Browsing by Author "Sadhasivam, Senthilkumar"
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Item Bayesian modeling to predict malignant hyperthermia susceptibility and pathogenicity of RYR1, CACNA1S and STAC3 variants(Future Medicine, 2019-09-27) Sadhasivam, Senthilkumar; Henker, Richard A.; Brandom, Barbara W.; McAuliffe, John J.; Anesthesia, School of MedicineAim: Identify variants in RYR1, CACNA1S and STAC3, and predict malignant hyperthermia (MH) pathogenicity using Bayesian statistics in individuals clinically treated as MH susceptible (MHS). Materials & methods: Whole exome sequencing including RYR1, CACNA1S and STAC3 performed on 64 subjects with: MHS; suspected MH event or first-degree relative; and MH negative. Variant pathogenicity was estimated using in silico analysis, allele frequency and prior data to calculate Bayesian posterior probabilities. Results: Bayesian statistics predicted CACNA1S variant p.Thr1009Lys and RYR1 variants p.Ser1728Phe and p.Leu4824Pro are likely pathogenic, and novel STAC3 variant p.Met187Thr has uncertain significance. Nearly a third of MHS subjects had only benign variants. Conclusion: Bayesian method provides new approach to predict MH pathogenicity of genetic variants.Item Considerations for the Utility of the CPIC Guideline for CYP2D6 Genotype and Codeine Therapy(Oxford University Press, 2015-05) Crews, Kristine R.; Caudle, Kelly E.; Dunnenberger, Henry M.; Sadhasivam, Senthilkumar; Skaar, Todd C.Item The effect of a one-time 15-minute guided meditation (Isha Kriya) on stress and mood disturbances among operating room professionals: a prospective interventional pilot study(F1000Research, 2019-03-26) Rangasamy, Valluvan; Thampi Susheela, Ammu; Mueller, Ariel; F. H. Chang, Tracy; Sadhasivam, Senthilkumar; Subramaniam, Balachundhar; Anesthesia, School of MedicineBackground: Operating room professionals are exposed to high levels of stress and burnout. Besides affecting the individual, it can compromise patient safety and quality of care as well. Meditation practice is getting recognized for its ability to improve wellness among various populations, including healthcare providers. Methods: Baseline stress levels of perioperative healthcare providers were measured via an online survey using a Perceived Stress Scale (PSS) questionnaire. An in-person meditation workshop was demonstrated during surgical grand rounds and an international anesthesia conference using a 15-minute guided Isha Kriya meditation. The participants were then surveyed for mood changes before and after meditation using a Profile of Mood States (POMS) questionnaire. Results: Surgeons and anesthesiologists were found to have higher median (interquartile range) Perceived Stress Scores as compared to nurses respectively (17 [12, 20] and 17 [12, 21] vs 14 [9, 19]; P = 0.01). Total mood disturbances were found to be significantly reduced after meditation in both the surgical grand rounds (pre-meditation median [IQR] 99 [85, 112] vs 87 [80, 93] post-meditation; P < 0.0001) and anesthesia conference cohorts (pre-meditation 92 [86, 106] vs 87 [81, 92] post-meditation; P < 0.0001). Conclusions: Isha Kriya, a guided meditation, is easy to learn and takes less than 15 minutes to complete. This meditation technique improves mood changes and negative emotions among operating room professionals and could be used as a potential tool for improving wellness.Item Gender, genetics, and analgesia: understanding the differences in response to pain relief(Dovepress, 2018-11-08) Packiasabapathy, Senthil; Sadhasivam, Senthilkumar; Anesthesia, School of MedicineGenetic variations and gender contribute significantly to the large interpatient variations in opioid-related serious adverse effects and differences in pain relief with other analgesics. Opioids are the most commonly used analgesics to relieve moderate-to-severe postoperative pain. Narrow therapeutic index and unexplained large interpatient variations in opioid-related serious adverse effects and analgesia negatively affect optimal perioperative outcomes. In surgical, experimental, chronic, and neuropathic pain models, females have been reported to have more pain than males. This review focuses on literature evidence of differences in pain relief due to multiple genetic variations and gender of the patient.Item Genetics of perioperative pain management(Lippincott, Williams & Wilkins, 2018-12) Packiasabapathy, Senthil; Horn, Nicole; Sadhasivam, Senthilkumar; Anesthesia, School of MedicinePURPOSE OF REVIEW: The current review will discuss the current literature on genetics of pain and analgesia, with special emphasis on perioperative setting. We will also discuss pharmacogenetics-based management guidelines, current clinical status and future perspectives. RECENT FINDINGS: Recent