Hypothermia Protocols: The Big Chill AARON ELLENBOGEN, DO, MPH, FACN

Transcription

1 Hypothermia Protocols: The Big Chill AARON ELLENBOGEN, DO, MPH, FACN

2 And you thought the brain freeze from a Slurpee was bad 2

3 u Hypothermia u Hypo, meaning under, less than, beneath u Thermia meaning state of heat u The core temperature of the body drops below that level required for normal metabolism and body functions. u Severe/profound hypothermia is usually an accidental occurrence; mild hypothermia is practiced regularly in colder temperatures and in multiple winter sports and activities. 3

4 Hypothermia Classification Stage Clinical feature Degree Temperature Stage 1 Awake, shivering Mild degrees Stage 2 Drowsy, not shivering Moderate degrees Stage 3 Unconscious, not shivering Severe degrees Stage 4 No vital Signs Profound <19 degrees Wong KC. Physiology and pharmacology of hypothermia 4

5 Hypothermia Has a Long and Colorful History u Even back to the Edwin Smith papyrus, written some 5000 years ago u Hippocrates advocated the use of snow and ice packing to reduce hemorrhage in the wounded. u Whole body cooling was used as a tetanus therapy in 4 th -5 th century BCE u Hypothermia was used during wartime as an anesthetic procedure prior to amputation and during transport of critically wounded soldiers. Wang H, Olivero W, Wand D, Lanzino G. Cold as a Therapeutic Agent Polderman K. Applications of hypothermia in the ICU: opportunities and pitfalls of a promising treatment modality.

6 Hypothermia Has a Long and Colorful History 1938: Dr. Temple Fay used hypothermia to treat intractable pain, and developed his own cooling blanket with tubing for continuous infusion of chilled fluids. 6

7 Hypothermia Has a Long and Colorful History u 1950s Positive effect of hypothermia shown during cardiac surgery on animals u Beneficial effects of hypothermia on elevated ICP in experimental TBI with dogs, showing a direct effect between body temperature, increased ICP, and brain volume u First clinical trial for hypothermia in comatose patients following cardiac arrest, comparing 33 C with normothermia, and reporting a 50% survival in the hypothermia group, compared with 14% in the normothermia group Bigelow WG, McBirnie JE. Further experiences with hypothermia for intracardiac surgery in monkeys and groundhogs. Rosomoff HL, Holaday DA. Cerebral blood flow and cerebral oxygen consumption during hypothermia Williams GR, Jr, Spencer FC. The clinical use of hypothermia following cardiac arrest.

8 u Two pivotal trials, both randomized and controlled, brought therapeutic hypothermia into our modern protocols Bernard SA, Gray TW, Buist MD et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest.

9 Therapeutic Hypothermia Post Cardiac Arrest u Therapeutic hypothermia (TH) is the standard of care for post cardiac arrest care. u Begin protocol within hours of cardiac arrest u International Liaison Committee on Resuscitation (ILCOR) Nolan JP, et al. Therapeutic Hypothermia After Cardiac Arrest; An Advisory Statement by the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation. 2003

10 Therapeutic Hypothermia Post Cardiac Arrest u Mild to moderate cooling has been shown in multiple trials to improve neurologic outcome following global cerebral ischemia u Previous studies using hypothermia protocols below 32 degrees saw a marked increase in problematic side effects: ucardiac arrhythmias ucoagulopathy udifficulties maintaining temperature goals due to shivering behaviors.

11 New areas for TH u These successes have opened up questions of efficacy of TH in other types of cerebral injury u traumatic brain injury u focal ischemic problems such as stroke and intracranial bleeding. u Data of some positive effects has been quite strong, however, TH for focal ischemia is still considered experimental Hoesch RE, Geocadin RG. Therapeutic hypothermia for global and focal ischemic brain injury - a cool way to improve neurologic outcomes.

