l’ipotermia terapeutica nell’arresto cardiaco facilita il ... · and unconsciousness exclusion...
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L’ipotermia terapeutica nell’arresto cardiaco facilita il recupero?
Dott. I. Brunetti
Universita’ degli Studi di Genova U.O.C Anestesia e Terapia Intensiva
SI
MA
Cosa abbiamo imparato negli ultimi 10 anni ?
SURVIVAL AFTER RESUSCITATION #
Aliv
e
100
75
50
25 Post-ROSC
0 ROSC Hosp Adm Discharge
75% decede in Ospedale
Mortalità)intraospedaliera)
71,4%)
• Of approximately 24000 arrests admitted to ICU in the UK: → 29% discharged Nolan et al, Anaesthesia 2007
Background
Secondary Injury
Free)radicals)
Excitatory)amino)aicds)
Inflammatory)response:)cytokines,)neutrophiles)
Brain)metabolism)
Edema)formaCon)
Immediate)early)gene)expression)
Nitric)oxide)
Loss)of)microtubuli)
Fritz&HG&et&al.:&Exper&Toxic&Pathol&2004;&56:91>102&
Primary Injury
Effects of Hypothermia on Brain Damage
Secondary Injury
Free)radicals)
Excitatory)amino)acids)
Inflammatory)response:)cytokines,)neutrophiles)
Brain)metabolism)
Edema)formaCon)
Immediate)early)gene)expression)
Nitric)oxide)
Loss)of)microtubuli)
Primary Injury
Effects of Hypothermia on Brain Damage
Hypothermia
Fritz&HG&et&al.:&Exper&Toxic&Pathol&2004;&56:91>102&
Background
• Quasi-randomised, odd and even days!• 84 eligible patients, 77 included !• Unscheduled interim analysis after 62 patients!• Unusual outcome measure!• Uneven groups (43 vs 34)!• Temperature in control group (37.1 -37.3 °C) • Hospital discharge as outcome
N!Engl!J!Med.!2002!Feb!21;346(8):557;63.!
N!Engl!J!Med.!2002!Feb!21;346(8):557;63.!
Good)outcome:)normal)or)with)minimal)or)moderate)disability)
Less risk of bias/systematic errors!
Included only 8 % of patients with ROSC N!Engl!J!Med!2002;346:549;56!
HACA-trial
N!Engl!J!Med!2002;346:549;56!
HACA-trial:!Hypothermia Improves Survival !
HACA-trial: Hypothermia Compared with No Temperature Control = Fever!
N!Engl!J!Med!2002;346:549;56!
2010 GUIDELINES • Use of therapeutic hypothermia to include also
comatose survivors of cardiac arrest with: • non-shockable rhythms • in-hospital arrests • paediatric patients
• The lower level of evidence for use after cardiac arrest from non-shockable rhythms is acknowledged.
2002 RACCOMANDATION
2005 GUIDELINES
Swicht from Hypothemia to Target Temperature Management
Nielsen et al Int J Card 2010
Earlier!Trials:!!
• Possible!risk!of!systemaIc!errors!
• Possible!risk!of!being!underpowered!
• InvesIgated!a!selected!group!
Hypothermia after Cardiac Arrest: A Metaanalysis
Effect of Prehospital Induction of Mild Hypothermia on Survival and Neurological Status Among Adults With
Cardiac Arrest: A Randomized Clinical Trial Kim F et al. JAMA. doi:10.1001/jama.2013.282173 ,
Inclusion criteria ROSC, tracheal intubation, intravenous access, successful, placement of esophageal temperature probe, and unconsciousness Exclusion criteria Traumatic cardiac arrest, age younger than 18 years, being awake, following commands, and temperature of less than 34°C!
!All causes of cardiac arrest were considered, including those presenting with VF and those without VF.
Effect of Prehospital Induction of Mild Hypothermia on Survival and Neurological Status Among Adults With
Cardiac Arrest: A Randomized Clinical Trial Kim F et al. JAMA. doi:10.1001/jama.2013.282173 ,
✓ Eligible patients were randomized to receive standard care alone (control) or standard care plus induction of mild hypothermia (intervention)
✓ Intervention group: up to 2 L of 4 °C normal saline,7 to 10 mg of pancuronium, and 1 to 2 mg of diazepam. The saline was infused through a peripheral intravenous line, 18-gauge or larger, using a pressure bag inflated to 300 mmHg,with a goal temperature of less than 34 °C
✓ The intervention and control groups were otherwise treated the same according to standard prehospital resuscitation protocols
Effect of Prehospital Induction of Mild Hypothermia on Survival and Neurological Status Among Adults With
Cardiac Arrest: A Randomized Clinical Trial Kim F et al. JAMA. doi:10.1001/jama.2013.282173 ,
Effect of Prehospital Induction of Mild Hypothermia on Survival and Neurological Status Among Adults With
Cardiac Arrest: A Randomized Clinical Trial Kim F et al. JAMA. doi:10.1001/jama.2013.282173 ,
Effect of Prehospital Induction of Mild Hypothermia on Survival and Neurological Status Among Adults With
Cardiac Arrest: A Randomized Clinical Trial Kim F et al. JAMA. doi:10.1001/jama.2013.282173 ,
✓ Early, rapid cooling did not improve survival or neurological status at discharge in patients with VF or without VF
✓ Rapid fluid administration was associated with higher rates of rearrest during transport and increased transient pulmonary edema, which resolved within the first 24 hours
✓ The results of the current study do not support routine use of cold intravenous fluid in the prehospital setting to improve clinical outcomes
17!th!November!,!2013!
