Possible role of QRS duration in the right ventricle as a perioperative monitoring parameter for right ventricular function: a prospective cohort analysis in robotic mitral valve surgery.

Background: The clinical importance of the right ventricle (RV) has recently been recognized; however, assessing its function during cardiac surgery remains challenging owing to its complex anatomy. A temporary transvenous pacing catheter is a useful tool in the small surgical field of minimally invasive cardiac surgery, and an electrocardiogram recorded through the catheter is composed of the direct electrophysiological activity of the RV. Therefore, we hypothesized that QRS duration in the RV (QRSRV) could be a useful monitoring parameter for perioperative RV function. Methods: We conducted a prospective cohort analysis involving adult patients undergoing robotic mitral valve repair. A bipolar pacing catheter was inserted using x-ray fluoroscopy, and the QRSRV duration was assessed at four time points: preoperative baseline, during one-lung ventilation, after weaning from cardiopulmonary bypass, and before the end of surgery. At the same time points, right ventricular fractional area change (RVFAC) measured by transesophageal echocardiography and QRS duration at V5 lead of the body surface electrocardiogram (QRSV5) were also evaluated. Results: In the 94 patients analyzed, QRSRV duration was significantly prolonged during robotic mitral valve repair (p = 0.0009), whereas no significant intraoperative changes in RVFAC were observed (p = 0.2). By contrast, QRSV5 duration was significantly shortened during surgery (p < 0.00001). Multilinear regression showed a significant correlation of QRSRV duration with RVFAC (p = 0.00006), but not with central venous pressure (p = 0.9), or left ventricular ejection fraction (p = 0.3). When patients were divided into two groups by postoperative QRSRV > 100 or ≤100 ms, 25 patients (26.6%) exhibited the prolonged QRSRV duration, and the mean increase in the postoperative QRSRV from preoperative baseline was 12 ms (p = 0.001), which was only 0.6 ms in patients with QRSRV ≤ 100 ms (p = 0.6). Cox regression analysis showed that prolonged postoperative QRSRV duration was the only significant parameter associated with a longer ICU stay after surgery (p = 0.02; hazard ratio, 0.55). Conclusion: Our data suggest that QRSRV duration is a useful parameter for monitoring the RV during cardiac surgery, possibly better than a commonly used echocardiographic parameter, RVFAC. An electrophysiological assessment by QRSRV duration could be a practical tool for the complex anatomy of the RV, especially with limited modalities in perioperative settings.

Thoracic epidural analgesia prolongs postoperative QT interval on electrocardiogram in major non-cardiac surgery: a randomized comparison and a prospective cohort analysis.

Introduction: Prolongation of QT interval on electrocardiogram can be associated with perioperative lethal arrhythmia. Epidural analgesia is a commonly used modality to relieve surgical pain by blocking sensory nerves, which also blocks the autonomic nervous system and can affect QT interval. Since patient monitoring becomes much less frequent after surgery than intraoperative period, we investigated the effects of epidural analgesia on postoperative QT interval with a randomized clinical trial and a prospective cohort study. Methods: In a randomized study, we assigned 60 patients undergoing thoracic epidural analgesia to an epidural analgesia or no-epidural analgesia group, in which 3 ml/h of 0.25% epidural levobupivacaine (7.5 mg/h) was administered only in the epidural analgesia group during surgery. The primary outcome was the postoperative heart rate-corrected QT interval. In a prospective cohort study, patients were assigned to receive 5 ml/h epidural levobupivacaine (12.5 mg/h). The plasma concentration of levobupivacaine was measured using liquid chromatography-mass spectrometry. Results: The median postoperative corrected QT interval interval with 3 ml/h epidural levobupivacaine was significantly longer than that without epidural analgesia. Using multiple regression analysis for the factors known to affect postoperative corrected QT interval interval, epidural analgesia was found to be an independent variable for prolongation, and the mean difference of the corrected QT interval interval with or without epidural analgesia was 23 ms after adjustment. The median plasma concentration of levobupivacaine at the end of surgery was 164 ng/ml with 3 ml/h epidural levobupivacaine, and the correlation coefficient to the postoperative corrected QT interval interval was 0.14, showing a not significant correlation. A prospective cohort study showed that 5 ml/h epidural levobupivacaine significantly prolonged postoperative corrected QT interval interval compared to preoperative baseline. The median plasma concentration of levobupivacaine was 166 ng/ml with 5 ml/h, the correlation coefficient of which showed no significant correlation. Conclusion: Thoracic epidural analgesia could enhance postoperative corrected QT interval prolongation after general anesthesia. The mechanism is possibly caused by blocking neighboring or part of the cardiac sympathetic nerves, rather than by systemic effects of epidurally administered levobupivacaine. Clinical trial number: UMIN000013347 for the randomized study and UMIN000041518 for the prospective cohort study, which were registered at University hospital Medical Information Network Center.

