Heterogeneity and bias in animal models of lipid emulsion therapy: a systematic review and meta-analysis

Abstract

Introduction

Clinicians utilize lipid emulsion to treat local anesthetic toxicity and non-local anesthetic toxicities, a practice supported by animal experimentation and clinical experience. Prior meta-analysis confirmed a mortality benefit of lipid emulsion in animal models of local anesthetic toxicity but the benefit of lipid emulsion in models of non-local anesthetic toxicity remains unanswered. Further, swine suffer an anaphylactoid reaction from lipid emulsions calling into question their role as a model system to study lipid, so we examined swine and non-swine dependent outcomes in models of intravenous lipid emulsion.

Methods

We conducted a systematic review and meta-analysis examining the use of lipid emulsion therapy in animal models of cardiac toxicity. We quantified mortality using a random-effects odds-ratio method. Secondary outcomes included survival in the following subgroups: local-anesthetic systemic toxicity, non-local anesthetic toxicity, swine-based models, and non-swine models (e.g., rat, rabbit and dog). We assessed for heterogeneity with Cochran’s Q and I². We examined bias with Egger’s test & funnel plot analysis.

Results

Of 2784 references screened, 58 met criteria for inclusion. Treatment with lipid emulsion reduced chance of death in all models of toxicity with an odds ratio of death of 0.26 (95% CI 0.16–0.44, Z-5.21, p < 0.00001, Cohen’s-d = 0.72, n = 60). Secondary outcomes confirmed a reduced chance of death in models of local anesthetic toxicity (OR 0.16 {95% CI 0.1–0.33}) and non-local anesthetic toxicity (OR 0.43 {95% CI 0.22–0.83}). Heterogeneity (Cochran’s Q 132 {df = 59, p < 0.01}, I² = 0.55) arose primarily from animal-model and disappeared (I² < = 0.12) when we analyzed swine and non-swine subgroups independently. Swine only benefited in models of local anesthetic toxicity (OR 0.28 {95% CI 0.11–0.7}, p = 0.0033) whereas non-swine models experienced a homogeneous benefit across all toxins (OR 0.1 {95% CI 0.06–0.16}, p < 0.00001). Egger’s test identified risk of bias with outliers on funnel plot analysis.

Discussion

Lipid emulsion therapy reduces mortality in animal models of toxicity. Heterogeneity arises from the animal-model used. Swine only benefit in models of local anesthetic toxicity, potentially due to lipid dose, experimental design or swine’s anaphylactoid reaction to lipid. Outlier analysis reinforced the need for appropriate dosing of lipid emulsion along with airway management and chest compressions in the setting of cardiac arrest.

Keywords:

• Intravenous lipid emulsion
• meta-analysis
• systematic review
• swine
• pig
• porcine
• toxicity
• heterogeneity

Disclosure statement

Neither Dr Fettiplace nor Dr Pichurko have any conflicts of interest that would prevent them from neutral assessment of the literature regarding lipid emulsion therapy. Neither Dr Fettiplace nor Dr Pichurko is involved in consultancies, employment, advocacy groups related to lipid emulsion therapy; neither receives fees or honoraria related to ILE; neither holds grants, patents, stocks or shares related to ILE; finally, neither is involved in supervisor-student or personal-professional relationships where there is an imbalance of power related to ILE.

Additional information

Funding

Dr Fettiplace is a resident in Anesthesiology at The Massachusetts General Hospital. He received protected research time to work on this manuscript and his salary is supported by Partners Healthcare (Boston, MA) and Direct Graduate Medical Education payments from The Centers of Medicare & Medicaid (Washington, DC). Dr Pichurko is an Assistant Professor supported by the Department of Anesthesiology at the University of Wisconsin (Madison, WI).