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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 7  |  Issue : 4  |  Page : 186-192

A study of critical care issues in pediatric liver transplantation


1 Department of Pediatrics, Institute of Child Health, Sir Ganga Ram Hospital, New Delhi, India
2 Department of Pediatrics, Division of Pediatric Gastroenterology and Hepatology, Institute of Child Health, Sir Ganga Ram Hospital, New Delhi, India
3 Department of Surgical Gastroenterology and Liver Transplantation, Sir Ganga Ram Hospital, New Delhi, India

Date of Submission07-Apr-2020
Date of Decision23-Apr-2020
Date of Acceptance09-May-2020
Date of Web Publication13-Jul-2020

Correspondence Address:
Dr. Anil Sachdev
Department of Pediatrics, Institute of Child Health, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi - 110 060
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JPCC.JPCC_46_20

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  Abstract 


Objective: The objective is to study the intra- and postoperative cardiopulmonary complications, metabolic derangements, and mortality in the recipients of orthotopic liver transplantation (OLT).
Materials and Methods: Medical records of all children who underwent OLT at our institution from January 2003 to December 2019 were reviewed, and the clinical and laboratory data were collected.
Results: Eighty-two patients (48 males) underwent living-related OLT and one received cadaveric liver. The median age of recipients was 6 years (range: 4 months–16 years). The two common indications for OLT were biliary atresia (n = 27, 32.9%) and Wilson's disease (n = 20, 24.3%). Common metabolic problems during intraoperative phase included hypokalemia (43.9%) and hyperglycemia (57.3%). The mean duration of postoperative ventilation was 35.8 ± 51.4 h. Fifty-two patients were extubated within 24 h of surgery. Pleural effusion was most common present in 52 patients postoperatively. It did not interfere with mechanical ventilation. Hypertension, hypotension, and oliguria were recorded in 28, 31, and 22 patients, respectively. There were 11 graft rejection episodes. Ten children required re-operations. There were 4 (4.8%) early deaths, aged ≤1 year, in the first 2 weeks of transplantation.
Conclusion: Medical and surgical complications are common in patients after liver transplantation. Intensive monitoring and laboratory workup help in detection of these complications. Early and 1-year survival rates are comparable to that in the developed world.

Keywords: Liver transplantation, living donor, pediatric, posttransplantation critical care, postoperative complications


How to cite this article:
Sachdev A, Wadhwa N, Mehta N, Gupta D, Gupta N, Kaur J. A study of critical care issues in pediatric liver transplantation. J Pediatr Crit Care 2020;7:186-92

How to cite this URL:
Sachdev A, Wadhwa N, Mehta N, Gupta D, Gupta N, Kaur J. A study of critical care issues in pediatric liver transplantation. J Pediatr Crit Care [serial online] 2020 [cited 2020 Aug 13];7:186-92. Available from: http://www.jpcc.org.in/text.asp?2020/7/4/186/289522




  Introduction Top


The immediate postoperative management of liver transplantation patients is complex, and with multidisciplinary approach, the outcome has improved in children in the last 20 years.[1],[2],[3],[4],[5] The perioperative management is associated with a high morbidity despite improvement in understanding the pathophysiology of liver diseases; better patient selection; improved anesthetic, surgical, and intensive care management; and the use of safer immunosuppressant drugs.[5],[6],[7],[8] The overall mortality is low, but most of the deaths occur in the first 7 days after transplant.[9] There are very few pediatric studies focused on immediate intensive care of liver transplantation patients.[1],[4],[6] The main objectives of this retrospective analysis were to study the intra- and postoperative cardiopulmonary complications, metabolic derangements, and mortality in the recipients of orthotopic liver transplantation (OLT).


  Materials and Methods Top


Study design and population

Eighty-two consecutive pediatric patients (age ≤16 years) who underwent OLT from January 2003 to December 2019 at our institution formed the study cohort. The institutional ethics and research committee approval was obtained for the study. Consent was also taken before scrutinizing the medical charts. The medical and nursing records were reviewed, and the data were collected and divided into three periods: preoperative, intraoperative, and postoperative.

Preoperative data

It included demographic features, clinical findings, primary liver disease, comorbid conditions, laboratory investigation results, history of previous surgery, and donor's relation to the recipient.

