In Brief Diabetes Acute Care of Patients With / From Research to Practice

Pancreas transplantation is considered the best treatment option for patients with type 1 diabetes and renal failure. In this article, the authors describe peri- operative glucose control in patients undergoing pancreas or kidney-pancreas transplantation.

Glucose Control During and After Pancreatic Transplantation

After decades of controversy sur- graft survival rates are 72% for PAKT rounding the therapeutic validity of and 71% for PA.1,2 pancreas transplantation (PTX), the The Diabetes Control and Comp- M. Hosein Shokouh-Amiri, MD; procedure has become accepted as the lications Trial (DCCT) has clearly Robert J. Stratta, MD; Kashif A. preferred treatment for patients with shown that improved glycemic control Latif, MD; and Osama Gaber, MD insulin-requiring diabetes mellitus and lowers the risk of secondary diabetic advanced diabetic nephropathy. The complications.3 However, intensive trade-offs for normal glucose home- insulin therapy did not result in nor- ostasis are the operative risks of the malization of hemoglobin A1c (HbA1c) transplant procedure and the need for levels, was associated with a threefold chronic immunosuppression. Free islet increased risk of severe hypoglycemia, grafts have the same potential but do and was resource-intensive. The not approach PTX in terms of consis- results of the DCCT provide a strong tency of results. rationale for pancreas transplantation. From December 1966 to October 2000, more than 15,000 PTX proce- Recipient Selection dures were performed worldwide and Patient selection is aided by a compre- reported to the International Pancreas hensive medical evaluation before Transplant Registry (IPTR).1 In the transplantation (Tables 1 and 2) per- past decade, the majority (82%) of formed by a multidisciplinary team PTX procedures have been performed that confirms the diagnosis of dia- in combination with a kidney trans- betes, determines the patient’s ability plant (simultaneous kidney-pancreas to withstand the operative procedure, transplant [SKPT]) in patients with establishes the absence of any exclu- end-stage diabetic nephropathy. The sion criteria (Table 3), and documents current 1-year actuarial patient and end-organ complications for future kidney and pancreas (with complete tracking after transplantation.4 The insulin independence) graft survival primary determinants for recipient rates after SKPT are 95, 92, and 84%, selection are the presence of diabetic respectively.1,2 Solitary PTX proce- complications, degree of nephropathy, dures comprise the remaining activity, and cardiovascular risk (Table 1). including either sequential pancreas- With increasing experience, previ- after-kidney transplants (PAKT, 12%) ous absolute contraindications have or transplant of pancreas alone (PA, become relative contraindications, 6%). The current 1-year patient sur- and relative contraindications have vival rate after solitary PTX is 95%, become risk factors for PTX (Table and the 1-year actuarial pancreas 3). Binocular blindness or history of a 49 Diabetes Spectrum Volume 15, Number 1, 2002 otherwise and need to undergo an Table 1. Indications for Pancreas Transplantation: extensive cardiovascular and peripher- Eligibility Guidelines al vascular evaluation. Potential male recipients >100 kg and female recipi- I. Medical Necessity A. Presence of insulin-treated diabetes mellitus: ents >80 kg, depending on their height 1. Documentation of insulin dose and body habitus, have a higher rate 2. Type 1 or type 2 diabetes of surgical complications after PTX. B. Ability to withstand surgery and immunosuppression (as assessed by pretrans- For this reason, a BMI >30 kg/m2 is plant medical evaluation): considered an absolute contraindica- 1. Adequate cardiopulmonary function tion and BMI >27.5 kg/m2 is a relative a. Cardiac stress testing ± coronary angiography to rule out signifi- contraindication for solitary PTX. cant coronary artery disease or other cardiac contraindications b. Patients with significant coronary artery disease should have it Preoperative Preparations for corrected before transplant Pancreas Transplantation 2. Absence of other organ system failure (other than kidney) C. Emotional and sociopsychological suitability Patients are allowed nothing by D. Presence of well-defined diabetic complications (any two of the following): mouth once an organ becomes avail- 1. Proliferative retinopathy able. Patients’ blood glucose is 2. Nephropathy (hypertension, proteinuria, or decline in glomerular filtra- checked every 2 h, and insulin is sup- tion rate) plemented as needed to keep the 3. Symptomatic peripheral or autonomic neuropathy blood glucose between 100 and 150 4. Microangiopathy mg/dl. If blood glucose is labile, then 5. Accelerated atherosclerosis (macroangiopathy) an insulin infusion is started. This 6. Glucose