Induced Hypothermia After Anoxic Brain Injury

Marc M. Grossman MD FACEP

Vol. Asst. Professor of Emergency Medicine

and Neurology

University of Miami-Miller School of Medicine

Jackson Memorial Hospital Emergency Services

Medical Director, Coral Gables Fire-Rescue

Associate Medical Director

City of Miami Fire-Rescue

Goals:

Describe advances in care of anoxic brain injuries

Discuss the use of Induced Hypothermia in selected patient populations

Modalities Indications Contraindications

Discuss the cooling by EMS and In-Hospital

Cardiac Arrest Outcomes

400,000 to 500,000 arrests / year in U.S.A

3 / 4 Out-of-hospital

1 / 4 In-hospital

Survival to hospital discharge

Approximately 2 to 5% with good neurological outcome

Return of Spontaneous Circulation

45% 55%

2 to 8% 5 to 15%

Cardiopulmonary Resuscitation on Television — Miracles and Misinformation

Susan J. Diem, M.D., M.P.H., John D. Lantos, M.D., and James A. Tulsky, M.D.NEJM June 13, 1996 Volume 334:1578-1582 Number 24

American Heart Association Recommendations

Unconscious adult patients with return of spontaneous circulation (ROSC) after out-of hospital cardiac arrest should be cooled to 32°C to 34°C (89.6°F to 93.2°F) for 12 to 24 hours when the initial rhythm was ventricular fibrillation (VF). Class IIa

Similar therapy may be beneficial for patients with non-VF arrest out of hospital or for in-hospital arrest. Class IIb

AutoPulse IIb ResQPod IIa

Circulation. 2005;000:IV-84-IV-88

In the news

New York Times:December 4, 2008 City Pushes Cooling Therapy for Cardiac Arrest By ANEMONA HARTOCOLLIS

Potential Applications for Therapeutic Temperature Modulation:

Ischemic Stroke Intracranial Hemorrhage Subarachnoid Hemorrhage Traumatic Brain Injury Spinal Cord Injury Anoxic Encephalopathy (Post Cardiac

Arrest) Acute Myocardial Infarction Burns

Brain Hypoxia and Reperfusion Injury

Brain Swelling Maximum brain swelling is known to occur

between days 2 -5 after ischemia. Patients with uncontrolled elevated ICP have a

prolonged stay in ICU and worsened outcomes …Induced moderate hypothermia can decrease

ICP & may improve mortality in patients with severe ischemic brain edema.

Schwab, Schwartz, Spranger, Keller, Bertram, Hacke, 1998

Deleterious Effects of Hyperthermia(heat bad)

Elevated temperatures after ischemia increase the zone of injury around the penumbra (“Brain Fever”).

Fever correlates with greater mortality and worse outcome.

Increased neurotransmitter release. Increased blood brain barrier permeability. Increased cellular brain damage.

Cerebral protection and Hypothermia: Mechanisms of Action (cold good)

Decreasing Excitatory Aminoacid secretion. Downregulation of Glutamate receptors. Diminished production reactive Oxygen radicals. Reduced consumption of tissue antioxidants. Reduced inflammatory response. Lowering cerebral metabolic rate. Changes in cerebral blood flow.

Physiologic Effects of Induced Hypothermia

CNS– For each 1°C decrease in temperature, the cerebral metabolic rate

decreases by 6–7% – Hypothermia decreases intracranial pressure – Hypothermia may act as an anticonvulsant

Cardiovascular• Decreases heart rate

Decreases spontaneous depolarization of the cardiac pacemaker cells Prolongs action potential duration (of both the depolarization and

repolarization), Slows myocardial impulse conduction,

Increases systemic vascular resistance Intense shivering increases metabolic rate and oxygen demand

Need sedation and/or paralytic agents Stroke volume and mean arterial blood pressure are maintained

The electrocardiogram may show a notch on the downstroke of the QRS complex (the Osbourne wave or J wave): present in 80% of patients, all below 32º

Aslam AF, et al. American J Med. 2006; 119:297-301

Osborn Wave (< 32° C)

Osbourne Wave

Accidental Deep Hypothermia and Circulatory Arrest

46 patients with deep hypothermia (core temperature < 28oC or 82.4oF)– Mostly mountaineering accidents or suicide attempts– 32 patients re-warmed with cardiopulmonary bypass with 15 long term survivors

• Average time to rewarming greater than 2 hours– Average follow-up greater than 6 years ->No hypothermia related sequelae which

impaired quality of life– Neurologic and neuropsychological defefits seen early had fully or almost

completely resolved (One patient with cerebral atrophy on MRI – possibly related)• Conclusions: This clinical experience demonstrates that young,

otherwise healthy people can survive accidental deep hypothermia with no or minimal cerebral impairment, even with prolonged circulatory arrest.

