Decreased Electroencephalographic Alpha Power During Anesthesia Induction Is Associated With EEG Discontinuity in Human Infants.

BACKGROUND: Electroencephalogram (EEG) discontinuity can occur at high concentrations of anesthetic drugs, reflecting suppression of electrocortical activity. This EEG pattern has been reported in children and reflects a deep state of anesthesia. Isoelectric events on the EEG, a more extreme degree of voltage suppression, have been shown to be associated with worse long-term neurologic outcomes in neonates undergoing cardiac surgery. However, the clinical significance of EEG discontinuities during pediatric anesthesia for noncardiac surgery is not yet known and merits further research. In this study, we assessed the incidence of EEG discontinuity during anesthesia induction in neurologically normal infants and the clinical factors associated with its development. We hypothesized that EEG discontinuity would be associated with sevoflurane-induced alpha (8-12 Hz) power during the period of anesthesia induction in infants. METHODS: We prospectively recorded 26 channels of EEG during anesthesia induction in an observational cohort of 54 infants (median age, 7.6 months; interquartile range [IQR] [4.9-9.8 months]). We identified EEG discontinuity, defined as voltage amplitude <25 microvolts for >2 seconds, and assessed its association with sevoflurane-induced alpha power using spectral analysis and multivariable logistic regression adjusting for clinically important variables. RESULTS: EEG discontinuity was observed in 20 of 54 subjects (37%), with a total of 25 discrete events. Sevoflurane-induced alpha power in the posterior regions of the head (eg, parietal or occipital regions) was significantly lower in the EEG discontinuity group (midline parietal channel on the electroencephalogram, International 10-20 System [Pz]; 8.3 vs 11.2 decibels [dBs]; P = .004), and this association remained after multivariable adjustment (adjusted odds ratio [aOR] = 0.51 per dB increase in alpha power [95% CI, 0.30-0.89]; P = .02). There were no differences in the baseline (unanesthetized) EEG between groups in alpha power or power in any other frequency band. CONCLUSIONS: We demonstrate that EEG discontinuity is common during anesthesia induction and is related to the level of sevoflurane-induced posterior alpha power, a putative marker of cortical-thalamic circuit development in the first year of life. This association persisted even after adjusting for age and propofol coadministration. The fact that this difference was only observed during anesthesia and not in the baseline EEG suggests that otherwise hidden brain circuit properties are unmasked by general anesthesia. These neurophysiologic markers observed during anesthesia may be useful in identifying patients who may have a greater chance of developing discontinuity.

Electroencephalographic Findings and Clinical Behavior During Induction of Anesthesia With Sevoflurane in Human Infants: A Prospective Observational Study.

Seizures and interictal epileptiform discharges (IEDs) have been described during sevoflurane. We prospectively estimated their incidence in 54 otherwise neurologically healthy infants by obtaining the full-head video electroencephalogram (EEG). No infants had clinical seizures, but 1 had an electrographic seizure; 3 others had focal IEDs (7.4%; 95% confidence interval [CI], 2.1%-17.9%). We detected no differences in demographic or clinical characteristics between normal and abnormal EEG groups. Diffuse slowing was the most common initial EEG change followed by fast (α, ß) activity in all head leads. Larger studies with more statistical power are needed to further investigate the hypotheses generated with this research.

Reasons for article retraction in anesthesiology: a comprehensive analysis.

BACKGROUND: Increasing awareness of scientific misconduct has prompted various fields of medicine, including orthopedic surgery, neurosurgery, and dentistry to characterize the reasons for article retraction. The purpose of this review was to evaluate the reasons for and the rate of article retraction in the field of anesthesia within the last 30 years. METHODS: Based on a reproducible search strategy, two independent reviewers searched MEDLINE, EMBASE, and the Retraction Watch website to identify retracted anesthesiology articles. Extracted data included: author names, year of publication, year of the retracted article, journal name, journal five-year impact factor, research type (clinical, basic science, or review), reason for article retraction, number of citations, and presence of a watermark indicating article retraction. RESULTS: Three hundred and fifty articles were included for data extraction. Reasons for article retraction could be grouped into six broad categories. The most common reason for retraction was fraud (data fabrication or manipulation), which accounted for nearly half (49.4%) of all retractions, followed by lack of appropriate ethical approval (28%). Other reasons for retraction included publication issues (e.g., duplicate publications), plagiarism, and studies with methodologic or other non-fraud data issues. Four authors were associated with most of the retracted articles (59%). The majority (69%) of publications utilized a watermark on the original article to indicate that the article was retracted. Journal Citation Reports journal impact factors ranged from 0.9 to 48.1 (median [interquartile range (IQR)], 3.6 [2.5-4.0]), and the most cited article was referenced 197 times (median [IQR], 13 [5-26]). Most retracted articles (66%) were cited at least once by other journal articles after having been withdrawn. CONCLUSIONS: Most retracted articles in anesthesiology literature were retracted because of research misconduct. Limited information is available in the retraction notices, unless explicitly stated, so it is challenging to distinguish between an honest error and research misconduct. Therefore, a standardized reporting process with structured retraction notices is desired.

