INDUCED NORMOTHERMIA IN ICU
PATIENTS WITH NEUROLOGIC
INSULT
Jessica Liu, PharmD
University of Washington Medical Center
Pharmacy Practice Resident
October 30, 2014
CONCEPT OF NORMOTHERMIA

Prevention of Secondary Brain Injury
Can occur hours to days after primary injury (ex:
stroke, trauma, intracranial hemorrhage, infection,
seizure, delayed perfusion)
 Damage caused by inflammation, edema, fever


Idea that lowering body temperature may have a
neuroprotectice effect, but how low do we go?
CONCEPT OF NORMOTHERMIA

Fever has long been known to cause harm in severe acute
neurologic injury, however, preliminary results in animal
hypothermia and its potential benefit has provided mixed
results


Evidence that neuroprotective effects of hypothermia lessened
due to inherent side effects (infection, shivering)
“Aggressive treatment of fever in the ICU w/o risk
elevation through the side effects of therapeutic
hypothermia led to the concept of controlled
prophylactic normothermia. This concept is based upon
strict control of body core temperature with a target of
36.5°C beginning as early as possible with the goal of
complete fever prevention.” (Broessner 2012)
(Polderman 2009)
GOALS OF DECREASING BODY TEMPERATURE

Decrease cellular demand for O2

Stabilize the blood brain barrier

Stabilize cell membranes

Prevent ischemia, which in turn inhibits
formation of reactive oxygen species,
inflammatory cascades, and mitochondrial
dysfunction
TEMPERATURE MODULATING DEVICES

Arctic Sun
Cooling blanket
www.allbiomedical.com
www.medivance.com
TEMPERATURE MODULATING DEVICES

Cooling Catheter
Bair Hugger
www.solutions.3m.com
www.medgadget.com
CONSIDERATIONS OF TEMPERATURE
MODULATION

Fever

Infection

Shivering
FEVERS ARE BAD NEWS…
“Up to 90% of patients develop at least one febrile
episode within 7 days after being admitted to the
ICU.” (Marion 2004)
 Many pathophysiological mechanisms affected by
fever:

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Free radical production
Local thermopooling
Disruption of blood brain barrier
Increased intracranial pressure
Increased enzymatic inhibition of protein kinases
Increased metabolic demand
STUDIES SHOW FEVERS ASSOCIATED WITH
WORSE OUTCOMES IN BRAIN INJURIES

“Impact of fever on outcome in patients with
stroke and neurologic injury: a comprehensive
meta-analysis” (Greer, Stroke 2008)


Comprehensive meta-analysis of all studies
addressing fever in brain-injured patients
Studies pulled from Medline articles published since
January 1, 1995
Pooled analyses indentified 39 studies covering 14,431
patients
 Study outcomes included fever/higher body temperature
and normothermia/lower body temperature

STUDIES SHOW FEVERS ASSOCIATED WITH
WORSE OUTCOMES IN BRAIN INJURIES

Relative risk of worse outcome with fever:




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Mortality 1.5
Glasgow Outcome Scale 1.3
Barthel Index 1.9
Modified Rankin Scale 2.2
Canadian Stroke Scale 1.4
Intensive Care LOS 2.8
Hospital LOS 3.2
In all 7 outcome measures, meta-analysis
indicates fever associated with worse outcomes
regardless of the type of neurological insult
(ischemia, hemorrhagic, traumatic)
ANTIPYRETICS & FEVER MANAGEMENT

Acetaminophen the preferred
agent (Kasner 2002)
Inhibits cyclooxygenase-mediated
prostaglandin synthesis to lower
hypothalamic set point
 650mg-1000mg Q4-6h (max 4g/day)
can cause a small reduction in core
body temperature and help promote
hypothermia
 Key agent in achieving
thermoregulation in stroke patients

INFECTION RISKS WITH FEVER CONTROL

Why do we get fevers?

Pyrogens are produced by the body in response to an
infection  pyrogens bind to receptors on the
hypothalamus  binding signals the body to increase
body temperature  increase in temperature thought
to help kill off infection
INFECTION RISKS WITH FEVER CONTROL

Aggressive fever control may actually cause more
harm

Bicenter, prospective, randomized trial comparing
conventional fever control vs. aggressive fever control
(Broessner, et al. Stroke. 2009)
CFC temperature goal: T ≤ 37.9°C
 AFC temperature goal: T = 36.5°C
 Median total fever burden significantly higher in CFC
group (4.3°C vs. 0.0°C, P <0.0001)
 Infectious complications higher in AFC group (94% vs. 78%)
 However, no difference in major adverse effects including:
sepsis, bacteremia, and cerebral edema


Unnecessary antibiotic use? Antibiotic associated
problems?
BENEFIT OF FEVER CONTROL REMAINS
UNCLEAR…

Prospective, randomized trial to assess influence of
prophylactic, endovascularly based normothermia vs.
conventional temperature management on inflammatory
parameters in patients with severe cerebrovascular
disease (Broessner, et al. Stroke. 2010)
Study found no difference in patients’ neurological outcomes 6
months post endovascular cooling treatment
 “Although fever has been identified to be an independent
predictor and risk factor of unfavorable outcome, especially in
patients with severe neurological disease, many studies have
consistently failed to ameliorate outcome by inducing normoor hypothermia…the inflammatory response might be
negatively altered through thermoregulatory measures
possibly nullifying a potential benefit of normothermia.”

