Goodfellow Speaker Series - Paracetamol versus ibuprofen

Paracetamol versus ibuprofen: What to do with the hot infant on Monday?

SPEAKER SERIES

Making Education Easy 2022

the authors

Professor Stuart Dalziel Paediatric Emergency Physician MBChB FRACP PhD

Stuart Dalziel is a specialist paediatrician with subspecialty training in paediatric emergency medicine. He is the Director of Emergency Medicine Research at Starship Children’s Hospital, Te Whatu Ora Te Toka Tumai Auckland, and the Cure Kids Chair of Child Health Research at the University of Auckland. He received his undergraduate training from the University of Otago, with postgraduate training in paediatrics in both New Zealand and the United Kingdom, culminating with a Fellowship at Great Ormond Street Hospital in London.

Stuart has a PhD in epidemiology from the University of Auckland and is involved in both local and international emergency medicine research groups. Stuart is the current chair of Pediatric Emergency Research Network (PERN, the global paediatric emergency medicine research network), the immediate past chair of Paediatric Research in Emergency Departments International Collaborative (PREDICT, Australasia’s paediatric emergency medicine research network) and holder of numerous research grants from the Health Research Council (HRC) in New Zealand.

Stuart’s research interests are focused around acute paediatric presentations, specifically respiratory and neurological presentations, as well as long-term effects of perinatal and early-life treatments.

The physiology of fever

Fever is a physiological mechanism that is beneficial in fighting infection as it:

• Retards the growth and reproduction of bacteria and viruses

• Enhances neutrophil production and T-lymphocyte proliferation

• Aids in the body’s acute-phase reaction

The degree of fever does not correlate with the severity of the illness or fever. For infants, most fevers are short, benign and appear to be protective.

It is important to differentiate between fever and hyperthermia. In hyperthermia, abnormal homeostasis results in heat production exceeding the body’s ability to dissipate heat. Adverse outcomes are associated with an elevated body temperature, particularly above 41-42oC.

Why treat fever?

The main reason for treating fever in children is to reduce pain and distress. Long-term complications can develop in paediatric patients if pain and distress is not treated. For example, in neonates under-treatment of pain results in hormonal, physiological and behavioural responses that can be long-standing with repeated or severe exposure. However, rather than treating pain and distress, frequently fever is treated to reduce body temperature. Reducing the body temperature is the main reason why parents or caregivers administer paracetamol or ibuprofen to children at home. Fever is the reason for one-third of all child presentations to primary care or emergency departments. Many caregivers have unfounded fears and misconceptions about childhood fever which has been termed “fever phobia”.1

Fever phobia and New Zealand caregivers

Dr Eunicia Tan Emergency Physician MBChB FACEM

Eunicia Tan is an Emergency Physician and CoDirector of Emergency Medicine Research at Middlemore Hospital, Te Whatu Ora – Counties Manukau District, and Senior Lecturer at the University of Auckland. She received her undergraduate medical training from the University of Auckland, with postgraduate diplomas in Paediatrics and Clinical Education. She is currently undertaking doctoral studies investigating the effects of antipyretics on respiratory disease and eczema in infancy. Areas of interest include emergency medicine, paediatrics, clinical education and mixed methods research.

To determine the prevalence of fever phobia in New Zealand, a cross-sectional survey was conducted among 502 caregivers of children aged <5 years presenting to emergency departments in the Auckland or Waikato regions.2 Fever phobia was present in 74% of respondents; 49% had a high level of concern about fever and 62% had incorrect beliefs about the consequences of fever.2 Despite the high prevalence of fever phobia in the survey, almost half (48%) of caregivers did not know what body temperature constituted a fever. Caregiver responses about analgesia dosing revealed mixed results. Although the majority (88%) of caregivers knew the correct dosing and dosing interval for paracetamol, less than half (43%) were aware of the correct dosing and dosing interval for ibuprofen.

