A Piece of the Northland in the ICUwcm/@mwa/documents/...A Piece of the Northland in the ICU ... 300,000 –450,000 people annually in the US ... leukocyte infiltration →tissue injury

Scott Mikesell, DO, FACC, FSCAIDirector, Cardiac Catheterization Laboratory St. Luke’s Cardiology AssociatesDuluth, Minnesota

A Piece of the Northland in the ICU

None

65-year-old male

At home working in his garden

Loses consciousness

Wife▪ Calls 911

▪ Initiates CPR

EMS arrives

Ventricular fibrillation

Perfusing rhythm within 10 minutes

Repeated episodes of VF resulting in multiple shocks and CPR

Unresponsive after restoration of spontaneous circulation (ROSC)

Initial ECG: inferior STEMI Further VT/VF in ED Taken to cath lab for PCI ER personnel

IV iced saline

Ice packs

Cath Lab – RCA culprit ICU

Surface cooling pads applied

Therapeutic hypothermia x 24 hours

Rewarmed

Day 7 – awake, alert, interactive Discharged home

EpidemiologyBiologyEvidenceManagement, expectations, side effects Patient selection

Out-of-hospital cardiac arrest (OHCA)

300,000 – 450,000 people annually in the US

40,000 survive to hospitalization

Systemic, neurologic & cardiac sequelae

One third survive to hospital discharge

Lloyd-Jones D, Adams R, Carnethon M et al. Heart disease and stroke statistics-2009 update. Circulation 2009;119:e21-e181

Holzer, M. Targeted Temperature Management for Comatose Survivors of Cardiac Arrest. NEJM 2010; 363:1256-64.

• 80% remain comatose for >1 hour post-resusciatation

• < 50% recover good neurologic activity as defined by the Cerebral Performance Category scale (CPC), range 1-5, higher scores = worse


– 1 = Good recovery

– 2 = Moderate disability (independent ADLs)

– 3 = Severe disability (dependent daily support)

– 4 = Coma or vegetative state

– 5 = Brain death


• 1950s - cardiac and neurologic surgeries

• Late 1950s - after cardiac arrest

– uncertain benefits

– difficulties with implementation

• 1990s - studies in animal models

– histological benefits

– functional benefits

• 2002 - randomized clinical trials of TH

A condition in which an organism's temperature drops below that required for normal metabolism and body function.

- Stratified into four categories: ▪ Mild (32 - 35ºC or 90 - 95ºF)

▪ Moderate (28 - 32ºC or 82.4 - 90ºF )

▪ Severe (20 - 28ºC or 68 - 82.4ºF)

▪ Profound ( < 20ºC or < 68ºF)

• Brain stores of oxygen lost in seconds• Glucose, ATP lost within 5 minutes• Loss of transmembrane electrochemical

gradient• Loss of synaptic, axonal function• Glutamate is released leading to excitotoxic cell

death• Intracellular calcium accumulates leading to cell

death (necrosis and apoptosis)• Vulnerable areas = hippocampus, neocortex,

cerebellum, corpus striatum, thalamusHolzer, M. Targeted Temperature Management for Comatose Survivors of Cardiac Arrest. NEJM 2010; 363:1256-64.

Restoration of circulation, reperfusion and reoxygenation – further neuronal damage due to -

– Microcirculation failure – transient hyperemia

– Followed by prolonged global/microfocalhypoperfusion

– Reactive oxygen species (lipid peroxidation, oxidative damage)

– Inflammatory response leading to endothelial activation, leukocyte infiltration → tissue injury

– Brain edema limiting perfusionHolzer, M. Targeted Temperature Management for Comatose Survivors of Cardiac Arrest. NEJM 2010; 363:1256-64.

ischemia

glutamate release

oxygen-free radicals

calcium shifts

mitochondrial dysfunction

reperfusion

excitotoxicity

inflammatory

cascades

cell death

blood brain barrier disruption & cerebral edema

hypothermia

lower metabolic rate

less oxygen consumption

Geocadin RG, Koenig MA, Jia X et al. Management of brain injury after resuscitation from cardiac arrest. Neurol Clin. 2008;22:487-506.