Walpoth BH, et al. N Engl J Med. 1997; 337:1500-1505.

“They’re not dead until they’re warm and dead”

Induced Hypothermia After Cardiac Arrest:

Recent Human Studies

Induced Hypothermia in Comatose Survivor in Out-of-Hospital Arrests

Rational: – Cerebral ischemia may persist for several

hours after resuscitation– Hypothermia decreases cerebral oxygen

demand 77 patients randomized to either hypothermia

vs standard care– Initial cardiac rhythm of ventricular

fibrillation at the time of arrival of the ambulance

– Initiated by paramedics in the field continued in the hospital

– 43 patients in hypothermia group (core temperature 33o C, 91.5o F) within 2 hours of ROSC and maintained for 12 hours

Cold packs to head in the field and hospital

Cold packs to torso in the field and hospital

Iced saline 4oC

Intubation and MV

Cold packs to limbs and neck in hospital

Core temperature monitored

Midazolam/vecuronium in the hospital

Bernard SA, et al. N Engl J Med. 2002; 346:557-563.

Remove all clothing in the field

Induced Hypothermia in Comatose Survivor in Out-of-Hospital Arrests

Bernard SA, et al. N Engl J Med. 2002; 346:557-563.

Hypothermia(n=43)

Normothermia(n=34)

Normal or minimal disability (able to care for self, discharged directly home)

15 (35%) 7 (21%)

Moderate disability (discharged to a rehabilitation facility)

6 (14%) 2 (6%)

Severe disability, awake but completely dependent (discharged to a long-term nursing

facility)0 1 (3%)

Severe disability, unconscious (discharged to a long-term nursing facility)

0 1 (3%)

Death 22 (51%) 23 (68%)

Mild Hypothermia in Survivors of V-fib Arrests

Patients arriving to the ER with:– Witnessed arrest, V-fib or pulseless

V-tach– ROSC less than 60 minutes

Patients randomized to either hypothermia vs standard care– Patients in hypothermia group (core

temperature 32 - 34o C) for 24 hours, followed by passive rewarming for 8 hours

– External cooling device– Ice packs if necessary– IV midazolam, fentanyl and

pancuronium

HACA Study Group. N Engl J Med. 2002; 346:557-563.

Mild Hypothermia in Survivors of V-fib Arrests

Outcome Normothermia Hypothermia P value

Favorable Neuro Outcome 54/137 (39%) 75/136 (55%) 0.009

Death 76/138 (55%) 56/137 (41%) 0.02

HACA Study Group. N Engl J Med. 2002; 346:557-563.

Complication Normothermia Hypothermia

Bleeding 19% 26%

Pneumonia 29% 37%

Sepsis 7% 13%

Renal failure 10% 10%

Pulm edema 4% 7%

Seizures 8% 7%

Arrhythmias 32% 36%

“From evidence to clinical practice: Effective implementation of therapeutic hypothermia to improve patient outcome after cardiac

arrest”Oddo, et al, Crit. Care Med., 2006 34(7):1865

  Outcome

Vfib/Vtach

CPC 1 Total

Recovery

CPC 2 Moderate Disability

CPC 3 Severe

Disability

CPC 4 Vegetative

State

CPC 5 Death

Therapeutic hypothermia

18/43 (41.9) 6/43 (13.9) 2/43 (4.7) 0/43 (0) 17/43 (39.5)

Standard resuscitation

6/43 (14.0) 5/43 (11.6) 8/43 (18.6) 0/43 (0) 24/43 (55.8)