The specific misconceptions about fever among caregivers included 50% believing fever was associated with brain damage, 38% believing it was associated with death, 35% with coma, 28% heart damage and 17% associated fever with blindness.2

Non-evidence-based fever management practices were common among caregivers; 89% of caregivers stated they would keep checking their child’s temperature until the fever went away, 61% would wake the child from sleep to give paracetamol or ibuprofen and 51% would wake them from sleep to check their temperature.2 Regarding treatment, 82% of caregivers would always give paracetamol and/or ibuprofen regardless of the cause of the child’s fever and 48% would always give both paracetamol and ibuprofen, even though this practice is not recommended by international best practice guidelines.

This publication is a summary of the RNZCUC sponsored session: The use of paracetamol and ibuprofen in young infants from the 2022 Goodfellow Symposium. Professor Stuart Dalziel, University of Auckland and Starship Children’s Hospital, delivered guidance on the management of pain and distress in febrile infants. He also provided a comprehensive head-to-head review on the use of paracetamol versus ibuprofen in infants, much of the data for which was generated by his colleague Dr Eunicia Tan (University of Auckland and Middlemore Hospital). The full talk can be accessed online at Virtual Platform (eventsair.com)

About

Paracetamol versus ibuprofen: What to do with the hot infant on Monday?

Primary care was most frequently identified as a source of information about childhood fever, with 88% of caregivers identifying general practitioners as a source of information, followed by general practice nurses at 42%. Thus, primary care has a key role in dispelling myths about fever and educating caregivers about appropriate fever management and paracetamol and ibuprofen use.

Is temperature reduction beneficial?

There is inconclusive evidence that temperature reduction is beneficial in febrile infants. Potential benefits of reducing body temperature include relief of patient discomfort, and reduction of insensible water loss. Further, in adults there is no evidence that reducing the temperature in fever improves mortality and morbidity, even in the severely unwell.

Summary of treatment aims for fever

Given the lack of evidence for treating fever, multiple international and local Starship guidelines agree that the primary goal of treating the febrile child should be to improve their overall comfort, and not simply for fever reduction.3,4

A systematic review and meta-analysis was conducted by Dr Eunicia Tan and Professor Dalziel to help determine whether paracetamol or ibuprofen is the most effective medicine for febrile infants.5 The primary efficacy outcome was fever or pain at <4 hours. Secondary outcomes were fever or pain at 4-24 hours, 1-3 days, and >3 days. The review included 19 studies involving 241,138 infants from 7 countries in both hospital and community settings.

Ibuprofen was associated with less fever (when assessed as a continuous variable) in the first 4 hours and less fever from 4-24 hours, but with no difference between the two medications after 24 hours (Figure 1).5 Similarly, when fever was assessed

as categorical outcome, infants treated with ibuprofen were more likely to be afebrile within the first 4 hours and from 4-24 hours of treatment onset compared to infants treated with paracetamol, with no significant difference beyond 24 hours.

When Tan et al (2020) assessed the analgesic effects of paracetamol and ibuprofen in infants, no studies reporting pain outcomes within 4 hours of treatment were identified among more than 240,000 infants.5 In other words, there is no evidence from randomised controlled trials (RCTs) for acute relief of fever-related pain and distress, the international best practice recommendation for paracetamol or ibuprofen use in febrile infants. Evidence from RCTs showed a benefit of ibuprofen in continuous and categorical pain outcomes at 4-24 hours (Figure 2), suggesting a clinical benefit at this time but not beyond. Collectively, these findings provide weak evidence to support ibuprofen use over paracetamol to treat fever-related pain and distress.

The short-term (≤28 days) and long-term (>28 days) safety data for paracetamol or ibuprofen indicated that adverse events were uncommon or rare for either medicine.5 After assessing data from almost 28,000 infants, there was no significant difference in the rates of serious adverse events, renal impairment, gastrointestinal (GI) bleeding, hepatotoxicity, asthma or wheeze. These findings suggest that paracetamol and ibuprofen have equivalent safety when used in febrile infants.

Alternating or combining paracetamol and ibuprofen

Parents and health professionals often combine or alternate paracetamol and ibuprofen when treating febrile infants. A Cochrane review of 6 RCTs, including 915 infants, found some evidence that combining or alternating the two medicines results in less fever compared to monotherapy.6 However, improvements in child discomfort were inconclusive, and the review was unable to address the safety of combining or alternating paracetamol and ibuprofen, including the issue of potential overdose.

