Targeted Temperature Management in Critical Care:  Mechanism of Benefit, Clinical Use and Recommendations, and Relevant Formal Guidelines

1. Targeted Temperature Management in Critical Care:
Mechanism of Benefit, Clinical Use and Recommendations, and Relevant Formal Guidelines
Bassel Ericsoussi, MD
Fellow, Pulmonary and Critical Care Medicine
University of Illinois Medical Center at Chicago

2. Q1
A 35-year-old pregnant woman collapses on the street, and emergency medical
personnel who are called to the scene find that she is not breathing and that she
has no pulse. The first recorded cardiac rhythm is ventricular fibrillation.
ACLS measures, including intubation, a total dose of 2 mg of epinephrine, and six
defibrillation attempts, restore spontaneous circulation (ROSC) 22 minutes after
the onset of the event.
On admission to the emergency department, her condition is hemodynamically stable
and she has adequate oxygenation and ventilation, but she is still comatose. A
neurologic examination reveals reactive pupils and a positive cough reflex. The
core body temperature is 30°C. And she was found profoundly coagulopathic. A
diagnosis of the post–cardiac arrest syndrome with coma is made.
An intensive care specialist evaluates the patient and recommends the immediate
initiation of targeted temperature management (TTM).
Do you agree with this plan?

3. THE CLINICAL PROBLEM
• 350,000 - 450,000/yr out-of-hospital cardiac
arrests in the USA
• 100,000 attempted rescusetation of these
arrests
• 40,000 patients survive to hospital admission
• 1/3 of these admitted pts survive to hospital
discharge
Schulman SP, et al. Neurol Clin 2006;24:41-59.

4. The Cost of Care During The First 6
Months After a Cardiac Arrest
• $200,000 for a pt with good recovery or
moderate disability
• $300,000 for a comatose pt, or pt in a persistent
vegetative state, or pt suffering from varying
degrees of cognitive dysfunction and other
neurologic deficits
• less than $10,000 for a pt with brain death
• The incremental cost for an average pt
– Targeted temperature management: $30,000
– Conventional care: $100,000
Merchant RM, et al. Circ Cardiovasc Qual Outcomes 2009;2:421-8.

5. “POST–CARDIAC ARREST SYNDROME”
• Brain injury
– 80% of pts remain comatose > 1 hr after
resuscitation
• Myocardial dysfunction
• Systemic ischemia
• Reperfusion responses
• Consequences of the disorder that caused the
cardiac arrest.
Nolan JP, et al. Resuscitation 2008;79:350-79.

6. PATHOPHYSIOLOGY OF CARDICAC ARREST AND BRAIN
INJURY
• In animal models of cardiac arrest
– Stores of oxygen in the brain are lost in seconds
– Stores of glucose and ATP are lost within 5
minutes
Greer DM, et al. Semin Neurol 2006;26: 373-9.

7. PATHOPHYSIOLOGY OF CARDICAC ARREST AND BRAIN
INJURY
• Tissue hypoxia:
– Loss of transmembrane electrochemical gradients
– Failure of synaptic transmission, axonal
conduction, and action-potential firing
Hoesch RE, et al. Crit Care Clin 2008;24:25-44.

8. PATHOPHYSIOLOGY OF CARDICAC ARREST AND BRAIN
INJURY
• Neuronal necrosis and apoptosis due to
– The release of glutamate
– The accumulation of intracellular calcium
Redmond JM, et al. J Thorac Cardiovasc Surg 1994;107:776-86.
Szydlowska K, et al. Cell Calcium 2010;47:122-9.

9. REPERFUSION INJURY
• Restoration of circulation can cause further
neuronal damage over a period of hours to
days
– Vasomotor paralysis, followed by hypoperfusion
Sterz F, et al. Resuscitation 1992;24:27-47.
– Reoxygenation produces lipid peroxidation and
oxidative stress
Ernster L, et al. Crit Care Med 1988;16:947-53.
– Endothelial activation, leukocyte infiltration, and
further tissue injury
Wong CHY, et al. Curr Med Chem 2008;15:1-14.

