High-dose Epinephrine Research Articles

A potentially lifesaving error: unintentional high-dose adrenaline administration in anaphylaxis-induced cardiac arrest; a case report

BackgroundCardiopulmonary resuscitation is a crucial skill for emergency medical services. As high-risk-low-frequency events pose an immense mental load to providers, concepts of crew resource management, non-technical skills and the science of human errors are intended to prepare healthcare providers for high-pressure situations. However, medical errors occur, and organizations and institutions face the challenge of providing a blame-free error culture to achieve continuous improvement by avoiding similar errors in the future. In this case, we report a critical medical error during an anaphylaxis-associated cardiac arrest, its handling and the unexpected yet favourable outcome for the patient.Case presentationDuring an out-of-hospital cardiac arrest due to chemotherapy-induced anaphylaxis, a patient received a 10-fold dose of epinephrine due to shortcomings in communication and standardization via a central venous port catheter. The patient converted from a non-shockable rhythm into a pulseless ventricular tachycardia and subsequently into ventricular fibrillation. The patient was cardioverted and defibrillated and had a return of spontaneous circulation with profound hypotension only 6 min after the administration of 10 mg epinephrine. The patient survived without any residues or neurological impairment.ConclusionsThis case demonstrates the potential deleterious effects of shortcomings in communication and deviation from standard protocols, especially in emergencies. Here, precise instructions, closed-loop communication and unambiguous labelling of syringes would probably have avoided the epinephrine overdose central to this case. Interestingly, this serious error may have saved the patient’s life, as it led to the development of a shockable rhythm. Furthermore, as the patient was still in profound hypotension after administering 10 mg of epinephrine, this high dose might have counteracted the severe vasoplegic state in anaphylaxis-associated cardiac arrest. Lastly, as the patient was receiving care for advanced malignancy, the likelihood of termination of resuscitation in the initial non-shockable cardiac arrest was significant and possibly averted by the medication error.

2024 RECOVER Guidelines: Advanced Life Support. Evidence and knowledge gap analysis with treatment recommendations for small animal CPR.

To systematically review the evidence and devise clinical recommendations on advanced life support (ALS) in dogs and cats and to identify critical knowledge gaps. Standardized, systematic evaluation of literature pertinent to ALS following Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Prioritized questions were each reviewed by Evidence Evaluators, and findings were reconciled by ALS Domain Chairs and Reassessment Campaign on Veterinary Resuscitation (RECOVER) Co-Chairs to arrive at treatment recommendations commensurate to quality of evidence, risk:benefit relationship, and clinical feasibility. This process was implemented using an Evidence Profile Worksheet for each question that included an introduction, consensus on science, treatment recommendations, justification for these recommendations, and important knowledge gaps. A draft of these worksheets was distributed to veterinary professionals for comment for 4weeks prior to finalization. Transdisciplinary, international collaboration in university, specialty, and emergency practice. Seventeen questions pertaining to vascular access, vasopressors in shockable and nonshockable rhythms, anticholinergics, defibrillation, antiarrhythmics, and adjunct drug therapy as well as open-chest CPR were reviewed. Of the 33 treatment recommendations formulated, 6 recommendations addressed the management of patients with nonshockable arrest rhythms, 10 addressed shockable rhythms, and 6 provided guidance on open-chest CPR. We recommend against high-dose epinephrine even after prolonged CPR and suggest that atropine, when indicated, is used only once. In animals with a shockable rhythm in which initial defibrillation was unsuccessful, we recommend doubling the defibrillator dose once and suggest vasopressin (or epinephrine if vasopressin is not available), esmolol, lidocaine in dogs, and/or amiodarone in cats. These updated RECOVER ALS guidelines clarify the approach to refractory shockable rhythms and prolonged CPR. Very low quality of evidence due to absence of clinical data in dogs and cats continues to compromise the certainty with which recommendations can be made.