literature suggests that the interindividual variability in pain and postoperative analgesic response is at least in part because of one's genetic make-up. Some of the well characterized polymorphisms that are associated with surgical pain and opioid-related postoperative adverse outcomes are described in catechol-O-methyl transferase, CYP2D6 and μ-opioid receptor (OPRM1), ATP-binding cassette subfamily B member 1, ABCC3, organic cation transporter 1 genes. Clinical Pharmacogenetics Implementation Consortium has put forth recommendations on CYP2D6 genotype-based opioid selection and dosing. The list of drug-gene pairs studied continue to expand. SUMMARY: Pharmacogenetic approach marks the dawn of personalized pain medicine both in perioperative and chronic pain settings.Item Inner Engineering Practices and Advanced 4-day Isha Yoga Retreat Are Associated with Cannabimimetic Effects with Increased Endocannabinoids and Short-Term and Sustained Improvement in Mental Health: A Prospective Observational Study of Meditators(Hindawi, 2020-06-05) Sadhasivam, Senthilkumar; Alankar, Suresh; Maturi, Raj; Vishnubhotla, Ramana V.; Mudigonda, Mayur; Pawale, Dhanashri; Narayanan, Santhosshi; Hariri, Sepideh; Ram, Chithra; Chang, Tracy; Renschler, Janelle; Eckert, George; Subramaniam, Balachundhar; Anesthesia, School of MedicineBackground Anxiety and depression are common in the modern world, and there is growing demand for alternative therapies such as meditation. Meditation can decrease perceived stress and increase general well-being, although the physiological mechanism is not well-characterized. Endocannabinoids (eCBs), lipid mediators associated with enhanced mood and reduced anxiety/depression, have not been previously studied as biomarkers of meditation effects. Our aim was to assess biomarkers (eCBs and brain-derived neurotrophic factor [BDNF]) and psychological parameters after a meditation retreat. Methods This was an observational pilot study of adults before and after the 4-day Isha Yoga Bhava Spandana Program retreat. Participants completed online surveys (before and after retreat, and 1 month later) to assess anxiety, depression, focus, well-being, and happiness through validated psychological scales. Voluntary blood sampling for biomarker studies was done before and within a day after the retreat. The biomarkers anandamide, 2-arachidonoylglycerol (2-AG), 1-arachidonoylglycerol (1-AG), docosatetraenoylethanolamide (DEA), oleoylethanolamide (OLA), and BDNF were evaluated. Primary outcomes were changes in psychological scales, as well as changes in eCBs and BDNF. Results Depression and anxiety scores decreased while focus, happiness, and positive well-being scores increased immediately after retreat from their baseline values (P < 0.001). All improvements were sustained 1 month after BSP. All major eCBs including anandamide, 2-AG, 1-AG, DEA, and BDNF increased after meditation by > 70% (P < 0.001). Increases of ≥20% in anandamide, 2-AG, 1-AG, and total AG levels after meditation from the baseline had weak correlations with changes in happiness and well-being. Conclusions A short meditation experience improved focus, happiness, and positive well-being and reduced depression and anxiety in participants for at least 1 month. Participants had increased blood eCBs and BDNF, suggesting a role for these biomarkers in the underlying mechanism of meditation. Meditation is a simple, organic, and effective way to improve well-being and reduce depression and anxiety.Item Methadone-based Multimodal Analgesia Provides the Best-in-class Acute Surgical Pain Control and Functional Outcomes With Lower Opioid Use Following Major Posterior Fusion Surgery in Adolescents With Idiopathic Scoliosis(Wolters Kluwer, 2020-07-27) Ye, Jian; Myung, Karen; Packiasabapathy, Senthil; Yu, Jeffrey S.; Jacobson, Joseph E.; Whittaker, Stephanie C.; Castelluccio, Peter; Drayton Jackson, Meghan; Sadhasivam, Senthilkumar; Anesthesia, School of MedicineIntroduction: Posterior spinal fusion for idiopathic scoliosis is extremely painful, with no superior single analgesic modality. We introduced a methadone-based multimodal analgesia protocol, aiming to decrease the length of hospital stay (LOS), improve pain control, and decrease the need for additional opioids. Methods: We analyzed 122 idiopathic scoliosis patients with posterior instrumented spinal fusion. They were matched by age, sex, surgeon, and the number of levels fused before and after the implementation of the new protocol. This analysis included 61 controls (intrathecal morphine, gabapentin, intravenous opioids, and adjuncts) and 61 patients on the new protocol (scheduled methadone, methocarbamol, ketorolac/ibuprofen, acetaminophen, and oxycodone with intravenous opioids as needed). The primary outcome was