The idea that the brain could be conserved in the field post-trauma from out-of-hospital cardiac arrest (OHCA) was suggested over half a century ago in 1948 (Safar et al, 2000). The notion put forward was to protect the brain from hypoxia in order that the patient could be transported to hospital for more advanced treatments (Lyon, 2012). Until the 1990s, researchers assumed that hypothermia created neurological protection to the brain by reducing cerebral metabolism. As a result of this, physicians mistakenly understood that the lower the body temperature the more the protective effects became apparent in terms of decreasing amounts of brain metabolism and oxygen consumption (Polderman, 2008). From this it may be the case that simplistic low level and out-of-date comprehension of the research based evidence in mild hyperthermia treatment (MHT) by paramedics may mislead treatments in the pre-hospital setting and increase morbidity and mortality in traumatic brain injury (TBI). This review attempts to inform this evidence-based debate and create a clear picture for the UK paramedic practitioner who is considering using mild-moderate hypothermia (between 32–34 ºC core temperature) in the field in the minutes after TBI has been inflicted in order to attempt to protect the brain against worsening of the brain trauma and increase the chances of the patient's survival.
Background
It remains the case that a major cause of mortality and morbidity in North America for patients below 45 is traumatic brain injury (TBI) (Rutland-Brown et al, 2006). In the US it ranges to 1.4–1.7 million (per annum) incidents of TBI ending up in 300 000 admissions, over 50 000 deaths and a rate of significant disability of over 80 000 each year (Rutland-Brown et al, 2006). In England and Wales TBI rates are 13 000 per annum equating to 24 per 100 000 of population. Indeed, the rate of 1, 80 TBI deaths per annum is recorded for 2009 (National Health Services Wales, 2009; NHS England 2009–10 HES data 2009–10; ONS Mortality statistics, 2009).
Mild-moderate hypothermia (between 32–34 ºC core temperature) induced prior to, during the TBI event or post may protect the brain against worsening of the brain injury itself across both animal and human trials and may improve survival rates (Moore et al, 2011). Therapeutic hypothermia (TH) is becoming a more common method in the handling of nontraumatic cardiac arrest as well as traumatic brain injury (TBI). Patients in these situations may profit from a measured state of mild hypothermia treatment (MHT), post–trauma, the patient is aided towards recovery (Moore et al, 2011). New treatments using MHT, which are still in research stages, are already being applied by ambulance providers (Lyon, 2012; Weaver, 2012) and hospitals in the UK and abroad as part of random controlled studies (Sydenham et al. 2009). Evidence suggests that TBI patients profit from a measured state and time of mild hypothermia ( Jiang, 2000). So, if paramedics institute a rapid cooling protocol in the pre-hospital setting post–head injury, there may be a patient gain in terms of reduction in neurological deficits. While evidence is still incomplete for the benefit the incorporation of MHT into UK ambulance services, this paper pursues the use of mild therapeutic hypothermia (MHT) in traumatic brain injury. By debating the benefits, human costs and attempting to conceive realistic directions for future pre-hospital research this essay to review will look at the role for induced hypothermia in the pre-hospital setting management of TBI.
The debate about pre-hospital mild hyperthermia treatment for TBI
Now, the intricacy of the hypothermic process is more apparent (Table 1). Indeed, as the core temperature reduces from normotensive levels, the metabolic rate decreases but also oxygen use reduces, glucose consumption reduces, carbon dioxide (CO2) production decreases and these all join to ameliorate damage as oxygen supply becomes limited or finally interrupted (Polderman, 2009). So, for instance, in the pre-hospital and hospital setting the care provider may need to consider adjustments in ventilator settings or bag/valve/mask ventilation rate to maintain normocapnia.