2024 RECOVER Guidelines: Updated treatment recommendations for CPR in dogs and cats.

After the 2012 Reassessment Campaign on Veterinary Resuscitation (RECOVER) CPR Guidelines, this is an update of evidence-based consensus guidelines for Basic Life Support (BLS), advanced life support (ALS), and periarrest monitoring. These RECOVER CPR Guidelines were generated using a modified version of the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system for evidence evaluation and translation of this evidence into clear and actionable clinical instructions. Prioritized clinical questions in the Population, Intervention, Comparator, and Outcome (PICO) format were used as the basis to conduct systematic literature searches by information specialists, to extract information from relevant publications, to assess this evidence for quality, and finally to translate the findings into treatment recommendations. These recommendations were reviewed by the RECOVER writing group and opened for comment by veterinary professionals for 4weeks. Transdisciplinary, international collaboration in university, specialty, and emergency practice. A total of 40 worksheets were prepared to evaluate questions across the 3 domains of BLS, ALS and Monitoring, resulting in 90 individual treatment recommendations. High-dose epinephrine is no longer recommended, and atropine, if used, is only administered once. Bag-mask ventilation is prioritized over mouth-to-nose ventilation in nonintubated animals. In addition, an algorithm for initial assessment, an updated CPR algorithm, a rhythm diagnosis tool, and an updated drug dosing table are provided. While the majority of the BLS and ALS recommendations remain unchanged, some noteworthy changes were made due to new evidence that emerged over the past 10years. Indirectness of evidence remains the largest impediment to the certainty of guidelines formulation and underscores an urgent need for more studies in the target species of dogs and cats.

Cumulative epinephrine dose during cardiac arrest and neurologic outcome after extracorporeal cardiopulmonary resuscitation

BackgroundEpinephrine is recommended without an apparent ceiling dosage during cardiac arrest. However, excessive alpha- and beta-adrenergic stimulation may contribute to unnecessarily high aortic afterload, promote post-arrest myocardial dysfunction, and result in cerebral microvascular insufficiency in patients receiving extracorporeal cardiopulmonary resuscitation (ECPR). MethodsThis was a retrospective cohort study of adults (≥ 18 years) who received ECPR at large academic ECMO center from 2018 to 2022. Patients were grouped based on the amount of epinephrine given during cardiac arrest into low (≤ 3 mg) and high (> 3 mg) groups. The primary endpoint was neurologic outcome at hospital discharge, defined by cerebral performance category (CPC). Multivariable logistic regression was used to assess the relationship between cumulative epinephrine dosage during arrest and neurologic outcome. ResultsAmong 51 included ECPR cases, the median age of patients was 60 years, and 55% were male. The mean cumulative epinephrine dose administered during arrest was 6.2 mg but ranged from 0 to 24 mg. There were 18 patients in the low-dose (≤ 3 mg) and 25 patients in the high-dose (> 3 mg) epinephrine groups. Favorable neurologic outcome at discharge was significantly greater in the low-dose (55%) compared to the high-dose (24%) group (p = 0.025). After adjusting for age, those who received higher doses of epinephrine during the arrest were more likely to have unfavorable neurologic outcomes at hospital discharge (odds ratio 4.6, 95% CI 1.3, 18.0, p = 0.017). ConclusionAfter adjusting for age, cumulative epinephrine doses above 3 mg during cardiac arrest may be associated with unfavorable neurologic outcomes after ECPR and require further investigation.

An unconventional dose of epinephrine for a diagnostic test of catecholaminergic polymorphic ventricular tachycardia: A case report

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare heritable arrhythmogenic disease, and the Mayo Clinic protocol-guided epinephrine test is commonly used for diagnostic purposes. Whether the Mayo Clinic protocol is enough for patients who are insensitive to catecholamine remains an unknown question. Our patient was a19-year-old female who presented with recurrent stress-induced syncope and was saved by cardiopulmonary resuscitation. The initial physical examination and complementary tests (ECG, blood laboratory, cardiac ultrasound, and cranial magnetic resonance angiography) showed no abnormalities on admission. Treadmill exercise testing shows non-sustained and polymorphic tachycardia. A subsequent epinephrine test was performed, and polymorphic ventricular tachycardia was not induced until using a high dose of epinephrine above Mayo Clinic protocol. Therefore, it is suggested that an unconventional dose of epinephrine may be needed fordiagnostic tests of CPVT for some insensitive individuals.

