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Three Part Question

In [an adult with beta-blocker overdose] is [intralipid/intravenous lipid emulsion] beneficial in [treating resistant hypotension and refractory arrhythmias]?

Clinical Scenario

A 30-year-old man attends your emergency department after a deliberate overdose of his father's atenolol tablets. He is bradycardic, hypotensive and has had seizures. Despite fluids, atropine and a glucagon infusion, he remains hypotensive and you start treatment with inotropes. He remains unresponsive to treatment and very hypotensive and you wonder if an intravenous lipid infusion would help.

Search Strategy

MEDLINE 1950 to August 2011
EMBASE 1980 to August 2011
Google Scholar Cochrane Database.
Lipid rescue website (http://www.lipidrescue.org)

Lipid registry website (http://www.lipidregistry.org/)

{intralipid.af} OR {lipid AND emulsion.af} OR {intravenous AND fat AND emulsion.af} OR {intravenous AND lipid AND emulsion.af} OR {fat AND emulsion.af} OR {intravenous AND lipid AND therapy.af} OR {liposyn*.af}) AND ({β AND blocker*.af} OR {atenolol.af} OR {carvedilol.af} OR {labetolol.af} OR {metoprolol.af} OR {oxprenolol.af} OR {pindolol.af} OR {propranolol.af} OR {sotalol.af} OR {bisoprolol.af} OR {esmolol.af})

Search Outcome

Medline and Embase found 225 papers, of which 13 were relevant. Four systematic reviews, one of which related to the history and mechanism of intravenous lipid emulsion, seven case reports, one case series. The systematic reviews quoted the individual case report and series.

