Systematic review of head cooling in adults after traumatic brain injury and stroke

Article history

The research reported in this issue of the journal was commissioned by the HTA programme as project number 07/37/32. The contractual start date was in May 2009. The draft report began editorial review in June 2011 and was accepted for publication in November 2011. As the funder, by devising a commissioning brief, the HTA programme specified the research question and study design.The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

This project was funded by the NIHR Health Technology Assessment programme (project number 07/37/32) and the authors’ institutions received money through this. Only BH received salary from the grant (through employer, University of Edinburgh). PA holds a grant from the European Society of Intensive Care Medicine for a trial of therapeutic hypothermia in traumatic brain injury (Eurotherm3235 trial). Otherwise none declared.

Copyright statement

© Queen’s Printer and Controller of HMSO 2012. This work was produced by Harris et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to NETSCC.

2012 Queen’s Printer and Controller of HMSO

The conditions and incidence: traumatic brain injury and stroke

Brain injuries resulting from stroke and trauma are common and costly in human and resource terms. In England, approximately 130,000 people have a stroke each year, of whom about one-quarter die and half of the survivors are left dependent on others. 1 The incidence of head injury is similar to that for stroke,2 although the incidence of death is lower, at 6–10 per 100,000 population per year. 3 However, head injury is more common in younger people, and it has been estimated that 4700 of those admitted to hospital each year would be unable to return to work at 6 weeks. 2 A Scottish study found that 78% of patients with a severe injury had moderate or severe disability 1 year later. 4

Aside from the often devastating consequences for patients and their families, these brain insults are expensive. Morbidity from head injury ‘far exceeds the capacity of UK neurorehabilitation services’3 and the costs of stroke to the NHS are estimated at £2.8B per year, with the cost to the wider economy about £1.8B more in disability and lost productivity. 1

Although the primary mechanisms of brain injury are different in trauma, haemorrhage and ischaemia [whether focal, as in ischaemic stroke, or global, as in cardiac arrest and neonatal hypoxic–ischaemic encephalopathy (HIE)], the result is a cascade of excitotoxity, apoptosis and inflammation. 5,6 Inflammation, cell death and infection, if present, mean that increased temperature is common after both stroke and brain injury. 7,8 There is no universally agreed definition of the threshold for pyrexia or where and how temperature should be measured in these patients but, in one study, nearly 68% of patients had a rectal temperature ≥ 37 °C within 48 hours after severe traumatic brain injury (TBI)9 and 54% had an axillary temperature of > 37.5 °C within 48 hours after stroke. 10

Increased temperature is associated with worse outcome after both stroke and TBI. 9,11 The exact nature of the relationship in humans is hard to determine, as the time of onset of raised temperature has an influence and temperature elevation can be a marker of more severe injury and of infection, both of which are also associated with worse outcome,12 although one systematic review11 suggests that infection may not play a significant part in the relationship in stroke. There is considerable evidence from animal research that reducing temperature, and, more especially, inducing hypothermia, reduces the extent of injury and that the sooner cooling is instigated the more effective it is. 6 However, there is insufficient high-quality prospective evidence to show that normothermic or hypothermic temperature interventions improve functional outcome in humans after TBI and stroke. 13–15 This may be because it is difficult to cool patients early and quickly enough and/or because the side effects of hypothermia, such as increased infection, may outweigh the benefits in some circumstances.

Nevertheless, the usual clinical goal in TBI and stroke is to reduce raised temperature to normothermia, although consistently achieving this can be difficult. 16,17 In stroke it is recommended that temperature is treated if > 37.5 °C. 18 In brain injury, body temperature control is recommended in the context of treating raised intracranial pressure (ICP). 19 There are no standard recommendations on the site of temperature measurement or methods of temperature reduction. In practice, choice of site of measurement is variable20,21 and cooling interventions are usually systemic. Pharmacological intervention, generally with paracetamol, is the most common first-line treatment, followed by a variety of physical systemic cooling interventions, which include cooling blankets, ice packs and fanning. 21,22

The intervention: non-invasive head cooling

Physical cooling methods can be classified into those targeted systemically and those targeted at the head to cool the brain directly, and include invasive and non-invasive methods. Non-invasive head cooling is the subject of this review and therefore invasive methods, such as antegrade and retrograde cerebral perfusion and devices applied to brain tissue, which are mainly used during surgery,23 are not included.

Methods of non-invasive head cooling are categorised into:

• Heat loss from the upper airways This takes place by convection with gas or fluid flow or by conduction with nasal or pharyngeal balloons – whether or not these devices are truly non-invasive is a moot point, but they have been included in this review.

• Heat loss through the skull This takes place by convection (fanning, hoods delivering cold air or water) or by conduction (passive, e.g. ice, gel caps or active, e.g. liquid cooling); some of the devices also have a neck band that theoretically may help cool the brain by reducing the temperature of the carotid blood supply. 24,25

Heat loss occurs as flow down temperature gradients from warm to cool. Convective cooling methods use air/gas flow to remove heat; molecules are removed in bulk and transfer heat in the process. Convective methods also allow heat loss by evaporation, a form of convection in which bulk movement of molecules is achieved by water loss (changing water into water vapour requires large amounts of heat). With conductive methods energy (heat) moves but the molecules do not. Heat from the head is conducted through the wall of the device and either actively removed by the circulating liquid coolant or passively absorbed by the frozen material (ice/gel). Devices containing frozen material will warm up in this process and must be replaced regularly to maintain cooling efficiency.

Non-invasive head-cooling methods are generally quick and easy to apply and may be suitable for pre-hospital use, which are important considerations in reducing time to cooling if neuroprotection is the aim. They also have potentially wide application because they can be used in patients with a range of severity of illness, not just the most severely ill.

How the intervention might work

Although cooling interventions are more commonly delivered systemically, the logic behind head cooling is that it targets cooling where it is needed because it is brain rather than trunk temperature that is important in cerebral protection. It is also thought that head cooling may reduce the complications of hypothermia because less body temperature reduction is required, although the evidence for this is not robust. 23

The great advantage of cooling, by comparison with most other neuroprotective interventions, is that it has many potentially beneficial effects with regard to secondary injury mechanisms and therefore cerebral protection. Hypothermia has even been described as ‘the ultimate neuroprotective cocktail’. 7 The effects of cooling are not fully understood but include reduction in metabolic rate, modulation of cerebral blood flow, and the inflammatory response and reduction of excitotoxic damage and cerebral oedema. 6,26 Because cooling can be very effective in reducing refractory ICP this is the most usual reason for instigating therapeutic hypothermia in severe traumatic and haemorrhagic brain injury. 27,28 In ischaemic stroke it is considered possible that therapeutic hypothermia could extend the time window within which restoration of blood supply, for example with thrombolysis, might be effective. 29

Measurement of temperature reduction

If cooling, however delivered, is to have a neuroprotective effect, brain temperature must be reduced. The primary measure of the effectiveness of head cooling with regard to temperature reduction is a decrease in intracranial temperature. For the purposes of this review, intracranial temperature is defined as temperature inside the skull and within the dura. In the absence of intracranial temperature data, the secondary measure for this review is reduction in core trunk temperature with head cooling, measured in an artery (usually pulmonary), the oesophagus, bladder or rectum, on the assumption that for core trunk temperature to be reduced there must have been some reduction in intracranial temperature. (For further explanation see Appendix 1.)

Cardiac arrest and neonatal hypoxic–ischaemic encephalopathy

The principal focus of this review is head cooling in TBI and stroke, in which the primary problem is in the brain. However, in global (whole body) ischaemia, following cardiac arrest, therapeutic hypothermia is considered to improve outcome, specifically with return of circulation after ventricular fibrillation,30–32 although doubts have been raised over the quality of the evidence. 33 Therefore, during the protocol review process, we were asked to include the cardiac arrest literature on head cooling in our searches because this could contribute information about how effective these interventions are in reducing temperature, and on their ease of use and side effects. Studies in cardiac arrest were not relevant for assessment of functional outcome in this review. However, in our opinion, it is not yet clear to what extent whole-body cooling, which includes myocardial cooling, contributes to improved outcome with hypothermia after cardiac arrest, and whether or not head cooling alone is as effective as systemic cooling in this systemic ischaemic injury. There is no comparative randomised controlled trial (RCT) but there is some evidence, for example, that myocardial reperfusion injury, which can be ameliorated by hypothermia, may contribute to post-arrest morbidity and mortality. 34,35

Neonatal HIE is the other global ischaemic condition in which therapeutic hypothermia has been shown to be of benefit. 36,37 Head cooling has been commonly used as the means of achieving hypothermia in neonatal HIE but whether or not it has advantages over systemic cooling has not yet been assessed in a comparative RCT. 36,38 However, a recent systematic review and meta-analysis in neonatal HIE includes a subgroup analysis of systemic hypothermia (seven studies) and head cooling (six studies) compared with normothermia, which shows that more adverse functional outcomes were reduced with systemic cooling than with head cooling. 38 It is relatively easy to cool infants with head cooling as they have a smaller body–head ratio than adults and therefore have less counterwarming from the trunk; also their skulls are not closed because their fontanelles have not fused. Intracranial temperature is not measured clinically in infants with neonatal HIE, but head cooling has a considerable ‘knock-on’ effect on body temperature and body warming is required to control systemic hypothermia. 39 The effect of head cooling on temperature in neonates does not extrapolate to adults, but neonatal head-cooling research could contribute information on adverse effects of methods and devices therefore it was included in the review for this purpose.

The reason for undertaking this review

Systematic reviews of cooling interventions after brain injury and stroke have not differentiated between cooling methods. The only Cochrane review of a specific cooling intervention, for example, is that of paracetamol for fever in children. 40 In the reviews of cooling for acute stroke14 and of hypothermia for head injury15 the effect of temperature reduction on outcome has been the focus rather than the method(s) of achieving this, although a distinction was made between pharmacological and physical methods in stroke. Yet physical cooling methods differ in their effectiveness and complications. The reason for using head cooling is that, theoretically, it may have advantages over systemic cooling. Cooling is targeted to the site of injury where it is most needed, therefore requiring less body temperature reduction relative to brain temperature, which means that it may have fewer side effects than systemic physical methods. In order to determine whether or not head cooling has an effect and whether or not there are advantages it was necessary to review head cooling as an intervention.

Differences between protocol and review

The review protocol can be found in Appendix 2. We had consultancy support from Brenda Thomas, Cochrane Stroke Group Trials Search Co-ordinator, and on her advice the outline search strategy in the protocol was considerably extended to include, for example, EMBASE classic, the British Library’s Electronic Table of Contents (Zetoc), British Nursing Index (BNI) and BNI Archive, and Web of Science conference proceedings. Had time allowed we would also have included additional country-specific databases in addition to those in the protocol (e.g. WanFang, Panteleimon, IndMED, KoreaMed), Web of Science cited reference search (forward search) and more hand-searching. The formal patent search was omitted owing to lack of time. Of the head-cooling reports in the review (see Figure 1, which corresponds to the results of stage 2, trial identification and selection in the protocol) only studies that could potentially have been RCTs were screened, assessed and had data extracted by two reviewers.

Criteria for considering studies for this review

Search methods for identification of studies

Appendix 3 (search strategies) contains details of the searches and search terms. The searches were not restricted by publication status, date or language.

Data collection and analysis

Papers in languages other than English

A number of papers in foreign languages required full-text review: French (13), Italian (1), Slovakian (1), German (11), Japanese (3), Russian (8) and Chinese (26). Some of these had no, or an inadequate, English abstract so that it was not clear, for example, if the research was in humans or animals or whether head cooling or systemic cooling had been used without reading at least part of the paper. We had assistance from colleagues and friends with the requisite languages and used Google Translate (http://translate.google.com) to eliminate papers that were not relevant.

A Chinese-speaking intensive care doctor helped with the Chinese papers. She read them all, translated parts and went through them in detail with BH to assess quality and extract data. This did not highlight any that, on grounds of quality, warranted formal professional translation but we did have the study comparing head cooling with systemic cooling translated, as this was a particular comparison of interest with very few studies. 44 Because the other Chinese studies were not formally translated in full it has been possible only to report the main points and reasons for exclusion Appendix 6 (see Characteristics of Excluded Studies) compared with some of the studies in English where we have reported in more detail, although this is sometimes simply because there was more detail to report (the Chinese papers were mostly short).

Papers on head cooling in neonatal HIE in languages other than English were not assessed because this was not the primary condition of interest and there are recent systematic reviews (see Appendix 5, References to studies in neonatal hypoxic–ischaemic encephalopathy), which were also consulted for information on adverse effects of head-cooling methods and devices, i.e. the reason why papers on neonatal HIE were of interest.

Data extraction

BH and PA independently extracted data from RCTs using a standard form (see Appendix 4). They were not blinded to authors, journal or results. Disagreements were resolved by discussion. BH extracted data from all other studies. Where multiple reports of a trial were available, discrepancies between the reports were noted. Where there was missing information attempts were made to contact investigators.

Assessment of risk of bias

Randomised controlled trials were assessed for adequacy of the randomisation and allocation concealment process, potential for selection bias after allocation and level of masking (blinding of treatment provider, patient, outcome assessor, investigators and analysers of the data) (see Appendix 4).

Data synthesis

We were unable to carry out the full analysis plan specified in the protocol (see Appendix 2) because there were insufficient good-quality RCTs to undertake formal outcome analysis.

Briefly, had there been suitable RCT data, the following analysis was planned. For temperature data the difference in means would have been calculated with 95% confidence intervals (CIs). If sufficient good-quality trials for a meta-analysis had been found then a weighted mean difference would have been calculated. Pooled relative risk and 95% CIs for all-cause mortality and good neurological outcome would have been calculated using a random-effects model. Statistical heterogeneity would have been assessed using the chi-squared test.

However, it was recognised in the protocol that, depending on what was found, description of results might be all that was possible and the available temperature data are tabulated as a descriptive record of the effect of head cooling. No attempt has been made to draw any statistical inference. Data on adverse effects are reported descriptively.

Description of studies

Refer to Appendix 6 for detailed information on studies included, excluded, awaiting assessment and ongoing. Studies that included mixed populations of TBI and stroke are classified as studies in brain injury.

Results of the search

Figure 1 shows the results of the search and selection process. In the box ‘Head-cooling reports in the review’ the number of studies is given of each type found, with the number of reports in parentheses, i.e. some studies had more than one report associated with them. There were 46 studies (with 52 associated reports) in TBI, stroke and brain injury and 12 studies (15 reports) in cardiac arrest.

FIGURE 1.

Search results. a, Some studies had more than one report and the number in parentheses refers to the total number of reports. b, Where it was possible to de-duplicate search results on import to Reference Manager duplicates were counted. Otherwise, a record was not kept of whether the citation was excluded because it was a duplicate (less common) or irrelevant.

From the information available we were unable to reliably determine that there were any high-quality RCTs in TBI or stroke with blinded outcome assessment (see Appendix 6, Characteristics of included studies and Apendix 6, Characteristics of excluded studies).

