Chapter 21 – Neuroterrorism and Drug Overdose in the Neurocritical Care Unit


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 (CNS). 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).

Chapter 21 Neuroterrorism and Drug Overdose in the Neurocritical Care Unit

John J. Lewin III, Mohit Datta , and Geoffrey S. F. Ling


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 (CNS). 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 [Reference Chyka, Seger, Krenzelok and Vale1].

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. After 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 [Reference Chyka, Seger, Krenzelok and Vale1,2].

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 is achieved, 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 [Reference Proudfoot, Krenzelok and Vale3].

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.


Cocaine is a stimulant derived from the leaves of Erythroxylon coca. It inhibits presynaptic uptake of excitatory catecholamines, dopamine, and norepinephrine. Its euphoric and central excitatory effect is mainly due to the accumulation of these 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. Hemorrhagic stroke is usually secondary to elevated blood pressures or underlying vasculitis due to chronic cocaine use. Chronic cocaine use is associated with vasculopathy, which may predispose to the above stroke syndromes. Subarachnoid hemorrhage is a rare but serious presentation associated with cocaine use.

Management of these stroke syndromes is essentially the same as standard American Heart Association guidelines for acute stroke management. Cocaine use is not a contraindication for IV tissue plasminogen activator. Management of known cocaine-associated coronary vasospasm is largely symptomatic with oxygen, aspirin, and nitroglycerine. Rare cases may need angioplasty and stenting. If the cardiac enzymes continue to trend up, the patient should be referred for emergent angiography to rule out coronary thrombus. β-1-specific β-blockers (e.g. esmolol, metoprolol) are contraindicated in the acute blood pressure management of cocaine overdose as they may lead to unopposed α-1 receptor-mediated coronary vasospasm and/or a paradoxical increase in blood pressure.

Coconsumption of alcohol and cocaine (seen in >80% cocaine abusers) leads to altered cocaine metabolism. Transesterification leads to an active metabolite cocaethylene, which has similar pharmacodynamic properties to cocaine in the CNS and acts on the same receptors, thereby potentiating the stimulant and euphoric effects of cocaine. Cocaethylene has independent myocardial and CNS toxic effects.


Heroin is an opioid, and overdose leads to similar clinical presentation as outlined in the opioid section of this chapter. Heroin is chemically the diacetylated form of morphine and was first synthesized in the late nineteenth century. Bayer marketed the drug as “Heroin” and ever since then that has become the common street name for the drug. The acetylated form of morphine is more lipid-soluble and hence easily crosses the blood–brain barrier, leading to that instant “rush” experienced by IV heroin abusers. Heroin is metabolized by deacetylation and 6-acetyl morphine is the breakdown product that may be detected in urine and indicates heroin use. Heroin use can also lead to noncardiogenic pulmonary edema in rare cases and may require ICU management for ventilator support. Treatment is largely supportive.


Alcohol is a widely abused drug, and as such patients are routinely admitted to the NCCU for nonalcohol-related problems, but are concurrently in various stages of inebriation or withdrawal.

Alcohol is a sedative hypnotic drug. Like barbiturates, it is a global depressant. At low doses, inhibitory pathways are suppressed leading to net excitation. At progressively higher doses, drowsiness to lethargy to stupor and ultimately coma will ensue. Most inebriated patients can usually be managed conservatively and do not require intensive care monitoring. However, severely inebriated patients who present in stupor or coma may need airway protection. All patients should be hydrated to maintain euvolemia. Thiamine, 100 mg, IV/IM daily for five days is given to mitigate Wernicke–Korsakoff syndrome. Wernicke’s encephalopathy is due to acute thiamine deficiency, whereas Korsakoff psychosis is the long-term sequel.

In Wernicke’s encephalopathy, patients present with confusion, ataxia, ophthalmoplegia, and nystagmus. This syndrome leads to Korsakoff’s psychosis, which manifests as worsening confusion, confabulation, and amnesia. It is a result of lack of vitamin B1, which is thiamine. The classic lesions are mammillary body and thalamic degeneration. It is important to administer thiamine before glucose. During aerobic respiration, glucose is metabolized to pyruvate, which then enters the Krebs or citric acid cycle. However, this process requires thiamine. If glucose is administered when thiamine is deficient, Wernicke’s syndrome can be precipitated.