No further articles in Google Scholar. No related articles in the Cochrane Database. The Lipid rescue website mentions one case report.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Dolcourt et al, 2008 USA	52 yr old male with overdose of atenolol and verapamil, presented unconscious with HR 49, SBP 40, anuric, cold extremities.	Case report	ILE 20% given as 1.5 ml/kg bolus followed by an infusion of 0.25 ml/kg/min for 30 min. Patient conscious within minutes, BP 109/60 mm Hg within 3 h. Further shock 8 h after infusion. ILE given for 1 h improved BP. 4 h after end of infusion, shock recurred. A balloon pump. Patient died 12 h later	ILE 20% given as 1.5 ml/kg	Mixed overdose. One case.
Harchelroad et al, 2008 USA	46yr old female, overdose with atenolol, paracetamol and ethyl alcohol.	Case report	6 h After ingestion: HR 32, SBP 62. Treatment with 2 mg atropine, 5 mg glucagon, 2 L N saline improved HR 43, BP 96/53 mm Hg	Treated with 1 l 20% ILE over 2 h—HR 70, BP 110/72	Mixed overdose One case.
Meehan et al 2009 USA	Case 1: 53yr old male, overdose of carvedilol. Case 2: 22 yr old female, overdose of propranolol.	Case series.	Case 1: Treated with glucagon, insulin, maximal doses of dopamine and norepinephrine but remained hypotensive (60/30). Case 2: Asystole while in ICU. Treated with glucagon, atropine, epinephrine, sodium bicarbonate.	Case 1: ILE given as bolus and infusion, with improvement of HR 93, BP 108/62 and survival to discharge. Case 2: ROSC within minutes of treatment with ILE (HR 90, SBP 110) and survived to discharge.	Individual cases, time-span not given, dose of ILE not specified.
Carr et al, 2009 Canada	31yr old female presenting to ED 4 -5 hours post ingestion of 875mg carvedilol (12mg/kg).	Case report.	HR 73, BP 78/22, RR16, Sat02 97%. Treated with N saline, 5mg glucagon, calcium chloride and dopamine infusion. Hypotension persisted despite max dose of dopamine, epinephrine and high dose insulin.	100ml bolus of 20% ILE, followed by 150ml over 15minutes. Within 80minutes BP 132/70, later weaned off vasopressors and insulin and extubated.	One case. Time spans not given.
Dean et al, 2010 UK	27yr old female presenting to ED 1 hour after ingestion of 7gr propranolol.	Case report as correspondence.	On arrival in ED: GCS 3, generalized tonic clonic seizure, BP 60/30, PR 25. ECG: broad complex bradycardia. Treated with crystalloids, 3mg atropine, glucagon 5mg boluses and infusion (5mg/hr), insulin infusion (70U/hr) with 50% dextrose, lorazepam boluses (8mg) and phenytion infusion (which stopped seizures), isoprenaline infusion, and external cardiac pacing.	Patient’s condition deteriorated into cardiac arrest (PEA) with ROSC after 2 cycles of CPR. Adrenaline infusion started. SBP 40, PR 25- 30. Intralipid 20% started as 100ml bolus followed by 400ml infusion over 20min. Adrenaline requirements decreased 5minutes after starting intralipid, and stopped after 7 hours. ECG reverted to NSR.	One case.
Stellpflug et al (a), 2010 USA	48yr old male, ingested nebivolol, ethanol and possibly diazepam and cocaine.	Case report.	HR 71, BP 98/61, ECG: SR, QTc 483 ms, QRS 112 ms. Within 4 h, bradycardic, hypotensive and asystolic cardiac arrest. Standard resuscitation	ROSC 30 s after a 100 ml bolus of 20% ILE. HR 123, BP 251/162. ILE infusion and high-dose insulin. Survived to discharge	Mixed overdose? Effect of high-dose insulin. Duration of cardiac arrest and standard resuscitation drugs before ILE not stated
Stellpflug et al (b), 2010 USA	30yr old female with h/o HOCM, CHF and an AICD presenting with abdominal pain.	Case report.	HR 73, BP 89/46, but over 3 h HR 70, BP 64/41 and patient became confused. Treated with 2 l N saline. Admitted taking diltiazem, metoprolol and amiodarone 6 h before arrival in ED. Given 2 l N saline, 27 mEq calcium, high-dose insulin bolus of 0.5 U/kg followed by infusion up to 10 U/kg/h. Remained hypotensive, confused, anuric. CVP 20, ejection fraction ‘low’	100 ml bolus of 20% ILE, followed by infusion 1.5 l over 1 h. Within 15 min of bolus, BP 110/60 and confusion improved. Patient discharged from ICU 5 days later	Mixed overdose? Effect of high-dose insulin. (Authors argue against inotropic and vasodilatory effect of insulin as patient had HOCM).
Smith A. 2010	48yr old female with GCS 10 after overdose including propranolol and clonidine.	Case report on lipid rescue website.	Patient intubated and ventilated. HR dropped to 60 and SBP 70. No response to fluids. Glucagon improved HR but not BP. No response to naloxone, maximum epinephrine and vasopressin, high-dose insulin at 120 U/h and 50% dextrose. More acidotic over next 90 min	Patient given intralipid and moved to ICU. Within 1 h patient had BP 120/80 and became more rousable. Survived to discharge	Mixed overdose. Case described in a website, not formally published.
Jovic-Stosic et al, Serbia 2011	31-Year-old woman who had presented 2 h after an overdose of propranolol plus ethanol	Case report	Presented in a coma with BP of 65/35. Treated with diazepam for repeated seizures, intubated and ventilated. Conventional treatment with atropine, glucagon, HDI and sodium bicarbonate and dopamine infusion	Intralipid 100 ml bolus and 400 ml infusion were administered. The seizure activity stopped and the BP improved. The BP deteriorated again and a further intralipid infusion was given over 50 min. Patient regained consciousness and was extubated after a few hours	Single case report

Comment(s)

