The clinical evidence: Hypothermia for other indications

Sicily, October 18 TH 2006 The clinical evidence: Hypothermia for other indications K.H. Polderman, internist/intensivist University medical center Utrecht, The Netherlands

That is why we need temperature management systems!! 1. Why should we care about temperature? 2. The role of temperature in the development of tissue injury; 3. Brain temperature: Hot Spots 4. Conclusions. Body temperature in critically ill patients should be viewed in much the same way as the heart rate: excess may be harmful, and in many cases requires treatment!!

Acute disseminated encephalomyelitis Level IV Grand mal seizures Level IV Cardiac arrest due to noncoronary causes Level IV Sepsis/septic encephalopathy Level IV Preventing/delaying cardiac arrest in severe hypovolemic shock Level IV Perioperative (vascular, cardiac and neurosurgery) Level III Stroke Level III Post-anoxic encephalopathy VT/VF Level I Post-anoxic encephalopathy Asystole/PEA Level III Traumatic brain injury improving outcome Level IIA Mitigating myocardial injury during Ischemia/reperfusion Level III Potential indications for induced hypothermia Traumatic brain injury - reducing ICP Level I Reversing cardiac shock following cardiac surgery Level III Hepatic encephalopathy (reducing ICP) Level III Subarachnoid haemorrhage Level IV Fever in presence of neurological injury Level IIB Perinatal asphyxia Level I Preventing cardiac injury during cardiac surgery Level III Delayed spinal ischemia Level IV ARDS Level IV Bacterial meningitis Level IV Spinal cord contusion Level IV

Acute disseminated encephalomyelitis Level IV Grand mal seizures Level IV Cardiac arrest due to noncoronary causes Level IV Sepsis/septic encephalopathy Level IV Preventing/delaying cardiac arrest in severe hypovolemic shock Level IV Perioperative (vascular, cardiac and neurosurgery) Level III Stroke Level III Post-anoxic encephalopathy VT/VF Level I Post-anoxic encephalopathy Asystole/PEA Level III Traumatic brain injury improving outcome Level IIA Mitigating myocardial injury during Ischemia/reperfusion Level III Traumatic brain injury - reducing ICP Level I Reversing cardiac shock following cardiac surgery Level III Hepatic encephalopathy (reducing ICP) Level III Subarachnoid haemorrhage Level IV Fever in presence of neurological injury Level IIB Perinatal asphyxia Level I Preventing cardiac injury during cardiac surgery Level III Delayed spinal ischemia Level IV ARDS Level IV Bacterial meningitis Level IV Spinal cord contusion Level IV

Destructive steps following various types of injury (ischaemia/reperfusion, trauma): Harmful inflammatory processes Calcium influx into cell, excitotoxic cascade Metabolism & energy production; in later stages metabolic demands Membrane leakage, oedema formation, intra-cellular acidosis Free radical production Mitochondrial injury & dysfunction Reperfusion injury Apoptosis, calpain-mediated proteolysis, DNA injury Others??? Local brain hyperthermia, cerebral thermo-pooling Suppression of epileptic activity & seizures? Coagulation activation, formation of micro-thrombi Increased bloodbrain barrier permeability, oedema formation Increased vascular permeability, oedema formation

Details... Calcium influx into cell, excitotoxic cascade Free radical production Mitochondrial injury & dysfunction

Details... Apoptosis, calpain-mediated proteolysis, DNA injury

Discussions on (patho)physiology:

Always provoke tremendous enthusiasm from the audience.

So I ll try to keep things simple.

The point, for the purpose of this lecture, is that all of these processes:

Harmful inflammatory processes Calcium influx into cell, excitotoxic cascade Metabolism & energy production; in later stages metabolic demands Membrane leakage, oedema formation, intra-cellular acidosis Free radical production Mitochondrial injury & dysfunction Reperfusion injury Others??? are stimulated by fever Apoptosis, calpain-mediated proteolysis, DNA injury Local brain hyperthermia, cerebral thermo-pooling Suppression of epileptic activity & seizures? Coagulation activation, formation of micro-thrombi Increased bloodbrain barrier permeability, oedema formation Increased vascular permeability, oedema formation

