinically suitable accuracy to predict PMV after LDLT (P ⬍ .001). Patients in the PMV group showed significantly lower 1-year survival rate compared to those in the non-PMV group (56.3% vs 86.3%, P ⬍ .001). Nine (64.3%) of 14 deaths in the PMV group occurred within the first month after LDLT. DISCUSSION

Hyponatremia, a useful marker representing the severity of liver disease, is a typical indicator of poor clinical outcomes among patients with end-stage liver disease.12 In cases of a low MELD score (⬍21 points), the predictive accuracy of hyponatremia has been reported to be better than that of the MELD score.13 The 20% incidence of hyponatremia can reach 50% if the criterion is increased to 135 mEq/L; however, the identified incidence of hyponatremia (n ⫽ 44, 11.5%) in this study was not high.14 As expected, preoperative hyponatremia showed an association with postoperative mechanical ventilation in a simple comparison between the 2 groups. However, it was not selected as a final predictor after adjusting for other confounding factors, which made us consider a more powerful mechanism other than preoperative hyponatremia in association with long ventilator support after LDLT. Fluid and electrolyte management during liver transplantation may be complicated. Cirrhosis and portal hypertension lead to bleeding via several mechanisms, including Table 3. Independent Risk Factors for Prolonged Mechanical Ventilation After Living Donor Liver Transplantation According to a Multivariate Logistic Regression

Preoperative hepatoencephalopathy Intraoperative hypotension Intraoperative changes in hyponatremia (mEq/L) Mild: ⬍6.0 (reference subgroup) Moderate: 6.0–9.9 Severe: ⱖ10.0 Area under ROC curve: 0.75

␤

Odds Ratio

95% CI

1.50

4.49

1.87–10.77

.001

0.91

2.49

1.05–5.88

.038 .018

0.95 1.77

2.58 5.85

0.59–11.24 1.62–21.20 0.71–0.80

CI: confidence interval; ROC: receiver operating characteristic.

P

.206 .007 ⬍.001

INTRAOPERATIVE CHANGES IN HYPONATREMIA

platelet dysfunction or deficiency, reduction of coagulation factor synthesis, and impaired fibrinolytic substance clearance.15 Surgical dissection of highly developed collateral vessels due to portal hypertension can also induce massive bleeding. LDLT in particular may be associated with a greater likelihood of intraoperative body fluid and electrolyte disturbance due to the more complex surgical processes. These etiologies induce significant body fluid loss; subsequent administration of exogenous fluids or blood components is unavoidable. Most blood cell components, fluids and sodium bicarbonate to correct metabolic acidosis contain high concentrations of sodium. Therefore, maintaining the blood sodium level of hyponatremic patients within the preoperative range is difficult despite efforts at amelioration with low salt solutions. In our study, the blood sodium change in hyponatremic patients was 8.2 mEq/L despite efforts to depress the increase, which was nearly twice as much as that in nonhyponatremic patients (data not shown). This range in intraoperative sodium change was sufficient to produce great concern for postoperative sequelae. A wide range of hyponatremia changes during a short period can cause dangerous neurologic complications.16,17 The critical role of neurologic dysfunction excluding discontinuance of mechanical ventilation has already been shown to be a risk factor for long term mechanical ventilation in critically ill patients.18 A clinically accepted, safe range for the hyponatremia change is 6 to 8 mEq/L in 24 hours or 12 to 14 mEq/L in 48 hour ideally, it is less than 4 to 6 mEq/L in 24 hours. If the rate of change surpasses 10 mEq/L in 24 hours or 18 mEq/L in 48 hours, the risk of iatrogenic brain damage increases.11 Blood sodium levels in hyponatremic patients are usually controlled during liver transplantation based on this clinical reference. Our study suggested a few clinically important observations with regard to intraoperative changes in hyponatremia. First, the blood sodium change in nonhyponatremic patients caused no postoperative ventilatory problems. Only preoperative hyponatremia change was identified as an etiology for long postoperative ventilation following LDLT. Second, the incidence of PMV was correlated with a severity of hyponatremia change greater than 6 mEq/L. However, only severe hyponatremia change of ⱖ10 mEq/L during the entire LDLT period was a critical threshold with prognostic ability for a poor postoperative outcome. Third, the intraoperative change in hyponatremia was a more powerful predictor of PMV than was preoperative hyponatremia alone. Preoperative hyponatremia without consideration of a severe intraoperative change was insufficient to be chosen as a final predictor. PMV is a representative indicator of poor prognosis during the postoperative period after liver transplantation.1,3,19 The incidence of PMV in this study was nearly identical to that in previous reports, its association with a poor prognosis was identified by low around 50% 1-year survival rates. In particular, critical care during the first postoperative month is clearly recognized to determine the survival of patients with PMV after LDLT. The need for

