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Andrews PJD, Sinclair L, Rodriguez A, et al.
Hypothermia for intracranial hypertension after
traumatic brain injury
N Eng J Med 2015. Epub ahead of print http://dx.doi.org/10.1056/NEJMoa1507581
Background
Traumatic brain injury (TBI) is a leading cause of death and severe disability in young
adults. Despite its high societal impact, it is underrepresented in medical research and
there is limited evidence for many of the routinely used interventions [1]. Hypothermia can
reduce intracranial pressure (ICP) in patients with TBI, however its effect on outcome is
unknown: some trials have demonstrated benefit [2] but others have shown trends towards
harm or were prematurely stopped [3,4]. The aim of this study was to test the effect of
hypothermia on functional outcome.
Methods
This was an international, multicentre, randomised, controlled trial (Eurotherm3235),
which ran from 2009 to 2014. Participants were patients admitted to ITU following primary
closed head injury, with raised ICP after initial treatment. Hypothermia was induced by a
bolus of cold intravenous 0.9% NaCl and maintained with the cooling method usual for
the particular site. The primary outcome measured was the Extended-Glasgow Outcome
Score (GOS-E) at 6 months. Serious adverse events, ICP control and 6-month mortality
were also recorded.
Results
In total, 287 patients were randomised. The study was stopped early after there were
indications of harm with hypothermia treatment. Although not reaching statistical
significance, at 6-months post injury the hypothermia group had worse GOS-E scores:
adjusted common odds ratio for GOS-E score was 1.53 (95% CI, 1.02–2.30; p = 0.04).
Serious adverse events were more frequent in the hypothermia group (33 vs 10).
Discussion
Hypothermia plus standard care to reduce ICP did not result in outcomes better than
standard care alone. Early termination of the trial due to safety concerns will have
introduced the risk of bias and reduced validity, but results suggested worse outcomes in
the treatment group.
Conclusion
This is overall a well-designed, rigorously-conducted study which utilised a sensitive and
valid outcome measure [5]. It attempts to answer an important question to which there is
currently equipoise: whether hypothermia should be used to reduce ICP in TBI.
There are a number of weaknesses. Hypothermia was placed at an early stage in the
treatment algorithm, before osmotherapy. This may have affected timing of these other ICPlowering
treatments and caused confounding. Standard care and method of cooling were
not prescribed in the protocol which will have resulted in treatment variation in both groups;
however this allowed the study to be pragmatic and practical. Although outcome scoring
was blinded, there was lack of blinding to the intervention, which may have contributed to
the higher reporting of adverse events in the hypothermia group.
Despite these limitations, the study has produced a valuable result that will impact on clinical
management of patients with TBI. Further research may consider the role of hypothermia
later in the treatment sequence, in patients with refractory intracranial hypertension who
have exhausted other treatment options.
Lindsey Arrick
ST5 Anaesthetics, Derriford Hospital, Peninsula Deanery
References
1. Ker K, Perel P, Blackhall K, Roberts I. How effective are some common treatments
for traumatic brain injury? BMJ 2008; 337: a865.
2. Crossley S, Reid J, McLatchie R, et al. A systematic review of therapeutic
hypothermia for adult patients following traumatic brain injury. Critical Care 2014;
18: R75.
3. Clifton GL, Valadka A, Zygun D, et al. Very early hypothermia induction in patients
with severe brain injury (the National Acute Brain Injury Study: Hypothermia II): a
randomised trial. Lancet Neurology 2011; 10: 131-9
4. Clifton GL, Miller ER, Choi SC, et al. Lack of effect of induction of hypothermia after
acute brain injury. New England Journal of Medicine 2001; 344: 556–63.
5. Levin HS, Boake C, Song J, et al. Validity and sensitivity to change of the extended
Glasgow Outcome Scale in mild to moderate traumatic brain injury. Journal of
Neurotrauma 2001; 18: 575–84.
Freeman LM, Bloemenkamp KW, Franssen MT, et al.
Patient controlled analgesia with remifentanil
versus epidural analgesia in labour:
randomised multicentre equivalence trial
BMJ 2015; 350: h846
Background
Epidural analgesia and intravenous opioids are both utilised methods of pain
relief during labour, with the former previously considered to be the most
effective method [1]. However, with various studies showing comparable
maternal satisfaction with patient-controlled remifentanil [2,3], this was felt to
be a suitable alternative. However, these studies had limitations and the authors
wanted to conduct a study to accurately assess comparisons in analgesia.
Methodology
This was a multicentre randomised clinical trial within the Dutch consortium
for women’s health and reproductivity. Before the onset of active labour,
consenting women were randomised to either patient-controlled remifentanil or
epidural analgesia if pain relief was requested. However, patients were able to
receive the other analgesic strategy if they had inadequate pain relief. During
labour, women were asked to rate both pain scores as well as satisfaction with
pain relief on a visual analogue scale hourly from the onset of labour. This was
summarised using the area under the pain satisfaction curve with a higher
AUC representing higher satisfaction. Randomisation was performed through
a web-based randomisation program.
Results
A total of 1414 women were randomised into two comparable groups with 709
to the remifentanil group and 705 to the epidural group. Due to loss of follow
up, the analysis was based on 687 women in the remifentanil group and 671
in the epidural group with pain relief ultimately being used in 65% and 52%
of women, respectively. The area under the curve for total satisfaction with
pain relief was 30.9 in the remifentanil group vs 33.7 in the epidural analgesia
group. Results were only significant in subgroup analysis but not found to be
significant using intention to treat
Discussion
The total satisfaction with pain relief was better in the epidural analgesia
group than the remifentanil and this was significant in the subgroup of women
who actually received analgesia. Of note, oxygen saturation was significantly
lower (SpO2 65 years, undergoing elective non-cardiac surgery requiring
anaesthesia, anticipated to stay in hospital for >48hrs were included in the study.
Anaesthetists were blinded to the study hypothesis. Blood pressure changes were
defined as relative hypotension if there was a 20%, 30%, 40% decrease below the
patient’s pre-operative baseline for either systolic blood pressure (SBP) or mean
arterial pressure (MAP) or an absolute blood pressure decrease below 50 mmHg.
Fluctuations in blood pressure during surgery were quantified by calculating the
variance from the patient’s record. Delirium was assessed pre-operatively and on
the first two days postoperatively using the Confusion Assessment Method.
Results
No significant association was found between intra-operative hypotension and
postoperative delirium. There was a MAP decrease of >40% below the baseline for
more than 5 minutes in 12% of patients who did not develop delirium and in 10% of
those patients that developed delirium (p value