  Outcome

Asystole/PEA

CPC 1 Total

Recovery

CPC 2 Moderate Disability

CPC 3 Severe

Disability

CPC 4 Vegetative

State

CPC 5 Death

Therapeutic hypothermia

2/12 0/12 0/12 0/12 10/12

Standard resuscitation

0/11 0/11 1/11 0/11 10/11

Number Needed to Treat

Induced Hypothermia after V-Fib Arrest: 6 Beta-Blocker after Myocardial Infarction to

prevent sudden cardiac death: 42 Primary prevention of stroke using a daily low

dose of aspirin for one year: 102 Prevention of infection from dog bites using

antibiotics: 16

Abella Practice Survey: 2004

265 Physicians surveyed from Emergency Medicine, Critical Care and American Heart Association

“Are you cooling cardiac arrest patients?” 87% - “No. Have not started cooling patients” WHY? 49% “Not enough data” 32% “Not incorporated into AHA ACLS protocol” 28% “Cooling methods technically difficult or

slow”

AHA Guidelines Eliminate 1 Major Excuses!

The Other 13%

“We are cooling” (35 sites) What method are you using to cool

50% cooling blankets 15% Ice packing 13% Iced gastric lavage 2% cooling mist 2% cooling catheter (ONLY 1 site) 17% other methods

INDUCED HYPOTHERMIA:METHODS AND PROCEDURES

When to start cooling?When to start cooling?

Probably as soon as possible

Cardiac Arrest

ROSC

0 1 2 3 4 5 6 7 8

Time (hours)

Intra-arrest

Mouse model Abella 2004

60% survival

Soon after ROSC

Dog model

Sterz 1991, Kuboyama 1993

Good neurologic outcome after ROSC

Pretty Soon after ROSC

HACA 2002

Bernard 2002

Randomized clinical trails

How deep to cool??How deep to cool??

--34°C

--32°C

Therapeutic Window?

Too low may increase the occurrence of adverse events such as arrhythmias or bleeding problems

or negate the benefits of cooling

Overcooling??

Who to Cool: IndicationsWho to Cool: Indications Cardiac arrest with return of spontaneous circulation

(any initial rhythm) Men and Women age 18 years or older. Women of

childbearing age must have a negative pregnancy test (must be documented on the chart)

Coma after return of spontaneous circulation (ROSC) (Coma is defined as: not following commands, no speech, no eye opening, no purposeful movements to noxious stimuli. Brainstem reflexes and pathological/posturing movements are permissible.)

Endotracheal intubation with mechanical ventilation Blood pressure can be maintained at least 90 mm Hg

systolic either spontaneously or with fluid and pressors

Who to Cool: Relative Contraindications

Who to Cool: Relative Contraindications

Another reason to be comatose (e.g. head trauma, stroke, overt status epilepticus) where benefits/risks of cooling are unknown.

Pregnancy Temperature of <30°C after cardiac arrest Patients with a known bleeding diathesis, or with active

ongoing bleeding - hypothermia may impair the clotting system.

No limit on duration of resuscitation effort; however “down time” of less than 30 minutes most desirable

Do not resuscitate (DNR) or Do not intubate (DNI) code status and patient not intubated as part of resuscitation efforts

Systemic infection/sepsis- hypothermia inhibits immune function and is associated with an increased risk of infection

Recent major surgery within 14 days - hypothermia may increase the risk of infection and bleeding.

How to CoolHow to CoolExternal Cooling– Ice packs (0.9°C/hr) – Water Immersion (9.7°C/hr) – Cooling blankets (0.3–0.5°C/hr)– External cooling equipment with

conductive surface pads (Arctic Sun)

(2-3°C in 90 minutes) Internal Cooling– Iced lavage (minimally effective)– Iced IV saline or LR (1.6C over 25

mins )– Intravascular catheter based cooling

equipment

Other ways to cool off in Miami

US Army Research Institute ofEnvironmental Medicine

Water Immersion Laboratory

External CoolingExternal Cooling

External cooling with cooling blankets or surface heat-exchange device and ice  Eligibility should be confirmed, and materials should be gathered.

Obtain 2 cooling blankets and cables (one machine) to “sandwich” the patient. Each blanket should have a sheet covering it to protect the patient’s skin.

