Nephrol Dial Transplant (2005) 20: 1784–1789
doi:10.1093/ndt/gfh901
Advance Access publication 5 July 2005
Why thermosensing? A primer on thermoregulation
Jutta Passlick-Deetjen1 and Eva Bedenbender-Stoll2
1
Fresenius Medical Care, Bad Homburg v. d. H., Heinrich-Heine University, Düsseldorf, Germany and
Ginsterweg 8, 61169 Friedberg, Germany
2
Keywords: dialysate temperature; dialysis-induced
hypotension; haemodialysis; haemodialyis patient,
thermoregulation; thermosensing
Introduction
Symptomatic hypotension is a frequent complication
during haemodialysis treatment sessions. One of the
reasons is rapid blood volume reduction with inadequate vasoconstriction. Furthermore, heat accumulation during dialysis occurs and leads to decreased
peripheral resistance and thus decreased venous return.
As a consequence, cooler than the usual dialysate
temperatures were used and showed an advantage for
cardiovascular stability during haemodialysis [1–12].
This practice has not been applied in clinical routine
up to now, as patients dependent on their actual
temperature suffered from shivering. If future practice
would take the optimal individualized dialysate temperature of patients into account, the quality of dialysis
treatment could be further improved. The question,
however, is which is the optimal dialysate temperature,
and how can it be achieved? In order to answer this
question in more detail some principles of thermoregulation will be discussed.
Principles of thermoregulation
Humans are homeothermic organisms and body temperature regulation is tight as this is essential for cell
functioning [13,14].
General principles of heat gain and heat loss
of the body
The body constantly produces heat (energy) and
exchanges it with the environment. Body temperature
Correspondence and offprint requests to: Jutta Passlick-Deetjen,
MD, PhD, Fresenius Medical Care, 61346 Bad Homburg v. d. H.,
Germany. Email: [email protected]
is kept constant if energy gain equals energy loss
[15,16]. If energy gain does not equal energy loss the
extra heat is ‘stored’, or lost from the body [14].
There are three principal components of human
energy (heat) generation: basal metabolic heat
production, thermogenesis via food and physical
activity [17]. Further heat is produced through metabolism modulated by hormones (e.g. catecholamines and
thyroxin) [14], emotions and medication [17]. The basal
metabolic rate is the energy produced by a resting
individual in a thermoneutral environment (20–27 C)
in a supine position at complete rest after sleep, 12 h
after the last meal [15,17]. It is the energy amount
needed for basic functions such as respiration and
cardiac function to provide body cells with oxygen
and nutrients [16].
In humans the main heat exchange with the
environment takes place by convection, evaporation
and radiation via the skin. Sweating for thermoregulation sets in only when the ambient temperature exceeds
30 C [14].
Aschoff [reviewed in 13] was the first to suggest that
one should differentiate between ‘body core temperature’, which is maintained around 37 C and ‘body shell
temperature’, which depends largely on the environmental temperature [13]. In a cold environment the
shell is thick and skin temperature much lower than
in a warm environment, where the shell may be <1 cm.
Besides the air temperature, air movement and thermal
radiation, sweat secretion, skin blood flow and the
temperature of the underlying tissue also influence
body shell or skin temperature [14].
In order to regulate body core and shell temperature
the human brain coordinates a range of behavioural
and autonomic control mechanisms [18]. Body core
and shell temperature changes are sensed by either
cutaneous or deep body thermoreceptors [14]. Bare
nerve endings just underneath the skin are very temperature sensitive. They are classified as either warm
or cold receptors [14]. Cold receptors react in a range
of 5 to 43 C, warm receptors only above 30 C, their
static impulse frequency rises with temperature, reaches
a maximum and falls again at high temperatures.
There is some overlap of the static discharge of warm
and cold receptor populations in a range from about
Nephrol Dial Transplant (2005) 20: Editorial Comments
30 to 43 C [19]. [The data for cold receptors static
discharge frequency were obtained from animal experiments, data for warm receptors static discharge
frequency were obtained both in humans and experimental animals.] A dynamic response of nerves is given
if temperature changes rapidly. On sudden heating
of the skin, warm receptors respond with a transient
overshoot in frequency. On the other hand the activity
of cold receptors is suppressed. Sudden cooling causes
reverse effects [14].
Body core thermoreceptors are concentrated in
the hypothalamus but they are also located at
other core sites, including the midbrain, medulla,
spinal cord, cortex and deep abdominal structures
[14,15,20].
Skin and body core temperature receptors transmit
their information through afferent nerves to the brainstem, especially to the pre-optic/anterior hypothalamus
[14]. Neurons of the pre-optic/anterior hypothalamus
have a key function in coordinating many (but not all)
effector mechanisms by efferent connections [14,18].
