Reye Syndrome


Practice Essentials

Reye syndrome is characterized by acute noninflammatory encephalopathy and fatty degenerative liver failure. The syndrome was first described in 1963 in Australia by RDK Reye and described a few months later in the United States by GM Johnson.[17, 14] Cases with identical manifestations were described as early as 1929. In the United States, Reye syndrome became a reportable disease in 1973. Peak incidence was reported in 1979-80.[7, 8, 13]

Reye syndrome typically occurs after a viral illness, particularly an upper respiratory tract infection, influenza, varicella, or gastroenteritis, and is associated with the use of aspirin during the illness. A dramatic decrease in the use of aspirin among children, in combination with the identification of medication reactions, toxins, and inborn errors of metabolism (IEMs) that present with Reye syndrome–like manifestations, have made the diagnosis of Reye syndrome exceedingly rare.

With the recognition that Reye syndrome is rare, this condition should be considered in the differential diagnosis in any child with vomiting and altered mental status and classic laboratory findings. A high index of suspicion is essential. Given that manifestations of Reye syndrome are not unique to Reye syndrome but also are seen in a growing list of conditions, and given that no test is specific for Reye syndrome, the diagnosis must be one of exclusion.

All children with manifestations suggestive of Reye syndrome should be tested for IEM. Early recognition and treatment of Reye and Reye-like syndromes, including presumptive treatment for possible IEM (See Inborn Errors of Metabolism) is essential to prevent death and optimize the likelihood of recovery without neurologic impairment.

Some have suggested the term Reye syndrome or Reye-like syndrome should be used to describe clinical manifestations of diseases states regardless of etiology, while causes still without a known etiology after diagnostic workup should be referred to as Reye disease.


The pathogenesis of Reye syndrome, while not precisely elucidated, appears to involve mitochondrial injury resulting in dysfunction that disrupts oxidative phosphorylation and fatty-acid beta-oxidation in a virus-infected, sensitized host potentially with an underlying occult inborn error of fatty acid oxidation, urea cycle or mitochondrial disorder.[2, 16] The host has usually been exposed to mitochondrial toxins, most commonly salicylates (>80% of cases).

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 reduced in 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).



Influenza virus types A and B and varicella-zoster virus are the pathogens most commonly associated with Reye syndrome. Other pathogens include parainfluenza virus, adenovirus, coxsackievirus, measles, cytomegalovirus, Epstein-Barr virus, HIV, retrovirus, hepatitis virus types A and B, mycoplasma, chlamydia, pertussis, shigella, salmonella, and polio. Reye has occurred after immunization with live viral vaccines.


The association of Reye syndrome with salicylates, particularly aspirin, was demonstrated in several epidemiologic studies around the world. Less than 0.1% of children who took aspirin developed Reye syndrome, but more than 80% of patients diagnosed with Reye syndrome had taken aspirin in the past 3 weeks. A causal relation between Reye syndrome and salicylates has not been definitively established and has been questioned on the basis of biases and limitations in the studies,[1] but recommendations by government health agencies that children not be treated with salicylates led to an immediate and dramatic decrease in the incidence of Reye syndrome.

Results of in vitro studies are contradictory on impact of aspirin on beta-oxidation metabolism. One study demonstrated that salicylates decrease beta-oxidation of the long-chain fatty acid palmitate by cultured fibroblasts from children who recovered from Reye syndrome as compared with control subjects.[2] Another study showed that in two different cell lines, aspirin increased mitochondrial long-chain fatty acid oxidation, did not change oxidation of medium chain fatty acids, and inhibited peroxisomal fatty acid oxidation, which suggest that aspirin impairs long-chain fatty acid transport into mitochondria.[18] Some have postulated that salicylates stimulate the expression of inducible nitric oxide synthase (iNOS) because of the 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.

