Best Practice & Research Clinical Anaesthesiology
Vol. 17, No. 4, pp. 551 –568, 2003
doi:10.1016/S1521-6896(03)00050-8, www.elsevier.com/locate/jnlabr/ybean
5
Therapeutic hypothermia
Barbara Kabon
MD
Resident
Andreas Bacher
MD
Professor
Christian K. Spiss*
MD
Professor
Department of Anaesthesiology and General Intensive Care, University of Vienna, Waehringer Guertel 18-20,
Vienna A-1090, Austria
Hypothermia is common during anaesthesia and surgery owing to anaesthetic-induced inhibition
of thermoregulatory control. Perioperative hypothermia is associated with numerous
complications. However, for certain patient populations, and under specific clinical conditions,
hypothermia can provide substantial benefits. Lowering core temperature to 32 – 34 8C may
reduce cell injury by suppressing excitotoxins and oxygen radicals, stabilizing cell membranes, and
reducing the number of abnormal electrical depolarizations. Evidence from animal studies
indicates that even mild hypothermia provides substantial protection against cerebral ischaemia
and myocardial infarction. Mild hypothermia has been shown to improve outcome after cardiac
arrest in humans. Randomized trials are in progress to evaluate the potential benefits of mild
hypothermia during aneurysm clipping and after stroke or acute myocardial infraction. However,
as hypothermia can cause unwanted side-effects, further research is needed to better quantify the
risks and benefits of therapeutic hypothermia.
Key words: anaesthesia; hypothermia, induced; adverse effects; thermal management;
myocardial ischaemia; brain ischaemia; outcomes assessment.
Core temperature is precisely controlled between set points triggering thermoregulatory responses in the healthy awake individual. The temperature range not
triggering thermoregulatory responses (Interthreshold range) is approximately 0.2 8C
in unanaesthetized humans. During anaesthesia this temperature range increases
because physiological thermoregulatory responses normally triggered by hypothermia
do not occur (e.g. behavioural changes, shivering). Therefore, if normothermia is not
actively maintained, general anaesthesia may lead to unintentional hypothermia, which
is associated with numerous complications. However, deliberate hypothermia, as
* Corresponding author. Tel.: þ43-1-40-400-4118; Fax: þ43-1-40-400-4028.
E-mail address: [email protected] (C. K. Spiss).
1521-6896/03/$ - see front matter Q 2003 Elsevier Ltd. All rights reserved.
552 B. Kabon, A. Bacher and C. K. Spiss
a therapeutic adjunct for a variety of medical procedures, is becoming more
commonplace as it provides beneficial outcomes in certain patient populations.
Topical hypothermia as anaesthetic has been applied for decades, and deep global
hypothermia is the principal cerebroprotective technique for circulatory arrest
procedures. However, the use of deep hypothermia during neurosurgery has been
restricted by the need for extracorporeal circulation and post-operative/post-bypass
complications.1
It has been noted that small decreases in brain temperature can reduce ischaemiainduced neurologic injury.2 Changes in brain temperature markedly affect secondary
brain injury after trauma. In contrast to mild hypothermia that can ameliorate
ischaemia-induced brain injury, hyperthermia, even if delayed, may worsen neurological
outcome after neurotrauma.3 This suggests the importance of preventing hyperthermia
and fever as well as the possible benefits of therapeutic hypothermia (i.e. lowering core
temperature by 2 – 4 8C).
PATHOPHYSIOLOGY
The pathophysiology of cerebral ischaemia and trauma is complex and involves multiple
injury cascades that may be sensitive to temperature variations.4 Multiple pathophysiological mechanisms, including excitotoxicity, oxygen radical production, intracellular
signalling cascades, cerebral metabolism, membrane stabilization, activation of protein
kinases, cytoskeletal breakdown, and early gene expression are all sensitive to mild
temperature variations.5
The classical mechanism proposed for neuronal protection by hypothermia is the
reduction of oxygen and glucose consumption caused by a reduction in the rates of
enzymatic reactions. Experimentally, focal and global cerebral ischaemia are markedly
affected by small changes in brain temperature. Mild hypothermia ameliorates, and mild
hyperthermia exacerbates ischaemic-induced neuronal injury.6 In contrast to deep
hypothermia, where low temperatures protect the tissue by reducing the rates of
enzymatic reactions, suppression of cerebral metabolic rate alone cannot explain the
cerebral protective effect of mild and moderate hypothermia. Mechanisms involved
include reduction of ischaemia-induced excitatory neurotransmitter increase7, effects
on ion homeostasis and membrane permeability, recovery of post-ischaemic protein
synthesis8, prevention of protein kinase C down-regulation9 and the consumption of
free radical scavengers in the brain tissue.
In a model of spinal cord ischaemia, hypothermia also effectively attenuated release
of extracellular glutamate.10 In contrast, hyperthermia (39 8C) has been reported to
increase levels of extracellular glutamate compared to normothermic ischaemic
animals after middle cerebral artery occlusion.11
Several studies have reported that hypothermia attenuated lipid peroxidation and
free radical production.10,12 Using 2,3-dihydroxybenzoic acid (2,3-DHBA) as an
indicator for free radical production, Globus and colleagues first showed that postischaemic and traumatic hypothermia (30 8C/3 hours) significantly reduced the
extracellular levels of these radicals.