Another issue that arises is the decrease in insulin secretion and insulin sensitivity and changes in insulin infusion rates which would need to be considered in relation to the rate at which hypothermia induction or rewarming takes place (Polderman and Herold, 2009). Paramedics need to monitor blood glucose during MHT in TBI.
| Mechanism | Explanation | When/treatment |
|---|---|---|
| Metabolic changes | ↓ Cerebral metabolic rate by 6–8 % per 1 °C ↓ in core T→ ↓ in O2 consumption and CO2 production. Excessive ↑ in CO2 can ↑ cerebral oedema, and excessive ↓ in CO2 can ↑ ischaemia | Acute in induction/frequent BGs and ventilator setting adjustments to maintain normocapnia, slow rewarming |
| Electrolytes |
|
Keep electrolytes in high-normal range, slow rewarming (0.25 °C/h post cardiac arrest, slower for severe TBI) |
| Apoptosis and mitochondrial dysfunction |
|
Starts late in post-reperfusion phase, can continue for 72 h or more → In theory wide window for treatment |
| Ion pumps and neuroexcitotoxicity |
|
Disturbed Ca2+homeostasis begins minutes after injury and may continue for many hours → may be treatable. Animal studies suggest to initiate treatment early in the neuroexcitatory cascade |
| Inflammation |
|
Begins ≈ 1 h after ischaemia and persists for up to 5 days, suggesting a therapeutic window for these mechanisms |
| Free radicals |
|
|
| Blood–brain barrier/vascular permeability |
|
Brain oedema peaks after 24–72 h→this mechanism could offer a wide therapeutic window |
| Acidosis and cellular metabolism | Ion-pump failure, mitochondrial dysfunction, cellular hyperactivity and ↓ in cell membrane integrity → intracellular acidosis → ↑ harmful processes. Hypothermia can alleviate this, may improve brain glucose metabolism and when induced early enhances speed of metabolic recovery → ↓ toxic metabolite accumulation → ↓ acidosis | |
| Brain temperature |
|
|
| Coagulation |
|
Assess risk versus benefit |
| Vasoactive mediators |
|
|
| Improved tolerance of ischaemia (preconditioning) | In animal models ‘preconditioning’ with hypothermia improves tolerance for ischaemia. As brain injury is frequently complicated by ischaemic events after the initial insult, this could be a valuable neuroprotective mechanism | |
| Reduction of epileptic activity | Epileptic activity without signs and symptoms (non-convulsive) occurs frequently in brain-injured patients and if it occurs in the acute phase of brain injury the combined effect is destructive. Evidence indicates that hypothermia ↓ epileptic activity; another mechanism through which it could provide neuroprotection | |
| Early gene activation | Hypothermia → ↑early gene activation which is part of the protective cellular stress response to injury and → ↑ production of cold shock proteins that can be cytoprotective in the presence of ischaemic and traumatic injury | |
| Shivering | ↑ metabolic rate, O2 consumption, work of breathing, heart rate and myocardial O2 consumption | 34–35 °C/opiates, sedation, paralysis if required, other agents |
| Insulin sensitivity and secretion |
|
Induction and rewarming/ frequent BGL checks and insulin adjustments, slow rewarming |
| Cardiovascular/haemodynamic effects |
|
Avoid and correct hypovolaemia. Avoid stimulating HR |
| Coronary perfusion |
|
Sedate adequately-prevent shivering |
| Drug clearance |
|
Modify doses of certain drugs |
| Infection |
|
Low threshold for antibiotic treatment may be advisable ↑ in ‘cooling power’ required may indicate fever and infection |
| Gut | ↓ gut function and gastric emptying, ↓ metabolic rate | Reduce feeding target in maintenance phase |
↓: decrease (d), →: leads to, ↑: increase (d), T: temperature, O2: oxygen, CO2: carbon dioxide, BGs: blood gases, IR: ischaemia reperfusion, ATP: adenosine triphosphate, Ca2+: calcium, BBB: blood–brain barrier, NO: nitric-oxide, WCC: white cell count, ICH: intracranial hypertension, ICP: intracranial pressure, TxA2: thromboxane A2, °C: degrees celcius, BGL: blood glucose level, K+: potassium, Mg2+: magnesium, PO4−: phosphate, TBI: traumatic brain injury, HR: heart rate, BP: blood pressure, CO: cardiac output, ADH: antidiuretic hormone, CRP: C-reactive protein.
