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Background: Mast cell-derived mediators induce vasodilatation and fluid extravasation, leading to cardiovascular failure in severe anaphylaxis. We previously revealed a synergistic interaction between the cytokine IL-4 and the mast cell-derived mediator histamine in modulating vascular endothelial (VE) dysfunction and severe anaphylaxis. The mechanism by which IL-4 exacerbates histamine-induced VE dysfunction and severe anaphylaxis is unknown., Objective: We sought to identify the IL-4-induced molecular processes regulating the amplification of histamine-induced VE barrier dysfunction and the severity of IgE-mediated anaphylactic reactions., Methods: RNA sequencing, Western blot, Ca 2+ imaging, and barrier functional analyses were performed on the VE cell line (EA.hy926). Pharmacologic degraders (selective proteolysis-targeting chimera) and genetic (lentiviral short hairpin RNA) inhibitors were used to determine the roles of signal transducer and activator of transcription 3 (STAT3) and STAT6 in conjunction with in vivo model systems of histamine-induced hypovolemic shock., Results: IL-4 enhancement of histamine-induced VE barrier dysfunction was associated with increased VE-cadherin degradation, intracellular calcium flux, and phosphorylated Src levels and required transcription and de novo protein synthesis. RNA sequencing analyses of IL-4-stimulated VE cells identified dysregulation of genes involved in cell proliferation, cell development, and cell growth, and transcription factor motif analyses revealed a significant enrichment of differential expressed genes with putative STAT3 and STAT6 motif. IL-4 stimulation in EA.hy926 cells induced both serine residue 727 and tyrosine residue 705 phosphorylation of STAT3. Genetic and pharmacologic ablation of VE STAT3 activity revealed a role for STAT3 in basal VE barrier function; however, IL-4 enhancement and histamine-induced VE barrier dysfunction was predominantly STAT3 independent. In contrast, IL-4 enhancement and histamine-induced VE barrier dysfunction was STAT6 dependent. Consistent with this finding, pharmacologic knockdown of STAT6 abrogated IL-4-mediated amplification of histamine-induced hypovolemia., Conclusions: These studies unveil a novel role of the IL-4/STAT6 signaling axis in the priming of VE cells predisposing to exacerbation of histamine-induced anaphylaxis., Competing Interests: Disclosure statement This work was supported by National Institutes of Health grants DK073553, DK090119, AI138177, and AI112626; Food Allergy Research & Education; Department of Defense grant W81XWH-15-1-051730; Michigan Food Allergy Research Accelerator (M-FARA); and the Mary H. Weiser Food Allergy Center (to S.P.H.). Disclosure of potential conflicts of interest: S.P. Hogan receives research grant support from Regeneron Pharmaceuticals. The remaining authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Refractory vasodilatory shock (RVS) following massive calcium channel blocker (CCB) overdose remains a challenging clinical entity. Peripheral venoarterial extracorporeal membrane oxygenation (ECMO) has proven useful in several cases of CCB intoxication, however, its use in the pediatric population poses unique challenges given the generally small size of pediatric peripheral vasculature in comparison to the high flow rates necessary for adequate mechanical circulatory support. As a result of these challenges, our group has adopted a "primary" central ECMO cannulation approach to the treatment of children and adolescents admitted to our center with profound RVS after CCB ingestion. We present four cases within the last year using this approach. All patients were successfully discharged from the hospital with no late morbidity at most recent follow-up. Central ECMO support in cases of massive vasodilatory shock following CCB overdose is safe and effective and should be considered early in the clinical course of these critically ill patients., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2023.)

This report describes a case of shock symptoms in a 72-year-old woman with epilepsy who had been in a state of polypharmacy, taking multiple antipsychotic drugs. After receiving a normal dose of periciazine, she exhibited impaired consciousness, hypothermia, and hypotension and was admitted to hospital. Despite poor response to vasopressors, conservative treatment led to gradual improvement. Subsequent pharmacokinetic analysis showed non-toxic blood concentrations of periciazine, suggesting that even small doses of phenothiazines could result in toxic symptoms. This case highlights the importance of monitoring for adverse reactions when prescribing multiple antipsychotic drugs, particularly in older polypharmacy patients.

Background: Bradycardia, renal failure, atrioventricular (AV) node blocking, shock, and hyperkalemia syndrome is a potentially life-threatening clinical condition characterized by bradycardia, renal failure, atrioventricular (AV) node blocking, shock, and hyperkalemia. It constitutes a vicious circle in which the accumulation of pharmacologically active compounds and hyperkalemia lead to hemodynamic instability and heart failure., Case Presentation: A 66-year-old Caucasian female patient was admitted to the emergency department presenting with fatigue and bradycardia. Upon examination, the patient was found to be anuric and hypotensive. Laboratory investigations revealed metabolic acidosis and hyperkalemia. Clinical evaluation suggested signs of digoxin toxicity, with serum digoxin concentrations persistently elevated over several days. Despite the implementation of antikalemic measures, the patient's condition remained refractory, necessitating renal dialysis and administration of digoxin immune fab., Conclusion: Bradycardia, renal failure, atrioventricular (AV) node blocking, shock, and hyperkalemia syndrome is a life-threatening condition that requires prompt management. It is important to also consider potential coexisting clinical manifestations indicative of intoxication from other pharmacological agents. Specifically, symptoms associated with the accumulation of drugs eliminated via the kidneys, such as digoxin. These manifestations may warrant targeted therapeutic measures., (© 2024. The Author(s).)

Rectus sheath hematoma (RSH) is a rare clinical entity caused by the rupture of the epigastric arteries or the rectus abdominal muscle itself, leading to the accumulation of blood in this location. It is a potentially fatal condition that mimics an acute belly condition. It is crucial to identify and treat it early to avoid unfavourable outcomes. We present the case of an 85-year-old woman hospitalized for pneumonia and respiratory failure who developed refractory hypovolemic shock associated with an abdominal mass. Computed tomography with angiography was performed, which detected the presence of a large hematoma of the wall of both rectus abdominal. (www.actabiomedica.it).