A recent series of studies have identified other pathomechanisms that may also
underlie the beneficial effects of therapeutic hypothermia. Apoptotic cell death
participates in pathogenesis of neuronal cell death after traumatic and ischaemic injury.4
In this context, mild hypothermia has recently been reported to increase
the anti-apoptotic protein, Bsl 2, following cerebral ischaemia, a response that may
attenuate apoptotic cell death.13
Therapeutic hypothermia 553
It appears that hypothermia affects not only many steps in the course of the ischaemic
cascade but also suppresses several components of secondary brain injury, including
hypermetabolism and inflammation. The underlying temperature effects on inflammatory processes are most likely multifactorial. For example, post-injury hypothermia has
been reported to reduce the acute accumulation of polymorphonuclear leukocytes
macrophages/microglia after injury.14 – 17 Hypothermia has been shown to protect
against blood – brain barrier permeability in various ischaemia and trauma models.18 – 19
Additionally, recent data have shown that post-traumatic hypothermia reduces
expression and levels of the pro-inflammatory cytokine IL-1b after trauma.20
Nitric oxide (NO) is a highly diffusible radical that may be toxic to neurons.4 Posttraumatic hypothermia reduces the expression and activation of NO synthase and NO
production.21 Thus, hypothermia may reduce NO production and secondary damage
by targeting NO synthase activity and decreasing the generation of cytotoxic agents,
including proxynitrates.
HYPOTHERMIA AND TRAUMATIC BRAIN INJURY
Based on the potential beneficial effects of therapeutic hypothermia, several clinical
trials were performed to evaluate the effect of different levels of hypothermia on
neurological outcome in patients after brain injury (Table 1).
In 1993, Marion et al, randomly assigned 40 patients with severe closed head injuries
evaluated with Glasgow Coma Scale (GCS) scores of 3 –7 to either a normothermic or
a hypothermic group. Hypothermic patients were cooled to 32 – 33 8C (brain
temperature) within 10 hours after injury for the following 24 hours and then rewarmed over 12 hours. Hypothermia significantly reduced intracranial pressure (ICP)
(40%) and Cerebral blood flow (CBF) (26%) during the cooling period, and neither
parameter showed a significant rebound after re-warming. Three months after injury,
12 patients in the hypothermic group had moderate, mild, or no disabilities versus eight
patients in the normothermic group. Systemic complications were similar in both
groups. The authors conclude that therapeutic hypothermia (32 8C) after severe closed
head injury is a safe procedure and a trend toward better outcome in hypothermic
patients indicates a limitation of secondary brain injury.22
Shiozaki and colleagues used a different approach. The patients in this study were
included only if intracranial hypertension was refractory to all conventional treatment
modalities, including high-dose barbiturate therapy. Patients were then divided into two
groups: 16 patients received mild hypothermia with 17 patients serving as a
normothermic control group. Mild hypothermia significantly reduced ICP and therefore
increased cerebral perfusion pressure (CPP). Eight patients (50%) in the hypothermia
group and three (18%) in the control group survived. The results of this investigation
suggest that mild hypothermia is an effective method for controlling traumatic
intracranial hypertension in patients in whom conventional ICP therapy was infective.23
Clifton et al randomised 46 patients with severe brain injury (GCS 4– 7) to either
standard normothermic management or to management with systemic hypothermia
at 32– 33 8C. Surface cooling was initiated within 6 hours of injury and maintained for
48 hours. There were no cardiac or coagulopathy-related complications, and the
incidence of seizures was significantly lower in the hypothermia group. Mean Glasgow
Outcome Scale (GOS) score at 3 months after injury showed an increase of 16% in
the Good Recovery/Moderate Disability category as compared with Severe
Disability/Vegetative/Dead.24
554 B. Kabon, A. Bacher and C. K. Spiss
Table 1. Effect of hypothermia on ICP and outcomes in clinical TBI studies.
Good outcomea
Number of
patients
Duration
ofcooling
Effect on
ICP
Decrease
No change
Decrease
Decrease
Decrease
Decrease
Decreased
% of patients
with ICP .
20 mmHg
Decrease
if ICH
Decrease
Decrease
Decrease
Decrease
Author (year)
PRCT
Shiozaki et al (1993)23
Clifton et al (1993)24
Metz et al (1996)
Marion et al (1997)25
Nara et al (1998)
Tateishi (1998)
Clifton et al (2001)28
Yes
Yes
No
Yes
No
No
Yes
33
46
10
82
23
9
392
48 hours
48 hours
25 hours
24 hours
?
1– 6 days
48 hours
Shiozaki et al (2001)70
Yes
91
48 hours
Jiang et al (2000)
Zhi et al (2003)31
Gal (2002)
Tokutomi et al. (2003)
Yes
Yes
Yes
No
87
396
30
31
a
b
3– 14 days
1– 7 days
72 hours
48 –72 hours
Hypothermia
Group (%)
Normothermia
Group(%)
38
52
6
36
56b
33b
43
43
23
30
47b
62b
87
27b
38b
47
PRCT, prospective randomized clinical trial; ICP, intracranial pressure; ICH, intracranial hypertension.
Outcoms only for PRCTs.
Statistically significant differences.
This study was followed in 1997 by a randomized, controlled trial, in which Marion
et al compared the effects of moderate hypothermia and normothermia in 82 patients
with severe closed head injuries (GCS 3– 7). The patients assigned to hypothermia
were cooled to 33 8C within 10 hours after injury and kept at 32 –33 8C for 24 hours.
A specialist in physical medicine and rehabilitation unaware of the treatment
randomisation evaluated the patients 3, 6 and 12 months later, using the GOS. At 12
months, 62% of the patients in the hypothermia group and 38% in the normothermia
group had favourable outcomes (moderate, mild, or no disabilities). However,
hypothermia did not improve the outcomes in the patients with coma scores of 3 –4
on admission. Among the patients with scores of 5 – 7, hypothermia was associated
with significantly improved outcomes at 3 and 6 months, although not at 12 months.
