Cardiac Arrest Literature Summaries

THERAPEUTIC HYPOTHERMIA AND TARGETED TEMPERATURE MANAGEMENT

Nielsen N, et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013 Dec 5;369(23):2197-206. [PMID 24237006]

• MCRCT without allocation concealment
• 36 ICUs in Europe and Australia
• n = 939
• Patients: unconscious (GCS<8) adults (aged 18y or more) after out-of hospital cardiac arrest of presumed cardiac cause
  — exclusions: interval from ROSC to screening of >240 minutes, unwitnessed arrest with asystole as the initial rhythm, suspected or known acute intracranial hemorrhage or stroke, and a body temperature <30°C
• Intervention: targeted temperature management at 33°C
• Comparator: targeted temeperature management at 36°C (“normothermia”)
• Outcomes:
  — primary outcome: all-cause mortality
  — secondary outcomes: a composite of poor neurologic function or death at 180 days, as evaluated with the Cerebral Performance Category (CPC) scale and the modified Rankin scale; adverse events reported in day 1 of 7 of ICU stay
• Results:
  — No difference in outcomes between cooling to T33C compared T36C
  — mortality: 50% versus 48%
  — poor neurological function:  54% versus 52% using the CPC (risk ratio, 1.02; 95% CI, 0.88 to 1.16; P = 0.78); 52% for both groups using the modified Rankin scale
  — results of analyses adjusted for known prognostic factors were similar
  — Hypokalemia was more frequent in  T33°C (19%) vs T36°C (13%) (P=0.02); no other adverse effects had a statistically significant difference
• Commentary and criticisms:
  — the study included a protocol that clearly delineated their approach for the 26% of patients who had withdrawal of care before hospital discharge
  — neurological prognostication was performed a minimum of 72h after the intervention period ended (unless there was myoclonic status in the first 24h and absent N20 SSEPs)
  — physicians performing neurologic prognostication, assessors of neurologic follow-up and final outcome, study administrators, statisticians, and the authors were blinded
  — both groups underwent gradual rewarming to 37°C at 28h in hourly increments of 0.5°C, and at 36h mandatory sedation was discontinued or tapered
  — neurologically intact survival would have been a better patient-orientated primary outcome, but the authors chose all cause mortality as it is less susceptible to measurement bias
  — the trial was not powered to detect relative risk reductions <20%
  — baseline balance: slightly higher rates of MI and IHd in the T33 group, more diabetes mellitus in the T36 group; similar spread of presumed cause of death
  — modified intention-to-treat analysis (all except those that withdrew consent)
  — unlike the Bernard 2002 and HACA 2002 studies, this trial did not focus on VT/VF arrest patients only
  — following this study unanswered questions include: do certain subgroups of cardiac arrest paitents still benefit from T<36C?

Bernard SA et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002 Feb 21;346(8):557-63. [PMID 11856794]

• small pseudo-randomised (alternate days) trial without allocation concealment
• n = 77
• patients: those remained unconscious after resuscitation from OOHCA due to VF
• intervention: hypothermia = cooled to 33 C within 2 hours and maintained for 12 hrs
• control: standard care without targeted temperature management
• outcome: Absolute Risk Reduction (ARR) for death or severe disability of 23%, number needed to treat (NNT) was 4.5
• commentary and criticisms:
  — no record of baseline neurological status prior to the event
  — no record of GCS on arrival in ED
  — good outcome was defined as home or rehab facility at hospital discharge (rather than a structured assessment)
  — positive outcome of trial would have been lost if 1 patient in good outcome group had a bad outcome

Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002 Feb 21;346(8):549-56. [PMID 11856793]

• small MCRCT without allocation concealment
• n = 136
• patients: out-of-hospital cardiac arrest that remain unconscious
• intervention: cooled to 32-34 C for 24hrs within 4 hrs
• comparator: standard care without targetted temperature management
• outcome: ARR for unfavourable neurological outcome at 6 months (using a grading system) of 24%, and NNT of 4
• commentary and criticisms:
  — no active temperature control — usual care group were not actually normothermic, they tended to be hyperthermic
  — trial stopped early
  — only 8% of screened ED patients were included

Bernard SA et al. Induction of therapeutic hypothermia by paramedics after resuscitation from out-of-hospitalventricular fibrillation cardiac arrest: a randomized controlled trial. Circulation. 2010 Aug 17;122(7):737-42. [PMID 20679551]