IMPORTANCE OF SHIVER CONTROL

Shivering is the body’s physiological attempt to retain
heat. Vasoconstriction occurs and blood is shunted
away from the body’s extremities.
Motor response begins in the trunk and spreads to
extremities to generate heat
 Shivering occurs when the body’s temperature falls 1°C
below the vasoconstriction threshold (Sessler 2009)


Downside



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 basal metabolic rate 5x normal
 energy expenditure, O2 consumption, CO2 production,
and free radical formation
Retard cooling process as heat transferred from core to
periphery
Cerebral metabolic stress
Tachycardia, HTN
ASSESS FOR SHIVERING

Bedside Shivering Assessment Scale (BSAS)

Palpate masseter, pectorals, deltoids, and quadriceps
muscles Q1H
0 = no shivering
 1 = mild shivering localized to neck and/or chest
 2 = shivering involving neck and/or chest and arms
 3 = intermittent generalized shivering involving all 4 extremities
 4 = generalized, sustained, rigorous shivering

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Goal ≤ 1
Badjatia, et al. Stroke 2008
SHIVER MEDICATION MANAGEMENT

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Goal: to obtain shivering control with the least sedating
regimen possible
No sedation: acetaminophen, buspirone, magnesium
sulfate, skin counterwarming
Mild sedating agents: fentanyl, meperidine,
dexmedetomidine
Moderate sedation: opioids in combination with
dexmedetomidine
Heavy sedation: propofol
Neuromuscular blockade: vercuronium
BUSPIRONE & MEPERIDINE ACT
SYNERGISTICALLY


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Buspirone
 Acts on 5HT1A receptor
to lower threshold

Meperidine
 Acts on an α2B
adrenoreceptor subtype
Experimental trial in 8 volunteers over 4 randomly-assigned days
in 4 categories (Mokhtarani 2001):
1.
Large dose oral buspirone (60mg)
2.
Large dose IV meperidine (0.8 microgram/mL)
3.
Buspirone (30mg) + meperidine (0.4 microgram/mL)
4.
Control day with no drugs
Results:

minimal sedation with either drug or in combination

Buspirone alone had little affect on shiver reduction

Combo of low dose buspirone and meperidine acted
synergistically to provide a significant reduction in shivering
COLUMBIA ANTISHIVERING PROTOCOL
FUTURE QUESTIONS TO ASK:
When to initiate normothermia?
 Optimal length of therapy?
 Optimal target temperature?
 Optimizing medications for fever, shivering, and
infections.
 Does the type of traumatic brain injury matter?
 Differences in surface vs. endovascular cooling?

FUTURE CLINICAL TRIALS


If normothermia is going to become more mainstream in
the critical care of neurology patients, there needs to be a
strong push for prospective, randomized, control trials.
Current ongoing trial:

“Normothermia Protocol for Traumatic Brain Injury
Patients”

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Prospective, observational, outcome study
Study start date: May 2011
Estimated completion date: May 2013
Estimated Enrollment: 80 patients
Primary outcome measures:
 Effectiveness of normothermia protocol x 5 days
 Temperature vs. ICP
 Neurologic outcome
Secondary Outcome Measure: mortality (in-hospital, 3-6
months)
Sponsor: Medivance, Inc.
CONCLUSION
Body cooling in theory appears beneficial, but
more studies are needed to support its use in
clinical practice
 Infection can be a serious complication of
decreased body temperature
 Prolonged treatment periods may be required
 Adequate management of potential side effects is
essential

REFERENCES
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"Normothermia Protocol For Traumatic Brain Injury Patients". Clinicaltrials.gov. Published May 12, 2011. Accessed
September 22, 2013. http://clinicaltrials.gov/show/NCT01354509
Broessner G, Beer R, Lackner P, et al.: "Prophylactic, endovascularly based, long-term normothermia in ICU patients
with severe cerebrovascular disease: bicenter prospective, randomized trial". Stroke 2009, 40:e657-e665.
Broessner G, Lackner P, Fischer M, et al.: "Influence of prophylactic, endovascularly based normothermia on
inflammation in patient with severe cerebrovascular disease: a prospective, randomized trial". Stroke 2010, 41:29692972.
Badjatia N, et al.: "Metabolic impact of shivering during therapeutic temperature modulation. The bedside shivering
assessment scale". Stroke 2008, 39:3242-3247.
Greer DM, Funk SE, Reaven NL, et al.: "Impact of fever on outcome in patients with stroke and neurologic injury: a
comprehensive meta-analysis". Stroke 2008, 39:3029-3035.
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Sessler DI: "Thermoregulatory defense mechanisms". Critical Care Medicine 2009, 37(7 Suppl):S203-10.
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Broessner G, et al.: "Controlled prophylactic normothermia". Critical Care 2012, 16(Suppl 2):A10.
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Marion DW: "Controlled normothermia in neurologic intensive care". Critical Care Medicine 2004, 32(Suppl):S43-S45.
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Kasner SE, Wein T, Piriyawat P, et al.: "Acetaminophen for altering body temperature in acute stroke: a randomized
clinical trial". Stroke 2002, 33:130-4.
Mokhtarani M, Mahgoub AN, Morioka N, et al." "Buspirone and meperidine synergistically reduce the shivering
threshold". Anesth Analg 2001, 93:1233-9.
Polderman KH: “Mechanisms of action, physiological effects, and complications of hypothermia”. Critical Care
Medicine 2009, 37(7 Suppl):S186-202.