Article Reviews and Commentary

Acetaminophen Toxicity in Children
Committee on Drugs Pediatrics 2001;108:1020-1024

This document is a statement from the AAP Committee on Drugs regarding unintentional acetaminophen overdosing and subsequent toxicity. There are many liaisons and consultants to the Committee on Drugs listed at the conclusion of he statement, including Dr. Cote, from the AAP Section of Anesthesiology and Pain Treatment.

While most cases of acetaminophen overdose are intentional suicide gestures, in fatal overdoses in which reason for exposure were certain, 25% were unintentional therapeutic error or intentional misuse without suicidal intent. Among the 24 cases without suicidal intent, three of the deaths were in patients younger than 16 years. The statement lists several factors associated with acetaminophen hepatotoxicity. Included are: age < 10 years, delays in diagnosis and initiation of N-acetylcysteine (NAC) treatment, ingestion of acetaminophen along with other hepatotoxic drugs, use of adult rather than pediatric preparations. In cases of unintentional overdosing, improper measurement, use of sustained release preparations and co-administration of other over-the-counter acetaminophen containing preparations. Rectal administration of acetaminophen may also contribute to toxicity given the variable serum levels produced and the variable times when these levels are achieved. The specific conditions that may increase the risk of acetaminophen toxicity are listed in a table in the statement as follows: diabetes mellitus, obesity, chronic undernutrition, prolonged fasting, concomitant viral infection.

The paper discusses the report that a dose of 120-150 mg/kg as the minimal single acetaminophen dose associated with hepatotoxicity. Fasting is associated with increased acetaminophen toxicity in animal studies and human observations. The clinical presentation of acetaminophen toxicity has been divided into 4 phases. First, anorexia, nausea, vomiting, malaise and lethargy may actually lead to administration of additional acetaminophen. The second phase, the initial signs resolve and right upper quadrant pain and tenderness develop. Bililrubin and liver enzymes become elevated and prothrombin time is prolonged. Three to five days into the course of toxicity the third phase begins, consisting of malaise, vomiting as well as signs of hepatic failure ( hypoglycemia, jaundice, coagulopathy, encephalopathy). the fourth phase is either death or progression to recovery.

Treatment with N-acetylcycteine (NAC) should begin with 6-8 hours of acetaminophen and following a dose of activated charcoal. NAC has been given PO but there are investigators using it IV. The statement concludes with recommendations to health care providers which will likely decrease the incidence of acetaminophen toxicity.

Commentary by: Thomas J Mancuso, MD, FAAP

This paper is directed primarily to pediatricians who either prescribe acetaminophen to their patients or see children in the clinic who may have been given the medication, perhaps in excess inadvertently, by care-givers. However, it is a useful review of the data on treatment and a reminder that we should be sure that parents of children who are leaving our day surgery units understand the proper dosing schedule of acetaminophen, especially following the larger rectal doses currently in use.

The Ketogenic Diet: A 3-6 Year Follow-Up of 150 Children Enrolled Prospectively
Kuhlthau K, Ferris TG et al Pediatric 2001;108:898-905

This paper reports the effectiveness and side effects of the ketogenic diet in 150 consecutive children who remained on the diet for at least one year. The survey was done 3-6 years after enrollment. Of the 150 patient cohort, 20 were seizure-free and 21 had a 90%-99% decrease in seizure frequency. There were no known cardiac complications. The authors discuss other complications. Although nearly one-half of parents report that their children do not grow as well while on the diet, ongoing studies indicate that the children do grow, although at a low-normal rate. Approximately 10% of children develop kidney stones, some in the study requiring lithotripsy treatments. Although not seen in the children in this cohort, cardiomyopathy has been reported n children on the ketogenic diet. Hyperlipidemia, a theoretic concern, has not been a problem. The authors refer to a report indicating that when this does occur, adjustment of the diet brings the lipid levels toward normal.

