Knowledge of proper clinical management of drug overdose and chemical and biological toxin exposure is important for the neurocritical care specialist. Many of the common offenders principally affect the central nervous system .
Even those that do not will lead to a severely incapacitated state when overdosed such that the afflicted patient will require critical care in an intensive care unit (ICU). Typically, drug overdose that occurs outside of the hospital is first managed in the emergency department and then, if critical care is needed, in the medical ICU.
However, there are medications that are used in the neurocritical care unit (NCCU) that may lead to toxic overdose either through inadvertent provider error or because of changes in a patient’s drug elimination. The most common offending medications are analgesics, antipyretics, mood stabilizers, and sedative hypnotics.
Sadly, there is another circumstance in which the neurointensivist may be called on to treat patients suffering from toxic overdose: a chemical or biological terrorist act. In this situation, emergency medicine and medical critical care physicians will be quickly overwhelmed, and it is certain that the neurocritical care specialist will be called upon to assist.
Thus, a discussion of the clinical management of patients suffering from exposure to the leading known chemical weapons is warranted. The opinions presented herein belong solely to those of the authors. They do not nor do they imply belonging to or endorsement by the Uniformed Services University of the Health Sciences, U.S. Army, Department of Defense, or U.S. Government.
General Management of Drug Overdose
The most common medications leading to overdose are analgesics, antipyretics, sedative hypnotics, anticonvulsants, anticoagulants, antidepressants, bronchodilators, and antiarrhythmics. All are common medications used in the NCCU. General clinical management begins with the ABCs: airway, breathing, and circulation. For patients with compromised mental status, adequacy of the airway in terms of both patency and patient’s ability to protect it must be determined.
If the patient has a Glasgow Coma Scale (GCS) score <8, then an artificial airway should be placed, such as by endotracheal intubation. Mechanical ventilation and supplemental oxygen in such circumstances is not always needed, but may be if the patient has aspirated.
Appropriate hemodynamic management, consisting of fluid resuscitation, vasopressors, and/or inotropes may also be required in cases resulting in myocardial depression and/or vasodilation. After ensuring the above, the clinician will need to recognize if the patient’s condition is caused by a pharmacologic agent. The optimal way to identify the offending agent is to execute a careful and systematic approach beginning with taking a good history and culminating with laboratory tests.
History and review of systems are especially useful. During overdose, the patient may not be able to provide details, but the medical record and witness accounts may be illuminating.
The physical exam may also reveal specific clinical clues such as pinpoint pupils in narcotic overdose or nystagmus in anticonvulsant excess. Laboratory testing may provide the critical evidence, such as metabolic acidosis in aspirin toxicity or excessive drug levels in barbiturate overdose. After ascertaining that the patient is suffering from an overdose, pharmacokinetic-directed interventions should be initiated. Further drug absorption needs to be abated.
Activated charcoal is the most commonly used agent for this purpose. Owing to its extensive surface area, activated charcoal binds many drugs that have not yet been absorbed across the gastrointestinal tract. Once bound, the charcoal–drug mixture is excreted fecally.
There is also evidence that activated charcoal interferes with enteroenteric, enterogastric, and enterohepatic recirculation of absorbed drug. The most common side effect is emesis, which has largely been controlled by removing sorbitol from preparations. It should be noted that rigorous scientific evidence is lacking that supports activated charcoal efficacy.
In vitro adsorption studies are not always predictive of the drug’s effects in vivo. Therefore, human studies are necessary to determine efficacy of activated charcoal for any given drug or chemical.
In accordance with recent American Academy of Clinical Toxicologists and the European Association of Poison Centres and Clinical Toxicologists (AACT/EAPCCT) guidelines, if the drug was ingested within one hour, then activated charcoal can be given. If not, activated charcoal will have minimal impact.
