Anne M. Lynn

Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial

__Background__ In laboratory animals, exposure to most general anaesthetics leads to neurotoxicity manifested by neuronal cell death and abnormal behaviour and cognition. Some large human cohort studies have shown an association between general anaesthesia at a young age and subsequent neurodevelopmental deficits, but these studies are prone to bias. Others have found no evidence for an association. We aimed to establish whether general anaesthesia in early infancy affects neurodevelopmental outcomes. __Methods__ In this international, assessor-masked, equivalence, randomised, controlled trial conducted at 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand, we recruited infants of less than 60 weeks’ postmenstrual age who were born at more than 26 weeks’ gestation and were undergoing inguinal herniorrhaphy, without previous exposure to general anaesthesia or risk factors for neurological injury. Patients were randomly assigned (1:1) by use of a web-based randomisation service to receive either awake-regional anaesthetic or sevoflurane-based general anaesthetic. Anaesthetists were aware of group allocation, but individuals administering the neurodevelopmental assessments were not. Parents were informed of their infants group allocation upon request, but were told to mask this information from assessors. The primary outcome measure was full-scale intelligence quotient (FSIQ) on the Wechsler Preschool and Primary Scale of Intelligence, third edition (WPPSI-III), at 5 years of age. The primary analysis was done on a per-protocol basis, adjusted for gestational age at birth and country, with multiple imputation used to account for missing data. An intention-totreat analysis was also done. A difference in means of 5 points was predefined as the clinical equivalence margin. This completed trial is registered with ANZCTR, number ACTRN12606000441516, and ClinicalTrials.gov, number NCT00756600. __Findings__ Between Feb 9, 2007, and Jan 31, 2013, 4023 infants were screened and 722 were randomly allocated: 363 (50%) to the awake-regional anaesthesia group and 359 (50%) to the general anaesthesia group. There were 74 protocol violations in the awake-regional anaesthesia group and two in the general anaesthesia group. Primary outcome data for the per-protocol analysis were obtained from 205 children in the awake-regional anaesthesia group and 242 in the general anaesthesia group. The median duration of general anaesthesia was 54 min (IQR 41–70). The mean FSIQ score was 99·08 (SD 18·35) in the awake-regional anaesthesia group and 98·97 (19·66) in the general anaesthesia group, with a difference in means (awake-regional anaesthesia minus general anaesthesia) of 0·23 (95% CI –2·59 to 3·06), providing strong evidence of equivalence. The results of the intention-to-treat analysis were similar to those of the per-protocol analysis. __Interpretation__ Slightly less than 1 h of general anaesthesia in early infancy does not alter neurodevelopmental outcome at age 5 years compared with awake-regional anaesthesia in a predominantly male study population.Summary Background There is pre-clinical evidence that general anaesthetics affect brain development. There is mixed evidence from cohort studies that young children exposed to anaesthesia may have an increased risk of poorer neurodevelopmental outcome. This trial aims to determine if GA in infancy has any impact on neurodevelopmental outcome. The primary outcome for the trial is neurodevelopmental outcome at 5 years of age. The secondary outcome is neurodevelopmental outcome at two years of age and is reported here. Methods We performed an international assessor-masked randomised controlled equivalence trial in infants less than 60 weeks post-menstrual age, born at greater than 26 weeks gestational age having inguinal herniorrhaphy. Infants were excluded if they had existing risk factors for neurologic injury. Infants were randomly assigned to awake-regional (RA) or sevoflurane-based general anaesthesia (GA). Web-based randomisation was performed in blocks of two or four and stratified by site and gestational age at birth. The outcome for analysis was the composite cognitive score of the Bayley Scales of Infant and Toddler Development, Third Edition. The analysis was as-per-protocol adjusted for gestational age at birth. A difference in means of five points (1/3 SD) was predefined as the clinical equivalence margin. The trial was registered at ANZCTR, ACTRN12606000441516 and ClinicalTrials.gov, NCT00756600. Findings Between February 2007, and January 2013, 363 infants were randomised to RA and 359 to GA. Outcome data were available for 238 in the RA and 294 in the GA arms. The median duration of anaesthesia in the GA arm was 54 minutes. For the cognitive composite score there was equivalence in means between arms (RA-GA: +0·169, 95% CI −2·30 to +2·64). Interpretation For this secondary outcome we found no evidence that just under an hour of sevoflurane anaesthesia in infancy increases the risk of adverse neurodevelopmental outcome at two years of age compared to RA.

