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What is Hypothermic Life Support?

View the presentation, "Advanced Hypothermic Life Support", by Dr. Eric Harrison.

Therapeutic Hypothermia is the treatment of patients by intentionally reducing one’s internal core body temperature below normal ranges in order to improve patient outcome.  While an average internal body temperature is about 37°C (98.6°F), therapeutic hypothermia attempts to lower this temperature to between 32°C - 34°C (90°F - 93°F).

The history of using cold to treat patients reveals that it is actually an ancient idea.  Hippocrates, a Greek physician living 460-370 BC, noted men with severe head injuries survived better in the colder temperatures of winter rather than during the summer.  Hippocrates also treated patients through cooling, though the justification used then is understandably different from use in modern medicine.  (Adams, F).  Hypothermia was used the early 1800s in an attempt to improve patient outcome during resuscitation (Koran, 2008).  In a clinical trial by Fay in 1938, deep hypothermia was instituted in cancer patients in the theory that lower temperatures could decrease the rate of cancer cell metabolism and division.  In this case, internal temperatures were reduced to the extremely low levels of 27°C (80°F), which is not used today due to significant secondary complications (Fay, 1940).  In order to reduce such adverse effects today, patients are cooled down to a more mild range of 32°C - 34°C (90°F - 93°F).  Not only are these milder temperature goals safer, but more cost effective to induce and maintain.
In current medicine, therapeutic hypothermia is used in practical areas where the treatment has shown significant success in patient outcome.

Indications for Use

Cardiac Arrest, post-resuscitation

In 2003, the American Heart Association (AHA) included hypothermia into its guidelines for cardiopulmonary resuscitation and emergency cardiovascular care.  In the AHA 2005 guidelines, it is stated that “unconscious adult patients with return of spontaneous circulation after out-of-hospital cardiac arrest should be cooled to 32°C to 34°C (89.6°F to 93.2°F) for 12-24 hours when the initial rhythm was ventricular fibrillation (Class IIa).  Similar therapy may be beneficial for patients with non-ventricular fibrillation arrest out of hospital or for in-hospital arrest (Class IIb).” (Circulation, 2005).

These guidelines were placed after repeated clinical trials showed improved outcomes in patients when in situations described above.  In a study by Bernard et al. in 2002, 77 patients were enrolled, who had an initial ventricular fibrillation rhythm and were resuscitated to spontaneous circulation but remained unconscious.  These patients were randomly assigned to a control group, where internal temperatures were maintained at normothermic levels, or to an experimental group receiving therapeutic hypothermia.  The latter group had their core body temperatures lowered to 91.4°F (33°C) within two hours after return to spontaneous resuscitation, and were maintained at this temperature for 12 hours.  This report showed a significant difference of neurological outcome with patients who received hypothermic medicine having a better outcome.  During this study, no increase in adverse effects was noted in the experimental group (Bernard, 2002).

In a study by The Hypothermia After cardiac Arrest Study Group in 2002, patients were enrolled who had been resuscitated within 60 minutes after cardiac arrest due to a ventricular fibrillation or a nonperfusing ventricular arrhythmia.  A control group was maintained at normothermic levels and received standard therapy.  The experiment group underwent mild hypothermia treatment with an internal treatment goal of 32-34°C over a period of 24 hours.  In this patient population it was shown that hypothermic treatment significantly improved neurological outcomes and reduced mortality.   (Holzer, 2002)
Again no complications were significantly increased in the experimental group. (See “Adverse Risks”.)

Neonatal Encephalopathy

In May 2005, The National Institute of Child Health and Human Development (NICHD) convened a panel of experts, whom weighed the use of therapeutic hypothermia in perinatal hypoxic-ischemic encephalopathy.  The panel concluded that such treatment can potential decrease neurological morbidities and mortality in neonatal asphyxia, however more studies were desired to determine long term effects. (Higgins, 2006)

Hypoxic injuries during birth can lead to varying degrees of neonatal encephalopathy.  Moderate cases can produce memory impairment, decreased visual perception and delayed overall development.  Severe cases have an increased risk of cerebral palsy, mental retardation and death.
In a pilot study performed by Eicher et al. in 2005, sixty-five infants were included into either a control group treated by traditional supportive methods at 37°C or an experimental group, who were cooled within 6 hours of birth or hypoxic-ischemic event to 33°C for 48 hours.   Primary patient results were determined by looking at mortality or sever motor scores at one year of age.  Severe motor deficiencies were quantified using the Psychomotor Developmental Index with a score less than 70.  The study resulted in fewer outcomes of death or severe motor deficiencies in the hypothermia treated group (52%) when compared to the normothermia group (84%) (P=0.02).   (Eicher, 2005)