Harmful inflammatory processes Calcium influx into cell, excitotoxic cascade Metabolism & energy production; in later stages metabolic demands Membrane leakage, oedema formation, intra-cellular acidosis Free radical production Mitochondrial injury & dysfunction Reperfusion injury..and inhibited by hypothermia! Apoptosis, calpain-mediated proteolysis, DNA injury Others??? Local brain hyperthermia, cerebral thermo-pooling Suppression of epileptic activity & seizures? Coagulation activation, formation of micro-thrombi Increased bloodbrain barrier permeability, oedema formation Increased vascular permeability, oedema formation

Hypothermia improves neurological following various types of brain injury in a wide range of animal models & species:

Hamsters Guinea pigs.etc etc. Rats Hypothermia improves neurological following various types of brain injury in a wide range of animal models & species: Mice Cats Primates Dogs Pigs

Review summarizing some of the experimental data on brain injury: Auer RN. Ann N Y Acad Sci 2001;939:271-82 (review)

Auer RN. Ann N Y Acad Sci 2001;939:271-82 (review)

Dae MW et al. Am J Physiol Heart Circ Physiol 2002; 282: H1584 H1591

Normothermia Hypothermia Dae MW et al. Am J Physiol Heart Circ Physiol 2002; 282: H1584 H1591

Hypothermia Normothermia Dae MW et al. Am J Physiol Heart Circ Physiol 2002; 282: H1584 H1591

Duncker DJ et al. Am J Physiol (Heart Circ Physiol) 1996; 270: H 1189-99.

We tend to regard of fever as an adaptive/ protective mechanism, with additional value because it may be an (early) sign of infectious problems There is an (unspoken) underlying view that Fever is protective It helps the body fight infections Bacteria grow more slowly at higher temperatures, so fever is an adaptive mechanism But is this view completely correct??

Fever in neurological injury: Is extremely common Occurs in 50 to 60% of all patients with ischemic stroke; this figure rises significantly if the patient is admitted to the ICU Occurs in 70-80% of patients with severe head injury Occurs in a large majority pf patients with subarachnoid haemorrhage and intracerebral haemorrhage Azzimondi G et al, Stroke 1995; 26:2040 2043; Dávalos A. Cerebrovasc Dis 1997; 7:64 69; Hajat C et al. Stroke 2000; 31:410-14; Kammersgaard LP et al. Stroke 2002; 33:1759-6; etc.

Fever in neurological injury: In all these situations development of fever is associated with worse outcome: Azzimondi G et al, Stroke 1995; 26:2040 2043; Dávalos A. Cerebrovasc Dis 1997; 7:64 69; Hajat C et al. Stroke 2000; 31:410-14; Kammersgaard LP et al. Stroke 2002; 33:1759-6; etc.

Fever in neurological injury: In all these situations development of fever is associated with worse outcome: Higher mortality; Increased length of stay; Worse neurological outcome. Azzimondi G et al, Stroke 1995; 26:2040 2043; Dávalos A. Cerebrovasc Dis 1997; 7:64 69; Hajat C et al. Stroke 2000; 31:410-14; Kammersgaard LP et al. Stroke 2002; 33:1759-6; etc.

Fever in neurological injury: In all these situations development of fever is associated with worse outcome: This difference persists when multivariate analysis is performed, i.e. patients are matched for other variables Relative risk of poor outcome increases by around 2.2% for each o C rise in body temperature Azzimondi G et al, Stroke 1995; 26:2040 2043; Dávalos A. Cerebrovasc Dis 1997; 7:64 69; Hajat C et al. Stroke 2000; 31:410-14; Kammersgaard LP et al. Stroke 2002; 33:1759-6; etc.

Fever in neurological injury: In animal experiments, induction of even moderate hyperthermia significantly increases the extent of neurological damage and leads to greater morbidity and mortality Independent of initial severity of injury Hyperthermia facilitates the transformation of ischemic penumbra to infarction and ischemic necrosis This applies not only to hyperthermia occurring shortly after injury, but also to later periods. Busto R et al. J Cereb Blood Flow Metab 1987;7:729-738;. Ginsberg MD et al, Cerebrovasc Brain Metab Rev 1992; 4:189 225 Baena RC et al. Neurology 1997; 48:768-773; Coimbra C et al, Stroke 1996;27:1578-1585; Hickey RW et al. Crit Care Med 2003; 31:531-5; etc. etc. etc.

