Utilization of Donors Who have Suffered Cardiopulmonary Arrest and Resuscitation in Intestinal Transplantation : Transplantation

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Original Articles: Clinical Transplantation

Utilization of Donors Who have Suffered Cardiopulmonary Arrest and Resuscitation in Intestinal Transplantation

Matsumoto, Cal S.; Kaufman, Stuart S.; Girlanda, Raffaele; Little, Cheryl M.; Rekhtman, Yuliya; Raofi, Vandad; Laurin, Jaqueline M.; Shetty, Kirti; Fennelly, Erin M.; Johnson, Lynt B.; Fishbein, Thomas M.

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doi: 10.1097/TP.0b013e3181852f9a
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Abstract

Outcomes in clinical intestinal transplantation (ITx) have improved significantly during the past 10 to 15 years owing to numerous innovations, including an expanded immunosuppressive armamentarium leading to more effective immunosuppressive strategies, better understanding of intestinal transplant immunology, improved surgical techniques that have contributed to reduced surgical complications, and better methods of surveillance for infection with life-threatening agents such as cytomegalovirus and Epstein-Barr virus (1). Because of these improved outcomes, ITx has become more widespread; 175 cases were performed in the United States in 2006, up from 23 cases in 1994 (2). In earlier years, intestinal transplant teams could be selective in choosing donor organs for two reasons; first, the supply of potential intestinal grafts far exceeded the comparatively low demand and second, there were few if any criteria for defining the “marginal” intestinal graft. However, as ITx has become increasingly common, the “luxury of selectiveness” in graft procurement has diminished greatly, thereby requiring consideration of “extended donor criteria” in intestinal transplantation, just as has occurred in the evolution of other types of solid organ transplantation.

Cardiopulmonary resuscitation (CPR) of a person destined to become an organ donor has been associated with overall poor donor quality (3). This is especially a concern for the intestinal donor, because neurogenic and hormonally driven splanchnic vasoconstriction that is intended to preserve coronary and cerebral blood flow may result in clinically relevant intestinal ischemia (4). Intestinal ischemia may be severe enough to jeopardize initial graft viability. Ischemia may also undermine graft function by promoting attraction and adherence of immunocompetent leukocytes into the intestinal graft, increasing the risk of early acute rejection (5), and by disrupting the intestinal mucosal barrier, increasing the risk of bacterial translocation and infection (6).

Clinical outcomes of recipients who receive intestine grafts that have suffered ischemia within the setting of premorbid donor cardiopulmonary instability and CPR are largely unknown. We sought to analyze our experience in using intestinal grafts from donors who suffered cardiopulmonary arrest before death retrospectively and to evaluate the outcome of recipients of organs coming from resuscitated donors when compared with recipients of nonresuscitated donors.

METHODS

We analyzed the charts of patients who received a deceased donation of intestinal graft from November 2003 through December 2007. Donor data collected included routine chemistries, duration of CPR, time interval from CPR to operative donor cross-clamp, and cold ischemia time (CIT). Collected recipient information included intraoperative blood use and total operative time, patient and graft survival, initial hospital length of stay, time to total enteral nutrition, and duration of mechanical ventilation. Additionally, major complications including number and severity of rejection episodes were recorded.

Standard procurement and engraftment techniques for isolated intestine (IITx), liver and small intestine (LITx), multivisceral (MVTx), and modified multivisceral (MMVTx), that is, not including a liver graft, transplants were used as previously described (7, 8). Immunosuppression consisted of interleukin-2 receptor blockade with basiliximab (Simulect, Novartis, East Hanover, NJ) induction, and maintenance immunosuppression typically included steroids, tacrolimus (Prograf, Astellas Pharma, Deerfield, IL), and sirolimus (Rapamune, Wyeth, Madison, NJ). Surveillance endoscopy of ileal graft stomas was performed on protocol and as indicated (9). Rejection was diagnosed based on the histopathological criteria of Ruiz et al. (10). Postoperative blood cultures were obtained on protocol weekly and when clinically indicated. Enteric bacteremia was established by the identification of Enterococcus sp. and various gram-negative facultative organisms such as Klebsiella sp., Enterobacter, Escherichia coli, and Pseudomonas sp.

Statistical analysis was performed using Stats Direct software, version 2.6.5 (Cheshire, UK). Differences in categorical variables between the groups were compared using Fisher’s exact test. Continuous data were reported as mean±standard deviation. Differences in continuous variables were analyzed by the Mann-Whitney U test. Survival estimates were calculated using the Kaplan-Meier method, and comparisons of outcome among the groups were made using the log-rank test. P less than 0.05 was considered significant.

