Effect of Dexmedetomidine on Intraoperative Hemodynamics and Blood Loss in Patients Undergoing Spine Surgery: A Systematic Review and Meta-Analysis.

Objective Dexmedetomidine (Dex) is a highly selective α2 adrenoceptor agonist that reduces blood pressure and heart rate. However, its ability to provide stable hemodynamics and a clinically significant reduction in blood loss in spine surgery is still a matter of debate. This study aimed to investigate the effects of Dex on intraoperative hemodynamics and blood loss in patients undergoing spine surgery.Methods The Web of Science, MEDLINE, EMBASE, and the Cochrane Library were searched up to February 2023 for randomized controlled trials (RCTs) including patients undergoing spine surgeries under general anaesthesia and comparing Dex and saline. A fixed- or random-effect model was used depending on heterogeneity.Results Twenty-one RCTs, including 1388 patients, were identified. Dex added the overall risk of intraoperative hypotension (odds ratio [OR]: 2.11; 95% confidence interval [CI]: 1.24 - 3.58; P=0.006) and bradycardia (OR: 2.48; 95%CI: 1.57 - 3.93; P=0.0001). The use of a loading dose of Dex led to significantly increased risks of intraoperative hypotension (OR: 2.00; 95%CI: 1.06 - 3.79; P=0.03) and bradycardia (OR: 2.28; 95%CI: 1.42 - 3.66; P=0.0007). For patients receiving total intravenous anesthesia, there was an increased risk of hypotension (OR: 2.90; 95%CI: 1.24 - 6.82; P=0.01) and bradycardia (OR: 2.66; 95%CI: 1.53 - 4.61; P=0. 0005). For patients in the inhalation anesthesia group, only an increased risk of bradycardia (OR: 4.95; 95%CI: 1.41 - 17.37; P=0.01) was observed. No significant increase in the risk of hypotension and bradycardia was found in the combined intravenous-inhalation anesthesia group. The incidence of severe hypotension (OR: 2.57; 95%CI: 1.05 - 6.32; P=0.04), but not mild hypotension, was increased. Both mild (OR: 2.55; 95%CI: 1.06 - 6.15; P=0.04) and severe (OR: 2.45; 95%CI: 1.43 - 4.20; P=0.001) bradycardia were associated with a higher risk. The overall analyses did not reveal significant reduction in intraoperative blood loss. However, a significant decrease in blood loss was observed in total inhalation anesthesia subgroup (mean difference [MD]: -82.97; 95%CI: -109.04 - -56.90; P<0.001).Conclusions Dex increases the risks of intraoperative hypotension and bradycardia in major spine surgery. The administration of a loading dose of Dex and the utilization of various anesthesia maintenance methods may potentially impact hemodynamic stability and intraoperative blood loss.

Tizanidine Induced Hypotension: Report of a Case and Review of the Literature.

INTRODUCTION: Spasticity is a common sequelae of stroke, and often these patients receive anti-spastic drugs such as baclofen or tizanidine. Stroke patients have multiple co-morbidities such as hypertension, diabetes, and seizure. Tizanidine is an α2 and imidazole receptor agonist at a spinal and supraspinal level resulting in reduced central sympathetic outflow and causing hypotension rarely, especially in those receiving beta-blockers or angiotensin-converting enzyme inhibitors. CASE PRESENTATION: We report a 56-year-old hypertensive male presenting with altered sensorium who had recurrent intracerebral hemorrhage with left spastic hemiplegia and focal seizures. He was on amlodipine, atenolol, telmisartan and oxcarbazepine. After 3 doses of tizanidine 2mg, his blood pressure dropped from 140/90 to 80/40 mmHg and pulse from 82 bpm to 44 bpm. His blood counts, serum chemistry, procalcitonin, and Trop I were normal. ECG revealed sinus bradycardia. After 8 hours of withdrawing tizanidine, his blood pressure became 110/70 mmHg, and on the next day, it became 140/82 mmHg. His attendants were taught physiotherapy to minimize spasticity. CONCLUSION: This patient highlights the need for close monitoring of patients receiving tizanidine co-medication with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. These drugs have a synergistic effect on reducing the renin-angiotensin-aldosterone system, thereby hypotension and bradycardia.

Cilostazol treats transient heart failure caused by ATP1A3 variant-associated polymicrogyria.

