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Treating Sympathomimetic Toxicity

Roberts, James R. MD

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doi: 10.1097/01.EEM.0000476273.56614.28
    A benzodiazepine plus an antipsychotic is a common combination to treat amphetamine-induced agitation and psychosis. Lorazepam (2 mg) plus haloperidol (5 mg) is a frequently used therapeutic cocktail, and both are given IV. Despite being a popular intervention, few studies assess success. It may take 15-20 minutes for these drugs to take full effect, and additional doses of both medications are often required. Benzodiazepines alone are often ineffective, and massive doses are required in severe cases.

    It's not uncommon for emergency clinicians to be faced with patients displaying severe amphetamine or amphetamine-like toxicity, and it is urgent in many cases to control the patient's agitation, psychosis, and overall hyperadrenergic state. Often, one has to initiate therapy with limited clinical information and an absent history. A hyperadrenergic and psychotic state is characteristic for amphetamines, but also secondary to many related sympathomimetic drugs and designer drugs of abuse. Often nothing can be done medically for these patients until they are chemically sedated.

    Hypertension and tachycardia can be problematic, and may also require intervention. Many appropriate so-called antidotes have been adopted for use in the ED, and the clinician has a number of chemicals available to treat not only the agitation and psychosis but also the associated cardiovascular abnormalities. There does not appear, however, to be a standard approach.

    Treatment of Toxicity of Amphetamines, Related Derivatives, and Analogues: A Systematic Clinical Review

    Richards JR, Albertson TE, et al.

    Drug Alcohol Depend


    The authors from a variety of U.S. academic medical centers present a systematic literature review of the published treatments of amphetamine and amphetamine-like toxicity. They use the term ARDA to describe amphetamine-related derivatives and analogues that include ephedrine, pseudoephedrine, methylphenidate, MDMA/ecstasy, bath salts, and other related substances. The authors note that there are more than 15 million ARDA abusers worldwide, surpassing heroin and cocaine use combined. More than 150,000 U.S. ED visits were attributed to ARDA-related toxicity in 2011.

    Drug abusers are often unable to communicate or are not forthcoming about their illicit drug abuse, so the treating clinician must consider a wide spectrum of diagnoses and treatments. Medical conditions simulating ARDA toxicity include acute psychosis, thyrotoxicosis, sepsis, CNS infection, pheochromocytoma, head trauma, anticholinergic toxicity, various withdrawal states, intracranial hemorrhage, and hypoglycemia. Despite the ubiquity of the clinical scenario, no best physician-recommended antidotes have been forthcoming. The ARDA-intoxicated patient has excessive norepinephrine, dopamine, and serotonin levels through multiple mechanisms, plus a variety of alterations of the sympathetic nervous system and CNS. The often concomitant hyperadrenergic state can lead to coronary artery syndrome, stroke, pulmonary hypertension, and multisystem failure, including mortality.

    Medications for Treating Amphetamine and Amphetamine-like Agitation and Psychosis

    These authors concentrated their review on the published evidence for treating agitation and psychosis and for addressing the hyperadrenergic state caused by toxicity from ARDAs. Their analysis is based on an extensive literature search from a variety of sources. They note that no prior systematic reviews have been done on this topic. Interestingly, there are only 47 relevant papers in the entire literature, reporting on only 506 subjects. Actual data are scarce.

    A number of antipsychotics have been advocated to control the agitation and especially the psychosis secondary to ARDA toxicity. Included in the regimen are haloperidol and droperidol, ziprasidone, olanzapine, risperidone and aripiprazole. All of these antipsychotics can increase the QT interval and cause dystonic reactions, and they rarely precipitate neuroleptic malignant syndrome. The later-generation drugs, so-called atypical antipsychotics, are associated with fewer extrapyramidal side effects. Olanzapine and haloperidol have been reported to produce more extrapyramidal side effects than others. Recently, haloperidol and quetiapine were found about equally effective in quelling the symptoms of amphetamine-induced psychosis, but again more extrapyramidal effects were seen with haloperidol. Only one study reviewed the use of IV lorazepam combined with droperidol to control agitation. Droperidol worked slightly faster and was somewhat more effective in controlling agitation than other meds, but lorazepam often required repeat dosing to achieve similar effects.

    Comment: The older typical antipsychotics and the newer atypical antipsychotics all appear to be about equal in treating agitation and psychosis related to ARDA toxicity. Most are used IM, but this requires 20-30 minutes to effectuate the desired benefit. The package inserts states that haloperidol is for “IM injection only,” but many clinicians use a combination of lorazepam and haloperidol intravenously, given in aliquots until a desired effect is seen. The full effect of IV haloperidol and lorazepam requires about 15-20 minutes to unfold, longer if used IM. This slow onset is a potential downside. When effective doses of antipsychotics are given, sedation lasts six to eight hours.

