Neurobehavioral Abnormalities in Offspring of Young Adult Male Rats With a History of Traumatic Brain Injury.

Children of parents with traumatic brain injury (TBI) are more likely to develop psychiatric disorders. This association is usually attributed to TBI-induced changes in parents' personality and families' social environment. We tested the hypothesis that offspring of young adult male rats with TBI develop neurodevelopmental abnormalities in the absence of direct social contact with sires. Male Sprague-Dawley rats (F0 generation) in the TBI group underwent moderate TBI via a midline fluid percussion injury that involved craniectomy under sevoflurane (SEVO) anesthesia for 40 min on post-natal Day 60 (P60), while F0 rats in the control group were placed in a new cage, one per cage, for the equivalent time duration. A subset of F0 rats was sacrificed on P66 to assess acute changes in hypothalamic-pituitary-adrenal (HPA) axis and inflammation markers. The remaining F0 males were mated with naive females on P90 to generate offspring (F1 generation). The F0 males and F1 males and females were sequentially evaluated in the elevated plus maze, for pre-pulse inhibition of acoustic startle, in the Morris water maze, and for resting and stress levels of serum corticosterone starting on ∼P105 (F0) and ∼P60 (F1), followed by tissue collection for further analyses. Acutely, the F0 TBI males had messenger RNA (mRNA) transcripts altered to support an increased hypothalamic and hippocampal Na+-K+-Cl- (Slc12a2) Cl- importer / K+-2Cl- (Slc12a5) Cl- exporter ratio and decreased hippocampal glucocorticoid receptors (Nr3c1), as well as increased serum levels of corticosterone, interleukin-1ß (IL-1ß), and biomarkers of activated hippocampal microglia and astrocytes. Long-term, F0 TBI rats exhibited increased corticosterone concentrations at rest and under stress, anxiety-like behavior, impaired sensory-motor gating, and impaired spatial memory. These abnormalities were underpinned by reduced mRNA levels of hypothalamic and hippocampal mineralocorticoid receptors (Nr3c2), hippocampal Nr3c1, and hypothalamic brain-derived neurotrophic factor (Bdnf), as well as elevated serum levels of IL-1ß, and biomarkers of activated hippocampal microglia and astrocytes. F1 male offspring of TBI sires exhibited abnormalities in all behavioral tests, while their F1 female counterparts had abnormal pre-pulse inhibition responses only. F1 male offspring of TBI sires also had reduced mRNA levels of hippocampal Nr3c1 and Nr3c2, as well as hypothalamic and hippocampal Bdnf, whereas increases in inflammatory markers were more profound in F1 females. These findings suggest that offspring of sires with a history of a moderate TBI that involved craniectomy under SEVO anesthesia for 40 min, develop sex-dependent neurobehavioral abnormalities in the absence of direct social interaction between the sire and the offspring.

Analyzing the value of IONM as a complex intervention: The gap between published evidence and clinical practice.

OBJECTIVE: Intraoperative neurophysiological monitoring (IONM) was investigated as a complex intervention (CI) as defined by the United Kingdom Medical Research Council (MRC) in published studies to identify challenges and solutions in estimating IONM's effects on postoperative outcomes. METHODS: A scoping review to April 2022 of the influence of setting on what was implemented as IONM and how it influenced postoperative outcomes was performed for studies that compared IONM to no IONM cohorts. IONM complexity was assessed with the iCAT_SR tool. Causal graphs were used to represent this complexity. RESULTS: IONM implementation depended on the surgical procedure, institution and/or surgeon. "How" IONM influenced neurologic outcomes was attributed to surgeon or institutional experience with the surgical procedure, surgeon or institutional experience with IONM, co-interventions in addition to IONM, models of IONM service delivery and individual characteristics of the IONM provider. Indirect effects of IONM mediated by extent of tumor resection, surgical approach, changes in operative procedure, shorter operative time, and duration of aneurysm clipping were also described. There were no quantitative estimates of the relative contribution of these indirect effects to total IONM effects on outcomes. CONCLUSIONS: IONM is a complex intervention whose evaluation is more challenging than that of a simple intervention. Its implementation and largely indirect effects depend on specific settings that are usefully represented in causal graphs. SIGNIFICANCE: IONM evaluation as a complex intervention aided by causal graphs and multivariable analysis could provide a valuable framework for future study design and assessments of IONM effectiveness in different settings.

