Many clinical manifestations of toxicity develop immediately following cocaine use. These are typically associated with the sympathetic overactivity, and their duration of effect is predictable based on the pharmacokinetics of cocaine use. Other manifestations, such as those associated with tissue ischemia, may present in a delayed fashion, with a clinical latency of hours to even days after last cocaine use. The reasons for this delay are not clear but may relate to the presence of an altered sensorium associated with acute cocaine use and its anesthetic effects (see Cessation of Use below).
Vital sign abnormalities that develop during cocaine toxicity are characteristic of the sympathomimetic toxic syndrome. Thus, varying degrees of hypertension, tachycardia, tachypnea, and hyperthermia occur. Although any of these vital sign abnormalities can be life threatening, experimental and clinical evidence suggests that hyperthermia is the most critical.23,65,138 Initially, with typically used doses, and at any time with a massive dose, apnea, hypotension, and bradycardia can result, all from direct suppression (anesthesia) of brainstem centers.117,130,144 These effects are fleeting and rarely noted when patients present to health care, as either the sympathetic overdrive rapidly ensues, or sudden death results. Additional sympathomimetic findings include mydriasis, diaphoresis, and neuropsychiatric manifestations.
Cocaine produces end-organ toxicity in virtually every organ system in the body. These events result from vasospasm, hemorrhage secondary to increased vascular shear force (dP/dT), or enhanced coagulation. Each organ system is discussed separately in the following sections.
Seizures, coma, headache, focal neurologic signs or symptoms, or behavioral abnormalities that persist longer than the predicted duration of effect of cocaine should alert the clinician to a potential catastrophic CNS event. Hemorrhage can occur at any anatomic site in the CNS. Subarachnoid, intraventricular, and intraparenchymal bleeding are all well described in association with cocaine use.2,39,125,136,171,194 Early discussions suggested an underlying predisposition due to the presence of arteriovenous malformations or congenital aneurysms,228 but subsequent larger studies failed to support this analysis, suggesting that effects can occur independently of preexisting disease.2,156,218 Ruptured intracerebral aneurysms in cocaine users are almost exclusively in the carotid artery circulation.2,156,218 Presumably, CNS bleeding is a manifestation of abnormal shear force. Spontaneous extraaxial bleeding is also associated with cocaine use.183
Both vasospastic infarction and transient ischemic attack are reported in association with cocaine use.39,40,125 In one epidemiologic study, women younger than age 45 years who had strokes were seven times more likely to report cocaine use than controls.168 Patients can present with any of the classic physical findings associated with thrombotic or embolic stroke. Vasospasm can injure the spinal cord, resulting in paralysis from an anterior spinal artery syndrome.39,150
Seizures are commonly provoked by cocaine use.83,153 Cocaine use can serve as a trigger in patients with epilepsy, although an underlying focus is not necessary for seizures to occur.113
Headache is also well described in cocaine users. While the exact mechanism is unclear, hypertension or dysregulation of neurotransmitters may be contributory. In addition to typical tension headache, classic migraine and cluster headaches are also reported.166,185
Sympathetic excess produces mydriasis through stimulation of the dilator fibers of the iris with characteristic retention of the ability to respond to light. Like other mydriatics, cocaine can produce acute narrow angle-closure glaucoma.71 Vasospasm of the retinal vessels causes both unilateral and bilateral loss of vision.82,127 Additionally, although cocaine produces excellent corneal anesthesia, it is highly toxic to the corneal epithelium. Following application of cocaine to the eye, the superficial corneal layer is shed, resulting in pain and decreased acuity.172 The loss of eyebrow and eyelash hair from thermal injury associated with smoking crack cocaine is called madarosis.206
Chronic intranasal insufflation of cocaine can produce perforation of the nasal septum. This finding most likely results from repeated ischemic injury with resultant cartilage loss. This ischemia is usually asymptomatic, and necrotic tissue is sloughed. At least one reported case of wound botulism (Chap. 41) has been associated with intranasal insufflation. Presumably this resulted from accumulation of necrotic tissue in the nose, serving as a culture medium for Clostridium botulinum.115.
Angioedema and oropharyngeal burns, located as far distally as the esophagus, are associated with smoking crack cocaine.21,26,107,145 These effects are most likely the result of inhalation or ingestion of superheated fumes and hot liquid (from the smoking apparatus) rather than direct toxicity from cocaine.
Pneumothorax, pneumomediastinum, and pneumopericardium are reported following both smoked and intranasal cocaine use.134,173,187,212,215 These findings do not result directly from cocaine toxicity but rather are epiphenomena related to the mechanism of drug use. Following insufflation or inhalation, the user commonly performs a Valsalva maneuver in an attempt to retain the drug. Bearing down against a closed epiglottis increases intrathoracic pressure, and an alveolar bleb can rupture against the pleural, mediastinal, or pericardial surfaces.
Cocaine use exacerbates reversible airways disease, and it is common for patients to present with shortness of breath and wheezing.47,124,160,177 Like so many manifestations of cocaine toxicity, it is unclear whether this is a direct effect of cocaine or related to inhalation of some contaminant of the drug. However, as discussed above, the M2 agonistic effects of the pyrolysis metabolite AEME might be contributory.
Crack lung is the term given to an acute pulmonary syndrome that occurs after inhalational use of crack cocaine. The syndrome is a poorly defined constellation of symptoms, including fever, hemoptysis, hypoxia, acute respiratory distress syndrome, and respiratory failure. It is associated with diffuse alveolar and interstitial infiltrates on chest radiography.173 Histopathology shows diffuse alveolar damage and hemorrhage with inflammatory cell infiltration and hemosiderin-laden macrophages. Eosinophilia was noted in several cases.53 The syndrome has been variously attributed to impurities mixed with the crack, carbonaceous material generated from pyrolysis, and direct cocaine toxicity.