Epinephrine in Out-of-Hospital Cardiac Arrest: A Network Meta-analysis and Subgroup Analyses of Shockable and Nonshockable Rhythms

Epinephrine is the most commonly used drug in out-of-hospital cardiac arrest (OHCA) resuscitation, but evidence supporting its efficacy is mixed. What are the comparative efficacy and safety of standard dose epinephrine, high-dose epinephrine, epinephrine plus vasopressin, and placebo or no treatment in improving outcomes after OHCA? In this systematic review and network meta-analysis of randomized controlled trials, we searched six databases from inception through June 2022 for randomized controlled trials evaluating epinephrine use during OHCA resuscitation. We performed frequentist random-effects network meta-analysis and present ORs and 95%CIs. We used the the Grading of Recommendations, Assessment, Development, and Evaluation approach to rate the certainty of evidence. Outcomes included return of spontaneous circulation (ROSC), survival to hospital admission, survival to discharge, and survival with good functional outcome. We included 18 trials (21,594 patients). Compared with placebo or no treatment, high-dose epinephrine (OR, 4.27; 95%CI, 3.68-4.97), standard-dose epinephrine (OR, 3.69; 95%CI, 3.32-4.10), and epinephrine plus vasopressin (OR, 3.54; 95%CI, 2.94-4.26) all increased ROSC. High-dose epinephrine (OR, 3.53; 95%CI, 2.97-4.20), standard-dose epinephrine (OR, 3.00; 95%CI, 2.66-3.38), and epinephrine plus vasopressin (OR, 2.79; 95%CI, 2.27-3.44) all increased survival to hospital admission as compared with placebo or no treatment. However, none of these agents may increase survival to discharge or survival with good functional outcome as compared with placebo or no treatment. Compared with placebo or no treatment, standard-dose epinephrine improved survival to discharge among patients with nonshockable rhythm (OR, 2.10; 95%CI, 1.21-3.63), but not in those with shockable rhythm (OR, 0.85; 95%CI, 0.39-1.85). Use of standard-dose epinephrine, high-dose epinephrine, and epinephrine plus vasopressin increases ROSC and survival to hospital admission, but may not improve survival to discharge or functional outcome. Standard-dose epinephrine improved survival to discharge among patients with nonshockable rhythm, but not those with shockable rhythm. Center for Open Science: (https://osf.io/arxwq).

A CASE OF RECURRENT IDIOPATHIC ANAPHYLAXIS WHILE ON HIGH-DOSE ANTIHISTAMINE THERAPY

<h3>Introduction</h3> Idiopathic anaphylaxis (IA) is an acute mast-cell mediated reaction without an identifiable antigen. Over 80% of patients are reported to achieve remission with standard therapy consisting of an H1-antagonist and prednisone. Symptoms refractory to standard therapy are dubbed malignant IA. We present a case of malignant IA complicated by severe asthma refractory to high dose antihistamine, prednisone, and Omalizumab. <h3>Case Description</h3> A 44-year-old man with a history of severe asthma presented with recurrent anaphylaxis with unclear trigger while on antihistamine therapy and chronic prednisone. He was admitted and treated for a presumed asthma exacerbation. He required high doses of epinephrine during anaphylactic episodes and continued to have anaphylactic episodes despite high-dose antihistamine therapy and prednisone. A work-up for hereditary angioedema, serum IgE levels for appropriate allergens, mast cell disease, pheochromocytoma, and carcinoid syndrome was negative. Further investigations for systemic mastocytosis is pending results of N-Methylhistamine and 2,3-Dinor-11Beta-Prostaglandin F2 Alpha urine collection. Addition of Omalizumab led to decreased severity of episodes, but the episodes of anaphylaxis continue. Furthermore, the patient's asthma is not controlled despite optimal therapy with Symbicort and Spiriva Respimat. Due to his poor asthma control he may benefit from Dupilumab as a second biologic. We suspect the IL4-13 blockade will help control his asthma and IA. <h3>Discussion</h3> Our case adds to sparse literature on malignant IA complicated by severe asthma. Off label trials of two biologics may be warranted when dealing with treatment failure in such settings.

Vasodilation in patients with calcium channel blocker poisoning treated with high-dose insulin: a comparison of amlodipine versus non-dihydropyridines

