Electroencephalographic indices for clinical endpoints during propofol anesthesia in infants-an early phase propofol biomarker-finding study.

BACKGROUND: Unlike expired sevoflurane concentration, propofol lacks a biomarker for its brain effect site concentration (Ce), leading to dosing imprecision particularly in infants. Electroencephalography (EEG) monitoring can serve as a biomarker for propofol Ce, yet proprietary EEG indices are not validated in infants. We evaluated spectral edge frequency (SEF95) as a propofol anesthesia biomarker in infants. We hypothesized that the SEF95 targets will vary for different clinical stimuli and an inverse relationship existed between SEF95 and propofol plasma concentration. METHODS: This prospective study enrolled infants (3-12 months) to determine the SEF95 ranges for three clinical endpoints of anesthesia (consciousness-pacifier placement, pain-electrical nerve stimulation, and intubation-laryngoscopy) and correlation between SEF95 and propofol plasma concentration at steady state. Dixon's Up-Down method was used to determine target SEF95 for each clinical endpoint. Centered isotonic regression determined the dose-response function of SEF95 where 50% and 90% of infants (ED50 and ED90) did not respond to the clinical endpoint. Linear mixed-effect model determined the association of propofol plasma concentration and SEF95. RESULTS: Of 49 enrolled infants, 44 evaluable (90%) showed distinct SEF95 for endpoints: pacifier (ED50 21.4Hz, ED90 19.3Hz), electrical stimulation (ED50 12.6Hz, ED90 10.4Hz), and laryngoscopy (ED50 8.5Hz, ED90 5.2Hz). From propofol 0.5-6 µg/ml, a 1 Hz SEF95 increase was linearly correlated to a 0.24 (95% CI: 0.19 - 0.29, p<0.001) µg/mL decrease in plasma propofol concentration (marginal R 2 = 0.55). CONCLUSIONS: SEF95 can be a biomarker for propofol anesthesia depth in infants, potentially improving dosing accuracy and utilization of propofol anesthesia in this population.

γ-Aminobutyric Acid-Ergic Development Contributes to the Enhancement of Electroencephalogram Slow-Delta Oscillations Under Volatile Anesthesia in Neonatal Rats.

BACKGROUND: General anesthetics (eg, propofol and volatile anesthetics) enhance the slow-delta oscillations of the cortical electroencephalogram (EEG), which partly results from the enhancement of (γ-aminobutyric acid [GABA]) γ-aminobutyric acid-ergic (GABAergic) transmission. There is a GABAergic excitatory-inhibitory shift during postnatal development. Whether general anesthetics can enhance slow-delta oscillations in the immature brain has not yet been unequivocally determined. METHODS: Perforated patch-clamp recording was used to confirm the reversal potential of GABAergic currents throughout GABAergic development in acute brain slices of neonatal rats. The power density of the electrocorticogram and the minimum alveolar concentrations (MAC) of isoflurane and/or sevoflurane were measured in P4-P21 rats. Then, the effects of bumetanide, an inhibitor of the Na + -K + -2Cl - cotransporter (NKCC1) and K + -Cl - cotransporter (KCC2) knockdown on the potency of volatile anesthetics and the power density of the EEG were determined in vivo. RESULTS: Reversal potential of GABAergic currents were gradually hyperpolarized from P4 to P21 in cortical pyramidal neurons. Bumetanide enhanced the hypnotic effects of volatile anesthetics at P5 (for MAC LORR , isoflurane: 0.63% ± 0.07% vs 0.81% ± 0.05%, 95% confidence interval [CI], -0.257 to -0.103, P < .001; sevoflurane: 1.46% ± 0.12% vs 1.66% ± 0.09%, 95% CI, -0.319 to -0.081, P < .001); while knockdown of KCC2 weakened their hypnotic effects at P21 in rats (for MAC LORR , isoflurane: 0.58% ± 0.05% to 0.77% ± 0.20%, 95% CI, 0.013-0.357, P = .003; sevoflurane: 1.17% ± 0.04% to 1.33% ± 0.04%, 95% CI, 0.078-0.244, P < .001). For cortical EEG, slow-delta oscillations were the predominant components of the EEG spectrum in neonatal rats. Isoflurane and/or sevoflurane suppressed the power density of slow-delta oscillations rather than enhancement of it until GABAergic maturity. Enhancement of slow-delta oscillations under volatile anesthetics was simulated by preinjection of bumetanide at P5 (isoflurane: slow-delta changed ratio from -0.31 ± 0.22 to 1.57 ± 1.15, 95% CI, 0.67-3.08, P = .007; sevoflurane: slow-delta changed ratio from -0.46 ± 0.25 to 0.95 ± 0.97, 95% CI, 0.38-2.45, P = .014); and suppressed by KCC2-siRNA at P21 (isoflurane: slow-delta changed ratio from 16.13 ± 5.69 to 3.98 ± 2.35, 95% CI, -18.50 to -5.80, P = .002; sevoflurane: slow-delta changed ratio from 0.13 ± 2.82 to 3.23 ± 2.49, 95% CI, 3.02-10.79, P = .003). CONCLUSIONS: Enhancement of cortical EEG slow-delta oscillations by volatile anesthetics may require mature GABAergic inhibitory transmission during neonatal development.

