Comparative Analysis of the Hemodynamic Effects of Remimazolam and Propofol During General Anesthesia: A Retrospective Study.

PURPOSE: Hypotension is common during anesthesia induction. However, minimal hemodynamic effects of remimazolam anesthesia have been reported. We hypothesized that remimazolam would have weaker hemodynamic effects than would propofol. To test this, we simultaneously evaluated the hemodynamics using the estimated continuous cardiac output (esCCO) system and heart rate variability (HRV) during anesthesia induction. METHODS: This was a single-center, observational, retrospective study of patients undergoing dental surgery under general anesthesia between 2020 and 2022. Seventy patients were divided into two groups: remimazolam (R group; n=34) and propofol (P group; n=36). The information obtained from the anesthesia records, patient information, esCCO system parameters, and HRV were integrated and analyzed. The percentages of various parameters were set to 100% for the pre-induction phase as the baseline. RESULTS: The %MAP (noninvasive mean arterial blood pressure) decreased over a narrower range in the R compared to the P group (-17.8% (-26.3%, -11.9%) vs. -22.6% (-32.9%, -17.0%); P=0.039). The %HR (heart rate) increased significantly in the R group and decreased in the P group (+10.7% (+6.5%, +18.6%) vs. -6.5% (-14.5%, +8.4%); P<0.01). The %SVesCCO (stroke volume calculated using the esCCO system) decreased significantly in both groups, but the R group showed a smaller difference compared to the P group (- 5.1% (-7.7%, -2.1%) vs. -10.0% (-13.8%, -5.6%); P<0.01). The rates of change in %LF nu (normalized unit of low frequency) and %HF nu (normalized unit of high frequency) were lower for the R than for the P group, although the difference was not significant (+6.8% (-14.5%, 32.4%) vs. +9.2% (-7.2%, +59.7%), P=0.30; +7.9% (-51.0%, +66.9%) vs. +22.8% (-26.1%, +61.6%), P=0.57). CONCLUSION: Remimazolam demonstrated a lower MAP reduction rate than propofol. A compensatory increase in HR occurred with a decrease in stroke volume. However, the HR increase was not attributable to the autonomic nervous system.

Anti-inflammatory potential of remimazolam: A laboratory and clinical investigation.

BACKGROUND: Anesthetic agents, particularly intravenous anesthetics, may affect immune function and tumorigenic factors. We herein investigated whether the anti-inflammatory effects of anesthetic agents are attributed to their antioxidant properties. The antioxidant and anti-inflammatory effects of remimazolam, a new anesthetic, remain unclear. We hypothesized that remimazolam exerts anti-inflammatory effects due to its antioxidant properties, which may affect the postoperative inflammatory response. This retrospective clinical study examined this hypothesis using laboratory and clinical approaches. METHODS: The antioxidant effects of remimazolam and dexmedetomidine were assessed by electron spin resonance (ESR) spectroscopy, and postoperative inflammatory responses were compared in 143 patients who underwent transcatheter aortic valve replacement at Kindai University Hospital between April 2021 and December 2022. The primary endpoint was the presence or absence of the antioxidant effects of the anesthetics themselves using ESR. RESULTS: Remimazolam at clinical concentrations exerted antioxidant effects, whereas dexmedetomidine did not. Increases in C-reactive protein (CRP) levels on POD3 from preoperative values were significantly smaller in the remimazolam group than in the dexmedetomidine group (1.33 ± 1.29 vs. 2.17 ± 1.84, p = .014). CONCLUSIONS: Remimazolam exerted stronger anti-inflammatory effects than dexmedetomidine, and these effects were enhanced by its antioxidant properties, which may have affected postoperative CRP production.

Remimazolam-Based Anesthesia in Patients with Heart Failure Due to Mitral Regurgitation and Low Left Ventricular Function: A Case Series.

