Death of a living liver donor: Opening Pandora's box

Authors


  • See Editorial on Page 1169

  • This report was approved by the Institutional review committee.

TO THE EDITORS:

Living donor liver transplantation (LDLT) is an established modality of treatment for end-stage liver disease[1] and is the predominant form of transplantation in most Asian countries.[2] The benefit to the recipient, who would otherwise die waiting for a cadaveric organ, is undisputed.[3] Although a period of 23 years has passed since the first case of LDLT was reported,[4] the LDLT/deceased donor liver transplantation debate continues and is focused heavily on 2 aspects of LDLT: donor mortality and the ethics of LDLT (specifically issues related to donor autonomy and transplant commercialism). Both, sadly, have been under-reported. We present the details of a LDLT case at our institution in which the unfortunate occurrence of the donor's death led to the revelation of facts related to the ethics of LDLT that otherwise would not have come to light.

CASE REPORT

A 54-year-old gentleman from a neighboring country with symptoms of chronic liver disease was assessed. Investigations revealed hemochromatosis with cirrhosis and end-stage liver disease. He was advised to undergo liver transplantation.

His nephew was initially assessed as a potential living donor but was found unsuitable. They returned to their country and came back 2 months later with the recipient's niece, a 29-year-old woman, as a potential donor.

A detailed clinical history and an examination of the donor were noncontributory. Investigations revealed normal liver function tests and no cardiac or pulmonary comorbidities. Computed tomography (CT) volumetry showed that right lobe donation was feasible. The predicted liver remnant was 35% with a calculated graft-to-recipient weight ratio of 1.0 for the recipient. The donor underwent counseling with a detailed discussion regarding the risks of the procedure. The donor-recipient pair provided documentation attesting to their relationship, and this was authenticated by the ministry of external affairs of the donor's native country and their embassy. The hospital's legal team and the local government's living donor approval committee reviewed these documents. After a personal interview with the donor, her husband, and the recipient's family, approval for transplantation was given.

At the time of the donor hepatectomy, the liver was healthy. Right hepatectomy with partial inclusion of the middle hepatic vein was performed. The initial line of the parenchymal transection, dividing venous branches draining segment 4B, was to the left of the middle hepatic vein, and then it was moved to the right of the middle hepatic vein midway along its length to preserve venous drainage to segment 4A (Fig. 1). The transection was performed without inflow occlusion. The donor remained stable intraoperatively with good urine output. The estimated blood loss was 800 mL, and packed red cells (2 units) were transfused. The transfused units were tested for routine pathogens and were leuko-depleted (14 and 20 days old, respectively). The donor received 2 doses of prophylactic antibiotics. The duration of the donor's surgery was 7 hours 45 minutes. The recipient's surgery was uneventful.

Figure 1.

CT reconstruction of the hepatic vein system of the liver. The line of transection is marked. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

The donor was extubated the same evening and remained stable overnight. The morning after her surgery, she was comfortable with stable hemodynamics and oxygenation. Blood tests (liver enzymes, bilirubin, international normalized ratio, and lactate) and a Doppler ultrasound examination were satisfactory, and she was started on clear fluids by mouth.

During the course of the day, she started complaining of increasing pain in the right shoulder and right upper quadrant. She was treated with epidural boluses, but the pain persisted. A repeat Doppler ultrasound examination revealed a well-perfused liver remnant with triphasic flow in the left and middle hepatic veins. There was no significant free fluid or intra-abdominal collection. Blood lactate levels gradually increased during the course of day, and she became increasingly hypoxic and tachycardic by the evening (Fig. 2). Evening blood investigations showed marginal improvements in bilirubin and liver enzymes with worsening hematological parameters (Table 1).

Figure 2.

Graph showing the trend of the blood lactate level during the postoperative period until relaparotomy. The time of investigation is plotted on the x axis in a 24-hour format. The lactate level is plotted on the y axis.

Table 1. Comparison of Blood Tests in the Morning and Evening of the First Postoperative Day
ParameterPostoperative Day 1: 6 amPostoperative Day 1: 7 pm
Hemoglobin (gm/dL)10.99.3
White cell count (/cmm)16,4001100
Platelet count (/cmm)149,00087,000
International normalized ratio1.822.66
Bilirubin (mg/dL)4.233.46
Aspartate aminotransferase (U/L)323234
Alanine aminotransferase (U/L)321260

Because of her progressive deterioration with no evident cause, she was electively intubated and transferred for a contrast CT scan. CT revealed a well-perfused liver with appropriate enhancement of the hepatic artery, portal vein, and hepatic veins. There was mesenteric and retroperitoneal edema. No significant intra-abdominal pathology could be identified (Fig. 3). There was no evidence of a pulmonary embolism.

Figure 3.

CT scan from the portal phase before the second surgery. The liver remnant appeared swollen but had good portal perfusion (A). The pancreas was edematous with no definite areas of necrosis (B).