10. THE EFFECT OF THERAPEUTIC HYPOTHERMIA
• Limit neurologic injury after a patient’s
resuscitation from cardiac arrest
– Reduction in brain metabolism
– Reduction in oxygen utilization
– Reduction in ATP consumption
McCullough JN, et al. Ann Thorac Surg 1999;67:1895-9.
Laptook AR, et al. Pediatr Res 1995;38:919-25.
• Inhibit the release of glutamate and dopamine
Hachimi-Idrissi S, et al. Brain Res 2004;1019:217-25.

11. THE EFFECT OF THERAPEUTIC HYPOTHERMIA
(cont.)
• Inhibit apoptosis (reduction in calcium overload
and glutamate release)
Eberspächer E, et al. Acta Anaesthesiol Scand 2005;49:477-87.
• Suppress the inflammation that occurs after
global cerebral ischemia
Webster CM, et al. Neurobiol Dis 2009;33:301-12.
• Reduce reperfusion injury
Karibe H, et al. J Cereb Blood Flow Metab 1994;14:620-7.
• Decreases reoxygenation (lipid peroxidation and
oxidative stress)
Maier CM, et al. Neurobiol Dis 2002; 11:28-42.

12. CLINICAL EVIDENCE
• The first major clinical trials were published in
2002.
• One conducted in Australia and the other in
Europe
• The basis for clinical guidelines regarding the
use of therapeutic hypothermia in patients
who have had a cardiac arrest

13. THE AUSTRALIAN TRIAL
• 77 comatose survivors of a cardiac arrest
– Initial rhythm of VF or pulseless VT
• Randomized in two groups
– Normothermia
– Hypothermia
• Target temperature, 33°C
• Cooling duration, 12 hours
• Cooling performed with the use of ice packs
Bernard SA, et al. N Engl J Med 2002;346:557-63.

14. • Favorable neurologic recovery at hospital discharge
– Hypothermia group: 21/43 pts (49%)
– Normothermia group: 9/34 pts (26%)
– (P = 0.05)
– The odds ratio 5.25 (95% confidence interval [CI], 1.47 to 18.76; P = 0.01),
after adjustment for age and duration of the arrest
Bernard SA, et al. N Engl J Med 2002;346:557-63.

15. THE EUROPIAN TRIAL

16. • Multicenter trial
• 275 comatose survivors of a cardiac arrest of
cardiac cause
– VF
– Pulseless VT
• Randomized in 2 groups
– Normothermia
– Hypothermia
• Target temperature, 32 - 34°C
• Cooling duration, 24 hours
• Cooling with the use of cold air
Holtzer M. N Engl J Med 2002;346: 549-56. [Erratum, N Engl J Med 2002;346: 1756.]

17. Holtzer M. N Engl J Med 2002;346: 549-56. [Erratum, N Engl J Med 2002;346: 1756.]

18. • Favorable neurologic recovery after 6 months
(good recovery or moderate disability)
– Hypothermia: 75/136 pts (55%)
– Normothermia: 54/137 pts (39%)
• Significant reduction in the rate of death at 6
months
Holtzer M. N Engl J Med 2002;346: 549-56. [Erratum, N Engl J Med 2002;346: 1756.]

19. P value
0.02
Holtzer M. N Engl J Med 2002;346: 549-56. [Erratum, N Engl J Med 2002;346: 1756.]

20. CLINICAL USE OF THERAPEUTIC HYPOTHERMIA
• According to the two major trials
– Out-of-hospital comatose patients after cardiac
arrest
– Successfully resuscitated (return of spontaneous
circulation)
– Cardiac arrest with an initial rhythm
• VF
• Pulseless VT
– Hemodynamically stable

21. Q2
WHO SHOULD UNDERGO TARGETED
TEMPERATURE MANAGEMENT?
1. Comatose stable patient with out-of-hospital
post cardiac arrest, with schockable initial
cardiac rhythm (VF, pulseless VT) after ROSC
2. Comatose unstable patient with in-hospital
post cardiac arrest, with non-shockable initial
cardiac rhythm (Asyatole, PEA) after ROSC
3. Both groups may benefit from therapeutic
hypothermia