Electrolyte presence is affected by intracellular shift as well as tubular dysfunction (Polderman, et al, 2001). Keeping electrolytes in high-to-normal range is important during hypothermia management for a number of reasons: magnesium can ease levels of brain injury; a low phosphate level risks infection; and arrhythmias are related to low potassium and magnesium levels (Weisinger and Bellorin-Font, 1998; Polderman et al. 2003). Paramedics would use evidence based practice in fluid selection with regards MHT and TBI.
Following ischaemic brain damage or TBI with subsequent reperfusion taking place, cells may differ in their pathway. They can become necrotic or follow a pathway ending in programed cell death (apoptosis) or, indeed, recover. It is clear, however, that there is a limited window of opportunity for interventions such as MHT (Xu et al, 2002). This is a strong argument for a pre-hospital role of rapid induction of MHT by paramedics to provide optimal MHT for continuing in-hospital treatment in order to gain better results for the patient compared to hospital induction of MHT (US National Institute for Health (PRINCESS), 2012).
Another complexity of benefits of MHT is in relation to ion pumps and neuroexcitotoxicity that occurs with ischaemic-reperfusion damage. As a result, when cerebral oxygenation is interrupted the level of adenosine triphosphate (ATP) decreases rapidly along with phosphocreatine (Small et al. 1999). A complex cascade which involves numerous occurrences including, a calcium excessive influx into cells in the brain, glutamate receptor initiation in excess as well as an additional excitotoxic cascade (neuronal hyperexcitablity). All this leads to further cell death or injury even post-reperfusion and after glutamate levels have been normalised (Busto, et al, 1987; 1989; Siesjo et al. 1989Baker et al, 1991; Hall and Braughler, 1993; Globus et al, 1995; Auer, 2001; Leker and Shohami, 2002). These complex effects of MHT also include: an inflammatory response These complex issues around the effects of MHT in TBI also include: an inflammatory response in brain tissue in TBI which begins 1 hour after insult and last for up to 5 days and which MHT can ameliorate; MHT lowers the release of free radicals post insult that will oxidise and damage cell components; MHT reduces the disruption of blood brain barrier permeability; intra and extra cellular acidosis and metabolism; elevated brain temperature; coagulation MHT may induce beneficial anticoagulatory effects; vasoactive mediators; improved tolerance of ischemia; a reduction in the likelihood of epileptic fits; early gene activation; shivering and finally, cardiovascular haemodynamic effects (Moore et al, 2011). The point to be meade is that with MHT, instead of using one method for treatment of TBI such as mannitol (Brain Trauma Foundation, 2007)—MHT in TBI encorporates multiple layers of intricate and complex beneficial therapies at onbce (Moore, 2011). Certainly, these layers of beneficial treatment need to be considered and managed immediately while rapid MHT is instituted in the pre-hospital or in-hospital setting, and management of good and poor effects should be watched for carefully. It may be that paramedics can induce MHT rapidly but need to arrive promptly at hospital as the main effects of MHT need complex management by a multi-disciplinary team (Moor, 2011).
The evidence
Two randomised trials in 2002 showed this benefit of cooling patients who had presented with ventricular fibrillation (VF) (Bernard, et al, 2002; The Hypothermia after Cardiac Arrest Study Group, 2002). Indeed, though both of these trials used surface cooling, in the European trail, MTH was usually started several hours after hospital admission. MTH became a significant choice in out-of-hospital cardiac arrest (OHCA) treatment with the scientific statement of support released from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative and Critical Care; the Council on Clinical Cardiology and the Council on Stroke (Nolan, et al, 2008).