Pack the patient in ice (groin, chest, axillae, and sides of neck); use additional measures as needed to bring the patient to a temperature between 32ºC and 34ºC. Avoid packing ice on top of the chest, which may impair chest wall motion.

Monitor vital signs and oxygen saturation and place the patient on a continuous cardiac monitor, with particular attention to arrhythmia detection and hypotension.

Once a temperature below 34ºC is reached, remove ice bags, and the cooling blanket or heat-exchange device is used to maintain temperature between 32ºC and 34ºC.

Arctic Sun® 2002

Patient temperature is to a preset temperature by water flowing through Arctic Sun Energy Transfer Pads™

Cools 2-3°C in 90 minutes Precise temperature control

minimizes overshoot Designed to mimic water

immersion Uses cooled water, but pads

resistant to leaking unlike older water blanket systems

Energy Transfer Pads Hydrogel is conductive w/ adhesive

surface, provides direct skin contact Thin film layer provides low

thermal resistance High velocity water flow transfers

energy

No need to remove for radiographic imaging even with water flowing– MRI– CT Scan– X-ray– Cath lab

Pads are latex free

Internal Cooling:Currently Available Systems

Celsius Control SystemTM (Innercool Therapies) Catheter incorporates a flexible temperature control element

(TCE) that is cooled or warmed with saline solution circulated in closed-loop.

Placed in inferior vena cava & venous core blood is cooled/warmed as it flows past the TCE back to the heart.

Console receives feedback from intravascular sensor to achieve target temperature.

No fluid in infused into the patient.

Currently Available Systems

Coolguard system by Alsius. Currently in use by

Department of Neurosurgery at UM/JMH

Cooled saline flows within balloons & venous blood is cooled as it passes.

Desired temperature & rate of achievement set in control panel.

ICY catheter® Placed in IVC Multi-lumen MRI compatible

Subclavian catheter available.

Intravascular Cooling

Cooled saline flows within balloons

Closed-loop system

Venous blood is cooled as it passes by each

balloon

Therapeutic Hypothermic Procedure

Cool down (QUICK!) :Time to target temperature is essential. Goal to achieve desired temperature in < 6 hours. Aim for 2-4 hours. Animal studies suggest peak in glutamate release around 1 hr after injury thus early cooling probably better.

Sedation Shivering Control Treat Underlying Cause (STEMI?) Close monitoring: Tight glycemic control, K, Mg, B/P Check for underlying Seizures (EEG, AED) Slow and Controlled Rewarming

Prevent Shivering

Drips for sedation (whatever you have and are comfortable with)

Demerol and skin counterwarming: For Stroke and the awake patient, oral

buspirone (30 mg) and intravenous meperidine (0.4 mg/mL) have been shown to act synergistically to lower the shivering threshold from 35.7 C to 33.4 C while producing only minimal sedation (Mokhtarani et al., 2001; Doufas and Sessler, 2004).

Counter warming and Demerol:

Physiology of Re-warmingPhysiology of Re-warming

Most important: Spike in Intercranial Pressure, opposite from cooling phase This can Kill!

Vasodilatation– Avoid dehydration

Potassium shifts from intracellular to extracellular (rises with re-warming)– When to replace

Rewarming– Begin after target temp reached for 12 to 24 hours of total cooling– Aim for 0.25-0.5°C per hour until normothermic– Newer internal and external cooling devices have controlled re-warming

capability

Continuous Temperature MonitoringContinuous Temperature Monitoring

Tympanic Bladder Rectal Esophagus PA catheter

TH and StrokeFrom Dr. Myron GinsbergModerate therapeutic hypothermia represents one of the most solidly evidence-based

neuroprotective strategies currently available (Hemmen and Lyden, 2007). A large corpus of experimental studies over the past 20 years has provided incontrovertible evidence that moderate hypothermia is capable of conferring high-grade neuroprotection in focal and global cerebral ischemia by impeding a host of deleterious metabolic and biochemical injury mechanisms, with a therapeutic window appropriate for clinical application in ischemic stroke.

