Liver transplantation (LT) is a major surgical procedure, with recipients presenting with end-stage liver disease and the complications thereof. It follows that post-operative care is complex and requires continuous anticipation of potential co-morbidities and complications. Although the immediate post-operative period is characterized by a multi-organ dysfunction syndrome, standard supportive care usually leads to a progressive improvement within the first few days post-operatively. In addition to post-operative monitoring and management, anticipation of major complications associated with LT outcome is warranted: primary graft non-function (PNF), post-operative vasoplegia, sepsis and septic shock, abdominal compartment syndrome, and renal failure.
Post-Operative Monitoring and General Management
The goal of post-operative monitoring is prompt identification of complications for early initiation of goal-specific management ( Table 16.1 ). Complications may be due to pre-transplant patient condition (frailty, malnutrition, recurrent infection, renal failure, young age), surgical complications (vascular thrombosis or bleeding, perforation, biliary complication), or from the side effects of drugs conventionally used in transplantation, especially calcineurin inhibitors with their inherent renal and neural toxicities.
The target is to keep mean arterial pressure (MAP) in the normal range for patient age, and this means finding equilibrium between hypotension and hypertension both of which are frequent following pediatric LT. Monitoring tools include echocardiogram, aortic flow variability using transesophageal Doppler and Near Infrared Spectroscopy (NIRS). Hemodynamic targets include: Stroke Volume Index (SVi) >25 ml/m 2 , Cardiac Index (CI) > 3,5 L/min/m 2 , and Stroke Volume Variation (SVV) < 10% using a trans-esophageal aortic Doppler. Important therapeutic objectives of adequate hemodynamic management include decreasing blood lactate upon Pediatric Intensive Care Unit (PICU) admission and its normalization within the first hours. Use of fluid boluses and/or vasopressive drugs is standard of care. Fluid replacement should be guided using fluid responsiveness criteria (e.g., minimum urine output: 0.5-1 ml/kg/h very low central venous pressure [CVP], or small telesystolic left ventricular surface area).
Systemic hypertension is a classic side effect of both calcineurin inhibitors and volume overload. In addition, pain contributes to blood pressure (BP) elevation in the post-operative period. Systemic hypertension should be treated to reach normal range ± 2SD for recipient age.
Fluid overload is well recognized as a factor associated with adverse events in PICU. However, excessive fluid restriction may impair graft perfusion and renal function (vascular thrombosis, pre-renal azotemia). In the first days after transplantation, ongoing drain losses need to be compensated, usually with crystalloids. In case of significant drain losses or hypoalbuminemia (below 3 g/dl), use of 5% or 20% albumin may contribute to maintaining intravascular volume while mitigating fluid overload. Fresh frozen plasma (FFP) is seldom used as compensation fluid, as there is no evidence that it is beneficial. What more, it carries the combined risk of allo-sensitization and masking early graft dysfunction. In the absence of vascular anomalies, a negative fluid balance should be sought starting on post-operative day 2 or 3. This is attainable either by using diurectics or by limiting fluid loss replacement.
The post-operative period is characterized by the risk for frequent respiratory complications. Prompt extubation is the goal of early post-operative management. There is no benefit to prolonged mechanical ventilation. Contraindications to rapid wean from respiratory support include: active bleeding, hemodynamic instability, respiratory failure, or severe neurological impairment precluding endotracheal tube removal.
Typical respiratory complications include atelectasis, pleural effusion, and occasionally right phrenic nerve palsy. Pleural effusion is often associated with ascites and mandates assessment of hepatic venous outflow. It may require percutaneous drainage. Right phrenic nerve involvement is much rarer and can be suspected clinically, or when an elevated right hemi-diaphragm is observed on X-ray. Diagnosis is confirmed using ultrasound or fluoroscopy to assess diaphragm movement during spontaneous breathing. Diaphragmatic training through neurally adjusted ventilation may be of some benefit. Diaphragmatic plication may be warranted in case of repeated failure to wean from ventilator support.
