Nearly Fatal Hydroxychloroquine Overdose Successfully Treated with Midazolam, Propofol, Sodium Bicarbonate, Norepinephrine, and Intravenous Lipid Emulsion

Tricyclic antidepressants (TCAs) are highly lipophilic medications used to treat posttraumatic stress disorder and chronic pain. Intravenous lipid emulsion (ILE) is a recent antidote for lipophilic drug overdose with unclear effectiveness. ILE has been studied in TCA overdose in small animals, and cases are reported in humans, but controlled studies in a larger animal model are lacking. Given the high lipophilicity of amitriptyline, a TCA, the hypothesis was that ILE would be more effective than the standard antidote sodium bicarbonate in improving amitriptyline-induced hypotension. The objective was to determine if ILE improved hypotension (defined by a mean arterial pressure [MAP] < 60% baseline) compared to sodium bicarbonate for amitriptyline overdose in a critically ill porcine model. In this prospective, randomized, controlled trial, 24 female Sus scrofa swine weighing 45 to 55 kg were infused with amitriptyline at 0.5 mg/kg/min until the MAP reached 60% of baseline values. Animals were randomized to the experimental treatment group (ILE 7 mL/kg bolus, then 0.25 mL/kg/min) or the standard treatment group (sodium bicarbonate 2 mEq/kg plus an equal volume of saline). The primary outcome was a 50% improvement in MAP after ILE administration. We continuously monitored heart rate (HR), systolic blood pressure (sBP), MAP, and cardiac output. Electrocardiograms were recorded every 15 minutes. Serum pH, pCO2 , bicarbonate, lactate, and electrolytes were measured. Amitriptyline levels were measured by liquid chromatography/tandem mass spectrometry. Statistical methods used to detect a difference in MAP between the two treatment groups included repeated-measures analysis of variance, adjusted for treatment, time, and the interaction of treatment by time. A sample size of 12 animals per group provided a power of 0.8 and an alpha of 0.05 to detect a 50% difference in MAP. There was no difference at baseline between ILE and sodium bicarbonate groups in mean HR, sBP, MAP, or cardiac output. Mean amounts of amitriptyline to reach hypotension and time to hypotension were similar between groups. After hypotension there was no difference between groups for mean HR, sBP, MAP, or cardiac output. The median time from hypotension to death was greater for the sodium bicarbonate group (10 minutes [IQR = 6 to 61 minutes] vs. 5 minutes [IQR = 4.5 to 6 minutes] for the ILE group; p = 0.003), but overall survival was not different. One ILE and four sodium bicarbonate pigs survived. Additionally, no difference was detected in QRS intervals between the two groups. The mean (±SD) amitriptyline level in the lipid layer was 3.34 (±2.12) μg/mL, and in the aqueous layer, 4.69 (±2.44) μg/mL. The ILE fatty layer contained 38.2% of total measurable amitriptyline, while the aqueous layer contained 53.6%. Intravenous lipid emulsion treatment failed to improve amitriptyline-induced hypotension when compared to the standard treatment of sodium bicarbonate in a large animal model of severe TCA overdose. Larger groups with better survival may yield different results from the high mortality observed in this pilot study. Similar amounts of amitriptyline were found in the aqueous and lipid layers. These conclusions are limited to a single ILE regimen.

Hydroxychloroquine Toxicity Management: A Literature Review in COVID-19 Era.

