Measuring Energy Expenditure Before and After Fever in Critically Ill Children
Conditions: Child, Critical Illness, Fever
Sponsor: Great Ormond Street Hospital for Children NHS Foundation Trust

 
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Measuring the metabolic cost of fever: Indirect calorimetry in children with 
fever on the intensive care unit. 
 
 
 
Protocol Version 2 (07.08.2016) 
 
 
 
STUDY INVESTIGATORS: 
 
Principal Investigator:  Dr Samiran Ray 
 
 
 
PhD Student,  
Respiratory, Critical Care and Anaesthesia Section,  
UCL Great Ormond Street Institute of Child Health, London, UK 
 
 
 
samiran.ray@gosh.nhs.uk 
 
Chief Investigator: 
Professor Mark J Peters 
 
 
 
Professor Paediatric Intensive Care Medicine 
 
 
 
Respiratory, Critical Care and Anaesthesia Section, 
 
 
 
UCL Great Ormond Street Institute of Child Health, London UK 
 
 
 
mark.peters@ucl.ac.uk 
 
 
 
 
 
 
 
 

 
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INTRODUCTION 
 
Fever is a common immune response in children with infection or inflammation. While fever may 
potentiate the immune system to fight the pathogenic stimulus, energy is required to generate the 
raised temperature. This may be scarce in critical illness, particularly in children. We do not know 
how much energy is used in generating fever by children in the intensive care unit. This study aims to 
measure energy expenditure in children during and before/after they have a fever. We aim to do 
this using indirect calorimetry in at least 15 children, who are invasively ventilated on the intensive 
care unit. We will then calculate the average increase in energy expenditure required per 1oC rise in 
temperature in this population. If fever does not require a significant increase in energy expenditure 
in children on the intensive care unit, then treatment of fever may not have any benefits. If fever 
does require an increase in energy expenditure, this may counter the immunological benefits that 
fever confers. In such a case a randomised controlled trial comparing treatment and non-treatment 
of fever would be required. 
 
BACKGROUND 
 
Fever is an innate immune response to danger. Stimuli such as pathogens or tissue damage lead to a 
cascade of cytokine signals, including the release of pro-inflammatory cytokines such as TNF-α, Il-6 
and IL-1. Many of these pro-inflammatory cytokines act upon the thermoregulatory centre of the 
hypothalamus via the release of prostaglandins, to increase the body’s temperature set-point. The 
body responds by both reducing heat loss and increasing heat production to raise the body 
temperature1,2.  
 
The conservation of the fever response through billions of years of evolution (plants, insect, reptiles 
and mammals all increase their temperature in response to infection3-11) suggest that fever has a 
beneficial effect. Animal studies show the following immunological benefits of fever range 
hyperthermia: (i) increased neutrophil release from the bone marrow, (ii) increased neutrophil tissue 
infiltration, for example in lungs tissue, (iii) increased cytotoxic activity of innate immune cells such 
as neutrophils and NK cells, (iv) increased phagocytic activity, (v) increased antigen presentation by 
dendritic cells, (vi) increased cytokine production and release2. 
 
This correlates with some clinical outcome studies. Malaria induced fever was successfully used to 
treat neurosyphilis in the pre-antibiotic era12. Anti-pyretic treatment increases the duration of virus 
shedding and illness in varicella and rhinovirus infection14-15. Population level influenza rates may 
increase with regular anti-pyretic treatment16. In critically-ill patients, especially those with infection, 
a maximum temperature at intensive care unit admission of 38.5-39.5oC was associated with the 
lowest risk of mortality17-18. However randomised controlled trials treating fever with anti-pyretics or 
placebo in critical illness have not demonstrated any risks of treating fever19-23. 
 