Intraoperative data

It included the cardiorespiratory parameters, estimated blood loss, type and amount of blood components, colloids and crystalloids used, and hourly urine output. The duration of surgery, type and weight of graft, and complications were also recorded.

Postoperative data

It included the hemodynamics and ventilation data, type and duration of sedation, analgesics and muscle relaxants, and drugs required for hemodynamic stability (vasopressors, inotropes, and antihypertensive drugs), which were also recorded. All complications related to procedure were recorded. Hematological, biochemical, radiological, and microbiological data were also recorded.

All donors were medically fit and received clearance for organ donation from the authorization committee constituted by the Government of India. The adequacy of the hepatic vasculature and blood flow was assessed by triphasic computed tomography angiography and Doppler ultrasonography. All donors were ABO compatible.

OLT was done using standard surgical techniques along with biliary reconstruction using choledochostomy or choledochojejunostomy using Roux-en-Y anastomosis.[10] Left lobe or left lateral segment was used as a graft in majority of the patients.

All patients were managed at a four-bedded adult-pediatric liver transplant intensive care unit (ICU) by a team of consultants, fellows, and nurses from the different specialties. A pediatric intensivist provided round-the-clock cover until extubation or longer if demanded by the patient's condition. Intravenous antibiotics, piperacillin-tazobactam, metronidazole, and fluconazole were started 24 h before surgery. Antibiotics and antifungal therapy were continued for minimum of 7 days and were upgraded, and prolonged duration course was given depending on the clinical and laboratory evidence of infection. For immunosuppression, methylprednisolone, tacrolimus, and mycophenolate were used. Diagnosis of acute rejection was made on the basis of clinical, laboratory, and histological findings.

Wound drain and extrarenal fluid losses were replaced with 5% albumin and normal saline as required. As per organ transplantation unit protocol, the target values for international normalized ratio between 2 and 3.0, activated partial thromboplastin time between 2 and 2.5 times the normal control, hemoglobin >8 g/dL, and platelet counts >30,000/μL were used.

Statistical analysis

Statistical testing was conducted with the Statistical Package for the Social Sciences (SPSS) system version SPSS 17.0 (SPSS Inc. Chicago, IL, USA). Data were checked for normality before statistical analysis. Distribution of data was not normal, so mean ± standard deviation and median (range) were used for continuous variables. Categorical variables are expressed as frequencies (%).


  Results Top


A total of 82 patients underwent OLT. All transplantations were live donor except one which was cadaveric [Figure 1]. Out of the 81 live donor transplants, 77 were live related, 3 were second-degree relatives, and one was Domino (potential liver transplantation recipient with a single enzyme defect acts as a donor for another recipient). Two patients of primary hyperoxaluria underwent combined liver and renal transplants and required renal replacement therapy in the perioperative period [Table 1].
Figure 1: Year-wise distribution of liver transplantation cases

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Table 1: Primary liver disorder (n=82)

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The demographic features and other characteristics are summarized in [Table 2]. Twenty (24.3%) children were ≤1 year of age, and 24 (29.28.5%) children were ≤10 kg in weight. Thirty-one (37.8%) patients presented with fulminant hepatic failure requiring emergency transplantation. Out of the 27 biliary atresia (BA) patients, 15 patients had undergone portoenterostomy (Kasai's procedure) in the past. One patient of Wilson's disease underwent re-transplantation after 2 ½ years of the first surgery.
Table 2: Demographic profile with preoperative and intraoperative status of study patients (n=82)

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During surgery, an average intravenous fluid (dextrose saline) intake was 147.5 ± 80.2 ml/kg which included 25.5 ± 20.5 ml/kg of packed red blood cell (RBC), 22.5 ± 19.5 ml/kg of fresh frozen plasma (FFP), 14.5 ± 8.5 ml/kg of albumin, and 3.8 ± 7.5 ml/kg of platelets. Inotropic support with norepinephrine (0.05–0.1 μg/kg/min) alone was required in 19 patients. A combination of vasopressors and inotropes was used in seven cases. The average blood loss during surgery was 275.5 ± 269.5 ml (17.8 ± 14 ml/kg). Other complications included electrolyte disturbances, i.e., hyponatremia (<135 meq/L) in 14 (17.1%) patients and hypernatremia (>145 meq/L) in 5 (6.1%) patients. While hypokalemia (K+<3.5 meq/L) was detected in 36 (43.9%) patients requiring KCl infusion, one patient had hyperkalemia (6.9 meq/L) during surgery. Hyperglycemia (blood sugar >180 mg/dl) was noticed in 47 (57.3%) patients, but continuous insulin therapy was required for only 32 patients. The total surgery time was 9.5 ± 3.8 h. All patients survived the surgery.