Recognition of the structural similarity between aspirin metabolites and enzyme substrates for the mitochondrial trifunctional enzyme important in beta-oxidation led to identification of the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) component of the enzyme as the target of salicylate inhibition.[3] Absence of inhibition of beta-oxidation by salicylates in fibroblasts from patients with LCHAD deficiency substantiated the finding.

Other agents

Other Medications

Acetaminophen, outdated tetracycline, valproic acid, warfarin, zidovudine didanosine, and some neoplastic drugs have been associated with Reye syndrome or Reye-like syndrome. Nonsteroidal anti-inflammatory drugs, including sodium diclofenac and mefenamic acid, are thought to produce or worsen Reye syndrome. An association with antiemetics, such as phenothiazines, has been postulated but not substantiated. An association with acetaminophen was reported but has been refuted, although there may be a synergistic effect of acetaminophen and salicylates.[15]


Reye syndrome or Reye-like syndrome may also be associated with insecticides; herbicides; aflatoxins; isopropyl alcohol; paint; paint thinner; margosa (neem) 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). Bacillus cereus cereulide toxin has also been reported as producing Reye syndrome.

Inborn errors of metabolism

IEMs that produce Reye-like syndromes include fatty-acid oxidation defects, particularly medium-chain acyl dehydrogenase (MCAD) and long-chain acyl dehydrogenase deficiency (LCAD) inherited and acquired forms, urea-cycle defects, amino and organic acidopathies, primary carnitine deficiency, and disorders of carbohydrate metabolism. Undoubtedly, other IEMs that cause Reye-like syndrome will be identified.

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 an IEM rather than Reye syndrome.

IEMs may account for the heterogeneity of disease manifestations in patients younger than 5 years who have received a diagnosis of Reye syndrome, especially those younger than 1 year. The possibility that IEMs are more likely 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.

IEM is suggested by recurrence of symptoms, precipitating factors, including prolonged fasting, changes in diet, decompensation out of proportion to intercurrent illnesses, failure to thrive, neurologic abnormalities, neurologic dysfunction, and family members with similar symptoms and/or unexplained infant deaths.


United States statistics

In the United States, national surveillance for Reye syndrome began in 1973. It is believed that before the 1970s, most of the cases that met the criteria for Reye syndrome were diagnosed as encephalitis or drug intoxication.

The peak annual incidence of 555 cases reported to the Centers for Disease Control and Prevention (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.[4] During that period, the incidence 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 of Reye syndrome declined in number after 1980, when the government began issuing warnings about the association between this syndrome and aspirin. Whereas an average of 100 cases per year were reported in 1985 and 1986, the maximum number of cases reported annually between 1987 and 1993 was 36, with a range of 0.03-0.06 cases per 100,000 per year. Since 1994, 2 or fewer cases have been reported every year. While Reye syndrome reporting to CDC is no longer mandated, many local/state health boards continue to require reporting.

The dramatic decrease in the frequency of Reye syndrome since the 1980s is largely attributable to reduced aspirin use in children, as well as to discoveries of and advances in the diagnosis of inborn errors of metabolism (IEMs) and identification of toxins and drugs capable of producing symptoms that mimic Reye syndrome. The decrease may also be partially attributable to overreporting of cases during the peak years that did not fully meet criteria and underreporting of cases in subsequent years by physicians who did not consider the diagnosis.

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 was suggested by this initial observation.

International statistics

In the United Kingdom, 597 cases were reported between 1981 and 1996. After warnings of the association between Reye syndrome and aspirin were issued in 1986, the incidence of Reye syndrome decreased substantially, from a high of 0.63 per 100,000 children younger than 12 years in 1983-1984 to 0.11 cases per 100,000 in 1990-1991. Of the 597 cases, 155 were later reclassified, 76 of them as involving an IEM.[5] Similar rates have been reported from other countries.

