Anesthesia and the developing brain: A way forward for laboratory and clinical research.

All commonly used general anesthetics have been shown to cause neurotoxicity in animal models, including nonhuman primates. Opinion, however, remains divided over how cumulative evidence from preclinical and human studies in this field should be interpreted and its translation to current practices in pediatric anesthesia and surgery. A group of international experts in laboratory and clinical sciences recently convened in Genoa, Italy, to evaluate the current state of both laboratory and clinical research and discuss future directions for basic, translational, and clinical studies in this field. This paper describes those discussions and conclusions. A central goal identified was the importance of continuing to pursue laboratory research efforts to better understand the biological pathways underlying anesthesia neurotoxicity. The distinction between basic and translational experimental designs in this field was highlighted, and it was acknowledged that it will be important for future animal research to try to causally link structural changes with long-term cognitive abnormalities. While inherent limitations will continue to affect the ability of even large observational cohorts to determine if anesthesia impacts neurodevelopment or behavioral outcomes, the importance of conducting further large well-designed cohort studies was also emphasized. Adequately powered cohorts could clarify which populations are at increased risk, provide information on environmental and healthcare-related risk modifiers, and guide future interventional trials. If anesthetics cause structural or functional adverse neurological effects in young children, alternative or mitigating strategies need to be considered. While protective or mitigating strategies have been repeatedly studied in animals, there are currently no human data to support alternative anesthetic strategies in clinical practice. Lastly, it was noted that there is still considerable debate over the clinical relevance of anesthesia neurotoxicity, and the need to evaluate the impact of other aspects of perioperative care on neurodevelopment must also be considered.

Success of Intubation Rescue Techniques after Failed Direct Laryngoscopy in Adults: A Retrospective Comparative Analysis from the Multicenter Perioperative Outcomes Group.

BACKGROUND: Multiple attempts at tracheal intubation are associated with mortality, and successful rescue requires a structured plan. However, there remains a paucity of data to guide the choice of intubation rescue technique after failed initial direct laryngoscopy. The authors studied a large perioperative database to determine success rates for commonly used intubation rescue techniques. METHODS: Using a retrospective, observational, comparative design, the authors analyzed records from seven academic centers within the Multicenter Perioperative Outcomes Group between 2004 and 2013. The primary outcome was the comparative success rate for five commonly used techniques to achieve successful tracheal intubation after failed direct laryngoscopy: (1) video laryngoscopy, (2) flexible fiberoptic intubation, (3) supraglottic airway as part of an exchange technique, (4) optical stylet, and (5) lighted stylet. RESULTS: A total of 346,861 cases were identified that involved attempted tracheal intubation. A total of 1,009 anesthesia providers managed 1,427 cases of failed direct laryngoscopy followed by subsequent intubation attempts (n = 1,619) that employed one of the five studied intubation rescue techniques. The use of video laryngoscopy resulted in a significantly higher success rate (92%; 95% CI, 90 to 93) than other techniques: supraglottic airway conduit (78%; 95% CI, 68 to 86), flexible bronchoscopic intubation (78%; 95% CI, 71 to 83), lighted stylet (77%; 95% CI, 69 to 83), and optical stylet (67%; 95% CI, 35 to 88). Providers most frequently choose video laryngoscopy (predominantly GlideScope [Verathon, USA]) to rescue failed direct laryngoscopy (1,122/1,619; 69%), and its use has increased during the study period. CONCLUSIONS: Video laryngoscopy is associated with a high rescue intubation success rate and is more commonly used than other rescue techniques.

Lithium Protects Against Anaesthesia Neurotoxicity In The Infant Primate Brain.

