Abstract
Objective
To evaluate the factors that affects the postperfusion syndrome in cadaveric liver transplantations and the effect of the postperfusion syndrome on discharge from the hospital.
Methods
Patients who underwent cadaveric liver transplantations between 2007 and 2013 were scanned retrospectively. Intraoperative anaesthesia records, intensive care unit follow-up forms and discharge reports were examined from patient files. Overall, 43 patients having complete data were included in the study. The postperfusion syndrome is defined as asystoli or a decrease in mean arterial pressure of more than 30%, which occurred in the first 5 min of reperfusion and continued for 1 min. Patients were divided into two groups: those who had the postperfusion syndrome and those who did not.
Results
The number of patients who had the postperfusion syndrome was 25 of 43 (58.1%). The MELD score of patients without the postperfusion syndrome was calculated as 16.9±3.2 and that of patients with the postperfusion syndrome was 19.7±3.6. A statistically significant relationship was detected between the postperfusion syndrome occurrence and a high MELD score (p=0.013). The diastolic blood pressure just before reperfusion was statistically lower in the group with the postperfusion syndrome than in the other group (p=0.023, 50±8 vs. 58±11). According to the logistic regression analysis, the MELD score and the decrease in diastolic blood pressure before reperfusion were defined as independent predictive factors.
Conclusion
According to the study, the ratio for having the postperfusion syndrome was found to be 58.1%. The independent predictor factors affecting the postperfusion syndrome were detected as the MELD score and the decrease in diastolic blood pressure before reperfusion. The postperfusion syndrome during orthotropic liver transplantation is an important issue for anaesthesiologists. The awareness of the related factors with the postperfusion syndrome may help in the development of various preventive strategies.
Keywords: Liver transplantation, postperfusion syndrome, anaesthesia
Introduction
Liver transplantation is a surgery in which the intraoperative haemodynamic changes are intense despite improvements in the surgical techniques and anaesthesia administration. The condition of acute haemodynamic impairment and severe hypotension (a decrease in the mean arterial pressure by more than 30%), which develops within the first 5 minutes after reperfusion due to meeting of the grafted liver with the recipient blood and which continues for at least 1 minute, is defined as post-reperfusion syndrome (PRS). The period of reperfusion is a critical stage for the administration of anaesthesia. Although the aetiology of post-reperfusion syndrome is not clear, it is suggested that free oxygen radicals, endotoxins, inflammatory cytokines, metabolic acidosis, hypothermia and electrolyte imbalance have an effect on it (1, 2).
The aim of this retrospective study was to determine the factors affecting the development of PRS and to investigate the effect of PRS on discharge.
Methods
After receiving approval from the local ethics committee of our hospital, patients who underwent orthotopic liver transplantation from cadavers between January 2007 and November 2013 were retrospectively scanned, and 43 adult patients whose data were completely obtained were included in the study. Patients who had acute liver failure and toxic hepatitis and had undergone re-transplantation were excluded from the study.
A decrease by more than 30% in the mean arterial pressure, which developed in the first 5 minutes after reperfusion and continued for 1 minute, or the development of asystole was accepted as post-reperfusion syndrome. The patients were divided into two groups: Group 1 (patients developing PRS) and Group 2 (patients not developing PRS).
