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Intralipid emulsion rescue therapy: emerging therapeutic indications in medical practice.

Introduction

Although Intralipid emulsion rescue therapy is an approved antidote for local-anesthetic systemic toxicities, its application has been expanded and supported by case reports in recent years to include the reversal of other lipophilic drug toxicities. The documented drug classes now successfully reversed by Intralipid therapy include antiarrhythmics, anticonvulsants, antidepressants, antipsychotics, benzodiazepines, calcium channel blockers, diuretics, local anesthetics, and the benzodiazepine-agonist insomnia drugs. Although emergency medicine physicians and anesthesiologists now appreciate the widening application of Intralipid emulsion rescue therapy, other clinicians should embrace the effectiveness and expanding role of Intralipid in reversing a wide range of acute lipophilic drug toxicities. A successful case of Intralipid emulsion rescue therapy for a suicidal overdose of a calcium channel blocker refractory to standard resuscitative therapy is presented.

Report of a Case

Bologa and co-investigators described the case of an 81-year-old female who became unresponsive after ingesting a potentially lethal amount of 5.6 grams of diltiazem in a suicide attempt.1 The patient was found unconscious in her home and rushed to the closest emergency department (ED) by emergency medical services, approximately one hour after ingestion. The patient's past medical history included hypertension and ischemic heart disease. On admission to the ED, the patient was bradycardic (heart rate = 50 bpm), tachypneic (respiratory rate = 32), hypotensive (blood pressure = 80/40 mmHg), and hypoxic (transcutaneous oxygen saturation = 80% with a Glasgow Coma Scale score of 4. Arterial blood gas analysis demonstrated metabolic acidosis with pH 7.2 and bicarbonate level, 12.6 mmol/L. Resuscitative measures were immediately instituted, and the patient's trachea was intubated for mechanical ventilation. Four hours after admission, the patient remained refractory to all standard resuscitative measures, including intravenous crystalloid infusion, continuous calcium gluconate infusion, gastric lavage, orogastric activated charcoal, and continuous vasopressor support with an epinephrine infusion. Her clinical condition continued to deteriorate, and an electrocardiogram demonstrated new-onset, Mobitz II atrioventricular block.

In response to all of the failed standard resuscitative measures, Intralipid emulsion rescue therapy was initiated with a 100 ml bolus of 20% Intralipid emulsion and a subsequent infusion of 0.5 ml/kg/hr over twelve hours. Over the next twenty-four hours, the patient's hemodynamic and metabolic derangement were corrected and stabilized completely. The patient's trachea was extubated on hospital day two, and the patient was discharged on hospital day four without residual morbidity. To the authors' knowledge, this was the second reported successful reversal of diltiazem toxicity with Intralipid therapy. (1)

Discussion

This case report has described an elderly patient's toxic ingestion of 5.6 grams of the calcium channel blocker, diltiazem, with potentially fatal cardiovascular depression. (1) Toxicologists have recommended that immediate and aggressive therapeutic measures be instituted in all cases of calcium-channel blocker overdoses. (1) In this particular case, all standard resuscitative efforts failed. Intralipid emulsion therapy was instituted, reversed a potentially fatal poisoning, and contributed to a good outcome without residual neurological morbidity.

Currently, the most widely accepted mechanism of action of Intralipid emulsion rescue therapy is the lipid sink phenomenon. (2) This theory holds that Intralipid creates an intravascular lipid layer that extracts toxic drugs by diffusion from serum in the circulatory compartment to inhibit further circulation of toxins to target organs with cardiovascular and neurological depression. In addition to the lipid sink theory, Ozcan and co-investigators have proposed another theoretical mechanism of action by which Intralipid provides a substrate for increased fatty acid uptake for metabolism counteracting any inhibition of fatty acid transport by lipophilic toxins, such as local anesthetics and calcium channel blockers. (2) Regardless of its potential mechanisms of action, early Intralipid emulsion rescue therapy for most lipophilic drug toxicities may prove beneficial, especially in critical situations where standard resuscitative measures have failed.

Recent literature has described the successful reversal of ten separate drug class toxicities by Intralipid emulsion rescue therapy, including amphetamines (3), antiarrhythmics (4), anticonvulsants (5), antidepressants (5), antipsychotics (6), benzodiazepines (5), calcium channel blockers (1), diuretics (5), local anesthetics (7-9), and the benzodiazepine-agonist insomnia drugs (Table 1). (10) For non-local anesthetic overdoses, successful Intralipid rescue has been described most often in cases of antidepressant and calcium channel blocker overdoses. The antidepressant drugs successfully reversed by Intralipid include: dothiepin, amitriptyline, fluoxetine, sertraline, dosulepin, venlafaxine, and bupropion. The calcium channel blockers successfully reversed include diltiazem, as reported here, nifedipine, and verapamil.