Effects of interventions

Other applications of therapeutic head cooling

There were a number of databases in which limiting the search terms beyond cooling and brain/head terms was not feasible (see Appendix 3). These searches provided examples of a range of other conditions in which head cooling has been used as a therapy. The papers were not retained as part of the formal search results but the conditions are listed here for information, with selected citations. Head cooling has been used for headache,80 epilepsy,81 multiple sclerosis,82 sudden deafness from ischaemia of the inner ear,83 and to alleviate environmental, occupational and exertional heat strain. 84,85 A more common use of head cooling is to cool the scalp to reduce hair loss with certain types of chemotherapy. 71,86,87 There are several commercially available scalp-cooling devices. The Paxman Cooler and the DigniCap circulate coolant at around –5 °C and +5 °C, respectively, and the Penguin Cold Cap and ChemoCap contain frozen gel at –25 °C. Sizing the caps to fit closely improves contact and therefore cooling; sometimes hair is wetted prior to application to increase cooling effectiveness (e.g. with the DigniCap).

Historical reports of head cooling

The use of cooling for injuries has a very long history with documentary evidence as far back as Ancient Egypt (see Swan88 for a review), but references to head cooling are less common. However, the searches did produce some descriptions of therapeutic head cooling that are of historical interest, although with insufficient detail to be of use for the review.

In 1897, Charles Phelps, a New York surgeon, wrote a book on TBI – pistol wounds in particular. He advocates shaving the head to aid diagnosis but also to facilitate heat loss and to ‘permit the effective application of the ice-cap, which next to trephination, under indicated conditions, is most nearly a directly curative resource’ (p. 223). 89 The perceived benefit was reduction of temperature and swelling, and a case study is reported of a patient who repeatedly became lucid when the ice cap was in situ and feverish and delirious without it.

Oliver Waugh, a Canadian surgeon, described treatment of skull fractures in 1926. In cases of ‘mild’ skull fracture, i.e. patients who had experienced only brief disturbance of consciousness, ‘treatment should be an initial saline purgation (one ounce of Epsom salts), an ice cap applied to the head and absolute rest for from ten days to two weeks’ (p. 1476). 90 Patients with more severe injury had a lumbar puncture with removal of cerebrospinal fluid if the pressure was raised, an ice cap and regular Epsom salts orally or rectally ‘for its dehydrating effect on the brain’ (p. 1478). 90 Rest and quiet, with morphine if necessary, are emphasised. The rationale for using ice caps is not explicitly stated, but the implication is that it was primarily for reduction of swelling rather than reduction of temperature.

A 1962 German paper recommends ‘selective cranial hypothermia’ as an effective method of reducing hypoxic damage and cerebral oedema after inadvertent perioperative cardiac arrest. 91 The brain was cooled to 32–33 °C, about 1–1.5 °C lower than body temperature, and cooling maintained for 4–6 days depending on the patient’s condition, followed by slow rewarming. Details of the brain cooling method were to be the subject of a separate paper, but this seems not to have been published.

There are a number of papers in Russian on head cooling from the 1960s and 1970s. These contain descriptions of devices (see Appendix 7) and examples of conditions treated, which included TBI,92,93 epilepsy and even psychiatric patients in whom head cooling apparently provided temporary healing but did not prevent death. 94 There were no RCTs and insufficient detail on temperatures for formal inclusion in the review, but as they are relatively early reports of head cooling it seemed logical to include them in this historical section. Brain temperatures in the range of 22–30 °C with body temperatures of 33–36 °C are described. 92,94 Ear canal temperature (external auditory meatus/auditory canal wall near the tympanic membrane) was used as a proxy for intracranial temperature,93,95,96 but Ioffe and Sumskii92 also measured intracranial temperature directly in some of their patients using specially made temperature sensors. These were sited in the silicone drains which were placed in the parenchyma or subdural space during surgery, thus simultaneously achieving drainage and temperature measurement. 92

This is an early report of the use of intracranial temperature measurement in humans outside the operating theatre. Brain temperature was also sometimes inferred from a nomogram, developed from experimental work and clinical experience, to predict intracranial temperatures at various depths from observed body temperature, taking into account the patient’s weight and the start time of cooling. 97,98

Literature review, Glasgow Coma Scale and Glasgow Outcome Scale

There are currently no economic evaluation studies published on the cost-effectiveness of head cooling in adult patients with TBI. This is because there has been insufficient research and the clinical effectiveness of the treatment is not established.

The Glasgow Coma Scale (GCS) is a standardised neurological scale for recording and communicating the conscious state following a brain injury. The GCS can be transformed to a coma score and is used to evaluate patients from ‘3’ (deep coma or death) to ‘15’ (fully awake). It is commonplace to use the scores to classify patients’ injury as severe (GCS ≤ 8), moderate (GCS 9–12) or minor (GCS 13–15),99 and this approach will be taken in the economic evaluation. It should be noted, however, that this is not a linear scale.

The GOS and the extended GOS assess the longer-term effects through measuring the health and functional status of a patient after a treatment or an intervention. The GOS classifies patient outcome into five categories (eight in the extended scale), which range from death to good recovery. 100

Sources of data and eligibility

Data used to inform the economic modelling process were taken from the Scottish Intensive Care Society (SICS) WardWatcher database, which contains a record of patients who received treatment in the critical care unit of the Western General Hospital, Edinburgh. There is no single diagnostic category for TBI and Appendix 8 explains how patients were identified from that database. From September 1994 to July 2010, 1039 patients with TBI were admitted, but pre-sedation GCS was available only for 695 of these patients and outcome data (five-point GOS at 12 months) for 168, those admitted in 2007–9.

The data set is relevant as it was planned that head cooling would take place in critical care and be available to all TBI patients in such a unit. Therefore, any patient in the data set would be eligible for head cooling. Usually, a patient will be admitted to a critical care ward if he or she has a GCS score of ≤ 12, which includes both moderately and severely injured patients.

Limitations of the data

A severe limitation with the available information is lack of head-cooling outcome data. There are outcome data, i.e. the GOS data described above, which are available for 168 patients who received treatment for TBI in the critical care unit. But what is missing is a measure of effectiveness of head cooling for a patient with TBI.

Ideally, outcome data that are specific to head cooling would be available, and would include the health impact of the intervention and patients’ characteristics (e.g. age, gender, time and severity of injury, etc.). The outcome information might then be generalisable to the local data set used in this model. For example, if, according to a published study, head cooling is most effective when administered quickly to younger patients, and a male aged 25 years old with a short time to arrival to hospital is present in the data set, it would then be possible to predict the effect of head cooling on that patient. These data could then be combined with the cost information to provide some indication of the cost-effectiveness of the intervention.

However, the effect of head cooling is not yet established. It is not possible to say that if a patient with a certain set of characteristics receives head cooling then there is evidence to suggest there will be an improvement in health outcome. A method of counteracting the gaps in the literature is to use expert opinion, for example a clinician could suggest what may happen to a patient after head cooling. However, this method was discarded, as it was considered to be stretching the definition of ‘expert opinion to support the data’ too far by asking a clinician to suggest a whole set of outcomes for the data set.

It should be stressed that every effort was made to create a robust economic model. This included multiple meetings with hospital consultants at a variety of hospital locations across Scotland, meetings and discussions with academics associated with the University of Edinburgh, and thorough literature reviews. However, despite the search for available evidence, it was concluded there are very few data.

Similar head-cooling studies that include economic modelling, such as that of Gray and colleagues,101 are not relevant, as these papers are focused on neonates, whereas our interest is in adults. In fact, the paper by Gray and colleagues101 highlights the main issue surrounding the economic modelling of head cooling in adults, i.e. the lack of head cooling outcome data for adults. The outcome of head cooling in infants is modelled by taking data from a RCT. 39 Therefore, in their economic model Gray and colleagues101 can base their outcome data on published evidence, and it is exactly this sort of information which is missing for adults. It is not appropriate to alter a variable, for example head cooling reduces the number of deaths by an arbitrary amount that is not based on reliable evidence.

A large RCT with outcome data would provide a solution to the above problems and enable a more informative economic model to be developed.

Model

A simple diagrammatic model of the TBI pathway is provided in Figure 2. The pathway starts with assessment which includes GCS. From this point the patient would usually go to a specialised unit (critical care), a district general hospital (DGH) or home. The severe and some moderate patients tend to be admitted to critical care, which is where head-cooling treatment will be delivered. These are the patients for whom data are available, as explained above.

FIGURE 2.

The TBI pathway. A&E, accident and emergency department; DGH, district general hospital.

Methodology

Using the available data, the possible financial impact of head cooling on length of stay was modelled, i.e. if head cooling changes the length of stay of patients within the critical care unit would this have an economic impact? If the model assumes that the GCS can act as a rough proxy for how severely injured the patient is, then it is possible to model the financial impact of head cooling if it alters the length of stay associated with that level of injury.

Three scenarios are modelled:

• First, the cost associated with the status quo, which takes into account the proportional split of patients between moderate and severe levels of injury and the cost of treating these patients, is modelled.

• The second scenario investigates the financial cost if head-cooling increases by 1.5 days the length of stay of moderately and severely injured patients. This scenario was modelled in case applying head cooling lengthens patients’ stay in critical care as they undergo an additional treatment.

• The third scenario examines the financial cost of head cooling decreasing a patient’s length of stay by 1 day, with respect to moderately and severely injured patients. This scenario was modelled in case the health benefits of head cooling enabled the patient to be moved on from critical care earlier than in current practice.

Descriptive statistics

Presented below are background information contained in the data.

The mean lengths of stay of a moderately or severely injured patient, with the associated GCS scores, are tabulated below. The mean lengths of stay associated with scenarios 2 and 3 are also tabulated below.

In addition, the cost per bed-day and equipment costs are outlined below. It is assumed that no additional staff time would be needed to provide the head-cooling intervention, as these patients have 1 : 1 nursing care, which would usually be sufficient to accommodate delivery of cooling interventions. The cost per hospital bed-day is calculated from 2008–9 data published by Information Services Division (ISD) Scotland for the ICU at the Western General Hospital, Edinburgh. Equipment costs are based on the Olympic CoolCap System, which includes reuseable cooling caps [costs were provided by the UK supplier Genesys Medical Solutions (UK) Ltd in December 2010].

Results

It is expected that 69 patients per year would receive head cooling (because this was the average number of patients admitted to critical care each year in this data set). The proportional split between moderate and severe patients is 15% and 85%, respectively. The results of the three scenario models are presented below.

Discussion

The insight gained from the modelling above is limited. Essentially, the model is taking the GCS as a rough proxy for how severely injured the patient is and suggests that if head cooling could impact on length of stay then there may be a substantial change in costs owing to the expensive location of the treatment. 102 Head cooling is delivered in critical care, which generates a relatively expensive cost per bed-day. If the treatment alters the length of stay, and therefore the number of bed-days, then the change in cost between the current treatment and treatment with head cooling may be significant. However, it has been suggested by expert clinical opinion that head cooling may not impact on the length of stay of any section of the pathway outlined in Figure 2 (length of stay in critical care, DGH or rehabilitation).

The main benefit of head cooling for TBI is proposed to be improving the quality of life and reducing disability over the patient’s lifetime, i.e. what happens to patients after they go home and leave the mainly hospital-based pathway outlined in Figure 2. In addition, if there is an improvement in the long-term health of the patient then this will not only impact on the lifestyle of the patient, but will also require fewer health- and social-care support resources from the NHS and local authorities. This information will therefore significantly impact on whether or not the intervention is cost-effective, depending on the degree of health improvement and the size of the health and social costs.

Unfortunately, there are no UK lifetime TBI costs and no head-cooling cost data available in the literature, and therefore it is not possible to directly assess the long-term cost of TBI. We found the lack of lifetime costs for TBI surprising but requests for information to the Department of Health, the Scottish Office, the NHS Information Centre, the Trauma Audit and Research Network, and the Scottish Acquired Brain Injury Managed Clinical Network confirmed the lack of data. It stems, in part, from difficulty identifying patients who have had a TBI. The International Classification of Diseases, Tenth Edition, codes S00–S09, covers injuries to the head (S06 is specifically ‘intracranial injury’), but on initial admission to hospital it may not always be obvious whether or not brain injury is due to trauma, and patients may have other injuries and complex disease classification. In the USA there has been a concerted effort to collect data and consequently much more information is available,103,104 but, unfortunately, the health-care system is too different for this to translate to the UK. However, because this review has highlighted the lack of lifetime data on TBI, steps are now being taken in Scotland to address the situation and we are working with a group of people under the auspices of the Acquired Brain Injury Managed Clinical Network to improve data collection on TBI. We hope that, in the longer term, access to better data on the course of TBI will lead to benefits for these patients.

Although not related to TBI, Comas-Herrera and Wittenberg105 estimate that the lifetime health- and social-care costs of those aged ≥ 65 years in England are £31,500 per person at 2006–7 prices, averaged across males and females. The lifetime costs for a male reported in this study are £18,650 and £41,350 for a woman. These results compare favourably with those of Forder and Fernández,106 who estimate that the average lifetime expected cost of care for a male is £22,300, whereas for a female it is £40,400. The average for both genders is £31,700 per person in old age.

As seen in the descriptive statistics provided above, the average age of a patient with TBI is around 42 years, which is much lower than the 65 years used as the cut-off point for the estimates presented by Comas-Herrera and Wittenberg. 105 In addition, the individuals in their study are not reported to be disabled (although their health may deteriorate with age). The data in Comas-Herrera and Wittenberg105 highlight just how expensive health- and social-care costs can be and they may be much more if based on patients with TBI who have an average age of 42 years. It is reasonable to suggest that the long-term cost implications of TBI are substantial, which implies that if head cooling can improve the health of the patient and reduce the long-term costs of health and social care then it has a realistic chance of being cost-effective.

In addition to a lack of lifetime TBI cost data, there are also no available outcome data, i.e. health outcome data that evidence what happens to a patient after head cooling. There is no way to test the argument set out above – that head cooling may be cost-effective if it achieves positive health outcome and reduces the associated lifetime costs of health and social care. Thus, the model does not capture the main benefit of head cooling, which is the impact on quality of life and disability over the lifetime, and stops short of being a full economic evaluation, as there is no synthesis of outcome data with costs.

Conclusion: modelling of cost-effectiveness

The limited model presented here does display the sensitivity of the costs to changes in length of stay due to the expensive location of where head-cooling treatment is most likely to be delivered. Critical care has a relatively high cost per bed-day; thus, if length of stay changes, the impact on costs may be significant.

Unfortunately, good-quality data on outcome after head cooling are lacking and it is difficult to surmise from the model presented here whether or not the intervention is currently cost-effective. However, what the process has highlighted (and is the main conclusion of this model) is that if head cooling can positively impact on the quality of life for patients with TBI then the intervention may be cost-effective, owing to the high health- and social-care costs of severe brain injury and resulting disability.

Impact of head cooling on functional outcome

The searches found 46 studies of non-invasive head cooling in TBI, stroke and brain injury, of which three were assessed as RCTs with good allocation concealment (see Figure 1). Good-quality RCTs with blinded outcome assessment were prespecified for inclusion in analysis of functional outcome, but none of the three met this criterion and was suitable for this purpose.

