Pharmacologic interventions after an LD50 cocaine insult in a chronically instrumented rat model: Are beta-blockers contraindicated?

doi:10.1016/S0196-0644(05)80839-X

Annals of Emergency Medicine

Volume 20, Issue 7, July 1991, Pages 768-771

https://doi.org/10.1016/S0196-0644(05)80839-X Get rights and content

Study purpose:

To evaluate drug management of acute cocaine toxicity in a new animal model. The study null hypothesis was that no drug would affect outcome compared with a placebo control.

Model:

Chronically instrumented, conscious, unrestrained rats subjected to an LD₅₀ dose (1.4 mg/100 g body wt) of IV cocaine.

Methods:

Rapid injection of IV cocaine by IV vascular access port followed by injection of therapeutic study drugs. Outcome (survival vs death) with drug treatment was compared with a placebo group.

Pharmacologic interventions:

Normal saline placebo (0.2 mL/100 g), diazepam (0.5 mg/100 g), chlorpromazine (0.2 mg/100 g), propranolol (1.0 mg/100 g), labetalol (3.0 mg/100 g), or verapamil (0.1 mg/100 g) was given. There were ten rats in each treatment group. Allocation to treatment groups was nonrandomized.

Statistical methods:

Fisher's exact test.

Results:

IV injection of cocaine was followed by tonic-clonic seizure activity in all treatment groups. No study drug significantly improved survival compared with the placebo group. However, no animal treated with propranolol survived (P < .05 vs saline control), and only one of ten animals treated with labetalol survived (P = .14 vs placebo group).

Conclusion:

In this conscious animal model subjected to an LD₅₀ IV cocaine insult, chlorpromazine and diazepam, previously shown to be of value in other animal models, had no effect on survival. Verapamil also did not affect outcome. Outcome was adversely affected by treatment with β-blocking agents.

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Cited by (34)