A Retrospective Analysis of Clinical Research Misconduct Using FDA-Issued Warning Letters and Clinical Investigator Inspection List From 2010 to 2014.

BACKGROUND: The US Food and Drug Administration (FDA) conducts inspections of clinical investigation sites as a component of clinical trial regulation. The FDA describes the results of these inspections in the Clinical Investigator Inspection List (CLIIL). More serious violations are followed up in FDA warning letters issued to investigators. The primary objective of the current study is to qualitatively and quantitatively describe the CLIIL data and contents of FDA-issued warning letters from 2010 to 2014. METHODS: We retrospectively analyzed the CLIIL and FDA warning letters. For the CLIIL, we quantified the frequency of each violation among other data points. We compared recent data (2010-2014) to the previous 5 years (2005-2009). To analyze FDA warning letters, we developed a coding system to quantify the frequency of violations found. RESULTS: We analyzed 3637 inspections in the CLIIL database and 60 warning letters. Overall, there was a decrease or no change in all violations in the CLIIL database. The largest violation code reported was "failure to follow investigational plan" in both the 2005-2009 and 2010-2014 timeframes. Coding of FDA warning letters shows that the most common violations reported were failing to maintain accurate case histories (10.82%), enrolling ineligible subjects (8.85%), and failing to perform required tests (8.52%). CONCLUSIONS: The overall decrease in violations is encouraging. But, the high proportion of violations related to failure to follow the investigational plan is concerning as the complexity of trials increases. We conclude that more detailed information is necessary to accurately evaluate these violations. The current study provides a model for creating more granular data of violations to better inform clinical investigators and improve clinical trials.

Intraoperative inflation of laryngocele with LMA.

OBJECTIVES: Laryngoceles are pathologic air filled dilations of the laryngeal ventricle. They are most often benign and incidental findings. Resection may be necessary in the setting of infection, airway obstruction, dysphagia, and phonatory disturbances. External laryngoceles are almost universally treated with open resection via a lateral or midline cervical approach. Care must be taken to resect the laryngocele in its entirety to avoid recurrence. In cases of recurrent infection, normal surgical planes are often fibrosed and obscured increasing the risk of neurovascular sacrifice and functional losses. METHODS: We are reporting a case of recurrent infections in a large, palpable external laryngocele. During resection the patient was ventilated using an endotracheal tube (ETT). Additionally, a laryngeal mask airway (LMA) was inserted posterior to the ETT, resting in the hypopharynx and attached to a Jackson Rees circuit. Air was passed through the LMA to inflate the laryngocele and better define its borders. The LMA was also used to identify the root of the laryngocele in the paraglottic space and ensure its airtight closure. RESULTS: The LMA assisted our dissection and helped progress the surgery safely in a fibrosed surgical field. We have not seen this method described previously. The patient continues to be free of recurrence 2 years after surgery. CONCLUSION: While in most cases, with careful surgical technique, even a fibrotic and scarred laryngocele can be excised in its entirety without neurovascular sacrifice. In some cases where this may be difficult with a traditional approach, we offer the intra-operative trumpet maneuver as a viable method of better delineating the borders of a laryngocele.

Systemic inflammatory response does not correlate with acute lung injury associated with mechanical ventilation strategies in normal lungs.

