IU Indianapolis ScholarWorks :: Browsing by Author "Sadhasivam, Senthilkumar"

Browsing by Author "Sadhasivam, Senthilkumar"

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A Novel Perioperative Multidose Methadone-Based Multimodal Analgesic Strategy in Children Achieved Safe and Low Analgesic Blood Methadone Levels Enabling Opioid-Sparing Sustained Analgesia With Minimal Adverse Effects
(Wolters Kluwer, 2021) Sadhasivam, Senthilkumar; Aruldhas, Blessed W.; Packiasabapathy, Senthil; Overholser, Brian R.; Zhang, Pengyue; Zang, Yong; Renschler, Janelle S.; Fitzgerald, Ryan E.; Quinney, Sara K.; Anesthesia, School of Medicine
Background: Intraoperative methadone, a long-acting opioid, is increasingly used for postoperative analgesia, although the optimal methadone dosing strategy in children is still unknown. The use of a single large dose of intraoperative methadone is controversial due to inconsistent reductions in total opioid use in children and adverse effects. We recently demonstrated that small, repeated doses of methadone intraoperatively and postoperatively provided sustained analgesia and reduced opioid use without respiratory depression. The aim of this study was to characterize pharmacokinetics, efficacy, and safety of a multiple small-dose methadone strategy. Methods: Adolescents undergoing posterior spinal fusion (PSF) for idiopathic scoliosis or pectus excavatum (PE) repair received methadone intraoperatively (0.1 mg/kg, maximum 5 mg) and postoperatively every 12 hours for 3-5 doses in a multimodal analgesic protocol. Blood samples were collected up to 72 hours postoperatively and analyzed for R-methadone and S-methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene (EDDP) metabolites, and alpha-1 acid glycoprotein (AAG), the primary methadone-binding protein. Peak and trough concentrations of enantiomers, total methadone, and AAG levels were correlated with clinical outcomes including pain scores, postoperative nausea and vomiting (PONV), respiratory depression, and QT interval prolongation. Results: The study population included 38 children (10.8-17.9 years): 25 PSF and 13 PE patients. Median total methadone peak plasma concentration was 24.7 (interquartile range [IQR], 19.2-40.8) ng/mL and the median trough was 4.09 (IQR, 2.74-6.4) ng/mL. AAG concentration almost doubled at 48 hours after surgery (median = 193.9, IQR = 86.3-279.5 µg/mL) from intraoperative levels (median = 87.4, IQR = 70.6-115.8 µg/mL; P < .001), and change of AAG from intraoperative period to 48 hours postoperatively correlated with R-EDDP (P < .001) levels, S-EDDP (P < .001) levels, and pain scores (P = .008). Median opioid usage was minimal, 0.66 (IQR, 0.59-0.75) mg/kg morphine equivalents/d. No respiratory depression (95% Wilson binomial confidence, 0-0.09) or clinically significant QT prolongation (median = 9, IQR = -10 to 28 milliseconds) occurred. PONV occurred in 12 patients and was correlated with morphine equivalent dose (P = .005). Conclusions: Novel multiple small perioperative methadone doses resulted in safe and lower blood methadone levels, <100 ng/mL, a threshold previously associated with respiratory depression. This methadone dosing in a multimodal regimen resulted in lower blood methadone analgesia concentrations than the historically described minimum analgesic concentrations of methadone from an era before multimodal postoperative analgesia without postoperative respiratory depression and prolonged corrected QT (QTc). Larger studies are needed to further study the safety and efficacy of this methadone dosing strategy.
Advanced Meditation Alters Resting-State Brain Network Connectivity Correlating With Improved Mindfulness
(Frontiers Media, 2021-11) Vishnubhotla, Ramana V.; Radhakrishnan, Rupa; Kveraga, Kestas; Deardorff, Rachael; Ram, Chithra; Pawale, Dhanashri; Wu, Yu-Chien; Renschler, Janelle; Subramaniam, Balachundhar; Sadhasivam, Senthilkumar; Radiology and Imaging Sciences, School of Medicine
Purpose: The purpose of this study was to investigate the effect of an intensive 8-day Samyama meditation program on the brain functional connectivity using resting-state functional MRI (rs-fMRI). Methods: Thirteen Samyama program participants (meditators) and 4 controls underwent fMRI brain scans before and after the 8-day residential meditation program. Subjects underwent fMRI with a blood oxygen level dependent (BOLD) contrast at rest and during focused breathing. Changes in network connectivity before and after Samyama program were evaluated. In addition, validated psychological metrics were correlated with changes in functional connectivity. Results: Meditators showed significantly increased network connectivity between the salience network (SN) and default mode network (DMN) after the Samyama program (p < 0.01). Increased connectivity within the SN correlated with an improvement in self-reported mindfulness scores (p < 0.01). Conclusion: Samyama, an intensive silent meditation program, favorably increased the resting-state functional connectivity between the salience and default mode networks. During focused breath watching, meditators had lower intra-network connectivity in specific networks. Furthermore, increased intra-network connectivity correlated with improved self-reported mindfulness after Samyama.
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 Medicine
Aim: 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.
Brain structural connectome in neonates with prenatal opioid exposure
(Frontiers Media, 2022-09-16) Vishnubhotla, Ramana V.; Zhao, Yi; Wen, Qiuting; Dietrich, Jonathan; Sokol, Gregory M.; Sadhasivam, Senthilkumar; Radhakrishnan, Rupa; Radiology and Imaging Sciences, School of Medicine