Pancreatitis and laboratory interference are rarely reported complications of intravenous lipid emulsion (ILE) therapy. We report a case of significant laboratory interference after ILE administration. A 43-year-old female was admitted to the hospital after an unwitnessed ingestion of propranolol, tramadol, zolpidem, and alprazolam. She was intubated and treated with intravenous normal saline, insulin/glucose, and norepinephrine infusions due to hypotension. Two bolus doses and one maintenance dose of 20 % ILE were administered. Beginning approximately 2 h after ILE administration, laboratory assays were unable to be performed due to the presence of lipemia. The patient developed refractory hypotension and was transferred to a tertiary care center. Upon admission to the ICU, the patient received one additional bolus of 20 % ILE. Laboratory assays were again attempted but were unable to be adequately performed due to a pinkish-white discoloration of the patient's blood. Percutaneous femoral extracorporeal membrane oxygenation (ECMO) was initiated, but laboratory interference noted with the arterial blood gas analyzer prevented the analysis of oxygenation. The patient's hemodynamic condition did not improve; she expired 31 h after initial admission. In one previous report, centrifugation was effective in removing more than 90 % of glycerol-banked triglycerides, thus minimizing lipid interference with laboratory assays. We noted persistent laboratory interference for more than 20 h after ILE administration, despite ultracentrifugation of specimens. Clinicians should be aware that ILE administration may cause significant and prolonged interference with laboratory assays, which may affect the monitoring of critically ill patients.

Introduction. In cardiovascular collapse from diltiazem poisoning, extracorporeal membrane oxygenation (ECMO) may offer circulatory support sufficient to preserve endogenous hepatic drug clearance. Little is known about patient outcomes and diltiazem toxicokinetics in this setting. Case Report. A 36-year-old woman with a history of myocardial bridging syndrome presented with chest pain for which she self-medicated with 2.4 g of sustained release diltiazem over the course of 8 hours. Hemodynamics and mentation were satisfactory on presentation, but precipitously deteriorated after ICU transfer. She was given fluids, calcium, vasopressors, glucagon, high-dose insulin, and lipid emulsion. Due to circulatory collapse and multiorgan failure including ischemic hepatopathy, she underwent transvenous pacing and emergent initiation of venoarterial ECMO. The peak diltiazem level was 13150 ng/mL (normal 100–200 ng/mL) and it remained elevated at 6340 ng/mL at hour 90. Unfortunately, the patient developed multiple complications which resulted in her death on ICU day 9. Conclusion. This case describes the unsuccessful use of ECMO for diltiazem intoxication. Although past reports suggest that support with ECMO may facilitate endogenous diltiazem clearance, it may be dependent on preserved hepatic function at the time of cannulation, a factor not present in this case.

To the Editor: We read with much interest Levine et al.’s retrospective review of complications associated with the administration of intravenous lipid emulsion (ILE) therapy as a treatment for drug toxicity [1]. They report pancreatitis and adult respiratory distress syndrome following the administration of ILE. Another potential but less reported complication of ILE therapy may be deep venous thrombosis (DVT). We recently published a case report on a 30-year-old patient who developed an acute upper extremity DVT following ILE therapy for wide complex tachycardia and hypotension following an ingestion of diphenhydramine [2]. At the time of this occurrence, we had never encountered this complication following ILE administration at our institution and were not familiar with similar reports in the literature. We are aware that fat overload is a known complication of high-dose fat emulsion and can result in multiple complications including fat embolism [3]; however, this is generally a delayed event [4]. We also know that ILE can lead to thrombophlebitis [5]. While the development of a DVT could have been a coincidence, DVT formation is listed as a potential complication of ILE therapy in a review of data from the Toxicology Investigators’ Consortium (ToxIC) registry [6]. The review of the ToxIC registry demonstrated that three out of nine patients (33 %) that received ILE therapy developed DVTs. The authors of the manuscript attempted to judge the association between ILE and the adverse events using the Naranjo scale. They gave DVT a score of 1, which means that there was a possible association. It is not mentioned if DVTs were located in the limb where ILE was being infused or, if the treating physicians thought the acute DVT, was associated with the ILE. Our patient was not included as a part of this review. Given the novelty of ILE and relative lack of experience with this therapy, we believe that it is important to make clinicians aware of this possible association as DVT is a potentially life-threatening condition. While we still lack definitive proof that ILE causes DVT, we do wonder if there is an association and if it could be related to how it is administered. Central venous access (if available) may be preferable to giving ILE peripherally as was done with our patient. The rate of the infusion of the initial bolus could also be related to DVT formation. Lastly if more occurrences of DVT following ILE administration are reported, should this change what is already a somewhat ambiguous threshold for its administration?

