eMedicine Specialties > Emergency Medicine > Pediatric

Pediatrics, Reye Syndrome

Debra L Weiner, MD, PhD, Attending Physician, Division of Emergency Medicine, Children's Hospital, Boston; Assistant Professor, Department of Pediatrics, Harvard Medical School

Updated: Feb 3, 2009

Introduction

Background

Reye syndrome is characterized by acute noninflammatory encephalopathy and hepatic failure. In 1963, R. D. K. Reye first described this syndrome as a distinct entity in Australia, and, a few months later, G. M. Johnson described it in the United States. Cases with identical manifestations have been described as early as 1929.

Although the etiology of Reye syndrome is unknown, the condition typically occurs after a viral illness, particularly an upper respiratory tract infection (URTI), influenza, varicella, or gastroenteritis, and it is associated with the use of aspirin during the illness. The discovery of inborn errors of metabolism and identification of toxins that have manifestations similar to those of Reye syndrome and a dramatic decrease in the use of aspirin among children have made the diagnosis and occurrence of Reye syndrome exceedingly rare.

Given that manifestations of Reye syndrome are not unique to Reye syndrome but also are seen in other conditions and given that no test is specific for Reye syndrome, the diagnosis must be one of exclusion. A high index of suspicion is critical for diagnosis. With the recognition that Reye syndrome is rare, the diagnosis should be considered in the differential diagnosis in any child with vomiting and altered mental status. Diagnostic criteria from the Centers for Disease Control and Prevention (CDC) are as follows:^1,2

• Acute noninflammatory encephalopathy with an altered level of consciousness
• Hepatic dysfunction with a liver biopsy showing fatty metamorphosis or a more than 3-fold increase in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and/or ammonia levels
• No other explanation for cerebral edema or hepatic abnormality
• CSF with WBCs (usually lymphocytes) 8/mm³ or fewer (8 X 10⁹/L or fewer)
• Brain biopsy with cerebral edema without inflammation

Early recognition and treatment are essential to prevent death and to optimize the likelihood of recovery without neurologic impairment.

When the criteria were developed, specific testing for other conditions was not required. Retrospective reevaluation of patients with a diagnosis of Reye syndrome who survived has revealed that many, if not most, had an underlying inborn error of metabolism (IEM). Many of these IEMs had not even been described when the diagnosis of Reye syndrome was made. Inborn errors that may mimic Reye syndrome include fatty-acid oxidation defects, amino and organic acidopathies, urea-cycle defects, and disorders of carbohydrate metabolism. Future discovery of other IEMs may ultimately explain even more of these cases. Additional etiologies that may mimic Reye syndrome include viral infections, neuromuscular diseases, adverse drug reactions, and toxic exposures to chemicals and plants that cause hepatocellular damage and encephalopathy.

Pathophysiology

The pathogenesis is unclear, but it appears to involve mitochondrial dysfunction that inhibits oxidative phosphorylation and fatty-acid beta-oxidation in a virus-infected, sensitized host. The host has usually been exposed to mitochondrial toxins, most commonly salicylates (>80% of cases). Some have postulated that salicylates stimulate the expression of inducible nitric oxide synthase (iNOS) because of findings of iNOS stimulation in African children with fatal malaria, a disease that causes symptoms similar to those of Reye syndrome and is often treated with aspirin.

Histologic changes include cytoplasmic fatty vacuolization in hepatocytes, astrocyte edema and loss of neurons in the brain, and edema and fatty degeneration of the proximal lobules in the kidneys. All cells have pleomorphic, swollen mitochondria that are in reduced number, along with glycogen depletion and minimal tissue inflammation. Hepatic mitochondrial dysfunction results in hyperammonemia, which is thought to induce astrocyte edema, resulting in cerebral edema and increased intracranial pressure (ICP).

