Dexmedetomidine and Meperidine Additively Reduce the

Shivering Threshold in Humans

Anthony G. Doufas, MD, PhD; Chun-Ming Lin, MD; Mohammad-Irfan Suleman, MD;
Edwin B. Liem, MD; Rainer Lenhardt, MD; Nobutada Morioka, MD; Ozan Akça, MD;
Yunus M. Shah, MD; Andrew R. Bjorksten, PhD; Daniel I. Sessler, MD

Background and Purpose—Hypothermia might prove to be therapeutically beneficial in stroke victims; however, even
mild hypothermia provokes vigorous shivering. Meperidine and dexmedetomidine each linearly reduce the shivering
threshold (triggering core temperature) with minimal sedation. We tested the hypothesis that meperidine and
dexmedetomidine synergistically reduce the shivering threshold without producing substantial sedation or respiratory
depression.
Methods—We studied 10 healthy male volunteers (18 to 40 years) on 4 days: (1) control (no drug); (2) meperidine (target
plasma level 0.3 ␮g/mL); (3) dexmedetomidine (target plasma level 0.4 ng/mL); and (4) meperidine plus dexmedeto-
midine (target plasma levels of 0.3 ␮g/mL and 0.4 ng/mL, respectively). Lactated Ringer’s solution (⬇4°C) was infused
through a central venous catheter to decrease tympanic membrane temperature by ⬇2.5°C/h; mean skin temperature was
maintained at 31°C. An increase in oxygen consumption ⬎25% of baseline identified the shivering threshold. Sedation
was evaluated by using the Observer’s Assessment of Sedation/Alertness scale. Two-way repeated-measures ANOVA
was used to identify interactions between drugs. Data are presented as mean⫾SD; P⬍0.05 was statistically significant.
Results—The shivering thresholds on the study days were as follows: control, 36.7⫾0.3°C; dexmedetomidine, 36.0⫾0.5°C
(P⬍0.001 from control); meperidine, 35.5⫾0.6°C (P⬍0.001); and meperidine plus dexmedetomidine, 34.7⫾0.6°C
(P⬍0.001). Although meperidine and dexmedetomidine each reduced the shivering threshold, their interaction was not
synergistic but additive (P⫽0.19). There was trivial sedation with either drug alone or in combination. Respiratory rate
and end-tidal PCO2 were well preserved on all days.
Conclusions—Dexmedetomidine and meperidine additively reduce the shivering threshold; in the small doses tested, the
combination produced only mild sedation and no respiratory toxicity. (Stroke. 2003;34:1218-1223.)
Key Words: body temperature regulation 䡲 dexmedetomidine 䡲 hypothermia 䡲 meperidine 䡲 stroke 䡲 temperature

C onsiderable animal data indicate that even mild hypo-

thermia provides substantial protection against cerebral
ischemic or hypoxic brain injury.1,2 In humans, hypothermia
was reported to be an effective treatment for traumatic brain
injury,3 although a subsequent study failed to confirm this
observation.4 Mild hypothermia improves neurologic out-
comes in survivors of out-of-hospital cardiac arrest.5,6 In
acute stroke patients, body temperature is associated with
initial stroke severity, infarct size, and mortality,7 and low
body temperature on admission is an independent predictor of
good short-term outcome.8 Hypothermia also appears to
reduce intracranial pressure and might improve recovery
from catastrophic strokes resulting from middle cerebral
artery occlusion.9 Therapeutic mild to moderate hypothermia
thus remains a promising treatment for ischemic brain injury.
In preliminary trials testing the feasibility and safety of
therapeutic hypothermia in stroke patients,10,11 it proved
difficult to induce mild or moderate hypothermia in unanes-
thetized patients10 because effective thermoregulatory de-
fenses are maintained in most stroke victims.12 Induction of
therapeutic hypothermia is thus complicated by the need to
overcome arteriovenous shunt vasoconstriction and shivering
and to do so without provoking extreme thermal discomfort13
or sympathetic nervous system activation14—neither of which
would be appropriate in these fragile patients. Drugs known
to markedly impair thermoregulatory defenses are all anes-
thetics15 or major sedatives,16 which produce unacceptable
amounts of respiratory depression for patients outside critical
care settings. The search thus continues for a drug or drug
combination that sufficiently impairs thermoregulatory de-