Regulation of neuropathic pain by microglial Orai1 channels.

Microglia are important mediators of neuroinflammation, which underlies neuropathic pain. However, the molecular checkpoints controlling microglial reactivity are not well-understood. Here, we investigated the role of Orai1 channels for microglia-mediated neuroinflammation following nerve injury and find that deletion of Orai1 in microglia attenuates Ca2+ signaling and the production of inflammatory cytokines by proalgesic agonists. Conditional deletion of Orai1 attenuated microglial proliferation in the dorsal horn, spinal cytokine levels, and potentiation of excitatory neurotransmission following peripheral nerve injury. These cellular effects were accompanied by mitigation of pain hyperalgesia in microglial Orai1 knockout mice. A small-molecule Orai1 inhibitor, CM4620, similarly mitigated allodynia in male mice. Unexpectedly, these protective effects were not seen in female mice, revealing sexual dimorphism in Orai1 regulation of microglial reactivity and hyperalgesia. Together, these findings indicate that Orai1 channels are key regulators of the sexually dimorphic role of microglia for the neuroinflammation that underlies neuropathic pain.

Lipid emulsion facilitates reversal from volatile anesthetics in a rodent model.

BACKGROUND: Lipid emulsion infusion is a first-line therapy against the toxicity of local anesthetics and is a potential treatment for other drug overdoses, especially for highly lipophilic drugs. Considering the lipophilic property of volatile anesthetics, we hypothesized that lipid emulsion could reverse general anesthesia. METHODS: Using adult rats, we tested the effect of lipid emulsion infusion on time to emergence after discontinuation of sevoflurane and isoflurane, and further evaluated restoration of righting reflex under continuous sevoflurane anesthesia. Electroencephalogram during lipid emulsion infusion was also investigated under continuous sevoflurane inhalation. The effect of lipid emulsion on sevoflurane-induced respiratory and hemodynamic depressions was evaluated by measuring respiratory rate, PaCO2 (arterial partial pressure of CO2), blood pressure, and heart rate. The binding property of lipid emulsion on sevoflurane and isoflurane was assessed using in vitro setting with a conical flask. RESULTS: Lipid emulsion infusion significantly decreased time to emergence from sevoflurane anesthesia (131 ± 53 vs. 237 ± 69 s) and restored righting reflex during continuous sevoflurane inhalation, by comparing normal saline infusion. Consistent with the behavioral findings, the electroencephalogram under continuous sevoflurane showed decreased power of the δ bands at 5 min after the initiation of lipid emulsion infusion. In addition to reversing hypnosis, lipid emulsion recovered respiratory as well as hemodynamic depressions induced by sevoflurane. Decreased time to emergence was observed also in isoflurane anesthesia (203 ± 111 vs. 314 ± 154 s). To investigate the binding mechanism of lipid emulsion infusion, in vitro experiments revealed significantly decreased anesthetic concentrations of sevoflurane and isoflurane by mixing with lipid emulsion. CONCLUSIONS: Lipid emulsion facilitated reversal from volatile anesthetics, as shown by several parameters. As lipid emulsion could bind to volatile anesthetics and simply decrease their effects, our findings suggest that lipid emulsion is a potentially useful agent to reverse general anesthesia.

