Sulpicio G. Soriano

An assessment of the effects of general anesthetics on developing brain structure and neurocognitive function.

BACKGROUND:Neuronal cell death after general anesthesia has recently been documented in several immature animal models. Worldwide, volatile anesthetics are used in millions of young children every year during surgical procedures and imaging studies. The possibility of anesthesia-induced neurotoxicity during an uneventful anesthetic in neonates or infants has led to serious questions about the safety of pediatric anesthesia. However, the applicability of animal data to clinical anesthesia practice remains uncertain. In the present review, we assess the evidence for the effects of commonly used anesthetics on neuronal structure and neurocognitive function in newborn humans and animals. METHODS:Medical databases, including Medline, Cinahl, and Pubmed, abstract listings of the American Society of Anesthesiologists, International Anesthesia Research Society, Society for Pediatric Anesthesia, and Society for Neuroscience Annual Meetings, and personal files were queried regarding anesthesia-induced neurotoxicity. RESULTS:A growing number of studies in immature animal models demonstrate degenerative effects of several anesthetics on neuronal structure. A few studies reveal cognitive impairment in adult animals after neonatal anesthesia. There are no prospective studies evaluating neurocognitive function in children after neonatal exposure to anesthetics. However, several retrospective reviews demonstrate temporary neurological sequelae after prolonged anesthetic exposure in young children and larger studies identify long-term neurodevelopmental impairment after neonatal surgery and anesthesia. CONCLUSIONS:The evidence for anesthesia-induced neurodegeneration in animal models is compelling. Although this phenomenon has not been prospectively studied in young children, anecdotal data point toward the possibility for neurological impairment after surgery and anesthesia early in life. Given the serious implications for public health, further investigations of this phenomenon are imperative, both in laboratory animals and in young children.

Mice deficient in fractalkine are less susceptible to cerebral ischemia-reperfusion injury

Fractalkine (FKN), also known as neurotactin, is a CX(3)C chemokine that exists in both secreted and neuronal membrane-bound forms and is upregulated during brain inflammation. There is accumulating evidence that FKN induces chemotaxis by binding to its receptor CX(3)CR1 on leukocytes and microglia. We generated FKN-deficient mice to study the role of FKN in postischemic brain injury. After transient focal cerebral ischemia, FKN-deficient mice had a 28% reduction in infarction size and lower mortality rate, when compared to wild-type littermates. The findings of this study indicate a possible role for FKN in augmenting postischemic injury and mortality after transient focal cerebral ischemia.

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).

Mice Deficient in Mac-1 (CD11b/CD18) Are Less Susceptible to Cerebral Ischemia/Reperfusion Injury

BACKGROUND AND PURPOSE Macrophage-1 antigen (Mac-1) (CD11b/CD18), a leukocyte beta2 integrin, facilitates neutrophil adhesion, transendothelial migration, phagocytosis, and respiratory burst, all of which may mediate reperfusion-induced injury to ischemic brain tissue in conditions such as stroke. To determine the role of Mac-1 during ischemia and reperfusion in the brain, we analyzed the effect of transient focal cerebral ischemia in mice genetically engineered with a specific deficiency in Mac-1. METHODS Transient focal ischemia/reperfusion was induced by occluding the left middle cerebral artery for 3 hours followed by a 21-hour reperfusion period in Mac-1-deficient (n=12) and wild-type (n=11) mice. Regional cerebral blood flow was determined with a laser-Doppler flowmeter. Brain sections were stained with 2% 2,3,5-triphenyltetrazolium chloride to determine the infarct volume. Neutrophil accumulation was determined by staining the brain sections with dichloroacetate esterase to identify neutrophils. RESULTS Compared with the wild-type cohort, Mac-1-deficient mice had a 26% reduction in infarction volume (P<0.05). This was associated with a 50%, but statistically insignificant, reduction in the number of extravasated neutrophils in the infarcted areas of the brains in the mutant mice. There were no differences in regional cerebral blood flow between the 2 groups. CONCLUSIONS Mac-1 deficiency reduces neutrophil infiltration and cerebral cell death after transient focal cerebral ischemia. This finding may be related to a reduction in neutrophil extravasation in Mac-1-deficient mice.