Age-, sex-, and race-related demographics

Based on US CDC surveillance statistics for 1980-1997 for patients younger than 18 years, 1207 cases were reported in the United States.[4] Incidence peaks between age 5 and 14 years (median, 6 years; mean, 7 years); 13.5% were younger than 1 year. Reye syndrome rarely occurs in newborns or in children older than 18 years. Reye syndrome is equally distributed between the sexes. The racial distribution of Reye syndrome is 93% white and 5% African American, with the remaining percentage Asian, American Indian, and Native Alaskan. Of those younger than 1 year, 67% were African American and 12% were white.


The mortality rate has decreased from 50% to less than 20% as a result of early diagnosis, recognition of mild cases, and aggressive therapy. The 1980-1997 case review reports a mortality rate of 31.3%, 42.8% in those younger than 5 years and 24.2% in those older than 5 years, with a relative risk of 1.8% (95% confidence interval [CI], 1.5-2.1%). Decreased mortality also likely reflects an increase in diagnosis of inborn errors of metabolism (IEMs), which is critical for life-saving treatment of disease-specific metabolic derangements. Death is usually due to cerebral edema or increased intracranial pressure (ICP), but it may be due to myocardial dysfunction, cardiovascular collapse, respiratory failure, renal failure, gastrointestinal (GI) bleeding, status epilepticus, or sepsis.

Increased risk of mortality is associated with the following:

Patients who survive may recover completely. The 1980-1997 US data indicate full recovery in 62% of the 1134 patients with known outcomes. Survivors are at increased risk for long-term neurologic sequelae if ammonia levels exceed 45 µg/dL, if they have stage 2-5 disease, or if they are younger than 5 years. Approximately 3% of patients have neurologic sequelae if ammonia levels are below 45 µg/dL, whereas nearly 11% have sequelae if levels are above 45 µg/dL, with a relative risk of 4.1 (95% CI, 1.2-14).


According to Centers for Disease Control and prevention (CDC) surveillance statistics for 1980-1997, 93% of 1160 patients had at least 1 viral illness in the 3 weeks preceding the onset of Reye syndrome.[4] Illnesses included viral upper respiratory illness or influenza in 73%, varicella in 21%, gastroenteritis in 14%, and other illness with exanthem in 5%.[4] Salicylates were detectable in the blood of 82% of patients.[4]

Influenza B (most common), influenza A, and varicella-zoster virus (VZV) are the viral pathogens most often involved. Parainfluenza, adenovirus, coxsackieviruses A and B, echovirus, Epstein-Barr virus (EBV), rubella virus, measles virus, cytomegalovirus (CMV), herpes simplex virus (HSV), parainfluenza virus, and poliomyelitis virus are less commonly associated. Reye syndrome can occur after vaccination with live viral vaccines.

Abrupt onset of pernicious vomiting occurs 12 hours to 3 weeks (mean, 3 days) after symptoms of viral illness have resolved. Neurologic symptoms usually occur 24-48 hours after the onset of vomiting. Lethargy is typically 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 inborn error of metabolism (IEM) should be considered (see diagnostic considerations).

Physical Examination

Signs and symptoms of Reye syndrome include protracted vomiting, with or without clinically significant dehydration; hepatomegaly in 50%; minimal or absent jaundice; and lethargy progressing to encephalopathy, obtundation, coma, seizures, and paralysis. Notably, patients are afebrile. Some postulate that antiemetics mask early symptoms, and others propose that antiemetics may further predispose the individual to the disease.

Lovejoy initially divided Reye syndrome into clinical stages 1-5[6] ; Hurwitz subsequently developed a modified classification that divided the syndrome into stages 0-5, including a nonclinical stage (ie, stage 0). The CDC uses the Hurwitz classification but adds stage 6. Stage 0 does not meet the CDC case definition, because it does not meet the criteria for encephalopathy (see DDx). The stages used in the CDC classification of Reye syndrome are as follows:

Diagnostic criteria

The CDC developed the following diagnostic criteria for Reye syndrome[7, 8] :

When these criteria were developed, specific testing for other conditions was not required. Other etiologies, particularly inborn errors of metabolism (IEMs), should be ruled out before a definitive diagnosis is made.


