key: cord-0885277-n0xktyyf
authors: Do, Vincent; Haakinson, Danielle; Belfort De Aguiar, Renata; Cohen, Elizabeth
title: Implementing a pharmacist-led transition of care model for posttransplant hyperglycemia
date: 2021-04-04
journal: Am J Health Syst Pharm
DOI: 10.1093/ajhp/zxab151
sha: 14847c84d1d6a94f1271f4c72942befce892b415
doc_id: 885277
cord_uid: n0xktyyf

DISCLAIMER: In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: The implementation of a pharmacist-managed transition of care program for kidney transplant recipients with posttransplant hyperglycemia (PTHG) is described. METHODS: In September 2015, a collaborative practice agreement between pharmacists and transplant providers at an academic medical center for management of PTHG was developed. The goal of the pharmacist-run service was to reduce hospitalizations by providing care to patients in the acute phase of hyperglycemia while they transitioned back to their primary care provider or endocrinologist. For continuous quality improvement, preimplementation data were collected from August 2014 to August 2015 and compared to postimplementation data collected from August 2017 to August 2018. The primary endpoint was hospitalizations due to hyperglycemia within 90 days post transplantation. Secondary endpoints included emergency department (ED) visits due to hypoglycemia and the number of interventions performed, number of encounters completed, and number of ED visits or admissions for hypoglycemia. A Fisher’s exact test was used to compare categorical data, and a Student t test was used to compare continuous data. A P value of <0.05 was considered to be statistically significant. RESULTS: Forty-three patients in the preimplementation group were compared to 35 patients in the postimplementation group. There was a significant reduction in hospitalizations due to hyperglycemia in the postimplementation versus the preimplementation group (9 vs 1, P < 0.05); there was a reduction in ED visits due to hyperglycemia (5 vs 0, P = 0.06). There were no ED visits or hospitalizations due to hypoglycemia in either group. Clinical transplant pharmacists performed an average of 8.3 (SD, 4.4) encounters per patient per 90 days. CONCLUSION: A collaborative practice agreement was created and successfully implemented. A pharmacist-managed PTHG program could be incorporated into the standard care of kidney transplant recipients to help minimize rehospitalizations due to hyperglycemia.

A c c e p t e d M a n u s c r i p t Am J Health-Syst Pharm. 2021;78(x):xxx-xxx Up to 90% of kidney transplant recipients (KTRs) can experience posttransplant hyperglycemia (PTHG). 1 This high incidence is attributable to both previously diagnosed and newly diagnosed diabetes. The development of PTHG within the first few weeks after transplant surgery has a strong association with the development of posttransplant diabetes mellitus (PTDM), 2 with 7% to 30% of nondiabetic KTRs developing PTDM in the first posttransplant year. [3] [4] Alternatively, many patients' hyperglycemia does not persist beyond the immediate posttransplant phase. Therefore, intensive glucose monitoring and management is necessary in the early period after a kidney transplant. In 2014, the Yale New Haven Transplant Center (YNHTC) observed a high frequency of rehospitalizations due to PTHG in KTRs before patients had been transitioned to a diabetes care provider. As a way to improve management of PTHG, YNHTC reviewed its current management of PTHG and developed a program to allow for improvement.

The immediate posttransplant care of patients with PTHG can be a challenge. After kidney transplantation, patients experience various transplant-specific factors that increase their risk of developing PTHG. Induction therapy with high-dose glucocorticoids increases glucose transporter type 4 presentation on skeletal muscle, primarily impacting postprandial glucose storage while promoting catabolism of proteins, lipolysis, and gluconeogenesis. 5 For maintenance immunosuppression, tacrolimus has various metabolic effects that predispose patients to diabetes, including reducing insulin secretion due to the destruction of pancreatic β-cell mass and increased islet apoptosis. 6 Patients also undergo physiologic A c c e p t e d M a n u s c r i p t changes. Patients with end-stage renal disease (ESRD) who have a glomerular filtration rate (GFR) that falls below 15 to 20 mL/min/1.73 m 2 have a notable decrease in insulin clearance.

Hepatic insulin metabolism declines due to the accumulation of uremic toxins. [7] [8] After kidney transplantation, improvement in GFR (which may be unpredictable, especially in those with delayed graft function) eliminates many of these abnormalities, resulting in worsened control of preexisting diabetes or prediabetes. All these factors combined have a negative impact on glucose metabolism, resulting in a high incidence of PTHG.

Furthermore, initiation and monitoring of antihyperglycemic medications may lead to delayed discharges or readmissions due to inadequate monitoring or therapy. [9] [10] [11] Issues with transitions of care in the general population have been well established in the literature, including the need for improved communication between providers, patient education, and outpatient follow-up post discharge. 12 One in 3 adults may not see a physician, nurse practitioner, or physician assistant in 30 days following discharge.