Anesthetic Agents and the Immature Brain: Are These Toxic or Therapeutic?

ABOUT 1.5 million fetuses or newborns are exposed to anesthetic agents each year. After their initial report in Science suggesting that anesthetic drugs such as nitrous oxide, ketamine or other N-methyl-D-aspartate receptor antagonists lead to enhanced apoptosis in immature neurons, Olney et al. have reported that newborn rats exposed to commonly used anesthetic agents (isoflurane, midazolam, and nitrous oxide) also develop neurodegenerative changes in multiple areas of the brain, associated with long-term deficits in learning and memory. The same investigators have reported similar neurodegenerative changes in rat pups exposed to other anesthetic agents, anticonvulsant drugs, or ethanol and voiced their “concern that agents used in pediatric and obstetrical medicine for purposes of sedation, anesthesia, and seizure management may cause apoptotic neuronal death in the developing human brain.” This has led to public outcry over the long-term effects of anesthesia or sedation given to pregnant women or to newborn infants requiring surgical operations after birth. Calls for avoiding these agents in newborns raises the specter of surgical procedures being performed with minimal or no anesthesia, as was routine practice 20 years ago. Accumulating data on the development of the painresponsive and stress-responsive systems in the developing brain, together with increases in stress responses, morbidity, and mortality in lightly anesthetized neonates, have led to the routine use of anesthesia and postoperative analgesia even for critically ill newborns. Are the findings of Olney et al. significant enough to withhold anesthesia from neonates undergoing surgical operations or other invasive procedures? This issue needs to be addressed urgently, especially as no clinician would like to withhold anesthetics during a surgical procedure nor would any wish to expose their neonatal patients to potentially neurotoxic drugs.

Selective anesthesia-induced neuroinflammation in developing mouse brain and cognitive impairment.

Background:Recent population studies have suggested that children with multiple exposures to anesthesia and surgery at an early age are at an increased risk of cognitive impairment. The authors therefore have established an animal model with single versus multiple exposures of anesthetic(s) in young versus adult mice, aiming to distinguish the role of different types of anesthesia in cognitive impairment. Methods:Six- and 60-day-old mice were exposed to various anesthesia regimens. The authors then determined the effects of the anesthesia on learning and memory function, levels of proinflammatory cytokine interleukin-6 and tumor necrosis factor-&agr; in brain tissues, and the amount of ionized calcium-binding adaptor molecule 1–positive cells, the marker of microglia activation, in the hippocampus. Results:In this article, the authors show that anesthesia with 3% sevoflurane for 2 h daily for 3 days induced cognitive impairment and neuroinflammation (e.g., increased interleukin-6 levels, 151 ± 2.3% [mean ± SD] vs. 100 ± 9.0%, P = 0.035, n = 6) in young but not in adult mice. Anesthesia with 3% sevoflurane for 2 h daily for 1 day and 9% desflurane for 2 h daily for 3 days induced neither cognitive impairment nor neuroinflammation. Finally, an enriched environment and antiinflammatory treatment (ketorolac) ameliorated the sevoflurane-induced cognitive impairment. Conclusions:Anesthesia-induced cognitive impairment may depend on developmental stage, anesthetic agent, and number of exposures. These findings also suggest the cellular basis and the potential prevention and treatment strategies for anesthesia-induced cognitive impairment, which may ultimately lead to safer anesthesia care and better postoperative outcomes for children.

Repeated administration of ketamine may lead to neuronal degeneration in the developing rat brain

Background: This study was conducted to investigate, in vivo, the dose and duration effects of ketamine administration on neuronal degeneration in the developing rat brain.