Temperature reduction with head cooling

For assessing the effect of head cooling on temperature, studies and trials in cardiac arrest were eligible in addition to those in TBI and stroke. Twelve studies had useable data, including four RCTs and four in cardiac arrest (see Table 1). There was considerable heterogeneity (of patients, reasons for cooling and interventions) in these studies, making it difficult to summarise the data.

Two studies showed no effect,46,48 but in both cases this seems likely to be because of the methods used. In one of these, ambient temperature nasal airflow delivered to intubated, ventilated patients to replicate normal nose breathing showed no effect on intracranial temperature at a distance from the nasopharynx. 46 With this method the temperature gradient between the patient and the airflow was relatively small. In the other, ice bags on the head and neck for 5–30 minutes did not further reduce temperature in patients who were already on average hypothermic. 48 This method does not actively remove heat by coolant flow.

However, in broad terms the data indicate that liquid head- and neck-cooling devices and the Rhinochill intranasal cooling device can reduce intracranial and/or core trunk temperature by around 1 °C or more, within 1 hour in some studies (see Table 1). (These methods create a relatively steep temperature gradient between the patient and the coolant, and actively remove heat by coolant flow.) This is promising and, in particular, suggests that there may be a role for liquid head-cooling devices for induction and maintenance of modest temperature reduction in TBI and stroke (the Rhinochill device is not designed for prolonged use). A small observational study51 showed that it was possible to successfully treat fever refractory to standard management (paracetamol, metamizole, alcohol washing and ice packs) in this way (see Table 1). It is noteworthy that, even in the presence of active body warming, intracranial temperature was reduced with a liquid head-cooling device and could be reduced below core trunk temperature. 45,50

This is in contrast with mathematical modelling studies of head cooling, which are sometimes cited to support the view that external head cooling with various devices, including liquid cooling helmets, has a very limited effect on intracranial temperature. The modelling data, even when incoming carotid temperature is varied (which is more realistic than models that treat it as fixed at 37 °C) suggest that these devices reduce brain temperature only superficially, up to about 18 mm below the parenchymal surface. 107,108 Even if the usual site of parenchymal temperature measurement – at 1 cm below the brain surface – is considered too superficial to provide valid information on whether or not deeper brain is cooled, the data in this review include examples of ventricular temperature and core body temperature reduction with head cooling (see Table 1). It is hard to conceive that core trunk temperature would be reduced with head cooling, for example with the Rhinochill intranasal cooling device, in the absence of some deeper brain temperature reduction (see Appendix 1).

Head cooling compared with systemic cooling

The reason commonly given for using head cooling is that there may be fewer side effects than with systemic hypothermia. 109 Some investigators simply assume that cooling the head and keeping the body warm will minimise systemic complications of hypothermia. 45,50 Some head-cooling device providers have also made that assumption. The TraumaTec website states: ‘Selective brain cooling with the Neuro-Wrap™ avoids the complications seen with full body cooling … Complications of systemic hypothermia do not occur as systemic normothermia is maintained’ (www.traumatec.com/traumatec-brain-injury.htm; accessed 28 April 2011). Also, on the Benechill website, regarding the Rhinochill device: ‘it is core temperature reduction that causes problems in cooling – not brain temperature reduction’ (www.benechill.com/wp/resource/; accessed 28 April 2011).

Harris and colleagues45 were unable to achieve an intracranial temperature of 33 °C with head cooling while maintaining bladder temperature at 36 °C with active warming (see Table 1), although whether or not such a large temperature gradient is necessary or desirable remains to be determined. Because a statistically significant intracranial body temperature was not achieved, they concluded that their head-cooling device was not useful in management of TBI. Nevertheless, mean intracranial temperature was reduced below body temperature by 0.67 °C, and Wang and colleagues,50 also in the presence of active body warming, achieved a mean 1.6 °C reduction of intracranial temperature below body temperature. This is a reversal of the norm, in which intracranial temperature is usually higher than body temperature,110 and could well be considered clinically relevant for that reason, although whether there is therapeutic benefit or otherwise is not known. It is difficult to measure intracranial temperature gradients in humans but, in animals, head cooling in the presence of body warming to normothermia has been shown to significantly increase intracranial temperature gradients compared with systemic normothermia and hypothermia, although, again, it is not known if this is harmful. 111,112

This review found no high-quality RCT evidence on the relative complications and benefits of head compared with systemic cooling in adults and there are no RCTs making that comparison in neonatal HIE. However, there is some circumstantial evidence from other sources that is relevant to the question of whether or not a hypothermic brain and relatively warmer body may produce fewer complications than systemic hypothermia.

The side effects of systemic hypothermia at temperatures of 33–35 °C include pulmonary oedema, rebound increases in ICP on rewarming, higher temperatures post hypothermia, coagulation abnormalities, metabolic effects and immune suppression. 113 However, the reporting and definition of complications in clinical trials of systemic hypothermia is variable, which makes assessing their impact difficult. Nevertheless, systematic reviews of trials of systemic hypothermia after brain injury have shown a non-significant increase in occurrence of infections with cooling therapies (i.e. not only with hypothermic therapy) in stroke14 and of pneumonia in hypothermia for TBI. 15 But whether or not head cooling results in fewer complications than systemic hypothermia is likely to depend on the mechanisms by which the complications are caused, how the cooling and warming of the blood as it circulates through a cooler brain and relatively warmer body affects these, and how extreme the temperature gradients are.

With regard to infection, because immune response is modulated by the brain114,115 it seems unwise to assume that brain cooling, with the body relatively warmer, will cause less immune depression and infection than systemic cooling. The primary hormonal pathway for brain–immune system interactions is the hypothalamic–pituitary–adrenal axis115 and, consequently, it is thought that brain cooling does suppress immune function because the pituitary is cooled. 116 Furthermore, if immune defence is accelerated and more efficient at increased temperatures,117 reducing brain temperature even to the normothermic range might increase morbidity and mortality from infection.

Another undesirable effect of cooling is shivering, with the requirement for sedation to prevent it. Shivering and stress response to cold may occur even if brain temperature alone is reduced below the ‘set-point’, as cooling of the preoptic area of the hypothalamus is sufficient to cause heat production and retention responses. 118,119 Lim120 controlled brain temperature and core trunk temperature independently in anaesthetised dogs using bilateral carotid antegrade cerebral perfusion with independent control of body temperature. Cool brain–warm body and warm brain–cool body conditions both produced shivering. Therefore, brain cooling, even if the body is warm, may not prevent shivering.

If the question of whether or not head cooling does produce fewer complications than systemic cooling is to be answered then a good-quality RCT is needed. There is a small safety and efficacy study ongoing in stroke. The Cerebral Hypothermia in Ischaemic Lesion (CHIL) trial has a head-cooling arm in China, a systemic hypothermia arm in Australia and a normothermic control group, with blinded outcome assessment of the National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS) and Barthel Index (BI) at 90 days (see Appendix 6, Characteristics of ongoing studies).

Head-cooling terminology and search terms

There is no agreed terminology to describe cooling that is directed specifically at the head and brain. In the absence of this we have previously suggested the term direct brain cooling and developed the classification of head-cooling methods used in this review. 23 This was in part an attempt to provide an alternative to the term selective brain cooling, which has been commonly and erroneously used in clinical papers to describe head-cooling interventions. Selective brain cooling is a natural thermoregulatory mechanism in which brain temperature is reduced below carotid blood, defined in the Glossary of terms for thermal physiology. 121 Although applying cooling to the head can reduce brain temperature below body temperature (see Table 1), this is not physiological selective brain cooling.

Because the purpose of therapeutic cooling is to reduce brain temperature, investigators may use head- and brain-related terms to describe cooling, even when they have used systemic methods. Hayashi’s group in Japan for example refer to ‘brain hypothermia therapy’ and ‘cerebral hypothermia’ but they use whole-body cooling. 116,122

The lack of standard terminology makes literature searching more difficult. Key words are variable, if used at all, in relation to cooling method. Medical subject headings (MeSH) do not specifically help in searches for cooling interventions or cooling targeted at particular organs. Gastric hypothermia is the only named method in the MeSH tree structure for therapeutic cooling and brain cooling crosses a number of subject areas. We used MeSH terms within our searches but it would refine indexing and aid searching if cooling interventions were incorporated, at least on the basic level of whether they are invasive or non-invasive, brain directed or systemic.

A helpful consensus has recently been reached on a number of factors related to targeted temperature management in critical care123 and this could usefully be extended to agreeing terminology for cooling methods.

Poor reporting of methods and temperature data

Poor reporting of study methodology and/or temperature data were the main reasons why studies were excluded (see Appendix 6, Characteristics of excluded studies). Poor reporting has ethical implications as well as being frustrating for readers and reviewers. It is a recognised problem that is being actively addressed by the CONSORT (Consolidated Standards of Reporting Trials) group (www.consort-statement.org) with some success. 124

If the studies found for this review, even if not randomised, had reported temperatures satisfactorily there would have been more information on proof of concept of head cooling with regard to temperature reduction. But many did not adequately report the cooling interventions, the temperature outcomes, where temperature was measured or temperature management in control groups (see Appendix 6).

A consensus report from a meeting of five international critical care societies has recently been published, which includes criteria for reporting studies of targeted temperature management in critical care. The therapeutic effect, safety and reproducibility of temperature management should be reported just as with a drug, including:

Accurate reporting of the indication for temperature management, the interval between disease onset and cooling, the management profile, including the rates of decrement and increment as well as the temperatures achieved, and a comprehensive description of the effects on each body system. (p. 1114). 123

Therefore, in addition to rigour in reporting study design,125 information reported in head-cooling studies should include sufficient detail on the cooling method(s) to allow replication, the temperature measurement sites, actual temperatures in intervention and control groups at baseline and with cooling and during rewarming, temperature management strategy (e.g. normothermia or no intervention) and temperature in control groups, and complications/adverse effects from cooling. Providing this information is particularly important because head-cooling research is still largely at the explanatory stage of whether and to what extent different methods reduce temperature.

Chinese studies of head cooling

Twenty-six of the studies on head cooling found for this review were Chinese. The reports were generally relatively short and, unfortunately, none gave sufficient detail on methods to allow trial quality to be adequately assessed or sufficient information on temperature. Poor reporting was also found in a review of leading Chinese medical journals by the Chinese Cochrane Centre. 126 It may be partly explained by lack of formal training in research methods and failure of journals to adopt reporting criteria such as CONSORT,126,127 but is not limited to Chinese trials124 (and see Appendix 6).

Information on the method of randomisation was missing or scanty (e.g. ‘computerised’, ‘number method’) and sample size calculation and whether or not the analysis was on an intention-to-treat basis were not reported. It was unclear if analysis was prespecified and sometimes the time scales of result reporting were ambiguous (days on which blood tests were carried out, for example), which suggested that positive results may have been selected for reporting (e.g. see Xu and colleagues128). None of the Chinese studies reported on blinding of treatment allocation, analysis or outcome assessment. In cooling studies it is not necessarily feasible to blind investigators to treatment allocation but we considered that blinded outcome assessment was important and therefore prespecified in the review protocol that studies in which this was not undertaken would be excluded from the formal analysis.

Recently the Chinese Cochrane Centre conducted a study to assess the adequacy of randomisation of peer-reviewed trials published in Chinese that purported to be RCTs. 129 Trial investigators were interviewed on the telephone and of 2235 studies only 207 (6.8%; 95% CI 5.9% to 7.7%) were found to be authentic RCTs. Most of those interviewed (85.6%) did not fully understand randomisation when they claimed that their trials were randomised. However, 5.1% did understand randomisation and still claimed that their trials were properly randomised when they were not. Although we had limited success in contacting Chinese authors for this review, the corresponding author of one study who did respond said that the trial was not randomised, although in the paper it was reported to be randomised using a randomisation table. 75

Selection bias owing to inadequate randomisation may be one reason for the relatively high proportion of positive results that has been noted in Chinese trials. 129 Those found in the searches for this review were all positive and, although the inadequate reporting of methods has made it impossible to assess their quality, it is plausible that selection bias and bias from unblinded outcome assessment and analysis were contributing factors.

Typically, if hypothermia was the aim, only the target temperature for head cooling was reported or, for reduction of fever, for example, the temperature at which the cooling device was set. The actual temperatures prior to cooling and during induction, maintenance and reversion in the intervention groups were not reported nor was the site of temperature measurement always specified [when it was, this is noted under characteristics of included/excluded studies (see Appendix 6)]. General information on the time to reach target temperature was sometimes provided, for example Yang and colleagues130 noted that it took 30–60 minutes to achieve a brain temperature of 35 °C and 3–4 hours to reach 32–35 °C. The implication is that large reductions in brain temperature can be achieved rapidly with non-invasive head cooling, which could be important and clinically relevant if more detailed information was available. There was also little information on temperature management in control groups, for example normothermia. Most papers simply stated that groups were treated the same with the exception of cooling.

A number of the Chinese stroke studies assessed outcome with the neurological deficiency score (NDS) (see Appendix 6). This is not an assessment of functional outcome and is not considered well validated by the Cochrane Stroke Group. It was not one of our prespecified assessment tools (www.strokecenter.org/trials/scales/scales-overview.htm; accessed 24 April 2011).

Cerebral oedema volume was used as an outcome measure in several Chinese stroke studies and a Japanese stroke study (see Appendix 6), but the methods used were not adequately explained. This was not one of our prespecified outcomes because the validity of cerebral oedema volume as a measure of improvement in brain injury is not established and there is no agreed method of measuring it (e.g. see Degos and colleagues131 and Lescot and colleagues132).

Ethical review and informed consent was not always reported in the Chinese studies. Medical ethics in China has been described as ‘anaemic’, a state of affairs attributed to there having been no equivalent to the Nuremberg Code because Second World War atrocities were not addressed, as they were in Europe by the Nuremberg Trials. 133 However, there have been considerable developments in medical research ethics in China since the 1990s, which include the requirement for ethical review. 134 But there are philosophical differences between the principle of individual autonomy on which ethics in Europe and North America are based, and the traditional Chinese focus on ‘social harmony over individual interests’ (p. 1867). 134 No single approach necessarily has the monopoly on ethical ‘correctness’ and sensitivity to cultural differences is important. 135

Medical treatment is not free in China. 136 Hospitals receive little government subsidy and therefore have to sell services. Drugs and medical consumables in particular are relatively expensive and may be subject to corrupt pricing,137 and corrupt purchasing and prescribing in hospitals. 138 The issue of cost was touched on in some of the Chinese study reports and has implications for trial validity. In one study, patients who were allocated to head cooling but could not afford the head-cooling device were cooled with ice packs. 139 Ou and colleagues140 investigated different durations of head cooling and noted that longer cooling increased the cost for patients. This also meant that the timing of patients’ discharge from hospital was not necessarily dictated by their condition but by their ability to pay for continued care, which is a potentially confounding factor in studies where functional or neurological outcome after head cooling was followed up on hospital discharge (e.g. see Dong and colleagues141).