Additionally, patients who see a physician after discharge have a lower risk of rehospitalization. 13 Although transplant providers will follow patients closely after discharge, involvement of other specialists and primary care providers remains warranted. 14 In addition, posttransplant readmissions are costly and are associated with morbidity and mortality. A study showed that post-kidney transplant patients had a 6-fold increase in hospitalizations at 5 years compared to the general population. 15 These hospitalizations, especially during the early posttransplant period, are associated with longer lengths of stay and greater hospitalization charges. 16 Many studies have also suggested that posttransplant hospitalization costs sometimes exceed the cost of the transplant itself. [17] [18] The American Diabetes Association (ADA) recommends an outpatient follow-up visit with a primary care provider, endocrinologist, or diabetes educator within 1 month of A c c e p t e d M a n u s c r i p t discharge if patients are stable and have hyperglycemia as an inpatient, or an appointment in 1 to 2 weeks if the antihyperglycemic regimen has been changed. 19 This is a challenge, as patients with controlled diabetes or prediabetes may no longer be under the care of their previous endocrinologist or primary care provider. With increasing primary care physician workloads, physicians typically spend a small percentage of their time on diabetes care. One study reported that an average of 5 minutes is spent discussing diabetes management out of a 25-minute visit in a primary care clinic. 20 These challenges prevent the establishment of care in a time-effective manner and create a window where patients are at high risk for hyperglycemia and/or hypoglycemia, resulting in inadequate diabetes management and potentially poor outcomes.

YNHTC performs an average of 150 kidney transplants annually. YNHTC's immunosuppression protocol allows patients to receive induction therapy with rabbit antithymocyte globulin, alemtuzumab, or basiliximab, depending on sensitization and risk of rejection. Methylprednisolone is initiated at a dose of 500 mg on postoperative day 0, with rapid reduction of the glucocorticoid dose to 10 mg of prednisone by postoperative day 5.

Patients remain on prednisone for life unless they are greater than 65 years of age with low sensitization. Other immunosuppression therapies include tacrolimus and mycophenolate mofetil. Prior to implementation of the pharmacist-managed PTHG program described here, transplant nephrologists and/or advanced-practice registered nurses were managing patients with PTHG until patients could be transitioned to the YNHTC endocrinologist, a primary care provider, or an outside endocrinologist.

In 2014, YNHTC identified that a clinical transplant pharmacist could be an appropriate resource to ensure adequate transitions of care during this high-risk period because they were an available resource already well integrated into both the inpatient and A c c e p t e d M a n u s c r i p t outpatient transplant settings and able to provide continuity of care after hospital discharge. The purpose of this article is to describe our practice model and use of a collaborative practice agreement between transplant providers and pharmacists, including the planning, implementation, and quality assessment stages. were not recommended. Since many posttransplant patients experience postprandial hyperglycemia due to use of steroids, DPP-4 inhibitors are an ideal choice because they are oral medications whose use can result in postprandial glucose reductions, they pose a limited risk of hypoglycemia, and they have possible protective effects on beta islet cell function. 22-24 Linagliptin was preferred over sitagliptin due to its lack of renal-dependent clearance. Sulfonylureas were used if patients were not controlled on DPP-4 inhibitors ( Figure 1 ). Glipizide was preferred because it is metabolized by the liver into several inactive metabolites. As a result, although glipizide is renally cleared, dose adjustments are not required in patients with poor renal function. 25 Thiazolidinediones were not preferred due to the associated risks of weight gain, potential worsening of heart failure, and osteoporosis. 26 Sodium/glucose cotransporter 2 (SGLT-2) inhibitors were not indicated for use in the target population due to concern for increased risk of urinary tract infections and Patients who were on noninsulin antihyperglycemic agents were asked to determine their BG level once to twice daily, while those on insulin were asked to test 3 to 4 times daily. Patients were instructed to keep a BG diary to allow for efficient visits with the A c c e p t e d M a n u s c r i p t pharmacy team. At each pharmacy visit, patients relayed their BG values, allowing for dose adjustments as indicated.

In patients with significantly elevated BG levels (>250 mg/dL), clinical transplant pharmacists screened for signs or symptoms of diabetic ketoacidosis (DKA) or hyperglycemic hyperosmolar syndrome (HHS) and escalated to the transplant coordinator, nephrologist, or endocrinologist, as indicated, for further evaluation and triage. Insulin doses were increased per protocol in patients who did not require referral to another provider. In patients with hypoglycemia, contributing factors were evaluated and changes to therapy were completed.