Anaesthesia protocol
Anaesthesia induction was performed using 4–7 mg kg−1 thiopental, 1–3 μg kg−1 fentanyl and 0.5 mg kg−1 cisatracurium. Following endotracheal intubation, the maintenance of anaesthesia was provided with sevoflurane, 50% oxygen–50% air, 0.1 μg kg−1 min−1 remifentanil and 0.1–0.15 mg kg−1 h−1 cisatracurium. Mechanical ventilation was applied by ensuring that the tidal volume was 8–10 mL kg−1 and the respiratory rate was 10–16 breaths per minute. In addition to standard monitorisation (electrocardiography, peripheral oxygen saturation), central catheterisation from the internal jugular vein and invasive artery catheterisation from the radial/brachial artery were performed for all the patients. During surgery, the cardiac output (CO) and stroke volume variability (SVV) were followed with the help of the Flotract/Vigilea monitor over the invasive arterial wave. The patients who were haemodynamically unstable were subjected to invasive artery catheterisation before induction. The heart rate and systolic blood pressure were followed to be ±20% of the basal value during the surgery, and necessary interventions for haemodynamic changes were performed using anaesthetic drugs, cardiovascular drugs or fluids. For the patients developing post-reperfusion syndrome, ephedrine (5 mg) was used for hypotension and/or atropine iv bolus was given for bradycardia. Noradrenalin infusion (0.05–0.3 μg kg−1 min−1) was initiated when needed. When the Ca value became <1 mmol L−1 in the pre-reperfusion period, hypocalcaemia was treated with CaCl2. The patients were given 75–150 mg kg−1 n-acetylcysteine (NAC), 2.5 g c-vit, 500 mg prednol (200 mg after induction, 200 mg in the unhepatic period and 100 mg after operation) and 1–2 mg kg−1 mannitol in the unhepatic period. The patients whose haemodynamic and preoperative features were adequate were extubated in the operating room, while the others were followed as intubated in the intensive care unit.
Surgical technique
In the surgery, standard orthotopic liver transplantation, including the practisedpiggy-backpractised technique, was performed without portacaval shunting. Venovenous bypass was not used. Grafts were washed through the portal vein with 1000 mL 5% dextrose before reperfusion.
Collection of data
Intraoperative anaesthesia data, intensive care monitorisation forms and discharge epicrisis were obtained from the files of the patients and were then evaluated. Comorbid diseases, smoking habit, history of a previous surgery, encephalopathy, acid, ejection fraction, modified end-stage liver disease (MELD) score, Child-Pugh score in addition to individual features in the preoperative period; anaesthesia techniques, way of transplantation, development of PRS, durations of anaesthesia-surgery, cold ischaemia time, unhepatic time, erythrocyte suspension used (RBC) and amount of fresh frozen plasma (FFP), amount of NaCO3, laboratory monitorisation (blood gas parameters) in the intraoperative period, including haemodynamic data (heart rate-HR, systolic blood pressure-SAP, diastolic blood pressure-DAP, central venous pressure (CVP)) and body temperature, development of renal dysfunction in dissection-unhepatic-neohepatic periods, postoperative intensive care data, duration of staying on mechanical ventilator, durations of hospitalisation in the intensive care unit and hospital, early mortality (28 days) and mortality-morbidity after discharge were recorded.
Statistical analysis
Statistical analysis was performed by using Statistical Package for Social Sciences for Windows 14 (SPSS Inc; Chicago, IL, USA) software. The normal distribution of data was evaluated through the Kolmogorov–Smirnov test. For the numerical variables, normally distributed ones were presented as the mean±standard deviation, while non-normally distributed ones were presented as the median (minimum–maximum). Categorical variables were given in number and percentage and the chi-square test was employed for comparing categorical data. In the comparisons of two groups, the t-test was used for independent samplings in the analysis of the numerical variables displaying a normal distribution, while the Mann–Whitney U test was used for the analysis of numerical variables that did not display a normal distribution. For assessing the independent effects of variables on post-reperfusion syndrome, parameters with the values of p<0.05 in the t-tests (for independent samplings) and the Mann–Whitney U-tests were evaluated through a multivariate logistic regression model. For the prediction of post-reperfusion syndrome, diastolic blood pressure before the neohepatic period was evaluated and cut-off values of the MELD score were examined through ROC (receiver operating curve). The value of p≤0.05 was accepted as significant in the statistical analyses.
Results
Twenty-five of 43 patients (58.1%) included in the study developed PRS. No difference was found between the groups in terms of gender, age, smoking, the presence of oesophageal varices, previous encephalopathy, serum creatinine and Child scores (Table 1). A statistically significant relationship was detected between the development of PRS and the mean MELD score (p=0.013). The mean MELD score was 16.9±3.2 in patients not developing PRS and 19.7±3.6 in patients developing PRS.
Table 1.
