Therapeutic hypothermia

# Overview
Brain temperature during the first 24 hours after resuscitation from cardiac arrest has a significant effect on survival and neurological recovery.
Fever (Tmax) during the first 48 hours is associated with a decreased chance of good neurological recovery (OR 2.26  for each 1C over 37C). Cooling to 32-34C for 24 hours decreases chance of death (OR 0.74 ) and increases chance of good neurological recovery (OR 1.40 ). Cooling to 32-34C for 12 hours increases chance of good neurological recovery (OR 2.65 ).

# Mechanism of Effects
- Hypothermia activates the sympathetic nervous system causing vasoconstriction and shivering.
- Shivering increases O2 consumption by 40-100%.
- Sedatives, opiates, and neuromuscular blockers can counteract these responses and enhance the effectiveness of active cooling.
- However, initiating paralysis in a patient who is already hypothermic should be avoided as it can result in a precipitous drop in core body temperature.
- Elderly patients will cool more quickly than younger or obese patients. 
- Hypothermia shifts the oxyhemoglobin curve to the left and may result in decreased O2 delivery.
- However, the metabolic rate is also lowered, decreasing O2 consumption / CO2 production, cardiac output and cerebral blood flow.
- Ventilator settings may need to be adjusted due to decreased CO2 production, using temperature corrected blood gases. 
- Hypothermia initially causes sinus tachycardia, then bradycardia. With temp 30oC.
- Hypothermia can induce coagulopathy which is treatable with platelets and FFP.
- Hypothermia-induced diuresis is to be expected and should be treated aggressively with fluid and electrolyte repletion. Magnesium, phosphorus and potassium should be monitored closely and maintained in the normal (because it will rebound to very high) range.
- Decreased insulin secretion and sensitivity leads to hyperglycemia, which should be treated aggressively.
- Re-warming too rapidly can cause vasodilation, hypotension, and rapid electrolyte shifts.

# Eligibility Criteria for Post-Cardiac Arrest Therapeutic Hypothermia
Clinical practice guidelines by the American Heart Association state
- "We recommend TTM as opposed to no TTM for adults with OHCA with an initial shockable rhythm who remain unresponsive after ROSC (strong recommendation, low-quality evidence).
- "We suggest TTM as opposed to no TTM for adults with OHCA with an initial nonshockable rhythm who remain unresponsive after ROSC (weak recommendation, very-low-quality evidence).
- "We suggest TTM as opposed to no TTM for adults with IHCA with any initial rhythm who remain unresponsive after ROSC (weak recommendation, very-low-quality evidence)."
Clinical practice guidelines by the European Resuscitation Council and American Heart Association state
- "We recommend TTM as opposed to no TTM for adults with out-of-hospital cardiac arrest (OHCA) with an initial shockable rhythm who remain unresponsive after ROSC."
- We suggest targeted temperature management as opposed to no targeted temperature management for adults with OHCA with an initial nonshockable rhythm (weak recommendation, very low-quality evidence) who remain unresponsive after ROSC.
- "We suggest TTM as opposed to no TTM for adults with in-hospital cardiac arrest (IHCA) with any initial rhythm who remain unresponsive after ROSC."
- "We recommend selecting and maintaining a constant target temperature between 32 C and 36 C for those patients in whom temperature control is used." "We suggest that if TTM is used, duration should be at least 24 hours."

# Other Indications
Therapeutic hypothermia is an active area of research. Many trials are underway to see its possible benefits in conditions other than post-cardiac arrests like:
- Traumatic brain injury: Benefits are seen in patients with elevated intra cranial pressure  and those treated with long-term hypothermia. However, studies on pediatrics population found an increase in rates of pulmonary hypertension and seizures in pediatric patients treated with therapeutic hypothermia.
- Traumatic spinal cord injury
- Acute stroke
- Pediatric cardiac arrest
- Neonatal hypoxic ischemic encephalopathy

# Therapeutic Goals
Therapeutic hypothermia is practiced in many tertiary hospitals. The treatment goals followed in most of them are:
- Goal temperature- 32-34 degree celsius
- Active cooling for 24 hours.
- Rapid achievement of cooling temperature (within 3-4 hours) although one abstract reported no difference in outcomes based on a delay of more or less than 2 hours.
- Rewarming
Slow rewarming (may take 8-10 hours) is preferred over rapid rewarming as the latter may cause dilatation of the vessel and result in hypotension.
It can be achieved by discontinuation of methods used for cooling like cooling blankets, ice and drugs.
Continuous blood pressure monitoring should be done to avoid the development of hypotension.
It should be started 24 hours after the time of initiation of cooling.
Slow rewarming @ 0.3-0.5oC/hr
Target rewarming temperature 36C
- Slow rewarming (may take 8-10 hours) is preferred over rapid rewarming as the latter may cause dilatation of the vessel and result in hypotension.
- It can be achieved by discontinuation of methods used for cooling like cooling blankets, ice and drugs.
- Continuous blood pressure monitoring should be done to avoid the development of hypotension.
- It should be started 24 hours after the time of initiation of cooling.
- Slow rewarming @ 0.3-0.5oC/hr
- Target rewarming temperature 36C