A differential diagnosis of bowel perforation or ischemia was considered because of her continued deterioration, and she was taken for immediate laparotomy. Laparotomy revealed diffuse inflammatory changes in the abdomen (Fig. 4). The liver remnant appeared hyperemic and swollen. There was also extensive hemorrhagic edema of the stomach, in the retroperitoneum, and in the small bowel mesentery. The small bowel loops and colon appeared healthy except for small petechial hemorrhages. She continued to deteriorate hemodynamically with increasing acidosis, pulmonary edema, and features of disseminated intravascular coagulation. Ventilation and oxygenation became increasingly difficult during the operation. She was started on continuous venovenous filtration and cardiopulmonary bypass in order to get her past the acute crisis with the plan of converting her to extracorporeal membrane oxygenation. A period of 8 hours was spent in the operating theater in an attempt to stabilize her condition, but there was no improvement. Further measures were considered futile, and she was transferred back to the intensive care unit after temporary wound closure. She died in the intensive care unit 4 hours later, nearly 36 hours after the index operation. A request for a postmortem examination was turned down by the recipient's family because there is no legal mandate in India. A medicolegal postmortem was performed in her native country, the full results of which are not available.

Figure 4.

The congested appearance of the liver remnant and the hemorrhagic appearance of the stomach can be seen (A). Evidence of hemorrhaging in the transverse mesocolon and petechial hemorrhages in the small bowel can be seen (B).

After these events, we carried out an internal audit of the clinical course of this patient; we started from donor selection and moved to the preoperative evaluation and intraoperative events, the postoperative intensive care unit care and monitoring, the reaction and responsiveness after the deterioration of the patient, and ultimately the cause of her death. A review of the clinical course and intraoperative photographs suggested severe systemic inflammatory response syndrome (SIRS) due to possible acute severe pancreatitis. The initiating factor was postulated to be contrast injection during intra-operative cholangiography, which had opacified the pancreatic duct with some evidence of acinarization (Fig. 5). The findings of extensive retroperitoneal edema on laparotomy also supported a diagnosis of severe pancreatitis. Because of the rapidity of events that evening, a serum amylase assay was not requested.

Figure 5.

Completion cholangiogram with visualization of the pancreatic duct.

An unexpected and startling revelation surfaced a few days after the donor's death. Media in the patient's country reported that the donor was unrelated and was chosen after advertisements in the local print and electronic media. The donor's estranged husband had also informed the media that neither he nor the donor's parents were aware of her plan to donate. Our team questioned the recipient's spouse in an attempt to clarify the situation. She confessed that the donor was unrelated to the recipient and was chosen through advertisements. She stated that the donor had actually stayed with the recipient's family for a period to perfect the deception. Evidence documenting the relationship had been fabricated by the recipient's family and authenticated by their local judiciary and their country's embassy. The person who was presented on documents and in front of the committee as her husband was actually her boyfriend. The recipient's spouse said that she was desperate to save the life of her husband and did not see any other option. Further questioning also revealed that the donor had been offered financial compensation for the act. She claimed that advertisements soliciting potential donors were quite common in their country.

In light of these events, we invited 2 experienced external reviewers, Professor Tanaka (Kobe, Japan) and Professor John Fung (Cleveland Clinic, Cleveland, OH), to evaluate this particular event and review current practices in our unit. We also had a brain-storming session with Professor Francis Delmonico (United States) regarding the ethical aspects of this event and to identify deficient areas that could be improved.

The external reviewers concluded that severe SIRS was the most probable diagnosis. The cause of SIRS was not clear, but severe sepsis, acute pancreatitis, a peripheral pulmonary embolism, and postoperative liver failure were possible differential diagnoses. The review team made several recommendations, including a shortening of the donor operation time to less than 6 hours, routine donor liver biopsy either before the operation or on the back table, routine blood and body fluid cultures when any deviation from the expected clinical course is identified, the administration of the first dose of low-molecular-weight heparin during the operation rather than the previous night, and the provision of center-specific donor statistics during donor counseling. They also suggested the formation of a crisis team to deal with such rare but grave events. These recommendations have since been put into place.

DISCUSSION

Donor death after living liver donation is uncommon, and worldwide reported statistics quote a mortality rate ranging from 0.2% to 0.5%.[5-7] There is a concern that these events are under-reported, particularly in the East, where the perceived threat to a program's survival may act as a deterrent to the full disclosure of critical incidents. Some of these deaths are brought into public knowledge only through the lay literature.[6, 8] Transparent reporting is essential for developing a true picture of these uncommon events so that others do not need to relearn the lessons learned by one team.

Our LDLT program, led by the senior author (M.R.), started in August 2009. We have performed LDLT 277 times so far. This was our first donor death. Despite extensive internal and external reviews, a definitive cause for our donor's rapid deterioration and eventual death has remained unexplained. Her medical assessment was satisfactory. The intraoperative period was straightforward except for the need for a blood transfusion, which happens in approximately 15% of our right lobe donors. It was clear that she had developed intense SIRS, which led to her rapid deterioration.[9] A review of the clinical events later suggested a diagnosis of acute severe pancreatitis. However, it is not possible to definitively prove the etiology because biochemical evidence is lacking. After this incident and the external review recommendations, we revised our donor management protocol to keep the operating time to less than 6 hours, to occlude the lower common bile duct during intraoperative cholangiography to minimize the risk of contrast-induced pancreatitis, and to have a low threshold for performing an infection screen with blood and urine cultures and for escalating antibiotics after cultures.

