Objectives: Living donor liver transplant is the gold standard therapy for patients with terminal hepatic disorders for whom no alternative therapy is available. The primary aim was to assess different intraoperative factors that may predict early death after adult-to-adult living donor liver transplant. The secondary aim was to assess the effect of small-for-size syndrome on mortality. Materials and Methods: This retrospective multicenter cohort study was performed on records from 145 adults with cirrhosis who had received a right lobe living donor liver transplant. Patients were divided according to the occurrence of short-term mortality (death within the first month after transplant). The primary intraoperative parameters included graft weight, surgical duration, mean blood pressure, serum lactate and sodium bicarbonate, transfusions, durations of cold and warm ischemia and anhepatic phase, input and output during surgery, and portal venous pressures. Results: There were statistically significant variations between both cohorts for number of units of packed red blood cells, durations of cold and warm ischemia and anhepatic phase, preclamp and postreperfusion portal venous pressures, average urine output, mean serum lactate, mean blood pressure, and surgical duration (P < .001). Also, there were significant differences in the number of platelets, units of fresh frozen plasma, and mean sodium bicarbonate (P = .025, .003, and .035, respectively). Of the 25 patients who died within the early postoperative period, 20 had developed small-for-size syndrome (P < .001). Conclusions: A variety of intraoperative risk factors may affect early posttransplant mortality, which suggests the high complexity of living donor liver transplants and the need for well-trained experienced teams to perform these surgeries.
Key words : Liver donor, Short-term recipient mortality
Liver transplant (LT) is the gold standard therapy for patients with terminal hepatic disorders for whom no alternative treatment is obtainable.1
The most frequent reasons for LT in the United States are viral hepatitis, alcohol-related disease, and cholestatic liver disease. Other indications include hepatitis B, autoimmune hepatitis, metabolic hepatic disorders, fulminant liver cell failure, and hepatocellular carcinoma.2
The dearth of deceased donor liver grafts has led to a greater need for living donor LT (LDLT), which is gaining favor all over the world.3 Living donor LT is more complex than deceased donor LT, and therefore LDLT poses additional risks for the recipient.2
The predisposing causes of short-term death after LDLT are diverse and may be assigned to the following 3 categories: (1) preoperative factors (severity of cirrhosis, as measured by the Child-Turcotte-Pugh score; nutritional status; severity of end-stage liver disease, as measured by the Model for End-Stage Liver Disease [MELD] score; and graft size and quality), (2) intraoperative factors (transfusion needs, technical issues, portal pressure, and arterial blood pressure), and (3) postoperative factors (laboratory dysfunction, duration of hospital stay, and duration of intensive care unit [ICU] stay).4
Compared with deceased donor LT surgery, the intraoperative characteristics of LDLT are different, such as unique surgical techniques, vena cava clamp without extracorporeal circulation, and prolonged surgical duration.5
Most LDLT-related research has not focused on the intraoperative characteristics of LDLT or the effects of LDLT on early mortality. Awareness of predictors of short-term mortality after LDLT could facilitate the management of these risk factors with an aim to reduce or even prevent postoperative complications and thereby reduce the rate of mortality.
The primary aim of this study was to assess different intraoperative factors that may predict early death after adult-to-adult LDLT. The secondary aim was to explore the effect of small-for-size syndrome (SFSS) on early mortality.
Small-for-size syndrome is usually identified as functional affection of the liver allograft within the first postoperative week. It is characterized by bleeding tendency, hyperbilirubinemia, encephalopathy, and ascites after exclusion of other potential causes.6
Materials and Methods
The present retrospective multicenter cohort study included 145 adult patients with cirrhosis who had received elective adult-to-adult right lobe LDLT. This was a retrospective study, so informed consent was not required.
The research protocol was prepared according to ethical guidelines of the 1975 Declaration of Helsinki. Institutional ethics committee approval was obtained for the analysis of these retrospective data.
The members of the LT team, who were from different medical specialties such as surgery, hepatology, radiology, and anesthesiology, were responsible for proper selection of recipients and suitable living related donors (first-degree relatives). The recipients and donors signed preoperative consent forms and were appropriately informed about the procedure and the possible related complications, as well as the hazards and advantages of the operative procedures.
All donors were 20 years of age or older. Full donor workups included liver biopsy to assess the donor liver quality, for which macrovesicular steatosis of 15% or more was a contraindication to donation. In addition, ultrasonography, psychological assessment, computed tomography angiography, and computed tomography volumetry were performed.