Carvedilol Among Patients With Heart Failure With a Cocaine-Use Disorder
2019, JACC: Heart Failure
This study sought to assess the safety of carvedilol therapy among heart failure (HF) patients with a cocaine-use disorder (CUD).
Although carvedilol therapy is recommended among certain patients with HF, the safety and efficacy of carvedilol among HF patients with a CUD is unknown.
This was a single-center study of hospitalized patients with HF. Cocaine use was self-reported or defined as having a positive urine toxicology. Patients were divided by carvedilol prescription. Subgroup analyses were performed by strata of ejection fraction (EF) ≤40%, 41% to 49%, or ≥50%. Major adverse cardiovascular events (MACE) were defined as cardiovascular mortality and 30-day HF readmission.
From a cohort of 2,578 patients hospitalized with HF in 2011, 503 patients with a CUD were identified, among whom 404 (80%) were prescribed carvedilol, and 99 (20%) were not. Both groups had similar characteristics; however, those prescribed carvedilol had a lower LVEF, heart rate, and N-terminal pro–B-type natriuretic peptide concentrations at admission and on discharge, and more coronary artery disease. Over a median follow-up of 19 months, there were 169 MACEs. The MACE rates were similar between the carvedilol and the non-carvedilol groups (32% vs. 38%, respectively; p = 0.16) and between those with a preserved EF (30% vs. 33%, respectively; p = 0.48) and were lower in patients with a reduced EF taking carvedilol (34% vs. 58%, respectively; p = 0.02). In a multivariate model, carvedilol therapy was associated with lower MACE among patients with HF with a CUD (hazard ratio: 0.67; 95% confidence interval; 0.481 to 0.863).
Our findings suggest that carvedilol therapy is safe for patients with HF with a CUD and may be effective among those with a reduced EF.
Intravenous lipid emulsion in the resuscitation of cocaine-induced cardiovascular arrest in a rat model
2016, American Journal of Emergency Medicine
Citation Excerpt :
A recent report of online ILE monitoring network did not produce any experience among health care providers giving ILE for cocaine intoxication [10]. Our previous study found that ILE (15 mg/kg intravenously [IV]) pretreatment of rats that were subsequently given cocaine (10 mg/kg IV) [12,13] blunted the cardiac toxicity and decrease the occurrence of cardiovascular collapse in rats when compared with normal saline (NS) controls [14]. In the present study, we sought to study whether rats that had cardiovascular collapse from acute cocaine toxicity would regain spontaneous circulation if given ILE during chest compressions and compare recovery with an NS control group.
Intravenous lipid emulsion (ILE) is a potential antidote for severe overdose of certain lipophilic drugs. Cocaine overdose is often fatal and has no antidote. The use of ILE after cocaine-induced cardiac arrest has been suggested but is not well characterized.
The objective of the study is to determine if ILE would reverse cocaine-induced cardiac arrest in a rat model.
Twelve Sprague-Dawley rats with intra-arterial and intravenous access were sedated with isoflurane and split into 2 cocaine dose groups, then given either ILE or normal saline (NS) intravenously (IV)—group A, 7 animals received cocaine (10 mg/kg IV) with 6 of 7 given ILE (15 mg/kg IV) and 1 of 7 given NS (equal volume); group B, 5 animals received cocaine (5 mg/kg IV) with 3 of 5 given ILE (15 mg/kg IV) and 2 of 5 given NS (equal volume). Closed chest compressions were initiated for asystole and continued for 15 minutes with rhythm checks every minute.
All 12 rats experienced cardiac arrest after cocaine bolus. Resuscitation was successful in 1 of 7 rats in group A and 0 of 5 in group B.
Intravenous lipid emulsion administration did not affect outcome of cocaine-induced cardiac arrest compared with control in this model.
Pretreatment with intravenous lipid emulsion reduces mortality from cocaine toxicity in a rat model
2014, Annals of Emergency Medicine
Citation Excerpt :
After an additional 2 minutes, a 10 mg/kg dose of cocaine was administered as a rapid intravenous bolus. The cocaine dose was based on reported median lethal dose (LD50), ranging from 10 to 14 mg/kg.19,20 The animals were observed and continuously monitored until they reached one of 2 predefined endpoints (an undetectable MAP [<10 mm Hg] or return to baseline MAP for 5 minutes).
We compare the effects of intravenous lipid emulsion and normal saline solution pretreatment on mortality and hemodynamic changes in a rat model of cocaine toxicity. We hypothesize that intravenous lipid emulsion will decrease mortality and hemodynamic changes caused by cocaine administration compared with saline solution.
Twenty male Sprague-Dawley rats were sedated and randomized to receive intravenous lipid emulsion or normal saline solution, followed by a 10 mg/kg bolus of intravenous cocaine. Continuous monitoring included intra-arterial blood pressure, pulse rate and ECG tracing. Endpoints included a sustained undetectable mean arterial pressure (MAP) or return to baseline MAP for 5 minutes. The log-rank test was used to compare mortality. A mixed-effect repeated-measures ANOVA was used to estimate the effects of group (intravenous lipid emulsion versus saline solution), time, and survival on change in MAP, pulse rate, or pulse pressure.
In the normal saline solution group, 7 of 10 animals died compared with 2 of 10 in the intravenous lipid emulsion group. The survival rate of 80% (95% confidence interval 55% to 100%) for the intravenous lipid emulsion rats and 30% (95% confidence interval 0.2% to 58%) for the normal saline solution group was statistically significant (P=.045).
Intravenous lipid emulsion pretreatment decreased cocaine-induced cardiovascular collapse and blunted hypotensive effects compared with normal saline solution in this rat model of acute lethal cocaine intoxication. Intravenous lipid emulsion should be investigated further as a potential adjunct in the treatment of severe cocaine toxicity.
Comparison of in-hospital outcomes for beta-blocker use versus non-beta blocker use in patients presenting with cocaine-associated chest pain
2014, American Journal of Cardiology
Citation Excerpt :
