Senthilkumar Sadhasivam

Clinical pharmacogenetics implementation consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 Update

Codeine is bioactivated to morphine, a strong opioid agonist, by the hepatic cytochrome P450 2D6 (CYP2D6); hence, the efficacy and safety of codeine are governed by CYP2D6 activity. Polymorphisms are a major cause of CYP2D6 variability. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for codeine based on CYP2D6 genotype. This document is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP2D6 genotype and codeine therapy.

A comparison of dexmedetomidine with propofol for magnetic resonance imaging sleep studies in children.

BACKGROUND:Magnetic resonance imaging (MRI) sleep studies can be used to guide management of children with obstructive sleep apnea (OSA) refractory to conservative therapy. Because children with OSA are sensitive to the respiratory-depressant effects of sedatives and anesthetics, provision of anesthesia for imaging studies in this patient population can be challenging. Dexmedetomidine has been shown to have pharmacological properties simulating natural sleep with minimal respiratory depression. We hypothesized that, compared with propofol, dexmedetomidine would have less effect on upper airway tone and airway collapsibility, provide more favorable conditions during dynamic MRI airway imaging in children with OSA, have fewer scan interruptions, and require less aggressive airway interventions. METHODS:In this retrospective descriptive study, we reviewed the records of 52 children receiving dexmedetomidine and 30 children receiving propofol for anesthesia during MRI sleep studies between July 2006 and March 2008. Documentation of the severity of OSA by overnight polysomnography was available for 67 of the 82 subjects, who were analyzed separately. Data analyzed included demographics, severity of OSA, comorbidities, hemodynamic changes, use of artificial airways, additional airway maneuvers, and successful completion of the MRI scan. RESULTS:Demographics, OSA severity by polysomnography, anesthetic induction, and baseline hemodynamics were comparable in both groups. An interpretable MRI sleep study was obtained for 98% of children in the dexmedetomidine group and 100% in the propofol group. Of 82 children, MRI sleep studies were successfully completed without the use of artificial airways in 46 children (88.5%) in the dexmedetomidine group versus 21 children (70%) in the propofol group (P = 0.03). An artificial airway was required to complete the study in five children (12%) in the dexmedetomidine group versus nine children (35%) in the propofol group (P = 0.06). Additional airway maneuvers (chin lift and shoulder roll) were required to complete the study in one child (2%) in the dexmedetomidine group and three children (10%) in the propofol group (P = 0.14). Children in the dexmedetomidine group experienced reductions in heart rate, whereas those in the propofol group experienced reductions in arterial blood pressure; these reductions were statistically, but not clinically, significant. CONCLUSIONS:Dexmedetomidine provided an acceptable level of anesthesia for MRI sleep studies in children with OSA, producing a high yield of interpretable studies of the patient’s native airway. The need for artificial airway support during the MRI sleep study was significantly less with dexmedetomidine than with propofol. Dexmedetomidine may be the preferred drug for anesthesia during MRI sleep studies in children with a history of severe OSA and may offer benefits to children with sleep-disordered breathing requiring anesthesia or anesthesia for other diagnostic imaging studies.

Validation of the Bispectral Index Monitor for Measuring the Depth of Sedation in Children

The Bispectral Index (BIS) is an empirically calibrated number derived from adult electroencephalograph data that correlates with the depth of sedation in adults. We tested the hypothesis that the BIS score is a valid measure of the depth of pediatric sedation in a study designed to avoid limitations of a previously published report. BIS values from 96 healthy ASA physical status I–II children aged 1–12 yr undergoing sedation were continually recorded and electronically transferred to a computer. Two independent observers blinded as to BIS score evaluated sedation using the Observer’s Assessment of Alertness/Sedation (OAA/S) and the University of Michigan Sedation Scale (UMSS) at 3–5 min intervals. There was a significant correlation between BIS and UMSS and between BIS and OAA/S by both the Spearman’s rank correlation test and by prediction probability (P < 0.001). In children <6 yr, there was a significant correlation between BIS and the clinical sedation scores for subgroups undergoing invasive and noninvasive procedures (P < 0.001). There was also good agreement between the 2 independent observers who assessed clinical sedation scores (kappa = 0.51, P < 0.001). We conclude that the BIS monitor is a quantitative, nondisruptive and easy to use depth of sedation monitor in children.