Implementation of an electroencephalogram-guided propofol anesthesia education program in an academic pediatric anesthesia practice.

BACKGROUND: Propofol total intravenous anesthesia (TIVA) is increasingly popular in pediatric anesthesia, but education on its use is variable and over-dosage adverse events are not uncommon. Recent work suggests that electroencephalogram (EEG) parameters can guide propofol dosing in the pediatric population. This education quality improvement project aimed to implement a standardized EEG TIVA training program over 12 months in a large pediatric anesthesia division. METHODS: The division consisted of 63 faculty, 11 clinical fellows, 32 residents, and 28 nurse anesthetists at the Children's Hospital of Philadelphia. The program was assessed for effectiveness (a significant improvement in EEG knowledge scores), scalability (training 50% of fellows and staff), and sustainability (recurring EEG lectures for 80% of rotating residents and 100% of new fellows and staff). The key drivers included educational content development (lectures, articles, and hand-outs), training a cohort of EEG TIVA trainers, intraoperative teaching (teaching points and dosing tables), decision support tools (algorithms and anesthesia electronic record pop-ups), and knowledge tests (written exam and verbal quiz during cases). RESULTS: Over 12 months, 78.5% of the division (62/79) completed EEG training and test scores improved (mean score 38% before training vs 59% after training, p < .001). Didactic lectures were given to 100% of the fellows, 100% (11/11) of new staff, and 80% (4/5 blocks) of rotating residents. CONCLUSION: This quality improvement education project successfully trained pediatric anesthesia faculty, staff, residents, and fellows in EEG-guided TIVA. The training program was effective, scalable, and sustainable over time for newly hired faculty staff and rotating fellows and residents.

Isoelectric Electroencephalography in Infants and Toddlers during Anesthesia for Surgery: An International Observational Study.

BACKGROUND: Intraoperative isoelectric electroencephalography (EEG) has been associated with hypotension and postoperative delirium in adults. This international prospective observational study sought to determine the prevalence of isoelectric EEG in young children during anesthesia. The authors hypothesized that the prevalence of isoelectric events would be common worldwide and associated with certain anesthetic practices and intraoperative hypotension. METHODS: Fifteen hospitals enrolled patients age 36 months or younger for surgery using sevoflurane or propofol anesthetic. Frontal four-channel EEG was recorded for isoelectric events. Demographics, anesthetic, emergence behavior, and Pediatric Quality of Life variables were analyzed for association with isoelectric events. RESULTS: Isoelectric events occurred in 32% (206 of 648) of patients, varied significantly among sites (9 to 88%), and were most prevalent during pre-incision (117 of 628; 19%) and surgical maintenance (117 of 643; 18%). Isoelectric events were more likely with infants younger than 3 months (odds ratio, 4.4; 95% CI, 2.57 to 7.4; P < 0.001), endotracheal tube use (odds ratio, 1.78; 95% CI, 1.16 to 2.73; P = 0.008), and propofol bolus for airway placement after sevoflurane induction (odds ratio, 2.92; 95% CI, 1.78 to 4.8; P < 0.001), and less likely with use of muscle relaxant for intubation (odds ratio, 0.67; 95% CI, 0.46 to 0.99; P = 0.046]. Expired sevoflurane was higher in patients with isoelectric events during preincision (mean difference, 0.2%; 95% CI, 0.1 to 0.4; P = 0.005) and surgical maintenance (mean difference, 0.2%; 95% CI, 0.1 to 0.3; P = 0.002). Isoelectric events were associated with moderate (8 of 12, 67%) and severe hypotension (11 of 18, 61%) during preincision (odds ratio, 4.6; 95% CI, 1.30 to 16.1; P = 0.018) (odds ratio, 3.54; 95% CI, 1.27 to 9.9; P = 0.015) and surgical maintenance (odds ratio, 3.64; 95% CI, 1.71 to 7.8; P = 0.001) (odds ratio, 7.1; 95% CI, 1.78 to 28.1; P = 0.005), and lower Pediatric Quality of Life scores at baseline in patients 0 to 12 months (median of differences, -3.5; 95% CI, -6.2 to -0.7; P = 0.008) and 25 to 36 months (median of differences, -6.3; 95% CI, -10.4 to -2.1; P = 0.003) and 30-day follow-up in 0 to 12 months (median of differences, -2.8; 95% CI, -4.9 to 0; P = 0.036). Isoelectric events were not associated with emergence behavior or anesthetic (sevoflurane vs. propofol). CONCLUSIONS: Isoelectric events were common worldwide in young children during anesthesia and associated with age, specific anesthetic practices, and intraoperative hypotension.