This is not intended to single out Chinese studies for special criticism: it just happens that they formed a large proportion of the studies found by searches for this review. In summary, what we found with regard to reporting quality in the Chinese studies is consistent with a recent systematic review of the quality of Chinese RCTs142 and a review of reporting quality in leading Chinese medical journals,126 both undertaken by the Chinese Cochrane Centre. There are initiatives to improve trial conduct and reporting in China, and such initiatives are already having an effect elsewhere, although reporting is still not all that it should be. 143

Potential biases in the review process

This systematic review addresses clear research questions and used predefined inclusion criteria to select and appraise studies. We conducted extensive and sensitive searches but the possibility of publication bias remains. There may be, for example, more trials published in Chinese journals than we found. The majority of the trials found were small and/or, on the basis of the reports, of low methodological quality. If the trial reports did not reflect the true quality of the trials then it is possible that there are excluded trials that should have been included.

Agreements or disagreements with other reviews

Four previous reviews of head cooling were found: two, published in Chinese, in patients with cerebral haemorrhage,144,145 one that included human and animal studies in TBI146 and one that included human and animal studies in TBI, stroke, cardiac arrest and neonatal HIE. 23 None were systematic.

No head-cooling studies were included in the most recent Cochrane systematic reviews on hypothermia for traumatic head injury,15 modest cooling therapies (35 °C to 37.5 °C) for TBI,13 and cooling therapy for acute stroke (ischaemic or haemorrhagic). 14 Sydenham and colleagues15 excluded two head-cooling studies, one75 because the cooling intervention was of < 12 consecutive hours’ duration, the other147 was not a RCT, another study76 was awaiting assessment. Saxena and colleagues13 excluded five head-cooling studies46,47,50,76,147 for physiological end points46,47, methodological reasons76 and target temperature outside the review scope,50,147 respectively. den Hertog and colleagues14 excluded three head-cooling studies50,148,149 because the outcome measures were not relevant to the review (relevant outcome measures were functional outcome, mortality, mean temperature 24 hours after start of cooling, cerebral haemorrhage, complications).

Contribution of authors

Bridget Harris (Research Fellow, University of Edinburgh, and Clinical Research Specialist, Critical Care, NHS Lothian) managed the project, carried out the searches, wrote to investigators and manufacturers, organised obtaining individual patient data for the economic model and cleaned the data set, screened studies that were obtained on the searches for inclusion, extracted data, compiled the presentation of the data, undertook the presentation of the results to the public, and wrote the report.

Peter Andrews (Consultant, Critical Care Services and Honorary Professor, University of Edinburgh) assisted with project management, and provided expert opinion for the economic model, screening of studies for inclusion, extraction of data, and writing of the report.

Gordon Murray (Professor of Medical Statistics, University of Edinburgh) gave statistical and methodological advice and support, and assisted with writing the report.

John Forbes (Reader in Health Economics, University of Edinburgh) supervised the economic modelling and contributed to the report.

Owen Moseley (Health Economist, NHS Ayrshire and Arran) researched and wrote the exploratory model on cost-effectiveness of head cooling in patients with TBI.

Thanks to those who helped

We are most grateful to:

Brenda Thomas, Cochrane Stroke Group Trials Search Co-ordinator, for essential expert guidance and help with the searches and for searching the Cochrane Stroke Group trial register.

Karen Blackhall, Cochrane Injuries Group Trials Search Co-ordinator, for searching the Cochrane Injuries Group trial register.

Dr Cathie Sudlow, Mike McDowell, Dr Alasdair FitzGerald, Angela Kellacher and Lillian Ford for help sourcing individual patient outcome data in stroke and TBI.

Dr Wai Kwong for invaluable assistance with papers written in Chinese.

Dr Carlotta Bagna, Alison Bruce, Cristina Guarrera and Junko MacKenzie for assistance with papers written in Italian, German, Russian and Japanese, and Dora Wirth (Languages) Ltd for Russian and Chinese translations.

The members of the public who commented on, and discussed the findings of, the review.

We are also grateful to the following investigators and companies who did respond to our requests for information: Dr Jasmin Arrich; Dr Denise Barbut (Benechill Inc.); Dr Lucian Covaciu; Professor Wang Desheng; Dr Kenji Dohi; Dr Hinnerk Doll; Dr Inan Guler; Dr Rainer Kollmar; Dr Sven Poli; Dr Wusi Qiu; Professor Claudia Robertson; Dr Muzaffar Siddiqui; Professor Martin Smrcka; Professor Fritz Sterz; Dr Yoshimasa Takeda; Dr Frank Tortella; Dr William Walsh; Dr Huan (John) Wang; Ioannis Anastasakis, TechNiche International; Heidi Hughes, Cincinnati Sub-Zero Products Inc.; Becky Inderbitzen, Benechill Inc.; Richard Paxman, Paxman Coolers Ltd; Polar Products, Inc.; Susanne Richard, TraumaTec Inc.; Lindsay Shearer, Genesys Medical Solutions (UK) Ltd (Olympic Cool-Cap); Martin Waleij, Dignitana; and Todd Yelavich, Penguin Cold Caps NZ Ltd.

Disclaimers

The views expressed in this publication are those of the authors and not necessarily those of the HTA programme or the Department of Health.

Detailed project description

Systematic Review of Head Cooling in Adults after Traumatic Brain Injury and Stroke (Project Reference: 07/37/32)

Justification of support required

We are asking for salary for Bridget Harris (6 months WTE MH50, 70) and a contribution to time for Professor Andrews (6 weeks WTE), Professor Murray and Dr Forbes (4 weeks WTE each) over the 18 months we expect it will take us to complete the review. We believe this represents good value because we are deploying our time and expertise cost-effectively, with the least expensive member of the team (the lead applicant) having the largest workload but well supervised by the more experienced members with their excellent specialist skills.

The only NHS costs are Professor Andrews’ time which is costed at current Consultant National Rates.

Seven days consultancy costs for members of the Cochrane Stroke Group at £300/day are required for support with searches and conduct of the review (total £2100).

Dr Forbes will supervise the economic analysis with ten days assistance from an economics/operations research graduate with experience of decision modelling at £300/day (total £3000). For this analysis a software license (TreeAge Pro Suite) is required at a cost of £350.

We have estimated £3000 for translation costs. This is based on possibly requiring 6 papers of 3–3500 words each to be translated at a cost of £150/1000 words. It is hard to obtain translation costs without having the papers, but the cost/1000 words is based on discussion with the Cochrane Stroke Group, the School of Literature, Languages and Culture at the University of Edinburgh and commercial translating services.

We have estimated £300 for interlibrary loans and photocopying, although we aim to work electronically whenever possible in order to reduce paper use and avoid adding to greenhouse gas emissions.

FIGURE 1.

Flow diagram. Based on the QUORUM statement. 55

Major international medical bibliographic databases

British Nursing Index (BNI) and BNI Archive 1985 to May 2010 (last update)

Web of Science Conference Proceedings Citation Index-Science (CPCI-S) 1990 to 19 July 2010

After some initial investigation the search was confined to conference proceedings and did not include science citations, as these were likely to be found on other databases.

The Cochrane Library

Last update: CENTRAL, DARE, HTA, NHS EED 2011 Issue 1.

Last update: CDSR 2011 Issue 3.

Cochrane Central Register of Controlled Trials (CENTRAL)

Cochrane Database of Systematic Reviews (CDSR)

Database of Abstracts of Reviews of Effects (DARE)

Health Technology Assessment (HTA) database

NHS Economic Evaluation Database (EED)

Search terms for CENTRAL (search terms for CDSR, DARE, HTA, EED based on CENTRAL search terms):

1. #1 MeSH descriptor hypothermia this term only

2. #2 MeSH descriptor hypothermia, induced this term only

3. #3 MeSH descriptor cryotherapy this term only

4. #4 MeSH descriptor Cold Temperature this term only

5. #5 MeSH descriptor Ice this term only

6. #6 MeSH descriptor Refrigeration this term only

7. #7 MeSH descriptor Extreme Cold this term only

8. #8 MeSH descriptor Fever this term only with qualifiers: TH

9. #9 MeSH descriptor Shivering this term only

10. #10 (low* in Title, Abstract or Keywords near/6 temperature * in Title, Abstract or Keywords)

11. #11 (reduc* in Title, Abstract or Keywords near/6 temperature * in Title, Abstract or Keywords)

12. #12 (hypotherm* in Title, Abstract or Keywords or normotherm* in Title, Abstract or Keywords)

13. #13 (cool* in Title, Abstract or Keywords or cold in Title, Abstract or Keywords or chill* in Title, Abstract or Keywords or RapidCool in Title, Abstract or Keywords or QuickCool in Title, Abstract or Keywords or Rhinochill in Title, Abstract or Keywords or Benechill in Title, Abstract or Keywords or CoolSystems in Title, Abstract or Keywords)

14. #14 (fan in Title, Abstract or Keywords or fans in Title, Abstract or Keywords or fanned in Title, Abstract or Keywords or fanning in Title, Abstract or Keywords)

15. #15 (cryother* in Title, Abstract or Keywords or cryogen* in Title, Abstract or Keywords or cryotreat* in Title, Abstract or Keywords)

16. #16 (ice in Title, Abstract or Keywords or icy in Title, Abstract or Keywords or iced in Title, Abstract or Keywords or ice-pack in Title, Abstract or Keywords or icepack in Title, Abstract or Keywords or refrigerat* in Title, Abstract or Keywords or froz* in Title, Abstract or Keywords or freez* in Title, Abstract or Keywords)

17. #17 (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16)

18. #18 MeSH descriptor Brain explode all trees

19. #19 MeSH descriptor Head explode all trees

20. #20 MeSH descriptor Skull explode all trees

21. #21 (head in Title, Abstract or Keywords or cranium in Title, Abstract or Keywords or cranial in Title, Abstract or Keywords or skull in Title, Abstract or Keywords or scalp in Title, Abstract or Keywords or face in Title, Abstract or Keywords)

22. #22 (brain in Title, Abstract or Keywords or intracranial in Title, Abstract or Keywords or cerebral in Title, Abstract or Keywords or cortex in Title, Abstract or Keywords or cortical in Title, Abstract or Keywords or forebrain in Title, Abstract or Keywords or hemispher* in Title, Abstract or Keywords)

23. #23 (neck in Title, Abstract or Keywords or pharyn* in Title, Abstract or Keywords or nasopharyn* in Title, Abstract or Keywords or naso-pharyn* in Title, Abstract or Keywords or airway* in Title, Abstract or Keywords)

24. #24 (intra-nasal in Title, Abstract or Keywords or intranasal in Title, Abstract or Keywords or nasal in Title, Abstract or Keywords or transnasal in Title, Abstract or Keywords or trans-nasal in Title, Abstract or Keywords or nose in Title, Abstract or Keywords or nostril* in Title, Abstract or Keywords or naso-oral in Title, Abstract or Keywords or nasooral in Title, Abstract or Keywords or oro-nasal in Title, Abstract or Keywords or oronasal in Title, Abstract or Keywords)

25. #25 (hat in Title, Abstract or Keywords or helmet in Title, Abstract or Keywords or cap in Title, Abstract or Keywords or hood in Title, Abstract or Keywords or collar in Title, Abstract or Keywords)

26. #26 (#18 or #19 or #20 or #21 or #22 or #23 or #24 or #25)

27. #27 (#17 and #26)

28. #28 MeSH descriptor cerebrovascular disorders explode all trees

29. #29 (stroke in Title, Abstract or Keywords or poststroke in Title, Abstract or Keywords or post-stroke in Title, Abstract or Keywords or cerebrovasc* in Title, Abstract or Keywords or “brain vasc*” in Title, Abstract or Keywords or “cerebral vasc*” in Title, Abstract or Keywords or cva* in Title, Abstract or Keywords or apoplex* in Title, Abstract or Keywords or SAH in Title, Abstract or Keywords)

30. #30 (brain* in Title, Abstract or Keywords or cerebr* in Title, Abstract or Keywords or cerebell* in Title, Abstract or Keywords or cortical in Title, Abstract or Keywords or vertebrobasilar in Title, Abstract or Keywords or hemispher* in Title, Abstract or Keywords or intracran* in Title, Abstract or Keywords or intracerebral in Title, Abstract or Keywords or infratentorial in Title, Abstract or Keywords or supratentorial in Title, Abstract or Keywords or MCA in Title, Abstract or Keywords or “anterior circulation” in Title, Abstract or Keywords or “posterior circulation” in Title, Abstract or Keywords or “basal ganglia” in Title, Abstract or Keywords)

31. #31 (isch* in Title, Abstract or Keywords or infarct* in Title, Abstract or Keywords or thrombo* in Title, Abstract or Keywords or emboli* in Title, Abstract or Keywords or occlus* in Title, Abstract or Keywords or hypox* in Title, Abstract or Keywords or vasospasm in Title, Abstract or Keywords)

32. #32 (#31 and #31)

33. #33 (brain* in Title, Abstract or Keywords or cerebr* in Title, Abstract or Keywords or cerebell* in Title, Abstract or Keywords or intracerebral in Title, Abstract or Keywords or intracran* in Title, Abstract or Keywords or parenchymal in Title, Abstract or Keywords or intraventricular in Title, Abstract or Keywords or infratentorial in Title, Abstract or Keywords or supratentorial in Title, Abstract or Keywords or “basal gangli*” in Title, Abstract or Keywords or subarachnoid in Title, Abstract or Keywords)

34. #34 (haemorrhage* in Title, Abstract or Keywords or hemorrhage* in Title, Abstract or Keywords or haematoma* in Title, Abstract or Keywords or hematoma* in Title, Abstract or Keywords or bleed* in Title, Abstract or Keywords)

35. #35 (#33 and #34)

36. #36 (#28 or #29 or #32 or #35)

37. #37 MeSH descriptor Craniocerebral Trauma this term only

38. #38 MeSH descriptor Brain Injuries this term only

39. #39 MeSH descriptor brain concussion explode all trees

40. #40 MeSH descriptor Brain Hemorrhage, Traumatic explode all trees

41. #41 MeSH descriptor Diffuse Axonal Injury this term only

42. #42 MeSH descriptor Epilepsy, Post-Traumatic this term only

43. #43 MeSH descriptor Coma, Post-Head Injury this term only

44. #44 MeSH descriptor Head Injuries, Closed explode all trees

45. #45 MeSH descriptor Head Injuries, Penetrating this term only

46. #46 MeSH descriptor Intracranial Hemorrhage, Traumatic explode all trees

47. #47 MeSH descriptor skull fractures explode all trees

48. #48 MeSH descriptor brain edema this term only

49. #49 (head in Title, Abstract or Keywords or crani* in Title, Abstract or Keywords or cerebr* in Title, Abstract or Keywords or capitis in Title, Abstract or Keywords or brain* in Title, Abstract or Keywords or forebrain* in Title, Abstract or Keywords or skull* in Title, Abstract or Keywords or hemispher* in Title, Abstract or Keywords or intra-cran* in Title, Abstract or Keywords or inter-cran* in Title, Abstract or Keywords)

