Donor care before pancreatic tissue transplantation

Donor care before pancreatic tissue transplantation

Powner, David J

Publications are reviewed to identify factors related to donor care that may optimize the function of pancreatic tissue (whole or segmentai organ or islet cells) after transplantation. Short cold ischemia time, avoidance of hypotension, and treatment of donor hyperglycemia appear to be beneficial, although additional properly designed studies are needed to verify those findings. (Progress in Transplantation. 2005;15:129-137)

Notice to CE enrollees:

A closed-book, multiple-choice examination following this article tests your ability to accomplish the following objectives:

1. Describe the method used to select studies for the research review

2. Identify nonmodifiable factors that may affect pancreatic tissue transplantation

3. Describe 3 factors that may optimize the posttransplant function of pancreatic tissue

This article reviews publications that relate characteristics of organ donors to transplantation of the entire pancreas, a pancreas segment, or islet cells. Aspects of donor care cited in prior medical literature that might influence graft survival, function, or other outcomes are shown in Table 1. Indications for transplantation, outcome success, technical aspects of surgical implantation, and the preparation of islet cells have been reviewed elsewhere’4 and are not discussed further here. Similarly, successful recovery of pancreatic tissue from donors after cardiac death has been reported5-8 but is not reviewed here.

Publication Database

Publications were identified from a search of the PubMed database from 1976 to 2004, Cochrane Library Database of Systematic Reviews, the author’s files, and bibliographic references from those articles. Only manuscripts that described transplantation of human pancreatic tissue were considered. Reviewed publications are presented in Table 2 and summarized in Table 3.

All publications were observational studies, and all but 4 presented retrospective data from unblinded and nonstandardized donor care. No randomization occurred, although groups of donors were compared on the basis of different characteristics. Some publications separated the results presented depending on whether pancreas transplantation occurred separately, simultaneously with a kidney, or after a kidney had been transplanted; other publications presented combined data. Similarly, the surgical method for implantation of the pancreas (eg, duodenal anastomosis vs occlusion, bladder vs enteric drainage) may not have been specified. The effects of these surgical variations on pancreatic endocrine function after implantation are unclear. Components of donor care such as administration of steroids, insulin, or intravenous fluids were poorly reported. A variety of statistical methods were used to describe associations between donor and outcome variables. Combinations of unfavorable characteristics in the same donor may be additive in producing adverse effects, but this possibility was seldom considered. As previously discussed,21,24 the type of study design used by most of these investigators is convenient and may provide important information. However, the many unknown or unreported factors during donor care risk unintentional bias of the data and conclusions. Because of such limitations, specific aspects of donor care that clearly improve outcome are difficult to identify and defend. Similarly, these variations in study design exclude a true meta-analysis of the effects of any single variable because control over entry into the study was insufficient.

Database Review

Factors that exclude a donor pancreas from any form of transplantation generally include a history of glucose intolerance/diabetes mellitus, tumor, significant trauma, chronic pancreatitis, and acute pancreatitis at the time of explantation.6,11 Outcome variables used to evaluate whole or segmental pancreas transplantation included graft or recipient survival, exogenous insulin requirements of the recipient after transplantation, and insulin or C-peptide production by the recipient. The “quality” of islet cell preparations was evaluated by the yield of islet clusters semiquantitatively assessed as islet-cell equivalents; islets visualized by inspection of postpreparation fluid; islet equivalents per gram of pancreatic tissue processed, or similar measures. Separation of islet cells from other cells or material, as a measure of purity, was assessed by staining methods. Islet function was evaluated by perfusion glucose assay, and cell viability was determined by short-term culture techniques.19 Islet cell yield, purity, and viability were not evaluated in each publication and could be separately or collectively influenced by donor variables.

Some donor variables, although important in deciding if a pancreas is selected, cannot be affected by the procurement coordinator during donor care. These include the donor’s age, sex, cause of death, ABO blood type, results of some laboratory tests, body mass index (BMI), and some issues affecting the duration of care before brain death. Two “unchangeable” characteristics, age and BMI, however, are discussed here in more detail because they may influence ongoing donor treatment.