Morphine pharmacokinetics in early infancy.

: The pharmacokinetics of morphine in ten infants less than or equal to 10 weeks of age who were receiving morphine infusions were determined. Infants 1-4 days of age (newborns) showed longer elimination half-lives than the older infants (6.8 vs. 3.9 h). Clearance in the newborns is less than one-half that found in older infants (6.3 vs. 23.8 ml X min-1 X kg-1). The combination of lower clearance and longer elimination half-life in newborns (0-7 days) may well explain a prolonged duration of action for morphine in very young infants, but other etiologies are needed to explain the respiratory sensitivity believed to persist in older infants.

Summary Proceedings From the Neonatal Pain-Control Group

Recent advances in neurobiology and clinical medicine have established that the fetus and newborn may experience acute, established, and chronic pain. They respond to such noxious stimuli by a series of complex biochemical, physiologic, and behavioral alterations. Studies have concluded that controlling pain experience is beneficial with respect to short-term and perhaps long-term outcomes. Yet, pain-control measures are adopted infrequently because of unresolved scientific issues and lack of appreciation for the need for control of pain and its long-term sequelae during the critical phases of neurologic maturation in the preterm and term newborn. The neonatal pain-control group, as part of the Newborn Drug Development Initiative (NDDI) Workshop I, addressed these concerns. The specific issues addressed were (1) management of pain associated with invasive procedures, (2) provision of sedation and analgesia during mechanical ventilation, and (3) mitigation of pain and stress responses during and after surgery in the newborn infant. The cross-cutting themes addressed within each category included (1) clinical-trial designs, (2) drug prioritization, (3) ethical constraints, (4) gaps in our knowledge, and (5) future research needs. This article provides a summary of the discussions and deliberations. Full-length articles on procedural pain, sedation and analgesia for ventilated infants, perioperative pain, and study designs for neonatal pain research were published in Clinical Therapeutics (June 2005).

Clearance of Morphine in Postoperative Infants During Intravenous Infusion: The Influence of Age and Surgery

We analyzed morphine clearance values in infants receiving the drug by continuous IV infusion for analgesia after surgery, because we found lower steady-state morphine concentrations than we expected from our previous studies. Infants received morphine after a loading dose of 0.05 mg/kg and continuous infusion calculated to reach a steady-state concentration of 20 ng/mL. Blood was sampled twice on Postoperative Day 1 at times separated by at least 2 h, and morphine and morphine-6-glucuronide (M-6-G) concentrations were determined by high-performance liquid chromatography. Clearance of morphine was calculated as infusion rate divided by the steady-state morphine concentration. Morphine given to 26 infants by continuous IV infusion after major noncardiac surgery has rapidly increasing clearance values, from a median value of 9.2 mL [center dot] min-1 [center dot] kg-1 in infants 1-7 days old, 25.3 in infants 31-90 days old, and 31.0 in infants 91-180 days old to 48.9 in infants 180-380 days old. Adult clearance values are reached by 1 mo of age, more quickly than in infants of the same age previously studied who received morphine after cardiac surgeries. M-6-G was measured in all infants. The ratio of M-6-G to morphine concentrations was 1.9-2.1 in these infants, which is lower than ratios reported in older infants or adults by others, but higher than those reported in newborns. Infants with normal cardiovascular systems undergoing surgery clear morphine more efficiently than infants of the same age undergoing cardiac surgery. Implications: Morphine removal from the body is slow in newborns but increases to reach adult values in the first months of life. Calculating the clearance of morphine from blood samples drawn during continuous IV infusions after surgery shows that this maturation occurs more quickly in infants undergoing noncardiac surgery (by 1-3 mo of age) than in those receiving morphine after cardiac surgery (by 6-12 mo of age). (Anesth Analg 1998;86:958-63)

