Prolonged Anhepatic State as a Bridge to Retransplantation: A Challenging Case of a 35-Year-Old Male Liver Transplant Patient with a Temporary Portacaval Shunt

Background

Liver transplantation (LT) offers a life-saving intervention for patients with acute liver failure or end-stage liver disease [1]. While surgical and immunosuppressive advancements have improved LT outcomes, LT remains a complex procedure with potential complications [2]. One of the most significant challenges is primary nonfunction, which can require total hepatectomy, but retransplantation (reLT) depends on organ availability [3]. A temporary portacaval shunt (TPCS), known as an anhepatic state, has been used as a bridge to retransplantation in those cases [4,5].

Since Ringe et al (1988) first performed a total hepatectomy with a TPCS to stabilize a patient with fulminant hepatic failure while awaiting reLT [6], there have been several reports in the literature of both successful and unsuccessful cases [7–34]. However, there is still no consensus regarding the maximum duration of the anhepatic state that can be safely tolerated, given potential complications such as sepsis, hypotension, coagulopathy, metabolic acidosis, renal failure, electrolyte disturbances, hypoglycemia, and hypothermia [6,7,12,14].

Considering the risks associated with the anhepatic state [6,7,12,14], monitoring clinical and laboratory parameters, including infection, hemodynamics, coagulation status, renal function, metabolic alterations, and body temperature, is imperative. Here, we report a case of a 35-year-old man with autoimmune hepatitis who underwent a 57-h anhepatic state with a TPCS as a bridge to retransplantation, one of the most prolonged periods reported. We describe the patient’s clinical presentation, diagnosis, and management strategies during this life-threatening period in the Intensive Care Unit (ICU).

Case Report

A 35-year-old man with a diagnosis of autoimmune hepatitis who had previously been managed with diuretic therapy for refractory ascites and experienced 2 episodes of upper gastrointestinal bleeding was admitted to the hospital for LT from a deceased donor. The patient had a Child-Turcotte-Pugh score of C and a Model for End-Stage Liver Disease (MELD) score of 38. Upon admission, laboratory findings indicated anemia, thrombocytopenia, elevated liver function tests, hypoalbuminemia, and increased total and direct bilirubin (Table 1). The donor was a 48-year-old woman with hypertension who died from a hemorrhagic stroke.

LT was performed using the conventional technique, with ligation of the splenic artery and a choledochal-choledochal anastomosis, without complications. The total ischemia time was 4 h and 29 min, cold ischemia time was 4 h and 1 m, warm ischemia time was 28 min, and the anhepatic phase was 44 min. During the surgery, 3000 mL of crystalloid, 100 mL of albumin, and 1 unit of packed red blood cells were administered. Surgical prophylaxis included ceftriaxone and fluconazole.

Upon admission to the ICU, the patient received low-dose vasopressor support and oxygen via a nasal catheter. He presented with mild metabolic acidosis and an elevated international normalized ratio (INR) of 1.4 (Table 2), for which vitamin K was administered for 3 days.

On postoperative day (POD) 3, he experienced dyspnea and desaturation. A chest X-ray revealed bilateral pleural effusion, and 600 mL of serous fluid was drained via thoracentesis. Following the drainage, there was an improvement in ventilation, but hemoglobin levels dropped from 7.2 to 4.5 g/dL, and 3 additional units of packed red blood cells were provided.

On POD6, despite adjustments to immunosuppressants, transaminase levels suddenly increased, associated with progressive and loss of liver function tests (aspartate aminotransferase [AST]: 166–2100 IU/L, alanine aminotransferase [ALT]: 212–1820 IU/L). A computed tomography (CT) scan of the abdomen showed hepatic patent vessels. There was also a significant worsening of inflammatory parameters (white blood cells [WBC]: 8200–13 550 WBC/mm3, band cells: 4–10%, C-reactive protein [CRP]: 1.2–4.5 mg/dL) with negative blood and preservation fluid cultures. Antibiotic therapy was switched to empirical piperacillin with tazobactam.

On POD7, renal replacement therapy (RRT) was initiated due to the deterioration of renal function (creatinine: 1–1.7 mg/dL, blood urea nitrogen [BUN]: 31.7–49.9 mg/dL), metabolic acidosis, and hyperkalemia. However, acute liver failure with elevated transaminases, a non-coagulable INR, thrombocytopenia (platelets: 31 000 plt/mm3), hypervolemia, and metabolic acidosis persisted. A seventh-day syndrome hypothesis was proposed, although a liver biopsy was not conducted.

On POD9, the patient experienced decreased consciousness and tonic-clonic seizures, requiring orotracheal intubation and dispensation of phenytoin. A cranial CT scan showed no abnormalities. Plasmapheresis was conducted, and he was listed for retransplantation.