Complications of Reye syndrome include the following:

Approach Considerations

Workup to exclude inborn errors of metabolism (IEMs) 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. Various invasive procedures may be indicated. Computed tomography (CT) of the head may reveal cerebral edema, but the results are usually normal. Electroencephalography (EEG) may reveal slow-wave activity in the early stages and flattened waves in advanced stages. MRI characteristics of Reye syndrome are symmetric thalamic, white matter and basal ganglia lesions, in children with recent history of salycilates or immunosuppressive drugs intake.[9]

Laboratory Studies


An ammonia level as high as 1.5 times normal 24-48 hours after the onset of mental status changes is the most frequent laboratory abnormality. Ammonia tends to peak 56-60 hours after the onset of symptoms. The ammonia level may return to normal in stages 4 and 5.

Liver function tests

Levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increase to 3 times normal but may return to normal by stages 4 or 5. Bilirubin levels are higher than 2 mg/dL (but usually lower than 3 mg/dL) in 10-15% of patients. If the direct bilirubin level is more than 15% of total or if the total bilirubin level exceeds 3 mg/dL, consider other diagnoses.

Lipase and amylase levels are elevated. The serum bicarbonate level is decreased secondary to vomiting. Blood urea nitrogen (BUN) and creatinine levels are elevated.

Lactic dehydrogenase (LDH) 

LDH may be high or low.


While glucose is usually normal, it may be low, particularly during stage 5 and in children younger than 1 year.

Electrolytes, blood urea nitrogen (BUN), creatinine

Sodium may be low due to syndrome of inappropriate antidiuretic hormone (SIADH) or elevated due to diabetes insipidus (DI). Serum bicarbonate is usually decreased due to vomiting. BUN and creatinine are usually elevated.  Anion gap is usually elevated due to metabolic acidosis.

Coagulation studies

Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are prolonged more than 1.5-fold in more than 50% of patients. Levels of factors I (fibrinogen), II, VII, IX, and X may be low because of the disruption of synthetic activities in the liver. Consumption may also contribute to low levels of coagulation factors. Platelet counts are usually normal.

Fatty acids, amino acids

Levels of free fatty acids and amino acids (eg, glutamine, alanine, and lysine) may be elevated.

Blood gas

Venous blood gas should be obtained to evaluate for metabolic acidosis.


Urine specific gravity is increased; 80% of patients have ketonuria.

Cerebral spinal fluid (CSF)

CSF WBC count, by disease definition, does not exceed 8 cells/µL. Opening pressure is usually normal but may be elevated, particularly in stages 3-5.

Recognize that these derangements are not specific for Reye syndrome and may suggest other etiologies that should be considered.

Invasive Procedures

The following procedures may be helpful for workup, treatment, and monitoring:

Coagulopathy must be corrected before invasive procedures are performed.

Imaging Studies

Computed tomography

CT may reveal diffuse cerebral edema but may be normal.

Magnetic resonance imaging (MRI)

There are very few reports of MRI findings of Reye syndrome given the rarity of this condition since MRI has been available. Diffuse cerebral edema and diffusion restriction in thalamic midbrain, cerebral and subcortical white matter, and parasagittal cortex have been reported.

Other Tests

Electroencephalogram (EEG)

In early stages EEG may reveal slow wave activity, in later stages, flattened waves.[19]

Approach Considerations

No specific treatment exists for Reye syndrome; supportive care is based on the stage of the syndrome. Continue careful monitoring. Establish and maintain the patient’s airway, breathing, and circulation. Check the glucose level, particularly if the patient is younger than 1 year and/or has altered mental status. Administer dextrose to correct hypoglycemia. Admission to the intensive care unit (ICU) is warranted for continued monitoring and treatment.

Consider consultation with a neurologist for electroencephalography (EEG). Consider consultation with a neurosurgeon for monitoring and treatment of increased intracranial pressure (ICP). Consider consultation with a gastroenterologist or surgeon for liver biopsy. Consider consultation with a metabolic disease specialist if an inborn error of metabolism (IEM) is a possibility.