Demographic data
| Total | PRS (+) | PRS (−) | p | |
|---|---|---|---|---|
| Age | 45±11 | 46.28±11.67 | 42.56±11.4 | >0.05 |
| Gender (F/M) | 11/32 | 8/17 | 3/15 | >0.05 |
| Smoking (+/−) | 12/21 | 6/19 | 3/15 | >0.05 |
| Oesophageal varices (+/−) | 10/33 | 6/19 | 4/114 | >0.05 |
| Encephalopathy | 8/35 | 5/20 | 3/15 | >0.05 |
| MELD score | 18.5±3.6 | 19.7±3.6 | 16.9±3.2 | 0.013 |
| Child–Pugh classification (A/B/C) | 25/5/13 | 3/15/7 | 2/10/6 | >0.05 |
MELD: modified end-stage liver disease; PRS: post-reperfusion syndrome
No difference was observed when the intraoperative data of the groups (duration of anaesthesia, duration of surgery, cold ischaemia time, systolic blood pressure, heart rate, mean arterial pressure, CVP, K, pH, body temperature and Ca) were compared (Table 2). The unhepatic time was found to be longer in the group not developing PRS than in the group developing PRS (p=0.043, 107.22±38.31 min and 87.64±23.16 min, respectively). Diastolic blood pressure measured just before the reperfusion period was significantly lower in the group developing PRS than in the group not developing PRS (p=0.023, 50±8 mmHg vs. 58±11 mmHg). It was detected that PRS occurred in one patient after reperfusion and then asystole developed. After a 45-minute CPR, spontaneous circulation was provided.
Table 2.
Intraoperative data
| Total | PRS (+) | PRS (−) | p | |
|---|---|---|---|---|
| Duration of anaesthesia (hour) | 11.74 (8–19) | 11.68±1.71 | 11.81±2.15 | >0.05 |
| Duration of surgery (hour) | 10.58 (6–18) | 10.46±1.85 | 10.74±2.2 | >0.05 |
| Unhepatic time (minute) | 95.84 (32–185) | 87.64±23.16 | 107.22±38.31 | 0.043** |
| Cold ischaemia time (minute) | 474±123 | 468 (240–720) | 475 (200–680) | >0.05 |
| Intraoperative blood loss (mL) | 2498±2161 | 2820±2635 | 2050±1170 | >0.05 |
| Transfused RBC (unit) | 3.7±3.4 | 3.84±3.85 | 3.56±2.52 | >0.05 |
| Transfused FFP (unit) | 7.7±3.9 | 8.4±4.33 | 6.83±3.14 | >0.05 |
| NDBP | 56±9 | 58±11 | 50±8 | 0.023* |
RBC: erythrocyte suspension; FFP: fresh frozen plasma; NDBP: diastolic blood pressure before neohepatic period
The mean amount of bleeding was calculated as 2498±2161 mL, while the mean RBC that was used was 3.7±3.4 unit, the mean FFP was 7.7±3.9 packages, the mean amount of bicarbonate was 9.5±8.2 ampoule and the mean creatinine was 1.1±0.6. No difference was found between the groups in terms of these parameters.
Postoperative data can be seen in Table 3. The mean duration of hospitalisation in the intensive care unit was 7.63 (1–53) days and the mean duration of hospital stay was 33.88 (7–96) days. It was determined that 12 patients (27.9%) were extubated after the intervention and 31 patients (72.1%) were taken to the intensive care unit as intubated. The mean extubation time was calculated as 24.71±38.88 min. The mean extubation time was longer in the patients developing PRS (34.18±47.6 hours vs 13.21±20.8 hours, p=0.029). No difference was found with regard to the durations of hospitalisation in the intensive care unit and hospital. 28-day mortality was 11.6% (5 patients) and late mortality was 7% (3 patients).
Table 3.