The National Institute for Health and Care Excellence (NICE) recommends that alternating between paracetamol and ibuprofen should only be considered if distress persists or recurs before the next dose is due.3 NICE recommends that paracetamol and ibuprofen should not be given simultaneously to a child aged <5 years.

Outcome

Source

Temperature or change in temperature at <4 h

Aksoylar et al, 1997

Autret et al,1997

Erlewyn-Lajeunesse al, 2006 Van Esch et al, 1995

Subtotal (95% CI)

Temperature, 3 h

Mean reduction in temperature, 1 h Mean temperature, 1 h Mean temperature, 2 h

Heterogeneity : τ2 = 0.04; χ 2 = 5.91, P = .12; I 2 = 49%

Test for overall effect : z = 2.53; P = .01

Temperature or change in temperature at 4-24 h

Autret et al, 1994

Autret et al 1997

McIntyre and Hull, 1996

Sarrell et al 2006

Van Esch et al, 1995

Subtotal (95% CI)

Mean reduction in temperature, 0-4 h

Mean reduction in temperature, 4 h

Mean change from baseline temperature, 4 h

Fever, 1 d Mean temperature, 4 h

Temperature or change in temperature at 1-3 d

Sarrell et al, 2006

Subtotal (95% CI)

4 1

–0.90 (0.56) 37.95 (0.48) 37.96 (0.92)

38.40 (0.71) –1.02 (1.05)

–1.04 (0.85)

–1.60 (1.35)

Total 51 114 25 29 74 110 66

37.90 (0.71)

–0.97 (0.58) 37.76 (0.62) 37.60 (0.60)

Ibuprofen Mean (SD) –1.32 (1.00) –1.42 (0.85)

Favors Paracetamol Favors ibuprofen SMD (95% CI)

0.70 (0.30 to 1.10)

0.12 (–0.14 to 0.38)

216

0.34 (–0.24 to 0.92) 0.46 (–0.06 to 0.98) 0.38 (0.08 to 0.67)

Temperature or change in temperature at >3 d

Hay et al, 2008 Hay et al, 2008

Subtotal (95% CI)

Fever, 2 d

Heterogeneity : τ2 = 0.00; χ 2 = 0.06; P = .81; I 2 = 0% Test for overall effect : z = 0.43; P = .67

Paracetamol Mean (SD) 40.55 (1.31) 37.95 (1.28) 36.4 (0.89) 39.74 (1.37) 36.2 (0.93)

Heterogeneity : τ2 = 0.03; χ 2 = 9.23, P = .06; I 2 = 57% Test for overall effect : z = 2.20; P = .03 3

Temperature, 48 h Temperature, 5 d

Heterogeneity : not applicable Test for overall effect : z = 0.55; P = .58 Test for subgroup differences : χ 2 = 4.04; P = .26; I 2 = 25.8%

219 154 31 435 51 154 205 48 48

–1.80 (1.35) 40.6 (1.46) 37.38 (1.00) 36.4 (0.85) 39.66 (1.48) 36.1 (0.78)

77 112 69

Total 50 114 22 30 155 31 444 47 155 202 45 45

0.29 (–0.03 to 0.61) 0.45 (0.18 to 0.71) 0.15 (–0.19 to 0.49)

–0.04 (–0.26 to 0.19) 0.49 (–0.02 to 1.00) 0.24 (0.03 to 0.45)

0.00 (–0.40 to 0.40) 0.06 (–0.17 to 0.28) 0.04 (–0.15 to 0.24)

0.12 (–0.29 to 0.52) 0.12 (–0.29 to 0.52)

Figure 1: Antipyretic profile of paracetamol versus ibuprofen from randomised controlled trials with continuous variables.

–1.0 0 1.0 0.5 SMD (95% CI) –0.5

from Tan et al (2020).5

Weight , % 26.2 36.8 17.2 19.8 100 19.9 23.2 19.0 26.1 11.9 100 75.9 100

3 100 100

24.1

If we treat fever for pain and distress, which agent is better: paracetamol or ibuprofen?

