Arctic Sun / TTM

Here are the clinical teaching points for Targeted Temperature Management (TTM) after Cardiac Arrest structured in a Q&A format:

Indications for Targeted Temperature Management (TTM)

• Who should receive TTM after cardiac arrest?

  • Any patient with a Glasgow Coma Scale (GCS) score of less than 8 after return of spontaneous circulation (ROSC) should be considered for TTM, particularly if they are unresponsive to verbal commands or do not show purposeful movement.

• Does the type of cardiac arrest rhythm affect the decision to initiate TTM?

  • No, TTM is indicated for both shockable (e.g., ventricular fibrillation, ventricular tachycardia) and non-shockable rhythms (e.g., pulseless electrical activity [PEA], asystole). The Hyperion trial showed improved outcomes with TTM at 33°C after arrest with non-shockable rhythms.

• Does the location of cardiac arrest influence TTM use?

  • No, both in-hospital and out-of-hospital arrests can be considered for TTM if ROSC is achieved, provided the patient has stable hemodynamics on vasopressors or inotropes.

• What is the primary goal of TTM?

  • TTM aims to minimize post-cardiac arrest brain injury from hypoxia and ischemia, striving for a favorable neurological outcome, typically indicated by independence with minimal assistance on scales like the Cerebral Performance Category (CPC) or Modified Rankin Scale (mRS).

Evidence for TTM Effectiveness

• Does TTM improve neurological outcomes after cardiac arrest?
  • Yes, landmark trials from 2002 (Bernard et al. and the Hypothermia After Cardiac Arrest [HACA] study) found that TTM significantly improved neurological outcomes compared to normothermia, with the HACA study indicating a 55% versus 39% improvement, translating to a number needed to treat of 6-7.

Phases of Targeted Temperature Management

1. Induction Phase

   • What happens during the induction phase of TTM?
     • The patient is cooled to the target temperature as quickly as possible using either external (e.g., Arctic Sun) or intravascular cooling devices (e.g., Zoll).
   • How do these cooling methods differ?
     • Intravascular devices often reach target temperatures faster, with more stable control over temperature and rewarming, though neither method has shown superiority in mortality or neurological outcomes.

2. Maintenance Phase

   • What target temperature is recommended during the maintenance phase?
     • The target temperature is generally between 33°C and 36°C, depending on institution protocols, to be maintained for 24 hours.
   • Is there evidence for a specific target temperature within this range?
     • The 2013 TTM trial by Nielsen et al. showed no difference in outcomes between 33°C and 36°C after 24 hours of TTM maintenance, though a retrospective study suggested potential benefit of 33°C for patients with delayed initiation of CPR.

3. Rewarming Phase

   • How should rewarming be conducted after the maintenance period?
     • Rewarming should be gradual, at a rate of 0.2–0.5°C per hour, with a target final temperature of 36–37°C. Avoiding rebound fever is essential during this phase, typically managed by the feedback systems of cooling devices.

Complications of TTM

• What are the common complications associated with TTM?
  • Shivering: Managed with sedatives (e.g., propofol, dexmedetomidine) and analgesics (e.g., fentanyl). Neuromuscular blockade may be necessary if shivering persists.
  • Arrhythmias: Hypothermia can cause atrial fibrillation, ventricular tachycardia, and bradycardia.
  • Cold-Induced Diuresis: This can lead to hypovolemia and electrolyte imbalances such as hypokalemia, hypomagnesemia, and hypocalcemia.
  • Hyperglycemia: Hypothermia reduces insulin sensitivity, potentially requiring insulin infusions.
  • Bleeding: TTM impairs coagulation and platelet function, increasing bleeding risks, which must be weighed against benefits in patients with coagulopathy or active bleeding.
  • Infection Risk: Hypothermia can impair immune function, increasing infection risk. Prophylactic antibiotics (e.g., IV amoxicillin-clavulanate) have been shown to reduce early ventilator-associated pneumonia.

Summary

• Key Points on TTM:
  • TTM is recommended for comatose patients after cardiac arrest regardless of rhythm or location.
  • TTM involves three phases—induction, maintenance, and rewarming—with each phase requiring careful management to prevent complications.
  • Studies show that TTM improves neurological outcomes, but 33°C versus 36°C targets do not differ significantly in terms of efficacy.
  • Vigilant monitoring and intervention for complications, such as shivering, arrhythmias, diuresis, and infection, are crucial throughout the TTM process.