Commentary by:Thomas J Mancuso, MD, FAAP

Based on this and other reports, the ketogenic diet is becoming more and more important treatment for seizures. We should be familiar with the special needs of these patients, including the complications of the diet such as those mentioned in this paper. Intra-op fluid type and volume will differ in these children and preop evaluation for abnormalities of cardiac function and rhythm and kidney stones might be indicated. References cited in this report of interest in this regard include: Ballaban-Gil, Complications of the Ketogenic Diet Epilepsia 1998;39:744-748, Best, Cardiac complications in pediatric patients Neurology 2000;54:2328-2330, Vining The ketogenic diet indices dyslipidemia Epilepsia 1999;40(suppl 7):122

Bladder Retention of urine as a Result of Continuous Intravenous infusion of Fentanyl: 2 Cases Reports.
Das UG, Sasidharan P Pediatrics 2001;108:1012-1015

The authors mention the reasons for the use of fentanyl infusions in newborns receiving mechanical ventilation in the NICU including, minimizing resistance to mechanical ventilation, facilitation of synchrony between spontaneous and mechanical breaths, decrease of the stress response. In the first case, a 1.5 kg newborn surfactant soon after delivery and was begun on mechanical ventilation. Fentanyl, 3mcg/kg/hr, was started at this time and continued for several days. Evaluation of hypertension on the third hospital day revealed a distended bladder and bilateral hydronephrosis. After placement of a foley, the bladder was drained and a voiding cystogram 6 days later was wnl. The second case was similar but the hydronephrosis was noted in the evaluation of decrease urine output done at 2 days of age. In neither case were anatomic causes found for the urine retention.

Commentary by:Thomas J Mancuso, MD, FAAP

The authors recommend routine foley catheterization in newborns receiving fentanyl infusions. while these critically ill infants often have foely catheters for other reasons, i am uncertain about advocating placing this invasive monitor based on two case reports.

Screening Examination of Premature Infants for Retinopathy of Prematurity
AAP Section on Ophthalmology American Association for Pediatric Ophthalmology and Strabismus American Academy of Ophthalmology Pediatrics 2001;108:809-811

Commentary by:Thomas J Mancuso, MD, FAAP

This statement revises a previous statement originally published in 1997. The statement recommends examinations with dilated pupils using binocular indirect ophthalmoscopy to detect. ROP. In may cases, this may result in the exam being done with general anesthesia, often in the OR.

Romano, M, Dinh A Pediatrics 2001;108:471-473

A child, weighing 17.5 kg received 50 mg Clonidine confirmed by analysis of the compound administered. The authors report that this is the largest ingestion reported.

The child was found limp and unresponsive by the parents 20 minutes after the dose of clonidine was given. They took him to the ED. Admission VS: HR = 52/min, RR = 40/min, BP = 133/103 mmHg, Temp = 94 F. The child was listless, responsive to pain, and with small pupils. RA ABG showed: 7.59 PaCO2 21, Pa02 112 HC03 20. Toxicology screen was negative for other agents. In the PICU, RR = 5-6/min HR = 47/min. Intermittent bag/valve/mask ventilation was done. Atropine 0.2 mg was given and HR increased to 130/min. Naloxone 2.0 mg IV was given and RR increased to 16/min and became regular. Additional 2.0 mg doses of naloxone were given and later an infusion of 15 mg/hr was started. The infusion was titrated to RR and gradually decreased in the subsequent 25 hours when it was stopped. Nine doses of atropine were given for bradycardia. A serum level of clonidine of 64 ng/ml was obtained 42 hours after the ingestion. The child was discharged 42 hours after admission with no sequelae.

Commentary by:Thomas J Mancuso, MD, FAAP

Although it is of interest to review the treatment of this massive clonidine overdose since we are using this drug more often of late, as a premedication and as part of epidural/caudal analgesia, I trust that all of us much prefer to read about rather than author such a report.

Treatment of Pain with Gabapentin in a Neonate.
Behm MO, Kearns GL Pediatrics 2001;108:482-484

Gabapentin (GPB) is a GABA analog whose mechanism of action remains unknown that is approved for use in treatment of partial seizures and has been used as a adjunct in the managment of neuropathic pain in adults and children. The authors report the successful treatment of pain in an infant with amyoplasia congenita with severe contractures and dislocated joints.