hyperlability, insulin resistance, or hypoglycemia unawareness consists of a mixture of 250 units of with a significant impairment in quality of life regular insulin in 250 cc of 50% E. Absence of any contraindications F. Financial resources saline, with a final concentration of 1 unit of insulin/ml of infusion fluid. II. Type of pancreas transplant The initial basal rate is 0.2–0.3 A. Specific entry criteria based on degree of nephropathy: unit/kg/h, which is then titrated with 1. Simultaneous kidney-pancreas transplant: creatinine clearance <30 ml/min blood glucose determinations every 2. Sequential pancreas after kidney transplant: creatinine clearance ≥40 1–2 h to maintain the blood glucose ml/min (on calcineurin inhibitor); >55 ml/min if not on calcineurin in the range noted above according to inhibitor the scale shown in Table 4. 3. Pancreas transplant alone: creatinine clearance >60–70 ml/min and 24-h protein excretion <2 g Intraoperative Monitoring B. Primary determinants for recipient selection are the presence of diabetic com- plications, degree of nephropathy, and cardiovascular risk Essentially the same regimen of infu- sion is followed intraoperatively as major amputation are not necessarily not contraindications for PTX, as the preoperative infusion, with the contraindications for PTX, provided excellent outcomes have been report- strict rule to maintain euglycemia. that the patient is well adjusted to ed in patients with previous cardiac Following a successful pancreas trans- these otherwise irreversible diabetic interventions.5 However, sudden car- plantation,8 the transplanted pancreas complications. Inclusion and exclu- diac death, in the absence of signifi- will take over glycemic control. sion criteria for PTX are listed in cant structural heart disease, contin- Tables 1 and 3. ues to be a major cause of cardiac Postoperative Management The cardiac status of each candi- mortality after PTX.6 For this reason, Insulin therapy, as outlined in Table date must be assessed carefully a number of centers are beginning to 4, can take one of two forms. The because significant (and silent) coro- test cardiac autonomic function in first involves instituting aggressive nary artery disease is not uncommon these patients, using laboratory- insulin therapy with the objective of in this population. The cardiac evalua- evoked cardiovascular tests and 24-h “complete” insulin replacement to tion consists of a noninvasive func- heart-rate variability measurements.7 “rest” the -cells in the transplanted tional assessment, such as an exercise The new methodology may be able to pancreas for the first few days follow- or a pharmacological stress test, in detect alterations in autonomic func- ing surgery. The second is to let the addition to echocardiography. tion before the onset of disabling transplanted pancreas function as Coronary angiography is reserved for symptoms. soon as blood supply is restored to the specific indications such as age >45 In general, age >65 years, heavy transplanted organ. Each of these years, diabetes for >25 years, a posi- smoking, a left ventricular ejection approaches has its proponents. The tive smoking history, long-standing fraction <30%, recent MI, and severe advantages of each are discussed hypertension, previous major amputa- obesity (>150% ideal body weight or below. tion due to peripheral vascular disease, body mass index [BMI] >30 kg/m2) history of cerebrovascular disease, or are usually viewed as contraindica- Complete replacement cases in which the history, physical tions for PTX (Table 3).4 Most Some practitioners believe that pro- examination, or noninvasive cardiac patients <45 years of age are accept- viding complete replacement of studies reveal an abnormality.4 able candidates for PTX provided that insulin will “rest” the -cells in the A history of previous myocardial no significant coronary artery disease transplanted pancreas and therefore infarction (MI), angioplasty, stenting, is present. Diabetic patients >45 years preserve their function and avoid or coronary artery bypass grafting are of age are not candidates until proven injury from acute stress. After 3–4 50 Diabetes Spectrum Volume 15, Number 1, 2002 vantage of this protocol is that the Diabetes Acute Care of Patients With / From Research to Practice Table 2. Evaluation of Pancreas Transplant Candidates precise status of the function and via- bility of the transplanted organ is dif- 1. Interviews and Consults ficult to judge when insulin produc- A. History and physical examination by nephrologist, endocrinologist, and transplant surgeon tion is suppressed due to exogenous B. Ophthalmology evaluation, including visual acuity, fluorescein angiography, replacement. This could prevent retinal fundus photography with retinopathy score, and slit-lamp examination assessment of compromised pancreat- C. Transplant coordinator and medical social