Received August 27, 2002; final revision received December 5, 2002; accepted December 10, 2002.
From the Outcomes Research Institute and the Department of Anesthesiology (A.G.D., C.-M.L., M.-I.S., E.B.L., R.L., N.M., O.A., Y.M.S., D.I.S.),
Louisville, Ky; the Department of Anesthesiology (C.-M.L.), Chang Gung Memorial Hospital, Taipei, Taiwan; the Department of Anesthesia, Tokyo
Women’s Medical College (N.M.), Tokyo, Japan; the Department of Anaesthesia (A.R.B.), Royal Melbourne Hospital, Parkville, Australia; and the
Ludwig Boltzmann Institute (D.I.S.), University of Vienna, Vienna, Austria.
Dr Sessler has a personal financial interest in Radiant Medical, Inc.
Correspondence to Dr Anthony Doufas, Department of Anesthesiology, University of Louisville, University Hospital, 530 S Jackson St, Louisville, KY
40202. E-mail agdoufas@louisville.edu
© 2003 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org DOI: 10.1161/01.STR.0000068787.76670.A4

1218
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fenses without simultaneously producing unacceptable
toxicity.
Meperidine is probably the single most useful antishivering
drug. It is effective for postoperative shivering17 and, unlike
other drugs,16 decreases the shivering more than the vasocon-
striction threshold.18 Meperidine is a complex drug that
combines agonist effects at ␮-and ␬-opioid receptors, has
local anesthetic activity,19 and has anticholinergic proper-
ties.20 Although ␮-receptor agonists slightly and proportion-
ately reduce the shivering and vasoconstriction thresholds,16
the drug’s anticholinergic and ␬ effects apparently do not
explain meperidine’s special antishivering action.21 Unfortu-
nately, plasma concentrations near 1.3 ␮g/mL are required to
induce moderate hypothermia (ie, 33.5°C) with meperidine
alone18; at such concentrations, even young, healthy humans
no longer reliably breathe spontaneously.
The ␣2-receptor agonists are another important class of
antishivering drugs that, unlike meperidine, produce little
respiratory toxicity. Intravenous dexmedetomidine reduces
both the vasoconstriction and shivering thresholds.22 Interest-
ingly, meperidine is an agonist at ␣2B-adrenoceptors23—as is
dexmedetomidine. This suggests that the combination of
meperidine and dexmedetomidine might produce at least
additive—and perhaps synergistic—antishivering activity.
An additive or synergistic interaction would presumably
augment the antishivering effect of meperidine, with little or
no additional respiratory toxicity. We therefore tested the
hypothesis that meperidine and dexmedetomidine synergisti-
cally reduce the shivering threshold.
Methods
With approval of the Human Studies Committee at the University of
Louisville and informed consent, we studied 10 healthy male
volunteers. None was obese, taking medication, or had a history of
thyroid disease, dysautonomia, or Raynaud’s syndrome.
Protocol
The volunteers fasted for 8 hours before each study day. They were
minimally clothed and rested supine on a standard operating room
table. Ambient temperature was maintained near 21°C. Each volun-
teer was studied on 4 days: (1) control, no drug; (2) dexmedetomi-
dine at a target plasma concentration of 0.4 ng/mL; (3) meperidine at
a target plasma concentration of 0.3 ␮g/mL; and (4) dexmedetomi-
dine and meperidine combination at target concentrations of 0.4
ng/mL and 0.3 ␮g/mL, respectively. Each study day was separated
by at least 48 hours.
Dexmedetomidine was delivered by a target-controlled infusion
system starting 20 minutes before active cooling. The infusion pump
(Harvard Apparatus 22, Harvard Apparatus) was controlled by
STANPUMP software (version 4/98; http://anesthesia.stanford.edu/
pkpd/). The meperidine infusion profile was based on the plasma
drug-efflux technique,24,25 with coefficients estimated from pub-
lished pharmacokinetic data.26,27
A central catheter was introduced into the superior vena cava
through an antecubital vein. This catheter was used for cold-fluid
infusion and blood sampling. A venous catheter was inserted into the
other arm for drug administration. Throughout the study period,
mean skin temperature was maintained at 31°C by adjusting the
temperature of circulating-water (Cincinnati Sub-Zero) and forced-
air (Augustine Medical, Inc) warmers. Furthermore, the back, upper
body, and lower body were individually maintained at the designated
skin temperature.