Monitor and treat long-term neurologic sequelae. Prescribe outpatient anticonvulsants if ongoing seizures occur.

Reye syndrome has been successfully treated with liver transplantation.[12]

Stage-Specific Management

Supportive care is based on the clinical stage of the syndrome, with aggressive treatment provided to correct or prevent metabolic abnormalities, particularly hypoglycemia and hyperammonemia, and to prevent or control cerebral edema.

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 hypoglycemic, administer dextrose 25% as an intravenous (IV) bolus in a dose of 1-2 mL/kg. The use of bicarbonate to correct acidosis is controversial because of potential paradoxical cerebrospinal fluid (CSF) acidosis. In view of the lack of data regarding the degree of acidosis for which bicarbonate should be administered and the appropriate dosage, guidelines can only be suggested. If the initial pH is less than 7.0-7.2, consider administering sodium bicarbonate 0.5-2 mEq/kg/h to correct it to 7.25-7.3, with the dosage based on the deficit, calculated as follows:

Deficit in HCO3 (mEq) = weight (kg) × base excess × 0.3

Avoid rapid correction or overcorrection. Recognize that administration of sodium bicarbonate results in a significant sodium load.

Maintain electrolytes, serum pH, albumin, serum osmolality, glucose, and urine output in normal ranges. Consider restricting 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 administration of D10 or D20. Place a Foley catheter to monitor urine output.

Consider giving ondansetron 1-2 mg IV every 8 hours to decrease vomiting. Antacids may also be administered for gastrointestinal (GI) protection.

Stage 2

The standard of care consists of continuous cardiorespiratory monitoring, placement of central venous lines or arterial lines to monitor hemodynamic status, urine catheters to monitor urine output, ECG to monitor cardiac function, and EEG to monitor seizure activity. Endotracheal intubation may be required at this stage to maintain the airway, control ventilation, and prevent increased ICP. Use rapid-sequence agents that minimize the chance of increasing ICP. Place a nasogastric tube to decompress the abdomen.

Hyperammonemia can contribute to cerebral edema and therefore must be corrected aggressively. The US Food and Drug Administration (FDA) has not approved any medication for treatment of hyperammonemia specifically due to Reye syndrome. However, sodium phenylacetate–sodium benzoate is FDA-approved for the treatment of acute hyperammonemia and associated encephalopathy in patients with deficiencies in enzymes of the urea cycle.

Administer ondansetron 1-2 mg IV during the first 15 minutes of the initial dose of sodium phenylacetate–sodium benzoate. If the ammonia level is higher than 500 µg/dL or if the patient’s condition fails to respond to the initial dose of sodium phenylacetate–sodium benzoate, start dialysis, preferably hemodialysis. (See Inborn Errors of Metabolism.)

Prevent increased ICP. Elevate the head to 30°, keep the head in a midline orientation, use isotonic rather than hypotonic fluids, avoid overhydration, and administer furosemide 1 mg/kg as often as every 4-6 hours to control fluid overload.

Stages 3-5

Continuously monitor ICP, central venous pressure, arterial pressure, 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, proper positioning of the head, and appropriate fluid management (see above), include the following:

Treat seizures with phenytoin 10-20 mg/kg IV as a loading dose, followed by 5 mg/kg/day IV divided every 6 hours or fosphenytoin dosed as 10-20 mg/kg phenytoin equivalents.

Correct coagulopathy (prothrombin time >16 seconds). The data on treatment of coagulopathy in Reye syndrome, like those on most etiologies of coagulopathy in children, are limited. Options include fresh frozen plasma (FFP), cryoprecipitate, platelets, vitamin K, and 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 if invasive procedures (eg, ICP monitoring device placement or liver biopsy) are required. If the fibrinogen level is lower than 100 mg/dL, cryoprecipitate 10 mL/kg every 6 hours should be considered instead of FFP because cryoprecipitate has a higher concentration of fibrinogen.

