Thursday, May 15, 2014
For more than a century, aspirin was used to help safely relieve the symptoms of everything from headaches to stomach cramps. But in households with children, this commonplace medication is a potentially dangerous drug. That’s because the use of aspirin has been linked with Reye’s syndrome — a rare but serious illness that can affect the blood, liver and brain of children and teenagers recovering from a viral infection. Reye’s syndrome is a potentially fatal disease that causes numerous detrimental effects to many organs, especially the brain and liver.
In Reye’s syndrome, the level of ammonia and acidity in the blood typically rises while the level of blood sugar drops. At the same time, the liver may swell and develop fat deposits. Swelling also may occur in the brain and can cause emergencysymptoms such as seizures or convulsions. Reye’s syndrome can eventually lead to a coma and brain death.
The incidence of Reye’s syndrome has declined greatly since a peak in 1980. Many people assume the decline is due to the warnings against children taking aspirin, but that may be only part of the reason.
Better tests can diagnose metabolic conditions formerly thought to be Reye’s syndrome. Today children who develop Reye’s syndrome or conditions once thought to be Reye’s syndrome receive an earlier diagnosis and better treatment, which help improve recovery and reduce complications.
History
The syndrome is named after Dr R. Douglas Reye, who, along with fellow Australians Dr. Graeme Morgan and Dr. Jim Baral, published the first study of the syndrome in 1963 in the British medical journal, The Lancet (2:749-52), though the disease was first diagnosed as a unique illness in 1929. Also in 1963, Dr. George Johnson, along with colleagues, published a study about cases with a remarkably similar profile that his team observed occuring in South Carolina following an influenza B outbreak. Formally, the disorder is known as Reye-Johnson Syndrome, although it is more commonly called Reye’s Syndrome.
In 1980, studies in Ohio, Michigan and Arizona by Starko, et al. pointed to the use of aspirin during an upper respiratory tract infection and chicken pox as a potential indicator for the syndrome.
Aspirin use in children and adolescents decreased sharply in the mid-1980′s in North America, the UK, Europe and Australia. A decline in the incidence of Reye’s syndrome was almost immediately observed. The decrease in the number of cases of Reye’s syndrome was once thought to directly correspond to a decrease in aspirin use but that surmise has since come under some scrutiny. The decrease in the number of cases may also reflect a concurrent increased accuracy in diagnosis and the redesignation of misdiagnosed cases since the mid-1980′s — i.e., initially there were thought to be some 47 cases of Reye’s Syndrome in the UK in 1980/1981 but after a reassessment of susbsequent rediagnoses, that figure was revised downward to just 7 cases.
How many reported cases prior to 1980 might also be removed from the tallies, resulting in a decrease, if reassesments were conducted where possible? It is worth noting that a decrease in the number of cases has also been observed in countries where children’s aspirin is still in use. A dramatic worldwide decrease since 1996, regardless of salicylate use, has not been satisfactorily accounted for. Further case studies, primarily in the UK and Australia, have revealed 19 viruses singly and in conjunction with salicylates, pesticides and aflatoxin as potential factors contributing to the disease.
Causes
Reye’s syndrome tends to occur in previously healthy children about a week after common viral infections such as influenza or chickenpox. It can also develop after an ordinary upper respiratory infection such as a cold. The precise reason is unknown, but using aspirin to treat a viral illness or infection may trigger the condition in children.
Reye’s syndrome may be a metabolic condition — one without symptoms (asymptomatic) — that’s unmasked by viral illnesses. Reye’s syndrome occurs most commonly in children between the ages of 4 and 12.
Complications
While most children who survive Reye’s syndrome don’t suffer any long-term damage, this disorder can occasionally result in permanent liver damage, irreversible nervous system damage, coma and death.
Reye’s syndrome may include a combination of the following problems:
§ High levels of ammonia and acidity and a low level of sugar in the blood (hypoglycemia)
§ Fatty deposits in the liver and abnormal liver function tests
§ Poor blood clotting and bleeding caused by liver failure
§ Swelling of the brain, sometimes with coma and brain death
Earlier diagnosis and treatment can greatly reduce the chance of death.
stimulate the expression of inducible nitric oxide synthase (iNOS) because of findings of iNOS stimulation in African children with fatal malaria. Malaria 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).