12

13

14 Hypothesis of Neuroprotection in Hypothermia u Precise mode of neuroprotection in TH is unknown and likely multifactorial. u Decreased cerebral metabolic rates of substrates including glucose and oxygen u Slowing of ATP breakdown (seen in controlled situations rather than the natural history) u Brain oxygen consumption is reduced by about 5% with every degree of temperature reduction. Erecinska M, et al. Effects of hypothermia on energy metabolism in mammalian central nervous system. Hagerdal M, et al. The effect of induced hypothermia on upon oxygen consumption in the rat brain

15 Hypothesis of Neuroprotection in Hypothermia u Neutrophil accumulation is modulated by granulocyte and intracellular adhesion molecule-1 (ICAM-1) and is reduced related to downregulation (usually upregulated in response to ischemia) u Known reduction in free radical generation, in glutamate release and in inflammation u Reduces brain edema u Interrupts necrosis and apoptosis Inamasu J, et al. Intra-ischemic hypothermia attenuates intracellular adhesion molecule-1 (ICAM-1) and migration of neutrophil. Nakashima K, Todd MM. Effects of hypothermia on the rate of excitatory amino acid release after ischemic depolarization Wang LM et al. Moderate hypothermia prevents neural cell apoptosis following spinal cord ischemia in rabbits.

16 The Big Picture 16 u Therapeutic hypothermia is thought to reduce damage from excitotoxins, free radicals, and inflammation and necrosis, perhaps leading to longer survival of neurons and possible improvement after reperfusion. Lyden PD, Krieger D, et al. Therapeutic hypothermia for acute stroke

17 What We Don t Know u What is the best modality? u What is the best target temperature? u What is the best time period for cooling and rewarming? Does that differ, injury to injury? u What is the best time period for initiation of therapy? u How do we keep patients from shivering, thus creating heat? u Can we use other proven techniques to help outcome (thrombolysis)?

18 Modality: External (surface) vs. Endovascular Cooling 18 External /Surface No advanced equipment, widely available, easy to use Less risk of catheter placement and complications Slower cooling Shivering Temperature management is more difficult Need for intubation and sometimes paralysis, limits neurological examinations Endovascular Newly developed devices, expensive, specialized, limited number Catheters have become more specialized less need for large volumes and less thrombotic complications More rapid cooling Less shivering Better surety of temperature management

19 Modality u Use of more focal cooling devices u Cooling helmets uintranasal catheters u Hard to measure true intracranial temperature without more invasive monitoring.

20 Modality u There is no one good answer u The Cooling for Acute Ischemic Brain Damage (COOL-AID) study group u Two trials u One with each modality u Both trials were small and not well powered for discussion of safety or efficacy Krieger DW, DiGeorgia MA, et al. Cooling for Acute Ischemic Brain Damage (COOL AID): an open pilot study of induced hypothermia in acute ischemic stroke DiGeorgia MA, Krieger DW, et al. Cooling for Acute Ischemic Brain Damage (COOL AID II): a feasibility trial of endovascular cooling

21 Target Temperature u Mild-Moderate temperatures appear better than severe (i.e., C see better outcomes earlier than temperature less than 27 C) u Medical complications of severe hypothermia include coagulopathies, cardiac arrhythmias, infections and heart failure u Even mild intervention, such as control of fever shows improved outcomes

22 How Long Should Patient s Be Cooled?

23 What is the most effective time period for cooling? u Time period of treatment and treatment time window u Is this injury specific? u How to know? u Animal models of transient and permanent cerebral ischemia u 22 hours of cooling after transient MCA occlusion showed better neuroprotection then 3 hours of cooling. Yanamoto, et al. Combination of intra ischemic and post ischemic hypothermia provides potent and persistent neuroprotection against temporary focal ischemia in rats

24 What is the most effective time period for cooling? ua gerbil model of two vessel occlusion u Benefit of intra-ischemic cooling on hippocampal cell damage u Only when continued for longer periods 4-6 hours prevented damage u 2 hours showed less effect u hour showed no protective effect u 24 hours of hypothermia had best long-term outcome Dietrich WD, et al. Intraischemic but not postischemic brain hypothermia protects chronically following global forebrain ischemia in rats. Colbourne F, et al. Prolonged but delayed postischemic hypothermia: a long term outcome study in the rat middle cerebral artery occlusion model

25 What Is the Right Time Frame for Cooling? u Trial of 72 hours of cooling on fetal sheep u Both 2-hour and 6-hour delay conferred neuroprotection. u Appears that cooling performed for a short period of time has a smaller window of opportunity. Roelfsema V, et al. Window of opportunity of cerebral hypothermia for postischemic white matter injury in the near-term fetal sheep Maier CM, et al. Delayed induction and long-term effects of mild hypothermia in a focal model of transient cerebral ischemia, neurological outcome, and infarct size.