Intergenerational Perioperative Neurocognitive Disorder.

Accelerated neurocognitive decline after general anesthesia/surgery, also known as perioperative neurocognitive disorder (PND), is a widely recognized public health problem that may affect millions of patients each year. Advanced age, with its increasing prevalence of heightened stress, inflammation, and neurodegenerative alterations, is a consistent contributing factor to the development of PND. Although a strong homeostatic reserve in young adults makes them more resilient to PND, animal data suggest that young adults with pathophysiological conditions characterized by excessive stress and inflammation may be vulnerable to PND, and this altered phenotype may be passed to future offspring (intergenerational PND). The purpose of this narrative review of data in the literature and the authors' own experimental findings in rodents is to draw attention to the possibility of intergenerational PND, a new phenomenon which, if confirmed in humans, may unravel a big new population that may be affected by parental PND. In particular, we discuss the roles of stress, inflammation, and epigenetic alterations in the development of PND. We also discuss experimental findings that demonstrate the effects of surgery, traumatic brain injury, and the general anesthetic sevoflurane that interact to induce persistent dysregulation of the stress response system, inflammation markers, and behavior in young adult male rats and in their future offspring who have neither trauma nor anesthetic exposure (i.e., an animal model of intergenerational PND).

Intergenerational Perioperative Neurocognitive Disorder in Young Adult Male Rats with Traumatic Brain Injury.

BACKGROUND: The authors tested the hypothesis that the effects of traumatic brain injury, surgery, and sevoflurane interact to induce neurobehavioral abnormalities in adult male rats and in their offspring (an animal model of intergenerational perioperative neurocognitive disorder). METHODS: Sprague-Dawley male rats (assigned generation F0) underwent a traumatic brain injury on postnatal day 60 that involved craniectomy (surgery) under 3% sevoflurane for 40 min followed by 2.1% sevoflurane for 3 h on postnatal days 62, 64, and 66 (injury group). The surgery group had craniectomy without traumatic brain injury, whereas the sevoflurane group had sevoflurane only. On postnatal day 90, F0 males and control females were mated to generate offspring (assigned generation F1). RESULTS: Acutely, F0 injury rats exhibited the greatest increases in serum corticosterone and interleukin-1ß and -6, and activation of the hippocampal microglia. Long-term, compared to controls, F0 injury rats had the most exacerbated corticosterone levels at rest (mean ± SD, 2.21 ± 0.64 vs. 7.28 ± 1.95 ng/ml, n = 7 - 8; P < 0.001) and 10 min after restraint (133.12 ± 33.98 vs. 232.83 ± 40.71 ng/ml, n = 7 - 8; P < 0.001), increased interleukin-1ß and -6, and reduced expression of hippocampal glucocorticoid receptor (Nr3c1; 0.53 ± 0.08 fold change relative to control, P < 0.001, n = 6) and brain-derived neurotrophic factor genes. They also exhibited greater behavioral deficiencies. Similar abnormalities were evident in their male offspring, whereas F1 females were not affected. The reduced Nr3c1 expression in F1 male, but not female, hippocampus was accompanied by corresponding Nr3c1 promoter hypermethylated CpG sites in F0 spermatozoa and F1 male, but not female, hippocampus. CONCLUSIONS: These findings in rats suggest that young adult males with traumatic brain injury are at an increased risk of developing perioperative neurocognitive disorder, as are their unexposed male but not female offspring.

Frailty Assessment and Prehabilitation Before Complex Spine Surgery in Patients With Degenerative Spine Disease: A Narrative Review.