The authors concluded that treatment with moderate hypothermia for 24 hours in
patients with severe traumatic brain injury and coma scores of 5 –7 on admission
expedited neurological recovery and may have improved outcome.25 This study was
criticized mainly for two reasons.26 First, although the authors reported that the
causes and severity of injury were similar in the hypothermia and normothermia
groups, on the basis of the Computed tomography (CT) class the patients in the
hypothermic group were favoured. Marion responded that CT-defined severity of
injury has never been validated as an independent measure of outcome. There are
numerous examples (e.g. epidural haematoma, diffuse hypoxic brain injury) where the
initial CT appearance is not predictive of the neurological outcome.27 Second, patients
in the normothermic group were allowed to reach temperatures as high as 38.5 8C
Therapeutic hypothermia 555
before they were cooled to 37 8C. Therefore, the reported beneficial effect of
hypothermia may have been due in part to avoiding detrimental effects of
hyperthermia. Based on these results, a multicentre trial—the National Acute Brain
Injury Study: Hypothermia (NABIS-H)A—was launched28, eventually enrolling 392
patients. After the outcome at 6 months showed no differences regarding morbidity
and mortality, a subgroup analysis was performed. It showed a higher mortality rate if
the patient was more severely injured (GCS 3– 4) and experienced a higher
percentage of hours of hypotension [mean arterial pressure (MAP) , 70 mmHg]
during treatment. Additionally, ICP was not reduced in these patients. Therefore, the
National Institutes of Health (NIH) stopped the study. However, the general
conclusion that hypothermia is not beneficial in head-injured patients should not be
drawn from these results. The principal investigator, Clifton, searched for the reasons
for this apparently negative outcome of NABIS-H.29 One of the suggested reasons is
that hypothermia was maintained for only 48 hours after trauma. Clinical experience
shows that severe increases in intracranial pressure and thereby critical decreases in
cerebral perfusion pressure very often occur later and last longer during intensive
care in such patients. As such, the danger of secondary ischaemia is high, but by this
time NABIS-H patients were already normothermic. Furthermore, cooling might have
been initiated far too late (8.4 ^ 3.6 hours after trauma) to be effective during
primary cerebral ischaemia. There was also a lack of difference in core temperature
during this time between the control group and the treatment group because the
control group was also subjected to mild hypothermia during emergency resuscitation
and transport to the hospital. Additionally, there were no standardized treatment
protocols regarding the important physiological variables MAP, CPP, and PaCO2.
Sedation was performed with only low doses of morphine, and the patients were
immobilized with muscle relaxation rather than with adequate sedoanlagesia. Due to
these unanswered questions, the NIH will fund a second study after selection of
competent study centres based on track records and a test phase.
Polderman et al.30 hypothesized that severe side-effects of artificial cooling might
have masked the positive side-effects of therapeutic cooling. In a prospective clinical
trial a large group of patients with severe head injury were treated with hypothermia
using a strict protocol to prevent the occurrence of cooling-induced side-effects. A
total of 136 patients with a GCS of 8 or less on admission, and in whom intracranial
pressure remained above 20 mmHg in spite of therapy according to a step-up
protocol, were included. Those who responded to the last step, barbiturate coma,
constituted the control group ðn ¼ 72Þ: Those who did not respond to barbiturate
coma ðn ¼ 64Þ were treated with moderate hypothermia (32 – 34 8C). Although
average APACHE II scores were significantly higher, and average GCS at admission
slightly lower, in the hypothermia group, actual mortality rates were significantly
lower (62 versus 72% P , 0:05Þ in the patients treated with moderate hypothermia.
The number of patients with good neurological outcome was also higher in the
hypothermia group: 15.7 versus 9.7% for hypothermic patients versus controls,
respectively ðP , 0:02Þ: The larger effects were seen in patients with a GCS of 5 or
6 at admission. In contrast to other studies, hypothermia was maintained for
significant longer periods of time in this study. Discontinuation of cooling was guided
by ICP, and hypothermia was maintained as long as ICP above 20 mmHg if
hypothermia was discontinued. Thus, the average duration of hypothermia was 4.8
days in this study.
Recently, another prospective large clinical trial of hypothermia in 396 patients was
published by Zhi et al.31 Hypothermia was induced within 24 hours in 198 patients, who
556 B. Kabon, A. Bacher and C. K. Spiss
were kept at 32 – 35 8C for 1– 7 days after injury. The rectal temperature of control
patients was induced from 36.5 to 37.08. The initial Glasgow Coma Scale was similar in
both groups. Outcomes and mortality rate were significantly improved in the
hypothermia group. During mild hypothermia intracerebral pressure, hyperglycaemia
and blood lactic acid appreciably decreased. Vital signs, blood gas values and blood
electrolytes did not change significantly. It seems that a beneficial effect of mild
hypothermia can be achieved in younger patients with a GCS of 5 – 8 and elevated ICP of
20 up to 40 mmHg but is less effective in most severely injured patients (GCS 3– 4) or
patients without increased ICP. The increased risks of medical side-effects in
hypothermic elderly patients might lead to a poor outcome, thus outweighing the
benefits of hypothermia.
HYPOTHERMIA AND STROKE
Stroke is one of the most common causes of death in the USA, causing tremendous
morbidity as well as high associated costs to the health care system. While traditional
medical treatments provide some benefit, deliberate hypothermia as an adjunct therapy
might prove to be even more useful.