• RICH Investigators – Rapid infusion with Ice Cold Hartmans
• n = 234
• patients: out-of-hospital cardiac arrest with an initial rhythm of VF
  — exclusions: not intubated, previously dependent on others for ADLs before the cardiac arrest, already hypothermic (<34C), or pregnant women
• Intervention: prehospital rapid infusion of 2L of ice-cold Hartmans (with midazolam and pancuronium) then a further 2L in ED vs standard cooling to 33 C for 24 hours
• Comparison: cooling after hospital admission
• Outcome: Functional status at hospital discharge. Patients who were discharged directly home or to a rehab facility were considered to have a favorable outcome. Patients who died or were discharged to a long-term nursing facility, either conscious or unconscious, were considered unfavorable outcome.
• Results: no difference favourable outcome 47% in treatment group vs 53% in hospital cooling group, RR of favourable vs non-favourable outcome = 0.89 (p 0.433)
• Commentary and criticisms:
  — patient were 0.5 C colder who were treated in the field but there was no difference between groups @ 30 min
  — mean decrease in core temperature was 0.8 degrees C (P=0.01)
  — Patients allocated to paramedic cooling received a median of almost 2L (1900ml)
  — study stopped early due to interim analysis predicting no difference
  — short transporation times in this study (prehospital hypothermia might be beneficial if long prehospital transport times)
  — should rapid infusion occur before or after ROSC?

POST-ARREST CARE

Kilgannon JH et al. Association between arterial hyperoxia following resuscitation from cardiac arrest and in-hospital mortality. JAMA. 2010 Jun 2;303(21):2165-71 [PMID 20516417]

• hypothesis = that post-resuscitation hyperoxia is associated with increased mortality.
• too little oxygen -> hypoxic brain injury
• too much oxygen -> O2 radical production triggering cell injury and apoptosis
• multicenter cohort study
• 120 hospitals
• n = 6326 patients
• inclusion criteria: adults, nontraumatic cardiac arrest, CPR within 24 hours prior to ICU arrival, ABG analysis performed within 24 hours following ICU arrival
• patients divided into 3 groups based of PaO2 – hyperoxia (>300mmHg), hypoxia (significantly higher in-hospital mortality (OR = 1.8)
• not cooled

PROGNOSTICATION POST CARDIAC ARREST

Zandbergen EG, de Haan RJ, Stoutenbeek CP, Koelman JH, Hijdra A. Systematic review of early prediction of poor outcome in anoxic-ischaemic coma. Lancet. 1998 Dec 5;352(9143):1808-12. [PMID 9851380]

• 33 studies
• 14 prognostic variables looked at
• 3 variable had a specificity of 100% for poor outcome:
  1. absent pupillary reflexes @ day 3
  2. absent motor response to pain (worse than withdrawal) on day 3
  3. bilateral absence of early cortical SSEP within the first week
• other poor prognostic factors = an isoelectric EEG, burst suppression, myoclonus on stimulation.

Fugate JE et al. Predictors of neurologic outcome in hypothermia after cardiac arrest. Ann Neurol. 2010 Dec;68(6):907-14. [PMID 21061401]

• the predictive value of neurological prognostic indicators for patients treated with hypothermia after surviving cardiac arrest is unknown.
• prospective co-hort study
• single center study (US)
• n = 192 (103 hypothermia, 89 nonhypothermia)
• June 2006 to October 2009
• information gathered at 72 hours:
  — clinical examination (pupillary light reflex, corneals, extensor or absent motor response)
  — SSEP’s
  — EEG
• outcome measure: in-hospital mortality
  -> clinical examination (brainstem reflexes, motor response, myoclonus) remained an accurate predictor after therapeutic hypothermia
  -> myoclonic status invariably associated with death
  -> malignant EEG patterns (burst-suppression, generalized suppression, status epilepticus and non-reactivity) associated with death.
  -> serum neuron specific enolase (NSE) > 33ng measured at 1-3 days after cardiac arrest are associated with a poor outcome but has a high false-positive rate.
  -> CT showing global cerebral oedema associated with death.
  -> sedative medication and liver/renal dysfunction can alter examination accuracy
• Strengths
  — hmmm…
• Weaknesses
  — single center
  — non-hypothermia group (non-VF or inhospital)
  — residual sedatives may have compounded examination findings

MET TEAMS

Hillman K et al. Introduction of the medical emergency team (MET) system: a cluster-randomised controlled trial. Lancet. 2005 Jun 18-24;365(9477):2091-7. [PMID 15964445]

• multi-centre
• cluster randomised control trial
• 23 Australian Hospitals (12 MET trained and implemented, 11 did not)
• training (2 months), implementation (4 months), study period (6 months)
• n = 741,744
• primary outcomes: incidence of cardiac arrests, unplanned admissions to intensive care units and death.
  -> significant increases in emergency team calls
  -> no significant change in cardiac arrest, unplanned ICU admissions or deaths
• problems:
  -> observations were not frequent enough
  -> MET teams were not called when poor observations were measured
  -> there was a substantial decreased in unexpected deaths in both groups during the study period (contamination) -> 30% reduction!
  -> under powered as base line event rate was assumed to by 30 per 1000 when it was actually 7 per 1000.
• Post-hoc Analysis of the MERIT Study (Critical Care Med. 2009 Jan;37(1):349-50):
  — examination of the relationship between early emergency teams calls and incidence of serious adverse events (not associated with cardiac arrest or death)
  -> as the proportion of early emergency teams calls increases -> the rate of cardiac arrest and unexpected death decreases.