Frequency

United States

National surveillance for Reye syndrome began in 1973. The peak incidence of 555 cases reported to the CDC was in 1979-1980. Between December 1, 1980, and November 30, 1997, 1207 cases of Reye syndrome in patients younger than 18 years were reported.³ During that period, the incidence rate was 0.15-0.88 cases per 100,000 children per year and as high as 6 cases per 100,000 during regional outbreaks of influenza. Cases have declined since 1980 when the government began issuing warnings about the association between Reye syndrome and aspirin. In 1985 and 1986, an average of 100 cases per year were reported. In 1987-1993, the maximum cases reported were 36 per year, with a range of 0.03-0.06 cases per 100,000 per year; 2 or fewer cases have been reported every year since 1994.

Before the 1970s, most cases that met criteria for Reye syndrome are thought to have been diagnosed as encephalitis or drug intoxication. The dramatic decrease in the frequency of Reye syndrome since the 1980s is largely attributable to the decrease in aspirin use in children and discoveries of and advances in diagnosis of IEM and the identification of toxins and drugs that produce symptoms that mimic Reye syndrome. In addition, overreporting of cases during the peak years that did not fully meet criteria and possible underreporting of cases in recent years by physicians who do not consider the diagnosis may also account for the apparent decline.  

Seasonal occurrence initially peaked from December to April, which correlated with the peak occurrence of viral respiratory infections, particularly influenza. Since 1990, the seasonal variation has been less pronounced than this initial observation.

International

In the United Kingdom, 597 cases were reported between 1981 and 1996. The incidence of Reye syndrome decreased from a high in 1983-1984 of 0.63 per 100,000 children younger than 12 years to 0.11 cases per 100,000 in 1990-1991 after warnings of the association between Reye syndrome and aspirin were issued in 1986. Of the 597 cases, 155 were later reclassified, 76 as having an IEM.⁴

Similar rates have been reported from other countries.

Mortality/Morbidity

• The mortality has decreased from 50% to less than 20% as a result of early diagnosis, recognition of mild cases, and aggressive therapy.
• Death is usually due to cerebral edema or increased ICP, but it may be due to myocardial dysfunction, cardiovascular collapse, respiratory failure, renal failure, GI bleeding, status epilepticus, or sepsis.
• Patients who survive may have complete recovery, though neurologic impairment is common.

Race

The racial distribution of Reye syndrome in the United States, according to CDC surveillance statistics in 1980-1997 is 93% white; 5% African American; and the remainder Asian, American Indian, and Native Alaskan.³

Sex

Reye syndrome is equally distributed between the sexes.

Age

The peak ages are 5-14 years, with a median of 6 years and a mean of 7 years.

• Reye syndrome rarely occurs in newborns or in children older than 18 years.
• In African Americans, 67% of patients are younger than 1 year compared with only 12% in white patients.

Clinical

History

• According to CDC surveillance statistics from 1980-1997, 93% of 1160 patients had at least 1 viral illness in the 3 weeks preceding the onset of Reye syndrome.³   
  • Illnesses included viral upper respiratory illness or influenza in 73%, varicella in 21%, gastroenteritis in 14%, and other illness with exanthem 5%.³
  • Salicylates were detectable in the blood of 82% of patients.³
• Influenza B (most common), influenza A, and varicella-zoster virus are most often involved.
• Parainfluenza, adenovirus, coxsackieviruses A and B, echovirus, Epstein-Barr virus, rubella virus, measles virus, cytomegalovirus, herpes simplex virus, parainfluenza viruses, and poliomyelitis viruses are less commonly involved than the pathogens listed above.
• Reye syndrome can occur after vaccination with live viral vaccines.
• Abrupt onset of pernicious vomiting occurs 12 hours to 3 weeks after viral illness; the mean is 3 days.
• Neurologic symptoms usually occur 24-48 hours after onset of vomiting. Lethargy is usually the first neurologic manifestation.
• Diarrhea and hyperventilation may be the first signs in children younger than 2 years.
• Irritability, restlessness, delirium, seizures, and coma occur.
• Obtain an appropriate history in any child who presents with symptoms similar to those of Reye syndrome to determine whether an IEM should be considered.