Despite experimental evidence that hypothermia might positively affect injury after
cerebral ischaemia, clinical studies do not provide sufficient evidence (small sample size,
methodological problems, and the complexity of the underlying mechanism) that
hypothermia is effective as brain protective therapy. Results from animal models in
which hyperthermia worsened and hypothermia improved the effects of cerebral
ischaemia led to a prospective observational study.32
The possible beneficial effects of mild hypothermia in cerebral ischaemia due to
stroke were investigated in 390 stroke patients admitted within 6 hours of the
ischaemic event. The relationship between body temperature on admission and initial
stroke severity, infarct size, mortality, and outcome was investigated. Other covariates
(age, gender, stroke severity on admission, body temperature, infections, leucocytosis,
diabetes, hypertension, atrial fibrillation, ischaemic heart disease, smoking, previous
stroke and co-morbidity) were included in the analysis. The authors reported an
association between body temperature and initial stroke severity, infarct size, mortality
and neurologic outcome.
Because this study was observational a causal relationship could not be proven.
Subsequently, Schwab initiated a pilot study on the efficacy, feasibility, and safety of
induced moderate hypothermia in the therapy of patients with acute severe middle
cerebral artery infarction and increased ICP.33 Moderate hypothermia was induced in
25 patients with severe ischaemic stroke in the middle cerebral artery territory within
14 hours after stroke by external cooling. Patients core temperature was maintained
between 33 and 34 8C for 2 –3 days, and ICP, CPP and brain temperature were
continuously monitored. In all patients intraparenchymatous brain temperature
exceeded core temperature. This temperature gradient varied between individuals
and over the measurement period. Outcome at 4 weeks and 3 months after stroke
was analysed with the Scandinavian Stroke Scale (SSS) and the Barthel index. Fourteen
(56%) patients survived hemispheric stroke. Neurological outcome according to the
SSS score was 29 (range: 25 – 37) 4 weeks after stroke and 38 (range: 28 – 48) 3
months after stroke. During hypothermia, elevated ICP values could be significantly
reduced. Herniation caused by a secondary rise in ICP after re-warming was the cause
of death in all the remaining patients.
Therapeutic hypothermia 557
Schwab was able to reduce elevated ICP (mean initial ICP . 20 mmHg) by applying
hypothermia. In space-occupying middle cerebral artery (MCA) infarction, fatal
outcome was reported by the same institution in 80% of the patients with standard
treatment. The mortality rate in the hypothermic patients was only 44%. This
impressive reduction of the mortality from 80% in the historic control to 44% using
hypothermia unfortunately does not prove the effectiveness of hypothermic therapy,
but is a strong argument for a prospective randomised trail.
Because ICP seems to be of such a great importance in avoiding herniation, it may be
that a combination therapy of hypothermia and surgical ICP reduction by early
decompressive carniotomy is the most effective treatment regimen in patients with
hemispheric stroke, at least in younger patients. Preliminary study results showed that
mortality could be reduced to only 16%.34
HYPOTHERMIA AND CARDIOPULMONARY RESUSCITATION
Despite the development of new treatments, the overall survival rates from cardiac
arrest remain poor, with as many as 450 000 sudden deaths each year, yet the average
survival rate remains less than 5%. Approximately 80 per 100 000 Europeans are
affected by sudden cardiac arrest each year. Unfortunately, full cerebral recovery is still
a rare event. Almost 80% of patients who initially survive a cardiac arrest present with
coma lasting more than 1 hour. Of these patients, only 10 –30% survive with good
neurological outcome 1 year after cardiac arrest.
Current therapy after cardiac arrest concentrates on resuscitation efforts; but until
now no specific therapy for brain protection was available. Recently, two randomised
clinical trials in Australia and Europe showed a neurological benefit of mild therapeutic
hypothermia in survivors of out-of-hospital cardiac arrest. In the Australian study
(n ¼ 77 patients who remained comatose after restoration of spontaneous circulation),
49% of those treated with hypothermia were discharged home as compared with 26%
of the control patients ðP ¼ 0:046Þ:35 Hypothermia was associated with a lower cardiac
index, higher systemic vascular resistance and hyperglycaemia. There was no difference
in the frequency of adverse events.
In the European multicentre study 136 patients were included. Fifty-five percent of
the hypothermia group had a favourable outcome compared to 39% in the
normothermic group. Additionally, the mortality at 6 months was 41% in the
hypothermic group as compared to 55% in the normothermic group34. The target
temperatures in these two studies, between 32 and 34 8C, were maintained for 12 and
24 hours, respectively. In patients successfully resuscitated following out-of-hospital
cardiac arrest due to ventricular fibrillation, therapeutic mild hypothermia increased
the rate of favourable neurological outcome and reduced mortality. Nevertheless,
further experimental and clinical data are required to establish this rather simple
therapy for such patients as a widely used clinical routine. In an editorial in the New
England Journal of Medicine, Safar et al recommended the use of mild hypothermia in
survivors of cardiac arrest as early as possible and for at least 12 hours.36
HYPOTHERMIA AND MYOCARDIAL INFARCTION
During the past three decades, there have been tremendous advances in our
understanding of ischaemia. Ischaemia occurs when blood flow, oxygen and substrate
558 B. Kabon, A. Bacher and C. K. Spiss
delivery are inadequate to meet the metabolic demand of tissue. This is fundamentally
the same for myocardial cells and neuronal cells. Hypothermia has a protective effect
against ischaemia. Therapeutic hypothermia, though initially applied to the heart in the
setting of cardiac bypass surgery, recently has received considerable attention because
of its profound neuroprotective effects. Ironically, limitations of reperfusion therapy for
acute myocardial infarction have recently re-kindled interest in hypothermic myocardial
protection.