The Emerging Role of Bivalirudin for Therapeutic Anticoagulation in Patients With Coronavirus Disease 2019 Requiring Extracorporeal Membrane Oxygenation Support: Is It Time to Change the Routine Practice?

Tricyclic antidepressant (TCA) overdose is a leading cause of death among intentional overdoses. Intravenous lipid emulsion therapy is an emerging antidote for local anesthetic toxicity, and there is animal evidence that lipid therapy may be efficacious in TCA overdose. Furthermore, case reports in humans have described the use of lipid therapy to reverse the toxicity of other lipophilic drugs. Here we report a 25-year-old female presenting with coma and hemodynamic instability following intentional ingestion of amitriptyline. She had multiple episodes of pulseless wide-complex tachycardia despite conventional treatment with chest compressions, cardioversion, lidocaine, epinephrine, norepinephrine, magnesium sulphate, sodium bicarbonate, activated charcoal, and whole bowel irrigation. Twenty percent lipid emulsion was administered intravenously (an initial 150 mL bolus, followed by an infusion at 16 mL/h and a second bolus of 40 mL) over 39 hours (total dose 814 mL) yet resulted in no dramatic changes in hemodynamics or level of consciousness. However, there was a decrease in the frequency of wide-complex tachycardia during the lipid emulsion infusion and a recurrence of wide-complex tachycardia shortly after the infusion was stopped. The patient was discharged from the intensive care unit 11 days later with no lasting physiologic sequelae.

PICO question Is soybean oil-based intravenous lipid emulsion (IVLE) therapy more effective than olive oil-based (ClinOleic IVLE therapy) for reducing time to recovery in cats with permethrin toxicosis? Clinical bottom line Category of research question Treatment The number and type of study designs reviewed Five case reports and one randomised clinical trial Strength of evidence Weak Outcomes reported Soybean oil-based and ClinOleic IVLE therapies can be used safely as adjuvant treatments to reduce time to recovery in cats with permethrin intoxication. However, the evidence collected suggests that soybean oil-based IVLE therapy is better in reducing the recovery time after permethrin toxicosis as compared to ClinOleic IVLE therapy Conclusion The overall findings showed that the average recovery time after soybean oil-based IVLE therapy across patients with permethrin intoxication was 8.5 hours and the average time to recovery after olive oil-based emulsions (ClinOleic therapy) was 39 hours. This may suggest that soybean oil-based formulations are a better option for reducing the recovery time in cats after permethrin toxicity. Dermal decontamination, supportive care, muscle relaxers, and anticonvulsant drugs are examples of recommended treatments before the administration of any intralipid therapies and must be used based on the clinical signs of each patient How to apply this evidence in practice The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient’s circumstances and owners’ values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources. Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care.

