Targeted Temperature Management & Non-shockable Rhythms

HYPERION TRIAL

Dr Jose Chacko & Dr Swapnil Pawar

Targeted temperature management with a target of 32 degrees C to 36 degrees C (moderate therapeutic hypothermia) is currently advocated by ILCOR guidelines for all patients with coma after successful resuscitation from cardiac arrest. TTM Trial results published in 2013, however, showed inconclusive effects of this treatment in 19% of patients who had cardiac arrest with a nonshockable rhythm (asystole or pulseless electrical activity), and the use of hypothermia subsequently decreased in this situation. the study by Paul young et al showed the dramatic change in practices in ANZ post TTM publication in 2013. In the same subset of patients, Two retrospective case-series studies suggested beneficial effects of hypothermia on both neurologic outcomes and survival among these patients, two showed no effect and two suggested harm. This uncertainty requires resolution because nonshockable rhythms now predominate among patients with cardiac arrest. As we know, non-shockable rhythms are associated with a poor prognosis, with only 2 to 15% of patients having good neurologic outcomes as compared with nearly 65% of patients who have cardiac arrest with a shockable rhythm. So answering this question in this subset of the population is crucial
Hypothesis – whether moderate therapeutic hypothermia at 33ÅãC, as compared with targeted normothermia (37ÅãC), would improve neurologic outcome in patients with coma who had been successfully resuscitated after cardiac arrest with nonshockable rhythm.  

Design: Multi-center, randomized, controlled trial. Web-based randomization, enrollment in permuted blocks of varying sizes and with stratification according to center and cause of cardiac arrest (presumed cardiac vs. presumed noncardiac).
Setting: 25 intensive care units (ICUs) in France.
Study population 
Inclusion: 18 years of age or older and resuscitated from out-of-hospital or in-hospital cardiac arrest with a non-shockable rhythm. GCS of less than 8. 

Exclusion:  No-flow time (time from collapse to commencement of CPR) >10 minutes; a low-flow time (time from initiation of CPR to ROSC) of >60 minutes; major hemodynamic instability (adrenaline or noradrenaline >1 μg/kg/min); time from cardiac arrest to screening of more than 300 minutes; moribund condition; Child-Pugh class C cirrhosis of the liver (severe hepatic dysfunction); pregnancy or breast-feeding; status of being under guardianship; status of being an inmate at a correctional facility; previous inclusion in another randomized, controlled trial involving patients with cardiac arrest in which the neurologic outcome at 90 days was assessed as the primary endpoint; lack of health insurance; and decision by the next of kin for the patient not to participate.
Neurological outcome at 90 days, the primary outcome, was assessed using the CPC score. The assumption that 14% of patients with targeted normothermia would have a CPC score of 1 or 2 compared to 23% in the hypothermia group (absolute difference of 9%). The sample size calculated was 584 patients for 80% power, a two-sided significance level of 5%.

Intervention: Hypothermia to 33°C (±0.5°C) was induced and maintained for 24 hours. Slow rewarming followed at 0.25 to 0.5°C per hour, to 36.5 to 37.5°C; this temperature was maintained for 24 hours. Sedation to RAS of –5 (unresponsive). Sedation was weaned when during rewarming when body temperature rose above 36°C.
Control: Temperature maintained 36.5–37.5°C for 48 hours. Sedation was routinely administered only during the first 12 hours after randomization, according to the 2010 ILCOR guidelines. 
Common: Shivering: step 1. single intravenous bolus of a hypnotic agent and an opioid; step 2: intravenous bolus of a nondepolarizing neuromuscular blocker; step 3: continuous infusion of a nondepolarizing neuromuscular blocker. 
MAP of 65 mmHg and, if measured, central venous oxygen saturation (ScvO2) ≥70%; SaO2 >92%; PaCO2: 35–40 mm Hg; Hb 7 if no IHD, >10 if IHD; blood sugar control if outside 60–160 mg/dl. 
Decisions regarding the limitation of treatment followed current guidelines. All surviving patients were followed until day 90 after randomization.
Results: Among 584 patients who underwent randomization, three patients in the hypothermia group subsequently withdrew consent. Thus 581 patients, 284 who underwent hypothermia 297 randomized to the normothermia group were included in the analysis.
In hospital arrests: 27.4%; out of the hospital: 72.6%. Two-thirds of all patients had a non-cardiac cause for the arrest. Mean (±SD) temperature between 12 and 24 hours after randomization was 33.5 ± 1.1°C in the hypothermia group and 37.0 ± 0.7°C in the normothermia group. 
Primary outcome: CPC score of 1 or 2 on day 90 was significantly better in the hypothermia group; 29/284 (10.2%) vs. 17/297 (5.7%). Absolute difference: 4.5% CI: (0.1–8.9). The improved neurological outcome was evident in pre-defined subgroups: in-hospital vs. out of hospital cardiac arrest, cardiac vs. non-cardiac cause of arrest, and time to ROSC (15 min or less, compared to more than 15 min)

	Hypothermia (284 patients)	Normothermia (297 patients)
90-d mortality (No, %)	231 (81.3)	247 (83.2)
Died in ICU (No, %)	222 (78.2)	236 (79.5%)
Ventilation days (median, IQR)	4.5 (2–7)	4.0 (2–7)
ICU days (median, IQR)	4 (2–7)	4 (2.0–6.0)
Survival to ICU discharge (No, %)	62 (21.8)	61 (20.5)
Ventilation days (median, IQR)	11 (6–24)	10 (4–27)
ICU days (median, IQR)	6 (4–18)	6 (2–21)

The overall 90-d mortality was 82.3% (478/581 patients)Death following the withdrawal of life support in 64.4% (374/581)
Strengths: 

1. Multi-centric, randomized controlled trial, adequately powered for the primary outcome
2. The primary outcome studied, the neurological outcome at 90-d was a clinically appropriate endpoint
3. Secondary outcomes and subgroup analysis were relevant 
4. Therapy was standardized in both arms of the study
5. A protocolized approach was employed to maintain the desired temperature in both groups
6. Neurological outcomes were evaluated by an independent investigator, who was blinded to the allocation arm 

Weaknesses

1. Unblinded study; however, blinding was not practicable
2. A large number of exclusions; only 584 of 4466 patients who were screened were randomized; 627 patients were excluded as they were considered “moribund” 
3. The primary outcome was assessed by a telephonic interview
4. Many patients had a temperature of >38 after the period of controlled temperature
5. Three patients withdrew consent from the hypothermia group
6. Several different methods of cooling were employed, with variable efficacy. 
7. Data were missing on 3 patients, who were presumed to have died 
8. The fragility index was 1; a different outcome in one patient in either group would have made the results non-significant 
9. Several patients temperatures higher 38°C, particularly after the targeted temperature management phase. This raises the question of whether a target of 37C may more often lead to temperature overshoot, compared to aiming for a lower target of 36C as in the TTM study
10. The dichotomous primary outcome was assessed by a single, blinded interviewer using a scoring system that may be prone to inter-rater variability 

Author’s conclusions: Therapeutic hypothermia to 33°C for 24 hours led to a more favorable 90-d neurological outcome among patients who remained in a coma after resuscitation from cardiac arrest with a non-shockable rhythm. 

Our Take –

1. Don’t apply these results as a blanket rule for all patients with non-shockable rhythm.
2. Choose your patient population wisely – consider other prognostication markers before applying this modality.
3. One size doesn’t fit all.