Patients were discontinued from antihyperglycemic therapy if clinical transplant pharmacists identified that the course of hyperglycemia was transient. In patients who were within the lower range of the goal BG value and required less than 20 units of insulin a day, weekly reductions were done to attempt to remove standing insulin and reassess insulin requirements based on a sliding scale. Insulin bolus doses were reduced prior to reduction of basal insulin unless patients were experiencing significant nocturnal or morning hypoglycemia. Depending on patient response, patients' insulin doses were uptitrated, they were transitioned to noninsulin therapies, or antihyperglycemic agents were discontinued.

In patients who were within the goal BG range on oral antihyperglycemic agents, attempts were made to switch from multiple agents to a single agent or to discontinue single agents with close self-monitoring. A Fisher's exact test was used to compare categorical data, and a Student t test was used to compare continuous data. A P value of <0.05 was considered to be statistically significant.

A c c e p t e d M a n u s c r i p t

During the preimplementation timeframe, there were 103 KTRs, and 43 of those patients met the inclusion criteria. In the intervention timeframe, there were 120 KTRs, and 47 patients met inclusion criteria. No patients received multiple kidney transplants during the timeframe. Eleven patients were not screened appropriately for follow-up by pharmacy services, and 1 patient was managed by insulin pump therapy and therefore was not followed by transplant pharmacy personnel. As a result, 35 patients were followed by clinical transplant pharmacists for PTHG management and were therefore included in the analysis ( Figure 4) . Baseline characteristics were similar in the pre-and postimplementation groups (Table 1) .

There was a significant reduction in hospitalizations due to hyperglycemia in the postimplementation period versus the preimplementation period (1 vs 9 hospitalizations, P < 0.05); there was also a reduction in ED visits due to hyperglycemia (0 vs 5, P = 0.06). There were no episodes of admissions or ED visits due to hypoglycemia in either group. Table 2 .

Clinical transplant pharmacists have been continuously expanding their role in the inpatient and outpatient settings from improving medication adherence rates to participating in therapeutic drug monitoring. 28 Through an extensive literature review Eleven patients were not appropriately screened for referral to clinical transplant pharmacist services for PTHG management, which might have been due to the lack of an automated screening process, the lack of a standardized referral process, and/or unfamiliarity with a new program. None of these 11 patients were rehospitalized for hyperglycemia. Nine of the 11 patients were not discharged on antihyperglycemic agents or BG self-monitoring, which might suggest that these patients had limited hyperglycemia and did not need follow-up by pharmacy services. We are currently working to improve this process through EMR optimization to avoid missed opportunities for pharmacist-led posttransplant diabetes management.

Our pre-post study had several limitations. The retrospective nature of the study limited data collection to information available in the EMR, thereby excluding interventions by out-of-network providers as well as hospitalizations or ED visits that may have occurred outside of the transplant center's health system. However, at our institution all KTRs are cared for by our transplant center in the first year post transplant surgery, ensuring a high A c c e p t e d M a n u s c r i p t likelihood of data capture. Additionally, due to the retrospective nature of the review, selfmonitored BG values around the time of a pharmacy encounter were not captured and reviewed. Since this review, we have improved our standardized note template to include documentation of these values.

Currently, pharmacists perform weekly patient follow-up to allow for timely dose adjustments of oral antihyperglycemic agents and insulin products and re-education when required. This can be a lengthy process, as each visit is scheduled for at least 15 minutes but can be longer depending on the complexity of the patient. Institutions may not have the available workforce for this intensive service. However, our institution believes that with the reduction in hospitalizations, the pharmacists' time spent is justifiable.

Implementation of clinical transplant pharmacist-led service to manage PTHG may result in a decrease in hospitalizations due to hyperglycemia.

A c c e p t e d M a n u s c r i p t

The authors have declared no potential conflicts of interest.

Dr. Do developed the project, researched data, and wrote the manuscript. Dr. Haakinson, Dr. Cohen, and Dr. Belfort De Aguiar developed the project, contributed to the discussion, and reviewed and/or edited the manuscript. Dr. Do is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. M a n u s c r i p t A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t Initial In patients unable to check BG three times daily or prefer/require less injections, mixed insulins (e.g. NPH/regular 70/30) may be used as a substitute.

To convert from a basal/bolus to mixed insulin: calculate total daily dose of insulin from all sources. Reduce dose by 10-20% if the patient is at high risk for hypoglycemia (patient is controlled). Divide the amount evenly into two doses.

A c c e p t e d M a n u s c r i p t Adjust accordingly if patient has TWO glucose levels not at target 

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