One-liner…
Traumatic brain injury (TBI) is a leading cause of mortality and morbidity in paediatric populations, and fever is associated with worse outcomes.
Should we aim to prevent fever, or should we cool patients?
A 12-year-old boy presents with a significant head injury following a road traffic accident. At the scene, his lowest GCS was 5 (E1V2M2). His CT scan showed extensive cranial fractures, traumatic subarachnoid haemorrhage, and intraparenchymal haemorrhage. He went to theatres for an ICP (intra-cerebral pressure) bolt.
On return to the Paediatric Intensive Care Unit (PICU), strict neuroprotection measures continued, including strict targeted temperature control (36-37.5°c).
What is targeted temperature management?
Targeted temperature management (TTM) is the induction of varying degrees of patient temperature targeting within Paediatric Intensive Care Unit (PICU):
- Therapeutic hypothermia- induction of varying degrees of hypothermia.
- Targeted normothermia – strict fever prevention.
Therapeutic hypothermia involves the stepwise process of inducing a lower core temperature, maintaining this lower temperature, and then gradually rewarming over time.
This is achieved using different interventions, including conventional cooling techniques (such as cold saline and ice packs) and various surface and core cooling systems.
Targeted normothermia involves fever prevention and the maintenance of normothermia using similar techniques and medications, such as antipyretics.
Targeted temperature management requires constant monitoring of the core body temperature.
According to adult data, oesophageal core temperature measurement is more accurate than rectal.
How might targeted temperature management be useful in TBI?
In children and young people with traumatic brain injury (TBI) injury occurs in two stages: a primary brain injury and a secondary brain injury.
The primary brain injury occurs directly from the injury itself and is often irreversible.
Secondary brain injury is the complicated range of inflammatory and neurotoxic responses that occur after the initial injury and cause progressively raised intracranial pressure (ICP) and further injury to the brain.
Fever is a key cause of secondary brain injury. A raised temperature can increase the blood flow to the brain, blood volume within the brain, and the brain’s overall metabolic demand.
Fever is common among patients with TBI. In TBI, fever can occur due to impaired temperature control mechanisms, the systemic inflammatory response to trauma, or due to infection. Progressive secondary brain injury due to raised temperature can occur regardless of the underlying cause of the fever.
The aim of TTM is to control the body and brain’s temperature, thus reducing secondary brain injury and improving the neurological outcome. Therapeutic hypothermia is thought to decrease the brain’s metabolic demand, reduce inflammation and cell death, and reduce the risk of seizures. Targeted normothermia helps to prevent the secondary brain injury that may occur if there is a fever.
What are the potential complications of therapeutic hypothermia?
Since therapeutic hypothermia involves cooling the whole body and the brain, it can be associated with many different physiological changes, some of which might cause complications. The cold body temperature can cause cardiovascular, renal, metabolic, and immunological side effects.
Cooling the heart and blood vessels due to therapeutic hypothermia can lead to blood vessel constriction. This can reduce cardiac blood flow, increase the risk of cardiac damage, and lead to pulmonary hypertension. It can also increase blood pressure. Cardiac contractility is reduced when the core temperature goes below 33°C.
Hypothermia may also lead to a phenomenon called “cold-induced diuresis”. This is a diuretic response to the vasoconstriction and the increased Atrial natriuretic peptide (ANP), decreased Antidiuretic hormone (ADH), and tubular dysfunction. If this isn’t treated, it can lead to hypovolaemia and electrolyte imbalance, making fluid balance challenging.
Therapeutic hypothermia causes a decrease in metabolic rate and a reduction in tissue oxygen availability. This contributes to the development of metabolic acidosis. Unanticipated drug toxicity may occur due to changes in drug metabolism and elimination with cooling.
A suppressed inflammatory response is also seen with therapeutic hypothermia. Although this can be beneficial initially, it also increases the risk of infectious complications and coagulopathy with prolonged hypothermia.
What do the guidelines recommend?
The International Liason Committee on Resuscitation Pediatric Life Support Task Force (ILCOR), the Australian and New Zealand Committee on Resuscitation (ANZCOR), and the Resuscitation Council UK (RCUK) recommend TTM in the form of either therapeutic hypothermia or targeted normothermia for children with a return of spontaneous circulation and coma following a cardiac arrest.
In contrast, the Brain Trauma Foundation does not recommend therapeutic hypothermia to improve overall outcomes. However, therapeutic hypothermia is supported for controlling intracranial pressure. A 2024 consensus guideline on TBI management in adults recommends therapeutic hypothermia for the management of raised ICP when other treatments have failed to control ICP. Targeted normothermia is recommended across guidelines.
The difference in recommendations for paediatric patients with cardiac arrest and TBI raises an interesting consideration of the difference between the two conditions.
The injury in cardiac arrest is often sudden, temporary and similar across the brain, with reversibility depending on downtime. The brain has been deprived of oxygen.
In contrast, the type of injury in traumatic brain injury involves the primary irreversible injury from the trauma itself and then a progressive secondary injury. The injury is not uniform across the brain. There tends to be a mixture of localised and widespread components.