BACKGROUND: Some patients with ATP1A3 variant-associated polymicrogyria have recurrent transient heart failure. However, effective treatment for the transient cardiac condition remains to be elucidated. CASE REPORT: The patient started experiencing focal motor onset seizures in 12 h after birth, revealing bilateral diffuse polymicrogyria. The patient also experienced transient bradycardia (sinus bradycardia) attacks from 15 days old. Echocardiography revealed a reduced ejection fraction; however, no obvious electrocorticogram or electroencephalogram abnormalities were observed during the attacks. Initially, the attacks occurred in clusters daily. They later decreased in frequency, occurring at monthly intervals. Repeated episodes of transient bradycardia attacks and polymicrogyria indicated possible ATP1A3 gene abnormality and genetic testing revealed a novel heterozygous ATP1A3 variant (NM_152296: exon22:c.2977_2982del:p.(Glu993_Ile994del)), which was not found in the patient's parents. Cilostazol was administered at 3 months old for recurrent transient bradycardia attacks. Cilostazol significantly shortened the duration of bradycardia episodes and prolonged the interval between attacks. Cilostazol also effectively treats transient symptomatic bradycardia. CONCLUSION: Cilostazol could be a treatment option for recurrent transient bradycardia attacks associated with ATP1A3 gene abnormalities and polymicrogyria.

Which should you choose for post operative atrial fibrillation, carvedilol or metoprolol? A systemic review and meta-analysis.

BACKGROUND: Postoperative atrial fibrillation (POAF) is the most common arrhythmic complication following cardiac surgery. Current guidelines suggest beta-blockers for the prevention of POAF. In comparing metoprolol succinate with carvedilol, the later has sparked interest in its usage as an important medication for POAF prevention. METHODS: We considered randomized controlled studies (RCTs) and retrospective studies that evaluated the efficacy of carvedilol versus metoprolol for the prevention of POAF. After literature search, data extraction, and quality evaluation, pooled data were analyzed using either the fixed-effect or random-effect model using Review Manager 5.3. The Cochrane risk of bias tool was used to assess the bias of included studies. The incidence of POAF was the primary endpoint, while mortality rate and bradycardia were secondary outcomes. RESULTS: In meta-analysis 5 RCTs and 2 retrospective studies with a total of 1000 patients were included. The overall effect did not favor the carvedilol over metoprolol groups in terms of mortality rate [risk ratio 0.45, 95 % CI (0.1-1.97), P=0.29] or incidence of bradycardia [risk ratio 0.63, 95 % CI (0.32-1.23), P=0.17]. However, the incidence of POAF was lower in patients who received carvedilol compared to metoprolol [risk ratio 0.54, 95 % CI (0.42-0.71), P < 0.00001]. CONCLUSION: In patients undergoing cardiac surgery, carvedilol may minimize the occurrence of POAF more effectively than metoprolol. To definitively establish the efficacy of carvedilol compared to metoprolol and other beta-blockers in the prevention of POAF, a large-scale, well-designed randomized controlled trials are required.

Application of Dexmedetomidine in Epidural Labor Analgesia: A Systematic Review and Meta-Analysis on Randomized Controlled Trials.

OBJECTIVES: To summarize and appraise the use of dexmedetomidine in epidural labor analgesia, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). METHODS: We conducted the literature search about the RCTs of epidural labor analgesia with or without dexmedetomidine from inception until November 1, 2022, in the following databases: PubMed, Cochrane Library, and Embase. The primary outcome was visual analog scale (VAS) within 2 hours after epidural intubation. The secondary outcomes included the duration of the first and second labor stages, Apgar score, umbilical blood pH, dosage of analgesics, and side effects. RESULTS: Eight RCTs including 846 parturients were included. The VAS score of the dexmedetomidine group was significantly lower than that of the control group at the time of 15 minutes (mean difference [MD] -1.41, 95% confidence interval [CI] -2.23, -0.59), 30 minutes (MD -1.02, 95% CI -1.70, -0.33), 60 minutes (MD -0.90, 95% CI -1.36, -0.44), and 90 minutes (MD -0.70, 95% CI -1.16, -0.23). The incidence of pruritus in the dexmedetomidine group was lower than that of the control group （MD 0.28, 95% CI 0.11, 0.74), but the incidence of maternal bradycardia was higher (MD 6.41, 95% CI 1.64, 25.04). There were no significant difference in other outcomes. DISCUSSION: Dexmedetomidine combined with local anesthetic for epidural labor analgesia can improve the VAS score of parturients. Except for the increased incidence of maternal bradycardia, it seems to be safe for the parturients and fetuses.

Oral Albuterol Treatment in Three Pediatric Patients with Bradycardia: A Novel Therapy.

