Pediatric Annals

Management of Reye's Syndrome: Need for Early Diagnosis and Intravenous Treatment of Stage I Non-Comatose Cases

John C Partin, MD

Abstract

Reye's syndrome continues to stir public interest because of the publicity concerning its possible relationship with aspirin use. Public interest groups and the Food and Drug Administration (FCH) have activated media interest in the problem creating parental concern. For this reason it is important for practitioners to understand how to diagnose Reye's syndrome and how to answer parents' questions concerning the use of aspirin in acute childhood illness.

It is now clear that about two-thirds of the cases of Reye's syndrome can be diagnosed before the stage of agitated delirium and about one-third of these non-comatose cases have very serious liver injury as judged by ultrastructural analysis.1 Certain of these cases appear to be at risk for sudden progression to coma. We have recently shown that the risk of serious progression in hospitalized Stage I Reye's syndrome treated with intravenous glucose is about 6%, whereas Centers for Disease Control (CDC) data suggest that the overall national mortality for Stage I cases U 10%. 2 Many of the cases reported to the CDC are believed to have been treated initially without IV glucose infusion. Thus, early diagnosis and prompt glucose infusion appears to be a specific treatment for most, but not all, of Reye's syndrome cases which can be diagnosed during Stage I. Prompt treatment with intravenous glucose appears to reduce mortality and serious morbidity by at least tenfold. Reye's syndrome is very much a front line office practice problem.

Clinically, Reye's syndrome can be thought of as existing in three broad groups: 1) non-comatose, non-agitated delirium cases, 2) cases which exhibit extreme lethargy or agitated delirium, and 3) comatose cases. Non-comatose cases have the typical history of an antecedent illness, usually chickenpox or influenza, vomiting and either no detectable cortical depression or mild cortical depression. These are the cases referred to by the CDC and the Reye's syndrome Consensus Conference as Stage 0 and Stage 1 cases. Within this group is a sub-group doomed to progress to coma and death. We believe that some, but not all of these children can be prevented from progression if they are diagnosed early and treated with intravenous glucose. Pre-coma cases have: 1) a history of a definite antecedent illness, usually chickenpox or a flu-like respiratory illness within 1 week; 2) the unexpected onset of vomiting within I week of the onset of the antecedent illness and at a time when the parents believe the antecedent illness is improving; 3) elevation of the SGOT and SGPT, usually fourfold or more; these aminotransferases are usually well above 150 international units, and in our series the mean value was 940 units; 4) the blood ammonia may or may not exceed 100 µg/dl (normal blood ammonias do not exclude Stage I Reye's syndrome); 5) the prothrombin time may or may not be prolonged; 6) the lumbar puncture will be normal; and 7) the patient will not be jaundiced.

PREDICTORS OF SERIOUS METABOLIC INVOLVEMENT AND INCREASED PROBABILITY OF PROGRESSION IN NON-COMATOSE, STAGE I CASES

Patients who have clearly elevated SGPT or SGOT1 a blood ammonia greater than 100 µg/dl and a prothrombin time prolonged greater than 3 seconds, usually have severe ultrastructural changes in the liver and they appear to be at greater risk for progression to coma. Such patients should be managed in a pediatric intensive care unit.

Stage II Cases

Children with the typical history and clinical chemical findings of Reye's syndrome who progress to Stage II constitute a true medical emergency and must have the speedy implementation of intensive care treatment. Typically, Stage II cases demonstrate agitated delirium and flight and fright behavior. In addition,…

Reye's syndrome continues to stir public interest because of the publicity concerning its possible relationship with aspirin use. Public interest groups and the Food and Drug Administration (FCH) have activated media interest in the problem creating parental concern. For this reason it is important for practitioners to understand how to diagnose Reye's syndrome and how to answer parents' questions concerning the use of aspirin in acute childhood illness.