Background: High dose insulin (HDI), an inotrope and vasodilator, is a standard therapy for calcium channel blocker (CCB) poisoning. HDI causes vasodilation by stimulating endothelial nitric oxide synthase (eNOS). Most literature supporting HDI for CCB poisoning involves verapamil toxicity; however, amlodipine now causes more CCB poisonings. Unlike other CCBs, amlodipine stimulates eNOS and may cause synergistic vasodilation with HDI. The purpose of this study was to determine if amlodipine-poisoned patients treated with HDI had more evidence of vasodilation than similarly treated patients with non-dihydropyridine (non-DHP) poisoning. Methods: This was a retrospective study from a single poison center. Cases were identified via the generic code “Calcium Antagonists” in which the therapy “High Dose Insulin/Glucose” was “performed, whether or not recommended” from 2019–2021. Evidence of vasodilation was assessed via maximum number of vasopressor infusions per case, vasopressor doses, and use of rescue methylene blue to treat refractory vasoplegia. Results: Thirty-three patients were enrolled: 18 poisoned with amlodipine, 15 with non-DHPs (verapamil n = 10, diltiazem n = 5). The median number of maximum concomitant vasopressors in the amlodipine group was 3 (IQR: 2–5; range 0–6) and 2 in the non-DHP group (IQR: 1–3; range 0–5; p = 0.04); median difference in maximum concomitant vasopressors between groups was 1 (95% confidence interval: 0–2). Median maximum epinephrine dosing was higher in the amlodipine group (0.31 mcg/kg/min) compared to non-DHPs (0.09 mcg/kg/min; p = 0.03). Use of rescue methylene blue was more common in the amlodipine group (7/18 [39%]) than in the non-DHP group (0; p = 0.009). Conclusions: Amlodipine poisoned patients treated with HDI required more vasopressors, higher doses of epinephrine, and more often received rescue methylene blue than similarly treated patients with verapamil or diltiazem poisoning. These differences suggest amlodipine-poisoned patients had more evidence of vasodilation. Further study is warranted to determine if synergistic vasodilation occurs when HDI is used to treat amlodipine poisoning.

High dose of epinephrine does not improve survival of children with out-of-hospital cardiac arrest: Results from the French National Cardiac Arrest Registry.

ObjectivesThe pediatric resuscitation guidelines recommend the use of 0. 01 mg kg−1 epinephrine during a cardiac arrest; an epinephrine dose higher than that is not recommended. The first aim of this study was to determine the administration rate of high epinephrine dose during pediatric out-of-hospital cardiac arrest. The second aim was to compare the survival status in patients who received high or standard doses of epinephrine.MethodsThis was a multicenter comparative post-hoc study conducted between January 2011 and July 2021 based on the French National Cardiac Arrest Registry data. All prepubescent (boys < 12 years old, girls < 10 years old) victims of an out-of-hospital cardiac arrest were included. To compare survival status and control bias, patients who received a high epinephrine dose were matched with those who received a standard epinephrine dose using propensity score matching.ResultsThe analysis included 755 patients; 400 (53%) received a high dose and 355 (47%) received a standard dose of epinephrine. The median dose (mg kg−1) per bolus was higher in the high-dose group than that in the standard dose group (0.04 vs. 0.01 mg kg−1, P < 0.001). Before matching, there was no between-group difference in the 30-day survival rate or survival status at hospital discharge. Matching yielded 288 pairs; there was no between-group difference in the 30-day survival rate or survival at hospital discharge (High dose, n = 5; standard dose, n = 12; Odds ratios: 2.40, 95% confidence interval: 0.85–6.81). Only 2 patients in the standard dose group had a good neurological outcome.ConclusionMore than 50% of the patients did not receive the recommended epinephrine dose during resuscitation. There was no association between patients receiving a high dose or standard dose of epinephrine with the 30-day survival or survival status at hospital discharge. Collaboration across multiple cardiac arrest registries is needed to study the application of pediatric guidelines.

When COVID-19 prophylaxis leads to hydroxychloroquine poisoning

Hydroxychloroquine overdose was a relatively uncommon event prior to the COVID-19 pandemic. However, due to the massive increase in prescriptions, coupled with the search for possibly effective treatment COVID-19 infection, these overdoses have become more frequent. The management of severe hydroxychloroquine overdose does not have any well-established protocols. This report highlights the clinical course and successful management of a life-threatening hydroxychloroquine overdose. An 80-year-old man was admitted to the ICU in shock after a potentially lethal ingestion of hydroxychloroquine for COVID-19 prophylaxis in a COVID-19 negative patient. Treatments included sodium bicarbonate infusion, high dose diazepam, norepinephrine and epinephrine, and continuous electrolyte repletion. After 5 days in the intensive care unit, the patient recovered and was discharged home. In conclusion, hydroxychloroquine overdose can result in life-threatening rapid decompensation requiring gastric decontamination, alkalization, high dose diazepam, hemodynamic support, and frequent electrolyte replacement.