These clinical successes notwithstanding, the application of moderate therapeutic hypothermia to treat patients with acute ischemic stroke has proceeded slowly. In part, this is attributable to (a) the increased difficulty and complexity of patientmanagement (e.g., need for intensive care unit setting, sedation, shivering control, possible intubation, cooling-device management); and (b) concerns regarding possible adverse events, including pneumonia and (at lower temperatures) cardiac arrhythmias and coagulation disturbances. .

Recent improvements in shivering management and advances in cooling technology, however, have contributed to making therapeutic hypothermia in stroke patients more feasible at the present time.

M.D. Ginsberg / Neuropharmacology 55 (2008) 363e389

TRIALS INVESTIGATING TH WITH STROKE (FROM THE INTERNET STROKE CENTER,

STROKECENTER.ORG) 

CHILI:controlled Hypothermia in Large InfarctionCOAST-IIcooling in acute Stroke-IICombined Neuroprotective Modalities Coupled With Thrombolysis in Acute Ischemic Stroke: A Pilot Study of Caffeinol and Mild Hypothermia[SPOTRIAS]COOL AID ICooling Acute Ischemic Brain Damage - Safety and Feasibility StudyCOOL AID PilotCooling Acute Ischemic Brain Damage – PilotCOOL BRAIN-STROKECooling Helmet for Patients with Brain Ischemic and Hemorrhagic InfarctionsHemicraniectomy and Moderate Hypothermia in Patients With Severe Ischemic StrokeICTuS-LIntravenous Thrombolysis Plus Hypothermia for Acute Treatment of Ischemic Stroke[SPOTRIAS]IHAST1Hypothermia and intracranial aneurysm surgery:part 1IHAST2Intraoperative Hypothermia for Aneurysm Surgery Trial, Part 2Mild Hypothermia in Acute Ischemic Stroke: Safety and Feasibility StudyNOCSSNordic Cooling Stroke StudyNOTHOTNormothermia and Stroke Outcome

ICTuS Trial

RCT combines use of IV TH (Innercool) with IV-tPA for stroke. Investigation to try to extend the window for use of IV-tPA past 3 hours

One recent small morphometric analysis from the study shows that IV TH decreases acute post-ischemic cerebral edema

Trial ongoing and expanding

Guluma, et al Neurocrit. Care, 2008;8(1):42-7

More Protocols Online:http://www.med.upenn.edu/resuscitation/hypothermia/protocol

s.shtml

Case 1 36 y/o woman, no PMH Had allergic reaction and had order in clinic for

Benadryl iv and epi im Epi given iv, pt went into v-fib arrest Found “seizing”, defib quickly BIBA w/ pulse, breathing, gcs=4, decorticate

posturing, minimal brain stem reflexes Cooling initiated within 30 minutes of arrival to ER,

about 90 minutes post-arrest

Case 1

Initial temp: 38.1 degrees, ?aspiration pneumonia on cxr vs ards

Cooled with IVNS 2L at 4 degrees, Arctic Sun pads applied About 4 hours to get to goal temp Question of adequate sedation and paralytics?

Magnesium? Counter warming No obvious shivering noted Echo shows ef=18% Pt critically ill for 7 days

Case 1

On day 8, pt awoke EF=50% (?stunned myocardium vs myocarditis) Extubated that day No neurologic deficit, does not remember what

happened to her Discharged 6 days later to home with close follow-up

Case 2

52 y/o woman, h/o htn only, witnessed arrest, cpr and aed applied by co-workers

ROSC, total downtime about 4 minutes On arrival, gcs=8, pt agitated Cooling protocol enacted, IVNS and Arctic Sun

pads Goal temp reached in about 3 hours

Case 2

Pt found to have a left sided deficit and right MCA stroke by MRI

Thrombolytic not given Pt remained comatose but agitated for about 12 days Calmed down and was weaned off vent on day 13

successfully Discharged on day 23 to rehab Pt seen by me 2 months later, only deficit is slight slurring

of speech, otherwise fully ambulatory, cognition intact and carrying out ADLs, working again in a limited capacity

Case 3: Internal Cooling

26 year old female, s/p attempted hanging BIB-FR, cut down by PD, was in asystole,