Degenerative spine disease increases in prevalence and may become debilitating as people age. Complex spine surgery may offer relief but becomes riskier with age. Efforts to lessen the physiological impact of surgery through minimally invasive techniques and enhanced recovery programs mitigate risk only after the decision for surgery. Frailty assessments outperform traditional tools of perioperative risk stratification. The extent of frailty predicts complications after spine surgery such as reoperation for infection and 30-day mortality, as well as elements of social cost such as hospital length of stay and discharge to an advanced care facility. Symptoms of spine disease overlap with phenotypic markers of frailty; therefore, different frailty assessment tools may perform differently in patients with degenerative spine disease. Beyond frailty, however, cognitive decline and psychosocial isolation may interact with frailty and affect achievable surgical outcomes. Prehabilitation, which has reduced perioperative risk in colorectal and cardiac surgery, may benefit potential complex spine surgery patients. Typical prehabilitation includes physical exercise, nutrition supplementation, and behavioral measures that may offer symptomatic relief even in the absence of surgery. Nonetheless, the data on the efficacy of prehabilitation for spine surgery remains sparse and barriers to prehabilitation are poorly defined. This narrative review concludes that a frailty assessment-potentially supplemented by an assessment of cognition and psychosocial resources-should be part of shared decision-making for patients considering complex spine surgery. Such an assessment may suffice to prompt interventions that form a prehabilitation program. Formal prehabilitation programs will require further study to better define their place in complex spine care.

Utility of evoked potentials during anterior cerebral artery and anterior communicating artery aneurysm clipping.

Objective: To investigate the optimal combination of somatosensory- and transcranial motor-evoked potential (SSEP/tcMEP) modalities and monitored extremities during clip reconstruction of aneurysms of the anterior cerebral artery (ACA) and its branches. Methods: A retrospective review of 104 cases of surgical clipping of ruptured and unruptured aneurysms was performed. SSEP/tcMEP changes and postoperative motor deficits (PMDs) were assessed from upper and lower extremities (UE/LE) to determine the diagnostic accuracy of each modality separately and in combination. Results: PMDs were reported in 9 of 104 patients; 7 LE and 8 UE (3.6% of 415 extremities). Evoked potential (EP) monitoring failed to predict a PMD in 8 extremities (1.9%). Seven of 8 false negatives had subarachnoid hemorrhage. Sensitivity and specificity in LE were 50% and 97% for tcMEP, 71% and 98% for SSEP, and 83% and 98% for dual-monitoring of both tcMEP/SSEP. Sensitivity and specificity in UE were 38% and 99% for tcMEP, and 50% and 97% for tcMEP/SSEP, respectively. Conclusions: Combined tcMEP/SSEP is more accurate than single-modality monitoring for LE but is relatively insensitive for UE PMDs. Significance: During ACA aneurysm clipping, multiple factors may confound the ability of EP monitoring to predict PMDs, especially brachiofacial hemiparesis caused by perforator insufficiency.

Best Practices in Facial Nerve Monitoring.

OBJECTIVES/HYPOTHESIS: Facial nerve monitoring (FNM) has evolved into a widely used adjunct for many surgical procedures along the course of the facial nerve. Even though majority opinion holds that FNM reduces the incidence of iatrogenic nerve injury, there are few if any studies yielding high-level evidence and no practice guidelines on which clinicians can rely. Instead, a review of the literature and medicolegal cases reveals significant variations in methodology, training, and clinical indications. STUDY DESIGN: Literature review and expert opinion. METHODS: Given the lack of standard references to serve as a resource for FNM, we assembled a multidisciplinary group of experts representing more than a century of combined monitoring experience to synthesize the literature and provide a rational basis to improve the quality of patient care during FNM. RESULTS: Over the years, two models of monitoring have become well-established: 1) monitoring by the surgeon using a stand-alone device that provides auditory feedback of facial electromyography directly to the surgeon, and 2) a team, typically consisting of surgeon, technologist, and interpreting neurophysiologist. Regardless of the setting and the number of people involved, the reliability of monitoring depends on the integration of proper technical performance, accurate interpretation of responses, and their timely application to the surgical procedure. We describe critical steps in the technical set-up and provide a basis for context-appropriate interpretation and troubleshooting of recorded signals. CONCLUSIONS: We trust this initial attempt to describe best practices will serve as a basis for improving the quality of patient care while reducing inappropriate variations. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:S1-S42, 2021.

Transcranial Motor Evoked Potential Monitoring in a Patient With a Deep Brain Stimulator: A Case Report.

