Intravascular Cooling in the Treatment of Stroke (ICTuS):

Early Clinical Experience

Patrick D. Lyden, MD,*,† Robin L. Allgren, MD, PhD,‡ Ken Ng, MD,§
Paul Akins, MD,储 Brett Meyer, MD,* Fahmi Al-Sanani, MD,¶ Helmi Lutsep, MD,#
John Dobak, MD,‡ Bradley S. Matsubara, MD,‡ and Justin Zivin, MD, PhD*,†

We sought to evaluate the safety and feasibility of mild therapeutic hypothermia

using an endovascular temperature management system in awake acute ischemic
stroke patients. The Intravascular Cooling in the Treatment of Stroke (ICTuS) study
was an uncontrolled, multicenter development and feasibility study of conscious
patients (n ⫽ 18) presenting within 12 hours of onset of an acute ischemic stroke at
5 clinical sites in the United States. Enrolled patients were to undergo core
temperature management using an endovascular cooling system to induce and
maintain mild, therapeutic hypothermia (target temperature of 33.0°C) for a period
of either 12 or 24 hours, followed by controlled rewarming to 36.5°C over the
subsequent 12-hour period. Nine patients underwent 12 hours of cooling followed
by 12 hours of controlled rewarming, and 6 patients underwent 24 hours of cooling
followed by 12 hours of controlled rewarming. Three patients underwent ⬍1.5
hours of hypothermia due to clinical or technical issues. We also developed an
antishivering regimen using buspirone and meperidine administered prophylacti-
cally to suppress shivering. The endovascular cooling catheter was well tolerated,
with acceptable adverse event rates. Increasing the duration of hypothermia
administration from 12 hours to 24 hours did not appear to increase the incidence
or severity of adverse effects. Endovascular cooling with a proactive antishivering
regimen can be accomplished in awake stroke patients. Further studies are needed
to establish the safety and efficacy of this approach. Key Words: Hypothermia—
stroke— clinical trial—thrombolysis.
© 2005 by National Stroke Association

Hypothermia has proven to be a potent putative
neuroprotectant in preclinical experimental studies of
From the *Department of Neurosciences, University of California
San Diego School of Medicine, †Department of Neurology, Veterans
Administration Medical Center, San Diego, ‡Innercool Therapies
Inc., San Diego, California; §Department of Neurology, Ocala Re-
gional Medical Center, Florida; 储Department of Neurology, Mercy
General Hospital, Sacramento, California; ¶Department of Neurol-
ogy, University of Texas, Houston, Texas; and #Department of Neu-
rology, Oregon Health Sciences University, Portland, Oregon.
Received November 17, 2004; accepted December 28, 2004.
Address reprint requests to Patrick D. Lyden, MD, FAAN, UCSD
Stroke Center, OPC Third Floor, Suite #3, 200 W. Arbor Drive, San
Diego, CA 92103. E-mail: plyden@ucsd.edu.
1052-3057/$—see front matter
© 2005 by National Stroke Association
doi:10.1016/j.jstrokecerebrovasdis.2005.01.001
cerebral ischemia. Two clinical studies of patients
treated with 12-24 hours of hypothermia after cardiac
arrest (a period of global cerebral ischemia) exhibited
better neurologic outcomes and lower mortality than
normothermic controls.1,2 Thus hypothermia may hold
promise as a treatment for acute ischemic stroke. How-
ever, to be practical in the clinical setting, hypothermia
should be safe and easy to administer.
Previous clinical studies of hypothermia in stroke
patients used surface cooling methods, such as surface
cooling blankets, ice packs, and alcohol baths.3-6 Al-
though these methods can cool patients, they are cum-
bersome and slow, often requiring 3-8 hours to achieve
target temperatures (although recent innovations may
have reduced the time to reach target to about 90
minutes).7 In addition, maintaining control at a desired

Journal of Stroke and Cerebrovascular Diseases, Vol. 14, No. 3 (May-June), 2005: pp 107-114 107
108 P.D. LYDEN ET AL.

