Lipid emulsion improves survival in animal models of local anesthetic toxicity: a meta-analysis

Figures & data

Figure 1. Forest plot of survival with adjuvant intravenous lipid emulsion. Meta-analysis comparing odds ratio (OR) of death based on treatment with adjuvant intravenous lipid emulsion (ILE) compared to standard resuscitation with accompanying 95% confidence interval (95%CI). Odds-ratio less that 1 favors treatment with ILE while odds-ratio above 1 favors treatment without ILE. bupi: treated with bupivacaine; mepi: treated with mepivacaine; w/epi: comparison with epinephrine in both control and ILE group; no epi: comparisson with no epinephrine in both control and ILE group.

Table 1. Publications analyzed for survival benefit.

Publication	Animal model	Baseline treatment	Control treatment	Control survival	ILE treatment	ILE survival	Outcome metric	Confounders
Bushey et al. [7]	Pig	CPR, Epi	+Saline	4/12	+ILE	6/12	ROSC
De Queiroz et al. [9]	Pig	CPR, Epi	−	6/7	+ILE	10/10	ROSC (>10 min)	No volume control
De Queiroz et al. [9]	Pig	CPR	+Saline	1/7	+ILE	7/9
Hicks et al. [15]	Pig	CPR, Epi, Vp	+Saline	4/9	+ILE	3/10	ROSC (60 s)	Vasopressin
Mauch et al. [22]	Pig	CPR, Epi	−	5/7	+ILE	6/7	Survival	No volume control
Mauch et al. [23]	Pig	–	+Epi +Rescue Epi	7/7	+ILE +Rescue Epi	8/14	Survival	No CPR Uncontrolled rescue epinephrine No volume control
Gokahmetoglu et al. [14]	Rabbit	CPR, Epi	+Saline	0/12	+ILE	8/12	ROSC
Karcıoglu et al. [18]	Rabbit	CPR, Epi	+Saline	1/7	+ILE	3/7	ROSC (20 min)
Li et al. [20]	Rat	CPR, Epi	−	2/8	+ILE	5/8	ROSC (RPP >20%)	No volume control
Li et al. [20]	Rat	CPR	+Saline	0/8	+ILE	3/8
Litonius et al. [21]	Pig	CPR, Epi for asystole, Defib for VFib	+Ringers	8/10	+ILE	10/10	Survival
Litonius (mepi) et al. [21]	Pig		+Ringers	10/10	+ILE	9/10		Mepivacaine
Hiller et al. [16]	Rat	CPR	+Saline	1/5	+ILE	5/5	ROSC (15 min)
Weinberg et al. [29]	Rat	CPR	+Saline	2/5	+ILE	5/5	RPP >20%
Weinberg et al. [28]	Dog	CPR	+Saline	0/6	+ILE	6/6	RPP >20%
Karci et al. [17]	Rat	Standard resuscitation	−	0/7	+ILE	5/14	Survival	No volume control

CPR: cardio-pulmonary resuscitation (chest compressions and ventilation); Epi: epinephrine; Vp: vasopressin; ILE: intravenous lipid emulsion; Rescue Epi: doses of Epi delivered if mean arterial pressure <75% of baseline; RPP: rate pressure product.

Table 2. Publications excluded from meta-analysis.

Publication	Animal model	Control treatment	Control survival	ILE treatment	ILE survival	Notes
Bonfim et al. [5]	Pig	Saline	10/10	LCT	10/10	- Survivable dose of Bupi  - Hemodynamic study  - Indicates hemodynamic benefit to ILE
				MCT	10/10
Buckenmaier et al. [6]	Pig	–	0/5	ILE	0/6	- Unsurvivable insult - All animals intentionally dosed to death
Candela et al. [8]	Pig	Saline	9/9	LCT	7/7	- Survivable dose of Bupi  - EKG study  - Indicates faster reversal of EKG with ILE
				MCT	8/8
De Simone Melo et al. [10]	Pig	Saline	10/10	SMOFlipid	10/10	- Survivable dose - Hemodynamic study - Indicates benefit with SMOFLipid
Di Gregorio et al. [11]	Rat	CPR, Epi, Vp	3/6	CPR, ILE	6/6	- No Control, ILE vs Epi  - Indicates benefit of ILE over Epi & Vp or Vp
		CPR, Vp	1/6
Fettiplace et al. [12]	Rat	Saline	7/7	20% ILE	7/7	- Survivable dose  - Hemodynamic study  - Indicates dose-dependent benefit with ILE
		Null	7/7	30% ILE	7/7
	Rat	Saline	6/6	IO Lipid	6/6	- Survivable dose  - Hemodynamic study  - Indicates possibility to using IO delivery for benefit of ILE
				IV Lipid	6/6
Li et al. [19]	Rat	None		CPR + LCT	22/30	- No non-lipid control  - Comparison of LCT and MCT/LCT  - Indicates larger benefit with LCT compared to LCT/MCT mixture
				CPR + LCT/MCT	15/30
				CPR + LCT	23/32
				CPR + LCT/MCT	17/32
Mayr et al. [24]	Pig	CPR, Defib, Epi, Vp	5/5	CPR, Defib, ILE	0/5	- No Control, ILE vs Epi - Asphyxial arrest - Indicates benefit of Epi over ILE
Shi et al. [25]	Rat	Saline	6/6	ILE	6/6	- Survivable dose  - Pharmacokinetic study  - Indicates pharmacokinetic benefit with ILE
		Saline	50/50	ILE	50/50
Wat et al. [26]	Pig	Cardiac massage, Epi	5/5	Cardiac massage, 10-min delay, ILE	0/5	- No Control, ILE vs Epi - 10 min delay for ILE treatment - Indicates benefit of Epi over delayed ILE
Weinberg et al. [27]	Dog			Bupi + ILE	6/6	- Not a study of local anesthetic toxicity - Study on electrically induced fibrillation
Yoshimoto 2014 et al. [30]	Rat		–		–	- Survival data was not extractable - Study on hyperbaric bupivacaine

CPR: cardio-pulmonary resuscitation (chest compressions and ventilation); ILE: intravenous lipid emulsion; LCT: long-chain triglycerides; MCT: medium chain triglycerides; Bupi: bupivacaine; IO: intraosseous; Epi: epinephrine; Vp: vasopressin; Defib: defibrillation in the case of ventricular fibrillation.

Figure 2. Funnel plot of meta-analysis for intravenous lipid emulsion. Funnel plot accompanying data from Figure 1 to examine for graphical evidence of bias in survival numbers. Odds-ratio of death when treated with intravenous lipid emulsion (ILE) versus control plotted against standard error of natural log of odds-ratio (SE of ln(OR)). Funnel is centered at overall median weighted odds ratio with 95% confidence interval within the funnel

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