One can pontificate for days on toxicology issues in the ED, but prescient and sagacious readers should be cognizant that cardiac arrest and severe drug toxicity in the pre- and post-arrest phase are different scenarios. Don't confuse post- or pre–arrest toxicologic interventions with the actual cardiac arrest event.
ACLS aficionados will remember that the American Heart Association has always concluded that no drug or specific CPR device has ever been proven to alter the outcome of cardiac arrest. Only CPR and defibrillation seem to be life-saving. Not unexpectedly, this theme continues with the proclamation that there is no drug, antidote, or intervention that alters the outcome of cardiac arrest from a toxin.
Perhaps some interventions will stave off an arrest or provide support after the heart has been jump-started, but don't expect any magic antidote to resurrect the newly dead initially. This quote from the guidelines says it all: “There are (still) no data to support the use of specific antidotes in the setting of cardiac arrest” from any toxin. This month's column continues a dissection of the new guidelines with a focus on drug toxicity.
2010 American Heart Association Guidelines for Cardio pulmonary Resuscitation and Emergency Cardiovascular Care
Field JM, et al
2010;122(18 Suppl 3):S639
Severe poisonings alter cellular receptors, ion channels, and chemical pathways in a manner different from cardiac arrest secondary to coronary disease or other more common entities. Although managing cardiac arrest after toxic exposures similarly begins with airway, breathing, and circulation, cardiac arrest due to a medication overdose or toxin conjures up interventions of a special nature. Although a few antidotes have the potential to rapidly neutralize or reverse the toxic effects of drugs in the still living, the majority of one's arsenal to treat cardiorespiratory collapse secondary to a drug overdose is primarily basic support.
Patients with a plethora of random drug ingestions are frequent denizens of the emergency department. Despite what they do to themselves, most fare well. Death from an overdose is quite unusual, probably less than two percent. Those patients who do succumb to their ingestion usually die in the prehospital phase or likely have their fatal course well ensconced before seeing the paramedic or clinician. Pharmacologic insults are just so massive and normal metabolism and physiology so deranged that no mere mortal can make a meaningful intervention. The seriously poisoned who maintain vital signs in the ED have the best, albeit never guaranteed, chance of rescue from a modicum of antidotes and intensive supportive care.
But even if one knows the culprit substance, no physician in the world can change the course of an overdose of 100 amitriptyline pills, rescue a patient from downing a month's supply of a potent calcium channel blocker, change the ultimate outcome of a massive colchicine ingestion, or save one's cortex from the ravages of carbon monoxide.
Cardiac arrest due to a toxin first calls for well promulgated BLS and ACLS interventions. Sophisticated toxicology interventions can make the difference in a few individuals on the precipice of arrest, but choosing the correct tactic is often hampered by lack of history, inability to identify a specific toxin or level, and the overall nefarious and clandestine nature of myriad poisons available to the general public. Clinical trials on toxicology-related human cardiac arrest can never be accomplished. Most fatalities are unusual enough that there are no large case series, and the heterogeneity of the presentations further complicate the ability to unravel the best approaches. Unfortunately, there is essentially no prospective toxicology research involving human cardiac arrest so recommendations are based on expert consensus and seemingly reasonable treatments.
The AHA recognizes that gastrointestinal decontamination, once a generic mainstay in managing any toxin, has a minimal role in changing the outcome of a toxic ingestion. Oral charcoal, induced emesis, gastric lavage, and whole bowel irrigation have never been proven to alter morbidity or mortality. This is a difficult concept for the general public to appreciate. Certainly “pumping one's stomach” should be axiomatic in the layman's mind, but except on rare occasional and via mostly theoretical machinations, even this once sacred cow is a useless or minimally effective endeavor. Seemingly intuitive, these historic heroics can worsen outcome, and are essentially clinical dinosaurs looking for the nearest tar pit. Occasionally, multiple-dose activated charcoal, whole bowel irrigation, or even gastric emptying procedures are considered by the guidelines, but they should not be deemed standard of care because there are just too many variables. Note that none is considered basic toxicology management by consensus of national toxicology organizations, and are deemed complex, multifactorial, and associated with risk, according to the AHA.
Drugs Causing Cardiac Arrest
The AHA concludes that “there are no data to support the use of specific antidotes in the setting of cardiac arrest due to opioid overdose,” seemingly an odd conclusion given the pharmacologic wonders of naloxone. Resuscitation from cardiac arrest from opioids should follow standard BLS-ACLS protocols. All clinicians frantically clamor for naloxone, a rather unique world-class opioid antagonist, and we even give it via ET tube, but naloxone will not reverse cardiac arrest from an opioid.