Effect Of Caffeine and Adrenaline on Memory and Anxiety in Male Wistar Rats.

The present study was designed to investigate the effects of caffeine and adrenaline administration on memory and anxiety in male rats. Rats weighing about 140-200g were used for the study. They were divided into three groups (4 animals per group). Study groups 1; a,b,c,d were healthy rats administered normal saline, 5,10 and 15mg/kg bw caffeine intraperitoneally (i.p.), respectively for 6 weeks. Study groups 2; a,b,c,d administered normal saline, 0.1, 0.2 and 0.31mg/kg bw adrenaline (i.p.), respectively for 6 weeks. Study groups 3; a,b,c,d administered normal saline, 5mg/kg caffeine (i.p.) + 0.1mg/kg adrenaline (i.p.), 10mg/kg Caffeine (i.p.) + 0.2mg/kg Adrenaline (i.p.) and 15mg/kg Caffeine (i.p.) + 0.3mg/kg Adrenaline (i.p.) respectively for 6 weeks. The result showed no significant difference in spatial memory across all animals in study groups 1: b,c,d when compared to control (a). Study groups 2: (b, c) showed increase in spatial memory when compared to control (a). 2(d) showed a significant (p<0.05) decrease. Study groups 3: b, c, d showed no significant difference in spatial memory when compared to control (a). Study groups 1: b, c showed significant (p<0.05) reduction in duration for the short and long term memory test when compared to control. Study groups 2 showed reduction in duration for both the long and short term memory test when compared to control Study groups 3 no significant (p<0.05) difference in short and long term memory test across all animals in the group. It was also observed that adrenaline enhanced short and long term memory and only high dose of adrenaline distorted spatial memory. Study groups 1; (b,c) showed significant (p<0.05) increase in the number of entries to the open arm of the elevated plus maze when compared to control (a). Study groups 2; (b), showed significant (p<0.05) increase in the frequencies of entries to the closed arm of the elevated plus maze when compared to control (a). Study groups 2; (d), showed a significant (p<0.05) decrease in the frequency of entries to the open and closed arm when compared to control (a). The study revealed that co- administration of caffeine and adrenaline led to elevation of mood, increased activity and reduction of anxiety in Wistar rats. In addition, it was observed that only high dose of adrenaline increased anxiety. It was also observed that caffeine and adrenaline enhanced short and long term memory and only high dose of adrenaline distorted spatial memory.

High dose epinephrine in the management of life-threatening hypotension from post-surgical hemorrhage with an excellent outcome in a patient with Phaeochromocytoma: A case report

Epinephrine is widely used in the management of severe cardiovascular instability as well as in cardiac arrest. In cardiac arrest, epinephrine has a standard dose (1mg) given at fixed intervals. We present a report on the use of high dose epinephrine (35mg in 45 minutes) during the successful management of a patient with sustained profound hypotension as a result of massive hemorrhage following laparoscopic adrenalectomy.

Surgical adrenalectomy during rescue Extracorporeal Life Support for pheochromocytoma induced cardiogenic shock: a case report

Introduction : Pheochromocytoma, a rare catecholamine-producing tumor, has been described to provoke stress-induced Takotsubo-like cardiomyopathy and even severe refractory cardiogenic shock. In this case report, venoarterial extracorporeal membrane oxygenation (VA-ECMO) was used for hemodynamic stabilization and was continued during the resection of a large neuroendocrine tumor. Description : A 69-year old male, recently diagnosed with a pheochromocytoma, was referred to our center because of severe cardiogenic shock after induction of anesthesia for resection of the mass. Despite adequate alpha-and beta-adrenergic blockade for one month, he developed malignant hypertension with subsequently hemodynamic collapse. After successful cardiopulmonary resusci-tation he developed pulmonary oedema with severe hypoxemia and persistent hemodynamic lability. On arrival in our hospital, echocardiography revealed significant left ventricular impairment. Decision was made to commence him on VA-ECMO for a refractory cardiogenic shock with severe pulmonary oedema. Because of persistent blood pressure swings despite VA-ECMO and beta-adrenergic blockade, we decided to remove the tumor on mechanical circulatory support by an open surgical approach the next day. After clamping of the adrenal circulation, the patient experienced profound hypotension requiring high doses of epinephrine and a methylene blue infusion. Surgical resection was successful but complicated by a postoperative bleeding for which the patient underwent an emergent endovascular embolization of an adrenal artery. Over the next days, there was progressive cardiac recovery and the patient was weaned off VA-ECMO on the fourth postoperative day. The patient was discharged from the intensive care 27 days after admission and left the hospital on day 30. Discussion: VA-ECMO seems to be a feasible last resort therapy in refractory cardiogenic shock induced by pheochromocytoma crisis as suggested by a high survival rate in literature. Despite its support benefit during this type of shock, surgical removal of the tumor is rarely done with mechanical circulatory support and heparinization.