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vigilant monitoring and intensive care is emphasized during this period. Because ventilation time after reoperation was included in the definition of PMV, the final predictive model reflected both medical and surgical aspects with regard to the etiology of PMV occurrence. The results of the univariate analysis included most risk factors for PMV that has been identified in past studies.4,20,21 In particular, the role of hepartic encephalopathy as a risk factor for long mechanical ventilation was verified through our final predictive model after adjusting for other confounding factors. Hypotension on long-duration mechanical ventilation may contribute to PMV via changing cerebral energy metabolites or lung mechanics in animal studies.22,23 In our study, PMV was linked with preoperative cardiac problems and a greater requirement for fluids or transfusion during surgery (not statistically significant), which may to explain the role of intraoperative hypotension. However, a more detailed study design focused on circulation parameters will be necessary to establish a reasonable mechanism for hypotension during PMV. In conclusion, intraoperative changes in hyponatremia were associated with PMV after LDLT. In particular, a severe intraoperative change ⬎10 mEq/L was an independent risk factor predicting PMV in the immediate postoperative period. More strict, careful intraoperative management of patients with preoperative hyponatremia should be considered to prevent the occurrence of a fatal outcome from PMV after LDLT.

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3616 11. Sterns RH, Nigwekar SU, Hix JK: The treatment of hyponatremia. Semin Nephrol 29:282, 2009 12. Martin-Llahi M, Guevara M, Gines P: Hyponatremia in cirrhosis: clinical features and management. Gastroenterol Clin Biol 30:1144, 2006 13. Heuman DM, Abou-Assi SG, Habib A, et al: Persistent ascites and low serum sodium identify patients with cirrhosis and low MELD scores who are at high risk for early death. Hepatology 40:802, 2004 14. Gines P, Guevara M: Hyponatremia in cirrhosis: pathogenesis, clinical significance, and management. Hepatology 48:1002, 2008 15. Ozier Y, Steib A, Ickx B, et al: Haemostatic disorders during liver transplantation. Eur J Anaesthesiol 18:208, 2001 16. Snell DM, Bartley C: Osmotic demyelination syndrome following rapid correction of hyponatraemia. Anaesthesia 63:92, 2008 17. Lin SH, Chau T, Wu CC, et al: Osmotic demyelination syndrome after correction of chronic hyponatremia with normal saline. Am J Med Sci 323:259, 2002

PARK, KIM, CHOI ET AL 18. Kelly BJ, Matthay MA: Prevalence and severity of neurologic dysfunction in critically ill patients. Influence on need for continued mechanical ventilation. Chest 104:1818, 1993 19. Xia D, Yan LN, Xu L, et al: Postoperative severe pneumonia in adult liver transplant recipients. Transplant Proc 38:2974, 2006 20. Gonzalez E, Galan J, Villalain C, et al: Risk factors for acute respiratory failure after liver transplantation. Rev Esp Anestesiol Reanim 53:75, 2006 21. Li GS, Ye QF, Xia SS, et al: Acute respiratory distress syndrome after liver transplantation: etiology, prevention and management. Hepatobiliary Pancreat Dis Int 1:330, 2002 22. Geeraerts T, Ract C, Tardieu M, et al: Changes in cerebral energy metabolites induced by impact- acceleration brain trauma and hypoxic-hypotensive injury in rats. J Neurotrauma 23:1059, 2006 23. Sprung J, Mackenzie CF, Green MD, et al: Chest wall and lung mechanics during acute hemorrhage in anesthetized dogs. J Cardiothorac Vasc Anesth 11:608, 1997