E-DRUG: RFI: paracetamol AND ibuprofen in children? (6)
-------------------------------------------------------
dear E-druggers,
There is an interesting commentary on use of paracetamol in febrile children
in Australian Prescriber that may include relevant information. The direct
web link is
http://www.australianprescriber.com/index.php?content=/magazines/vol18no2/pa
racetamol.htm.
regards
Lynn
Lynn Weekes
Chief Executive Officer
National Prescribing Service Ltd
Level 7, 418A Elizabeth St, Surry Hills 2010
PO Box 1147, Strawberry Hills 2012
Phone: 02 8217 8700
Fax: 02 9211 7578
Web: www.nps.org.au <http://www.nps.org.au>
-----------
Paracetamol: use in children
Frank Shann, Intensive Care Unit, Royal Children's Hospital, Melbourne
(Aust Prescr 1995;18:33-5)
SYNOPSIS
It is sensible to use paracetamol to reduce the discomfort caused by minor
acute infections, surgical procedures and triple antigen. It is also
sensible to use paracetamol to reduce fever in patients with cardiac or
respiratory failure. However, there is little evidence to support the use of
paracetamol to treat fever in patients without heart or lung disease, or to
prevent febrile convulsions.
Paracetamol may prolong infection and reduce the antibody response in mild
disease, and increase morbidity and mortality in severe infection. The dose
in children is 10-15 mg/kg 4 hourly, to a maximum of 100mg/kg/day, and no
patient should receive more than 4 g/day.
Index words: fever, pain, analgesia, antipyretic.
Despite the widespread use of paracetamol, there is still confusion about
when it should be used and the correct dose.1
Indications for paracetamol
Fever
In patients with cardiac or respiratory failure who are febrile, it can be
helpful to give paracetamol to reduce oxygen consumption, carbon dioxide
production and cardiac output. However, in patients without heart or lung
disease, fever is harmful only at temperatures over 41oC. Such high
temperatures are usually caused by heat stroke or brain injury2, and, if so,
they do not respond to paracetamol or aspirin.
Febrile convulsions
There is no evidence that antipyretics prevent febrile convulsions; this is
probably because the convulsion is caused by the rapid rise in temperature
that usually occurs at the beginning of an illness.2 There are no controlled
trials comparing an antipyretic to placebo for febrile convulsions, but one
study comparing phenobarbitone plus antipyretic to placebo plus antipyretic
found a high risk of febrile convulsions in the placebo plus antipyretic
group, suggesting that antipyretic therapy did not protect against
convulsions.3 In a recent controlled trial in children who had had a febrile
convulsion4, children given paracetamol 15-20 mg/kg every 4 hours were just
as likely to have another convulsion as children given paracetamol only when
their rectal temperature exceeded 37.9oC.
Discomfort
It is sensible to give paracetamol to reduce the unpleasant symptoms caused
by mild acute infections. However, paracetamol does not have a dramatic
effect: a recent controlled trial5 found that paracetamol caused only a
modest improvement in activity and alertness in children with acute
infection, and that there was no significant improvement in mood, comfort,
appet ite or fluid intake. Because many patients with infection have fever
and discomfort, it is often assumed that fever causes discomfort but
strenuous exercise causes temperatures up to 40oC without causing
discomfort.
Triple antigen reactions
Two studies6,7 have shown that paracetamol reduces fever and abnormal
behaviour in children who have had triple antigen injection. A third study8
found that paracetamol had no significant effect, but only one dose of 10
mg/kg of paracetamol was given 4 hours after immunisation. A reduction in
adverse reactions to triple antigen is likely to improve immunisation rates.
Postoperative pain
There has been little systematic study of the use of paracetamol for
postoperative pain, but controlled trials of nonsteroidal antiinflammatory
drugs9 and experience with paracetamol suggest that paracetamol provides
adequate analgesia for minor surgery, and allows a reduced dose of opiates
after major surgery. Paracetamol should probably be given before surgery,
rather than waiting for pain to develop after surgery.9
The dose of paracetamol
While a single dose of 5 mg/kg of paracetamol results in some reduction in
the temperature of febrile children, there is a much larger fall with 10
mg/kg and an even larger and more prolonged fall with 20 mg/kg.10
The maintenance dose of paracetamol in children is 10-15 mg/kg 4 hourly10,
to a maximum of 100 mg/kg/day, and no patient should receive more than 4
g/day. An initial dose of 20 mg/kg can be given if it is felt that maximum
effect is needed quickly. A dose of 30 mg/kg 8 hourly gives levels in the
therapeutic range.10 A single dose of 30 mg/kg of paracetamol at bedtime can
increase the amount of sleep for the whole family when a child has mild
acute infection, but the danger of repeating this dose has to be emphasised.