If invasive procedures are to be performed, platelets should also be given as needed to restore the platelet count to a value higher than 50,000/µL. Vitamin K 1-10 mg IV may be administered instead of FFP or cryoprecipitate if the need for correction is not an emergency. Exchange transfusion is rarely required. (See Consumption Coagulopathy.)

Reye syndrome has been successfully treated with liver transplantation.[12]


Salicylates should be avoided in children, except in those who have conditions for which salicylates are a mainstay of therapy (eg, Kawasaki disease). Of approximately 200,000 children in Japan who were treated with aspirin for Kawasaki disease, only 1 was reported to have developed Reye syndrome. In children who require long-term salicylate therapy, use of these agents should be discontinued immediately at the first signs or symptoms of Reye syndrome.

It is critical to be alert for and recognize early symptoms of Reye syndrome. It is also important to be mindful of the possibility that an IEM may be the actual cause of the symptoms and, if this is the case, to be prepared to treat the IEM. Appropriate management of IEMs dramatically decreases morbidity and mortality. (See Inborn Errors of Metabolism.)

Influenza vaccine is recommended by the Centers for Disease Control and Prevention (CDC) for everyone older than 6 months.

Medication Summary

No specific treatment is available for Reye syndrome. Supportive care should be provided to treat hyperammonemia, hypoglycemia, acidosis, electrolyte disturbances, nausea, vomiting, seizures and increased intracranial pressure.

Corticosteroids are of no proven benefit with regard to managing increased intracranial pressure (ICP) and may even be harmful. Accordingly, they are not indicated in this setting.

The mainstay of treatment is supportive care is based on the clinical stage of the syndrome. Provide aggressive treatment to correct or prevent metabolic abnormalities, particularly hypoglycemia and hyperammonemia, and to prevent or control cerebral edema.

Hyperammonemia treatment consists of sodium benzoate/sodium phenylacetate IV. For highly elevated ammonia levels, 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 benzoate/sodium phenylacetate. Continuing the administration of sodium benzoate/sodium phenylacetate during hemodialysis may be considered.

Hypoglycemia treatment with dextrose 25% (D25) should be administered to treat hypoglycemia, and, as needed dextrose 10%) (D10) may be provided in IV maintenance fluids infused at 1-1.5 mL/min maintenance to provide 8-12 mg/kg/min. Serum glucose should be maintained in the 120-170 mg/dL range to avoid catabolism. Glucose can be modulated with an insulin dose of 0.2-0.3 units.

For life threatening increased intracranial pressure (ICP), mannitol or hypertonic (3%) saline should be administered. Hypertonic saline should not be given to patients with elevated sodium.

Sodium benzoate/sodium phenylacetate (Ammonul)

Clinical Context:  Sodium benzoate/sodium phenylacetate may be effective for treatment of hyperammonemia, though hemodialysis is preferred for ammonia levels higher than 500-600 µg/dL. It can be used until dialysis is started or along with dialysis.

Benzoate combines with glycine to form hippurate (which is excreted in urine); 1 mole of benzoate removes 1 mole of nitrogen. Phenylacetate conjugates (by acetylation) with glutamine in the liver and kidneys to form phenylacetylglutamine (which is excreted by the kidneys). The nitrogen content of phenylacetylglutamine per mole is identical to that of urea (2 mol).

The preparation contains 100 mg/mL each of sodium phenylacetate and sodium benzoate and is supplied as 50-mL vials. The intravenous (IV) dose must be diluted in at least 25 mL/kg of 10% dextrose, up to 600 mL. Sodium benzoate/sodium phenylacetate should not be directly mixed with other medications but may be piggybacked. It should be given in addition to the daily fluid requirement.