Physical

• Signs and symptoms of Reye syndrome include protracted vomiting, with or without clinically significant dehydration, encephalopathy in afebrile patients with minimal or absent jaundice, and hepatomegaly in 50% of patients. Some authorities postulate that antiemetics mask early symptoms, and others propose that antiemetics may further predispose the individual to the disease.
• Lovejoy initially described clinical stages I-V,⁵ Hurwitz modified to stages 0-5 to include a nonclinical stage (stage 0). The CDC uses the Hurwitz classification and adds stage 6. Stage 0 does not meet the CDC case definition because it does not meet the criteria for encephalopathy. The stages are as follows:  
  • Stage 0 - Alert, abnormal history and laboratory findings consistent with Reye syndrome, no clinical manifestations
  • Stage 1 - Vomiting, sleepiness, and lethargy
  • Stage 2 - Restlessness, irritability, combativeness, disorientation, delirium, tachycardia, hyperventilation, dilated pupils with sluggish response, hyperreflexia, positive Babinski sign, and appropriate response to noxious stimuli
  • Stage 3 - Obtunded, comatose, decorticate rigidity, and inappropriate response to noxious stimuli
  • Stage 4 - Deep coma, decerebrate rigidity, fixed and dilated pupils, loss of oculovestibular reflexes, and dysconjugate gaze with caloric stimulation
  • Stage 5 - Seizures, flaccid paralysis, absent deep tendon reflexes (DTRs), no pupillary response, and respiratory arrest
  • Stage 6 - Patients who cannot be classified because they have been treated with curare or other medication that alters level of consciousness

Causes

• Viral illness and salicylates are the most well-documented causes of Reye syndrome. For other drugs and toxins, whether the syndrome produced is Reye syndrome or a Reye-like syndrome is unclear. Several IEMs appear to cause Reye-like syndromes.
• Viral illness - Especially influenza B, influenza A, varicella-zoster virus
• Drugs  
  • Salicylates
    • Aspirin is the drug classically associated with Reye syndrome. The association with salicylates was demonstrated in several epidemiologic studies around the world. Fewer than 0.1% of children who took aspirin developed Reye syndrome, but greater than 80% of patients diagnosed with Reye syndrome had taken aspirin in the past 3 weeks.
    • The association was questioned based on bias and limitations of the studies, but recommendations by government health agencies that children not be treated with salicylates resulted in immediate and dramatic decrease in the incidence of Reye syndrome. 
    • A causal relationship between Reye syndrome and salicylates has not been definitively established, but an in vitro study demonstrates that salicylates decrease beta-oxidation of the long-chain fatty acid, palmitate, by cultured fibroblasts from children who recovered from Reye syndrome compared to controls.⁶ Recognition of structural similarity between aspirin metabolites and enzyme substrates for the mitochondrial trifunctional enzyme important in B-oxidation led to identification of the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) component of the enzyme as the target of salicylate inhibition. Absence of inhibition of beta-oxidation by salicylates in fibroblasts from patients with LCHAD deficiency substantiated the finding.
    • Paracetamol, outdated tetracycline, valproic acid, zidovudine, didanosine, and antiemetics are associated with Reye or Reye-like syndrome.
    • An association with antiemetics, such as phenothiazines, has been postulated but not substantiated.
  • Reye or Reye-like syndrome include insecticides; herbicides; aflatoxins; paint; paint thinner; margosa oil; hepatotoxic mushrooms; hypoglycin in ackee fruit (Jamaican vomiting sickness); and herbal medications with atractyloside, a diterpenoid glycoside found in the extracts of the tuber of Callilepis laureola (impila poisoning).
• IEMs: IEMs produce Reye-like syndromes. Most commonly, fatty-acid oxidation defects (particularly medium-chain fatty-acid oxidation defect [MCAD]), urea-cycle defects are found, but amino and organic acidopathies, primary carnitine deficiency, and disorders of carbohydrate metabolism are also found.  
  • Recurrence of symptoms and precipitating factors, including prolonged fast, change in diet or metabolic stressor, and family members with similar symptoms, suggest IEM. The percentage of patients with a previous diagnosis of Reye syndrome is 0.4%. The percentage of patients who have a sibling with a Reye syndrome history is 2.9%. It is likely that at least of some of these patients had IEM rather than Reye syndrome.
  • IEMs may also account for the heterogeneity of disease manifestations in patients younger than 5 years, especially those younger than 1 year, who have received a diagnosis of Reye syndrome. IEMs, rather than true Reye syndrome in patients younger than 5 years, may also explain why decreases in salicylate use and decreases in the incidence of Reye syndrome have been greatest in patients older than 5 years.
  • Preexisting failure to thrive, neurologic abnormalities, dysfunction, and decompensation out of proportion to intercurrent illnesses also suggest IEM.