In a patient not in cardiac arrest and following ventilation and airway control, naloxone may be considered. Because it essentially reverses respiratory depression and coma, the ED part of the opioid code is about finished when the endotracheal tube is placed. Although largely overrated in my opinion and not a valid reason to ever withhold naloxone in the ED, there is the rare case of fulminate naloxone-precipitated opioid withdrawal or fatal arrhythmia. Low-dose naloxone (0.04 to 0.4 mg) can be supported in some patients, and even higher doses are reasonable following massive opioid overdose, but naloxone is not a magical cure for opioid cardiac arrest.
For those not in cardiac arrest, naloxone can be given IV, IM, intranasally, or via the trachea. The duration of naloxone is said to be 45 to 70 minutes, clinically longer with larger doses. Of course, some longer acting opioids, such as methadone or sustained released oxycodone/ morphine exhibit recurrent toxicity when naloxone has dissipated. And swallowed opioids can have a delayed effect due to bowel paralysis that hampers systemic absorption, especially in a massive oral ingestion. So don't be in too much of a hurry to discharge that annoying IV drug abuser who wants to go home after you just saved his life, especially if the maximum effects of their pill popping are not yet extant. The exact observation period following naloxone reversal is unknown, and the AHA makes no specific recommendations. These guidelines also fail to mention opioid-induced pulmonary edema, an entity that is usually readily obvious, but may require a few hours to reach clinical manifestations.
As with opioids, no data support using antidotes for cardiac arrest due to benzodiazepines. Of course, death is almost invariably from respiratory arrest, not primarily cardiac in origin. The potent receptor antagonist flumazenil neatly reverses the binding of benzodiazepine in the central nervous system, rendering the offending benzodiazepine totally impotent. Although flumazenil will immediately reverse respiratory depression, the edict from the AHA is that even flumazenil has “no role in the management of cardiac arrest” from benzodiazepines. The AHA does not recommend flumazenil for patients with undifferentiated coma because it can produce seizures and be associated with arrhythmias, seizures, and other adverse effects.
This timid caveat is largely overstated, if you ask me, and only relevant under a select set of circumstances. If an isolated benzodiazepine overdose is present in a patient not addicted to benzodiazepines, there is little downside to a test (if not diagnostic) dose of flumazenil. This drug has the most benefit for reversing conscious sedation for an inadvertent benzodiazepine overdose in children or for those who impulsively reach for a friend's bottle of Xanax.
No data support the use of specific antidotes for cardiac arrest due to beta blockers. In some cases, when the patient is not in cardiac arrest but is about to be or after a fortuitous resuscitation, the AHA believes that high-dose vasopressors may be of value. Maybe, but many resistant cases can be refractory to any cardiovascular floggings. In a severe beta blocker overdose, nothing will reverse hemodynamic instability. Glucagon, high-dose insulin or glucose, or IV calcium have anecdotal but not antidotal success, but are commonly used and worth an aggressive try.
Glucagon does have some ability to reverse refractory beta blocker cardiac toxicity. I would posit that it be used prior to decomposition severe enough to require vasopressors. A dose of 3 mg to 10 mg administered over three to five minutes followed by an infusion of the same dose each hour is a reasonable recommendation, if you can find enough glucagon in the pharmacy. Glucagon can cause vomiting, so protect the airway. Another option is IV calcium, about 1-3 ampules of calcium gluconate as a bolus (slowly through a peripheral line is OK if you don't use calcium chloride), followed by a continuous infusion. Follow with 6 ampules of calcium gluconate in 1 L saline, begin at 1-2ml/kg/hr, and titrate up.
High-dose insulin, a rather roundabout way to treat beta blocker overdose (also possibly a calcium channel blocker overdose) may improve hemodynamic stability and increase survival in those not yet dead. It's touted to improve myocardial energy utilization. For clinicians unfamiliar with this intervention or hesitant to use large doses of insulin, try an IV bolus of 1 unit/kg of regular insulin, followed by similar doses continuously infused per hour. Hypoglycemia can be averted by the concomitant administration of dextrose and frequent ACCU-CHEKs about every 15 to 30 minutes. I concomitantly infuse 10% dextrose at about 100-125 ml/hr if hypoglycemia becomes difficult to treat. Hypokalemia will occur with continuous insulin infusions. Beta blocker overdose by itself can cause hypoglycemia, especially in children. Note the section on lipid emulsion as an antidote.
Calcium Channel Blockers
No data support using any antidote for cardiac arrest from calcium channel blockers. This is a heinous overdose that, when fully developed, would defy resuscitation by Osler himself. Despite the ubiquitous use of vasopressors, insulin/glucose, IV calcium, and other nonspecific tries at reversing the ion channelopathy, the ability to resuscitate a patient from calcium channel blocker cardiac arrest is dismal, if not statistically zero. Similar to the deadly beta blocker overdose, the pre-arrest/post-arrest hypotension and bradycardia from calcium channel blocker overdose can be resistant to all therapies. Of note, calcium channel blocker overdose is often heralded and suspected by hyperglycemia in a nondiabetic. One can also give glucagon a try. Note the section on lipid emulsion as an antidote.