LOS. Secondary outcomes included pain scores, total opioid use (morphine milligram equivalents), time to a first bowel movement, and postdischarge phone calls. Results: New protocol patients were discharged earlier (median LOS, 2 days) compared with control patients (3 days; P < 0.001). Total inpatient morphine consumption was lower in the protocol group (P < 0.001). Pain scores were higher in the protocol group on the day of surgery, similar on postoperative day (POD) 1, and lower by POD 2 (P = 0.01). The new protocol also reduced the median time to first bowel movement (P < 0.001), and the number of postdischarge pain-related phone calls (P < 0.006). Conclusion: Methadone-based multimodal analgesia resulted in significantly lower LOS compared with the conventional regimen. It also provided improved pain control, reduced total opioid consumption, and early bowel movement compared with the control group.Item Novel associations between CYP2B6 polymorphisms, perioperative methadone metabolism and clinical outcomes in children(Future Medicine, 2021-07) Packiasabapathy, Senthil; Aruldhas, Blessed W.; Zhang, Pengyue; Overholser, Brian R.; Quinney, Sara K.; Sadhasivam, Senthilkumar; Anesthesia, School of MedicineAim: Methadone exhibits significant variability in clinical response. This study explores the genetic influence of variable methadone pharmacokinetics. Methods: This is a prospective study of methadone in children undergoing major surgery. CYP2B6 genotyping, plasma methadone and metabolite levels were obtained. Clinical outcomes include pain scores and postoperative nausea and vomiting (PONV). Results:CYP2B6 poor metabolizers (*6/*6) had >twofold lower methadone metabolism compared with normal/rapid metabolizers. The incidence of PONV was 4.7× greater with CYP2B6 rs1038376 variant. AG/GG variants of rs2279343 SNP had 2.86-fold higher incidence of PONV compared with the wild variant (AA). Nominal associations between rs10500282, rs11882424, rs4803419 and pain scores were observed. Conclusion: We have described novel associations between CYP2B6 genetic variants and perioperative methadone metabolism, and associations with pain scores and PONV.Item Personalized pediatric anesthesia and pain management: problem-based review(Future Science Group, 2020-01) Packiasabapathy, Senthil; Rangasamy, Valluvan; Horn, Nicole; Hendrickson, Michele; Renschler, Janelle; Sadhasivam, Senthilkumar; Medicine, School of MedicinePharmacogenetics, the genetic influence on the interpersonal variability in drug response, has enabled tailored pharmacotherapy and emerging 'personalized medicine.' Although oncology spearheaded the clinical implementation of personalized medicine, other specialties are rapidly catching up. In anesthesia, classical examples of genetically mediated idiosyncratic reactions have been long known (e.g., malignant hyperthermia and prolonged apnea after succinylcholine). The last two decades have witnessed an expanding body of pharmacogenetic evidence in anesthesia. This review highlights some of the prominent pharmacogenetic associations studied in anesthesia and pain management, with special focus on pediatric anesthesia.Item Resting state functional MRI in infants with prenatal opioid exposure-a pilot study(Springer, 2021-04) Radhakrishnan, Rupa; Elsaid, Nahla M. H.; Sadhasivam, Senthilkumar; Reher, Thomas A.; Hines, Abbey C.; Yoder, Karmen K.; Saykin, Andrew J.; Wu, Yu-Chien; Radiology and Imaging Sciences, School of MedicinePURPOSE: Exposure to prenatal opioids may adversely impact the developing brain networks. The aim of this pilot study was to evaluate alterations in amygdalar functional connectivity in human infants with prenatal opioid exposure. METHODS: In this prospective IRB approved study, we performed resting state functional MRI (rs-fMRI) in 10 infants with prenatal opioid exposure and 12 infants without prenatal drug exposure at < 48 weeks corrected gestational age. Following standard preprocessing, we performed seed-based functional connectivity analysis with the right and left amygdala as the regions of interest after correcting for maternal depression and infant sex. We compared functional connectivity of the amygdala network between infants with and without prenatal opioid exposure. RESULTS: There were significant differences in connectivity of the amygdala seed regions to the several cortical regions including the medial prefrontal cortex in infants who had prenatal opioid exposure when compared with opioid naïve infants. CONCLUSION: This finding of increased amygdala functional connectivity in infants with in utero opioid exposure suggests a potential role of maternal opioid exposure on infants' altered amygdala function. This association with prenatal exposure needs to be replicated in future larger studies.