As these patients are typically malnourished, they should also receive folate, magnesium, multiple vitamins, and electrolyte replacement. If there is concern of ethanol withdrawal, then a benzodiazepine such as lorazepam may be given. Longer-acting benzodiazepines such as chlordiazepoxide or diazepam are effective but are often used less in the NCCU owing to their prolonged duration of action and potential for depressing mental status.

Opioid Analgesics

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 [Reference Hardman, Limbird and Gilman5].

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 [Reference Hardman, Limbird and Gilman5,Reference Haynes6].

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 long-term 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 [Reference Haynes6,Reference van Dorp, Yassen and Dahan7]. 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 [Reference van Dorp, Yassen and Dahan7].

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 [Reference van Dorp, Yassen and Dahan7].

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

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.


Unfractionated heparin (UFH) is a glycosaminoglycan with a molecular weight ranging from 3000 to 30,000 daltons. UFH is an antithrombotic agent that acts indirectly through antithrombin (AT) to inhibit several clotting factors: XIIa, XIa, IXa, Xa, IIa, and XIIIa. Blood clotting is fully inhibited in vitro at a concentration of 1 unit/mL of whole blood. A 10,000-unit bolus to a 70-kg male will lead to a blood concentration of 3 units/mL. The effect of this dose begins almost immediately and will last about 1.5 hours [Reference Powner, Hartwell and Hoots8Reference Hirsh, Anand, Halperin and Fuster10].

For UFH, partial thromboplastin times (PTTs) are measured at regular intervals. If the PTT is excessively high or there has been inadvertent overdose, then further administration is stopped. Usually, no further intervention is needed. However, if there is evidence of hemorrhage, then protamine sulfate, a heparin antagonist, may be given. Protamine acts by binding ionically to heparin to form an inactive complex.

The dose of protamine sulfate needed to reverse heparin effects fully is 1 mg/100 units of heparin with a maximum of 50 mg. Given heparin’s short half-life, only the last 2–3 hours of drug administered via a continuous infusion needs to be reversed. This is administered by slow IV bolus at a rate of <20 mg/min. Side effects of protamine sulfate are related to histamine release and are thus dyspnea, flushing, bradycardia, and hypotension. These are largely avoided by slow administration. There have been reports of hypersensitivity and are usually associated with patients allergic to fish [Reference Garcia, Baglin, Weitz and Sanama9,Reference Hirsh, Anand, Halperin and Fuster10].

When compared to UFH, subcutaneous administration of low molecular weight heparins (LMWHs) produces a more linear and reliable degree of anticoagulation. LMWHs have a higher ratio of antifactor Xa to antifactor IIa activity. This is relevant to toxicity as PTT cannot be used as a measure of LMWH anticoagulation, as the PTT is mediated via inhibition of thrombin (factor IIa). Antifactor Xa levels can be used as this is a pharmacodynamics measure of the anticoagulant effects of LMWHs. Many different LMWHs are available, and each possesses a different half-life, all of which are longer than UFH. The effects of UFH may last hours whereas LMWHs effects may last for hours to days. Also, unlike UFH, most LMWHs are primarily cleared via the kidneys, so renal dysfunction may prolong the half-life substantially [Reference Garcia, Baglin, Weitz and Sanama9Reference Laposata, Green and Van Cott11].

There is no well-established method for reversing the effects of LMWH. Protamine will only partially neutralize LMWH, about 60% of its effects. The dose is 1 mg of protamine for every 100 units of antifactor Xa activity. For enoxaparin, this is approximately 1 mg of protamine per milligram of enoxaparin to be reversed [Reference Powner, Hartwell and Hoots8,Reference Garcia, Baglin, Weitz and Sanama9].


Warfarin is a congener of dicumarol, which is derived from sweet clover. It is an antithrombotic agent that interferes with blood clotting by inhibiting the vitamin-K-dependent clotting cascade of factors II, VII, IX, and X.