Race and Unequal Burden of Perioperative Pain and Opioid Related Adverse Effects in Children

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.

Effect of increasing depth of dexmedetomidine anesthesia on upper airway morphology in children

Objective:  This prospective study examines the dose–response effects of dexmedetomidine on upper airway morphology in children with no obstructive sleep apnea (OSA).

Pharmacogenomics of opioids and perioperative pain management

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 childrens 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.

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. Relatively high allelic frequencies of defective OCT1 variants among Caucasians may explain their lower morphine clearance and possibly higher frequencies of adverse events compared with African-American children. Original submitted 21 December 2012; Revision submitted 7 May 2013.

Supplementing desflurane with intravenous anesthesia reduces fetal cardiac dysfunction during open fetal surgery.

Objective:  To lower the incidence and severity of fetal cardiovascular depression during maternal fetal surgery under general anesthesia.

Effect of Age and Sedative Agent on the Accuracy of Bispectral Index in Detecting Depth of Sedation in Children

OBJECTIVE. This study evaluated age- and sedative agent–related differences in bispectral index across observed sedation levels in a large sample of children <18 years of age. PATIENTS AND METHODS. With institutional review board approval and waiver of consent, data from 4 independently conducted studies were combined in a secondary analysis of 3373 observations from 248 children aged 1 month to 18 years. In these studies, bispectral index values of sedated children were recorded in a blinded fashion, and sedation depth was scored using the University of Michigan Sedation Scale (UMSS). Bispectral index was evaluated across UMSS scores for several age groups and during use of each sedative agent (with/without opioids). RESULTS. There was a moderate inverse correlation between bispectral index and UMSS for all age groups. There were significant differences in bispectral index across UMSS and between each sedation level except UMSS 3 to 4 in all the age groups and UMSS 0 to 1 in infants. The mean bispectral index and the cutoff values on the receiver-operating-characteristic curve for mild, moderate, and deep sedation were significantly lower in infants ≤6 months compared with older children at each sedation level. Bispectral index was reasonably sensitive and specific in differentiating mild (UMSS 0–1) from deeper (UMSS 3–4) levels of sedation but poorly differentiated between moderate and deep levels of sedation in all age groups. There was a moderate correlation between bispectral index and UMSS during the use of chloral hydrate, pentobarbital, propofol, and midazolam but poor correlation during ketamine or opioid use. Bispectral index values were significantly lower during deep sedation with propofol and pentobarbital compared with midazolam and chloral hydrate. CONCLUSIONS. Our findings suggest that, although bispectral index may differentiate light from deep sedation in most children, bispectral index must be interpreted cautiously in sedated children, with particular consideration given to patient age and use of sedative agents.

Real-Time Assessment of Perioperative Behaviors and Prediction of Perioperative Outcomes

Background and Aims: New onset maladaptive behaviors, such as temper tantrums, nightmares, bed-wetting, attention-seeking, and fear of being alone are common in children after outpatient surgery. Preoperative anxiety, fear and distress behaviors of children predict postoperative maladaptive behaviors as well as emergence delirium. Parental anxiety has also been found to influence children’s preoperative anxiety. Currently, there is no real-time and feasible tool to effectively measure perioperative behaviors of children and parents. We developed a simple and real-time scale, the Perioperative Adult Child Behavioral Interaction Scale (PACBIS) to assess perioperative child and parent behaviors that might predict postoperative problematic behavior and emergence excitement. METHODS: We used the PACBIS to evaluate perioperative behaviors during anesthetic induction and recovery in a sample of 89 children undergoing tonsillectomies and adenoidectomies, and their parents. Preoperative anxiety with the modified Yale Preoperative Anxiety Scale, compliance with induction of anesthesia with Induction Compliance Checklist, and incidence of emergence excitement were also recorded. RESULTS: The PACBIS demonstrated good concurrent validity with modified Yale Preoperative Anxiety Scale and Induction Compliance Checklist and predicted postanesthetic emergence excitement. DISCUSSION: The PACBIS is the first real-time scoring instrument that evaluates children’s and parents’ perioperative behavior. The specific behaviors identified by the PACBIS might provide targets for interventions to improve perioperative experiences and postoperative outcomes.