Vidya Chidambaran

Bio: Vidya Chidambaran is an academic researcher from Cincinnati Children's Hospital Medical Center. The author has contributed to research in topics: Opioid & Medicine. The author has an hindex of 22, co-authored 59 publications receiving 1531 citations. Previous affiliations of Vidya Chidambaran include Boston Children's Hospital & University of Cincinnati Academic Health Center.

Propofol: a review of its role in pediatric anesthesia and sedation

Abstract: Propofol is an intravenous agent used commonly for the induction and maintenance of anesthesia, procedural, and critical care sedation in children. The mechanisms of action on the central nervous system involve interactions at various neurotransmitter receptors, especially the gamma-aminobutyric acid A receptor. Approved for use in the USA by the Food and Drug Administration in 1989, its use for induction of anesthesia in children less than 3 years of age still remains off-label. Despite its wide use in pediatric anesthesia, there is conflicting literature about its safety and serious adverse effects in particular subsets of children. Particularly as children are not “little adults”, in this review, we emphasize the maturational aspects of propofol pharmacokinetics. Despite the myriad of propofol pharmacokinetic-pharmacodynamic studies and the ability to use allometrical scaling to smooth out differences due to size and age, there is no optimal model that can be used in target controlled infusion pumps for providing closed loop total intravenous anesthesia in children. As the commercial formulation of propofol is a nutrient-rich emulsion, the risk for bacterial contamination exists despite the Food and Drug Administration mandating addition of antimicrobial preservative, calling for manufacturers’ directions to discard open vials after 6 h. While propofol has advantages over inhalation anesthesia such as less postoperative nausea and emergence delirium in children, pain on injection remains a problem even with newer formulations. Propofol is known to depress mitochondrial function by its action as an uncoupling agent in oxidative phosphorylation. This has implications for children with mitochondrial diseases and the occurrence of propofol-related infusion syndrome, a rare but seriously life-threatening complication of propofol. At the time of this review, there is no direct evidence in humans for propofol-induced neurotoxicity to the infant brain; however, current concerns of neuroapoptosis in developing brains induced by propofol persist and continue to be a focus of research.

Race and unequal burden of perioperative pain and opioid related adverse effects in children.

Abstract: BACKGROUND: Interindividual variability in pain perception and analgesic response is a major problem in perioperative practice. Adult studies suggest pain management is influenced by patient’s race. The objective of this study is to evaluate the influence of race on perioperative pain treatment in children. METHODS: Prospective observational study evaluating effect of race on analgesia and opioid related adverse effects after tonsillectomy in African American and Caucasian children. A sample of 194 healthy children between 6 and 15 years of age were included. Race was self-identified by parents. All participants received standard perioperative care with a standard anesthetic and an intraoperative dose of morphine. Analgesia outcomes included maximum postoperative pain scores, postoperative opioid requirement, and analgesic interventions. Safety outcomes included incidences of opioid related adverse effects. RESULTS: African American children experienced significantly more postoperative pain than Caucasian children as measured by postoperative opioid requirement ( P = .0011), maximum postoperative pain scores ( P < .0001), and analgesic interventions ( P < .0001) in the recovery room. Although Caucasian children received relatively less opioids perioperatively, they had significantly higher opioid related adverse effects ( P = .039). African American children with obstructive sleep apnea were more likely to have prolonged post anesthesia recovery unit stay due to inadequate pain control. CONCLUSIONS: After similar uses of intraoperative morphine for tonsillectomy, there was an unequal burden of increased pain in African American children and increased opioid adverse effects in Caucasian children in the recovery room. Though Caucasian children received relatively less opioids perioperatively, they had higher incidences of opioid related adverse effects than African American children. * Abbreviations: FLACC — : facial expression, leg movement, activity, cry, and consolability NRS — : Numerical Rating Scale OSA — : obstructive sleep apnea PACU — : post anesthesia recovery unit

Pharmacogenomics of opioids and perioperative pain management.

