Association of sedation and anesthesia on cognitive outcomes in very premature infants: a retrospective observational study.

PURPOSE: Cognitive outcomes in preterm infants may be adversely affected by use of sedation and anesthetic agents. We investigated the associations between anesthetics/sedatives and full-scale intelligence quotient (FSIQ) measured at 36 months corrected age (CA) in very preterm infants (born < 29 weeks gestational age). METHODS: This retrospective cohort study included preterm infants born at < 29 weeks of gestation between 1 January 2006 and 31 December 2012, whose cognitive outcomes were assessed at 36 months CA. Imputed and complete case univariable and adjusted multivariable linear regressions were used to investigate the associations between FSIQ [standardized to mean (standard deviation) 100 (15)] and exposure to volatile anesthetics, propofol, benzodiazepines, barbiturates, and ketamine. These agents were the subject of a 2016 warning from regulatory authorities in the USA recommending caution for administration to children and pregnant women. RESULTS: A total of 731 infants met the inclusion criteria. Unadjusted associations were -7 (95% confidence interval [CI], -10 to -4; P < 0.001) and -6 (95% CI, -10 to -3; P < 0.001) FSIQ points with exposure to warned medications using imputed and complete case analyses, respectively. Imputed and complete case adjusted associations between FSIQ and warned medications were -3 (95% CI, -7 to 0; P = 0.045) and -4 (95% CI, -8 to 0; P = 0.071) FSIQ points, respectively. Adjusted associations between volatile anesthetic exposure only and FSIQ were -3 (95% CI, -6 to 0; P = 0.072) and -5 (95% CI, -9 to -2; P = 0.004) FSIQ points using imputed and complete case data sets, respectively. FSIQ was not associated with opioid exposure. CONCLUSION: Exposure of very preterm infants to anesthetics/sedatives on the United States Food and Drug Administration warning list was associated with a decrease in FSIQ points at 36 months CA. There was no association between opioid exposure and FSIQ.

RéSUMé: OBJECTIF : L'utilization d'agents sédatifs et anesthésiques pourrait avoir une incidence défavorable sur l'évolution cognitive des nourrissons prématurés. Nous avons analysé les associations existantes entre les anesthésiques/sédatifs et le quotient d'intelligence global (QIg) mesuré à 36 mois d'âge corrigé (AC) chez des enfants nés grands prématurés (nés < 29 semaines d'âge gestationnel). MéTHODES: Cette étude de cohorte rétrospective a inclus des nourrissons prématurés nés avant 29 semaines d'âge gestationnel entre le 1er janvier 2006 et le 31 décembre 2012 et dont les critères d'évaluation cognitifs ont été évalués à 36 mois d'AC. Des régressions linéaires à une seule variable et multivariables ajustée, sur les cas imputés et sur les cas complets, ont été utilisées pour rechercher les associations entre le QIg (standardisé à la moyenne 100 [± écart-type] [15]) et l'exposition à des anesthésiques volatils, du propofol, des benzodiazépines, des barbituriques et de la kétamine. Ces molécules ont fait l'objet d'une mise en garde en 2016 par les autorités de réglementation aux États-Unis, recommandant la prudence concernant leur administration à des enfants et à des femmes enceintes. RéSULTATS: Un total de 731 nourrissons présentait les critères d'inclusion. Les associations non ajustées ont été de -7 (intervalle de confiance [IC] à 95 % : -10 à -4; P < 0,001) et -6 (IC à 95 % : -10 à -3; P < 0,001) points de QIg avec l'exposition aux médicaments sous avertissement en utilisant, respectivement, des analyses de cas imputés et de cas complets. Les associations ajustées de cas imputés et complets entre le QIg et les médicaments sous avertissement ont été, respectivement, de -3 (IC à 95 % : -7 à 0; P = 0,045) et -4 (IC à 95 % : -8 à 0; P = 0,071) points de QIg. Les associations ajustées entre l'exposition aux anesthésiques volatiles, uniquement, et le QIg ont été de -3 (IC à 95 % : -6 à 0; P = 0,072) et -5 (IC à 95 % : -9 à 2; P = 0,004) points de QIg en utilisant, respectivement, les ensembles de données des cas imputés et des cas complets. Le QIg n'a pas été associé à une exposition aux opioïdes. CONCLUSION: L'exposition des nourrissons grands prématurés aux anesthésiques/sédatifs figurant sur la liste d'avertissement de la Food and Drug Administration des États-Unis a été associée à une diminution des points de QIg à 36 mois d'AC. Il n'y a pas eu d'association entre l'exposition aux opioïdes et le QIg.

