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Our results show that among patients in whom spontaneous circulation had been restored after cardiac arrest due to ventricular fibrillation, sys- temic cooling to a bladder temperature between 32o_{C and 34}o_{C for 24}

hours increased the chance of survival and of a favorable neurologic outcome . . . , as compared with standard normothermic life support.

— The Hypothermia after Cardiac Arrest (HACA) Study Group1

Research Question: Does moderate systemic hypothermia (e.g., 32°– 34°C for

24 hours) increase rates of neurologic recovery after resuscitation from cardiac arrest due to ventricular fibrillation (VF)?1

Funding: Grants from the Biomedicine and Health Programme (BIOMED 2)

implemented under the Fourth RTD Framework Programme 1994– 1998 of the EU, the Austrian Ministry of Science and Transport, and the Austrian Science Foundation. Kinetic Concepts (Wareham, United Kingdom) provided the TheraKool cooling device.

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Year Study Began: 1996 Year Study Published: 2002

Study Location: 9 participating sites in Austria, Belgium, Finland, Germany,

and Italy

Who Was Studied: Patients aged 18– 75 years who suffer a witnessed cardiac

arrest (i.e., VF or pulseless ventricular tachycardia as the initial cardiac rhythm, from a presumed cardiac origin for the arrest). Only an estimated downtime of 5– 15 minutes from the patient’s witnessed collapse to the first attempt at resuscitation by emergency medical personnel, and an interval of no more than 60 minutes from collapse to return of spontaneous circulation (ROSC), were allowable for enrolled patients.

Who Was Excluded: Patients were excluded if they met any of the following

criteria:

• A tympanic- membrane temperature <30o_{C on admission,}

• A comatose state before the cardiac arrest due to drug administration that depressed the central nervous system,

• Pregnancy,

• Response to verbal commands after ROSC and before randomization, • Sustained hypotension (mean arterial pressure <60 mm Hg) for >30

minutes after ROSC and before randomization,

• Sustained hypoxemia (arterial oxygen saturation <85%) for >15 minutes after ROSC and before randomization,

• A terminal illness that preceded the arrest,

• Factors that made participation in follow- up unlikely, • Enrollment in another study,

• Occurrence of cardiac arrest after the arrival of emergency medical personnel, or

• Known preexisting coagulopathy.

How Many Patients Enrolled: 275

Therapeutic Hypothermia for Cardiac Arrest, Part I 125

Study intervention:

• All patients: A temperature was taken on admission with an infrared tympanic thermometer. Further measurements were made from a bladder temperature probe that was placed with a Foley catheter during the study time period. All patients received sedation, analgesia, and a paralytic for 32 hours with intravenous administration of midazolam, fentanyl, and pancuronium, respectively.

• Mild hypothermia protocol: An external cooling device, consisting of a mattress with a cover that delivers cold air over the entire body, was used to reach the target bladder temperature range (32°– 34°C) within 4 hours after ROSC. If this goal range was not met, ice packs were also used. • Normothermia protocol: These patients received standard protocol-

driven intensive care.

Follow- Up: Neurologic outcome within the first 6 months after arrest (See

Table 18.1).

Table 18.1. Cerebral Performance Categories (CPC) Scale CPC 1: Good cerebral performance: conscious, alert, able to work

CPC 2: Moderate cerebral disability: conscious, can carry out independent activities

CPC 3: Severe neurologic disability: conscious, dependent on others for daily support

CPC 4: Coma or vegetative state CPC 5: Dead

Adapted from Jennett B, Bond M. Assessment of outcome after severe brain damage. Lancet. 1975;1(7905):480– 484.

Adults who suffered a witnessed cardiac arrest with ROSC no more than 60 minutes from time of collapse

Randomized (upon arrival in emergency department) Treated for 24 hours

Mild Hypothermia Protocol (32°–34°C); followed by passive rewarming over 8

hours

Normothermia Protocol (32°–<38°C) Figure 18.1 Summary of Study Design.

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Endpoints: Primary outcome:  Favorable neurologic outcome within

six months after cardiac arrest, as measured by the Pittsburgh Cerebral- Performance Category (CPC) Scale as a CPC 1 or CPC 2 (See Table 18.1). Secondary outcomes: Mortality within 6 months and rates of complications within 7 days after cardiac arrest. Complications recorded included bleeding of any severity, pneumonia, sepsis, pancreatitis, renal failure, pulmonary edema, seizures, arrhythmias, and pressure sores.

RESULTS

• At 6 months, more patients in the hypothermia group had a favorable neurologic outcome versus the normothermia group (See Table 18.2). • There was no significant difference in any of the tracked

complications; however, an analysis of total complications favored a trend toward a higher rate of infection in the hypothermia group.

