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Glucose Control During and After Pancreatic Transplantation

	Abstract

Top Abstract Introduction Recipient Selection Preoperative Preparations for... Intraoperative Monitoring Postoperative Management Assessment of the Transplanted... Discussion References

 
In Brief

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

	Introduction

Top Abstract Introduction Recipient Selection Preoperative Preparations for... Intraoperative Monitoring Postoperative Management Assessment of the Transplanted... Discussion References

 
After decades of controversy surrounding the therapeutic validity of pancreas transplantation (PTX), the procedure has become accepted as the preferred treatment for patients with insulin-requiring diabetes mellitus and advanced diabetic nephropathy. The trade-offs for normal glucose homeostasis are the operative risks of the transplant procedure and the need for chronic immunosuppression. Free islet grafts have the same potential but do not approach PTX in terms of consistency of results.

From December 1966 to October 2000, more than 15,000 PTX procedures were performed worldwide and reported to the International Pancreas Transplant Registry (IPTR).¹ In the past decade, the majority (82%) of PTX procedures have been performed in combination with a kidney transplant (simultaneous kidney-pancreas transplant [SKPT]) in patients with end-stage diabetic nephropathy. The current 1-year actuarial patient and kidney and pancreas (with complete insulin independence) graft survival rates after SKPT are 95, 92, and 84%, respectively.¹,² Solitary PTX procedures comprise the remaining activity, including either sequential pancreas-after-kidney transplants (PAKT, 12%) or transplant of pancreas alone (PA, 6%). The current 1-year patient survival rate after solitary PTX is 95%, and the 1-year actuarial pancreas graft survival rates are 72% for PAKT and 71% for PA.¹,²

The Diabetes Control and Complications Trial (DCCT) has clearly shown that improved glycemic control lowers the risk of secondary diabetic complications.³ However, intensive insulin therapy did not result in normalization of hemoglobin A_1c (HbA_1c) levels, was associated with a threefold increased risk of severe hypoglycemia, and was resource-intensive. The results of the DCCT provide a strong rationale for pancreas transplantation.

	Recipient Selection

Top Abstract Introduction Recipient Selection Preoperative Preparations for... Intraoperative Monitoring Postoperative Management Assessment of the Transplanted... Discussion References

 
Patient selection is aided by a comprehensive medical evaluation before transplantation (Tables 1 and 2) performed by a multidisciplinary team that confirms the diagnosis of diabetes, determines the patient’s ability to withstand the operative procedure, establishes the absence of any exclusion criteria (Table 3), and documents end-organ complications for future tracking after transplantation.⁴ The primary determinants for recipient selection are the presence of diabetic complications, degree of nephropathy, and cardiovascular risk (Table 1).

The cardiac status of each candidate must be assessed carefully because significant (and silent) coronary artery disease is not uncommon in this population. The cardiac evaluation consists of a noninvasive functional assessment, such as an exercise or a pharmacological stress test, in addition to echocardiography. Coronary angiography is reserved for specific indications such as age >45 years, diabetes for >25 years, a positive smoking history, long-standing hypertension, previous major amputation due to peripheral vascular disease, history of cerebrovascular disease, or cases in which the history, physical examination, or noninvasive cardiac studies reveal an abnormality.⁴

A history of previous myocardial infarction (MI), angioplasty, stenting, or coronary artery bypass grafting are not contraindications for PTX, as excellent outcomes have been reported in patients with previous cardiac interventions.⁵ However, sudden cardiac death, in the absence of significant structural heart disease, continues to be a major cause of cardiac mortality after PTX.⁶ For this reason, a number of centers are beginning to test cardiac autonomic function in these patients, using laboratory-evoked cardiovascular tests and 24-h heart-rate variability measurements.⁷ The new methodology may be able to detect alterations in autonomic function before the onset of disabling symptoms.