Vasospasm and subsequent thrombosis of the pulmonary artery or its branches can produce pulmonary infarction.42 Patients present with shortness of breath and pleuritic chest pain characteristic of a pulmonary embolus. Clinical signs and symptoms of ventilation–perfusion (V/Q) mismatch (Chap. 29), as well as abnormalities on arterial blood gas analysis, are noted.
Chest pain or discomfort is a common emergency department complaint in cocaine users.17 Cocaine use is associated with cardiac ischemia and infarction in young people and may account for as much as 25% of myocardial infarctions in patients younger than 45 years of age.170 Although myocardial infarction is of concern, only approximately 6% of patients with complaints referable to the heart will manifest biochemical evidence of myocardial injury.88,222 Many others will have an ischemic cardiac event, but for the remainder, the differential diagnosis is broad.118 Entities to consider include the pulmonary and esophageal etiologies described previously, referred abdominal symptoms (see Abdominal), chest wall injury,37,62,94,126,128 aortic dissection, coronary artery dissection,186,203 and dysrhythmias. No single sign or symptom or combination of signs and symptoms reliably identifies cardiovascular injury from among the discussed differential diagnosis.88
Catecholamine-induced direct myocardial catecholamine toxicity contributes to both acute and chronic cardiac disease. Takotsubo cardiomyopathy is a reversible form of left ventricular apical ballooning associated with myocardial ischemia in the absence of atherosclerotic lesions. It is thought to result from catecholamine toxicity on the myocardium during high levels of stress and is also reported after cocaine use.5 Chronic cocaine use is associated with a dilated cardiomyopathy,76,118 the etiology of which is presumed to be the result of repeated subclinical ischemic events. Patients may present with signs and symptoms of congestive heart failure or pulmonary edema. The pathologic finding of contraction band necrosis also suggests that there may be some direct catecholamine toxicity as this finding only commonly occurs with cocaine and amphetamine use, pheochromocytoma, and in patients receiving high-dose vasopressors.51,219
Abdominal pain, or other gastrointestinal complaints, suggests a broad differential diagnosis. Cocaine users have a disproportionate incidence of perforated ulcers.123,165,197 The etiology has not been elucidated but may be related to local ischemia of the gastrointestinal tract or increased acid production associated with sympathetic activity. Vasospasm produces ischemic colitis that can present with abdominal pain or bloody stools.128,155 More severe vasospasm, with or without thrombosis, can lead to intestinal infarction56,77,91,161 with attendant hypotension and metabolic acidosis. Signs and symptoms of bowel obstruction such as vomiting or distension might suggest body packing (gastrointestinal drug smuggling). Although less common, splenic157 and renal infarctions44,149,182 may also occur. Spontaneous hemoperitoneum is also reported, although occult trauma could not be definitively excluded.10
Animals frequently develop hepatotoxicity following cocaine administration. In human cocaine users, minor elevations of liver enzyme concentrations are common and rarely associated with symptoms.19,114 When more severe liver injury occurs, it is usually associated with multisystem organ dysfunction from hyperthermia or another type of hepatic injury.6 Isolated hepatic injury from cocaine is distinctly uncommon and may result from differences in metabolic pathways, as animals are known to make a hepatotoxic metabolite of cocaine that has not been described in humans.217
Rhabdomyolysis is common in all conditions that produce an agitated delirium and or hyperthermia; cocaine is no exception.31,93,179 Unlike most other toxicologic disorders, however, psychomotor agitation is not a prerequisite for cocaine-associated rhabdomyolysis.231 Muscle injury may result from vasospasm or direct muscle toxicity; however, the mechanism remains unclear. Patients with cocaine toxicity present with a spectrum of illness that ranges from asymptomatic enzyme and electrolyte abnormalities characteristic of rhabdomyolysis, to localized or diffuse muscle pain, to frank compartment syndrome and acute kidney injury.45
Limb ischemia associated with cocaine use is reported.66 Vasospasm, accelerated atherogenesis, and increased thrombogenesis (see Pathophysiology) place users at increased risk.
Traumatic injury is also fairly common in the setting of cocaine use.140 Clinicians should be aware of the possibilities of occult fractures or other injuries that may be masked by the anesthetic properties of cocaine or the patient’s altered level of consciousness.130,139
The neuropsychiatric effects of cocaine are most likely dose dependent. Low-dose administration produces alertness, exhilaration, hypersexual behavior, and other “desired” effects. These effects rarely bring users to health care facilities. As the cocaine dose increases, agitation, aggressive behavior, confusion, disorientation, and hallucinations can develop.
Other possible manifestations include a variety of movement disorders that most likely result from depletion or dysregulation of dopamine. Patients may develop acute dystonias22,50,216 or choreoathetoid movements that have been referred to as “crack-dancing.”38,67
The majority of obstetrical findings associated with cocaine use involve developmental problems in the fetus and neonate and are probably a result of a combination of chronic vascular insufficiency from cocaine-induced spasm of the uterine artery or distal vessels and other risk factors, such as poor maternal nutrition, cigarette smoking, and a lack of prenatal care (Chap. 31). These events are extensively reviewed elsewhere.24,48,196 Acute cocaine use during pregnancy is associated with abruptio placentae, causing patients to present with abdominal pain and vaginal bleeding.1,52 The remaining maternal and fetal complications comprise every possible complication described in nonpregnant patients.