Table 18.2. Summary of Neurologic Outcome and Mortality at Six Months

No./ Total No. (%)

Outcome Normothermia Hypothermia Risk Ratio

(95% CI) P Value Favorable Neurologic

Outcome 39 55 1.40 (1.08– 1.81) 0.009

Death 55 41 0.74 (0.58– 0.95) 0.02

Criticisms and Limitations: The criticisms of this study include the follow-

ing. In its design, the study was only blinded to the study outcome assessors, but not to the treating attending physicians. The original investigators noted this was due to the design of the cooling device. Of note, more bystander CPR was performed in the normothermia group than the hypothermia group, which may speak to some confounding effect from bystander CPR on neurologic out- come. As well, in the initial characterization of the study group, little detail was given regarding the neurological examination findings of patients, specifically brainstem reflexes, prior to randomization, other than being comatose (per- sonal communication). Therefore, it was unclear if the two groups were similar with regard to coma severity.

With regard to cooling, there were several limitations. The air mattress used for cooling in this trial was ineffective; 70% of patients also required ice packs to reach target temperature. The time to target cooling temperature also took on average 8 hours versus faster times in other comparative studies. As well, the

Therapeutic Hypothermia for Cardiac Arrest, Part I 127

normothermia group actually became hyperthermic on average, a variable not well controlled for in the study. This may have contributed to worse outcomes in this group.

Finally, due to the very strict inclusion and exclusion criteria, only 8% of the eligible patients were included in the trial. Questions over its generalizability to groups of patients with lower risk for brain damage and to those with cardiac arrest due to causes other than VF warrant further studies.

Other Relevant Studies and Information:

• Since the publication of this trial and the Australian trial in the following chapter,1,2 _{several smaller studies on therapeutic}

hypothermia have been performed.3,4

• Recent randomized controlled trials have sought to refine two key variables with therapeutic hypothermia: target temperature ranges for therapeutic hypothermia and time to target temperature (with the use of pre- hospital versus in- hospital cooling protocols.

• Nielsen et al.5 _{found that when comparing a targeted temperature}

range of 33°– 36°C (i.e., prevention of fever), cooling to 33°C provided no additional benefit versus cooling to 36°C. This may suggest a permissive hypothermia range of 33°– 36°C may be acceptable if clinicians feel uncomfortable cooling specific patients down to the lower range.

• Kim et al.6 _{performed the largest blinded randomized controlled}

trial in therapeutic hypothermia to answer a focused question as to whether out- of- hospital initiation of therapeutic hypothermia by rapid infusion of cold saline confers any benefit to neurological outcome. They found that there was an increased risk for systemic complications associated with a rapid 2- liter infusion of cold saline (i.e., pulmonary edema and risk for cardiac rearrest) that outweighed any benefit in neurologic outcome or survival.

Summary and Implications: The HACA trial was one of two studies that

demonstrated that active cooling for mild- to- moderate hypothermia improved the rate of favorable neurologic outcome and reduced mortality. In 2003, the International liaison Committee on Resuscitation’s Advanced life Support Task Force7 _{began recommending that (1)  unconscious adult patients with}

spontaneous circulation after out- of- hospital cardiac arrest should be cooled to 32°– 34o_{C for 12– 24 hours when the initial rhythm was VF, and (2) such}

cooling may also be beneficial for other rhythms for patients experiencing an in- hospital cardiac arrest.

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Especially in the context of the aforementioned more recent Nielsen et al. study,6 _{further studies are necessary to determine the ideal method, duration,}

and range for therapeutic hypothermia in this patient population.

References

1. Hypothermia after Cardiac Arrest Study G. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346: 549– 556.

2. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out- of- hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346: 557– 563.

3. Hachimi- Idrissi S, Corne l, Ebinger G, Michotte Y, Huyghens l. Mild hypo- thermia induced by a helmet device:  a clinical feasibility study. Resuscitation. 2001;51:275– 281.

4. laurent I, Adrie C, Vinsonneau C, et al. High- volume hemofiltration after out- of- hospital cardiac arrest: a randomized study. J Am Coll Cardiol. 2005;46(3):432– 437. 5. Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at

33°C versus 36°C after cardiac arrest. N Engl J Med. 2013;369(23):2197– 2206. 6. Kim F, Nichol G, Maynard C, et al. Effect of prehospital induction of mild hypo-

thermia on survival and neurological status among adults with cardiac arrest. JAMA. 2014;311(1):45– 52.

7. Nolan JP, Morley PT, Hoek Tl, Hickey RW. Therapeutic hypothermia after car- diac arrest. An advisory statement by the Advanced life Support Task Force of the International liaison Committee on Resuscitation. Resuscitation. 2003;57: 231– 235.

CLINICAL CASE: THERAPEUTIC HYPOTHERMIA FOR POST– CARDIAC ARREST

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Therapeutic Hypothermia

for Cardiac Arrest, Part II