Prolonged Use of Intravenous Lipid Emulsion in a Severe Tricyclic Antidepressant Overdose

Introduction

Intravenous lipid emulsion (ILE) resuscitation is now frequently being used for severe overdoses due to lipophilic drugs. However, the optimal dose, duration, and safety are still unclear.

Case Report

A patient with refractory cardiovascular collapse following an amitriptyline overdose was treated with ILE with initial improvement. Instability recurred after ILE discontinuation and lipid therapy was restarted, but high-dose treatment was complicated by severe lipemia. A low-dose infusion was instead used, and the patient did not experience further toxicity despite amitriptyline levels in the toxic range for 21 days. He survived to discharge without long-term sequelae.

Discussion

A low-dose infusion of ILE was well tolerated and may have successfully prevented recurrent toxicity in a case of severe tricyclic antidepressant overdose.     

Asystole Immediately Following Intravenous Fat Emulsion for Overdose

Use of intravenous fat emulsion (IFE) for the treatment of poisoned patients in extremis is increasing. Little literature exists describing failures and complications of IFE. We describe two cardiac arrests temporally associated with IFE. A 50-year-old woman presented after ingesting 80 total tablets of metoprolol 25 mg and bupropion 150 mg. Bradycardia and hypotension were refractory to calcium salts, catecholamines, and high dose insulin (HDI). With a pulse of 40/min and mean arterial pressure (MAP) of 30 mmHg, 100 mL of 20 % IFE was given; within 30 s, brady-asystolic arrest occurred. Pulses returned after 3 min of CPR. The patient died on hospital day 4 of multisystem organ failure (MSOF). A 53-year-old man presented after ingesting of 3,600 mg of diltiazem and 1,200 mg of propranolol. Bradycardia and hypotension were refractory to calcium salts, catecholamines, HDI, bicarbonate, and atropine. With a pulse of 30/min and a MAP of 40 mmHg, 150 mL of 20 % IFE was given; within 1 min, a brady-asystolic arrest occurred. Pulses returned after 6 min of CPR. The patient died on hospital day 7 of MSOF. Reported cases of IFE failures or potential complications are sparse. This report adds only case experience, not clarity. We report two cardiac arrests that were temporally associated with IFE.     

Treatment of Pieris Ingestion in Goats with Intravenous Lipid Emulsion

Seven goats and one ram presented with clinical signs including regurgitation, obtundation, anorexia, apparent pain, and bloat. The animals had escaped from their barn, and it was discovered that they had ingested leaves of Pieris japonica, Japanese pieris, a grayanotoxin-containing plant. Animals were treated with antibiotics, calcium borogluconate, B vitamins, and activated charcoal within the first 24-h postexposure, which was followed by the recovery of the ram and two goats and the death of two goats. Approximately 36 h after Japanese pieris ingestion, one of the three remaining anorectic goats was dosed with intravenous lipid emulsion (ILE). This goat recovered within a few hours. The remaining two goats were given ILE the next day and appeared to recover, but one died a week later of aspiration pneumonia.     

Complications Following Antidotal Use of Intravenous Lipid Emulsion Therapy

The primary objective is to identify and describe the complications associated with the use of intravenous lipid emulsion (ILE) therapy as an antidote for lipophilic drug toxicity. This study is a retrospective chart review of patients treated with ILE at two academic medical centers between 2005 and 2012. Based on previously reported complications, we hypothesized that pancreatitis, ARDS, and lipemia-induced laboratory interference might occur. Clinical definitions of these complications were defined a priori. Subjects treated with ILE who did not develop at least one complication were excluded. A total of nine patients were treated with ILE during the study period, six of whom experienced potential complications as a result of the ILE. Two patients developed pancreatitis, and four patients had lipemia-induced interference of interpretation of laboratory studies, despite ultracentrifugation. Laboratory interference precluded one patient from being an organ donor. Three patients developed ARDS; although temporally associated, a causal relationship between ILE and the development of ARDS cannot be clearly established. As ILE is increasingly used for less severe cases of drug toxicity, clinicians should be aware of potential complications associated with its use. A risk–benefit assessment for the use of ILE should be implemented on a case-by-case basis.     

Cardiotoxic Overdose Treated with Intravenous Fat Emulsion and High-Dose Insulin in the Setting of Hypertrophic Cardiomyopathy

High-dose insulin (HDI) and intravenous fat emulsion (IFE) are used in overdoses, although rarely combined. To our knowledge, IFE therapy has not been reported in overdoses of diltiazem, metoprolol and amiodarone. We report a severe overdose of these drugs treated with HDI and IFE in a patient with hypertrophic cardiomyopathy (HCM). We also discuss the potential clinical implications of the inotropic effects of HDI in the setting of HCM and the use and efficacy of IFE in this overdose.     