If you die from a digoxin overdose, you likely will stay dead. While digoxin poisoning used to be a death sentence from bradycardia and life-threatening arrhythmias, the use of antidigoxin Fab antibodies has made what used to be certain death from this overdose less of a certainty, if medical care is expeditious. There is no downside to this antidote, and it can be used empirically. Hyperkalemia greater than 5 mEq/L is a clue, if not hallmark, of acute but not chronic digoxin poisoning, and is one indication for five to 20 vials of empiric digoxin antibody.
Treat the patient, however, not solely the digoxin level. Note that following even therapeutic digoxin, there is a redistribution phase that makes the first alarming digoxin level a mere laboratory perturbation, not worthy of Digibind by itself.
While a number of agents are effective in managing cocaine-induced acute coronary syndrome, severe hypertension, or seizures, there is no true antidote for cocaine. There is little hope for resuscitating a cardiac arrest from this ubiquitous stimulant. Acute coronary syndrome is treated similarly to that caused by ischemic heart disease. Studies have demonstrated coronary artery narrowing/spasm secondary to cocaine, and it can respond to nitroglycerine, phentolamine, or verapamil. Beta-2 agonists appear to be safe but of minimal effect, and the nonselective propranolol may worsen coronary spasm.
Beta blockers are best avoided altogether, but adverse data are limited and many unknown cocaine-toxic patients have been given beta blockers without harm. In severe overdose, cocaine is essentially a sodium channel blocker/class IC antiarrhythmic, precipitating irreversible wide complex tachycardia. Most EPs will not know that bicarbonate may therefore be a quasi-antidote for cocaine cardiotoxicity. If one does not succumb to cardiac arrest, cocaine can cause multisystem failure, rhabdomyolysis, ARDS, coagulopathy, and renal failure as well as stroke and aortic dissection. Benzodiazepines, sometimes in gargantuan doses, are the safest way to combat not-yet-fatal cocaine poisoning.
While not a specific antidote, administering sodium bicarbonate for cardiac arrest due to cyclic antidepressant overdose should be considered. Like all interventions, it works best if given prior to death, and there is no proven way to reverse TCA-induced cardiac arrest. Bicarbonate is somewhat of an antidote for many aspects of TCA toxicity, probably due to the sodium content and the resultant alkalemia. Alkalinization of the serum (pH greater than 7.5) may increase protein binding of free TCA.
The standard approach is to give 1-2 ampules of crash cart bicarbonate followed by an infusion. By consensus, put 3 ampules of bicarbonate in 1 liter of D5W (now it's like normal saline), and infuse at 100-300 ml/hr. Most clinicians use significant QRS or QT prolongation as an indication for bicarbonate therapy. It is likely safe to give empiric bicarbonate in any situation where the EKG demonstrates a wide QRS, and a toxin is suspected. Numerous toxins can cause sodium channel blockade/wide QRS, including cocaine, propafenone, propoxyphene, methadone, procainamide, quinidine, and fluoride poisoning, to name a few bizarre ones not commonly considered.
Direct-acting vasopressors, like norepinephrine and not like dopamine, may be required for TCA hypotension. Note the section on lipid emulsion.
Local Anesthetic Toxicity
Most EPs will not encounter problems from local anesthetics, but anesthesiologists will tell you that too much of some, especially bupivacaine, can manifest refractory seizures and rapid cardiovascular collapse. These are often anesthetic misadventures. There is a rather unique semi-antidote for local anesthetic toxicity as well as for a number of other toxins that have lipid solubility. That intervention, with some reported anecdotal miracles, is IV lipid emulsion.
While bupivacaine cardiac arrest is the poster child for IV lipid emulsion therapy, this seemingly too-good-to-be-true nonspecific drug binder is well known to toxicologists, and now has gained the attention of the AHA. Unfortunately, these guidelines seem to ignore lipid emulsion for other toxins where it has rather impressive, but largely case-report success. Lipid emulsion (Intralipid), that white milky liquid used for parenteral feedings and a vehicle for propofol, has been used for calcium channel blocker, beta blocker, TCA, bupropion, qeutiapine, and anticonvulsant overdoses that by all analysis were historically bound for the morgue. It has no downside, so give it a try, earlier rather than later for the crashing overdose (Ann Emerg Med 2008;51:412), or visit the fascinating website www.LipidRescue.org.