Takotsubo syndrome after liver transplantation: An association with intraoperatively administered epinephrine and fentanyl.

Takotsubo syndrome (TTS) can develop after liver transplant (LT), but its predisposing factors are poorly understood. In this study, we aimed to determine if perioperative factors were associated with posttransplant TTS. Adult patients who underwent primary LT between 2006 and 2018 were included. Patients with and without TTS were identified and matched by propensity scores. Of 2181 LT patients, 38 developed postoperative TTS with a mean left ventricular ejection fraction of 25.5% (±7.8%). Multivariable logistic regression revealed two preoperative risk factors (alcoholic cirrhosis and model for end-stage liver disease-sodium scores) for TTS. Post-propensity match analyses showed that TTS patients had significantly higher doses of epinephrine and lower doses of fentanyl during LT compared with non-TTS patients. A higher dose of epinephrine and a lower dose of fentanyl was associated with a higher predicted probability of TTS. All TTS patients had full recovery of cardiac function and had comparable 1-year survival. In conclusion, TTS occurred at a rate of 1.7% after LT and was associated with two pretransplant risk factors. The higher doses of epinephrine and lower doses of fentanyl administered during LT were associated with posttransplant TTS. More studies on the relationship between intraoperative medications and TTS are warranted.

Circulating microRNAs predispose to takotsubo syndrome following high-dose adrenaline exposure.

Aims Takotsubo syndrome (TTS) is an acute heart failure, typically triggered by high adrenaline during physical or emotional stress. It is distinguished from myocardial infarction (MI) by a characteristic pattern of ventricular basal hypercontractility with hypokinesis of apical segments, and in the absence of culprit coronary occlusion. We aimed to understand whether recently discovered circulating biomarkers miR-16 and miR-26a, which differentiate TTS from MI at presentation, were mechanistically involved in the pathophysiology of TTS.Methods and results miR-16 and miR-26a were co-overexpressed in rats with AAV and TTS induced with an adrenaline bolus. Untreated isolated rat cardiomyocytes were transfected with pre-/anti-miRs and functionally assessed. Ventricular basal hypercontraction and apical depression were accentuated in miR-transfected animals after induction of TTS. In vitro miR-16 and/or miR-26a overexpression in isolated apical (but not basal), cardiomyocytes produced strong depression of contraction, with loss of adrenaline sensitivity. They also enhanced the initial positive inotropic effect of adrenaline in basal cells. Decreased contractility after TTS-miRs was reproduced in non-failing human apical cardiomyocytes. Bioinformatic profiling of miR targets, followed by expression assays and functional experiments, identified reductions of CACNB1 (L-type calcium channel Cavβ subunit), RGS4 (regulator of G-protein signalling 4), and G-protein subunit Gβ (GNB1) as underlying these effects.ConclusionmiR-16 and miR-26a sensitize the heart to TTS-like changes produced by adrenaline. Since these miRs have been associated with anxiety and depression, they could provide a mechanism whereby priming of the heart by previous stress causes an increased likelihood of TTS in the future.

Mild therapeutic hypothermia after out-of-hospital cardiac arrest: What does really matter?