There are no human studies about the use of intravenous lipid emulsion in β-blocker overdose. Studies on rodents and rabbits have shown that intralipid reduces QRS duration and improves bradycardia and hypotension in propranolol toxicity. Similar studies with metoprolol failed to show a significant improvement in blood pressure. Intravenous lipid emulsion is thought to act as a lipid sink, attracting the drugs away from tissues, and thus may be more effective with more lipophilic drugs such as propranolol compared with metoprolol. Several case reports provide anecdotal suggestions of benefit but no firm evidence is available and it is likely that there is publication bias. Intravenous lipid emulsion has recently been recommended by Toxbase as worth consideration in patients with a history of overdose of β blockers, who have cardiotoxic symptoms that are not responsive to standard treatment.(Toxbase)

Editor Comment

AICD, automatic implantable cardioverter-defibrillator; BP, blood pressure; CHF, congestive heart failure; CPR, cardiopulmonary resuscitation; CVP, central venous pressure; ED, emergency department; GCS, Glasgow Coma Scale; HOCM, hypertrophic cardiomyopathy; HR, heart rate; ICU, intensive care unit; ILE, intravenous lipid emulsion; NSR, normal sinus rhythm; PEA, pulseless electrical activity; PR, pulse rate; ROSC, return of spontaneous circulation; SBP, systolic blood pressure.

Clinical Bottom Line

There is no clear evidence about the effectiveness of intravenous lipid emulsion in beta blocker overdose.

References

1. Dolcourt BA, Aaron CK Intravenous fat emulsion for refractory verapamil and atenolol-induced shock: a human case report. Clin Toxicol 2008. 46;7:619-620.
2. Harchelroad FP, Palma A Efficacy and safety of intravenous lipid therapy in a beta-blocker overdose Clin Toxicol 2008;46:634
3. Meehan TJ, Gummin DD, Kostic MA et al. Beta Blocker toxicity successfully treated with intravenous fat emulsion: a case series. Clin Toxicol 2009. 47;7: 735 (1556-3650).
4. Carr D, Boone A, Hoffman RS et al. Successful resuscitation of a carvedilol overdose using intravenous fat emulsion. Clin Toxicol 2009. 47;7:726.
5. Dean P, Ruddy JP, Marshall S. Intravenous lipid emulsion in propranolol overdose. Anaesthesia 2010. 65:1148- 1150.
6. Stellpflug SJ, Harris CR, Engebretsen KM et al(a). Intentional overdose with cardiac arrest treated with intravenous fat emulsion and high-dose insulin. Clin Toxicol 2010. 48;3: 227-229.
7. Stellpflug SJ, Cole JB, Fritzlar SJ et al. (b). Overdose of diltiazem, metoprolol and amiodarone treated with intravenous fat emulsion and high dose insulin in an awake patient. Clin Toxicol 2010. 48;6: 612.
8. Smith A. Intralipid for combined propranolol/clonidine overdose. Lipid Rescue Website 8th November 2010
9. Brent J. A systematic review of the use of intravenous lipid therapy in the management of poisoned patients. Clin Toxicol 2010. 48;3: 241-242.
10. Cave G, Harvey M. Intravenous lipid emulsion as antidote beyond local anaesthetic toxicity: a systematic review. Acad Emerg Med 2009. 16:9;815- 824.
11. Cave G, Harvey M, Graudins A. Intravenous lipid emulsion as antidote: a summary of published human experience. Emerg Med Australasia 2011. 23; 123-141.
12. Jamaty C, Bailey B, Laroque A, Notebaert E, Sanogo K, Chauny JM. Lipid emulsions in the treatment of acute poisoning: a systematic review of human and animal studies. Clin Toxicol 48;1:1-27.
13. National Poisons Information Service (UK). TOXBASE Database [Online] NPIS http://www.toxbase.org/(accessed 20th Sept 2011)
14. Jovic-Stosic J, Gligic B, Putic V, et al. Severe Propanolol and ethanol overdose with wide complex tachycardia treated with intravenous lipid emulsion: A case report. Clin Toxicol (Phila) 2011;49:426–30.
15. Rothschild L, Bern S, Oswald S, et al. Intravenous lipid emulsion in clinical toxicology. Scand J Trauma Resusc Emerg Med 2010;18:51 (1757).