Lactated Ringer’s solution cooled to ⬇4°C was infused at rates
sufficient to decrease tympanic membrane temperature 1 to 2°C/h.
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Doufas et al Inhibition of Shivering 1219
Fluid was given until the shivering threshold was identified or a total
of 70 mL/kg was given.
Measurements
Heart rate was measured continuously with an electrocardiograph;
blood pressure was determined oscillometrically at 5-minute inter-
vals at the left ankle. A pulse oximeter continuously measured
arterial oxygen saturation. All temperatures were recorded with
thermocouples (Mon-a-Therm, Mallinckrodt Anesthesiology Prod-
ucts, Inc). Core temperature was recorded from the tympanic
membrane. Volunteers inserted the aural probe until they felt the
thermocouple touch the tympanic membrane; appropriate placement
was confirmed when volunteers easily detected gentle rubbing of the
attached wire. The aural canal was occluded with cotton, the probe
securely taped in place, and a gauze bandage positioned over the
external ear. Mean skin surface temperature was determined from 15
area-weighted sites.28,29 Temperatures were recorded from thermo-
couples connected to calibrated 16-channel electronic thermometers
having an accuracy of 0.1°C and a precision of 0.01°C (Iso-Thermex,
Columbus Instruments International Corp). Individual and mean skin
temperatures were computed by a data acquisition system, displayed
at 1-second intervals, and recorded at 1-minute intervals.
Arteriovenous shunt vasomotor tone was evaluated with forearm-
minus-fingertip and calf-minus-toe skin temperature gradients. There
is an excellent correlation between skin temperature gradients and
volume plethysmography.30 Vasoconstriction was defined by a
forearm skin temperature gradient exceeding 0°C.
Oxygen consumption, as measured with a metabolic monitor
(DeltaTrac, SensorMedics Corp) quantified shivering; the system
was used in canopy mode.31 Measurements were averaged over
1-minute intervals and recorded every minute. End-tidal PCO2 was
measured with a monitor (Ultima, Datex), and exhaust gases from
this monitor were returned to the oxygen consumption monitor.
Blood for meperidine and dexmedetomidine concentrations was
obtained just before the active cooling started and at the shivering
threshold. A blank sample was obtained each day before drug
administration. The samples were immediately centrifuged and
frozen at ⫺40°C until assayed.
For dexmedetomidine and meperidine, 1 mL plasma, 0.05 mL of
2 mg/L sufentanil (internal standard), 0.1 mL of 3 mol/L NaOH, and
6 mL of 2% pentanol in hexane were combined in a borosilicate glass
tube, capped, and vortexed for 10 seconds. The samples were
allowed to stand for 1 hour before centrifugation at 1000g for 10
minutes. The hexane phase was transferred to a second glass tube
and evaporated to dryness under nitrogen at 40°C. The residue was
reconstituted in 0.025 mL methanol, and the whole sample was
injected into a gas chromatograph. The chromatograph used a
programmable temperature vaporizer, a 30 m⫻0.25 mm column
(SGE Inc), and nitrogen-phosphorus detection. This method is linear
to at least 1000 ng/mL for both drugs. For dexmedetomidine, the
limit of quantification is 0.2 ng/mL, with a within-day coefficient of
variation of 6.1% at 2 ng/mL. For meperidine, the limit of quantifi-
cation is 5 ng/mL, with a within-day coefficient of variation of 5.0%
at 50 ng/mL (n⫽8).
Sedation was evaluated by using the responsiveness component of
the Observer’s Assessment of Alertness/Sedation (OAA/S) score
(Table 1).32 Behavioral responses (thermal comfort) were evaluated
by using a 100-mm-long visual analog scale: 0 mm defined the worst
imaginable cold, 50 mm defined thermal comfort, and 100 mm
identified the worst imaginable heat. A new, unmarked scale was
used for each test. On each study day, sedation score and thermal
comfort were obtained 3 times: (1) before drug administration, (2)
before active cooling started, and (3) at the shivering threshold.
Data Analysis
A sustained increase in oxygen consumption (VO2) of ⱖ25%
identified the shivering threshold. The baseline for this analysis was
the steady-state value (ⱕ5% variation in VO2) after drug infusion but
before core cooling had started. On each study day, hemodynamic,
respiratory, ambient temperature, and relative humidity data were
averaged for each volunteer across the cooling period; these values
1220 Stroke May 2003