50. #50 (injur* in Title, Abstract or Keywords or trauma* in Title, Abstract or Keywords or damag* in Title, Abstract or Keywords or wound* in Title, Abstract or Keywords or fracture* in Title, Abstract or Keywords or contusion* in Title, Abstract or Keywords)

51. #51 (#49 and #50)

52. #52 (brain in Title, Abstract or Keywords or cerebral in Title, Abstract or Keywords or intracranial in Title, Abstract or Keywords)

53. #53 (edema in Title, Abstract or Keywords or oedema in Title, Abstract or Keywords or swell* in Title, Abstract or Keywords)

54. #54 (#52 and #53)

55. #55 (TBI in Title, Abstract or Keywords or “diffuse axonal injur*” in Title, Abstract or Keywords)

56. #56 (#37 or #38 or #39 or #40 or #41 or #42 or #43 or #44 or #45 or #46 or #47 or #48 or #51 or #54 or #55)

57. #57 MeSH descriptor Heart Arrest this term only

58. #58 MeSH descriptor Heart Failure explode all trees

59. #59 MeSH descriptor Cardiopulmonary Resuscitation explode all trees

60. #60 MeSH descriptor Resuscitation this term only

61. #61 MeSH descriptor Heart Massage this term only

62. #62 (cardiac in Title, Abstract or Keywords or heart in Title, Abstract or Keywords or cardiopulmonary in Title, Abstract or Keywords or “cardio pulmonary” in Title, Abstract or Keywords or cardio-pulmonary in Title, Abstract or Keywords or circulat* in Title, Abstract or Keywords)

63. #63 (arrest in Title, Abstract or Keywords or resuscita* in Title, Abstract or Keywords or massage in Title, Abstract or Keywords or “life support” in Title, Abstract or Keywords or reanimat* in Title, Abstract or Keywords)

64. #64 (#62 and #63)

65. #65 (#57 or #58 or #59 or #60 or #61 or #64)

66. #66 MeSH descriptor Hypoxia-Ischemia, Brain this term only

67. #67 MeSH descriptor Hypoxia, Brain this term only

68. #68 MeSH descriptor Asphyxia Neonatorum this term only

69. #69 (brain in Title, Abstract or Keywords or cerebral in Title, Abstract or Keywords or global in Title, Abstract or Keywords)

70. #70 (hypox* in Title, Abstract or Keywords or anox* in Title, Abstract or Keywords)

71. #71 (ischaemi* in Title, Abstract or Keywords or ischemi* in Title, Abstract or Keywords)

72. #72 (#69 and #70 and #71)

73. #73 (hypox* in Title, Abstract or Keywords or anox* in Title, Abstract or Keywords)

74. #74 (ischaemi* in Title, Abstract or Keywords or ischemi* in Title, Abstract or Keywords)

75. #75 encephalopath* in Title, Abstract or Keywords

76. #76 (#73 and #74 and #75)

77. #77 (birth in Title, Abstract or Keywords or newborn in Title, Abstract or Keywords or encephalopath* in Title, Abstract or Keywords)

78. #78 (asphyxia* in Title, Abstract or Keywords or “respiratory failure” in Title, Abstract or Keywords)

79. #79 (#77 and #78)

80. #80 (#66 or #67 or #68 or #72 or #76 or #79)

81. #81 MeSH descriptor Infant, Newborn explode all trees

82. #82 (birth in Title, Abstract or Keywords or infant* in Title, Abstract or Keywords or neonat* in Title, Abstract or Keywords or newborn* in Title, Abstract or Keywords or “new born*” in Title, Abstract or Keywords or perinatal in Title, Abstract or Keywords or peri-natal in Title, Abstract or Keywords or baby in Title, Abstract or Keywords or babies in Title, Abstract or Keywords)

83. #83 (#81 or #82)

84. #84 (#80 and #83)

85. #85 (#36 or #56 or #65 or #84)

86. #86 (#27 and #85)

Cochrane specialised trials registers

Other trial registers

Last update: 6 March 2011 all registers.

Search terms: hypothermia and cooling (cool* where truncation was allowed); both terms were searched for separately if OR was not an option.

Ongoing trials were only included as relevant if in stroke or TBI. Trials in cardiac arrest and neonatal HIE which had not completed were excluded.

• World Health Organization International Clinical Trials Registry Platform (WHO ICTR) – this includes:

  1. – Australian New Zealand Clinical Trials Registry

  2. – Chinese Clinical Trial Registry

  3. – Clinical Trials Registry – India

  4. – Clinical Research Information Service - Republic of Korea

  5. – German Clinical Trials Register

  6. – Iranian Registry of Clinical Trials

  7. – Japan Primary Registries Network

  8. – Pan African Clinical Trial Registry

  9. – Sri Lanka Clinical Trials Registry

  10. – The Netherlands National Trial Register.

  11. – [Note: Each of the databases in WHO ICTR was searched individually because Brenda Thomas (Trials Search Co-ordinator Cochrane Stroke Group) had found that when the whole WHO ICTR was searched there were fewer results than when each element was searched individually.]

• Current Controlled Trials: the meta-register of controlled trials and International Standard Randomised Controlled Trial Number (ISRCTN) register

• ClinicalTrials.gov

• National Research Register archive

• Stroke Trials Registry.

Country-specific databases

Web search engines

Reference lists

Reference lists of books on hypothermia and of reviews and relevant studies were searched.

Conference proceedings

We searched the proceedings of all three International Hypothermia Symposia (Tokyo 2004, Miami 2007, Lund 2009) and of the Therapeutic Temperature Management Conference (Barcelona 2008).

Writing to investigators and device manufacturers

Investigators and manufacturers of head-cooling devices were written to with varying success. A read receipt was asked for on e-mails but, unfortunately, even when investigators indicated that they had read the e-mail a reply was not necessarily forthcoming. Manufacturers of devices are perhaps understandably reluctant to release details of ongoing human research, although there were notable exceptions, including Benechill, TraumaTec and Paxman.

The language barrier was a considerable problem in communicating with Chinese investigators, mostly rendering it impossible to make contact. Given the amount of research being undertaken in China and the ongoing work on quality improvement with regard to conduct and reporting, it would seem sensible to include someone who can read and write Chinese and understands the subject area as a member of the review team if at all possible. We have plans to do this for the next iteration of the review.

Patent search

A formal patent search was included in the search strategy in the protocol but was not undertaken owing to lack of time. Nevertheless, we had a number of patents on file as a result of ongoing alerts for head cooling information through Google, and this helped with identifying manufacturers of devices to contact.

References to studies included in this review

References to studies excluded from this review

References to studies in neonatal hypoxic–ischaemic encephalopathy

Akisu M, Huseyinov A, Yalaz M, Cetin H, Kultursay N. Selective head cooling with hypothermia suppresses the generation of platelet-activating factor in cerebrospinal fluid of newborn infants with perinatal asphyxia. Prostag Leukotr Ess 2003;69:45–50.

Alkharfy TM. A simplified method for head cooling: feasibility and safety. J Neonatal Perinat Med 2010;3:127–34.

Battin MR, Dezoete JA, Gunn TR, Gluckman PD, Gunn AJ. Neurodevelopmental outcome of infants treated with head cooling and mild hypothermia after perinatal asphyxia. Pediatrics 2001;107:480–4.

Battin MR, Penrice J, Gunn TR, Gunn AJ. Treatment of term infants with head cooling and mild systemic hypothermia (35.0 degrees C and 34.5 degrees C) after perinatal asphyxia. Pediatrics 2003;111:244–51.

Battin MR, Thoresen M, Robinson E, Polin RA, Edwards AD, Gunn AJ; Cool Cap Trial Group. Does head cooling with mild systemic hypothermia affect requirement for blood pressure support? Pediatrics 2009;123:1031–6.

Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005;365:663–70.

Gunn AJ, Gluckman PD, Gunn TR. Selective head cooling in newborn infants after perinatal asphyxia: a safety study. Pediatrics 1998;102:885–92.

Gunn AJ, Wyatt JS, Whitelaw A, Barks J, Azzopardi D, Ballard R, et al. ; CoolCap Study Group. Therapeutic hypothermia changes the prognostic value of clinical evaluation of neonatal encephalopathy. J Pediatr 2008;152:55–8.

Horn AR, Woods DL, Thompson C, Eis I, Kroon M. Selective cerebral hypothermia for post-hypoxic neuroprotection in neonates using a solid ice cap. S Afr Med J 2006;96:976–81.

Kilani RA. The safety and practicality of selective head cooling in asphyxiated human newborn infants, a retrospective study. J Med Liban 2002;50:17–22.

Kumazawa K, Ibara S, Kobayashi K, Tokuhisa T, Maruyama H, Maede Y, et al. Changes of blood glutamate levels in hypoxic ischemic encephalopathy patients undergoing brain hypothermia. In Hayashi N, Bullock R, Dietrich DW, Maekawa T, Tamura A, editors. Hypothermia for Acute Brain Damage: Pathomechanism and Practical Aspects. Tokyo: Springer Verlag; 2004. pp. 320–4.

Lin ZL, Yu HM, Lin J, Chen SQ, Liang ZQ, Zhang ZY. Mild hypothermia via selective head cooling as neuroprotective therapy in term neonates with perinatal asphyxia:an experience from a single neonatal intensive care unit. J Perinatol 2006;26:180–4.

Liu C-Q, Xia Y-F, Yuan Y-X, Li L, Qiu X-L. Effects of selective head cooling with mild hypothermia on serum levels of caspase-3 and IL-18 in neonates with hypoxic-ischemic encephalopathy. Chin J Contemp Pediatr 2010;12:690–2.

Rutherford MA, Azzopardi D, Whitelaw A, Cowan F, Renowden S, Edwards AD, et al. Mild hypothermia and the distribution of cerebral lesions in neonates with hypoxic-ischemic encephalopathy. Pediatrics 2005;116:1001–6.

Sarkar S, Barks JD, Bhagat I, Dechert R, Donn SM. Pulmonary dysfunction and therapeutic hypothermia in asphyxiated newborns:whole body versus selective head cooling. Am J Perinatol 2009;26:265–70.

Sarkar S, Barks JD, Bhagat I, Donn SM. Effects of therapeutic hypothermia on multiorgan dysfunction in asphyxiated newborns: whole-body cooling versus selective head cooling. J Perinatol 2009;29:558–63.

Shao XM, Zhou WH. Efficacy and safety of selective head cooling with mild systemic hypothermia after neonatal hypoxic ischemic encephalopathy. Hot Topics in Neonatology, 3 December 2005, Washington, DC.

Simbruner G, Haberl C, Harrison V, Linley L, Willeitner AE. Induced brain hypothermia in asphyxiated human newborn infants:a retrospective chart analysis of physiological and adverse effects. Intensive Care Med 1999;25:1111–17.

Thoresen M, Whitelaw A. Cardiovascular changes during mild therapeutic hypothermia and rewarming in infants with hypoxic-ischemic encephalopathy. Pediatrics 2000;106:92–9.

Whitelaw A, Thoresen M. Clinical experience with therapeutic hypothermia in asphyxiated infants. Dev Med Child Neurol Suppl 2001;86:30–1.

Wyatt JS, Gluckman PD, Liu PY, Azzopardi D, Ballard R, Edwards AD, et al. ; CoolCap Study Group. Determinants of outcomes after head cooling for neonatal encephalopathy. Pediatrics 2007;119:912–21.

Zhou W-H. Safety study of hypothermia for treatment of hypoxic-ischemic brain damage in term neonates. Acta Pharmacol Sin 2002;23:64–8.

Zhou W-H, Cheng G, Shao X, Liu X, Shan R, Zhuang D, et al. ; China Study Group. Selective head cooling with mild systemic hypothermia after neonatal hypoxic-ischemic encephalopathy: a multicenter randomized controlled trial in China. J Pediatr 2010;157:367–72.

References to studies awaiting assessment

We have been unable to obtain the papers for the first three of these and have had no response to requests for further information for the other two (see Appendix 6 for further details).

Bunatyan AA, Zolnikov SM, Smirnov OA. [Present day problems of anesthesiology and recovery of consciousness.] [Russian.] L’vov: 1969. p.294.

Bunatyan AA, Zolnikov SM, Smirnov OA. Fourth International Symposium on Anesthesiology, 1969, Varna, Bulgaria, p. 503.

Ioffe YS, Smirnov OA. In Comatose states following cranio-cerebral trauma. Moscow; 1969. p. 126.

Skulec R, Truhlar A, Knor J, Seblova J, Cerny V. The practice of therapeutic mild hypothermia in cardiac arrest survivors in the Czech republic. Minerva Anestesiol 2010;76:617–23.

Skulec R, Truhlar A, Ostadal P, Telekes P, Knor J, Tichacek M, et al. [Current cooling methods for induction of mild hypothermia in cardiac arrest survivors.] Vnitrni Lekarstvi 2009;55:1060–9.

References to ongoing studies

References to other applications of head cooling

Bagic A, Theodore WH, Bonwetsch R, Greenfield J, Sato S. Treating epilepsy with head-neck cooling without sedation. Epilepsia 2005;46:233.

Dougherty L. Comparing methods to prevent chemotherapy-induced alopecia. Cancer Nurs Pract 2006;5:31.

Hato N, Hyodo J, Takeda S, Takagi D, Okada M, Hakuba N, et al. Local hypothermia in the treatment of idiopathic sudden sensorineural hearing loss. Auris Nasus Larynx 2010;37:626–30.

Kramer BA, Kadar AG, Clark K. Use of the Neuro-Wrap system for severe post-electroconvulsive therapy headaches. J ECT 2008;24:152–5.

Macduff C, Mackenzie T, Hutcheon A, Melville L, Archibald H. The effectiveness of scalp cooling in preventing alopecia for patients receiving epirubicin and docetaxel. Eur J Cancer Care 2003;12:154–61.

Massey CS. A multicentre study to determine the efficacy and patient acceptability of the Paxman Scalp Cooler to prevent hair loss in patients receiving chemotherapy. Eur J Oncol Nurs 2004;8:121–30.

Reynolds, L. The effects of head and neck cooling on symptoms of multiple sclerosis. Thesis. Halifax, NS: Dalhousie University; 2007.

Simmons SE, Saxby BK, McGlone FP, Jones DA. The effect of passive heating and head cooling on perception, cardiovascular function and cognitive performance in the heat. Eur J Appl Physiol 2008;104:271–80.

Wickwire PJ, Bishop PA, Green JM, Richardson MT, Lomax RG, Casaru C, et al. Physiological and comfort effects of a commercial ‘cooling cap’ worn under protective helmets. J Occup Environ Hyg 2009;6:455–9.

References to historical reports of head cooling

Bukov VA, Bobkov IG, Smirnov OA, Zol’nikov SM. [The relationship between the temperature of various regions of the brain and the body in craniocerebral hypothermia in clinical practice.] Khirurgiia (Mosk) 1967;43:14–21.