In Australia, paracetamol is sold in preparations containing 60mg in 0.6 mL
(or 100 mg/mL), 100 mg/mL, 50 mg/mL, 120 mg in 5 mL (or 24 mg/mL) and 240 mg
in 5 mL (or 48 mg/mL). It is difficult to calculate a dose of 15 mg/kg from
these formulations. Parents often give a very low dose of paracetamol
because they use the infant dropper, designed for 100 mg/mL preparations, to
measure a dose of the more dilute preparations designed for use in older
children.10
Cost
Liquid preparations of paracetamol are expensive, with the MIMS price
varying from $1.11 to $5.39 per g of paracetamol (mean $2.52 per g). In
contrast, the MIMS price of 500 mg tablets of paracetamol is 10c to 45c per
g. Tablets are a much cheaper form of paracetamol than liquid preparations,
and some brands of paracetamol tablets are very much cheaper than others
(the brands listed in the Schedule of Pharmaceutical Benefits tend to be
less expensive).
Antipyretics may be harmful
Immunity
Too many parents and health workers think that infection is bad, infection
causes fever, and that therefore fever is bad. In fact, fever is often a
beneficial host response to infection, and moderate fever improves
immunity.11 Therefore, it may not be a good idea to give drugs that reduce
temperature to patients with severe infection. I have recently reviewed 1
the results of 9 controlled trials in mammals of the effect of paracetamol
or aspirin on mortality or virus excretion. Four trials found that aspirin
increased mortality in bacterial or viral infection. Viral shedding was
increased by paracetamol or aspirin in 3 studies, possibly increased in one,
and not affected in two (one used only pharyngeal washings, and one had only
9 subjects in the aspirin and placebo groups). One study found that antibody
production was impaired by both paracetamol and aspirin, but no effect on
antibody production was detected in the study with only 9 subjects in the
aspirin and placebo groups. This evidence suggests that aspirin and
paracetamol increase mortality in severe infection, and that they may
prolong the infection and reduce the antibody response in mild disease.
Direct toxicity
Despite the millions of children treated with paracetamol, very little
serious toxicity has been recognised (but note that the association between
aspirin and Reye's syndrome was not recognised for many years). Penna and
Buchanan 12 reviewed reports of 7 deaths and 11 cases of hepatotoxicity
associated with paracetamol in children. The children who died had had more
than 300 mg/kg/day of paracetamol for 1-6 days, except for one child where
the plasma level suggested that the actual dose may have been much higher
than the reported dose. The children who had hepatotoxicity but survived had
all had 150 mg/kg/day for 2-8 days, except for two children where there was
a discrepancy between the low reported doses and the high plasma levels of
paracetamol (which was probably due to miscalculation of the dose or
deliberate poisoning). Presumably, other cases of paracetamol toxicity in
children have occurred and have gone unrecognised or unreported, but the
evidence suggests that toxicity from paracetamol is rare with doses less
than 150mg/kg/day. The dose of paracetamol should not exceed 100mg/kg/day in
children, and no patient should receive more than 4 g/day.
In acute poisoning from paracetamol, treatment with acetylcysteine should be
started within 10 hours if possible. If the delay in starting acetylcysteine
is more than 10 hours or if there is established liver failure, a longer
course of acetylcysteine should be given.13,14 The best regimen has not been
determined; I suggest giving 150 mg/kg of acetylcysteine in 5% dextrose
intravenously over 15 minutes; then 12mg/kg/hour (200 microgram/kg/minute)
for 4 hours; then 6mg/kg/hour (100 microgram/kg/minute) for at least 16
hours if the delay in starting was less than 10 hours, for at least 28 hours
if the delay was 10-16 hours and at least 68 hours if the delay was more
than 16 hours. Acetylcysteine should be continued as long as the patient has
encephalopathy, abnormal liver function tests or paracetamol detected in the
serum.