In general, age >65 years, heavy smoking, a left ventricular ejection fraction <30%, recent MI, and severe obesity (>150% ideal body weight or body mass index [BMI] >30 kg/m²) are usually viewed as contraindications for PTX (Table 3).⁴ Most patients <45 years of age are acceptable candidates for PTX provided that no significant coronary artery disease is present. Diabetic patients >45 years of age are not candidates until proven otherwise and need to undergo an extensive cardiovascular and peripheral vascular evaluation. Potential male recipients >100 kg and female recipients >80 kg, depending on their height and body habitus, have a higher rate of surgical complications after PTX. For this reason, a BMI >30 kg/m² is considered an absolute contraindication and BMI >27.5 kg/m² is a relative contraindication for solitary PTX.

	Preoperative Preparations for Pancreas Transplantation

Top Abstract Introduction Recipient Selection Preoperative Preparations for... Intraoperative Monitoring Postoperative Management Assessment of the Transplanted... Discussion References

 
Patients are allowed nothing by mouth once an organ becomes available. Patients’ blood glucose is checked every 2 h, and insulin is supplemented as needed to keep the blood glucose between 100 and 150 mg/dl. If blood glucose is labile, then an insulin infusion is started. This consists of a mixture of 250 units of regular insulin in 250 cc of 50% saline, with a final concentration of 1 unit of insulin/ml of infusion fluid. The initial basal rate is 0.2–0.3 unit/kg/h, which is then titrated with blood glucose determinations every 1–2 h to maintain the blood glucose in the range noted above according to the scale shown in Table 4.

	Intraoperative Monitoring

Top Abstract Introduction Recipient Selection Preoperative Preparations for... Intraoperative Monitoring Postoperative Management Assessment of the Transplanted... Discussion References

	Postoperative Management

Top Abstract Introduction Recipient Selection Preoperative Preparations for... Intraoperative Monitoring Postoperative Management Assessment of the Transplanted... Discussion References

 
Insulin therapy, as outlined in Table 4, can take one of two forms. The first involves instituting aggressive insulin therapy with the objective of "complete" insulin replacement to "rest" the ß-cells in the transplanted pancreas for the first few days following surgery. The second is to let the transplanted pancreas function as soon as blood supply is restored to the transplanted organ. Each of these approaches has its proponents. The advantages of each are discussed below.

Complete replacement
Some practitioners believe that providing complete replacement of insulin will "rest" the ß-cells in the transplanted pancreas and therefore preserve their function and avoid injury from acute stress. After 3–4 days of total insulin replacement, patients are switched to an intermittent regimen that only delivers insulin to maintain euglycemia, and the ß-cells take over the primary function of producing insulin.

The main disadvantage of this method is the inaccuracy that comes when precise protocols are not used to replace basal and bolus insulin. If doses are adjusted without allowing for the stress of surgery and insulin resistance that may develop from the use of immunosuppressants such as steroids and FK506, erratic blood glucose levels may result. Another disadvantage of this protocol is that the precise status of the function and viability of the transplanted organ is difficult to judge when insulin production is suppressed due to exogenous replacement. This could prevent assessment of compromised pancreatic function.

Replacement of insulin as needed
The authors, with years of experience in the field of pancreas transplantation, use a simple approach that allows the ß-cells to autoregulate their secretion in response to blood glucose. Our studies (by the use of C-peptide) indicate that such patients can produce enough insulin in the graft as soon as the blood supply is restored to the pancreas after the transplant.

We prefer this approach when the islets are producing the insulin for the host. The blood glucose is checked every 2 h, and exogenous insulin, if needed, is given every 2 h to maintain euglycemia. A sudden increase in insulin requirement is a red flag that the function of the graft is affected. In this case, immediate intervention needs to be undertaken to protect the grafted organ (see below).

A need for supplemental insulin in the early postoperative period can be expected because of the immunosuppressive medications, which can also cause insulin resistance. Once the dose of steroids is tapered, the need for additional coverage declines.

Postoperative hyperglycemia also responds very well to the newer classes of oral antidiabetic medications, such as the insulin sensitizers, as long as strict guidelines for the use of such medicines are followed. If the need for supplemental insulin is caused by inadequate production of insulin by the graft (determined by C-peptide assay) or because of its small size for the host, then oral agents, such as sulfonylureas, may be beneficial.