During myocardial ischaemia, dysregulation of cellular metabolism in addition to
reperfusion injury contributes to myocardial injury and cell death that extends in a
wave-front pattern from the epicentre of necrosis. The precise mechanisms by which
hypothermia provides protection during myocardial ischaemia-reperfusion are not well
defined. However, the beneficial effect of myocardial cooling appears to be independent
of hypothermia-induced bradycardia, as the effect persists when heart rate is
maintained with pacing.37,38 One possible explanation is that hypothermia reduces
metabolic demand in the myocardium at risk as a result of down-regulation of cardiac
myocyte metabolism—which thus limits the area of myocardium at risk. In both dogs
and isolated perfused rapid hearts, hypothermia has been shown to preserve
myocardial ATP stores during ischaemia.39,40 Thus, maintenance of cell membrane
integrity might be preserved. The data from these studies from the scientific and clinical
rationale for the application of systemic hypothermia in reperfusion strategies for acute
myocardial infarction (AMI).
The safety and tolerability of hypothermia as adjunctive therapy to limit infarct size
has been observed in pre-clinical animal studies (Figure 1) and in phase I clinical studies
involving human volunteers with AMI. Catheter-based induction of systemic
hypothermia in animal models of myocardial infarction (MI) has demonstrated
cardioprotective effects, including decreased infarct size, preserved microvascular
flow and maintained cardiac output.41,42
Recently, a pilot study examining the feasibility of endovascular cooling during
primary percutaneous cardiac intervention (PCI) demonstrated trends in reduced
infarct volume with no increase in haemodynamic instability or cardiac dysrhythmias.43
Among 42 AMI patients presenting within 6 hours of symptom onset, randomisation to
endovascular cooling (Radiant Medical Inc., Redwood City, CA) as an adjunct to
primary PCI resulted in a median infarct size, which was non-significantly smaller
compared with the control group (2 versus 8% of the left ventricle, P ¼ 0:80Þ: No
significant adverse events (bradyarrhythmias, in particular) were observed in the
cooling group, whose mean target core temperature, assessed by nasoesophageal
50
Normothermia
Hypothermia
40
%
p<0.0001
30
20
10
0
AAR (%LV)
Infarct size (%AAR)
Figure 1. Mean infarct size in pigs after a 60-minute occlusion of the left anterior descending coronary artery.
Endovascular cooling was started 20 minutes after coronary occlusion and continued for 15 minutes after
reperfusion. AAR ¼ Are at risk.
Therapeutic hypothermia 559
monitoring, was 33.2 8C. Cooling was maintained for 3 hours after reperfusion.
Re-warming to 36.5 8C was then performed over 1 – 2 hours. Nine patients
experienced mild episodic shivering, requiring an increase in pharmacotherapy (in 4
patients) and a small increase in target core temperature (in 5 patients). Importantly,
door-to-balloon times were similar in the cooling group, re-affirming the practical
application of this therapy in contemporary practice. Finally, if proven effective, trial
design employing this therapy have been proposed for other AMI treatment algorithms
(e.g. fibrinolytic therapy, facilitated PCI). Based on these data, a multicentre randomized
clinical trial was initiated in September, 2001, and will enroll approximately 400 patients
in North America, Australia and Europe. The study is designed to detect a 30%
difference in infarct size with treatment at 30 days.
TEMPERATURE MONITORING
Because brain temperature is not easily obtained in humans, various other
measurement sites have been studied. Because the jugular vein is anatomically close
to the brain and transports venous return from the brain, blood temperature at this site
was thought to reflect brain temperature. However, simultaneous measurements of
brain, jugular venous blood and body core temperatures in patients with severe head
injuries showed that brain temperature is on average 1.1 8C higher than both body core
temperature and jugular venous blood, which correlate well.44 This difference between
brain and body core temperature increases with low cerebral perfusion pressures and
decreases under a high dose of barbiturates.
Understanding intracerebral temperature gradients, especially intraoperatively,
requires a knowledge of the relationship between surface temperatures and
temperatures taken at standard sites. Owing to cooling of the exposed cerebral
cortex, the brain temperature during surgery is approximately half a degree lower than
the oesophageal, tympanic and bladder temperatures. However, core temperature
measurements tend to underestimate brain temperature in patients presenting with
traumatic brain injury.45
TEMPERATURE MANAGEMENT
Core body temperature, which is normally regulated to within a few tenths of a degree
centigrade, varies as much as 6 8C during anaesthesia. Hypothermia is the typical
disturbance during anaesthesia and results from anaesthetic-induced inhibition of
thermoregulatory control combined with cold exposure.
All anaesthetics so far tested markedly decrease the shivering threshold as well as
the gain and maximum intensity of shivering. Reduction in the cold responses is
especially important if hypothermia is induced for therapeutic reasons. Induction of
therapeutic hypothermia in awake patients is complicated by the need to overcome
arterio-venous shunt vasoconstriction and shivering, and to do so without provoking
extreme thermal discomfort. However, most anaesthetics, especially when used in
doses sufficient to markedly impair thermoregulatory defences, have side-effects such
as sedation and respiratory depression. The search thus continues for a drug, or drug
combination, that sufficiently impairs thermoregulatory defences without simultaneously producing unacceptable toxicity. While meperidine and dexmedetomidine
560 B. Kabon, A. Bacher and C. K. Spiss
Table 2. Potential Confounding Factors and Major Results.
Control
Large-dose
buspirone
Large-dose
meperidine
Small-dose
combination
Ambient Temperature (8C)
Relative Humidity (%)
Mean Arterial Blood Pressure (mmHg)
Heart Rate (b.p.m.)