Carbon monoxide is the leading cause of unintentional poisoning deaths in this country. This toxin not only reduces the ability of hemoglobin to deliver oxygen, but has a substantial albeit poorly defined immediate and delayed devastating toxicity to the brain and myocardium. Delayed or permanent neurological injuries are common in survivors who are seriously poisoned. In the absence of an exposure history, making the diagnosis in those minimally poisoned is a clinical coup in itself, but there is little to do for those severely poisoned or already moribund.
It would be unusual for a patient with cardiac arrest from carbon monoxide poisoning to leave the hospital. Routine care is suggested, and while hyperbaric oxygen has its supporters and the intervention is “considered” by the AHA, current evidence concludes that there is no proven benefit from this intervention. An ACEP clinical policy referenced in the guidelines concludes that improvement in neurologic outcome for CO poisoning is possible but unproven. (Ann Emerg Med 2008;51:138.) Although the AHA says HBO should be considered, supportive data are conflicting or, more precisely, simply lacking. A recent Cochrane Collaboration (2010) concluded that HBO has yet to be proven.
Cyanide poisoning can be encountered in suicide as well as in victims of smoke inhalation. Death is often rapid and toxicity irreversible. Recently the use of hydroxocobalamin, a cyanide scavenger, has been demonstrated to have antidote properties. It sucks up the cyanide, turning it into vitamin B12 (cyanocobalamin).
The often-used cyanide antidote kit containing sodium nitrite/sodium thiosulphate is theoretically helpful but no longer state of the art. Interestingly, the AHA states that 100% oxygen and hydroxocobalamin, with or without sodium thiosulphate, is a class I recommendation for cyanide poisoning. This antidote is often not available, and unfortunately, cyanide poisoning is quickly fatal. The clinician frequently does not know that cyanide was culprit, or one does not have the time to administer any antidote. In a suicidal ingestion of cyanide, the outcome is almost always a fatality. The EP may offer succor for the smoke inhalation victim, so consider cyanide and treat empirically if reasonable on clinical grounds (hypotension, coma, metabolic acidosis) prior to transfer to the burn center. There is no downside.
The AHA has no new or different guidelines for this condition, and it is sort of a toxin. The primary cause of death in lightning strike is cardiac arrest from VF or asystole. Survival following cardiac arrest from lightning strike is rare, but those who are saved are almost always the recipient of good bystander CPR and rapid defibrillation.
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Dr. Roberts is the chairman of emergency medicine and the director of the division of toxicology at Mercy Catholic Medical Center, and a professor of emergency medicine and toxicology at the Drexel University College of Medicine, both in Philadelphia.
Cochrane Statement on the Use of Hyperbaric Oxygen for Carbon Monoxide Poisoning
“Many people are poisoned by carbon monoxide gas each year, either intentionally (e.g., in suicide attempts) or by accident. Carbon monoxide interferes with oxygen transport in the body, and can also directly damage a variety of organs including the brain. The usual treatment involves removing the affected person from the source of the gas, general supportive care, and administering oxygen, which hastens the elimination of carbon monoxide from the body. High-pressure oxygen (hyperbaric oxygen) is only available at a few hospitals, and it is sometimes used to speed this process even further. However, the review of published trials found conflicting, potentially biased, and generally weak evidence regarding the usefulness of hyperbaric oxygen for the prevention of neurological injury.”
Source: Cochrane Reviews; http://bit.ly/CochraneHBO.
New Treatment for C. difficile
Clostridium difficile, a bacterial infection that can cause diarrhea and more serious intestinal conditions, affects several million people each year, approximately double the incidence of a decade ago. But there may be a new way to effectively treat the infection.
Researchers at the David Geffen School of Medicine at UCLA and the University of Texas Medical Branch at Galveston discovered a molecular process by which the body can defend against the effects of C. difficile infection.
“We are treating a disease caused by antibiotics with yet another antibiotic, which creates the conditions for re-infection from the same bacteria,” said study author Dr. Charalabos Pothoulakis, the director of UCLA's Inflammatory Bowel Disease Center and a professor of medicine in digestive diseases. “Identification of new treatment modalities to treat this infection would be a major advance.”
C. difficile, which is most commonly acquired by hospital patients, causes diarrhea and colitis by releasing two potent toxins into the gut lumen that bind to intestinal epithelial cells, initiating an inflammatory response. Researchers found that human cells in the gut are capable of releasing molecules that will neutralize these toxins, rendering them harmless. The researchers are preparing to launch clinical trials using their discovery as a new C. difficile therapeutic approach.
Readers are invited to ask specific questions and offer personal experiences, comments, or observations on InFocus topics. Literature references are appreciated. Pertinent responses will be published in a future issue. Please send comments to firstname.lastname@example.org. Dr. Roberts requests feedback on this month's column, especially personal experiences with successes, failures, and technique.
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