Background: Shock in drug poisoning is a life-threatening condition and current management involves fluid resuscitation and vasopressor therapy. Management is limited by the toxicity of high-dose vasopressors such as catecholamines. Clinical trials have shown the efficacy of angiotensin II as an adjunct vasopressor in septic shock. The aim of this review is to assess the use of angiotensin II in patients with shock secondary to drug overdose., Methods: Medline (from 1946), Embase (from 1947) and PubMed (from 1946) databases were searched until July 2021 via OVID. Included studies were those with shock due to drug poisoning and received angiotensin II as part of their treatment regimen. Of the 481 articles identified, 13 studies (case reports and scientific abstracts) were included in the final analysis with a total of 14 patients. Extracted data included demographics, overdose drug and dosage, angiotensin II dosage, time of angiotensin II administration, haemodynamic changes, length of hospital stay, mortality, complications, cardiac function and other treatment agents used., Results: Thirteen studies were included consisting of 6 case reports, 6 scientific abstracts and 1 case series. Overdose drugs included antihypertensives (n = 8), psychotropics (n = 4), isopropanol (n = 1) and tamsulosin (n = 1). Out of a total of 14 patients, 3 patients died. Ten patients had their haemodynamic changes reported. In terms of MAP or SBP changes, three patients (30%) had an immediate response to angiotensin II, four patients (40%) had responses within 30 min, one patient (10%) within two hours and two patients (20%) did not have their time reported. Two patients were shown to have direct chronotropic effects within 30 min of angiotensin II administration. The median hospital stay for patients was 5 days (IQR = 4). The time from overdose until angiotensin II administration ranged from 5 to 56 h. Other vasopressors used included phenylephrine, noradrenaline, adrenaline, vasopressin, dobutamine, dopamine, methylene blue and ephedrine. A median of 3 vasopressors were used before initiation of angiotensin II. Twelve patients received angiotensin II as their final treatment., Conclusions: Angiotensin II may be useful as an adjunct vasopressor in treating shock secondary to drug poisoning. However, the current literature consisted of only very low-quality studies. To truly assess the utility of angiotensin II use in drug-induced poisoned patients, further well-designed prospective studies are required., (© 2022. The Author(s).)

This study analysed the clinical patterns and outcomes of elderly patients with organophosphate intoxication. A total of 71 elderly patients with organophosphate poisoning were seen between 2008 and 2017. Patients were stratified into two subgroups: survivors (n = 57) or nonsurvivors (n = 14). Chlorpyrifos accounted for 33.8% of the cases, followed by methamidophos (12.7%) and mevinphos (11.3%). Mood, adjustment and psychotic disorder were noted in 39.4%, 33.8% and 2.8% of patients, respectively. All patients were treated with atropine and pralidoxime therapies. Acute cholinergic crisis developed in all cases (100.0%). The complications included respiratory failure (52.1%), aspiration pneumonia (50.7%), acute kidney injury (43.7%), severe consciousness disturbance (25.4%), shock (14.1%) and seizures (4.2%). Some patients also developed intermediate syndrome (15.5%) and delayed neuropathy (4.2%). The nonsurvivors suffered higher rates of hypotension (P < 0.001), shock (P < 0.001) and kidney injury (P = 0.001) than survivors did. Kaplan-Meier analysis indicated that patients with shock suffered lower cumulative survival than did patients without shock (log-rank test, P < 0.001). In a multivariate-Cox-regression model, shock was a significant predictor of mortality after intoxication (odds ratio 18.182, 95% confidence interval 2.045-166.667, P = 0.009). The mortality rate was 19.7%. Acute cholinergic crisis, intermediate syndrome, and delayed neuropathy developed in 100.0%, 15.5%, and 4.2% of patients, respectively.

The emerging role of BRAF and MEK tyrosine-kinase inhibitors has shown new opportunities of treatment for patients with advanced melanoma and BRAF mutations. Its use is associated with some toxicities, as pyrexia, that clinicians may not be familiarized with. We present the case of a patient diagnosed with stage IV melanoma BRAF Val600E mutated who was started on dabrafenib and trametinib and developed three severe episodes of fever, hypotension and acute phase reactants elevation during the first 3 months of therapy, in the absence of microbiological demonstration of infection. The episodes were initially managed as a septic shock with broad-spectrum antibiotics and vasoactive drugs, while treatment with dabrafenib and trametinib was withheld. After two subsequent dose reduction of dabrafenib, the patient did not experience new episodes of fever., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Vancomycin (VCM) is effective in fighting Gram-positive bacteria related severe infections, and topical application of VCM powder is widely used in orthopedic surgery to prevent wound infection. However, VCM could lead to infusion rate-dependent antibody-and complement-independent anaphylaxis reaction by inducing direct release of histamine., Case Presentation: We retrospectively analyzed seven cases of severe hypotension and shock during wound closure or immediately after orthopedic surgery with unidentifiable reasons. We found that these cases were all associated with local application of VCM powder during wound closure process. Two patients experienced sudden cardiac arrest. Most of the cases (6/7) with circulatory collapse were discharged without severe sequelae. While one case with application of 3 g VCM developed cardiac arrest and remained in a coma due to hypoxic-hypoxic encephalopathy. The clinical presentations and the time of the shock onset were considered to be related with a VCM induced anaphylaxis reaction. However, as this was a retrospective study, and there was no laboratory examination performed, the conclusion was made upon differential diagnosis based on clinical manifestations and the timing of the shock., Conclusions: Local application of VCM may not be as safe as was once believed and may lead to a related anaphylaxis. As VCM induced infusion-rate dependent, non-IgE mediated anaphylaxis is characterized by delayed occurrence, severe hypotension and even circulatory collapse, surgeons and anesthesiologists should be extra vigilant during and after VCM application.