Background and Objectives: Remimazolam is a new ultrashort-acting benzodiazepine anesthetic. Remimazolam appears to be useful in patients with severe valvular disease because of its minimal cardiovascular impact. In this retrospective case series study, we assessed the efficacy and safety of remimazolam for maintaining hemodynamic stability during anesthetic induction and maintenance. Cases: MitraClip was performed on 18 cases with severe mitral regurgitation with low left ventricular function who presented with heart failure, and remimazolam was administered for general anesthesia with induction (12 mg/kg/h) and maintenance (1 mg/kg/h). The impact of remimazolam on the hemodynamics at anesthetic induction and during anesthetic maintenance was investigated retrospectively using electronic medical records. Blood pressure decreased significantly during anesthetic induction with remimazolam (78.5 [72, 81.25] and 66.1 [62.2, 74.2], median [IQR], p = 0.0001), but only mildly, by about 10 mmHg. There was no significant change in the cardiac index (2.0 [1.8, 2.4] vs. 1.9 [1.8, 2.3], p = 0.57642) or pulse rate (73.5 ± 8.85 vs. 74.7 ± 11.7, mean ± SD, p = 0.0876) during anesthetic induction with remimazolam. All patients underwent MitraClip without major hemodynamic concerns, with no or small increases in inotropes. Conclusions: Remimazolam may be used safely in patients with severe mitral regurgitation and low left ventricular function presenting with heart failure.

A retrospective comparative study of anesthesia with remimazolam and remifentanil versus dexmedetomidine and remifentanil for transcatheter aortic valve replacement.

Remimazolam, an ultrashort-acting benzodiazepine, allows for rapid and reliable arousal. Rapid awakening using remimazolam may be beneficial in transcatheter aortic valve replacement (TAVR), as it allows rapid detection of neurologic deficits. The purpose of this study was to compare arousal time and outcomes between monitored anesthesia care (MAC) with remimazolam and remifentanil and conventional MAC with dexmedetomidine, propofol, and remifentanil. This study was a single center retrospective study. All TAVR cases performed under MAC (MAC-TAVR) at our institution between 2019 and 2021 were included. Patients were classified by anesthesia method into remimazolam and dexmedetomidine groups. Among 258 MAC-TAVR patients, 253 were enrolled. After propensity score matching, 76 patients were assigned to each group. The time from end of drug-administration to arousal [20.0 (16.0, 24.0) min vs. 38.5 (30.0, 56.3) min, p < 0.0001] and the time from attempted-arousal to arousal [1.0 (1.0, 1.0) min vs. 12.5 (3.0, 26.8) min, p < 0.0001] were significantly shorter in the remimazolam group. There was no significant difference in the length of ICU stay [2.0 (2.0, 2.0) days vs. 2.0 (2.0, 2.0) days, p = 0.157] and postoperative hospital stay [6.0 (4.0, 9.0) days vs. 5.0 (4.0, 8.0) days, p = 0.262].Trial registration: Clinical trial number: R03-123, Registry URL: https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000051635 Registration number: UMIN000045195, Principal investigator's name: Atsuhiro Kitaura, Date of registration: 20 August 2021.

Successful Nafamostat Mesilate Administration for Andexanet Alfa-Induced Heparin Resistance.

Andexanet alfa is an analog of activated factor X and is used as an antagonist of anti-activated factor X agents. Andexanet alfa is useful for hemostasis in emergent bleeding during direct oral anticoagulant administration, which contributes to safety. In patients undergoing surgery with cardiopulmonary bypass because of heparin resistance, anesthesiologists are faced with a choice of anticoagulants. Herein, we experienced anesthesia for vascular prostheses with cardiopulmonary bypass for acute aortic dissection in a patient who had received andexanet alfa preoperatively. Heparin was initially used as the anticoagulant during cardiopulmonary bypass; however, despite the administration of large doses and antithrombin III preparations, anticoagulation was insufficient. Therefore, nafamostat mesilate was administered and sufficient anticoagulation was attained. The patient completed surgery under cardiopulmonary bypass, coagulation function was recovered shortly after withdrawal, and no obvious adverse effects were observed.

Two Cases of Inadequate Response to Remimazolam.