SUMMARY: A major complication of surgical scoliosis correction is permanent injury of the spinal cord. Intraoperative neuromonitoring continually evaluates spinal cord function through monitoring sensory and corticospinal motor tracts. There is no literature or manufacturer recommendation on whether transcranial motor evoked potential (tcMEP) monitoring can be performed safely in the presence of a deep brain stimulator (DBS) system. A 17-year-old adolescent boy with severe neuromuscular scoliosis presented for a posterior spinal fusion. The patient suffered from generalized dystonia treated with a DBS terminating in the left and right globus pallidus internus. The competing goals of monitoring motor function during the spinal fusion and preserving the integrity of the DBS system were discussed preoperatively. The DBS system was deactivated for the duration of surgery, and tcMEPs were used sparingly at the lowest suitable stimulation voltage. Intraoperative management focused on facilitating neurophysiologic monitoring through a total intravenous anesthetic of propofol, methadone, and remifentanil. The tcMEPS remained unchanged throughout the operation and the patient emerged able to move his lower extremities to command. Postoperatively, the DBS system was turned back on and showed retained settings, normal functioning, and unchanged impedance of the DBS leads. Neither the patient nor his parents reported any subjective changes in the symptoms of dystonia. The authors conclude that monitoring tcMEPs in the presence of a DBS implant may be done safely, when the clinical circumstances suggest that the added information gained from tcMEPs outweighs the theoretical risk to the DBS system and the course of the medical condition treated by the DBS.

Methadone and a Clinical Pathway in Adolescent Idiopathic Scoliosis Surgery: A Historically Controlled Study.

STUDY DESIGN: Historically controlled clinical trial. OBJECTIVES: Patients presenting for correction of adolescent idiopathic scoliosis (AIS) by posterior spinal fusion may benefit from structured clinical pathways. We studied the effects of implementing a published clinical pathway for the perioperative care of patients with AIS that required intraoperative use of methadone at our institution. METHODS: We performed a historically controlled clinical trial of patients undergoing posterior spinal fusion for AIS by comparing a retrospectively collected control group of 25 patients with a prospective experimental group of 14 patients receiving methadone, gabapentin, propofol, and remifentanil as part of a new clinical pathway. RESULTS: Use of the pathway decreased average pain scores evaluated by the Numeric Rating Scale in the 24 hours following surgery (4.8 [4-6] to 3.4 [2-4], P = .03 [-2.6 to -0.2; t = -2.3]) and postoperative opioid consumption by 76% (41 [29-51] mg to 10 [4-17] mg, P < .001 [-45 to -15; Welch's t = 4.9]) during the same period. Improved analgesia and reduced reliance on opioids facilitated other postoperative elements of the clinical pathway and shortened the average hospital length of stay by 1 day (4 [3-6] days to 3 [3-5] days, P = .001 [-2 to -1; U = 67, Z = -3.3]). CONCLUSIONS: Multimodal analgesia and a clinical pathway add value in the perioperative care of patients undergoing posterior spinal fusion for AIS by improving analgesia and shortening hospitalization. The prospective arm of the trial was registered at clinicaltrials.gov under NCT02481570.

Neuroanesthesiologists as interoperative neurophysiologists: a collaborative cognitive apprenticeship model of training in a community of clinical practice.

Directing intraoperative neurophysiologic monitoring (IONM) is a patient care activity for which no formal training programs exist, even though the need for well-trained practitioners is readily evident while caring for patients with diseases of the brain, spinal cord, spinal column, or nervous system. Here, we present the theoretical basis and institutional experience for a successful model of learning a new and complex set of skills: the medical direction of IONM. In a major academic institution, a clinical community of practice absorbed new members with professional backgrounds ranging from a recent neuroanesthesia fellowship to several decades of neuroanesthesia practice and trained them in a collaborative cognitive apprenticeship model to medically direct IONM. Our community of practice comprises experienced technicians, a diplomate of the American Board of Neurophysiologic Monitoring (DABNM), and six neuroanesthesiologists. This group forms the base of the scaffolding or structure where the apprenticeship and learning take place. The clinical community of practice has trained eight new members in the medical direction of IONM. The group has also trained four outside anesthesiologists-one of whom went on to become certified as a DABNM-who went on to develop the IONM program at a major children's hospital. This collaborative cognitive apprenticeship in anesthesiology to learn the medical direction of IONM is quite innovative as it integrates new members and expands the range of existing ones. In our model, the entire community is elevated by the reciprocal interactions of master clinicians, novice apprentices, and the community of practice.