Transient spinal shock is a previously unreported complication of intrathecal contrast. A 63-year-old man presented with the chief complaint of worsening back pain. Computed topography of lumbar spine without contrast showed a lytic lesion. After international normalized ratio (INR) correction, patient was sent for CT myelogram. After intrathecal contrast injection, the patient dropped his blood pressure profoundly and developed clinical manifestations of spinal shock. Emergent intravenous bolus fluids were initiated resulting in improvement in blood pressure. Patient's spinal shock resolved within hours. CT myelogram was normal except previously known lytic lesion. It was concluded that the transient shock was most likely due to contrast injection. We believe that this is the first reported case of transient spinal shock following CT myelogram using water-soluble iodinated non-ionic contrast agent administered intrathecally., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Presenting a case of acute theophylline and salbutamol overdose with distributive shock. Twenty one years old lady presented with history of consumption of 3 gram of theophylline and 40 mg of salbutamol. On admission she had altered sensorium with the systolic blood pressure of 60 mmHg, unrecordable diastolic blood pressure and heart rate of 147/min. Investigations revealed severe metabolic acidosis, hypokalemia, hypocalcemia which was managed by intravenous fluids, vasopressors, infusion of injection calcium gluconate and injection potassium chloride. As her hemodynamic status did not improve, she has been initiated on 1.5 mL/kg of lipid emulsion as bolus and then 0.5 mL/kg/h as infusion. Her hemodynamic status improved gradually and she was discharged in 24 h. Lipid emulsion had been used in local anesthetics and many tablet overdoses. In this patient timely administration of lipid emulsion resulted in early recovery of shock., (Copyright © 2020. Published by Elsevier Inc.)

Introduction: Although medication toxicity is uncommon in neonates, there are several medications used in this population that pose a risk. Phenytoin has an increased risk of toxicity given its narrow therapeutic window and variations in drug elimination., Case Report: We describe the case of a 3-day-old male infant who developed cardiovascular collapse secondary to severe phenytoin toxicity (max phenytoin level 86 μg/mL) and was placed on extracorporeal membrane oxygenation support (ECMO). Several ancillary treatments were utilized in an attempt to decrease serum phenytoin concentrations and limit toxicity including albumin boluses, phenobarbital administration, intravenous lipid infusion, and folic acid supplementation., Discussion: Although uncommon, drug toxicity should be considered in patients with acute changes who are exposed to medications with potential toxicity. With elevated levels of phenytoin, the half-life can be prolonged resulting in longer exposure to elevated levels of the drug as seen in our patient. This case report highlights the importance of ECMO utilization for cardiac support in neonates with medication toxicity and other potential ancillary treatments to decrease serum phenytoin concentrations.

Background: Sugammadex is a reversal agent for non-depolarizing neuromuscular blockers and widely used worldwide on account of its rapid and effective reversal from neuromuscular blockade, despite its advantages, multiple cases of sugammadex-induced anaphylactic shock have been reported., Case: A 42-year-old man developed anaphylactic shock in the postanesthesia care unit. Initially, sugammadex was suspected as the causative agent, but an intradermal skin test revealed negative results. A further skin test was performed with sugammadex-rocuronium complex that yielded positive results., Conclusions: Anesthesiologists and healthcare providers should be aware of the possibility of anaphylaxis from the sugammadex-rocuronium complex, as well as from sugammadex or rocuronium alone.

Background: Ticagrelor as a P2Y12 receptor antagonist is recommended in patients with acute coronary syndrome without a primary cardiosurgical therapy. Severe relevant side effects, especially anaphylactic reactions, have not yet been described in the current literature., Case Presentation: We describe the first documented case in the current literature with a severe anaphylaxis after ticagrelor in a 76-year-old male patient with ST-elevation myocardial infarction. The diagnosis seems to be objectivated by the observed time-related life-threatening event after repetitive administration of ticagrelor and the rapid stabilization after adequate anaphylactic treatment., Conclusion: This case should raise the awareness that a supposedly safe drug can still cause an anaphylactic shock., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (Georg Thieme Verlag KG Stuttgart · New York.)

The detection of drug-induced anaphylactoid reactions remains a global challenge,still lacking mature and reliable animal models or test methods. Therefore,the purpose of this paper is to explore and establish the test methods and evaluation standards for anaphylactoid reactions that apply to injection drugs. Based on the anaphylactoid reaction symptoms of mice induced by intravenous injection drugs C48/40 and Tween 80,a list of systemic anaphylactoid reaction symptoms in mice was sorted out and an evaluation standard of anaphylactoid reactions symptoms was established by applying symptom intensity coefficient K( that can represent these verity of anaphylactoid reaction symptoms) and its calculation formula Accordingly,histamine,tryptase,and Ig E were selected as blood indicators of anaphylactoid reactions,so that a test method combining symptoms evaluation and blood makers detection was established.This test method could be used to evaluate the characteristics of anaphylactoid reactions: coefficient K,blood histamine levels were highly and positively correlated with C48/80 and Tween 80 dose; The log value of histamine was highly and positively correlated with K; tryptase level may rise,or remain steady,or drop,possibly associated with the characteristics of the tested object and time for blood taking; and Ig E level would drop or remain steady,but it would not rise,which can be clearly distinguished from type I allergic reactions. On this basis,tiohexol,iopromide,paclitaxel,Xuesaitong Injection,Shuanghuanglian Injection and Shengmai Injection were used to investigate the applicability. The testing results showed a high degree of consistency with the actual clinical situation. The results suggest that the method of systemic anaphylaxis test in mice has high sensitivity,specificity and good consistency with clinical practice.It is suggested to be further validated and popularized.