    IM atypical antipsychotics alone can often effectively quell amphetamine agitation and psychosis, but it may take 20-30 minutes to be totally effective. Extrapyramidal side effects, and rarely neuroleptic malignant syndrome, can occur. Once adequately sedated, it may take six to eight hours for those treated to recover enough to be coherent.

    None of these drugs has significant consequences or serious cardiorespiratory effects, although the QT prolongation seen with all of the antipsychotics is always of some concern. Droperidol has a bad reputation for causing serious QT prolongation, and has essentially been abandoned. All treated patients therefore should be under ECG monitoring, something not always possible at the onset of therapy. The drugs should be withheld and another class chosen if QT prolongation occurs. Some clinicians will give empiric magnesium (2-4 g slowly IV) for a QT longer than 500 msec, hoping to prevent Torsades dysrhythmia.

    All of the benzodiazepines enhance the inhibitory effects of GABA, and oversedation and respiratory depression can be encountered. Occasionally paradoxical agitation is seen. It appears that benzodiazepines alone are not the ideal choice for severe agitation and psychosis, so they are often combine with an antipsychotic. Failure to achieve adequate sedation is not uncommon when less-than-aggressive doses of benzodiazepines are used.

    Comment: Benzodiazepines, including lorazepam, diazepam, and midazolam, are commonly used empirically, and it often requires large or repeated doses to be effective. Combining benzodiazepines with an antipsychotic, usually haloperidol, with both drugs given IV, is a very popular initial treatment for the undifferentiated patient. The often-used IV dose of 2 mg lorazepam and 5 mg haloperidol can be underdosing, however, and can fail to fully quell severe agitation and psychosis. When given IV, the clinician can determine benzodiazepine effects within five to 10 minutes, but it requires 15-20 minutes for even IV haloperidol to kick in. Additional medication can be added as needed with these relatively modest initial doses. Clinicians can be resistant to using multiple or high doses of benzodiazepines, and turn to paralysis and intubation after failure of less-than-adequate doses. The more aggressive clinician uses very high doses of benzodiazepines usually without the need for intubation, but these patients must be carefully monitored.

    Dexmedetomidine is a central alpha-adrenergic agonist similar to clonidine that inhibits CNS sympathetic outflow. The effect is sedation and analgesia and no respiratory depression. A powerful sedative, it has scant adverse cardiovascular complications. Two studies have been published on this relatively new drug, but it's not generally used in the ED. Further evaluation of this medication may prove it to be a more superior intervention.

    Comment: Dexmedetomidine is used fairly frequently in the ICU to control undifferentiated agitation. I do not have any personal experience with it, but it is very popular and gaining acceptance in the ED. Its lack of deleterious effects on respiratory drive is a huge benefit, and it's therefore often used for initial sedation for all comers in the ICU. Following an initial loading dose, a continuous IV infusion is required, making it more difficult for ED use. Hypotension and bradycardia can be seen when used for prolonged periods of time.

    No trials demonstrate the benefit of ketamine, propofol, or a combination to treat ARDA-induced agitation and psychosis, but ketamine has been successfully used for controlling generalized and undifferentiated agitation in the ED. Propofol or a combination of propofol and ketamine have been used successfully, but the drugs have a relatively short duration of action and may require additional doses or a continuous infusion. Most emergency clinicians have never used a continuous ketamine infusion.

    Comment: Last month's column discussed the use of ketamine for undifferentiated acute agitation or excited delirium, and it is favorably viewed by a number of clinicians. No extensive studies on ketamine for such use in the ED exist, but it is being used more frequently and appears to be quite effective with minimal side effects. The hypertension, tachycardia, and emergence reactions attributed to ketamine are probably overrated and are not contraindications for use in the ED.

    Beta blockers have been suggested for treating the hyperadrenergic state from ARDA toxicity. They will ameliorate the increased heart rate and hypertension, and a number of agents have been used, including atenolol, carvedilol, metoprolol, and propranolol. There are warnings and a few case reports of adverse effects of beta blockers when used to treat the sympathomimetic effects of ARDAs. This is thought to be caused by beta blockade and subsequent unopposed alpha agonism, leading to hypertensive crisis. The authors of this study conclude that this problem has not been proven with any certainty, and case reports of such downsides often glean the wrong conclusions. A number of studies have found benefits of beta blockers with no adverse effects.

    Ketamine is a favorite intervention to treat undifferentiated excited delirium, but it is not well studied. Ketamine IM/IV works in only a few minutes. Hypertension and tachycardia, usually minimal, and emergence reactions are side effects. Ketamine does not act long enough for many cases, and additional sedation is often required.