Balancing the immunological benefits of fever are several potential detrimental effects. 
Hyperthermia can cause protein degeneration, leading to direct cell damage and death. This can lead 
to loss of gastrointestinal tract integrity, decrease in glomerular filtration rate, liver dysfunction, 
myocardial damage and arrhythmias, brain injury and lowering of the seizure threshold24. Most of 
these deleterious effects occur in sterile forms of pyrexia, especially at high grade temperatures. 
However in critical illness the generation of fever itself may be deleterious. Energy is required to 
produce heat: in fever, this can be through uncoupling of the electron transport chain leading to 
heat dissipation in brown fat, or through shivering24. As critical illness is characterised by an 

 
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imbalance of energy delivery and consumption, the energy requirements to generate a fever may be 
unaffordable25.  
 
The energy requirements of fever have previously been measured in adult patients on the intensive 
care unit. Manthous et al studied 12 febrile patients on the intensive care unit during cooling after 
sedation and paralysis. For each 1oC drop in temperature, the reduction of energy expenditure was 
10% of the baseline. This was also accompanied with a reduction in cardiac output, and no change in 
oxygen extraction (the ratio between oxygen consumption and delivery)26.  Similar associations 
between temperature reduction and decrease in energy expenditure with cooling have been 
demonstrated in the context of brain injury27-28. 
 
In children, energy expenditure has been shown not to be raised in febrile infants admitted to 
hospital. In a cohort of 12 children, although 8 had an increase in energy expenditure when febrile, 
overall there was no difference29. However this was conducted in children who were not critically 
unwell or in intensive care. It is possible that these children were able to increase their temperature 
by preventing heat loss. Children in intensive care may not have the ability to do so, due to disease 
related factors such as shock and vasoplegia, or treatment related factors, such as exogenous 
vasodilators. Children admitted to hospital with over 40% burns had an increase in energy 
expenditure with fever by up to 30% of baseline30. These children were likely to have more 
unregulated surface heat loss due to skin barrier compromise, but equally were likely to be 
hypermetabolic following their initial injury. In an analysis of cytokine levels and metabolic rate in 
critically-ill children, Briassoulis et al found that the predominant metabolic pattern in acute critical 
illness in children was that of hypometabolism, during which energy expenditure did not correlate 
with levels of IL-6 and IL-10, both fever-inducing cytokines31. 
 
Therefore we still do not know if energy expenditure is increased in children with febrile illness in 
the intensive care unit. Given the immune benefits of fever, there may be an argument to not treat 
fever in critically ill children as any advantage in host response may be beneficial. However, if the 
energy expenditure associated with fever is high, treatment of fever may have a benefit. 
 
 
AIM OF STUDY 
 
To understand the changes, if any, in the energy expenditure of critically-ill children with fever  
 
 
STUDY OBJECTIVES 
 
To measure the energy expenditure using indirect calorimetry in mechanically ventilated children 
admitted to the intensive care unit before, during and after fever. 
 
 
HYPOTHESIS 
 
Null hypothesis: Fever will be associated with <10% difference of baseline energy expenditure per 
1oC change in temperature in critically-ill children ventilated on the intensive care unit 
 
Alternative hypothesis: Fever will be associated with a >10% difference of baseline energy 
expenditure per 1oC change in temperature 

 
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STUDY DESIGN 
 
Prospective observational cohort study  
 
 
STUDY POPULATION 
 
Children admitted to the paediatric intensive care unit at Great Ormond Street Hospital with 
suspected infection, following trauma or major surgery, who are likely to develop a fever. 
 
ELIGIBILITY CRITERIA 
 
Inclusion criteria: 
- 
Children >10kg (The MedGraphic Ultima CCM calorimeter has been used safely in children as 
low as 10kg) 
- 
Children with suspected infection, following trauma, or post-major surgery 
 
Exclusion criteria: 
- 
Children post brain injury 
- 
Children with refractory status epilepticus 
- 
Children post cardiac arrest 
- 
Children post cardiac bypass 
- 
Children with cardiac arrhythmias 
- 
Children not invasively ventilated 
- 
Children with a greater than 5% leak around their endotracheal tube 
- 
Children with a fraction of inspired oxygen (FiO2)>0.60 
- 
Children above 16 years of age 
 
 
STUDY OUTCOMES 
 
Primary outcome: Change in energy expenditure per degree Centigrade change in temperature 
 
Secondary outcome: Change in oxygen extraction ratio (ratio of oxygen consumption to oxygen 
delivery) per degree Centigrade change in temperature using oxygen delivery data from the Lidco 
Rapid (LIDCO Ltd, UK) cardiac output monitor if in place. 
 
