The halothane era in pediatric anesthesia: The convergence of a cardiac depressant anesthetic with the immature myocardium of infancy.

Introduced in the late 1950s, halothane became the anesthetic of choice for inhalational induction of children for over 40 years. Halothane enjoyed a generally favorable safety record during its time, but its cardiac contractility depressant effect-well tolerated by most age groups-was profoundly heightened in neonates and infants, leading to increased incidences of hypotension and cardiac arrest. The neonatal myocardium is immature and is characterized by poor ventricular compliance, poor contractility due to fewer contractile elements, immature sympathetic innervation with decreased norepinephrine stores, and immature mechanisms for storage and exchange of calcium in the sarcoplasmic reticulum. In vitro studies of myocardial contractility of mammalian fetal and adult myocardium demonstrated that the fetal heart was twice as sensitive to halothane as the adult. Clinical studies demonstrated that most neonates and infants less than 6 months of age experienced hypotension during halothane induction of anesthesia and significantly (p < .01) greater decreases in blood pressure than older children at equipotent concentrations of halothane. Intraoperative cardiac arrest during the halothane era occurred over twice as frequently in neonates aged less than 1 month than in infants aged 1-12 months and nearly 10 times more frequently than children 1-5 years of age. Halothane was associated with 66% of intraoperative drug-related cardiac arrests in children. The halothane era began to close in the late 1990s with the introduction of sevoflurane, which had a more favorable hemodynamic profile. Shortly thereafter, halothane was completely displaced from pediatric anesthesia practice in North America.

Labetalol Infusion Attenuates Paradoxical Hypertension and Decreases Plasma Renin Activity After Repair of Coarctation of the Aorta in Children.

OBJECTIVE: Paradoxical hypertension after repair of coarctation of the aorta in children is associated with the release of catecholamines and activation of the renin-angiotensin system. The objective of the present study was to describe the effects of labetalol infusion on blood pressure, plasma catecholamine levels, and plasma renin activity in a series of children undergoing repair of coarctation of the aorta. DESIGN: Prospective, observational cohort study. SETTING: Tertiary children's hospital with university affiliation. PARTICIPANTS: The study was comprised of 15 consecutive children older than 1 year undergoing repair of coarctation of the aorta. INTERVENTIONS: Intravenous infusion of labetalol, up to 20 µg/kg/min, was administered when patients became hypertensive after release of the aortic cross-clamp. Supplementation with nitroprusside was allowed as needed. MEASUREMENTS AND MAIN RESULTS: Blood pressure was maintained below baseline values throughout the labetalol infusion. Plasma norepinephrine increased from 160 ± 81 pg/mL (preoperative) to 657 ± 268 pg/mL (6 h after release of aortic cross-clamp). Plasma renin activity decreased from 16.6 ± 9.7 ng/kg/h (at cross-clamp release) to 2.2 ± 2.2 ng/kg/h (6 h after cross-clamp release). Nitroprusside was added for 12 patients, at a highest mean dose of 2.4 ± 2.5 µg/kg/min. CONCLUSIONS: Labetalol inhibited activation of the renin-angiotensin system and helped control paradoxical hypertension after coarctation repair in children.

Building an International Community of Paediatric Anaesthesiologists: An interview with Dr Edward Sumner.

Dr Edward Sumner (1940) enjoyed a remarkably productive career as consultant pediatric anesthetist at the Great Ormond Street Hospital for Children. His leadership in clinical care helped his department rise to eminence. He trained hundreds of registrars in pediatric anesthesia and educated thousands more through invited lectures and by co-editing leading textbooks of neonatal and pediatric anesthesia. During his long tenure as Editor-in-Chief of Pediatric Anesthesia, he led the growth of the young journal to prominence. Based on an interview and a long-standing professional and personal friendship of forty-four years, this article reviews Ted Sumner's outstanding contributions to the specialty of pediatric anesthesia and to the development of a strong international community of pediatric anesthesiologists.

A small-molecule fusion inhibitor of influenza virus is orally active in mice.

Recent characterization of broadly neutralizing antibodies (bnAbs) against influenza virus identified the conserved hemagglutinin (HA) stem as a target for development of universal vaccines and therapeutics. Although several stem bnAbs are being evaluated in clinical trials, antibodies are generally unsuited for oral delivery. Guided by structural knowledge of the interactions and mechanism of anti-stem bnAb CR6261, we selected and optimized small molecules that mimic the bnAb functionality. Our lead compound neutralizes influenza A group 1 viruses by inhibiting HA-mediated fusion in vitro, protects mice against lethal and sublethal influenza challenge after oral administration, and effectively neutralizes virus infection in reconstituted three-dimensional cell culture of fully differentiated human bronchial epithelial cells. Cocrystal structures with H1 and H5 HAs reveal that the lead compound recapitulates the bnAb hotspot interactions.