Functional near-infrared spectroscopy to assess pain in neonatal circumcisions.

INTRODUCTION: Pain assessment is challenging in neonates. Behavioral and physiological pain scales do not assess neocortical nociception, essential to pain encoding and central pain pathway development. Functional near-infrared spectroscopy (fNIRS) can assess neocortical activation to noxious stimuli from changes in oxy-(HbO) and total-hemoglobin concentrations (HbT). This study aims to assess fNIRS nociceptive functional activation in the prefrontal cortex of neonates undergoing circumcision through changes in HbO and HbT, and the correlation between changes in fNIRS and Neonatal Infant Pain Scale (NIPS), a behavioral pain assessment scale. METHODS: In healthy term neonates, HbO, HbT, and NIPS were recorded during sequential circumcision events 1-Prep before local anesthetic injection; 2-Local anesthetic injection; 3-Prep before incision; 4-Oral sucrose; 5-Incision; 6-Gomco (hemostatic device) attached; 7-Gomco twisted on; and 8-Gomco removed. fNIRS and NIPS changes after each event were assessed with Wilcoxon signed-rank test and summarized as median and interquartile range (IQR). Changes in fNIRS vs. NIPS were correlated with Spearman coefficient. RESULTS: In 31 neonates fNIRS increased (median [IQR] µmol/L) with noxious events: Local injection (HbO: 1.1 [0.5, 3.1], p < .001; HbT: 2.3 [0.2, 7.6], p < .001), Gomco attached (HbO: 0.7 [0.1, 1.7], p = .002; HbT: 0.7 [-0.2, 2.9], p = .02), and Gomco twisted on (HbO: 0.5 [-0.2, 1.7], p = .03; HbT: 0.8 [-0.1, 3.3], p = .02). fNIRS decreased with non-noxious event: Prep before incision (HbO: -0.6 [-1.2, -0.2] p < .001; HbT: -1 [-1.8, -0.4], p < .001). Local anesthetic attenuated fNIRS increases to subsequent sharp stimuli. NIPS increased with subsequent sharp stimuli despite local anesthetic. Although fNIRS and NIPS changed in the same direction, there was not a strong correlation between them. CONCLUSIONS: During neonatal circumcision, changes in fNIRS differed between different types of painful stimuli, which was not the case for NIPS, suggesting that fNIRS may complement NIPS to assess the quality of pain.

Prevalence of Isoelectric Electroencephalography Events in Infants and Young Children Undergoing General Anesthesia.