Limit neurologic injury– Reduction in brain metabolism (less oxygen and

ATP utilization)

– Inhibition of release of glutamate and dopamine

– Induction of brain-derived neurotrophic factor (less glutamate)

– Inhibition of calcium overload & pro-apoptotic factors

– Induction of anti-apoptotic factors

– Limited inflammation/edemaHolzer, M. Targeted Temperature Management for Comatose Survivors of Cardiac Arrest. NEJM 2010; 363:1256-64.

Scirica B M Circulation. 2013;127:244-250

Copyright © American Heart Association, Inc. All rights reserved.

Management of TH

Multicenter, randomized, controlled trial with blinded assessment of outcome.

Inclusion -▪ Positive ROSC

▪ Witnessed VT/VF arrest

▪ Age 18 – 75 years old

▪ Estimated time to resuscitation of 5 – 15 minutes by EMP

▪ Interval no greater than 60 minutes from collapse to restoration of spontaneous circulation

Holzer, M. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. NEJM 2002; 346:549-56.

Multicenter, randomized, controlled trial with blinded assessment of outcome.

Exclusion -– Temperature < 30o C on admission

– Comatose state prior to arrest d/t drug administration

– Pregnancy

– Hypotension (MAP < 60 mmHg) for > 30 min. post-ROSC

– Hypoxemia (SpO2 < 85% for > 15 min. post-ROSC)

– Terminal illness

– “Factors that made participation in follow-up unlikely”

– Enrollment in another study

– Cardiac arrest post-EMP arrival

– Known coagulopathy


Primary outcome– Favorable neurologic outcome within 6 months

CPC Scale– 1, 2, 3, 4, 5

–Blinded assessment


Secondary end points– Mortality at 6 months– Rate of complications during the 1st 7 days post-ROSC– Bleeding of any severity, pneumonia, sepsis, pancreatitis,

renal failure, pulmonary edema, seizures arrhythmias and pressure sores were all recorded

Therapies –– ACS management– Standard ICU management– Sedation + paralysis (shivering), mechanical

ventilation– Temperature monitoring via bladder– Cooling via TheraKool device (cooling blanket) to 32 –

34o C within 4 hours post-ROSC– Ice packs if not at goal– 24 hours at target temperature– Passive rewarming





Inclusion –

– Initial rhythm of VT/VF

– Successful ROSC

Exclusion –

– Age < 18 for men, < 50 for women

– Cardiogenic shock (SBP < 90 mmHg despite Epi)

– Coma due to other causes

– No ICU bed

Bernard, S. et al. Treatement of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. NEJM 2002; 346:557-63.

Therapies –– Hypothermia versus normothermia– EMPs initiated hypothermia in the field with cold packs– Sedation, paralysis, mechanical ventilation– Standard ICU management– ACS therapy– Lidocaine bolus followed by infusion– PRN KCl for levels < 4.0– Insulin– Aspirin– PA catheter– Cooling via ice packs– Active rewarming





Good outcome of hypo- to normothermia = 49% to 26%; p = .046

Unadjusted odds ratio = 2.65 (1.02 – 6.88; p = .046)

Adjusted odds ratio (age, time to ROSC) = 5.25 (1.47 – 18.76; p = .011)

Delay in initiation of cooling negates beneficial neurologic effects (glutamate)

Cardiac arrest in mice with intra-arrest cooling, improved outcome as compared to post-arrest

Cardiac arrest in dogs with cooling while in VF for 40 minutes preserved organ viability and improved outcome

Clinical trials demonstrate at least 60 minutes to cooling goals in the community clinical scenario

Nozari, A. et al. Critical time window for intra-arrest cooling with cold saline flush in a dog model of cardiopulmonary resuscitation. Circulation 2006; 113:2690-2696.




Patients with cardiac arrest are at increased risk for refibrillation

Concern for refibrillation while cooled as well as increased risk for arrhythmias while hypothermic

Previous investigation demonstrated improved defibrillation with severe hypothermia (30oC) with less post-defibrillation ventricular asystole

Boddiker, K. et al. Hypothermia improves defibrillation success and resuscitation outcomes from ventricular fibrillation. Circulation 2005; 111:3195-3201.




Cooling improves neurologic outcome post-ROSC

Post-reperfusion injury rapidly evolves post-ROSC

Earlier cooling improves outcomes in animal models

Earlier and moderate hypothermia improves successful defibrillation and prevents post-ROSC arrhythmias in animal models

Retrospective analysis of patients with out-of-hospital cardiac arrest (OHCA)

Included if experienced non-traumatic OHCA and ≥ 18 years old

Excluded if pregnant, arrest secondary to drowning, DNR order or obvious signs of death

Garrett JS. et al. The association between intra-arrest therapeutic hypothermia and return of spontaneous circulation among individuals experiencing out of hospital cardiac arrest. Resuscitation 2010; 82:21-5.




