Jan 31, 2014 - 2211-419X ª 2014 Production and hosting by Elsevier on behalf of African .... TTM can be achieved using inexpensive methods16 there is. 161.
AFJEM 174 31 January 2014 African Journal of Emergency Medicine (2014) xxx, xxx–xxx
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African Federation for Emergency Medicine
African Journal of Emergency Medicine www.afjem.com www.sciencedirect.com
EDITORIAL ARTICLES
Yesterday, today and tomorrow in Targeted Temperature Management 5 Q1 7 6 9 10 11 12 13
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‘‘Tomorrow and tomorrow and tomorrow,’’ mused Macbeth,1 and indeed we are all interested in tomorrow. Despite the exponential development of many medical fields, we, as practitioners, are often faced with the dilemma: what I did for patients yesterday has been proven to be bad today. Who knows what tomorrow will bring. . .?
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Introduction
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The recent publication of two trials relating to the fields of Therapeutic Hypothermia (TH) and Targeted Temperature Management (TTM) has created a great deal of confusion for Emergency Physicians attempting to practise evidencebased medicine.2,3 While hypothermia was considered to be the gold standard, it is likely that prevention of hyperthermia was more important. So what is the impact of the new studies on our practice, and what are the ramifications in resourcepoor settings?
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Yesterday and today
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Following extensive animal modelling in the 1960s, Safar et al. pioneered the concept of induced hypothermia following cardiac arrest.4 However, it was not until the publication of three landmark trials early in the 21st century that TH was considered not only a viable therapeutic modality, but rather an absolute necessity. In 2001, Idrissi et al. performed a small single-centre study using TH for out-of-hospital pulseless electrical activity (PEA) or asystole and demonstrated a staggering four times improvement in survival to hospital discharge with a favourable neurological outcome. These results did not meet statistical significance due to the small size of the trial.5 In 2002, Holzer et al. published the now infamous HACA trial – a large multi-centre trial using TH for out-of-hospital Peer review under responsibility of African Federation for Emergency Medicine.
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ventricular fibrillation (VF). The authors demonstrated not only a statistically significant improvement in survival rates at hospital discharge with a favourable neurological outcome, but also that this advantage was maintained six months later.6 Bernard et al. published a small multi-centre trial focusing on TH following out-of-hospital VF in the same year. They, too, demonstrated the statistically significant improvement in survival rates at hospital discharge with a favourable neurological outcome in the hypothermic group.7 The International Liaison Committee on Resuscitation (ILCOR) published an advisory statement in 2003 that unconscious patients with return of spontaneous circulation (ROSC) after out-of-hospital VF cardiac arrest should have TH at 32–34 C for 12–24 h. They also advised that it may be of benefit for other cardiac arrest rhythms and for in-hospital arrests.8 The current American Heart Association (AHA) and ILCOR guidelines recommend TH as a Class 1 intervention in comatose patients following ROSC after out of hospital cardiac arrest secondary to VF.9,10 These recommendations suggest that induced hypothermia may be considered in comatose patients following ROSC after in-hospital cardiac arrest (any rhythm) and out-of-hospital cardiac arrest (PEA and asystole).10,11 Furthermore, healthcare providers are advised to monitor core temperature after ROSC and intervene to prevent hyperthermia – particularly in the first 48 h.10,11
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Today and tomorrow?
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As 21 February 2002 marked the beginning of the TH era, so the landmark articles from 17 November 2013, 11 years later, have reinforced the core concepts of TH (control the temperature and prevent hyperthermia and fever) with the release of both the TTM trial in the NEJM and the induction of pre-hospital mild hypothermia by Kim in JAMA.2,3 The TTM trial was designed to detect a 20% reduction in the hazard ratio for death when comparing post-cardiac arrest induced hypothermia between two different temperatures – 33 and 36 C. They analysed the data of 939 patients who had ROSC after both shockable and non-shockable rhythms. This trial showed that there was no statistically significant outcome benefit between the two patient groups and, in fact, demon-
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strated possible harm for those patients who were assigned to the lower temperature as they had a higher risk of hypokalaemia. Although this trial had a fairly rigorous protocol, some queries remain:
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While the trial did not demonstrate a 20% reduction in hazard ratio, there may still be a benefit albeit smaller and this might only be detected if there were larger patient numbers included in the trial. This trial differed substantially from the original trials in that both patient groups had the intervention and hyperthermia was prevented i.e. there was still active management of the patients’ temperature. The optimum temperature target is still unknown. In both groups, there was a delay in instituting the intervention. From animal studies,12–14 we know this can be detrimental although from the Kim trial, there was no effect (see below). In the 33 C group, re-warming took place at the faster side of the recommended rewarming rate (0.5 C per hour). Although there are no studies which have outlined the optimum rewarming rate in cardiac arrest patients, it is plausible that slow rewarming will better preserve the neuroprotective effects of hypothermia.15 Therefore a faster rewarming may also have negatively impacted this group.