Arguments against MHT in TBI
However, there may be no need for pre-hospital cooling to be instigated by ambulance paramedics on TBI patients. MHT currently used in OHCA shows there is no significant evidence from pre-hospital studies linking improved outcome for patients even though there have been clinical trials of scale (Bernard et al, 2010; 2012). In a systematic review of 23 in-hospital trials by Sydenham et al (2009), in the Cochrane Database of Systematic Reviews, it was found that of 1614 patients in these randomised control trials there remained a lack of evidence that hypothermia was effective in the clinical management of TBI. Patients were randomised into two groups: the first group was kept normotensive; and the second group cooled to the maximum of 35 ºC for longer than 12 hours. Cooling treatments included using the whole body, such as administering a blanket and circulating cold water, or alternatively the head, using techniques such as a helmet which circulated cold water directly to the affected area. Information was analysed to include pneumonia, disability and death within each trial, and although fewer patients became severely disabled or died as a result of MHT, they also became more susceptible to, or died as a result of pneumonia (Sydenham et al. 2009).
These findings may have also been an effect of low methodological quality, as they can tend to overestimate the properties of treatments. The low–quality trials in particular, showed MHT to be active in reducing levels of death and disability in TBI. The good quality randomised controlled trials, however, showed no such positive effects. MHT did not lower the likelihood of dying or catching pneumonia. As there was the inclusion of low quality trials, the findings appear contradictory, however, the authors still concluded that most effects, positive or negative, with regards MHT of TBI may be as a result of chance and anomoly. Further research may be conducted in the future, but hypothermia should still only be used in randomised control trials where there was good allocation concealment (Sydenham et al. 2009).
From these studies it shows that there may be no role for induced hypothermia in the management of head injury in the pre-hospital setting in UK, that MHT is related to increased morbidity and mortality, and that any positive outcomes may be down to chance alone. MHT can be seen as a brutal method of treatment onto a severely damaged brain, and as so many intricate complications may arise as its effects cascade heavily onto the damaged hypoxic tissues (Moore, 2011). Furthermore, there exists no definitive evidence from random controlled trials that confirm its usefulness in the in-hospital environment (Sydenham et al. 2009), however, t should be noted that, in the main, these trials have used cooled intravenous saline to induce MTH in a slow manner.
In the UK, the National Institute for Health and Clinical Excellence (NICE) (2011) endorses MTH where patients are cooled to a core of 32–34 ºC after return of spontaneous circulation (ROSC) in the pre-hospital setting. The method it suggests is by cooling blankets and/or ice packs as well as invasive endovascular procedures such as infusion of cold saline solution (NICE, 2011). Using intravenous saline is a cost–effective and easy method, as paramedics often use it to treat hypotension. However, the problem is the slow speed of induction of MHT which may account for poor results in trials (Moore, 2011). On the other hand however, intranasal cooling, although unproven, is much faster (National Horizon Scanning Centre, 2012) and can deliver positive results where slow induction has failed to do so (Moore, 2011).
Benefits of fast pre hospital intranasal cooling
Pre-hospital cooling may be related to greater defence of brain function and brain tissue (Moore, 2011). Current approaches of using intranasal cooling in the pre-hospital setting with OHCA are being trialled. More positive results for patients who are rapidly cooled at point cardiac arrest or TBI injury may become apparent (Castrén, 2010; Lyon, 2012; PRINCESS, 2012). Transnasal evaporative chilling demonstrates adequate heat transfer ability for it to be effective at rapid cooling. In intra-arrest conditions, transnasal evaporative cooling has sufficient heat transfer capacity for cooling of the patient. It can be used as MHT in TBI and has been shown to advance survival in pigs (Castrén, 2010).