Sevoflurane Depresses Myocardial Contractility Less than Halothane during Induction of Anesthesia in Children

Background Cardiovascular stability is an important prerequisite for any new volatile anesthetic. We compared echocardiographically derived indices of myocardial contractility during inhalation induction with sevoflurane and halothane in children. Methods Twenty children were randomized to receive either halothane or sevoflurane for inhalation induction of anesthesia. No preoperative medications were given. Myocardial contractility was evaluated at baseline and at sevoflurane and halothane end-tidal concentrations of 1.0 minimum alveolar concentration (MAC) and 1.5 MAC. Results There were no differences between groups in patient age, sex, physical status, weight, or height. Equilibration times and MAC multiples of sevoflurane and halothane were comparable. Vital signs remained stable throughout the study. Left ventricular end-systolic meridional wall stress increased with halothane but remained unchanged with sevoflurane. Systemic vascular resistance decreased from baseline to 1 MAC and 1.5 MAC with sevoflurane. Halothane depressed contractility as assessed by the stress-velocity index and stress-shortening index, whereas contractility remained within normal limits with sevoflurane. Total minute stress and normalized total mechanical energy expenditure, measures of myocardial oxygen consumption, did not change with either agent. Conclusions Myocardial contractility was decreased less during inhalation induction of anesthesia with sevoflurane compared with halothane in children. Although the induction of anesthesia with sevoflurane or halothane was equally well tolerated, the preservation of myocardial contractility with sevoflurane makes it an attractive alternative for inducing anesthesia in children.

Anaesthetic neurotoxicity and neuroplasticity: an expert group report and statement based on the BJA Salzburg Seminar

Although previously considered entirely reversible, general anaesthesia is now being viewed as a potentially significant risk to cognitive performance at both extremes of age. A large body of preclinical as well as some retrospective clinical evidence suggest that exposure to general anaesthesia could be detrimental to cognitive development in young subjects, and might also contribute to accelerated cognitive decline in the elderly. A group of experts in anaesthetic neuropharmacology and neurotoxicity convened in Salzburg, Austria for the BJA Salzburg Seminar on Anaesthetic Neurotoxicity and Neuroplasticity. This focused workshop was sponsored by the British Journal of Anaesthesia to review and critically assess currently available evidence from animal and human studies, and to consider the direction of future research. It was concluded that mounting evidence from preclinical studies reveals general anaesthetics to be powerful modulators of neuronal development and function, which could contribute to detrimental behavioural outcomes. However, definitive clinical data remain elusive. Since general anaesthesia often cannot be avoided regardless of patient age, it is important to understand the complex mechanisms and effects involved in anaesthesia-induced neurotoxicity, and to develop strategies for avoiding or limiting potential brain injury through evidence-based approaches.

Efficacy of Tranexamic Acid in Pediatric Craniosynostosis Surgery: A Double-blind, Placebo-controlled Trial

Background:Extensive blood loss is common in pediatric craniosynostosis reconstruction surgery. Tranexamic acid (TXA) is increasingly used to reduce perioperative blood loss in various settings, but data on its efficacy are limited in children. The purpose of this randomized, double-blind, placebo-controlled, parallel trial was to evaluate the efficacy of TXA in pediatric craniosynostosis correction surgery. The primary and secondary outcome variables were reduction in perioperative blood loss and reduction in blood transfusion, respectively. Methods:Forty-three children, ages 2 months to 6 yr, received either placebo or TXA in a loading dose of 50 mg·kg−1, followed by an infusion of 5 mg·kg−1·h−1 during surgery. TXA plasma concentrations were measured. Results:The TXA group had significantly lower perioperative mean blood loss (65 vs. 119 ml·kg−1, P < 0.001) and lower perioperative mean blood transfusion (33 vs. 56 ml· kg−1, P = 0.006) compared to the placebo group. The mean difference between the TXA and placebo groups for total blood loss was 54 ml·kg−1 (95% CI for the difference, 23–84 ml·kg−1) and for packed erythrocytes transfused was 23 ml·kg−1 (95% CI for the difference, 7–39 ml·kg−1). TXA administration also significantly diminished (by two thirds) the perioperative exposure of patients to transfused blood (median, 1 unit vs. 3 units; P < 0.001). TXA plasma concentrations were maintained above the in vitro thresholds reported for inhibition of fibrinolysis (10 &mgr;g·ml−1) and plasmin-induced platelet activation (16 &mgr;g·ml−1) throughout the infusion. Conclusions:TXA is effective in reducing perioperative blood loss and transfusion requirement in children undergoing craniosynostosis reconstruction surgery.