It is now clear that about two-thirds of the cases of Reye's syndrome can be diagnosed before the stage of agitated delirium and about one-third of these non-comatose cases have very serious liver injury as judged by ultrastructural analysis.1 Certain of these cases appear to be at risk for sudden progression to coma. We have recently shown that the risk of serious progression in hospitalized Stage I Reye's syndrome treated with intravenous glucose is about 6%, whereas Centers for Disease Control (CDC) data suggest that the overall national mortality for Stage I cases U 10%. 2 Many of the cases reported to the CDC are believed to have been treated initially without IV glucose infusion. Thus, early diagnosis and prompt glucose infusion appears to be a specific treatment for most, but not all, of Reye's syndrome cases which can be diagnosed during Stage I. Prompt treatment with intravenous glucose appears to reduce mortality and serious morbidity by at least tenfold. Reye's syndrome is very much a front line office practice problem.

Clinically, Reye's syndrome can be thought of as existing in three broad groups: 1) non-comatose, non-agitated delirium cases, 2) cases which exhibit extreme lethargy or agitated delirium, and 3) comatose cases. Non-comatose cases have the typical history of an antecedent illness, usually chickenpox or influenza, vomiting and either no detectable cortical depression or mild cortical depression. These are the cases referred to by the CDC and the Reye's syndrome Consensus Conference as Stage 0 and Stage 1 cases. Within this group is a sub-group doomed to progress to coma and death. We believe that some, but not all of these children can be prevented from progression if they are diagnosed early and treated with intravenous glucose. Pre-coma cases have: 1) a history of a definite antecedent illness, usually chickenpox or a flu-like respiratory illness within 1 week; 2) the unexpected onset of vomiting within I week of the onset of the antecedent illness and at a time when the parents believe the antecedent illness is improving; 3) elevation of the SGOT and SGPT, usually fourfold or more; these aminotransferases are usually well above 150 international units, and in our series the mean value was 940 units; 4) the blood ammonia may or may not exceed 100 µg/dl (normal blood ammonias do not exclude Stage I Reye's syndrome); 5) the prothrombin time may or may not be prolonged; 6) the lumbar puncture will be normal; and 7) the patient will not be jaundiced.

PREDICTORS OF SERIOUS METABOLIC INVOLVEMENT AND INCREASED PROBABILITY OF PROGRESSION IN NON-COMATOSE, STAGE I CASES

Patients who have clearly elevated SGPT or SGOT1 a blood ammonia greater than 100 µg/dl and a prothrombin time prolonged greater than 3 seconds, usually have severe ultrastructural changes in the liver and they appear to be at greater risk for progression to coma. Such patients should be managed in a pediatric intensive care unit.

Stage II Cases

Children with the typical history and clinical chemical findings of Reye's syndrome who progress to Stage II constitute a true medical emergency and must have the speedy implementation of intensive care treatment. Typically, Stage II cases demonstrate agitated delirium and flight and fright behavior. In addition, we now consider children who demonstrate marked somnolence, ioss of memory or slurred speech as early Stage II and we manage them in the pediatric intensive care unit.

Treatment of Stage II Cases

Stage II (agitated delirium) is usually short lived and, unfortunately, is frequently a transition stage to coma. When stimulated, these patients struggle desperately and may require severe physical restraint. The need for restraint is reduced if all work up procedures are completed quickly and then the patient is exposed to minimal and quiet skillful manipulation. In some cases it may be necessary to sedate and intubate these patients. We treat Stage II cases with maintenance electrolytes and 10% glucose at a rate of 1,800 cc/m2/24 hours unless they are seriously dehydrated due to vomiting, in which case corrective water and electrolytes are administered.

Treatment of Stage III (Comatose) Patients

There is no proven treatment for the coma of Reye's syndrome beyond intensive supportive care with immediate endotracheal intubation and the exercise of measures to control intracranial pressure when it supervenes. Patients should be managed in a pediatric intensive care unit. All comatose patients should be intubated immediately and ventilated in a manner to avoid anoxia and to maintain the pCO2 at about 25 torr. Pavulon and Demerol may be used, with caution, to reduce muscular tone and struggling against the respirator. Glucose should be infused to maintain the blood glucose in the high normal range, near the renal tubular transport maximum. Gross spilling of sugar into the urine should be avoided. In cases with high aspirin levels, we continue to use exchange transfusion with fresh (up to 5 days old) citrated whole blood.

