Martyn Harvey

Intralipid infusion ameliorates propranolol-induced hypotension in rabbits

ObjectiveRecent case reports of successful amelioration of lipid-soluble drug toxidromes with Intralipid infusion have prompted interest in the scope of lipid emulsions as antidotal therapy. Propranolol is a highly lipid-soluble, nonselective beta-blocker with additional local-anaesthetic properties. We explored the hypothesis that propranolol toxicity may be similarly attenuated by Intralipid infusion in a rabbit model.MethodsTwenty sedated, invasively monitored, and mechanically ventilated New Zealand White rabbits underwent propranolol infusion at 4.2 mg/min to a target mean arterial pressure (MAP) of 60% baseline MAP. Animals subsequently received 6 ml/kg 20% Intralipid, or 6 ml/kg 0.9% saline solution over a 4-minute period. Pulse rate and MAP were recorded at 2.5-minute intervals to 15 minutes.ResultsMAP was greatest in the Intralipid group (median 69 mmHg, interquartile range [IQR] 17.5 mmHg Intralipid vs. median 53 mmHg, IQR 12.75 mmHg saline;p = 0.029) at 15 minutes. No difference was observed in first derivative of MAP, or pulse rate between groups.ConclusionsPropranolol-induced hypotension is ameliorated by Intralipid infusion in this intact rabbit model. The mechanism of action remains to be elucidated.

Intralipid infusion diminishes return of spontaneous circulation after hypoxic cardiac arrest in rabbits.

BACKGROUND: Infusion of lipid emulsion has been shown to reverse lipophilic drug-induced cardiovascular collapse in laboratory models and humans. The effect of high dose lipid in nondrug-induced cardiac arrest is, however, uncertain. In a rabbit model of asphyxial pulseless electrical activity (PEA) we compared lipid augmented with standard advanced cardiac life support (ACLS) resuscitation. METHOD: Adult New Zealand White rabbits underwent hypoxic PEA via tracheal clamping. After 2 min of cardiac arrest, basic life support cardiopulmonary resuscitation was commenced and 3 mL/kg 20% Intralipid or 3 mL/kg 0.9% saline solution infused. Adrenaline (100 &mgr;g/kg) was administered at 4 and 5 min. Return of spontaneous circulation (ROSC), hemodynamic metrics, and survival to 50 min were recorded. RESULTS: Seven of 11 saline-treated rabbits developed ROSC versus 1 of 12 Intralipid-treated animals; P = 0.009. No significant difference in survival to 50 min was observed (3/11 saline vs 0/12 Intralipid; P = 0.211). CONCLUSION: In this model of hypoxia-induced PEA, standard ACLS resulted in greater coronary perfusion pressure and increased ROSC compared with ACLS plus lipid infusion. Lipid emulsion may be contraindicated in cardiac arrest complicated by significant hypoxia.

The Role of Fat Emulsion Therapy in a Rodent Model of Propranolol Toxicity: A Preliminary Study

IntroductionIn animal models, lipid emulsion therapy has been shown to ameliorate toxicity from a number of lipid soluble agents. This preliminary study addresses the hypothesis that pretreatment with lipid emulsion protects against propranolol toxicity in rodents.MethodsTen spontaneously ventilating Rattus norvegicus rats were pretreated with either lipid emulsion or 0.9% normal saline before undergoing a constant infusion of propranolol until death. An electrocardiogram (ECG) sampling of heart rate and a QRS duration was performed at two-minute intervals until demise.ResultsThere was no significant difference in lethal doses of propranolol between groups. Comparison of percent change in QRS prolongation and heart rate reduction was performed at 60% of the mean lethal dose in control animals. The percent change in QRS duration was reduced (from −0.9 to 17.3, p = 0.016) in the intralipid pretreatment group. Attenuation of propranolol-induced bradycardia observed in the lipid emulsion group approached statistical significance (0% vs. 10.3%, p = 0.06).InterpretationThe results suggest that lipid emulsion may be effective in ameliorating propranolol toxicity in rats. Previous work gives reason to postulate a pharmacokinetic mechanism for this effect. The results represent encouraging exploratory work, and further work is planned to evaluate the role of lipid emulsion therapy in propranolol toxicity.