Postoperative data
| Total | PRS (+) | PRS (−) | p | |
|---|---|---|---|---|
| Duration of ventilation (hour) | 24.71 (1–168) | 34.18±47.6 | 13.21±20.8 | >0.05 |
| Duration of hospitalisation in the intensive care unit (day) | 7.63 (1–53) | 8.8±10.01 | 6±3.2 | >0.05 |
| Duration of hospital stay (day) | 33.88 (7–96) | 31.64±16.7 | 37±19.8 | =0.029* |
| 28-day mortality (n) | 5 (11.6%) | 1 | 4 | >0.05 |
| Late mortality (n) | 3 (7%) | 1 | 2 | >0.05 |
In the multivariate logistic regression analysis, MELD score and low pre-reperfusion diastolic blood pressure were identified as independent predictive variables for PRS.
In the ROC analyses, when the MELD score is >16, the development of PRS was predicted with 80% sensitivity and 61.1% specificity (EAA 0.793, 95% CI: 0.583–0.861, Figure 1). When N1DKB was ≤49, the development of PRS was predicted with 48.8% sensitivity and 94.4% specificity (EAA 0.704, 95% CI: 0.546–0.834, Figure 2).
Figure 1.
ROC curve for MELD score
MELD: modified end-stage liver disease
Figure 2.
ROC curve for pre-neohepatic diastolic blood pressure
Discussion
The main conclusion of our study can be summarised with two findings. First, an increased MELD score and decreased diastolic blood pressure before reperfusion are independent predictive variables for PRS. Second, intraoperative PRS causes an extension in the duration of mechanical ventilation support in the postoperative period. In our study, the rate of PRS was calculated as 58.1% in the patients undergoing orthotopic liver transplantation from cadavers. In the literature, the rates reported by researchers are in a wide range. While the initial studies revealed incidences between 2% and 30%, recent studies have reported the incidence to be approximately 50%. In the study of Ibtesam et al. (4), in which the severity of PRS developing in all 338 patients was evaluated, the rate of PRS was reported to be 55%; they stated that age, RBC and FFP usage were higher in the severe PRS group. Ayanoğlu et al. (5) found PRS incidence to be 48.9% in their study conducted on 145 patients. Our results were similar to those of the studies of Ibtesam et al. (4) and Ayanoğlu et al. (5). Although not significant, blood loss was higher in the group developing PRS, and this occurred mostly after reperfusion. This situation may have resulted from the delay in controlling bleeding and in providing haemostasis because a longer time had passed for haemodynamic stabilisation.
In our study, a statistically significant relationship was found between the development of PRS and an increased MELD score, and an increased MELD score was defined as an independent predictive variable. It was observed that the development of PRS was predicted with 80% sensitivity and 61.1% specificity when the MELD score was higher than 16. Similar to our result, Matsuzaki et al. (6) found a relationship between cardiac arrest associated with intraoperative PRS and an increased MELD score. In the review of Karapanagiotou et al. (7), they reported that the durations of mechanical ventilation and hospitalisation in the intensive care unit were longer in patients with a MELD score above 25.
While no difference was found between the groups in terms of mean arterial pressure and systolic arterial pressure before reperfusion, the values of diastolic blood pressure were different between the groups and a decreased diastolic blood pressure was identified as an independent predictive variable for PRS. After providing an adequate preload with the measurement of cardiac output, SVV, CVP and SVR, which were used as routine intraoperative haemodynamic monitorisation methods, cardiac output and blood pressure were elevated through inotrope and vasopressor when needed. Primarily, a bolus dose of noradrenalin was used for patients. and infusion was initiated for patients needing it after reperfusion. In the study of Zhang et al. (8), only dopamine or dopamine and noradrenalin infusion was started after anaesthesia induction in patients undergoing orthotopic liver transplantation. They also demonstrated that the use of vasopressors for infusion provided stable haemodynamics, while noradrenalin protected kidney functions better.
The development of PRS during orthotopic liver transplantation is very important for anaesthetists. Free oxygen radicals are also considered to be accountable for the occurrence of PRS. Sahmeddini et al. (9) found in their study that the application of mannitol was effective in decreasing the development of PRS. In our study, it was detected that our patients were routinely given vitamin C, n-acetylcysteine (NAC) and mannitol.
In our study, no significant difference was revealed between the groups in terms of serum K level, serum Ca level, body temperature and arterial blood gas parameters. This result was similar to the results of Aggarwal et al. (3) and Nanshima et al. (10).