Introduction: Infants with prenatal opioid exposure (POE) are shown to be at risk for poor long-term neurobehavioral and cognitive outcomes. Early detection of brain developmental alterations on neuroimaging could help in understanding the effect of opioids on the developing brain. Recent studies have shown altered brain functional network connectivity through the application of graph theoretical modeling, in infants with POE. In this study, we assess global brain structural connectivity through diffusion tensor imaging (DTI) metrics and apply graph theoretical modeling to brain structural connectivity in infants with POE. Methods: In this prospective observational study in infants with POE and control infants, brain MRI including DTI was performed before completion of 3 months corrected postmenstrual age. Tractography was performed on the whole brain using a deterministic fiber tracking algorithm. Pairwise connectivity and network measure were calculated based on fiber count and fractional anisotropy (FA) values. Graph theoretical metrics were also derived. Results: There were 11 POE and 18 unexposed infants included in the analysis. Pairwise connectivity based on fiber count showed alterations in 32 connections. Pairwise connectivity based on FA values showed alterations in 24 connections. Connections between the right superior frontal gyrus and right paracentral lobule and between the right superior occipital gyrus and right fusiform gyrus were significantly different after adjusting for multiple comparisons between POE infants and unexposed controls. Additionally, alterations in graph theoretical network metrics were identified with fiber count and FA value derived tracts. Conclusion: Comparisons show significant differences in fiber count in two structural connections. The long-term clinical outcomes related to these findings may be assessed in longitudinal follow-up studies.
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.
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 Medicine
Background: 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.
Effects of oxycodone pharmacogenetics on postoperative analgesia and related clinical outcomes in children: a pilot prospective study
(Taylor & Francis, 2023) Aruldhas, Blessed W.; Quinney, Sara K.; Packiasabapathy, Senthil; Overholser, Brian R.; Raymond, Olivia; Sivam, Sahana; Sivam, Inesh; Velu, Sanjana; Montelibano, Antoinette; Sadhasivam, Senthilkumar; Medicine, School of Medicine
Background: Variability in the pharmacokinetics and pharmacodynamics of oxycodone in children undergoing surgery could be due to genetic polymorphisms. Materials & methods: The authors studied the association between clinical outcomes and pharmacogenes in children undergoing major surgery. A total of 89 children (35 undergoing pectus excavatum repair and 54 undergoing spinal fusion) were recruited. Results: OPRM1 SNP rs6902403 showed an association with maximum pain score and total morphine equivalent dose (p < 0.05). Other polymorphisms in OPRM1 SNP, PXR, COMT and ABCB1 were also shown to be associated with average morphine equivalent dose, length of hospital stay and maximum surgical pain (p < 0.05). Conclusion: This study demonstrates novel associations between the above pharmacogenes and oxycodone's pharmacokinetics as well as postoperative outcomes in children.
Gender, genetics, and analgesia: understanding the differences in response to pain relief
(Dovepress, 2018-11-08) Packiasabapathy, Senthil; Sadhasivam, Senthilkumar; Anesthesia, School of Medicine
Genetic 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.
Genetics of perioperative pain management
(Lippincott, Williams & Wilkins, 2018-12) Packiasabapathy, Senthil; Horn, Nicole; Sadhasivam, Senthilkumar; Anesthesia, School of Medicine
PURPOSE 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.
Global Brain Functional Network Connectivity in Infants With Prenatal Opioid Exposure
(Frontiers Media, 2022-03-14) Radhakrishnan, Rupa; Vishnubhotla, Ramana V.; Zhao, Yi; Yan, Jingwen; He, Bing; Steinhardt, Nicole; Haas, David M.; Sokol, Gregory M.; Sadhasivam, Senthilkumar; Radiology and Imaging Sciences, School of Medicine
Background: Infants with prenatal opioid and substance exposure are at higher risk of poor neurobehavioral outcomes in later childhood. Early brain imaging in infancy has the potential to identify early brain developmental alterations that may help predict behavioral outcomes in these children. In this study, using resting-state functional MRI in early infancy, we aim to identify differences in global brain network connectivity in infants with prenatal opioid and substance exposure compared to healthy control infants. Methods and materials: In this prospective study, we recruited 23 infants with prenatal opioid exposure and 29 healthy opioid naïve infants. All subjects underwent brain resting-state functional MRI before 3 months postmenstrual age. Covariate Assisted Principal (CAP) regression was performed to identify brain networks within which functional connectivity was associated with opioid exposure after adjusting for sex and gestational age. Associations of these significant networks with maternal comorbidities were also evaluated. Additionally, graph network metrics were assessed in these CAP networks. Results: There were four CAP network components that were significantly different between the opioid exposed and healthy control infants. Two of these four networks were associated with maternal psychological factors. Intra-network graph metrics, namely average flow coefficient, clustering coefficient and transitivity were also significantly different in opioid exposed infants compared to healthy controls. Conclusion: Prenatal opioid exposure is associated with alterations in global brain functional networks compared to non-opioid exposed infants, with intra-network alterations in graph network modeling. These network alterations were also associated with maternal comorbidity, especially mental health. Large-scale longitudinal studies can help in understanding the clinical implications of these early brain functional network alterations in infants with prenatal opioid exposure.

Browsing by Author "Sadhasivam, Senthilkumar"

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