The Effect of Fat Emulsion on Hemodynamics Following Treatment With Propranolol and Clonidine in Anesthetized Rats

Abstract

Objectives: There is evidence indicating that intravenous fatty emulsion (IFE) is beneficial in restoring circulatory function in certain types of drug overdose. The authors investigated the hemodynamic effects of IFE compared to epinephrine in rats treated with propranolol and clonidine.Methods: Anesthetized male Sprague-Dawley rats were instrumented for measurement of hemodynamics. Rats were randomly assigned to one of six groups (n = 6-8), and each received a clonidine infusion (150 lg/kg) or an equivalent volume of normal saline (0.9% NaCl) over 1 hour. Each rat then received normal saline (1.0 mL/kg) or propranolol (15 to 20 mg/kg). Thereafter, each rat received a dose of IFE (20% solution; 1.0 mL/kg) or epinephrine (2.0 lg/kg) or an equivalent volume of normal saline (1.0 mL/kg).Results: Propranolol alone or with clonidine significantly (p < 0.05) reduced a number of hemodynamic parameters (mean arterial pressure, 37% to 70%; heart rate, 30% to 51%; cardiac contractility [dP/ dtmax], 50% to 67%; and abdominal aortic blood flow, 50% to 83%), while increasing PR intervals (65% to 85%) and QTc intervals (26% to 64%). Saline and epinephrine treatment after propranolol and clonidine combined resulted in no survivors in saline and two out of six in epinephrine group. IFE resulted in significant survival (seven out of eight) for 30 minutes in rats treated with propranolol alone, and propranolol combined with clonidine (seven out of eight).Conclusions: These data demonstrate that IFE is effective for resuscitating rats overdosed on propranolol combined with clonidine. The effect of IFF is unlikely due to a direct positive inotropic or chronotropic action on the myocardium. IFE is also more effective than epinephrine treatment in this paradigm.

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

“…Each rat received a bolus dose of propranolol (15 mg/kg IV; administered over two minutes); this dose of propranolol invariably causes hypotension and eventual cardiovascular collapse without intervention. [ 16 ] Immediately following propranolol administration, rats were given either Intralipid 20% (1 mL/kg [n = 9], 2 mL/kg [n = 6], or 3 mL/kg [n = 6] IV) or ClinOleic 20% (1 mL/kg [n = 8], 2 mL/kg [n = 6], or 3 mL/kg [n = 6] IV), or saline (1 mL/kg [n = 4]) as a bolus over a 30 second period. The starting dose of ILE (i.e.…”

“…1 mL/kg) was based on our previous work demonstrating Intralipid 20% could reverse the hypotension and prevent the cardiovascular collapse associated with this dose of propranolol. [ 16 ] Following return to baseline blood pressure, rats were monitored for up to two hours following ILE administration, at which time surviving rats were euthanized by isoflurane overdose and excision of the heart. Rats that lived for 120 minutes post-propranolol administration were considered as survivors.…”

“…We previously showed that Intralipid 20% (1mL/kg IV) administration is an effective strategy in reversing toxicity with the beta-adrenergic antagonist propranolol in rats. [ 16 ] While differences between ILEs in their ability to bind[ 17 , 18 ] and reverse the toxic effects of local anesthetics have been described,[ 19 , 20 ] no such studies have been conducted in the context of beta-blockers. Guidelines currently recommend the use of Intralipid 20% for local anesthetic toxicity, but recommendations for ILE for treatment of non-local anesthetic drug toxicity are neutral.…”

“…As high doses of ILE can be associated with adverse clinical outcomes (including acute kidney injury, cardiac arrest, ventilation perfusion mismatch, acute lung injury, venous thromboembolism, hypersensitivity, fat overload syndrome, pancreatitis, extracorporeal circulation machine circuit obstruction, allergic reaction, and increased susceptibility to infections,[ 24 , 25 ]) we used doses (1, 2, or 3 mL/kg) of ILE which though lower than those used to treat local anesthetic toxicity in rats (a range of 4-16mL/kg[ 26 , 27 ]) we have shown effectively reverses propranolol toxicity. [ 16 ] The primary endpoint was survival time, and secondary endpoints were time to recovery of 50%, 75%, and 90% of baseline hemodynamic parameters.…”

Past, Present, and Future of Lipid Resuscitation Therapy

“…Another group of drugs that pose a risk of overdose, particularly in elderly populations, are cardiac medications, especially β‐blockers and calcium channel blockers. Overdoses with β‐blockers, propranalol 108 , 132 ‐ 134 and metoprolol 107 , 114 , 135 , 136 have been treated with LRT. However, animal studies have not demonstrated similarly promising results.…”