Cold ischaemia time is another factor that is thought to be responsible for the occurrence of PRS and when this time is above 6 hours, it is accepted to be a risk factor for the development of PRS (2). Although there was no statistically significant relationship between the development of PRS and cold ischaemia time in our study, this time was observed to be above 6 hours in 18 of the 25 patients developing PRS.
Another factor that is suggested to affect the development of PRS is unhepatic time. While there are some studies showing that an extended unhepatic time increases the development of PRS (2), some other studies suggest that a short unhepatic time also has a negative effect on PRS (5). Consistent with the study of Ayanoğlu et al., a statistically significant short unhepatic time was observed in the group developing PRS in our study.
Early extubation is recommended for patients who are stable in terms of haemodynamic and respiratory aspects after liver transplantation (11). In our study, while 12 patients (27.9%) were extubated in the operating room, 31 patients (72.1%) were transferred to the intensive care unit as intubated. A positive relationship was detected between the duration of mechanical ventilation and the development of PRS. The duration of mechanical ventilation was observed to be longer in patients developing intraoperative PRS.
Post-reperfusion syndrome is generally one of negative results after transplantation (2). In our study, 28-day mortality was 11.6% and late mortality was 7%. However, no relationship was found between PRS and the duration of intensive care, the duration of hospitalisation and mortality. In literature, a statistically significant relationship was detected between PRS and mortality developing in 15 days in the study of Paugam-Burtz et al. (2). In our study, the absence of a relationship between PRS and mortality was attributed to the low number of patients.
Conclusion
Greater knowledge of the important clinical factors related to post-reperfusion syndrome can help in deciding on strategies for the prevention of this syndrome. Supporting patients with decreased diastolic blood pressure before reperfusion via vasopressors and inotropes (noradrenalin infusion) or fluid replacement and providing close haemodynamic monitorisation can be effective in preventing the development of PRS or decreasing its severity. It is important that physicians must be ready for the possible development of PRS in patients with advanced-stage liver failure and a high MELD score before surgery. In addition, strategies for supporting intraoperative anaesthesia management must be determined. The number of patients waiting for transplantation due to end-stage liver disease is increasing. Because patients with a high MELD score are at the top of the list of the patients who will undergo liver transplantation from cadavers, it should be remembered that the risk of PRS development may be increased in the intraoperative management of these patients.
Table 4.
Multivariate analysis
| Risk factor | p | OR | 95% CI |
|---|---|---|---|
| MELD | 0.002 | 0.793 | 0.583–0.861 |
| BNDBP | 0.01 | 0.704 | 0.546–0.834 |
NDBP: Pre-neohepatic diastolic blood pressure; MELD: Modified endstage liver disease; CI: confidence interval
When MELD score is >16, the development of PRS is predicted with 80% sensitivity and 61.1% specificity (AUC 0.793, 95% CI: 0.583 to 0.861, p=0.002)
When N1DKB is ≤49, the development of PRS is predicted with 94.4% specificity and 48.8% sensitivity (AUC 0.704, 95% CI: 0.546 to 0.834, p=0.01)
Footnotes
Ethics Committee Approval: Local Ethics committee approval was received for this study from the local ethics committee of Türkiye Yüksek İhtisas Education and Research Hospital.
Informed Consent: Informed consent for this study was not taken because retrospective study.
Peer-review: Externally peer-reviewed.
Author Contributions: Concept – B.A., A.D., Ü.K.; Design – B.A., A.D., Ü.K.; Supervision – B.A., A.D., Ü.K., A.Ö., E.B.B.; Resources – R.K., C.H., D.K.; Materials – R.K., C.H.; Data Collection and/or Processing – C.H., R.K.; Analysis and/or Interpretation – B.A., A.D., Ç.Y.G., D.K., Ü.K., A.Ö., E.B.B.; Literature Search – B.A., A.D., Ç.Y.G.; Writing Manuscript – B.A., A.D.; Critical Review – B.A., A.D., Ü.K., Ç.Y.G., D.K., A.Ö., E.B.B.; Other – R.K., C.H., A.Z.
Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: The authors declared that this study has received no financial support.
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