All patients remained intubated and ventilated during transportation to liver transplant ICU located in the operation theater complex. After a mean stay of 8.3 ± 3.8 days in liver transplant ICU, patients were shifted with parents to an isolation room with reverse barrier nursing. The mean duration of arterial and central lines was 3.5 ± 2.1 and 6.5 ± 2.5 days, respectively.

The mean duration of mechanical ventilation was 35.8 ± 51.4 h (median: 22.5, range: 4.5–336 h). The mean duration of pressure-regulated volume control mode of ventilation was 27.3 ± 37.9 h (median: 14; range: 2.3–216 h), while synchronized intermittent mandatory ventilation with pressure support (PS) and continuous positive airway pressure with PS were used as weaning modes. Fifty-two (63.4%) patients were extubated within 24 h. Pleural effusion was mild and did not interfere with ventilation. Thoracocentesis was not required in any case [Table 3]. Eight patients developed chest infection, progressing to septicemia in four patients. Six patients required re-intubation due to postoperative severe sepsis and respiratory failure. Two children required tracheostomy for prolonged ventilation support.
Table 3: Postoperative complications related to liver transplant in children (n=82)

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Arterial hypertension (mean arterial pressure >90th centile for age) was observed in 28 patients from postoperative day 3 onward. Only four patients (nil-by-mouth) required sodium nitroprusside for 48 h, while the rest all were given oral nifedipine, amlodipine, and enalapril. None of these patients developed any end-organ dysfunction. Postoperatively, inotrope support was required in 31 (37.8%) patients. Norepinephrine alone was used in 20 (24.3%) patients and also in combination with dopamine in 8 patients and with epinephrine in one case. Two patients required multiple inotropes and vasopressors.

Oliguria (urine output <1 ml/kg/h for infants <1 year or <0.5 ml/kg/h for children >1 year) developed in 22 (26.5%) patients. Fifteen patients responded to fluid boluses, and four patients required furosemide infusion in the first 72 h after surgery. Peritoneal dialysis for renal failure secondary to sepsis with multiorgan dysfunction was used in one patient. Two other patients with sepsis developed acute kidney injury and fluid overload required continuous renal replacement therapy (CRRT). Two patients of combined kidney-liver transplant also required CRRT.

Blood components were used in 55 patients during liver transplantation ICU stay. Packed RBC, FFP, and platelets were used on 40, 25, and 21 occasions alone or in combination. Packed RBC 18.5 ± 22.3 ml/kg, FFP 12.8 ± 10.6 ml/kg, and platelet concentrate 5.1 ± 6.2 ml/kg were transfused during ICU stay.

There were 11 episodes of acute graft rejection in the first week of transplantation and were managed with high dose methylprednisolone. A total of ten children required re-operations in the first 72 h. Vascular complications included hepatic artery thrombosis in three cases, and four patients developed portal vein thrombosis requiring re-exploration and surgical embolectomy, followed by low-molecular-weight heparin (LMWH). One patient developed partial blockade of portal vein, which resolved with LMWH. Another two patients developed bile leak, and re-operation was done in one case. Re-exploration within 24 h was done two children for intra-abdominal bleeding. Another child had intra-abdominal fluid collection postoperatively, and ultrasound-guided intraperitoneal drain was inserted. Majority of the patients (71/82) had bowel movement and were fed by enteral route within 72 h.

All patients were started on piperacillin-tazobactam, metronidazole, fluconazole, and teicoplanin postoperatively as a part of the protocol. Antibiotics were upgraded on the development of sepsis. The antibiotics were upgraded as per the microbiology antibiogram reports, and a de-escalation strategy was followed. Only 15 (18.3%) patients had culture positive blood stream infections. These included Acinetobacter baumanii (n=5), Staphylococcus hemolyticus (n=3), Escherichia coli (n=2), and methicillin resistant Staphylococcus aures (n=1) and vancomycin resistant Enterococcus (n=2), Candida albicans (n=1) and 3 patients developed Cytomegalovirus infection.

