Post-cardiac arrest Sedation Promotes Electroencephalographic Slow-wave Activity and Improves Survival in a Mouse Model of Cardiac Arrest.

BACKGROUND: Patients resuscitated from cardiac arrest are routinely sedated during targeted temperature management, while the effects of sedation on cerebral physiology and outcomes after cardiac arrest remain to be determined. The authors hypothesized that sedation would improve survival and neurologic outcomes in mice after cardiac arrest. METHODS: Adult C57BL/6J mice of both sexes were subjected to potassium chloride-induced cardiac arrest and cardiopulmonary resuscitation. Starting at the return of spontaneous circulation or at 60 min after return of spontaneous circulation, mice received intravenous infusion of propofol at 40 mg · kg-1 · h-1, dexmedetomidine at 1 µg · kg-1 · h-1, or normal saline for 2 h. Body temperature was lowered and maintained at 33°C during sedation. Cerebral blood flow was measured for 4 h postresuscitation. Telemetric electroencephalogram (EEG) was recorded in freely moving mice from 3 days before up to 7 days after cardiac arrest. RESULTS: Sedation with propofol or dexmedetomidine starting at return of spontaneous circulation improved survival in hypothermia-treated mice (propofol [13 of 16, 81%] vs. no sedation [4 of 16, 25%], P = 0.008; dexmedetomidine [14 of 16, 88%] vs. no sedation [4 of 16, 25%], P = 0.002). Mice receiving no sedation exhibited cerebral hyperemia immediately after resuscitation and EEG power remained less than 30% of the baseline in the first 6 h postresuscitation. Administration of propofol or dexmedetomidine starting at return of spontaneous circulation attenuated cerebral hyperemia and increased EEG slow oscillation power during and early after sedation (40 to 80% of the baseline). In contrast, delayed sedation failed to improve outcomes, without attenuating cerebral hyperemia and inducing slow-wave activity. CONCLUSIONS: Early administration of sedation with propofol or dexmedetomidine improved survival and neurologic outcomes in mice resuscitated from cardiac arrest and treated with hypothermia. The beneficial effects of sedation were accompanied by attenuation of the cerebral hyperemic response and enhancement of electroencephalographic slow-wave activity.

Inhaled nitric oxide improves post-cardiac arrest outcomes via guanylate cyclase-1 in bone marrow-derived cells.

RATIONALE: Nitric oxide (NO) exerts its biological effects primarily via activation of guanylate cyclase (GC) and production of cyclic guanosine monophosphate. Inhaled NO improves outcomes after cardiac arrest and cardiopulmonary resuscitation (CPR). However, mechanisms of the protective effects of breathing NO after cardiac arrest are incompletely understood. OBJECTIVE: To elucidate the mechanisms of beneficial effects of inhaled NO on outcomes after cardiac arrest. METHODS: Adult male C57BL/6J wild-type (WT) mice, GC-1 knockout mice, and chimeric WT mice with WT or GC-1 knockout bone marrow were subjected to 8 min of potassium-induced cardiac arrest to determine the role of GC-1 in bone marrow-derived cells. Mice breathed air or 40 parts per million NO for 23 h starting at 1 h after CPR. RESULTS: Breathing NO after CPR prevented hypercoagulability, cerebral microvascular occlusion, an increase in circulating polymorphonuclear neutrophils and neutrophil-to-lymphocyte ratio, and right ventricular dysfunction in WT mice, but not in GC-1 knockout mice, after cardiac arrest. The lack of GC-1 in bone marrow-derived cells diminished the beneficial effects of NO breathing after CPR. CONCLUSIONS: GC-dependent signaling in bone marrow-derived cells is essential for the beneficial effects of inhaled NO after cardiac arrest and CPR.

A Sulfonyl Azide-Based Sulfide Scavenger Rescues Mice from Lethal Hydrogen Sulfide Intoxication.

