Download Aspects of thermoregulation physiology

Aspects of thermoregulation physiology
Sara Pitonia, Helen L. Sinclairb and Peter J.D. Andrewsb
a
Department of Anesthesiology and Intensive Care
Unit, Policlinico Universitario ‘Agostino Gemelli’,
Università Cattolica del Sacro Cuore of Rome, Rome,
Italy and bDepartment of Anaesthesia, Critical Care
and Pain Management, University of Edinburgh,
Edinburgh, Scotland, UK
Correspondence to Sara Pitoni, MD, Department of
Anesthesiology and Intensive Care Unit, Policlinico
Universitario’Agostino Gemelli’, Università cattolica del
Sacro Cuore, Largo Agostino Gemelli 8, 00168 Rome,
Italy
Tel: +39 06 30154507; fax: +39 06 3013450;
e-mail: [email protected]
Current Opinion in Critical Care 2011,
17:115–121
Purpose of review
The review covers the main aspects of thermoregulation physiology and highlights the
implications for therapeutic hypothermia trials. Prevention of shivering and other
hypothermia side-effects is of key importance because controlling thermoregulatory
responses may be essential for demonstrating neuro-protective properties of
hypothermia in several pathologic conditions in which its role is still uncertain, such as in
traumatic brain injury and stroke.
Recent findings
Several recommendations and clinical reviews have been produced in the past 2 years
about the application and feasibility of therapeutic hypothermia. Many drugs have been
tested in healthy volunteers and anaesthetized patients to abolish shivering but the best
protocol for managing side-effects has not yet been defined. A possible strategy might
be to simultaneously apply physical methods, such as skin warming, and combination
drug therapy. Different drug protocols can be applied, depending on the nature of the
care setting.
Summary
During moderate hypothermia treatment, conducted in an intensive care environment,
shivering can be treated with sedatives, opioids (meperidine in particular), and a2agonists, combined with active skin counter-warming. However, new randomized
controlled clinical trials in intensive care patients are required to improve our knowledge
regarding this treatment.
Keywords
brain protection, hypothermia, shivering, thermoregulation
Curr Opin Crit Care 17:115–121
ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
1070-5295
Introduction
Physiology of thermoregulation
Many researchers have investigated the potential for
therapeutic hypothermia to improve outcome after acute
brain injury [1–4]. The larger surface area-to-body
weight ratio in humans compared with laboratory animals
and the unsuitability of general anaesthetics for sedation
in critical care make management of clinical therapeutic
hypothermia more difficult. Central to these issues are
host temperature defence mechanisms and the clinician’s
ability to overcome them.
In humans CBT is maintained in a narrow range known as
the interthreshold range. Under normal physiological
conditions temperature can only increase or decrease
by a few tenths of a degree Celsius without reaching
a threshold triggering autonomic thermoregulatory
responses (sweating or shivering). In humans, the entire
sweating-to-shivering range spans only approximately
0.68C [7,8].
Prospective, randomized trials have shown, in a variety of
patient populations, that even mild hypothermia causes
numerous adverse effects. Shivering is one of the most
common hypothermia-induced complications resulting in
an increase in oxygen consumption, raised metabolic rate,
increased work of breathing, morbid cardiac events,
general stress-like response and patient discomfort
[5,6]. Shivering develops when core body temperature
(CBT) reaches the shivering threshold temperature.
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Thermoregulatory responses to cold in humans are not
associated with significant sex differences in total metabolic heat production normalized for body mass or surface
area [9]. However, the upper and lower thresholds may
vary in, for example, women and at the extremes of age.
Temperature in premenopausal women varies throughout the menstrual cycle due to the effect of the female
reproductive hormones [10]. In infants and the elderly,
central thermoregulation seems to be substantially
similar to that seen in young adults. However, infants
DOI:10.1097/MCC.0b013e3283447905
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116 Neuroscience
rely on nonshivering thermogenesis and brown adipose
tissue rather than shivering. Brown adipose tissue, which
in neonates lies mainly in the dorsal interscapular depot,
maintains CBT by uncoupling the oxidative phosphorylation process in mitochondria through the expression of
an uncoupling protein (UCP 1). Brown adipose tissue in
adults was considered vestigial but a cervical-supraclavicular depot has been recently demonstrated; its presence
possibly correlates with body metabolic activities but its
role in cold-induced thermogenesis has yet to be proved
[11,12].