Adapted

Source Pain score or change in pain score at <4 h

Subtotal (95% CI)

Heterogeneity: not applicable

Test for overall effect: not applicable

Sarrell et al, 2006

Subtotal (95% CI)

Paracetamol 2.5 (1.0) 11.77 (2.64)

Mean (SD) Ibuprofen 2.2 (0.9) 11.48 (2.58)

Mean (SD) SMD (95% CI)

Not estimable 0.11 (–0.11 to 0.33) 0.31 (0.05-0.58) 0.20 (0.03 to 0.37)

Paracetamol versus ibuprofen: What to do with the hot infant on Monday?

Favors Paracetamol Favors ibuprofen Weight , % 58 42 100

Paracetamol

Heterogeneity: χ 2 = 1.34; P = .25; I 2 = 25%

Source

Test for overall effect: z = 2.26; P = .02

Pain score or change in pain score at <4 h

Pain score or change in pain score at 4-24 h Autret et al, 1997 –1 0 0.5 1 SMD (95% CI) –0.5

Subtotal (95% CI)

Heterogeneity: not applicable Test for overall effect: not applicable

Pain score or change in pain score at 4-24 h Autret et al, 1997

Sarrell et al, 2006

Subtotal (95% CI)

Outcome CHEOPS NCCPC, 1 d

Mean (SD)

2.5 (1.0) 11.77 (2.64)

Total 112

0 154 266

Ibuprofen 2.2 (0.9) 11.48 (2.58)

Mean (SD) SMD (95% CI) Not estimable 0.11 (–0.11 to 0.33) 0.31 (0.05-0.58) 0.20 (0.03 to 0.37)

Total 114

0 155 269

Favors Paracetamol Favors ibuprofen Weight , % 58 42 100

Heterogeneity: χ 2 = 1.34; P = .25; I 2 = 25% Test for overall effect: z = 2.26; P = .02

Source

1

–1 0 0.5 1 SMD (95% CI) –0.5

Improved pain score at <4 h

Subtotal (95% CI) Total events

Hay et al, 2008

Continuous variable A Categorical variable B

Subtotal (95% CI) Total events

Source Improved pain score at <4 h

Heterogeneity: not applicable Test for overall effect: z = 2.54; P = .01

Outcome

Subtotal (95% CI)

Total events

Heterogeneity: not applicable Test for overall effect: not applicable Improved pain score at 4-24 h

Hay et al, 2008

Subtotal (95% CI)

Total events

Normal on discomfort scale, 24 h

Ibuprofen Events Total 0 50

Paracetamol Events Total Odds ratio (95% CI)

0 52

0 36 52 36

0 22 50 22

Not estimable 2.86 (1.27-6.45) 2.86 (1.27-6.45)

Favors Paracetamol Favors ibuprofen Weight , % 100 100

Figure 2: Analgesic profile of paracetamol versus ibuprofen from RCTS with pain as a continuous variable (A) and a categorical variable (B). Adapted from Tan et al (2020).5

Managing fever in young infants

Heterogeneity: not applicable Test for overall effect: z = 2.54; P = .01

Summarising paracetamol versus ibuprofen in young infants

• Ibuprofen

Less fever at <4 hours and at 4-24 hours

Less pain at 4-24 hours

• Pain

No data for pain outcomes at <4 hours

Antipyretics recommended for distress/ discomfort (NICE, AAP, WHO)

• Adverse events are uncommon or rare

• Paracetamol and ibuprofen have equivalent safety

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Historically, all febrile infants aged <3 months who presented to a hospital were screened for sepsis and given IV antibiotics. Over the last two decades, clinicians became more selective. In general, all infants aged <6 weeks were treated and infants aged 6-12 weeks underwent urinalysis, blood culture and chest X-ray if respiratory signs were present.