(+)ROSC Could not clear c-spine despite (-) CT Brain &

Neck External Pads would require too much

movement and manipulation to apply and maintain

Internal Cath started and patient cooled Minimal patient movement required, ideal

situation for cath cooling

City of Miami Fire Rescue:1st EMS Agency with SWAT Medics1st Defib in Field1st with Telemetry communication with hospital (Jackson Memorial Hospital)650 Paramedics, 82,000 Runs/year, 80% EMS24 ALS Rescue Trucks, 2 ALS Engines1 ALS Supervisor /shift1 Paramedic Instructor1 Q/A Capt., 1 Lt.1 Medical Director, 1 Associate Medical Director

EMS and Therapeutic Hypothermia

“Unconscious adult patients with spontaneous circulation after out-of-hospital VF cardiac arrest should be cooled to 32-34oC. Cooling should be started as soon as possible and continued for at least 12-24 hours.”

NolanJP, Deakin CD, Soar J, et al. European Resuscitation Council Guidelines for Resuscitation 2005 Section 4. Adult advanced life support. Resuscitation 2005; 67 (Suppl 1): S39-S86.

5 Fire Rescue Departments in Dade County (Cities of Miami, Coral Gables, Key Biscayne, Hialeah and Miami Beach) as well as FDNY and Seattle

Fire Dept. and several others are moving toward Induced Hypothermia in the field and only bringing those patients to “Hypothermia Centers”

EMS Cooling JMH cooling for other indications for about 6 years In 2006, began to meet: ICU, ER, NSG, Neuro regarding cooling ROSC as

per AHA-ACLS Guidelines Took about a year to get a protocol together and start cooling, but very

slow progress In 2008, EMS interest in cooling took off, and grant to get coolers in

every rescue truck Put out request to all STEMI hospitals and others to begin cooling to be

considered Resuscitation Centers Some interest from many hospitals Gave some training to hospitals, they met with reps from 2 companies Started cooling October 2008, still gathering data Now have 8 facilities in Miami-Dade who cool and receive these patients May have 3 more on line before the end of the year Example of EMS driven advances in care for hospitals

Cases from EMS Cooling

84 y/o F, asystole arrest, HD, CRF, HTN, downtime 8 minutes, ROSC, cooled, awoke on day 4, home via rehab for vent-dep.

56 y/o M, htn hx, down at store, defib AED by CGPD, ROSC, cooled in field, cath 90%LAD, PTCA, D/C to home

47 y/o F h/o obesity, htn, dm, down in café, early CPR, defib, ROSC, cooled and d/c to rehab then home

Kevin Everett

Early CPR! (the earlier the better)

References CLIFTON, G.L., MILLER, E.R. ET. AL. (2001). LACK OF EFFECT OF INDUCTION OF

HYPOTHERMIA AFTER ACUTE BRAIN INJURY. NEW ENGLAND JOURNAL OF MEDICINE, 344, 556-563.

FRITZ, H.G.& BAUER, R. (2004). SECONDARY INJURIES IN BRAIN TRAUMA:EFFECTS OF HYPOTHERMIA. JOURNAL OF NEUROSURGICAL ANESTHESIOLOGY, 16(1), 43-52.

MCILVOY, L.H. (2005). THE EFFECT OF HYPOTHERMIA AND HYPERTHERMIA ON ACUTE BRAIN INJURY, AACN CLINICAL ISSUES, 16(4), 488-500.

WRIGHT, J.E. (2005). THERAPEUTIC HYPOTHERMIA IN TRAUMATIC BRAIN INJURY. CRITICAL CARE NURSING QUARTERLY, 28(2), 150-161.

ZHI, D., ZHANG, S., & LIN, X. (2003). STUDY ON THERAPEUTIC MECHANISM AND CLINICAL EFFECT OF MILD HYPOTHERMIA IN PATIENTS WITH SEVERE HEAD INJURY. SURGICAL NEUROLOGY, 59, 381-5.

HEMMEN TM, LYDEN PD (2007) NEW APPROACHES TO CLINICAL TRIALS IN NEUROPROTECTION: INTRODUCTION INDUCED HYPOTHERMIA FOR ACUTE STROKE STROKE 2007 FEB;38(2 SUPPL):794-9

Induced Hypothermia After Cardiac Arrest

Questions??M.Grossman1@Miami.edu