Clinically significant bradycardia is an uncommon problem in children, but one that can cause significant morbidity and sometimes necessitates implantation of a pacemaker. The most common causes of bradycardia are complete heart block (CHB), which can be congenital or acquired, and sinus node dysfunction, which is rare in children with structurally normal hearts. Pacemaker is indicated as therapy for the majority of children with CHB, and while early mortality is lower in postnatally diagnosed CHB than in fetal CHB, it is still up to 16%. In young children, less invasive transvenous pacemaker systems can be technically challenging to place and carry a high risk of complications, often necessitating surgical epicardial pacemaker placement, which usually entails a median sternotomy. We report three cases of pediatric patients referred for pacemaker implantation for different types of bradycardia, treated at our institution with oral albuterol with therapeutic results that avoided the need for surgical pacemaker implantation at that time.

Mechanism of Lingbao Huxin Dan in the treatment of bradyarrhythmia complicated with coronary heart disease: a network pharmacology analysis.

OBJECTIVE: To investigate the mechanism of action of the Lingbao Huxin Dan in treating bradycardia arrhythmia with coronary heart disease (BA-CHD) by network pharmacology. METHODS: The active ingredients of the Lingbao Huxin Dan were screened on the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and Bioinformatics tools designed for the analysis of molecular mechanisms of Chinese medicine platform; target prediction was conducted with the SwissTargetPrediction database, and Cytoscape 3.8 was used to construct a drug ingredient-target network. The Genecards, Online Mendelian Inheritance in Man, and DrugBank databases were searched for disease targets. Venn plots were used to display the common targets of BA-CHD and active ingredients. The STRING platform was used to construct a protein-protein interaction network. The Metascape data platform was used for Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to construct a signaling pathway network of the active ingredients of the Lingbao Huxin Dan. RESULTS: There were 121 active ingredients, 899 related targets, 39 targets important in BA-CHD and 14 targets which intersected between the active ingredients and BA-CHD. There were 27 core therapeutic ingredients, 153 biological processes, 18 cell ingredients and 20 molecular functions obtained by GO enrichment analysis. The KEGG pathway analysis yielded 19 signaling pathways. CONCLUSION: RBA-CHD may treat BA-CHD by regulating adrenergic receptor beta-1, alpha 1-α adrenergic receptor, calcium voltage-gated channel subunit alpha1 C, alpha-1ß-adrenergic receptor, nitric oxide synthase 2, beta-2 adrenergic receptor, voltage-dependent calcium channel subunit alpha-2/delta-1, an- giotensin-converting enzyme, Raf-1 proto-oncogene serine/threonine-protein kinase, and other targets, potentially by affecting adrenergic receptor binding and calcium channel opening, to regulate the activity of cardiomyocytes.

High-dose IV magnesium in mesothelioma patients receiving surgery with hyperthermic intraoperative cisplatin: Pilot studies and design of a phase II randomized clinical trial.

INTRODUCTION: Hyperthermic intraoperative cisplatin (HIOC) is associated with acute kidney injury (AKI). Administration of high-dose magnesium attenuates cisplatin-induced AKI (CP-AKI) in animal models but has not been rigorously examined in humans. METHODS: We tested the feasibility and safety of different doses of magnesium in mesothelioma patients receiving HIOC. In Pilot Study 1, we administered a 36-h continuous infusion of magnesium at 0.5 g/h, targeting serum magnesium levels between 3 and 4.8 mg/dL. In Pilot Study 2A, we administered a 6 g bolus followed by an infusion starting at 2 g/h, titrated to achieve levels between 4 and 6 mg/dL. We eliminated the bolus in Pilot Study 2B. RESULTS: In Pilot Study 1, all five patients enrolled completed the study; however, median postoperative Mg levels were only 2.4 mg/dL. In Pilot Study 2A, two of four patients (50%) were withdrawn due to bradycardia during the bolus. In Pilot Study 2B, two patients completed the study whereas two developed postoperative bradycardia attributed to the magnesium. CONCLUSIONS: A 0.5 g/h infusion for 36 h did not achieve therapeutic magnesium levels, while an infusion at 2 g/h was associated with bradycardia. These studies informed the design of a randomized clinical trial testing whether intravenously Mg attenuates HIOC-associated AKI.

Effect of GR205171 on autonomic dysreflexia induced by colorectal distension in spinal cord injured rats.