酮咯酸异丙酯静脉注射脂肪乳剂的处方前研究

目的 对酮咯酸前体药物酮咯酸异丙酯进行处方前研究。方法 合成酮咯酸异丙酯,建立HPLC-UV方法并进行方法学验证。对酮咯酸异丙酯溶解度、油水分配系数和降解规律等理化性质进行研究,考察加速降解实验中的原料稳定性和原辅料相容性。结果 酮咯酸异丙酯在水中难溶（溶解度52.66 μg·mL^-1）,但可以和油相混溶,其LogP值为3.95±0.03。酮咯酸异丙酯的分析方法线性关系良好,仪器精密度良好（RSD<2%）,回收率较高（>99.5%）。在给定条件下,酮咯酸异丙酯的溶液稳定性随pH和温度升高而降低。酮咯酸异丙酯可在大鼠血浆和肝匀浆溶液中迅速降解,例如,在50%大鼠血浆溶液或20%肝匀浆溶液中,酮咯酸异丙酯的降解速率常数（k_obs）分别为0.51 min^-1和0.15 min^-1。酮咯酸异丙酯在高温、高湿环境下较稳定,但对光照敏感;原辅料相容性同样证实了这一点。结论 酮咯酸异丙酯在溶解度、分配系数、降解规律、原料稳定性和原辅料相容性方面,具备了制成静脉注射乳剂的适宜条件,为开发新型酮咯酸注射剂提供了实验依据。     

In Vitro Studies Indicate Intravenous Lipid Emulsion Acts as Lipid Sink in Verapamil Poisoning

Intravenous lipid emulsion (ILE), a component of parenteral nutrition, consists of a fat emulsion of soy bean oil, egg phospholipids, and glycerin. Case reports suggest that ILE may reverse hypotension caused by acute poisoning with lipophilic drugs such as verapamil, but the mechanism remains unclear. The methods used are the following: (1) measurement of ILE concentration in serum samples from a patient with verapamil poisoning treated with ILE, (2) measurement of free verapamil concentrations in human serum mixed in vitro with increasing concentrations of ILE, and (3) measurement of murine ventricular cardiomyocyte l-type Ca²⁺ currents, intracellular Ca²⁺, and contractility in response to verapamil and/or ILE. Maximum patient serum ILE concentration after infusion of 1 L ILE over 1 h was approximately 1.6 vol%. In vitro GC/MS verapamil assays showed that addition of ILE (0.03–5.0 vol%) dose-dependently decreased the free verapamil concentration in human serum. In voltage-clamped myocytes, adding ILE to Tyrode’s solution containing 5 μM verapamil recovered l-type Ca²⁺ currents (I_Ca). Recovery was concentration dependent, with significant I_Ca recovery at ILE concentrations as low as 0.03 vol%. ILE had no effect on I_Ca in the absence of verapamil. In field-stimulated intact ventricular myocytes exposed to verapamil, adding ILE (0.5 %) resulted in a rapid and nearly complete recovery of myocyte contractility and intracellular Ca²⁺. Our in vitro studies indicate that ILE acts as a lipid sink that rapidly reverses impaired cardiomyocyte contractility in the continued presence of verapamil.     

Prolonged Laboratory Interference After Administration of Intravenous Lipid Emulsion Therapy

Background

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.

Case Report

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.

Case Discussion

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.

Conclusion

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.     

Formulation Design and Optimization for the Improvement of Nystatin-Loaded Lipid Intravenous Emulsion

Nystatin (NYS) is a polyene macrolide with broad antifungal spectrum restricted to topical use owing to its toxicity upon systemic administration. The aims of this work were the design, development, and optimization of NYS-loaded lipid emulsion for intravenous administration. A closed circuit system was designed to apply ultrasound during the elaboration of the lipid intravenous emulsions (LIEs). Additionally, a comparison with the commercially available Intralipid® 20% was also performed. Manufacturing conditions were optimized by factorial design. Formulations were evaluated in terms of physicochemical parameters, stability, release profile, and antimicrobial activity. The average droplet size, polydispersity index, zeta-potential, pH, and volume distribution values ranged between 192.5 and 143.0 nm, 0.170 and 0.135, ? 46 and ? 44 mV, 7.11 and 7.53, 580 and 670 nm, respectively. The selected NYS-loaded LIE (NYS-LIE54) consisted of soybean oil (30%), soybean lecithin (2%), solutol HS® 15 (4%), and glycerol (2.25%) was stable for at least 60 days. In vitro drug release studies of this formulation suggested a sustained-release profile. Equally, NYS-LIE54 showed the best antimicrobial activity being higher than the free drug. Thus, it could be a promising drug delivery system to treat systemic fungal infections.     