Exposure to hydrogen sulfide (H2S) can cause neurotoxicity and cardiopulmonary arrest. Resuscitating victims of sulfide intoxication is extremely difficult, and survivors often exhibit persistent neurological deficits. However, no specific antidote is available for sulfide intoxication. The objective of this study was to examine whether administration of a sulfonyl azide-based sulfide-specific scavenger, SS20, would rescue mice in models of H2S intoxication: ongoing exposure and post-cardiopulmonary arrest. In the ongoing exposure model, SS20 (1250 µmol/kg) or vehicle was administered to awake CD-1 mice intraperitoneally at 10 min after breathing 790 ppm of H2S followed by another 30 min of H2S inhalation. Effects of SS20 on survival were assessed. In the post-cardiopulmonary arrest model, cardiopulmonary arrest was induced by an intraperitoneal administration of sodium sulfide nonahydrate (125 mg/kg) in anesthetized mice. After 1 min of cardiopulmonary arrest, mice were resuscitated with intravenous administration of SS20 (250 µmol/kg) or vehicle. Effects of SS20 on survival, neurological outcomes, and plasma H2S levels were evaluated. Administration of SS20 during ongoing H2S inhalation improved 24-h survival (6/6 [100%] in SS20 vs 1/6 [17%] in vehicle; p = .0043). Post-arrest administration of SS20 improved 7-day survival (4/10 [40%] in SS20 vs 0/10 [0%] in vehicle; p = .0038) and neurological outcomes after resuscitation. SS20 decreased plasma H2S levels to pre-arrest baseline immediately after reperfusion and shortened the time to return of spontaneous circulation and respiration. These results suggest that SS20 is an effective antidote against lethal H2S intoxication, even when administered after cardiopulmonary arrest.

Sulfide catabolism ameliorates hypoxic brain injury.

The mammalian brain is highly vulnerable to oxygen deprivation, yet the mechanism underlying the brain's sensitivity to hypoxia is incompletely understood. Hypoxia induces accumulation of hydrogen sulfide, a gas that inhibits mitochondrial respiration. Here, we show that, in mice, rats, and naturally hypoxia-tolerant ground squirrels, the sensitivity of the brain to hypoxia is inversely related to the levels of sulfide:quinone oxidoreductase (SQOR) and the capacity to catabolize sulfide. Silencing SQOR increased the sensitivity of the brain to hypoxia, whereas neuron-specific SQOR expression prevented hypoxia-induced sulfide accumulation, bioenergetic failure, and ischemic brain injury. Excluding SQOR from mitochondria increased sensitivity to hypoxia not only in the brain but also in heart and liver. Pharmacological scavenging of sulfide maintained mitochondrial respiration in hypoxic neurons and made mice resistant to hypoxia. These results illuminate the critical role of sulfide catabolism in energy homeostasis during hypoxia and identify a therapeutic target for ischemic brain injury.

Unexpected deposits in the anesthetic circuit: a possible cause of PEEP/Pmax valve malfunction.

PEEP is regulated by the internal PEEP/maximum peak inspiratory pressure limit (Pmax) valve. Malfunctioning of the PEEP/Pmax valve can result in the creation of unintentional or unstable PEEP, and a reduction of inspired tidal volume. Some of our Dräger Fabius® anesthesia machines were noted to exhibit changes in expiratory waveforms and unstable PEEP during general anesthesia. We considered that the cause was associated with PEEP/Pmax valve malfunction, and then investigated the problems in collaboration with the manufacturer. Seven of the 22 Dräger Fabius® anesthesia workstations at our department exhibited problems with their PEEP/Pmax valves. We replaced the PEEP membrane and sealing washers in these seven anesthesia machines, and the problems were temporarily resolved. After a short interval, however, one of the seven machines began to show a similar phenomenon. We then asked the manufacturer to overhaul the PEEP/Pmax valve and the entire breathing circuit of the machine. On close investigation, we found that the valve components and the internal surface of the breathing circuit were contaminated with unexpected deposits. The build-up of deposits occurred within a year after the previous regular inspection. Our troubleshooting process determined the issue with the PEEP/Pmax valve, which could go unnoticed because the valve is encased inside the breathing circuit, and requires disassembly for close inspection. Our findings should raise awareness regarding the importance of the preventive maintenance cycle as a safety precaution to keep the anesthetic circuit free of unexpected contamination.