# Contraindications
For contraindications:
- Meets eligibility criteria for Post-Cardiac Arrest Care Pathway
- Comatose at enrollment with a Glasgow Coma Motor Score <6 pre-sedation (i.e., patient doesnt follow commands)
- No other obvious reasons for coma
- No uncontrolled bleeding
- Hemodynamically stable with no evidence of:
- Uncontrollable dysrhythmias
- Severe cardiogenic shock
- Refractory hypotension (MAP <60 mm Hg) despite preload optimization and use of vasoactive medications
- No existing, multi-organ dysfunction syndrome, severe sepsis, or comorbidities with minimal chance of meaningful survival independent of neurological status
The following have been proposed, but the origin of these statements is not known:
- Prolonged arrest time (> 60 minutes)
- Thrombocytopenia or other coagulopathies (hypothermia may impair the clotting factors)
- Pregnancy (Therapeutic hypothermia can potentially be performed on pregnant female in consultation with OB/Gyn)
- Major surgery within 14 days (it may increase risk of infections and bleeding in this group of patients)
- Sepsis and other systemic infections (decreased immune function due to hypothermia)
- Coma from other causes like drug intoxication
- Patients who have signed a 'Do not resuscitate' (DNR)

# Cooling Techniques

## Surface Cooling with Ice Packs
- Head, neck, axilla, and groin are preferred sites (these areas have good heat exchange)
- Advantage - Inexpensive
- Disadvantages
Difficulties in achieving and maintaining rapid rates of cooling
Variable and unpredictable rates of cooling
- Difficulties in achieving and maintaining rapid rates of cooling
- Variable and unpredictable rates of cooling

## Blankets or Surface Heat-Exchange Device and Ice
- During cooling phases blankets, the cooling device's (heat-exchange pads) and ice packs are applied. Ice packs are removed once  target temperature is achieved. The temperature is maintained with blanket or heat exchange pads.
- Disadvantages
Difficulties in achieving and maintaining rapid rates of cooling
Variable and unpredictable rates of cooling
- Difficulties in achieving and maintaining rapid rates of cooling
- Variable and unpredictable rates of cooling

## Surface Cooling Helmet
- The helmet has a solution of aqueous glycerol that helps in achieving hypothermia.
- Disadvantage - Slow, unpredictable attainment of target temperature

## Transnasal evaporative cooling
Devices available: Rhinochill.
Advantages: rapid pre-hospital cooling, operates independently of power supply
The PRINCE trial showed decreased time to target temperature compared to control; however, the study was not adequately powered to assess neurologic outcomes and overall survival.

## Catheter Based Internal Cooling Methods / Endovascular Heat-Exchange Catheters
- Devices available: Celsius Control System and Cool Line System
- Placed in femoral vein
- Advantages
Both endovascular cooling and rewarming are faster
Good at maintaining target temperature
Low rates of complications
Minimization of shivering
Decreased need for chemical paralysis
- Both endovascular cooling and rewarming are faster
- Good at maintaining target temperature
- Low rates of complications
- Minimization of shivering
- Decreased need for chemical paralysis

## Infusion of Cold Fluids
- Achieved by infusion of normal saline or lactated Ringer solution
- Advantage - rapid cooling
- Disadvantage - rate of cooling is unpredictable
- No increased risks of pulmonary edema, cardiac arrhythmias or other major complications were found.