TABLE 1. Responsiveness Component of the Observer’s
Assessment of Alertness/Sedation Scale
Score Responsiveness
5 Responds readily to name spoken in normal tone
4 Lethargic response to name spoken in normal tone
3 Responds only after name is spoken loudly and/or repeatedly
2 Responds only after mild prodding or shaking
1 Does not respond to mild prodding or shaking
were then averaged for all volunteers. Core and mean skin temper-
ature data, as well as thermal comfort scores (visual analog scale) at
the shivering threshold, were averaged across the volunteers for each
study day. Sedation levels at the shivering threshold were presented
as the number of subjects having 3 different OAA/S scores (5/4/3;
see Table 1) on each study day. Results on the 4 study days were
compared by Friedman’s repeated-measures ANOVA and Student-
Newman-Keuls tests. Drug concentrations before core cooling were
compared with those at the shivering threshold by using a paired t
test to confirm our steady-state assumption. The same test was used
to compare drug concentrations between each drug day with the
combination day.
The synergistic interaction between dexmedetomidine and meper-
idine was evaluated with the statistical methodology described by
Slinker.33 The study was designed as a 2-factor experiment with 2
levels for each factor: the presence and absence of each of the 2
drugs. With this model, a statistically significant positive interaction
term between the 2 drugs indicates that they act synergistically or
antagonistically. A nonsignificant interaction term indicates that the
drugs’ effects on the shivering threshold are additive. A repeated-
measures ANOVA was used because each volunteer received all 4
treatments. Results are expressed as mean⫾SD; differences and the
interaction term were considered statistically significant when
P⬍0.05.
Results
The volunteers were 24⫾4 years old, weighed 75⫾11 kg, and
were 178⫾8 cm tall. Ambient temperature, relative humidity,
TABLE 2. Potential Confounding Factors and Important Results
Control
Ambient temperature, °C 21.3⫾1.5
Relative humidity, % 29⫾6
Mean arterial pressure, mm Hg 102⫾2
Heart rate, bpm 65⫾10
Spo2, % 100⫾1
Respiratory rate, breaths/min 15⫾5
End-tidal Pco2, mm Hg 43⫾5
mean arterial pressure, heart rate, respiratory rate, average
end-tidal PCO2, and SpO2 were similar on each study day. The
mean skin temperature was maintained near 31°C. All of the
volunteers were vasoconstricted before the cold-fluid infu-
sion was started. On each of the 3 drug study days, plasma
concentrations remained stable throughout the cooling pe-
riod; in other words, concentrations at the beginning and end
of the cooling period did not differ significantly. There were
no differences in plasma concentrations between the drug and
combination days for either dexmedetomidine or meperidine.
Sedation level at the shivering threshold, as defined by the
OAA/S score, did not differ significantly on dexmedetomi-
dine and meperidine days; the combination of dexmedetomi-
dine and meperidine caused only mild sedation (Table 2).
Meperidine reduced the shivering threshold by 1.2°C—
from 36.7⫾0.3°C on the control day to 35.5⫾0.6°C
(P⬍0.001), and dexmedetomidine only reduced the shivering
threshold by 0.7⫾0.5°C—to 36.0⫾0.5°C (P⬍0.001). The
combination of meperidine and dexmedetomidine reduced
the shivering threshold by 2.0⫾0.5°C—to 34.7⫾0.6°C
(P⬍0.001; the Figure). There was no interaction between the
2 drugs in terms of effect on the shivering threshold
(P⫽0.19). The combination of dexmedetomidine and meper-
idine thus additively reduced the shivering threshold.
Discussion
Dexmedetomidine22 and meperidine18 each as a function of
dose linearly reduce the shivering threshold. Our results
indicate that their combination further reduces the shivering
threshold and that this interaction is additive. These data thus
support supplementing meperidine with dexmedetomidine if
the opioid alone is insufficient to block shivering.
Dexmedetomidine Meperidine Combination
21.2⫾1.1 21.4⫾0.8 21.3⫾0.8
29⫾8 29⫾9 30⫾7
101⫾2 97⫾11 99⫾11
62⫾10 67⫾11 62⫾8
100⫾0 100⫾0 100⫾0
15⫾4 16⫾5 14⫾4
45⫾5 46⫾5 46⫾5

Dexmedetomidine, ng/mL 0.36⫾0.09 0.37⫾0.09

Meperidine, ␮g/mL 0.33⫾0.07 0.35⫾0.10
Total lactated Ringer’s, L 0.9⫾0.1 1.3⫾0.5* 1.5⫾0.5* 2.1⫾0.3*
Core cooling rate, °C/h 1.1⫾0.3 1.4⫾0.4 1.8⫾0.3* 1.9⫾0.5*
OAA/S score, 5/4/3 10/0/0 7/3/0 5/5/0 1/8/1*
Thermal comfort, VAS 22⫾13 20⫾11 26⫾12 27⫾9
Mean skin temperature, °C 31.0⫾0.1 31.0⫾0.0 30.9⫾0.1 30.9⫾0.1
Core temperature, °C 36.7⫾0.3 36.0⫾0.5* 35.5⫾0.6* 34.7⫾0.6*
Data are presented as means⫾SDs or as the number of subjects at each of the three (5/4/3) score
levels on the Observer’s Assessment of Alertness/Sedation (OAA/S) scale. Values in the upper section
were first averaged over the infusion period and then averaged among the volunteers; values in the
lower section are at the shivering threshold. VAS indicates visual analog scale.
Dexmedetomidine and meperidine levels did not differ significantly between the drug and
combination days. *Statistically significant difference from control.