Universal protection against influenza infection by a multidomain antibody to influenza hemagglutinin.

Broadly neutralizing antibodies against highly variable pathogens have stimulated the design of vaccines and therapeutics. We report the use of diverse camelid single-domain antibodies to influenza virus hemagglutinin to generate multidomain antibodies with impressive breadth and potency. Multidomain antibody MD3606 protects mice against influenza A and B infection when administered intravenously or expressed locally from a recombinant adeno-associated virus vector. Crystal and single-particle electron microscopy structures of these antibodies with hemagglutinins from influenza A and B viruses reveal binding to highly conserved epitopes. Collectively, our findings demonstrate that multidomain antibodies targeting multiple epitopes exhibit enhanced virus cross-reactivity and potency. In combination with adeno-associated virus-mediated gene delivery, they may provide an effective strategy to prevent infection with influenza virus and other highly variable pathogens.

Potent peptidic fusion inhibitors of influenza virus.

Influenza therapeutics with new targets and mechanisms of action are urgently needed to combat potential pandemics, emerging viruses, and constantly mutating strains in circulation. We report here on the design and structural characterization of potent peptidic inhibitors of influenza hemagglutinin. The peptide design was based on complementarity-determining region loops of human broadly neutralizing antibodies against the hemagglutinin (FI6v3 and CR9114). The optimized peptides exhibit nanomolar affinity and neutralization against influenza A group 1 viruses, including the 2009 H1N1 pandemic and avian H5N1 strains. The peptide inhibitors bind to the highly conserved stem epitope and block the low pH-induced conformational rearrangements associated with membrane fusion. These peptidic compounds and their advantageous biological properties should accelerate the development of new small molecule- and peptide-based therapeutics against influenza virus.

The phenylephrine concentration-response relationship for blood pressure after nasal delivery in children.

BACKGROUND: Intranasal phenylephrine is commonly used to vasoconstrict the nasal mucosa, reducing bleeding associated with nasotracheal intubation or endoscopic sinus surgery. There are few data quantifying either absorption pharmacokinetics or phenylephrine concentration effect on blood pressure in children. METHODS: Published observations of plasma concentration and blood pressure changes after phenylephrine nasal administration (0.1 mL kg-1 , 0.25% or 0.5%) in children (n = 52, 2-12 years, 10-40 kg) were pooled with those in adults (23-81 years) given phenylephrine 2.5% (n = 10) and 10% (n = 10) eyedrops. Further pharmacokinetic (PK) data were available from healthy volunteers given oral phenylephrine 10 mg alone, with blood for concentration assay taken at 5, 15, 30, 45 minutes and 1, 2, 3, 6 hours (n = 28). Intravenous time-concentration data were available from four healthy volunteers given phenylephrine 1 mg and who had blood taken for assay on 17 occasions over the subsequent 4 hours. Data were analyzed using an integrated pharmacokinetic-pharmacodynamic (PK-PD) model using nonlinear mixed-effects models. Allometry, scaled to a 70-kg person, was used for PK size standardization. Effect was described using an EMAX model. RESULTS: A two-compartment model was used to fit PK data while an additional compartment, linked by an equilibration half-time (T1/2 keo), was used to describe effect. PK parameter estimates for the nasal formulation were clearance (CL) 160 L h-1 , central volume of distribution (V1) 13.3 L, intercompartment clearance (Q) 25.3 L h-1 , peripheral volume of distribution (V2) 225 L, absorption half-time (Tabs) 6.2 minutes, absorption lag time (Tlag) 1.5 minutes, and bioavailability (F) 0.183. Bioavailability and absorption of the ophthalmic solution were concentration dependent (F 0.13, Tabs 5.5 minutes for 2.5% solution; F 0.15, Tabs 9.6 minutes for 10% solution). Absorption of the oral formulation was slow (Tabs 48 minutes) with poor bioavailability (F 0.0128). The pediatric PD interrogation revealed a baseline mean arterial pressure of 60 mm Hg, a maximum effect (EMAX ) of 25 mm Hg, and an EC50 of 10.3 µg L-1 . The effect on vasculature was immediate and T1/2 keo was not estimable. CONCLUSION: Absorption of phenylephrine through the nasal mucosa was rapid and similar to the ophthalmic formulation. Bioavailability was also similar to the ophthalmic formulation. The maximum effect (EMAX ) in children was half that in adults (EMAX 50 mm Hg).