ABSTRACTBackground: Following national and regional recommendations, intravenous lipid emulsion (ILE) has become established in clinical practice as a treatment for acute local anesthetic (LA) toxicity, although evidence of efficacy is limited to animal studies and human case reports. A collaborative lipid emulsion workgroup was therefore established by the American Academy of Clinical Toxicology to review the evidence on the effect of ILE for LA toxicity. Methods: We performed a systematic review of the literature published through 15 December 2014. Relevant articles were determined based on pre-defined inclusion and exclusion criteria. Pre-treatment experiments, pharmacokinetic studies not involving toxicity and studies that did not address antidotal use of ILE were excluded. Results: We included 113 studies and reports. Of these, 76 were human and 38 animal studies. One publication included both a human case report and an animal study. Human studies included one randomized controlled crossover trial involving 16 healthy volunteers. The subclinical LA toxicity design did not show a difference in the effects of ILE versus saline. There was one case series and 73 case reports of ILE use in the context of toxicity (83 patients) including CNS depression or agitation (n = 45, 54%), seizures (n = 49, 59%), hypotension, hypertension, EKG changes, arrhythmias (n = 39, 47%), cardiac arrest (n = 18, 22%), cardiopulmonary resuscitation, and/or requirement for endotracheal intubation and/or mechanical ventilation (n = 35, 42%). There were 81 (98%) survivors including 63 (76%) with no reported sequelae from the LA poisoning or ILE, although the presence or absence of sequelae was not reported in 15 (18%) cases. Animal studies included 29 randomized controlled studies, three observational studies, five case series, and one case report; bupivacaine was used in 29 of these reports (76%). Of 14 controlled experiments in animals, eight showed improved survival or time to return of spontaneous circulation and five no benefit of ILE versus saline or non-ILE treatments. Combining ILE with epinephrine improved survival in five of the six controlled animal experiments that studied this intervention. The studies were heterogeneous in the formulations and doses of ILE used as well as the doses of LA. The body of the literature identified by this systematic review yielded only a very low quality of evidence. Conclusion: ILE appears to be effective for reversal of cardiovascular or neurological features in some cases of LA toxicity, but there is currently no convincing evidence showing that ILE is more effective than vasopressors or to indicate which treatment should be instituted as first line therapy in severe LA toxicity.

Introduction. Intravenous lipid emulsion (ILE) has been shown to ameliorate toxicity from lipophilic xenobiotics, attributed in part through sequestration to circulating lipid droplets (sink). We postulated additional benefit with plasma exchange therapy undertaken subsequent to lipid injection, hypothesising enhanced blood carriage of lipophilic toxin to increase yield when combined with an extracorporeal method of elimination. Methods. Instrumented rabbits underwent clomipramine infusion at 3.2 mg/kg/min to target mean arterial pressure (MAP) of 50% baseline, then continuously at 2 mg/kg/min to death or 90 min. Resuscitation with saline (Control), sodium bicarbonate (BIC), ILE, or lipid emulsion plus cycled plasma exchange (LEPE), was commenced on attaining target MAP. Results. Greater survival was observed in animals receiving lipid emulsion from both LE and LEPE groups (Control median 12.0 [IQR 10.5–20] min, BIC median 30 [IQR 19–33] min, LE 85 [IQR 30–90] min, LEPE 90 min; P < 0.0001). No difference was observed in MAP, Heart Rate, or Electrocardiograph QRS duration between surviving LE and LEPE animals at 90 min. Mean plasma exchange of 52%circulating plasma volume returned only 0.04% of the administered clomipramine load in LEPE group animals. Conclusions. Infusion of lipid emulsion resulted in greater survival in this rabbit model of intravenous clomipramine toxicity. Plasma exchange performed in conjunction with administration of lipid emulsion failed to result in significant extracorporeal clomipramine elimination. Intravascular lipid sequestration of clomipramine appears an inadequate sole explanation for the beneficial effects of lipid emulsion.