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Reductions in the shivering threshold (compared with the con-
trol day) for the dexmedetomidine (Dex), meperidine (Mep), and
2-drug combination (Combo) days. Also shown is the expected
reduction for the combination of dexmedetomidine and meperi-
dine assuming an additive effect, calculated as the sum of the
individual effects of dexmedetomidine and meperidine (Dex &
Mep). Two-way repeated-measures ANOVA did not show a sig-
nificant interaction between the effects of the 2 drugs on the
shivering threshold (P⫽0.19).
Our data provide indirect support for the theory that the
special antishivering effect of meperidine is mediated by its
central ␣2-activity,23 because both dexmedetomidine and
meperidine are central ␣2-receptor agonists. The additive
interaction between dexmedetomidine and meperidine con-
trasts with our previous observation that meperidine and
buspirone interact synergistically.34 The synergistic reduction
in the threshold induced by meperidine and buspirone is
likely the result of the drugs’ acting through independent
mechanisms.
As in previous studies,22,35 dexmedetomidine alone pro-
duced trivial sedative effect and no apparent ventilatory
depression. Slightly more sedation was detected when the
drug was combined with meperidine; however, our volunteers
remained essentially alert and continued to breathe well
throughout the study. The mixture of dexmedetomidine and
meperidine thus joins meperidine and buspirone as a combi-
nation that provides substantial inhibition of shivering while
causing only minimal sedation or ventilatory compromise.
Minimal sedation and well-preserved ventilation are key
because therapeutic hypothermia, to be practical, will need to
be induced in patients who are monitored in a typical ward
setting.
Although meperidine and buspirone interact synergisti-
cally, dexmedetomidine has greater antishivering activity
than buspirone at clinically relevant concentrations.22,34 How-
ever, it is also considerably more sedating. The extent to
which either combination inhibits shivering and the safety
margins will thus depend on the specific doses used. Addi-
tional clinical experience will be required to determine which
combination and doses provide optimal antishivering activity
with minimal sedation and respiratory compromise.
There is currently little evidence that hypothermia protects
against ischemia in humans, although the evidence is over-
whelming in animals. There is certainly little basis for
recommending a specific target temperature for therapeutic
hypothermia. Nonetheless, target temperatures from 33°C to
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Doufas et al Inhibition of Shivering 1221
34°C are being used clinically by some physicians and in
ongoing clinical trials. The combination of meperidine and
dexmedetomidine reduced the shivering threshold to 34.7°C,
which some might consider insufficiently hypothermic. How-
ever, the observed shivering threshold of 34.7°C must be
interpreted in light of 2 factors. The first is that we set mean
skin temperature to 31°C, which is ⬇3°C less than typical for
stroke patients in a ward or intensive care unit setting. We
used this low skin temperature with the aim of raising the
shivering threshold to minimize the risk from infusion of
large amounts of cold fluid. Because skin temperature con-
tributes 20% to control of vasoconstriction and shivering,36
each degree centigrade of cutaneous warming will compen-
sate for ⬇0.2°C core hypothermia; the threshold at a more
typical skin temperature would have been near 34°C. More
aggressive cutaneous warming would further reduce the
threshold. The second factor is that we used small doses of
each drug to limit the amount of cold fluid we needed to
administer to our volunteers and the hypothermia they expe-
rienced. The dexmedetomidine plasma concentrations could
easily be doubled. Similarly, the meperidine concentration
could be increased, especially in patients who are carefully
monitored. Increasing either mean skin temperature or drug
doses would further reduce the shivering threshold and bring
it well within the range of temperatures that are commonly
targeted. An additional factor to consider is that most stroke
victims are elderly. Advanced age per se impairs thermoreg-
ulatory responses.37,38 It should thus be possible to induce
comparable hypothermia in the elderly with even smaller
drug doses or to induce greater hypothermia with similar drug
doses.
Because mean-skin temperature was maintained near 31°C,
our volunteers were already vasoconstricted before core
cooling started. It was thus impossible to evaluate the
vasoconstriction threshold. However, we have simulta-