Background: A woman in her fifties was admitted to hospital with decreased awareness and circulatory failure. She had been treated with left atrial cryoablation a few weeks before admission and had been cardioverted a few days after the procedure because of relapse of atrial fibrillation., Case Presentation: On admission, the patient had systolic blood pressure of 80 mm Hg and an ECG with broad QRS-complexes at 380 ms. We suspected intoxication and she was intubated to administer activated charcoal after gastric lavage. She was cardiovascularly unstable and in need of intravenous infusion of noradrenaline and adrenaline. Further investigations at her home suggested that she had poisoned herself with 4-5 g flecainide, 0.3 g oxazepam and 0.5 g meclizine. After administration of 500 mmol sodium bicarbonate and 5 mmol calcium chloride, the QRS complexes narrowed temporarily. On day 2, due to sustained bradycardia and hypotension despite receiving adrenergic medications, a temporary pacemaker was implanted, leading to improved heart rate and blood pressure. She experienced several complications including hypertensive pulmonary oedema, atrial fibrillation, extensively prolonged QT interval because of polypharmacy and Takotsubo cardiomyopathy. She was discharged from the hospital in good health on day 17. At a follow-up visit at the outpatient clinic 12 weeks later, cardiac function had normalised. The QT interval was now normal; however, there were persistent T-wave inversions in leads I, aVL and V4-6., Interpretation: Flecainide blocks sodium channels in cardiomyocytes. Intoxication with flecainide is rare, with mortality rates of about 10 %. Sodium bicarbonate in larger doses has been reported to stabilise patients with flecainide intoxication due to modification of the binding of flecainide to sodium receptors in cardiomyocytes, and due to alkalisation which makes flecainide detach from sodium receptors. Our patient had a temporary effect with narrowing of QRS complexes after receiving sodium bicarbonate. She also showed a beneficial effect from implantation of a temporary pacemaker, although earlier case reports have described problems with high thresholds and capture failure.

Clinical and pathological case files of lethal snakebites were reviewed from the Magway Region General Hospital, Magway, Myanmar, over a five-year period (January 2013 December 2017). A total of 2069 postmortem examinations were performed which included 84 cases of lethal snake bite (4.1%). The annual numbers ranged from 10 out of a total of 268 autopsies in 2013 (3.7%), to 31 out of a total of 501 autopsies in 2016 (6.2%). There were 54 males (64%) and 30 females (36%) (M:F = 1.9:1; age range 5-75yrs, mean 33yrs). The most common time for lethal envenomation was August (16/84-19%), the middle of the monsoon season. 45/84 (54%) had acute renal failure, 27/84 (32%) were shocked, and the remaining 12/84 (14%) had disseminated intravascular coagulation. Twenty cases (24%) died within 24 h after envenomation. Fang marks were identified on the legs (either right or left) in 73/84 cases (87%) and on the arms in five cases (6%). The predominant findings at autopsy were of acute renal injury (82/84-98%), pituitary haemorrhage/necrosis (36/84-43%), and adrenal gland haemorrhage (30/84-36%). Despite the reduction in fatalities over the years snakebite from Russell's viper in particular remains an important contributor to mortality in central Myanmar despite the availability of antivenom., (Copyright © 2019. Published by Elsevier Ltd.)

Extended-release dipyridamole plus aspirin is widely used for secondary prevention of ischemic stroke, although the molecular pharmacodynamics of dipyridamole are not completely determined. Adverse effects of fixed-dose combination of aspirin and dipyridamole include headache, bleeding, and gastrointestinal events. Previously, intravenous infusion of dipyridamole in cardiac stress testing has been associated with cardiogenic shock and pulmonary edema. Herein, we report a case study of a 72-year-old man, presented with a transient ischemic attack who suffered a circulatory collapse after an oral dose of 200 mg extended-release dipyridamole. The possible molecular mechanisms of dipyridamole on the cardiovascular system are reviewed. This is the first case report of a circulatory collapse induced by an oral intake of dipyridamole., (Copyright © 2018. Published by Elsevier Inc.)

Background: Sepsis is a multi-system syndrome that remains the leading cause of mortality and critical illness worldwide, with hemodynamic support being one of the cornerstones of the acute management of sepsis. We used an ovine model of endotoxemic shock to determine if 0.9% saline resuscitation contributes to lung inflammation and injury in acute respiratory distress syndrome, which is a common complication of sepsis, and investigated the potential role of matrix metalloproteinases in this process., Methods: Endotoxemic shock was induced in sheep by administration of an escalating dose of lipopolysaccharide, after which they subsequently received either no fluid bolus resuscitation or a 0.9% saline bolus. Lung tissue, bronchoalveolar fluid (BAL) and plasma were analysed by real-time PCR, ELISA, flow cytometry and immunohistochemical staining to assess inflammatory cells, cytokines, hyaluronan and matrix metalloproteinases., Results: Endotoxemia was associated with decreased serum albumin and total protein levels, with activated neutrophils, while the glycocalyx glycosaminoglycan hyaluronan was significantly increased in BAL. Quantitative real-time PCR studies showed higher expression of IL-6 and IL-8 with saline resuscitation but no difference in matrix metalloproteinase expression. BAL and tissue homogenate levels of IL-6, IL-8 and IL-1β were elevated., Conclusions: This data shows that the inflammatory response is enhanced when a host with endotoxemia is resuscitated with saline, with a comparatively higher release of inflammatory cytokines and endothelial/glycocalyx damage, but no change in matrix metalloproteinase levels.

Background: Severe systemic reactions resembling septic shock have been described following trimethoprim-sulfamethoxazole (TMP-SMX) administration. Nearly all cases described in the literature occurred in HIV-infected patients., Case Presentation: We present a 42-year-old woman with a history of systemic lupus erythematosus (SLE) who was admitted to the Intensive Care Unit (ICU) twice with fever and circulatory shock after taking a dose of TMP-SMX 800-160 mg. She had no respiratory distress, urticarial rash or eosinophilia on presentation. Infectious workup during both admissions was negative and treatment with antibiotics, steroids and vasopressors was de-escalated with clinical improvement. She was found to be HIV negative, however, labs revealed a low CD4+ count., Conclusions: TMP-SMX can rarely result in a severe, non-anaphylactic circulatory shock; if initially unrecognized, patients may undergo repeat drug exposure with an associated high morbidity risk. While more commonly reported in HIV individuals, this case demonstrates that TMP-SMX related circulatory shock can occur in a HIV negative patient.