Introduction let's talk about targeted temperature management ttm after cardiac arrest first we will review indications for ttm after cardiac arrest with rosk then we will review the three phases of ttm in doing so we will describe the results of the landmark ttm trial and finally we will identify potential complications of ttm Indications first let's review indications for ttm all patients with a glasgow coma scale of less than eight after rosk should receive targeted temperature management essentially if the patient is not showing purposeful movement and or unresponsive to verbal commands or could reasonably be considered comatose they should be considered for ttm

does the arrest rhythm matter while trials historically included a higher proportion of patients post-shockable rhythm arrest meaning ventricular fibrillation and ventricular tachycardia we now have data demonstrating improved outcomes with ttm after non-shockable rhythm arrest pea and asystole the hyperion trial from a favorable neurologic outcome at 90 days with ttm at 33 degrees after a rest with a non-shockable rhythm therefore the answer is no post-arrest patients with shockable and non-shockable rhythm should receive ttm does a rest location matter again no both out of hospital and in-hospital arrests should be considered for ttm if rask is obtained note hemodynamic instability is not a contraindication to ttm as long as the patient is on stable doses of vasopressors and inotropes our ultimate goal with targeted temperature management is to prevent or decrease post-cardiac arrest brain injury from hypoxia and ischemia in most clinical trials this is defined as a favorable neurologic outcome on either the cerebral performance category cpc or the modified rankin scale favorable by both metrics typically means the ability to live independently with minimal assistance does ttm accomplish this goal yes in addition to the previously discussed hyperion trial two landmark trials from 2002 comparing ttm to normothermia by bernard at all and the hypothermia after cardiac arrest study group demonstrated improved outcomes with ttm compared to normothermia and 55 percent versus 39 by the haca study group this equates to a number needed to treat of six to seven to prevent one unfavorable neurologic outcome or death Induction Phase after the decision is made to initiate ttm the patient will move through three phases induction or cooling maintenance and rewarming first let's discuss the induction phase the patient should be cooled to the goal temperature as rapidly as possible of note after cardiac arrest and rosk many patients will present with a temperature less than 36 degrees celsius due to mixing of cool peripheral blood with warmer core blood there are two major methods for cooling external or surface cooling and intravascular in our hospital system the external cooling system is also referred to by the brand name arctic sun the intravascular cooling system may be referred to by the manufacturer title zoll external cooling devices typically utilize gel pads while intravascular devices infuse cold fluids in a closed loop system the intravascular device typically has three additional lumens that can be utilized for other infusions if needed both devices are connected to a terminal that provides continuous temperature feedback to achieve the set target temperature how do these two methods differ in an analysis of the

trial intravascular cooling devices were associated with a shorter time to target temperature decreased temperature variability and rewarming rate there was no difference in mortality or neurologic outcomes after induction we enter the maintenance phase what should our target temperature be