 
STUDY PROCEDURES 
 
Screening and Recruitment 
- 
All patients will be screened each morning (Mon-Fri) by the PI for weight, ventilation status 
and likelihood of developing  a fever (The PI is part of the wider clinical team) 
- 
The PI will ask the clinical team on call if calorimetry is suitable for the identified patient/s 
- 
If the clinical team feel this is appropriate, the PI will ask consent of the parents to 
undertake indirect calorimetry 
 

 
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Study procedure 
1. Once consented, calorimetric measurement will be undertaken using the MedGraphic 
Ultima CCX, Minnesota, USA). This will be done in the following steps: 
a. Assess the patient for stability:  
i. no change in inotropes (dopamine, adrenaline, noradrenaline, vasopressin, 
milrinone, dobutamine) in previous hour 
ii. no change in ventilator settings including FiO2 in the previous hour 
iii. FiO2 <0.6 
iv. tidal volume ventilation >60ml (ideally greater than 100ml) 
v. air leak around endotracheal tube (ETT)<5% 
vi. no increases in sedation in past hour 
vii. no major stimulatory events (physiotherapy, turning, suction) in the 
previous hour 
 
b. Record demographic data, ventilator settings and measurements, calorie intake, 
heart rate, blood pressure, cardiac index (if monitored), drug infusion rates, use of 
paralysis, COMFORT or sedation score, temperature 
c. If the patient is stable, then start measurement of energy expenditure (calibrate 
prior to measurement, attach gas sampler to end of ETT to ventilator end of 
capnograph/flow sensor. 
d. Stop measurement immediately if any deterioration in ventilation with 
measurement 
e. After 30 minutes (or sooner if steady state is reached i.e. 5 consecutive minutes of 
less than 10% variation in O2 and CO2 concentrations ) stop measurement 
2. If patient develops temperature >38oC (axillary or central measurement) within the next 4 
hours (or longer only if all variables are the same as baseline), repeat step 4 a-c prior to anti-
pyretic administration (with half hourly data collection). The calorimeter will be left on the 
patient for continuous data collection until the temperature falls below 38oC.  
3. If continuous measurement is not possible because of clinical needs (nursing or medical 
request, need for suctioning, patient instability), a 3rd measurement will be taken when the 
temperature is below 38oC 
 
If the patient is febrile at screening, measurement will start at step 2 
 
 
Patient safety 
The calorimeter fits in to the ventilator circuit. This requires very brief disconnection of the circuit to 
attach the sampling connector. Disconnection of this nature is routine practice in the intensive care 
unit (for example during suctioning) and is well tolerated. 
The calorimeter samples air from the ventilator circuit at a constant rate of 100ml/min. This may 
affect ventilation in small children. The Medgraphic Ultima CCM is licensed for use for pateints with 
tidal volumes of 100ml or more. This will usually equate to children around 15kg. However our 
collaborators in Addenbrooke’s Hospital, Cambridge (Dr N Pathan) have used the Medgraphic Ultima 
CCM safely in children down to 10kg. 
During measurement we will monitor the child’s respiratory rate, oxygen saturation levels and end 
tidal CO2. If any of these values change significantly, as judged by the bedside nurse or the PI, 
calorimetry will be discontinued. 
 

 
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Data collection 
Data will be collected for 
- 
Demographic data (ID, weight, height, age, sex, diagnosis) 
- 
Inspired and expired O2 and CO2; VO2 and VCO2; Respiratory Quotient; Energy expenditure 
(as measured and displayed by the MedGraphics Ultima CCM calorimeter) 
- 
Physiological variables (heart rate, blood pressure) 
- 
IF CARDIAC OUTPUT MONITOR IN PLACE: stroke volume and cardiac index (as measured by 
Lidco Rapid, LIDCO Ltd, UK) and latest haemoglobin 
- 
Inotrope infusion doses 
- 
COMFORT or sedation score as recorded 
- 
Paralysis (yes/no) 
- 
Temperature 
- 
Nutritional intake in last 24 hours or since admission 
 
Data apart from demographic data will be collected at the start of each recording and hourly if 
continuous recording 
If cardiac monitoring is in place, continuous data (as recorded by the Lidco Rapid) will be used to 
calculate oxygen delivery. 
 
