REBEL Crit Cast Episode 1.0 – Overview of Targeted Temperature Management (TTM) Post Cardiac Arrest

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Evidence for Cooling in Adults and Children:

HACA Trials (New England Journal of Medicine 2002) [1]

• 275 patients suffering out of hospital arrest with shockable rhythm
• Evaluated 32 – 34°C vs standard normothermia
• Improved survival rate with good neurologic outcome at 6 months (55% vs. 39%)
• Decreased mortality rate at 6 months (41% vs. 55%)
• Used Cerebral Performance Category score (CPC) to classify good neurological outcome
  • 1 = Returning back to baseline with mild deficits
  • 2 = Moderate disability, able to return to work and living
  • 3 = Indicating severe disability
  • 4 = Persistent vegetative state
  • 5 = Brain dead

Bernard Trial (New England Journal of Medicine 2002) [2]

• 77 patients suffering out of hospital arrest with shockable rhythm
• Evaluated 33°C vs standard normothermia
• Improved survival rate with good neurological outcome at discharge (49% vs 26%)
• Questioned if improved survival rate was secondary to prevention of fever which in turn provided neurological protection

Targeted Temperature Management (TTM) (2013) [3]

• 939 patients, with out-of-hospital cardiac arrest over 36 ICUs
  • 80% shockable rhythms, 20% were PEA and asystole
• Evaluated which “dose” (temperature) was more effective, 36°C vs 33°C
• Also used CPC and modified Rankin scores
• Findings suggested NO difference in mortality rate at end of trial (50% vs 48%)
• No difference at 6 months, or survivability with favorable CPC
• Updated ILCOR (International Liaison Committee on Resuscitation) guidelines state that a range of treatment between 32° – 36°C is acceptable

Hyperion Trial (2019) [4]

• 584 patients from 25 different ICUs
  • Non-shockable rhythms (i.e. PEA or asystole)
• Compared 90-day mortality and outcome of 33°C vs 37°C
• Rate of survivability with good outcome was statistically significant in 33°C (10.2% vs. 5.7%)
• No difference in mortality rate between target temperatures (85%)

THAPCA [5][6]

• In-Hospital: 257 children aged >48hrs and <18 years of age
  • Compared therapeutic hypothermia (33.0°C) vs therapeutic normothermia (36.8°C)
  • Primary efficacy outcome: Survival at 12 months after cardiac arrest with a score of 70 or higher on the Vineland Adaptive Behavior Scales, second ed (VABS-II, on which scores range from 20 to 160, with higher scores indicating better function)
  • Trial terminated early due to futility
  • No difference in primary outcome (Hypothermia = 36% vs Normothermia = 39%)
• Out of hospital: 260 children, aged >48hrs and <18 years (Average age of 1 – 2 years)
  • 70% of patients had a respiratory cause of cardiac arrest; ½ had chronic medical conditions
  • Compared 33°C (Therapeutic hypothermia) vs. 37°C (Therapeutic normothermia)
  • Primary efficacy outcome: survival at 12 months after cardiac arrest with a Vineland Adaptive Behavior Scales, second ed (VABS-II)
  • No significant difference in primary outcome between therapeutic hypothermia (20%) vs therapeutic normothermia (12%)
  • There was a trend towards improvement of neurological outcome using 33° C, however not statistically significant

Cochrane Neonatal HIE Review 2012 [7]

• Pediatrics with Hypoxic-ischemic encephalopathy (HIE) recommended to cool to 33 – 35°C for infants at 34-36 wks
• 7 trials including 1214 newborns
• Cooling helps to improve survival with good neurological outcome
• Less data for pediatrics, personally recommend 33°C

Brain Injury and Therapeutic Hypothermia:

Mechanism

• Global ischemic injury occurs during cardiac arrest
• Once brain injury sets in, it can be irreversible
• Providers may have one chance at preventing secondary brain injury
• After obtaining ROSC, ischemia reperfusion injury (IRI) takes place
• Post-cardiac arrest, mitochondria switch from aerobic to anaerobic metabolism causing:
  • Acidemia
  • Increased phosphate and lactate production
  • Influx of calcium ions
    • Apoptosis
    • Glutamate release, which increases the risk of seizures 5-20%

How Does Therapeutic Hypothermia Work?

• A few of the major neuroprotective mechanisms of hypothermia include:
  • Decrease in cerebral metabolic rate
  • Decrease in acidemia and calcium influx
  • Decrease in glutamate release, which may decreases risk of seizures
  • Decrease in cerebral edema
  • Decrease in free radical production which causes cellular injury and death
  • Decrease in cytokine release which can lead to fever even days after arrest

Adverse Effects of Targeted Temperature Management (33°C)?