RESULTS

Characteristics of Transplant Donors

A total of 67 intestinal transplants were performed in 65 patients from November 2003 to December 2007. Of the 67 grafts used, 12 of the 67 (18%) came from donors experiencing a cardiac arrest and subsequent CPR (dCPR). Mean duration of CPR was 19.3±12.7 min (range, 1–52 min). Causes of death of dCPR and non-CPR donors (non-dCPR) are listed in Table 1. Fifty percent of the dCPR donors died of respiratory arrest and 71% of the non-dCPR donors died of head trauma, both categories were significantly more than their counterpart (P=0.003 and P=0.018, respectively). Additional details concerning medical status of dCPR and non-dCPR individuals are presented in Table 2. Average lengths of donor hospital stay until time of cross-clamp in the dCPR and non-dCPR groups were 115.3±61.7 hr and 96.9±86.1 hr, respectively (P=ns). With the exception of one person aged 44 years, all dCPR donors were younger than 18 years; the youngest was 6 weeks old; ages of non-dCPR donors were similar. On average, both donor groups experienced declines in both aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of comparable magnitude from their peaks until cross-clamp, eventuating in terminal AST and ALT levels that were the same in the two groups. However, whereas both AST and ALT invariably declined in all 12 dCPR patients by the time of death, AST and ALT did increase in a minority of non-dCPR patients, 6 of 55 (11%) and 12 of 55 (22%), respectively. In fact, the only difference in the terminal laboratory profiles of the two donor types was the marginally lower total bilirubin in the dCPR group, although within normal limits in both. Terminal serum creatinine was likewise similar between the two groups.

T1-12
TABLE 1:
Cause of donor death: donors with CPR (dCPR) and without CPR (non-dCPR)
T2-12
TABLE 2:
Donor characteristics: CPR donors vs. non-CPR donors

Characteristics of Transplant Recipients

Of the 67 transplants performed, 16 (24%) were MVTx, 3 (5%) were MMVTx, 21 (31%) were LITx, and 27 (40%) were IITx. Of the 12 dCPR grafts, two were used for MVTx, one for MMVTx, seven for LITx, and two for IITx. Thus, as indicated in Table 3, fully 75% of the dCPR recipients received a liver graft, when compared with only 50% of recipients of a non-dCPR graft (P<0.001). Mean age between the dCPR and non-dCPR recipients was similar, 13.6±16.4 years (range, 8 months–45 years) and 19.1±19.6 years (range, 5 months–62 years), respectively. All (100%) dCPR graft recipients were outpatients at the time of transplant versus 34 of the 55 (62%) recipients of a nonresuscitated graft (P=<0.001).

T3-12
TABLE 3:
Recipient type and recipient outcome parameters: CPR donors vs. non-CPR donors

Outcomes in dCPR Versus Non-dCPR Intestinal Graft Recipients

Differences in the two populations of intestinal transplant recipients had no impact on indicators of technical challenge in the operating room, including CIT, intraoperative blood use, and case-time (Table 3). Similarly, recovery after transplantation as assessed by days of mechanical ventilation, length of stay, and time to total enteral nutrition, that is, withdrawal of parenteral feeding, did not differ between dCPR and non-dCPR recipients.

The two major determinants of patient and graft survival after ITx are graft rejection, both frequency and severity, and the reciprocal consideration, frequency and severity of episodes of the opportunistic infections that are promoted by immunosuppressive therapy. Impact of these factors on recipient outcome is as follows.

Acute Cellular Rejection

Of the 12 recipients who received a dCPR intestinal graft, three (IITx in two and LITx in one) had a single episode of histologically mild, early rejection, that is, within 90 days of transplant, all of which resolved on average of 12 days (range, 7–21 days) after standard intensification of steroid therapy. A fourth patient experienced a late rejection after reduced immunosuppression in the setting of fungal sepsis and a mycotic pseudoaneurysm; this patient later died (see below). The remaining eight patients with a dCPR graft had no episodes of rejection during a mean follow-up of 427 days. Of the 55 non-dCPR patients, 9 (17%) had an episode of early rejection (IITx in three, LITx in three, and MVTx in three) and 8 (14.5%) experienced late rejection, which did not differ from prevalence of early and late rejection in dCPR transplant recipients. A Kaplan-Meier plot depicting freedom from early rejection in the dCPR (75%) and non-dCPR (83%) recipient groups is shown in Figure 1.