Liver transplantation is the treatment of choice for patients with end-stage liver disease. The popular acceptance of deceased organ donation, the presence of a successful liver transplant program, and the availability of professional expertise cannot be presumed in most countries. Hence, patients needing a transplant will explore treatment options in neighboring countries where they are available. In India, as in most other Asian countries, deceased donor liver transplantation is still in its infancy with a wide gap between demand and organ availability. Even in states in which there has been progress in deceased donation,[10-12] the mortality rate for waiting-list patients is more than 50%. In accordance with legislation, deceased donor organs are offered to Indian nationals by priority. They can be offered to foreign nationals only if there is no suitable Indian recipient, and this in reality never happens. Foreign patients needing a transplant hence primarily come to India for LDLT. Our LDLT program caters to both Indian and foreign patients, the latter forming 25% of our recipient cohort. According to Indian law, only close family relatives of recipients can donate their organs. Our preference is to consider first-degree relatives as living donors. When there is no suitable first-degree relative, then second-degree relatives are assessed. A review of our practice showed that donors were first-degree relatives (including spouses) in 215 cases (82%), whereas the remaining 62 (22%) were second-degree relatives.

The current system of authorization for LDLT for foreign nationals has been made quite rigorous to stop unrelated organ donation and donation for financial considerations. It aims to share the responsibility of authentication with the patient's country of origin in order to enhance accountability.[13] The process is based on the Human Organ Transplant Act of India. The purpose of this process is to ascertain the donor-recipient relationship and ensure that there is no pecuniary benefit involved in the donation process, that the donor has voluntarily consented to donate with no element of coercion, and that the patient, donor, and donor's dependents are aware of the nature, normal course, and complications of the surgery. In order to do this, as a first step, documents supporting the aforementioned requirements are submitted (Table 2). These documents are signed by the recipient, the donor, and a judicial magistrate. In the case of foreign patients, these documents are additionally attested by the embassy of the country of origin of the patient and the donor. The documents are scrutinized by the hospital authorities and, if they are found to be satisfactory, are submitted to the state authorization committee. The next step involves the counterchecking of these documents by the committee, and in the case of foreigners, confirmation is sought from their embassies regarding the authenticity of the submitted documents. Then, a personal interview is conducted by the committee with the recipient, donor and the donor dependent. After this, the final approval is sent to the hospital, and the date for transplantation is finalized (Fig. 6).

Table 2. List of Documents to Be Submitted by the Recipient and the Donor During the Application for Approval for Living Donor Transplantation
• Relationship certificate for the recipient-donor pair
• Photographs of the patient, donor, and donor's dependent
• Authenticated family tree diagram showing the relationship of the recipient and the donor
• Approval by the Indian Government Authorization Committee
• Letter from an embassy for foreign patients
• Authenticity certificate issued for the letter from the embassy
• Recipient's consent for liver transplantation
• Donor's consent for donor hepatectomy
• Donor dependent's consent for donor hepatectomy
• No-objection certificate from the donor's dependent
• Declaration by the patient, donor, and donor's dependent about their awareness and acceptance of potential postoperative complications
Figure 6.

Flowchart showing the process for obtaining approval for living donor transplantation.

This system with its multiple levels of screening and built-in safeguards was developed to clean up the image of organ trade once associated with the Indian transplant scenario.[11, 14] It is clear that the system failed in the present case. We believe that the recipient family's previous experience with the nephew's assessment helped them to understand the system and beat it. The obvious question here is whether there are operating agencies that facilitate the required falsification and deception. Our investigation and interview with the family failed to reveal any such possibility in this case.

Even though living liver donor mortality is being recognized as a when event rather than an if event, its effect on team morale is out of proportion to the actual medical outcome.[15] In addition, knowledge of having been deceived by the patient provokes serious introspection into our practice. Can we as transplant physicians and surgeons continue to exercise our professional knowledge in treating patients when patients take advantage of our vulnerability associated with this intention to treat? Because this transplant was a routine procedure until the donor died, can we be sure that all other previous “related” transplants performed by us or in other units have been truly related? Finally, will any number of bureaucratic hurdles placed by authorities to minimize unrelated transplants be sufficient to thwart a sick patient wanting a transplant and a committed donor donating for pecuniary benefit?

  • Mettu Srinivas Reddy, M.S., F.R.C.S., Ph.D. Gomathy Narasimhan, M.S. Pradeep Thomas Cherian, F.R.C.S. Mohamed Rela, M.S., F.R.C.S.

  • Institute of Liver Diseases and Transplantation Global Hospital and Health City Chennai, India

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