Clinically Induced Hypothermia in the Management of Severe Head Injury:

A Review of the Evidence

PAGE

1. Title Page

2. Acknowledgements

3. Contents

4-5. Abstract

6-7. Introduction

8-11. Methods
9. i) Inclusion & Exclusion Criteria
10. ii) Limitations of Search
11. iii) Critical Framework

12-26. Critical Review of the Data
13. i) Study Aims & Design
19. ii) Sampling & Controls
25. iii) Results

27-36. Discussion
32. i) Implications for Practice

37-41. References

42. Appendix 1) – The Four Stages of Research

43. Appendix 2) – Database Search (Hard Copy Only)

44-49. Appendix 3) – Example (1) Using the CASP Framework

50-55. Appendix 3) – Example (2) Using the CASP Framework

56. Appendix 4) – Summary of Studies (Hard Copy Only)

57. Appendix 5) – Intracranial Pressures

58. Appendix 6) – Type 1 & 2 Errors

59. Appendix 7) – The Hawthorne Effect

60. Appendix 8) – The Glasgow Outcome Score

61. Appendix 9) – The Hierarchy of Evidence

ABSTRACT

Medically induced hypothermia has been used as a neuro-protector to try and limit the consequences of severe brain injury for more than fifty years but it is only recently that its effectiveness has been assessed using randomised controlled trials. Under certain circumstances clinically induced hypothermia has already been proven to be beneficial by providing a degree of neuroprotection in post-cardiac arrest patients. As such it has recently been incorporated into the UK resuscitation guidelines. However, its benefits for treating severe head injury remain debateable.

Hypothermia’s main accepted property in head injury is its ability to reduce intracranial hypertension. Prolonged intracranial hypertension is a precursor closely associated with poor outcome and death as it generally reflects the severity of the injury. Reducing intracranial pressure (ICP) with hypothermia should therefore theoretically reduce or limit secondary brain injury and thus improve outcome. Evidently, in clinical practice this is not always the case as although many studies have confirmed hypothermia’s ICP lowering effects not all of them have been able to significantly support the above statement. Some researchers even rebutted the use of hypothermia in their studies reporting that its use increases the incidence of complications.

To assess the conflicting evidence, a full systematic literature review was performed using a number of database search engines and nine studies were carefully selected for critical analysis.

Examination of the literature demonstrated a lack of substantial evidence was available that supported the use of therapeutic hypothermia in order to improve the outcome of severely brain injured patients. Despite several small single centre studies concluding that subsets of patients may have an improved outcome. Conversely two large multicentre studies dismissed hypothermia as beneficial, to the extent that the studies were terminated early by patient safety and monitoring boards.

This review has offered some explanations to the diverse results, in doing so it has explored the reported complications and assessed their impact on cancelling out any benefits that clinical hypothermia may offer. It is concluded that many of these related complications can be avoided if pre-empted. However, more research is still required to confirm whether hypothermia would be advantageous. Nevertheless, the information gained from this study has greatly helped the author in managing patients that have suffered a severe head injury.

INTRODUCTION

Head injury is a common and serious health problem, documented as a leading cause of death and disability in individuals below the age of 44 in the Western world (Sahuquillo 2007). It is a major source of severe and long lasting morbidity, often requiring lifelong nursing care. Although pre-hospital mortality remains high, improvements in transportation (including air ambulances), resuscitation, brain imaging and surgical intervention have challenged clinicians to maintain survival in individuals that may have previously died, ultimately testing them to achieve a good quality of life in the post head injured patient. (Sahuquillo 2007).

Brain injury is normally thought of in terms of primary and secondary insults. First published in the 1970’s this remains a useful concept as it differentiates between the unavoidable irreversible primary injury and the potentially avoidable secondary one (Adams 1977). Primary brain injury occurs immediately at the time of injury, whereas secondary injury is a cascade of events that contributes to intracranial hypertension resulting in a reduction in cerebral perfusion pressure and ischaemia (Marmarou 1991). The cerebral perfusion pressure (CPP) is determined by the Monro-Kellie hypothesis. In closed head injuries, the skull has a fixed volume and the pressure within it is determined by the equilibrium between the CPP, the mean arterial pressure (MAP) and the intracranial pressure (ICP) using the equation: CPP = MAP − ICP
Therefore, assuming a constant blood pressure, as ICP rises CPP must fall. Minimising the ICP, should minimise ischaemia and brain damage resulting from localised pressure thus leading to a global increase in perfusion and therefore oxygen delivery to the brain. There is class I evidence that cooling to a mild hypothermic state of ≤35oC reduces intracranial hypertension by limiting cerebral oedema. In addition it is thought that moderate hypothermia of 33oC has neuroprotective effects by stabilising cerebral cell membranes by reducing the release of cytokines thus preventing apoptosis and inhibiting free radical production. Further, at temperatures of 32oC metabolism is decreased by 30-50%, this is thought to be one of the reasons why hypothermia induces bradycardia as less cardiac output is required to meet metabolic demands (Polderman 2004). However, despite these beneficial effects the impact on improving outcome is less clear (Polderman, 2008).