Fever in neurological injury: In all animal models for stroke, global ischemia, TBI and intracranial hemorrhage: Active warming is harmful; Spontaneous development of hyperthermia is harmful; Maintaining normothermia is protective; And mild hypothermia significantly decreases the extent of injury Azzimondi G et al, Stroke 1995; 26:2040 2043; Dávalos A. Cerebrovasc Dis 1997; 7:64 69; Hajat C et al. Stroke 2000; 31:410-14; Kammersgaard LP et al. Stroke 2002; 33:1759-6; etc.

Fever in neurological injury: In all animal models for stroke, global ischemia, TBI and intracranial hemorrhage: Active warming is harmful; Spontaneous development of hyperthermia is harmful; Maintaining normothermia is protective; And mild hypothermia significantly decreases the extent of injury Hyperthermia is especially harmful during periods of ischemia (i.e., during secondary injury) Azzimondi G et al, Stroke 1995; 26:2040 2043; Dávalos A. Cerebrovasc Dis 1997; 7:64 69; Hajat C et al. Stroke 2000; 31:410-14; Kammersgaard LP et al. Stroke 2002; 33:1759-6; etc.

So, hyperthermia after injury seems to be a bad thing.

Romano et al., Brain temperature exceeds systemic temperature in head-injured patients. Crit care Med 1998;562-567

Range of this phenomenon: In healthy individuals: 0,1-2 o C In injured brains: up to 4 o C!!

Harmful inflammatory processes Calcium influx into cell, excitotoxic cascade Metabolism & energy production; in later stages metabolic demands Membrane leakage, oedema formation, intra-cellular acidosis Free radical production Mitochondrial injury & dysfunction Reperfusion injury Others??? Processes influenced by temperature Apoptosis, calpain-mediated proteolysis, DNA injury Local brain hyperthermia, cerebral thermo-pooling Suppression of epileptic activity & seizures? Coagulation activation, formation of micro-thrombi Increased bloodbrain barrier permeability, oedema formation Increased vascular permeability, oedema formation

Hyperactivity due to exitoxicity and inflammatory processes leads to extra generation of heat This occurs specifically in injured area s of the brain!

So, hyperthermia after injury seems to be a bad thing. We should probably symptomatically treat fever in patients with neurological injuries

What about patients with TBI?

To interpret the data correctly we need to look briefly at the concept and role of intracranial pressure (ICP)

Destructive steps following various types of injury (ischaemia/reperfusion, trauma): Harmful inflammatory processes Calcium influx into cell, excitotoxic cascade Metabolism & energy production; in later stages metabolic demands Membrane leakage, oedema formation, intra-cellular acidosis Free radical production Reperfusion injury Others??? Remember the destructive mechanisms that occur after ischemia or trauma? Mitochondrial injury & dysfunction Apoptosis, calpain-mediated proteolysis, DNA injury Local brain hyperthermia, cerebral thermo-pooling Suppression of epileptic activity & seizures? Coagulation activation, formation of micro-thrombi Increased bloodbrain barrier permeability, oedema formation Increased vascular permeability, oedema formation

These destructive processes influence two measurable parameters: Pressure Temperature

Direct neuronal disruption Cytotoxic oedema Ischemia Intracranial hypertension

Direct neuronal disruption Blood-brain barrier injury Cytotoxic oedema Vasogenic oedema Ischemia Intracranial hypertension Hyperemia

Direct neuronal disruption Blood-brain barrier injury Cytotoxic oedema Vasogenic oedema Ischemia Intracranial hypertension Hyperemia Hematoma

Direct neuronal disruption Blood-brain barrier injury Cytotoxic oedema Vasogenic oedema Ischemia Intracranial hypertension Hyperemia Hematoma CSF volume (due to blocking of ventricular drainage) Increased cerebral blood volume

ICP-Volume Curve ICP (mm Hg) 100 80 60 40 20 0 ICP does not rise initially due to compensatory mechanisms Volume When ICP is high, small volume marked ICP

Cerebral Autoregulation Normal Head injury 60 160 Cerebral Perfusion Pressure (mmhg) Cerebral Blood Flow

So: ICP may be a marker for ongoing cerebral injury ICP may be a cause of additional cerebral injury

So: ICP may be a marker for ongoing cerebral injury ICP may be a cause of additional cerebral injury So, when a treatment is initiated, a decrease in ICP probably indicates that the therapy is effective; And lowering ICP may itself improve outcome. This issue has been studied mainly in patients with TBI and stroke, but may also apply to SAH and perhaps CPR.