Table 1. ICTuS inclusion and exclusion criteria

Inclusion criteria
1. Age 18 to 85 inclusive
2. Symptoms of acute ischemic stroke still present by the time consent obtained
3. Stroke onset within 12 hours; awoke with stroke allowed if time since last known to be symptom-free is within
12 hours
4. Any subtype of ischemic stroke with NIHSS ⱖ4 at the time hypothermia begins
Exclusion criteria
1. Etiology other than ischemic stroke
2. Item 1a on NIHSS ⱖ1
3. Symptoms resolving or so mild that baseline NIHSS ⬍4 at the time hypothermia begins
4. Contraindications to hypothermia, such as patients with known hematologic dyscrasias that affect thrombosis
(e.g., cryoglobulinemia, Sickle cell disease, serum cold agglutinins) or vasospastic disorders such as Raynaud’s or
thromboangiitis obliterans
5. Comorbid conditions likely to complicate therapy, for example:
a. End-stage cardiomyopathy
b. Uncompensated arrhythmia
c. Myopathy
d. Liver disease severe enough to elevate bilirubin level
e. History of pelvic or abdominal mass likely to compress inferior vena cava
f. Dementia severe enough to prevent valid consent
g. End-stage AIDS
6. Intracerebral hematoma; minimal hemorrhagic transformation acceptable
7. Any intraventricular hemorrhage
8. Systolic blood pressure ⬎210 or ⬍100, diastolic blood pressure ⬎110 or ⬍50 mmHg
9. Severe coagulopathy, e.g., INR ⬎ 3.0 ⫻ control or PTT ⬎ 50 seconds
10. Pregnancy in women of childbearing potential, confirmed by positive urine pregnancy test
11. Medical conditions likely to interfere with patient assessment