Mulroy and other investigators have now reported the significant impact of the route of administration of local anesthetics on an increasing prevalence rates of local anesthetic systemic toxicity reactions.11-14 The prevalence of local anesthetic systemic toxicity in epidural anesthetics ranged from 1. (2-11) per 10,000 anesthetics; and the prevalence of local anesthetic systemic toxicity reactions in ultrasound-guided nerve blocks (n = 12,668) was 8 serious local anesthetic reactions per 1,000 nerve blocks. (12-14)

For non-local anesthetic overdoses, McKenzie and co-investigators reported the prevalence rate of antidepressant overdoses to be 3.26 per 10,000 administrations with selective serotonin reuptake inhibitors and tricyclic antidepressants predominating among all antidepressants, both of which have been successfully reversed by Intralipid emulsion rescue therapy. (15) Calcium channel blocker overdoses, another potential target class of drugs for Intralipid rescue, are also increasing in prevalence with St-Onge and co-investigators reporting 11,764 cases of toxicity reactions in 2011 during a systematic review of calcium channel blocker poisonings. (16)

Early recognition of local anesthetic systemic toxicities and lipophilic drug toxicities is essential for improving patient outcomes and reversing potentially fatal drug overdoses. In the setting of local anesthetic systemic toxicity, Rothschild and co-investigators note, "intralipid emulsion (ILE) should be used in local anesthetic toxicity at the onset of neurological or cardiovascular symptoms. There is no known alternative antidote for the treatment of local anesthetic toxicities resistant to standard ACLS agents." (17)

The optimal dosing of 20% Intralipid consists of a 1.5 ml/kg bolus with a subsequent continuous infusion of 0.25 ml/kg/minute. (18) However, the typical resuscitative measures employed in the setting of an acute, non-local anesthetic, lipophilic drug toxicity have varied and were based on the suspected class of overdosed drug. Aside from standard cardiopulmonary measures in calcium channel blocker overdoses, additional commonly employed resuscitative therapies have included gastric lavage, multi-dose oral or nasogastric activated charcoal, flumazenil infusion, naloxone infusion, insulin and glucagon intravenous boluses, continuous calcium gluconate infusion, intravenous antiarrhythmics as indicated, and vasopressor support during mechanical ventilation. Unlike local anesthetic systemic toxicities, no ideal Intralipid regimen has been developed for use in non-local anesthetic toxicities, including calcium channel blocker poisonings. (18)

Recent reports of successful, non-local anesthetic toxicity reversals with use of Intralipid offer frequently effective alternative strategies for patients who may remain refractory to standard resuscitative efforts. Clinicians should attempt to utilize Intralipid in non-local anesthetic, lipophilic drug toxicities by modeling the dosing regimen used for local anesthetic systemic toxicities. In summary, Intralipid emulsion therapy is a well-known, accepted antidote to local anesthetic systemic toxicities. In addition, recent reports have described an expanded role of Intralipid emulsion rescue therapy in reversing a range of lipophilic drug toxicities.

Intralipid emulsion rescue therapy has provided another strategy for the reversal of many drug toxicities, most likely by providing a lipid layer safety net for drug overdose passive diffusion. It has been shown to be beneficial to a number of non-local anesthetic, lipophilic drug class toxicities including antidepressants, calcium channel blockers, and other drug classes (Table 1). Clinicians are urged to embrace the expanded role of Intralipid emulsion rescue therapy not only for local anesthetic drug toxicities, but also for other lipophilic drug overdoses. Further research is recommended to identify the optimal initial dosing and maintenance schedules for Intralipid emulsion rescue therapy for non-local anesthetic drug overdoses and to establish firm indications for its use in conjunction with standard resuscitative efforts.

REFERENCES

(1.) Bologa C, Lionte C, Coman A, Sorodoc L. Lipid emulsion therapy in cardiodepressive syndrome after diltiazem overdose--case report. Am J Emerg Med 2013; 31(7): 1154.e

(2.) Ozcan MS, Weinberg G. Intravenous Lipid Emulsion for the Treatment of Drug Toxicity. J Intensive Care Med 2012; 29(2): 59-70.

(3.) Arora NP, Berk WA, Aaron C K, Williams KA. Usefulness of intravenous lipid emulsion for cardiac toxicity from cocaine overdose. Am J Cardiol 2013; 111(3): 445-7.

(4.) Jovic-Stosic J, Gligic B, Putic V. Severe propranolol and ethanol overdose with wide complex tachycardia treated with intravenous lipid emulsion: a case report. Clin Toxicol (Phila) 2011; 49(5): 426-30.

