Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 8  |  Issue : 4  |  Page : 483-490

Perioperative N-acetylcysteine for patients undergoing living donor orthotopic liver transplantation


Department of Anesthesiology, Intensive Care, and Pain Management, Faculty of Medicine, Ain-Shams University, Cairo, Egypt

Date of Submission31-May-2014
Date of Acceptance10-Jan-2014
Date of Web Publication29-Dec-2015

Correspondence Address:
Hanaa A.A. El Gendy
Department of Anesthesia and Intensive Care, Faculty of Medicine, Ain-Shams University, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1687-7934.172668

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  Abstract 

Purpose
The current study evaluates the efficacy of perioperative intravenous use of NAC as a pharmaco-protective agent in liver transplant recipients.
Methods
One hundred patients undergoing living donor liver transplantation (LDLT) were included in this prospective, randomized, double-blind, two parallel groups placebo-controlled trial; Group N (50 patients) received 150mg/kg of IV NAC infusion IV over 15 min before surgery, followed by12.5 mg/kg/h NAC for 4 h after induction of general anesthesia and a subsequent dose of 6.25 mg/kg/h continuous infusion for 3 postoperative days and Group C (50 patients) received equal volume of 0.9% saline IV continuous infusion at the same rate and volume for 3 postoperative days. Both groups will be followed for 14 days after their LT. Primary outcome include postoperative acute kidney injury (POAKI) assessed using RIFLE criteria on admission, day 7 and day 14. Secondary outcomes include severity of the post reperfusion syndrome (PRS) and the incidence of primary graft non-function (PGNF), renal functions test, total dose of loop diuretics and dopamine, adverse events, survival, as well as the length of ICU and hospital stays.
Results
There was no significant difference (P = 0.8) in the incidence of mild PRS, but the incidence of severe PRS was significantly reduced (P = 0.03) in Group N. RIFLE classification was significantly reduced on admission (P = 0.001), day 7(P = 0.002), and day 14(P = 0.003) respectively in Group N compared to Group C. PGNF was significantly reduced (P = 0.03) in Group N [1 (2%)] than Group C [7(14%)]. During 14 days there was a significant decrease in total dose of loop diuretics, need for dopamine, hospital length of stay, ICU length of stay, renal replacement therapy and the incidence of complications (5 vs. 14 P = 0.02) in Group N than Group C. But there was no significant difference in mechanical ventilator days, and patient survival among groups.
Conclusions
Perioperative intravenous NAC administration in patients undergoing living donor liver transplantation decreased incidence of postoperative acute kidney injury, severity of PRS and PGNF along with decreased length of ICU and hospital stay with no adverse events , But did not significantly reduce mechanical ventilator days and mortality.

Keywords: Liver transplantation, Post-reperfusion syndrome, Acute kidney injury, N-acetylcyscteine, Length of ICU stay, Mortality


How to cite this article:
El Gendy HA, Elsharnouby NM, Koraa A. Perioperative N-acetylcysteine for patients undergoing living donor orthotopic liver transplantation. Ain-Shams J Anaesthesiol 2015;8:483-90

How to cite this URL:
El Gendy HA, Elsharnouby NM, Koraa A. Perioperative N-acetylcysteine for patients undergoing living donor orthotopic liver transplantation. Ain-Shams J Anaesthesiol [serial online] 2015 [cited 2019 Jun 26];8:483-90. Available from: http://www.asja.eg.net/text.asp?2015/8/4/483/172668


  Introduction Top


N -acetylcysteine (NAC) plays a role in the treatment of acetaminophen toxicity [1] and the prevention of acute kidney injury (AKI) in radiocontrast exposure [2] , cardiac surgery and sepsis [3],[4] . NAC is a rich source of sulfhydryl (SH) groups, which replenish glutathione (GSH) stores [5] . GSH as a free radical scavenger decreases toxic free radical-induced damage that may contribute to impaired liver graft function and AKI after orthotropic liver transplant [6] . Furthermore, findings of experimental studies evaluating NAC in liver transplantation showed improvement of liver function in rat liver [7] , a better survival rate and reduction of graft nonfunction in pigs with liver ischemia [8] .

We conducted this study to evaluate the effect of perioperative NAC for decreasing post-orthotopic liver transplantation (OLT) AKI and improving liver graft function.