	Assessment of the Transplanted Organ

Top Abstract Introduction Recipient Selection Preoperative Preparations for... Intraoperative Monitoring Postoperative Management Assessment of the Transplanted... Discussion References

 
It is expected that from the time of pancreas allograft reperfusion, patients should become insulin-independent. Any abnormality of glycemic control should be investigated immediately, because some of the causes need immediate intervention in order to prevent graft loss. The usual causes of graft dysfunction are:

1. inadequate islet cell mass transplanted;
   
2. high doses of corticosteroid and FK506 in the peritransplant period;
   
3. allograft pancreatitis; or
   
4. technical problems with blood supply to the pancreas allograft.
   

Pancreas allograft function is monitored meticulously by both serum and drain fluid amylase, lipase, and frequent blood glucose measurement, and the need for exogenous insulin requirement. Any allograft dysfunction will warrant the following work-up:

1. Serum C-peptide measurement to assess ß-cell function. However, this assay is not immediately available at all facilities.
   
2. A Doppler ultrasonography of the allograft to verify the presence of flow to and from the allograft and the presence of fluid collection around the pancreas or swelling of the gland.
   
3. If the gland is difficult to visualize because of gas overlying the graft, a CT with contrast to demonstrate the viability of the allograft and/or the presence of pancreatitis. Radionucleotide study is of limited use.
   
4. An angiogram to demonstrate any blood flow problem to the allograft.
   

Patients are discharged 7–10 days after surgery, usually with no need for supplemental insulin. Thereafter, they are followed up by a team of specialists, including the transplant team, endocrinologist, clinical psychologist, and physiatrist. We believe the chance for best outcomes is enhanced with a team approach. However, one physician, usually the surgeon, has to be in charge.

	Discussion

Top Abstract Introduction Recipient Selection Preoperative Preparations for... Intraoperative Monitoring Postoperative Management Assessment of the Transplanted... Discussion References

 
Most PTX recipients find the transition to transplantation easier than continued insulin therapy. There is now compelling evidence that PTX is not only acutely life-enhancing, but also chronically life-saving.⁹ It is hoped that the beneficial changes in carbohydrate and lipid metabolism that occur early after PTX will translate into long-term improvements in diabetic end-organ complications and decrease the risk of atherosclerotic vascular disease.

In addition to correcting dysmetabolism and freeing patients from exogenous insulin therapy, data are emerging on the effects of PTX on the course of secondary complications.⁹,¹⁰ With regard to nephropathy,¹¹ preliminary evidence suggests that successful PA transplantation can induce regression of early, but not advanced, microscopic lesions of diabetic nephropathy and stabilize renal function, whereas successful PAKT can prevent the recurrence of diabetic nephropathy in a kidney transplant.

The progression of diabetic retinopathy appears to be less favorably influenced by a functioning PTX. However, with longer follow-up (more than 4 years), data are accumulating to suggest that retinopathy may be stabilized.

Peripheral and autonomic neuropathies improve or stabilize in most PTX recipients, which may actually translate into a survival advantage. Improvements in nerve conduction velocity, gastric function, cardiac function, and a beneficial effect on microcirculatory blood flow have been demonstrated.¹⁰ These effects may place patients at a lower overall risk for the development of peripheral ulcers or amputations.

There is also evidence that a functioning PTX may ablate the hyperlipidemic effects of immunosuppression and actually improve lipid metabolism over time. However, long-term studies are needed to fully document and characterize the effects of successful PTX on the diabetic condition.

Solitary PTX has assumed an increasingly important role in the treatment of diabetes and currently accounts for more than 20% of PTX activity in the United States. In the future, advances in immunosuppressive strategies and diagnostic technology will only enhance the already good results achieved with solitary PTX. Further documentation of the long-term benefits and effects of PTX may lead to wider availability and acceptance, particularly from a reimbursement standpoint.

Effective control of rejection, with earlier diagnosis or better prevention, may soon permit solitary PTX to become an accepted treatment option in diabetic patients without advanced complications. Such a policy, if applied correctly, might actually reduce the number of diabetic patients requiring kidney transplantation in the future.