Anesthetic Neuroprotection in Experimental Stroke in Rodents: A Systematic Review and Meta-analysis.

BACKGROUND: Patients undergoing endovascular therapy for acute ischemic stroke may require general anesthesia to undergo the procedure. At present, there is little clinical evidence to guide the choice of anesthetic in this acute setting. The clinical implications of experimental studies demonstrating anesthetic neuroprotection are poorly understood. Here, the authors evaluated the impact of anesthetic treatment on neurologic outcome in experimental stroke. METHODS: Controlled studies of anesthetics in stroke using the filament occlusion model were identified in electronic databases up to December 15, 2015. The primary outcome measures, infarct volume, and neurologic deficit score were used to calculate the normalized mean difference for each comparison. Meta-analysis of normalized mean difference values provided estimates of neuroprotection and contributions of predefined factors: study quality, the timing of treatment, and the duration of ischemia. RESULTS: In 80 retrieved publications anesthetic treatment reduced neurologic injury by 28% (95% CI, 24 to 32%; P < 0.0001). Internal validity was high: publication bias enhanced the effect size by 4% or less, effect size increased with study quality (P = 0.0004), and approximately 70% of studies were adequately powered. Apart from study quality, no predefined factor influenced neuroprotection. Neuroprotection failed in animals with comorbidities. Neuroprotection by anesthetics was associated with prosurvival mechanisms. CONCLUSIONS: Anesthetic neuroprotection is a robust finding in studies using the filament occlusion model of ischemic stroke and should be assumed to influence outcomes in studies using this model. Neuroprotection failed in female animals and animals with comorbidities, suggesting that the results in young male animals may not reflect human stroke.

A systematic review and quantitative analysis of neurocognitive outcomes in children with four chronic illnesses.

BACKGROUND: Concern has been expressed that infants and children exposed to uneventful surgery and anesthesia may incur neurological injury that becomes manifest in poor scholastic performance or future learning difficulties. A recent meta-analysis of seven clinical studies examined the relationship between learning or behavior difficulties and pediatric exposure to anesthesia/surgery and reported an odds ratio of 1.4; however, the level of association and causal factors remain unclear. The purpose of our study is to provide context to the pediatric anesthesia neurotoxicity question by reviewing the evidence linking four childhood illnesses with neurocognitive development. In the present review, we have sought to quantify the magnitude of the impact of chronic illness on neurocognitive development through a systematic review of publications that report the developmental trajectory of patients with four childhood diseases: cystic fibrosis (CF), hemophilia A, end-stage renal disease (ESRD) and end-stage liver disease (ESLD). METHODS: Studies were identified by searching the electronic databases OVID MEDLINE and Pubmed and scanning reference lists of articles by two authors. Limits were applied to the English language and to humans. We used the following search terms: CF, hemophilia A, ESRD, ESLD in combination with academic performance, educational status, educational measurement, learning, achievement, developmental delay, learning disabilities, intellectual disabilities, behavioral disorders, intelligence quotient (IQ), cognition, school problems, absenteeism, school attendance, anxiety, learning regression, or developmental regression. The search strategy was reviewed independently by all four authors. Eligibility assessment was performed independently in an unblinded standardized manner by two authors who chose relevant articles from the overall search results by scanning the titles and abstracts of articles and from the references within citations. The full-text publications were reviewed by all four authors. All pertinent data related to the objectives were collected and independently reviewed by two authors. The data were summarized in the form reported in the studies. When possible, reported data were submitted to analysis with the Mantel-Haenszel method using a random effects model. Analyses were performed using the Review Manager computer program. RESULTS: In the studies retrieved, the main outcomes were measures of intellectual or cognitive characteristics, as exemplified by the Wechsler battery of tests. Reporting of measures of achievement (for example, GPA) was rare. Children with CF and hemophilia A did not appear disadvantaged by their disease as general intelligence levels were comparable with the general population norms. In children with ESRD, mean IQ reported during dialysis improved after transplantation. Although they improved relative to their pretransplantation cognitive functioning, children with ESLD who received transplants are approximately eight IQ points below the population norm. CONCLUSIONS: Overall, the results suggest that the burden of chronic childhood illness, by itself, does not impair cognitive development in children with hemophilia A and CF. Children with ESRD and ESLD, despite optimal management, show a mild cognitive deficit compared with the population norm. Given the impact of these four specific chronic illnesses on neurocognitive outcome in children and the improvement in IQ post-transplant in both ESRD and ESLD, the results suggest that the effect of an uncontrolled confounding illness on neurocognitive development is small.