Lack of Association Between Adrenoreceptor Genotype and the Vasoconstriction Response to Dexmedetomidine.

An exaggerated vasoconstriction response to dexmedetomidine, an α-2 adrenergic agonist, has been associated with 2 genotypes: a deletion in the α-2B adrenoreceptor gene ( ADRA2B deletion) and SNP rs9922316 in the gene for protein kinase C type ß ( PRKCB). We hypothesized that children with a marked systemic vascular resistance index (SVRI) increase following intravenous dexmedetomidine bolus would carry these genotypes. Following institutional review board approval, DNA samples from 16 children with transplanted hearts who participated in a study in the cardiac catheterization laboratory of hemodynamic responses to dexmedetomidine boluses underwent genotyping by polymerase chain reaction (PCR) amplification and PCR Sanger sequencing for the ADRA2B deletion and for PRKCB rs9922316. A wide range of SVRI (-12% to +76%, median 33%) and mean arterial blood pressure (MAP; -7% to +50%, median 26%) responses to dexmedetomidine was observed. The responses were not significantly different among genotype groups. An association between exaggerated SVRI or MAP responses and either ADRA2B deletion or PRKCB rs9922316 was not observed.

Hemodynamic responses and plasma phenylephrine concentrations associated with intranasal phenylephrine in children.

INTRODUCTION: Intranasal phenylephrine, an alpha-1 adrenergic agonist, causes vasoconstriction of the nasal mucosa and is used to reduce bleeding associated with nasotracheal intubation or endoscopic sinus surgery. The purpose of this study was to describe the hemodynamic effects associated with plasma phenylephrine concentrations following topical intranasal administration of 0.25% and 0.5% phenylephrine in children. METHODS: After Institutional Review Board and parental approval, 77 children between the ages of 2 and 12 years were studied in a prospective, double-blind manner and randomized into three groups. Group 1 received intranasal saline, while groups 2 and 3 received 0.1 mL/kg of 0.25% or 0.5% phenylephrine, respectively. All received the same anesthetic of halothane, N2 O, O2 , and vecuronium. After inhalation induction, endtidal halothane and PaCO2 were maintained at 1.5% and 35 mm Hg, respectively. Heart rate and rhythm, systolic, diastolic, and mean, noninvasive arterial blood pressures were recorded and venous blood was obtained for measurement of plasma phenylephrine concentration by high-performance liquid chromatography at baseline and at 2, 5, 10, and 20 minutes following intranasal spray application of the study drug. Nasotracheal intubation was performed immediately following the 5-minute measurements, and the presence of bleeding was assessed. Hemodynamic data were compared by analysis of variance for repeated measures. Bleeding and arrhythmia incidence among groups were analyzed using chi-squared tests. Phenylephrine levels were correlated with hemodynamic values via regression analysis. RESULTS: Fifty-two patients received intranasal phenylephrine. Increases in blood pressure correlated with increasing plasma phenylephrine concentration. Systolic blood pressure increased 8%, and mean blood pressure increased 14%, which were statistically significant but clinically insignificant. Heart rate did not change, and the incidence of arrhythmia was low and similar among groups. Bleeding following nasotracheal intubation was less frequent in Group 3 (11/27 subjects) than in Group 1 (17/25). Peak plasma phenylephrine concentrations were observed by 14±7 minutes following intranasal administration, and were highly variable among individuals (37.8±39.7 and 49.6±93.9 ng/mL [mean±SD] in Groups 2 and 3). DISCUSSION: Administration of intranasal phenylephrine, 0.25% and 0.50%, results in rapid but highly variable systemic absorption that is associated with mild increases of blood pressure that are clinically insignificant. Bleeding associated with nasotracheal intubation was less following administration of 0.5% intranasal phenylephrine than following intranasal saline.

Breathing circuit compliance and accuracy of displayed tidal volume during pressure-controlled ventilation of infants: A quality improvement project.