Shivering, cold induced diuresis - hypovolemia hypoK, hypoMg, hypoCa

insulin sensitivity hyperglycemia insulin gtt

and how long should we keep patients at that temperature to answer this question let's review the landmark ttm trial by nielsen at all from 2013. the ttm trial was a large multi-center rct across 36 icus in europe and australia comparing ttm at 33 degrees versus 36 degrees celsius in the ttm trial protocol patients were cooled to the target temperature maintained at target temperature for 28 hours and then gradually rewarmed to 37 degrees celsius in 0.5 degrees celsius increments with the goal of maintaining a temperature less than 37.5 for at least main inclusion criteria were gcs less than 8 after out of hospital cardiac arrest with greater than 20 minutes of spontaneous circulation after rosk what did these arrests look like 90 were witnessed 73 received bystander cpr with a median time of one minute until bls minutes until rosk approximately 80 percent were shockable rhythms at the end of the trial and approximate three year period there was no significant difference in mortality or poor neurologic function at 180 days between the 33 and 36 degree groups there was no difference in rates of shivering fever or adverse outcomes between groups with the exception of slightly more hypokalemia in the 33 degree group the authors concluded that ttm at 33 degrees does not confer additional benefit compared to 36 degrees next the tth-48 trial compared ttm at 33 degrees for 48 vs 24 hours there was no difference in favorable neurologic outcomes at 6 months with a higher rate of adverse events and longer icu length of stay in the 48 hour group the decision to target 33 or 36 degrees is institution dependent why might 33 degrees celsius be preferred a retrospective cohort study from 2012 assessing 1200 cardiac arrest patients over an 18-year period found a maximum benefit of ttm at 33 degrees with respect to favorable neurologic outcome and survival in patients with no flow time or time from collapse to initiation of cpr of greater than 8 minutes notably this finding was not replicated in a post-hoc analysis of the ttm trial to recap patients should be maintained at the target temperature for 24 hours with some evidence to indicate that 33 degrees celsius may be preferred for patients with longer no-flow times Complications what complications of ttm should we be aware of shivering is the most common human response to hypothermia and slows the rate of cooling first line to control shivering is adequate analgesia and sedation fentanyl is a first-line agent for analgesia sedation can be achieved with propofol dex metatamine or midazolam if unable to control shivering with sedative and analgesic infusions neuromuscular blockade can be utilized adjunctive agents include acetaminophen and beusperone arrhythmia is also common afib occurred in 26 to 28 of patients in the ttm trial bt occurred in 15 to 18 percent and bradycardia in five to six percent of patients hypothermia causes a cold induced diuresis which can lead to hypovolemia as well as numerous electrolyte abnormalities including hypokalemia hypomagnesemia and hypocalcemia hypothermia decreases insulin sensitivity and secretion leading to hyperglycemia control of hyperglycemia may require initiation of an insulin infusion hypothermia impairs coagulation and platelet function and increases the risk of bleeding coagulopathy and or active bleeding may be a contraindication to ttm and risk versus benefit must be considered in these situations finally hypothermia impairs immune system function and increases the risk of infection approximately 50 percent of patients in the ttm trial develop pneumonia a 2019 placebo-controlled rct demonstrated that a two-day course of iv amoxicillin clavulanate after cardiac arrest decreased the incidence of early ventilator-associated pneumonia defined as the first seven days of hospitalization iv ampicillin sulbactam or another similar antibiotic can be utilized after the maintenance period the patient is re-warmed to 36 to 37 degrees celsius re-warming should occur at a rate of 0.2 to 0.5 degrees celsius per hour it is critical during the rewarming period to avoid rebound fever therefore patients should be locked in at a temperature between 36 to 37 degrees utilizing the feedback system of the external or intravascular cooling device neurologic prognostication with the assistance of a neurologist or neuro-critical care specialist can typically begin as early as 72 hours after the arrest prognostication includes consideration of the clinical exam including motor response to pain pupillary and corneal reflexes imaging including ct mri and eeg and biomarkers including neuron specific enolase a protein released from injured neurons Summary in this video we reviewed indications for targeted temperature management after cardiac arrest with rosk and identified that all comatose patients should be considered for ttm regardless of etiology or location of arrest we then reviewed the three phases of ttm induction maintenance and rewarming during which we described the results of the landmark ttm trial which found no difference in outcome between ttm at 33 versus 36 degrees finally we reviewed potential complications of ttm including shivering arrhythmia cold induced diuresis hyperglycemia bleeding and increased risk of infection thank you for watching

References in order of appearance: 1. HYPERION: Lascarrou J-B, Merdji H, Le Gouge A, et al. Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm. New England Journal of Medicine. 2019;381(24):2327-2337. 2. Bernard SA, Gray TW, Buist MD, et al. Treatment of Comatose Survivors of Out-of-Hospital Cardiac Arrest with Induced Hypothermia. New England Journal of Medicine. 2002;346(8):557-563. 3. Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest. New England Journal of Medicine. 2002;346(8):549-556. 4. De Fazio C, Skrifvars MB, Søreide E, et al. Intravascular versus surface cooling for targeted temperature management after out-of-hospital cardiac arrest: an analysis of the TTH48 trial. Critical Care. 2019;23(1):61. 5. Nielsen N, Wetterslev J, Cronberg T, et al. Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest. New England Journal of Medicine. 2013;369(23):2197-2206. 6. TTH48: Kirkegaard H, Søreide E, de Haas I, et al. Targeted Temperature Management for 48 vs 24 Hours and Neurologic Outcome After Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial. Jama. 2017;318(4):341-350. 7. Possible benefit of 33 C: Testori C, Sterz F, Holzer M, et al. The beneficial effect of mild therapeutic hypothermia depends on the time of complete circulatory standstill in patients with cardiac arrest. Resuscitation. 2012;83(5):596-601. 8. Dankiewicz J, Friberg H, Bělohlávek J, et al. Time to start of cardiopulmonary resuscitation and the effect of target temperature management at 33°C and 36°C. Resuscitation. 2016;99:44-49. 9. Nolan JP, Soar J, Cariou A, et al. European Resuscitation Council and European Society of Intensive Care Medicine Guidelines for Post-resuscitation Care 2015: Section 5 of the European Resuscitation Council Guidelines for Resuscitation 2015. Resuscitation. 2015;95:202-222. 

10. François B, Cariou A, Clere-Jehl R, et al. Prevention of Early Ventilator-Associated Pneumonia after Cardiac Arrest. New England Journal of Medicine. 2019;381(19):1831-1842.