Particular care should be given to avoiding hypovolemia because of the associated risk of vascular thrombosis. Therefore, continuous follow-up of drain losses is essential. Drain losses must be initially fully compensated with colloids and/or crystalloids, and adapted thereafter to mitigate fluid overload. The drain fluid should be routinely checked for bilirubin, amylase and trigyceride levels to ascertain the origin of the leak. In case of massive ascites and hypoalbuminemia, albumin may be of benefit to compensate losses.
Color and composition of fluid is relevant for management. For example, in case persistently high ascites output, the following should be ruled out: portal vein thrombosis, Budd-Chiari syndrome, intestinal perforation, and chylous ascites. In case of loss of more than once the circulating blood volume despite medical management or drainage of > 5 ml/kg/h of blood-stained fluid, surgical hemostatic procedures should be considered. Only once bleeding is under control, anticoagulation according to local protocol should be initiated. Both bleeding and thrombosis are feared complications following LT. While active bleeding warrants immediate cessation of anticoagulation, correction of severe hemostasis anomalies, and discussion with the surgical team, it is crucial to remember that platelet transfusion can result in vascular thrombosis during disseminated intravascular coagulation (DIC). Both in case of resuscitation and in routine management, it is generally accepted that target hemoglobin should be in the 8-10 g/dL range in the early post-operative phase. Therefore, daily abdominal ultrasound with Doppler is valuable to monitor for thrombosis during the early post-operative phase. Evidence of thrombosis warrants immediate discussion with the transplant surgeon. Vascular complications are further described in Chapter 20 .
Abdominal compartment syndrome (ACS) is another complication that should be sought and anticipated. ACS is a major concern because it is associated with high risk of vascular thrombosis and mortality. Invasive bladder pressure monitoring is necessary both to diagnose and monitor ACS. Intra-abdominal hypertension (IAH) with an intravesical pressure > 20 mmHg is a critical sign of ACS, warranting aggressive management.
The following are the main criteria to assess liver function in the first few hours following surgery: prothrombin time, serum lactate, metabolic acidosis, liver enzymes kinetics, and the patient’s neurological status. Liver enzymes typically display a transient rise during the first 2-3 days following LT, then progressively decrease within the first week. A rise of glutamyl-transferase at the end of the first week after LT is thought to be a sign of bile duct regeneration. Immunosuppressive therapy must be initiated promptly per local protocol (see Chapter 18 ).
The post-operative period is at risk for renal failure due to numerous factors like fluid shifts, hemodynamic instability and use of nephrotoxic drugs. Oliguria should be managed aggressively using furosemide (challenge using a higher dose if needed, up to 0.5-1 mg/kg/h) if necessary, while ensuring sufficient intravascular volume. If the patient remains anuric with fluid overload, continuous renal replacement therapy (CRRT) should not be delayed. Some patients may have presented with pre-transplant renal failure (hepato-renal syndrome, tubulopathy, Alagille syndrome), which may add to the challenges of managing fluid and renal function.
Bacterial, fungal, and viral infection occur at different times after LT. Bacterial infections typically occur within the first 30 days after LT. Fungal infections are rare and may also occur early after LT, especially in the background of a necrotic liver lesion, pancreatitis, biliary dilatation, or intra-abdominal hematoma. Viral infections tend to happen later on and are reviewed in detail in Chapter 19 . HSV 1/2, HHV6, and adenovirus are of importance during the early post-operative phase, as they may lead to graft loss in case of systemic infection. In case of early respiratory symptoms and profound hypoxemia, Pneumocystis jirovecii infection should be considered.
Most post-transplant protocols include a broad-spectrum antibiotic, typically a β -lactam antibiotic, for 2-5 days. Some also use an anti-fungal for 14 days. Finally, most protocols introduce Pneumocystis prophylaxyis within a few days of transplant, as well as CMV prophylaxis, although prophylaxis versus careful viremia surveillance is a matter of debate ( Chapter 19 ).
In addition to the system-based anticipatory management outlined above for the successful management of the pediatric LT recipient, a few specific areas merit a more comprehensive overview, which is the aim of the next section.