Differential Diagnoses

Other Problems to Be Considered

Differential diagnosis includes conditions that can cause vomiting and altered level of consciousness. The distinction between Reye and Reye-like syndrome is often unclear.

Workup

Laboratory Studies

• Ammonia: Ammonia level as high as 1.5 times normal (up to 1200 mcg/dL) 24-48 hours after the onset of mental status changes is the most frequent laboratory abnormality. Ammonia level may return to normal in stages 4 and 5.
• Transaminases levels: ALT and AST levels increase to 3 times normal but may return to normal by stages 4 or 5.
• Bilirubin: Bilirubin levels are >2 mg/dL (usually <3 mg/dL) in 10-15% of patients. If direct bilirubin level is >15% of total or total is >3 mg/dL, consider other diagnoses.
• Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are prolonged >1.5-fold in more than 50% of patients.
• Lipase and amylase: These levels are elevated.
• Serum bicarbonate: This level is decreased secondary to vomiting.
• BUN and creatinine: These levels are elevated.
• Glucose: Expect hypoglycemia, particularly in children younger than 1 year.
• Lactic dehydrogenase (LDH): This level may be high or low.
• Anion gap and venous blood gas: Determine anion gap and venous blood gas level to evaluate for metabolic acidosis.
• Urine specific gravity and ketones: Specific gravity is increased; 80% of patients have ketonuria.

Imaging Studies

• Head CT scanning may reveal cerebral edema, but the results are usually normal.

Other Tests

• Free fatty acids and amino acids (eg, glutamine, alanine, lysine): These levels may be elevated.
• Factors II, VII, IX, X, fibrinogen: These levels may be low due to the disruption of synthetic activities in the liver. Consumption may also contribute to low levels of coagulation factors. Platelets are usually normal.
• Electroencephalogram (EEG) may reveal slow-wave activity in the early stages and flattened waves in advanced stages.
• CSF opening pressure, CSF WBCs: Lumbar puncture (LP) should only be performed in hemodynamically stable patients. Opening pressure may or may not be increased; WBCs (usually lymphocytes) are 8/mm³ or fewer (8 X 10⁹/L or fewer).
• Workup to exclude IEM must be performed and should include evaluation for defects of fatty-acid oxidation, amino and organic acidurias, urea-cycle defects, and disorders of carbohydrate metabolism. For additional information, see the eMedicine article Pediatrics, Inborn Errors of Metabolism.

Procedures

• Vascular access - Arterial and/or central venous
• Lumbar puncture if patient is hemodynamically stable and no signs of increased ICP
• Intubation to maintain airway and ventilation and to manage intracranial pressure
• Nasogastric tube placement to decompress the abdomen
• Bladder catheterization to monitor urine output
• Percutaneous liver biopsy may be indicated to exclude IEM or toxic liver disease.
• Placement of an intracranial device for intracranial pressure monitoring is indicated for patients with increased intracranial pressure.
• Coagulopathy must be corrected before invasive procedures.

Treatment

Prehospital Care

• Establish and maintain the patient's airway, breathing, and circulation.
• Check the glucose level, particularly if the patient is younger than 1 year,  has an altered mental status, or both.
• Administer dextrose to manage hypoglycemia.