In a larger randomized clinical trial conducted by Shankaran, et al. in 2005, 102 infants with moderate or severe encephalopathy were placed in a hypothermic group cooled to 33.5°C and then compared to a group of 106 infants with comparable injuries who remain at normal temperatures.  The primary outcomes of death, moderate and severe disability when combined show a decreased outcome in the hypothermic group (44%) when compared to the standard treatment group (62%) (P=0.01).  The incidences of serious adverse effects were similar in both the control and experimental group. (Shankaran, 2005)

In 2007, three independent meta-analysis studies, reviewing randomized trials, provided good evidence for the safety and efficacy of hypothermic medicine treatment in perinatal hypoxic-ischemic encephalopathy of term infants.   These systematic reviews used end results of mortality and severe/moderate disability in patients at 18-22 months of age.  The studies demonstrated that therapeutic hypothermia use in term infants suffering from significant hypoxic encephalopathy have convincingly better outcomes of mortality and neurological functioning when compared to patients that underwent standard treatment.  (Jacobs, 2007)(Shah, 2007)(Schulzke, 2007)

Reported adverse risks in these studies included bradycardia that did not decrease perfusion, thrombocytopenia that was not reported as clinical significance.  Also no hypoglycemic or electrolyte disturbances were shown.   (Schulzke, 2007)(Shankaran 2005)(Jacobs, 2007). (See “Adverse Risks”.)
These reviews and studies provided important data for use of hypothermic treatment, yet a larger clinical trial was requested to further understand the benefits and risk for treatment in this population with long-term follow up.

An ongoing study by Shankaran et al, is further studying whole-body cooling for birth asphyxia in term infants.  This large multicenter trial is primarily studying the effects of hypothermic treatment on mortality and moderate and severe disability at 18-22 months of age, with follow-up assessed at 6-7 years. (Shankaran, 2009).

Increased Intracranial Pressures in a Traumatic Brain Injury Patient

While hypothermic medicine has yet to show clinical significance in initiating treatment of all patients suffering a traumatic brain injury (TBI), the treatment has shown effect and is recommended for treatment in children with severe TBI who suffer from refractory increased intracranial pressures (ICPs). 
Though this treatment does reduce high ICPs, its effect on neurological outcome and mortality has not been proven.

Heat Stroke

Heat Stroke, the most severe form of heat related injury, occurs when internal body temperature rise above 104°F (40°C) with acute mental status changes, including impaired attention and memory, drowsiness, debilitating personality changes and delirium. (Abderrezak, 2007)(winter 2010 training supplement)(Hamdy, 2002)(Bross, 1994).   This is a medical emergency, and in untreated patients, signs may progress to seizures, coma and death.  (Hamdy, 2002)(bouchama, 2002 – heat stroke)(klenk et al., 2010 – heat related mortality in residents of nursing homes, age aging)(romero, 2000).

The traditional treatment of heat stroke is to reduce internal body temperatures by the quickest means possible.  (Buchheit, 2009).  The duration a patient suffers from increased internal temperature the higher rate of mortality and morbidity (smith, 2005)(vicario, 1986)(abderrezak, 2007).  Therefore, treatment should begin as soon as possible to lower core temperatures below 39°C (102°F). 

With the production of sophisticated hypothermic devices, internal body temperatures can be lowered at faster rates.  For instance the rudimentary placement of ice packs strategically on a patient can diffuses heat at 0.9°C/hr, (Bernard s, et al, 2002) while other products can cool at much faster rates.  For instance, specially designed pre-frozen pads can be applied to the patient suffering from heat injuries to lower core temperatures at a rate of 3.3°C/hr.  (uray, 2008).  (See “Different Methods to induce Therapeutic Hypothermia.”

Though not proven in clinical studies, a theory is that the increased lowering rate of a patient’s internal body temperature from the dangerous high levels will improve patient outcome.