0.1 1 10 0.5 2 5 Odds ratio (95% CI) 0.2

There are now guidelines for the evaluation and management of well-appearing febrile infants aged 8 to 60 days, published by the American Academy of Pediatrics.7 These guidelines are informed by data supporting age-based risk stratification (Figure 3). The rate of invasive bacterial infections is substantially higher in the first 7 days of life and subsequently decreases dramatically. 2010-11 2011-12 2012-13 2013-14 2014-15 2015-16 2016-17 incidence in 2016/17

Figure 3: The incidence if invasive bacterial infections in infants aged <1 year in England (2010/11 to 2016/17). Adapted from Ladhani et al (2019).8

Paracetamol versus ibuprofen: What to do with the hot infant on Monday?

New Zealand guidelines for fever in infants under 2 months

Starship Hospital recently published guidelines for management of fever without focus in infants <2 months (Table 1).4 In infants, fever is defined as ≥38.0oC. As this occurs in >40% of infants within 48 hours of immunisation, clinical judgement is required when considering investigations following immunisations. The remainder of febrile infants <2 months of age should be managed according to the guidelines

Urinary tract infections (UTIs) are the most common serious bacterial infection in infants <2 months of age, and Escherichia coli is the most frequent cause of communityacquired bacteraemia in this group. Infants with the following risk factors have an increased infection risk:

• Preterm (<37 weeks)

• Age <2 weeks whose perinatal course was complicated by maternal fever, infection or antibiotic use

• High suspicion of herpes simplex virus, e.g. vesicles, seizures, mucous ulcers, maternal history

• Immunodeficiency

• Neonatal infection or surgery

• Congenital or chromosomal abnormalities

• Current or recent antibiotic use

Clinical characteristics Recommendation

Infants <2 months with fever who are unwell appearing

Infants ≤21 days with fever

Infants 22-28 days with fever who are well appearing

A full septic screen and IV antibiotics

A partial septic screen including FBC + CRP + culture, urinalysis (clean catch or catheter), chest X-ray if respiratory signs and senior review to determine if lumbar puncture and/or IV antibiotics required

Bacteraemia risk in febrile infants aged ≤21 days is 3.9-5.1%, in those with a UTI bacteraemia is present in approximately 20%; meningitis risk is 0.5-1.3%.

Bacteraemia risk in well appearing febrile infants aged 22-28 days is 1.65%, in those with a UTI bacteraemia is present in 7.5-10%; meningitis risk is 0.4-0.6%.

Infants 29-60 days with fever who are well appearing

Urinalysis (clean catch or catheter), chest X-ray if respiratory signs, +/FBC + CRP + culture, and senior review to determine if lumbar puncture and/or IV antibiotics required

Bacteraemia risk in well appearing infants aged 29 to 60 days is 1.12.2%, in those with a UTI bacteraemia is present in 5-10%; meningitis risk is 0.25%.

Summarising management of fever in young infants:

• Risk of serious bacterial infection stratified by age

• Refer all unwell infants

All treated

• Refer well infants <28 days

All ≤21 days treated

22 to 28 days partial septic screen and admitted

• Well appearing 29 to 60 days

Urine as a minimum

Observation +/- other investigations

Immunisations

Paracetamol and ibuprofen have been shown to reduce immune responses to vaccines, but not vaccine efficacy. Neither paracetamol nor ibuprofen are routinely recommended by the Immunisation Advisory Centre (IMAC) when immunisations are administered.9 IMAC recommend that paracetamol or ibuprofen should only be given to infants who are miserable or distressed following vaccination.9

The only exception to the IMAC advice is the Bexsero (4CMenB) vaccine against meningitis B. Bexsero is funded for special groups in New Zealand, although parents are also purchasing it. Administration of the Bexsero vaccine is known to increase post-immunisation fever and the risk of febrile seizure is approximately 4 in 1,000 vaccinations.10,11 Prophylactic paracetamol or ibuprofen reduces the risk of fever following immunisation with Bexsero.12 IMAC recommends that paracetamol or ibuprofen be given 30 minutes before the vaccine, with two further doses 6 hours apart.