Respiratory effects of intravenous morphine infusions in neonates, infants, and children after cardiac surgery

We evaluated the respiratory effects of intravenous morphine infusions in 30 patients (2 to 570 days old, mean 155 days) after cardiac surgery. PaCO2 during spontaneous breathing and CO2 response curves during rebreathing were obtained on morphine infusions at drug steady state and during drug washout. Steady state morphine serum levels > 20 ng/mL resulted in hypercarbia (PaCO2 > 55 mm Hg) and depressed CO2 response curve slopes (< 10 mL.min-1.mm Hg ETCO2(-1).kg-1) in 67% and 70% of patients, respectively (P < 0.05, compared to those with levels < 20 ng/mL). During washout, morphine levels more than 15 ng/mL resulted in hypercarbia in 46%, whereas levels less than 15 ng/mL were associated with hypercarbia in 13% (P = 0.025). No age-related differences in respiratory effect were seen in these studies at the same serum morphine level. Careful observation of any patient receiving morphine remains necessary, but neonates and young infants seem to have the same respiratory response to morphine infusions as older infants and children at the same blood level.

Caudal morphine for postoperative analgesia in children: a comparison with caudal bupivacaine and intravenous morphine.

We compared the efficacy, duration, and side effects of preservative-free morphine injected into the caudal space in children, with caudal bupivacaine and with intravenous morphine administration for relief of postoperative pain. Forty-six children, ages 1-16 yr, were randomly assigned to receive intravenous morphine (control group), caudal bupivacaine (0.25%, 1 ml/kg), or caudal morphine (0.5 mg/ml, 0.1 mg/kg). In half the patients given caudal morphine, the morphine was mixed with a dose of lidocaine adequate to produce sacral analgesia, to confirm correct caudal injection of the morphine. Caudal injections were performed at the end of surgery. Time until the first required postoperative intravenous morphine dose was recorded for each patient. The duration of analgesia was significantly greater with caudal morphine (median 12 hr, P less than 0.02) than with caudal bupivacaine (median 5 hr), and both were greater than with intravenous morphine in control patients (median 45 min). Urinary retention, pruritus, and nausea appeared with slightly greater frequency in the caudal morphine group, but no delayed respiratory depression occurred. Caudal morphine (0.5 mg/ml, 0.1 mg/kg) provided 8-24 hr of analgesia in children without a significantly greater incidence of side effects than caudal bupivacaine or intravenous morphine.

Morphine infusion after pediatric cardiac surgery

After cardiac surgery, 44 children received a continuous iv infusion of morphine sulfate at 10 to 30 Mg/kg-h. During weaning from assisted ventilation and during spontaneous ventilation serum morphine levels less than 30 ng/ml were not associated with elevated Paco2. Five extubated patients breathed

Optimizing Pediatric Dosing: A Developmental Pharmacologic Approach

Many physiologic differences between children and adults can result in age‐related differences in pharmacokinetics. Understanding the effects of age on bioavailability, volume of distribution, protein binding, hepatic metabolic isoenzymes, and renal elimination can provide insight into optimizing doses for pediatric patients. We performed a search of English‐language literature using the MEDLINE database regarding age and pharmacokinetics (1979‐July 2008). We then evaluated the literature with an emphasis on drugs with one primary elimination pathway, such as renal clearance or a pathway involving a single metabolic isoenzyme. Our mechanistic‐based analysis revealed that children need weight‐corrected doses that are substantially higher than adult doses for drugs that are metabolically eliminated solely by the specific cytochrome P450 (CYP) isoenzymes CYP1A2, CYP2C9, and CYP3A4. In contrast, weight‐corrected doses for drugs eliminated by renal excretion or metabolism involving CYP2C19, CYP2D6, N‐acetyltransferase 2, or uridine diphosphate glucuronosyltransferases are similar in children and adults. In children, bioavailability of drugs with high first‐pass metabolism is decreased for drugs metabolized by CYP1A2, CYP2C9, and CYP3A4. Limited data suggest that by age 5 years, bioavailability of drugs affected by efflux transporters should be equivalent to that of adults. Using a pharmaco‐kinetics‐based approach, rational predictions can be made for the effects of age on drugs that undergo similar pathways of elimination, even when specific pharmacokinetic data are limited or unavailable.