Respiratory Rate (breaths/minute)
Average End-Tidal PCO2 (mmHg)
[Meperidine] (ng/ml)
[Buspirone] (mg/ml)
19.6 ^ 0.7
45 ^ 6
93.1 ^ 11.1
70.0 ^ 6.3
13.8 ^ 3.3
43.5 ^ 3.5c
–
–
19.8 ^ 0.7
38 ^ 8
97.6 ^ 13.9
60 ^ 10.4
15.8 ^ 1.9c
39 ^ 1.1
–
1.9 ^ 1.2
19.9 ^ 0.6
39 ^ 2
91.9 ^ 14.6
71.3 ^ 6.3
11.1 ^ 2.2b
50.8 ^ 4
605 ^ 310
–
20.1 ^ 1.0
39 ^ 4
91 ^ 13.9
72.9 ^ 9
13.3 ^ 2.3
46.1 ^ 6.9b
302 ^ 149
0.7 ^ 0.4
Bispectral Index (BIS)
OAA/S at Shivering
Lactated Ringer’s Solution (L)
Mean Skin Temperature at Shivering (8C)
Core Temperature at Shivering (8C)
98 ^ 0
20 ^ 0
1.3 ^ 0.3
32 ^ 0.1
35.7 ^ 0.2
98 ^ 0
20 ^ 0
1.9 ^ 0.94
31.9 ^ 0.1
35.0 ^ 0.8
97 ^ 1
19 ^ 1
4.7 ^ 1
31.5 ^ 0.6
33.4 ^ 0.3
98 ^ 0
20 ^ 0
4.7 ^ 0.9
31.7 ^ 0.3
33.4 ^ 0.7
"OAA/S" is Observer’s Assessment of Analgesia and Sedation. Values above the center line were first
averaged over the infusion period, and then averaged among the volunteers; values below the line are at
designated times. Data are presented as means ^ SDs.a Statistically differences from High-Dose
Buspirone;c significant differences from High-Dose Meperidine;d significant differences from the low-dose
combination.
in low doses each reduced the shivering threshold, their interaction was additive and
resulted in a decrease in the shivering threshold of approximately 2 8C to a core
temperature of approximately 34.5 8C.20 There was trivial sedation with either drug
alone, or in combination. An even more pronounced decrease in the shivering
threshold of approximately 3 8C can be reached by the combination of low-dose
meperidine and buisperone.21 (Table 2).
Under the condition of blocked thermoregulatory responses, active cooling can be
used for rapid reductions of core temperature. In animals, methods used to reduce
core temperature include packing in ice, fanning, partial immersion in cold water,
nasopharyngeal cooling, and cardiopulmonary bypass. These methods are theoretically
applicable in humans, although packing in ice will build up extreme temperature
gradients likely to irritate the skin, and immersion is difficult under clinical conditions.
Cooling a patient to mild or moderate hypothermia is usually performed by
conductive (liquid-circulating water mattress), convective (forced air cooling via fullbody blankets or air beds) surface cooling, cold infusions, gastric lavage, by simply
leaving the anaesthetized patient uncovered in a cool environment (e.g. operating
room, ICU), or through a combination of these methods. A new approach to
controlling temperature in critically ill patients uses intravascular cooling devices.
Surface cooling techniques
Hypothermia during anaesthesia and sedation develops due to heat loss via the skin
surface. Thus, skin surface warming or cooling has become the most common thermal
treatment.
Therapeutic hypothermia 561
With the combination of convective cooling (Polar Air, Augustine Medical Inc., Eden
Prairie, MN, USA) and cold infusions, a target temperature of 32 8C was reached in
210 ^ 53 minutes in patients undergoing open-skull brain surgery.46 Patients were
anaesthetized with a continuous infusion of propofol and fentanyl. Sequential
temperature measurements showed roughly linear decreases in temperature at a
rate of approximately 1 8C/hour.
Baker et al obtained similar results using conductive cooling with cold water
blankets.47 In this study in patients undergoing craniotomy with isoflurane/fentanyl/
N2O anaesthesia, a temperature of 34.3 ^ 0.4 8C was reached at a rate of
1 ^ 0.4 8C. A study comparing convective cooling using a forced air generator and
a convective blanket with conductive cooling using a full-length liquid-circulating
water mattress found no significant differences in the cooling rates.48
In the National Acute Brain Injury Study—Hypothermia (NABIS-H), cooling was
performed by application of ice, gastric lavage with ice fluids, and the use of room
temperature air in the ventilator circuit.28 To maintain the target temperature of 33 8C
in the hypothermic group, temperature control pads were additionally applied in the
intensive care bed (kinetic treatment table). However, cooling to the target
temperature of only 33 8C (in the already mildly hypothermic patients) took more
than 4 hours, even with the combination of these cooling techniques.29
Krieger et al investigated induced hypothermia in combination with thrombolysis in
acute ischaemic stroke patients.49 For the induction of moderate hypothermia the
patient was positioned on a cooling blanket which was set at automatic mode at 4 8C.
Additionally, ice water and whole-body alcohol rubs were performed concurrently. It
was aimed to maintain a target temperature of 32 8C for , 48 hours, and this was
achieved within 3.5 ^ 1.5 hours. The authors concluded that refinements of the
cooling process were necessary. Further data are certainly needed to evaluate the
effectiveness of convective versus conductive cooling during longer time periods, for
example, at the ICU, or with lower target temperatures.
In a European multicentre trial on mild hypothermia after cardiac arrest, head
cooling with a blanket in combination with systemic external cooling by a specially
designed mattress (TheraKair, KCI International, San Antonio, TX, USA) was used.50 In
this clinical setting (cardiopulmonary resuscitation outside the hospital, transport to
the hospital, and further cooling with the above described technique), a pulmonary
artery temperature of 33 ^ 1 8C was reached within 62 ^ 33 minutes after cardiac
arrest.