temperature is difficult. For example, in 1 study, the Methods

target temperature of 33°C was reached after 3.5 hours,
but in 9 of 10 patients there was an overshoot to cooler
temperatures (as low as 28.4°C).4 Because lower tem-
peratures can exacerbate adverse effects of hypother-
mia, the ability to control patient temperatures and
avoid overcooling during hypothermia is important.
Suppressing shivering during hypothermia is also crit-
ical, because shivering generates heat and can essentially
negate the desired cooling. In most previous hypother-
mia studies,4-6,8 to suppress shivering, patients were se-
dated (with, e.g., fenantyl and propofol), paralyzed (i.e.,
neuromuscular blockade), intubated, and mechanically
ventilated. These measures may be less well tolerated in
elderly stroke patients than in relatively younger cardiac
arrest patients. For example, in a study of surface cooling,
shivering was controlled with intravenous (IV) meperi-
dine in awake patients, but patients were cooled to only
35.5°C over 5 hours.3
Developing better methods of administering hypother-
mia in a controlled manner while adequately suppressing
shivering is an important prerequisite to the execution of
large pivotal efficacy studies of hypothermia therapy in
stroke. In the present study, we sought to develop a safe
and feasible method for inducing hypothermia in awake
stroke patients. A similar experience using a different
cooling device was published recently.9
The Intravascular Cooling in the Treatment of Stroke
(ICTuS) study was a phase 1 prospective, uncontrolled,
multicenter development/feasibility and safety study of
12 or 24 hours of hypothermia in awake stroke patients.
The planned sample size was ⬃20 patients in 5 centers
(see Appendix 1 for a list of the study sites). The study
target population was awake patients with acute isch-
emic stroke; the full inclusion and exclusion criteria are
given in Table 1. The treatment protocol is illustrated in
Figure 1. Patients meeting the inclusion/exclusion crite-
ria were enrolled into the study after providing written
informed consent, undergoing a complete history and
physical examination, and exhibiting acceptable results
of the following tests: vital signs, oxygen saturation,
prothrombin time, activated partial thromboplastin time,
international normalized ratio, serum electrolytes, biliru-
bin, blood urea nitrogen, creatinine, basic liver function
tests, complete blood count with platelet count, brain
computed tomography (CT) or magnetic resonance im-
aging scan, and neurologic examination using the Na-
tional Institutes of Health Stroke Scale (NIHSS).10
Cooling to a target temperature of 33.0°C was initiated
within 12 hours of stroke onset (patients awakening with
stroke were timed from the last normal observation) and
maintained for 12 or 24 hours. The 12-hour group was
INTRAVASCULAR COOLING IN THE TREATMENT OF STROKE
Figure 1. Study protocol: Outline of the basic procedures in ICTuS. N/A,
not applicable; mNIHSS, the abbreviated NIHSS used by the bedside nurse;
AE, adverse event; SAE, serious adverse event.
completed first, and then patients were enrolled into the
24-hour cohort. At the conclusion of hypothermia treat-
ment, patients were gradually rewarmed over 12 hours to
36.5°C (normothermia). Each patient was examined using
the NIHSS, Barthel index (BI), and modified Rankin scale
at the conclusion of treatment, 24 hours after the conclu-
sion of treatment, on discharge from the hospital, and 30
days after stroke.11,12 A lower extremity venous ultra-
sound examination was performed within 24 hours of
catheter removal. Brain CT scans were obtained 36 to 48
hours after stroke onset and 30 days after the stroke.
Endovascular cooling was performed with the Celsius
Control™ system (Innercool Therapies, San Diego, CA),
consisting of a catheter (#9 Fr) connected to a control
console. The catheter has a heparin-coated flexible metal-
lic heat-transfer surface, which facilitates the extraction of
heat from the blood as it flows by the catheter. The
catheter is connected to a console that controls the tem-
perature and flow rate of the fluid circulated within the
catheter and adjusts them in response to patient temper-
ature feedback (provided by an esophageal or nasopha-
ryngeal temperature probe connected to the console) as
needed to achieve and maintain the target hypothermic
or normothermic temperature.
109
A vascular access sheath was inserted into a femoral vein
of each patient. The catheter was then inserted through the
sheath and advanced until the tip of the catheter rested in
the inferior vena cava, below the diaphragm. In patients
who received tissue plasminogen activator (rt-PA) for
stroke, sheath placement was delayed until 30 minutes after
the rt-PA infusion ended. Proper catheter placement was
confirmed with an abdominal flat plate radiograph or flu-
oroscopy before cooling.
Two temperature-monitoring devices were placed, de-
pending on patient comfort, using 2 of 3 possible sites:
tympanic membrane, bladder, and esophagus. The pur-
pose was to determine the feasibility of the bladder or
espophageal probes for feedback control of the console.
The tympanic probe was planned as a safety backup in
the event that the controlling probe became disconnected.
Each patient was monitored continuously in an intensive
care setting and checked hourly for hematoma or infec-
tion at the catheter entry site, peripheral pulses, blood
pressure, pulse, respiration, oxygen saturation, cardiac
rhythm, and manual tympanic temperature. An abbrevi-
ated NIHSS was obtained every 4 hours. Any deteriora-
tion (e.g., a 2-point increase in the NIHSS) was reported
to the responsible investigator immediately. Similarly,
any potential adverse event, including vital signs outside
of normal parameters, was reported immediately to the
responsible investigator.
After catheter placement, a warming blanket (electric
or convective air) was placed over the patient shortly
after cooling began to reduce shivering. In addition, we