Intergenerational Effects of Sevoflurane in Young Adult Rats.

BACKGROUND: Sevoflurane administered to neonatal rats induces neurobehavioral abnormalities and epigenetic reprogramming of their germ cells; the latter can pass adverse effects of sevoflurane to future offspring. As germ cells are susceptible to reprogramming by environmental factors across the lifespan, the authors hypothesized that sevoflurane administered to adult rats could induce neurobehavioral abnormalities in future offspring, but not in the exposed rats themselves. METHODS: Sprague-Dawley rats were anesthetized with 2.1% sevoflurane for 3 h every other day between postnatal days 56 and 60. Twenty-five days later, exposed rats and nonexposed controls were mated to produce offspring. RESULTS: Adult male but not female offspring of exposed parents of either sex exhibited deficiencies in elevated plus maze (mean ± SD, offspring of both exposed parents vs. offspring of control parents, 35 ± 12 vs. 15 ± 15 s, P < 0.001) and prepulse inhibition of acoustic startle (offspring of both exposed parents vs. offspring of control parents, 46.504 ± 13.448 vs. 25.838 ± 22.866%, P = 0.009), and increased methylation and reduced expression of the potassium ion-chloride ion cotransporter KCC2 gene (Kcc2) in the hypothalamus. Kcc2 was also hypermethylated in sperm and ovary of the exposed rats. Surprisingly, exposed male rats also exhibited long-term abnormalities in functioning of the hypothalamic-pituitary-gonadal and -adrenal axes, reduced expression of hypothalamic and hippocampal Kcc2, and deficiencies in elevated plus maze (sevoflurane vs. control, 40 ± 24 vs. 25 ± 12 s, P = 0.038) and prepulse inhibition of startle (sevoflurane vs. control, 39.905 ± 21.507 vs. 29.193 ± 24.263%, P < 0.050). CONCLUSIONS: Adult sevoflurane exposure affects brain development in male offspring by epigenetically reprogramming both parental germ cells, while it induces neuroendocrine and behavioral abnormalities only in exposed males. Sex steroids may be required for mediation of the adverse effects of adult sevoflurane in exposed males.

Proof of principle: Preoperative cognitive reserve and brain integrity predicts intra-individual variability in processed EEG (Bispectral Index Monitor) during general anesthesia.

BACKGROUND: Preoperative cognitive reserve and brain integrity may explain commonly observed intraoperative fluctuations seen on a standard anesthesia depth monitor used ubiquitously in operating rooms throughout the nation. Neurophysiological variability indicates compromised regulation and organization of neural networks. Based on theories of neuronal integrity changes that accompany aging, we assessed the relative contribution of: 1) premorbid cognitive reserve, 2) current brain integrity (gray and white matter markers of neurodegenerative disease), and 3) current cognition (specifically domains of processing speed/working memory, episodic memory, and motor function) on intraoperative neurophysiological variability as measured from a common intraoperative tool, the Bispectral Index Monitor (BIS). METHODS: This sub-study included participants from a parent study of non-demented older adults electing unilateral Total Knee Arthroplasty (TKA) with the same surgeon and anesthesia protocol, who also completed a preoperative neuropsychological assessment and preoperative 3T brain magnetic resonance imaging scan. Left frontal two-channel derived EEG via the BIS was acquired preoperatively (un-medicated and awake) and continuously intraoperatively with time from tourniquet up to tourniquet down. Data analyses used correlation and regression modeling. RESULTS: Fifty-four participants met inclusion criteria for the sub-study. The mean (SD) age was 69.5 (7.4) years, 54% were male, 89% were white, and the mean (SD) American Society of Anesthesiologists score was 2.76 (0.47). We confirmed that brain integrity positively and significantly associated with each of the cognitive domains of interest. EEG intra-individual variability (squared deviation from the mean BIS value between tourniquet up and down) was significantly correlated with cognitive reserve (r = -.40, p = .003), brain integrity (r = -.37, p = .007), and a domain of processing speed/working memory (termed cognitive efficiency; r = -.31, p = .021). Hierarchical regression models that sequentially included age, propofol bolus dose, cognitive reserve, brain integrity, and cognitive efficiency found that intraoperative propofol bolus dose (p = .001), premorbid cognitive reserve (p = .008), and current brain integrity (p = .004) explained a significant portion of intraoperative intra-individual variability from the BIS monitor. CONCLUSIONS: Older adults with higher premorbid reserve and less brain disease were more stable intraoperatively on a depth of anesthesia monitor. Researchers need to replicate findings within larger cohorts and other surgery types.