Rhinochill intranasal is a cooling device designed to cool the brain post cerebral insult by spraying a mixture of coolant-oxygen into the nasal cavity. Designed for cardiac arrest and TBI or stoke it provides rapid cooling (Castrén, 2010) to the brain intranasally. The potential for use by paramedics in the pre-hospital phase of TBI is reasonable as it can be emplyed as a hand held portable device, is battery operated, and is also simple to use after training. The device consists of a control unit, the coolant in a bottle and the transnasal catheter that delivers the transnasal evaporative cooling and allows early preservative brain cooling at the scene of injury (National Horizon Scanning Centre, 2012). Clearly, further research on improving results from OHCA is required, and paramedics should not be distracted by the promise of MTH when basic resuscitation is more urgent and when transport to hospital journeys are small (Lyon, 2012).
The underlying question or role of MTH in the pre-hospital setting of TBI is whether it is important to cool the patient as near to the time of brain injury as possible. Moore et al (2011) indicate this when discussing the evidence from animal models of a ‘therapeutic window’ where it is time critical to induce the MTH in patients with TBI as early as possible in order to gain beneficial effects in randomised control trials that take place in hospital. Although, two significant studies of adults and children (Clifton et al, 2001; Hutchinson et al, 2008) found no improvement of neurological outcome from using MTH in TBI their studies may have been compromised by ‘slow onset of cooling’. Moore (2011) suggests that in both above studies, induction of MTH in TBI was delayed from injury time and would only start on hospital arrival and was delayed again through a lack of rapid fast induction cooling methods.
For instance, in the Clifton et al (2001) study, the time taken to get to the target temperature was 8.4 hours. Again, in the Hutchinson et al (2008), study the time delay was 10.2 hours. Moore et al's view of the negative impact of delay to cooling to optimum MTH of 32–35 ºC (Moore et al, 2011) was partially substantiated by a sub-group in the Clifton Trial who were patients already hypothermic on hospital arrival.
This sub-group of patients had significantly better results in terms of long-term neurological measures and outcomes than the control group of normothermic TBI patients (Clifton et al, 2001). Moore et al (2011) suggests that in order to test if earlier hypothermia in terms of controlled MTH in TBI patients in the pre-hospital setting would produce improved results for future in-hospital part of the randomised control trials—paramedics should initiate MTH in the very location of the TBI injury and at the earliest point to injury possible.
Within TBI research, experimental models show that hypothermia started pre-injury shows a reduction in mortality and neurological damage and therefore shows improved neurological outcomes (Clifton et al, 1991; Jiang et al. 1992; Lyeth et al, 1993). Indeed, animal studies have indicated that when hypothermia is started within a few hours post-primary injury, there may be improved neurological results as aconsaquence (Colbourne, 1995; Clark, 1996; Markgraf, 2001; Roelfsema et al, 2004; Lawrence et al. 2005). This indicates that early pre-hospital MTH by paramedics to the patient may have beneficial effects, as MTH can successfully guard white matter after ischemia in equivalent animal models—however, these positive effects only appear if induced early after the injury to the animal (Roelfsema et al, 2004).
Whether animal studies are transferable to humans is a difficult and often infuriating question to consider. Indeed, over the last two decades many trials of hypothermia and TBI patients have supported the view that MTH is favourable, however, some confounding factors remain such as; the rate of induction; the actual period of hypothermia, and lastly, the rate of re-warming the patient back to body temperature (Marion et al, 1997; Liu et al, 2006).