Conclusion
The antipyretic action of paracetamol is useful in febrile patients with
cardiac or respiratory failure. The analgesic action is useful in minor
acute infection, for postoperative pain and after vaccination with triple
antigen.
There is little evidence to support the use of paracetamol to treat fever in
patients without heart or lung disease, or to prevent febrile convulsions.
Indeed, paracetamol may decrease the antibody response to infection, and
increase morbidity and mortality in severe infection. It should be explained
to parents that fever is usually a helpful response to infection, and that
paracetamol should be used to reduce discomfort, but not to treat fever.
Although an initial dose of 20 mg/kg of paracetamol can be given, this is
rarely necessary. The maintenance dose in children is 10-15 mg/kg 4 hourly.
Hepatotoxicity has been reported with doses of 150 mg/kg/day, and no patient
should be given more than 100 mg/kg/day (up to a maximum of
4 g/day).
R E F E R E N C E S
1. Shann F. Paracetamol: when, why and how much [editorial; comment]. J
Paediatr Child Health 1993;29:84-5.
2. Schmitt BD. Fever in childhood. Pediatrics 1984;74:929-36.
3. Camfield PR, Camfield CS, Shapiro SH, Cummings C. The first febrile
seizureantipyretic instruction plus either phenobarbital or placebo to
prevent recurrence. J Pediatr 1980;97:16-21.
4. Schnaiderman D, Lahat E, Sheefer T, Aladjem M. Antipyretic effectiveness
of acetaminophen in febrile seizures: ongoing prophylaxis versus sporadic
usage. Eur J Pediatr 1993;152:747-9.
5. Kramer MS, Naimark LE, RobertsBrauer R, McDougall A, Leduc DG. Risks and
benefits of paracetamol antipyresis in young children with fever of presumed
viral origin [see comments]. Lancet 1991;337:591-4. Comments in: Lancet
1991;337:1045,1347-8.
6. Ipp MM, Gold R, Greenberg S, Goldbach M, Kupfert BB, Lloyd DD, et al.
Acetaminophen prophylaxis of adverse reactions following vaccination of
infants with diphtheriapertussistetanus toxoidspolio vaccine. Pediatr Infect
Dis J 1987;6:721-5.
7. Lewis K, Cherry JD, Sachs MH, Woo DB, Hamilton RC, Tarle JM, et al. The
effect of prophylactic acetaminophen administration on reactions to DTP
vaccination. Am J Dis Child 1988;142:62-5.
8. Uhari M, Hietala J, Viljanen MK. Effect of prophylactic acetaminophen
administration on reaction to DTP vaccination. Acta Paediatr Scand
1988;77:747-51.
9. Dahl JB, Kehlet H. Nonsteroidal antiinflammatory drugs: rationale for use
in severe postoperative pain [see comments]. Br J Anaesth 1991;66:703-12.
Comment in: Br J Anaesth 1992;68:118.
10. Shann F. Paracetamol and fever. Aust Pharm 1991;10:217-20.
11. Roberts NJ Jr. Impact of temperature elevation on immunologic defenses.
Rev Infect Dis 1991;13:462-72.
12. Penna A, Buchanan N. Paracetamol poisoning in children and
hepatotoxicity. Br J Clin Pharmacol 1991;32:143-9.
13. Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral
Nacetylcysteine in the treatment of acetaminophen overdose. Analysis of the
national multicenter study (1976 to 1985) [see comments]. N Engl J Med
1988;319:1557-62. Comment in: N Engl J Med 1989;320:1417-8.
14. Keays R, Harrison PM, Wendon JA, Forbes A, Gove C, Alexander GJ, et al.
Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure:
a prospective controlled trial. Br Med J 1991;303:1026-9.
--
To send a message to E-Drug, write to: e-drug@healthnet.org
To subscribe or unsubscribe, write to: majordomo@healthnet.org
in the body of the message type: subscribe e-drug OR unsubscribe e-drug
To contact a person, send a message to: e-drug-help@healthnet.org
Information and archives: http://www.essentialdrugs.org/edrug