Exposure of infant animals, including non-human primates (NHPs), to anaesthetic drugs causes apoptotic death of neurons and oligodendrocytes (oligos) and results in long-term neurodevelopmental impairment (NDI). Moreover, retrospective clinical studies document an association between anaesthesia exposure of human infants and significant increase in NDI. These findings pose a potentially serious dilemma because millions of human infants are exposed to anaesthetic drugs every year as part of routine medical care. Lithium (Li) at clinically established doses is neuroprotective in various cerebral injury models. We therefore investigated whether Li also protects against anaesthesia neurotoxicity in infant NHPs. On postnatal day 6 NHPs were anaesthetized with the widely used anaesthetic isoflurane (ISO) for 5 h employing the same standards as in a human pediatric surgery setting. Co-administration of Li completely prevented the acute ISO-induced neuroapoptosis and significantly reduced ISO-induced apoptosis of oligodendroglia. Our findings are highly encouraging as they suggest that a relatively simple pharmacological manipulation might protect the developing primate brain against the neurotoxic action of anaesthetic drugs while not interfering with the beneficial actions of these drugs. Further research is needed to determine Li's potential to prevent long-term NDI resulting from ISO anaesthesia, and to establish its safety in human infants.

First-Attempt Intubation Success of Video Laryngoscopy in Patients with Anticipated Difficult Direct Laryngoscopy: A Multicenter Randomized Controlled Trial Comparing the C-MAC D-Blade Versus the GlideScope in a Mixed Provider and Diverse Patient Population.

BACKGROUND: Intubation success in patients with predicted difficult airways is improved by video laryngoscopy. In particular, acute-angle video laryngoscopes are now frequently chosen for endotracheal intubation in these patients. However, there is no evidence concerning whether different acute-angle video laryngoscopes can be used interchangeably in this scenario and would allow endotracheal intubation with the same success rate. We therefore tested whether first-attempt intubation success is similar when using a newly introduced acute-angle blade, that is an element of an extended airway management system (C-MAC D-Blade) compared with a well-established acute-angle video laryngoscope (GlideScope). METHODS: In this large multicentered prospective randomized controlled noninferiority trial, patients requiring general anesthesia for elective surgery and presenting with clinical predictors of difficult laryngoscopy were randomly assigned to intubation using either the C-MAC D-Blade or the GlideScope video laryngoscope. The hypothesis was that first-attempt intubation success using the new device (D-Blade) is no >4% less than the established device (GlideScope), which would determine noninferiority of the new instrument versus the established instrument. The secondary outcomes we observed included intubation success with multiple attempts and airway-related complications within 7 days of enrollment. RESULTS: Eleven hundred patients were randomly assigned to either video laryngoscope. Intubation success rate on first attempt was 96.2% in the GlideScope group and 93.4% in the C-MAC D-Blade group. Although the absolute difference between the 2 groups was only 2.8%, the 90.35% upper confidence limit of the difference exceeded the predefined margin (4.98%), indicating a rejection of the noninferiority hypothesis for first-attempt intubation success. For attending anesthesiologists, and upon multiple attempts, intubation success did not differ between systems. Pharyngeal injury was noted in 1% of the patients, and the incidence did not differ between interventional groups. CONCLUSIONS: Head-to-head comparison in this large multicenter trial revealed that the newly introduced C-MAC D-Blade does not yield the same first-attempt intubation success as the GlideScope in patients with predicted difficult laryngoscopy except in the hands of attending anesthesiologists. Additional research would be necessary to identify potential causes for this difference. Intubation success rates were very high with both systems, indicating that acute-angle video laryngoscopy is an exceptionally successful strategy for the initial approach to endotracheal intubation in patients with predicted difficult laryngoscopy.

Evidence-based guidelines for the management of large hemispheric infarction : a statement for health care professionals from the Neurocritical Care Society and the German Society for Neuro-intensive Care and Emergency Medicine.

Large hemispheric infarction (LHI), also known as malignant middle cerebral infarction, is a devastating disease associated with significant disability and mortality. Clinicians and family members are often faced with a paucity of high quality clinical data as they attempt to determine the most appropriate course of treatment for patients with LHI, and current stroke guidelines do not provide a detailed approach regarding the day-to-day management of these complicated patients. To address this need, the Neurocritical Care Society organized an international multidisciplinary consensus conference on the critical care management of LHI. Experts from neurocritical care, neurosurgery, neurology, interventional neuroradiology, and neuroanesthesiology from Europe and North America were recruited based on their publications and expertise. The panel devised a series of clinical questions related to LHI, and assessed the quality of data related to these questions using the Grading of Recommendation Assessment, Development and Evaluation guideline system. They then developed recommendations (denoted as strong or weak) based on the quality of the evidence, as well as the balance of benefits and harms of the studied interventions, the values and preferences of patients, and resource considerations.

