Low dose Intralipid resuscitation improves survival compared to ClinOleic in propranolol overdose in rats

Abstract

BackgroundMedication overdose is a prevalent issue and despite mixed reports of efficacy, the use of intravenous lipid emulsions, notably Intralipid®, for the management of toxicity from lipid-soluble drugs is becoming increasingly prevalent. Whether alternative lipid emulsion formulations have similar efficacy for resuscitation compared to Intralipid is not known. Here, we compared the efficacy of Intralipid and ClinOleic® for resuscitation following overdose with the lipid-soluble beta-adrenergic antagonist propranolol.MethodsMale Sprague-Dawley rats (age 3–4 months) were anesthetized with isoflurane and instrumented for direct hemodynamic assessments. In Study One, rats (n = 22) were pre-treated with Intralipid 20% (n = 12) or ClinOleic 20% (n = 10) to determine whether the hemodynamic effects of propranolol could be prevented. In Study Two, rats were randomly assigned to Intralipid 20% (1, 2, or 3 mL/kg IV, n = 21) or ClinOleic 20% (1, 2, or 3 mL/kg IV, n = 20) resuscitation groups following propranolol overdose (15 mg/kg IV). In Study Three the effect of Intralipid 20% (1 mL/kg IV, n = 3) and ClinOleic 20% (1 mL/kg IV, n = 3) in the absence of propranolol was investigated. The primary endpoint in all studies was survival time (up to a maximum of 120 minutes), and secondary endpoints were time to achieve 50%, 75%, and 90% of baseline hemodynamic parameters.ResultsIn Study One, pre-treatment with Intralipid prior to propranolol administration resulted in prolonged survival compared to pre-treatment with ClinOleic at low doses (1 mL/kg; P = 0.002), but provided no benefit at higher doses (3 mL/kg; P = 0.95). In Study Two, Intralipid conferred a survival advantage over ClinOleic, with 18/21 rats surviving 120 minutes in the Intralipid group and only 4/20 survivors in the ClinOleic group (P<0.0001). Median survival times (with interquartile ranges) for rats treated with Intralipid, and ClinOleic, and saline were 120 (80.5–120) min, 21.5 (3.25–74.5) min, and 1 (0.25–2.5) min respectively (P<0.001). Only 3/21 rats in the Intralipid group survived less than 30 minutes, whereas 12/20 ClinOleic treated rats had survival times of less than 30 minutes. The number of rats achieving 75%, and 90% of baseline mean arterial pressure was also greater in the Intralipid group (P<0.05 for both values). Treatment in Study Three did not alter survival times.ConclusionsLow-dose Intralipid (1, 2, or 3 mL/kg IV) confers a survival advantage up to 120 minutes post-propranolol overdose (the end-point of the experiment) and better hemodynamic recovery compared to ClinOleic (1, 2, or 3 mL/kg IV) in rats with propranolol overdose. As health care centres choose alternate intravenous lipid emulsions, limited availability of Intralipid could impact efficacy and success of overdose treatment for lipid-soluble drugs.

Low-Dose Propranolol Prevents Functional Decline in Catecholamine-Induced Acute Heart Failure in Rats

“…Groups with higher propranolol doses (15 mg/kg) had decreased survival rates, akin to E and NE only groups. This is consistent with working groups studying propranolol overdose in rat models [ 14 ]. Trials of greater propranolol doses (20, 25 mg/kg) were administered, however due to 100% mortality, only low-dose and high-dose propranolol were selected for therapeutic investigation.…”

Evaluation of the Role of Intravenous Lipid Emulsion as a Putative Treatment for Acute Aluminum Phosphide Poisoning.

“…These findings may lead to a common concept that at low doses, ILE act mainly to alter the pharmacokinetic profile of lipid-soluble toxins, whereas at high doses the direct cardiac effects occur. This is consistent with the observation that high doses of Intralipid (6-16 mL/kg) (Macala et al, 2018), despite the improvement of cardiac sodium channel blockade effect indicated by QRS prolongation), did not ameliorate overall survival in the wake of toxicity. Three low doses of ILE 20% were used in the present study: 1, 2, 3 ml/kg over 1 min as initial bolus dose immediately following poisoning identification.…”

“…The composition of Intralipid 20% may provide better sequestration of lipidsoluble agents than other ILE consisting of a greater proportion of medium-chain fatty acids (Mazoit et al, 2009, Tang et al, 2016. Thus, health practitioners must avoid replacing intrepid 20% with other ILE without revising the resuscitative properties of these formulations (Macala et al, 2018).…”

“…The recommended upper limit of 10ml/kg over the first 30 minutes was followed. It is important to note that three initial doses were used: 100 ml, 200 ml, and 300 ml (The Association of Anaesthetists of Great Britain & Ireland, 2010;Gosselin et al, 2016, Macala et al, 2018.…”

Predicting Inter-individual Variability During Lipid Resuscitation of Bupivacaine Cardiotoxicity in Rats: A Virtual Population Modeling Study

“…Over the 2 decades since lipid resuscitation was first proposed [2], researchers have used in vitro [3][4][5] and in vivo [2,4,[6][7][8][9][10][11][12][13][14][15][16] experiments, clinical case reports [17,18], and systematic reviews [19][20][21][22][23][24] to explore the value of intravenous lipid emulsions (ILE) as an antidote for drug toxicity. For the case of local anesthetic toxicity, committees developed guidelines and recommendations based largely on animal models and without formalized clinical trials [25][26][27].…”