Ioffe I, Sumskii LI. [Cranio-cerebral hypothermia in the treatment of patients with cranio-cerebral injuries.] [Russian.] Zh Vopr Neirokhir Im NN Burdenko 1977;1:9–14.

Ivanov VV, Kolenko EA. [Local and cerebral hypothermia using thermoelectric apparatus in severe craniocerebral trauma.] [Russian.] Vestn Khir Im II Grek 1969;102:105–7.

Lojka J, Kravcova V, Kovacikova E, Gajdosova D, Nadvornik P. [1st experiences with craniocerebral hypothermia.] [Slovak.] Rozhl Chir 1973;52:812–16.

Phelps C. Traumatic injuries of the brain and its membranes. In The classics of neurology and neurosurgery library. New York, NY: Appleton and Company; 1897. pp. 223–4.

Schlag G. Cardiac arrest and resuscitation. Zbl Chir 1962;87:1273–90.

Smirnov O, Meshcherinov I. Analytical method for determination of temperature distribution in the human head during craniocerebral hypothermia induced by ‘Kholod-2F’ apparatus. Biomed Eng 1970;4:192–7.

Ugriumov VM, Zotov I, Bezukh MS. [Cranio-cerebral hypothermia and neuro-vegetative blockade in the systematic treatment of injuries to the skull and brain.] [Russian.] ZhVopr Neirokhir 1975;6:11–17.

Waugh OS. Acute cranial-cerebral injuries. Can Med Assoc J 1926;16:1475–9.

Zhmurko SF. [Cranio-cerebral hypothermia in patients with acute cranio-cerebral injury.] [Russian.] Khirurgiia 1971;47:40–3.

Contents

• Characteristics of included studies:

  1. – traumatic brain injury

  2. – stroke – ischaemic, haemorrhagic, mixed

  3. – brain injury – heterogeneous cerebral problems including TBI and stroke

  4. – cardiac arrest

• Characteristics of excluded studies:

  1. – traumatic brain injury

  2. – stroke – ischaemic, haemorrhagic, mixed

  3. – brain injury – heterogeneous

  4. – cardiac arrest

  5. – studies in volunteers

• Studies awaiting assessment:

  1. – randomised controlled trials

  2. – other studies

• Characteristics of ongoing studies:

  1. – stroke

  2. – brain injury.

Within these headings, papers are listed in date (oldest first) and then alphabetical order. The full reference details for all the papers in this appendix can be found in Appendix 5.

Studies in neonatal HIE were included in the report only if they provided information on complications/adverse effects/advantages of head cooling and are not included in Characteristics of studies. The studies are listed in Appendix 5 (see References to studies in neonatal hypoxic–ischaemic encephalopathy).

Characteristics of included studies

Characteristics of excluded studies

Studies awaiting assessment

Characteristics of ongoing studies

Ongoing studies of head cooling in cardiac arrest are not included.

Contents

• Introduction.

• Heat loss from the upper airways.

  1. – Convective head-cooling methods and devices: nasal gas/nebulised coolant.

  2. – Active conductive (liquid) head-cooling methods and devices: nasal and pharyngeal balloons.

• Heat loss through the skull.

  1. – Convective head-cooling methods and devices (air or water directed on the head).

  2. – Active conductive (liquid) head-cooling devices (circulating cold fluid).

  3. – Passive (non-circulating)conductive head-cooling methods and devices.

• Scalp-cooling devices.

  1. – Liquid (active) scalp-cooling caps.

  2. – Frozen gel (passive) scalp-cooling caps.

• Non-invasive neck-cooling devices.

• Personal cooling garments.

Introduction

Devices included in this appendix are those that have been developed for brain injury or cardiac arrest or have been used in patients with these conditions. Where there is a current web address for companies this has been included to provide some indication of which devices are ‘active’.

Methods of non-invasive head cooling are categorised into:

• Heat loss from the upper airways By convection with gas or fluid flow or by conduction with nasal or pharyngeal balloons. Whether or not the devices used are truly non-invasive is a moot point.

• Heat loss through the skull By convection (fanning, hoods/caps delivering cold air or water) or by conduction (active, e.g. liquid cooling, or passive, e.g. ice, gel caps). Some of the devices also have a neck band, which, theoretically, may help cool the brain by reducing the temperature of the carotid blood supply. 24,25

Liquid (active) cooling helmets contain circulating water with and without antifreeze. Heat from the head is transferred by conduction through the helmet wall and then removed by the circulating coolant. 202 They have the benefit of being able to be maintained at a constant temperature and some have the facility for temperature adjustment. This is potentially important because there is a possibility of tissue freezing and necrosis if scalp temperature is reduced too much. Passive (non-circulating) cooling caps, containing frozen gel, for example, will thaw and have to be refrozen periodically but are simple and relatively inexpensive. The cheapest method is ice packs round the head. However, whether active or passive, the helmet/cap needs to be in close contact with the scalp for optimum heat removal and may be pressurised to achieve this.

With the possible exception of the liquid cooling device developed at Harbin Medical University in China, no head-cooling devices described here have automatic (closed-loop) temperature feedback. In a comparative study of systemic cooling devices, those with automatic temperature control were shown to be more effective and less labour intensive than manually controlled devices. 17

At the end of this appendix there are brief sections on scalp-cooling devices, which have sometimes been used in brain injury, non-invasive neck-cooling devices and personal cooling garments.

Neonatal head-cooling devices are not included here because they are unsuitable for adults, for example the Olympic Cool-Cap (Natus Medical Inc., San Carlos, CA, USA) is specifically designed and sized for neonates. For reviews that include examples of head-cooling techniques used in neonatal HIE see Thoreson,203 which includes an early method used in the USSR comprising induction by cold water spray over the head and maintenance with a liquid cooling cap, and also Robertson and colleagues,204 which includes the Olympic Cool-Cap and some low-technology methods including fans and water bottles.

Heat loss from the upper airways

Convective head-cooling methods and devices: nasal gas/nebulised coolant

Nasopharyngeal cooling through a Foley catheter (Figure 3)

Mellergard184 cut off the tip of a Foley catheter at an angle and passed the catheter through the patient’s nostril with the opening facing upwards. The balloon was inflated with sodium chloride 0.9% and the catheter pulled back until the balloon stopped behind the choane nasi. Oxygen at 5–10 l/minute was flowed through the catheter via a copper coil in a bucket of iced water.

FIGURE 3.

‘A schematic figure of how nasopharyngeal cooling was attempted through a Foley catheter positioned behind the choane nasi. As seen in the inserted rectal and intraventricular temperature curves, nasopharyngeal cooling had very limited effect on brain temperature’184 (figure 2). Reproduced with permission from Mellergard P. Changes in human intracerebral temperature in response to different methods of brain cooling. Neurosurgery 1992;31:671–7.

Reproduced with permission from Mellergard P. Changes in human intracerebral temperature in response to different methods of brain cooling. Neurosurgery 1992;31:671–7.

Placing the catheter this for back completely bypassed the nose and therefore did not utilise its capacity for heat loss which may partly explain the lack of cooling effect. However, in patients with a base of skull fracture this might mean less risk of pneumocephalus but the method would still be contraindicated because passing the catheter through the nose could risk worsening the fracture or the catheter entering the brain.

Thermo-radiating brain cooling (Figure 4)

A cooling induction method used by Dohi and colleagues;63,175,176 8–12 l/minute chilled air (24 °C) via a 16 fg Foley ‘balloon’ catheter in one nostril, the other nostril was occluded with an epistaxis balloon and the air exited through the mouth. It is not completely clear but it seems that the Foley catheter balloon was inflated to prevent air leaking back out of the nostril, which may have reduced the heat loss from the nose and contributed to nasal erosion. 63 The importance of enabling the air to exhaust from the mouth is emphasised. 175 This method is contraindicated with base of skull fracture and sinusitis. 63

FIGURE 4.

(a) Thermo-radiating Brain Cooling (TRBC) was performed by nasopharyngeal cooling. (b) Scheme of TRBC: artificial nasopharyngeal circulation with chilled air (24 °C, 9–12 l/minute)175 (figure 2, p. 431). Reproduced with permission from Dohi K, Jimbo H, Ikeda Y, Matsumoto K. Pharmacological brain cooling (PBC) by indomethacin; a non-selective cyclooxygenase (COX) inhibitor in acute hemorrhagic stroke. Nosotchu 2000;22:429–34.

Reproduced with permission from Dohi K, Jimbo H, Ikeda Y, Matsumoto K. Pharmacological brain cooling (PBC) by indomethacin; a non-selective cyclooxygenase (COX) inhibitor in acute hemorrhagic stroke. Nosotchu 2000;22:429–34.

Bilateral nasal airflow

Continuous bilateral nasal airflow was used in two crossover trials in brain-injured patients. 46,47 In the first trial the air was delivered through a sponge-tipped oxygen catheter in each nostril, at room temperature and humidity and a rate of 115 ml/kg/minute (approximating normal, resting minute volume). 46 In the second, unhumidified air from the compressed air supply at twice the patients’ minute ventilation volumes, plus 20 parts per million (ppm) nitric oxide gas (mucosal vasodilatation to facilitate heat loss), and an 85-g lead weight over the facial vein on each side of the nose, to facilitate intracranial venous drainage, considered important in heat loss from the upper airway. Two methods of delivery were used. First, a Whispaflow valve with a paediatric (uncuffed) tracheal tube in each nostril and, second (and more successfully from the ease of delivery point of view), a double-airflow meter with oxygen tubing in each nostril. 47 Nasal airflow is contraindicated with base of skull fracture and possibly with facial fractures.

Rhinochill Intranasal Cooling System (Benechill Inc., San Diego, CA, USA): www.benechill.com/ (Figures 5 and 6)

This is a portable, battery-powered nasal cooling device that is primarily intended for induction of cooling, particularly pre-hospital in patients experiencing cardiac arrest. Bilateral nasal prongs (with rounded tips and spray ports on the dorsal surface) are inserted and inert perfluorocarbon coolant mixed with oxygen is nebulised in the nasal cavity where it evaporates, removing heat in the process. Gas exits through the nostrils or mouth along with any perfluorocarbon, which does not evaporate. There is an overpressure relief valve. There is no closed-loop temperature feedback. It is not designed for prolonged use (about 1 hour) and perfluorocarbon is expensive. Rhinochill has been trialled in humans after cardiac arrest49,59 and used in brain-injured patients. 54 Contraindications to use include base of skull, and possibly nasal and orbital, fractures and an unprotected airway.

FIGURE 5.

The Rhinochill device. Photo reproduced with permission from Benechill Inc., www.benechill.com.

Photo reproduced with permission from Benechill Inc., www.benechill.com.

FIGURE 6.

Rhinochill device. (a) Tubing set. (b) Control unit59 (figure 1, p. 944). Reprinted from Resuscitation81. Busch H-J, Eichwede F, Fodisch M, Taccone FS, Wobker G, Schwab T, et al. Safety and feasibility of nasopharyngeal evaporative cooling in the emergency department setting in survivors of cardiac arrest, 943–9, 2010, with permission from Elsevier.

Reprinted from Resuscitation 81. Busch H-J, Eichwede F, Fodisch M, Taccone FS, Wobker G, Schwab T, et al. Safety and feasibility of nasopharyngeal evaporative cooling in the emergency department setting in survivors of cardiac arrest, 943–9, 2010, with permission from Elsevier.

Rapid hypothermia induction device (Figure 7)

This device has been developed for use pre-hospital by biomedical engineering students and Professor Harikrishna Tandri at Johns Hopkins University. It consists of an air tank, a pressure regulator and control mechanism, and two nasal prongs that are inserted into the nostrils. Cold, dry air is flushed through the nostrils to increase evaporative heat loss from the nose and cool the brain. Animal tests have been carried out but we have had no response to a request for information on whether human testing has been conducted.

FIGURE 7.

The Rapid Hypothermia Induction Device, in development at Johns Hopkins University, is used by emergency or ambulance personnel to rapidly administer therapeutic hypothermia treatment to victims of cardiac arrest. Reproduced with permission from http://nciia.org/bmeidea2010 (accessed 4 March 2011).

Active conductive (liquid) head-cooling methods and devices: nasal and pharyngeal balloons

QuickCool Intranasal System (QuickCool AB, Lund, Sweden): www.quickcool.se/ (Figures 8 and 9)

This device comprises a portable pump and single patient use thin-walled balloon catheters. The catheters are inserted bilaterally into the nostrils and perfused with cold saline to cool the brain and to a lesser extent the body. There is no closed-loop temperature feedback. The device has been tested in healthy volunteers,65 used in patients206 and is currently being trialled in cardiac arrest, TBI and subarachnoid haemorrhage (SAH) (see Appendix 5, References to ongoing studies). The healthy volunteer testing (n = 9) used magnetic resonance spectroscopy to measure brain temperature: ‘After 60 minute of intranasal cooling brain temperature reduction was –1.7 ± 0.8 °C as measured by MRSI and –1.8 ± 0.9 °C as measured by phase mapping method’ (p. 36). 65

FIGURE 8.

Photo: QuickCool AB, Lund.

FIGURE 9.

‘Schematic representation of the cooling circuit used. Cold saline fills the nasal balloons by gravity and is actively aspirated by pumps in order to be directed through the heat-exchanger machine. The height of the bag related to nasopharynx is proportional to the pressure inside the balloons’205 (figure 1, p. 85). Reproduced from Resuscitation 76. Covaciu L, Allers M, Enblad P, Lunderquist A, Wieloch T, Rubertsson S. Intranasal selective brain cooling in pigs, 83–8, 2008, with permission from Elsevier.

Reproduced from Resuscitation 76. Covaciu L, Allers M, Enblad P, Lunderquist A, Wieloch T, Rubertsson S. Intranasal selective brain cooling in pigs, 83–8, 2008, with permission from Elsevier.

Pharyngeal cooling cuff (Daiken Medical Company Ltd, Japan): www.daiken-iki.co.jp/ (Figures 10 and 11)

This is designed for use in cardiac arrest. 207 The pharyngeal cooling cuff is inserted into the pharynx after tracheal intubation and saline at 5 °C is circulated through it at 500 ml/minute at a pressure of 50 cmH₂O. There is no closed-loop temperature feedback. The close proximity of the carotids to the pharynx is said to facilitate cooling of carotid blood and thence the brain.

FIGURE 10.

Pharyngeal cooling. Reproduced with permission from www.cc.okayama-u.ac.jp/∼cool/e-intou.html (accessed 17 April 2011).

FIGURE 11.

Pharyngeal cooling cuff: equipped with pressure and temperature sensors that transmit perfusion data to the circulator. Reproduced with permission from www.cc.okayama-u.ac.jp/∼cool/e-cuff.html (accessed 17 April 2011).

This cooling device was used during resuscitation after cardiac arrest in the Japanese i-Cool trial, which has completed but not reported yet [www.controlled-trials.com/ISRCTN98089900 (accessed 4 March 2011)]. A significant decrease in tympanic temperature was shown and another trial is planned to look at neurological outcome (Dr Yoshimasa Takeda, Principal Investigator, Okayama University Medical School, Okayama, Japan, 18 April 2011, personal communication).