We report the inadequate efficacy of remimazolam in two patients undergoing long-term benzodiazepine analog therapy. Remimazolam is a recently developed ultrashort-acting benzodiazepine. It is primarily used as an anesthetic in surgical procedures, as it has minimal effect on cardiac function and antagonists are available. It is expected to become more widely used in the future. On the other hand, similar to other benzodiazepines, benzodiazepine tolerance can also pose a challenge with remimazolam. Herein, we report two cases who were taking long-term oral benzodiazepine analogs. One patient did not fall asleep despite a sufficient dose of remimazolam and required a change to propofol. The other patient required a high dose of remimazolam to fall asleep; however, multiple signs of arousal were noted intraoperatively. Our findings suggest that remimazolam may not be an ideal anesthetic in long-term benzodiazepine analog users. Comprehensive assessment of preoperative medications and careful monitoring of intraoperative sedation levels are necessary. Furthermore, it may be advisable to consider the use of alternative agents such as propofol.

Nine-Second Cardiac Arrest in a Patient With Anti-mitochondrial Antibody-Positive Myopathy Under General Anesthesia.

A small percentage of cases of dermatomyositis are positive for anti-mitochondrial antibodies (AMA), a known marker for primary biliary cirrhosis. AMA-positive myositis is a rare disease that has been reported to be accompanied by myocarditis, resulting in low left ventricular function, supraventricular arrhythmias, and abnormalities of the conduction system. We present a case of AMA-positive myocarditis resulting in sinus arrest during general anesthesia. A 66-year-old female with AMA-positive myocarditis underwent artificial femoral head replacement for osteonecrosis of the femoral head under general anesthesia. During general anesthesia, a nine-second sinus arrest occurred without any inducement. The sinus arrest was thought to be influenced by not only over-suppression caused by severe supraventricular tachycardia derived from sick sinus syndrome but sympathetic depression caused by general anesthesia. Because of the potential for life-threatening cardiovascular events during anesthesia in patients with AMA-positive myositis, it was considered essential to provide adequate preoperative management and intraoperative monitoring during anesthesia for patients with this disease. Herein, we report our case with a literature review.

Cardiac Arrest Following Torsades de Pointes Caused by Hypokalemia and Catecholamines in a Patient with Congenital Long QT Syndrome Type 1 After Surgical Aortic Valve Replacement: A Case Report.

BACKGROUND Prevention of lethal arrhythmias in congenital long QT syndrome type 1 (LQT1) requires avoidance of sympathoexcitation, drugs that prolong QT, and electrolyte abnormalities. However, it is often difficult to avoid all these risks in the perioperative period of open heart surgery. Herein, we report hypokalemia-induced cardiac arrest in a postoperative cardiac patient with LQT1 on catecholamine. CASE REPORT A 79-year-old woman underwent surgical aortic valve replacement for severe aortic stenosis. Although the initial plan was not to use catecholamine, catecholamine was used in the Postoperative Intensive Care Unit with attention to QT interval and electrolytes due to heart failure caused by postoperative bleeding. Serum potassium levels were controlled above 4.5 mEq/L, and no arrhythmic events occurred. On postoperative day 4, the patient was started on insulin owing to hyperglycemia. Cardiac arrest occurred after the first insulin dose; the implantable cardioverter defibrillator was activated, and the patient's own heartbeat resumed. Subsequent examination revealed that a marked decrease in serum potassium level had occurred after insulin administration. The electrocardiogram showed obvious QT prolongation and ventricular fibrillation following R on T. Thereafter, under strict potassium management, there was no recurrence of cardiac arrest events. CONCLUSIONS A patient with LQT1 who underwent open heart surgery developed ventricular fibrillation after Torsades de Pointes, probably due to hypokalemia after insulin administration in addition to catecholamine. It is important to check serum potassium levels to avoid the onset of Torsades de Pointes in patients with long QT syndrome. In addition, the impact of insulin administration was reaffirmed.

Remimazolam anesthesia for transcatheter mitral valve repair in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome: a case report.