Efforts were made to improve the cooling rates of surface cooling using vasodilators,
such as prostaglandin E1.51 However, no benefit was found from intravenous
prostaglandin E1 administration on the speed of cooling during deliberate mild
hypothermia in neurosurgical patients.
Recently, a new thermoregulatory device (Allon; MTRE Advanced Technologies Ltd,
Or-Akiva Industrial Park, Israel) has been developed. The Allon technology consists of a
microprocessor-controlled heating/cooling unit, body temperature sensors and a
garment that wraps around the patient. Water is circulated by a pump and is controlled
and maintained at a set point (ranging from 18 to 39.5 8C) in a closed loop between the
garment and the unit. So far the Allon system has been shown to provide excellent
perioperative temperature control.52 However, currently no data are available in regard
to therapeutic hypothermia and hyperthermia treatment.
Rapid cooling is critically important when treating acute neurological injuries, such as
stroke, circulatory arrest or cerebral trauma. Convective or conductive surface cooling
has been shown to be effective in patients without fever. However, these techniques are
562 B. Kabon, A. Bacher and C. K. Spiss
less than effective when applied to fever control, and the time to reach the target
temperature in all of the cited studies was relatively long.
Cold intravenous fluid
Given that convective and surface cooling techniques are often insufficient to induce
sufficiently rapid cooling, many clinicians have sought other methods of instigating
therapeutic hypothermia. Among the techniques tested is the infusion of cold
intravenous fluids. In a volunteer study, 40 ml/kg of saline (20 or 4 8C) was introduced
during general anaesthesia over 30 minutes.53 Core temperature immediately
decreased by 1.4 ^ 0.2 and 2.5 ^ 0.4 8C, respectively. Although these results appear
promising, the clinical value of this technique is limited by several factors. First,
temperature decrease is actually not very pronounced. Second, the amount of fluid
necessary to achieve cooling is very high and may be harmful in some patients. Third,
efficacy in critically ill patients with fever would likely be even less than that observed in
the healthy volunteers.
Intravascular cooling techniques
A major problem of conventional cooling techniques is their lack of efficacy in patients
with fever. Fever occurs in 47– 83% of patients at neurosurgical intensive care units.54,55
In recent years, a large body of evidence has accumulated showing that such a
temperature elevation clearly worsens the degree of neuronal injury in animals and
humans.2,56
In a study of 220 critically ill patients, fever control was performed either with
acetaminophen or a combination of acetaminophen and convective cooling.57 Even with
the combination therapy, maintenance of normothermia was achieved in only 44% of
patients with fever. The authors concluded that more effective interventions are needed to
maintain normothermia in patients at risk for fever-related brain damage.
In a prospective pilot study, Schmutzhard et al investigated the safety and
efficacy of a novel intravascular cooling device (Cool Gard system, Cool Line
catheter, ALSIUS, Irvine, CA, USA) to control body temperature in neurological
intensive care patients.58 The intravascular cooling device, the Cool Line catheter,
connects to an external cooling system, the Cool Gard system, similar to those
used for cooling blankets. The system circulates temperature-controlled sterile
saline through two small balloons mounted on the distal end of the catheter. The
patient’s blood is gently cooled as it passes over the balloons. As in cooling blanket
equipment, the system responds to temperature probes measuring the patient’s
rising temperature and adjusts the temperature of the sterile saline flowing within
the catheter. The authors quantified the catheter’s ability to prevent fever by
calculating the fever burden, i.e. the fever– time product, concluding that the device
is highly efficacious in prophylactically controlling the body temperature in this
patient population.
A similar technique was used for cooling patients with acute myocardial infarction
during primary angioplasty.43 Patients were cooled to a target temperature of 33 8C
using the SetPoint Endovascular Temperature Management System (Radiant Medical,
Redwood City, CA, USA). This device consists of a helically wound heat exchanger
inserted into the inferior vena cava and a microprocessor-controlled temperature
controller. Cooling was performed successfully in 95% of the patients, with a
mean target temperature of 33.2 ^ 0.6 8C maintained for approximately 3 hours.
Therapeutic hypothermia 563
The patients were re-warmed for 65 ^ 26 minutes. Shivering was treated with
convective heating and pharmacologically. Nevertheless, aside from successfully cooling
of the patients the effect of cooling on limiting infarct size was not significant in this
preliminary investigation.
Studies using convective and/or conductive cooling techniques to cool subjects
presenting with traumatic brain injury, stroke and cardiac arrest found that the time
required to cool subjects to the desired temperature was often 6– 8 hours. This may
explain some of the variability in results between studies. With the help of this new
technique, cooling could be accomplished reliably within the critical therapeutic
window of opportunity.
SIDE-EFFECTS OF HYPOTHERMIA
Mild to moderate hypothermia might be a potential experimental and clinical
protectant in cerebral and myocardial ischaemia and neurotrauma. However, serious
side-effects may occur, and careful definition of the criteria to induce and perform
therapeutic hypothermia is required. Since the mid 1990s, prospective, randomised
trials have confirmed numerous hypothermia-induced complications that may adversely
alter patient outcome. As anaesthetic drugs impair thermoregulation, hypothermia is
often observed in patients during general, as well as epidural, anaesthesia and sedation.
Major outcome studies have shown that hypothermia adversely affects coagulation59,
surgical wound infections60 and morbid cardiac events.61 Hypothermia also alters drug
metabolism62, and can increase time to discharge63, increase patient discomfort, and
induce shivering.