Although there is very little information regarding post-operative analgesia following adult and pediatric LT, this area is nevertheless of great importance. Post-operative pain following LT, like after any major abdominal surgeries, is severe, and its management remains a priority. Until recently, patients were sedated and ventilated post-operatively with high doses of opioids for the first 12 hours, covering the most painful period. More recently, along with fast-track surgery, 90% of adult patients are awake very early after LT, thus requiring prompt and efficient pain management. In children, sedation is often discontinued as soon as the patient leaves the operating room in order to evaluate graft function promptly by the patient’s ability to wake up. In the absence of severe cardio-circulatory or respiratory failure, weaning from mechanical ventilation is usually the next step. In the event of primary graft non-function, delayed graft function, or renal failure, analgesia requirements are typically less owing to delayed drug clearance and subsequent accumulation. Conversely, if the liver is working well, analgesic metabolism improves significantly over time with minimal accumulation.
One of the factors that can influence post-operative pain is the management of intraoperative analgesia. The use of strong morphinomimetics with an intermediate half-life, such as fentanyl and sufentanil, covers immediate post-operative pain. Sufentanil has the advantage of less accumulation and longer residual analgesia. Moreover, the administration of high doses of fentanyl intraoperatively allows for a later use of post-operative analgesia. In adults, in the current context of fast-track surgery, teams tend to reduce the morphine administered intra-operatively and use short-acting opiods such as remifentanil. However, the pharmacokinetics of remifentanil requires anticipation of post-operative analgesia due to the risk of pain recurrence and hyperalgesia.
Nevertheless, in children morphine remains the leading analgesic drug for multimodal post-operative analgesia. However, contrary to conventional beliefs, opioid analgesia is avoidable. There is a significant risk of accumulation and respiratory depression for two reasons: (1) the idiosyncrasies of morphine pharmacokinetics in young children, and (2) frequent post-operative renal failure. Morphine can be administrated by patient-controlled analgesia (PCA) in children from age 6-7 years. Nurse-controlled analgesia (NCA) should be further promoted. Continuous morphine infusion should be carefully administered in the youngest children and in those with altered renal function.
The contribution of minor analgesics to post-operative pain management is variable. At recommended doses, paracetamol/acetaminophen is generally well tolerated after LT and no hepatotoxicity has been reported, even in cases of graft dysfunction. However, the toxic dose of paracetamol varies greatly from one individual to another, and therefore its prescription is not recommended in the immediate post-operative period, even with regular monitoring of routine liver function tests. Non-steroidal anti-inflammatory agents are not recommended after LT because of possible serious side effects (infection, gastrointestinal bleeding, renal failure, drug interaction, liver injury). Tramadol is used in adults after LT, but not in pediatrics. Due to its hepatic metabolism via numerous cytochromes, including CYP2D6, its action is unpredictable with potentially greater than expected morphine agonist effects. In addition, the intravenous form is not approved for use in children under 15 years of age.
Combined or synergistic strategies may afford the use of lower doses of different analgesics, while presenting with some disadvantages as well. For example, the use of the alpha-2 adrenergic agonist clonidine potentiates the analgesic action of opiates, as it has an analgesic action when administered intravenously. On the other hand, it comes with side effects such as sedation and inhibition of thermoregulation, which allows the control of shivering. It causes sympathetic inhibition that in turn may result in hypotension and bradycardia. While clonidine depresses ventilation slightly, it does not cause urinary retention. Like opiates, it slows intestinal transit time, but it is not neurotoxic. Other examples of combined strategies include nefopam, a non-morphinic central analgesic that, when used as a continuous infusion for 72 hours, reduces morphine consumption. However, its use is restricted to children over the age of 15.
The use of local or regional analgesia is limited by peri-operative hemostasis disorders. Thoracic epidurals are therefore rarely recommended, owing to the rare but significant risk of epidural hematoma. On occasion, its use can be discussed in patients with a normal pre-operative clotting profile, such as non-cirrhotic patients undergoing LT for refractory pruritus or metabolic indications. Some data suggest that transverse abdominal plane (TAP) block with a single injection of local anesthesia reduces morphine consumption, pain scores, and mechanical ventilation. Local anesthetic infiltration via wound catheter infusion looks promising. A recent meta-analysis has suggested its efficacy in patients following open liver resection.