Correlation of Plasma and Peritoneal Diasylate Clomipramine Concentration with Hemodynamic Recovery after Intralipid Infusion in Rabbits

OBJECTIVES Drug sequestration to an expanded plasma lipid phase has been proposed as a potential mechanism of action for lipid emulsions in lipophilic cardiotoxin overdose. The authors set out to document plasma and peritoneal diasylate clomipramine concentration after resuscitation with lipid emulsion in a rabbit model of clomipramine-induced hypotension. METHODS Twenty sedated mechanically ventilated New Zealand White rabbits were allocated to receive either 12 mL/kg 20% Intralipid or 12 mL/kg saline solution, following clomipramine infusion to 50% baseline mean arterial pressure (MAP). Hemodynamic parameters and serum clomipramine concentration were determined to 59 minutes. Peritoneal dialysis with 20% Intralipid or saline solution was evaluated for clomipramine concentration. RESULTS Mean arterial pressure was greater in lipid-treated animals as assessed by repeated-measures analysis of variance (F[1,14] = 6.84; p = 0.020). Lipid infusion was associated with elevated plasma clomipramine concentration and reduced initial volume of distribution (Vd; 5.7 [+/-1.6] L/kg lipid vs. 15.9 [+/-7.2] L/kg saline; p = 0.0001). Peritoneal diasylate clomipramine concentration was greater in lipid-treated animals (366.2 [+/-186.2] microg/L lipid vs. 37.7 [+/-13.8] microg/L saline; p = 0.002). CONCLUSIONS Amelioration of clomipramine-induced hypotension with lipid infusion is associated with reduced initial Vd and elevated plasma clomipramine concentration consistent with intravascular drug-lipid sequestration. Concomitant peritoneal dialysis with lipid emulsion enhances clomipramine extraction.

Lipid emulsion may augment early blood pressure recovery in a rabbit model of atenolol toxicity

Dear Editor, Lipid emulsion has been identified as a potential antidote in the treatment of poisoning with drugs of high lipophilicity [1]. Both pharmacokinetic and pharmacodynamic mechanisms have been forwarded to explain this therapeutic effect. One explanation is that lipophilic drug sequestration within intravascular lipid droplets may decrease free plasma concentration and thus target organ tissue levels. Alternatively, bolus administration of free fatty acids may augment cardiac performance via overcoming pharmacologically induced impediments to myocardial oxidative phosphorylation, or through elevation of intramyocyte calcium concentration [1]. Demonstration of effect for lipid emulsion in a hydrophilic drug toxidrome would lend support for a metabolic explanation of lipid’s effects. Atenolol is a hydrophilic beta-blocker with a water:octanol coefficient of 0.23. We determined to explore the hemodynamic response to lipid resuscitation from atenololinduced hypotension in a previously established intact rabbit model of drug-induced hypotension [2,3]. This study was undertaken at the Ruakura Agresearch facility, Hamilton New Zealand, and was approved by the Ruakura Animal Ethics Committee. The conditions of rabbit husbandry in addition to sedation, instrumentation, and mechanical ventilation protocols were identical to our previously published work [3]. The study was 80% powered at the 0.05 significance level for a 1.5 standard deviation (approximately 10 mmHg [2]) in blood pressure with 10 subjects in each group. Following preliminary dose ranging experiments (6 animals), atenolol 25 mg/mL was infused at 1 mL/min to a target mean arterial pressure (MAP) of 60% baseline. In a number of subjects however reduction in MAP with atenolol infusion was precipitous following a prolonged period of relative stability, with irreversible cardiovascular collapse seen prior to stabilization at the intended toxic endpoint. At toxicity, 6-mL/kg 20% Intralipid or 6-mL/kg 0.9% saline solution was infused over a 4-minute period, in line with our previous work. Comparison of hemodynamic metrics was conducted at baseline, toxicity, immediately postresuscitation, and 15 minutes postresuscitation. Statistical analysis was undertaken using Graphpad InStat(3.06) software (GraphPad Software Inc, La Jolla, CA 92037). Fischer’s exact and Mann Whitney tests were used as appropriate. Statistical significance set at the 0.05 level. Six of 10 subjects survived to stabilization at the predefined point of toxicity in the lipid group, with 8 surviving to this point in the saline group. All animals subsequently survived to the time-point immediately postresuscitation. Two saline-treated subjects died in the 15 minutes postresuscitation, with no further subjects dying in the lipid group ( p 0.48). Baseline animal characteristic and MAP are shown in Table 1. No statistically significant difference was observed for MAP or pulse rate at any time between groups. A trend toward greater MAP in the lipid-treated group immediately postresuscitation approached significance (p = 0.10). The observed increment in MAP following resuscitation was greater in the lipid-treated group (Figure 1). Early recovery from atenolol toxicity may have been augmented by lipid resuscitation in this model with the change in blood pressure immediately postresuscitation greater in the lipid group. This finding lends inferential support to a metabolic explanation for the effects of lipid in beta-blocker toxicity. Beta-blockers are known to cause inhibition of mitochondrial oxidative phosphorylation [4]. It is conceivable that lipid could serve to reverse this inhibition through an effect of mass action on mitochondrial free fatty acid provision, or alternatively through increasing intramyocyte calcium. Methodologic limitations mitigate against clearly attributing the observed association to lipid. Although absolute reduction in median MAP during atenolol infusion was equivalent between groups, proportionate reduction was greater in the saline group. It is therefore possible that members of the saline group were Lipid Emulsion May Augment Early Blood Pressure Recovery in a Rabbit Model of Atenolol Toxicity The Poison Pen Correspondence to the Editor