Orai1 Channels Are Essential for Amplification of Glutamate-Evoked Ca2+ Signals in Dendritic Spines to Regulate Working and Associative Memory.

Store-operated Orai1 calcium channels function as highly Ca2+-selective ion channels and are broadly expressed in many tissues including the central nervous system, but their contributions to cognitive processing are largely unknown. Here, we report that many measures of synaptic, cellular, and behavioral models of learning are markedly attenuated in mice lacking Orai1 in forebrain excitatory neurons. Results with focal glutamate uncaging in hippocampal neurons support an essential role of Orai1 channels in amplifying NMDA-receptor-induced dendritic Ca2+ transients that drive activity-dependent spine morphogenesis and long-term potentiation at Schaffer collateral-CA1 synapses. Consistent with these signaling roles, mice lacking Orai1 in pyramidal neurons (but not interneurons) exhibit striking deficits in working and associative memory tasks. These findings identify Orai1 channels as essential regulators of dendritic spine Ca2+ signaling, synaptic plasticity, and cognition.

Left Ventricular Hypertrophy Increases Susceptibility to Bupivacaine-induced Cardiotoxicity through Overexpression of Transient Receptor Potential Canonical Channels in Rats.

BACKGROUND: Local anesthetics, particularly potent long acting ones such as bupivacaine, can cause cardiotoxicity by inhibiting sodium ion channels; however, the impact of left ventricular hypertrophy on the cardiotoxicity and the underlying mechanisms remain undetermined. Transient receptor potential canonical (TRPC) channels are upregulated in left ventricular hypertrophy. Some transient receptor potential channel subtypes have been reported to pass relatively large cations, including protonated local anesthetics; this is known as the "pore phenomenon." The authors hypothesized that bupivacaine-induced cardiotoxicity is more severe in left ventricular hypertrophy due to upregulated TRPC channels. METHODS: The authors used a modified transverse aortic constriction model as a left ventricular hypertrophy. Cardiotoxicity caused by bupivacaine was compared between sham and aortic constriction male rats, and the underlying mechanisms were investigated by recording sodium ion channel currents and immunocytochemistry of TRPC protein in cardiomyocytes. RESULTS: The time to cardiac arrest by bupivacaine was shorter in aortic constriction rats (n =11) than in sham rats (n = 12) (mean ± SD, 1,302 ± 324 s vs. 1,034 ± 211 s; P = 0.030), regardless of its lower plasma concentration. The half-maximal inhibitory concentrations of bupivacaine toward sodium ion currents were 4.5 and 4.3 µM, which decreased to 3.9 and 2.6 µM in sham and aortic constriction rats, respectively, upon coapplication of 1-oleoyl-2-acetyl-sn-glycerol, a TRPC3 channel activator. In both groups, sodium ion currents were unaffected by QX-314, a positively charged lidocaine derivative, that hardly permeates the cell membrane, but was significantly decreased with QX-314 and 1-oleoyl-2-acetyl-sn-glycerol coapplication (sham: 79 ± 10% of control; P = 0.004; aortic constriction: 47± 27% of control; P = 0.020; n = 5 cells per group). Effects of 1-oleoyl-2-acetyl-sn-glycerol were antagonized by a specific TRPC3 channel inhibitor. CONCLUSIONS: Left ventricular hypertrophy exacerbated bupivacaine-induced cardiotoxicity, which could be a consequence of the "pore phenomenon" of TRPC3 channels upregulated in left ventricular hypertrophy.

Regulation of chemoconvulsant-induced seizures by store-operated Orai1 channels.