attempted to design an antishivering protocol using IV
meperidine. A conservative regimen was attempted in
the first 9 patients, but proved inadequate to control
shivering. The conservative regimen consisted of small
escalating doses of IV meperidine administered on an
as-needed basis in response to shivering. The regimen
was then modified for the subsequent patients to a more
proactive approach. The proactive protocol used prophy-
lactic administration of loading doses of meperidine
(range, 85-188 mg total loading dose, depending on
weight and gender) plus 30 mg of oral buspirone before
the start of cooling, followed by a prophylactic mainte-
nance infusion of meperidine (16-44 mg/hr) and 15 mg of
oral buspirone every 8 hours throughout the cooling
period.13 The combination of buspirone and meperidine
is thought to synergistically suppress shivering.13
All patients received antithrombotic prophylaxis with
intermittent lower extremity compression, a combination
of oral aspirin and subcutaneous heparin, or both com-
pression and aspirin/heparin. The compression method
was preferred. Unproven stroke therapies, such as high-
dose steroids, mannitol, hyperventilation, or craniec-
tomy, were not permitted. If thrombolytic therapy was
used, then the patient was required to be fully eligible for
thrombolysis according to the NINDS thrombolytic pro-
tocol.14 In particular, antiplatelet and anticoagulant drugs
110
Figure 2. Cooling curves for patients treated with conservative versus
proactive antishivering. Temperature #1: first recorded vitals; #2: cooling
begins; #3: 1 hour into cooling; #4: lowest tolerated temperature; #5: start
of rewarming; #6: end of rewarming. The groups are statistically significantly
different at the 1-hour and lowest-tolerated temperatures (#3 and #4).
were prohibited for 24 hours after thrombolysis; only
compression devices were allowed for deep venous
thrombosis (DVT) prevention in these patients.
The primary purpose of this trial was to establish
whether endovascular cooling was feasible in awake
stroke patients. Important in this assessment was patient
safety. Any adverse events occurring during hypother-
mia, during rewarming, and after catheter removal until
hospital discharge were noted. Particular attention was
given to venous clotting, puncture site hematoma, car-
diac dysrythmias, and infectious and hematologic com-
plications from the indwelling catheter. Any serious ad-
verse events were noted through the 30-day follow-up
visit. Follow-up CT brain scans were obtained 36-48
hours after treatment and checked for evidence of hem-
orrhage. All CT scans were forwarded to the coordinating
center and read by 1 examiner blinded to the patients’
status and treatment phase.
Results
A total of 18 patients (5 women and 13 men) were
recruited into the trial. The mean (⫾ standard deviation
[SD]) patient age at the time of enrollment was 66.2 ⫾
11.7 years (range, 38.9-81.4 years). Mean patient weight
was 90.7 ⫾ 21.8 kg (range, 63-154 kg). The mean time
interval from the onset of stroke symptoms to presenta-
tion was 3.3 ⫾ 3.3 hours (range, 0.7-13.0 hours). Overall,
5 patients (28%) presented within 3 hours of stroke onset
and received rt-PA.
All 18 enrolled patients underwent placement of a
femoral venous introducer sheath. Nine patients under-
went 12 hours of hypothermia followed by 12 hours of
controlled rewarming. Six patients underwent 24 hours
of hypothermia followed by 12 hours of controlled re-
warming. In 1 patient, hypothermia was discontinued
after 67 minutes due to the family’s withdrawal of study
P.D. LYDEN ET AL.
consent. Two patients underwent placement of the fem-
oral introducer sheath for the catheter but did not receive
any hypothermia (due to hypotension in 1 and inability
to correctly insert the catheter in the other). The mean
(⫾ SD) time interval from the onset of stroke symptoms
to catheter introducer sheath insertion was 7.4 ⫾ 2.9
hours (range, 3.1-15.0 hours).
For the 16 patients for whom cooling was initiated, the
mean (⫾ SD) time interval from the onset of stroke
symptoms to the start of cooling was 8.0 ⫹mn; 3.8 hours
(range, 4.3-20.3 hours). Of the 15 patients who were
cooled according to protocol (i.e., for 12 or 24 hours), 8
(53%) were treated with the initial, more conservative
antishivering regimen; the remaining 7 patients (47%)
were treated with the proactive antishivering regimen.
The mean (⫾ SD) temperature on admission for all 15
patients who were cooled was 36.5°C ⫾ 0.4°C (range,
35.8-37.0°C). The average temperature when cooling was
initiated for the conservative group was 36.7 ⫾ 1.0°C
(range, 35.1-37.6°C). For patients in the proactive group,
temperature at the start of cooling was 35.8 ⫾ 0.7°C
(range, 34.8-36.8°C) (P ⫽ .41).
One hour into the cooling process, the mean ⫾ SD
temperature was 36.1 ⫾ 0.7°C (range, 35.1⫹mn;37.0°C) in
the conservative group and 34.4 ⫾ 0.6°C (range, 33.3-
35.5°C) in the proactive group (P ⫽ .00028). During the
first hour of cooling, the proactive group had a signifi-
cantly faster average rate of temperature change of
–1.41 ⫾ 0.82°C/hr (range, ⫺0.60°C/hr to ⫺2.60° C/hr),
compared with just ⫺0.56 ⫾ 0.58°C/hr (range, ⫹0.30°C/
hr– ⫺1.33°C/hr) for patients in the conservative group (P
⫽ .036). Similarly, the mean lowest achievable tempera-
ture was significantly colder for the patients in the pro-
active group than those in the conservative group: 33.7 ⫾
0.7°C (range, 32.7-34.6°C) versus 35.6 ⫾ 1.0°C (range,
33.5-36.7°C) (P ⫽ .0012), respectively. However, the time
to reach the coldest temperature did not differ between
the cooling regimens, averaging 7 hours. Temperature
versus time in the patient groups treated with the con-
Table 2. All adverse events
Adverse event n
DVT 4
Bradycardia 4
Hypokalemia 4
Nausea and/or vomiting 3
Groin site hematoma 2
Atrial fibrillation 2
Catheter site pain 1
Shivering 1
Atrioventricular block 1
Supraventricular tachycardia 1
Renal insufficiency 1
INTRAVASCULAR COOLING IN THE TREATMENT OF STROKE 111