The Child-Turcotte-Pugh score and the MELD score were used for preoperative recipient assessment. Milan criteria were used for assessment of patients with hepatocellular carcinoma. Evaluation of recipient history included age, sex, concomitant diseases, primary liver disease, and symptoms of end-stage liver disease such as recurrent spontaneous bacterial peritonitis, recurrent encephalopathy, refractory ascites, and variceal bleeding.
Full clinical examinations included assessment of body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) and evaluation for signs of terminal hepatic disease. The full preoperative workup included liver function assessment, necessary consultations, and imaging.
Anesthesia and immunosuppression
General anesthesia was induced with propofol (2 mg/kg), fentanyl (2 ?g/kg), and rocuronium (0.9 mg/kg), followed by sevoflurane (2% minimum alveolar concentration) and additional fentanyl (1 ?g/kg/h) and rocuronium (0.5 mg/kg/h) as needed to maintain anesthesia. The radial artery was punctured to collect samples and to monitor blood pressure. Volume-controlled ventilation was initiated with a tidal volume of 6 to 8 mL/kg, with tidal CO2 between 30 and 40 mm Hg and a fraction of inspired oxygen of 0.5.
The rate of crystalloid infusion during the procedure was modified, as needed, according to hemodynamic preload (with a central line placed into the right internal jugular vein) and urine output.
Phenylephrine (0.5 ?g/kg bolus) was used to enhance renal perfusion when urine output volume dropped below the reference standard. Furosemide (10-20 mg) was used to mitigate incessant positive fluid balance or when volume overload was suspected. Diuretics were not indicated to manage intraoperative oliguria.
The hematocrit was periodically assessed and maintained between 25% and 30% with transfusion of packed red blood cells (PRBC) as needed. Thromboelastography was used to manage intraoperative coagulopathy by the infusion of fresh frozen plasma (FFP), cryoprecipitate, and platelets as necessary.
Calcium chloride was added if serum calcium concentration dropped below 80% of the lower reference value. Sodium bicarbonate was given if the serum pH dropped below 7.15 despite proper minute ventilation.
During the operation, immunosuppression was induced with 0.5 g of methylprednisolone (Solumedrol, Pfizer) and 20 mg of intravenous basiliximab (Simulect, Novartis). Within the postoperative interval, patients were given calcineurin inhibitors (tacrolimus or cyclosporine) in addition to mycophenolate mofetil to induce immunosuppression.
Donor surgery technique
Surgery included right hepatectomy (liver segments V-VIII) with conservation of the middle hepatic vein, which was retained in the donor. Cholangiography was used to determine accurate specification of the components of the hepatic hilum and isolation of the right hepatic vein.
Removal of the hepatic parenchyma was performed with an ultrasonic surgical aspirator. The approach was along the right aspect of the middle hepatic vein trunk, and all its branches were sutured during cutting. Tributaries of the middle hepatic vein with a caliber greater than 0.5 cm were reconnected in the recipient to attain a proper venous drainage.
After complete division of the liver parenchyma, the right hepatic graft was removed after cutting the bile duct, hepatic artery, portal branch, and right hepatic vein, respectively.
Back table procedure
On the back table, histidine-tryptophan-ketoglutarate solution was used to irrigate the liver graft via the right portal vein.
Intraoperative graft/recipient weight ratio was measured (in grams, as percent) according to the actual weight of the graft. If congestion was seen in the right paramedian region during irrigation with histidine-tryptophan-ketoglutarate solution, then revascularization of outflow drainage for middle hepatic vein branches (V5 or V8) was performed independently of the inferior vena cava.
The operative approach for the recipient included 2 distinct phases, ie, removal of the liver and implantation of the graft.
Hepatectomy of the liver. Laparotomy was performed on the recipient. The hepatic ligaments were cut after the division of the hilar components. Then, the bile duct and hepatic artery were separated. Vascular clamps were applied to the portal vein, and the liver was removed by portal vein transection.
Implantation of the graft. For right lobe grafts, the right hepatic vein was connected to the inferior vena cava by end-to-side technique. Then the recipient portal vein was connected to the graft right portal vein. After portal venous reperfusion, anastomosis of the hepatic artery was performed with end-to-end technique. The bile ducts were connected with duct-to-duct approach in most cases. After the portal vein was reconstructed, the clamps were removed and the hepatic parenchyma was perfused with portal venous flow.