Body temperature is not homogeneous and is described
as CBT, skin surface temperature (SST) and mean
skin temperature (MST). CBT is the most reliable
parameter to describe human thermal status. SST is used
to evaluate local vasoconstriction. MST is used to calculate cutaneous heat loss and to estimate central thermoregulatory control [13,14].
Thermoregulatory control is dependent on thermal
stimuli from both skin and core. Cutaneous and visceral
thermoreceptors sense absolute and relative changes in
temperature. Cutaneous thermoreception is sensed by
the transient receptor potential (TRP) family of cation
channels, widely expressed in sensory neurons. The
subtype TRPM8, activating when environmental temperature is below 278C, senses modest cooling. Other
potential cold-sensing mechanisms are other TRPs, such
as TRPA1 and TRPV1, and non-TRP channel-mediated
cold-sensing mechanisms. Body core thermoreceptors are
located in the brain, spinal cord and abdomen. Afferent
signals ascend via thermosensory neurons through pathways such as the spinothalamocortical tract and lateral
parabrachial neurons. They are integrated at various
levels: spinal cord, brain stem and hypothalamus. The
cold signals activate the lateral parabrachial nucleus
neurons, which promote excitatory inputs to drive
GABAergic interneurons to inhibit other inhibitory
output neurons in the medial preoptic subregions of
the preoptic area. This results in a disinhibition of
thermogenesis-promoting neurons in dorsomedial hypothalamus and the rostral ventromedial medulla. These
fibres activate spinal sympathetic and somatic motor
circuits to increase thermogenesis [15–17]. The anterior
hypothalamus coordinates all thermoregulatory responses
with a hierarchical organization but some of the lower
levels, like the spinal cord, can mount simple responses
such as vasoconstriction [18,19].
Efferent responses: vasoconstriction and
shivering
Thermal homeostasis is strictly controlled by both behavioural and autonomic responses. Autonomic responses
are governed by inputs sensed by core and surface
Key points
The complex thermoregulation system in humans
controls CBT and produces autonomic reactions,
such as shivering, which can negate the benefits of
hypothermia treatment.
Several studies have been conducted to control
shivering during moderate hypothermia application
(35–328C of CBT) but a standard management
protocol, whose efficacy has been proved by a
randomized and controlled trial, has not been fully
developed yet.
New RCT on ICU patients are needed to implement antishivering therapy and better understand
the pharmacokinetic changes during hypothermia.
receptors. Thermal inputs sensed by surface body receptors contribute most to thermal perception and response.
However, MST contributes only 20% to autonomic thermoregulatory responses, whereas thermal inputs sensed
by core body receptors determine approximately 80% of
autonomic responses, from deeper tissue and the central
nervous system (CNS) [8,17,20].
Thermoregulation in intensive care patients is largely
autonomic and manifests as arterio-venous shunt vasoconstriction and shivering at low CBT. Vasoconstriction
reduces heat loss by constricting peripheral thermoregulatory shunts. Thermoregulatory shunts are limited to the
peripheral digits but have a profound and prompt effect
on CBT. They can contract at the cold threshold and
divert blood flow to the trunk and head, avoiding heat
‘waste’ in the periphery. Vasoconstriction is metabolically
efficient as it initially halves fingertip heat loss and
subsequently increases the temperature gradient from
the core to peripheral tissues. This gradient ranges from
2 to 48C in hospital environments [18].
Each thermoregulatory response is characterized by a
threshold, a maximum intensity and a gain. Shivering
threshold is the CBT at which shivering occurs, usually
35.58C. Shivering maximum intensity reaches its peak
over a range of around 18C below the shivering threshold.
The gain, which is the magnitude of the shivering
response to cold stimulus, with intensity of response
increasing as CBT decreases, is not as great as it is for
vasoconstriction [6,21].