Stage I
Persistent, heavy vomiting that is not relieved by eating
Generalized lethargy
General mental symptoms, e.g. confusion
Stage II
Stupor caused by minor brain inflammation
Hyperventilation
Fatty liver (found by biopsy)
Hyperactive reflexes
Stage III
Possible coma
Possible cerebral edema
Rarely, respiratory arrest
Also, symptoms above continue
Stage IV
The ever-deepening coma
Large pupils with minimal response to light
Minimal but still present hepatic dysfunction
Stage V
Very rapid onset after happening of stage IV
Death is imminent
Deep coma
Strong seizures
Respiratory failure
Flaccidity
Extremely high blood ammonia (above 300mg per 100mL of blood)
Spinal tap (lumbar puncture)
This procedure helps to rule out other diseases with similar signs and symptoms, such as infection of the lining and fluid that surround your brain and spinal cord (meningitis) or inflammation or infection of the brain (encephalitis). Local anesthesia is used to numb the puncture site in the lower back. A needle is then inserted through the lower back into the space around the spinal cord to collect a small sample of cerebrospinal fluid (CSF). The CSF can be analyzed for protein, sugar, and red and white blood cells. The sample is also routinely cultured to identify bacterial and viral infections.
Liver biopsy
Generally, this procedure is done by inserting a thin needle through the skin on the upper right side of the abdomen and into the liver in order to draw a tissue sample from the liver for laboratory analysis. This analysis is then used to rule out other possible diseases that may be affecting the liver.
Detecting rare metabolic disorders
Doctors may want to evaluate the possibility that the child has one of the rare, inherited metabolic disorders that can mimic the signs and symptoms of Reye’s syndrome. The list of these metabolic disorders is long, and most of them have long unfamiliar terms, such as medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. Most, if not all, of these conditions are inherited and may occur with varying degrees of severity in other family members.
The key to diagnosing or excluding these unusual conditions is obtaining blood and urine samples during the acute phase of the illness and having them analyzed in a qualified biochemical genetics laboratory. Many of these metabolic conditions are termed mitochondrial diseases because the problems arise from the part of body cells called the mitochondria.
If a child dies of a Reye’s-like illness, it may be important to obtain blood and urine to check for these metabolic conditions. Collecting samples of liver and brain tissue shortly after death could be the key to diagnosing a condition that might affect other family members. It may even be possible to analyze tissue from an autopsy done many years ago to clarify whether a death was due to a metabolic cause.
Lab Studies
On liver function testing, ammonia levels are as much 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 levels may return to the reference range in stages 4 and 5. Levels of transaminases, ALT, and AST increase to 3 times normal but may return to the reference ranges by stages 4 or 5.
Bilirubin levels are >2 mg/dL (usually <3 mg/dL) in 10-15% of patients. If direct bilirubin is more than 15% of total. If the total is >3 mg/dL, consider other diagnoses.
The prothrombin time (PT) and activated partial thromboplastin time (aPTT) are prolonged >1.5-fold in >50% of patients.
Lipase and amylase levels are elevated.
Serum bicarbonate levels are decreased secondary to vomiting.
BUN and creatinine levels are elevated.
Expect hypoglycemia, particularly in children younger than 1 year. A serum glucose test is indicated for all children with altered mental status.
Lactic dehydrogenase (LDH) levels may be high or low.
Obtain an anion gap test for metabolic acidosis.
Urine specific gravity is increased; 80% of patients have ketonuria.
These laboratory abnormalities may be transient.
Imaging Studies
Head CT scanning may reveal cerebral edema, but the results are usually normal.
Other Tests
Levels of free fatty acids and amino acids (eg, glutamine, alanine, lysine) may be elevated.
Factor assays show decreased factors II, VII, IX, and X and in fibrinogen due to the disruption of synthetic activities in the liver.
An electroencephalogram (EEG) may reveal slow-wave activity in the early stages and flattened waves in advanced stages.
On CSF testing, opening pressure may or may not be increased. WBCs (usually lymphocytes) may be 9 X 109/L (<9/mm3).
An extensive metabolic 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.
Procedures
Percutaneous liver biopsy may be indicated to exclude IEM or toxic liver disease.