PHARMACOTHERAPY IN ARREST

Wenzel V et al. A comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation. N Engl J Med. 2004 Jan 8;350(2):105-13. [PMID 14711909]

• triple blinded multi-centre randomised trial
• n = 1219
• initial vasopressin (40IU) vs adr (1mg) then increments of epinephrine/ adrenaline
  -> rates of admission unchanged
  -> higher survival to hospital admission for patients resuscitated with vasopressin from asystole

Olasveengen TM, Sunde K, Brunborg C, Thowsen J, Steen PA, Wik L. Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial. JAMA. 2009 Nov 25;302(20):2222-9 [PMID 19934423]

• RCT
• Norwegian
• 2003-2008
• n = 851
• ACLS with IV drug administration vs ACLS and no drug administration
• primary outcome = survival to hospital discharge
• secondary outcomes = 1 year survival, survival with favourable neurological outcome, hospital admission with ROSC, quality of CPR (chest compression rate, pauses, ventilation rate)
• inclusion criteria: > 18 years, non-traumatic, OHCA
• exclusion criteria: cardiac arrest witnessed by ambulance crew, resuscitation initiated by physicians, cardiac arrest induced by anaphylaxis or asthma
  -> increased short term survival in IV drug group
  -> no difference to survival to hospital discharge, quality of CPR or long term survival
• Weaknesses
  — 3 min of CPR prior to defibrillation in VF
  — 10% of no drugs group received drugs during resuscitation
  — not powered correctly

COMPRESSION ONLY CPR

Rea TD et al. CPR with chest compression alone or with rescue breathing. N Engl J Med. 2010 Jul 29;363(5):423-33 [PMID 20818863]

• MRCT (Washington and London x 2 sites)
• chest compressions only vs chest compression + rescue breathing
• primary outcome: survival to hospital discharge
• secondary outcomes: favourable neurological outcome, ROSC
• inclusion criteria: >18 years, OHCA, dispatcher initiated CPR instruction to bystanders
• exclusion criteria: all ready having CPR, trauma, drowning, asphyxiation, less than 18 yrs, DNR orders
• n = 1941
  -> no difference in survival
  -> no difference in favourable neurological outcome
  -> trend towards increased survival in chest compression alone group in those who had a cardiac arrest and a shockable rhythm
  -> bystanders more likely to perform CPR than rescue breathing
• Criticisms
  — one site unable to provide neurological status at discharge!
  — despite having nearly 2000 patient it required 4200 to obtain 80% power

Svensson L et al. Compression-only CPR or standard CPR in out-of-hospital cardiac arrest. N Engl J Med. 2010 Jul 29;363(5):434-42 [PMID 20818864]

• RCT
• n = 1276
• Swedish
• compression only CPR only vs Standard CPR
• primary end point = 30 day survival
• secondary end points = 1 day survival, first detected cardiac rhythm, survival to discharge from hospital
• inclusion criteria: witnessed, unconsciousness, abnormal or no breathing
• exclusion criteria: arrest caused by: trauma, airway obstruction, drowning, intoxification, age < 8, difficulty communicating, no CPR started, knowledge of how to perform CPR -> no difference between the groups in all aspects
• Criticisms
  — some differences between baseline characteristics of groups – standard CPR group (younger)
  — 113 patients assigned to compressions only got ventilation
  — needed 1000 patient in each arm -> only got 600

SOS-KANTO study group. Cardiopulmonary resuscitation by bystanders with chest compression only (SOS-KANTO): an observational study. Lancet. 2007 Mar 17;369(9565):920-6. [PMID 17368153]

• outcome measures @ 30 days (good outcomes)
  -> 2.2% no CPR
  -> 3.1% standard CPR
  -> 6.2% external cardiac massage only
  -> external cardiac massage may be better than standard CPR

Automated external defibrillators (AED)

Bardy et al. Home Use of Automated External Defibrillators for Sudden Cardiac Arrest. N Engl J Med 2008; 358:1793-1804

• n = 7001 patients
• mean age 62 years
  -> AED group produced 4 survivors (out of 3500 patients)
  -> need to arrest at home and be witnessed for an AED to be beneficial

Chan PS et al. Automated external defibrillators and survival after in-hospital cardiac arrest. JAMA. 2010 Nov 17;304(19):2129-36. [PMID 21078809]

• AED’s improve survival in out-of-hospital cardiac arrest.
• data on effectiveness in hospitalized patients are limited.
• cohort study
• n = 11,695
• 204 US hospitals following the introduction of AEDs to general hospital wards
• 82.2% had a nonshockable rhythm (asystole and PEA)
• 17.8% had a shockable rhythm (VF and pulseless VT)
• AED’s used in 38.6% of time
• 18% survival to hospital discharge
  -> overall AED use associated with a lower rate of survival
  -> AED use in nonshockable cardiac arrest associated with a significantly lower survival
  -> AED use in shockable cardiac arrest not associated with survival!