KEY POINTS: Temporal lobe epilepsy is a complex neurological disease caused by imbalance of excitation and inhibition in the brain. Growing literature implicates altered Ca2+ signalling in many aspects of epilepsy but the diversity of Ca2+ channels that regulate this syndrome are not well-understood. Here, we report that mice lacking the store-operated Ca2+ channel, Orai1, in the brain show markedly stronger seizures in response to the chemoconvulsants, kainic acid and pilocarpine. Electrophysiological analysis reveals that selective deletion of Orai1 channels in inhibitory neurons disables chemoconvulsant-induced excitation of GABAergic neurons in the CA1 hippocampus. Likewise, deletion of Orai1 in GABAergic neurons abrogates the chemoconvulsant-induced burst of spontaneous inhibitory postsynaptic currents (sIPSCs) on CA1 pyramidal neurons in the hippocampus. This loss of chemoconvulsant inhibition likely aggravates status epilepticus in Orai1 KO mice. These results identify Orai1 channels as regulators of hippocampal interneuron excitability and seizures. ABSTRACT: Store-operated Orai1 channels are a major mechanism for Ca2+ entry in many cells and mediate numerous functions including gene expression, cytokine production and gliotransmitter release. Orai1 is expressed in many regions of the mammalian brain; however, its role in regulating neuronal excitability, synaptic function and brain disorders has only now begun to be investigated. To investigate a potential role of Orai1 channels in status epilepticus induced by chemoconvulsants, we examined acute seizures evoked by intraperitoneal injections of kainic acid (KA) and pilocarpine in mice with a conditional deletion of Orai1 (or its activator STIM1) in the brain. Brain-specific Orai1 and STIM1 knockout (KO) mice exhibited significantly stronger seizures (P = 0.00003 and P < 0.00001), and higher chemoconvulsant-induced mortality (P = 0.02) compared with wildtype (WT) littermates. Electrophysiological recordings in hippocampal brain slices revealed that KA stimulated the activity of inhibitory interneurons in the CA1 hippocampus (P = 0.04) which failed to occur in Orai1 KO mice. Further, KA and pilocarpine increased the frequency of spontaneous IPSCs in CA1 pyramidal neurons >twofold (KA: P = 0.04; pilocarpine: P = 0.0002) which was abolished in Orai1 KO mice. Mice with selective deletion of Orai1 in GABAergic neurons alone also showed stronger seizures to KA (P = 0.001) and pilocarpine (P < 0.00001) and loss of chemoconvulsant-induced increases in sIPSC responses compared with WT controls. We conclude that Orai1 channels regulate chemoconvulsant-induced excitation in GABAergic neurons and that destabilization of the excitatory/inhibitory balance in Orai1 KO mice aggravates chemoconvulsant-mediated seizures. These results identify Orai1 channels as novel molecular regulators of hippocampal neuronal excitability and seizures.

Comparison between hemodynamic effects of propofol and thiopental during general anesthesia induction with remifentanil infusion: a double-blind, age-stratified, randomized study.

PURPOSE: Propofol is commonly used with remifentanil for induction of general anesthesia (GA); however, it often leads to hypotension. Intraoperative hypotension is associated with postoperative adverse events. By contrast, thiopental has less negative inotropic effects on hemodynamics compared to propofol, which could be suitable to prevent hypotension during GA induction. In the present age-stratified, randomized, assessor-blinded study, using the ClearSight® system, we compared the hemodynamic effects of propofol and thiopental during GA induction under remifentanil infusion in non-cardiac surgery. METHODS: Patients were divided into young (20-40 year), middle (41-70 year), and elderly (> 70 year) groups (n = 20, each group). General anesthesia was induced with remifentanil 0.3 µg/kg/min, followed by propofol (2.0, 1.5, and 1.2 mg/kg) or thiopental (5.0, 4.0, and 3.0 mg/kg) in the young, middle, and elderly groups, respectively. The primary outcome was the difference in the decrease in mean arterial blood pressure between patients receiving propofol and thiopental in each age group. The secondary outcomes included other hemodynamic parameters and minimal bispectral index values measured up to 10 min after tracheal intubation. RESULTS: The decrease in mean arterial blood pressure was greater in patients receiving propofol than those receiving thiopental (- 45.4 vs - 26.6 mmHg and - 45.7 vs - 28.9 mmHg, P = 0.003 and 0.007, respectively), whereas no significant difference was observed in the young age group (P = 0.96). CONCLUSIONS: Thiopental is a more suitable agent than propofol for avoiding hypotension during GA induction under remifentanil infusion in the middle and elderly patients.