worker interview, including com- ic function. pletion of quality-of-life questionnaire D. Gynecology consultation for all females (pelvic examination with Pap smear) Replacement of insulin as needed E. Dental evaluation The authors, with years of experience F. When indicated, additional evaluations may be required by orthopedic in the field of pancreas transplanta- surgery, podiatry, psychology, psychiatry, neurology, or gastroenterology. tion, use a simple approach that 2. Cardiovascular, Respiratory, and Peripheral Vascular Evaluations allows the -cells to autoregulate A. Standard testing includes orthostatic vital signs, 12-lead electrocardiogram, their secretion in response to blood chest radiograph, echocardiography, and exercise treadmill, stress thallium, glucose. Our studies (by the use of C- or dobutamine stress echocardiography. peptide) indicate that such patients B. Additional studies may include arterial blood gases, 24-h Holter monitoring, can produce enough insulin in the autonomic and peripheral vasomotor reflexes, Doppler arterial studies, graft as soon as the blood supply is ankle/brachial index, transcutaneous oxygen monitoring, plethysmography, restored to the pancreas after the carotid Doppler examination, aortography with run-off, or pulmonary func- transplant. tion tests as indicated. C. Cardiology consultation with or without coronary angiography as indicated We prefer this approach when the islets are producing the insulin for the 3. Metabolic and Endocrine Evaluation host. The blood glucose is checked A. Standard testing includes fasting blood glucose, HbA1c, and fasting lipid every 2 h, and exogenous insulin, if panel (cholesterol, triglycerides, and HDL cholesterol). needed, is given every 2 h to maintain B. Fasting and stimulated C-peptide levels are used to assess type of diabetes, if euglycemia. A sudden increase in needed insulin requirement is a red flag that C. Additional studies may include oral or intravenous glucose challenge, anti- insulin and islet cell antibodies, proinsulin level, and lipoprotein profile. the function of the graft is affected. In this case, immediate intervention 4. Genitourinary/Renal Evaluation needs to be undertaken to protect the A. Standard testing includes electrolytes, blood urea nitrogen, serum creatinine, grafted organ (see below). urinalysis with culture, and 24-h urine for protein and creatinine clearance. A need for supplemental insulin in B. Voiding cystourethrogram and urodynamics when indicated the early postoperative period can be C. Radiometric glomerular filtration rate if needed expected because of the immunosup- D. In addition, kidney biopsy may be indicated. E. Calcineurin inhibitor challenge test when indicated pressive medications, which can also F. Hormonal profiles as indicated cause insulin resistance. Once the dose G. Evaluation of erectile dysfunction when indicated of steroids is tapered, the need for additional coverage declines. 5. Serology and Immunology Evaluation Postoperative hyperglycemia also A. ABO blood type and HLA tissue type responds very well to the newer class- B. Cytotoxic antibodies es of oral antidiabetic medications, C. Viral titers (Epstein Barr virus, Herpes Simplex virus, Varicella-Zoster virus, Human Immunodeficiency virus, Hepatitis B virus, Hepatitis C virus, and such as the insulin sensitizers, as long Cytomegalovirus); polymerase chain reaction quantitation when indicated as strict guidelines for the use of such D. Venereal Disease Research Laboratory/fluorescent treponemal antibody test medicines are followed. If the need for for syphilis supplemental insulin is caused by inadequate production of insulin by 6. Other Laboratory Tests the graft (determined by C-peptide A. Complete blood count with differential and platelets, prothrombin time, assay) or because of its small size for partial thromboplastin time, chemistry profile, amylase, lipase B. Abdominal ultrasound of kidneys and gallbladder the host, then oral agents, such as sul- C. Mammography in females >35 years of age fonylureas, may be beneficial. D. Hemoccult 3; contrast studies or endoscopy when indicated E. Nerve conduction studies, gastric emptying scan, electromyography (when Assessment of the Transplanted indicated) Organ F. Hypercoagulable work-up (when indicated) It is expected that from the time of pancreas allograft reperfusion, patients should become insulin-inde- days of total insulin replacement, when precise protocols are not used to pendent. Any abnormality of glycemic patients are switched to an intermit- replace basal and bolus insulin. If control should be investigated imme- tent regimen that only delivers insulin doses are adjusted without allowing diately, because some of the causes to maintain euglycemia, and the - for the stress of surgery and insulin need immediate intervention in order cells take over the primary function of resistance that may develop from the to prevent graft loss. The usual causes producing insulin. use of immunosuppressants such as of graft dysfunction are: The main disadvantage of this steroids and FK506, erratic blood glu- 1. inadequate islet cell mass trans- method is the inaccuracy that comes cose levels may result. Another disad- planted; 51 Diabetes Spectrum Volume 15, Number 1, 2002 Table 3. Absolute and Relative Contraindications and Risk that occur early after PTX will trans- late into long-term improvements in Factors for Pancreas Transplantation diabetic end-organ complications and decrease the risk of atherosclerotic I. Absolute Contraindications A. Insufficient cardiovascular reserve (one or more of the following): vascular disease. 