Before treatment, it is critical that airway protection is established to minimize aspiration of charcoal or emesis. Once airway protection is accomplished, activated charcoal can be administered via a nasogastric tube. The recommended dose for adults is 25–100 g (1–2 g/kg). Dilute with a minimum of 240 mL of water for each 20–30 g of activated charcoal as an aqueous slurry. A
fter the initial dose, charcoal can be administered every hour, every two hours, or every four hours at doses equivalent to 12.5 g/h. Activated charcoal should be continued until relevant laboratory parameters (i.e. drug concentrations) improve. There is no recommended maximum dose. For some agents, elimination may need to be enhanced through optimizing elimination conditions, such as alkalizing the urine.
Urine alkalinization can be considered when the drug is a weak acid and is water soluble, such as barbiturates, salicylates, methotrexate, and lithium. Urinary alkalinization can be achieved in a number of ways. The suggested clinical approach is to dilute 150 mEq of sodium bicarbonate in 1 L of D5W or sterile water.
Close monitoring and supplementation of serum potassium should be performed, so as to minimize development of hypokalemia. The infusion rate should be two to four times higher than the usual IV fluid maintenance rate, which results in 200–400 mL/h for most adults. The goal urine pH is 7.5–8.5 with additional boluses and/or adjustments to the infusion rate as needed. Urine pH should be monitored every 15–30 minutes until the goal urine pH isachieved, and then every hour thereafter.
At the beginning, baseline serum potassium and other electrolytes, creatinine, glucose, and arterial pH are needed. Abnormalities should be corrected. Although reported complications are rare, there is the potential for causing hypokalemia, hypocalcemia, reduced oxygen delivery to tissue as the oxyhemoglobin dissociation curve is shifted to the left, cerebral vasoconstriction, and fluid overload pulmonary edema. Every hour thereafter, serum potassium and arterial pH should be checked. Arterial pH should not exceed 7.50. Urine output should not exceed 200 mL/h.
Recreational Drug Abuse and Overdose
Recreational drug abuse continues to be a major health concern all over the world and has reached epic proportions in certain metropolitan cities in developed countries. Drug abuse and its associated risk-taking behavior makes this population especially vulnerable to HIV, hepatitis C, and hepatitis B, and these comorbidities can make their clinical presentation and subsequent management particularly challenging. The common offenders are cocaine, heroin, amphetamines, marijuana, lysergic acid diethylamide (LSD), 3,4-methylenedioxy methamphetamine (MDMA), morphine, codeine, various inhalants, and derivatives of the above-mentioned compounds.
A detailed description of all these agents and their toxicities are beyond the scope of this chapter; however, we would like to highlight a few points in reference to cocaine and heroin overdose, and alcohol abuse. excitatory neurotransmitters and subsequent up-regulation of their receptors.
The neurotoxic and cardiotoxic effects of cocaine are mostly due to downstream effects of norepinephrine, up-regulation of endothelin receptors in vessel walls, platelet activation and aggregation, and sodium channel blockade (responsible for its local anesthetic effect). Patients with an acute overdose usually present with an acute cerebrovascular accident or coronary syndrome, or both.
The clinical presentation may be that of acute stroke or myocardial infarction (MI), but often the patient is agitated, confused, or comatose secondary to the intracranial pathology or due to concomitant drugs in the system. Pupils are large and the patient is usually flushed and diaphoretic due to sympathetic overstimulation. Blood pressure is often very high and not uncommonly the patient presents with hypertensive urgency/emergency.
The electrocardiogram (ECG) may show changes consistent with an acute coronary syndrome and/or left ventricular failure. A prolonged QTc interval is often seen secondary to its sodium channel blocking effects. CNS syndromes include ischemic and hemorrhagic stroke. Etiology for thrombosis may be intracranial dissection secondary to uninhibited α-agonist action of norepinephrine, in situ thrombosis due to platelet activation and platelet-rich thrombi.
Morphine is the prototypic drug of the opioid class of drugs. Derived from opium, it is an alkaloid. Most of the clinically used narcotic analgesics are derivatives of morphine or are chemically closely related.