Introduction:Esophagectomy is a major surgery with a high degree of catabolic and post-surgical inflammatory response accompanied by high morbidity and significant mortality. Post-surgical nutritional support via enteral administration of ω-3 fatty acids has been seen to be effective although its bad tolerance. There are few clinical trials with parenteral ω-3 fatty acids in these patients. We propose to investigate the effect of combining a parenteral fish oil lipid emulsion with the standard enteral nutrition (EN) support.Materials and methods:Prospective, single-center, randomized, double-blind study in esophagectomized patients, and treated after surgery with parenteral lipid emulsions of ω-3 fatty acids or a mixture of ω-6 long-chain triglycerides/short-chain triglycerides 50%. These emulsions will be added to the standard nutritional support in continuous infusion until 5 days of treatment have been completed. Patients will be randomized 1:1:1 in Group A receiving 0.4 g/kg/d of fish-oil lipid emulsion and 0.4 g/kg/d of a lipid emulsion mixture of ω-6 long-chain fatty acids (LCT) plus medium-chain fatty acids (MCT) (total dose of 0.8 g/kg/d of lipid emulsion); Group B receiving 0.8 g/kg/d of fish oil lipid emulsion and Group C receiving 0.8 g/kg/d of LCT/MCT emulsion.The main objective is to determine whether 5 days administration of intravenous ω-3 fatty acid lipid emulsion is effective in normalizing interleukin-6 levels compared with LCT/MCT emulsions, and whether a 0.8 g/kg/d dose is more effective than 0.4 g/kg/d. Secondary outcomes include other inflammatory markers such as C-reactive protein, tumor necrosis factor alpha and interleukin-10, and parameters of morbidity, safety, nutrition and mortality.Samples will be collected at the time when surgery is indicated and on days 0, 1, 3, 5 and 21 to determine inflammatory, nutritional, hepatic and safety parameters. In addition, clinical follow-up will be continued throughout the hospital admision and up to 1 year after surgery.Discussion:Studies of ω-3 fatty acids administered parenterally in esophagectomized patients are scarce. This study proposes to investigate the effect of combining fish-oil lipid emulsions administered parenterally with EN support. Potential benefits include fast incorporation of lipids to the cellular membranes and to the inflammatory cascade, and the use of only 1 pharmaconutrient.Trial Registration:FAR-NP-2017-01 EudraCT number: 2016-004978-17.https://reec.aemps.es/reec/public/detail.html searching the EudraCT number.Version Identifier:Version 2, 08/06/2017.

To recognize cardiac stun syndrome and electromechanical dissociation in patients receiving extracorporeal membrane oxygenation (ECMO), and to define patients at risk. Retrospective review. Tertiary neonatal ICU. Four newborn patients with cardiorespiratory failure who developed signs of cardiac stun syndrome and electromechanical dissociation early in the ECMO course. Initially, these patients had metabolic acidosis, chest roentgenograms showing pulmonary granularity and moderate cardiomegaly, and symptoms of severe respiratory distress. Cardiac dysfunction was apparent after ECMO was begun, with poor perfusion, pale color, narrow pulse pressure, and tachycardia despite normovolemia. Within 1 to 2 hrs, electromechanical dissociation occurred manifested by the absence of pulse pressure, palpable pulse, cardiac sounds, and apical impulse while on 50% to 70% bypass. All patients survived. Patients received ECMO, calcium gluconate, sodium bicarbonate, and dobutamine. Patients with cardiac stun syndrome have symptoms similar to severe respiratory distress syndrome, and may require ECMO support. In the ECMO patient, cardiac stun syndrome and electromechanical dissociation can be confused with low circuit volume, pneumothorax, or cardiac tamponade. Early recognition of electromechanical dissociation may improve care and outcome. Cardiac stun syndrome can be treated successfully with ECMO.