1. Coronary angiographic evidence of significant non-correctable or untreat- In addition to correcting dysmetab- able coronary artery disease olism and freeing patients from exoge- 2. Recent myocardial infarction nous insulin therapy, data are emerg- 3. Ejection fraction <30% ing on the effects of PTX on the B. Active infection course of secondary complications.9,10 C. History of malignancy diagnosed within past 3 years (excluding non- With regard to nephropathy,11 prelim- melanoma skin cancer) inary evidence suggests that successful D. Positive human immunodeficiency virus serology PA transplantation can induce regres- E. Positive Hepatitis B surface antigen serology sion of early, but not advanced, F. Active, untreated peptic ulcer disease G. Ongoing substance abuse (drug or alcohol) microscopic lesions of diabetic H. Major ongoing psychiatric illness nephropathy and stabilize renal func- I. Recent history of noncompliance tion, whereas successful PAKT can J. Inability to provide informed consent prevent the recurrence of diabetic K. Any systemic illness that would severely limit life expectancy or compromise nephropathy in a kidney transplant. recovery The progression of diabetic L. Significant, irreversible hepatic or pulmonary dysfunction retinopathy appears to be less favor- M. Positive crossmatch ably influenced by a functioning PTX. However, with longer follow-up II. Relative Contraindications (more than 4 years), data are accumu- A. Age <18 or >65 years B. Recent retinal hemorrhage lating to suggest that retinopathy may C. Symptomatic cerebrovascular or peripheral vascular disease be stabilized. D. Absence of appropriate social support network Peripheral and autonomic neu- E. Extreme obesity (>150% ideal body weight or BMI >30 kg/m2) ropathies improve or stabilize in most F. Active smoking PTX recipients, which may actually G. Severe aorto-iliac vascular disease translate into a survival advantage. Improvements in nerve conduction III. Risk Factors velocity, gastric function, cardiac A. History of myocardial infarction, congestive heart failure, previous open function, and a beneficial effect on heart surgery, or cardiac intervention microcirculatory blood flow have B. History of major amputation or peripheral bypass graft 10 C. History of cerebrovascular event or carotid endarterectomy been demonstrated. These effects D. History of hypercoagulable syndrome may place patients at a lower overall risk for the development of peripheral ulcers or amputations. 2. high doses of corticosteroid and the presence of pancreatitis. There is also evidence that a func- FK506 in the peritransplant period; Radionucleotide study is of limited tioning PTX may ablate the hyperlipi- 3. allograft pancreatitis; or use. demic effects of immunosuppression 4. technical problems with blood 4. An angiogram to demonstrate any and actually improve lipid metabolism supply to the pancreas allograft. blood flow problem to the allo- over time. However, long-term studies Pancreas allograft function is moni- graft. are needed to fully document and tored meticulously by both serum and Patients are discharged 7–10 days characterize the effects of successful drain fluid amylase, lipase, and fre- after surgery, usually with no need for PTX on the diabetic condition. quent blood glucose measurement, supplemental insulin. Thereafter, they and the need for exogenous insulin are followed up by a team of special- Table 4. Blood Glucose requirement. Any allograft dysfunc- ists, including the transplant team, Control by Frequent tion will warrant the following work- endocrinologist, clinical psychologist, Measurements and up: and physiatrist. We believe the chance Corresponding Insulin 1. Serum C-peptide measurement to for best outcomes is enhanced with a assess -cell function. However, team approach. However, one physi- Requirements this assay is not immediately avail- cian, usually the surgeon, has to be in able at all facilities. charge. Blood Glucose Infusion Rate 2. A Doppler ultrasonography of the (mg/dl) allograft to verify the presence of Discussion <50 Suspend drip 50–75 Reduce by 50% flow to and from the allograft and Most PTX recipients