Targeted temperature management: beneficial or not?

Targeted temperature management: the journey so far

TTM is not a novel phenomenon, with concepts of hypothermia as a therapeutic measure having been applied historically (Marion et al, 1996). In ancient Greece, the physician Hippocrates favoured packing soldiers' wounds with ice and snow to promote vasoconstriction and minimise blood loss (Polderman, 2004). As time has progressed, so has medical research and recommendation for its use.

After two landmark human studies were published simultaneously in 2002, TTM began to be used medically for conditions where neurological function was at risk (Bernard et al, 2002; Hypothermia after Cardiac Arrest Study Group, 2002). Data suggested that survival and neurological recovery were positively correlated with the rapid administration of TTM (Zhao et al, 2008). In 2003, the American Heart Association and the International Liaison Committee on Resuscitation adopted and authorised the use of TTM in cardiac arrest, with the criterion of being instigated in ventricular fibrillation (VF) arrests only (Nolan et al, 2008; Lee and Asare, 2010). Later, a review by the Canadian Association of Emergency Physicians Critical Care Committee (2004) stated that TTM should not be retained for only use in VF arrests, recommending its use in all presenting cardiac arrest rhythms.

The treatment goal for TTM is to achieve a core body temperature of 32–36° degrees as quickly as possible as, for every hour of delay, mortality increases by 20% (Leong et al 2017). To date, a large proportion of hospitals worldwide continue to embrace TTM within intensive care units for care and management after return of spontaneous circulation (ROSC). As TTM's neuroprotective properties are time-dependent, it has been suggested that introducing it into the prehospital field could be beneficial and transform post-arrest survival statistics.

Presently, helicopter emergency medical services (HEMS) are often dispatched to attend OHCA incidents, as survival from OHCA is largely dependent on prehospital events. Often carrying a prehospital doctor and critical care paramedics, HEMS are capable of employing advanced medical support methods at the roadside including prehospital anaesthesia, advanced airway interventions, inotropic support and initiating therapeutic hypothermia. However, these provisions are limited because HEMS dispatch is often sporadic. With HEMS resources sparse, they are routinely retained for the most critical of jobs. Therefore, the use of TTM is not widespread. Yet evidence suggests that prehospital TTM could be an advantageous therapy for all OHCA patients. In addition, local adoption of TTM is restricted as, in the UK, roadside paramedics are not currently permitted to administer anaesthetic agents or muscle paralytics, or initiate cooling.

In a effort to increase local adoption of TTM as a standard of resuscitative care, this article examines and explores TTM treatment options that could be easily instigated by local providers.

Pathophysiology and effects of TTM

OHCAs continue to have substandard consequences, with 50% of patients worldwide developing some form of neurological disability (Iordanova et al, 2017). Outcomes can vary from reversible harm with full recovery to irreversible damage and brain death. TTM can help to hinder and alleviate some of these mechanisms, since pathophysiological responses are susceptible to temperature change.

Although its mechanisms are not fully understood, the induction of hypothermia generates a cool internal environment, which inhibits cellular functions that contribute to cell death (Scales et al, 2017). Incidences that are diminished include excitotoxicity, inflammatory responses and cellular injury (Tripathy and Mahapatra, 2015). As the body's core temperature falls, for every 1°C of cooling, oxygen demand required for metabolic pathways is suppressed by 6% (McCullough et al, 1999). Yet Yenari and Han (2012) suggest that TTM can help increase cerebral neuronal healing by promoting cerebral blood flow, easing intercranial pressure and protecting blood-brain barrier integrity.

A prospective, randomised controlled trial (RCT) by Bernard et al (2010) speculated that early induction of TTM by paramedics in post-ROSC patients before they arrive at hospital would prove advantageous. This trial ascertained whether prompt prehospital TTM administration would be more favourable than delayed initiation of TTM in hospital. In this study, 398 eligible participants were randomised by attending paramedics who carried 10 sealed envelopes, with the indicated treatment choice inside, either paramedic cooling (intervention) or hospital cooling (control). Out of the 398 participants, only 234 patient records were obtainable: 118 in the prehospital and 116 in the hospital cooling group. Each group was analysed for matching baseline characteristics such as age, sex, cardiac rhythm and total cardiac arrest time. Results for both groups were comparable, with findings for the above traits all associated with positive post-cardiac arrest outcomes.

Treatment options

A variety of methods used to induce TTM have been studied, each differing in their ease of use, effectiveness and level of invasion (Polderman and Herold, 2009). This includes external and internal approaches such as: ice packs along the axilla (armpits), groin and side of neck; cooling pads or blankets; and the infusion of cool intravenous fluids.