Summarising immunisations:

• Do not routinely give paracetamol or ibuprofen prior to immunisation, unless the Bexsero vaccine is administered

• Paracetamol and ibuprofen are both safe and effective around Bexsero immunisations

Febrile convulsions

Case:

A 12-month-old infant presents with a chief complaint of seizure. The infant has had a runny nose for two days but has been eating and drinking normally. The history of the seizure is consistent with a simple febrile seizure which lasted less than 1 minute. After a 10-minute post-ictal period, the infant is now back to their usual self.

There is no significant past medical history. The infant is not taking regular medications and has no allergies.

On examination: temperature = 39OC (tympanic), HR = 130/min, RR = 25/min, SaO2 = 98%.

The infant is settled with the caregiver and playing with toys. Other than clear coryza, there is no other focus for the fever on examination.

A febrile seizure is defined by the International Liaison Against Epilepsy (2017) as: “a seizure occurring in childhood after one month of age associated with a febrile illness not caused by an infection of the central nervous system (CNS), without previous neonatal seizures or a previous unprovoked seizure, and not meeting the criteria for other acute symptomatic seizures.”

Typically, febrile seizures occur in children aged 6 months to 6 years, the convulsion is a brief tonic/clonic seizure with recovery within one hour. The prevalence of febrile convulsions is influenced by ethnicity and is more common in infants of Indian or Japanese descent.

Investigations

Investigations should focus on the cause of the fever, which is usually viral, e.g. upper respiratory tract infection (RTI). If the infant has had gastroenteritis, their blood sugar should be assessed. The possibility of pneumonia should be excluded on clinical examination. A potential UTI should be excluded by urinalysis if there is no other focus.

Febrile convulsions are highly distressing for caregivers and can cause a posttraumatic disorder in some. However, the prognosis for young children with febrile convulsions is excellent and the risk of future epilepsy is very similar to those without convulsions. One-third of infants, however, will have further febrile convulsions and up to one-quarter will experience another seizure with the current episode.

Preventing further seizures

A Cochrane review found insufficient evidence to support either the continuous or intermittent use of antiepileptics or antipyretics for prevention of future episodes in children with febrile seizures.13 However, there is good evidence that additional seizures during the current illness can be prevented. An RCT of 423 children aged 6-60 months with febrile convulsions found that regularly providing rectal paracetamol for 24 hours (10 mg/kg) reduced the recurrent seizure rate from 24% for no treatment, to 9% with paracetamol (p<0.001).14

Table 1: Starship Hospital management recommendations for infants with fever4

4 Evidence7

IV = intravenous, UTI = urinary tract infection, FBC = full blood count, CRP = C-reactive protein

Paracetamol versus ibuprofen: What to do with the hot infant on Monday?

The PIPPA Tamariki study

Summarising febrile convulsion:

Investigations should focus on the cause of the fever; normally only urinalysis is required

• Refer if:

Seizures are complex (prolonged or focal)

The child is outside of the usual age range

Recovery does not occur

There is concern about a potential CNS infection

• There is little additional risk of later epilepsy

•

Parents are generally concerned about the risk of recurrent seizures

• There is no evidence to prevent future episodes

• Oral paracetamol (15 mg/kg) every six hours for 24 hours may prevent further seizures during the current illness

Long-term safety of paracetamol and ibuprofen

Paracetamol and ibuprofen are the medicines most commonly prescribed or purchased over-the-counter (OTC) for infants. By age 9 months, 95% of New Zealand infants have been exposed to paracetamol and/or ibuprofen.15

No RCTs have been conducted on the long-term safety of paracetamol or ibuprofen. However, the systematic review and meta-analysis performed by Tan et al (2020) identified three non-RCTs containing 195,855 children aged <2 years and found no difference in renal or GI outcomes with either medicine.5 They also found that among 57,516 infants, ibuprofen use prior to age 2 years was associated with significantly lower odds of asthma later in life, compared to paracetamol use.5

The burden of asthma in New Zealand is substantial with 1 in 7 children aged >5 years and 1 in 9 adults using asthma medication.16 Māori children aged >5 years are 1.6 times more likely to use asthma medication than non-Māori children. Asthma accounts for >3,500 childhood and >4,600 adult admissions to hospital each year. Māori children are 2.9 times more likely and Pacific children 3.7 times more likely to be admitted to hospital due to asthma.