Our goal was to provide comprehensive data on the effectiveness of ketamine in refractory status epilepticus (RSE) and to describe the potential consequences of long-term ketamine infusion. Ketamine, an N-methyl D-aspartate (NMDA) receptor antagonist, blocks excitatory pathways contributing to ongoing seizure. While ketamine use is standard in anaesthetic induction, no definitive protocol exists for its use in RSE, and little is known about its adverse effects in long-term, high-dose administration. We present two cases of RSE that responded rapidly to ketamine infusion, both with fatal outcomes secondary to metabolic acidosis and cardiovascular collapse. We performed a systematic review of the application and consequences of ketamine use in RSE. PubMed, Ovid, MEDLINE and PMC were searched for articles describing ketamine treatment for RSE according to a predetermined search strategy and inclusion criteria. The systematic review revealed wide discrepancies in ketamine dosing (infusion maintenance dose range 0.0075-10.5 mg/kg/hour), but good outcomes in medically managed RSE (75% of studies reported moderate or complete seizure control in adults, 62.5% in paediatrics). Additionally, literature review elucidated a potentially causal relationship between prolonged ketamine infusion and both cardiovascular and metabolic dysregulation. Ketamine is effective in RSE by antagonising excitotoxic NMDA receptors. However, there is high variability in ketamine dosing and scarce data on its safety in long-term infusion. Metabolic acidosis and haemodynamic instability associated with the use of long-term, high-dose ketamine infusions must be of concern to clinicians administering ketamine to critically ill patients.

Objective To investigate the impact of goal-oriented hemoperfusion (HP) with monitoring of the paraquat concentration on the prognosis of patients with acute paraquat poisoning. Methods This prospective observational study involved patients with acute paraquat poisoning admitted from March 2012 to September 2015. The patients received either goal-oriented or routine HP. All other treatments were the same between the two groups. The primary endpoint was 28-day mortality after poisoning. The secondary endpoints were the incidence of organ dysfunction within 7 days and 7-day mortality. Results Eighty-four patients were enrolled (49 in the control group and 35 in the goal-oriented group). The two groups were similar in terms of clinical characteristics. There was no significant difference in the incidence of organ dysfunction between the two groups within 1 week of admission. Mortality on day 7 was significantly lower in the goal-oriented than control group, but there was no difference on day 28. However, 28-day mortality was significantly lower in the goal-oriented group among patients with an oral dose of ≤50 ml. Conclusions HP with monitoring of the urine paraquat concentration as goal-oriented therapy can reduce the early mortality of paraquat poisoning.

Metformin-associated lactic acidosis (MALA) is a rare complication among patients who are diabetic, commonly presenting with non-specific findings, and developing mostly among those with other risk factors for lactic acidosis. We report the development of MALA in a 67-year-old man with diabetes who presented with progressive abdominal pain and bloody diarrhoea. On presentation the patient was in shock, with signs suggestive of peritonitis, and with severe lactic acidosis, renal failure and non-specific findings on abdominal CT. Neither the patient nor family could provide details of his home pharmaceuticals. Circulatory resuscitation with intravenous crystalloids and vasopressors was commenced, along with empiric broad-spectrum antibiotics. Emergent laparotomy did not show pathological findings. Emergent haemodialysis, initiated postoperatively, resulted in rapid resolution of shock and lactic acidosis. A list of patient's medications, provided afterwards by the family, included metformin. Microbiological studies remained negative and renal function normalised by the time of patient's hospital discharge after 9 days., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Spleen tyrosine kinase (Syk), a non-receptor tyrosine kinase, plays an important role in allergic diseases and inflammation. Syk triggers several intracellular signalling cascades including Toll-like receptor signalling to activate inflammatory responses following fungal infection but the role of this enzyme in zymosan (ZYM)-induced non-septic shock and its impacts on hypotension and inflammation in rats is not well understood. This study was conducted to determine the effects of Syk inhibition on ZYM-induced alterations in the expression and/or activities of Syk, inhibitor ĸB (IĸB)-α, and nuclear factor-ĸB (NF-ĸB) p65. We also examined the effect of Syk inhibition on inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, and tumour necrosis factor (TNF)-α, and activity of myeloperoxidase (MPO) that contribute to hypotension and inflammation. Administration of ZYM (500 mg/kg, ip) to male Wistar rats decreased blood pressure and increased heart rate. These changes were associated with increased expression and/or activities of Syk, NF-κB p65, iNOS and COX-2 and decreased expression of IκB-α with enhanced levels of nitrite, nitrotyrosine, 6-keto-PGF 1α , and TNF-α and activity of MPO in renal, cardiac and vascular tissues. ZYM administration also elevated serum and tissue nitrite levels. The selective Syk inhibitor BAY 61-3606 (3 mg/kg, ip) given 1 hour after ZYM injection reversed all of these changes induced by ZYM. These results suggest that Syk/IĸB-α/NF-ĸB pathway activation contributes to hypotension and inflammation caused by the production of vasodilator and proinflammatory mediators in the zymosan-induced non-septic shock model., (© 2017 John Wiley & Sons Australia, Ltd.)

Background: Treatments of patients with amlodipine (a calcium channel blocker, CCB) overdose/poisoning remain challenging and death is certain if not intervened timely. Furthermore, for the society, the availability and common use of this drug can drive more vulnerable groups, especially children, towards an accidental/suicidal poisoning., Case Report: Herein, we describe the case of an 18 year-old-adolescent girl who took 150 mg of amlodipine with the suicidal intentions and was admitted in our hospital approximately 4-hours after the ingestion. She developed circulatory failure and tachypnea. Decontamination, calcium, glucagon, and dual vasopressors were started, however, persistent hypotension led to the initiation of hyperinsulinemiceuglycemia therapy. She recovered fully and discharged without any complications in few days. This case educates not only about the successful use of variant drugs in the management of CCB overdose/poisoning, but also calls for the attention of the society for a safe storage of often used drugs, especially away from the children/adolescents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Objective: The aim of this report is to describe a case of atrial fibrillation and shock precipitated by deliberate self-poisoning with theophylline., Clinical Presentation and Intervention: An 85-year-old male with severe theophylline intoxication in a suicide attempt was admitted with severe cardiac arrhythmia and shock; despite poor prognosis, he fully recovered gradually after proper diagnosis and treatment. Theophylline is a rather forgotten medication; thus, intoxication is not usually considered among the etiologies of potentially treatable cardiologic emergencies, especially when its use is intentionally concealed., Conclusion: This case highlights the importance of identifying a comprehensive medication history using all available sources of information as early as possible in an emergency department presentation., (© 2018 The Author(s) Published by S. Karger AG, Basel.)