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In the pre-hospital trial by Kim, where both VF and nonVF cardiac arrest patients received early induction of mild hypothermia compared to standard hospital induction, there was no benefit found with regard to neurological outcomes or survival. There was, however, potential harm as those patients receiving the cold intravenous fluids had a higher risk of re-arrest pre-hospital as well as an increased risk of pulmonary oedema in the first 24 h post-admission.
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Application in the resource-poor environment
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When considering the potential implementation of TTM in resource-poor settings, there are several factors that need to be carefully considered. Firstly, there is no evidence for or against the use of TTM following cardiac arrest in resource-limited settings. Indeed, if the evidence for TTM following cardiac arrest is unclear in the best-resourced areas of the world, then the evidence favouring TTM in low and middle income countries must be even more uncertain. Furthermore, whether the available evidence from well-resourced settings can be directly translated into such different populations is doubtful. Secondly, TTM must be considered as only one component of a bundle of elements constituting post-cardiac arrest care. Unless the other constituents of care can be effectively administered TTM alone is likely to be of limited benefit, or may even be harmful. There are basic minimum infrastructure and staffing requirements that must be fulfilled for TTM to be feasibly implemented. While it is easy to induce hypothermia in the ED using one of several available methods (especially with a target temperature of 36 C), the important part of TTM is the avoidance of hyperthermia for up to 72 h post-cooling. This requires intensive resources extending beyond the ED.
Editorial Clearly the level of resources at any particular facility will determine whether a post-cardiac arrest TTM programme should be instituted:
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If resources in any particular facility are routinely consumed in the management of conditions with similar (or poorer) prognosis than arrythmogenic cardiac arrest, such as decompensated heart failure or stage 4 malignancies, then it is reasonable to motivate strongly for complete and comprehensive post-cardiac arrest care, including TTM. Generally a hospital below the level of a tertiary or academic centre will not be able to deliver comprehensive post-cardiac arrest care since the requirements would include the availability of technical equipment, an intensive care unit, specialised imaging facilities, highly differentiated clinical services and an infrastructure able to complete the protocol correctly.
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152 It is an important principle that post-cardiac arrest care must be delivered in every facility where these patients are 153 seen. Whether this is complex resuscitative care or palliative 154 care will depend on the available resources and clinical sce155 nario. Every facility should, however, have a written policy 156 on the palliative care plan for the post-cardiac arrest patient. 157 The only studies available on TTM in resource-poor set158 tings are those in neonates. While there is some evidence that 159 TTM can be achieved using inexpensive methods16 there is 160 no evidence of equivalence. Other studies have either recom- Q8 161 mended not to use TTM outside academic centres17 or have 162 yet to produce real results.18 163
Conclusion
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In a resource-rich environment, there is no doubt that TTM is of benefit for comatose patients following ROSC after cardiac arrest. It does appear however, that some refinement in protocols is required to optimise patient care. TTM in the resourcepoor environment is not as clear-cut, and needs a careful balancing act between resources consumed and benefit achieved, but comprehensive post-cardiac arrest care must be included if TTM is to be considered. The old bush-medicine lore certainly applies: do what you can – where you are – with what you have; but TTM should probably not be prioritised above other aspects of post-cardiac arrest care. Oh, and use 36 C rather than 33 C.