There are data showing an association between paracetamol use in early life and later asthma. A study of 205,000 children from 31 countries found paracetamol exposure in the first year of life was associated with a 1.46-fold increased risk of asthma at age 6-7 years.17 It is unclear to what extent paracetamol may be contributing to asthma onset compared to the viral illnesses that paracetamol is often prescribed to treat.

Several studies have tried to adjust for the potential confounding effect of illness on the development of asthma. A large prospective cohort study evaluating 25,394 individuals for asthma at age 7 years found that after adjusting for RTIs, paracetamol use early in life was associated with a 1.27-fold increased risk of asthma at age 7 years.18

Epidemiological evidence of an association between paracetamol use in early life and the pathogenesis of asthma fulfils all but one of the Bradford-Hill criteria of causation (Table 2).19 Similarly, there is also evidence that early paracetamol use may lead to an increased risk of developing rhinoconjunctivitis and eczema later in life.17

The potential role for paracetamol in the development of asthma is being examined by the PIPPA Tamariki study conducted by Dr Tan, Professor Dalziel and others.20

The primary objective of the study is to determine:

• Does paracetamol treatment, compared with ibuprofen treatment, as required for pain or fever in the first year of life, increase the risk of asthma at 6 years of age?

Secondary objectives of the study include determining if paracetamol in the first year influences:

• Bronchiolitis in the first year • Wheeze, eczema and atopy at 3 years of age • Eczema and atopy at 6 years of age • Long-term safety

PIPPA Tamariki is a multicentre, open-label RCT that will randomise 3,922 infants born at ≥32 weeks gestation in New Zealand to receive only paracetamol or only ibuprofen for the treatment of fever and pain, if required in the first year of life.20 Paracetamol or ibuprofen are provided at study enrolment for as-needed use with dosing from the New Zealand Formulary for Children.21

What to do if you see a PIPPA Tamariki baby

• Add a patient alert • Check before vaccination • Continue to prescribe the allocated medication • For questions or adverse events contact: 0800 PIPPA T (0800 747 728) pippatamariki@auckland.ac.nz pippatamarikiwgtn@mrinz.ac.nz pippatamariki@adhb.govt.nz

If the PIPPA Tamariki study reports a positive result, this may provide a novel framework for potentially reducing the onset of childhood asthma by 20% that may be globally applicable. Paracetamol use in the first year of life could be easily reduced and may contribute to a reduction in the ethnic inequality of asthma prevalence. There would also be significant economic benefits from a reduction in disease following a positive result.

A negative result from the study would close the line of enquiry and reassure parents and health professionals that there is no increased risk of asthma associated with paracetamol use in the first year of life. This would be important long-term safety data with global significance.

PIPPA Tamariki is funded for 11 years and recruitment began in March 2018. There are currently over 3,000 infants enrolled in the study.

TAKE-HOME MESSAGES

• Fever phobia is very common - GPs are key providers of information

• Do not treat temperature, treat pain and discomfort

• Paracetamol and ibuprofen have similar efficacy and short-term safety

• Refer all unwell infants and infants <28 days with fever

• Do not use paracetamol or ibuprofen routinely after immunisation

• Use paracetamol regularly for the first 24 hours post febrile convulsion

• Long-term safety for paracetamol and ibuprofen is unanswered with major questions regarding paracetamol and later asthma that the PIPPA Tamariki study will address

Questions and answers

Following his presentation, Professor Dalziel provided the following answers to questions from the audience:

1. What guidance could Professor Dalziel provide on the use of ibuprofen in the context of viral illness, necrotising fasciitis, a diagnosis of asthma, and COVID-19 illness?

There is very good evidence from large studies that ibuprofen is safe in viral illness and safe for young children, including for renal events. Emergency Department nurses and doctors are very comfortable using ibuprofen as their first-choice analgesic for children. Neonatologists also use ibuprofen to help close patent ductus arteriosus, i.e. it is safe in critically unwell children.