STUDY DESIGN: Preclinical pharmacology. OBJECTIVES: To determine whether blocking substance P signaling attenuates the hypertension and bradycardia evoked by colorectal distension (CRD) in spinal cord injured (SCI) rats. SETTING: University laboratory in Pennsylvania, U.S.A. METHODS: Tachykinin NK1 receptor antagonists were administered 30 min prior to CRD three weeks after complete spinal cord transection at the 4th thoracic (T4) level. The dose range, route of administration, and pretreatment time was based on published data demonstrating occupancy of brain NK1 receptors in rodents. RESULTS: Subcutaneous (SC) administration of 10-30 mg/kg GR205171 ((2S,3S)-N-[[2-methoxy-5-[5-(trifluoromethyl)tetrazol-1-yl]phenyl]methyl]-2-phenylpiperidin-3-amine dihydrochloride) reduced CRD-induced hypertension and bradycardia by 55 and 49%, respectively, compared with pretreatment values. There was no effect of GR205171 on resting blood pressure or heart rate. In contrast, the same dose range of CP-99,994 ((2S,3S)-N-[(2-methoxyphenyl)methyl]-2-phenyl-3-piperidinamine dihydrochloride) had no effect on CRD-induced cardiovascular responses. CONCLUSIONS: The effective dose range of GR205171 to alleviate autonomic dysreflexia is consistent with the blockade of NK1 receptors on pelvic sensory afferents in the lumbosacral spinal cord, which may in turn prevent the over-excitation of sympathetic preganglionic neurons (SPNs) that regulate blood pressure and heart rate. The findings provide preclinical support for the utility of NK1 receptor antagonists to treat autonomic dysreflexia in people with SCI. The difference in the effects of the two NK1 receptor antagonists may reflect the ~200-fold lower affinity of CP-99,994 than GR205171 for the rat NK1 receptor.

ALK Inhibitor Treatment Patterns and Outcomes in Real-World Patients with ALK-Positive Non-Small-Cell Lung Cancer: A Retrospective Cohort Study.

BACKGROUND: Randomized trials have demonstrated that anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) can be safe and efficacious treatments for patients with ALK-positive advanced non-small-cell lung cancer (aNSCLC). However, their safety, tolerability, effectiveness, and patterns of use in real-world patients remain understudied. OBJECTIVE: We sought to assess the overall treatment pattern characteristics, safety, and effectiveness outcomes of real-world patients with ALK-positive aNSCLC receiving ALK TKIs. PATIENTS AND METHODS: This retrospective cohort study using electronic health record data included adult patients with ALK-positive aNSCLC receiving ALK TKIs between January 2012 and November 2021 at a large tertiary medical center, University of California, San Francisco (UCSF), with alectinib or crizotinib as the initial ALK TKI therapy. Our primary endpoints included the incidence of treatment changes (treatment dose adjustments, interruptions, and discontinuations) during the initial ALK TKI treatment, the count and type of subsequent treatments, rates of serious adverse events (sAEs), and major adverse events (mAEs) leading to any ALK TKI treatment changes. Secondary endpoints included the hazard ratios (HRs) for median mAE-free survival (mAEFS), real-world progression-free survival (rwPFS), and overall survival (OS) when comparing alectinib with crizotinib. RESULTS: The cohort consisted of 117 adult patients (70 alectinib and 47 crizotinib) with ALK-positive aNSCLC, with 24.8%, 17.9%, and 6.0% experiencing treatment dose adjustments, interruptions, and discontinuation, respectively. Of the 73 patients whose ALK TKI treatments were discontinued, 68 received subsequent treatments including newer generations of ALK TKIs, immune checkpoint inhibitors, and chemotherapies. The most common mAEs were rash (9.9%) and bradycardia (7.0%) for alectinib and liver toxicity (19.1%) for crizotinib. The most common sAEs were pericardial effusion (5.6%) and pleural effusion (5.6%) for alectinib and pulmonary embolism (6.4%) for crizotinib. Patients receiving alectinib versus crizotinib as their first ALK TKI treatment experienced significantly prolonged median rwPFS (29.3 versus 10.4 months) with an HR of 0.38 (95% CI 0.21-0.67), while prolonged median mAEFS (not reached versus 91.3 months) and OS (54.1 versus 45.8 months) were observed in patients receiving alectinib versus crizotinib but did not reach statistical significance. Yet, it is worth noting that there was a high degree of cross-over post-progression, which could significantly confound the overall survival measures. CONCLUSIONS: We found that ALK TKIs were highly tolerable, and alectinib was associated with favorable survival outcomes with longer time to adverse events (AE) requiring medical interventions, disease progression, and death, in the context of real-world use. Proactive monitoring for adverse events such as rash, bradycardia, and hepatotoxicity may help further promote the safe and optimal use of ALK TKIs in the treatment of patients with aNSCLC.