The international normalized ratio (INR) of the prothrombin time (PT) is used to monitor the antithrombotic effects of warfarin. The management of warfarin therapy and elevated INR can be complex, and is beyond the scope of this chapter. The reader is referred to the American College of Chest Physicians’ Guidelines for more information [Reference Ageno, Gallus and Wittkowsky12].

In the event of serious bleeding, further warfarin administration is stopped and a prothrombin complex concentrate (PCC) should be administered. PCCs come in a variety of formulations carrying differing amounts of clotting factors. The one PCC that is FDA-approved to reverse the effects of vitamin K antagonists is Kcentra®, which contains the vitamin-K-dependent clotting factors II, VII, IX and X in the inactivated form as well as protein C and protein S.

Dosing of all PCCs is based on the Factor IX component. In the case of warfarin reversal, the recommended dosing of Kcentra® is based on the INR (INR 2–3.9 = 25 units/kg, INR 4–6 = 35 units/kg, and INR >6 = 50 units/kg) [13]. The reader is referred to the specific PCC product information for comprehensive dosing instructions and administration information. In addition, one can consider giving 1–10 mg of vitamin K by slow IV infusion. If needed, vitamin K can be repeated every 12 hours. In the event of life-threatening bleeding, both a PCC and 10 mg of IV vitamin K should be administered.

Direct Thrombin Inhibitors

Direct thrombin inhibitors, such as argatroban and bivalirudin, are a newer class of anticoagulants used in the settings of heparin-induced thrombocytopenia, and acute coronary syndromes. There are no well-studied reversal agents for this class of drug. Aside from stopping the infusion, consideration may be given to activated prothrombin complex concentrate (aPCC) or PCC [Reference Nutescu, Dager, Kalus, Lewin and Cipolle14].


The barbiturates are classic sedative hypnotic drugs. All share common chemical features, for example, the barbituric acid core. As such they have similar spectrums of action, such as inducing drowsiness and suppressing central ventilatory control centers. Pentobarbital may be considered the prototype of this class of drugs. However, more commonly used agents are thiopental, phenobarbital, amobarbital, and secobarbital [Reference Hardman, Limbird and Gilman5].

All are global CNS depressants. At therapeutic doses, they have minimal effect on the peripheral nervous system and tissue such as skeletal, cardiac, or smooth muscle. At toxic doses, these drugs have a depressant effect on the medullary vasomotor area and lead to cardiovascular compromise. Clinically, patients become increasingly lethargic with increasing dosage. An ECG will show slowing that progresses to burst suppression at high doses. At toxic doses, patients will be comatose, in respiratory arrest, hypotensive, and hypothermic [Reference Hardman, Limbird and Gilman5].

Medical management is primarily supportive, involving airway, mechanical ventilation, and cardiovascular care. If the drug was administered orally, activated charcoal should be given and to facilitate elimination, the urine may be alkalinized. Urinary alkalinization is more useful for long-acting agents such as phenobarbital which has a pKa of 7.2 and is water soluble. Extracorporeal removal via hemoperfusion may be considered. However, this is usually reserved for patients who are in extremis and are worsening in spite of conventional therapy [Reference Proudfoot, Krenzelok and Vale3,Reference Mohammed Ebid and Abdel-Rahman15].


Benzodiazepines are also sedative hypnotics. However, they are chemically distinct from barbiturates. Benzodiazepines contain a benzene ring fused to a seven-membered diazepine ring. Diazepam is the prototype of this class of drugs. Other commonly used congeners are midazolam, lorazepam, alprazolam, and clonazepam [Reference Hardman, Limbird and Gilman5].

These therapeutic agents share common clinical features. At low therapeutic doses, they cause sedation and muscle relaxation, and do not cause myocardial or ventilatory depression. At higher doses, there is increasing CNS depression from hypnosis to stupor. However, even at very high doses, none of these agents will cause true general anesthesia. To achieve surgical anesthesia, they must be used in combination with other drugs [Reference Hardman, Limbird and Gilman5].