BACKGROUND: Mechanical ventilation (MV) can lead to ventilator-induced lung injury secondary to trauma and associated increases in pulmonary inflammatory cytokines. There is controversy regarding the associated systemic inflammatory response. In this report, we demonstrate the effects of MV on systemic inflammation. METHODS: This report is part of a previously published study (Hong et al. Anesth Analg 2010;110:1652-60). Female pigs were randomized into 3 groups. Group H-Vt/3 was ventilated with a tidal volume (Vt) of 15 mL/kg predicted body weight (PBW)/positive end-expiratory pressure (PEEP) of 3 cm H(2)O; group L-Vt/3 with a Vt of 6 mL/kg PBW/PEEP of 3 cm H2O; and group L-Vt/10 with a Vt of 6 mL/kg PBW/PEEP of 10 cm H(2)O, for 8 hours. Each group had 6 subjects (n = 6). Prelung and postlung sera were analyzed for inflammatory markers. Hemodynamics, airway mechanics, and arterial blood gases were monitored. RESULTS: There were no significant differences in systemic cytokines among groups. There were similar trends of serum inflammatory markers in all subjects. This is in contrast to findings previously published demonstrating increases in inflammatory mediators in bronchoalveolar lavage. CONCLUSION: Systemic inflammatory markers did not correlate with lung injury associated with MV.

MicroRNA-145, a novel smooth muscle cell phenotypic marker and modulator, controls vascular neointimal lesion formation.

Phenotypic modulation of vascular smooth muscle cells (VSMCs) plays a critical role in the pathogenesis of a variety of proliferative vascular diseases. Recently, we have found that microRNA (miRNA) miR-145 is the most abundant miRNA in normal vascular walls and in freshly isolated VSMCs; however, the role of miR-145 in VSMC phenotypic modulation and vascular diseases is currently unknown. Here we find that miR-145 is selectively expressed in VSMCs of the vascular wall and its expression is significantly downregulated in the vascular walls with neointimal lesion formation and in cultured dedifferentiated VSMCs. More importantly, both in cultured rat VSMCs in vitro and in balloon-injured rat carotid arteries in vivo, we demonstrate that the noncoding RNA miR-145 is a novel phenotypic marker and a novel phenotypic modulator of VSMCs. VSMC differentiation marker genes such as SM alpha-actin, calponin, and SM-MHC are upregulated by premiR-145 or adenovirus expressing miR-145 (Ad-miR-145) but are downregulated by the miR-145 inhibitor 2'OMe-miR-145. We have further identified that miR-145-mediated phenotypic modulation of VSMCs is through its target gene KLF5 and its downstream signaling molecule, myocardin. Finally, restoration of miR-145 in balloon-injured arteries via Ad-miR-145 inhibits neointimal growth. We conclude that miR-145 is a novel VSMC phenotypic marker and modulator that is able of controlling vascular neointimal lesion formation. These novel findings may have extensive implications for the diagnosis and therapy of a variety of proliferative vascular diseases.

Anesthesiology Training in the Time of COVID-19: Problems and Solutions.

From March to June of 2020, Montefiore Medical Center faced one of the most acute surges in hospital admissions and critical illness ever experienced in the United States due to the severe acute respiratory syndrome coronavirus 2 pandemic. The pandemic had not yet spread to most of the country, and there was a relative deficit of knowledge regarding treatments, prognosis, and prevention of the virus, making this experience relatively unique and challenging. As part of a surge plan, our institution converted nonclinical spaces, such as conference rooms, to inpatient care settings and placed elective surgeries on hold to free up resources. A central deployment office suspended anesthesiology resident rotations and instead assigned them to intensive care settings based on need. For the Montefiore Medical Center Department of Anesthesiology, preserving its academic mission and commitment to Graduate Medical Education was essential. Adaptations included changing the residency rotation structure to biweekly, converting didactics online, ensuring adequate case numbers for graduating residents, actively pursuing wellness interventions, and prioritizing the safety of the residents caring for patients with coronavirus disease 2019 (COVID-19). In this brief report, the authors discuss solutions devised to maintain the quality of anesthesiology resident education and training as much as possible during the COVID-19 surge.

Adaptation and restructuring of an academic anesthesiology department during the COVID-19 pandemic in New York City: Challenges and lessons learned.

The novel SARS-CoV-2 pandemic starting in 2019 profoundly changed the world, and thousands of residents of New York City were affected, leading to one of the most acute surges in regional hospital capacity. As the largest academic medical center in the Bronx, Montefiore Medical Center was immediately impacted, and the entire hospital was mobilized to address the needs of its community. In this article, we describe our experiences as a large academic anesthesiology department during this pandemic. Our goals were to maximize our staff's expertise, maintain our commitment to wellness and safety, and preserve the quality of patient care. Lessons learned include the importance of critical care training presence and leadership, the challenges of converting an ambulatory surgery center to an intensive care unit (ICU), and the management of effective communication. Lastly, we provide suggestions for institutions facing an acute surge, or subsequent waves of COVID-19, based on a single center's experiences.