Refractory bradycardia and hypotension in patients with autonomic dysfunction treated with pseudoephedrine.

We describe a man in his 40s with a history of chronic intranasal cocaine use and C5-C7 incomplete quadriplegia complicated by neurogenic orthostatic hypotension, admitted to the intensive care unit for worsening bradycardia and hypotension requiring initiation of dopamine and an increase of his home midodrine dose. The patient experienced refractory bradycardia and hypotension with weaning of dopamine, and therefore a recommendation was made to add pseudoephedrine to his current regimen. This case describes the addition of pseudoephedrine to facilitate weaning off intravenous vasopressors within 24 hours in a patient with refractory bradycardia and hypotension secondary to autonomic dysfunction.

Retrospective evaluation of ketamine versus droperidol on time to restraint removal in agitated emergency department patients.

PURPOSE: Acute agitation and violent behavior in the emergency department (ED) can lead to significant patient morbidity and contribute to the growing problem of workplace violence against health care providers. To our knowledge, there is no available literature directly comparing intramuscular ketamine to intramuscular droperidol in ED patients presenting with undifferentiated agitation. The purpose of this investigation was to compare the effectiveness and safety of these agents for acute agitation in the ED. METHODS: This was a retrospective observational study conducted at an urban, academic ED. The primary endpoint was time from the first dose of study medication to restraint removal. Safety endpoints included incidence of bradycardia (heart rate < 60 bpm), hypotension (systolic blood pressure < 90 mmHg), hypoxia (oxygen saturation < 90% or need for respiratory support), and incidence of intubation for ongoing agitation or respiratory failure. RESULTS: An initial 189 patients were screened, of which, 92 met inclusion criteria. The median time from initial drug administration to restraint removal was 49 min (IQR 30, 168) in the ketamine group and 43 min (IQR 30, 80) in the droperidol group (Median difference 6 min; 95% CI [-7, 26]). There was no significant difference in rates of bradycardia (3% vs 3%, 95% CI [-7%, 8%]), hypotension (0% vs 2%, 95% CI [-5%, 2%]), or hypoxia (7% vs 10%, 95% CI [-15%, 9%]) in the ketamine versus droperidol groups respectively. One patient in the ketamine group was intubated for ongoing agitation, and one patient in the droperidol group was intubated for respiratory failure. CONCLUSIONS: Intramuscular droperidol and intramuscular ketamine were associated with similar times from drug administration to restraint removal in patients presenting to the ED with undifferentiated agitation. Prospective studies are warranted to evaluate IM droperidol and IM ketamine head-to-head as first line agents for acute agitation in the ED.

Review article: Risk of cardiovascular events in patients with inflammatory bowel disease receiving small molecule drugs.

BACKGROUND: In the context of an ageing inflammatory bowel disease (IBD) population, cardiovascular comorbidities become particularly relevant. Novel small molecule drugs (SMDs) for the treatment of moderate-to-severe IBD have been recently approved, including Janus kinase (JAK) inhibitors and sphingosine-1-phosphate receptor (S1P) modulators. Data from rheumatoid arthritis population have raised concerns about the risk of cardiovascular events with the use of tofacitinib, which was extrapolated to other immune-mediated diseases and other JAK inhibitors. S1P receptor modulation has been associated with potential cardiovascular events, especially bradycardia and cardiac conduction abnormalities. AIM: To review the incidence of cardiovascular events with the use of SMDs in patients with IBD and to provide practical recommendations on mitigation strategies. METHODS: Published literature was reviewed; recommendations were synthesised by experts in both cardiovascular diseases and IBD. RESULTS: Evidence from the IBD population does not indicate a higher risk of cardiovascular events with tofacitinib and other JAK inhibitors. The risk is higher in patients with intermediate to high cardiovascular risk. S1P modulators may be associated with a dose-dependent, first-dose effect, transient risk of conduction abnormalities (bradycardia and AV block). Screening and monitoring of cardiovascular risk factors should be done in all patients with IBD. Risk stratification for cardiovascular disease should be performed before starting treatment with SMDs. CONCLUSIONS: Available evidence of both JAK inhibitors and S1P modulators indicates a reassuring safety profile of SMDs from the cardiovascular perspective in the overall IBD population. Efforts should be made to identify patients with IBD at a higher risk of cardiovascular events.