Shivering is less efficient than vasoconstriction as defence
from cold because much of the heat generated by the
peripheral muscles is released to the environment rather
than being retained in the core. Sustained shivering can
double the basal metabolic rate in young, fit people but is
considerably less effective in the elderly [22]. The metabolic impact of shivering is proportional to its intensity
and affected muscle mass. It seems reasonable to assume
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Aspects of thermoregulation physiology Pitoni et al. 117
that postanaesthetic shivering increases oxygen consumption in healthy individuals by approximately 40–120%
[23]. This is an undesirable effect particularly in patients
with neurologic, posthypoxic and traumatic brain injury.
During hypothermia treatment, shivering can generate
significant heat and can make the induction of hypothermia very difficult. However, owing to the reduction
in effectiveness of temperature defence mechanisms in
older people, reaching a target temperature with induced
hypothermia may be easier in these patients [24]. A
common measure for quantifying shivering is required
in all patients, regardless of age. The Bedside Shivering
Assessment Scale (BSAS) is a simple and reliable tool to
evaluate and treat the metabolic stress of shivering [25]
(see below).
Columbia Bedside Shivering Assessment Scale (BSAS)
(adapted from [18]):
(1) Palpate masseter, pectoralis, deltoids and quadriceps
muscles:
(a) 0: No shivering.
(b) 1: Mild shivering localized to the neck and/or
chest.
(c) 2: Shivering involving neck and/or chest and at
least two extremities.
(d) 3: Intermittent generalized shivering involving
more than two extremities.
Shivering quantification during maintenance of hypothermia is a crucial issue to establish the correct treatment. Figure 1 shows the Shivering Detection Guidelines for a large, prospective, randomized controlled trial
of titrated hypothermia in patients with raised intracranial pressure after traumatic brain injury (www.
eurotherm3235trial.eu).
Therapies to prevent shivering
There are physical and pharmacological methods to
modulate defences to hypothermia. The most relevant
ones are described below.
Physical methods
MST contributes around 20% to the control of vasoconstriction and shivering, and 50% to thermal comfort [17].
An increase in MST can provide an improvement in
patient’s comfort and a reduction in shivering intensity.
Each 18C of cutaneous warming compensates for approximately 0.28C core hypothermia [20]. Focal body zone
warming could be effective in reducing shivering
threshold. Some studies demonstrated that focal facial,
hand or feet warming suppressed shivering. However,
other studies reported that neither lower-arm nor facial
warming could substantially reduce shivering [26–28].
Generalized skin warming appears to be more effective
in reducing shivering and minimizing hypothermia sideeffects [29]. Logically, an increase in MST sufficient to
prevent shivering is more likely to be achieved with
general than focal warming. Thus, general skin-surface
warming could be a useful method to reduce shivering
during direct core cooling either via infusion of cold fluids
and endovascular heat exchangers.
Volatile and intravenous anaesthetics
Volatile anaesthetics profoundly blunt normal control
of body temperature. They widen the interthreshold
range to 4.08C [30]. Enflurane, isoflurane, sevoflurane
and desflurane reduce the thermoregulatory cold defence
threshold with a nonlinear dose–response manner, so that
impairment increases at higher doses [31,32]. They also
favour hypothermia inhibiting maximal norepinephrineinduced thermogenesis in brown adipocytes, without
affecting the systemic sensitivity to norepinephrine
[33]. Volatile agents can be used routinely only in surgical
environment to control postanaesthetic shivering.
Propofol is often administered to patients undergoing
hypothermia in intensive care because of its beneficial
effects in neuro-protection, its antiseizure properties
and its pharmacokinetic characteristics. However, some
propofol side-effects, such as hypotension and bradycardia,
can be enhanced by hypothermia treatment, with additive
effect.
Propofol has been demonstrated to widen the interthreshold range and linearly reduce the shivering threshold in
a dose-dependent manner. Propofol infusion at sedative
doses, producing a plasma concentration of 2 mg/ml, lowers the shivering threshold to approximately 358C. A
plasma concentration of 4 mg/ml, compatible with general
anaesthesia, further lowers the threshold to approximately 348C [34]. As hypothermia significantly alters
the concentration present at the drug effect site, further
studies are needed to understand the pharmacokinetic
changes during therapeutic hypothermia.