## Arctic Sun medical device
The Arctic Sun Temperature Management System is a non-invasive Targeted Temperature Management System medical device used to modulate patient temperature with precision by circulating chilled water in pads directly adhered to the patient's skin. Using varying water temperatures and a sophisticated computer algorithm, a patient's body temperature can be controlled within 0.2C. The Arctic Sun Temperature Management System is produced by Medivance, Inc. of Louisville, Colorado.
The Arctic Sun has been explained as dry water immersion. It is a non-invasive precision temperature management system that is often used to induce hypothermia in comatose patients that have suffered from Sudden Cardiac Arrest (SCA) and patients at risk for ischemic brain damage. The unique thing about the Arctic Sun is the gel pads, which stick to a patients body using an adhesive called hydrogela substance that adheres to the skin without removing hair follicles. The gel pads cover only a portion of a patients body and subsequently leave most of the body free for augmenting medical procedures. The device operates under negative pressure and circulates water through these pads at a temperature between 442 C (39108 F). Water is pulled through the pads, which minimizes the risk of leakage. By controlling the temperature of the water running through the gel pads, the Arctic Suns adjusts a patients temperature. Arctic Sun can also rewarm patients. Controlled rewarming has been cited in the literature as beneficial in preventing reperfusion injury. Because of the Arctic Suns noninvasive nature, treatment can be delivered without the host of adverse events associated with invasive procedures such as cooling catheters.
A fomer complaint levied against the Arctic Sun relates to the risk of skin injury. a study published in 2007 found that the Arctic Sun was, "highly effective in lowering patients temperature rapidly without inducing skin irritations.. 
Further, when comparing MDR's registed by Medivance vs the cooling catheters and conventional cooling blankets and wraps, one will find far fewere incidence of patient injury.
Invasive cooling catheter companies have claimed that catheters can lower body temperature at a faster rate, which is relevant because most of the clinical data suggests that the sooner cooling initiates the better a patients outcome. However, there exists a 75 minute delay on average between admittance and catheter insertion.  Even with a physician readily available to place the cooling catheter, the operating instructions underline the importance of the device set up with takes a minimum of 25 minutes. When objectively evaluating the published data the average cooling rate for cooling catheters is 1.12C.  Treatment with the Arctic Sun can be administered within 10 minutes by unsupervised nursing professionals.
Historically, clinicians reported that catheters cool at a quicker rate, however, a 2011 study published in the Society of Critical Care Medicine where 167 patients treated either with the Arctic Sun or the Alsius Coolgard Cather showed the following:
There was no significant difference in survival with good neurologic function, either to hospital discharge or at follow-up. Time from cardiac arrest to achieving mild therapeutic hypothermia was equal with both devices (surface, 273 min, core, 270 min).
- Cooling was initiated immediately in the emergency department on hospital arrival with ice packs around groin, armpits and neck and infusion of up to 3 L of refrigerated saline
- All patients were deeply sedated
- No device-specific patient injuries were observed; skin injuries with the Arctic Sun or DVT with Coolgard
- No differences in shivering: 
- Article quote: Skin temperature is known to influence thermoregulatory control, and it previously has been speculated that core cooling could result in less shivering.
However, this could not be confirmed in the present study, because there was no difference in the rate of shivering in surface-cooled or core-cooled patients.
- No differences were observed in Lengths of ICU stay, durations of respirator dependency, rates of MTH discontinuation, and post cooling
Conclusions: Surface and core cooling of out-of hospital cardiac arrest patients following the same established postresuscitation treatment protocol resulted in similar survival to hospital discharge and comparable neurologic function at follow-up.
In a case attracting much media attention in May 2008, the Arctic Sun was used to induce hypothermia in a 59 year old woman in West Virginia who had suffered 3 cardiac arrests within a 24 hour period. For more than 17 hours the woman had no measurable brain waves, according to her doctors, and her heart had been stopped for a prolonged period of time. The family decided to take her off life support. Shortly after being disconnected from the ventilator, the woman surprisingly recovered, regaining consciousness, motor function, and speech.

# Complications
- Arrhythmias
- Sepsis
- Bleeding, coagulopathy
- Electrolytes disturbances
- Shivering
Delaying coronary intervention till after neurologic recovery is not harmful according to the COACT trial

# Barriers to usage
Although clinical practice guidelines do not list contraindications, the CRICS-TRIGGERSEP randomized controlled trial listed inclusion criteria:
- No-flow time (from collapse to initiation of cardiopulmonary resuscitation ) of more than 10 minutes
- Low-flow time (from initiation of CPR to return of spontaneous circulation) of more than 60 minutes
- Major hemodynamic instability (continuous epinephrine or norepinephrine infusion >1 g per kilogram of body weight per minute)
- Time from cardiac arrest to screening of more than 300 minutes
- Moribund condition
- ChildPugh class C cirrhosis of the liver (severe hepatic dysfunction)
- Pregnancy or breast-feeding
- Decision by the next of kin for the patient not to participate
Targeted Temperature Management may be underused:
- In 2015, 27% of comatose survivors of out-of-hospital cardiac arrest received TTM according to the Resuscitation Outcomes Consortium Investigators of the Resuscitation Outcomes Consortium

# Evidence of effectiveness
Clinical practice guidelines summarize management for adults and children.
A systematic review by the Cochrane Collaboration suggests benefit. A second systematic review and the more recent CRICS-TRIGGERSEP randomized controlled trial focusing on survivors of non-shockable rhythms suggests benefit.
A systematic review of pre-hospital TTM found no improvement in neurological survival
A more recent, living systematic review suggests benefit for in-hospital TTM.