Regarding ibuprofen and necrotising fasciitis, there is a concern around chickenpox or varicella infection although the evidence is weak at best. There was no evidence of an increased risk of necrotising fasciitis associated with ibuprofen from a study of well over 50,000 infants. Case control studies have found an association between chickenpox and necrotising fasciitis, and also between ibuprofen use, paracetamol use and necrotising fasciitis. It is therefore difficult to tease out the risk factors. Professor Dalziel thinks there may be a slight association between necrotising fasciitis and chickenpox, therefore in children who are unwell with chickenpox the cautious approach is to not administer ibuprofen.

Professor Dalziel noted that when he went to medical school, NSAIDs were thought to be bad in terms of the risk of asthma later in life. However, more recent evidence from children and adults shows that ibuprofen use is associated with less asthma in the subsequent 4 weeks, compared to paracetamol use. The evidence is therefore contrary to what had been previously taught, i.e. paracetamol may be worse than NSAIDs in triggering asthma. Professor Dalziel is extremely comfortable prescribing NSAIDs to children with asthma.

The issue of ibuprofen and COVID-19 is an example of why clinical science is important and illustrates the pitfalls of social media. At the start of the pandemic, a letter was published in Lancet Respiratory Medicine suggesting that the receptors

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2. MacMahon D, et al C, Stuart R., Christopher Jd. Fever phobia in caregivers presenting to New Zealand emergency departments. Emerg Med Australas. 2021;33(6):1074-1081. doi:10.1111/1742-6723.13804

3. National Institute for Health and Care Excellence. Fever in under 5s. Published online 2019. www.nice.org. uk/guidance/ng143

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involved in COVID infection could potentially interact with ibuprofen in a way that could lead to worse outcomes. This information exploded on social media and WHO provided preliminary cautionary advice. It is now known, however, that ibuprofen is not associated with worse outcomes in COVID infections, compared with paracetamol. Professor Dalziel is very comfortable using ibuprofen in children and adults with COVID.

2. What is the role of paracetamol for future febrile illnesses following an episode of febrile convulsion?

This issue was the subject of the referenced Cochrane review. Prophylactic use of paracetamol or anticonvulsants did not reduce the risk of future febrile convulsions outside of the current illness.

3. Should all febrile infants aged <28 days be referred to hospital?

Yes. Remembering that the definition of a fever is ≥38oC and that in children aged <3 months temperature should be measured rectally. Tympanic measurement of temperature can be problematic in children aged <3 months, although this method is fine in older children and preferred to axillary measurements.

4. What guidance can be provided on paracetamol dosing in obese children?

Professor Dalziel noted there is a moderate safety margin in paracetamol dosing, therefore he feels comfortable not adjusting for lean body mass when he prescribes to an obese child, i.e. 15 mg/kg regardless of their bodyweight every 4 hours to a maximum of 4 doses in a 24-hour period.

5. What guidance can be provided about the co-administration of paracetamol and ibuprofen?

Professor Dalziel recommends providing one medicine at a time and he provides ibuprofen first because there is evidence that it is better than paracetamol for pain and discomfort. Sequential administration provides another short-term option if the first medicine is not working. Secondly, the evidence suggests there is little if any benefit in co-administering the two medicines.

As a final point, Professor Dalziel noted that he does not prescribe ibuprofen for children with cancer, as they may have problems with platelet number and function.

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14. Murata S, et al. Acetaminophen and Febrile Seizure Recurrences During the Same Fever Episode. Pediatrics. 2018;142(5):e20181009.

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19. Weatherall M, et al. The association between paracetamol use and asthma: causation or coincidence? Clin Exp Allergy. 2015;45(1):108-113.

20. Tan E, et al. Randomised controlled trial of paracetamol or ibuprofen, as required for fever and pain in the first year of life, for prevention of asthma at age 6 years: paracetamol or ibuprofen in the primary prevention of asthma in Tamariki (PIPPA Tamariki) protocol. BMJ Open. 2020;10(12):e038296.

21. NZFC. New Zealand Formulary for Children. Published 2022. www.nzfchildren.org.nz/nzf_1

Paracetamol versus ibuprofen: What to do with the hot infant on Monday?