What is the evidence behind targeted temperature management?
Kochanek et al. explored the evidence in a 2019 systematic review, which forms part of the Brain Trauma Foundation Guidelines, as did Utsumi et al. in a 2023 systematic review and meta-analysis.
The Brain Trauma Foundation Guidelines were developed in a two-step process. Step one involved a systematic review, and step two synthesized these to produce evidence-based guidelines. The recommendations were then graded based on the strength of the supporting evidence, with a level I recommendation based upon high-quality evidence, level II moderate-quality, and level III low-quality evidence.
The guidelines by Kochanek et al. include ten studies:
- Two meta-analyses.
- Five randomised controlled trials (RCTs).
- Three secondary analyses.
The sample sizes ranged from 16 to 225 patients, and the patients’ ages ranged from 0 to 18. Four RCTs showed no significant difference in mortality or outcomes.
One RCT showed a significant reduction in ICP during cooling; however, neurological outcomes were not evaluated. Additionally, none of the studies stratified TBI by type/severity at presentation. Nine of the ten studies included were moderate to low quality. Concealment and randomisation were frequently vague or impossible to conduct.
There was also marked variation in the way that therapeutic hypothermia was used (different durations, temperature ranges, and re-warming rates) in the included patients. Overall, the evidence was of moderate quality, which led to a level II recommendation that:-
Prophylactic moderate(32–33°C) hypothermia is not recommended over normothermia to improve overall outcomes.
However, there may be a patient cohort that benefits from therapeutic hypothermia, and the guidelines provide a level III recommendation on the use of moderate (32–33°C) hypothermia for ICP control. This is based upon three randomised controlled trials which showed that ICP decreased within the first 24 hours of moderate hypothermia, although there was no long-term benefit observed.
The most recent meta-analysis by Utsumi et al. found no significant difference in neurological outcome, mortality or arrhythmias between normothermia and TH at 24, 48, and 72 hours. It included no new randomised controlled trials since the systematic review and guideline development by Kochanek et al. in 2019. Utsumi pooled six studies to analyse outcomes at three time points. In contrast, Kochanek reviewed each meta-analysis, as well as the RCT and secondary analyses, separately to assess overall results and potential moderators of effect.
After four days, the patient’s neuroprotection parameters slowly loosened.
He was extubated with a GCS of 15 and then stepped down after 11 days in the PICU.
Nine weeks post-admission, the patient went home fully conscious, with above-expected levels on neuropsychological assessment.
Take home points:
Targeted temperature management (TTM) refers to range of clinical interventions to regulate strict systemic temperature including therapeutic hypothermia and targeted normothermia.
Maintaining normothermia is important to prevent secondary brain injury that is worsened by fever.
There is not enough evidence for prophylactic moderate hypothermia (32-33°C) hypothermia over normothermia to improve overall outcomes.
Moderate therapeutic hypothermia (32–33°C) may play a role in reducing raised intracranial pressure but has associated risks.
About PICSTAR
PICSTAR is a trainee-led research network open to all doctors, nurses and allied health trainees within Paediatric Intensive Care. We are the trainee arm of the Paediatric Critical Care Society – Study Group (PCCS-SG) and work with them on research, audit and service evaluation.
If you would like to join PICSTAR and get involved in projects, have ideas you would like to propose or get advice/mentorship via PCCS-SG, don’t hesitate to contact us at picstar.network@gmail.com. See their website for more: https://pccsociety.uk/research/picstar/
References
Jo KW. Target temperature management in traumatic brain injury with a focus on adverse events, recognition, and prevention. Acute Crit Care. 2022;37(4):483-490. Doi:10.4266/acc.2022.01291
Kochanek PM, Tasker RC, Carney N, et al. Guidelines for the Management of Pediatric Severe Traumatic Brain Injury, Third Edition: Update of the Brain Trauma Foundation Guidelines [published correction appears in Pediatr Crit Care Med. 2019 Apr;20(4):404]. Pediatr Crit Care Med. 2019;20(3S Suppl 1): S1-S82. doi:10.1097/PCC.0000000000001735
Lavinio A, Coles JP, Robba C, et al. Targeted temperature control following traumatic brain injury: ESICM/NACCS best practice consensus recommendations. Crit Care. 2024;28(1):170. Published 2024 May 20. Doi:10.1186/s13054-024-04951-x
Lefrant JY, Muller L, de La Coussaye JE, et al. Temperature measurement in intensive care patients: comparison of urinary bladder, oesophageal, rectal, axillary, and inguinal methods versus pulmonary artery core method. Intensive Care Med. 2003;29(3):414-418. doi:10.1007/s00134-002-1619-5
Omairi AM, Pandey S. Targeted Temperature Management. In: StatPearls. Treasure Island (FL): StatPearls Publishing; June 25, 2023.
Utsumi S, Amagasa S, Yasuda H, Oishi T, Kashiura M, Moriya T. Targeted Temperature Management in Pediatric Traumatic Brain Injury: A Systematic Review and Network Meta-Analysis. World Neurosurg. 2023; 173:158-166.e2. Doi: 10.1016/j.wneu.2023.01.056