Pharyngeal cooling device, Germany

A German pharyngeal device that circulates cool water has been tested in rats. 208,209 There is no human research as yet (Dr Doll, University of Witten-Herdecke, Cologne, Germany, 18 April 2011, personal communication).

Heat loss through the skull

Convective head-cooling methods and devices (air or water directed on the head)

Head fanning

Fanning the head or face with ambient air using electric fans is a simple and relatively cheap method of cooling the head. It does not produce large brain temperature reductions47 and will not on its own induce hypothermia but may help to reduce fever. 66 Face fanning can be uncomfortable. 197 Bilateral head fanning doubles the airflow and increases turbulence around the head, which will increase heat loss. It is sometimes assumed that the use of fans in ICU is associated with infection risk,67 but a review found no published data showing that electric fans spread infection in clinical areas. 68

RapidCool Hypothermia System (MedCool Inc., Wellesley, MA, USA) (Figure 12)

This device (United States Patent 7507250) was tested in patients after cardiac arrest but is not commercially available. It ‘… directs jets of cold water (1 °C to 4 °C) through the hair directly to the scalp. Water is removed from the cooling cap by an aspiration system located about the inner rim of the cap, fixed just above the ears of the patient’ (p. 461). 194

FIGURE 12.

MedCool rapid head-cooling device194 (figure 1, p. 461). Reproduced from Am J Emerg Med 27. Wandaller C, Holzer M, Sterz F, Wandaller A, Arrich J, Uray T, et al. Head and neck cooling after cardiac arrest results in lower jugular bulb than esophageal temperature, 460–5, 2009, with permission from Elsevier.

Reproduced from Am J Emerg Med 27. Wandaller C, Holzer M, Sterz F, Wandaller A, Arrich J, Uray T, et al. Head and neck cooling after cardiac arrest results in lower jugular bulb than esophageal temperature, 460–5, 2009, with permission from Elsevier.

Kholod 2, Kholod 2-F and Thermokholod FV devices, USSR (Figures 13–17)

These are variations of a convective head-cooling device using water or water and alcohol [Kholod 2 (Figure 13) and 2-F (Figures 14 and 15)] and air [Thermokholod FV (Figure 16)], respectively. They were developed in the USSR in the mid-1960s and used in TBI, cerebral hypoxia (e.g. after cardiac arrest), epilepsy and surgery and do not seem to have had closed-loop temperature feedback. 96,97,210,211 Very limited patient data are reported, although ‘many clinical trials’ are mentioned. 210 Smirnov says of the Thermokholod FV that ‘As clinical tests have shown, the brain can be cooled at various controlled rates (up to 0.3 °C/minute) and the reduced temperature continuously maintained with an accuracy of ± 0.5 °C’ (p. 259). 211 The Kholod 2 and 2-F could also be used for warming. Because body temperature reduced as a result of head cooling, Smirnov and colleagues210 developed two body-warming devices – one electric and one using air delivered through a transparent ‘tent’ weighted at the sides (Figure 17) – to maintain body temperature (31–36 °C) during head cooling or for warming during surgery. 210 The electric body-warming device had closed-loop temperature control to the patient’s rectal temperature.

FIGURE 13.

Diagram of Kholod 2 helmet. Apparatus for cooling (heating) of the brain (helmet). 1, Main pipe; 2, openings for escape of heat carrier; 3, hollow elements (tubes); 4, collector; 5, stops restricting length of flow210 (figure 2, p. 344). Smirnov O. New method for cooling (or heating) of the body and an apparatus for craniocerebral hypothermia. Biomed Eng 1968;2:343–7. With kind permission from Springer Science and Business Media.

Smirnov O. New method for cooling (or heating) of the body and an apparatus for craniocerebral hypothermia. Biomed Eng 1968;2:343–7. With kind permission from Springer Science and Business Media.

FIGURE 14.

The ‘Kholod 2-F’ cold unit. 1, Control panel; 2, access door; 3, casing; 4, front wheel locking lever; 5, carrying handles; 6, collecting chamber for heat carrier; 7, helmet210 (figure 3, p. 345). Smirnov O. New method for cooling (or heating) of the body and an apparatus for craniocerebral hypothermia. Biomed Eng 1968;2:343–7. With kind permission from Springer Science and Business Media.

Smirnov O. New method for cooling (or heating) of the body and an apparatus for craniocerebral hypothermia. Biomed Eng 1968;2:343–7. With kind permission from Springer Science and Business Media.

FIGURE 15.

Kholod 2-F device Photo: RIA Novosti 01.11.1970. Reproduced with permission from http://visualrian.com/images/item/31265 (accessed 8 March 2011).

FIGURE 16.

The air and Freon system of the ‘Thermokholod FV’ apparatus. 1, VS-0.7–3 refrigerating plant; 2, heat exchanger; 3, TRV-2M heat-regulating valve; 4, centrifugal ventilator; 5, lower air pressure conduit; 6, upper air pressure conduit; 7, intake air conduit; 8, apparatus for jet cooling; 9, air collector211 (figure 3, p. 258). Smirnov O. A method of increasing the efficiency of air hypotherms and an apparatus for craniocerebral cooling. Biomed Eng 1969;3:257–60. With kind permission from Springer Science and Business Media.

Smirnov O. A method of increasing the efficiency of air hypotherms and an apparatus for craniocerebral cooling. Biomed Eng 1969;3:257–60. With kind permission from Springer Science and Business Media.

FIGURE 17.

Apparatus for air heating (cooling) of the body. 1, Hot-air machine; 2, flexible hose; 3, funnel; 4, weights; 5, pneumatic casing; 6, ties210 (figure 5, p. 345). Smirnov O. New method for cooling (or heating) of the body and an apparatus for craniocerebral hypothermia. Biomed Eng 1968;2:343–7. With kind permission from Springer Science and Business Media.

Smirnov O. New method for cooling (or heating) of the body and an apparatus for craniocerebral hypothermia. Biomed Eng 1968;2:343–7. With kind permission from Springer Science and Business Media.

The complete ‘craniocerebral hypothermy’ system therefore consisted of three separate units: the head cooling (or warming) unit (Kholod 2, Kholod 2-F or Thermokholod FV), the body warming (or cooling) unit and a temperature measurement unit which could measure four temperatures (tympanic membrane, nasopharynx, oesophagus and rectum). It seems that intracranial temperature was inferred from tympanic temperature on the basis of experimental data in dogs.

The Kholod 2 and 2-F units are described by Smirnov. 210 They used water, or a 10–20% mixture of water and alcohol, as a coolant and had a helmet with a collecting chamber, an electric pump, a heat exchanger and a temperature controller, housed in a wheeled cabinet. The helmet was specially moulded to the head (anthropologists were consulted over the shape so that it would fit a range of head sizes) and had evenly distributed tubes, with openings on the head side and the coolant collecting chamber, which also acted as a head rest, under the head. The helmet was adjusted to the patient’s head by a hinge and with the collecting chamber was height adjustable; in the Kholod 2-F these were detachable. Coolant was pumped through the heat exchanger into the top of the helmet, through the tubes and sprayed out perpendicularly onto the head. ‘Stops’ restricted the reach of the coolant jets – quite how is not clear but presumably this was to avoid liquid spraying beyond the helmet. The coolant drained into the collecting chamber, which had openings for this purpose, and was recirculated. Coolant temperature could be automatically controlled between –3°C and +14°C during cooling and between 33°C and 43°C during warming. This method of head cooling was said to be more effective than other methods, such as rubber helmets, because it was convective rather than conductive and overcame ‘adverse conditions produced by the hair’.

The Thermokholod FV (Figure 16) blew cold air over the head and could be used over head dressings. 211 It seems to have been developed to avoid the problems associated with spraying water on the head in the presence of wounds. Air was delivered to the surface of the head in a way that broke up the current: ‘… into separate streams and distributed them evenly over the treated surface in such a way as to ensure run-off of “exhausted” air. In this way breakdown of the boundary layer of air at the surface of the head was achieved and a compulsory convective heat exchange assured between the surface of the head and the air current’ (p. 259). 211

‘Fluidocraniotherm’

This device is similar to the Thermokholod FV but was developed and used in-house at the NV Sklifosovskiy Scientific Research Institute of Emergency Medicine, Moscow, for craniocerebral hypothermia, i.e. ‘predominant cooling of the brain through the external layers of the head’. 92 It cooled by forced convection of air. The reason given for using air was that it was suitable directly after surgery; wounds were covered with ‘cerigelum’ or a collodion dressing. Fifty-six patients were cooled with the ‘Fluidocraniotherm’. Some received repeat cooling if their intracranial pressure and cerebral blood flow measurements showed their condition was worsening (how these were measured is not described). The device had an inbuilt fan which blew air into a helmet covering the whole head down to the eyebrows. The air temperature was controllable between –5°C and 40°C and the patient’s temperature was measured either in the ear canal, oesophagus, rectum or (n = 15) brain (see Chapter 4, Historical reports of head cooling for method). Target brain temperature (cortex) was 28–30°C with rectal temperature of 33–43°C. In patients without brain temperature monitoring (n = 41), brain temperature was inferred from nomograms (see Chapter 4, Historical reports of head cooling). Temperature control seems to have been manual rather than closed-loop. Cooling was delivered for 6–29 hours, during which time patients were anaesthetised. Once temperature was lowered (after 2–18 hours), cooling was maintained by ice packs on the head and over major blood vessels, and 1% aminopyrine given two or three times daily.

Prototype convective cooling hood (KCI, Ferndown, Dorset, UK)

This device was tested in volunteers (n = 5) with magnetic resonance spectroscopy brain temperature measurement; it is not commercially available. 24 A hood and collar made of a double layer of nylon, with holes for air flow in the inner layer, delivered air at approximately 14.5 °C and 15 m s^–1 through neoprene insulated tubing from the cooling machine in the scanner control room. The hood and collar could be independently clamped off to allow head and/or neck cooling to be delivered.

Active conductive (liquid) head-cooling devices (circulating cold fluid)

Swedish Air Force head-cooling helmet

Mellergard borrowed an Air Force cooling helmet for clinical use. It was:

… made of fabric enclosing the whole head and part of the neck [with] a system of thin plastic channels on the inside, through which water circulated. The water was supplied from a thermostat bath, with an optional temperature range between 5 and 40 °C, and was continuously circulated through an electromechanical pump. 184

Cincinnati Sub-Zero (CSZ) head wrap (Cincinnati Sub-Zero Products Ltd, Cincinnati, OH, USA): www.cszmedical.com/ (Figures 18 and 19)

This is part of the whole-body hypothermia single-patient use Kool-Kit system, which is an example of a combined head and body device, though either part can be used on their own. Cold water is circulated through the head wrap by the Blanketrol III unit. The head wrap is not pressurised. The company thought that the head wrap had been used on its own for head cooling but had no details of any studies. Our searches showed it had been used by Gaida and colleagues. 51

FIGURE 18.

Cincinnati Sub-Zero (CSZ) head wrap. Photo reproduced with permission from CSZ Products Ltd, http://www.cszmedical.com/Products/Hyper-Hypothermia/wholebodyhypothermia.htm (accessed 25 April 2011).

FIGURE 19.

Blanketrol III. Photo reproduced with permission from CSZ Products Ltd, http://www.cszmedical.com/Products/Hyper-Hypothermia/Blanketrol-III.aspx (accessed 25 April 2011).

TraumaTec Neuro-Wrap (TraumaTec Inc., San Antonio, TX, USA) www.traumatec.com/ (Figure 20)

This is very similar to the CSZ head wrap but portable and is currently being trialled in Neurosciences ICU patients53 (see Appendix 5, References to ongoing studies). The following information was kindly provided by Professor Claudia Robertson the principal investigator:

The TraumaTec Neuro-Wrap is a helmet-shaped water blanket of soft plastic, with flaps that fit snugly over the head and circumferentially around the neck. The cranial flaps are designed to accommodate ICP monitors, head dressings, or other clinical paraphernalia, and can be adjusted to ensure maximal surface contact. The Wrap has high-flow fluid channels to create conductive heat transfer from the scalp and carotid arteries, thus achieving cooling of the brain. Fluid circulation is provided by a small portable refrigeration/pumping unit, designed specifically for this device.

(Professor Robertson, 3 January 2011, personal communication)

FIGURE 20.

TraumaTec Neuro-Wrap. Photo courtesy of Susanne Richard, TraumaTec, Inc., San Antonio, TX.

Cool Brain Cooling Helmet (Figure 21)

This device originated as a spin-off from the National Aeronautics and Space Administration (NASA) space suit technology and was used in the COOL BRAIN stroke study50. It consists of two components, the head/neck liner (Figure 21) and the conditioning unit. The inner liner is made of thin, urethane laminated nylon fabric with a circulating liquid cooling heat exchanger. Over that is a pneumatic liner which is pressurised to improve contact with the head and neck. The whole is adjustable to improve the fit and has access openings on each side over the Kocher points and anteriorly at the midline of the neck. The conditioning unit is portable (mains or battery power). It contains an insulated ice reservoir with heat exchanger and the control system for temperature and coolant circulation. This device is now commercially available as the WElkins EMT system (WElkins, LLC, Roseville, CA, USA; URL: welkinsmed.com).

FIGURE 21.

‘Helmet worn by William Elkins, a NASA scientist, who invented this technology. The cooling helmet has an outer pneumatic liner pressurized to allow close contact with the cranium and neck. The device also is adjustable to fit a significant range of head sizes’50 (figure 1, p. 273). Reproduced with permission from Wang H, Olivero W, Lanzino G, Elkins W, Rose J, Honings D, et al. Rapid and selective cerebral hypothermia achieved using a cooling helmet. J Neurosurg 2004;100:272–7.

Reproduced with permission from Wang H, Olivero W, Lanzino G, Elkins W, Rose J, Honings D, et al. Rapid and selective cerebral hypothermia achieved using a cooling helmet. J Neurosurg 2004;100:272–7.

Discrete Cerebral Hypothermia System, CoolSystems Inc. (Alameda, CA, USA) (Figure 22)

Harris and colleagues45 described their experience with this device. Pros were ease and speed of application, facilitated by the portability of the device, and ease of use. Cons were problems with regulation of water temperature, inadequate contact of the cap with the head (this was despite the cap being pressurised) and the desired intracranial temperature and intracranial/bladder temperature gradient not being achieved. The researchers suggested that a coolant other than water might be better.

FIGURE 22.

‘The Discrete Cerebral Hypothermia System cooling cap. (a) Photograph of the cooling cap. (b) Photograph of a patient from our study wearing the cooling cap. The ICP and temperature monitor can also be seen’45 (figure 1, p. 1257). Reproduced with permission from Harris OA, Muh CR, Surles MC, Pan Y, Rozycki G, Macleod J, et al. Discrete cerebral hypothermia in the management of traumatic brain injury: a randomized controlled trial. J Neurosurg 2009;110:1256–64 [Erratum appears in J Neurosurg 2009;110:1322.]