Factors Not Amenable to Change

Age

Age and BMI may affect donor hyperglycemia. During normal aging, the number of insulin-producing cells (beta cells) within the pancreas declines. This reduced beta-cell mass in older donors might make control of blood sugar levels more difficult. A lower beta-cell mass may also reduce the capacity of the transplanted organ to support the recipient’s need for insulin after transplantation and reduce the yield of beta cells during islet separation. Age may also affect the interstitial supporting structure within the pancreas, an important factor during islet cell preparation. Older donors often have smaller amounts of or less firm interstitial tissue within the pancreas binding beta cell islets to other tissue, potentially increasing the yield of islet cell clusters during the digestive process. Conversely, the same aging process may lead to more fibrotic tissue throughout the pancreas, making in vitro digestion more difficult. Younger donors may normally have more structured interstitial tissue that is resistant to digestion19 and, thus, produce a lower yield of islet cells. Therefore, age appears to be an important consideration in selection for islet cells but may influence glucose control in all donors.

Older donor age adversely affected patients’ survival, graft survival, or graft function after whole or segmentai transplantation in 4 studies.6,11,13,14 One study6 involved whole pancreas removal, whereas the others addressed islet cell transfer. The “cut-off ages used were 40, 45, 45 and 45 years, respectively, and the oldest donors, when cited, were 54 years old,11 58 years old,13 and 69 years old.14 Age was not associated with an adverse effect in 4 publications.8,9,12,17 All 4 of those studies addressed whole organ transplantation and found similar “cut-off ages of 45 years old9,17 and 50 years old12 and oldest donors of 50 years old,17 53 years old,9 and 57 years old.12 Age was not evaluated in 3 studies.10,15,16

Both younger or older donor age adversely affected yield, purity, function, or viability of islet preparations in 3 studies,18-20 did not have an effect in 1 study,21 and was not assessed in 1 study.22 Donor ages less than 18 years18,19 and 20 years20 were associated with low yields. Increased yields from older donors were offset by reduced islet cell function from donors at about 50 years old.

Body Mass Index

The body mass index (weight in kilograms divided by height in meters squared [kg/m^sup 2^]) may also influence allocation and care decisions. A larger, and most likely more obese, donor with a larger BMI may have more beta-cell mass19 but less insulin reserve, because adipose tissue is relatively resistant to insulin effect. Those donors may be prone to hyperglycemia during donor care. Similar to the offsetting influences of age in islet cell preparations, pancreata from donors with a high BMI may be more easily fractionated during islet cell preparation and produce higher yields of islet cells. Conversely, lower yields may occur because of a longer digestion time of larger organs.18

Donor body weight was evaluated in only 1 publication6 describing whole pancreas transplantation. Body weight was not converted to BMI because height data were not available. Body weight exceeding 90 kg (200 lb) was not associated with changes in 1- and 5-year survival of recipients but decreased graft survival was suggested (although the difference was not statistically significant) when combined with older donor age.

The effect of BMI or weight on islet cell transfer was assessed in 4 studies. One study19 showed better yield with higher BMI, 2 studies20,21 reported no effect, and 1 study18 cited worse yield at donor weights exceeding 90 kg (200 lb).

Amylase

Although acute and chronic pancreatitis or direct injury may exclude the pancreas from donation, an elevated serum amylase level alone may not be sufficient. Serum amylase level may be increased after blunt trauma not affecting the abdomen, brain injury, intracranial hemorrhage, or stroke.25-28 One islet study19 found an association between elevated amylase level in the donor and failed islet isolation, but 7 other studies did not (Table 3).

Factors Amenable to Change During Donor Care

Blood Glucose Level

Donor hyperglycemia appears to be associated with some adverse effect according to several studies. Two important issues related to this variable remain unresolved, however. First, if hyperglycemia reflects a prediabetic condition indicating a marginal beta-cell reservoir that may be inadequate to sustain the recipient, perhaps donation of that pancreas should be declined. However, if the hyperglycemia reflects only transient donor “stress diabetes” due to circulating catecholamines, elevated levels of endogenous or administered corticosteroids, high serum levels of glucagon, administration of glucose-containing solutions, or resistance to insulin, the pancreas may be acceptable.

