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

Therapeutic Hypothermia (also called targeted temperature management (TTM)) is a deliberate reduction of the core body temperature to 32 – 34°C, in patients who suffer cardiac arrest with return of spontaneous circulation, but also don’t regain consciousness. In REBEL Crit Cast episode 1, I will go through the evidence for cooling adults and children, potential adverse effects, and what temperature to shoot for.

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

Click here for Direct Download of Podcast 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%)

(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%)

: 257 children aged >48hrs and <18 years of age 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

260 children, aged >48hrs and <18 years (Average age of 1 – 2 years) 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

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

Post Transcribed By: Corinthia Stephanas Gonzales

Post Peer Reviewed By: Salim R. Rezaie, MD (Twitter: @srrezaie)