Rationale: Tolvaptan (TLV) is a new vasopressin type 2 receptor antagonist effective in patients with heart failure (HF). Accumulating evidences have revealed that treatment with TLV does not alter the blood pressure significantly., Patient Concerns: An 84-year-old man was diagnosed with acute exacerbation of chronic HF due to ischemic cardiomyopathy, arrhythmia, mitral and aortic regurgitation. Treatment with TLV increased the urine volume and improved the dyspnea. After 4 days use of TLV (3.75 mg QD, 7.5 mg QD, 7.5 mg QD, and 15 mg QD, respectively), decrease in blood pressure to less than 90/60 mmHg was observed continuously and the lowest blood pressure was 80/37 mmHg. He was apyretic and felt only thirsty. Central venous pressure was 12 cmH2O., Diagnoses: Because no other medications were changed and no signs of hypovolemic, septic, allergic, or cardiac shock were detected, we suspected an adverse reaction to TLV., Intervention: Intravenous hydration was performed with 250 mL of normal saline., Outcomes: His blood pressure increased gradually and the statue of hypotention lasted for 14 hours. The dose of TLV was decreased to 7.5 mg/d from the next day to discharge. During this period, his blood pressure was stable at about 125/60 mmHg., Lessons: TLV has side effect of severe hypotension that is consistent with its physiological activity. The dose should be increased gradually to achieve the desired effect, while attention should be paid to potential drug interactions., (Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: Inquiries relating to ibuprofen overdose have more than tripled in the last ten years in our poison control center. Although the vast majority of cases have a benign clinical course, there are few severe or even fatal cases present with refractory circulatory failure., Case Presentation: We describe a case of a 48 year-old male with suicidal mono-ingestion of approximately 72 g ibuprofen. Despite an initial rapid spontaneous drop in the total ibuprofen plasma concentration (IPC) from 550 to 275 mcg/mL within the first 5 h after admission, the patient developed a circulatory failure, refractory to aggressive fluid resuscitation and high doses of vasopressors. Due to ibuprofen's favorable pharmacokinetics (>95% bound to albumin, low volume of distribution) and in the absence of specific therapeutic alternatives thereby avoiding escalating vasopressor doses, therapeutic plasma exchange (TPE) for extracorporeal elimination of ibuprofen was considered as a therapeutic rescue option. An improvement of hemodynamics with a significant reduction of vasopressors was observed with TPE-initiation. However, neither the observed IPC-profile nor a pharmacokinetic (PK) simulation provided evidence for a quantitative effective elimination of ibuprofen by TPE. Based on PK-modeling we calculated an overall ibuprofen half-life of 17.2 h for the entire observation period over 5 days., Conclusions: To our knowledge this is the first report of a severe ibuprofen-mono intoxication treated with TPE and providing serial IPCs over a period of five days, indicating an estimated fivefold overall-elimination half-life of 17.2 h. Despite TPE clinically improved persistent hemodynamic instability, this procedure was neither consistent with the observed IPC-profile nor correlated with a meaningful quantitative elimination of ibuprofen.

Although edema toxin (ETx) and lethal toxin (LTx) contribute to Bacillus anthracis shock and lethality, the mechanisms underlying their cardiovascular effects are unclear. We have previously shown that ETx but not LTx inhibited phenylephrine-stimulated contraction of aortic rings prepared from healthy rats and that adefovir, a selective inhibitor of ETx cAMP production, blocked this effect. Here, we examined arterial function in rats that received 24-h ETx or LTx infusions. Compared with control rats, ETx reduced mean arterial pressure (MAP) and survival over 48 h ( P ≤ 0.0003) and increased plasma cAMP at 4, 24, and 48 h ( P < 0.0001) and nitric oxide (NO) at 24 and 48 h ( P ≤ 0.01). Compared with control animals, at 24- and 48-h phenylephrine stimulation of aortic rings from ETx animals produced decreased maximal contractile force (MCF; P = 0.05 and 0.006) and in vivo phenylephrine infusion in ETx animals produced decreased proportional increases in MAP ( P < 0.0001 and P = 0.05). In ETx-treated animals, compared with placebo-treated animals, adefovir treatment prevented all lethality ( P = 0.01), increased MAP ( P ≤ 0.0001), decreased plasma and aortic tissue cAMP at 24 and 48 h, respectively ( P ≤ 0.03), and plasma NO at both times ( P ≤ 0.004), and increased phenylephrine-stimulated increases in MCF in aortic rings and MAP in vivo at 48 h ( P = 0.02). LTx decreased MAP and survival also, but it did not alter the response to phenylephrine of MCF in aortic rings prepared from LTx animals or of MAP in vivo. In conclusion, in rats, hypotension and lethality are associated with reduced arterial contractile function with ETx but not LTx and adefovir improves ETx-induced hypotension and lethality. NEW & NOTEWORTHY The most important aspects of the present study are the findings that 1 ) in vivo challenge with anthrax edema but not lethal toxin depresses arterial contractile function measured both ex vivo and in vivo and 2 ) adefovir inhibits the effects of edema toxin on arterial hypotension and improves survival with lethal dose of edema toxin challenge., (Copyright © 2017 the American Physiological Society.)