Ivabradine-Induced Bradycardia is Accompanied by Reduced Stress-Related Anxiety.

BACKGROUND: Hypertensive individuals with higher heart rates and anxiety have greater cardiovascular morbidity and mortality. Despite the correlation between hypertension, heart rate, and anxiety, scant attention has been paid to the effect of hypertension drug therapy on behavioral outcomes in cardiovascular disease. Ivabradine, an inhibitor of hyperpolarization-activated, cyclic nucleotide-gated funny channels (HCNs), has been used clinically to reduce heart rates and has been shown to improve quality of life in patients with angina and heart failure. We postulated that in addition to lowering heart rate, ivabradine could reduce anxiety in mice exposed to a significant stress paradigm. METHODS: Mice underwent a stress induction protocol, subsequently they received either vehicle or ivabradine (10 mg/kg) via osmotic minipumps. Blood pressure and heart rates were measured with tail cuff photoplethysmography. Anxiety was assessed quantitatively through the open field test (OFT) and the elevated plus maze (EPM). Cognition was assessed with an object recognition test (ORT). Pain tolerance was measured by the hot plate test or subcutaneous injection of formalin. HCN gene expression was measured with RT-PCR. RESULTS: Ivabradine reduced resting heart rate in the stressed mice by 22%. Stressed mice treated with ivabradine displayed significantly greater exploratory behavior in the OFT, EPM, and ORT. The expression of central HCN channels was significantly reduced following stress. CONCLUSION: It is suggested from our findings that ivabradine can reduce anxiety following significant psychological stress. Reductions in heart rate may directly improve quality of life by reducing anxiety in patients with hypertension and high heart rates.

Remdesivir Use in Pediatric Patients for SARS-CoV-2 Treatment: Single Academic Center Study.

BACKGROUND: Millions of children in the United States have been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with many infections leading to hospitalization. For pediatric patients, especially younger children, treatment options are limited. Remdesivir has demonstrated a positive safety and efficacy profile in adults, but little data is published regarding remdesivir use in pediatric patients. Additional data for SARS-CoV-2 treatments in pediatric patients is required to prevent further SARS-CoV-2-related morbidity and mortality. At a single pediatric academic medical center, the safety and efficacy of remdesivir was evaluated. METHODS: A retrospective review of patients admitted to a pediatric academic medical center who received remdesivir over a 17-month period was completed. All pediatric patients who received at least 1 dose of remdesivir were included. Safety and efficacy were assessed using national organization's definitions of clinical improvement, bradycardia, hypertension, acute kidney injury and drug-induced liver injury. RESULTS: There were 48 pediatric patients included in this study with 29% of patients admitted to the pediatric intensive care unit. Less than one-third of patients received the full treatment course of remdesivir, with over half of patients not completing therapy due to symptomatic improvement or hospital discharge. Majority of patients required some level of supplemental oxygen support. The median World Health Organization score was consistent throughout all 5 days of therapy. No patients experienced significant bradycardia, hypertension, acute kidney injury, or drug-induced liver injury. CONCLUSIONS: Remdesivir may correlate with clinical stability or improvement and demonstrates safety when used in pediatric patients. A randomized controlled trial is needed to confirm these findings.

Irritant-evoked reflex tachyarrhythmia in spontaneously hypertensive rats is reduced by inhalation of TRPM8 agonists l-menthol and WS-12.