Low-dose dexmedetomidine provides hemodynamics stabilization during emergence and recovery from general anesthesia in patients undergoing carotid endarterectomy: a randomized double-blind, placebo-controlled trial.

PURPOSE: Carotid artery stenosis is a major risk factor for ischemic stroke. Carotid endarterectomy protects patients with severe atherosclerotic carotid artery stenosis against stroke. In such patients, arterial blood pressure is often difficult to control and perioperative hemodynamic instability is associated with high morbidity and mortality after carotid endarterectomy. We performed a randomized double-blind placebo-control trial to evaluate the effects of low-dose dexmedetomidine on hemodynamic stability during the emergence and the recovery phases of general anesthesia in patients undergoing carotid endarterectomy. METHODS: Forty-seven patients (68-84 years) were randomly assigned to receive either dexmedetomidine (DEX group) or 0.9% saline (control group). Infusion of dexmedetomidine 1.0 µg/kg/hr for 1 h, followed by 0.2 µg/kg/hr or the same dose of saline was started after carotid artery declamping in the DEX and in the control group, respectively. At the end of surgery, nicardipine was used to maintain systolic arterial pressure within 20% of preoperative values. We compared the maximum dose of nicardipine, time to extubation, plasma catecholamine levels, arterial blood gases, the Richmond Agitation Sedation Scales, visual analogue scale (VAS) in the postanesthesia care unit, and adverse events within 30-days between the control and Dex groups. RESULTS: The baseline clinical characteristics were similar in the two groups. The maximum dose of nicardipine (p = 0.021), plasma norepinephrine level (p = 0.033), sedation score and VAS were significantly lower in the Dex group than the control group. There were no differences between the two groups regarding time to extubation, arterial blood gases, and adverse events. CONCLUSIONS: Low-dose dexmedetomidine improves hemodynamic stability during emergence and recovery from general anesthesia in patients receiving carotid endarterectomy. TRIAL REGISTRY NUMBER: UMIN000010607.

Superior Efficacy of Lipid Emulsion Infusion Over Serum Alkalinization in Reversing Amitriptyline-Induced Cardiotoxicity in Guinea Pig.