We install an intracranial pressure (ICP) monitor in all comatose cases. Many comatose cases will have nearly normal ICP when relaxed and we have observed brain death in the face of normal pressures. When the ICP is elevated mannitol may be effective in doses ranging from 250mg/kg to 1000mg/kg. One should use the lower dose initially. Furosemide may be useful in some cases and glycerol has been used in cases refractory to mannitol. Extreme hyperosmolarity must be avoided because it can directly damage brain and kidney and because it is inevitably associated with hypovolemia and consequently diminished cerebral perfusion pressure. It does no good to temporarily reduce ICP if at the same time one induces brain ischemia. The serum osmolarity should be maintained between 310 and 320 mosm, not higher.

Barbiturate coma has proved disappointing in the management of Reye's syndrome. Regimens which constitute extreme polypharmacy undoubtedly produce worse results than careful intensive supportive management, because one loses control of all clinical estimates of brain function and also of regulation of cerebral perfusion.

Recent Epidemiologic Considerations

In the US, Reye's syndrome cases almost always occur in clusters (outbreaks) in association with influenza or chickenpox. Since 1980 the incidence of Reyes syndrome has dropped and the 1984 Reye's syndrome "season" was associated with the lowest incidence of the disease in many years. * Whether there will be a persistent reduction of the number of Reye's syndrome cases associated with what appears to be a reduction in the use of aspirin in children remains to be determined. There has not been a major outbreak of influenza B since the winter of 1980. While it is clear that Reye's syndrome occurs in association with influenza A strains, it is not clear whether some strains may be more or less likely to be associated with Reye's syndrome. It must be remembered that we do not know the etiology of Reye's syndrome.

THE ASPIRIN QUESTION

There is no doubt that, "there is a reasonable doubt about the safety of aspirin when it is used in acute childhood illnesses which are antecedent to Reye's syndrome."4 The pilot study of the FDA study of acute childhood illness showed that 97% of Reye's syndrome cases had consumed aspirin, whereas only 23% to 59% of the four groups of age matched, sex matched control cases consumed aspirin. } This rather tightly controlled pilot study, small though it be, suggests that aspirin is a significant risk factor for the development of clinically apparent Reye's syndrome. Aspirin-consuming children with an acute illness known to be antecedent to Reye's syndrome appear to have a 10 to 25 times greater probability of developing Reye's syndrome than do children with a similar illness who have not taken aspirin. It is the author's opinion that aspirin should not be used as an ordinary analgesic/antipyretic in infants and children. Aspirin should be used for its specific indications, as in Kawasaki disease, juvenile arthritis, acute rheumatic fever and similar serious illness. And in these conditions, one must discontinue aspirin during influenza and chickenpox. Some investigators suggest that the risk of Reye's syndrome is substantially increased among children with juvenile arthritis on aspirin than among children in the general population.

SUMMARY

Clinicians and nurses should obtain a history of antecedent illness occurring within 2 weeks of the onset of vomiting. Ninety percent of school-age children will give a history of an antecedent illness (varicella or influenza-like respiratory illness) within 1 week of the onset of vomiting. The vomiting of Reye's syndrome is usually persistent, lasting for 24 to 96 hours before the onset of serious brain signs. We believe that any child with the history of flu or chickenpox within 1 week of the onset of vomiting, which lasts for more than 12 hours, and is unusually severe or is associated with lethargy, should have an SGPT (alanine aminotransferase). This laboratory measure is clearly elevated in most cases of Reye's syndrome.

REFERENCES

1. Heubi JE, Dougherty CC, Partin JS. et al: Giade I Reyes Syndrome - Outcome and predictors of progression to deeper coma grades. N Engl J Mid 1984; H 1:1539-1542.

2. Lichtenstein PK. Heubi JE1 Daugherty CC. er al: Grade I Reye's syndrome: A frequent cause of vomiting and liver dysfunction after varicella and upper respiratory-tract infection. N Engl Med 1963; 309:133.139.

3. Reye's Syndrome-United States. 1984. MMWR 1985; 34:13-16.

4. CDC Surgeon General's Advisory on the use of salicylates and Reye's Syndrome. MMVfR 1982; 31:289-290.

10.3928/0090-4481-19850701-10

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