Reproduced with permission from Harris OA, Muh CR, Surles MC, Pan Y, Rozycki G, Macleod J, et al. Discrete cerebral hypothermia in the management of traumatic brain injury: a randomized controlled trial. J Neurosurg 2009;110:1256–64 [Erratum appears in J Neurosurg 2009;110:1322.]

However, Harris and colleagues45 were aiming to achieve an intracranial temperature of 33 °C, while bladder temperature was maintained at 36 °C with body warming. This is a challenging target. The lack of success is attributed to deficiencies in the head-cooling device but it is questionable whether such a large brain/body temperature difference is achievable in humans without isolating the cerebral and corporal circulation from each other (e.g. Schwartz and colleagues212), although even steeper gradients have been achieved in animals (e.g. Natale and D’Alecy213 and Barone and colleagues214).

Device used at The Affiliated Hospital of Hangzhou Teachers College, Hangzhou, Zhejiang, China (Figures 23 and 24).

This was a cooling cap with circulating water (4 °C) (Figure 23) and an adjustable neck band containing frozen ‘blue ice’ packs (Figure 24). 75,147 The water was circulated by a ‘hypothermia machine’ (KN 01, EBM, Beijing, China) and the neck packs were replaced every 3–4 hours as they thawed.

FIGURE 23.

The cooling cap through which cold water circulated (Qiu and colleagues76,147 Liu and colleagues75). Photo courtesy of Dr Wusi Qiu.

FIGURE 24.

The ‘blue ice’ packs for neck cooling (Qiu and colleagues.,76,147 Liu and colleagues75). Photo courtesy of Dr Wusi Qiu.

Device developed at The First Clinical Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China

Zhang and colleagues182 and Tang and colleagues181 contain information on the development of a head-cooling device. Zhang and colleagues182 is a study in two healthy volunteers with the head-cooling device showing reduction of cerebral glucose metabolism with positron emission tomography. Tang and colleagues181 refers to using the device in stroke patients but provides no details and we have been unable to find more information. The other Chinese studies conducted in Harbin found for the review appear to use the same device. 148,149,183 It is a circulating water device and described as ‘experimental apparatus for medical brain hypothermia controllable semiconductor protection type refrigeration apparatus TER-40A from the Harbin Institute of Technology Education thermal Research Development Office’. 183 The Chinese centre for the CHIL trial (see Appendix 5, References to ongoing studies) is Harbin, and we have contacted the Chief Investigator for CHIL (in Australia) for more information. Our request has been received but we have had no response yet.

Device developed by the Equipment Department, Jilin Provincial Brain Hospital, Siping, Jilin, China

Description of a computerised cooling device that circulates water through a hat and pads at temperatures of between 3 °C and 25 °C. 215

Human brain hypothermia system developed by the Electronics and Computer Education Department, Faculty of Technical Education Gazi University, Ankara, Turkey

The system comprises ‘a microcontroller-based control card, four different temperature measurement circuits, a electronic control card module, a water circulation system, a switching mode power supply, and a helmet’ (p. 502). 216 The temperature range is –5 °C to 46.15 °C because it is intended that the device could also be used for hyperthermic tumour therapy. This device is undergoing animal testing and has not yet been used in humans (Dr Guler, 28 February 2011, personal communication).

Helmet for emergency cooling in head injury, Japan

A device is described which was developed by a team from Niigata Sangyo University, Tokyo Denki University and Sapporo Medical University, School of Medicine. It uses a Peltier chip to cool water, which circulates through the helmet. 217,218 We have had no response to a request for information on whether or not this has been used in humans.

Device developed at the Institute of Semiconductors, Academy of Sciences of the USSR, A.P. Polenov Leningrad Scientific-Research Neurosurgical Institute, USSR (Figures 25 and 26)

This device (Figure 25) had been used clinically for 2 years, although details were not reported, and was said to have fewer complications than other methods of head cooling such as ‘spray helmets’ (possibly the Kholod 2) and to be easier to use, provide better temperature control and more reliable than devices that required the coolant to be replaced or Freon refrigerator devices. It had two separate parts: a helmet containing a thermopile and a control unit. The helmet had three layers (Figure 26). The outer part was reinforced glass fibre with 17 serially connected thermocouples [‘intermetallic compounds on a base of bismuth telluride with branches having p- and n-type conductivity’ (p. 240)]219 which generated cold. The middle layer, in which the thermocouple cold-junction collectors sat, contained a heat-transfer liquid with a low freezing point. This middle layer was filled and drained through a tube on the outside of the helmet. The inner layer was stretchy rubber which was conformed to the head by adjusting the quantity of heat-transfer liquid. A rubber hood covered with insulating material was placed over the whole helmet to hold it tight to the head. The control unit had a temperature measurement circuit, supplied the current (high current rectifier) and circulated the water which removed the heat from the thermopile.

FIGURE 25.

General view of electronic device for hypothermia of the brain219 (figure 1, p. 241). Kolenko E, Bezukh M. Electronic device for hypothermia of the brain. Biomed Eng 1971;5:239–41. With kind permission from Springer Science and Business Media.

Kolenko E, Bezukh M. Electronic device for hypothermia of the brain. Biomed Eng 1971;5:239–41. With kind permission from Springer Science and Business Media.

FIGURE 26.

Schematic cross-section of helmet. 1, Thermocouples; 2, collectors; 3, rubber membrane219 (figure 2, p. 241). Kolenko E, Bezukh M. Electronic device for hypothermia of the brain. Biomed Eng 1971;5:239–41. With kind permission from Springer Science and Business Media.

Kolenko E, Bezukh M. Electronic device for hypothermia of the brain. Biomed Eng 1971;5:239–41. With kind permission from Springer Science and Business Media.

Rubber, water circulating head-cooling device, USSR (Figure 27)

This is described as an easy-to-use helmet device, made of readily obtainable parts, which circulates water at 8–10 °C. 220 Use of the device in nine patients with TBI is mentioned but few details are given.

FIGURE 27.

1, Rubber helmet; 2, rubber tubing; 3, tap to run water into serpentine coil (4) in a case (5) with insulation (6). The waste runs out into a washbasin220 (p. 47, translated from Russian). Reproduced with permission from Reut NI. [Technic of continuous therapeutic craniocerebral hypothermia in acute craniocerebral injury.] [Russian.] Ortop Travmatol Protez 1970;31:47–8.

Reproduced with permission from Reut NI. [Technic of continuous therapeutic craniocerebral hypothermia in acute craniocerebral injury.] [Russian.] Ortop Travmatol Protez 1970;31:47–8.

Helmet for focal or global head cooling, USSR (Figure 28)

This device is described as being suitable for severe TBI with haemorrhage. No patient data are reported. 221 It seems to have been designed for either focal cooling, if one pocket has coolant flow, or more global head cooling if all pockets are used.

FIGURE 28.

Helmet, which reduces temperature for focal and global hypothermia: a, front; b, side; c, back221 (p. 68, translated from Russian). Reproduced with permission from Okhrimenko NN, Zaikin VS. [Use of regional hypothermia of the head for treating acute disorders of the cerebral circulation.] [Russian.] Voen Med Zh 1974;1:68–9.

Reproduced with permission from Okhrimenko NN, Zaikin VS. [Use of regional hypothermia of the head for treating acute disorders of the cerebral circulation.] [Russian.] Voen Med Zh 1974;1:68–9.

Passive (non-circulating) conductive head-cooling methods and devices

Ice packs

Ice packs to the head have been used for cooling in brain injury52 and cardiac arrest. 48 In patients during out-of-hospital resuscitation, Callaway and colleagues48 put three bags each containing 500 ml of shaved ice around the head and draped a fourth bag across the neck. Forte and colleagues’ patients52 had had decompressive craniectomy and the ice packs were applied to the site of bone removal; unsurprisingly, this may be more effective in reducing temperature than in patients with an intact cranium.

Rubber cooling helmet filled with ice and salt, Chita Medical Institute, Chita, USSR (Figures 29 and 30)

Zhmurko93 reports on the cooling helmet designed and used at the Chita Medical Institute (now the Chita State Academy of Medicine). This was adapted from a locally made rubber anti-gas helmet and was made in different sizes so that it could be fitted tightly to the head to help ensure uniform cooling. It had two layers, between which was a mixture of ground up ice or snow with 33% salt. This mixture produced a temperature of –21°C and could maintain hypothermia for up to 3 hours; if longer cooling was required the helmet was refilled.

FIGURE 29.

Rubber cooling helmet filled with ice and salt (figure 1 from Zhmurko93). Reproduced with permission from Zhmurko SF. [Cranio-cerebral hypothermia in patients with acute cranio-cerebral injury.] [Russian.] Khirurgiia 1971;47:40–3.

Reproduced with permission from Zhmurko SF. [Cranio-cerebral hypothermia in patients with acute cranio-cerebral injury.] [Russian.] Khirurgiia 1971;47:40–3.

FIGURE 30.

Rubber cooling helmet shown on head (figure 2 from Zhmurko93). Reproduced with permission from Zhmurko SF. [Cranio-cerebral hypothermia in patients with acute cranio-cerebral injury.] [Russian.] Khirurgiia 1971;47:40–3.

Reproduced with permission from Zhmurko SF. [Cranio-cerebral hypothermia in patients with acute cranio-cerebral injury.] [Russian.] Khirurgiia 1971;47:40–3.

Sovika head and neck cooling device (Sovika GmbH, Jesewitz, Germany) www.sovika.de/ (Figures 31 and 32)

This is a portable reusable device with gel-filled pads. It is stored flat at 4 °C and wrapped round the head and neck conforming to shape. This device is currently being trialled in the i-Cool pilot study in stroke patients (see Appendix 5, References to ongoing studies).

FIGURE 31.

Sovika head and neck cooling device. Photo courtesy of Sovika GmbH, Jesewitz, Germany.

FIGURE 32.

Sovika head and neck cooling device in situ. Photo courtesy of Sovika GmbH, Jesewitz, Germany.

Other makes of gel cap

Other gel caps that have been used for head cooling are the Hypotherm Gel Kap (Flexoversal, Hilden, Germany),184 the Frigicap (a scalp-cooling cap for chemotherapy) (Figure 33) refrigerated to –4 °C, applied over a paper cap and replaced hourly to keep the cap temperature low,69 and an elastogel cap (Figure 34) by Southwest Technologies (Kansas, MO) (www.elastogel.com/product-catalog/hot-a-cold-therapy/head-facial-therapy), which was carried in a mobile fridge at –5 °C to use in out-of-hospital cardiac arrest. 70

FIGURE 33.

Frigicap containing aqueous glycerol69 (figure 1, p. 277). Reproduced from Resuscitation 51. Hachimi-Idrissi S, Corne L, Ebinger G, Michotte Y, Huyghens L. Mild hypothermia induced by a helmet device: a clinical feasibility study, 275–81, 2001, with permission from Elsevier.

Reproduced from Resuscitation 51. Hachimi-Idrissi S, Corne L, Ebinger G, Michotte Y, Huyghens L. Mild hypothermia induced by a helmet device: a clinical feasibility study, 275–81, 2001, with permission from Elsevier.

FIGURE 34.

Elastogel cap on a patient after cardiac arrest70 (figure 1, p. 98). Reproduced with permission from Storm C, Schefold JC, Kerner T, Schmidbauer W, Gloza J, Krueger A, et al. Prehospital cooling with hypothermia caps (PreCoCa): a feasibility study. Clin Res Cardiol 2008;97:768–72.

Reproduced with permission from Storm C, Schefold JC, Kerner T, Schmidbauer W, Gloza J, Krueger A, et al. Prehospital cooling with hypothermia caps (PreCoCa): a feasibility study. Clin Res Cardiol 2008;97:768–72.

Scalp-cooling devices

Scalp-cooling devices are listed separately here because they are not marketed for use in brain injury. However, some of them may be suitable for brain cooling.

Non-invasive neck-cooling devices

There are some devices designed to be used only on the neck with the intention that cooling the carotids will cool the brain but there are limited patient data available.

Water-circulating Arctic Sun pads (Medivance Inc., Louisville, KY, USA; www.medivance.com/) that are specially shaped for placement over the carotid triangles were used in nine patients with SAH and intractable fever. 222 Mean brain temperature reduced by about 0.5 °C within a few hours but the reduction was not sustained. Emcools have developed their cooling pads for neck cooling (Stroke.Pad, Emcools, Vienna, Austria) but there are few data as yet. 223

There is a patent for a non-invasive neck cooling device that holds removable cold inserts over the carotids (US Patent 6682552 – Brain cooling device and monitoring system) intended for pre-hospital use in stroke patients. This was developed by Ramsden and colleagues224 at the University of Saskatchewan, Saskatoon, SK, Canada, but requests for information about whether it has actually been used in patients have met with no response.

The Sandhu Cerebral Cooling Collar (LifeCore Technologies Inc., Cleveland, OH, www.lifecoretech.com) is somewhat similar, with a removable cool pack that fits round the front of the neck. Ethical approval has been obtained to compare this device with a systemic surface cooling device (Gaymar Industries Inc., Orchard Park, NY) for fever control in stroke patients in neuro ICUs (investigator Dr Michael DeGeorgia, University Hospitals of Cleveland, Case Medical Center, Cleveland, OH). (Scott Raybuck, Life Core Technologies LLC, Cleveland, OH, personal communication).

Whether these latter two devices are much different from commercially available personal cooling neck collars, for example Black Ice (Lakeland, TS, USA), is not yet clear.

Personal cooling garments

There is a somewhat grey area between medical devices for therapeutic clinical head cooling and the myriad personal cooling systems for preventing heat strain, for example in multiple sclerosis and for military and firefighting personnel. Some of these personal cooling systems include head- and neck-cooling components, which are either soaked in water to activate and cool by evaporation or contain phase-change packs (e.g. Polar Products Inc., Arkon, OH, USA; http://store.polarsoftice.com). There are some liquid cooling garments but these are usually vests and not for head cooling. Polar Products active ice head cap is an exception and is designed for migraine sufferers. It has not been used in brain injury, although the company think it could be suitable for that purpose.

Kim and Labat225 describe the design process for a liquid cooling hood which formed part of the Minnesota Advanced Cooling Suit (MACS)-Delphi developed for use by astronauts (https://taskbook.nasaprs.com/Publication/index.cfm?action%20=%20public_query_taskbook_content%26TASKID%20=%207267; accessed 2 May 2011). The new design was made of mesh with tubing threaded through it (Figure 35).

FIGURE 35.

Minnesota Advanced Cooling Suit (MACS)-Delphi hood new design225 (figure 5, p. 825). Kim DE, Labat K. Design process for developing a liquid cooling garment hood. Ergonomics 2010;53:818–28, reprinted by permission of Taylor & Francis Ltd, http://www.tandf.co.uk/journals.

Kim DE, Labat K. Design process for developing a liquid cooling garment hood. Ergonomics 2010;53:818–28, reprinted by permission of Taylor & Francis Ltd, http://www.tandf.co.uk/journals.

Head-cooling therapy after brain injury

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Health Technology Assessment programme

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