F1-12
FIGURE 1.:
Freedom from early rejection (FFR) in recipients of resuscitated (dCPR) and nonresuscitated (non-dCPR) donor organ grafts.

Bacteremia

Prevalence of enteric bacteremia within 90 days of intestinal transplant was 33.3% in recipients of a dCPR graft, occurring on average at 22.0±18.1 days after surgery, compared with a 19.1% prevalence commencing at mean time of 29.2±24.5 days after transplant in recipients of non-dCPR grafts (P=ns). The most common enteric pathogens in both groups were members of genus Enterococcus (n=10), 71% being vancomycin-resistant Enterococcus faecium.

Survival

One-year patient and graft survival for the recipients of dCPR organs was 79%. In recipients of organs from non-dCPR organs, both 1-year patient and graft survivals were 82%, which did not differ from that of dCPR recipients (Fig. 2). Of the two nonsurviving recipients of a dCPR graft, both deaths occurred after the early (<90 days) postoperative period. One patient, a 19-year-old man, who received an IITx had a native duodenal perforation, refractory rejection after reduced immunosuppression to treat abdominal sepsis, and he eventually succumbed to multiorgan system failure. Inability to feed because of the perforation precluded assessment of graft function. The second patient, a 45-year-old man with pseudo-obstruction, received an MVTx with initially excellent graft function, allowing cessation of parenteral nutrition 20 days after transplant. However, the patient succumbed to disseminated fungemia after resection of a mycotic pseudoaneurysm at the aortic anastomosis 8 months after transplant. Characteristics of the dCPR grafts of nonsurvivors and survivors are listed in Table 4.

F2-12
FIGURE 2.:
One-year patient survival in recipients of resuscitated (dCPR) and nonresuscitated (non-dCPR) donor organ grafts.
T4-12
TABLE 4:
Characteristics of donor grafts in surviving and non-surviving recipients of a resuscitated graft

DISCUSSION

Cardiopulmonary arrest and CPR of a person who is initially stabilized but later experiences cerebral death inevitably raise a concern of possible ischemic injury to organs potentially usable for transplantation. In this study, we sought to determine if CPR of donating individuals has a deleterious effect on the early clinical outcome of recipients of an intestinal graft obtained from such individuals. Retrospectively comparing incidence of infection, incidence of rejection, quality of graft function as inferred from time required to end parenteral nutrition, early survival, and other parameters such as length of postoperative mechanical ventilation and length of hospital stay, we were unable to demonstrate any differences in outcome between recipients of an intestinal graft that had originated from a person who required CPR at some time before death compared with recipients of an intestinal graft that had not been subjected to CPR. Consequently, we conclude that deceased individuals should not automatically be excluded as potential donors of an intestinal graft simply because of a history of CPR.

These findings not withstanding, there are sound reasons to question utilization of a dCPR intestinal graft. In the normal resting state, intestinal blood flow ranges between 50 and 70 mL/min/100 g of tissue, whereas during standard CPR for cardiac arrest, visceral organ perfusion is only 0 to 10 mL/min/100 g tissue (11). Unfortunately, clinicians have few means of determining the extent of ischemic intestinal injury after a successful CPR before postmortem abdominal exploration. For practical purposes, only if ischemic injury progresses from initial, mild villous injury to mucosal slough with submucosal hemorrhage that produces gross gastrointestinal bleeding is it clear that organ donation is precluded (12). The liver is also vulnerable to ischemic injury after a cardiac arrest and subsequent CPR, which is not surprising, as the liver receives approximately 70% of its blood flow from the portal vein. Consequently, evidence of contemporaneous liver injury in the form a sudden, marked increase in serum aminotransferase levels serves as a surrogate marker of ischemic intestinal injury (6). If appropriate circulation to the liver is restored with successful CPR, comparatively rapid hepatic recovery is typical. Totsuka et al. (13) confirmed the feasibility of using post-CPR hepatic grafts in isolated liver transplantation with mean donor AST and ALT concentrations in the 200 to 300 IU/L range in their patients. In the present series, intestinal grafts obtained from patients with aminotransferase levels no greater than 100 IU/L at the time of procurement functioned well irrespective of the magnitude of the original increases after cardiac arrest. This success vindicated our policy of basing hepatic recovery, and by implication, intestinal recovery, on adequate improvement in hepatocellular enzyme levels. Additionally, donor renal function, which also suffers an ischemic insult during the process of CPR, was evaluated in both groups and displayed no significant difference in the terminal values. This suggests that the ischemic insult from the performance of donor CPR was insufficient to provide irreversible renal injury, which is one more surrogate marker as to the extent of CPR ischemic injury to a potential intestinal graft.

