[e-drug] Management of fever in children in an outpatient setting (5)

["Andy Gray" <Graya1@ukzn.ac.za>]

E-DRUG: Management of fever in children in an outpatient setting (5)
------------------------------------------------------

Hi all

I have found two Australian Prescriber articles useful as teaching
resources on this subject. The full texts are provided below. Some
countries may have standardised strengths of paediatric paracetamol
available (for example, 120mg/ml and 120mg/1.2ml drops in South Africa)
or restrictions on the sale of larger quantities in general stores (only
pharmacists may sell more than 100ml of the 120mg/5ml or 20ml of the
120mg/1.2ml drops in South Africa). Yet another problem is the
widespread use of combination products (e.g. paracetamol 120mg + codeine
phosphate mg + promethazine 6.5mg/5ml), commonly recommended by
pharmacists and prescribed by medical practitioners. There is growing
use of an IV infusion formulation (Perfalgan(r), sold by BMS) in South
African private (for-profit) hospitals, but not, to my knowledge in
ambulatory care settings. There are two strengths of suppository
registered in South Africa (125mg and 250mg), but these are not widely
used. Patient (and carer) acceptance of rectal preparations seems to
vary considerably between countries.

regards
Andy
~~~
http://www.australianprescriber.com/magazine/18/2/33/5/
Paracetamol: use in children 
Frank Shann, Intensive Care Unit, Royal Children's Hospital, Melbourne

Summary

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. 

Key words: fever, pain, analgesia, antipyretic

(Aust Prescr 1995;18:33-5)

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. 

This article has been reprinted (with minor modifications) from the
Journal of Paediatrics and Child Health 1993;29:84-5. 

~~~
http://www.australianprescriber.com/magazine/23/3/60/1/
Paracetamol: overused in childhood fever 
Peter Hewson, Paediatrician, Geelong, Vic.

Summary

Paracetamol has a mild beneficial effect on the symptoms of viral
illness in childhood. However, the child may still remain unwell. Data
suggest that fever may have an immunological benefit and that
paracetamol may not decrease the number of recurrent febrile
convulsions. There are good reasons, particularly related to toxicity,
for limiting the use of paracetamol in children. 

Key words: fever, toxicity, overdose, febrile seizures.

(Aust Prescr 2000;23:60-1)

Introduction 

Some years ago Frank Shann warned us of the routine use of paracetamol
in febrile young children.1 (See also 'Paracetamol: use in children'
Aust Prescr 1995;18:33-5). Evidence continues to mount against its
indiscriminate use. The mild symptomatic benefit must be balanced
against the increasing incidence of mistaken dosage and toxicity. As we
live in a society which relies on drugs, both doctors and pharmacists
should remind parents about the dangers of paracetamol. 

Reasons for caution 

Immunological 

Humans and other animals given paracetamol are likely to shed virus for
longer than controls.2 

Toxicity 

Several factors increase the risk of toxicity. 

Cultural factors 

It has previously been mistakenly accepted that all febrile children
with infective illness require medication. We need to question this
phenomenon as another example of society's reliance on drugs. The
widespread use of antipyretic drugs (mainly paracetamol) means that
mistakes in dosage will inevitably occur. 

Psychological 

Parental fever phobia has been documented.3 Parents and doctors
understandably need to feel they have something to offer sick, miserable
children. However, cuddles, comfort and fluids are likely to be a safer
and healthier alternative to drugs. 

Drug toxicity 

Whilst the frequency and dangers of intentional paracetamol overdosage
are well known4, until recently, only occasional accidental overdoses
were reported. However, a recent report found that over a 13-year period
11 of 18 cases of fulminant hepatic failure were associated with
accidental paracetamol ingestion. Two children died and one suffered
serious neurological sequelae.5 In another study of 47 children who were
mistakenly given toxic doses of paracetamol 24 (55%) of the children
died.6 In the UK, package restrictions limiting the number of tablets
per package have been introduced in an attempt to decrease the risk of
self-poisoning. Similar steps may be necessary to minimise accidental
overdosage in children. 

The toxicity appears to occur when maximum total per kilogram daily
doses are exceeded (90 mg/kg/day) and when repeated doses are given to
children with pre-existing liver disease e.g. viral hepatitis. 

Preparation variability 

There are 23 non-tablet paracetamol preparations available on the
Australian market. The available mixtures have various strengths
including 24 mg/mL, 50 mg/mL and 100 mg/mL. An 8 kg infant only requires
three mistaken 5 mL doses of the 100 mg/mL infant preparation (instead
of the 24 mg/mL paediatric mixture) before a potentially hepatotoxic
dose is reached (more than 150 mg/kg/24 hours). 

Difficulty in proving benefit 

The best study investigating the possible symptomatic benefits of
paracetamol compared the drug to placebo.7 The double-blind trial, using
parental observations, analysed 225 febrile children's mood, comfort,
appetite, fluid intake, activity and alertness. In the paracetamol
treated group, activity and alertness significantly improved by one
grade, mood and eating improved but not significantly, while drinking
was worse. The parents' descriptions of comfort were equal in both
groups. Interestingly, parents were unable to tell whether their child
had been treated with paracetamol or placebo. The duration of fever was
the same in both groups. Thus while some benefit was obtained, it does
not justify its use if the risk of toxicity is real. 