26 Shivering as a Complication of TH u Humans have little recourse against the cold. u NorthFace doesn t count u Cutaneous vasoconstriction (keep blood close to organs rather than close to skin, where heat can be convected away). u Shivering is our only way of producing heat and our primary protection against hypothermia. Lyden PD, Krieger D, et al. Therapeutic hypothermia for acute stroke

27 Shivering as a complication of TH u Difficult to maintain cooling and reach target temperature when patients are shivering u Shivering and cold are uncomfortable u Raises blood pressure u Increases stress response u Leads to elevated cortisol levels and glucose levels, etc. Lyden PD, Krieger D, et al. Therapeutic hypothermia for acute stroke

28 Management of Shivering u Medications to reduce shivering work by acting on the hypothalamus to change thermoregulatory control. u Most narcotics and anesthetic agents work this way u Sedation and respiratory depression increase the need for airway protection. u Meperidine is an extremely effective medication for prevention of shivering u Low dosing (25mg) does not cause excessive sedation and decreases the shivering threshold by 2 degrees u Synergistic effects with Buspirone, again without significant sedation or respiratory depression. Mokhtarani M, et al. Buspirone and Meperidine synergistically reduce the shivering threshold. Lyden PD, Krieger D, et al. Therapeutic hypothermia for acute stroke

29 Management of Shivering u External warming u Awake patients can be cooled to 33 degrees, while utilizing external warming device u Trick the body into feeling warmer u Reducing shivering as well u Paralytics can be utilized u Interfere with neurologic examination u Appear to increase vent time Lyden PD, Krieger D, et al. Therapeutic hypothermia for acute stroke

30 Other Complications of Hypothermic u Coagulopathy is well documented Protocols u Platelet function is decreased at and below 35 C u Coagulation cascade is affected below 32 C u Extension of aptt is not consistently described, although has been noted u Theoretical risk of pneumonia and other infections, including wound infections. u Not well documented in TH of 24 hours Polderman KH. Mechanisms of action, physiological effects and complications of hypothermia.

31 Other Complications of Hypothermic Protocols u Electrolyte disorders can occur u Hypokalemia during cooling u Hyperkalemia with rewarming u GI motility is reduced u Ileus can develop u Patients should not be fed u Insulin levels go down u Patients can develop hyperglycemia u Caution when rewarming if blood sugar treated strictly

32 Therapeutic Hypothermia in Acute Ischemic Stroke

33 Therapeutic Hypothermia in Acute Stroke u Conventional therapies u Intravenous tpa for thrombolysis u Intra-arterial tpa more directed thrombolysis u Clot retrieval devices u These therapies help restore blood flow, thus return of substrate to the brain and are proven effective u Can TH be utilized as an adjunctive therapy?

34 Therapeutic Hypothermia in Acute Stroke u Numerous animal studies performed and published u TH elicits a more positive outcome, including smaller area of actual infarct with temporary occlusion of a major artery u If the occlusion of the artery was permanent, the effect of TH was lost u Reperfusion was necessary for any benefit to recovery Ridenour TR, et al. Mild hypothermia reduces infarct size resulting from temporary but not permanent focal ischemia in rats. Corbett D, et al. Persistent neuroprotection with prolonged post ischemic hypothermia in adult rats subjected to transient middle cerebral artery occlusion. Morikawa E, et al. The significance of brain temperature in focal cerebral ischemia: histopathological consequences of middle cerebral artery occlusion in the rat. Kader A, et al. The effect of mild hypothermia on permanent focal ischemia in the rat.