    Additional Comment: I noted in the last month's column that UpToDate advises not using beta blockers because of the potential for unopposed alpha-adrenergic effect, eschewing it for either sympathomimetics or cocaine. This makes good physiological sense, but apparently it is not a proven or common problem in clinical practice. Warnings against use of beta blockers are possibly overstated, but this topic has not been rigorously reviewed by any prospective studies.

    Calcium channel blockers, alpha blockers, and vasodilators may have value, but their pluses and minuses are not well described in the literature and there appear to be better choices.

    The authors emphasize that as of December 2014 no evidence-based systematic reviews were published regarding the pharmacological treatment of agitation, psychosis, and hyperadrenergic symptoms from ARDAs. This is quite puzzling given the commonality of such cases. These authors say initial control of agitation and psychosis with antipsychotics is a reasonable choice, with the understanding that extrapyramidal side effects might occur and the slow onset may be problematic. They note that the American Association of Emergency Psychiatry recommends antipsychotics as first-line treatment of generalized agitation of unknown cause.

    Concerning the hyperadrenergic state, it is difficult to know when specific treatment is required, and no clear guidelines exist. Sedation with benzodiazepines may be all that is needed. These authors conclude that beta blockers are a reasonable choice. They conclude that the unopposed alpha stimulation after beta blockade is controversial and poorly documented with regard to ARDA toxicity. The use of beta blockers for treating cocaine- and methamphetamine-associated chest pain appears in guidelines. Using beta blockade for the hyperadrenergic state associated with thyrotoxicosis or pheochromocytoma does not appear to supplement significant alpha-adrenergic agonism.

    The authors conclude that the best treatment for ARDA toxicity has not been elucidated, and further studies are required. One problem with the miniscule literature that is extant is that the severity of the derangements are not always quantified, exactly when interventions are required is variable, and doses of the medications used are lacking. I would posit that a number of medications will be proven safe and effective, and specific choices will ultimately be up to the individual clinician. Before a winner is selected, the clinician simply has to choose a medication with which he is familiar, coupled with the ability to alter any intervention as needed. Time spent in physical restraints should be minimal for the severely agitated or delirious individual.

    Reader Feedback: Readers are invited to ask questions and offer personal experiences on InFocus topics. Literature references are appreciated. Pertinent responses will be published in a future issue. Please send comments to [email protected].

    Dr. Roberts: Propofol and ketamine given together is not ketofol. (“No Proven Efficacy for Ketofol over Propofol Alone,” EMN 2015;37[11]:6; This is like a martini with a discreet olive on a pick. Propofol is the martini and ketamine is the olive, also known as propofol and ketamine. But then picture the olive blended into the martini. That is ketofol: propofol with ketamine.

    Beginning March 26, 1992, I replaced diazepam with propofol in Vinnik's diazepam-ketamine sedation for elective cosmetic surgery. Unfortunately, I described my variation as propofol-ketamine, suggesting to many that the two drugs were combined. They are not.

    Effective use of ketamine in adults (and children over 50 pounds) can only be assured by saturating the NMDA receptors with a 50 mg IV ketamine independent of body weight. The NMDA receptors of most concern reside in the midbrain, a very small portion of the brain that does not vary significantly with body weight. I have used this 50 mg dose for more than 23 years of clinical practice, and I have observed immobility to noxious local analgesia injection (dissociation) in 100-pound women and 250-pound men. Clearly, the dissociative effect has nothing to do with body weight.

    Preventing historically negative ketamine side effects (hallucinations, dysphoria, hypertension, and tachycardia), is readily accomplished using an incremental propofol induction to create a loss of life reflex and loss of verbal response prior to giving the 50 mg IV ketamine dose. One then needs to wait only two to three minutes before injecting locally or incising the skin.

    A more elegant and numerically reproducible approach is to use the bispectral (BIS) monitor to measure the cortical response to the incremental propofol induction. (Watch video of this at Real-time use of the BIS involves trending EMG as the secondary trace, recognizing EMG spikes as incipient arousal, and titrating additional propofol to drive the EMG spike back to baseline.

    The net effect of this approach is to create non-opioid preemptive analgesia. Fewer than five percent of more than 4,000 patients having a wide variety of painful cosmetic procedures (subpectoral breast augmentation, classical abdominoplasty) required very modest amounts of postoperative fentanyl.

    A clinical pathway for those interested is posted on EMN's website at

    — Barry Friedberg, MD, Newport Beach, CA

    Dr. Roberts responds: Thanks, Dr. Friedberg, for your comments. It appears that you have significant experience with ketamine, and are a fan of its use. Emergency clinicians would not use BIS monitoring because they usually have a very short procedure time. I don't fully understand your comments on the drug combination labeling, but I do like a martini now and then. It's rather cool and interesting that an anesthesiologist reads Emergency Medicine News. Keep it up.

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