neously determined the shivering and vasoconstriction
thresholds in numerous previous studies.22 The shivering
threshold has always been ⬇1°C less than the vasoconstric-
tion threshold, except in the presence of meperidine, when
there is a greater difference.18 It is therefore reasonable to
assume that the vasoconstriction threshold in our volunteers
would have been at least 1°C higher than the shivering
threshold.
The vasoconstriction threshold is of considerable interest,
because vasoconstriction is an effective thermoregulatory
response. Vasoconstriction is the primary autonomic defense
against cool environments and— once triggered—it prevents
further hypothermia, even in anesthetized patients.39 It might
thus be difficult to reduce core temperature below the
vasoconstriction threshold with surface cooling. Internal
cooling, such as we used, has no such limitation because heat
is removed directly from the core thermal compartment. A
further advantage of internal cooling is that patient comfort,
which depends largely on skin temperature,40 can be im-
proved by simultaneous cutaneous heating.
We induced core hypothermia by intravenous infusion of
cold fluid. This method is unlikely to be suitable in stroke
victims, especially if the target temperature is relatively low,
because large volumes of fluid would be required. However,
1222 Stroke May 2003
it is an excellent model for a new generation of internal
heat-exchanging catheters that induce core hypothermia with-
out any net exchange of fluid.41 Direct core cooling has
distinct advantages when compared with conventional sur-
face cooling: (1) It is much faster, because heat is removed
directly from the core, rather than being required to pass
through peripheral tissues, which insulate the core.42 (2) Less
heat needs to be removed, and peripheral tissues stay rela-
tively warm. Consequently, redistribution of heat from the
periphery to the core or constraint of metabolic heat to the
core has the potential to speed the return to normothermia
during rewarming, if that is neccessary.43 (3) Core cooling
can be combined with simultaneous surface warming, which
reduces the shivering threshold36 and improves thermal com-
fort.40 The rates of core cooling were restricted to a range of
1°C/h to 2°C/h, because we had previously shown that rates
of that magnitude do not affect the shivering threshold and
are unlikely to produce dynamic thermoregulatory
responses.44
We evaluated sedation with the well-accepted OAA/S
scale that is designed to detect substantial variations in
alertness and has been validated prospectively.32 Although it
does not have the resolution to detect subtle degrees of
sedation, it is unlikely that minimal amounts of sedation are
clinically important in the context of therapeutic hypothermia
for stroke and other life-threatening conditions. A more
serious issue is ventilatory compromise that could limit
administration of dexmedetomidine and meperidine in a
typical ward setting. Respiratory rate and end-tidal PCO2 were
well maintained with either drug and with the combination;
however, we did not evaluate CO2 response curves or other
measures of subtle ventilatory compromise.
In summary, dexmedetomidine and meperidine additively
reduced the shivering threshold in healthy adults. The doses
we tested decreased the threshold by ⬇2°C, with only
minimal sedation or respiratory toxicity. This combination
might thus facilitate studies evaluating the putative benefits
of therapeutic hypothermia.
Acknowledgments
This study was supported by Radiant Medical Inc (Redwood City,
Calif); National Institutes of Health grant GM 58273 (Bethesda,
Md); the Joseph Drown Foundation (Los Angeles, Calif); and the
Commonwealth of Kentucky Research Challenge Trust Fund (Lou-
isville, Ky). STANPUMP software is freely available from Steven L.
Shafer, MD, Anesthesiology Service (112A), PAVAMC, 3801
Miranda Ave, Palo Alto, CA 94304. The Mon-a-therm thermocou-
ples were kindly provided by Tyco-Mallinckrodt Anesthesiology
Products, St Louis, Mo. Abbott, Inc, Abbot Park, Ill, donated the
dexmedetomidine. We would like to thank Gilbert S. Haugh and
Nancy L. Alsip for their statistical and editorial assistance.
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Dexmedetomidine and Meperidine Additively Reduce the Shivering Threshold in Humans
Anthony G. Doufas, Chun-Ming Lin, Mohammad-Irfan Suleman, Edwin B. Liem, Rainer
Lenhardt, Nobutada Morioka, Ozan Akça, Yunus M. Shah, Andrew R. Bjorksten and Daniel I.
Sessler

Stroke. 2003;34:1218-1223; originally published online April 10, 2003;

doi: 10.1161/01.STR.0000068787.76670.A4
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