Possible Future Indications

Traumatic Brain Injury

Traumatic Brain Injury (TBI) is any assault on the brain that disrupts neurological activity.  While patients may remain stable after the primary insult, progressing secondary mechanisms can lead to neurological deterioration (Park, 2008).  Hypothermic medicine may be a possible future indication to improve neurological outcomes after TBI by reducing the evolving secondary effects.  (See “How Therapeutic Hypothermia Works”.)
To date, clinical trials have reached mixed conclusions.  Trials have used unique temperature goals for treatment, different methods and times to reach such goals, and different durations at therapeutic temperature.  Such variance in procedure and experimental populations has made it difficult to assess significance.
In an article by Hutchison, et al in 2008, therapeutic hypothermia showed no effect in treating children with TBI, when treatment was provided within eight hours.  The experimental group showed no improvement in neurological ability at 6 months, or significant difference in mortality when compared to the normothermic control group.  (Hutchison, 2008)
In an article written by Markgraf et al. in 2001, research showed the effect of hypothermic treatment within rats.  The results here suggest that early initiation of hypothermic medicine after an induced TBI improved neurological outcomes when the subject was cooled to 30°C within four hours. (Markgraf, 2001)  This may imply that there is a therapeutic window also in humans.  If treatment is given before a particular time after injury, significant effect may be shown.  An ongoing study by Clifton et al. on adults diagnosed with TBI, is examining the neurological outcome of early hypothermic medicine by centrally cooling the body to 33°C and maintaining that temperature for 48 hours. (Clifton, 2009)
Presently, there is no clinical support to use Therapeutic Hypothermia in TBI.  (Harris, 2002)(Clifton, 2009)

Spinal Cord Injury

In the United States, Spinal Cord Injury (SCI) affects over 11,000 people per year, resulting in severe neurological disabilities.  Like TBI, much of the research attempting to develop treatment for SCI is looking at reducing secondary injuries. (See “How Therapeutic Hypothermia Works”.)
Therapeutic Hypothermia has been shown to have decreased neurological outcomes when fever was present post-injury.   However the use of Hypothermic treatment has not provided significant evidence to become standard of care.  Additional clinical and experimental evidence is required before such conclusive statements of effectiveness and safety can be made.
The AANS/NSS joint sections of the spine and the AANS/NCNS joint section of trauma recommend that there is not sufficient evidence to recommend for or against therapeutic hypothermia in SCI. (Dietrch, 2008)

Stroke

Though hypothermia has shown to have neuroprotective qualities in laboratory animals during anoxic brain injuries such as stroke, larger studies need to be conducted in the clinic to determine efficacy in humans.

Myocardial Infarct

While therapeutic hypothermia does protect the central nervous system from anoxic injury due to poor circulation after ventricular fibrillation or ventricular tachycardia, therapeutic hypothermia has not been shown to protect the heart during MI.  The thought here is that if hypothermia does reduce metabolic demand in the heart, then during ischemic injury to the myocardium, hypothermia may protect the injured cells.   However, no studies to date show a significant improvement in clinical groups.

How does Therapeutic Hypothermia work?

While the exact mechanism for how hypothermic treatment works to improve patient outcome is still debatable, it is likely being produced through various methods.  This is probably in contrast to most medications that only function through a singular method of action. (Dietrch, 2008)
Proposed methods include the decrease of cerebral edema and swelling after a head injury. (Young, 1983)(Jiang, 1993)(Markgraf, 2001).  In a study by Markgraf in 2001 using rats, early administration of hypothermic treatment within four hours was shown to reduce maximal ICPs at 24 and 48 hours (Markgraf, 2001). 

Mild hypothermia may also reduce the metabolic rate of neurons (Jiang, 1993)(Kochanek, 2005) or attenuate the buildup of neurotransmitters glutamate and dopamine(Busto, 1989)(Globus, 1995), which may damage neurons with excitotoxicity (Yi, 2006).  Decreasing core body temperatures may attenuate neuronal death by turning off several chemical pathways of cellular apoptosis (Xu, 1998)(Ji 2002).  It may also inhibit the inflammatory response by preserving the blood brain barrier (Smith, 1996) or reducing pro-inflammatory cytokines (Wang, 2002).

After trauma the reperfusion of brain tissue forms free oxygen radicals that damage the cellular membrane of neurons leading to cell death (Park, 2008).  In the lab, hypothermic treatment has enhanced the function of superoxide dismutase, an enzyme that limits the damage of free radicals to ultimately protect the cellular membrane.    

As stated before, it is possible that using therapeutic hypothermia may induced better patient outcome by more than one of the purposed mechanism of actions listed above.

Different Methods to induce Therapeutic Hypothermia

Various methods exist with which to administer mild hypothermia.  In medical literature, no truly superior method of therapeutic hypothermia has been established in regards to outcome.()  
The simplest method is surface cooling, where a device is placed along the skin to diffuse heat away from the periphery.  Such techniques include placing ice packs typically to strategic locations such as in the axilla, groin, and on the sides of the neck.  Another example of surface cooling is submerging a patient in an ice bath. 

The water-circulating surface cooling device consists of blankets placed directly on the patient with cold water circulating through those blankets.  Gel-coated surface cooling devices work upon the same principles as the cooling blankets.  Though in the gel-coated, the device is adhered by gel to the body in particular body locations, such as the back, abdomen and bilateral thighs.   More recently, helmets and caps have been designed to produce cooling in a more localized area.