High circulating concentrations of catecholamines, glucagon, cortisol, and insulin are well documented following brain injury and brain death.21,29-31 These hormones and changes in pancreatic hormone production31,32 may lead to hyperglycemia by altering insulin production/release, changing the normal cellular response to insulin (insulin resistance), increasing production of glucose from nutrient stores, or by increasing production of cytokines.33 The concentration of hemoglobin that has bonded with glucose, Hgb A^sub 1c^, in donor blood may help resolve the question of preclinical diabetes versus a stress response. Hgb A^sub 1c^ is commonly used during patient care as a marker of prolonged hyperglycemia and may be elevated (>6%) in diabetics.16,33 Similarly, blood levels of C-peptide and insulin reflect ongoing production of insulin by the pancreas and may be low in diabetic donors. Where evaluated, Hgb A^sub 1c^ was normal during donor care,15,16,34 and hyperglycemia was generally correlated with increasing insulin and C-peptide production.16,34 These studies suggest that hyperglycemia in the donor may often reflect cellular resistance to insulin and not failure of the pancreas.16,34 Unfortunately, during donor care, laboratory measures of Hgb A^sub 1c^, insulin, or C-peptide levels are usually not available quickly enough to influence treatment or allocation decisions.16

Second, is hyperglycemia itself harmful, as recently documented in other critically ill patients? Should it be controlled during donor care, and if so, what is an optimal blood sugar level? Recent data from patient (not donor) care in surgical intensive care units (ICUs) show increased mortality and morbidity (eg, infection, accentuated inflammatory response, increased transfusion requirements, and renal failure) associated with hyperglycemia.35,36 Although many advantages ascribed to “tight” glucose control do not apply to organ donation, modification of the extensive inflammatory response after brain death may be beneficial. Glucose control targeted to about 6.1 mrnol/L (110 mg/dL), as proposed by ICU patient data, may risk hypoglycemia, making frequent measurements of blood sugar levels essential. One study, however, proposes that donor hyperglycemia with its corresponding increase in circulating insulin level may improve pancreatic recovery in the recipient and more quickly treat glucose intolerance in the recipient.15

Twelve publications described studies that evaluated the association between blood glucose level and some outcome measure (Tables 2 and 3). Five studies12,18,,19,21,22 showed hyperglycemia had an adverse effect on 1 or more outcomes, 7 studies did not.8,10,11,14-17 When hyperglycemia was considered harmful and a discriminating glucose concentration was reported, the concentrations were >11.1 mmol/L (>200 mg/dL),’2·’8 >8.9 mmol/L (>160 mg/dL),21 >6.9 mmol/L (>125 mg/dL),22 and >180 mg/dL (>10.0 mmol/L).19 In 1 study,21 no apparent harmful effect was reported from a maximum blood sugar of 16.7 mmol/L (300 mg/dL). In only 1 publication10 was insulin treatment of donors reported. A sliding scale was used, but the route and dosing schedule to maintain blood sugar at about 5.6 mmol/L (100 mg/dL) were not reported. In that study, blood glucose level had no adverse effect.

In summary, it appears that hyperglycemia has a bigger effect on islet preparation than on whole organ transplantation. Although the database reviewed is weak, incomplete, and inadequately reported, control of donor glucose levels may be helpful, provided significant hypoglycemia is avoided. A single publication21 suggested no harmful effect of hyperglycemia upon pancreatic tissue, and 1 study15 suggested that donor hyperglycemia may “prime” the pancreas for more rapid glucose control in the recipient. However, the osmotic effect of a high blood glucose level may easily contribute to polyuria.37 Hyperglycemia may also adversely influence beneficial inflammatory mediators and white cell function.33 Recent related publications about glucose control among ICU patients recommend use of an intravenous infusion of insulin to carefully titrate blood sugar levels36,38 However, because donors may not receive continuing nutrition or dextrose infusions, there may be a risk of hypoglycemia during a continuous infusion of insulin. Likewise, the response to a subcutaneous sliding scale may be suboptimal if insulin absorption is compromised by hypotension. Insulin, given as an intravenous bolus, is rapidly used and has a very short duration of action. Therefore, glucose control during donor care may be difficult and should be accomplished through a careful policy and procedure approved and supervised by the organ procurement organization’s medical team.

Cold Ischemia Time and Length of ICU Admission

Cold ischemia time (CIT) and warm ischemia time have the same importance to whole pancreas transplantation as they would have for transplantation of any other solid organ.24 In this series, 1 publication17 reported an adverse effect beyond about 8 or 9 hours, and another publication13 reported short-term effects when CIT exceeded 20 hours. Other studies9,11 found no effect.