Clinical Experience with Intravenous Lipid Emulsion for Drug-Induced Cardiovascular Collapse

Intravenous lipid emulsion (ILE) is an emerging therapy for refractory cardiotoxicity due to lipid-soluble drugs. The purpose of this study was to assess survival to hospital discharge, effects on hemodynamic parameters, and adverse event occurrence for patients who were treated with ILE as part of the resuscitative effort for drug-induced cardiotoxicity. This is a multicenter retrospective chart review of inpatients at three tertiary referral medical centers receiving ILE for drug-induced cardiotoxicity between November 2007 and March 2009. Nine cases with drug-induced cardiovascular collapse, defined as cardiac arrest or refractory shock, were selected for review if patients received either bolus or infusion of ILE in any combination. No interventions were done. The main outcome measures were survival to hospital discharge, effect on hemodynamic parameters, and adverse event. Hemodynamic vital signs (heart rate, systolic blood pressure, diastolic blood pressure, calculated mean arterial pressure [MAP]) were measured before administration of ILE and up to five measurements (if available) were recorded after administration of ILE. Attribution of adverse events was determined by assignment of Naranjo adverse drug reaction (ADR) likelihood score (3) with adjudication of three medical toxicologists; disagreements were settled by majority consensus. Of nine cases identified based on inclusion criteria (three cardiac arrest, six refractory shock), five (55%) survived to hospital discharge. ILE regimens were bolus alone in five patients and bolus plus infusion in four patients. Hemodynamic trends in response to ILE demonstrated no difference in MAP immediately pre- and post-administration of ILE (p = NS). Administration of infusion (versus boluses alone) did not demonstrate a statistically significant improvement in MAP. Adverse events due to ILE therapy that were categorized as “possible” or “probable” based on Naranjo scores included lipemia, digit amputation, lung injury, renal failure, and deep venous thrombosis. ILE administered to patients with drug-induced cardiovascular collapse was associated with 55% survival but with clinically significant adverse effects. At this time, ILE should be restricted to cardiotoxicity involving cardiac arrest or refractory shock until further prospective studies can better evaluate risks and benefits of ILE therapy.     

Intravenous Lipid Emulsion Alters the Hemodynamic Response to Epinephrine in a Rat Model

Intravenous lipid emulsion (ILE) is an adjunctive antidote used in selected critically ill poisoned patients. These patients may also require administration of advanced cardiac life support (ACLS) drugs. Limited data is available to describe interactions of ILE with standard ACLS drugs, specifically epinephrine. Twenty rats with intra-arterial and intravenous access were sedated with isoflurane and split into ILE or normal saline (NS) pretreatment groups. All received epinephrine 15 μm/kg intravenously (IV). Continuous mean arterial pressure (MAP) and heart rate (HR) were monitored until both indices returned to baseline. Standardized t tests were used to compare peak MAP, time to peak MAP, maximum change in HR, time to maximum change in HR, and time to return to baseline MAP/HR. There was a significant difference (p = 0.023) in time to peak MAP in the ILE group (54 s, 95 % CI 44–64) versus the NS group (40 s, 95 % CI 32–48) and a significant difference (p = 0.004) in time to return to baseline MAP in ILE group (171 s, 95 % CI 148–194) versus NS group (130 s, 95 % CI 113–147). There were no significant differences in the peak change in MAP, peak change in HR, time to minimum HR, or time to return to baseline HR between groups. ILE-pretreated rats had a significant difference in MAP response to epinephrine; ILE delayed the peak effect and prolonged the duration of effect of epinephrine on MAP, but did not alter the peak increase in MAP or the HR response.     

Pilot Trial of Intravenous Lipid Emulsion Treatment for Severe Nifedipine-Induced Shock

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.     