Medical management is primarily supportive. If the only overdose drug is a benzodiazepine, then conservative management is best. Typically, even with very high doses, patients do not require airway protection, mechanical ventilation, or cardiovascular support. If this is their only medical problem, they do not require ICU care. When combined with other CNS depressants, such as alcohol or opioids, high levels of benzodiazepines can contribute to a patient’s comatose state. In such cases, more aggressive medical management is indicated, including advanced critical care [Reference Hardman, Limbird and Gilman5,Reference Amrein, Hetzel, Hartmann and Lorscheid16].

Another therapeutic option is flumazenil, a benzodiazepine antagonist. For management of known or suspected benzodiazepine overdose, the initial dose of flumazenil is 0.2 mg given intravenously over 30 seconds. If the desired response is not obtained after waiting 30 additional seconds, a dose of 0.3 mg can be administered over 30 seconds. Additional doses of 0.5 mg can be given over 30 seconds at one-minute intervals up to a total cumulative dose of 3 mg. The onset of action is rapid, often within one or two minutes. It can reverse any effects of benzodiazepines. The duration of action is about 45 minutes. Thus, when treating an overdose of long-acting agonists, additional doses of flumazenil may be needed. As this drug blocks GABA/benzodiazepine receptors, it has the potential to lower seizure threshold. As such, flumazenil can precipitate withdrawal (including refractory seizures and status epilepticus) in patients who chronically take benzodiazepines. This agent is generally reserved for patients who are comatose and have ventilatory and cardiovascular compromise in which benzodiazepine overdose is thought to contribute [Reference Hardman, Limbird and Gilman5,Reference Amrein, Hetzel, Hartmann and Lorscheid16].

Tricyclic Antidepressants

Tricyclic antidepressants (TCAs) are widely used medications. The prototypes of this drug class are imipramine and amitriptyline. Other TCAs are nortriptyline, desipramine, doxepine, amoxapine, and others. Their therapeutic mechanisms of action are serotonin and norepinephrine reuptake inhibition. These agents also have anticholinergic effects that contribute to their toxicity [Reference Hardman, Limbird and Gilman5].

The classic “TCA triad” of toxicity is Tonic–clonic seizures, Cardiovascular, and Anticholinergic. In addition to seizures, patients can develop delirium, agitation, and confusion, but will progress with increasing doses to obtundation and coma. Cardiovascular effects are described as “quinidine-like,” as conduction is slowed. The ECG changes include widened QRS complexes, prolonged PR intervals, AV conduction blocks, and, if severe, ventricular arrhythmias. Vasodilation and decreased myocardial contractility can lead to fatal hypotension and dysrhythmia. The ECG has prognostic value. If QRS is >100 ms, there is an increased risk of seizure and >160 ms, increased risk of dysrhythmia. Anticholinergic effects are delirium, hyperthermia, flushing, anhydrosis, dry mouth, anuria, ileus, and mydriasis. The clinical course of TCA toxicity is typically 48 hours [Reference Hardman, Limbird and Gilman5,Reference Kerr, McGuffie and Wilkie17].

Therapy is mainly conservative. For seizures, lorazepam (1–4 mg, IV) can be used. Phenytoin should be avoided as it can exacerbate TCA cardiovascular effects. If hypotension occurs, fluid resuscitation and vasopressor therapy should be initiated. Vasopressors that can be considered are epinephrine and norepinephrine, whereas dopamine is not recommended as it requires release of endogenous norepinephrine to be effective, which may be blocked by TCAs. In the event of arrhythmias, sodium bicarbonate (1–2 mEq/kg) should be given with a goal of arterial pH 7.45–7.55. Class 1a and 1c antiarrhythmics are contraindicated [Reference Kerr, McGuffie and Wilkie17].

Chemical and Biological Terrorism

Chemical and biological terrorism is a serious domestic concern. In 1984, a Salmonella attack was perpetuated in Oregon by the Rajneeshee cult and more recently, in 2001, the Amerithrax letter attacks. Outside of the United States, there have been many attacks on civilians. One particularly successive attack was the sarin attack in Tokyo. These and others underscore the importance of vigilance for both civilian and military medical systems worldwide. Awareness of this potential threat is important to the neurocritical care practitioner to ensure proper clinical management of patients [18].