Collectively, these are known as opioids and include drugs such as codeine, oxycodone, meperidine, fentanyl, methadone, buprenorphine, heroin, and hydromorphone. As such, the therapeutic strategy for managing morphine overdose can be applied to these other opioids. The typical clinical presentation of narcotic analgesic overdose is a triad of “coma, respiratory depression, and pinpoint pupils.” The primary mechanism leading to death from overdose is respiratory arrest.
Although morphine and its congeners can lead to peripheral vascular dilation via histamine release, severe hypotension is not characteristic of opioid overdose. Thus, cardiac and cardiovascular compromise is uncommon until profound hypoxia occurs. Seizures are more typically related to meperidine and propoxyphene toxicity.
The therapy of choice for emergent reversal of opioid overdose is immediate administration of naloxone, an opioid antagonist, at 0.4 mg, IV or 0.8 mg, IM. In nonemergent situations, 0.4 mg can be diluted in 9 mL of 0.9% NaCl to make a 40 μg/mL solution. Between 40 and 80 μg (1–2 mL) IV is given every two minutes until the opioid effects are adequately reversed.
Giving naloxone in this manner ensures the minimally effective reversal dose, to allow for better pain control and minimization of withdrawal phenomenon. This is particularly relevant for patients with chronic pain on longterm opioid therapy. The ideal route of administration is intravenous but it can be given via an endotracheal tube as well (the dose is 2 to 2.5 times the IV dose). Naloxone should not be given orally because it is rapidly degraded via first-pass effect through the liver. Naloxone is effective for reversing all opioid effects. The response is within a minute or two and lasts for up to an hour.
If recovery is incomplete, higher doses may be used, but one should consider also the possibility that another class of drug may be contributing as well. An important aspect of naloxone therapy is the short duration of action. Thus, repeated doses of naloxone may be needed until the causative agent is completely eliminated.
In the ICU setting, this can be via an IV infusion or periodic dosing. Untoward effects of naloxone are uncommon. However, naloxone can precipitate an acute opioid withdrawal syndrome because it causes agonists such as morphine to vacate opioid receptors. Rarely, when given in very high doses, naloxone can result in pulmonary edema, agitation, and cardiac arrhythmia.
Chronic use of opioids leads to physical dependence. Thus, abrupt cessation or reversal of dosing will lead to withdrawal Controlled withdrawal from opioid dependence and management of symptoms are achieved differently from acute intoxication and are beyond the scope of this chapter.
Commonly Used Therapeutics in the NCCU
Phenytoin and fosphenytoin (a pro-drug of phenytoin) are more commonly used drugs in the NCCU. Overdose is uncommon, but has significant potential consequences should this occur. At blood concentrations exceeding therapeutic levels, >20 μg/mL, the most common clinical findings are nystagmus, ataxia, diplopia, and vertigo.
This is related to the excitatory effect in the cerebellum. As blood levels further increase, to >40 μg/mL, patients may experience hyperactivity, hallucinations, and confusion. At severely toxic levels, >40 μg/ mL, patients become lethargic and, at >50 μg/mL, may progress to decerebrate rigidity and coma. Cardiac complications of arrhythmias and hypotension are more commonly associated with intravenously administering the drug too rapidly. However, at toxic levels, these cardiovascular effects can be seen.
Phenytoin is eliminated via a saturable hepatic microsomal enzyme system. Thus, elimination follows zero-order kinetics, which means a certain amount of drug is metabolized over time, as opposed to a certain percentage. As the blood concentration becomes higher, the time to eliminate the drug fully becomes progressively longer. Medical care is primarily supportive. If the overdose was oral, then activated charcoal may be given. Hepatic function will need to be determined and carefully monitored as an untoward sequel may be hepatic failure.
Author: John J. Lewin III, Mohit Datta, and Geoffrey S. F. Ling