22. AREAS OF UNCERTAINTY
Who Should Undergo Targeted Temperature Management
• Both groups have the same pathophysiology
of brain damage
– Global ischemia
– Reperfusion
• Both groups may benefit from therapeutic
hypothermia

23. SHOULD WE APPLY TARGETED TEMPERATURE
MANAGEMENT IN THE FOLLOWING SCENARIO?
– In-hospital comatose patients after cardiac arrest
– Cardiac arrest with an initial rhythm
• Asystole
• PEA
– Hemodynamically unstable: Cardiogenic shock

24. IS HYPOTHERMIA AFTER CARDIAC ARREST EFFECTIVE IN BOTH
SHOCKABLE AND NONSHOCKABLE PATIENTS?
Large Cohort Study
Dumas F , et al. Is hypothermia after cardiac arrest effective in both shockable and nonshockable patients?: insights from a large
registry. Circulation. Mar 1 2011;123(8):877-86.

25. VF/Pulsless VT
Dumas F , et al. Is hypothermia after cardiac arrest effective in both shockable and nonshockable patients?: insights from a large
registry. Circulation. Mar 1 2011;123(8):877-86.

26. PEA/Asystole
Dumas F , et al. Is hypothermia after cardiac arrest effective in both shockable and nonshockable patients?: insights from a large
registry. Circulation. Mar 1 2011;123(8):877-86.

27. IS HYPOTHERMIA AFTER CARDIAC ARREST EFFECTIVE IN BOTH
SHOCKABLE AND NONSHOCKABLE PATIENTS?
• Pilot randomized clinical trial
• Prehospital induction of mild hypothermia in out-of-
hospital cardiac arrest patients with a rapid infusion of
4 degrees C normal saline
• 125 patients total
• 74 had non-VF arrest This study was not intended or
– PEA (n=34) powered to detect differences in
– Asystole (n=39) clinical outcome at discharge.
– Unknown rhythm (n=1)
• The survival to hospital discharge was worse in the
cooled group (6%) than in the non-cooled group (20%)
Kim F, et al. Pilot randomized clinical trial of prehospital induction of mild hypothermia in out-of-hospital cardiac arrest patients with a rapid
infusion of 4 degrees C normal saline.Circulation. Jun 19 2007;115(24):3064-70.

28. IS HYPOTHERMIA AFTER CARDIAC ARREST EFFECTIVE IN BOTH
SHOCKABLE AND NONSHOCKABLE PATIENTS?
Kim F, et al. Pilot randomized clinical trial of prehospital induction of mild hypothermia in out-of-hospital cardiac arrest patients with a rapid
infusion of 4 degrees C normal saline.Circulation. Jun 19 2007;115(24):3064-70.

29. IS HYPOTHERMIA AFTER CARDIAC ARREST EFFECTIVE IN BOTH
SHOCKABLE AND NONSHOCKABLE PATIENTS?
• TTM is not associated with good outcome in non
shockable patients
– Worse prognosis and higher mortality
• The practitioner should consider the most likely
etiology of the cardiac arrest
– PEA arrest due to septic shock
• Poor candidates for hypothermia
• Brain might benefit
• Impairment to the immune system from hypothermia may
be more significant
– PEA arrest due to respiratory arrest
• Hypothermia is not recommended

30. PATIENTS IN CARDIOGENIC SHOCK MAY ALSO SAFELY
UNDERGO TTM
• Retrospective analysis
• 56 cardiac arrest survivors treated with TTM
Cardiogenic Shock Relatively Stable
(n=28) (n=28)
In-hospital mortality 57.1% 21.4%
P=0.013
Favorable neurological outcome 67.9% 82.1%
anytime during hospitalization
P=0.355
Favorable discharge neurological 39.3% 71.4%
outcome
(P=0.031)
• TTM should be considered in cardiac arrest survivors with cardiogenic shock after
ROSC
Skulec R, at al. Acta Anaesthesiol Scand 2008;52:188-94.