In a simplified model the area of the pre-optic/anterior
hypothalamus can be related to a thermostat, which
initiates thermoregulatory responses when the temperature sensed is different from a specific thermoregulatory
set point [14,21].
The reflex control of e.g. sweating and skin blood
flow depends on the integrated body core and skin
temperature. Each of these responses has a core temperature threshold, which depends on mean skin
temperature. Any change of core temperature elicits
a 9 thermoregulatory response compared to the
same change in skin temperature [14]. For example,
if body core temperature during dialysis increases
from 36.5 to 37.0 C, which frequently happens, this
has a 9 greater effect on skin blood flow compared
to an increase in mean skin temperature of 0.5 C.
Other autonomic changes, like metabolic heat production by muscle activity and shivering, evaporation
of water by sweating and behavioural changes, such
as adjusting environmental temperature or clothing,
are all part of temperature regulation [22].
Control of skin blood flow
Most heat exchange of the body with the environment
occurs via the skin [23]. In a person who is not sweating,
the body controls convective and radiative heat loss
by varying skin blood flow. Lowering skin blood
flow results in an adaptation of skin temperature
to ambient temperature, whereas an increase in skin
blood flow brings skin temperature nearer to core
temperature [14].
Neural reflex control of skin blood flow is mediated
through two populations of sympathetic nerves: the
known adrenergic vasoconstrictor system and a less
well understood sympathetic vasodilator system,
which is responsible for 80–90% of the substantial
cutaneous vasodilatation that occurs with whole body
heat stress [21].
1785
In most circumstances it is sufficient to decrease and
increase sympathetic vasoconstrictor nerve activity in
order to regulate body temperature within narrow
limits [24]. During heat stress, however, this tonic
sympathetic vasoconstriction is released and cutaneous
active vasodilatation is initiated, causing a rise in skin
blood flow, convection of heat from internal organs
and striated muscles to the body surface and an increase
in skin temperature [25].
The neural mechanism of cutaneous active vasodilatation is not completely understood. Apparently it
is mediated by cholinergic nerves; the transmitter,
however, is not only acetylcholine, but co-transmitters,
such as vasoactive intestinal polypeptide, are also
released to elicit a response [23].
Under thermoneutral conditions and at rest total
skin blood flow is 200–500 ml/min (5–10% of cardiac
output) [23,26]. Active vasodilatation in response to
heat stress, as in haemodialysis, can increase skin blood
flow to 8 l/min, which is about 60% of the cardiac
output [23,24].
Individual differences in temperature regulation
Thermoregulation of body core temperature is influenced by physiological (e.g. time of day, age, gender)
and pathological (e.g. fever) factors [adapted from 14].
Body core temperature undergoes diurnal variation
with a nadir in the early morning and a peak in the
evening [27].
In elderly individuals the thermoregulatory response
to cold exposure is often inadequate [28–30]. This may
partly be due to decreased heat conservation during
cold exposure caused by ineffective vasoconstriction
[29–32] or reduction of metabolically active tissue
[31]. Decreased sweat gland function and/or reduced
skin vasodilatory response may underlie the reduced
thermoregulatory response to heat stress in elderly
individuals [28].
Furthermore, thermoregulation depends on gender.
For example, after heat stress women had higher
skin temperatures and lower sweat rates than men,
but when subjects were matched for body fatness, heat
storage and tolerance time, there was no difference
between genders [33]. Some gender-related differences
may be caused by different body composition
and anthropometry [34] as well as by hormonal differences, body water regulation, exercise capacity [35] or
others [34].
The challenge of thermoregulation
in haemodialysis patients
Body temperature in healthy subjects and
in haemodialysis patients
In the late 19th century Wunderlich et al. took axillary
temperature readings from 25 000 patients and found
1786
Nephrol Dial Transplant (2005) 20: Editorial Comments
body temperatures in a range between 36.2 and 37.5 C,
with 37 C as the mean temperature. He also recognized
a circadian pattern as well as gender and age related
differences. In spite of these individual differences,
37 C has been uncritically accepted as the ‘normal
body temperature’ [36]. Investigations comparing
a thermometer that is believed to have beeen one
of Wunderlich’s thermometers with more modern
instruments showed, however, that the calibration of
Wunderlich’s instrument may have been too high by
1.4 C to 2.2 C [37]. More recent studies measured
mean body temperature in healthy subjects aged 18–40
years around 36.8 C [38] or 36.86 C in subjects aged
64 years and older [39].