Anesthetic management and outcome in patients during endovascular therapy for acute stroke.

BACKGROUND: Studies of endovascular treatment for acute ischemic stroke have identified general anesthesia as a predictor for poor outcome in comparison with local anesthesia/sedation. This retrospective study attempts to identify modifiable factors associated with poor outcome, while adjusting for baseline stroke severity, in patients receiving general anesthesia. METHODS: We reviewed charts of 129 patients treated between January 2003 and September 2009. The primary outcome was the modified Rankin Score of 0-2 for 3 months poststroke. Predictors of neurologic outcome included baseline National Institutes of Health Stroke Scale score, blood glucose concentration, and age. Additional risk factors evaluated were prolonged stroke onset-treatment interval and systolic blood pressure less than 140 mmHg. Choice of local anesthesia or general anesthesia was recorded. RESULTS: The study group was 96 out of 129 patients for whom modified Rankin Scale scores were available; 48 patients received general anesthesia and 48 local anesthesia. The proportion of patients with "good" outcomes were 15% and 60% in the general anesthesia group and local anesthesia group, respectively (P < 0.001). Lowest systolic blood pressure and general anesthesia were correlated (r = -0.7, P < 0.001). Independent predictors for good neurologic outcome were local anesthesia, systolic blood pressure greater than 140 mmHg, and low baseline stroke scores. CONCLUSIONS: Adjusted for stroke severity, patients who received general anesthesia for treatment are less likely to have a good outcome than those managed with local anesthesia. This may be due to preintervention risk not included in the stroke severity measures. Hypotension, more frequent in the general anesthesia patients, may also contribute.

Preventing persistent postsurgical pain: A systematic review and component network meta-analysis.

BACKGROUND AND OBJECTIVES: Evidence for perioperative methods to prevent persistent postsurgical pain (PPP) is uncertain, in part because few treatments have been directly compared. Here we have used component network meta-analysis (cNMA) to incorporate both direct and indirect evidence in the evaluation of the efficacy and tolerability of pharmacological and neural block treatments. DATABASES AND DATA TREATMENT: We searched the Cochrane Central Registry of Controlled Trials, Embase, MEDLINE, ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry up to January 2021 for randomized, double-masked, controlled trials that reported the prevalence of PPP. We assessed trial quality with the Cochrane risk of bias tool (RoB 2.0). We analysed the results with frequentist cNMA models. The primary outcome was the relative risk (RR) of PPP. We assessed efficacy in relation to a clinically important effect size of RR = 0.9, which is a 10% improvement with treatment. RESULTS: The analysis included 107 trials (13,553 participants) of 13 treatments. The effects of complex interventions were the multiplicative effects of their components. Compared with placebo, serotonin-norepinephrine reuptake inhibitors (SNRIs), neural block alone, or in combination with NMDA receptor blockers or gabapentanoids were effective. Treatments with benefit in the immediate post-operative period predicted a reduced risk of PPP. CONCLUSIONS: Several treatments and treatment combinations effectively reduce PPP prevalence. Pain outcomes in the immediate postoperative period are an important mediator of PPP. Multimodal interventions can be analysed using cNMA. SIGNIFICANCE: Systematic reviews of PPP prevention usually focus on the efficacy of specific treatments in comparison with control interventions. In this study we used component network meta-analysis to compare interventions to each other, including both pharmacological and neural block techniques, and multimodal interventions. Interventions that are not effective alone may improve the efficacy of multimodal interventions that include neural block techniques. Immediate postoperative benefit was an important mediator for reduction of PPP. STUDY REGISTRATION: PROSPERO: CRD42018085570 https://www.crd.york.ac.uk/prospero/.

Plaque Characteristics on CT Angiography Do Not Improve the Ability to Predict Hemodynamic Instability During and After Carotid Angioplasty and Stenting.