BACKGROUND: In infants and young children, anesthetic dosing is based on population pharmacokinetics and patient hemodynamics not on patient-specific brain activity. Electroencephalography (EEG) provides insight into brain activity during anesthesia. The primary goal of this prospective observational pilot study was to assess the prevalence of isoelectric EEG events-a sign of deep anesthesia-in infants and young children undergoing general anesthesia using sevoflurane or propofol infusion for maintenance. METHODS: Children 0-37 months of age requiring general anesthesia for surgery excluding cardiac, intracranial, and emergency cases were enrolled by age: 0-3, 4-6, 7-12, 13-18, and 19-37 months. Anesthesia was maintained with sevoflurane or propofol infusion. EEG was recorded from induction to extubation. Isoelectric EEG events (amplitude <20 µV, lasting ≥2 seconds) were characterized by occurrence, number, duration, and percent of isoelectric EEG time over anesthetic time. Associations with patient demographics, anesthetic, and surgical factors were determined. RESULTS: Isoelectric events were observed in 63% (32/51) (95% confidence interval [CI], 49-76) of patients. The median (interquartile range [IQR]) number of isoelectric events per patient was 3 (0-31), cumulative isoelectric time per patient was 12 seconds (0-142 seconds), isoelectric time per event was 3 seconds (0-4 seconds), and percent of total isoelectric over anesthetic time was 0.1% (0%-2.2%). The greatest proportion of isoelectric events occurred between induction and incision. Isoelectric events were associated with higher American Society of Anesthesiologists (ASA) physical status, propofol bolus, endotracheal tube use, and lower arterial pressure during surgical phase. CONCLUSIONS: Isoelectric EEG events were common in infants and young children undergoing sevoflurane or propofol anesthesia. Although the clinical significance of these events remains uncertain, they suggest that dosing based on population pharmacokinetics and patient hemodynamics is often associated with unnecessary deep anesthesia during surgical procedures.

Statistical Analysis Plan for "An international multicenter study of isoelectric electroencephalography events in infants and young children during anesthesia for surgery".

This Statistical Analysis Plan details the statistical procedures to be applied for the analysis of data for the multicenter electroencephalography study. It consists of a basic description of the study in broad terms and separate sections that detail the methods of different aspects of the statistical analysis, summarized under the following headings (a) Background; (b) Definitions of protocol violations; (c) Definitions of objectives and other terms; (d) Variables for analyses; (e) Handling of missing data and study bias; (f) Statistical analysis of the primary and secondary study outcomes; (g) Reporting of study results; and (h) References. It serves as a template for researchers interested in writing a Statistical Analysis Plan.

Guide to the statistical analysis plan.

Biomedical research has been struck with the problem of study findings that are not reproducible. With the advent of large databases and powerful statistical software, it has become easier to find associations and form conclusions from data without forming an a-priori hypothesis. This approach may yield associations without clinical relevance, false positive findings, or biased results due to "fishing" for the desired results. To improve reproducibility, transparency, and validity among clinical trials, the National Institute of Health recently updated its grant application requirements, which mandates registration of clinical trials and submission of the original statistical analysis plan (SAP) along with the research protocol. Many leading journals also require the SAP as part of the submission package. The goal of this article and the companion article detailing the SAP of an actual research study is to provide a practical guide on writing an effective SAP. We describe the what, why, when, where, and who of a SAP, and highlight the key contents of the SAP.

Characterization of the functional near-infrared spectroscopy response to nociception in a pediatric population.

BACKGROUND: Near-infrared spectroscopy can interrogate functional optical signal changes in regional brain oxygenation and blood volume to nociception analogous to functional magnetic resonance imaging. AIMS: This exploratory study aimed to characterize the near-infrared spectroscopy signals for oxy-, deoxy-, and total hemoglobin from the brain in response to nociceptive stimulation of varying intensity and duration, and after analgesic and neuromuscular paralytic in a pediatric population. METHODS: We enrolled children 6 months-21 years during propofol sedation before surgery. The near-infrared spectroscopy sensor was placed on the forehead and nociception was produced from an electrical current applied to the wrist. We determined the near-infrared spectroscopy signal response to increasing current intensity and duration, and after fentanyl, sevoflurane, and neuromuscular paralytic. Heart rate and arm movement during electrical stimulation was also recorded. The near-infrared spectroscopy signals for oxy-, deoxy-, and total hemoglobin were calculated as optical density*time (area under curve). RESULTS: During electrical stimulation, nociception was evident: tachycardia and arm withdrawal was observed that disappeared after fentanyl and sevoflurane, whereas after paralytic, tachycardia persisted while arm withdrawal disappeared. The near-infrared spectroscopy signals for oxy-, deoxy-, and total hemoglobin increased during stimulation and decreased after stimulation; the areas under the curves were greater for stimulations 30 mA vs 15 mA (13.9 [5.6-22.2], P = .0021; 5.6 [0.8-10.5], P = .0254, and 19.8 [10.5-29.1], P = .0002 for HbO2 , Hb, and HbT , respectively), 50 Hz vs 1 Hz (17.2 [5.8-28.6], P = .0046; 7.5 [0.7-14.3], P = .0314, and 21.9 [4.2-39.6], P = .0177 for HbO2 , Hb, and HbT , respectively) and 45 seconds vs 15 seconds (16.3 [3.4-29.2], P = .0188 and 22.0 [7.5-36.5], P = .0075 for HbO2 and HbT , respectively); the areas under the curves were attenuated by analgesics but not by paralytic. CONCLUSION: Near-infrared spectroscopy detected functional activation to nociception in a broad pediatric population. The near-infrared spectroscopy response appears to represent nociceptive processing because the signals increased with noxious stimulus intensity and duration, and were blocked by analgesics but not paralytics.