Table 3. Serious adverse events

Patient Cooling Device During Study day of

ID (hrs) related? hypothermia? SAE SAE

03-03 0 No No 2 Hemorrhagic transformation of infarct (fatal)

05-02 1 No No 2 Neurologic decompensation (fatal)
01-01 12 Yes No 1 Femoral DVT
04-01 12 No Yes 0 Bradycardia
05-03 12 No No 13 Pneumonia, aspiration
01-02 24 No No 14 Myocardial infarction
No No 17 Ventricular tachycardia
05-04 24 No Yes 0 Absence seizure-like activity
No No 12 Hypertension, uncontrolled
05-06 24 No No 6 Pulmonary embolism
05-07 24 No No 1 Hemorrhagic transformation of infarct (fatal)

SAE, serious adverse event.

servative and proactive antishivering regimens is shown
graphically in Figure 2.
Three deaths occurred during the study, none directly
related to the catheter system, hypothermia, or study
procedures (Table 2). No unanticipated device-related
adverse effects were reported. There were 11 reported
serious adverse events in 9 patients, 1 of whom (a femoral
DVT) was considered related to the Celsius Control™
system or to hypothermia (Table 2). A total of 24 adverse
events were reported (Table 3), 7 of which were consid-
ered possibly related to the catheter system: DVT (n ⫽ 4),
insertion site hematoma (n ⫽ 2), and pain at the cathe-
terization site (n ⫽ 1). An additional 7 adverse events
were considered hypothermia-related: bradycardia (n ⫽
3), nausea/vomiting due to IV meperidine given as part
of the antishivering regimen (n ⫽ 3), and shivering (n ⫽
1). The 3 cases of bradycardia did not result in hypoten-
sion. Prolonged administration of hypothermia (⬍1.5
hours vs 12 hours vs 24 hours) was not associated with an
increase in bleeding, infectious, hemodynamic, or meta-
bolic complications. The incidence rates of these adverse
effects reported here are in keeping with previously
published pilot studies of mild-to-moderate induced hy-
pothermia for the treatment of ischemic stroke or cardiac
arrest.1-6,8
The 4 study patients with DVT were asymptomatic,
and the DVT was detected on the protocol-specified
follow-up lower extremity ultrasound performed at 24
hours. They all resolved without clinical sequelae after
treatment with heparin/coumadin therapy. Three of
these DVTs were rated by the investigators as “proba-
bly” or “definitely” related to the catheter use, because
they occurred at the femoral site of catheter insertion.
The fourth DVT was probably unrelated to the use of
the catheter, because it was found in the lower extrem-
ity contralateral to the side in which the catheter was
placed. However, if one assumes that all 4 reported
DVTs were catheter-related, the overall incidence
(22%; 4/18) in this study is consistent with rates re-
ported in the literature for femoral catheters, as well as

Table 4. All reported bleeding complications

Patient Cooling Device Hypothermia

ID (hrs) related? related?* t-PA? SAE? Description

03-03 0 No No Yes Yes Hemorrhagic transformation of infarct (fatal)

Yes No Yes No Hematoma, left groin
05-02 1 No No No No GI bleeding (unspecified source)
02-01 12 No No Yes No GI bleeding (hematemesis, superficial gastric ulcer)
03-01 12 No No No No Hematuria (Foley catheter trauma)
04-01 12 No No No No Hemorrhagic transformation of infarct
12 Yes No No No Hematoma, right groin
04-02 12 No No No No Hematuria (Foley catheter trauma)
05-03 12 No No No No Hematuria
05-07 24 No No Yes Yes Hemorrhagic transformation of infarct (fatal)

SAE, serious adverse event.