Cooling with fluids

A prospective, multicentre observational trial conducted by Bruel et al (2008) investigated if prehospital induction of therapeutic hypothermia during advanced life support was feasible, effective and safe. In clinical practice, often a fluid bolus is routinely administered during intra-arrest to increase circulating volume during CPR and treat hypovolaemia (Resuscitation Council (UK), 2015). Keeping in accordance with current European guidelines, Jacobs et al (2004) and Bruel et al (2008) wanted to see if changing this to an infusion of cool fluids would prove valuable as a neuroprotective strategy. Outcomes from Bruel et al (2008) showed that 20 (60.6%) patients were successfully resuscitated. A review at 6 months found that, out of these 20, four (20%) were alive, and three of them had no neurological deficit.

Kämäräinen et al (2009) conducted a larger RCT to examine the efficacy and safety of inducing TTM with cooled Ringer's solution (Hartmann's) after ROSC in OHCA. Of a cohort of 44 patients, 18 were randomised to receive treatment, which was a rapid infusion of 4°C Ringer's solution, with the remaining 25 allocated to normal care. The infusion was set at a rate of 100 ml/minute until a target nasopharyngeal temperature of 33°C was achieved. Nasopharyngeal temperatures were obtained in the control group for comparison purposes. Baseline temperatures attained on scene before intervention were alike in both groups; however, secondary temperatures recorded on hospital arrival highlighted discrepancies, with nasopharyngeal temperatures being notably lower in the treatment group (34.1°C) than in the control group (35.2°C). Although Kämäräinen et al (2009) state that infusion of cold fluid therapies by paramedics intra-arrest is feasible, simple and effective, they advise caution to avoid over-cooling, as minuscule amounts when infused can decrease core body temperature rapidly.

Hartmann's or saline?

Bernard et al (2010) hypothesised that using cold intravenous fluids for TTM was an appealing option, since paramedics already employ aspects of fluid resuscitation in OHCA, although they found no significant differences in survival and neurological outcome at discharge. However, an RCT, referred to as the Rapid Infusion of Cold Normal Saline (RINSE) trial, was conducted by Bernard et al (2016) with the primary goal of establishing whether TTM caused by the infusion of cold saline had any measurable effect on rates of survival-to-hospital discharge.

A total of 1198 patients were appointed who received either TTM during CPR (618 patients) or standard care (580 patients). Scrutiny of results uncovered no significant trend between the infusion of cold saline and improved hospital discharge outcomes, with 10.2% of TTM patients alive at hospital discharge compared with 11.2% of those receiving standardised care. Bernard et al (2016) suggested that intravenous cold saline administered at some stage during CPR could inhibit ROSC.

Moreover, in 2012, Bernard et al found that TTM achieved with a cool Hartmann's solution had favourable effects regarding both hospital discharge and patient rehabilitation. This Rapid Infusion of Cold Hartmann's (RICH) Trial (Bernard et al, 2012), aspired to evaluate the consequences of substituting an ice-cold saline infusion with an ice-cold Hartmann's one during active CPR and resuscitation. Results produced were encouraging, with 17% (8) patients receiving prehospital Hartmann's-induced TTM being neurologically intact at time of discharge, supporting ice-cold Hartmann's as the preferred choice of crystalloid for this type of cooling. This speculation had previously been seen when comparing findings related to in-hospital cooling, as only three patients (7%) were discharged having made a full neurological recovery.

An explanation of these results was provided by Berthet et al (2009), who suggested that the lactate concentration of Hartmann's solution has a strong influence. Blood lactate is an important alternative energy source for the brain, particularly in ischaemic conditions where oxygen and thus adenosine triphosphate supply is depleted, which provides a vital protective role against excitotoxicity (van Hall et al, 2009). As well as its neuroprotective properties, lactate has been seen to improve cardiac function. Berthet et al (2009) argue that it is these valuable mechanisms that make it a helpful therapeutic tool.

With regard to its clinical application, the administration of Hartmann's for some ambulance services is difficult, because it has been removed from frontline inventory.

Patient safety concerns

In terms of patient safety, a major concern associated with using fluids to induce hypothermia is the generation of pulmonary oedema and subsequent re-arrest.

A hypothermia working group based in New York City (NYC Project Hypothermia Working Group and John Freese Fire Department of New York, 2018) sought to measure the incidence of pulmonary oedema after induction of TTM with ice-cold fluids and assess its impact on immediate outcomes. During the designated study period, 4727 non-traumatic cardiac arrest resuscitations were recorded with 31.7% achieving ROSC and 7.6% (361 patients) experiencing pulmonary oedema. They concluded that, although clinical signs of pulmonary oedema were apparent in some OHCA patients receiving large quantities of ice-cold fluids, when compared with the control group the number of cases were minimal.

Kämäräinen et al (2009) identify that, although safety and patient welfare concerns must be addressed and considered, the occurrence of pulmonary oedema and over-cooling secondary to infusion-induced TTM is sporadic. With readily available remedies to combat adverse effects such as furosemide, the probability of pulmonary oedema is low and chance alone should not contraindicate crystalloid use for TTM (Kämäräinen et al, 2009).