Emergency Department Care

No specific treatment exists. Continue careful monitoring. Supportive care is based on the stage, with aggressive treatment to correct or prevent metabolic abnormalities, particularly hypoglycemia and hyperammonemia, and to prevent or control cerebral edema. Care by stage is as follows:

• Stages 0-1  
  • Keep the patient quiet.
  • Frequently monitor vital signs and laboratory values.
  • Correct fluid and electrolyte abnormalities, hypoglycemia, and acidosis. If the patient is initially hypoglycemic, administer dextrose 25% as an intravenous (IV) bolus at a dose of 1-2 mL/kg. Use of bicarbonate to correct acidosis is controversial because of potential paradoxical CSF acidosis. Furthermore, given the lack of data regarding degree of acidosis for which bicarbonate should be administered and appropriate dose, guidelines can only be suggested. Consider administration of sodium bicarbonate (NaHCO₃) 0.5-2 mEq/kg/h if the initial pH is less than 7.0-7.2 to correct to 7.25-7.3 based on deficit (deficit HCO₃ in mEq = weight (kg) X base excess X 0.3); avoid rapid correction or overcorrection. Recognize that administration of sodium bicarbonate results in significant sodium load. 
  • Maintain fluids, electrolytes, serum pH, albumin, serum osmolality, urine output, and glucose values. Consider restriction of fluids to two thirds of maintenance. Overhydration may precipitate cerebral edema. Use colloids (eg, albumin) as necessary to maintain intravascular volume. Dehydration may compromise cardiovascular volume and reduce cerebral perfusion. Glucose should be maintained in the 100-125 mg/dL range. This will require D₁₀ -D₂₀. Place a Foley catheter to monitor urine output.
  • Ondansetron (Zofran) 1-2 mg IV q8h may be administered to decrease vomiting. Antacids may also be administered for gastrointestinal protection.
• Stage 2  
  • Continuous cardiorespiratory monitoring, placement of central venous lines and/or arterial lines and urine catheters to monitor urine output, and ECG and/or EEG are standard of care.
  • Endotracheal intubation may be required at this stage to maintain airway and control ventilation and to prevent increased intracranial pressure. Use rapid-sequence agents that minimize the chance of increasing intracranial pressure. Place a nasogastric tube to decompress the abdomen.
  • Correct hyperammonemia. Hyperammonemia can contribute to cerebral edema. The US Food and Drug Administration (FDA) has not approved any medication to treat hyperammonemia specifically due to Reye syndrome. Sodium phenylacetate/sodium benzoate (Ammonul), a medication that treats hyperammonemia, is FDA approved for the treatment of acute hyperammonemia and associated encephalopathy in patients with deficiencies in enzymes of the urea cycle. Administer ondansetron during the first 15 minutes of the initial dose of sodium phenylacetate/sodium benzoate. If the ammonia level is more than 500 mcg/dL or if the patient's condition fails to respond to the initial dose of sodium phenylacetate/sodium benzoate, start dialysis, preferably hemodialysis. See eMedicine article Pediatrics, Inborn Errors of Metabolism.
  • Prevent increased ICP. Elevate the head to 30 degrees, keep the head midline, use isotonic rather than hypotonic fluids, avoid overhydration, and administer furosemide (Lasix) 1 mg/kg up to every 4-6 hours to control fluid overload. 
• Stages 3-5  
  • Continuously monitor ICP, central venous pressure, arterial pressure, and/or end-tidal carbon dioxide.
  • Perform endotracheal intubation if the patient is not already intubated.
  • Treat increased ICP by following standard guidelines which, in addition to correction of hyperammonemia, positioning of the head, and appropriate fluid management, include ventilation to maintain PCO₂ in the normal range, aggressive management of fever to prevent increased cerebral metabolism and increased cerebral blood flow that results from hyperpyrexia, analgesia and sedation for agitation or prior to painful interventions, paralytic agents to control shivering, and if other measures fail, mannitol 0.25-0.5 g/kg/dose IV infused over 10-20 minutes up to every 2-4 hours. Use of barbiturate coma and hypothermia are controversial.
  • Treat seizures with phenytoin 10-20 mg/kg IV as a loading dose followed by 5 mg/kg/d IV divided every 6 hours or fosphenytoin dosed as 10-20 mg/kg phenytoin equivalents (PEs).
  • Correct coagulopathy (PT >16 seconds). 
    • Data for treatment of coagulopathy in Reye syndrome, as well as for most etiologies of coagulopathy in children, are limited. Options include fresh frozen precipitate (FFP), cryoprecipitate, platelets, vitamin K, exchange transfusion. FFP 10-15 mL/kg every 12-24 hours provides rapid correction and volume expansion and should be administered particularly if active bleeding is present, or invasive procedures such as intracranial pressure monitoring device placement and/or liver biopsy are required. Cryoprecipitate, 10 mL/kg every 6 hours, which has a higher concentration of fibrinogen, should be considered instead of FFP if fibrinogen is less than 100 mg/dL. 
    • Platelets as needed to restore platelet count to greater than 50,000/mm³ should also be given if invasive procedures are to be performed. Vitamin K 1-10 mg intravenously may be administered instead of FFP or cryoprecipitate if correction is not emergent. Exchange transfusion is rarely required. See eMedicine article Consumption Coagulopathy.