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References
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1. Shakespeare W. Macbeth. Online[cited 17 December 2013] Available from: http://nfs.sparknotes.com/macbeth/page_202.html. 2. Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, et al. Targeted temperature management at 33 C versus 36 C after cardiac arrest. N Engl J Med 2013;369(23):2197–206. 3. Kim F, Nichol G, Maynard C, Hallstrom A, Kudenchuk PJ, et al. Effect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest: a randomized clinical trial. JAMA 2013. http://dx.doi.org/10.1001/ jama.2013.282173 Epub ahead of print. 4. Kochanek PM, Drabek T, Tisherman S. Therapeutic hypothermia: the safar vision. J Neurotrauma 2009;26(3):417–20.
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5. Hachimi-Idrissi S, Corne L, Ebinger G, Michotte Y, Huyghens L. Mild hypothermia induced by a helmet device: a clinical feasibility study. Resuscitation 2001;51:275–81. 6. Holzer Mon behalf of the Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl JMed 2002;346(8):550–6. 7. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346(8):558–63. 8. Nolan JP, Morley PT, Vanden Hoek TL, Hickey RW. Therapeutic hypothermia after cardiac arrest. An advisory statement by the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation. Resuscitation 2003;57:231–5. 9. American Heart Association. 2005 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2005;112:IV-1–IV-203. 10. American Heart Association. 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Circulation 2010;122(18):S640–993. 11. Nolan JP, Hazinski MF, Billi JE, Boettiger BW, Bossaert L, et al. 2010 International consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations. Resuscitation 2010;81S:e1–e25. 12. Kuboyama K, Safar P, Radovsky A, Tisherman SA, Stezoski SW, Alexander H. Delay in cooling negates the beneficial effect of mild resuscitative cerebral hypothermia after cardiac arrest in dogs: a prospective, randomized study. Crit Care Med 1993;21:1348–58. 13. Abella BS, Zhao D, Alvarado J, Hamann K, Vanden Hoek TL, Becker LB. Intra-arrest cooling improves outcomes in a murine cardiac arrest model. Circulation 2004;109:2786–91. 14. Takata K, Takeda Y, Sato T, Nakatsuka H, Yokoyama M, Morita K. Effects of hypothermia for a short period on histologic outcome and extracellular glutamate concentration during and after cardiac arrest in rats. Crit Care Med 2005;33:1340–5. 15. Polderman KH, Herold I. Therapeutic hypothermia and controlled normothermia in the intensive care unit: practical considerations, side effects, and cooling methods. Crit Care Med 2009;37:1101–20. 16. Kim JJ, Buchbinder N, Ammanuel S, Kim R, Moore E, Neil O’Donnell N, et al. Cost-effective therapeutic hypothermia treat-
3 ment device for hypoxic ischemic encephalopathy. Med Devices Evid Res 2013;6:1–10. 17. Walla SN, Lee ACC, Niermeyerc S, English M, Keenane WJ, et al. Neonatal resuscitation in low-resource settings: What, who, and how to overcome challenges to scale up? Int J Gynaecol Obstet 2009;107(Suppl. 1):S47–64. 18. Robertson NJ, Hagmann CF, Acolet D, Allen E, Nyombi N, et al. Pilot randomized trial of therapeutic hypothermia with serial cranial ultrasound and 18–22 month follow-up for neonatal encephalopathy in a low resource hospital setting in Uganda: study protocol. Trials 2011;12:138.
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Roger Dickerson * Q2 Department of Emergency Medicine, Chris Hani Baragwanath Q4 242 Academic Hospital, South Africa Division of Emergency Medicine, University of the Witwatersrand, South Africa Q3 * Correspondence to Roger Dickerson. Department of Emergency Q5 249 246 Medicine, Chris Hani Baragwanath Academic Hospital, South Africa. Q6 247 248
Mike Wells Department of Emergency Medicine, Netcare Union Hospital, South Africa Division of Emergency Medicine, University of the Witwatersrand, South Africa Lara N. Goldstein Department of Emergency Medicine, Helen Joseph Hospital, South Africa Division of Emergency Medicine, University of the Witwatersrand, South Africa
Received 10 January 2014; accepted 10 January 2014
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