 
STATISTICAL ANALYSIS 
 
Sample size: Not enough data exists to ascertain the standard deviation of energy expenditure using 
the Medgraphics Ultima CCM calorimeter in critically ill children over the time period to be 
measured. However a standard deviation of 10% has been observed in critically ill children by groups 
who have measured energy expenditure in large numbers of children (personal communication from 
Dr R Meyer, Imperial College, London). Based on this, for a 10% effect size, with a one-tailed α of 
0.05 and (1-β) of 0.8, a sample size of 10 children would be needed, provided a 1oC of temperature is 
seen. An analysis of temperature change following over 5000 doses of paracetamol in febrile 
children suggested a mean reduction of temperature by 0.7oC. Based on this therefore we will need 
10 x 1/0.7 = 15 patients 
However it is likely that our sample will have several confounders which will need to be taken into 
account by multi-variable analysis. Therefore we will aim to recruit at least 15 children with 
measurements with and without fever (ideally before-during and after fever), but will try and recruit 
as many children as possible over the 12 month study period. Approximately 300 patients admitted 
to PICU at Great Ormond Street Hospital per year are above 10kg. Of these, approximately 75-100 
patients are electively admitted, 30 post-major surgery (mostly spinal surgery). 30% of children post 
spinal surgery develop a fever in the first 24 hours. In addition the remaining 200 children are 
admitted as an emergency. 80% of children admitted as an emergency are treated for a suspected 
infection, the remainder post trauma. Again 30-50% of children admitted with an infection or 
trauma develop a fever within the first 24 hours.  Therefore each year approximately 75-80 patients 
will be >10kg, ventilated, and will develop a fever within the first 24 hours of admission, with a 
proportion developing fever later on in admission (e.g. from nosocomial infections). 
 
 
Statistical analysis: Uni-variable analysis using paired t-tests will be undertaken by comparing the 
energy expenditure with and without fever, divided by the change in temperature.  Multi-variable 
analysis using a multi-level regression model will be used using  

 
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- 
Change in energy expenditure as the outcome variable 
- 
Patient ID as the random effect variable 
- 
Change in temperature, COMFORT score, vasoactive inotrope score, heart rate, blood 
pressure, and paralysis as a binary variable as fixed effect variables 
 
If cardiac output monitoring is in place, then the oxygen extraction can be calculated as VO2/DO2, 
where, 
DO2 = {cardiac index x ((oxygen saturation of haemoglobin x haemoglobin concentration) + 0.0031 x 
partial pressure of oxygen)} 
and VO2 is measured from the calorimeter 
 
 
ETHICAL CONSIDERATIONS 
The study will be conducted in accordance to Good Clinical Practice principles and the principles of 
the Declaration of Helsinki. 
 
Informed consent will be sought from parents/guardians with parental responsibility prior to 
measurement. Consent forms will be stored in the Great Ormond Street Critical Care Research Office 
securely.  
 
Data will be stored and processed electronically in a secure password protected NHS IT network 
according the principles of the institutional information governance policy.  Patient identifiable data 
will be minimised to unique patient hospital number.  The storage of data will be consented for. 
 
Baseline energy expenditure data may be shared with collaborators anonymously to further the 
understanding of metabolic activity in critically ill children. Consent for this will explicitly sought. 
 
 
OUTCOMES AND SIGNIFICANCE 
If the null hypothesis is true, then the treatment of fever in critically-ill children can be questioned, 
especially given the immunological benefits. If the alternative hypothesis is true, then the overall 
risk- benefit balance of treating or not treating fever in critically illness will have to be assessed in 
the form of a randomised controlled clinical trial.  
Research findings will be disseminated in national and international intensive care conferences, and 
peer-reviewed medical/scientific journals 
 
 
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