31. Q3
TARGETED TEMPERATURE
MANAGEMENT SHOULD NOT BE
CONSIDERED?
1. Pt with body core temperature below 30 C on
admission
2. Pt who was comatose before the cardiac arrest
3. Pregnant patient
4. Pt who is terminally ill
5. Pt with profound blood coagulopathy
6. All of the above

32. Holzer M. Targeted Temperature Management for Comatose Survivors of Cardiac Arrest. N Engl J Med 2010;363:1256-64.

33. THE TIME DEPENDENCE OF TREATMENT
• No data are available from large-scale clinical
trials in humans
• Animal models
• Should be initiated as early as possible and
not later than 10 hours after the cardiac arrest
• Delay in the initiation of TTM may diminish
the beneficial effects
Kuboyama K, et al. Crit Care Med 1993;21:1348-58.
Colbourne F, et al. J Neurosci 1995;15:7250-60.

34. The Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl
J Med 2002;346: 549-56. [Erratum, N Engl J Med 2002;346: 1756.]

35. ANESTHESIA AND ANALGESIA PROTOCOL DURING
TTM
• Shivering may occur when you reach a body temperature of 35 C
• Sedation, analgesia, and paralysis to prevent shivering
– should be initiated when you reach a body temperature of 35 C
• Shivering can lead to
– Stress like response
– Increased oxygen consumption
– Increase in the heart rate
– Excessively laborious breathing
– Impede the cooling process
• 68 ICUs from various countries
– Midazolam: the most used sedative (5 mg/h and 0.3 mg/kg/h)
– Fentanyl : The most used analgesic (0.5 and 10 μg/kg/h)
– Pancuronium: the most used paralytic followed by cisatracurium
Chamorro C, et al. Anesth Analg 2010;110:1328-35.

36. COOLING METHODS
• Surface cooling
– Ice packs around the head, neck, torso, and limbs (in the
Australian trial)
– Cold-air mattress covering the entire body (in the European
trial)
• Core cooling
– Intravascular cooling catheters (made of metal or containing
balloons filled with cold saline)
– Intravenous infusion of cold fluids
• 30 ml/kg (2 L for a patient who weighs 70 kg)of cold (4°C) lactated
Ringer’s solution administered intravenously over the course of 30
minutes
• Combination of core-cooling and surface-cooling methods

38. MEASUREMENT OF THE CORE BODY TEMPERATURE
• The temperature in the bladder and rectum
may be slow to reflect a change in core body
temperature
• Core body temperature should be measured
at:
– Central monitoring sites: the esophagus (with the
use of a multipurpose temperature probe)
– Central venous system (with the use of a Swan–
Ganz catheter)
Stone JG, et al. Anesthesiology 1995;82:344-51.

39. Q4
WHAT WOULD YOU EXPECT DURING
TARGETED TEMPERATURE
MANAGEMENT?
1. Left shift in the oxyhemoglobin dissociation
curve
2. Tissue hypoxia
3. Respiratory alkalosis
4. All of the above

40. OXYHEMOGLOBIN DISSOCIATION CURVE
HEMOGLOBIN'S OXYGEN AFFINITY

41. IATROGENIC DYSCARBIA DURING MILD THERAPEUTIC
HYPOTHERMIA
• ABG should be measured at least every 4 hrs
• Left shift in the oxyhemoglobin dissociation curve
– Increased affinity of hemoglobin for oxygen
– At the tissue level the hemoglobin will not release oxygen
as easily which could result in tissue hypoxia
• Hypoxia will stimulate the O2 chemorecepters up-
regulating the respiratory cycle
– Hyperventilation
– Decreased PCO2 (Respiratory alkalosis)
– Increased pH
• The O2 Content, CO2 Content, and HCO3- will not
change
Falkenbach P, et al. Resuscitation 2009; 80:990-3.

42. O2, CO2 Content, and HCO3- will not change

43. ABG TEMPERATURE CORRECTION: TO CORRECT OR
NOT TO CORRECT; THAT IS THE QUESTION
• “corrected" : corrected to the pt’s body temperature.
The ABG analyzer readings at the patient's body
temperature
• "non-corrected" : The ABG analyzer readings at 37
• Final recommendation is to assess the acid-base and
oxygenation status by looking at the non-corrected
ABG (at 37 degree) regardless of the patient's actual
temperature
• We need to adjust mechanical ventilation to meet the
patient’s needs
– The goal of achieving normal [PaCO2] and sufficient
oxygenation

44. METABOLIC DISTURBANCES IN HYPOTHERMIA
• Regular measurement of electrolyte and
glucose levels is necessary
• Hypothermia can induce
– Hypokalemia
– Hypomagnesemia
– Hypophosphatemia
– Hyperglycemia
Polderman KH, et al. J Neurosurg 2001; 94:697-705.