Islet cell publications usually measure CIT from aortic cross-clamping to later intraductal injection of the enzyme preparation used for tissue separation. The total preservation time includes the actual digestion and separation processes and may add 4 to 5 hours. Four studies18-21 reported an adverse effect of CIT beyond 6 hours,20 8 hours,18,19 and 17 hours.21

The organ procurement coordinator might influence CIT through decisions about allocation and by expediting processes in the operating room that speed organ removal and transport to the site of islet cell preparation or organ implantation.

Similarly, in 2 studies11,21 researchers found that the length of admission time for the donor in the ICU may have contributed to an adverse effect. Expeditious donor care, under the direction of the procurement coordinator, may likewise contribute to better outcomes.

Hypotension, Use of Vasoactive Drugs, or Cardiac Arrest

These events were reportedly harmful to pancreatic tissue in 3 studies.8,19,22 Assessment criteria included the following:

a. Systolic blood pressure less than 90 mm Hg; mean arterial blood pressure less than 60 mm Hg for more than 15 minutes; dopamine dosage greater than 15 µg/kg per minute, norepinephrine dosage greater than 5 µg/kg per minute, or duration and number of cardiac arrests.19

b. Minimum systolic blood pressure greater than 68 ± 44.7 mm Hg. However, considerable overlap in reported blood pressure and dopamine doses was observed between the acceptable and low islet yield groups.22

c. Delayed graft function, but no long-term graft survival was impaired when more than 10 µg/kg per minute of dopamine was needed.8

Studies11,12,17,18,20,21 showing no effect included dopamine dosages from O to 50 µg/kg per minute (mean 15 µg/kg per minute), episodes of nonspecified hypotension,17 comparison of vasopressor received versus none given (no doses specified),12 mean blood pressure 65 mm Hg versus 60 mm Hg in comparison groups,21 systolic blood pressure less than 90 mm Hg for a brief time,18 and systolic blood pressure less than 80 mm Hg for more than 10 minutes.20

Again, the considerable overlap observed in the preceding data most likely indicates that although hypotension alone may be sufficient to produce transplant failures, often other factors must contribute. Although a review of data from the Eurotransplant International Foundation indicated a possible beneficial effect of use of vasoactive drugs,39 it is generally agreed that appropriate donor care so as to avoid cardiac arrest, hypotension, and vasoactive drugs is preferred.

Conclusion

Of approximately 20 variables (Table 1) considered in these publications, only a limited number can routinely be influenced by organ procurement coordinators. Expeditious care in the ICU and operating room may improve pancreatic tissue function after transplantation by limiting ICU length of care and cold ischemia time. Properly titrated blood pressure and avoidance of hypotension (mean arterial pressure

CE Test Test ID 4000-J40: Donor care before pancreatic tissue transplantation.

Learning objectives: 1. Describe the method used to select studies for the research review 2. Identify nonmodifiable factors that may affect pancreatic tissue transplantation 3. Describe 3 factors that may optimize the posttransplant function of pancreatic tissue

1. Publications were identified from a search of the PubMed database from what years?

a. 1972 to 2004

b. 1974 to 2004

c. 1976 to 2004

d. 1978 to 2004

2. Which one of the following sources was used to help identify publications for the research review?

a. Psyclnfo

b.Medline

c. Cochrane Library Database of Systematic Reviews

d. A panel of experts

3. How many of the reviewed studies used a randomized design?

a. None

b. One

c. Two

d. Three

4. It impossible to conduct a true meta-analysis of the effects of any single variable on posttransplant pancreatic tissue for what reason?

a. Too few studies have been conducted,

b. Insufficient data in existing studies,

c. Some studies used animal models,

d. There were variations in study designs.

5. Which one of the following excludes a donor pancreas from transplantation?

a. Head trauma

b. Diabetes mellitus

c. History of acute pancreatitis

d. Hypoglycemia

6. What affect does aging have on the number of beta cells in the pancreas?

a. No affect at all

b. The affects are highly variable

c. The number of beta cells increase

d. The number of beta cells decrease

7. What donor ages were associated with low islet cell yields?

a. Younger than 14 and 16 years

b. Younger than 16 and 18 years

c. Younger than 18 and 20 years

d. Younger than 20 and 22 years

8. How is body mass index calculated?

a. Body weight (in kg) divided by height (in meters^sup 2^)

b. Body weight (in kg) divided by height (in meters)

c. Body weight (in lb) divided by height (in inches^sup 2^)

d. Body weight (in lb) divided by height (in inches)

9. Which of the following events was reportedly harmful to pancreatic tissue?

a. Cardiac arrest

b. Hypertension

c. Short cold ischemia time

d. Use of vasodilators

10. According to the data reviewed, what is the optimal level of blood glucose in donors?

a. 7.0 to 8.1 mmol/L

b. 7.2 to 8.3 mmol/L

c. 7.4 to 8.5 mmol/L

d. 7.6 to 8.7 mmol/L

References

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16. Masson F, Thicoipe M, Gin H, et al. The endocrine pancreas in brain-dead donors. Transplantation. 1993;56:363-367.