Portal venous pressure (PVP) was assessed intraoperatively by an antithrombotic catheter inserted into the jejunal or ileal mesenteric vein, an omental vein, the inferior mesenteric vein, or the portal vein itself. The tip of the catheter was placed in the recipient’s mesenteric vein and set in position with a suture. The catheter was linked to a pressure transducer. The reference range for direct assessment of PVP was 7 to 12 mm Hg. The PVP was measured twice: (1) at laparotomy (10 minutes before portal venous clamp), before hepatectomy; and (2) at postreperfusion (10 minutes after graft reperfusion), after vascular anastomoses were finished. Mean portal pressure was calculated from the sum preclamp portal pressure and postreperfusion portal pressure, divided by 2.
For this study, intraoperative parameters included graft weight, graft/recipient weight ratio, surgical time, intraoperative central venous pressure, mean blood pressure, serum lactate, mean serum sodium bicarbonate, transfusions (number of transfused PRBC, units of FFP, platelets, and units cryoprecipitate), cold and warm ischemia and anhepatic phase durations, use of furosemide or epinephrine, mean blood glucose, and input and output during surgery (average urine output, crystalloid infusion, and net fluid balance during surgery). In addition, the preclamp, postreperfusion, and mean intraoperative PVP were included.
The selected patients were divided according to the occurrence of short-term mortality (within the first month). After surgery, patients were followed from postoperative day 1 until 30 days after LT or until mortality. In the early postoperative period, patients were observed in the ICU; after they stabilized, patients were observed in the department. Postoperative assessment included a detailed history and clinical examination in addition to full laboratory and imaging evaluations.
Data were entered with SPSS (version 25). Data are shown as mean values and SD for quantitative data and as frequencies (number of patients) and relative frequencies (percent of total) for categorical data. The unpaired t test was used for comparisons between cohorts. Categorical variables were compared with the chi-square test. However, the exact test was used if the anticipated frequency was less than 5. Logistic regression was used to detect independent risk factors of short-term mortality. P < .05 was considered statistically significant.
This study included 145 selected adult recipients of right lobe LDLT. The selected recipients ranged in age from 21 to 70 years with a mean age of 46.9 years (SD, 17.53 years) for the group, a mean BMI of 27.47 (SD, 2.98), and a mean MELD score of 17.66 (SD, 3.52).
Some donor data and preoperative recipient laboratory data are shown in Table 1. Table 2 shows some relevant preoperative data of the recipients. Table 3 summarizes the main intraoperative details that were assessed. Intraoperative furosemide was used for 62 patients (42.8%), whereas intraoperative epinephrine was used for 68 patients (46.9%).
For patients in this study, the PVP was modulated (by splenectomy) if the mean PVP exceeded 20 mm Hg; this was required in 12 patients. The portal pressure decreased to a mean of 17.5 mm Hg, and all of these patients experienced a smooth postoperative course.
Postoperatively, there were 25 deaths (17.2%), as well as 29 patients who developed SFSS (20.0%) in the early postoperative period. The causes for early mortality after LDLT included infection (14 patients, including sepsis, pneumonia, and peritonitis); rejection (3 patients), multiorgan affection (2 patients), vascular problems including hepatic artery occlusion and portal vein occlusion (4 patients), and myocardial infarction (2 patients).
Table 4 summarizes some of the postoperative characteristics of the patients. There were no donor mortalities in this cohort. Comorbidities occurred in 12 donors, including infection (9 patients) and pulmonary embolism (3 patients).
Patient group subanalyses
Cases were categorized into 2 groups of patients according to early mortality. There were 25 cases that resulted in death of the patient and 120 cases without mortality. Both groups were compared with regard to preoperative, intraoperative, and postoperative data. Comparisons of preoperative data revealed statistically significant differences for recipient age, MELD score, donor age, and donor fatty changes by biopsy (P < .001).
Comparisons of other preoperative parameters are shown in Table 5 and Table 6. For intraoperative variables (ie, the main focus of this study), there were statistically significant variations between the groups for the number of PRBC units, cold and warm ischemia times, duration of the anhepatic stage, graft/recipient weight ratio, portal pressures (preclamp, postreperfusion, and mean), mean intraoperative central venous pressure, average urine flow rate, crystalloid infusion, net fluid balance during surgery, mean serum lactate, mean blood pressure, and surgery duration (P < .001). Significant differences were also shown in the number of platelets, units of FFP, and mean sodium bicarbonate (P = .025, .003, and .035, respectively).
Comparisons between both groups for other intraoperative parameters are shown in Table 7. Table 8 summarizes the comparisons of postoperative parameters between the 2 groups. Of note, the development of SFSS greatly affected short-term recipient mortality; of the 25 patients who died within the early postoperative period, 20 of them had developed SFSS (P < .001).