Consultations

• Consider consultation with a neurologist for EEG.
• Consider consultation with a neurosurgeon for monitoring and treatment of increased ICP.
• Consider consultation with a gastroenterologist or surgeon for liver biopsy.
• Consider consultation with a metabolic disease specialist if IEM is possible.

Medication

No specific treatment is available. Supportive care to reduce hyperammonemia with sodium phenylacetate/sodium benzoate may be required. For highly elevated levels of ammonia, hemodialysis may be the appropriate initial treatment if it is readily available, and it is also recommended for patients whose condition fails to respond to initial course of sodium phenylacetate/sodium benzoate. Continuing the administration of sodium phenylacetate/sodium benzoate with hemodialysis may be considered.

In terms of managing increased ICP, steroids are of no proven benefit, they may be harmful, and they are not indicated.

Ammonia detoxicants

Treatment of hyperammonemia; enhances elimination of nitrogen. Sodium phenylacetate/sodium benzoate is FDA approved for treatment of hyperammonemia due to urea-cycle defects and is available only from a specialty wholesaler, Ucyclyd Pharma, Inc (in the United States and Canada, 24-hour toll-free number: 888-829-2593; 8125 N. Hayden Road, Scottsdale, AZ 85258). For more information, see Ammonul prescribing information.

Sodium phenylacetate and sodium benzoate (Ammonul)

May be effective to treat hyperammonemia. For levels >500-600 mcg/dL, hemodialysis preferred. Can be used until dialysis started or with dialysis. Benzoate combines with glycine to form hippurate (excreted in urine). One mole of benzoate removes 1 mole of nitrogen. Phenylacetate conjugates (by acetylation) with glutamine in liver and kidneys to form phenylacetylglutamine (excreted by kidneys). Nitrogen content of phenylacetylglutamine per mole identical to that of urea (2 mol). Preparation contains 100 mg/mL each of sodium phenylacetate and sodium benzoate; supplied as 50-mL vials. Must dilute IV dose in at least 25 mL/kg of dextrose 10% up to 600 mL. Do not directly mix with other medications; may be piggybacked. Give in addition to daily fluid requirement.

Dosing

Adult

Loading: 55 mL (5.5 g)/m² IV over 90-120 min through central line
Maintenance: 55 mL (5.5 g)/m²/d IV over 24 h through central line

Pediatric

<20 kg:
Loading: 2.5 mL (250 mg)/kg IV over 90-120 min through central line
Maintenance: 2.5 mL (250 mg)/kg/d IV over 24 h through central line
>20 kg: Administer as in adults

Interactions

Penicillin may decrease effects; probenecid may inhibit renal excretion of products; valproate may antagonize efficacy

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Closely monitor patients with hepatic or renal impairment; caution in neonatal hyperbilirubinemia (competes for bilirubin-bindings sites on albumin); because of sodium content, caution in congestive heart failure, severe renal dysfunction, or sodium retention with edema; common adverse effects include nausea, vomiting, tinnitus, and visual disturbance; may cause hyperglycemia or hypokalemia; if needed, may be given with furosemide for edema, insulin to maintain euglycemia, or ondansetron 0.15 mg/kg (not to exceed 8 mg q8h) during initial 15 min of priming infusion to offset GI effects; overdose may result in death

Antiemetic agents

Administer ondansetron to decrease vomiting and during initiation of sodium phenylacetate and sodium benzoate.

Ondansetron (Zofran)

Controls nausea and vomiting associated with Reye syndrome and with IV administration of sodium benzoate and phenylacetate.
Selective 5-HT3-receptor antagonist that blocks serotonin both peripherally and centrally. Prevents nausea and vomiting associated with IV administration of sodium benzoate and phenylacetate.