Currently there are no guidelines on the use of hypothermia in head injuries issued by authoritative UK bodies such as the National Institute for Clinical Excellence. In the authors current unit hypothermia is not used. This contradicts nursing practice in a previous unit where hypothermia was implemented as part of a strict head injury protocol to help control intracranial pressures. This conflicting care prompted the author to question if the best possible care was being provided to this group of patients. This led to evaluating the current evidence to ascertain whether clinical hypothermia impacts on recovery, based on the Glasgow Outcome Score (GOS) whilst also determining whether the potential benefits of this treatment outweigh the risks associated with its use in practice.

To study this issue further the following research questions have been proposed:

1. Does the use of therapeutic hypothermia in the management of severely head injured patients (GCS (8) improve outcome?

2. Do the benefits outweigh the risks?

METHODS

Research is initiated by interests and standards as discussed by Braa and Vidgen (1997) and is argued to be a practiced skill by Benton & Cormack (2000) that should be a basic requirement for all nurses. However there remains no clear agreement on the methods that should be employed (NHS Centre for Reviews & Disseminations 1996). Jones (2000) describes four stages for conducting research that mirrors the approach that I adopted. This was the identification of an inconsistency in practice that led to the research question that was first debated with colleagues prior to an inductive literature search and critical review of relevant articles (appendix1).

Being able to carry out an effective literature search forms the foundations for the final quality of any research project. For this literature review both manual and electronic searches were conducted as this is thought of as best practice as suggested by Hek et al (1996). Polit and Hungler (1995) identify many advantages to using an electronic search as prominently this method can often save much time and effort. Articles are commonly put onto database’s before they are published in journals which makes searching a database advantageous in that it may contain more up to date material than other sources of information. The facility to input combinations of keywords enable more relevant results from the database. The combinations of keywords used for this review were “hypothermia” or “cooling” and “head injury” or “brain injury”. The search was initially conducted using the Universities portal but the National Library for Health portal became favoured for its ease of use (appendix 2). The databases searched included those grouped under ‘Evidence Based Reviews’ which incorporated the Cochrane Collaboration. As well as producing systemic reviews of health care interventions the Cochrane Collaboration promotes the search for evidence from clinical trials and intervention studies. The strength of the Cochrane is of such that their reviews are used in the formulation of NICE guidelines.

NICE and international guidelines were searched from the ‘Guidance’ register and finally databases such as CINAHL & MEDLINE were searched. With over 1 million records CINAHL has reference to virtually all English language journals allied to health as well as to books and nursing dissertations. It’s for this reason why the CINAHL database is recognised as being extremely important for all nurses conducting research (Aveyard 2007). MEDLINE is also an essential database for nursing research, recognised as a premier resource of information due to its coverage of over 5,000 medical and nursing journals in 70 countries (Polit & Beck 2008). Search strategies where limited to English language from the past ten years. 191 results were obtained using the Ovid search software utilised in the Universities portal and similarly 195 results via the National Library for Health system. The results were virtually duplicated which was reassuring in that all applicable databases had been searched.

‘Google’, ‘Google Scholar’ and ‘Google Books’ was also extensively used; The advantage was the simplicity that ‘truncation’ and ‘boolean’ methods were not required. This helped to check that no other articles had been missed by previous searches and offered other avenues to access full text and related articles. It also made it easy to identify pertinent books by typing in subject headings. A search for “grey literature” was also conducted using links from the university electronic library, but no suitable data was retrieved.

Inclusion & Exclusion Criteria
As results were assessed and retrieved several reviews were read in order to obtain a broad overview of the topic before recalling several more articles judged to be the most relevant from the citations and referencing in the reviews. This is stressed by Khan et al (2001) as being paramount to ensure that key literature is not missed. One in particular was Marion et al’s (1997) study. This study was initially overlooked due to the 10 year search restriction but because it is cited in virtually all subsequent therapeutic hypothermia studies and therefore appeared to be a seminal piece of research an exception to its age was given. Another study by Clifton et al (1993) could also be interpreted as being seminal research as it too was also cited a lot by other authors, but because this was four years older than Marion et al’s (1997) it was decided that the time line had to be drawn. If further exceptions for its inclusion were made it may have been regarded as having a bias of control over what studies were chosen for this review. Especially because it was felt enough newer material already existed to be able to justify its inclusion.