High Concentrations of Nitric Oxide Inhalation Therapy in Pregnant Patients With Severe Coronavirus Disease 2019 (COVID-19).

BACKGROUND: Rescue therapies to treat or prevent progression of coronavirus disease 2019 (COVID-19) hypoxic respiratory failure in pregnant patients are lacking. METHOD: To treat pregnant patients meeting criteria for severe or critical COVID-19 with high-dose (160-200 ppm) nitric oxide by mask twice daily and report on their clinical response. EXPERIENCE: Six pregnant patients were admitted with severe or critical COVID-19 at Massachusetts General Hospital from April to June 2020 and received inhalational nitric oxide therapy. All patients tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A total of 39 treatments was administered. An improvement in cardiopulmonary function was observed after commencing nitric oxide gas, as evidenced by an increase in systemic oxygenation in each administration session among those with evidence of baseline hypoxemia and reduction of tachypnea in all patients in each session. Three patients delivered a total of four neonates during hospitalization. At 28-day follow-up, all three patients were home and their newborns were in good condition. Three of the six patients remain pregnant after hospital discharge. Five patients had two negative test results on nasopharyngeal swab for SARS-CoV-2 within 28 days from admission. CONCLUSION: Nitric oxide at 160-200 ppm is easy to use, appears to be well tolerated, and might be of benefit in pregnant patients with COVID-19 with hypoxic respiratory failure.

A retrospective review of 10-year trends in general anesthesia for cesarean delivery at a university hospital: the impact of a newly launched team on obstetric anesthesia practice.

BACKGROUND: The indications for general anesthesia (GA) in obstetric settings, which are determined in consideration of maternal and fetal outcome, could be affected by local patterns of clinical practice grounded in unique situations and circumstances that vary among medical institutions. Although the use of GA for cesarean delivery has become less common with more frequent adoption of neuraxial anesthesia, GA was previously chosen for pregnancy with placenta previa at our institution in case of unexpected massive hemorrhage. However, the situation has been gradually changing since formation of a team dedicated to obstetric anesthesia practice. Here, we report the results of a review of all cesarean deliveries performed under GA, and assess the impact of our newly launched team on trends in clinical obstetric anesthesia practice at our institution. METHODS: Our original database for obstetric GA during the period of 2010 to 2019 was analyzed. The medical records of all parturients who received GA for cesarean delivery were reviewed to collect detailed information. Interrupted time series analysis was used to evaluate the impact of the launch of our obstetric anesthesia team. RESULTS: As recently as 2014, more than 10% of cesarean deliveries were performed under GA, with placenta previa accounting for the main indication in elective and emergent cases. Our obstetric anesthesia team was formed in 2015 to serve as a communication bridge between the department of anesthesiology and the department of obstetrics. Since then, there has been a steady decline in the percentage of cesarean deliveries performed under GA, decreasing to a low of less than 5% in the latest 2 years. Interrupted time series analysis revealed a significant reduction in obstetric GA after 2015 (P = 0.04), which was associated with decreased use of GA for pregnancy with placenta previa. On the other hand, every year has seen a number of urgent cesarean deliveries requiring GA. CONCLUSIONS: There has been a trend towards fewer obstetric GA since 2015. The optimized use of GA for cesarean delivery was made possible mainly through strengthened partnerships between anesthesiologists and obstetricians with the support of our obstetric anesthesia team.

Reference value for expiratory time constant calculated from the maximal expiratory flow-volume curve.