(5.) Cevik SE, Tasyurek T, Guneysel O. Intralipid emulsion as an antidote in lipophilic drug intoxications. Am J Emerg Med 2014; 32(9): 1103-08.

(6.) Finn SD, Uncles DR, Willers J, Sable N. Early treatment of a quetiapine and sertraline overdose with Intralipid. Anaesthesia 2009; 64(2): 191-4.

(7.) Cordell CL, Schubkegel T, Light TR, Ahmad F. Lipid infusion rescue for bupivacaine induced cardiac arrest after axillary block. J Hand Surg Am 2010; 35:144-6.

(8.) Foxall G, McCahon R, Lamb J, Hardman JG, Bedforth NM. Levobupivacaine-induced seizures and cardiovascular collapse treated with Intralipid. Anaesthesia 2007; 62(5):516-518.

(9.) Lange DB, Schwartz D, DaRoza G. Use of intravenous lipid emulsion to reverse central nervous system toxicity of an iatrogenic local anesthetic overdose in a patient on peritoneal dialysis. Ann Pharmacother 2012; 46(12): e37.

(10.) Hillyard SG, Barrera-Groba C, Tighe R. Intralipid reverses coma associated with zopiclone and venlafaxine overdose. Eur I Anaesthesiol 2010; 27(6): 582-3.

(11.) Mulroy MF. Systemic toxicity and cardiotoxicity from local anesthetics: incidence and preventative measures. Reg Anesth Pain Med 2002; 27(6): 556-61.

(12.) Brown DL, Ransom DM, Hall JA, et al. Regional anesthesia and local anesthetic-induced systemic toxicity: seizure frequency and accompanying cardiovascular changes. Anesth Analg 1995; 81: 321-328.

(13.) Tanaka K, Watanabe R, Harada T, Dan K. Extensive application of epidural anesthesia in a university hospital: Incidence of complications related to technique. Reg Anesth 1993; 18: 34-38.

(14.) Sites BD, Taenzer AH, Herrick MD, et al. Incidence of local anesthetic systemic toxicity and postoperative neurologic symptoms associated with 12,668 ultrasound-guided nerve blocks: an analysis from a prospective clinical registry. Reg Anesth Pain Med 2013; 37(5): 478-82.

(15.) McKenzie MS, McFarland BH. Trends in antidepressant overdoses. Pharmacoepidemiol Drug Saf 2007; 16(5): 513-23.

(16.) St-Onge M, Dube PA, Gosselin S, et al. Treatment for calcium channel blocker poisoning: a systematic review. Clin Toxicol (Phila) 2014; 52(9): 926-44.

(17.) Rothschild L, Bern S, Oswald S, Weinberg G. Intravenous lipid emulsion in clinical toxicology. Scand J Trauma Resusc Emerg Med 2010; 18: 51.

(18.) Harvey M, Cave G, Kazemi A. Intralipid infusion diminishes return of spontaneous circulation after hypoxic cardiac arrest in rabbits. Anesth Analg 2009; 108(4): 1163-8.

Sam H. Muller, BS; School of Medicine, Department of Anesthesiology, Louisiana State University Health Sciences Center, New Orleans. James H. Diaz, MD, DrPH; School of Medicine, Department of Anesthesiology, Louisiana State University Health Sciences Center, New Orleans and School of Public Health, Louisiana State University Health Sciences Center, New Orleans. Alan David Kaye, MD, PhD; School of Medicine, Department of Anesthesiology, Louisiana State University Health Sciences Center, New Orleans and School of Medicine, Department of Pharmacology, Louisiana State University Health Sciences Center, New Orleans.
Table 1. Drug Toxicities Successfully Reversed with Intralipid Therapy

Drug Class                 Specific Drugs

Amphetamines               Cocaine
Anliarrhytlmiies           Mcioprolol, Propranolol
Anticonvulsants            Lamotrigine
Antidepressants            Dothiepin, Amitriptyline, Fluoxetine,
                           Sertraline. Dosulepin, Venlafaxine,
                           Bupropion
Antipsycholics             Quetiapine, Olanzapine
Benzodiazepines            Alprazolam, Phenazeparr
Calcium Channel Blockers   Diltiazem, Nifedipine. Verapamil
Diuretics                  Hydrochlorothiazide:
Local Anesthetics          Bupivaeaine, Levobupivacaine, Lidocaine,
                           Mepivauaine, Ropivacaine
Benzodiazepine Agonist     Zopielone
  Insomnia Drugs

Total: 10 Drug Classes
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Author:Muller, Sam H.; Diaz, James H.; Kaye, Alan David
Publication:The Journal of the Louisiana State Medical Society
Article Type:Clinical report
Date:May 1, 2016
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