Outcome for the extremely premature neonate: how far do we push the edge?

Significant advances in perinatal and neonatal medicine over the last 20 years and the recent emergence of fetal surgery has resulted in anesthesia providers caring for a growing number of infants born at the margin of viability. Anesthetic management in this patient population has to take into consideration the immature function of many vital organ systems as well as the effects of the underlying disease processes, which can frequently lead to severe physiological derangements. Accordingly, premature infants presenting for major surgeries early in life can represent a significant anesthetic challenge. However, even with advanced anesthetic and surgical management and optimal intensive care, extremely premature infants face substantial postoperative morbidity and mortality, as well as prolonged hospital courses. In this article, we will discuss the following questions: How far have we come in improving outcomes of extreme prematurity? And what will the future medical and societal challenges be, as we continue to redefine the limits of viability?

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. AIM: We hypothesized that supplemental intravenous anesthesia (SIVA) with propofol and remifentanil would lower the need for high-dose inhalational anesthesia and provide adequate maternal depth of anesthesia and uterine relaxation. SIVA technique would minimize prolonged fetal exposure to deep inhalational anesthetics and significant intraoperative fetal cardiovascular depression. BACKGROUND: Fetal hypoxia and significant fetal hemodynamic changes occur during open fetal surgery because of the challenges such as surgical manipulation, hysterotomy, uterine contractions, and effects of anesthetic drugs. Tocolysis, a vital component of fetal surgery, is usually achieved using volatile anesthetic agents. High concentrations of volatile agents required to provide an appropriate degree of uterine relaxation may cause maternal hypotension and placental hypoperfusion, as well as direct fetal cardiovascular depression. METHODS: We reviewed medical records of 39 patients who presented for ex utero intrapartum treatment and mid-gestation open fetal surgery between April 2004 and March 2009. Out of 39 patients, three were excluded because of the lack of echocardiographic data; 18 patients received high-concentration desflurane anesthesia and 18 patients had SIVA with desflurane for uterine relaxation. We analyzed the following data: demographics, fetal medical condition, anesthetic drugs, concentration and duration of desflurane, maternal arterial blood pressure, intraoperative fetal echocardiogram, presence of fetal bradycardia, and need for intraoperative fetal resuscitation. RESULTS: Adequate uterine relaxation was achieved with about 1.5 MAC of desflurane in the SIVA group compared to about 2.5 MAC in the desflurane only anesthesia group (P = 0.0001). More fetuses in the high-dose desflurane group compared to the SIVA group developed moderate-severe left ventricular systolic dysfunction over time intraoperatively (P = 0.02). 61% of fetuses in the high-dose desflurane group received fetal resuscitative interventions compared to 26% of fetuses in the SIVA group (P = 0.0489). CONCLUSION: SIVA as described provides adequate maternal anesthesia and uterine relaxation, and it allows for decreased use of desflurane during open fetal surgery. Decreased use of desflurane may better preserve fetal cardiac function.

Maternal pulmonary edema during fetoscopic surgery.

Minimally invasive fetal surgery uses small endoscopes placed percutaneously through the mother's abdominal wall in order to operate on a fetus, placenta or umbilical cord. We report a case of postoperative pulmonary edema in a mother who underwent minimally invasive fetal surgery for the treatment of twin reverse arterial perfusion sequence. The procedure involves ultrasound and fetoscopic guidance to interrupt umbilical vessel blood flow to one twin. Saline irrigation is used during the procedure to facilitate surgical exposure. We hypothesize that the pulmonary edema resulted from irrigating fluid (totaling net 8 L) absorbed i.v. through myometrial venous channels accessed by passage of the operating trocars.