On the same day, a hepatectomy was conducted due to acute liver failure, and a TPCS was performed. Upon readmission to the ICU, thromboelastographic abnormalities were observed, and transfusions of blood products were administered. The patient also required high doses of vasopressors, continuous venovenous hemofiltration dialysis (CVVHD) due to oliguria, correction of persistent metabolic acidosis and hypocalcemia, support with mechanical ventilation, administration of dextrose to prevent hypoglycemia, and maintenance of normothermia with warming blankets. Due to high drainage rates through the Blake drains, refractory shock, and unsuccessful correction of the blood abnormalities, an exploratory laparotomy was necessary to control bleeding from a site on the left abdominal wall.

After 57 h of the anhepatic phase with a TPCS, he underwent reLT from a deceased 57-year-old man with a history of social alcohol consumption and hypertension who died from a hemorrhagic stroke. After reLT, the patient showed a gradual improvement in coagulopathy. His dependence on vasopressors decreased, and mechanical ventilator settings were reduced. CVVHD was maintained, accompanied by regular administration of calcium gluconate, dextrose infusion, and warming blankets.

On POD3 after reLT, laboratory test results showed deterioration (WBC: 16 250–24 580 WBC/mm3, band cells: 5–12%, CRP: 5.4–12.5 mg/dL; Table 3), with positive blood cultures for Pseudomonas aeruginosa and Staphylococcus coagulase-negative, and a positive polymerase chain reaction test for cytomegalovirus. Antibiotic therapy was switched to meropenem. Ganciclovir could not be used at this moment due to significant thrombocytopenia (platelets: 40 000 plt/mm3).

The patient continued to require RRT and exhibited decreasing transaminase levels but increasing bilirubin levels (AST: 370–102 IU/L, ALT: 308–123 IU/L, total bilirubin: 7.3–21.8 mg/dL, direct bilirubin: 5.1–20.1 mg/dL). There was subsequent clinical and laboratory worsening (WBC: 11 250–15 200 WBC/mm3, band cells: 4–7%, CRP: 5.1–7.6 mg/dL), which prompted the addition of amikacin to the treatment regimen. Following the resolution of thrombocytopenia, a combination of immuno-suppression and ganciclovir was reintroduced, but the patient continued to deteriorate.

Sedation was terminated on POD4 after reLT to perform a neurological assessment, but the patient remained unresponsive. An electroencephalogram (EEG) showed a depressed tracing without an epileptiform pattern. On POD17 after the reLT, his neurological condition did not improve, and there were no trunk reflexes. A cranial CT scan revealed bilateral acute ischemic brain injuries, mainly in the posterior circulation and cerebellar hemispheres, with hemorrhagic transformation, compression of the fourth ventricle, and small subfalcine herniation to the right. Neurosurgical intervention was not feasible, and a protocol for brain death was initiated. The EEG showed cerebral electrical silence, and the patient was declared deceased due to intracerebral hemorrhage.

Discussion

This case report describes the complexities and challenges faced during a prolonged 57-h anhepatic state using a TPCS as a bridge to reLT in a 35-year-old man with autoimmune hepatitis. Prior to the LT, the patient had decompensated cirrhosis with refractory ascites and 2 episodes of upper gastrointestinal bleeding, being categorized with a Child-Turcotte-Pugh score of C and a MELD score of 38 [35]. The procedure was successful, with no complications. However, on POD7, the patient presented with elevated transaminase levels, worsening inflammatory parameters, and deterioration of renal function with the initiation of RRT. These clinical and laboratory findings pointed toward a potential seventh-day syndrome [36], although a liver biopsy was not conducted to confirm the diagnosis.

Seventh-day syndrome is characterized by the sudden, unexpected failure of a normally functioning liver graft 1 week after LT [36]. While the underlying pathophysiology remains unclear, studies show marked apoptosis of hepatocytes, Fas receptor activation, and antibody-mediated rejection as mechanisms leading to the development of the syndrome [37–40]. Treatment options include the immediate start of desensitization, which can be achieved through plasma exchange, intravenous immunoglobulin, or anti-CD20 antibody [40,41].

Our patient presented with acute liver failure 7 days after the surgery without any other explainable etiology, which increases the likelihood of our hypothesis of seventh-day syndrome (as shown in Table 2) [35]. Our approach was to start the desensitization with plasmapheresis and list the patient for reLT. This approach prevents the life-threatening multiorgan failure and intense systemic inflammatory response that the necrotic graft can cause if not immediately removed [42,43]. Indeed, after the initiation of plasmapheresis, the patient had an improvement in hemodynamics and mechanical ventilator settings. However, he still experienced several complications during the 57-h anhepatic state, including hypotension, coagulopathy, metabolic acidosis, renal failure, persistent hypocalcemia, hypoglycemia, and hypothermia.