BACKGROUND: The expiratory time constant (RCEXP), which is defined as the product of airway resistance and lung compliance, enable us to assess the mechanical properties of the respiratory system in mechanically ventilated patients. Although RCEXP could also be applied to spontaneously breathing patients, little is known about RCEXP calculated from the maximal expiratory flow-volume (MEFV) curve. The aim of our study was to determine the reference value for RCEXP, as well as to investigate the association between RCEXP and other respiratory function parameters, including the forced expiratory volume in 1 s (FEV1)/ forced vital capacity (FVC) ratio, maximal mid-expiratory flow rate (MMF), maximal expiratory flow at 50 and 25% of FVC (MEF50 and MEF25, respectively), ratio of MEF50 to MEF25 (MEF50/MEF25). METHODS: Spirometric parameters were extracted from the records of patients aged 15 years or older who underwent pulmonary function testing as a routine preoperative examination before non-cardiac surgery at the University of Tokyo Hospital. RCEXP was calculated in each patient from the slope of the descending limb of the MEFV curve using two points corresponding to MEF50 and MEF25. Airway obstruction was defined as an FEV1/FVC and FEV1 below the statistically lower limit of normal. RESULTS: We retrospectively analyzed 777 spirometry records, and 62 patients were deemed to have airway obstruction according to Japanese spirometric reference values. The cut-off value for RCEXP was 0.601 s with an area under the receiver operating characteristic curve of 0.934 (95% confidence interval = 0.898-0.970). RCEXP was strongly associated with FEV1/FVC, and was moderately associated with MMF and MEF50. However, RCEXP was less associated with MEF25 and MEF50/MEF25. CONCLUSIONS: Our findings suggest that an RCEXP of longer than approximately 0.6 s can be linked to the presence of airway obstruction. Application of the concept of RCEXP to spontaneously breathing subjects was feasible, using our simple calculation method.

Intraoperative hemodynamics monitoring in a patient with pheochromocytoma multisystem crisis: a case report.

BACKGROUND: Pheochromocytoma is a rare catecholamine-secreting tumor. To evaluate the intraoperative hemodynamics with precision is difficult. CASE PRESENTATION: A 42-year-old man, who suddenly developed a life-threatening pheochromocytoma multisystem crisis that occurred during preoperative prophylactic medication, underwent urgent bilateral adrenalectomy. For the purpose of evaluating the intraoperative hemodynamics, we monitored both pulmonary artery catheter-based cardiac output (PACO) and arterial pressure-based cardiac output (APCO; FloTrac™). APCO fluctuated in poor agreement with the change in PACO, especially in the state of cytokine storming. CONCLUSIONS: Overall, the value of stroke volume variation derived from FloTrac™ changed in tandem with the intraoperative volume status, indicating its utility as a marker of circulatory hemodynamics.

Relationship between pre-anesthetic and intra-anesthetic airway resistance in patients undergoing general anesthesia: A prospective observational study.

Surgery patients in Japan undergo routine spirometry testing prior to general anesthesia. The use of a flow sensor during general anesthesia has recently become common. However, it is not certain whether the information derived from flow-volume curves is being adequately used for mechanical ventilation management during general anesthesia. So far, there have been no attempts to calculate airway resistance using flow-volume curves. Therefore, we performed a prospective, observational study to investigate the relationship between pre-anesthetic and intra-anesthetic airway resistance in patients scheduled for surgery under general anesthesia. We calculated pre-anesthetic and intra-anesthetic airway resistance in each patient, based on the slopes of flow-volume curves obtained prior to and during general anesthesia. We also calculated endotracheal tube resistance to correct the intra-anesthetic airway resistance values calculated. A total of 526 patients were included in the study, and 98 patients had a forced expiratory volume in the first second/forced vital capacity ratio of < 70%. Pre-anesthetic airway resistance was significantly higher in patients with airflow obstruction than in those without airflow obstruction (p < 0.001), whereas no significant difference in intra-anesthetic airway resistance was found between patients with and without airflow obstruction during mechanical ventilation (p = 0.48). Pre-anesthetic and intra-anesthetic airway resistance values were closer to each other in patients without airflow obstruction, with a mean difference < 1.0 cmH2O L-1s-1, than in those with airflow obstruction, although these respiratory parameters were significantly different (p < 0.001). Intra-anesthetic airway resistance was not related to the FEV1/FVC ratio, regardless of the degree to which the FEV1/FVC ratio reflected pre-anesthetic airway resistance. As compared with patients with airflow obstruction, the mean difference between pre-anesthetic and intra-anesthetic airway resistance was small in patients without airflow obstruction.

17α-estradiol is generated locally in the male rat brain and can regulate GAD65 expression and anxiety.