MicroRNA expression signature and the role of microRNA-21 in the early phase of acute myocardial infarction.

Several recent reports have suggested that microRNAs (miRNAs) might play critical roles in acute myocardial infarction (AMI). However, the miRNA expression signature in the early phase of AMI has not been identified. In this study, the miRNA expression signature was investigated in rat hearts 6 h after AMI. Compared with the expression signature in the noninfarcted areas, 38 miRNAs were differentially expressed in infarcted areas and 33 miRNAs were aberrantly expressed in the border areas. Remarkably, miR-21 expression was significantly down-regulated in infarcted areas, but was up-regulated in border areas. The down-regulation of miR-21 in the infarcted areas was inhibited by ischemic preconditioning, a known cardiac protective method. Overexpression of miR-21 via adenovirus expressing miR-21 (Ad-miR-21) decreased myocardial infarct size by 29% at 24 h and decreased the dimension of left ventricles at 2 weeks after AMI. Using both gain-of-function and loss-of-function approaches in cultured cardiac myocytes, we identified that miR-21 had a protective effect on ischemia-induced cell apoptosis that was associated with its target gene programmed cell death 4 and activator protein 1 pathway. The protective effect of miR-21 against ischemia-induced cardiac myocyte damage was further confirmed in vivo by decreased cell apoptosis in the border and infarcted areas of the infarcted rat hearts after treatment with Ad-miR-21. The results suggest that miRNAs such as miR-21 may play critical roles in the early phase of AMI.

Low tidal volume and high positive end-expiratory pressure mechanical ventilation results in increased inflammation and ventilator-associated lung injury in normal lungs.

BACKGROUND: Protective mechanical ventilation with low tidal volume (Vt) and low plateau pressure reduces mortality and decreases the length of mechanical ventilation in patients with acute respiratory distress syndrome. Mechanical ventilation that will protect normal lungs during major surgical procedures of long duration may improve postoperative outcomes. We performed an animal study comparing 3 ventilation strategies used in the operating room in normal lungs. We compared the effects on pulmonary mechanics, inflammatory mediators, and lung tissue injury. METHODS: Female pigs were randomized into 3 groups. Group H-Vt/3 (n = 6) was ventilated with a Vt of 15 mL/kg predicted body weight (PBW)/positive end-expiratory pressure (PEEP) of 3 cm H(2)O, group L-Vt/3 (n = 6) with a Vt of 6 mL/kg PBW/PEEP of 3 cm H(2)O, and group L-Vt/10 (n = 6) with a Vt of 6 mL/kg PBW/PEEP of 10 cm H(2)O, for 8 hours. Hemodynamics, airway mechanics, arterial blood gases, and inflammatory markers were monitored. Bronchoalveolar lavage (BAL) was analyzed for inflammatory markers and protein concentration. The right lower lobe was assayed for mRNA of specific cytokines. The right lower lobe and right upper lobe were evaluated histologically. RESULTS: In contrast to groups H-Vt/3 and L-Vt/3, group L-Vt/10 exhibited a 6-fold increase in inflammatory mediators in BAL (P < 0.001). Cytokines in BAL were similar in groups H-Vt/3 and L-Vt/3. Group H-Vt/3 had a significantly lower lung injury score than groups L-Vt/3 and L-Vt/10. CONCLUSION: Comparing intraoperative strategies, ventilation with high PEEP resulted in increased production of inflammatory markers. Low PEEP resulted in lower levels of inflammatory markers. High Vt/low PEEP resulted in less histologic lung injury.

Perioperative Efficiency vs. Quality of Care - Do We Always Have to Choose?