Inhalation of noxious irritants activates nociceptive sensory afferent nerves innervating the airways, inducing reflex regulation of autonomic networks and the modulation of respiratory drive and cardiovascular (CV) parameters such as heart rate and blood pressure. In healthy mammals, irritant-evoked pulmonary-cardiac reflexes cause parasympathetic-mediated bradycardia. However, in spontaneously hypertensive (SH) rats, irritant inhalation also increases sympathetic drive to the heart. This remodeled pulmonary-cardiac reflex may contribute to cardiovascular risk caused by inhalation of air pollutants/irritants in susceptible individuals with cardiovascular disease (CVD). Previous studies have shown that the cooling mimic l-menthol, an agonist for the cold-sensitive transient receptor potential melastatin 8 (TRPM8), can alleviate nasal inflammatory symptoms and respiratory reflexes evoked by irritants. Here, we investigated the impact of inhalation of TRPM8 agonists l-menthol and WS-12 on pulmonary-cardiac reflexes evoked by inhalation of the irritant allyl isothiocyanate (AITC) using radiotelemetry. l-Menthol, but not its inactive analog d-menthol, significantly reduced the AITC-evoked reflex tachycardia and premature ventricular contractions (PVCs) in SH rats but had no effect on the AITC-evoked bradycardia in either SH or normotensive Wistar-Kyoto (WKY) rats. WS-12 reduced AITC-evoked tachycardia and PVCs in SH rats, but this more potent TRPM8 agonist also reduced AITC-evoked bradycardia. l-Menthol had no effect on heart rate when given alone, whereas WS-12 evoked a minor bradycardia in WKY rats. We conclude that stimulation of TRPM8-expressing afferents within the airways reduces irritant-evoked pulmonary-cardiac reflexes, especially the aberrant reflex tachyarrhythmia in SH rats. Airway menthol treatment may be an effective therapy for reducing pollution-associated CV exacerbations.NEW & NOTEWORTHY Irritant-evoked pulmonary-cardiac reflexes are remodeled in spontaneously hypertensive (SH) rats-causing de novo sympathetic reflexes that drive tachyarrhythmia. This remodeling may contribute to air pollution-associated risk in susceptible individuals with cardiovascular disease. We found that inhalation of TRPM8 agonists, l-menthol and WS-12, but not the inactive analog d-menthol, selectively reduces the reflex tachyarrhythmia evoked by allyl isothiocyanate (AITC) inhalation in SH rats. Use of menthol may protect susceptible individuals from pollution-associated CV exacerbations.

Servicio de indicación farmacéutica a pacientes tratados con medicamentos de estrecho margen terapéutico / Minor ailment service for patients treated with narrow therapeutic index drug

Se estudian los casos de dos pacientes que demandan nuestro servicio de indicación farmacéutica porque presentan sintomatología digestiva inespecífica. Ambos están siendo tratados con fármacos de estrecho margen terapéutico (carbonato de litio y digoxina, respectivamente). Durante la indicación, el análisis de la medicación revela la posibilidad de que la clínica que ambos manifiestan guarde relación con estos tratamientos en distinta medida: en el caso del carbonato de litio, por tratarse de una reacción adversa frecuente en tratamientos prolongados, y en el de la digoxina, porque la sintomatología va acompañada de bradicardia. En consecuencia, se proponen dos intervenciones, siendo una de ellas la derivación urgente al médico de atención primaria. El análisis de los tratamientos farmacológicos crónicos prescritos a los pacientes, especialmente aquellos de estrecho margen terapéutico, durante el proceso de indicación, es un punto clave para discriminar entre clínica debida exclusivamente a síntomas menores y otras situaciones que pueden incluso comprometer la vida. (AU)

Impact of intravenous calcium with diltiazem for atrial fibrillation/flutter in the emergency department.

OBJECTIVE: The purpose of this study was to evaluate the effect of early intravenous (IV) calcium on systolic blood pressure (SBP) when administered with IV diltiazem in subjects with atrial fibrillation (AF) or flutter (AFL) with rapid ventricular response (RVR) in the Emergency Department (ED). METHODS: This was a multicenter, retrospective cohort study that evaluated adults admitted to the ED with documented AF or AFL, heart rate (HR) > 120 bpm, SBP 90 to 140 mmHg, and received treatment with IV diltiazem for rate control. The primary outcome was the change in SBP 60 min (+/- 30 min) after initial IV diltiazem administration. Secondary outcomes included time to initial rate control (HR < 100 bpm), time to sustained rate control (HR < 100 bpm for 3 h), change in HR, rates of hypotension, bradycardia, hypercalcemia, and line extravasation within 24 h of initial diltiazem administration. RESULTS: There were 198 subjects in the diltiazem monotherapy group and 56 subjects in the diltiazem with calcium group meeting the inclusion criteria. The primary outcome, median change in SBP 60 min after initial IV diltiazem administration, was similar between groups (-2 mmHg vs -1.5 mmHg; p = 0.642), but this difference was not statistically significant. All secondary outcomes were found to be similar between groups. Although not statistically significant, hypotension occurred more often in the diltiazem with calcium group (20.2% vs 32.1%; p = 0.060) while bradycardia occurred more often in the diltiazem monotherapy group (4.5% vs 0%; p = 0.213). In terms of achieving rate control, the administration of calcium with diltiazem did not significantly change the time to initial rate control (1.4 h vs 1.8 h; p = 0.141) or time to sustained rate control (7.9 h vs 7.7 h; p = 0.570) compared to diltiazem alone. CONCLUSIONS: In the setting of AF/AFL with RVR, administration of IV calcium with IV diltiazem did not show a significant impact on clinical or safety outcomes compared to IV diltiazem monotherapy.