Our main strategies employed to manage such complications were as follows: (1) vasopressors, predominantly norepinephrine, to sustain a mean arterial blood pressure of 65 mm Hg; (2) administration of 2 packs of fresh frozen plasma every 8 h and 1 vial of vitamin K per day, targeting an INR lower than 2; (3) packed red blood cell units and platelet transfusions, when needed; (4) an exploratory laparotomy was necessary to control severe bleeding from the left abdominal wall; (5) RRT to address hypervolemia and metabolic acidosis; (6) consistent monitoring of serum calcium levels and administration of calcium gluconate to counteract hypocalcemia; (7) continuous dextrose infusion to ensure serum glucose levels remained above 100 mg/dL; (8) warming blankets for normothermia; and (9) regular laboratory tests and intensive monitoring in the ICU. Although unavailable at our facility, the molecular adsorbent recirculating system is another potential approach for patients with acute hepatic failure, which selectively removes albumin-bound toxins from the blood. Recent studies have indicated its effectiveness in anhepatic states [25,29,30].

We consider our case report unique because it was one of the most prolonged periods described in the literature. The anhepatic state has been used in various cases. The most prolonged period without sequelae was 99 h in a 7-month-old female patient [29]. We conducted a literature review of cases of anhepatic states as a bridge to retransplantation, with a total of 29 published articles. Further details of the characteristics of each study can be found in Table 4. In successful cases, the systemic inflammatory response attributed to primary nonfunction seemed to improve during the initial anhepatic state [9–13,21,25–28,32–34].

However, the anhepatic state can be unsuccessful due to several complications. Notably, sepsis emerges as a significant concern. Ringe et al (1993) reported that out of 19 patients undergoing an anhepatic state, 9 died from sepsis [16]. Their subsequent study in 1995 confirmed this concern, with most patients dying from disseminated infections [8]. Similarly, in the study by Domínguez-Fernández et al (2001), half of the patients who underwent transplantation following an anhepatic state died due to sepsis [17]. Sanabria Mateos et al (2016) reported a mean anhepatic state duration of 15.5 h among 6 patients, with all displaying systemic inflammatory response syndrome within the first postoperative week, and the incidence of sepsis was high at 50% [15]. Further reports of sepsis are detailed in Table 4 [7–34]. Despite our patient being on a tailored broad-spectrum antibiotic and antifungal regimen, sepsis was still a clinical challenge, as evidenced by deteriorating laboratory parameters (Table 2).

The absence of liver function in anhepatic states can lead to other complications, such as hypotension, coagulopathy, metabolic acidosis, renal failure, hypocalcemia, hypoglycemia, and hypothermia [6,7,12,14]. While the mechanisms underlying these complications are not fully understood, they may be explained in the context of the liver’s multifaceted roles in physiological homeostasis. For example, the liver’s importance as an immune organ might predispose anhepatic states to sepsis [44–46]. Hypotension is another frequent manifestation, likely due to the accumulation of vasoregulatory substances that the liver typically metabolizes, including nitric oxide and endothelin [47–49]. Coagulation disturbances, notably coagulopathy, are anticipated, given the liver’s central role in clotting pathways [50,51], a challenge underscored in our case and corroborated by others (Table 4). The liver’s involvement in lactate clearance and ammonia-to-urea conversion may elucidate the emergence of metabolic acidosis and renal failure [52,53]. Hemodynamic shifts in the anhepatic state might also contribute to renal tubular injury [54,55]. The frequent administration of citrated blood products in these patients to correct coagulopathy can exacerbate hypocalcemia, amplifying the risk of bleeding [26]. Hypoglycemia is another potential complication, as the liver serves as the primary glycogen storage site [56]. Lastly, anhepatic states tend to present with hypothermia, emphasizing the need for thermal interventions like warming blankets [10,14,22,31].

The anhepatic state can also have long-term complications. In our case, the patient underwent a 57-h prolonged anhepatic state but died 14 days after reLT due to cerebral hemorrhage. Although we managed coagulopathy with specific management strategies, the outcome was unfortunate. In other cases, there have been reported neurological deficits, such as neuropathy and dysarthria [12,18], chronic renal insufficiency [14,23], and infections [19,20,27,29–31]. Further research is needed to better elucidate the mechanisms underlying those long-term complications.

Conclusions

In conclusion, this case highlights one of the most prolonged periods of anhepatic state using a TPCS as a bridge to reLT. We emphasize the complexities and challenges associated with this technique, including sepsis, hypotension, coagulopathy, metabolic acidosis, renal failure, electrolyte disturbances, hypoglycemia, and hypothermia. Vigilant monitoring and intensive care are imperative to manage these complications and improve outcomes. Our patient had cerebral death from a hemorrhagic stroke, and documenting such cases is essential for enhancing our understanding and improving future patient care. Further research is needed to deepen our knowledge of anhepatic states with a TPCS, identify strategies to minimize complications, and refine protocols for LT recipients.