35 Therapeutic Hypothermia After Recanalization in Patients with Acute Ischemic Stroke (HARIS) u Trial design u 2 groups at 2 stroke centers. u All patients received iv-tpa u Resultant TICI 2b score(partial filling of one-half or greater of the arterial territory) confirmed by endovascular technique. u Center A - mild hypothermia protocol, all patients were intubated for 48 hour hypothermia and rewarming periods. u Center B - normothermia, standard of care therapy. Hong et al. Therapeutic Hypothermia After Recanalization in Patients with Acute Ischemic Stroke (HARIS)

36 HARIS Results 36 Hypothermia group unihss initial: 17 (15-18) ucerebral edema: 18 uhemicraniectomy: 4 umortality: 6 uclassified good outcome: 19 uclassified poor outcome: 20 Normothermia group NIHSS initial: 15.5 (12-17) Cerebral edema: 30 Hemicraniectomy: 5 Mortality: 5 Classified good outcome: 7 Classified poor outcome: 28

37 Conclusion From HARIS Trial Therapeutic hypothermia is associated with a decreased risk of brain edema, hemorrhagic transformation, and better clinical outcomes.

38 Traumatic Brain Injury and Therapeutic Hypothermia 38

39 Traumatic Brain Injuries (TBI) u A leading cause of morbidity and mortality in young people. u Most challenging problem in severe TBI: development of intracranial hypertension (ICH) due to brain swelling (cerebral edema) and its secondary complications of ischemia. u ICH: sustained intracranial pressures > mmhg u ICH: focus of multiple therapies, including uindirect therapies with osmotic therapy (mannitol and hypertonic saline) udirect therapies including decompressive hemicraniectomy and CSF drainage.

40 Management of Traumatic Brain Injuries u Major focus of TBI management is treatment of elevated intracranial pressure (ICP) u Fever prevention u Elevation of bed and increasing venous drainage u Normovolemia and normoglycemia u Sedation u Hyperventilation

41 Traumatic Brain Injuries u Fever in this population a most important factor u Cerebral metabolic rate is increased by fever and fever is a potent vasodilator; both increase risk of cerebral edema. u TH reduces production of cytokines by activated microglia as well as suppresses neutrophil accumulation u TH reduces post traumatic inflammation Rosomoff HL. Protective effects of hypothermia against pathological processes of the nervous system Rangel-Castillo et al. Management of intracranial hypertension.

42 Traumatic Brain Injuries u At least 11 randomized clinical trials looking at moderate TH for severe TBI umultiple single center and several multicenter trials u Although many single centers showed a positive benefit of hypothermia, the multicenter trials did not, and use of TH has fallen out of favor as a standard of care.

43 Traumatic Brain Injuries u Review of study literature, however, shows that ICP was reduced on average 10mmHg during treatment period u Reviewed the variety of treatments of ICP. u Consensus that while TH did not show consistent response for improvement of long term neurologic outcomes, neither did other therapies. Thus therapeutic hypothermia is really not a failure, and should be considered, perhaps in combination with other therapies. Schreckinger M, Marion DW. Contemporary Management of Traumatic Intracranial Hypertension: Is There a Role for Therapeutic Hypothermia?

44 Traumatic Brain Injuries u TBI is a continuum u Mild, moderate, severe u Even in severe TBI, the mechanism of injury appears to play an important role in the success or not of therapies. u Contusion vs. diffuse edema vs. hemorrhage may respond differently to various therapies Lescot, et al. Treatment of intracranial hypertension Saatman et al. Classification of traumatic brain injury for targeted therapies

45 Traumatic Brain Injuries u Very severe injuries, with ICPs over 40 mmhg and diffuse swelling may not respond to a multitude of treatment options. u Duration of therapies for TH are not entirely clear. u Complication of therapy has been the development of severe rebound ICPs with rewarming u Thought to be one reason that the multicenter trials did not show improved functional outcomes with TH

46 Traumatic Brain Injuries u Time period for TH may be better if extended to five days rather than two days in terms of ICP and rewarming phenomena, although appears to be at a cost of infection and pulmonary complications from cooling. u TCD may be an effective tool in determining which patients would benefit from a longer cooling protocol Iida, et al. Hyperemia prior to acute brain swelling during rewarming of patients who have been treated with moderate hypothermia for severe head injuries.

47 Conclusions u Exciting potential target for neuroprotection and recovery in catastrophic neurologic injury u It has clearly been shown to improve outcomes in cardiac arrest u Although mechanism may be different TH may be effective in focal injury ustroke u Traumatic brain injury u Additional research is needed