Dosing

Adult

32 mg IV infused over 15 min beginning 30 min before start of IV sodium benzoate and phenylacetate infusion

Pediatric

1-2 mg IV q8h

Interactions

Although there is potential for cytochrome P-450 inducers (barbiturates, rifampin, carbamazepine, and phenytoin) to change half-life and clearance of ondansetron, dosage adjustment is not usually required

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May cause headache

Follow-up

Further Inpatient Care

• Admission to the intensive care unit (ICU) is warranted for continued monitoring and treatment.

Further Outpatient Care

• Monitor and treat long-term neurologic sequelae.

Inpatient & Outpatient Medications

• Prescribe outpatient anticonvulsants if ongoing seizures occur.

Transfer

• Arrange for ICU admission to a facility that can monitor and manage increased ICP in children.

Deterrence/Prevention

• Avoid salicylates in children except for in children with conditions for which salicylates are a mainstay of therapy such as Kawasaki disease. Of approximately 200,000 children in Japan treated with aspirin for Kawasaki disease, only one child was reported to have developed Reye syndrome. For children who require long-term use of salicylates, discontinue use immediately at the first signs or symptoms of Reye syndrome.
• Recognize early symptoms.
• An IEM may be the actual etiology of the symptoms. Evaluate and treat this possibility.  
  • Appropriate management of IEMs dramatically decreases morbidity and mortality.
  • See the eMedicine article, Pediatrics, Inborn Errors of Metabolism.
• In addition to recommending influenza vaccine for all children aged 6-59 months age, the CDC recommends influenza and varicella vaccines for children and adolescents aged 5-18 years who require salicylates long term.

Complications

• Brain herniation, status epilepticus, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), and diabetes insipidus
• Acute respiratory failure, aspiration pneumonia
• Cardiovascular collapse
• GI bleeding, pancreatitis
• Acute renal failure
• Sepsis
• Death

Prognosis

• The mortality rate has decreased in recent years from 50% to less than 20%. In 1980-1997, the overall case mortality rate in the United States, as the CDC reports, was 31%.
• Some patients have a poor prognosis.  
  • Patients younger than 5 years have a relative risk of 1.8.
  • The literature is contradictory regarding the cutoff value of ammonia that best predicts prognosis. While most reports indicate that values of >300 mcg/dL are associated with poor prognosis, Belay et al 1999, reported that an ammonia level of 45 mcg/dL was the most accurate predictor, with a relative risk of 3.4.³
  • Rapid progression from stage 1 to stage 3 or presentation with stage 4 or 5 is associated with a poor prognosis. The death rate based on stage at time of admission is 18% for stage 0 and 90% for stage 5.
  • The prognosis is worse with liver and muscle involvement than with either involvement of liver alone (ie, AST/ALT >1, LDH isoenzymes 1-5, elevated creatine kinase MM [CK-MM], creatine kinase MB [CK-MB]).
  • Hypoproteinemia unresponsive to fresh frozen vitamin K and FFP indicates a poor prognosis.
• Survivors have an increased risk of long-term neurologic sequelae, particularly if ammonia levels are >45 mcg/dL, if they have stage 2-5 disease, and/or if they are younger than 2 years.  
  • The ammonia level is the best predictor.
  • Approximately 3% of patients have neurologic sequelae if levels are <45 mcg/dL, and 11% have sequelae if levels are >45 mcg/dL.

Patient Education

• Salicylates are contraindicated in children, particularly in children with influenzalike illness or varicella.