Radiographs of the newborn taken shortly after birth because of contractures of the extremities and neck extension showed severe extension contracture of the neck, bilateral dislocated hips, clubfeet, dysplastic shoulders with probable dislocation flexion contractures of the fingers. A head ultrasound was unremarkable. Acetaminophen was given without clinical indication of analgesia. The possibility of adverse side effects from long term Ibuprofen use led to the choice of gabapentin. GPB was started at a dose of 7.0 mg/kg Q day with acetaminophen administered 60-90 minutes prior to manipulations. The dose was adjusted upwards to 10 mg/kg Q day. Sedation was not noted, either in hospital or at home. Pain was assessed using a combination of the neonatal faces coding system and Barriers postoperative pain scale.

Commentary by:Thomas J Mancuso, MD, FAAP

Most of us are familiar with the use of GPB in the treatment of neuropathic pain in adults and children. This medication has been found to be relatively safe. I would not undertake treatment of newborns and young infants without more data then this one case report. However, the safety of the drug in children and adults does add some credence to it's described use. In 2-6 year olds, doses of up to 100 mg/kg have been used in the treatment of seizures and have been well tolerated. Sedation, dizziness, fatigue and ataxia are among the most common side effects. Sedation is often temporary. In this newborn, treated with 10 mg/kg/day, sedation was not noted at all. Once treatment with GPB was begun, the infant appeared to be very comfortable, interacting with the mother, smiling and playful.

Physical Growth and Current Health Status of Infants Who Were of Extremely Low Birth Weight and Controls at Adolescence.
Saigal S Stoskopf BL et al Pediatrics 2001; 108:407-415

The authors of this paper wanted to compare a group of former extremely low birth weight (ELBW) infants with controls with regard to physical growth, current health status, and utilization of health care resources. A longitudinal cohort design was used to compare the 154 ELBW survivors with 125 controls.

In describing the ELBW survivors the authors noted the following:

• 28% had neuro sensory impairments
• 8.3% were < 5th percentile in height
• mean height was 159 cm, 6 cm below the mean of the controls
• 6% were < 5th percentile in weight
• mean weight was 51 kg, 6 kg below the mean of the controls
• mean head circumference was 54.2 cm, 1.8 cm less than the controls mean
• 15.5% were , 5th percentile for head circumference

Developmental delay, clumsiness, emotional problems, learning and visual problems were much more common in the ELBW survivors. The ELBW survivors had significant catch-up in height and weight between the ages of 8 and teen aged years. Not surprisingly, the ELBW survivors had a higher incidence of seizures than controls.

Commentary by Thomas J Mancuso, MD, FAAP

This is a large and long follow-up of ELBW survivors which shows the expected troubles these children have with learning and neuro sensory impairments. Of note for anesthesiologists, the authors did not report that the ELBW survivors had significantly greater pulmonary or respiratory problems. The authors report that although more of the ELBW survivors had with asthma and recurrent bronchitis, the difference did not reach statistical significance as it had when the subjects were younger. Seventeen of the 154 ELBW survivors had asthma while 10/125 controls had asthma.

Toxicity of Over-the-Counter Cough and Cold Medications.
Gunn VL, Taha SH et al Pediatrics 2001;108/3/e52

Over-the-counter (OTC) medications have not been shown to have a significant benefit to the children who are given them. nevertheless, these medication do have toxicities. The authors present 3 cases of adverse outcomes including 1 fatality which occurred over a 13 month period. The authors explore the toxicities of OTC medications in this paper. The cases included a 36 ex-preterm month-old child with lethargy, vomiting, tachypnea and tachycardia who was admitted to the PICU with an initial diagnosis of possible VPS malfunction. Urine toxicology revealed bropheniramine which was considered the reason for the mental status and vital sign changes. Another 3 year old underwent evaluation for possible cardiomyopathy due to persistent tachycardia. The etiology was finally determined to be excessive sympathomimetic effects due to an acetaminophen preparation chloropheniramine and pseudoephedrine. Of note, the parents repeatedly reported that the only medication they had been giving to their child was Tylenol.

Commentary by Thomas J Mancuso, MD, FAAP

Although it would be unlikely that a child would come to the OR for VPS revision because of a misdiagnosis as described in the first case above, this paper does highlight the importance of learning the types and composition of all OTC medications being administered by parent to their children who come to the OR for procedures. Many OTC cough and cold preparations contain several medications and parents often refer to the main drug only as occurred in the second case. As mentioned in an earlier review, there is now a published compendium of herbal remedies as well as an accompanying web site available.