Abstract: Inadequate pain relief and adverse effects from analgesics remain common in children and adults during the perioperative period. Opioids are the most commonly used analgesics in children and adults to treat perioperative pain. Narrow therapeutic index and a large interpatient variability in response to opioids are clinically significant, with inadequate pain relief at one end of the spectrum and serious side effects, such as respiratory depression and excessive sedation due to relative overdosing, at the other end. Personalizing analgesia during the perioperative period attempts to maximize pain relief while minimizing adverse events from therapy. While various factors influence response to treatment among surgical patients, age, sex, race and pharmacogenetic differences appear to play major roles in predicting outcome. Genetic factors include a subset of genes that modulate the proteins involved in pain perception, pain pathway, analgesic metabolism (pharmacokinetics), transport and receptor signaling (pharmacodynamics). While results from adult genetic studies can provide direction for pediatric studies, they have limited direct applicability, as children's genetic predispositions to analgesic response may be influenced by developmental and behavioral components, altered sensitivity to analgesics and variation in gene-expression patterns. We have reviewed the available evidence on improving and personalizing pain management with opioids and the significance of individualizing analgesia, in order to maximize analgesic effect with minimal adverse effects with opioids. While the early evidence on individual genotype associations with pain, analgesia and opioid adverse outcome are promising, the large amount of conflicting data in the literature suggests that there is a need for larger and more robust studies with appropriate population stratification and consideration of nongenetic and other genetic risk factors. Although the clinical evidence and the prospect of being able to provide point-of-care genotyping to enable clinicians to deliver personalized analgesia for individual patients is still not available, positioning our research to identify all possible major genetic and nongenetic risk factors of an individual patient, advancing less expensive point-of-care genotyping technology and developing easy-to-use personalized clinical decision algorithms will help us to improve current clinical and economic outcomes associated with pain and opioid pain management.

OCT1 genetic variants influence the pharmacokinetics of morphine in children

Abstract: Aim: Large interindividual variability in morphine disposition could contribute to unpredictable variability in morphine analgesia and adverse events. Caucasian children have more adverse effects and slower morphine clearance than African–American children. To study variations in intravenous morphine pharmacokinetics in children, we examined the influence of genetic polymorphisms in OCT1. Methods: In 146 children undergoing adenotonsillectomy, 146 concentration–time profiles (2–4 measurements per patient) were available. Population pharmacokinetic analysis characterized the profiles in NONMEM® and tested OCT1 variants as covariates. Results: Allometrically scaled post hoc Bayesian morphine clearance in homozygotes of loss-of-function OCT1 variants (n = 9, OCT1*2–*5/*2–*5) was significantly lower (20%) than in wild-type (n = 85, OCT1*1/*1) and heterozygotes (n = 52, OCT1*1/*2–*5; p < 0.05). Conclusion: Besides bodyweight, OCT1 genotypes play a significant role in intravenous morphine pharmacokinetics. Rela...

Morphine clearance in children: Does race or genetics matter?

Abstract: Objective Interindividual variability in analgesic response and adverse effects of opioids because of narrow therapeutic indices are major clinical problems. Morphine is an opioid commonly used in children to manage perioperative pain. Al-though size and age often are considered primary covariates for morphine pharmacokinetic models, the impact of other factors important in personalizing care such as race and genetic variations on morphine disposition is not well documented. Design Genotype blinded clinical observational pharmacokinetic study. One hundred forty-six African American and Caucasian children scheduled for elective outpatient adenotonsillectomy were enrolled in our prospective genotype blinded observational study with standard perioperative clinical care. Setting Tertiary care pediatric institution. Interventions Morphine bolus for intraoperative analgesia in children and pharmacokinetic analyses in different races. Main outcome measures Pharmacokinetics and pharmacogenetics of intravenous morphine in a homogeneous pediatric outpatient surgical pain population were evaluated. Results The authors observed that African American children have higher morphine clearance than Caucasian children. The increased clearance is directed toward the formation of morphine-3-glucuronide formation, rather than the formation of morphine-6-glucuronide. Common uridine diphosphate glucuronosyl transferase (UGT) 2B7 genetic variations (2161C>T and 802C>T) were not associated with observed racial differences in morphine's clearance although the wild type of the UGT2B7 isozyme is more prevalent in the African Americans. Conclusions Race of the child is an important factor in perioperative intravenous morphine's clearance and its potential role in personalizing analgesia with morphine needs further investigation.