Other strategies for the treatment of diabetes are being actively investigated, including islet cell and fetal pancreas transplants, gene therapy, implantable insulin pumps, and biohybrid artificial pancreas units. Although any or all of these complementary methods may have a role in the treatment of diabetes in the future, it will be difficult for these alternative strategies to improve on the metabolic efficiency of the vascularized PTX that is achieved at present.

	Acknowledgments

 
We gratefully acknowledge the expertise of Joyce Lariviere in preparation of this manuscript.

	Footnotes

 
M. Hosein Shokouh-Amiri, MD; Robert J. Stratta, MD; and Osama Gaber, MD, are professors of surgery in the Department of Surgery (Division of Transplantation), and Kashif A. Latif, MD, is a fellow in endocrinology and metabolism in the Department of Medicine at the University of Tennessee, in Memphis.

	References

Top Abstract Introduction Recipient Selection Preoperative Preparations for... Intraoperative Monitoring Postoperative Management Assessment of the Transplanted... Discussion References

 

¹ Sutherland DER, Gruessner AC: International Pancreas Transplant Registry Update. IPTR Newsletter 12:1–23, 2000

² Gruessner AC, Sutherland DER: Pancreas transplant outcomes for United States cases reported to the United Network for Organ Sharing (UNOS) and non-U.S. cases reported to the International Pancreas Transplant Registry (IPTR) as of October 2000. In Clinical Transplants 2000. Cecka JM, Terasaki PI, Eds. Los Angeles, UCLA Immunogenetics Center, 2001, p. 45–72

³ The DCCT Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986, 1993[Abstract/Free Full Text]

⁴ Stratta RJ, Taylor RJ, Wahl TO, Duckworth WC, Gallagher TF, Knight TF, Fischer JL, Neumann TV, Miller S, Langnas AN, Ozaki CF, Bynon JS, Larsen JL, Weide LG, Cassling RS, Taylon AJ, Shaw BW Jr: Recipient selection and evaluation for vascularized pancreas transplantation. Transplantation 55:1090–1096, 1993[Medline]

⁵ Sutherland DE, Gruessner RW, Dunn DL, Matas AJ, Humar A, Kandaswamy R, Mauer SM, Kennedy WR, Goetz FC, Robertson RP, Gruessner AC, Najarian JS: Lessons learned from more than 1,000 pancreas transplants at a single institution. Ann Surg 233:463–501, 2001[Medline]

⁶ Hathaway DK, El-Gebely S, Cardoso S, Elmer DS, Gaber AO: Autonomic cardiac dysfunction in diabetic transplant recipients succumbing to sudden cardiac death. Transplantation 59:634–637, 1995[Medline]

⁷ Cashion AK, Hathaway DK, Milstead EJ, Reed L, Gaber AO: Changes in patterns of 24-hour heart rate variability after kidney and kidney-pancreas transplant. Transplantation 68:1846–1850, 1999[Medline]

⁸ Gaber AO, Shokouh-Amiri MH, Hathaway DK, Gaber LW, Elmer D, Kitabchi AE, Stentz F. Pancreas transplantation with portal venous and enteric drainage eliminates hypertension and reduces postoperative complications. Transplant Proc 25:1176–1178, 1993[Medline]

⁹ Stratta RJ: Pancreas transplantation: long-term aspects and effect on quality of life. In Pancreatic Transplantation. Hakim NS, Stratta RJ, Gray DWR, Eds. Oxford, U.K., Oxford University Press. In press

¹⁰ Stratta RJ: Impact of pancreas transplantation on complications of diabetes. Curr Opin Org Transplant 3:258–273, 1998

¹¹ Fioretto P, Steffes MW, Sutherland DER, Goetz FC, Mauer M: Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 339:69–75, 1998[Abstract/Free Full Text]

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Shokouh-Amiri, M. H. Articles by Gaber, O. Search for Related Content PubMed Articles by Shokouh-Amiri, M. H. Articles by Gaber, O. Social Bookmarking                What's this?