N!Engl!J!Med!2013;369:2197;206!
Rationale
✓ There is a need for a sufficiently large clinical trial evaluating two target temperature management regimens!
- both avoiding fever! ✓ The study population should be inclusive
and representative
N!Engl!J!Med!2013;369:2197;206!
Main%objec+ve)
To!assess!the!efficacy!and!safety!of!a!!
target!temperature!management!of!!
33°C!versus!36°C!!
aUer!resuscitaIon!from!!
out;of;hospital!cardiac!arrest!of!cardiac!
cause.!
N!Engl!J!Med!2013;369:2197;206!
N!Engl!J!Med!2013;369:2197;206!
• Minimum!850!paIents!(87%!predicted!power)!
• Maximum!950!(depends!on!funding)!
• Open!intervenIon!
• Standardised!rules!for!prognosIcaIon!
• Standardised!rules!for!withdrawal!of!life!
support!
• Blinded!outcome!assessment!
Design
N!Engl!J!Med!2013;369:2197;206!
• )INCLUSION)CRITERIA!
• !All!cardiac!arrest!!from!cardiac!cause!
• !All!!iniIal!Rhythms!• !Unconscious!!on!admission!to!the!hospital!more!than!20!min!!!consecuIve!minutes!of!spontaneous!circulaIon!aUer!ROSC!
• )EXCLUSION)CRITERIA!
• !Time!from!ROSC!to!screening!more!than!240!min!• !Unwitenessed!!asystolia!• !Suspected!or!known!acute!intracranial!hemorrhage!or!stroke!
Design
N!Engl!J!Med!2013;369:2197;206!
Endpoints
✓ Primary)endpoint:)Survival!unIl!the!end!of!the!trial!
✓ Secondary)endpoints:)!
• Landmark!mortality!and!neurology!180!
days!
• Neurological!funcIon!(CPC,!mRS,!MMSE,!
IQCODE)!
• Safety!aspects!
N!Engl!J!Med!2013;369:2197;206!
• Temperature intervention 36 hours • All patients sedated and ventilated minimum 36
hours • Feed-back controlled cooling devices in all patients • Intravascular or surface devices
Intervention
Inclusion 240 min
ROSC
Prognostication Half year follow up
ICU, hospital discharge
72 hours 36 h 180 days 956 d
TIMELINE
N!Engl!J!Med!2013;369:2197;206!
N!Engl!J!Med!2013;369:2197;206!
Results
Results
N!Engl!J!Med!2013;369:2197;206!
Results
N!Engl!J!Med!2013;369:2197;206!
Results
N!Engl!J!Med!2013;369:2197;206!
N!Engl!J!Med!2013;369:2197;206!
P=0.51
No difference in survival
Survival
Outcome TTM33
TTM36
HR or RR (95% CI) P Value
PRIMARY OUTCOME Mortality at the end of trial Dead no./total no. (%)
235/473 (50)
225/466 (48)
HR=1.06 (0.89-1.28)
0.51
SECONDARY OUTCOMES Neurological function at follow-up CPC 3-5–no./total no. (%) mRS 4-6–no./total no. (%) Serious adverse events Any event–no./total no. (%)
252/469 (54) 245/469 (52)
439/472 (93)
242/464 (52) 239/464 (52)
417/464 (90)
RR=1.02 (0.88-1.16) RR=1.01 (0.89-1.14)
RR=1.03 (1.00-1.08)
0.78 0.87
0.09
100% follow-up
99% follow-up
Outcomes
Results consistent in pre-defined subgroups
Subgroups
Conclusions
In!unconscious!survivors!of!out;of;hospital!
cardiac!arrest!of!presumed!cardiac!cause:!
!• Hypothermia) at) a) targeted) temperature)
of) 33°C) did) not) confer) a) benefit) as)compared) with) a) targeted) temperature)of)36°C.)
N!Engl!J!Med!2013;369:2197;206!
NOT ONLY TEMPERATURE MANAGMENT
!Must!be!considered!!
➢ Hemodynamics)and)Vasopressor)Support)aYer)CA!
)➢ )Shock)vs)no)Shock)
➢ )Normoxia,)Hyperoxia)and)Hypoxia)aYer)CA)
➢ )Mechanical)VenClaCon)aYer)CA))➢ Cardiac)Arrest)Center))
)
))
MulImodal!Physiological;Based!Management!!!aUer!Cardiac!Arrest!
!Sutherasan!Y!et!al!Minerva!Anestesiol!2014!Mar!19![Epub!ahead!of!print]!