Aim: The rate of hypersensitivity reactions to platinum salts (PS) and taxanes (TX) is on the increase. The aim of our study was to show the value of skin testing and efficacy of rapid drug desensitization., Patients and Methods: This was a retrospective study conducted between January 2007 and February 2016 in patients consulting for immediate or delayed hypersensitivity to PS and TX. Skin prick tests (pT) and intradermal reaction tests (IDR) were performed according to the ENDA/EAACI recommendations. We used a 12-step desensitization protocol for rapid drug desensitization., Results: Among the 99 patients included (30 men, 69 women, age 60.4) PS were suspected in 86 cases and taxanes in 13 cases. Skin tests were positive in 25 patients (7 pT, 18 IDR), 23 for platinum salts and 2 for taxanes. Rapid drug desensitization was proposed in 50 patients and performed in 33 (30 PS and 3 TX), proved effective in 29 patients, with protocol adaptation being necessary in 7 cases, and was ineffective in 4 patients. The skin tests for the latter 4 patients were positive. Seventy-five percent of patients with positive skin tests to oxaliplatin presented hypersensitivity reactions during desensitization, i.e. twice as many as patients having negative skin tests. Two percent of patient for PS and 7% for TX had cross reactivity., Conclusion: This French study confirms the efficacy of the 12-step protocol that allows patients to receive chemotherapy after hypersensitivity reaction. Skin test permits the detection of cross-reactions but their practice must be considered based on the patient's history., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

High dose insulin euglycemia therapy - an important addition to the treatment arsenal in severe toxic myocardial depression Fifty-nine patients who developed hemodynamic symptoms necessitating treatment with vasopressors or inotropes after poisoning with calcium channel blockers (CCB) and beta blockers (BB) between January 2010 and August 2016 were identified by a search of the Poisons Information Centre database. In-hospital circulatory arrest occurred in 16/59 (27 %) and the mortality rate was 7/59 (12 %). Two cases of analytically confirmed combined BB and CCB poisoning were treated with high dose insulin therapy (HIE) and are presented in detail. The outcome in both cases was good. They were the only cases in the study population treated with HIE, although signs of cardiac dysfunction was present in 55/59 (93%) and in all cases of circulatory arrest. Animal studies and international clinical cases indicate that HIE is a safe and effective method to improve cardiac function in CCB and BB poisoning, and its implementation in Sweden may improve the outcome for this at risk population.

TNF is a master proinflammatory cytokine whose pathogenic role in inflammatory disorders can, in certain conditions, be attributed to RIPK1 kinase-dependent cell death. Survival, however, is the default response of most cells to TNF stimulation, indicating that cell demise is normally actively repressed and that specific checkpoints must be turned off for cell death to proceed. We identified RIPK1 as a direct substrate of MK2 in the TNFR1 signalling pathway. Phosphorylation of RIPK1 by MK2 limits cytosolic activation of RIPK1 and the subsequent assembly of the death complex that drives RIPK1 kinase-dependent apoptosis and necroptosis. In line with these in vitro findings, MK2 inactivation greatly sensitizes mice to the cytotoxic effects of TNF in an acute model of sterile shock caused by RIPK1-dependent cell death. In conclusion, we identified MK2-mediated RIPK1 phosphorylation as an important molecular mechanism limiting the sensitivity of the cells to the cytotoxic effects of TNF.

The use of intravenous lipid emulsion (ILE) therapy as antidote in systemic toxicity of certain agents has gained widespread support. There are increasing data suggesting use of ILE in reversing from local anesthetic-induced systemic toxicity severe, life-threatening cardiotoxicity, although findings are contradictory. Efficiency of ILE was demonstrated in animal studies in the treatment of severe impairment of cardiac functions, via a mechanism for trapping lipophilic drugs in an expanded plasma lipid compartment ("lipid sink"). In patients with hemodynamic compromise and/or cardiovascular collapse due to lipid-soluble agents, ILE may be considered for resuscitation in the acute setting by emergency physicians. The most common adverse effects from standard ILE include hypertriglyceridemia, fat embolism, infection, vein irritation, pancreatitis, electrolyte disturbances and allergic reactions. The advantages of ILE include an apparent wide margin of safety, relatively low cost, long shelf-life, and ease of administration.

Calcium channel blockers (CCBs) have a narrow therapeutic index, and their intake in excess is associated with a critical clinical presentation of sustained hypotension and non-cardiogenic pulmonary edema, which are difficult to treat. Unfortunately, the available treatments fail to resuscitate a significant number of patients poisoned by CCBs, rendering them the main cardiovascular drugs involved in death due to overdose. Importantly, in all cases reported until now in the literature, CCB intoxication was known at the time of patients' presentation and the medical challenge solely consisted of the therapeutic approach. In this case report, we describe our experience in treating a 72-year-old patient with recurrent episodes of sustained hypotension refractory to crystalloid and vasoconstrictor infusions. Prolonged pharmacologic support and intermittent sessions of hemofiltration induced stabilization and recovery. The results of an extensive diagnostic workup to elucidate the cause were unfruitful. The recurrent and paroxysmal nature of the clinical presentation along with its incidence after the patient left the protected setting of the hospital led the diagnostic approach to search for a possible external factor, which was shown to be, after toxicological investigation, unintentional amlodipine intoxication., (Copyright © 2016 Hellenic Society of Cardiology. Published by Elsevier B.V. All rights reserved.)

We present the case of a 47-year-old man with schizophrenia who developed acute and persistent circulatory failure after receiving injections of paliperidone palmitate. We measured blood concentrations of paliperidone and performed resection of hip tissues, where paliperidone palmitate was suspected to be present, in order to reduce the side effects. Unfortunately, the resection could not save the patient from prolonged and severe side effects and he died of multiple organ failure. We suggest that resection of the tissues suspected of containing paliperidone palmitate can help reduce its severe side effects. However, identifying the site of injection is essential., (Copyright © 2017 Elsevier Inc. All rights reserved.)