Difficulty in proving worth in preventing febrile convulsions 

Febrile convulsions are associated with higher temperatures8,9, but it
is not known if lowering the temperature would have prevented these
convulsions. Rate of rise of temperature is also thought important as
25% of convulsions seem to occur prior to, or at the commencement of,
the fever. Previously, antipyretic prophylaxis has not been shown to be
effective in reducing febrile seizures.10,11 

Early data suggested antipyresis (including sponging) was of limited
benefit in preventing recurrent febrile seizures. Further evidence now
suggests that sponging does bring down the temperature faster than
paracetamol or ibuprofen in the first 30 minutes, however, the effect of
the drugs lasts for longer.12 

Other medication options

Ibuprofen has been shown to be at least as effective as
paracetamol13,14 but is more likely to produce gastrointestinal and
renal adverse effects. One suspects that if ibuprofen is used as widely
as paracetamol then inevitably its toxicity and adverse effects will
become a problem. 

Further population studies are required to establish the safety and
pitfalls of a regimen using a limited number of doses of paracetamol
and/or ibuprofen. 

While aspirin is also effective, its widespread use cannot be
recommended because of its gastrointestinal and platelet effects, and an
association with the rare Reye's syndrome. 

Summary 

Paracetamol has a mild symptomatic benefit in childhood febrile
illness
Paracetamol toxicity data are increasingly worrying 
The various strengths of paracetamol mixtures are a major health hazard

Paracetamol has not yet been shown to prevent febrile convulsions 

Recommendations 

There should be a concerted medical and pharmaceutical campaign to warn
of the indiscriminate use of antipyretics in mild viral febrile illness
in childhood. 

An initial paracetamol dose of 15 mg/kg could be given, followed by
three doses of 15 mg/kg over the next 24 hours if irritability
continues. 

No more than these four doses of paracetamol to be given for any one
illness unless under medical or pharmacist supervision. 

Each bottle of paracetamol mixture should have the mg/mL concentration
in huge letters on the label, with the words 'Beware, potentially toxic'
on the 100 mg/mL bottle. Consideration should be given to withdrawal of
all but the lowest strength.

Treat the child, not the thermometer. 

R E F E R E N C E S 
1. Shann F. Paracetamol: when, why and how much [editorial]. J Paediatr
Child Health 1993;29:84-5.
2. Graham NM, Burrell CJ, Douglas RM, Debelle P, Davies L. Adverse
effects of aspirin, acetaminophen, and ibuprofen on immune function,
viral shedding, and clinical status in rhinovirus-infected volunteers. J
Infect Dis 1990;162:1277-82. 
3. Schmitt BD. Fever phobia: misconceptions of parents about fevers. Am
J Dis Child 1980;134:176-81. 
4. Fagan E, Wannan G. Reducing paracetamol overdoses [editorial]. Br
Med J 1996;313:1417-8.
5. Miles FK, Kamath R, Dorney SF, Gaskin KJ, O'Loughlin EV. Accidental
paracetamol overdosing and fulminant hepatic failure in children. Med J
Aust 1999;171:472-5. 
6. Heubi JE, Barbacci MB, Zimmerman HJ. Therapeutic misadventures with
acetaminophen: Hepatotoxicity after multiple doses in children. J
Pediatr 1998;132:22-7. 
7. Kramer MS, Naimark LE, Roberts-Brauer R, McDougall A, Leduc DG.
Risks and benefits of paracetamol antipyresis in young children with
fever of presumed viral origin. Lancet 1991;337:591-4.
8. Tarkka R, Rantala H, Uhari M, Pokka T. Risk of recurrence and
outcome after the first febrile seizure. Pediatr Neurol 1998;18:218-20.

9. 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. 
10. Berg AT, Shinnar S, Shapiro ED, Salomon ME, Crain EF, Hauser WA.
Risk factors for a first febrile seizure: a matched case-control study.
Epilepsia 1995;36:334-41. 
11. Uhari M, Rantala H, Vainionpaa L, Kurttila R. Effect of
acetaminophen and of low intermittent doses of diazepam on prevention of
recurrences of febrile seizures. J Pediatr 1995;126:991-5. 
12. Aksoylar S, Aksit S, Caglayan S, Yaprak I, Bakiler R, Cetin F.
Evaluation of sponging and antipyretic medication to reduce body
temperature in febrile children. Acta Paediatr Jpn 1997;39:215-7. 
13. McIntyre J, Hull D. Comparing efficacy and tolerability of
ibuprofen and paracetamol in fever. Arch Dis Child 1996;74:164-7. 
14. Walson PD, Galletta G, Chomilo F, Braden NJ, Sawyer LA, Scheinbaum
ML. Comparison of multidose ibuprofen and acetaminophen therapy in
febrile children. Am J Dis Child 1992;146:626-32. 


~~~~~~~~~~~~~~~~~~~
Andy Gray MSc(Pharm) FPS
* Senior Lecturer
Dept of Therapeutics and Medicines Management
* Study Pharmacist
Centre for the AIDS Programme of Research 
in South Africa (CAPRISA)
Nelson R Mandela School of Medicine
University of KwaZulu-Natal
PBag 7 Congella 4013
South Africa
Tel: +27-31-2604334/4298 Fax: +27-31-2604338
email: graya1@ukzn.ac.za or andy@gray.za.net

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