45. Q5
A 62-year-old man collapses on the street, and emergency medical personnel who are
called to the scene find that he is not breathing and that he has no pulse. The first
recorded cardiac rhythm is ventricular fibrillation.
ACLS measures, including intubation, a total dose of 2 mg of epinephrine, and six
defibrillation attempts, ROSC 22 minutes after the onset of the event.
On admission to the emergency department, his condition is hemodynamically stable
and he has adequate oxygenation and ventilation, but he is still comatose. A
neurologic examination reveals reactive pupils and a positive cough reflex. The
core body temperature is 35.5°C. A diagnosis of the post–cardiac arrest syndrome
with coma is made.
Targeted temperature management was initiated. 6 hours later the core body
temperature is 30 C and the patient starts bleeding from the CVC insertion site
with profound hematuria. What would you do next:
1. Transfuse platelets due to mild hypothermia induced thrombocyotpenia
2. Transfuse FFP
3. Transfuse Cryo
4. Raise the temperature level until these side effects resolve

46. COAGULATION DISORDER IN HYPOTHERMIA
• Higher risk of bleeding
• Inhibits human platelet activation
• Leukopenia and thrombocytopenia
– Typically do not require intervention
– Rarely severe thrombocytopenia may develop
• It is reasonable to raise the temperature level
until these side effects resolve
Michelson AD, et al. Thromb Haemost 1994;71:633-40.

47. NONCONVULSIVE SEIZURES IN HYPOTHERMIA
• Nonconvulsive seizures can occur during
hypothermia
• It is reasonable to perform continuous EEG
monitoring to detect these seizures and to
treat them if they occur
• Unknown if it improves the long-term
outcome
Rundgren M, et al. Intensive Care Med 2006;32: 836-42.

48. HEMODYNAMIC INSTABILITY DURING HYPOTHERMIA
• Rewarming may not be helpful
– Vasodilatation can occur during rewarming
• Fluid replacement
• Inotropics
• Pressors
Holtzer M. N Engl J Med 2002;346: 549-56. [Erratum, N Engl J Med 2002;346: 1756.]

49. REWARMING
• After maintenance of hypothermia for 24 hours
• Slowly (0.3 to 0.5°C per hour) to normal core temperature(36.5 to
37.5°C)
• Temperature should be kept within the normal range for up to 48
hrs
• Above normal body temperatures should be avoided
– Hyperthermia could worsen the outcome
– Unfavorable neurologic ischemia
– Excitotoxicity
• Rewarming methods
– Passive rewarming is preferred
– Blowing warm air over the patient
– Covering the patient with blankets
• Paralytic agents are discontinued at 35°C
Zeiner A, et al. Cell Calcium 2010;47:122-9.

50. The Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl
J Med 2002;346: 549-56. [Erratum, N Engl J Med 2002;346: 1756.]

51. ADVERSE EFFECTS
• 41 clinical trials were conducted between 1997
and 2010
• Complications related to the cooling device: 1%
(29 events in 3133 pts)
– IV cooling Catheter (balloons filled with cold saline)
• 3 cases of bleeding
• 8 cases of infection
• 10 cases of DVT
– IV cold fluid infusion
• 8 cases of pulmonary edema

52. ADVERSE EFFECTS
• Complications related to the hypothermia
– Hypothermia: 74% (223/300 pts)
– Standard treatment: 71% (201/285 pts)
– (P = 0.31)

54. ADVERSE EFFECTS
• No reports in the randomized trials of
– Thrombocytopenia
– ARDS
– Cerebrovascular insult
– Bradycardia

55. J WAVES OR OSBORNE WAVES IN HYPOTHERMIA

56. ADVERSE EFFECTS
• Observational study
• 986 patients
• The most commonly observed adverse events
– Pneumonia (41%)
– Hyperglycemia (37%)
– Cardiac arrhythmias (33%)
– Seizures (24%)
– Electrolyte disturbances
• Hypophosphatemia 19%
• Hypomagnesemia 18%
• Hypokalemia 18%
Nielsen N, et al. Acta Anaesthesiol Scand 2009;53:926-34.