  Materials and methods Top


After approval of the Institutional Review Board and written informed consent from patients were obtained, patients were enrolled to this prospective randomized, double-blind, placebo-controlled trial on two parallel groups over a period of 4 years. Patients included in the study were adults more than 18 years of age, with new meld score 9-12, scheduled to undergo right-lobe living donar liver transplant for the first time, with baseline serum creatinine less than 1-1.2 mg/dl or creatinine clearance 97-140 ml/min and patients with mild renal dysfunction with serum creatinine 2-2.5 mg/dl or creatinine clearance 85-125 ml/min.

Exclusion criteria included allergy to NAC, a history of asthma, fulminate hepatic failure, re-do orthotropic liver transplant (OLT), pre-existing renal failure requiring hemodialysis or continuous hemofiltration, simultaneous other organ transplant (i.e. pancreas, heart, and small bowel) and pregnancy.

After the donor candidates were given detailed explanation several times by hepatologists and transplant surgeons, preoperative checks for donor candidates were performed only if they still had a strong will to donate their partial liver after the risks of liver resection were explained. Principal exclusion criteria of the donors were:

  1. Age more than 60 years,
  2. Fatty liver diagnosed by liver-kidney contrast in an ultrasound study or liver/spleen ratio in CT,
  3. Remnant liver volume estimated to be less than 30% of the total liver volume,
  4. Graft-versus recipient weight ratio estimated to be less than 0.8%,
  5. Donors with a BMI greater than 35 kg/m 2 , and
  6. Abnormal biliary anatomy and steatosis greater than 30% [9],[10],[11] .
All patients were assessed and received the standard preoperative care for patients undergoing liver transplantation according to the unit protocol. Routine monitoring including ECG, oxygen saturation (SpO 2 ) and noninvasive blood pressure were established. Patients were randomized using a computer-generated randomization list into two parallel groups: Group N received NAC 150 mg/kg infusion intravenously over 15 min before surgery, followed by 12.5 mg/kg/h NAC for 4 h after the induction of general anesthesia and a subsequent dose of 6.25 mg/kg/h continuous infusion for 3 days postoperatively. Group C received an equal volume of 0.9% saline continuous intravenous infusion at the same rate and volume for 3 days.

Both standard anesthetic and piggyback liver transplant for hepatic transplantation were performed by the same anesthesia and surgical team that was blinded to the study medication. Intraoperatively, patients were monitored with ECG, invasive arterial blood pressure (left radial artery), noninvasive blood pressure, continuous central venous pressure (CVP), body temperature, oxygen saturation (SaO 2 ), capnometry (EtCO 2 ), and urine output (ml). Intraoperative hemodynamics (mean arterial blood pressure (MAP) and heart rate (HR)) and intraoperative blood loss, graft weight, graft weight to recipient weight ratio, norepinephrine dose, arterial blood gas, blood products transfused, need for epinephrine, need for dopamine and intraoperative adverse events were recorded. At the end of the surgery, patients were transferred to the ICU intubated and mechanically ventilated until fully conscious, able to breathe and protect the airway.

Patients were monitored, and they received the standard protocol for postoperative management after liver transplantation. Liver function test, renal function tests, the total dose of loop diuretics, the need for dopamine (1-3 mg/kg/min), patient survival, and the duration of hospital and ICU stay were recorded. Hemodynamic parameters (MAP and HR), blood gas analysis, blood products transfused, urine output (UOP) (ml/Kg/hr), adverse drug reactions, and medications were recorded daily for 2 weeks post-LDLT.

Postoperative immunosuppressive protocols includes calcinurine inhibitors (FK or cyclosporine), and steroids with or without mycophynolate and steroids. Piperacillin/tazobactam was used as early prophylaxis for bacterial infections, metronidazole as prophylaxis for anaerobic infections and fluconazole as prophylaxis for fungal infections. The hemodynamic goals were used to adjust fluid administration in the ICU, maintaining the CVP at ~5-8 cmH 2 O, mean arterial pressure more than 70 mmHg, and urine output more than 1 ml/kg/h [12] . Patients admitted to the ICU received 2-4% albumin as fluid resuscitation within 6 h besides blood products as needed.

Care was taken to ensure patients achieved volemic balance, a minimal urine output of 1.5 ml/kg/h during the intraoperative phase and 1 ml/kg/h throughout the ICU stay; if these levels were not reached, furosemide was administered at a starting dose of 20 mg, and if necessary, followed by stepwise increases up to 500 mg continuous intravenous infusion [13] .