Midazolam is a benzodiazepine with sedative and anticonvulsant purposes commonly administered in intensive
care. Its metabolism changes during hypothermia, producing a five-fold increase in blood concentration due to a
100-fold decrease in systemic clearance when administered in continuous infusion. Midazolam is less effective
for shivering control than propofol although it has fewer
haemodynamic effects [35,36].
Opioids
Pure m-receptor agonists and combined m and k-agonists
are commonly used to treat cooled patients. Regimens of
alfentanil, fentanyl and morphine have been demonstrated to be less effective than meperidine, and a higher
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118 Neuroscience
Figure 1 Eurotherm3235Trial – Shivering Detection Guideline
Prior to induction of hypothermia
Opiate and propofol or midazolam infusions
Paracetamol 1g 6 hourly enteral/IV
Ensure that extremities are covered
Induction of hypothermia (cold saline +/− cooling method or device)
Observe continuously for obvious signs of shivering
Assess for signs of shivering using the Shivering Assessment Tool
every 15 minutes until target temperature achieved
Maintenance of hypothermia (cooling method or device)
Observe continuously for obvious signs of shivering
Assess for signs of shivering using the Shivering Assessment Tool
every 30 minutes during the first 2 hours and hourly thereafter
(and if there is any indication of shivering between these times)
Shivering Assessment Tool
Observe ECC and/or BIS trace continuously for artefact
Formal Assessment
Observe patient for 2 minutes during which time visually inspect and palpate jaw,
neck, chest, arms and legs.
Score shivering as follows:
0 = No shivering
1 = Mild: shivering localized to jaw, neck and/or chest only
2 = Moderate: shivering involves gross movement of arms or legs, in addition to
neck, chest and 2 extremities
3 = Severe: shivering involves gross movements of the trunk and arms and legs
If the patient scores ≥ 1 using this scale, please refer to the Prevention of Shivering
Guideline overleaf.
Badjatia et al. Stroke 2008; 39;3242-3247
incidence of re-shivering was found [37]. Alfentanil, in
particular, inhibits fever by reducing the body response to
pyrogens [38]. Meperidine’s effectiveness is probably due
to its multireceptor activity, only partly mediated by its
agonism at the k receptor, which constitutes around 10% of
its total opioid action [39]. In fact when meperidine was
compared with nalbuphine, which is an agonist/antagonist
opioid with potent affinity for K-receptors, it was found to
be more effective and quicker acting in equianalgesic
doses [40]. Meperidine a-2b adrenoreceptor activity seems
to play a much more important role than k-agonism in
decreasing the shivering threshold twice as much as the
vasoconstriction threshold [41]. Despite its remarkable
antishivering properties, meperidine alone or combined
with skin warming, in sedated intensive care patients, was
not sufficient to prevent shivering during induction of
therapeutic hypothermia [42].
a-2 Central agonists
Clonidine and dexmedetomidine are effective in the
treatment of postoperative shivering and pain control.
They generate an increase in the interthreshold range
indicative of central thermoregulatory inhibition, similar
to several anaesthetic agents [43,44]. Comparative studies have demonstrated that intraoperative administration of a-2 central agonists can be as beneficial against
shivering as meperidine [45]. a-2 central agonists, significantly affecting heart rate and blood pressure, can be
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Aspects of thermoregulation physiology Pitoni et al. 119
safely combined with other antishivering drugs such
as meperidine, buspirone and nefopam to effectively
treat shivering. The interactions are not synergistic but
additive and the gain and maximum shivering intensity
remain unchanged.
Muscle relaxants
These agents are very effective at stopping shivering.
However, they do not suppress the central neurological
triggers, but directly antagonize the neuro-muscular
receptors. The use of paralysing agents can mask insufficient sedation and seizure activity in patients with
traumatic or postanoxic brain injury and, if prolonged,
may increase the risk of developing critical illness polyneuro-myopathy. Muscle relaxants have a possible role
as a nonrecurring ‘last resort’ treatment to suppress
shivering in haemodynamically unstable patients with
hypotension
Other agents
Nefopam, ketanserin and ondansetron are used respectively as analgesic, antihypertensive and antiemetic
drugs. They all have antiserotonin activity that is thought
to support the inhibiting effect of serotonin on the
anterior hypothalamus.