INTRODUCTION: Anesthesia machines have evolved to deliver desired tidal volumes more accurately by measuring breathing circuit compliance during a preuse self-test and then incorporating the compliance value when calculating expired tidal volume. The initial compliance value is utilized in tidal volume calculation regardless of whether the actual compliance of the breathing circuit changes during a case, as happens when corrugated circuit tubing is manually expanded after the preuse self-test but before patient use. We noticed that the anesthesia machine preuse self-test was usually performed on nonexpanded pediatric circuit tubing, and then the breathing circuit was subsequently expanded for clinical use. We aimed to demonstrate that performing the preuse self-test in that manner could lead to incorrectly displayed tidal volume on the anesthesia machine monitor. The goal of this quality improvement project was to change the usual practice and improve the accuracy of displayed tidal volume in infants undergoing general anesthesia. METHODS: There were four stages of the project: (i) gathering baseline data about the performance of the preuse self-test and using infant and adult test lungs to measure discrepancies of displayed tidal volumes when breathing circuit compliance was changed after the initial preuse self-test; (ii) gathering clinical data during pressure-controlled ventilation comparing anesthesia machine displayed tidal volume with actual spirometry tidal volume in patients less than 10 kg before (machine preuse self-test performed while the breathing circuit was nonexpanded) and after an intervention (machine preuse self-test performed after the breathing circuit was fully expanded); (iii) performing department-wide education to help implement practice change; (iv) gathering postintervention data to determine the prevalence of proper machine preuse self-test. RESULTS: At constant pressure-controlled ventilation through fully expanded circuit tubing, displayed tidal volume was 83% greater in the infant test lung (mean±SD TV 15±5 vs 9±4 mL; mean [95% CI] difference=6.3 [5.6, 7.1] mL, P<.0001) and 3% greater in the adult test lung (245±74 vs 241±72 mL; difference=5 [1, 10] mL, P=.0905) when circuit compliance had been measured with nonexpanded tubing compared to when circuit compliance was measured with fully expanded tubing. The clinical data in infants demonstrated that displayed tidal volume was 41% greater than actual tidal volume (difference of 10.4 [8.6, 12.2] mL) when the circuit was expanded after the preuse self-test (preintervention) and 7% greater (difference of 2.5 [0.7, 4.2] mL) in subjects when the circuit was expanded prior to the preuse self-test (postintervention) (P<.0001). Clinical practice was changed following an intervention of departmental education: the preuse self-test was performed on expanded circuit tubing 11% of the time prior to the intervention and 100% following the intervention. CONCLUSION: Performing a preuse self-test on a nonexpanded pediatric circuit that is then expanded leads to falsely elevated displayed tidal volume in infants less than 10 kg during pressure-controlled ventilation. Overestimation of reported tidal volume can be avoided by expanding the breathing circuit tubing to the length which will be used during a case prior to performing the anesthesia machine preuse self-test. After department-wide education and implementation, performing a correct preuse self-test is now the standard practice in our cardiac operating rooms.

The Anesthetic Challenges of Lung Biopsy-Associated Intrathoracic Hemorrhage in a Child With Suprasystemic Pulmonary Hypertension.

Children with suspected pulmonary hypertension must undergo extensive and invasive evaluations to establish a definitive diagnosis. A previously healthy 4-year old girl, newly diagnosed with suprasystemic pulmonary hypertension required multiple lung biopsies. Each procedure was associated with significant bleeding. The challenging anesthetic management of lung biopsy in the presence of suprasystemic pulmonary hypertension is described.

Landmark papers in pediatric cardiac anesthesia: documenting the history of the specialty.

Pediatric cardiac anesthesia has developed over the past eight decades into a specialty delivering complex clinical care and contributing remarkable scientific progress. The history of this development can be traced through journal articles that mark the strides of the specialty. This article discusses journal articles, chosen by the author, that he considers had a significant impact on the practice of pediatric cardiac anesthesia or are of historical interest.

HA Antibody-Mediated FcγRIIIa Activity Is Both Dependent on FcR Engagement and Interactions between HA and Sialic Acids.

Interactions with receptors for the Fc region of IgG (FcγRs) have been shown to contribute to the in vivo protection against influenza A viruses provided by broadly neutralizing antibodies (bnAbs) that bind to the viral hemagglutinin (HA) stem. In particular, Fc-mediated antibody-dependent cellular cytotoxicity (ADCC) has been shown to contribute to protection by stem-binding bnAbs. Fc-mediated effector functions appear not to contribute to protection provided by strain-specific HA head-binding antibodies. We used a panel of anti-stem and anti-head influenza A and B monoclonal antibodies with identical human IgG1 Fc domains and investigated their ability to mediate ADCC-associated FcγRIIIa activation. Antibodies which do not interfere with sialic acid binding of HA can mediate FcγRIIIa activation. However, the FcγRIIIa activation was inhibited when a mutant HA, unable to bind sialic acids, was used. Antibodies which block sialic acid receptor interactions of HA interfered with FcγRIIIa activation. The inhibition of FcγRIIIa activation by HA head-binding and sialic acid receptor-blocking antibodies was confirmed in plasma samples of H5N1 vaccinated human subjects. Together, these results suggest that in addition to Fc-FcγR binding, interactions between HA and sialic acids on immune cells are required for optimal Fc-mediated effector functions by anti-HA antibodies.