Both groups were followed for 14 days after their LDLT. The primary outcome included postoperative AKI assessed using RIFLE criteria [Table 1] [14] . Secondary outcomes included the severity of the postreperfusion syndrome (PRS) and liver graft function [the incidence of primary graft nonfunction (PGNF)], renal function test, the total dose of loop diuretics and dopamine, adverse events, survival, and the duration of ICU and hospital stays.
Table 1 Risk, injury, failure, loss, and end-stage kidney (RIFLE) classification [14]

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PRS was considered when the mean arterial blood pressure was 30% lower than the previous value immediately at the end of the anhepatic stage and lasted for at least 1 min within the 5 min after unclamping [15],[16],[17] . PRS was classified as mild when the decrease in blood pressure and/or heart rate was less than 30% of the anhepatic levels and was short-lived (5 min); for this classification, it also needed to respond to calcium chloride (1 g intravenously) and/or epinephrine intravenous boluses (100 mg) without requiring continuous infusion of vasopressor agents. Severe PRS was considered if there was hemodynamic instability such as persistent hypotension (>30% of the anhepatic level), asystole or hemodynamically significant arrhythmias; patients who required a vasopressor infusion during the intraoperative period whether or not that infusion continued through the postoperative period [18] . The primary graft function (PGF) was assessed using postoperative liver function tests (bilirubin total/direct, ALT/AST, lactate, prothrombin time (PT), international normalizing ratio (INR), aspartate aminotransferase, alanine aminotransferase) on a daily basis during the first week after transplantation. PGF was defined using Nanashima's classification: ALT and/or AST levels more than 1500 IU/l within 72 h after LDLT was considered PGNF. Those with values less than 1500 IU/l were considered as PGF [19] .

The urine output (ml/Kg/hr), serum creatinine, and RIFLE criteria were recorded daily, whereas the maximum RIFLE criteria was calculated on admission, on day 7 and on day 14 after liver transplantation. The incidence of postoperative AKI was defined according to the maximum RIFLE criteria [20] .

Statistical analysis

Data were analyzed using computer statistical software system SPSS® version 15 (Statistical Packages for the Social Sciences, Chicago, IL). Data was presented as mean and standard deviation (SD), median or numbers and percentages. Analysis of data between the groups was performed using the Student t test for independent samples for parametric data (mean age, weight, and pre-transplant creatinine, Intraoperative blood products, cold ischemia time, warm ischemia time, graft weight, graft weight to recipient weight ratio (GWRWR), duration of surgery, HR, UOP, CVP, duration of mechanical ventilation, length of ICU stay, and coagulation parameters: PT, and INR) or the Mann-Whitney test for nonparametric data. Categorical data between study groups (sex, RIFLE classification ,incidence pneumonia, and mortality rate) were compared using the c2 or Fisher exact test. AP value less than 0.05 was considered statistically significant. Sample size was calculated using primary analysis as the incidence of acute kidney injury. Sample size was determined assuming an incidence of post-LDLT AKI of 60% and an effect size of 30% as that used by previous study. A sample size of 100 subjects achieves nearly 90% power to detect this difference [21] .


  Results Top


One hundred and eight patients were assessed for randomization. Five surgical interventions were aborted before the operation, and three individuals refused to participate in the study. One hundred patients were randomized using a computer-generated randomization list in one of two parallel groups: Group N (50 patients) and Group C (50 patients). The study group included 68 men and 32 women with a mean (SD) age of 48 (7) years, weight 80 (9) kg, baseline serum creatinine 1.2 (0.4) and median NMELD 11. The etiology of the study group included 34% hepatitis C, 26% hepatitis B, 20% Hepatitis B and C, 14% HCC, and 6% of other etiologies. The mean age, weight and pretransplant creatinine were not significantly different between groups [Table 2].
Table 2 Patients' characteristic data

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Intraoperative blood products, the cold ischemia time, the warm ischemia time, the duration of surgery, HR, UOP, CVP, the need for epinephrine, and the need for dopamine were not significantly different between groups. There was a significant increase in the mean blood pressure, with a significant reduction in both the lactate level during the neohepatic phase and the intraoperative norepinephrine dose in Group N compared with Group C. However, the mean blood pressure and the lactate level were not significantly different in the preanhepatic and the anhepatic phase. There was no significant difference in the incidence of mild PRS, but the incidence of severe PRS was significantly reduced in Group N [Table 3].
Table 3 Intraoperative data