Successful resuscitation from bupivacaine‐induced cardiovascular collapse with intravenous lipid emulsion following femoral nerve block in an emergency department

We report a case of a 69‐year‐old woman with femoral neck fracture undergoing bupivacaine femoral nerve block for preoperative analgesia in an ED. Seizure and cardiovascular collapse developed immediately after instillation of local anaesthetic. Resuscitation including 20% lipid emulsion was successful in achieving normalization of haemodynamic parameters and ECG QRS duration. No adverse sequelae of lipid administration were observed. We recommend the immediate availability of lipid emulsion in emergency room settings where local anaesthetics are used.

Epinephrine Injection in Lipid-Based Resuscitation from Bupivacaine-Induced Cardiac Arrest: Transient Circulatory Return in Rabbits

BACKGROUND: IV lipid emulsion has demonstrated to be effective therapy for bupivacaine-induced cardiotoxicity. However, the role of epinephrine when coadministered with lipid emulsion in toxin-induced cardiac arrest is unclear. We postulated superior resuscitation outcome in the absence of epinephrine in a rabbit model of bupivacaine-induced cardiac arrest resuscitated with IV lipid emulsion. METHODS: Twenty sedated, instrumented New Zealand White rabbits received 10 mg/kg IV bupivacaine producing asystole. Mechanical ventilation and external chest compressions were commenced at 30 seconds. At 1 minute, animals received 5 mL/kg 20% lipid emulsion in addition to 1 of 4 additional IV treatments (n = 5 all groups): 0.9% saline, 2.5 &mgr;g/kg epinephrine, 10 &mgr;g/kg epinephrine, 100 &mgr;g/kg epinephrine; all at 1 mL/kg. Lipid emulsion bolus was repeated at 4 minutes. Return of spontaneous circulation and hemodynamic metrics were obtained to 15 minutes. Saline group animals additionally received high-dose epinephrine (100 &mgr;g/kg) treatment at 15 minutes, and were monitored to 20 minutes. RESULTS: High-dose epinephrine administration was associated with increased rate of return of spontaneous circulation compared with saline control (0 of 5 saline-treated animals; 0 of 5 animals in the 2.5 &mgr;g/kg epinephrine group; 3 of 5 in the 10 &mgr;g/kg group [P = 0.167]; and 4 of 5 in the 100 &mgr;g/kg group [P = 0.048]). Spontaneous but decreasing circulation was maintained at 15 minutes in 4 of 5 animals in the 100 &mgr;g/kg group alone (P = 0.048); mean arterial blood pressure at 15 minutes was 12.8 (SEM 2.8) mm Hg saline, 12.0 (2.5) mm Hg 2.5 &mgr;g/kg epinephrine, 20.6 (2.7) mm Hg 10 &mgr;g/kg epinephrine, and 26.4 (3.9) mm Hg 100 &mgr;g/kg epinephrine (P = 0.008). Four of five animals in the saline-treated group exhibited return of spontaneous circulation after delayed epinephrine treatment (P = 0.048). High-dose epinephrine administration was associated with a significant increase in coronary perfusion pressure before return of spontaneous circulation. CONCLUSIONS: Epinephrine seemed to be necessary for return of spontaneous circulation, but was subsequently associated with declining hemodynamic variables in this rabbit model of bupivacaine-induced cardiac arrest. Further study is required to define the role of epinephrine in lipid-based resuscitation from local anesthetic-induced cardiac arrest.

