A 14-year-old girl presented to the emergency department at 5:30 am with headache, vomiting, and lethargy. The preceding evening she had been out of the house socializing with friends, and had returned home at the expected time. However, her parents perceived her to be less active than usual and easily irritated before she went to sleep. At 4:30 am, she awakened and vomited twice. She was bothered by a sharp, bitemporal headache (the "worst of her life") that brought her to tears. Her parents gave her some acetaminophen and settled her back in bed. An hour later, she was difficult to arouse and an ambulance was summoned.
The patient had no previous hospitalizations and was not taking any medications. There was no known history of head trauma, recent fevers, or substance abuse.
On arrival to the emergency department, the patient was poorly responsive. She would open her eyes only briefly to physical or loud verbal stimuli, and she could infrequently provide soft, one-word answers to simple questions. Her airway was patent. Despite her somewhat shallow breathing, her hemoglobin oxygen saturation was 98% in room air. The pressure on the medical team became more palpable when it was noted that she was hypertensive with a blood pressure of 196/97 mm Hg. Her heart rate was 52 beats per minute and she was afebrile.
An examination of the head revealed no evidence of traumatic injury. Her pupils were equal and reactive, and no papilledema was evident. No signs of meningeal inflammation were elicited. The lungs were clear to auscultation, and the cardiac examination was unremarkable except for a mild sinus bradycardia. Her abdomen was soft without organomegaly. No rashes were evident. Cranial nerve function was intact and deep tendon reflexes were symmetric.
The combination of severe headache, vomiting, obtundation, hypertension, and bradycardia likely indicated high intracranial pressure. The rapidity of the illness suggested intracranial hemorrhage, rather than tumor or pseudotumor, as the working diagnosis. Without a history or signs of traumatic injury, subarachnoid hemorrhage due to rupture of an arteriovenous malformation or a vascular aneurysm seemed most likely.
Nontraumatic subarachnoid hemorrhage from intracerebral aneurysm or arteriovenous malformation is rare within the pediatric population. The overall incidence is estimated to be 10.5 per 100,000 person-years,1 with only 0.5% to 3.1% of these cerebral aneurysms diagnosed in childhood.2 Despite the rarity of the condition, early recognition of subarachnoid hemorrhage is crucial because it has a 3% to 26% prehospital mortality rate, and a significant proportion of those patients arriving to the hospital alive may die before definitive neurosurgical care is provided.1 Papilledema may not be found in an adult during the first 24 hours following an acute rise in intracranial pressure, so it was not unexpected that it was absent in this patient. The classic progression from increase in intracranial pressure to cerebral herniation includes headache, vomiting, depression in the level of consciousness, occulomotor nerve compression, hemiparesis or decerebrate posturing, and, finally, alteration of brain stem control of vital signs. The brain stem response to cerebral herniation, often referred to as CuSrUTIg7S triad, includes bradycardia, hypertension, and irregular respirations. A fixed and dilated pupil with loss of medial gaze indicates an operative emergency.
Even without these pupillary signs, emergent evaluation of our patient's brain was warranted. To much surprise and relief, the results of a computed tomography scan of the brain were normal.
A cranial computed tomography scan can have normal results in the presence of subarachnoid hemorrhage,3 and lumbar puncture may be needed to confirm the diagnosis in some cases. However, hypertension and bradycardia are terminal signs of cerebral herniation, and such brain injury would not be missed. Furthermore, the respiratory pattern, results of the motor examination, and pupillary response remained normal. With intracranial hemorrhage excluded, it was time to cast a wider diagnostic net.
The girl's slender body habitus did not indicate a potential third-trimester pregnancy complicated by toxemia. A central nervous system infection seemed unlikely given the lack of fever, meningeal irritation, or tachycardia, but remained a consideration. Several intoxicants can cause hypertension, but cocaine, amphetamines, and anticholinergic drugs would all be expected to result in agitation and tachycardia. An additional consideration was that this patient was suffering from hypertensive encephalopathy due to renal parenchymal disease, pheochromocytoma, or endocrine disease.
The laboratory investigation included a white blood cell count, platelet count, and serum hemoglobin concentration that were within laboratory standards for age and sex. The serum creatinine concentration was normal. An electrocardiograph revealed sinus bradycardia with normal intervals. Urinalysis was unremarkable, and pregnancy was excluded. Interestingly, a urine toxicology screen for drugs of abuse was positive for amphetamine.
Amphetamines are drugs that physiologically mimic the sympathetic nervous system, such as those commonly prescribed to children for attention-deficit hyperactivity disorder. They are also found in many over-the-counter decongestant products and diet aids. Amphetamines, including methamphetamine and synthetic derivatives such as 3,4-memylenedioxymemamphetamine ("ecstasy"), are also popular recreational drugs of abuse. Hypertension is an expected occurrence after overdose with these drugs, but bradycardia would not be expected from sympathomimetic excitation of the heart.
In the evaluation of a patient with suspected drug overdose, close examination of the mental status, vital signs, pupillary size and reactivity, bowel function, and skin can be productive in identifying recognizable toxic syndromes.4 The characteristic autonomic "toxidromes" are presented in Table 1. The presence of equal and reactive pupils was an important clue to exclude cerebral herniation. The recognition that the pupils were mydriatic to 6 mm in diameter was another clue in identifying this patient's toxidrome. It was also noted that the patient was sweating, but had normal bowel activity to auscultation. Hypertension, mydriasis, and diaphoresis seemed to corroborate amphetamine intoxication if the bradycardia could be explained.