Class Summary

Ammonia detoxicants are used for treatment of hyperammonemia; they enhance elimination of nitrogen. Sodium benzoate/sodium phenylacetate (Ammonul) is approved by the US Food and Drug Administration (FDA) for treatment of hyperammonemia caused by urea-cycle defects. Bioequivalent generics are available in the U.S.

Sodium bicarbonate

Clinical Context:  Administration of sodium bicarbonate 0.25-2mEq/kg can be considered for acidosis with a pH <7.0-7.2

Class Summary

Bicarbonate treatment is controversial due to paradoxical CNS acidosis.

Ondansetron (Zofran, Zuplenz)

Clinical Context:  Selective 5-HT3 receptor antagonist that blocks serotonin both peripherally and centrally.

Class Summary

Off-label use of ondansetron may be considered to control nausea and vomiting associated with Reye syndrome and with IV administration of sodium benzoate/sodium phenylacetate.

Lorazepam (Ativan)

Clinical Context:  Widely used off-label in children to abort and/or prevent seizures and status epilepticus. Contains benzyl alcohol, so it is contraindicated in neonates and its association with gasping syndrome.

Fosphenytoin (Cerebyx)

Clinical Context:  Indicated for the treatment of generalized tonic-clonic seizures (eg, status epilepticus).

Class Summary

Seizures may occur with increased ICP and ammonia levels.

What is Reye syndrome?What is the pathophysiology of Reye syndrome?Which pathogens are associated with Reye syndrome?What is the role of salicylates in the etiology of Reye syndrome?In addition to salicylates, which medications cause Reye syndrome?What is the role of toxins in the etiology of Reye syndrome?Which inborn errors of metabolism are associated with Reye syndrome?What is the prevalence of Reye syndrome in the US?What is the global prevalence of Reye syndrome?Which patient groups have the highest incidence of Reye syndrome?What is the prognosis of Reye syndrome?What are the risk factors for Reye syndrome mortality?What are the survival rates for Reye syndrome?Which clinical history findings are characteristic of Reye syndrome?What are the signs and symptoms of Reye syndrome?What is the CDC classification of Reye syndrome?What are the CDC diagnostic criteria for Reye syndrome?What are the possible complications of Reye syndrome?Which conditions should be included in the differential diagnoses of Reye syndrome?Which factors suggest an inborn error of metabolism (IEM) etiology for Reye syndrome?What are the differential diagnoses for Reye Syndrome?What is included in the workup of Reye syndrome?What is the role of lab testing in the workup of Reye syndrome?Which invasive procedures are performed in the diagnosis and treatment for Reye syndrome?What is the role of imaging in the diagnosis of Reye syndrome?What is the role of electroencephalogram (EEG) in the diagnosis of Reye syndrome?How is Reye syndrome treated?What is stage-specific treatment for Reye syndrome?How is stage 0-1 Reye syndrome treated?How is stage 2 Reye syndrome treated?How is stage 3-5 Reye syndrome treated?How is Reye syndrome prevented?What is the role of medications in the treatment of Reye syndrome?Which medications in the drug class Anticonvulsants are used in the treatment of Reye Syndrome?Which medications in the drug class Antiemetics are used in the treatment of Reye Syndrome?Which medications in the drug class Alkalinizing Agents are used in the treatment of Reye Syndrome?Which medications in the drug class Hyperammonemia Treatment Agents are used in the treatment of 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

Disclosure: Nothing to disclose.

Chief Editor

Kirsten A Bechtel, MD, Associate Professor of Pediatrics, Section of Pediatric Emergency Medicine, Yale University School of Medicine; Co-Director, Injury Free Coalition for Kids, Yale-New Haven Children's Hospital

Disclosure: Nothing to disclose.


Richard G Bachur, MD Associate 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: Nothing to disclose.

Garry Wilkes, MBBS, FACEM Director of Emergency Medicine, Bunbury Hospital; Medical Consultant, St John Ambulance, WA Ambulance Service; Adjunct Associate Professor, Edith Cowan University; Clinical Associate Professor, Rural Clinical School, University of Western Australia

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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.


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