In TBI, a large proportion of injury occurs in the period after injury Primary injury: direct result of trauma Secondary injury: what comes later. The previously listed destructive processes result in brain oedema formation, with increased intracranial pressure. This causes further injury to the damaged brain, with compression, [local] circulatory problems and further ischaemia. Vicious cycle! Direct neuronal disruption These mechanisms are more complex than in global ischemia Ischemia Hematoma Cytotoxic oedema Intracranial hypertension CSF volume (due to blocking of ventricular drainage) Blood-brain barrier injury Vasogenic oedema Hyperemia Increased cerebral blood volume

So, what about the clinical evidence?

Hypothermia in cardiac arrest: Several trials with historical controls: all positive! Three RCTs: all positive! P values <0.01! Decreased mortality in one trial! Improved long-term neurological outcome!

Hypothermia in traumatic brain injury:

Hypothermia in traumatic brain injury: Several trials with historical controls: all positive Several small RCTs: : positive in subgroups, no clear positive result P values: NS One multi-centred RCT: negative result!!??why is it so hard to show conclusive benefits??

Induced hypothermia in TBI: 29 clinical studies: conflicting results! 4 meta-analyses: conflicting results!

For this reason, the use of hypothermia in TBI is far more controversial than in CPR!

Induced hypothermia in TBI: the clinical evidence 29 clinical studies (2103 patients) 27 clinical studies in adults (2034 patients) 19 controlled studies (1812 patients) One small study reported patients subsequently included in larger trial Thus there are 18 evaluable studies Three in patients with normal ICP, one with patients included in subsequent study (total 131 patients) 15 controlled studies in patients with high ICP (1665 patients) 4 meta-analyses (including varying numbers of these studies) Two studies in pediatric patients

Hypothermia effective in TBI? Positive studies: Shiozaki et al. J Neurosurg 1993;79:363-86 Clifton et al. Journal of Neurotrauma 1993;10:263-71 Metz et al. J Neurosurg 1996;85:533-41 Marion et al. N Engl J Med 1997;336:540-6 Tateishi et al. Neurosurgery 1998; 42:1065-9 Bernard et al. Crit Care 1999;3:167-72 Jiang J et al, J Neurosurg 2000;93:546-9 Polderman KH et al, J Neurosurg 2001;94:697-705 Polderman KH et al. Intensive Care Med 2002;28:1563-73 Tokutomi T et al. Neurosurgery 2003;52:102-11 Zhi D et al. Surg Neurol 2003; 59:381-5 Qiu WS et al. Chinese J Traumatol 2005; 27-32 Jiang et al, J Cereb Blood Flow Metab 2005 (online advance publication, doi:10.1038/sj.jcbfm.9600253) (n=33) (n=46) (n=10) (n=82) (n=9) (n=43) (n=87) (n=41) (n=136) (n=31) (n=396) (n=82) (n=215)

Hypothermia effective in TBI? Positive studies: Shiozaki et al. J Neurosurg 1993;79:363-86 Clifton et al. Journal of Neurotrauma 1993;10:263-71 Metz et al. J Neurosurg 1996;85:533-41 Marion et al. N Engl J Med 1997;336:540-6 Tateishi et al. Neurosurgery 1998; 42:1065-9 Bernard et al. Crit Care 1999;3:167-72 Jiang J et al, J Neurosurg 2000;93:546-9 Polderman KH et al, J Neurosurg 2001;94:697-705 Polderman KH et al. Intensive Care Med 2002;28:1563-73 Tokutomi T et al. Neurosurgery 2003;52:102-11 Zhi D et al. Surg Neurol 2003; 59:381-5 Qiu WS et al. Chinese J Traumatol 2005; 27-32 Jiang et al, J Cereb Blood Flow Metab 2005 (online advance publication, doi:10.1038/sj.jcbfm.9600253 (n=33) (n=46) (n=10) (n=82) (n=9) (n=43) (n=87) (n=41) (n=136) (n=31) (n=396) (n=82) (n=215)

Therapeutic hypothermia: Effect on ICP and outcome in TBI Included patients with GCS <9 Standard ICP/CPP management protocol (CPP >70 mmhg, ICP < 20 mmhg) Mechanical ventilation + standard sedation & analgesia Surgical evacuation of lesion if necessary Mannitol and CSF drainage, paralysis Polderman et al, Intensive Care Med. 2002; 28:1563-73.