Effects of combined brief etomidate anesthesia and postnatal stress on amygdala expression of Cl- cotransporters and corticotropin-releasing hormone and alcohol intake in adult rats.

Early life stressors, including general anesthesia, can have adverse effects on adult neural and behavioral outcomes, such as disruptions in inhibitory signaling, stress responsivity and increased risk of psychiatric disorders. Here we used a rat model to determine the effects of combined exposure to etomidate (ET) neonatal anesthesia and maternal separation on adult amygdala expression of genes for corticotropin-releasing hormone (Crh) and the chloride co-transporters Nkcc1 and Kcc2, as well as ethanol intake. Male and female Sprague-Dawley rats were subjected to 2 h of ET anesthesia on postnatal days (P) 4, 5, or 6 followed by maternal separation for 3 h on P10 (ET + SEP). During the P91-P120 period rats had daily 2 h access to three 0.05% saccharin solutions containing 0%, 5%, or 10% ethanol, followed by gene expression analyses. The ET + SEP group had increased Crh mRNA levels and Nkcc1/Kcc2 mRNA ratios in the amygdala, with greater increases in Nkcc1/Kcc2 mRNA ratios in males. A moderate increase in 5% ethanol intake was evident in the ET + SEP males, but not females, after calculation of the ratio of alcohol intake between the last week and first week of exposure. In contrast, control males tended to decrease alcohol consumption during the same period. A brief exposure to ET combined with a subsequent episode of stress early in life induced significant alterations in expression of amygdala Crh, Nkcc1 and Kcc2 with greater changes in the Cl- transporter expression in males. The possibility of increased alcohol intake in the exposed males requires further confirmation using different alcohol intake paradigms.

Not Everything That Shakes Is a Seizure: A Case Report.

Not everything that shakes is an epileptic seizure. We present a patient who repeatedly exhibited severe shaking at emergence from general anesthesia. Her nonepileptic myoclonus was mistaken for a refractory seizure and treated with benzodiazepines and intravenous anesthetics. The resulting depressed level of consciousness rendered myoclonus clinically indistinguishable from refractory seizures. Over the course of 6 procedures, we found that levetiracetam, a first-line antiepileptic drug, effectively suppressed her myoclonus. The episodic nature of perioperative anesthesia care presents a challenge for differentiating myoclonus from seizure while balancing the concerns raised by different surgical procedures, rare comorbidities, and the subjective patient experience.

Drugs in space: Pharmacokinetics and pharmacodynamics in astronauts.

Space agencies are working intensely to push the current boundaries of human spaceflight by sending astronauts deeper into space than ever before, including missions to Mars and asteroids. Spaceflight alters human physiology due to fluid shifts, muscle and bone loss, immune system dysregulation, and changes in the gastrointestinal tract and metabolic enzymes. These alterations may change the pharmacokinetics and/or pharmacodynamics of medications used by astronauts and subsequently might impact drug efficacy and safety. Most commonly, medications are administered during space missions to treat sleep disturbances, allergies, space motion sickness, pain, and sinus congestion. These medications are administered under the assumption that they act in a similar way as on Earth, an assumption that has not been investigated systematically yet. Few inflight pharmacokinetic data have been published, and pharmacodynamic and pharmacokinetic/pharmacodynamic studies during spaceflight are also lacking. Therefore, bed-rest models are often used to simulate physiological changes observed during microgravity. In addition to pharmacokinetic/pharmacodynamic changes, decreased drug and formulation stability in space could also influence efficacy and safety of medications. These alterations along with physiological changes and their resulting pharmacokinetic and pharmacodynamic effects must to be considered to determine their ultimate impact on medication efficacy and safety during spaceflight.

Role of environmental stressors in determining the developmental outcome of neonatal anesthesia.