A randomized, double-blinded study of remifentanil versus fentanyl for tonsillectomy and adenoidectomy surgery in pediatric ambulatory surgical patients.

UNLABELLED We compared, in a double-blinded manner, the anesthetic maintenance and recovery properties of remifentanil with a clinically comparable fentanyl-based anesthetic technique in pediatric ambulatory surgical patients. Anesthesia was induced with either halothane or sevoflurane and nitrous oxide and oxygen. Patients were randomized (computer generated) to receive either remifentanil or fentanyl in a blinded syringe with nitrous oxide and oxygen in one of four possibilities: halothane/remifentanil, halothane/fentanyl, sevoflurane/remifentanil or sevoflurane/fentanyl. In patients receiving remifentanil, a placebo bolus was administered, and a continuous infusion (0.25 microg. kg(-1). min(-1)) was begun. In patients receiving fentanyl, a bolus (2 microg/kg) was administered followed by a placebo continuous infusion. The time from discontinuation of the anesthetic to extubation, discharge from the postanesthesia care unit (PACU), and discharge to home, as well as pain scores, were assessed by a blinded nurse observer. Systolic blood pressure and heart rate were noted at selected times, and adverse events were recorded. Remifentanil provided faster extubation times and higher pain-discomfort scores. PACU and hospital discharge times were similar. There were no statistical differences among the groups for adverse events. There were statistically, but not clinically, significant differences in hemodynamic variables. We noted that continuous infusions of remifentanil were intraoperatively as effective as bolus fentanyl. Although patients could be tracheally extubated earlier with remifentanil, this did not translate to earlier PACU or hospital discharge times. In addition, remifentanil was associated with higher postoperative pain scores. The frequent incidence of postoperative pain observed in the postoperative recovery room suggests that better intraoperative prophylactic analgesic regimens for postoperative pain control are necessary to optimize remifentanils use as an anesthetic for children. IMPLICATIONS This is a study designed to examine the efficacy and safety of a short-acting opioid, remifentanil, when used in pediatric patients. The frequent incidence of postoperative pain observed in the postoperative recovery room suggests that better intraoperative prophylactic analgesic regimens for postoperative pain control are necessary to optimize remifentanils use as an anesthetic for children.

Effect of pH and Pco2 on pulmonary and systemic hemodynamics after surgery in children with congenital heart disease and pulmonary hypertension

Fourteen children with congenital heart disease and associated pulmonary hypertension (preoperative mean pulmonary artery pressure (MPAP) 48 mm Hg +/- 1 SEM were examined to determine the effect of arterial carbon dioxide tension (PaCO2) and pH on pulmonary and systemic hemodynamics after surgical repair. Baseline measurements were obtained with hyperventilation to PaCO2 20 to 30 mm Hg (pH 7.56 +/- 0.01 mm Hg). The addition of carbon dioxide to inspired gas to achieve a PaCO2 40 to 45 mm Hg (pH 7.35 +/- 0.01) resulted in a significant increase in MPAP, from 32 +/- 5 mm Hg to 47 +/- 8 mm Hg (p less than 0.05). An increase in mean cardiac index (CI) from 2.7 +/- 0.3 L/min/m2 to 3.3 +/- 0.3 L/min/m2 (p less than 0.05) explained in part the associated increase in MPAP. For a subgroup of eight patients with postoperative MPAP greater than 30 mm Hg (at pH 7.35 to 7.40), pulmonary vascular resistance index (PVRI) also significantly increased (p less than 0.05) as PaCO2 was increased, implying a direct pulmonary vasodilating effect of alkalosis. Removal of carbon dioxide from inspired gas returned hemodynamic values to baseline. The higher the MPAP at physiologic pH the greater the absolute amount of MPAP reduction and PVRI reduction (p less than 0.05) with alkalosis. No complications from alkalosis were seen. We suggest that a trial of hypocarbic alkalosis in the child with severe residual pulmonary hypertension after surgical repair of congenital heart disease is warranted to reduce right ventricular afterload.