Nine studies were finally retrieved as being particularly relevant: two multi-centre prospective randomised control trials, four single centre prospective randomised control trials, two single centre controlled trials and one retrospective single centre study. One further study was identified that is currently in progress that merits inclusion within the discussion. One study from China appeared useful from the English abstract but it had to be excluded as full text translation was not available from the internet or British library.

Limitations of Search
The author feels that the literature search was thorough but there were some limitations. There were no studies retrieved that were conducted in UK, however it is argued that the research topic selected, that results obtained in other developed countries will be directly transferable to UK practice. Also despite this being a nursing dissertation there were no primary studies found in any nursing journals. However, medical journals form a large part of evidence based nursing and the papers are relevant to all members of the critical care multi-disciplinary team that aim to deliver best possible care to those with severe head injury. Nursing journals were reviewed in great detail and offered some useful material to compliment the studies.

Critical Framework

Cutcliffe & Ward (2006) state that there are many published approaches to critiquing quantitative studies in nursing research to be aware of. They also postulate that there may not be a perfect approach so offer six diverse frameworks formulated for quantitative designs. On evaluation of the frameworks it was easy to appreciate Cutcliffe & Ward’s (2006) statement as it was very difficult to narrow a single framework down as all six had their strengths and limitations. Polit & Hungler’s (1997) was given much praise by Cutcliffe & Ward. It is very thorough and would probably be the framework of choice if I was only drawing conclusions from one study, but with nine studies and a limited word count, I was more drawn towards Ryan-Wenger’s (1992) guidelines because of their matter of fact scientific approach. However their framework has been criticised for being too conventional and deductive in nature Hek, Judd & Moule’s (2002) framework was also considered as this had proved successful with previous work, but was ruled out because the framework was not designed solely for quantitative research hence several of the questions offered were subjective in nature. The Critical Appraisal Skills Program (CASP) ‘making sense of evidence’ was eventually chosen as it is specifically designed for evaluating Random Control Trials (RCTs) which was appropriate for the all of the subject papers; it is also concise and straight forward without jargon. The CASP approach is also not without its faults, it is one of the few frameworks that do not cover ethical issues. It is therefore fortunate that other tools were assessed for suitability first, so that ethical issues were not overlooked. A CASP framework was filled out to summarise each article in order to assist the critical review. Two examples of these can be found at appendix 3. A more succinct table was then produced from these that provided a concise fact sheet of all nine of the articles at a glance (appendix 4).

CRITICAL REVIEW

The chosen studies all examined the efficacy of hypothermia in patients that had suffered closed head injury; all were conducted in intensive care units that specialised in neurology. Generally, the studies have utilised similar applications for cooling the hypothermic study groups to temperature ranges of 32-35oC. A common method employed is the use of cold water circulating mattress and forced cold air. All of the studies have based statistical significance on the traditional p value of 20 mm/Hg, with Shiozaki using an ICP >25 mm/Hg. Both studies stated that raised ICP is clearly related to higher mortality and morbidity rates so their hypothesis was to prove whether or not the use of mild to moderate hypothermia improved outcome by lowering ICP.

The relationship between intracranial hypertension and poor outcome is already established and widely accepted. As far back as 1982 Saul & Ducker reported a 69% mortality rate in a study when ICP was greater than 25 mm/Hg compared to 15% in those with an ICP below 25mm/Hg (Saul & Ducker 1982). This relationship is also evident for morbidity, as shown by Marshal et al (1979) where 77% of patients with head injuries who had an ICP below 15 mm/Hg had a good outcome as opposed to 43% when ICP was greater than 15mm/Hg (Marshal et al 1979), indicating that that the more elevated the ICP the more severe the head injury is likely to be. This is consistent with Feliciano et al (2008) statement that patients with a GCS ≤8 have more than a 50% chance of developing intracranial hypertension. This explains why reducing intracranial hypertension in the intensive care department is crucial to limit secondary brain injury and death. The effect of hypothermia reducing ICP levels was demonstrated in all of the studies under review with the exception of Shiozaki et al (2001). This was because this study design was virtually the opposite of his 1998 study in that he was now evaluating the effects of hypothermia in patients that had relatively normal / moderate intracranial pressures, i.e.