BACKGROUND: Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is characterized by cardiac depression, respiratory failure, myopathy, and anesthesia for affected patients is challenging. Although several anesthetics have been safely employed, there are no reports on remimazolam used in those patients. CASE PRESENTATION: A 47-year-old male with MELAS syndrome was diagnosed with mitral regurgitation and scheduled for transcatheter mitral valve repair under general anesthesia. Anesthesia was induced with remimazolam and remifentanil (0.3 µg/kg/min). Remimazolam was administered at 12 mg/kg/h until loss of consciousness for approximately 1 min. Anesthesia was maintained with 1.1-1.2 mg/kg/h of remimazolam and 0.1 µg/kg/min of remifentanil without circulatory collapse or severe metabolic acidosis. The tracheal tube was removed in the operating room. CONCLUSION: Remimazolam may be a new option for anesthesia for MELAS syndrome patients with depressed heart function.

A 32-Year-Old Man Diagnosed with Type II Brugada Syndrome on Preoperative Electrocardiogram 1 Week Before Elective Tympanoplasty.

BACKGROUND Brugada syndrome is a potentially fatal cardiac arrhythmia characterized by incomplete right bundle-branch block (RBB) and characteristic ST-segment elevation in the anterior electrocardiogram (ECG) leads. This report is of a case of type 2 Brugada syndrome, and discusses the importance of preoperative history and ECG evaluation. CASE REPORT A 32-year-old man was scheduled for tympanoplasty. His preoperative ECG revealed saddleback-type J waves in V2 (>2 mm) and ST increase (>1 mm) detected 1 week before elective surgery, but the ECG 1 year before showed normal. He had no notable past history. Anesthesia was induced with remifentanil and propofol, and maintained with sevoflurane in combination with remifentanil. Routine monitoring of vital signs was supplemented with V2 monitoring on the ECG. The heart rate was maintained at above 60 beats/min using ephedrine. The course of the operation was uneventful. CONCLUSIONS We managed anesthesia for a patient with a type 2 Brugada syndrome ECG without events, probably because he had no notable past history such as syncope. Type 2 and type 3 Brugada syndrome ECGs are difficult to recognize, and patients with them are considered to be less risky than a patient with a type I ECG. However, as Brugada syndrome ECG is dynamic and changeable, a type 2 or 3 Brugada syndrome ECG can change to a type I ECG under some conditions, and thus should not be overlooked, and the patient's past history or symptoms, such as syncope, should be carefully investigated.

Advanced glycation end-products reduce lipopolysaccharide uptake by macrophages.

Hyperglycaemia provides a suitable environment for infections and the mechanisms of glucose toxicity include the formation of advanced glycation end-products (AGEs), which comprise non-enzymatically glycosylated proteins, lipids, and nucleic acid amino groups. Among AGE-associated phenotypes, glycolaldehyde-derived toxic AGE (AGE-3) is involved in the pathogenesis of diabetic complications. Internalisation of endotoxin by various cell types contributes to innate immune responses against bacterial infection. An endotoxin derived from Gram-negative bacteria, lipopolysaccharide (LPS), was reported to enhance its own uptake by RAW264.7 mouse macrophage-like cells, and an LPS binding protein, CD14, was involved in the LPS uptake. The LPS uptake induced the activation of RAW264.7 leading to the production of chemokine CXC motif ligand (CXCL) 10, which promotes T helper cell type 1 responses. Previously, we reported that AGE-3 was internalised into RAW264.7 cells through scavenger receptor-1 Class A. We hypothesized that AGEs uptake interrupt LPS uptake and impair innate immune response to LPS in RAW264.7 cells. In the present study, we found that AGE-3 attenuated CD14 expression, LPS uptake, and CXCL10 production, which was concentration-dependent, whereas LPS did not affect AGE uptake. AGEs were reported to stimulate the receptor for AGEs and Toll-like receptor 4, which cause inflammatory reactions. We found that inhibitors for RAGE, but not Toll-like receptor 4, restored the AGE-induced suppression of CD14 expression, LPS uptake, and CXCL10 production. These results indicate that the receptor for the AGE-initiated pathway partially impairs the immune response in diabetes patients.