find the transi- 75–100 Reduce by 25% the presence of fluid collection tion to transplantation easier than 100–150 No change around the pancreas or swelling of continued insulin therapy. There is 150–175 Increase rate 2cc/h the gland. now compelling evidence that PTX is 175–200 Increase rate 4cc/h 3. If the gland is difficult to visualize not only acutely life-enhancing, but 200–225 Increase rate 6cc/h because of gas overlying the graft, also chronically life-saving.9 It is 225–250 Increase rate 8cc/h a CT with contrast to demonstrate hoped that the beneficial changes in Check ketones the viability of the allograft and/or carbohydrate and lipid metabolism 52 Diabetes Spectrum Volume 15, Number 1, 2002 Solitary PTX has assumed an pancreas transplant. Transplantation Diabetes Acute Care of Patients With / From Research to Practice increasingly important role in the References 68:1846–1850, 1999 treatment of diabetes and currently 1Sutherland DER, Gruessner AC: International 8Gaber AO, Shokouh-Amiri MH, Hathaway accounts for more than 20% of PTX Pancreas Transplant Registry Update. IPTR DK, Gaber LW, Elmer D, Kitabchi AE, Stentz F. activity in the United States. In the Newsletter 12:1–23, 2000 Pancreas transplantation with portal venous and enteric drainage eliminates hypertension and 2 future, advances in immunosuppres- Gruessner AC, Sutherland DER: Pancreas trans- reduces postoperative complications. Transplant sive strategies and diagnostic technol- plant outcomes for United States cases reported Proc 25:1176–1178, 1993 to the United Network for Organ Sharing ogy will only enhance the already 9 good results achieved with solitary (UNOS) and non-U.S. cases reported to the Stratta RJ: Pancreas transplantation: long-term International Pancreas Transplant Registry aspects and effect on quality of life. In Pancreatic PTX. Further documentation of the (IPTR) as of October 2000. In Clinical Transplantation. Hakim NS, Stratta RJ, Gray long-term benefits and effects of PTX Transplants 2000. Cecka JM, Terasaki PI, Eds. DWR, Eds. Oxford, U.K., Oxford University may lead to wider availability and Los Angeles, UCLA Immunogenetics Center, Press. In press 2001, p. 45–72 acceptance, particularly from a reim- 10Stratta RJ: Impact of pancreas transplantation bursement standpoint. 3The DCCT Research Group: The effect of inten- on complications of diabetes. Curr Opin Org Effective control of rejection, with sive treatment of diabetes on the development Transplant 3:258–273, 1998 earlier diagnosis or better prevention, and progression of long-term complications in 11 insulin-dependent diabetes mellitus. N Engl J Fioretto P, Steffes MW, Sutherland DER, Goetz may soon permit solitary PTX to Med 329:977–986, 1993 FC, Mauer M: Reversal of lesions of diabetic become an accepted treatment option nephropathy after pancreas transplantation. N in diabetic patients without advanced 4Stratta RJ, Taylor RJ, Wahl TO, Duckworth Engl J Med 339:69–75, 1998 WC, Gallagher TF, Knight TF, Fischer JL, complications. Such a policy, if Neumann TV, Miller S, Langnas AN, Ozaki CF, applied correctly, might actually Bynon JS, Larsen JL, Weide LG, Cassling RS, reduce the number of diabetic patients Taylon AJ, Shaw BW Jr: Recipient selection and Acknowledgment requiring kidney transplantation in evaluation for vascularized pancreas transplanta- the future. tion. Transplantation 55:1090–1096, 1993 We gratefully acknowledge the exper- Other strategies for the treatment 5Sutherland DE, Gruessner RW, Dunn DL, tise of Joyce Lariviere in preparation of diabetes are being actively investi- Matas AJ, Humar A, Kandaswamy R, Mauer of this manuscript. gated, including islet cell and fetal SM, Kennedy WR, Goetz FC, Robertson RP, Gruessner AC, Najarian JS: Lessons learned pancreas transplants, gene therapy, from more than 1,000 pancreas transplants at a implantable insulin pumps, and bio- single institution. Ann Surg 233:463–501, 2001 M. Hosein Shokouh-Amiri, MD; Robert J. Stratta, MD; and Osama hybrid artificial pancreas units. 6 Hathaway DK, El-Gebely S, Cardoso S, Elmer Gaber, MD, are professors of surgery Although any or all of these comple- DS, Gaber AO: Autonomic cardiac dysfunction mentary methods may have a role in in diabetic transplant recipients succumbing to in the Department of Surgery the treatment of diabetes in the future, sudden cardiac death. Transplantation (Division of Transplantation), and it will be difficult for these alternative 59:634–637, 1995 Kashif A. Latif, MD, is a fellow in strategies to improve on the metabolic 7Cashion AK, Hathaway DK, Milstead EJ, Reed endocrinology and metabolism in the efficiency of the vascularized PTX L, Gaber AO: Changes in patterns of 24-hour Department of Medicine at the that is achieved at present. heart rate variability after kidney and kidney- University of Tennessee, in Memphis.

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