In haemodialysis patients different mean body
temperatures were measured. Fine and Penner [2]
showed that 62.5% of 128 HD patients had predialysis
body temperatures below 36.5 C. In contrast, Pérgola
et al. [36] showed that the body temperature of haemodialysis patients was only slightly lower than in healthy
subjects when artefacts from circadian changes were
taken into consideration. Another study in 24 HD
patients (during 81 treatments) showed that 88% of the
patients had pre-dialytic body temperatures below
37 C but there were large inter- and intra-individual
differences in the values for pre-dialytic body temperature [M. Krämer, unpublished data], probably based on
circadian rhythm, age and gender.
Despite these investigations, dialysate temperature
is usually uniformly fixed at 37 C. Based on the
above mentioned regulatory mechanisms in response
to changes in body core temperature, there is an
obvious need to individualize dialysate temperature.
But if individualization is necessary, the precondition is exact measurement of body temperature.
Unfortunately the different methods of body temperature estimation yield substantially different results.
What is the best method for estimating
body temperature in order to adapt and
individualize dialysate temperature?
Oral, tympanic and axillary temperatures are not very
accurate. Oesophageal temperature measurement is
difficult, and uncomfortable as a thermistor has to be
inserted; furthermore irritation of nasal passages may
influence the result. Rectal temperature measurement
seems to be an accurate method for estimating core
temperature, but is not suitable as it is labour intensive
and has a prolonged response time [40].
During dialysis, however, the most practical site to
assess body temperature would be the vascular access,
which is mostly placed on the arm. In the arterial and
venous lines of the extracorporeal blood circulation,
temperature can be measured non-invasively with,
e.g., a blood temperature monitor (BTM), which is
a device integrated in standard HD machines.
After correction of arterial blood temperature for
recirculation, approximate body temperature can be
estimated [41].
Influence of the extracorporeal circuit on
body temperature
In the past a standard dialysate temperature 37 C was
used because of the assumption that this may be a
physiological temperature [42] and that a dialysate
temperature above core temperature compensates for
heat loss from the extracorporeal circuit [43]. But in
fact patients experience heat gain during such standard
haemodialysis and their body temperature increases
by up to 0.67 C [44] with the respective consequences.
The temperature rise may be caused by transfer of
heat into the body, by endogenous heat production
and by a reduced heat loss via the skin, which leads to
heat accumulation [45].
In order to avoid net uptake of heat (energy) initially,
so-called thermoneutral dialysis was applied in a study
by Maggiore et al. [46]. This procedure implies that
there is no heat transfer from the extracorporeal blood
and the dialysate (Energy ¼ 0 KJ/h) to the patient.
Nevertheless, the body core temperature increased on
average by 0.47 C. This observation led to the conclusion that external transfer of heat is not the only cause
of heat gain during dialysis.
In contrast to some results which showed that
haemodialysis patients have resting energy expenditure
(REE) comparable to that of healthy persons [47–49],
Ikizler et al. [50] studied 10 dialysis patients and found
higher than normal REE levels, which further increased
during haemodialysis. Considering that patients had
no residual renal function the higher REE is all the
more notable as a functioning kidney accounts for
8% of REE [50]. The rise in metabolic rate, i.e. REE,
during dialysis may be caused by the dialysis procedure
per se. Presumably shifts of solutes and water between
body compartments lead to energy-expending processes. Sympathetic activation as the result of blood
volume reduction may also increase muscle activity and
muscular energy production [45].
Another reason for the increase of body temperature
may be the decreased dissipation of heat via the body
surface. The physiological response to acute blood
volume reduction as a result of ultrafiltration is an
increase in sympathetic vasoconstriction of the peripheral blood vessels. Consequently, skin blood flow
declines and heat exchange between the body and the
environment decreases [45]. This mechanism was first
described by Gotch et al. [51] and confirmed by a study of
Rosales et al. [52]. In this study haemodialysis patients
were treated with the BTM (Fresenius Medical Care,
Bad Homburg, Germany) which kept body temperature
constant (isothermic dialysis) [52]. They demonstrated
that the amount of energy that must be withdrawn
in order to keep the body temperature constant was
perfectly correlated to the ultrafiltration volume.
Why thermosensing?
Accumulation of heat induced by ultrafiltration continues until a threshold body core temperature is
Nephrol Dial Transplant (2005) 20: Editorial Comments
1787
Fig. 1. Possible causes for heat accumulation during haemodialysis resulting in hypotension.
reached. At this point sympathetic vasoconstriction
ceases, and active vasodilatation begins. Peripheral
resistance decreases with a hypotensive episode as
the end result [45]. Figure 1 summarizes possible causes
of heat accumulation and triggers of symptomatic
hypotension during dialysis.
The fact that high dialysate temperatures (37 C)
cause haemodynamic instability has been confirmed
by numerous studies [1–12]. In spite of its proven
advantage for cardiovascular stability cold dialysis
has not been widely used in dialysis practise. Patients
often complain that they feel ‘cold’ when dialysate temperature is lowered but not individualized
[2,8,53].