Invasive methods include rapid infusion of lactated Ringer’s at 4°C, which can be combined with a form of surface cooling.  Another invasive method is placing a central venous catheter within the inferior vena cava.  Cooled saline can then be circulated through that catheter which is adjacent with a large volume of blood returning to the heart.  Due to this direct contact heat in the blood can be transferred to the catheter and reduce core body temperatures.

Each method carries its own particular risks.  Submerging a patient in an ice bath would be contraindicated for a patient with decreased consciousness.  All invasive procedures can result in hemorrhage and the introduction of infection into the bloodstream.  (See “Adverse Risks”.)

The choice of modality to induce mild hypothermia depends on more than one factor.  When a care provider chooses a method, he or she should consider the rate at which the method reduces core body temperature, as indications and possible future indications may show better efficacy when treatment is provided in shorter time frames.  Also the comparison of adverse risks individually associated with the unique modalities.  The feasibility of each method should also be considered, as some techniques are cumbersome and may block access to the patient for line placement or other tasks.   Another issue one should consider is the cost of purchase and operation of the method.

Adverse Risks of Therapeutic Hypothermia

In some studies, Therapeutic Hypothermia has had the adverse problems include discomfort, excessive shivering (buchheit, 2009) and hypotension (Clifton, 2009).  These issues can be managed with medications; for instance shivering can be managed with a benzodiazepine.  However the inclusion of further medication carries with it a new set of concerns and possible risks to the patient.

Infection

Though increased infections and bacteremia have been shown in some trials (todd et al), other clinical trials have found no increase in clinical significant infection (Bernard,2002)(Holzer, 2002).

Blood Loss

Though shown to increase blood loss during certain surgical procedures (rajagoapalan, 2008), mild hypothermia showed no increased blood loss in patients undergoing cerebral aneurysm clipping.  In a study performed by Todd, M. et al in 2005 mild hypothermia showed no significant neurological protection to patients undergoing surgery for intracranial aneurysms.  However the report also shows no increased blood loss during these procedures for patients at 33°C when compared to the control normothermic patients at 36.5°C.  (todd et al., 2005)  In other studies gauging the effect of hypothermia, increased blood loss was not found.  However in these studies, blood loss was not the primary analysis.  (Bernard, 2002)(Clifton, 2001)(todd et al., 2005)

Pediatrics

In studies using mild hypothermia at 33.5°C to treat anoxic encephalopathy in patients younger than 22 months, the need for blood and platelet transfusions and volume expanders was comparable to the control group.  Also, no findings of electrolyte disturbances or hypoglycemia were found in relation to the control group.  (Shankaran, 2008)(Jacobs, 2007)

References

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  • Fay T.  (1940) Observations on Prolonged Human refrigeration.  New York State Journal of Medicine.  40: 1351-1354
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  • Hutchison JS, et al. (2008). Hypothermia Therapy after Traumatic Brain Injury in Children.  New England Journal of Medicine.  358(23):2447-56.
  • Shankaran S, et al. (2009).  Randomized Controlled Trial of Hypothermia for Hypoxic-Ischemic Encephalopathy in Term Infants.
  • Higgins RD, et al. (2006).  Hypothermia and Perinatal Asphyxia: Executive Summary of the National Institute of Child Health and Human Development Workshop.  The Journal of Pediatrics. 148:170-175
  • Eicher DJ, Wagner CL, Katikaneni LP, et al. (2005) Moderate Hypothermia in neonatal encephalopathy: efficacy outcomes.  Journal of Pediatric Neurology. 32:11-17
  • Schulzke SM, Rao S, Patole SK. (2007) A Systematic Review of Colling for Neuroprotection with Hypoxic Ischemic Encephalopathy – are we there yet? BMC Pediatrics. 7:30
  • Shankaran S, Laptook AR, Ehrenkranz RA, et al and the NICHD Neonatal Research Network.  (2005) Whole-Body Hypothermia for Neonates with Hypoxic-Ischemic Encephalopathy. The New England Journal of Medicine. 353:1574-1584
  • Shankaran S, Pappas A, Laptood AR, et al for the NICHD and Human Development Neonatal Research Network. (2008)  Outcomes of safety and effectiveness in a multicenter randomized, controlled trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy.  Pediatrics. 2008;122:e791-798
  • Parts of this website report were taken from the article:
  • Jess Arcure BS, MSc, and Eric Harrison MD. (2009) “Review Article of the Use of Early Hypothermia in the Treatment of Traumatic Brain Injuries.” Journal of Special Operations Medicine. Vol. 9, Edition 3 p22-25

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