Accuracy of bedside ultrasound for the detection of soft tissue foreign bodies by emergency doctors

Objective:  To assess the ability of emergency physicians and emergency trainees to detect soft tissue foreign bodies using typical ultrasound equipment.

The effect of lipid emulsion on depth of anaesthesia following thiopental administration to rabbits

Intravenous lipid emulsion has proven benefit in lipophilic drug‐induced cardiotoxicity. Its effect in reversal of central nervous system depression secondary to overdose with lipophilic psychotropic agents remains uncertain. Twenty adult New Zealand White rabbits were anaesthetised with 20 mg.kg−1 thiopental and randomised to receive either 4 ml.kg−1 saline 0.9% or 4 ml.kg−1 lipid emulsion 20% immediately afterwards. Depth of anaesthesia was monitored using bispectral index (BIS) at 1‐min intervals. Duration of anaesthesia was measured as time to regain the righting reflex (ability of the animal to right spontaneously from dorsal recumbency to sternal recumbency). The BIS was greater in the control group (p = 0.011). The greatest BIS differential was observed immediately following treatment (mean (SD) BIS 75.0 (9.5) for saline vs 58.6 (10.4) for lipid, 95% CI 5.75–27.1; p < 0.001). No difference was observed in duration of anaesthesia (mean (SD) 15.5 (0.8) min for saline vs 15.6 (0.7) min for lipid, p = 0.86). Lipid emulsion administration may serve to increase central nervous system depression in the early phase of lipophilic toxin distribution.

Effect of intravenous lipid emulsion and octreotide on enteric thiopentone absorption; a pilot study

Intravenous lipid emulsion (ILE) preparations have recently emerged as novel antidotes for poisonings with highly lipid soluble drugs. Both pharmacokinetic and pharmacodynamic mechanisms have been proposed as explanations for the benefi cial effects observed following ILE administration. The predominant pharmacokinetic hypothesis purports sequestration of lipophilic toxins away from target organs and into a newly created circulating lipid phase – the so called “ lipid sink ” . 1 It has nevertheless been postulated that administration of ILE early in the course of enteric overdose may lead to more rapid toxin absorption from gastrointestinal (GI) tract as enteric perfusion with blood of increased affi nity for lipophilic substances comes in contact with luminal contents of similar lipophilicity. 2,3 Increased toxin absorption may thereby speed up the development of systemic toxicity. Octreotide is a long-acting synthetic somatostatin analogue with an established utility in reducing the frequency of recurring hypoglycaemia following sulfonylurea poisoning. 4 In addition to suppression of neuroendocrine and exocrine intestinal secretion, octreotide is known to reduce splanchnic blood fl ow and to increase intestinal transit time. 5 Although the benefi t of octreotide administration in sulphonylurea overdose has largely been attributed to an effect on inhibition of pancreatic insulin secretion, additional benefi ts may occur through delayed drug absorption secondary to these later effects. 6 Furthermore, the potential for octreotide to modulate absorption of alternate ingested xenobiotics through reduction in enteric blood fl ow remains unexplored. We were interested to examine the effects of these two antidotes on the speed of developed toxicity for an enterically administered lipophillic toxin in an intact animal model. Specifi cally, we determined to document survival following both ILE and octreotide, administration in enteric thiopentone overdose in whole rats. Death by respiratory depression (as a marker of central nervous system [CNS] thiopentone toxicity) was utilised as the primary outcome variable. Thiopentone was elected as CNS toxin of interest given its high lipid solubility and predictable redistribution kinetics 7 with established modulation following ILE administration. 8