OJAnesOpen Journal of Anesthesiology2164-5531Scientific Research Publishing10.4236/ojanes.2021.114009OJAnes-108258ArticlesMedicine&Healthcare Calcineurin Inhibitor Use and Myoclonus Association. Is There a Clinical Implication? RicardoE. Verdiner1*RubenCasado Arroyo2MohammadRauf Chaudhry3NarjeetKhurmi1KarlPoterack1AndyGorlin1ArunJayaraman1GustavoRodriguez4Department of Anesthesiology, Mayo Clinic Arizona, Phoenix, USADepartment of Medicine, Universite Libre de Bruxelles, Brussels, BelgiumDepartment of Neurology, Texas Tech University, Health Science Center of El Paso, Lubbock, USADepartment of Neurology, Texas Tech University, Lubbock, USA020420211104859826, February 20213, April 2021 6, April 2021© Copyright 2014 by authors and Scientific Research Publishing Inc. 2014This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

Background: Calcineurin Inhibitors (CNIs) play a pivotal role in anti rejection therapy for transplant patients. Neurotoxicity is a known side effect that usually manifests as encephalopathy but myoclonus has also been described. Perioperative myoclonus as a manifestation of neurotoxicity, has not been well studied. Methods: We retrospectively reviewed data from 842,762 patients from the Nationwide Inpatient Sample (NIS) database from January 2011 to December 2014. Of those records we compared 56,423 patients requiring CNIs and undergoing Heart Transplant (HT) with 786,339 patients undergoing Coronary Artery Bypass Graft (CABG) surgery as controls. The objective was to study the rates of myoclonus in patients undergoing cardiac surgery, especially those requiring CNIs, and study the outcome of those patients with myoclonus. The NIS database from January 2011 to December 2014 was the source for the analysis. Patients with underlying epilepsy or hypo-ischemic encephalopathy based on ICD-9-CM codes were excluded from the study. Results: A total of 147 patients (0.26%) were found to have myoclonus in the HT group versus 338 patients (0.04%) in the CABG group, p < 0.0001. No differences in the demographics were seen except for kidney disease which was higher in the HT group. The difference remained statistically significant after adjusting for confounders. Patients with myoclonus in both groups were more likely to have acute kidney injury and have a prolonged length of stay. Only patients with myoclonus in the CABG group had higher rates of discharge disposition to a nursing home and higher rates of in-Hospital mortality. A trend towards higher in-Hospital mortality was found in patients with myoclonus in the HT group. Conclusion: In this study we have compared the rate of myoclonus found in HT patients versus CABG patients. We have identified calcineurin inhibitors as potentially contributing to myoclonus due to its neurotoxic effects. The study also suggests that other disease processes like renal failure may also have an impact on the rate of myoclonus even in the absence of calcineurin inhibitors. Higher rates of myoclonus were seen in patients undergoing HT when compared to patients undergoing CABG, suggesting that CNIs may increase the risk for myoclonus. Myoclonus may be a clinical indicator of patient overall health including a more permeable blood brain barrier. In-Hospital mortality was higher in patients with myoclonus undergoing CABG and a trend towards significance in the HT group suggesting that it may be a marker of poor prognosis. More studies are needed to corroborate our findings.

Calcineurin Inhibitors Myoclonus Neurotoxicity Perioperative Mortality Renal Failure Tacrolimus Mycophenolate Endothelial Health Blood Brain Barrier1. Introduction

Movement disorders like tremors and less commonly myoclonus have been reported as adverse reactions of several classes of drugs. Myoclonus is clinically described as a sudden shock-like contraction of a muscle or group of muscles. Myoclonus can further be divided into physiologic and pathologic. Physiologic myoclonus is benign and often seen while falling asleep (hypnic myoclonus) or causing hiccupps (diaphragmatic myoclonus). Pathologic myoclonus can be categorized by three main causes: 1) hypoxia 2) drug toxicity and 3) metabolic disturbances [1].

Drug associated myoclonus usually resolves when the causative drug is removed [2]. For example, anesthetic agents have been described as a cause of myoclonus. In a 2017 study by Jansen et al., drugs associated with inducing/maintaining general anesthesia were the seventh most common drug class to cause myoclonus. Anesthetic agents, however, have a short term exposure to the patient as opposed to the anti-organ rejection drug class, which are a part of the long term management of transplanted patients. The CNI class includes cyclosporin and tacrolimus. Historically, they have been linked to neurotoxicity usually manifested as encephalopathy but myoclonus has also been reported [3] - [8]. Reactions like myoclonus are typically categorized as mild and acceptable given the life-extending outcome the drug is expected to provide [9]. Nevertheless, the association between antirejection drugs and perioperative myoclonus may have long term clinical implications. We sought to quantify the prevalence of myoclonus in heart transplant patients and its clinical relevance using a national dataset.