Primary Non-Function of the Graft
Primary non-function (PNF) remains a rare but very serious complication after LT. With sepsis, PNF is the second cause of death in children following LT. It is associated with fulminant and irreversible multiple organ dysfunction requiring emergency re-transplantation. PNF typically occurs in the first 24-72 hours following LT. The natural course of successful LT is characterized by liver enzymes that peak in the first 2-3 days after transplantation then gradually decrease with progressive improvement of coagulation factors and bilirubin over the first few weeks. PNF is characterized by continuous rise of liver enzymes, persistent cholestasis, and a major coagulopathy with active clinical bleeding. Failure to wake up from anesthesia is a major adverse prognostic sign and may be associated with cerebral edema, threatening patient survival. In addition, persistent hypoglycemia, vasoplegia, ongoing bleeding, and hyperlactatemia are all signs of PNF. Following the operation, the surgical team may report a graft with a dusky color and firm texture and difficulties to control diffuse bleeding. Numerous scores or criteria have been developed that could be used in the clinical setting to define PNF. In case of a split liver transplant, progress of the other recipient should be followed as this could help direct management and expectations. The differential diagnosis of PNF includes early hepatic artery thrombosis, portal vein thrombosis, ischemia-reperfusion injury, and small-for-size graft.
There are numerous risk factors for PNF. Risk factors related to the donor include liver steatosis, advanced donor age, and acute intoxication (e.g., amphetamines). Steatosis may be assessed using frozen section liver biopsy at the time of organ harvest. Steatosis in excess of 30% has been shown to be associated with higher risk of PNF. Transplant-related factors include the prolonged cold ischemia time and small-for-size graft.
The only effective treatment for PNF is emergency re-transplantation. In the interim, management is supportive. Hemodynamic difficulties could occur due to liver dysfunction, and vasopressor therapy may be necessary. In the absence of effective liver function, bleeding is a major risk. Disseminated intravascular coagulopathy may also occur. Metabolic disturbances with lactic acidosis and refractory hypoglycemia need to be anticipated and treated. Hyperammonemia could lead to cerebral edema with intracranial hypertension, which should be monitored using transcranial Doppler and treated using osmotherapy, vasopressors, or high-flow continuous veno-venous hemofiltration (CVVH). Renal failure is managed using CRRT.
Abdominal Compartment Syndrome
Intra-abdominal hypertension (IAH) may be encountered during the first 2 days after LT in children. Its incidence may be as high as 37% to 61%. In children with IAH > 20 mmHg (Grade III & IV), 20-51% develop abdominal compartment syndrome (ACS) with renal and/or (SAME ROW) cardio-respiratory failure. The two major risks for IAH are graft size and intraoperative fluid resuscitation. In addition, severity of fluid overload as well as reduced intra-abdominal perfusion pressure (i.e., mean arterial pressure–intra-abdominal pressure < 40-50 mmHg) may be related to the development of ACS. Regular intravesical pressure monitoring is required to detect IAH and altered abdominal perfusion. When IAH > 15mmHg, careful monitoring of cardio-respiratory and renal function is mandatory, together with aggressive therapy to reduce fluid overload while maintaining normal systemic arterial pressure.
From a surgical perspective, risk factors for IAH include increased abdominal tension and absence of vicryl plate to facilitate abdominal closure. Reduced portal flow after abdominal closure may be suggestive of significant IAH development and related complications. Besides ACS, IAH is associated with an increased risk of vascular thrombosis.
ACS should be treated aggressively using some or all of the following: management of intra-abdominal bleeding including surgical intervention if necessary, ascitic drainage, vasopressors, and muscle relaxation, all of which can contribute to improving abdominal perfusion pressure.