BACKGROUND: Hemodynamic instability is commonly seen during carotid angioplasty and stenting. Although prophylactic treatment with anticholinergics is beneficial, selected use in high-risk patients is desirable. This study examines whether plaque characteristics on computed tomography angiography in addition to demographic factors improve predictive capability. METHODS: We retrospectively collected information from 298 carotid angioplasty procedures between January 2013 and December 2018. Nine individuals were excluded due to a previous ipsilateral endarterectomy. Our primary outcome was a decrease of 20% or more in heart rate or blood pressure at angioplasty. Data were analyzed using χ2 tests and regression statistics. RESULTS: Of the 289 patients included for analysis, 57 had intraoperative instability and 26 had postoperative instability. Radiologist interpretation was found to have a risk ratio of 1.63 (95% confidence interval: 1.00-2.65) for intraoperative instability (P=0.080). Intraoperative instability was significantly associated with subsequent postoperative instability (P=0.005). Our regression model included previous endarterectomy and diabetes as predictive factors with a sensitivity of 11.3% and a specificity of 100.0%. Anticholinergic usage was associated with hypotension without coexisting bradycardia with a risk ratio of 2.36 (95% confidence interval: 1.06-5.26; P=0.047). CONCLUSIONS: Individuals without a previous contralateral endarterectomy and/or history of diabetes are at lower risk of hemodynamic instability. The addition of computed tomography angiographic variables does not improve this prediction. Future prospective, randomized work is required to improve our ability to identify and treat individuals at high risk of instability during carotid angioplasty and stenting.

Low concentrations of pentobarbital enhance excitability of rat hippocampal neurons.

BACKGROUND: Although the excitation phase observed during anesthetic induction and emergence is familiar to anesthesiologists, the cellular mechanisms of this phenomenon are not well understood. At anesthetic concentrations approximately one-tenth those required for surgical anesthesia, subjects demonstrate increased responsiveness to noxious stimulation. We previously estimated that the decrease in nociceptive reflex threshold is maximal at pentobarbital concentrations of approximately 5 microM. Here we used the rat hippocampal slice preparation to examine whether 5 microM pentobarbital increases the excitability of neurons. METHODS: Intracellular recordings were obtained from CA1 neurons during stimulation of the Schaffer collateral pathway. We examined the effect of pentobarbital on resting intrinsic membrane properties and stimulus-response relationships. Excitability was evaluated with the relationship between the synaptic signal strength, as indicated by the excitatory postsynaptic potential slope, and the probability of spiking (E-S relationship). RESULTS: Pentobarbital increased the excitability of hippocampal neurons, as shown by an increased probability of spiking at any given synaptic signal strength (P = 0.002), an effect known as "E-S potentiation." Pentobarbital was associated with an increase in the input resistance of the neuron and a shift of the action potential threshold towards more negative values. Pentobarbital did not increase the excitatory postsynaptic potential slope at any given stimulus strength. CONCLUSIONS: At a 5 microM concentration, pentobarbital increased E-S coupling by enhancing the excitability of the postsynaptic neurons. Pentobarbital induced changes in intrinsic membrane properties that may contribute to increased excitability.

Pentobarbital enhances gamma-aminobutyric acid-mediated excitation without altering synaptic plasticity in rat hippocampus.

BACKGROUND: Synaptic plasticity is thought to provide a molecular mechanism for learning and memory. N-methyl-d-aspartate receptor-mediated plasticity requires that N-methyl-d-aspartate receptor activation coincides with postsynaptic depolarizing potentials (DPSP(A)'s). Pentobarbital, in high concentrations, enhances DPSP(A)'s, but high concentrations suppress synaptic plasticity, probably by impairing glutamatergic transmission. Here we tested the hypothesis that low concentrations of pentobarbital can enhance DPSP(A)'s and modify the induction of synaptic plasticity. METHODS: Studies were performed in vitro on rat hippocampal slices. With glutamate transmission blocked, intracellular recording from CA1 neurons was used to investigate the influence of 5 microM pentobarbital on DPSP(A)'s and neuron excitability evoked by high frequency (100 Hz) stimulation. With glutamate transmission intact, extracellular recording was used to examine the effect of 5 microM pentobarbital on the induction of long-term depression and long-term potentiation of synaptic transmission by conditioning stimuli applied to the Schaffer collateral pathway. RESULTS: High frequency stimulation generated typical DPSP(A)'s that were mediated by gamma-aminobutyric acid(A) receptors and dependent upon HCO3-. Pentobarbital (5 microM) increased the amplitude, but not the width, at half-maximal amplitude of DPSPA's (P < 0.01). Pentobarbital increased the probability of action potential generation during the DPSP(A)'s. Pentobarbital did not alter the induction of long-term depression or long-term potentiation. CONCLUSIONS: Despite increasing the amplitude of DPSP(A)'s, 5 microM pentobarbital did not alter the induction of synaptic plasticity by a range of conventional conditioning stimuli. These results do not support the hypothesis that excitatory effects of pentobarbital may alter synaptic plasticity.

Levetiracetam reduces anesthetic-induced hyperalgesia in rats.