Context. Although extracorporeal membrane oxygenation (ECMO) was used in many patients following its introduction in 1972, most hospitals had abandoned this experimental treatment for adult patients. Recently, improvements in the ECMO circuitry rendered it more biocompatible. The surprisingly low mortality in patients with severe acute respiratory distress syndrome who were treated with ECMO in the influenza A/H1N1 pandemic of 2009 resurrected interest in ECMO in many intensive care units around the world. Objectives. This article reviews the different techniques of ECMO, the indications, contraindications and complications of its use, its role in poisoned patients and the ethics of its use. Methods. We searched Pubmed, Toxnet, Cochrane database and Embase from 1966 to September 2012 using the search terms (‘‘extracorporeal membrane oxygenation’’, ‘extracorporeal life support’, ‘ECMO’, ‘ECLS’, ‘assist-device’, and ‘intox*’ or ‘poison*’). These searches identified 242 papers of which 116 described ECMO in conditions other than intoxications or were reviews. In total 46 publications selected for this manuscript were case reports or case series involving poisoned patients. ECMO techniques. Two types of ECMO are used: veno-venous ECMO (VV-ECMO) or veno-arterial ECMO (VA-ECMO). VV-ECMO is used for patients with severe ARDS to secure adequate oxygenation of the organs while protecting the lungs from harmful ventilation pressures or prolonged inspiratory fraction of oxygen. VA-ECMO can be used whenever the patient remains in shock despite adequate fluid resuscitation and is refractory to administration of inotropes and vasopressors. Indications. The organ support that can be applied with ECMO makes it especially useful in patients with severe poisoning as the clinical impact of the intoxication is often temporary; ECMO can be used as a ‘bridge to recovery’. Contraindications. Absolute contraindications are uncontrolled coagulopathy and severe intracranial bleeding, which precludes the use of anticoagulation therapy. Relative contraindications to ECMO include advanced age, severe irreversible brain injury, untreatable metastatic cancer, severe organ dysfunction (some suggest a Sequential Organ Failure Assessment (SOFA) score > 15), and high pressure positive pressure ventilation for more than 7 days. Complications. The most common complication of ECMO is either bleeding at the cannulation site (in VV-ECMO) or bleeding at the surgical entry site (in VA-ECMO). Overall bleeding complications currently occur in 10–36% patients, and intracranial haemorrhage is seen in up to 6% of patients. ECMO should be reserved, therefore, for the most severely ill poisoned patients with a high risk of death. ECMO in poisoned patients. There are no randomised trials of ECMO in poisoned patients with refractory shock or who have ARDS caused by an intoxication. VV-ECMO can be considered in patients with type l and ll respiratory failure. In patients with life-threatening haemodynamic instability, VA-ECMO can be considered when shock persists despite volume administration, inotropes and vasoconstrictors, and (sometimes) intra-aortic balloon counterpulsation. Typical examples include poisoning due to calcium channel antagonists, beta-blockers, tricyclic antidepressants, chloroquine and colchicine. Ethics of ECMO use. It is only ethical to use such a costly intervention (£19,252 and US$ 31,000 per quality-adjusted life year) if the treatment has a real purpose such as a ‘bridge to recovery’, a ‘bridge to transplant’, or a ‘bridge to permanent assist device’ (in the case of persistent cardiac failure). Conclusions. In the last decade, ECMO equipment has improved considerably, rendering it more biocompatible, and it has been used more frequently as an assist device for patients needing oxygenation as well as circulatory support. ECMO is considered a good salvage therapy for patients who are severely poisoned with ARDS or refractory circulatory shock.

Peripartum use of Extracorporeal Membrane Oxygenation (ECMO) in a Patient Suffering from COVID-19 Severe Acute Respiratory Distress Syndrome (ARDS): A Case Report

In this focused update, the American Heart Association provides updated guidance for resuscitation of patients with cardiac arrest, respiratory arrest, and refractory shock due to poisoning. Based on structured evidence reviews, guidelines are provided for the treatment of critical poisoning from benzodiazepines, β-adrenergic receptor antagonists (also known as β-blockers), L-type calcium channel antagonists (commonly called calcium channel blockers), cocaine, cyanide, digoxin and related cardiac glycosides, local anesthetics, methemoglobinemia, opioids, organophosphates and carbamates, sodium channel antagonists (also called sodium channel blockers), and sympathomimetics. Recommendations are also provided for the use of venoarterial extracorporeal membrane oxygenation. These guidelines discuss the role of atropine, benzodiazepines, calcium, digoxin-specific immune antibody fragments, electrical pacing, flumazenil, glucagon, hemodialysis, hydroxocobalamin, hyperbaric oxygen, insulin, intravenous lipid emulsion, lidocaine, methylene blue, naloxone, pralidoxime, sodium bicarbonate, sodium nitrite, sodium thiosulfate, vasodilators, and vasopressors for the management of specific critical poisonings.