BACKGROUND: Tricyclic antidepressants (TCAs) are a major cause of fatal drug poisoning due to their cardiotoxicity. Alkalinization by sodium bicarbonate (NaHCO3) administration, the first-line therapy for TCA-induced cardiotoxicity, can occasionally yield insufficient efficacy in severe cases. Because most TCAs are highly lipophilic, lipid emulsion may be more effective than alkalinization. However, it remains to be determined whether lipid emulsion is more beneficial than alkalinization in reversing amitriptyline-induced cardiotoxicity. METHODS: Hemodynamic variables were recorded from in vivo guinea pig models and Langendorff-perfused hearts. Whole-cell patch-clamp experiments were conducted on enzymatically isolated ventricular cardiomyocytes to record fast sodium currents (INa). Lipid solutions were prepared using 20% Intralipid. The pH of the alkaline solution was set at 7.55. We assessed the effect of lipid emulsion on reversing amitriptyline-induced cardiotoxicity, in vivo and in vitro, compared to alkalinization. The data were evaluated by Student t test, 1-way repeated-measures analysis of variance, or analysis of covariance (covariate = amitriptyline concentration); we considered data statistically significant when P < .05. RESULTS: In the in vivo model, intervention with lipids significantly reversed the amitriptyline-induced depression of mean arterial pressure and prolongation of QRS duration on electrocardiogram more than alkalinization (mean arterial pressure, mean difference [95% confidence interval]: 19.0 mm Hg [8.5-29.4]; QRS duration, mean difference [95% confidence interval] -12.0 milliseconds [-16.1 to -7.8]). In the Langendorff experiments, perfusion with 1% and 2% lipid solutions demonstrated significant recovery in left ventricular developed pressure (LVdevP), maximum change rate of increase of LVdevP (dP/dtmax) and rate-pressure product compared with alkaline solution (LVdevP [mm Hg], alkaline 57 ± 35, 1% lipid 94 ± 12, 2% lipid 110 ± 14; dP/dtmax [mm Hg/s], alkaline 748 ± 441, 1% lipid 1502 ± 334, 2% lipid 1753 ± 389; rate-pressure product [mm Hg·beats·minute], alkaline 11,214 ± 8272, 1% lipid 19,025 ± 8427, 2% lipid 25,261 ± 4803 with analysis of covariance). Furthermore, lipid solutions (0.5%-4%) resulted in greater recovery of hemodynamic parameters at 3 µM amitriptyline. Amitriptyline inhibited INa in a dose-dependent manner: the half-maximal inhibitory concentration (IC50) was 0.39 µM. The IC50 increased to 0.75 µM in the alkaline solution, 3.2 µM in 1% lipid solution, and 6.1 µM in 2% lipid solution. Furthermore, the lipid solution attenuated the use-dependent block of sodium channels by amitriptyline more than alkaline solution. On 30 consecutive pulses at 1 Hz, the current decreased to 50.1 ± 2.1, 60.3 ± 1.9, and 90.4% ± 1.8% in standard, alkaline, and 1% lipid solution, respectively. Even 0.5% lipid solution showed greater effects than the alkaline solution in all experiments. CONCLUSIONS: Lipid emulsion significantly suppressed amitriptyline-induced INa, inhibition, which was likely related to the marked improvement in hemodynamic status observed in vivo and in isolated perfused hearts. These results suggest the superiority of lipid emulsion as the first-line therapy for TCA-induced cardiotoxicity compared to alkalinization therapy.

Anesthetic management of three pediatric cases with Pena-Shokeir syndrome.

Pena-Shokeir syndrome is a rare, early lethal disease. It is characterized by fetal growth restriction; craniofacial deformities, for example micrognathia and microcephaly; multiple ankyloses; and pulmonary hypoplasia. For patients with this syndrome, maintenance of airway and control of perioperative respiratory complications are important for anesthetic management. We report 3 pediatric cases of Pena-Shokeir syndrome undergoing tracheostomy and arthrolysis under general anesthesia using sevoflurane, nitrous oxide, fentanyl, and vecuronium bromide. Anesthetic procedures including mask ventilation, tracheal intubation, and extubation were successfully performed without complications during and after surgery. In patients with Pena-Shokeir syndrome, inhalational anesthetics can be safely used for induction and maintenance of anesthesia, although it is important to assume that difficult airway management might be encountered.

Anesthesia in an adult patient with tracheal hemangiomas: one-lung ventilation for lung lobectomy.

Primary tracheal tumors are rare in adults, and careful airway management is required during anesthesia for affected patients. We report the case of a patient with tracheal hemangiomas undergoing nontracheal operation. A 61-year-old woman was scheduled for a lung operation. During preoperative examination, hemangiomas were detected on the tracheal mucosa. As she was asymptomatic and the degree of airway stenosis was small, treatment was not required for the hemangiomas, and left upper lobectomy for lung cancer was scheduled. After induction of general anesthesia, a regular tracheal tube was inserted under fiberoptic bronchoscopy, with care taken to prevent damage to the hemangiomas. An endobronchial blocker was inserted for one-lung ventilation. The operation was performed uneventfully, and the tracheal tube was replaced postoperatively with a laryngeal mask airway while the patient was under deep anesthesia and neuromuscular blockade. The mask was removed after confirming lack of bleeding from the hemangiomas. No hypoxia or other complications occurred during or after the operation.