ICP?20 ICP > 20 Muscle Relaxants ICP > 20 Babiturate-coma (n=72) Hypothermia (n=64) ICP > 20

Methods Protocol with meticulous attention for the prevention of side effects Especially fluid balance and electrolyte levels (measured on site in the ICU, every 30-60 minutes) Prevention of hyperglycaemia in both groups (glucose levels measured on site in ICU) Prevention of even brief episodes of hypotension and hypovolemia Included administration of antibiotic prophylaxis (SDD) ICP-driven protocol (average cooling period 4.8 days)

Survival and neurological outcome Polderman et al, Intensive Care Med 2002; 28:1563-73

Some perspective: Hypothermia was used only as a treatment of last resort Predicted ICU mortality was 86% (hypothermia) vs. 80% (controls) There is bias against the hypothermia group The beneficial effects of hypothermia in this study are likely to be underestimated.

Hypothermia Effective in TBI? Negative studies: Clifton et al. N Engl J Med 2001;344:556-563 (n=392)* Shiozaki et al. J Neurosurg 2001; 94:50-4 (n=91) *NABISH-1 (National Acute Brain Injury Study using Hypothermia)

Hypothermia Effective in TBI? Negative studies: Clifton et al. N Engl J Med 2001;344:556-563 (n=392)* Shiozaki et al. J Neurosurg 2001; 94:50-4 (n=91) Editorial NEJM: a good idea proved ineffective *NABISH-1 (National Acute Brain Injury Study using Hypothermia)

The results of this study have led to the large-scale abandonment of induced hypothermia as treatment for TBI in ICU s worldwide

How can this be explained???

Possible explanations: Hypothermia does not work in TBI.

Possible explanations: Hypothermia does not work in TBI. All the positive single-center studies are wrong, or hypothermia is simply too difficult to manage in TBI patients in normal settings All the animal data must be disregarded; the differences between human and animal brains are simply too great Although post-hypoxic injury plays a role in TBI (and hypothermia is effective to treat post-hypoxic injury), other mechanisms must be more important

Or: Possible explanations:

Possible explanations: Or: There was a problem with this study. Inappropriate application and usage of hypothermia Insufficient attention to potential side effects!!

Problems with the NABISH 1 study: Substantial inter-centre variance (better outcome in larger centres) Modest protocol goals (CPP 50) More hypotensive episodes 2 hours in hypothermia group (10% vs. 3%) Briefer episodes not reported (not registered??????) Episodes of hypovolemia??? Hypothermia-induced electrolyte disorders???? Hypothermia-induced insulin resistance and hyperglycemia? Re-warming after 48 hours irrespective of ICP Target temperatures reached only after 8.4 hours Problems with sedation and analgesia Etc etc Polderman et al, Intensive Care Med 2004; 30:1860-64; Polderman et al, J Neurosurg 2001;94:853-55; Clifton GL, J Neurosurg 2001; 95:751-55

Problems with the NABISH 1 study: Substantial inter-centre variance (better outcome in larger centres) Modest protocol goals (CPP 50) More hypotensive episodes 2 hours in hypothermia group (10% vs. 3%) Briefer episodes not reported (not registered??????) Episodes of hypovolemia??? Hypothermia-induced electrolyte disorders???? Hypothermia-induced insulin resistance and hyperglycemia? Re-warming after 48 hours irrespective of ICP Target temperatures reached only after 8.4 hours Problems with sedation and analgesia In spite of all these problems, benefits were still observed in subgroup of patients with hypothermia at admission Polderman et al, Intensive Care Med 2004; 30:1860-64; Polderman et al, J Neurosurg 2001;94:853-55; Clifton GL, J Neurosurg 2001; 95:751-55

One size fits all??? No! Some patients may require prolonged deep hypothermia to block (all) the ongoing destructive mechanisms; others may require only mild hypothermia, or even just fever control.