In 1984, the Rajneeshee cult deposited a strain of Salmonella typhimurium on doorknobs, urinal handles, supermarket produce, and salad bars throughout an Oregon community. This resulted in 751 cases of severe gastroenteritis. Nearly 1000 patients sought treatment, which overwhelmed the local medical care system. Fortunately, there were no fatalities. This attack had followed the Tylenol® cyanide poisonings in the Chicago area in 1982, where seven fatalities were reported related to product tampering and placement of potassium cyanide into medication capsules. Similar attacks, possibly related to the intense media coverage of the Tylenol® scare, occurred subsequent to the original Tylenol® tampering case. The original case remains unsolved [Reference Fletcher19].

Internationally, one of the most striking cases of biological warfare-related civilian disasters is the Sverdlovsk (now Yekaterinburg) anthrax infections beginning in April of 1979. An apparent accidental release of aerosol containing weapons-grade Bacillus anthracis spores occurred in this region of the former Soviet Union. Exposed civilians over a 4-km area developed symptoms consistent with inhalation anthrax. There were 77 patients identified with inhalation anthrax, and of these, only 11 survived. To date, this is the most deadly anthrax event [Reference Woods20,Reference Wampler and Blanton21].

Perhaps the most illustrative episode is the Tokyo subway sarin gas poisonings in 1995 perpetuated by the Aum Shinrikyo cult. This is a good example of what can happen to a modern medical care system when encountering a terrorist attack. Initially, within the first few hours, a few hundred patients were brought to the hospital. However, ultimately, more than 5500 patients sought medical treatment. Among the casualties were unprotected healthcare providers who developed secondary contamination when treating victims. There were 12 deaths from the attacks, and at least 50 were seriously injured from organophosphate poisoning, including seizures. One important finding is that the vast majority of patients, about 80%, did not have evidence of nerve-agent exposure. Instead, they had a wide variety of complaints that were largely not attributable to sarin exposure. This very large category of patients has been called “the worried well.” However, their impact of significantly burdening a very busy medical care system during a critical period cannot be underestimated. This attack serves as a case study for the potential for modern biological and chemical terrorism, and the medical, social, and political consequences of such [18,22,Reference Kristof23].

In a terrorist attack, the demands placed on the individual provider and local medical care system can be overwhelming. Traditional approaches to triage and care delivery will be inadequate. Thus, it is crucial that preparation for such events is done in advance and that the system as a whole practices. In the event of a terrorist attack in which many casualties result, neurocritical care specialists may find themselves assisting outside of the NCCU, such as in a triage area, emergency department, or decontamination lane.

Biological Agents

Biological agents are attractive weapons to terrorists as these agents are inexpensive, relatively easy to procure, and present a time delay to onset of action that allows for successful deployment and escape from authorities. It has long been held that these agents are difficult to refine to a weapons grade, that is, in a size and form that is easily disseminated to cause maximal effect. In reality, weaponization of biological agents is within the ability of terrorists. From the Amerithrax letters case, FBI and other experts concluded that a very high grade of refined anthrax spores were used. The terrorist was able to achieve a particle size of 1–5 pm in diameter, which is ideal to cause pulmonary anthrax, the most lethal manifestation of this disease [Reference Woods24].


Bacillus anthracis is the bacteria responsible for anthrax. It has been manufactured in a weaponized form by the United States and several other nations, including the former USSR. Several days after the events of September 11, 2001, the anthrax mail attacks commenced, resulting in at least 22 cases of anthrax and five deaths. The historical potential for anthrax to present as a hemorrhagic meningoencephalitis makes this agent of particular interest to the neurocritical care physician [Reference Meyer25].

Inhalation anthrax is especially rare. Thus, it is advised that even a single case of inhalation anthrax should prompt local health officials to suspect a terrorist attack. Historically, this has been referred to as “wool sorter’s disease,” owing to its association with processing of hides, furs, and wool in industrial mills.

Clinical symptoms present after an incubation period of one to six days, although there are reports of cases of inhalational anthrax that presented up to six weeks after exposure. Initial symptoms are nonspecific, such as fever, malaise, headache, and respiratory complaints. Patients with inhalational anthrax do not show typical signs of routine upper respiratory infections, and pneumonia is uncommon. Physical examination findings are limited, but often patients present with tachycardia.