Favourable research into MTH in TBI
Looking into these variables an early study in 2000 with a one year follow-up evaluation of 87 cases Jianget al (2000) found that long-term MHT significantly progresses to positive consequences in patients treated in hospital with severe TBI. The aim was to systematically evaluate protective effects of longer term MHT (three to 14 days between 33–35 ºC) on outcome with TBI showing Glasgow Coma Score of less-or-equal-to eight. One group (consisted of 43 patients) was in the MHT scenario with temperatures between 33–35 ºC for between three to 14 days. Their rewarming was based on intracranial pressure (ICP) settling back to a normal level. The second group (consisted of 44 patients) were in the normothermia setting and had temperature maintained between 37–38 ºC. Outcomes were examined one year after the experiment was conducted using the Glasgow Coma Scale, and results show that one year later TBI mortality rate was 25.58 % representing 11 out of 43 patients with favourable outcomes consisting of good recovery or moderate disability at a level of 46.51 in 20 of the 43 patients ( Jiang, Yu and Zhu, 2000). However, in the normothermia group mortality rates of 45.45% (20 out of 44) and indeed, the rate of favourable outcomes was also worse at 27.27 % which was only 12 out of the 44 patients (P < 0.05). In addition, MHT reduced ICP (P < 0.01) and even inhibited hyperglycaemia (P < 0.05). Rates of complications were of non-significance between groups.
The POLAR (Prophylactic HypOthermia to Lessen trAumatic brain injuRy) consists of randomised, blinded, controlled trials using hypothermia in patients who have sustained major TBI (ClinicalTrials.gov Identifier:NCT00987688). These trials, conducted in 2012 are directed at six sites across New Zealand and Australia and are endorsed by the Australian and New Zealand Clinical Trials Group (ANZICS CTG). These modern trials plan to use a cohort of 500 TBI patients aged 18–60 who suffer severe TBI and are subsequently intubated (Glasgow Coma Scale eight or less). Severe TBI patients will be randomised to be given either early and continuous hypothermia (33 º C) for between 72 hours and seven days or normothermia (36.5–37.5 º C). So, in the pre-hospital setting, paramedics will be using pre-hospital randomisation, rapidly induce hypothermia on scene with cold fluids and subsequent rewarming will take place 72 hours or later (up to seven days) and when intracranial pressure (ICP) is controlled. Outcome measures will be Glasgow Outcome Scale (GOS) of five to six (Nichol and Cooper, 2009).
Conclusions
In conclusion, in terms of the role of induced hypothermia in the management of head injury in the pre-hospital setting in UK paramedic practice—the jury is still very much out. With no significant evidence supporting MHT either in OHCA (Bernard et al, 2010; 2012) or TBI (Clifton, et al 2001; Hutchinson et al, 2008) there cannot be the suggestion of placing MHT for TBI into mainstream pre-hospital paramedic practice in 2012/13 onwards with concomitant detailed national (Joint Royal Colleges Ambulance Liaison Committee (JRCALC), 2006) and local guidelines. The only present role for MHT in TBI in UK paramedic practice is in randomised, blinded, controlled trials (preferably large scale clinical trials) such as POLAR (Nichol and Cooper, 2009).
Future research and action
A sensible pre-hospital trial protocol development includes ambulance services and the receiving hospital/s working as multi-disciplinary teams. For instance, with the East of England Trauma Network Launch on 25 May 2012, any new procedures being used in random controlled studies for MHT and TBI in the pre-hospital area would fit well. It would give paramedics facing severe pre-hospital TBI scenarios (where MHT may be used as part of the randomisation of the trial) a major receiving trauma centre hospital to go to and modern trauma network to support them (East of England Trauma Network (2012). In terms of current research, the vast majority of TBI research and practice with MTH is in-hospital. In looking at whether pre-hospital MTH within the context of TBI has a role—a further meta-analysis research is needed of relationships between inhospital results and pre-hospital paramedic rapid induction of MHT in TBI. Clearly, the two may be inseparable.
However, it might be the case that MTH for TBI should only be initiated in-hospital and perhaps the POLAR study will help to confirm or deny this (Nichol and Cooper, 2009). If, however, MHT is initiated in the pre-hospital field it would need to be stably maintained from point of induction through to handover at hospital and onwards until the time iof controlled rewarming. Issues that need to be addressed include methods of cooling, shivering prevention using sedation and reliable monitoring of core temperature (Upchurch, 2007). In addition, the local hospital/s ability to maintain 24 hour MTH patient services would be critical to any new system for TBI hypothermia treatments.