Harmful inflammatory processes Calcium influx into cell, excitotoxic cascade Metabolism & energy production; in later stages metabolic demands Membrane leakage, oedema formation, intra-cellular acidosis Free radical production Mitochondrial injury & dysfunction Reperfusion injury Others??? A rise in ICP may retrigger some or all of these destructive processes Apoptosis, calpain-mediated proteolysis, DNA injury Local brain hyperthermia, cerebral thermo-pooling Suppression of epileptic activity & seizures? Coagulation activation, formation of micro-thrombi Increased bloodbrain barrier permeability, oedema formation Increased vascular permeability, oedema formation

Hypothermia treatment should be Direct neuronal disruption guided by ICP! Blood-brain barrier injury Cytotoxic oedema Vasogenic oedema Ischemia Intracranial hypertension Hyperemia Hematoma CSF volume (due to blocking of ventricular drainage) Increased cerebral blood volume

Meta-analysis JAMA 2003;289:2992-9 (not including the last four recently published positive studies)

So, I don t think the NABISH 1 study is the final answer

Factors determining the success of cooling in TBI: Speed of cooling Duration of cooling ICP guided Speed of re-warming Response to rebound intracranial hypertension Other ( general ) ICU treatment!!

Conclusions

Conclusions Temperature monitoring and manipulation are (or should be) key aspects of providing intensive care to our patients Usually high is bad, normal is good; In some situations cold may be better (provided temp stays above 30 degrees) When using hypothermia, knowledge of physiology and potential side effects is essential

Conclusions There is (very) strong evidence for the overall concept that induced hypothermia can provide neuroprotection, and probably cardioprotection Strongest clinical evidence in selected patients with post-anoxic encephalopathy following CPR and in perinatal asphyxia/ neonatal encephalopathy Hypothermia should definitely be applied for these indications! (level 1 evidence)

Conclusions Other indications with (relatively) strong evidence: Controlling fever in patients with neurological injury Witnessed cardiac arrest not meeting all the inclusion criteria of the two RCTs ICP control in hepatic encepalopathy Hypothermia should very probably be applied for these indications! (level IIA-IIB evidence)

Conclusions More difficult area s: Traumatic brain injury Hypothermia is highly effective in controlling ICP (level 1 evidence) Should be used in protocols guided by ICP Data on outcome conflicting; preponderance of evidence suggests positive effects if appropriately applied, BUT risk of side effects appears to be significantly higher Hypothermia should be considered for this indication in centers with enough experience with its usage (ICP control: level I, neurological outcome improvement: IIA evidence) A new (European?) multi-centered study is probably needed to conclusively settle the issue

Other area s: Stroke Conclusions Subarachnoid hemorrhage Decreasing myocardial injury following infarction Promising, but insufficient data available to make any recommendation

Acute disseminated encephalomyelitis Level IV Grand mal seizures Level IV Cardiac arrest due to noncoronary causes Level IV Sepsis/septic encephalopathy Level IV Preventing/delaying cardiac arrest in severe hypovolemic shock Level IV Perioperative (vascular, cardiac and neurosurgery) Level III Stroke Level III Post-anoxic encephalopathy VT/VF Level I Post-anoxic encephalopathy Asystole/PEA Level III Traumatic brain injury improving outcome Level IIA Mitigating myocardial injury during Ischemia/reperfusion Level III All other indications: further studies (urgently) required!! Traumatic brain injury - reducing ICP Level I Reversing cardiac shock following cardiac surgery Level III Hepatic encephalopathy (reducing ICP) Level III Subarachnoid haemorrhage Level IV Fever in presence of neurological injury Level IIB Perinatal asphyxia Level I Preventing cardiac injury during cardiac surgery Level III Delayed spinal ischemia Level IV ARDS Level IV Bacterial meningitis Level IV Spinal cord contusion Level IV

Thank you!

And keep your eye on the temperature!

Some breaking news; A new high-speed cooling device has recently been developed!

I have managed to obtain video footage of a demonstration:

the cooling devices!

Initial user of surface cooling was yielding highly promising results; But then, unawareness of a potential side effect led to improper application, inducing a severe side effect that negated all the positive results achieved up to that point! Awareness of these risks and of the underlying physiology, and taking proper precautions to avoid these problems, will be the key to success.

My final conclusion: induced hypothermia: can be risky, but is potentially highly rewarding!

Thank you!

.and have fun with hypothermia!

But beware, because temperature manipulation can have severe side effects..

Conclusions

The Hypothermia after Cardiac Arrest Study Group. N Engl J Med 2002; 346:549-56

Some breaking news; A new high-speed cooling device has recently been developed! It needs some work regarding side effects and re-warming, but the cooling rates are without question spectacular, and surpass all of the devices tested previously