Propofol suppresses the His-ventricular conduction in paediatric patients.

WHAT IS KNOWN AND OBJECTIVE: Propofol is the most commonly used intravenous anaesthetic worldwide and is considered to be safe for all ages. However, there have been some reports that propofol induces severe atrioventricular (AV) blocks in humans and some studies demonstrated that propofol suppressed the cardiac conduction system in animals. A precise mechanism by which the block is induced has not been elucidated yet in humans. The objective of this study was to investigate the effects of propofol on the cardiac conduction system and the cardiac autonomic nervous balance in children. METHODS: We enrolled 23 paediatric patients (age: 6-15 years; males: 16, females: 7) who were scheduled to undergo radiofrequency catheter ablation (RFCA) under general anaesthesia. Anaesthesia was induced with 2 mg/kg propofol and 0.5 µg/kg/min remifentanil, and tracheal intubation was performed with the aid of 1 mg/kg rocuronium. Anaesthesia was maintained with 5-7 mg/kg/h propofol and 0.2 µg/kg/min remifentanil during the RFCA. After the completion of the RFCA, anaesthesia was further maintained with 5 mg/kg/h propofol and 0.2 µg/kg/min remifentanil for at least 10 min (LC: low propofol concentration state), followed by the injection of 2 mg/kg propofol and the infusion of 10 mg/kg/h propofol for 10 min (HC: high propofol concentration state). The sinus node recovery time (SNRT), sinoatrial conduction time (SACT), atrial-His (AH) interval and the His-ventricular (HV) interval were measured at the end of both the LC and HC. Cardiac autonomic regulation was simultaneously assessed based on heart rate variability. RESULTS AND DISCUSSION: Propofol significantly suppressed intrinsic cardiac HV conduction, but did not affect the SNRT, SACT or the AH interval. As HV blocks, which occur below the His bundle, are often life-threatening, the HV conduction delay may be a cause of severe AV blocks induced by propofol. Propofol directly suppressed parasympathetic nerve activity, and sympathetic nerve activity was also suppressed. WHAT IS NEW AND CONCLUSION: These results indicate that propofol suppresses the HV conduction and might help to elucidate the mechanism by which propofol causes lethal AV blocks.

Can left ventricular hypertrophy on electrocardiography detect severe aortic valve stenosis?

BACKGROUND: Severe aortic stenosis (AS) is increasing in the aging society and is a serious condition for anesthetic management. However, approximately one-third of patients with severe AS are asymptomatic. Echocardiography is the most reliable method to detect AS, but it takes time and is costly. METHODS: Data were obtained retrospectively from patients who underwent surgery and preoperative transthoracic echocardiography (TTE). LVH on ECG was determined by voltage criteria (Sv1 + Rv5 or 6 ≥3.5 mV) and/or the strain pattern in V5 and V6. Severe AS was defined as a mean transaortic pressure gradient ≥40 mmHg or aortic valve area ≤1.0 cm2 by TTE. RESULTS: Data for 470 patients aged 28-94 years old were obtained. One hundred and twenty-six patients had severe AS. LVH on ECG by voltage criteria alone was detected in 182 patients, LVH by strain pattern alone was detected in 80 patients and LVH by both was detected in 55 patients. Multivariable logistic analysis revealed that LVH by the strain pattern or voltage criteria, diabetes mellitus, and age were significantly associated with severe AS. The AUC for the ROC curve for LVH by voltage criteria alone was 0.675 and the cut-off value was 3.84 mm V, and the AUC for the ROC for age was 0.675 and the cut-off value was 74 years old. CONCLUSION: Our study suggests that patients who are 74 years old or over with LVH on ECG, especially those with DM, should undergo preoperative TTE in order to detect severe AS.

Anesthesia management in a patient with very long-chain acyl-Coenzyme A dehydrogenase deficiency.