Mild therapeutic hypothermia (MTH) is a recommended treatment of comatose patients after out-of-hospital cardiac arrest (OHCA). The aim of the study was to examine determinants of clinical outcome in OHCA survivors treated with MTH and variables associated with MTH induction time. Presented herein is an analysis of combined results from a retrospective and a prospective observational study which included 90 OHCA survivors treated with MTH from January 2010 to March 2018. Multivariate regression analysis was performed to determine variables associated with poor neurologic outcome (Cerebral Performance Category 3-5), mortality, and prolonged induction time. At hospital discharge, 59 (65.6%) patients were alive, of whom 36 (61%) had a good neurologic outcome. Older patients (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.03-1.12) with lower Glasgow Coma Scale (GCS) (OR 0.49, 95% CI 0.30-0.80) were at higher risk of poor neurological outcome. The predictors of in-hospital death included: older age (OR 1.08, 95% CI 1.02-1.13), lower GCS score (OR 0.47, 95% CI 0.25-0.85), presence of cardiogenic shock (OR 3.43, 95% CI 1.11-10.53), and higher doses of adrenaline (OR 1.27, 95% CI 1.04-1.56). Longer induction was associated with shorter cardio-pulmonary resuscitation (CPR) (unstandardized coefficient -3.95, 95% CI -7.09 to -0.81) and lower lactate level (unstandardized coefficient -18.55, 95% CI -36.10 to -1.01). Unfavorable neurologic outcome in OHCA patients treated with MTH is associated with age and lower GCS score. Risk factors for in-hospital mortality include age, high-dose adrenaline administration, lower GCS score and presence of cardiogenic shock. CPR duration and lactate level were predictive of prolonged MTH induction time.

The effect of high-dose intramuscular epinephrine on the recovery of spontaneous circulation in an asphyxia\u2010induced cardiac arrest rat model

BackgroundObtaining vascular access can be challenging during resuscitation following cardiac arrest, and it is particularly difficult and time-consuming in paediatric patients. We aimed to compare the efficacy of high-dose intramuscular (IM) versus intravascular (IV) epinephrine administration with regard to the return of spontaneous circulation (ROSC) in an asphyxia-induced cardiac arrest rat model.Methods Forty-five male Sprague-Dawley rats were used for these experiments. Cardiac arrest was induced by asphyxia, and defined as a decline in mean arterial pressure (MAP) to 20 mmHg. After asphyxia-induced cardiac arrest, the rats were randomly allocated into one of 3 groups (control saline group, IV epinephrine group, and IM epinephrine group). After 540 s of cardiac arrest, cardiopulmonary resuscitation was performed, and IV saline (0.01 cc/kg), IV (0.01 mg/kg, 1:100,000) epinephrine or IM (0.05 mg/kg, 1:100,000) epinephrine was administered. ROSC was defined as the achievement of an MAP above 40 mmHg for more than 1 minute. Rates of ROSC, haemodynamics, and arterial blood gas analysis were serially observed.ResultsThe ROSC rate (61.5%) of the IM epinephrine group was less than that in the IV epinephrine group (100%) but was higher than that of the control saline group (15.4%) (log-rank test). There were no differences in MAP between the two groups, but HR in the IM epinephrine group (beta coefficient = 1.02) decreased to a lesser extent than that in the IV epinephrine group with time.ConclusionsIM epinephrine induced better ROSC rates compared to the control saline group in asphyxia-induced cardiac arrest, but not compared to IV epinephrine. The IM route of epinephrine administration may be a promising option in an asphyxia-induced cardiac arrest.

The study of the cardioprotective action of the thick extract of parsnip herb

Topicality. Modern drugs used to treat diseases of the cardiovascular system generally have a number of side effects. In this regard, the problem of developing and studying safe and effective drugs for the use in cardiology becomes relevant for scientists. Pharmacological drugs with the metabolic and cytoprotective action of plant origin are increasingly used for the treatment of cardiovascular diseases; however, their range is quite limited. The latest information on the use of herbal medicines based on the promising types of the medicinal plant raw material of the domestic flora, in particular parsnip (Pastinaca sativa L.) herb, determines the urgency of creating new potential cardioprotectors of plant origin. Aim. To study amino acids and phenolic compounds in the thick extract of parsnip herb, as well as the cardioprotective activity of this extract. Materials and methods. The thick extract of parsnip herb (TEPH) was chosen as the study object. The study of the amino acid composition of TEPH was performed by ion exchange liquid chromatography on a T 339 automatic analyzer. Phenolic compounds were studied by high performance liquid chromatography (HPLC). Identification of components was performed by retention time and compliance of UV spectra with standard substances, the quantitative content was determined by calculating the area of peaks on the chromatogram. The study of the effectiveness of the use of the plant substance of TEPH for the correction of disorders in the body of rats under conditions of heart disease with high doses of adrenaline was performed at the premises of the Central Research Laboratory of the NUPh. The experiment was performed on 25 nonlinear white male rats weighing 180-220 g. The drug “Tricardin” LLC “Ternopharm” (Ukraine) was used as a reference drug. Results and discussion. As a result of the study of the amino acid composition of TEPH, 18 amino acids were identified; their total content was almost 10 % in the extract. Rutin and chlorogenic acid in the amount of 3.37 mg/100 g and 0.41 mg/100 g, respectively, were identified in the extract by HPLC. The results of the study of the effect of the thick extract of parsnip on the integrated indicators of the state of white rats on the model of acute adrenaline myocarditis indicate that when treating animals with TEPH in the doses of 100 mg/kg and 200 mg/kg the heart mass coefficient increased by 1.25 and 1.2 times compared to the group of intact animals, indicating a decrease in the manifestations of exudation compared to animals of the control pathology. Conclusions. Amino acids and phenolic compounds in TEPH have been studied. As a result, the presence of 18 amino acids has been found; their content in the extract is almost 10 %. The extract contains 3.37 mg/100 g of rutin and 0.41 mg/100 g of chlorogenic acid. The study conducted has confirmed the cardioprotective properties of TEPH, indicating the relevance of further comprehensive physicochemical, pharmacological and preclinical pharmacological studies of this herbal medicine and emphasizing the prospects for its further study, implementation in production and use in the treatment of cardiovascular diseases.