There is NO difference in major adverse events between cooling to 33°C vs 36 or 37°C. This is just a myth!

Increased Risk of Coagulopathy

• Some patients may come in with major life threatening bleeding already, ( intracranial or GI)
• ILCOR guidelines offers dosing range of 32 – 36°C; target 36° for these patients to decrease risk of further bleeding

Arrhythmia

• Can cause bradycardia
• Monitor blood pressure and perfusion
• Possible use of low dose vasopressors
• If too unstable, increase temperature until satisfactory

Increased Insulin Resistance

• Typically treated with insulin infusion: goal 140-180 mmol/L
• Can also use high dose insulin as acceptable
• If continued hyperglycemia, despite high dose insulin infusion, then increase temperature
• Tight glucose control can lead to hypoglycemia, which can also lead to poor neurologic outcomes

Electrolyte Abnormalities

• Cold-induced diuresis caused by vasoconstriction, leading to increased urine output
• Hypokalemia, hypomagnesemia, hypophosphatemia, hypocalcemia
• Hypokalemia is main concern because it can cause dysrhythmias
• Monitor potassium closely as patients can become hyperkalemic during rewarming
• Tip: Keep potassium low normal prior to rewarming to avoid hyperkalemia

Drug Metabolism

• Hypothermia can affect the liver and its ability to metabolize certain drugs
• Possible prolonged effects of analgesics and sedation medeications

Infection Risk

• Ventilator associated pneumonia
• Can decrease leukocyte function
• Literature does not report this or sepsis as increased risk

Musculoskeletal

• Shivering increases oxygen demand and consumption
• Treat aggressively with sedation or paralytic
• Sedation preferred over paralysis as goal is to decrease oxygen consumption

Therapeutic Hypothermia from Beginning to End:

• Expedite cooling to 33° C within the first 4 hours (podcast I stated 6 hours, but faster the better)
• Keep at targeted temperature for 12-24 hours (ICECAP Trial enrolling patients soon to determine duration of cooling)
• Use of intravascular cooling device (closed-loop feedback) offers tightest control
• Slowly rewarm by 72 hours, be mindful of this stage as patients can still spike fevers
• Target normothermia for a few days after rewarming

References:

1. Hypothermia After Cardiac Arrest Study Group. Mild Therapeutic Hypothermia to Improve the Neurologic Outcome After Cardiac Arrest. NEJM 2002. PMID: 11856793
2. Bernard SA et al. Treatment of Comatose Survivors of Out-of-Hospital Cardiac Arrest with Induced Hypothermia. NEJM 2002. PMID: 11856794
3. Nielsen N et al. Targeted Temperature Management at 33°C Versus 36°C After Cardiac Arrest. NEJM 2013. PMID: 24237006
4. Lascarrou JB et al. Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm. NEJM 2019. PMID: 31577396
5. Moler FW et al. Therapeutic Hypothermia After In-Hospital Cardiac Arrest in Children. NEJM 2017. PMID: 28118559
6. Moler FW et al. Therapeutic Hypothermia After Out-of-Hospital Cardiac Arrest in Children. NEJM 2015. PMID: 25913022
7. Tagin MA et al. Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy: An Updated Systematic Review and Meta-Analysis. Arch Pediatr Adolesc Med 2012. PMID: 22312166

References:

1. Hypothermia After Cardiac Arrest Study Group. Mild Therapeutic Hypothermia to Improve the Neurologic Outcome After Cardiac Arrest. NEJM 2002. PMID: 11856793
2. Bernard SA et al. Treatment of Comatose Survivors of Out-of-Hospital Cardiac Arrest with Induced Hypothermia. NEJM 2002. PMID: 11856794
3. Nielsen N et al. Targeted Temperature Management at 33°C Versus 36°C After Cardiac Arrest. NEJM 2013. PMID: 24237006
4. Lascarrou JB et al. Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm. NEJM 2019. PMID: 31577396
5. Moler FW et al. Therapeutic Hypothermia After In-Hospital Cardiac Arrest in Children. NEJM 2017. PMID: 28118559
6. Moler FW et al. Therapeutic Hypothermia After Out-of-Hospital Cardiac Arrest in Children. NEJM 2015. PMID: 25913022
7. Tagin MA et al. Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy: An Updated Systematic Review and Meta-Analysis. Arch Pediatr Adolesc Med 2012. PMID: 22312166