Nefopam is a nonsedative benzoxazocine analgesic drug
inhibiting the re-uptake of monoamines. It has been
shown to slightly reduce the shivering threshold without
impairing other thermoregulation responses such as vasoconstriction or sweating. Used in conjunction with alfentanil, it seems to reduce the shivering threshold more
than with clonidine [46].
Ketanserin and ondansetron both slightly reduce postoperative, short-term, shivering [47–49]. However, it is
likely that neither of these drugs is effective enough
to blunt thermoregulation responses in therapeutic
hypothermia.
Magnesium, administrated as an adjunctive antishivering
therapy, has been shown to reduce the shivering intensity, resulting in muscle relaxation without further sedation [50]. In fact, low serum magnesium is associated with
more severe shivering, as assessed by the BSAS. Magnesium is also reported to increase the cooling rate and
comfort in volunteers treated with meperidine. During
hypothermia treatment serum magnesium concentrations
should be maintained in the high-normal range, particularly in patients with neurologic injuries, but not at
supranormal levels [25,51,52].
Drug combinations
There is no single ‘ideal’ drug available to suppress
shivering, particularly when due to induced hypothermia.
A combination of drugs can be used to minimize cooling
side-effects and reduce drug toxicity. As mentioned
above, some studies have demonstrated that meperidine
can be safely combined with a2-agonists, buspirone and
nefopam to reduce shivering. The combination of meperidine and dexmedetomidine has shown an additive antishivering effect of the drugs, leading to a reduction in
shivering threshold to 34.78C [53]. Meperidine and buspirone co-administration has shown a synergistic interaction leading to a greater than expected reduction of
shivering threshold [54].
Conclusion
The optimal thermoregulatory approach to minimize
shivering during hypothermia combines surface warming
during core cooling, together with drugs acting synergistically or additively. Sedation with propofol and
m-agonists can be of benefit in reducing shivering in
an intensive care environment, whereas meperidine
and clonidine can also be administrated in a nonintensive
care environment. Of key importance is that electrolytes
are maintained within normal range, with particular
attention being paid to magnesium levels.
Many of the above principles of therapy, combining
pharmacological and physical methods with standardized
shivering detection assessment, are incorporated in the
Management Guidelines for the Eurotherm Trial (see
Fig. 2).
During the past few years, significant variability in the
sedation and analgesia management of hypothermia
has been observed. Studies have been conducted on
many drugs using different designs, settings (surgical,
not surgical), sample sizes, patients (volunteers, surgical
patients, intensive care patients) and hypothermia
treatment (depth, duration, induction and speed of
re-warming). Considerable effort has been made to
implement antishivering therapy. Some systematic
reviews and recommendations have been conducted to
highlight the most frequently used drugs and to outline
their specific role in blunting hypothermia side-effects
[55,56].
Further studies are, however, needed to test pharmacological protocols in patients undergoing therapeutic
hypothermia. Future research should be randomized
controlled trials including a sufficient number of intensive care patients, under standardized hypothermia
conditions.
Key elements for the successful use of therapeutic cooling, especially for prolonged treatments, as seems to be
the case for stroke and traumatic brain injury, are likely to
be awareness and proper management of the physiological consequences and side-effects of treatment.
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120 Neuroscience
Figure 2 Eurotherm3235Trial – Detection and Management of Shivering Guideline – ISRCTN 34 555 414
Is shivering detected?
Yes
Continue monitoring for
detection of shivering
No
Is seizure activity suspected/confirmed?
No
Administer anticonvulsant
therapy
Yes
Is the patient deeply sedated* and/or BIS 40-60?
No
Yes
Increase sedation** to achieve
deeply sedated state
Active skin
counterwarming
using forced air
convection blanket
at 40-43°C (if available)
Is shivering detected?
Yes
No
Continue monitoring for
detection of shivering
Add Midazolam (if not being given)
Add Pethidine (if opiate not being given)
Add Clonidine infusion Only if HR > 45 bpm
Is shivering detected?
Yes
No
Continue monitoring for
detection of shivering
Consider muscle relaxant
* Definition of ‘deeply sedated’ – no response to voice, but movement or eye opening to
physical stimulation
** Increase in Propofol dose every 10 minutes until deeply sedated state is achieved and/or BIS
40–60
4
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
of special interest
of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (p. 206).
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