Correction of any coagulopathy before the procedure is important.
Intravenous fluids. These may include glucose to increase low blood sugar; electrolyte solutions containing sodium, potassium and chloride to correct blood chemistry values; and basic solutions to treat acidity.
Insulin. Small amounts of insulin can increase sugar metabolism.
Corticosteroids. A corticosteroid medication can reduce brain swelling and inflammation.
Diuretics. A diuretic, such as mannitol, can increase fluid loss through urination and help reduce brain swelling.
Physicians may want to continuously monitor your child’s blood pressure using a thin, flexible tube (arterial catheter). An arterial catheter is threaded into an artery and is commonly used to monitor blood gases and acidity, as well as blood pressure.
If Reye’s syndrome reaches an advanced stage, treatment may include the use of a ventilator to help assist a child with breathing.
Prevention
To reduce the risk of Reye’s syndrome, avoid giving aspirin or medications that contain aspirin to your child to treat viral illnesses. Other names for aspirin include:
Acetylsalicylic acid
Acetylsalicylate
Salicylic acid/Salicylate
If a child or teenager has the flu or chickenpox, use other medications such as acetaminophen (Tylenol, others), ibuprofen (Advil, Motrin, others) or naproxen sodium (Aleve) to reduce fever or relieve pain. Unless specifically advised by your child’s doctor, don’t give aspirin to anyone younger than 19. Check the label on any medication you’re going to give your child, because aspirin can show up in some unexpected places. Some products that contain aspirin include Alka-Seltzer, some Excedrin products and Pepto-Bismol. Also, check with your doctor before giving your child any alternative or folk remedies. Some of these also contain aspirin. If a full ingredient list isn’t available, don’t give the medicine to your child without checking with your doctor first.
Some children with chronic diseases, such as juvenile rheumatoid arthritis, may need treatment long term with drugs that contain aspirin. Doctors advise that these children receive the varicella (chickenpox) and influenza vaccines to reduce their risk of developing Reye’s syndrome. In fact, the varicella vaccine is now recommended for all healthy children between 12 and 15 months old. It’s also recommended that children between six and 24 months of age receive the influenza vaccine each October. Never having these two diseases helps prevent Reye’s syndrome.
Medical/Legal Pitfalls
Failure to identify hypoglycemia and treat it
Failure to recognize that progression of disease may be extremely rapid
Overhydrating the patient with exacerbation of cerebral edema
Failure to aggressively treat cerebral edema (the major cause of morbidity and mortality)
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
Stage I
Monitor vital signs and check level of consciousnessfor increasing lethargy. Take vital signs more often as the patient’s condition deteriorates.
Monitor fluid intake and output to prevent fluid overload. Maintain urine output at 1.0ml/kg/hr; plasma osmolality 290mOsm; and blood glucose 150mg/ml (Goal: Keep glucose high, osmolality normal, ammonia low).Also, restrict protein.
Stage II
Watch for seizures and maintain precautions.
Immediately report any signs of coma that require invasive, supportive therapy, such as intubation.
Keep head of bed at 30° angle.
Stage III
Monitor ICP (should be <20 before suctioning) or give thiopental IV as ordered, as necessary, hyperventilate the patient.
If patient lapses into coma, immediately give 50% dextrose in water IV as ordered.
When ventilating the patient, maintain PCO2 between 23 and 30 mmHg and PO2between 80 and 100 mmHg.
Closely monitor cardiovascular status with pulmonary artery catheter or central venous pressure line.
Give good skin and mouth care and range-of-motion exercises.
Stage IV
Check patient for loss of reflexes and signs of flaccidity.
Give the family the extra support they need, considering their child’s poor prognosis.
Stage V
Help the family to face the patient’s impending death.
Davidson, S.L. Diseases Causes & Diagnosis Current Therapy Nursing Management Patient Education (Educational Publishing House. 1990)
Kumar Et Al. Robbins & Cotran Pathologic Basis of Disease (Elsevier Saunders Inc. 7th edition. 2005)
Huether, S. Et Al. Understanding Pathophysiology (Mosby, Inc. 2nd edition. 2000)
Reye’s Syndrome; http://en.wikipedia.org/wiki/Reye’s_syndrome