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On admission to the ICU, liver function tests (AST, ALT, serum bilirubin, serum albumin, PT, and INR), MAP, CVP, PRBC, and FFP were not significantly different between the groups, whereas the serum creatinine and the serum lactate levels were significantly reduced in Group N compared with Group C [Table 4]. The RIFLE classification was assessed on admission with a significant reduction (P = 0.001) in Group N compared with Group C. There was a significant increase in the number of patients with no AKI [43 (86%) vs. 24 (62%), P = 0.0001], with significant reduction in risk [5 (10%) vs. 13 (26%), P = 0.04], injury [2 (4%) vs. 9 (18%), P = 0.02], and failure [0 vs. 4 (8%), P = 0.04] in Group N compared with Group C [Figure 1].
Figure 1: A bar chart presenting the number of patients classified using the RIFLE classification on admission in Group N and Group C. *Significant difference in the RIFLE classification between Group C and Group N.

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Table 4 Postoperative data on admission

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PGF was assessed using Nanashima's classification within 72 h. PGNF was significantly reduced (0.03) in Group N [1 (2%)] compared with Group C [7(14%)] [Figure 2].
Figure 2: A bar chart presenting the primary graft function (PGF) as assessed by Nanashima's classification within 72 h. *Significant difference in the primary graft nonfunction (PGNF) between Group C and Group N

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During the first 7 and the second 7 days postoperatively, there was no significant difference between both groups with regard to reduction in liver function tests (AST, ALT, serum bilirubin, serum albumin, PT, and INR), whereas the serum lactate level and the serum creatinine level were significantly reduced in Group N, with a significant increase in UOP [Table 5] and [Table 6].
Table 5 Data during the first 7 postoperative days

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Table 6 Data during the second 7 postoperative days

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The RIFLE classification was significantly reduced (0.002) on day 7 and (0.003) day 14. On day 7, there was a significant increase in the number of patients with no AKI [47 (94%) vs. 31 (48%), P = 0.0001], with significant reduction in risk [2 (4%) vs. 8 (16%), P = 0.048], injury [1 (2%) vs. 7 (14%), P = 0.03], and failure [0 vs. 4 (8%), P = 0.04] in Group N compared with Group C [Figure 3]. Also, on day 14, there was a significant increase in the number of patients with no AKI [48 (96%) vs. 34 (68%), P = 0.0001], with significant reduction in risk [2 (4%) vs. 8 (16%), P = 0.046], injury [0 vs. 4 (8%), P = 0.04], and failure [0 vs. 4 (8%), P = 0.04] in Group N compared with Group C [Figure 4].
Figure 3: A bar chart presenting the number of patients classified using the RIFLE classification on day 7 in Group N and Group C. *Significant difference in the RIFLE classification between Group C and Group N

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Figure 4: A bar chart presenting the number of patients classified using the RIFLE classification on day 14 in Group N and Group C. *Significant difference in the RIFLE classification between Group C and Group N.

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During the 14 days, there was a significant decrease in the total dose of loop diuretics, the need for dopamine dose, the hospital duration, the ICU stay, renal replacement therapy and the incidence of complications (5 vs. 14, P = 0.02) in Group N compared with Group C. However, there was no significant difference in the number of ventilator days, patient survival, the incidence of postoperative bleeding, graft rejection, vascular thrombosis (hepatic artery stenosis), hypotensive episodes, and infection. None of the patients in the study group suffered any cardiovascular event [Table 7].
Table 7 Postoperative data during 14 days

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  Discussion Top


Previous clinical trials reported that NAC has a hepatoprotective effect in patients receiving OLT and improved the function of the liver allograft [22],[23] . In cirrhotic patients, the total clearance of NAC could be less than half that of healthy individuals [24] . Moreover, ESLD is associated with GSH depletion. It was suggested that while intracellular levels may be reduced, plasma levels do not represent GSH stores or the ability to increase GSH production during exposure to stress [21] .