Anesthesia for the young child undergoing ambulatory procedures: current concerns regarding harm to the developing brain.

PURPOSE OF REVIEW: Sedation and anesthesia are often necessary for children at any age, and are frequently provided in ambulatory settings. Concerns have mounted, based on both laboratory studies including various mammalian species and retrospective human clinical studies, that the very drugs that induce sedation and anesthesia may trigger an injury in the developing brain, resulting in long-lasting neurobehavioral consequences. RECENT FINDINGS: New retrospective studies further augment these concerns. Specifically, recent studies support that a single anesthesia exposure before age 3 may increase the risk for long-term disabilities in language acquisition and abstract reasoning, and that exposure to two or more anesthetics before age 2 nearly doubles the risk for an attention-deficit hyperactivity disorder diagnosis by age 19. However, methodological limitations preclude final conclusions or change in practice based on these reports, as retrospective studies cannot prove causation. Ongoing prospective clinical studies such as 'General Anesthesia and Apoptosis Study', 'Pediatric Anesthesia NeuroDevelopment Assessment', and 'Mayo Safety in Kids' trials will offer more answers in the future. Meanwhile, laboratory experiments continue to describe differential morphologic injury to individual structures in the neuropil, and have identified mitochondrial dysfunction and neuroinflammation as potential links in the injury process. Additionally, concepts for protection against anesthesia-induced neurotoxicity continue to be tested in the laboratory. SUMMARY: Results from ongoing prospective clinical trials and translational research will help clarify whether anesthesia-associated neurotoxicity affects the developing human brain, including whether it causes long-term disability, and may further identify the injury mechanisms and potential strategies for protection. Currently, the available evidence does not support a change in practice.

A retrospective study of the performance of video laryngoscopy in an obstetric unit.

We evaluated the performance of tracheal intubation using video laryngoscopy in an obstetric unit. We analyzed airway management details during a 3-year period, and observed 180 intubations. All cases were managed with direct or video laryngoscopy. Direct laryngoscopy resulted in 157 out of 163 (95% confidence interval [CI], 92%-99%) first attempt successful intubations and failed once. Video laryngoscopy resulted in 18 of 18 (95% CI, 81%-100%) successful intubations on first attempt. The failed direct laryngoscopy was rescued with video laryngoscopy. The patients managed with video laryngoscopy frequently required urgent or emergency surgery and had predictors of difficult direct laryngoscopy in 16 of 18 cases. Video laryngoscopy may be a useful adjunct for obstetric airway management, and its role in this difficult airway scenario should be further studied.

Comparative effectiveness of the C-MAC video laryngoscope versus direct laryngoscopy in the setting of the predicted difficult airway.

BACKGROUND: Video laryngoscopy may be useful in the setting of the difficult airway, but it remains unclear if intubation success is improved in routine difficult airway management. This study compared success rates for tracheal intubation with the C-MAC® video laryngoscope (Karl Storz, Tuttlingen, Germany) with conventional direct laryngoscopy in patients with predicted difficult airway. METHODS: We conducted a two arm, single-blinded randomized controlled trial that involved 300 patients. Inclusion required at least one of four predictors of difficult intubation. The primary outcome was successful tracheal intubation on first attempt. RESULTS: The use of video laryngoscopy resulted in more successful intubations on first attempt (138/149; 93%) as compared with direct laryngoscopy (124/147; 84%), P = 0.026. Cormack-Lehane laryngeal view was graded I or II in 139/149 of C-MAC attempts versus 119/147 in direct laryngoscopy attempts (P < 0.01). Laryngoscopy time averaged 46 s (95% CI, 40-51) for the C-MAC group and was shorter in the direct laryngoscopy group, 33 s (95% CI, 29-36), P < 0.001. The use of a gum-elastic bougie and/or external laryngeal manipulation were required less often in the C-MAC intubations (24%, 33/138) compared with direct laryngoscopy (37%, 46/124, P = 0.020). The incidence of complications was not significantly different between the C-MAC (20%, 27/138) versus direct laryngoscopy (13%, 16/124, P = 0.146). CONCLUSION: A diverse group of anesthesia providers achieved a higher intubation success rate on first attempt with the C-MAC in a broad range of patients with predictors of difficult intubation. C-MAC laryngoscopy seems to be a useful technique for the initial approach to a potentially difficult airway.