One patient developed generalized tonic-clonic seizures due to hypocalcemia. No other neurological complication was noticed in any patient.

Hypokalemia was present in 34 patients (41.4%) requiring either oral or intravenous potassium replacement. Hyperglycemia was observed in 27 patients (32.9%), and 22 of these required insulin infusion.

There were 4 (4.8%) deaths in this cohort of patients in the first 2 weeks of transplantation, and all were ≤1 year. One baby died of abdominal compartment syndrome due to refractory postoperative bleeding and others died of complications of sepsis [Table 4]. One-year survival in our cohort was 92.7%.
Table 4: Characteristics of nonsurvivors of liver transplantation

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  Discussion Top


OLT is an accepted treatment of fulminant hepatic failure and end-stage liver disease in both children and adults.[1],[2],[3],[4],[5],[6],[11],[12],[13],[14] The main principles of immediate postoperative intensive care include maintenance of hemodynamics, fluid and electrolyte balance, correction of coagulopathy, early weaning from mechanical ventilation, prevention and early detection of thrombotic and infectious complications, and organ dysfunction, especially respiratory and renal.

At our institute, a total of 82 patients underwent liver transplantation, with BA (32.9%) being the most common cause, a profile similar to that reported by various previous studies.[3],[5],[12],[14],[15],[16],[17] In our series, the most common complications encountered were respiratory, cardiovascular, infectious, and metabolic, a profile almost similar to other studies.[1],[5],[14]

Pediatric liver transplantation remains a challenge for the treating team, not only with regard to medical or surgical techniques but also for families, especially in the developing countries. Two other major problems are acceptability about OLT by parents and by referring medical fraternity and arranging finances. All expenses were arranged and paid by the family. The number of pediatric OLTs at our institution has not been very high due to certain reasons. Our institution is not a dedicated liver transplant center. Another probable reason is mushrooming of many corporate and private hospitals in major cities and metros in India in the last decade. Similar initial problems were experienced by others.[5]

Systemic hypertension and hypotension in the postoperative period were seen in almost equal number of patients in our cohort. Sibal et al.[5] reported hypertension in only 4 out of 50 OLT cases. Hypertension is multifactorial in origin, with common causes being positive fluid balance in the initial postoperative period, pain and anxiety, use of drugs such as steroids with cyclosporine, altered plasma renin, atrial natriuretic factor and arginine vasopressin levels, and renal dysfunction further leading to fluid and salt overload. The recommended treatment includes salt restriction, diuretics, and angiotensin-converting enzyme inhibitors.[18] Postoperative hypotension is seen in children with subclinical hypovolemia, occult hemorrhage, metabolic acidosis, electrolyte imbalance, especially hypocalcemia, hypokalemia, and hypomagnesemia.[7] Thirty-one patients required postoperative inotropic support which was weaned off within 72 h in most patients.

Liver transplant recipients are at risk for postoperative respiratory infections, septicemia, and abdominal infections.[5] Respiratory complications include pleural effusion, atelectasis, diaphragmatic palsy, and pneumonia.[19] Right-side pleural effusion was the most common respiratory complication in our study, but none of the patients required chest drainage. Similar results have been reported previously.[1],[5] Glanemann et al.[20] reported significantly higher morbidity and mortality with prolonged duration of mechanical ventilation in a large cohort of adult liver recipients. The volumes of intraoperative blood loss, intraoperative urine output, and postoperative renal failure have been recognized as independent risk factors for prolonged ventilation.[21] Therefore, early or immediate postoperative tracheal extubation has been proposed for patients undergoing OLT.[22],[23],[24] In our series, majority (63.4%) of the patients were extubated within 24 h. Bacterial and fungal infections are one of the major complications that strongly influence the morbidity and mortality following liver transplantation.[8] Our patients were empirically started on a protocol-based antibiotic and antifungal therapy before transplantation. Postoperatively, 18.3% of the patients had culture-positive infection. Common sites were lungs and bloodstream. Early, severe viral infections are caused by Epstein–Barr virus, Cytomegalovirus, and herpes simplex.[10] Three patients in our cohort had Cytomegalovirus infection posttransplantation and were treated with intravenous ganciclovir.