Volume of chilled saline versus likelihood of ROSC

Frequency of ROSC per initial rhythm

PEA/asystole may not behave similar to VT/VF

No harm, no foul No evidence for benefit in

PEA/asystole

OHCA in Paris, France is managed by at least 1 physician, firefighters, paramedics

Post-ROSC, ICU or cardiac catheterization laboratory

Dumas, F. et al. Is hypothermia after cardiac arrest effective in both shockable and non-shockable patients? Circulation 2011; 123:877-886.




PEA/Asystole

VT/VF

Multicenter RCT (36 hospitals, 10 countries, Europe and Asia)

N=939 T = 33 Co = 473

T = 36 Co = 466 Standardized rules for prognostication Standardized rules for withdrawal of life support Blinded prognostication and outcome assessment

Inclusion criteria Age ≥ 18y OHCA of presumed cardiac cause Sustained ROSC for 20 minutes GCS < 8 after sustained ROSC

Exclusion criteria Pregnancy Known bleeding diathesis (other

than medical coagulopathy, eg, warfarin)

Suspected/confirmed ICH or stroke

Unwitnessed cardicac arrest with initial rhythm asystole

DNR or known prognosis < 6 months

Pre-arrest CPC 3 or 4 > 4 hrs from ROSC to screening SBP < 80 despite pressor,

inotrope, IABP Temp < 30 C

oon admit

Intervention Group Target Temp at 33 C

o

Intervention period of 36 hrscommenced at randomization

Mandatory sedation Cooled to target in < 6 hrs

after randomization Maintained at 33 C

ountil 28

hours after screening, then rewarmed at 0.5C/hr

Mandatory sedation stopped/tapered at 36 hrs

Maintain temp below 37.5 Co

until 72 hrs after CA

Comparison Group Target Temp at 36 C

o

Similar treatment to intervention group

Body Temperature during the Intervention Period.

Outcomes

Primary: mortality at 180 days

Secondary

▪ Composite of poor neurologic function or death▪ CPC 3-5

▪ Modified Rankin scale 4-6

▪ At or around 180 days

Probability of Survival through the End of the Trial.

Results

No difference in mortality▪ T=33 C

o235/473 died (50%)

▪ T=36 Co

225/466 died (48%)

▪ HR=1.06 (95% CI 0.89-1.28), P = 0.51

No difference in composite mortality/poor neurologic outcomes▪ CPC: T=33 C

o54%, T36C 52%, RR=1.02 (0.88-1.16), P = 0.78

▪ mRS: T=33 Co

52%, T36C 52%, RR=1.01 (0.89-1.14), P = 0.87

Serious adverse events were common, and slightly higher in T=33 Co

(93%) vs T=36 Co

(90%), RR=1.03 (1.00-1.08), P = 0.09

Conclusions No difference found between Target Temp at T=36

Co

compared to T=33 Co

Good outcomes in both groups may reflect active prevention of hyperthermia

Modern aggressive care that includes attention to temperature works▪ Makes survival more likely than death when a patient

hospitalized after CPR

Remaining Issues

Patient selection

Optimum target temperature

Timing of cooling initiation

Duration of therapy

Rate of rewarming

In versus out-of-hospital

VT/VF versus non-VT/VF

American Heart Association post–cardiac arrest care algorithm.

Scirica B M Circulation. 2013;127:244-250

Copyright © American Heart Association, Inc. All rights reserved.

Cincinnati Sub-Zero Blankerol III Artic Sun

Bradycardia Oozing Hypotension Diuresis Arrhythmias Hypokalemia Hyperglycemia Prolonged drug metabolism

Mild hypothermia improve neurologic outcomes in witnessed VT/VF arrest

Intra-arrest hypothermia may be beneficial for improved ROSC

Neurologic outcomes after intra-arrest may be improved, randomized evidence is lacking

Documents

A Piece of the Northland in the ICUwcm/@mwa/documents/...A Piece of the Northland in the ICU ... 300,000 –450,000 people annually in the US ... leukocyte infiltration →tissue injury