Therapeutic hypothermia induces similar physiological and pathophysiological
changes throughout the body, potentially leading to serious side-effects:
† Hypovolaemia, fluid imbalance and electrolyte disorders (magnesium depletion)
caused by hypothermia-induced diuresis as well as hypothermia per se.30 Magnesium
appears to play a key role in neurological injury, caused by potential prevention of
reperfusion injury.64 Furthermore, loss of magnesium is associated with constriction
of cerebral and coronary arteries.65 In clinical studies, hypomagnesaemia is
associated with adverse outcome.66
† Decreased insulin sensitivity and insulin secretion might lead to hypothermiainduced hyperglycaemia. In surgical ICU patients hyperglycaemia is associated with
higher morbidity and mortality in comparison to patients in whom glucose levels
were well controlled.67
† Hypothermia is initially associated with sinus tachycardia, after which bradycardia
develops. Mild hypothermia decreases cardiac output by 25% and leads to an
increase in vascular resistance.
† Hypothermia is associated with increased bleeding time. It effects platelet count,
platelet function, the kinetics of clotting enzymes and steps in the coagulation
cascade.68,69 However, no clinical trial in patients with intracranial haemorrhage,
stroke or post-anoxic coma has reported increases intracranial bleeding associated
with hypothermia.
† There is evidence that hypothermia may impair immune function by suppression of
inflammatory responses. Indeed, some clinical studies reported higher risk of
pneumonia and wound infections in patients kept hypothermic over longer periods
of time.33,70,71
564 B. Kabon, A. Bacher and C. K. Spiss
† In awake patients, hypothermia can cause shivering, increasing oxygen consumption
and discomfort.
† Metabolism and clearance of drugs may be altered.
† In many cases hypothermic patients may require intubation, mechanical ventilation,
sedation and pharmacological paralysis. Thus, neurological monitoring and
assessment may be limited.
These consequences may have a much greater negative impact in patients with
severe head injury compared to other categories of patients.
HYPERTHERMIA
Fever is common in critically ill neurosurgical patients, especially those with a prolonged
length of stay in the ICU or those with a cranial disease.55 Throughout the past decade
it has been clearly shown that temperature elevation and fever worsens the degree of
neuronal injury in both animals and humans. Compared with normothermic rats,
intraischaemic hyperthermia significantly increased the extent and severity of brain
damage at 1 day after the ischaemic insult.72 Similarly, asphyxiated rats with
hyperthermia induced at 24 hours had worse histopathology damage scores than
rats subjected to asphyxia without induced hyperthermia. This suggests that avoidance
of hyperthermia induced by active warming at critical time periods after cardiac arrest
might be important.73
In ischaemic stroke the association between hyperthermia and early neurological
deterioration is known to increase morbidity and mortality.32 Fever in patients with
subarachnoid haemorrhage is associated with vasospasm and poor outcome
independent of the severity of the haemorrhage.74 The deleterious effects of
hyperthermia have also been shown in patients with intracranial haemorrhage.75
An observational cohort study performed in 117 patients at a paediatric intensive
care unit found that early hyperthermia after traumatic brain injury is independently
associated with lower Glasgow Coma Scale scores and prolonged ICU stays.76 Postoperative hyperthermia was also related to a worsened cognitive function in patients
undergoing coronary artery bypass graft surgery.77
In patients who experienced a witnessed cardiac arrest of presumed cardiac cause,
the temperature was recorded on admission to the emergency department and after 2,
4, 6, 12, 18, 24, 36 and 48 hours.78 The lowest temperature within 4 hours and the
highest temperature during the first 48 hours after restoration of spontaneous
circulation were recorded and correlated to the best-achieved cerebral performance
categories score within 6 months. The temperature on admission showed no
statistically significant difference ðP ¼ 0:39Þ: Patients with a favourable neurological
recovery showed a higher lowest temperature within 4 hours (35.8 8C (35.0 – 36.1 8C)
versus 35.2 8C (34.5 –35.7 8C); P ¼ 0:002Þ and a lower highest temperature during the
first 48 hours after restoration of spontaneous circulation (37.7 8C (36.9 – 38.6 8C)
versus 38.3 8C (37.8– 38.9 8C); P , 0:001Þ (data are given as the median (interquartile
range)). For each degree Centigrade higher than 37 8C, the risk of an unfavourable
neurological recovery increased, with an odds ratio of 2.26 (95% confidence interval,
1.24 – 4.12).78
Therapeutic hypothermia 565
CONCLUSION
Therapeutic hypothermia has great potential in treating various neurological injuries.
However, at this point in time the beneficial effect of therapeutic hypothermia has
clearly been shown in patients after circulatory arrest only. There is evidence that
therapeutic hypothermia might be beneficial in patients after brain trauma, stroke and
myocardial infarction. Prospective, randomized trials are needed before a final
conclusion can be drawn. Additionally, the optimal target core temperature, initiation
of cooling therapy, during of cooling and re-warming strategies still need to be
evaluated.
Practice points
† initiate therapeutic hypothermia as soon as possible following injury
† a target core temperature between 32 and 34 8C should be achieved
† return to normothermia only when ICP has been below 20 mmHg for at least
24 hours
† online temperature monitoring is crucial
† be prepared to recognize and treat possible side-effects of hypothermia
† treatment of hyperthermia and fever is beneficial
Research agenda
† prospective, randomized trials to better quantify therapeutic hypothermia
benefits in patients with brain trauma, stroke and myocardial infection
† trials to establish standard of care
† trials to evaluate optimal target core temperature for therapeutic
† trials to evaluate duration of therapeutic hypothermia
† trials to evalute re-warming strategies
† further studies to determine the best use of promising technology.
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