In accordance to previous studies, we evaluated the perioperative use of NAC in patients undergoing right-lobe living donor OLT. There was an increase in the number of patients with no AKI and reduction in the number of patients classified as risk, injury, and failure using the RIFLE classification with a significant reduction in the severity of PRS among the patients receiving NAC 150 mg/kg infusion intravenously over 15 min before surgery, followed by12.5 mg/kg/h NAC for 4 h after the induction of general anesthesia and a subsequent dose of 6.25 mg/kg/h continuous infusion for 3 days postoperatively.

We used NAC because a previous study by Bromley et al. [22] reported that intraoperative NAC modified hemodynamic variables as it is a mild vasodilator: it reduced the systemic vascular resistance index and MAP with an increased cardiac index and oxygen delivery, which may be beneficial in patients at risk of tissue hypoxia. In their study Bromely et al. [22] used intraoperative NAC at a dose of 150 mg/kg infusion intravenously over 15 min, followed by 12.5 mg/kg/h NAC for 4 h, and a subsequent dose of 6.25 mg/kg/h till the end of the surgery, and proved that improved oxygen consumption was statistically significant only immediately after the loading dose, possibly because the plasma NAC concentration was high at this time but decreased later, but they did not measure plasma NAC, and the optimal dose range for NAC is not known.

In our study, the use of NAC was accompanied by an increase in the MAP with reduction in both the lactate level during the neohepatic phase and the intraoperative norepinephrine dose. There was no effect on the intraoperative UOP. The PRS is an important intraoperative risk factor for impaired graft function, morbidity and mortality of the recipient. The incidence of PRS varies widely from 5.9 to 61.3% due to the lack of standard criteria to score PRS severity [25] . We used the Piggyback technique for the implantation of the liver graft without interrupting the IVC flow as it was found to decrease the incidence of PRS [26] .

Several studies have investigated hemodynamic changes that occurred at reperfusion as a criteria to score PRS [15],[18] and confirmed its practicality and usefulness. We therefore used these hemodynamic changes to score the PRS: the incidence of PRS was 12% in NAC group and 26% in Group C and did not significantly differ between the groups. However, PRS severity was significantly reduced in the NAC group.

Himli et al. [18] reported the correlation between PRS severity and the patient allograft outcome, and suggested that prevention of its occurrence or attenuation of the resultant hemodynamic and coagulation changes may theoretically improve the outcome.

Several studies evaluated the protective effect of NAC on the kidneys from the toxic effect of intravenous contrast agents [2] . The metabolic activity of NAC is achieved through the SH group [27] , and was found to support the synthesis of GSH under conditions with high demand for GSH [28] . GSH is synthesized mainly in the liver cells where the availability of cysteine is the rate-limiting substrate when GSH is depleted [29] during ischemia or oxidative stress [30],[31],[32] .

However, in an animal study, the use of NAC was found to prevent hepatic damage during ischemia-reperfusion [33] . A study by Hilmi et al. [21] was conducted to evaluate a loading dose of 140 mg/kg of NAC given after the induction of general anesthesia followed by a subsequent dose of 70 mg/kg every 4 h for a total of 12 doses, and reported an increase in GSH levels for about 48 h, but did not affect the recovery of the graft function assessed by liver function tests. They used the maximum RIFLE criteria over the first 2 weeks' primary endpoint, which was not different between the groups, with the occurrence of exactly the same AKI (32%) in both groups.

In the present study, on admission and during 7 and 14 days, there was a significant reduction in the incidence of patients classified as risk, injury, and failure using the maximum RIFLE classification, and in the serum lactate and the serum creatinine levels, with an increase in the UOP in the NAC group.

Liver functions were not significantly affected on admission, but PGNF was significantly reduced (0.03) in Group N [1 (2%)] compared with Group C [7(14%)] on assessment of PGF using Nanashima's classification within 72 h. Nanashima's criteria was reported to be a simpler, more convenient, dependable assessment of the hepatic allograft function as early as possible and puts one on guard to prevent PGNF [19] .

The current study has potential limitations including a lack of measurement of the serum GSH level, and the use of longer therapy with a high dose of NAC infusion is warranted.


  Conclusion Top


Perioperative intravenous NAC in patients undergoing right-lobe living donor OLT was safe as there was a decreased incidence of postoperative complications, and a decrease in the dose of loop diuretics, the need for dopamine dose, renal replacement therapy, the hospital duration and the ICU stay, but no effect on the number of ventilator days and mortality.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
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