Introduction: ATTEMPTS to enforce optimization practices for operating room (OR) efficiency are often interpreted as a "pressure for production" which threatens patient safety. The aim of this study is to assess if and how improvements in OR efficiency affect patient safety and thus the quality of care. Methods: In an attempt to optimize OR efficiency, a new OR management approach "Integrated Practice Improvement Solutions" (IPIS) was developed at the Weiler Division of Montefiore Medical Center in 2011. IPIS is a flexible managerial system based on elements of multiple practice improvement methodologies incorporated into an open source framework. It was implemented in 2012. The data presented covers the period from 2012 through 2014 when the system was temporarily discontinued due to administrative restructuring. Data from 2011 was used as a baseline. The impact of IPIS on patient safety and quality of care was assessed based on quality improvement and patient safety (QIPS) Committee reports covering the same period of time. Results: IPIS implementation resulted in an increase in surgical workload by an average of 10.7%, an increase in OR and anesthesia revenues by 18.5% and 6.9%, respectively, and decreases in turnover time by 15% and overtime for the anesthesia staff by 26%. Based on QIPS reports, the total number of complications potentially attributable to "production pressure" was 0.25%, 0.2% and 0.16% in 2012, 2013 and 2014, respectively compared to 0.21% in 2011 (p = 0.56). Conclusions: Gradual implementation of a methodologically structured improvement in OR efficiency has no negative impact on patient safety and quality of care.

Assessment of Didactic Transesophageal Echocardiography Education During Anesthesia Residency.

BACKGROUND: Transesophageal echocardiography can be a useful monitor during noncardiac surgery, in patients with comorbidities and/or undergoing procedures associated with substantial hemodynamic changes. The goal of this study was to investigate if transesophageal-echocardiography-related knowledge could be acquired during anesthesia residency. METHODS: After institutional review board approval, a prospective observational study was performed in two anesthesiology residency programs. After a 41-week didactic transesophageal-echocardiography-education curriculum residents' exam scores were compared to baseline. The educators' examination was validated against the National Board of Echocardiography's Examination of Special Competence in Advanced Perioperative Transesophageal Echocardiography. RESULTS: After the 41-week course, clinical anesthesia (CA)-3 exam scores increased 12% compared to baseline (P = .03), CA-2 scores increased 29% (P = .007), and CA-1 scores increased 25% (P = .002). Pearson correlation coefficient between the educators' exam score and the special competence exam percentile rank was 0.69 (P = .006). Pearson correlation coefficient between the educators' exam score and the special competence exam scaled score was 0.71 (P = .0045). CONCLUSIONS: The 41-week course resulted in significant increases in exam scores in all 3 CA-classes. While didactic knowledge can be learned by anesthesiology residents during training, it requires significant time and effort. It is important to educate residents in echocardiography, to prepare them for board examinations and to care for the increasingly older and sicker patient population. Further work needs to be done to determine optimal methods to provide such education.

Behavior and cellular evidence for propofol-induced hypnosis involving brain glycine receptors.

BACKGROUND: It is well documented that several general anesthetics, including propofol, potentiate glycine receptor function. Furthermore, glycine receptors exist throughout the central nervous system, including areas of the brain thought to be involved in sleep. However, the role of glycine receptors in anesthetic-induced hypnosis has not been determined. METHODS: Experiments were conducted in rats where the loss of righting reflex (LORR) was used as a marker of the hypnotic state. Propofol-induced LORR was examined in the presence and absence of strychnine (a glycine receptor antagonist), GABAzine (a gamma-aminobutyric acid A receptor antagonist), as well as ketamine (an antagonist of N-methyl-D-aspartic acid subtype of glutamate receptors). Furthermore, the effects of propofol on the currents elicited by glycine and gamma-aminobutyric acid were analyzed in neurons isolated from the posterior hypothalamus of rats. The effects of strychnine and GABAzine on propofol-induced currents were also evaluated. RESULTS: Strychnine and GABAzine dose-dependently reduced the percentage of rats exhibiting LORR induced by propofol. Furthermore, strychnine significantly increased the onset time and reduced the duration of LORR induced by propofol. In contrast, strychnine did not affect the LORR induced by ketamine. In addition, propofol markedly increased the currents elicited by glycine and GABA of hypothalamic neurons. Conversely, strychnine and GABAzine both profoundly attenuated the current induced by propofol. CONCLUSION: Strychnine, the glycine receptor antagonist, dose-dependently reduced propofol-induced LORR in rats and propofol-induced current of rat hypothalamic neurons. These results suggest that neuronal glycine receptors partially contribute to propofol-induced hypnosis.

Measurement of resident fatigue using rapid number naming.