Logistic regression analysis of significant perioperative factors revealed that the length of ICU stay was the only independent predictor of early recipient death (P < .001) (Table 9).
Liver transplant is a well-established therapeutic strategy for decompensated hepatic disorder. The necessity for hepatic grafts has led to expanded criteria for organ allocation and thereby increased the risk of negative consequences. Only limited data have been published regarding the use and accuracy of intraoperative factors as risk factors for short-term death after LT.7
The present study addressed the various intraoperative predictive factors that are associated with early recipient death after LDLT. Herein, several different intraoperative factors are suggested to significantly affect short-term recipient mortality.
Transfusion of PRBC and other blood products is a common scenario during LT procedures; however, surgery without transfusion has been more widely adopted.8 Enormous transfusion during LT leads to considerable morbidity and mortality, as well as the associated higher cost of treatment.9
In this patient cohort, higher numbers of PRBC, platelets, and units of FFP significantly affected the rate of early recipient mortality, with PRBC being the most crucial factor. These results agree with those from Bertacco and colleagues, who stated that a substantial volume of blood transfusion during LT is a critical predictive factor for short-term death.10 Also, another study ascertained the possible clinical utility of PRBC as a prognostic predictor for early mortality after LT.11
Intraoperative anesthetic strategies and surgical methods may affect postoperative patient survival. Duration of the surgery, intraoperative hemodynamic instability,12 and cold and warm ischemia times have been shown to have substantial effects on LDLT outcomes.13 Moreover, higher central venous pressure may preclude outflow from the liver allograft, which may result in allograft dysfunction.14
In this study, low mean blood pressure, prolonged durations of cold and warm ischemia times and anhepatic phase, higher intraoperative central venous pressure, and longer duration of surgery were shown to have significant effects on early mortality post-LDLT. A previous study similarly demonstrated that prolonged anhepatic time was a possible risk factor for early mortality.15 Another study showed that prolonged cold ischemia time was associated with higher postoperative mortality.16
In adult-to-adult LDLT, high PVP after reperfusion may cause serious problems, particularly in small-for-size grafts, which may lead to higher rates of comorbidity and early mortality.17 The present study showed that graft/recipient weight ratio and preclamp, postreperfusion, and mean portal pressures had considerable effects on early mortality. These results support the results reported by Sholkamy and colleagues, who demonstrated that PVP is a substantial hemodynamic factor for graft survival and early patient mortality after LDLT.18
In contrast, in another study that compared recipient outcomes in standard grafts versus small-for-size grafts, rates of early mortality after LDLT with right lobe small-for-size grafts were comparable with early mortality rates after LDLT with normal grafts.19
The risk of SFSS is an impediment to the wide implementation of LDLT; moreover, it is an important risk factor for unfavorable early outcomes after LDLT.20 The present work showed a significant effect of SFSS on early patient mortality after LDLT. These results support the results reported by Shoreem and colleagues, who showed that SFSS led to an elevated death rate, for which the most common reason for the incidence of mortality was the syndrome itself, as well as its consequent comorbidities.21
The modulation of PVP by splenectomy, portocaval shunting, and splenic arterial ligation is a fundamental method for the prevention of SFSS, and the generally acceptable limit of PVP during LDLT is between 15 and 20 mm Hg.22
Portal venous pressure has a substantial effect on short-term prognosis after LDLT. Portal venous pressure should be maintained within a certain threshold to enhance proper graft regeneration. If PVP surpasses certain values, then it may harm the graft. Portal venous pressure should be routinely assessed in every recipient who undergoes LDLT. The amendment of PVP may be helpful factor in LDLT because it may lower the incidence of SFSS and promote better LDLT outcomes.18 In the present study, patients with high PVP underwent splenectomy, which resulted in a smooth postoperative course.
Lactic acidosis is characterized by elevated lactic acid levels, and metabolic acidosis is characterized by a high anion gap.23 Many studies have addressed the relationship between arterial lactate levels and postoperative outcome in liver resections; however, only a few studies have focused on lactic acid levels during LDLT.
The present study showed that higher mean serum lactate and lower mean intraoperative sodium bicarbonate could significantly affect postoperative early recipient mortality. In agreement with this, Jipa and colleagues have shown that elevated arterial lactate values during LT correlated with higher postoperative mortality after LT.24 In addition, Kim and colleagues demonstrated that lactic acid levels and sodium bicarbonate infusion were linked to a higher death rate after LT.25
A strict intraoperative fluid replacement strategy guided by continuous monitoring may facilitate positive outcomes after LDLT.14 The present study showed that intraoperative oliguria, higher volumes of crystalloid infusion, and a more positive fluid balance during surgery significantly increased the rate of recipient mortality during the early postoperative period.