A solution to the bradycardia conundrum was found through consideration of the distinct toxidromes occurring imthin the cholinergic and the sympathomimetic toxic syndromes. The parasympathetic, or cholinergic, receptors include those with both muscarinic and nicotinic effects. Likewise, varied alpha-adrenergic and betaadrenergic receptors exist within the sympathetic system. The major clinical actions of the various sympathetic receptors are summarized in Table 2. A specific alpha-adrenergic agonist might be expected to produce hypertension and mydriasis without tachycardia. Indeed, the physiologic baroreceptor response to hypertension should be reduction in heart rate.
The clinical effect of most sympathoinimetic drugs is short-lived. The patient's blood pressure and consciousness improved within a few hours. She had not been prescribed any stimulants and denied substance abuse. However, she stated that she had had a minor headache after arguing with a friend the preceding evening. She had taken a few "sinus pills" from the medicine cabinet before retiring to bed, and took a few more after finding no relief in half an hour's time. These pills were confirmed to contain phenylpropanolamine.
Until recently, the sympathomimetic agents most commonly used in over-the-counter decongestants in the United States were pseudoephedrine, ephedrine, phenylephrine, and phenylpropanolamine. Pseudoephedrine and ephedrine are typical mixed adrenergic agonists with both alpha-mediated and beta-mediated effects. Phenylephrine and phenylpropanolamine are alpha-selective drugs that, in overdose, are capable of producing the characteristic toxicity seen in our patient.
Decades of concern have surrounded adverse events such as psychosis, cardiac arrhythmia,5 and hypertensive crisis associated with the use of phenylpropanolarnine. Horowitz et al. found that 12 of 37 young, healthy, normotensive adults given an 85-mg preparation of phenylpropanolamine had a rise in supine diastolic blood pressure to more than 100 mm Hg, with one subject achieving a blood pressure of 190/142 mm Hg.6 Despite mounting reports of seizures and intracerebral hemorrhage associated with the use of phenylpropanolamine,7 it remained a popularly used and prescribed diet aid and decongestant.
Clinical Effects of Sympathetic Receptors
Since 1979, more than 50 cases of intracranial hemorrhage have been reported following the use of phenylpropanolamine, most occurring in adolescent or young women.8 Still, Americans continued to consume more than 4.5 billion doses of the drug each year.9 Finally, in 2000, a jump from anecdotal observation to epidemiologic investigation of this phenomenon occurred. In a case-control study of 702 subjects and 1,376 matched control subjects, it was found that the adjusted odds ratio for the association between the use of appetite suppressants containing phenylpropanolarnine and the risk of a hemorrhagic stroke among women was 16.58.8 Subsequent to this study, the U.S. Food and Drug Administration recommended that phenylpropanolamine be removed from formulations of over-the-counter cold remedies and appetite suppressants.
The clinical presentation of our patient is one of instant recognition for many medical toxicologists, and illustrates the usefulness of toxidrome assessment of the potentially poisoned patient. It was fortunate that the hypertensive encephalopathy was not accompanied by intracerebral bleeding in this case. After the long-overdue removal of phenylpropanolamine products from the shelves of U.S. drugstores, this lesson may seem less valuable. However, removal of a product from retailers does not necessarily translate to removal of the product from our patients' medicine cabinets. Additionally, interest in herbal supplements, not regulated by the Food and Drug Administration, is increasing within the United States. One of the most popular herbal products is ephedra, touted as a stimulant, a diet aid, and an enhancer of sexual performance. Ephedra alkaloids have a toxicity profile similar to that of phenylpropanolamine,10 and present another "high-pressure" toxic syndrome for which physicians should be vigilant.
1. Becker KJ. Epidemiology and clinical presentation of aneurysmal subarachnoid hemorrhage. Neurosurg Clin N Am. 1998;9:435-444.
2. Khoo LT, Levy ML. Intracerebral aneurysm. In; Albright L, Pollack L Adelson D, eds. Principles and Practice of Pediatric Neurosurgery. New York: Thieme Medical Publishers; 1999:973-1001.
3. Edlow JA, Wyer PC. Evidence-based emergency medicine/clinical question: how good is a negative cranial computed tomographic scan result in excluding subarachnoid hemorrhage? Ann Emerg Med. 2000;36:507-516.
4. Osterhoudt KC, Shannon M, Henretig FM. Toxicologic emergencies. In: Fleisher GR, Ludwig S, eds. Textbook of Pediatric Emergency Medicine, 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2000:887-942.
5. Peterson RB, Vasquez LA. Phenylpropanolamine-induced arrhythmias. JAMA 1973;223:324.
6. Horowitz JD, Lang WJ, Howes LG, et al. Hypertensive responses induced by phenylpropanolamine in anorectic and decongestant preparation. Lancet. 1980;1:60-61.
7. Bale JF Jr, Fountain MT, Shaddy R. Phenylpropanolamine-associated CNS complications in children and adolescents. Am ) Dis Child. 1984;138:683-685.
8. Kernan WN, Viscoli CM, Brass LM, et al. Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med. 2000,343:1826-1832.
9. Rubin R. FDA warns of cold remedy dangers. USA Today. November 7, 2000:1-3.
10. Haller CA, Benowitz NL. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med. 2000;343:1833-1838.
Clinical Effects of Sympathetic Receptors