Routine clinical practice effectiveness of the Glidescope in difficult airway management: an analysis of 2,004 Glidescope intubations, complications, and failures from two institutions.

INTRODUCTION: The Glidescope video laryngoscope has been shown to be a useful tool to improve laryngeal view. However, its role in the daily routine of airway management remains poorly characterized. METHODS: This investigation evaluated the use of the Glidescope at two academic medical centers. Electronic records from 71,570 intubations were reviewed, and 2,004 cases were identified where the Glidescope was used for airway management. We analyzed the success rate of Glidescope intubation in various intubation scenarios. In addition, the incidence and character of complications associated with Glidescope use were recorded. Predictors of Glidescope intubation failure were determined using a logistic regression analysis. RESULTS: Overall success for Glidescope intubation was 97% (1,944 of 2,004). As a primary technique, success was 98% (1,712 of 1,755), whereas success in patients with predictors of difficult direct laryngoscopy was 96% (1,377 of 1,428). Success for Glidescope intubation after failed direct laryngoscopy was 94% (224 of 239). Complications were noticed in 1% (21 of 2,004) of patients and mostly involved minor soft tissue injuries, but major complications, such as dental, pharyngeal, tracheal, or laryngeal injury, occurred in 0.3% (6 of 2,004) of patients. The strongest predictor of Glidescope failure was altered neck anatomy with presence of a surgical scar, radiation changes, or mass. CONCLUSION: These data demonstrate a high success rate of Glidescope intubation in both primary airway management and rescue-failed direct laryngoscopy. However, Glidescope intubation is not always successful and certain predictors of failure can be identified. Providers should maintain their competency with alternate methods of intubation, especially for patients with neck pathology.

Laser resection of the prostate: implications for anesthesia.

Holmium:yttrium-aluminum-garnet and potassium-titanyl-phosphate lasers make it possible to perform transurethral prostate resection with almost no absorption of irrigant and minimal blood loss. Subarachnoid block is usually administered for classical transurethral resection of the prostate, so that the patient can be monitored for the onset of transurethral resection of the prostate syndrome secondary to irrigant absorption. New laser resection techniques may allow the patient and anesthesiologist to choose options most appropriate for the patient's medical conditions and preference. In this study, we review the urologic literature to provide an overview of current laser technology for prostate reduction surgery. We also screened this literature for evidence of potential effects on anesthesia care for special patient groups as well as for overall perioperative management. Our findings suggest that the anesthesiologist may now safely offer general anesthesia for endourologic laser surgery, even on an ambulatory basis. This includes patients with cardiovascular disease or receiving continuous anticoagulation therapy. We found no studies specifically aimed at evaluating best anesthetic practices for patients undergoing laser procedures. Therefore, clinical research is needed to better define the risks and benefits of the various anesthetic alternatives.

Brain protection by anesthetic agents.