The above-mentioned points lead to the conclusion
that there is not one single optimal dialysate temperature. There are major inter- and intra-individual
differences in body core and skin temperatures of
haemodialysis patients. The risks of hypotensive episodes varies also: such episodes are more frequent
during the warm summer months [54–56].
Dialysis treatment per se has an effect on the patients’
thermoregulatory system and cardiac stability. The
dialysate temperature should therefore be continuously
adjusted in order to maintain the body temperature
of the patient at the predialysis value throughout the
dialysis session. This goal can only be achieved by
blood temperature controlled dialysis under isothermic
conditions. Isothermic dialysis keeps body core temperature constant and removes the extra heat, which is
produced by the dialytic process and by the individually
variable metabolic and sympathetic response of the
dialysis patient. Patients with low body core temperatures and with an increased risk of suffering from
symptomatic hypotension will benefit especially from
isothermic dialysis.
Thermosensing during dialysis—optimal conditions
for cardiovascular stability
Maggiore et al. [46] compared the effects of BTMcontrolled dialysis with thermoneutral (dialysate
temperature equals patient’s temperature) and isothermic (patient’s temperature is kept constant) conditions
on 95 hypotensive-prone haemodialysis patients.
During isothermic dialysis the temperature of the
patient was kept constant by adjusting the dialysate
temperature according to the actually measured
‘arterial’ temperature at the vascular access.
During thermoneutral HD the frequency of hypotensive episodes was nearly identical to that observed
with standard HD during the screening phase. However
with, isothermic dialysis, the incidence of sessions
with hypotensive episodes decreased from 50 to 25%.
Blood pressure decrease and the increase in heart rate
were less pronounced during isothermic HD than
during thermoneutral HD.
The results document that haemodynamic stability
is improved with isothermic HD vs standard HD
(screening phase) [46] possibly because of increased
peripheral vascular resistance [4,57], increased norepinephrine levels [4] or increased left ventricular
contractility [58].
Conclusion
Because of the considerable variations in body temperature and its regulation, it does not make sense to
believe in the Communist dogma that ‘one dialysate
temperature fits all’ at all times of the year and
throughout the day. As a consequence the dialysis
treatment must be adapted to the patient’s individual
1788
condition and response to treatment. Nephrologists
should take into consideration that a change in core
temperature by a few tenths of a degree Centigrade—
not uncommon during dialysis—causes a huge change
in skin blood flow response. Therefore, dialysate
temperature should be individualized.
Conflict of interest statement. J. Passlick-Deetjen is an employee of
Fresenius Medical Care. E. Bedenbender-Stoll declares no conflicts
on interest.
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doi:10.1093/ndt/gfi016
Advance Access publication 26 July 2005
Melagatran anticoagulation during haemodialysis—‘Primum
non nocere’
Michael J. Flanigan
University of Iowa Hospitals, Iowa City, USA
‘Primum non nocere’ or ‘First do no harm’ is attributed
to Galen’s translation of the Hippocratic Corpus
(Epidemics, Bk. I, Sect. XI.), ‘Declare the past, diagnose
the present, foretell the future; practice these acts. As
to diseases, make a habit of two things—to help, or at
least to do no harm’ [1,2].
In this issue of Nephrology Dialysis Transplantation,
Per-Ola Attman and colleagues describe an elegant,
heparin-free, haemodialysis anticoagulation scheme
using the direct thrombin inhibitor melagatran. They
use dialysate as a drug delivery vehicle and thus
regulate melagatran serum levels with precision.
The authors define and monitor efficacy and safety
Correspondence and offprint requests to: Michael J. Flanigan,
Department of Internal Medicine, University of Iowa Hospitals,
Iowa City, IA 52242-4060, USA.
Email: michael-fl[email protected]
end-points. Drug efficacy is assessed by inspecting the
dialysis system for clotting, recording dialyser iohexol
clearance and monitoring trans-dialyser pressure
gradients. Drug safety is assessed by measuring postdialysis needle puncture haemostasis times. The report
includes both intra- and inter-dialysis pharmacokinetic data [3]. The authors note that melegatran is
dialysable, has no antidote and might potentiate
bleeding. They propose that the prolonged melagatran
half-life following dialysis (14±4 h) may facilitate
arteriovenous (A-V) fistula and central dialysis catheter
patency. They do not, however, announce that surgery,
trauma or dental work in the 24 h following dialysis
could precipitate uncontrollable haemorrhage [4,5].
Dialysis anticoagulation has a long history. Early
dialysis systems exposed blood to variously stagnant and turbulent flow characteristics, bioreactive
materials and pyrogenic dialysate. These dialysis