The net effect of these pathophysiological insults is the promotion of myocardial ischemia through multiple pathways (Figure 1), many of which could be modified with BB therapy. Clinical guidelines recommend withholding of BB therapy in patients with cocaine-associated ACS, primarily because of concerns about unopposed α-adrenergic stimulation4–6 and the potential for coronary vasoconstriction, increased blood pressure, and decreased coronary blood flow with BB therapy.21–25 However, recent clinical studies have challenged this presumption, and some have even suggested lower incidence of ACS in patients with cocaine use who are treated with BBs.1–3
Beta blockers are indicated for management of acute coronary syndromes, but they generally are withheld in patients with cocaine-associated chest pain because of concerns for adverse outcomes related to the unique physiological effects of cocaine. Because few clinical studies have evaluated this interaction, we identified patients with toxicology screen results positive for cocaine treated for chest pain at 2 academic hospitals. Clinical characteristics and in-hospital outcomes were compared between patients with and without β-blocker therapy. We then constructed propensity scores to evaluate the independent relation between β-blocker use and the composite primary end point of myocardial infarction, stroke, ventricular arrhythmia, or all-cause mortality after adjusting for clinical characteristics. Of 376 consecutive patients with cocaine-related chest pain, β blockers were used in 164 (44%). Compared with no β blockers, patients treated with β blockers were more likely to describe anginal chest pain, to have known cardiovascular risk factors, and to receive other antiatherosclerotic therapies. Despite these higher risk clinical characteristics, patients treated with β blockers experienced similar peak troponin levels, individual adverse events, and rates of the composite primary end point (15.9% vs 12.3%, p = 0.32). The primary end point also was similar after propensity score analysis (odds ratio 1.37, 95% confidence interval 0.64 to 2.93, p = 0.42), including specific comparisons of beta-1 selective (odds ratio 1.83, 95% confidence interval 0.79 to 4.24) and nonselective (odds ratio 0.90, 95% confidence interval 0.33 to 2.42) β blockers, when compared with patients not receiving β blockers. In conclusion, no differences in outcomes were observed between patients treated versus not treated with β-blocker therapy in the setting of cocaine-related chest pain.
Rethinking cocaine-associated chest pain and acute coronary syndromes
2011, Mayo Clinic Proceedings
Citation Excerpt :
Regarding systemic cardiovascular hemodynamics, most of the data with β-blockers in the setting of recent cocaine use are derived from case reports, animal studies, and small retrospective case studies and include both selective and nonselective β-blockers. The results are inconsistent with studies that show both improvement80–83 and worsening84–86 of hemodynamics. Because of significant patient underreporting or denial6 and often delayed results from urine drug screening, CCP patients may receive β-blockers before the treating physician is aware of the cocaine abuse.
Every year more than 500,000 patients present to the emergency department with cocaine-associated complications, most commonly chest pain. Many of these patients undergo extensive work-up and treatment. Much of the evidence regarding cocaine's cardiovascular effects, as well as the current management of cocaine-associated chest pain and acute coronary syndromes, is anecdotally derived and based on studies written more than 2 decades ago that involved only a few patients. Newer studies have brought into question many of the commonly held theories and practices regarding the etiology, diagnosis, and treatment of this common clinical scenario. However, there continues to be a paucity of prospective, randomized trials addressing this topic as it relates to clinical outcomes. We searched PubMed for English-language articles from 1960 to 2011 using the keywords cocaine, chest pain, coronary arteries, myocardial infarction, emergency department, cardiac biomarkers, electrocardiogram, coronary computed tomography, observation unit, β-blockers, benzodiazepines, nitroglycerin, calcium channel blockers, phentolamine, and cardiomyopathy; including various combinations of these terms. We reviewed the abstracts to confirm relevance, and then full articles were extracted. References from extracted articles were also reviewed for relevant articles. In this review, we critically evaluate the limited historical evidence underlying the current teachings on cocaine's cardiovascular effects and management of cocaine-associated chest pain. We aim to update the reader on more recent, albeit small, studies on the emergency department evaluation and clinical and pharmacologic management of cocaine-associated chest pain. Finally, we summarize recent guidelines and review an algorithm based on the current best evidence.
Cocaine, Myocardial Infarction, and β-Blockers: Time to Rethink the Equation?
2008, Annals of Emergency Medicine

View all citing articles on Scopus

: Funded in part by the Emergency Medicine Foundation, Mead-Johnson Laboratories, and the Saint John's Heart Institute.

: Presented in part at the Society for Academic Emergency Medicine Annual Meeting in San Diego, May 1989. Recipient of Best Resident Poster Presentation Award.

View full text

Laboratory investigationPharmacologic interventions after an LD50 cocaine insult in a chronically instrumented rat model: Are beta-blockers contraindicated?

Study purpose:

Model:

Methods:

Pharmacologic interventions:

Statistical methods:

Results:

Conclusion:

Am J Cardiol

Ann Emerg Med

Ann Emerg Med

Ann Emerg Med

Ann Emerg Med

Am Heart J

Am J Emerg Med

Am J Med

A decade of trends in cocaine use in the household population

Natl Inst Drug Abuse Monogr Set

Local anesthetics

Medical complications of cocaine abuse

N Engl J Med

Medical risks of cocaine use

West J Med

Neurologic aspects of cocaine abuse

West J Med

Cocaine

Laboratory investigation
Pharmacologic interventions after an LD₅₀ cocaine insult in a chronically instrumented rat model: Are beta-blockers contraindicated?