PURPOSE OF REVIEW: Patients at risk for perioperative stroke, or those who have suffered recent cerebral injury, may benefit from neuroprotective properties of anesthetic agents during surgery. This manuscript reviews recent clinical and experimental evidence for neuroprotective effects of common anesthetic agents, and presents potential mechanisms involved in anesthetic neuroprotection. RECENT FINDINGS: Although strong experimental data support a neuroprotective potential of several anesthetic agents, specifically isoflurane and xenon, consistent long-term protection by either agent has not been demonstrated. Unfortunately, there is a lack of clinical studies that would support the use of any one anesthetic agent over the others. Mechanisms of neuroprotection by anesthetic agents appear to involve suppression of excitatory neurotransmission, and potentiation of inhibitory activity, which may contribute to the reduction of excitotoxic injury. Activation of intracellular signaling cascades that lead to altered expression of protective genes may also be involved. SUMMARY: Solid experimental evidence supports neuroprotection by anesthetic agents. It is too early to recommend any specific agent for clinical use as a neuroprotectant, however. Further study is warranted to unravel relevant mechanisms and to appreciate the potential clinical relevance of experimental findings.

The antibiotic erythromycin induces tolerance against transient global cerebral ischemia in rats (pharmacologic preconditioning).

BACKGROUND: Cerebral ischemic tolerance can be induced by a variety of noxious stimuli, but no clinically applicable regimen for preconditioning has been described. Therefore, the authors tested the ability of a pharmacologic preconditioning strategy using the well-known macrolide antibiotic erythromycin to induce tolerance against transient global cerebral ischemia in vivo. They also investigated whether tolerance induction by erythromycin involves transcriptional and translational changes of cerebral B-cell leukemia/lymphoma-2 (bcl-2) expression. METHODS: Male Wistar rats were treated with erythromycin (25 mg/kg intramuscularly) or vehicle and subjected to 15 min of transient global cerebral ischemia 6, 12, or 24 h after pretreatment. Neurologic deficit was evaluated once daily, and neuronal cell survival was assessed after 7 days of reperfusion. Additional animals were similarly pretreated, and cerebral bcl-2 messenger RNA (mRNA) and protein expression was analyzed 6 and 24 h later. RESULTS: Erythromycin improved postischemic neuronal survival in hippocampal CA1 and CA3 sectors and reduced functional deficit, with 12 h being the most efficient pretreatment interval. Bcl-2 mRNA in hippocampus was transiently up-regulated 6 h after erythromycin, but neuronal Bcl-2 protein remained unchanged. CONCLUSIONS: Erythromycin can induce cerebral ischemic tolerance in vivo (pharmacologic preconditioning), suggesting a potential clinical strategy of preemptive neuroprotection. Changes in bcl-2 expression after erythromycin were small and transient. The induction of bcl-2-related pathways, although important for other preconditioning regimens, may therefore be less relevant for the neuroprotective effects of pharmacologic preconditioning using erythromycin.

Nitration of the striatal Na,K-ATPase alpha3 isoform occurs in normal brain development but is not increased during hypoxia-ischemia in newborn piglets.

Neonatal hypoxia-ischemia (HI) can result in significant sensorimotor abnormalities, including movement and posture disorders. These neurological impairments are believed to result from basal ganglia (striatum) damage, but the exact cause of this injury is not known. One mechanism involved in brain injury after HI is the generation of reactive oxygen species, which damage cellular macromolecules. We tested the hypothesis that inactivation of plasma membrane enzyme Na,K-ATPase during striatal neurodegeneration after HI emerges with peroxynitrite attack on the enzyme. In vitro, reaction of peroxynitrite (100-500 microM) with purified Na,K-ATPase produced nitration of the alpha (catalytic) and beta (transport) subunits, as quantified by immunoblots of the reaction products for nitrotyrosine. To evaluate for peroxynitrite damage to Na,K-ATPase in vivo, striatal plasma membrane fractions from 1-week-old piglets subjected to asphyxic cardiac arrest and recovery were also studied by immunoprecipitation. During the progression of striatal neurodegeneration and loss of enzyme function 3-24 h after arrest, nitration of the alpha3 (neuronal) isoform of Na,K-ATPase was not increased relative to sham control. Suprisingly, however, nitration of this alpha isoform occurs during normal brain development and peaks at 2 weeks of age. We conclude that Na,K-ATPase is a target of peroxynitrite, but that this mechanism is not responsible for enzyme inactivation after HI. Protein nitration may serve as marker of other normal, noninjurious cell processes in the developing brain.