17. Tamsma JT, Schaapherder AFM, van Bronswijk H, et al. Islet cell hormone release immediately after human pancreatic transplantation. Transplantation. 1993;56:1119-1123.

18. Zeng Y, Torre MA, Karrison T, Thistlethwaite JR. The correlation between donor characteristics and the success of human islet isolation. Transplantation. 1994;57:954-958.

19. Lakey JRT, Warnock GL, Rajotte RV, et al. Variables in organ donors that affect the recovery of human islets of Langerhans. Transplantation. 1996;61:1047-1053.

20. Brandhorst D, Hering BJ, Brandhorst H, Federlin K, Bretzel RG. Influence of donor data and organ procurement on human islet isolation. Transplant Proc. 1994;26:592-593.

21. Benhamou PY, Watt PC, Mullen Y, et al. Human islet isolation in 104 consecutive cases. Transplantation. 1994;57: 1804-1810.

22. Fiedor P, Goodman ER, Sung RS, Shimomura K, Kwiatkowski PA, Hardy MA. Factors that can affect cadaveric islet graft function include hemodynamic changes in the donor prior to organ harvest. Transplant Proc. 1996;28:169-170.

23. Powner DJ, Hernandez M. A review of thyroid hormone administration during adult donor care. Prog Transplant. In press.

24. Powner DJ. Factors during donor care that may affect liver transplantation outcome. Prog Transplant. 2004;14:241-249.

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27. Bouwman DL, Altshuler J, Weaver DW. Hyperamylasemia: a result of intracranial bleeding. Surgery. 1983;94:318-323.

28. Pezzilli R, Billi P, Barakat B. et al. Serum pancreatic enzymes in patients with coma due to head injury or acute stroke. Int J Clin Lab Res. 1997;27:244-246.

29. Powner DJ, Hendrich A, Lagler RG, Ng RH, Madden RL. Hormonal changes in brain dead patients. Crit Care Med. 1990;18:702-708.

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31. Yoshida H, Hiraide A, Yoshioka T, Sugimoto T. Transient suppression of pancreatic endocrine function in patients following brain death. Clin Transplant. 1996;10:28-33.

32. Brunicardi FC, Dyen Y, Brostrom L, et al. The circulating hormonal milieu of the endocrine pancreas in healthy individuals, organ donors, and the isolate perfused human pancreas. Pancreas. 2000;21:203-211.

33. AlKharfy KM, Kellum JA, Matzke GR. Unintended immunomodulation: part I. Effects of common clinical conditions on cytokine biosynthesis. Shock. 2000;13:333-345.

34. Thicoipe M, Favarel-Garrigues JF, Masson F, et al. Endocrine pancreas after brain death: preliminary results. Transplant Proc. 1991;23:2481-2482.

35. Groeneveld ABJ, Beishuizen A, Visser FC. Insulin: a wonder drug in the critically ill? Crit Care. 2002;6:102-105.

36. van den Berghe G, Wouters PJ, Bouillon R, et al. Outcome benefit of intensive insulin therapy in the critically ill: insulin dose versus glycemic control. Crit Care Med. 2003;31:359-366.

37. Powner DJ, Kellum JA, Darby JM. Abnormalities in fluids, electrolytes, and metabolism of organ donors. Prog Transplant. 2000;10:88-96.

38. Brown G, Dodek P. Intravenous insulin nomogram improves blood glucose control in the critically ill. Crit Care Med. 2001;29:1714-1719.

39. Schnuelle P, Berger S, de Boer J, Persijn G, van der Woude FJ. Effects of catecholamine application to brain-dead donors on graft survival in solid organ transplantation. Transplantation. 2001;72:455-463.

David J. Powner, MD

Vivian L. Smith Center for Neurologic Research, University of Texas Health Science Center at Houston, Tex

Copyright North American Transplant Coordinators Organization Jun 2005

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