α2-Adrenergic Disruption of β Cell BDNF-TrkB Receptor Tyrosine Kinase Signaling.

Adrenergic signaling is a well-known input into pancreatic islet function. Specifically, the insulin-secreting islet β cell expresses the Gi/o-linked α2-adrenergic receptor, which upon activation suppresses insulin secretion. The use of the adrenergic agonist epinephrine at micromolar doses may have supraphysiological effects. We found that pretreating β cells with micromolar concentrations of epinephrine differentially inhibited activation of receptor tyrosine kinases. We chose TrkB as an example because of its relative sensitivity to the effects of epinephrine and due to its potential regulatory role in the β cell. Our characterization of brain-derived neurotrophic factor (BDNF)-TrkB signaling in MIN6 β cells showed that TrkB is activated by BDNF as expected, leading to canonical TrkB autophosphorylation and subsequent downstream signaling, as well as chronic effects on β cell growth. Micromolar, but not nanomolar, concentrations of epinephrine blocked BDNF-induced TrkB autophosphorylation and downstream mitogen-activated protein kinase pathway activation, suggesting an inhibitory phenomenon at the receptor level. We determined epinephrine-mediated inhibition of TrkB activation to be Gi/o-dependent using pertussis toxin, arguing against an off-target effect of high-dose epinephrine. Published data suggested that inhibition of potassium channels or phosphoinositide-3-kinase signaling may abrogate the negative effects of epinephrine; however, these did not rescue TrkB signaling in our experiments. Taken together, these results show that (1) TrkB kinase signaling occurs in β cells and (2) use of epinephrine in studies of insulin secretion requires careful consideration of concentration-dependent effects. BDNF-TrkB signaling in β cells may underlie pro-survival or growth signaling and warrants further study.

Amelioration of adrenaline induced oxidative gastrointestinal damages in rat by melatonin through SIRT1-NFκB and PGC1α-AMPKα cascades

Adrenaline at high pharmacological doses may lead to oxidative damages in diverse organs including gut. In this study, we attempt to elucidate the potentially protective effects of melatonin on gastrointestinal (GI) tissue damages induced by adrenaline. Rats were injected (s.c.) with different doses (0.125, 0.25 and 0.50 mg/kg) of adrenaline bitartrate (AD) for 15 days with or without melatonin (2.5, 5 and 10 mg/kg; orally). The results showed that adrenaline caused massive histological and ultra-structural GI injuries and melatonin (20 mg/kg) effectively protected these injuries. The protective mechanisms are related to the antioxidant and anti-inflammatory activities of melatonin indicated by increased glutathione levels and antioxidant enzymes as well as decreased oxidative stress markers and pro-inflammatory cytokines in GI tissues. The signal pathways of melatonin include up-regulating expression of Nrf2, SIRT1 and Bcl2, while down-regulating NFκB, TNFα and Bax. Melatonin also targeted mitochondrial energy homeostasis and biogenesis by up-regulating expression of PGC1α, AMPKα and SOD2 and reduced leakage of cytochrome c. The SIRT1-NFκB and PGC1α-AMPKα signal transduction pathways seem to play the central roles involving in melatonin’s protective effects on gastric damages induced by the high doses of adrenaline.