Racial differences in sleep-disordered breathing in African-Americans and Caucasians

Abstract: In this case-control family study of sleep-disordered breathing (SDB), we describe the distributions of SDB and SDB risk factors in African-Americans and Caucasians. A total of 225 African-Americans and 622 Caucasians, ages 2 to 86 yr, recruited as members of families with an individual with known sleep apnea (85 index families) or as members of neighborhood control families (63 families) were studied with an overnight home sleep-study, questionnaires, and physical measurements. A subsample underwent cephalometry. Outcome measures were the respiratory disturbance index (RDI) and a binary variable indicating the presence of increased apneic activity (IAA). In both races, a strong relationship was demonstrated between the (log transformed) RDI and age and age2. African-Americans with SDB were younger than Caucasians with SDB (37.2 +/- 19.5 versus 45.6 +/- 18.7 yr, p < 0.01). In subjects < or = 25 yr, RDI level and IAA prevalence were higher in African-Americans (odds ratio, adjusted for obesity, sex, proban...

The IASP classification of chronic pain for ICD-11: chronic postsurgical or posttraumatic pain.

Abstract: Chronic pain after tissue trauma is frequent and may have a lasting impact on the functioning and quality of life of the affected person. Despite this, chronic postsurgical and posttraumatic pain is underrecognised and, consequently, undertreated. It is not represented in the current Interna

Nonsteroidal anti‐inflammatory drugs and perioperative bleeding in paediatric tonsillectomy

Abstract: Background Nonsteroidal anti-inflammatory drugs (NSAIDs) are used for pain relief following tonsillectomy in children. However, as they inhibit platelet aggregation and prolong bleeding time they could cause increased perioperative bleeding. The overall risk remains unclear. This review was originally published in 2005 and was updated in 2010 and in 2012. Objectives The primary objective of this review was to assess the effects of NSAIDs on bleeding with paediatric tonsillectomy. Our secondary outcome was to establish whether NSAIDs affect the incidence of other postoperative complications when compared to other forms of analgesia. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 10); MEDLINE (inception until October 2012); EMBASE (inception until October 2012); Current Problems (produced by the UK Medicines Control Agency), MedWatch (produced by the US Food and Drug Administration) and the Australian Adverse Drug Reactions Bulletins (to May 2010). The original search was performed in August 2004. We also contacted manufacturers and researchers in the field. Selection criteria We included randomized controlled trials assessing NSAIDs in children, up to and including 16 years of age, undergoing elective tonsillectomy or adenotonsillectomy. Data collection and analysis Two authors independently assessed trial quality and extracted the data. We contacted study authors for additional information, where necessary. Main results We included 15 studies that involved 1101 children in this updated review. One study was added as a result of our 2012 search, another previously included study was removed due to lack of randomization. Fourteen included studies compared NSAIDs with other analgesics or placebo and reported on bleeding requiring surgical intervention. The use of NSAIDs was associated with a non-significant increase in the risk of bleeding requiring surgical intervention: Peto odds ratio (OR) 1.69 (95% confidence interval (CI) 0.71 to 4.01). Ten studies involving 365 children reported perioperative bleeding requiring non-surgical intervention. NSAIDs did not significantly alter the number of perioperative bleeding events requiring non-surgical intervention: Peto OR 0.99 (95% CI 0.41 to 2.40) but the confidence intervals did not exclude an increased risk. Thirteen studies involving 1021 children reported postoperative vomiting. There was less vomiting when NSAIDs were used as part of the analgesic regime than when NSAIDs were not used: Mantel Haenszel (M-H) risk ratio (RR) 0.72 (95% CI 0.61 to 0.85). Authors' conclusions There is insufficient evidence to exclude an increased risk of bleeding when NSAIDs are used in paediatric tonsillectomy. They do however confer the benefit of a reduction in vomiting.