2. Methods2.1. Data Source and Cleansing

The United States Nationwide Inpatient Sample (NIS) is the largest all-payer inpatient care database designed to represent a 20% stratified sample of US hospitals or approximately 5 - 8 million hospital stays using data from approximately 1000 hospitals. The NIS has been used in various studies to identify, track, and analyze national trends in healthcare utilization, access, charges, quality, and outcomes [10]. Given the size of the database, it was the preferred source for this study. More details on the design of the NIS are available at http://www.hcup-us.ahrq.gov.

The NIS database from 1 January 2011 to 31 December 2014 was used to analyze data from 842,762 patients. To avoid double representation, patients whose disposition or admission type indicated a transfer to or from another short-term hospital were excluded. Patients with a hospital charge of less than $100 were likely coded incorrectly and were also excluded from the analysis. Similarly, patients with a negative LOS or LOS exceeding 365 days were eliminated from the dataset [11].

The International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM) procedure code V42.1 was used to identify the 56,423 patients admitted for heart transplant. This approach has been used previously to estimate in-hospital mortality related to heart transplant in a large sample in the United States [12]. 786,339 patients admitted for CABG surgery were selected as the control group, using the ICD-9-CM procedure codes: 36.10, 36.11, 36.12, 36.13, 36.14, 36.15 and 36.16 [13]. Patients who developed myoclonus during the same hospitalization were determined using ICD-9-CM diagnosis code: 333.2. The presence of underlying epilepsy or hypo-ischemic encephalopathy was determined using ICD-9-CM diagnosis codes 345.0x-345.5x, 345.7x-345.9x, 780.39 and 768.70, respectively and were removed from the study cohort.

2.2. Variables

The variables obtained for this study were: age, sex, and medical comorbidities i.e., hypertension (HTN), diabetes mellitus, coagulopathy, chronic lung disease, and renal failure [10] [14]. This information came from the Agency for Health Research and Quality comorbidity data files. Medical co-morbidities, i.e. dyslipidemia, and atrial fibrillation (Afib) were determined by using the ICD-9CM secondary diagnosis codes (272.40), and (427.31) respectively. ICD-9 secondary codes were used to identify in-hospital complications such as acute kidney injury (584.9, 39.95, 54.98), pneumonia (486, 481, 482.8, and 482.3), urinary tract infection (590.0, 590.9), and sepsis (995.91, 995.92, 996.64, 038, and 999.3). The length of stay, discharge disposition, and in-hospital mortality were determined using the variables ‘‘LOS”, “DISPUNIFORM”, and ‘‘died’’ from Agency for Health Research and Quality comorbidity data files. Prolonged length of stay (PLOS) was defined as length of stay more than 7 days.

2.3. Outcomes

The outcomes of interest were prolonged length of stay greater than seven days, discharge disposition of alive patients to a nursing home and in-hospital mortality.

2.4. Statistical Analysis

The SAS 9.4 software (SAS Institute, Cary, NC) was used to convert NIS database data into weighted counts to generate national estimates, following Healthcare Cost and Utilization Project recommendations. Univariate analysis, Chi-square for categorical, and Analysis of variance (ANOVA) test for continuous variables were performed to identify differences in study variables and outcome endpoints. A statistically significant p-value was considered if <0.05.

This study was exempted from approval by the Texas Tech University Health Sciences Center El Paso Institutional Review Board as NIS is a public database with no personal identifying information.

3. Results

A total of 56,423 patients underwent HT during the study period of which 147 (0.26%) patients had myoclonus while 786,339 patients underwent CABG of which 338 (0.04%) had myoclonus {p < 0.0001}. Two medical comorbidities were different between the two groups in the univariate analysis. A total of 9 patients (6.5%) in the HT + myoclonus group had atrial fibrillation and 131 patients (38.8%) in the CABG + myoclonus group {p < 0.0001}. 94 (64%) patients in the HT + myoclonus group had renal failure and 96 (28.4%) patients in the CABG + myoclonus group {p = 0.0002}. When comorbidities were adjusted for in the data set, the higher rates of myoclonus in the HT group remained statistically significant with a 5-fold difference observed, Table 1 & Table 2.

Patients with myoclonus in both groups had higher complications rates of acute kidney injury compared to patients without myoclonus in their respective groups, Table 3 & Table 4. Similarly, patients with myoclonus in both groups had higher prolonged length of stay compared to patients without myoclonus. Patients in the CABG + myoclonus group had higher discharge disposition of alive patients to nursing home and higher In-Hospital mortality rates than patients without myoclonus, {p = 0.002 and p = 002}. This was not true for patients in the HT + myoclonus group, however there was a trend towards a statistically significant difference for higher in-Hospital mortality {p = 0.08}, Table 5. All data regarding prolonged length of stay, discharge disposition of alive patient to a nursing home and in-hospital mortality were collected from the NIS database.

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