Miscellaneous

Medicolegal Pitfalls

• Failure to identify, treat hypoglycemia
• Failure to identify, treat hyperammonemia
• Overhydrating the patient with exacerbation of cerebral edema
• Failure to aggressively treat cerebral edema (the major cause of morbidity and mortality)
• Failure to recognize that progression of disease may be extremely rapid
• Failure to evaluate for, diagnose other etiology (ie, IEM, toxin)

Special Concerns

• Reye syndrome is now exceedingly rare.
• Evaluate patients for an IEM that mimics Reye syndrome, particularly (but not exclusively) patients younger than 3 years.
• Consider a metabolic disease (eg, amino or organic acidemia, defect in the urea cycle or fatty-acid oxidation [particularly medium-chain acyl-CoA dehydrogenase deficiency]) if the following conditions pertain:
  • No viral prodrome
  • No exposure to aspirin or toxin with association to Reye syndrome
  • Patients younger than 3 years (especially those <1 y)
  • Patient or family history of Reye syndrome–type illness
  • Preexisting failure to thrive
  • Baseline neurologic abnormalities
  • Liver dysfunction and/or elevated ammonia level, particularly if it is >1200 mcg/dL and/or if it is elevated longer than 1 week with or without waxing and waning

References

1. CDC. Reye Syndrome 1990 Clinical Case Definition. Available at http://www.cdc.gov/ncphi/disss/nndss/casedef/reye_syndrome_current.htm.

2. CDC. National Reye syndrome surveillance--United States, 1982 and 1983. MMWR Morb Mortal Wkly Rep. Feb 3 1984;33(4):41-2. [Medline].

3. Belay ED, Bresee JS, Holman RC, Khan AS, Shahriari A, Schonberger LB. Reye's syndrome in the United States from 1981 through 1997. N Engl J Med. May 6 1999;340(18):1377-82. [Medline].

4. New World Encyclopedia. Reye's Syndrome. Last updated September 5, 2008. Available at http://www.newworldencyclopedia.org/entry/Reye%27s_syndrome.

5. Lovejoy FH Jr, Smith AL, Bresnan MJ, Wood JN, Victor DI, Adams PC. Clinical staging in Reye syndrome. Am J Dis Child. Jul 1974;128(1):36-41. [Medline].

6. Glasgow JF, Middleton B, Moore R, Gray A, Hill J. The mechanism of inhibition of beta-oxidation by aspirin metabolites in skin fibroblasts from Reye's syndrome patients and controls. Biochim Biophys Acta. May 31 1999;1454(1):115-25. [Medline].

7. Brunner RL, O'Grady DJ, Partin JC, Partin JS, Schubert WK. Neuropsychologic consequences of Reye syndrome. J Pediatr. Nov 1979;95(5 Pt 1):706-11. [Medline].

8. Casteels-Van Daele M, Van Geet C, Wouters C, Eggermont E. Reye syndrome revisited: a descriptive term covering a group of heterogeneous disorders. Eur J Pediatr. Sep 2000;159(9):641-8. [Medline].

9. CDC. Centers for Disease Control and Prevention. Follow-up on Reye syndrome-United States. MMWR CDC Surveill Summ. 1980;29:321.

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Keywords

Reye's syndrome, Reye syndrome, acute noninflammatory encephalopathy, inborn error of metabolism, IEM, Reye syndrome in children, hepatic failure, upper respiratory tract infection, URTI, influenza, varicella, gastroenteritis, use of aspirin, aspirin use in children

Contributor Information and Disclosures

Author

Debra L Weiner, MD, PhD, Attending Physician, Division of Emergency Medicine, Children's Hospital, Boston; Assistant Professor, Department of Pediatrics, Harvard Medical School
Disclosure: Nothing to disclose.

Medical Editor

Garry Wilkes, MBBS, FACEM, Director of Emergency Medicine, Bunbury Health Service, Western Australia Country Health Service; Adjunct Associate Professor, School of Exercise, Biomedical and Health Sciences, Faculty of Computing, Health and Science, Edith Cowan University; Medical Director, St John Ambulance Service
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Grace M Young, MD, Associate Professor, Department of Pediatrics, University of Maryland Medical Center
Grace M Young, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Emergency Physicians
Disclosure: Nothing to disclose.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Richard G Bachur, MD, Assistant Professor of Pediatrics, Harvard Medical School; Associate Chief and Fellowship Director, Attending Physician, Division of Emergency Medicine, Children's Hospital of Boston
Richard G Bachur, MD is a member of the following medical societies: American Academy of Pediatrics, Society for Academic Emergency Medicine, and Society for Pediatric Research
Disclosure: none None None

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