Vascular complications were observed in eight patients. Seven patients required surgical exploration. The incidence of risk of hepatic artery thrombosis varies from 5% to 18% and is 3–4 times more frequent in pediatric patients, especially infants.[10],[15],[25],[26] All our patients with hepatic artery thrombosis were <10 months of age. The overall incidence of vascular thrombosis is similar in whole, split-liver transplantation and living donor transplantation.[8] The possible surgical reasons for increased risk of vascular thrombosis in pediatric patients are related to vessel size, type of vessel anastomosis, and number of anastomosis attempts to have good vessel flow. Two medical reasons related to vessel thrombosis are use of FFP and no use of anticoagulants in the perioperative period.[25] However, it is not our routine practice to use anticoagulation in postoperative patients. Renal dysfunction commonly observed as decrease in urine output was seen in 22 (26.5%) patients. Majority responded to fluid boluses and furosemide. The etiology of renal dysfunction is multifactorial and includes hepatorenal syndrome, abdominal compartment syndrome, nephrotoxic drugs, and acute tubular injury.[5],[27] Renal failure is implicated as an independent prognostic factor for the graft survival.[17] Dialysis did not improve the survival in a study from Pittsburgh.[27]

Postoperative neurological complications were rare in our series. The reported incidence of neurological complications including seizures and encephalopathy has been variable.[1],[4],[6]

Metabolic and electrolyte abnormalities are common and are related to the pretransplant nutritional status, intraoperative events, fluid shifts, and citrated banked blood. Normal glucose metabolism is a sign of well-functioning graft. Hypoglycemia is an ominous sign. Hyperglycemia is a consequence of surgical stress, steroids, calcineurin inhibitors, and associated diabetes mellitus.[7]

There are advantages of living donor transplantation in adults and children as compared to cadaveric. Living donor transplantation is not associated with ethical or religious issues and has psychological advantages. There are lesser complications and lower duration of mechanical ventilation and hospital stay.[28],[29] In the present study, four patients died during their stay in the ICU because of sepsis and multiorgan failure. The reported early mortality rate within the first 28 days is 8%.[30],[31] It has also been observed that patient and graft survival has improved over the years probably due to better patient selection, diagnosis, disease severity, type of graft, improvement in the perioperative intensive monitoring, and care and surgical experience.[5],[6],[10] All the early non-survivors in our series were infants with severe hepatic disease preoperatively and developed severe sepsis and multi-organ dysfunction after liver transplantation. One-year survival in our cohort was comparable to published reports.[31],[32]


  Conclusion Top


Medical and surgical complications are common in patients after liver transplantation. Intensive monitoring and laboratory workup help in detection of these complications. Early and 1-year survival rates are comparable to that in the developed world.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Cintorino D, Spada M, Clarizia S, Vasta F, Mandalà L, Aricò M, et al. Pediatric liver transplantation: Preliminary results at Istituto Mediterraneo Trapianti e Terapie ad Alta Specializzazione. Transplant Proc 2005;37:2597-8.  Back to cited text no. 3
    
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Ganschow R, Nolkemper D, Helmke K, Harps E, Commentz JC, Broering DC, et al. Intensive care management after pediatric liver transplantation: A single-center experience. Pediatr Transplant 2000;4:273-9.  Back to cited text no. 4
    
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Bahador A, Salahi H, Nikeghbalian S, Dehghani SM, Dehghani M, Kakaei F, et al. Pediatric liver transplantation in Iran: A 9-year experience. Transplant Proc 2009;41:2864-7.  Back to cited text no. 7
    
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Khan D, Esquivel CO, Makowka L, Madrigal-Torres M, Yunis E, Iwatsukl S, et al. Causes of death after liver transplantation in children treated with cyclosporine and steroids. Clin Transplant 1989;3:150-5.  Back to cited text no. 10
    
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Ikegami T, Taketomi A, Soejima Y, Yoshizumi T, Sanefuji K, Kayashima H, et al. Living donor liver transplantation for acute liver failure: A 10-year experience in a single center. J Am Coll Surg 2008;206:412-8.  Back to cited text no. 14
    
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[PUBMED]  [Full text]  
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