Increasing evidence suggests that 17ß-estradiol, a sex hormone, is synthesized by neurons. In addition, 17α-estradiol, the stereoisomer of 17ß-estradiol, is reported to be the dominant form in the male mouse brain. However, probably because the method to detect these isomers requires unusual and precise experimental design, the presence of this endogenous 17α-estradiol has not been reported subsequently and the actual role is therefore not well elucidated. We first quantified the estradiol level in hippocampal extracts using gas chromatography/mass spectrometry. As a result, 17α-estradiol was found in all of the male rats tested, while that of 17ß-estradiol was detected only in a certain subset. The estrogen-biosynthesis inhibitor letrozole decreased the expression of the major presynaptic GABA synthesizing enzyme GAD65 in cultured neurons and the effect was abrogated by exogenously supplied 17α-estradiol. Next, injection of the inhibitor into the brain reduced the 17α-estradiol level, indicating its biogenesis in the brain. Under the same conditions, immuno-staining of GAD65 was also decreased. Furthermore, the inhibitor treatment increased anxiety index of rats in the open field and this was ameliorated by the addition of 17α-estradiol. We showed that 17α-estradiol was generated in the brain and acted as a regulator of inhibitory neurotransmission as well as behavior. These results may have implications for a variety of diseases, such as the menopausal depression and Alzheimer's disease that have been reported to be related to estrogen levels.

[A Case of Epidural Hematoma Associated with Epidural Anesthesia].

We report a case of epidural hematoma in an elderly patient with normal coagulability and without difficulty in epidural catheterization. A 76-year-old man with a history of cervical myelopathy was scheduled for gastrojejunostomy under combined epidural and general anesthesia. He had normal bleeding time, coagulation test results, and platelet count. He underwent an epidural catheterization without difficulty. On the first postoperative day, he noticed that could not move his legs with analgesia. After stopping continuous epidural perfusion, he could move legs slightly, but paraplegia remained. On the second postoperative day, MRI of the spine demonstrated a hematoma-like lesion, and severe thoracic and lumbar spinal canal stenosis. Severe vertebral deformation, especially in cases of the elderly, is a potential risk for epidural hematoma after epidural catheterization, because a small hematoma may compress the spinal cord. A careful preoperative evaluation whether to perform epidural catheterization and postoperative observation are required for elderly patients with severe vertebral deformation.

Influence of brain-derived neurotrophic factor on pathfinding of dentate granule cell axons, the hippocampal mossy fibers.

Mossy fibers, the dentate granule cell axons, are generated throughout an animal's lifetime. Mossy fiber paths and synapses are primarily restricted to the stratum lucidum within the CA3 region. Brain-derived neurotrophic factor (BDNF), a neurotrophin family protein that activates Trk neurotrophin receptors, is highly expressed in the stratum lucidum in an activity-dependent manner. The addition of a Trk neurotrophin receptor inhibitor, K252a, to cultured hippocampal slices induced aberrant extension of mossy fibers into ectopic regions. BDNF overexpression in granule cells ameliorated the mossy fiber pathway abnormalities caused by a submaximal dose of K252a. A similar rescue was observed when BDNF was expressed in CA3 pyramidal cells, most notably in mossy fibers distal to the expression site. These findings are the first to clarify the role of BDNF in mossy fiber pathfinding, not as an attractant cue but as a regulator, possibly acting in a paracrine manner. This effect of BDNF may be as a signal for new fibers to fasciculate and extend further to form synapses with neurons that are far from active BDNF-expressing synapses. This mechanism would ensure the emergence of new independent dentate gyrus-CA3 circuits by the axons of new-born granule cells.

Contextual learning induces an increase in the number of hippocampal CA1 neurons expressing high levels of BDNF.