These findings are consistent with the results of Thongprayoon and colleagues, who reported that urine output, crystalloid administration, and fluid balance during surgery were all significantly associated with a higher rate of early mortality after LT; they attributed these results to a higher rate of post-LT acute kidney injury.26
In the field of LDLT, no specific vasopressor medication seems to be more favorable over others, and yet vasopressor medication remains a necessity for LDLT, to avoid possible episodes of hypotension. Furosemide has been used as a bolus before reperfusion, which may induce diuresis and improve oliguria.14 In the present work, intraoperative furosemide or epinephrine did not have a notable effect on early postoperative morality.
Critical disease with subsequent prolonged duration of stay in an ICU has been linked to a higher death rate and more severe exhaustion of resources.27 In this study, logistic regression analysis revealed the ICU period to be the only independent predictor of short-term death. This agrees with results reported by Elkholy and colleagues, who demonstrated the length of ICU stay was independently linked to short-term death after LDLT.28 In the present study, the logistic regression analysis seemed to be logical; that is, patients with significant postoperative comorbidities are usually treated in the ICU, and these comorbidities could potentially lead to higher post-LDLT early mortality rates.
In the present study, the intraoperative factors associated with increased rates of early postoperative mortality were shown to be multiple, complex, and interrelated. For example, recipients with lower intraoperative mean blood pressure (with possible associated hypoperfusion and subsequent high lactic acid and low sodium bicarbonate levels) may be at greater risk of early mortality, and, notably, such patients usually receive a higher volume of crystalloid infusion than other patients. This example demonstrates the interconnectivity of multiple intraoperative factors and suggests that these factors are best managed as a set of factors (rather than singly), because any single factor may substantially affect another.
Additionally, this study showed that a surgical approach that incorporates PVP adjustment could expand the LDLT pool of potential allografts that would otherwise be restricted by assessments of graft size and quality, without exposing the donor to greater risk.
In conclusion, a variety of intraoperative risk factors may affect early post-LDLT mortality, and this reflects the complexity of LDLT and emphasizes the need for highly experienced trained teams.
The present study has some limitations. The retrospective design of the study led to the exclusion of some perioperative factors with incomplete data. This study did not address specified phases of LDLT or the unstable hemodynamics or metabolic disorders that may be associated with those phases. The correlation of intraoperative variables to phases of LDLT should be considered in future studies of the association of these variables with postoperative mortality.
Novelty of study
In the field of LDLT, few published studies have investigated the association between intraoperative factors and early postoperative mortality rates.
Although studies on intraoperative factors that may affect posttransplant death may not result in the proper preoperative selection of patients or treatment strategies, such studies may serve as a new guide or a supplement to actual preoperative risk factors for early complications. Greater knowledge and understanding of potential negative outcomes may better prepare physicians for the complexity of LDLT surgery (both intraoperatively and postoperatively), which may lead to more favorable overall prognoses after LDLT. Therefore, new emphasis on these factors is a worthy aspect of this study.
Volume : 19
Issue : 8
Pages : 817 - 825
DOI : 10.6002/ect.2021.0084
From the 1Department of Surgery, Great Western Hospitals NHS Foundation Trust, Swindon, United Kingdom; the 2Internal Medicine Department, the 3General Surgery Department, the 4Department of Endemic Medicine and Hepatology, the 5Department of Anaesthesia, Surgical ICU and Pain Management, Faculty of Medicine, Cairo University; and the 6General Surgery Department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Ahmed Abdallah Salman, Internal Medicine Department, Faculty of Medicine, Cairo University, 110 L, Hadayek Alahram, Giza, 11311 Egypt
Phone: +20 10 0046 8664
Table 1. Preoperative Laboratory Data
Table 2. Preoperative Patient Characteristics
Table 3. Intraoperative Patient Characteristics
Table 4. Postoperative Patient Characteristics
Table 5. Preoperative Data Comparison Between Mortality Groups
Table 6. Preoperative Data Comparison Between Mortality Groups
Table 7. Intraoperative Data Comparison Between Mortality Groups
Table 8. Postoperative Data Comparison Between Mortality Groups
Table 9. Logistic Regression to Detect Independent Predictors of Early Mortality