We report a case of sudden shock during caesarean section under combined spinal epidural anesthesia. The patient was a 29-year-old woman. During the operation vital signs had been almost stable until a female-baby was born. But after the delivery of the placenta, the patient developed an episode of coughing and dyspnea followed by unconsciousness and bradycardia. She was given adrenaline and intubated, appearing ventricular fibrillation on a EKG. Cardiopulmonary resuscitation was immediately started and sinus rhythm returned. Hypotension followed and a small dose of adrenaline was infused for three days. She made good progress and was discharged without significant sequela. Cardiopulmonary collapse type of amniotic fluid embolism (AFE) is doubtful in this case. The necessity of rapid and appropriate treatment for emergency obstetric cases was discussed.

Our objective was to determine how circulatory failure develops following systemic administration of potassium cyanide (KCN). We used a noninhaled modality of intoxication, wherein the change in breathing pattern would not influence the diffusion of CN into the blood, akin to the effects of ingesting toxic levels of CN. In a group of 300 to 400 g rats, CN-induced coma (CN i.p., 7 mg/kg) produced a central apnea within 2 to 3 min along with a potent and prolonged gasping pattern leading to autoresuscitation in 38% of the animals. Motor deficits and neuronal necrosis were nevertheless observed in the surviving animals. To clarify the mechanisms leading to potential autoresuscitation versus asystole, 12 urethane-anesthetized rats were then exposed to the lowest possible levels of CN exposure that would lead to breathing depression within 7 to 8 min; this dose averaged 0.375 mg/kg/min i.v. At this level of intoxication, a cardiac depression developed several minutes only after the onset of the apnea, leading to cardiac asystole as PaO2 reached value approximately 15 Torr, unless breathing was maintained by mechanical ventilation or through spontaneous gasping. Higher levels of KCN exposure in 10 animals provoked a primary cardiac depression, which led to a rapid cardiac arrest by pulseless electrical activity (PEA) despite the maintenance of PaO2 by mechanical ventilation. These effects were totally unrelated to the potassium contained in KCN. It is concluded that circulatory failure can develop as a direct consequence of CN-induced apnea but in a narrow range of exposure. In this "low" range, maintaining pulmonary gas exchange after exposure, through mechanical ventilation (or spontaneous gasping), can reverse cardiac depression and restore spontaneous breathing. At higher level of intoxication, cardiac depression is to be treated as a specific and spontaneously irreversible consequence of CN exposure, leading to a PEA., Competing Interests: The authors declare that they have no conflict of interest.

The danger of anaphylaxis, a rare but life threatening complication of general anesthesia (GA) can be summarized in two: 1. General Anesthesia masks the typical early signs of allergy which can be seen in an awake patient. 2. Anaphylaxis during GA manifests mostly as circulatory/ventilatory failures which can be interpreted as adverse effects of anesthetics or surgery and this can lead to critical delay of effective therapy. A 19-year-old female admitted for posterior spinal fusion and instrumentation (the 5th surgery in patient's life) desaturated seconds after intubation. Cardiopulmonary resuscitation (CPR) was started and the absence of cutaneous signs along with a loud holosystolic murmur were questioned. The patient was promptly resuscitated and allergy to rocuronium was confirmed by intradermal tests 6weeks later. Factors influencing decision making and potential etiology of the newly heard holosystolic murmur during anaphylaxis are discussed., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Animal studies and human case reports show promise in using lipid rescue to treat refractory calcium channel antagonist toxicity. However, the majority of research and clinical experience has focused on non-dihydropyridine agents. Thus, we sought to investigate the value of lipid emulsion (ILE) therapy for dihydropyridine-induced shock. This IACUC-approved study utilized seven swine that were sedated with alpha-chloralose, mechanically ventilated, and instrumented for drug delivery and hemodynamic measures. After stabilization and basal measures, nifedipine (0.01875 mg/kg/min) was infused until imminent cardiac arrest (seizure, end tidal CO2 < 10 mmHg, bradydysrhythmia, or pulseless electrical activity). Animals then received a 7 mL/kg bolus of 20% lipid emulsion via central catheter. Lipid circulation was visually confirmed by the presence of fat in peripheral arterial blood. Hemodynamics were continuously monitored until 10 min after lipid bolus. Surviving animals were euthanized. Pre- and post-lipid treatment parameters were analyzed using the Wilxocon signed rank test (p <0.05 significant). Nifedipine toxicity was characterized by vasodilatory hypotension, impaired vascular contractility, and tachycardia with terminal bradycardia. The median time to imminent cardiac arrest from start of nifedipine infusion was 218 min. Lipid treatment did not improve hemodynamics or restore circulation in any animal. There was no benefit from lipid rescue in this model of nifedipine toxicity. Further study of ILE for dihydropyridine toxicity is warranted but initial animal model results are not promising., Competing Interests: Compliance with Ethical Standards Funding Funding for this research was provided by the Carolinas Healthcare Foundation and the John A. Marx, MD Fund. Conflicts of Interest The authors have no conflicts of interest to disclose.

The purpose of this case report is to educate fellow anesthesiologists of a complicated differential diagnosis for sudden cardiovascular collapse after spinal anesthesia. We report a case where anaphylaxis occurred while under spinal anesthesia and resulted in difficult resuscitation. A 58-year-old woman undergoing bilateral knee replacements under spinal anesthesia experienced sudden seizure and cardiovascular collapse from acute anaphylactic shock while administering a cephalosporin. Local anesthetic toxicity, high spinal, and anaphylaxis were considered due to overlapping of symptoms. Successful resuscitation required prolonged advanced cardiac life support with substantially larger doses of epinephrine. Anaphylactic shock under spinal anesthesia is an acute and life-threatening complication, worsened by the spinal-induced sympathectomy, and aggressive resuscitation is warranted. Despite the presence of overlapping symptoms of differential diagnoses, rapid identification of the cause of cardiovascular collapse is crucial given that resuscitation treatment modalities may conflict. Timing of antibiotic administration should be adjusted for spinal anesthesia cases to allow time to detect possible anaphylaxis., (Copyright © 2016 Elsevier Inc. All rights reserved.)