Remifentanil and propofol undergo separation and layering when mixed in the same syringe for total intravenous anesthesia.

BACKGROUND: Propofol and remifentanil can be combined to deliver total intravenous anesthesia (TIVA). Propofol and remifentanil are sometimes mixed in the same syringe. Since remifentanil is a solution and propofol is an emulsion, we hypothesized that they would separate over time when mixed in the same syringe. METHODS: Nine 60-ml polypropylene syringes were prepared as follows: Group A: 1.25 ml of remifentanil solution (1 mg·ml(-1) ) was added to 48.75 ml of propofol (10 mg·ml(-1) ) in three syringes. Group B: 2.5 ml of remifentanil (1 mg·ml(-1) ) was added to 47.5 ml of propofol (10 mg·ml(-1) ) in three syringes. Group C: 5 ml of remifentanil (1 mg·ml(-1) ) was added to 45 ml of propofol (10 mg·ml(-1) ) in three syringes. The remifentanil lyophilized powder was reconstituted with sterile water and added to the propofol by injection through the port on the bottom of the syringe. The syringe was then inverted five times in succession to mix the drugs. The syringes were mounted in an upright vertical position (plunger on top, port on bottom) with wire on a pegboard. Samples of the mixture were taken from the bottom port (via a 3-way stopcock) and from the top of the syringe (via a stopcock on an 18-gauge needle placed 5 mm through the plunger) at the following time intervals (min) from baseline: T0, T10, T30, T60, T120, T180, T240, T300. Remifentanil and propofol were quantified using specific and validated HPLC/MS/MS assays with automated online sample preparation. RESULTS: Concentrations of remifentanil were significantly greater at the top than the bottom of the syringes in groups A and B. Concentrations of propofol were significantly greater at the bottom than the top of the syringes in all groups. CONCLUSION: Our data indicate that remifentanil solution and propofol emulsion are immiscible: remifentanil separates from propofol and rises to the top. Thus, concentrations of remifentanil and propofol delivered to patients from the same syringe during TIVA are not those expected and cannot be reliable. Remifentanil and propofol should be administered in separate syringes when used in combination for TIVA.

A Decline in Intraoperative Renal Near-Infrared Spectroscopy Is Associated With Adverse Outcomes in Children Following Cardiac Surgery.

OBJECTIVES: Renal near-infrared spectroscopy is known to be predictive of acute kidney injury in children following cardiac surgery using a series of complex equations and area under the curve. This study was performed to determine if a greater than or equal to 20% reduction in renal near-infrared spectroscopy for 20 consecutive minutes intraoperatively or within the first 24 postoperative hours is associated with 1) acute kidney injury, 2) increased acute kidney injury biomarkers, or 3) other adverse clinical outcomes in children following cardiac surgery. DESIGN: Prospective single center observational study. SETTING: Pediatric cardiac ICU. PATIENTS: Children less than or equal to age 4 years who underwent cardiac surgery with the use of cardiopulmonary bypass during the study period (June 2011-July 2012). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A reduction in near-infrared spectroscopy was not associated with acute kidney injury. Nine of 12 patients (75%) with a reduction in renal near-infrared spectroscopy did not develop acute kidney injury. The remaining three patients had mild acute kidney injury (pediatric Risk, Injury, Failure, Loss, End stage-Risk). A reduction in renal near-infrared spectroscopy was associated with the following adverse clinical outcomes: 1) a longer duration of mechanical ventilation (p = 0.05), 2) longer intensive care length of stay (p = 0.05), and 3) longer hospital length of stay (p < 0.01). A decline in renal near-infrared spectroscopy in combination with an increase in serum interleukin-6 and serum interleukin-8 was associated with a longer intensive care length of stay, and the addition of urine interleukin-18 to this was associated with a longer hospital length of stay. CONCLUSIONS: In this cohort, the rate of acute kidney injury was much lower than anticipated thereby limiting the evaluation of a reduction in renal near-infrared spectroscopy as a predictor of acute kidney injury. A greater than or equal to 20% reduction in renal near-infrared spectroscopy was significantly associated with adverse outcomes in children following cardiac surgery. The addition of specific biomarkers to the model was predictive of worse outcomes in these patients. Thus, real-time evaluation of renal near-infrared spectroscopy using the specific levels of change of a 20% reduction for 20 minutes may be useful in predicting prolonged mechanical ventilation and other adverse outcomes in children undergoing cardiac surgery.