BACKGROUND: The majority of studies evaluating neurocognition in humans who had procedures under anesthesia early in life found long-term deficits even though the typical anesthesia duration normalized to the human life span is much shorter than that shown to induce developmental abnormalities in rodents. Therefore, we studied whether subsequent environmental stressors contribute to deficiencies programmed by a brief neonatal etomidate exposure. METHODS: Postnatal days (P) 4, 5, or 6, Sprague-Dawley rats, pretreated with vehicle or the Na+-K+-2Cl- (NKCC1) inhibitor, bumetanide, received two injections of etomidate resulting in anesthesia for 2h. To simulate stress after anesthesia, the animals were exposed to a single maternal separation for 3h at P10. 3-7days after exposure to etomidate the rats had increased hypothalamic NKCC1 mRNA and corticotropin releasing hormone (CRH) mRNA and decreased K+-2Cl- (KCC2) mRNA levels with greater changes in males. In rats neonatally exposed to both etomidate and maternal separation, these abnormalities persisted into adulthood. These animals also exhibited extended corticosterone responses to restraint stress with increases in total plasma corticosterone more robust in males, as well as behavioral abnormalities. Pretreatment with the NKCC1 inhibitor ameliorated most of these effects. CONCLUSIONS: Post-anesthesia stressors may exacerbate/unmask neurodevelopmental abnormalities even after a relatively short anesthetic with etomidate, leading to dysregulated stress response systems and neurobehavioral deficiencies in adulthood. Amelioration by bumetanide suggests a mechanistic role for etomidate-enhanced gamma-aminobutyric acid type A receptor-mediated depolarization in initiating long-lasting alterations in gene expression that are further potentiated by subsequent maternal separation.

Neurophysiological monitoring and spinal cord integrity.

An integral part of a major spine surgery is the intraoperative neurophysiological monitoring (IONM). By providing continuous functional assessment of specific anatomic structures, IONM allows the rapid detection of neuronal compromise and the opportunity for corrective action before an insult causes permanent neurological damage. Thus, IONM functions not just as a diagnostic tool but may also improve surgical outcomes. Effective clinical application requires a thorough understanding of the scope and limitations of IONM modalities not only by the monitoring team but also by the surgeon and anesthesiologist. Intraoperatively, collaboration and communication between monitorist, surgeon, and anesthesiologist are critical to the effectiveness of IONM. In this study, we review specific monitoring modalities, focusing on the relevant anatomy, physiology, and mechanisms of neuronal injury during major spine surgery. We discuss how these factors interact with anesthetic and surgical management. This review concludes with the current controversies surrounding the evidence in support of IONM and directions of future research.

Propofol, but not etomidate, increases corticosterone levels and induces long-term alteration in hippocampal synaptic activity in neonatal rats.

Animal studies provide strong evidence that general anesthetics (GAs), administered during the early postnatal period, induce long-term cognitive and neurological abnormalities. Because the brain growth spurt in rodents is delayed compared to that in humans, a fundamental question is whether the postnatal human brain is similarly vulnerable. Sevoflurane and propofol, GAs that share positive modulation of the gamma-aminobutyric acid type A receptor (GABAAR) function cause marked increase in corticosterone levels and induce long-term developmental alterations in synaptic activity in rodents. If synaptogenesis is affected, investigation of mechanisms of the synaptic effects of GAs is of high interest because synaptogenesis in humans continues for several years after birth. Here, we compared long-term synaptic effects of etomidate with those of propofol. Etomidate and propofol both positively modulate GABAAR activity, but in contrast to propofol, etomidate inhibits the adrenal synthesis of corticosterone. Postnatal day (P) 4, 5, or 6 rats received five injections of etomidate, propofol, or vehicle control during 5h of maternal separation. Endocrine effects of the anesthetics were evaluated by measuring serum levels of corticosterone immediately after anesthesia or maternal separation. The frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs) in hippocampal CA1 pyramidal neurons were measured at P24-40 and P≥80. Only propofol caused a significant increase in serum corticosterone levels (F(4.26)=17.739, P<0.001). In contrast to increased frequency of mIPSCs in the propofol group (F(4.23)=8.731, p<0.001), mIPSC activity in the etomidate group was not different from that in the vehicle groups. The results of this study together with previously published data suggest that anesthetic-caused increase in corticosterone levels is required for GABAergic GAs to induce synaptic effects in the form of a long-term increase in the frequency of hippocampal mIPSCs.