OBJECTIVE: Sleep deprivation has a negative effect on neurocognitive performance. The King-Devick test (KDT), which tests speed and accuracy of number-reading, requires integrity of saccades, visual processing, and cognition. This study investigated effects of sleep deprivation in on-call residents using KDT. METHODS: A prospective cohort study was conducted among 80 residents. KDT was performed at the beginning and end of an overnight call shift for the residents in the experimental group. A control group was tested at the beginning of 2 consecutive day shifts. Estimates of hours of sleep, Karolinska Sleepiness Scale (KSS)(1 = extremely alert, 9 = extremely sleepy), and time and accuracy of KDT were recorded. RESULTS: 42 residents were tested before and after overnight call shifts and 38 served as controls. Change in test time differed between the groups, with the experimental group performing 0.54(SD = 4.0) seconds slower after their night on call and the control group performing 2.32(SD = 3.0) seconds faster on the second day, p < 0.001. This difference was larger in surgical compared to medical residents. CONCLUSIONS: Sleep deprivation was inversely correlated with neurocognitive performance as measured by KDT, with more effect on surgical than medical residents. Further research could investigate whether this test could help determine fatigue level and ability to continue working after a long shift.

Nanomolar propofol stimulates glutamate transmission to dopamine neurons: a possible mechanism of abuse potential?

Anesthesiologists among physicians are on the top of the drug abuse list, and the mechanism is unclear. Recent studies suggest occupation-related second-hand exposure to i.v. drugs, including propofol, may play a role. Growing evidence indicates that propofol is one of the choices of drugs being abused. In this study, we show that propofol at minute concentrations increases glutamatergic excitatory synaptic transmission and discharges of dopamine neurons in the ventral tegmental area (VTA). We found that acute application of propofol (0.1-10 nM) to the VTA in midbrain slices of rats increased the frequency but not the amplitude of spontaneous excitatory postsynaptic currents (EPSCs) mediated by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. We observed that propofol increased the amplitude but decreased the paired-pulse ratio of EPSCs evoked by stimulation in the absence and the presence of gabazine (SR 95531), a GABA(A) receptor antagonist. Moreover, the propofol-induced facilitation of EPSCs was mimicked by 6-phenyl-4-azabicyclo[5.4.0]undeca-7,9,11-triene-9,10-diol (SKF38393), an agonist of dopamine D(1) receptor, and by 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride (GBR 12935), a dopamine reuptake inhibitor, but blocked by (+/-)-7-bromo-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine hydrochloride (SKF83566), a D(1) antagonist, or by depleting dopamine stores with reserpine. Finally, 1 nM propofol increased the spontaneous discharge rate of dopamine neurons. These findings suggest that propofol at minute concentrations enhances presynaptic D(1) receptor-mediated facilitation of glutamatergic synaptic transmission and the excitability of VTA dopamine neurons, probably by increasing extracellular dopamine levels. These changes in synaptic plasticity in the VTA, an addiction-related brain area might contribute to the development of propofol abuse and the increased susceptibility to addiction of other drugs.

Labetalol facilitates GABAergic transmission to rat periaqueductal gray neurons via antagonizing beta1-adrenergic receptors--a possible mechanism underlying labetalol-induced analgesia.

Labetalol, a combined alpha1, beta1, and beta2 adrenoceptor-blocking drug, has been shown to have analgesic properties in vivo. To determine the underlying mechanisms, we examined its effects on GABAA receptor-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) and spontaneous firings of rat ventrolateral periaqueductal gray (PAG) neurons, either mechanically dissociated, or in acute brain slices. These PAG neurons mediate opioid-mediated analgesia and pain transmission and are under tonic control of GABAergic interneurons. An increase in GABAergic transmission to these neurons yields an inhibitory hyperpolarized state and may interrupt pain signal transmission. Using patch clamp techniques, we found that labetalol reversibly increases the frequency of sIPSCs without changing their mean amplitude. This indicates that labetalol enhances GABAergic synaptic transmission by a presynaptic mechanism. Metoprolol, a specific beta1-adrenoceptor antagonist, also reversibly enhanced sIPSC frequency. In the presence of metoprolol, labetalol-induced increase in sIPSC frequency was significantly attenuated or even abolished. These results suggest that labetalol shares the same pathway as metoprolol in enhancing GABAergic transmission via an inhibition of presynaptic beta1-adrenoceptors. We further showed that labetalol reversibly reduced the firing rate of PAG neurons. This reduction was significantly attenuated in the presence of bicuculline, a selective antagonist of GABAA receptors. These data indicate that labetalol-induced inhibition of PAG cell firing is attributable to its potentiation of GABAergic transmission. Based on these data, we postulate that labetalol-induced analgesia is at least in part ascribed to its antagonistic effects on presynaptic beta1-adrenoceptors.