57. AREAS OF UNCERTAINTY
What is The Optimal Regimen of Sedation, Analgesia, and
Relaxation
• Many different protocols
• In the randomized trials to facilitate and to facilitate
cooling and prevent shivering
– Midazolam
– Fentanyl
– Pancuronium/vecuronium
• Midazolam level accumulates during hypothermia
Fukuoka N, et al. Resuscitation 2004;60:225-30.
• Paralytic agents are thought to increase the risk of
myopathy associated with critical illness
– No prospective trial has shown such an association
De Jonghe B, et al. JAMA 2002;288:2859-67
Chamorro C, et al. Anesth Analg 2010;110:1328-35.

58. AREAS OF UNCERTAINTY
• The optimal time to initiate hypothermia?
– As early as possible
– Not later than 10 hrs after the cardiac arrest
– Animal models (No data are available from large-
scale clinical trials in humans)
Kuboyama K, et al. Crit Care Med 1993;21:1348-58.
Colbourne F, et al. J Neurosci 1995;15:7250-60.

59. AREAS OF UNCERTAINTY
• The optimal length of time that should be
taken to reach the target temperature?
– It should be fast
– 4-8 hrs (in the European trial)

60. The Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl
J Med 2002;346: 549-56. [Erratum, N Engl J Med 2002;346: 1756.]

61. AREAS OF UNCERTAINTY
• The optimal duration of hypothermia?
• The major randomized trials (the European)
– Cooling duration, 24 hours
• Longer exposure to hypothermia (>24hrs)
might be required in the setting of more
severe injury
– Studies in rodents
Colbourne F, Corbett D. Delayed and prolonged post-ischemic hypothermia is neuroprotective in the gerbil. Brain Res 1994;654:265-72.

62. AREAS OF UNCERTAINTY
• The optimal level of hypothermia?
• The major randomized trials (the Australian
and the European)
– Target temperature, 32 - 34°C
• Milder levels of hypothermia (35°C) might
have similar protective effects
– Studies in rats
Logue ES, et al. Acad Emerg Med 2007;14:293-300.

63. AREAS OF UNCERTAINTY
• The effect of the rewarming rate on the
neurologic outcome after cardiac arrest?
• The major randomized trials (the Australian
and the European)
– 0.3 to 0.5°C / hr to normal core temperature(37°C)

64. THE 2005 GUIDELINES
• The core body temperature of unconscious adult
patients with spontaneous circulation after an
out-of-hospital ventricular fibrillation cardiac
arrest should be lowered to 32 to 34°C
• Cooling should be started as soon as possible
after the arrest and should be continued for at
least 12 to 24 hours
• Patients who have had a cardiac arrest due to
nonshockable rhythms and patients who have
had a cardiac arrest in the hospital may also
benefit from induced hypothermia
European Resuscitation Council guidelines for resuscitation 2005. Resuscitation 2005;67:Suppl 1:S1-S189.
2005 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation
2005;112:Suppl:IV1-IV203

65. RECOMMENDATIONS
• Insert an additional temperature probe in the esophagus
– The temperature in the bladder and rectum may be slow to reflect a
change in core body temperature
• Maintain a core temperature of 33°C for 24 hours
– Initiate rapid cooling by the infusion of 2000 ml of cold (4°C) lactated
Ringer’s solution with the use of a pressure bag through a largebore
cannula over the course of 30 minutes
– Combined with the application of refrigerated cooling pads (or the use
of a catheter-based endovascular cooling device)
• Monitor the patient’s electrolyte levels and blood counts
• Rewarm the patient slowly, at a rate of 0.4°C per hour, until
normothermia
• Then discontinue the sedatives, the analgesics, and the paralytic
agent as tolerated
– D/c paralytic agent at 35 °C