That said, implicit to using an intestinal graft in this circumstance is the absence of a history of feeding intolerance, abdominal distention, or gastrointestinal bleeding information, which should be routinely provided by the local organ procurement agency. If a donor who suffered CPR has no manifestation of these clinical signs of irreversible intestinal ischemia, our evaluation then focuses on the hepatic and renal function and hemodynamic trends of the donor. Terminal aminotransferase levels less than 100 IU/L, normal serum creatinine levels, and the weaning of vasopressor support are all initial criteria we use in the evaluation of the potential intestinal donor who suffered CPR. In our series, those criteria for dCPR grafts, along with our standard donor criteria (age<50 years, no previous bowel surgery or trauma, negative lymphocytoxic crossmatch, and no clinical signs of infection), allowed us to successfully select grafts from an otherwise “marginal” donor pool as those grafts functioned equally as well as donors grafts without CPR.

As this was a retrospective study, concluding that selected dCPR grafts are equivalent to non-dCPR grafts requires establishing that recipient groups receiving the two graft types were similar. In theory, an erroneous impression of graft equivalence could be gained if dCPR allocation was biased to a less ill recipient population, thereby compensating for inherently compromised, that is, inferior, dCPR grafts. In fact, we found that precisely the opposite was the case; dCPR grafts were more likely to be used in the setting of more complex procedures, LITx and MMVTx, in a presumably sicker population of patients who had end-stage liver disease as well as intestinal failure. Even though no dCPR graft recipient was hospitalized at the time of transplant, we assume that the necessity of matching liver as well as bowel prompted us to accept organs for grafting that we would more likely have avoided if only an intestinal graft was needed in light of the high probability of waiting-list mortality for combined liver and intestinal grafts (14).

Intestinal ischemia is also thought to promote translocation of bacteria and endotoxin from the intestine to the systemic circulation (15, 16). Gaussorgues et al. (17) established evidence of ischemia-induced bacterial translocation in 39 patients who suffered out-of-hospital cardiac arrest; 12 of the 39 patients subsequently developed bacteremia, with enteric organisms that were also recovered from the patients’ stools. Several studies have also identified an increased incidence of enteric bacteremia after ITx, correlating with such recipient factors as increased CIT, acute rejection, and Epstein-Barr virus-associated posttransplant lymphoproliferative disease (18, 19). In our analysis, we found no difference in the incidence of enteric bacteremia in the early postoperative period between the recipients of dCPR and non-dCPR grafts, suggesting that ischemia during CPR in our patients did not compromise the mucosal barrier. The incidence of enteric bacteremia in both the dCPR and non-dCPR graft groups was similar to previously reported rates of bacteremia after ITx (20, 21).

Intestinal ischemia also amplifies the cytokine milieu, particularly in the mucosa, that, as has been proposed in other tissues, may increase immunogenicity of the intestine (22). Because such candidate cytokines include tumor necrosis factor-α, which is also thought to be a major effector of acute graft rejection (23, 24), ischemic solid organ graft injury may cause, or more likely, increase the risk of graft rejection in the presence of other stimulant factors. Acute rejection occurred within 90 days after transplant in 3 of the 12 recipients with a dCPR graft, all of which were histologically and clinically mild. Although patient numbers were relatively small, we found no clinically significant difference in rates of early acute rejection between recipients of dCPR and non-dCPR grafts, suggesting that ischemia of the severity occurring in these grafts was insufficient to influence the immunologic outcome of our recipients.

Conversely, an intriguing and provocative question is whether graft ischemia occurring before donor death, sometimes termed “ischemic preconditioning,” might actually protect the graft from subsequent perioperative ischemia/reperfusion injury and, perhaps, immunologic activation; this phenomenon has been demonstrated in several organs such as the heart and the liver (25, 26). In this study, we did not assess serial histology or tissue, fecal, or blood levels of soluble inflammatory mediators after transplant. However, we observed no obvious survival advantage to dCPR graft recipients, and the question of ischemic preconditioning in intestinal transplantation remains an area of future research.

CONCLUSION

With careful screening and selection of donors who have experienced a cardiac arrest and CPR before establishment of brain death, recipients can obtain outcomes that are comparable with those using donors without this history. A history of donor cardiac arrest should not automatically exclude the intestine for transplantation.

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Keywords:

Intestinal transplant; Organ procurement; Marginal donor

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