The diagnosis is based on epidemiologic data and chest radiographic findings of widened mediastinum and pleural effusions. This is likely due to a hemorrhagic mediastinitis. Chest radiography or chest computed tomography (CT) should be performed in all suspected cases. In the 2001 attack, these were abnormal in every patient with inhalational anthrax. Organisms are not usually isolated from the sputum of patients. Instead, the majority of cases have been confirmed by blood culture, which can detect anthrax in its early stage. Other laboratory abnormalities include elevated transaminases, elevated white blood cell count with a polymorphonuclear leukocyte (PMN) predominance (average of 9800 cells/dL in the 2001 Amerithrax attacks).

As the disease progresses, subsequent symptoms include respiratory distress and the development of septic shock. Death may follow severe pulmonary symptoms in one to two days unless intensive care support and proper antimicrobial management is instituted.

Mortality reports vary widely from 45% to 99%, likely the result of modern intensive care management of the inhalation form of the disease. Evidence of this was taken from the Amerithrax letters of 2001 in the United States, which were associated with the lower end of this mortality spectrum owing to aggressive treatment and recognition of the disease [Reference Woods24].

Cutaneous anthrax is the most common naturally occurring form of the disease. The most salient feature of cutaneous anthrax is a painless skin lesion that, over the course of days, can progress to a vesicle, ulcer, and then eschar with surrounding edema. These lesions can be cultured unless the patient has begun systemic antibiotic treatment. Gram stain will often show Gram-positive bacilli. Mortality from the cutaneous form of anthrax is approximately 20%.

Gastrointestinal anthrax is another highly fatal form of this disease and occurs after eating infected meat. This is another possible mode of terrorist attack. Gastrointestinal anthrax can present as an acute gastroenteritis, acute abdomen with peritoneal signs, or diarrheal illness. Stool culture is not very sensitive for anthrax and the diagnosis is usually made via polymerase chain reaction (PCR) and immunostaining of either peritoneal or ascetic fluid. Mortality from gastrointestinal anthrax ranges from 60% to 80% [Reference Woods24,Reference Osterbauer and Dobbs26].

Anthrax-associated hemorrhagic meningoencephalitis is seen in approximately 50% of cases of inhalational anthrax and can present after either the inhalational or cutaneous route of infection. This usually manifests as multifocal intracerebral hemorrhage well visualized on head CT. If the patient has severe pulmonary symptoms or cutaneous manifestations concerning for anthrax, prompt sampling of the cerebrospinal fluid (CSF) should be performed. Often the organism can be seen on Gram stain of the CSF, as Bacillus anthracis appears as large Gram-positive bacilli singly or in short chains, with squared-off ends. Other CSF findings are low glucose level, elevated protein, red blood cells, and a leukocytosis >500 cells/mL. Hemorrhagic meningoencephalitis from anthrax is an ominous condition, as death usually ensues within one week of diagnosis.

Other neurologic manifestations of anthrax include headache, mental status changes, visual field deficits, and changes in acuity. These symptoms can present with any mode of infection [Reference Meyer25,Reference Osterbauer and Dobbs26].

Treatment of anthrax is dependent on the mode of bacterial inoculation. With inhalational anthrax, the emphasis is on ventilatory support and intravenous antimicrobials (Table 21.1). With early institution of antibiotics, survival may approach >50%. In adults, initial therapy should begin with ciprofloxacin 400 mg IV q 12 h or doxycycline 200 mg IV followed by 100 mg IV q 12 h. In children, the doses are ciprofloxacin 10–15 mg/kg (maximum 400 mg) IV q 12 h, or doxycycline (100 mg IV q 12 h for children >8 years and >45 kg, and 2.2 mg/kg IV q 12 h for children <8 years or <45 kg). The use of tetracyclines in children is generally discouraged.

Aug 17, 2020 | Posted by in ANESTHESIA | Comments Off on Chapter 21 – Neuroterrorism and Drug Overdose in the Neurocritical Care Unit
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