IF IM in a crisis: Intranasal fentanyl versus intravenous morphine in adult vaso-occlusive crisis.

IMPORTANCE: Studies have demonstrated the benefits of INF in reducing pain scores in pediatric patients with VOC due to sickle cell disease (SCD) and in adult patients with chronic pain conditions other than VOC, such as cancer. However, there is limited literature that exists describing the role of INF in adult patients with VOC due to SCD. Current literature demonstrates that the use of IV morphine for VOC patients leads to reduced pain. Therefore, comparing the use of INF with IV morphine will establish the degree of effectiveness of INF for VOC patients. OBJECTIVE: To determine if intranasal fentanyl is equally as effective as IV morphine for treating VOC-associated pain in adult SCD patients. DESIGN: This study was a retrospective non-inferiority cohort study. Electronic health records were utilized to identify eligible patients between January 1, 2021 to February 28, 2022. Patients who received INF as an initial opioid upon presentation to the ED where allocated to the intervention group. On the other hand, individuals who received IV morphine as an initial opioid upon presentation to the ED were allocated to the control group. SETTING: A multi-site healthcare system containing five hospitals. PARTICIPANTS: Patients 18 years of age or older, admitted to the ED with VOC due to SCD, and received INF or IV morphine as an initial opioid upon presentation to the ED. MAIN OUTCOMES AND MEASURES: The primary outcome was to evaluate the percent change in pain reduction after the initial dose of opiate between groups. Secondary outcomes include time to first rescue medication, total morphine milligram equivalent (MME) of IV opiates, hypotension, bradycardia, respiratory distress requiring opiate reversal within 6 h post- study drug administration, readmission within 48 h, and ED disposition. RESULTS: A total of 230 patients were reviewed within the study period, 95 subjects met inclusion criteria, 31 subjects were included in the INF arm and 64 subjects in the IV morphine arm. The primary outcome showed an average percent pain reduction of 17.25% in the INF arm and 17.15% in the IV morphine arm. The point estimate difference was 0.1% (95% CI -9.3%-9.5%; non-inferiority (p < 0.0001). The median dose of IV opiates was 8 MME in the INF group, and 6 MME in the IV morphine group (p = 0.0268). The time from study drug to first rescue medication administration was 22.4 min and 27.3 min in the INF and IV morphine groups, respectively (p = 0.2231). There was no incidence of hypotension or respiratory distress requiring opiate reversal in either arm. Bradycardia occurred in 12.9% and 7.7% (p = 0.2042), readmission rates within 48 h due to VOC was 6.5% and 20.9% (p = 0.0553), and discharge from the ED to home was 16% and 66% (p = 0.0196) in INF and IV morphine arms, respectively. CONCLUSION: INF provided similar pain reduction compared to IV morphine in the treatment of adults with VOC presenting to the ED. IV morphine arm showed a statistically significant difference in discharge to home from the ED, however there was a trend in readmission within 48 h. The study showed no significant difference in hypotension, respiratory distress, or bradycardia between the groups. The INF group had no significant impact on time to drug administration compared to IV morphine, however it was within 1 h of patient presentation which complies with American Society of Hematology (ASH) guidelines. In conclusion, our study showed that INF was non-inferior when compared to IV morphine in reducing pain scores after drug administration. Therefore, INF is an effective alternative to IV morphine for pain management in adults presenting to the ED for VOC particularly in those with limited IV access.

C-L Case Conference: Torsades de Pointes in a Patient With Lifelong Medical Trauma, COVID-19, Remdesivir, Citalopram, Quetiapine, and Hemodialysis.

We present a case of Torsades de Pointes (TdP) in a patient with COVID-19 infection and multiple TdP risk factors including QT-interval prolongation, hemodialysis, bradycardia, and treatment with remdesivir, citalopram, and quetiapine. The case was complicated by post-resuscitation anxiety superimposed on a history of medical trauma since childhood. Top experts in the field of consultation-liaison psychiatry, trauma informed care, and cardiac electrophysiology provide perspectives on this case with a review of the literature. Key teaching topics include identification of TdP risk factors in patients with a complex illness; the necessity for prompt electrophysiology consultation in clinical scenarios with high risk for TdP; and the approach to patients with medical trauma using a trauma-informed lens. We highlight the contributions of COVID-19, the pharmacokinetics of QT-interval-prolonging psychotropic medications, the risks of hemodialysis, and the role of remdesivir-induced bradycardia in this first reported case of TdP in a patient treated with remdesivir.