We examined behaviorally induced expression of brain-derived neurotrophic factor (BDNF) in area CA1 of the hippocampus. Sprague-Dawley rats were trained in a contextual fear conditioning (CFC) task, sacrificed 4h later, and their brains were processed for immunohistochemistry. We found distinctively high levels of BDNF immunoreactivity in a small number ( approximately 1%) of CA1 neurons in untrained animals. The number of these exceptional neurons, which are identified as BDNF(++) in this study, was increased by up to approximately 3% after CFC. This increase was blocked in the presence of a memory-impairing dose of a NMDA receptor antagonist (MK801 0.3 mg/kg, i.p.) given 30 min prior to training. The BDNF signal intensity in BDNF(++) neurons correlated with that of surrounding glutamic acid decarboxylase (GAD) 65. This correlation between GAD65 and BDNF signal intensities suggests that BDNF upregulation was associated with increased signaling via inhibitory GABAergic synapses that would lessen further intervening neuronal activity. Our observation that neurons which upregulate BDNF expression following a learning experience are rich in GAD65-enriched afferent synapses suggests that these neurons may have distinct roles in memory consolidation.

Conserved role of brain-derived neurotrophic factor in Val66Met: target-selective reinforcement of GABAergic synapses.

Brain-derived neurotrophic factor has been implicated in higher cognitive functions, and several neurological and psychiatric disorders. Recently, a variant brain-derived neurotrophic factor (BDNFMet), having a substitution referred to as Val66Met, was reported as a product of a bdnf allele with a common single nucleotide polymorphism. It has been reported that BDNFMet is impaired in its potential for activity-dependent release. We sparsely transfected cultured hippocampal neurons with BDNFMet or wild-type BDNFVal cDNAs and examined the amount of GABA-synthetic enzyme glutamic acid decarboxylase 65 (GAD65) in the adjacent region, probably in the GABAergic synapses. BDNFMet transfection increased the GAD65 level to the same extent as transfection with BDNFVal. Our findings suggest that the activity-independent secretion of brain-derived neurotrophic factor may be sufficient to induce inhibitory regulation.

Estrogen produced in cultured hippocampal neurons is a functional regulator of a GABAergic machinery.

Accumulating evidence suggests that estrogen is produced locally by the neurons in the brain. We observed that a 48-hr treatment with the estrogen receptor antagonists ICI 182780 and tamoxifen decreased the level of glutamate decarboxylase (GAD)-65, a rate-limiting gamma-aminobutyric acid (GABA)-synthesizing enzyme, in a dissociated hippocampal neuronal culture. Aromatase is an essential enzyme for estrogen biosynthesis. Treatment with an aromatase inhibitor decreased the GAD 65 level, indicating that estrogen biogenesis functions to maintain the level of this enzyme for GABAergic neurotransmission. Furthermore, insofar as the effect of ICI 182780 was observed equivalently in the presence of either brain-derived neurotrophic factor (BDNF) or BDNF-receptor inhibitor K252a, estrogen probably regulates GAD level independently of brain-derived neurotrophic factor (BDNF). Thus, estrogen produced by neurons is considered to be an intrinsic regulatory factor for neuronal networks that maintain GABAergic neurotransmission.

BDNF locally potentiates GABAergic presynaptic machineries: target-selective circuit inhibition.

Inhibitory neurotransmission is critical for neuronal circuit formation. To examine whether inhibitory neurotransmission receives target-selective modulation in the long term, we expressed the cDNA of brain-derived neurotrophic factor (BDNF), which has been shown to induce the augmentation of GABAergic synapses in vivo and in vitro, in a small population of cultured hippocampal neurons. At 48 h after transfection, the expression level of glutamic acid decarboxylase 65 (GAD65), a GABA synthetic enzyme that resides mainly in GABAergic terminals, was selectively enhanced around the BDNF-expressing neurons, in comparison with the neighboring control neurons interposed between the BDNF-expressing neurons and inhibitory neurons. Exogenous BDNF application for 48 h also increased the GAD level and enhanced the GABA release probability. These potentiating effects were attenuated in inhibitory synapses on neurons expressing a dominant negative form of the BDNF receptor (tTrkB). This suggests that postsynaptic BDNF-TrkB signaling contributes to the target-selective potentiation of inhibitory presynaptic machineries. Since BDNF is expressed in an activity-dependent manner in vivo, this selectivity may be one of the key mechanisms by which the independence of functional neuronal circuits is maintained.