However, Peberdy et al (2010) note that, while cool fluid therapy may be given to start the process, further modalities must be used to conserve hypothermia. One technique that has been proposed is the induction of TTM through the combined use of intravenous fluids and ice packs.

Cooling with ice packs and cooling pads

Scales et al (2017) undertook an RCT (ICEPACS [Initiation of Cooling by Emergency medical services to Promote the Adoption of in-hospital therapeutic hypothermia in Cardiac arrest Survivors]) to investigate the use of surface ice packs as a potential prehospital cooling approach. They wanted to examine if this simple provision could assist in dispensing such a complex therapy and improve TTM success.

Uray et al (2014), in their retrospective observational study, had similar goals. Uray et al (2014) highlighted that cooling pads were extremely efficient and optimum TTM temperatures were reached rapidly, with oesophageal temperatures dropping from 36.6°C to 33°C in just over an hour (70 minutes). Of all 15 participants enrolled, 93% survived for 24 hours and 36% to hospital discharge. An evaluation carried out after 6 months of completion revealed that all 36% continued to display full neurological recovery. Scales et al's (2017) study discovered that the time to target temperature measurements were similar among both intervention (5.4 hours) and control groups (4.8 hours), indicating that prehospital cooling induced solely with strategically placed ice packs (neck, axillae and groin) does not increase ‘successful’ TTM (defined as achieving the target temperature within 6 hours of hospital arrival). However, with greater survival figures, both surface methods are advantageous for patient prognosis. Despite this, considerations must be given to the logistical implications of this mode of TTM delivery in the prehospital environment.

Shivering contributes to problems associated with temperature modulation and was observed when these cooling techniques were used. Shivering is an involuntary reflex that is activated when the hypothalamus thermostat detects temperatures lower than 36–37°C (Urry et al, 2016). Skin temperature alone can influence the occurrence of shivering by up to 20% (Presciutti et al, 2012). For this reason, the overall value of surface cooling techniques for TTM have been questioned as therapy effects may be blunted through shivering stimulated by the initial contact with skin.

Help or hinder?

To establish TTM's neuroprotective abilities, Tiainen et al (2007) examined the effects of therapeutic hypothermia on cognitive functioning. This was further examined in Look et al's (2018) RCT, which evaluated the survival-to-hospital discharge and neurological outcomes associated with both internal and external cooling modalities. On reviewing the results, it was evident that patients whose cardiac arrest was cardiac in origin and who sustained ROSC showed a better neurological outcome and a decreased risk of developing cardiac arrhythmias when receiving internal cooling than those in normothermia control conditions. These findings led Look et al (2018) to construe that internal cooling could potentially boost survival in carefully selected patients. In clinical practice, this could prove problematic as it is not always possible to determine the aetiology of arrest. Influential factors at each cardiac arrest can lead to different decisions and variability in practice. Variations in context and circumstance are vast, and therefore this recommendation may not be transferable to clinical practice as paramedics cannot always deduce the origin of every cardiac arrest (Brandling et al, 2016).

Prehospitally, paramedics must be cautious in their management of cardiac arrests where TTM is induced as the myocardium is easily susceptible to manipulations and treatment procedures performed. This is compounded by the effect of anti-arrhythmic drugs and electrical defibrillation being minimised in hypothermic conditions (Lakshmanan et al, 2013). Harris and Jones (2018) report that paramedics must take particular care in such circumstances when initiating such treatment, as this can predispose to malignant arrhythmias.

Conclusion

Vulnerability to irreversible neurological insult is high among all patients who have had a cardiac arrest. With guidelines recommending the rapid administration of TTM after cardiac arrest for its neuroprotective qualities, the innovation of expanding and employing this technique in the prehospital field has been subject to debate, scrutiny and review. Strongly supported by pathophysiological evidence, the use of TTM has been shown to promote neurological functioning and suppress other systemic complications, thus proving to be effective in both reducing the degree of impact of cardiac arrest on cerebral performance and improving patient prognosis.

In relation to TTM modalities, all methods evaluated in the present review were deemed suitable for use in the prehospital environment. In regard to practicality, it is clear that TTM achieved with cold fluids is both uncomplicated and cost-effective, with stock being both versatile and readily available.

Although there are some procedural limitations associated with TTM, when reviewed, the majority rarely transpire in the prehospital setting. With most evidence reporting minimal clinical side effects and promoting its preservation abilities, TTM in the prehospital setting could be established as the new cornerstone of neuroprotective strategies.

While the literature endorses the beneficial use of TTM in the management of all patients in OHCA (Dumas et al, 2011), its adoption in the UK is not widespread. Local awareness as well as experience in skill implementation is poor, yet the routine administration of TTM could become part of standard resuscitative care. It is recommended that researchers embark on further UK studies to deduce and distinguish which technique best satisfies prehospital demand and current UK working practices.

Key Points

CPD Reflection Questions