BACKGROUND: As part of an increase in excitability, small doses of pentobarbital, propofol, and midazolam induce an increased sensitivity to pain. Specific therapy to prevent or reduce this excitability may offer advantages over current clinical management with analgesics and sedatives. The pharmacological profile of the novel antiepileptic drug, levetiracetam, suggests that it may reduce the intensity of the excitatory stages of anesthesia. METHODS: We examined the influence of levetiracetam on the reduction of the nociceptive reflex threshold in rats by sedative doses of pentobarbital, propofol, and midazolam. Measurements of nociceptive reflex threshold to pressure and heat were made and then repeated after intraperitoneal injection of saline or one of three doses of levetiracetam (100, 200, 500 mg/kg). Pentobarbital (30 mg/kg), propofol (30 mg/kg), or midazolam (1.9 mg/kg) were then administered. The reflex threshold was measured every 10 min, starting at 5 min after the sedative injection, until 65 min had elapsed. RESULTS: Levetiracetam did not alter nociceptive reflex threshold in nonsedated animals (P = 0.11) or influence the degree or duration of sedation. The three anesthetic/sedative drugs reduced the nociceptive reflex threshold by 20%-30% of control values. Levetiracetam reduced the hyperreflexia associated with pentobarbital and midazolam (P < 0.05), but not propofol. CONCLUSIONS: These findings support further investigation into the role of levetiracetam in the prevention of anesthetic-induced excitability.

Spinal carbonic anhydrase contributes to nociceptive reflex enhancement by midazolam, pentobarbital, and propofol.

BACKGROUND: Systemic administration of acetazolamide blocks nociceptive hyperreflexia induced by pentobarbital. The authors assessed the effect of intrathecal carbonic anhydrase inhibitors (CAIs) on nociceptive reflex enhancement by pentobarbital, propofol, and midazolam. METHODS: Twenty-seven rats with chronic indwelling subarachnoid catheters were studied. Nociceptive paw reflex latency (PWL) for paw withdrawal from radiant heat was measured in forelimbs and hind limbs. Measurements were obtained under control conditions, 15 min after lumbar intrathecal injection of 10 microl artificial cerebrospinal fluid containing the CAIs acetazolamide or ethoxyzolamide, and during the 55 min after intraperitoneal injection of three sedative drugs: 30 mg/kg pentobarbital, 50 mg/kg propofol, or 1.9 mg/kg midazolam. RESULTS: Control values of PWL averaged 10.9 +/- 1.5 s in the forelimbs and 11.1 +/- 1.6 s in the hind limbs (P = 0.18). Intrathecal injection of 50 microm ethoxyzolamide reduced PWL by 8% and 4% in the forelimbs and hind limbs, respectively (P = 0.01); all other CAI injections had no effect on PWL. Following anesthetic injection, PWL in the forelimbs was reduced by approximately 35-40% of control values; in the hind limbs, CAI treatment decreased the PWL reduction to 8-16% for pentobarbital (P < 0.001), 30-32% for propofol (P < 0.02), and 9-16% for midazolam (P < 0.001). The hind limb reduction of hyperreflexia by CAI was less for propofol than for midazolam or pentobarbital (P < 0.002). CONCLUSION: Spinal carbonic anhydrase contributes to nociceptive hyperreflexia induced by pentobarbital and midazolam and to a lesser extent with propofol. These findings are consistent with a role for carbonic anhydrase in nociceptive signal enhancement by these drugs.

Intraoperative mobile magnetic resonance imaging for craniotomy lengthens the procedure but does not increase morbidity.

PURPOSE: To evaluate anesthetic aspects of care provided for craniotomy using mobile intraoperative magnetic resonance imaging (iMRI). METHODS: Anesthetic factors were studied using a retrospective case-control design. The primary outcome measures were the duration of the surgical intervention; the recovery score and body temperature on arrival; and length of stay in the post-anesthetic care unit. Secondary outcome measures were estimated blood loss, perioperative transfusion requirements, and fluids administered. RESULTS: Seventy-six patients undergoing craniotomy in the MRI theatre were compared with a case-matched control group of patients who underwent neurosurgical interventions in the conventional operating room during the same time period. The only outcome measure that differed between the two groups of patients was the duration of surgery: the mean duration of procedures for patients who underwent imaging was 407 +/- 143 min compared to 285 +/- 122 min in the conventional operating theatre (P < 0.000). Actual time spent imaging accounted for approximately 100 min (83%) of the increased duration. CONCLUSION: Our results do not support concerns that the iMRI suite is a "hostile" environment for the delivery of anesthesia for craniotomy. With the exception of an increased duration of the procedure, patients undergoing anesthesia with iMRI showed no differences from those operated in the conventional operating theatres.