Post-operative vasoplegia is a common occurrence after LT. It is secondary to ischemic-reperfusion injury of the graft, massive intra-operative bleeding and transfusions, as well as pre-operative circulatory condition of the patient. Vascular, and more specifically splanchnic, pathophysiology in cirrhotic patients is complex. Increase in the production of the endothelium-derived circulatory vasodilator, nitric oxide (NO), in the splanchnic vascular bed is well recognized. There is evidence that a number of other mechanisms are also involved, including the increased production of other endogenous vasodilators and impairment of compensatory vasoconstriction responses. Alterations of the renin-angiotensin axis are now recognized as an important mechanism in cirrhotic patients and this may take some time to recover post LT.
Management of post-operative vasoplegia relies on both fluid resuscitation and continuous vasopressor perfusion.
Post-operative vasoplegia may be exacerbated by acidosis, either metabolic or respiratory. Hyperchloremia may further aggravate the acid-base equilibrium, which in turn can be further exacerbated by hypoalbuminemia. Therefore, albumin administration may be helpful.
Norepinephrine is the preferred potent, systemic vascular vasoconstrictor. Hydrocortisone is sometimes used as an adjunct treatment to vasopressors. The rationale for hydrocortisone use in LT patients is further supported by the high incidence of adrenal insufficiency in the patients with liver disease, which has been observed in as many as half of children in acute liver failure.
The effects of fluid resuscitation and in vasopressor support need to be regularly assessed by echocardiogram or continuous aortic Doppler. Aortic outflow variation is superior to the inferior vena cava diameter variation in predicting fluid responsiveness. When vasoplegia is unresponsive to vasopressors, or in case of severe metabolic disturbances (such as severe acidosis), CRRT may be warranted. Although myocardial dysfunction is rare and usually related to relaxation defects (diastolic dysfunction/restrictive cardiomyopathy), veno-venous or veno-arterial extracorporeal membrane oxygenation (ECMO) may exceptionally be needed for myocardial failure or severe ARDS.
Post-Operative Bacterial Sepsis and Septic Shock
Children after LT are highly susceptible to bacterial infections. Immunosuppressive therapy, invasive ventilation, altered nutritional status, extensive and sometimes repeated abdominal surgery, as well as disrupted muco-cutaneous barriers enhance the risk of post-operative infections. Pre-transplantation immunological status is characterized by altered opsonization, phagocytosis, cellular and humoral immunity related to acute and chronic liver failure. Immunologically, the post-operative period is remarkable for progressive restoration of humoral immunity and this is concurrent with the introduction of immunosuppressive therapy. Although bacterial sepsis occurs most often in the first 2 weeks following LT, it can also occu later during post-operative follow-up. Differential diagnosis includes fungal ( Aspergillus spp, Pneumocystis jirovecii ) and viral infections with herpes viridea (CMV, EBV, HHV 1-2, HHV6) and adenovirus.
Post-operative bacterial infection occurs in about half of children receiving liver grafts, with severity varying from superficial wound infections to septic shock. Approximately 37-50% of all deaths following LT are related to infectious complications. In several series, infection is recognized as the primary cause of death, occurring in 3.1-7.5% of transplanted children. Younger age and infants weighing less than 5 kg have been shown to have higher infection-related mortality. Septic shock is associated with a 27% mortality after LT. In a recent study, severe sepsis or septic shock and pneumonia were strongly associated with post-operative mortality. In this study, nosocomial infections accounted for 38% of post-LT infections including surgical site infections (SSI), ventilator-associated pneumonia, catheter-associated urinary tract infection, and central line–associated bloodstream infection. Importantly, SSI are associated with vascular thrombosis and occurrence of abdominal compartment syndrome. Gram-negative bacteria account for the majority of pathogens, although a significant number of septic patients will have no bacteria identified. Multidrug-resistant (MDR) bacteria carriage before LT is associated with the development of post-operative SSI, often resulting from excessive use of broad spectrum antimicrobial therapy in patients without positive microbial evidence during the pre-transplant period. Therefore, it is currently standard of care to consider the patient’s positive microbiologic profile for selection of appropriate antibiotic therapy after LT.
Immunosuppression monitoring is essential to target therapy correctly and avoid excessively high trough levels. Although there is no single standard-of-care immunosuppressive regimen, one pediatric study suggested that some combinations may be associated with fewer infections than others. Other risk factors for infection are summarized in Table 16.2 .