BACKGROUND: In a patient with very long-chain acyl-Coenzyme A dehydrogenase (VLCAD) deficiency, metabolism of fatty acids is impaired and a supply of alternative energy is limited when glucose level is insufficient on starvation. CASE PRESENTATION: A 37-year-old woman with VLCAD deficiency was diagnosed with an ovarian cyst and was scheduled for laparoscopic ovarian cystectomy. Glucose was administered intravenously with the start of fasting. Anesthesia was induced with remifentanil, midazolam, and thiamylal, maintained with desflurane and remifentanil. Body temperature was maintained at 36.2-36.7 °C. During anesthesia, hypoglycemia did not occur, creatine kinase levels were in the normal range, and myoglobinuria was not detected. No shivering was observed after extubation. CONCLUSIONS: Glucose was administered to avoid perioperative hypoglycemia. Body temperature was controlled to avoid shivering, which would otherwise increase skeletal muscle energy needs. Blood creatine kinase did not increase, and myoglobinuria was not detected; thus, rhabdomyolysis was unlikely to develop.

Ephedrine-Induced Increases in Blood Pressure and Heart Rate Due to Suspected Cardiac Sympathetic Denervation Supersensitivity in a Patient with Parkinson's Disease Under Spinal Anesthesia.

BACKGROUND Denervation supersensitivity to sympathomimetic drugs has been noted in patients with Parkinson's disease (PD) whose cardiac sympathetic nerves are denervated. This phenomenon is not as well recognized as other complications of PD patients, but anesthesiologists should be aware of it because sympathomimetic drugs can sometimes be dangerous to these patients. CASE REPORT A 60-year-old woman was scheduled for total hip joint replacement under combined spinal-epidural anesthesia and sedation. She had been diagnosed as PD (stage 4 on the Hoehn and Yahr scale) with a history of orthostatic hypotension. Her ¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy revealed marked reduction of ¹²³I-MIBG accumulation in the heart. In the operating room, we placed an epidural catheter through the Th12-L1 space, and spinal anesthesia (2.6 mL of 0.5% normobaric bupivacaine) was administered. During the surgery, we infused propofol at 100 mg·hr⁻¹ for sedation. When 4 mg of ephedrine was administered intravenously because of marked decrease in patient's blood pressure, we observed unexpectedly large increases in the systolic blood pressure, from 78 mmHg to 168 mmHg, and the heart rate increased from 52 to 84 beats per minute (bpm). This phenomenon recurred each time 4 mg of ephedrine was administered. CONCLUSIONS We report a case in which ephedrine induced unexpectedly large increases in blood pressure and heart rate in a patient who suffered from PD with severe cardiac sympathetic nerve denervation. We speculate that this phenomenon was caused by denervation supersensitivity of the patient's heart.

Effects of scavenger receptors-1 class A stimulation on macrophage morphology and highly modified advanced glycation end product-protein phagocytosis.

Advanced glycation end-products (AGEs), which comprise non-enzymatically glycosylated proteins, lipids, and nucleic acid amino groups, play an important role in several diseases and aging processes including angiopathy, renal failure, diabetic complications, and neurodegenerative diseases. Among AGE-associated phenotypes, toxic AGEs, glyceraldehyde-derived AGE-2, and glycolaldehyde-derived AGE-3 are involved in the pathogenesis of diabetic complications. In addition, macrophages are reported to remove extracellular AGEs from tissues via scavenger receptors, leading to the progression of atherosclerosis. In the present study, we found that AGE-2 and AGE-3 enhanced their own endocytic uptake by RAW264.7 mouse macrophage-like cells in a concentration-dependent manner. Furthermore, we demonstrated, for the first time, the morphology of phagocytic macrophages and the endocytosis of AGE particles. The toxic AGEs induced the expression of a scavenger receptor, CD204/scavenger receptors-1 class A (SR-A). Notably, an antibody against CD204 significantly prevented toxic AGE uptake. Moreover, an SR-A antagonistic ligand, fucoidan, also attenuated the AGE-2- and AGE-3-evoked uptake in a concentration-dependent manner. These results indicated that SR-A stimulation, at least in part, plays a role in AGE uptake.