Intravenous Lipid Emulsion Given to Volunteers does not Affect Symptoms of Lidocaine Brain Toxicity

Intravenous lipid emulsion has been suggested as treatment for local anaesthetic toxicity, but the exact mechanism of action is still uncertain. Controlled studies on the effect of lipid emulsion on toxic doses of local anaesthetics have not been performed in man. In randomized, subject‐blinded and two‐phase cross‐over fashion, eight healthy volunteers were given a 1.5 ml/kg bolus of 20% Intralipid^® (200 mg/ml) or Ringer's acetate solution intravenously, followed by a rapid injection of lidocaine 1.0 mg/kg. Then, the same solution as in the bolus was infused at a rate of 0.25 ml/kg/min. for 30 min. Electroencephalography (EEG) was recorded, and 5 min. after lidocaine injection, the volunteers were asked to report subjective symptoms. Total and un‐entrapped lidocaine plasma concentrations were measured from venous blood samples. EEG band power changes (delta, alpha and beta) after the lidocaine bolus were similar during lipid and during Ringer infusion. There were no differences between infusions in the subjective symptoms of central nervous system toxicity. Lidocaine was only minimally entrapped in the plasma by lipid emulsion, but the mean un‐entrapped lidocaine area under concentration–time curve from 0 to 30 min. was clearly smaller during lipid than Ringer infusion (16.4 versus 21.3 mg × min/l, p = 0.044). Intravenous lipid emulsion did not influence subjective toxicity symptoms nor affect the EEG changes caused by lidocaine.     

Intravenous Lipid Emulsion Does Not Augment Blood Pressure Recovery in A Rabbit Model of Metoprolol Toxicity

Intravenous lipid emulsion (ILE) has been demonstrated to be an effective treatment for systemic toxicity associated with local anaesthetics and increasingly non-local anaesthetic agents of high lipophilicity. Effect for ILE has been demonstrated in animal models of propranolol poisoning; however, any benefit for ILE in more hydrophilic β-blockers remains uncertain. We determined to examine the effect of ILE on haemodynamic recovery following induction of hypotension with the relatively hydrophilic β-blocker, metoprolol. Twenty sedated, invasively monitored and mechanically ventilated adult New Zealand white rabbits underwent metoprolol infusion to mean arterial pressure (MAP) 60% baseline. Intravenous rescue was given according to the following groups: 6 mL/kg 20% lipid emulsion or 6 mL/kg 0.9% saline solution over 4 min. Haemodynamic parameters were obtained in 15 min. MAP was 70 (interquartile range (IQR), 58–82) mmHg saline group and 79 (IQR, 72–89) mmHg ILE group at baseline, and 38 (IQR, 33–40) mmHg saline group and 41 (IQR, 40–43) mmHg ILE group, respectively, following metoprolol infusion. No statistically significant difference between ILE and saline-treated groups was observed in MAP, or pulse rate, at any time point following rescue therapy. ILE was not effective in reversal of metoprolol-induced hypotension in this rabbit model. These findings lend inferential support for the ‘lipid sink’ as principal mechanism for the beneficial effect observed with ILE administration in other models of lipophilic β-blocker-induced toxicity.     

维通静脉注射乳安全性研究

目的：对维通静脉注射乳（WIE）进行安全性检查。方法用豚鼠进行过敏性实验,用小鼠进异常毒性实验,用家兔进行刺激性和溶血性实验研究维通静脉注射乳安全性。结果 WIE未引起豚鼠的变态反应,未引起家兔血红细胞溶血性反应,未引起小鼠异常毒性反应。结论本方法生产的维通静脉注射液性质安全,具有一定的应用价值。     

含药脂肪乳剂的靶向作用研究进展

作为药物载体的脂肪乳剂由于其自身毒性小,能减小药物的毒性和副作用,增加药物疗效,并具有良好的靶向作用,从而在临床上逐渐得到应用。综述了含药脂肪乳剂作为被动靶向制剂和主动靶向制剂两方面的应用进展。     

TC-1静脉脂肪乳剂的制备

目的 研制和生产TC-1静脉脂肪乳剂,以期为临床提供解救高血压危象的新型药物制剂。方法 处方配比为TC-1 0.5 mg·mL-1、精制蛋黄卵磷脂1.2%、甘油2.2%。注射用大豆油20%;通过初乳制备、高压匀化、灌装封口、热压灭菌等工序制得TC-1静脉脂肪乳注射液,并在（5±2）℃条件下考察制剂6个月内的稳定性。结果 3批小批量试验的检验结果,用动态光散射法测定平均粒径〈0.3 μm、粒度分布均匀、无〉1 μm粒子,稳定性均符合中国药典2010年版及日本药局方的要求。结论 确定了超高压微射流均质机-MiniDeBEE制备含药静脉脂肪乳的关键设备条件、工艺参数,解决了工程配套问题,所取得的成果有利于脂肪乳剂的生产。TC-1静脉脂肪乳注射液的成功研制,为含药静脉脂肪乳的制备及稳定性研究提供了一套切实可行的方法。