*No ⫽ “not related” or “probably not related”; Yes ⫽ “probably related” or “definitely related.”
112
Figure 3. Day-2 head CT scans for the 3 patients with hemorrhagic
transformations. (A) A 72-year-old patient who received rt-PA within 3
hours of stroke and no cooling (patient 03-03). (B) A 63-year-old patient
who received no rt-PA and 12 hours of cooling (patient 04-01). (C) A
74-year-old patient who received rt-PA and 24 hours of cooling (patient
05-07).
DVT rates reported for patients hospitalized for acute
stroke.15,16
In the 1 patient who received hypothermia for ⬃1 hour
(a 73-year-old man with a known history of coronary
artery disease), intermittent supraventricular tachycardia
(SVT) was reported as an adverse event beginning close
to the initiation of cooling. This patient became agitated
after administration of fentanyl and midazolam in prep-
aration for catheter placement, which prompted his wife
to withdraw study consent after only 67 minutes of
cooling and may have contributed to his SVT. Two pa-
tients had the onset of atrial fibrillation (AF) during
hypothermia. Both of these patients were enrolled in the
12-hour group and had a known history of intermittent
AF; the arrhythmia required no treatment and resolved
without sequelae in both cases. There were 2 cases of
bradycardia in the 24-hour group that were present before
cooling started but increased in severity during the hypo-
thermic period. Hypokalemia was reported in 4 patients.
All bleeding complications are summarized in Table 4.
Hemorrhagic transformation of the incident cerebral in-
farction occurred in 3 of 18 patients (16.7%), as illustrated
in Figure 3. Two patients died as a result of intracranial
bleeding; 1 patient was not cooled and did receive rt-PA,
Table 5. Infections reported through day 30
⬍1.5 hrs (n ⫽ 3)
Reported adverse event No. % No.
Fever 1 33%
Leukocytosis 0 0%
Pneumonia, aspiration 1 33%
Upper respiratory tract infection 0 0%
Urinary tract infection 0 0%
Yeast infection 0 0%
P.D. LYDEN ET AL.
and the other patient was cooled in the 24-hour group
and also received rt-PA. The third patient with hemor-
rhagic transformation was cooled as part of the 12-hour
group but did not receive rt-PA. In this case of left main
coronary artery infarction, bleeding involved the left basal
ganglia with extension into the external capsule but was
nonfatal and was not considered a serious adverse event.
Two groin site hematomas were reported after femoral
vein puncture; neither was considered serious. rt-PA was
given to 1 of these patients but not to the other. Other
bleeding complications were minor (i.e., not considered
significant adverse events) and were considered “not
related” or “probably not related” to hypothermia: hema-
turia due to Foley catheter–associated trauma (n ⫽ 2) and
gastrointestinal bleeding (n ⫽ 2).
Average platelet counts decreased slightly in all 3
groups of patients. For patients exposed to ⬍1.5 hours of
hypothermia, platelet counts decreased from 222.0k ⫾
40.5k (range, 181k-262k) to 212.0k ⫾ 29.1k (range, 182k-
240k). For patients in the 12-hour group, platelet counts
decreased from 219.1k ⫾ 63.9k (range, 149k-372k) to
199.5k ⫾ 50.5k (range, 124k-199k). For patients in the
24-hour group, platelet counts decreased from 198.8k ⫾
45.3k (range, 125k-250k) to 186.4k ⫾ 47.8k (range, 108k-
225k). However, thrombocytopenia was not considered
to be an adverse event for any patient. The infections
reported through day 30 for the study patients are sum-
marized in Table 5, sorted by duration of hypothermia.
Discussion
The ICTuS study was a development/feasibility study
designed to treat acute stroke patients with endovascular
hypothermia. Throughout the course of the trial, several
protocol refinements allowed us to derive the final pro-
tocol. Cooling performance was enhanced by prophylac-
tic thermoregulatory suppression; when a conservative
antishivering regimen (i.e., surface warming blanket and
Duration of hypothermia
12 hrs cooling, 12 24 hrs cooling, 12
hrs rewarming hrs rewarming
(n ⫽ 9) (n ⫽ 6)
% No. %
2 22% 0 0%
0 0% 1 16%
3 33% 1 16%
1 11% 0 0%
2 22% 0 0%
0 0% 1 16%
INTRAVASCULAR COOLING IN THE TREATMENT OF STROKE 113

small boluses of meperidine in response to shivering) in conscious stroke victims without the need for paralysis
was used, the lowest achievable temperature was 35.6 ⫾ and mechanical ventilation to control shivering. A larger
1.0°C. In contrast, when a more proactive antishivering phase 1/2 protocol is needed to confirm the safety of this
regimen was used, in which oral buspirone plus a load- approach.
ing dose of IV meperidine followed by a continuous
infusion was administered prophylactically, the lowest Appendix 1: ICTuS Study Sites
achievable temperature in this study was 33.7 ⫾ 0.7°C
(unpaired t-test, P ⬍ .01). This final protocol must now be Site 01
tested in a larger phase 1/2 trial including appropriate Brett Meyer, MD
controls. A very similar protocol was recently used in a Nancy Kelly, RN
study of acute stroke patients, with acceptable safety UCSD Medical Center
results.9 San Diego, CA
The incidence and nature of the reported adverse
Site 02
events were consistent with previously published studies
Paul Akins, MD
of hypothermia in similar patient populations.1-6,8 In-
Deidre Wentworth, RN
creasing the duration of hypothermia administration
Mercy General Hospital
from 12 hours to 24 hours did not appear to increase the
Sacramento, CA
incidence or severity of adverse effects. The 11 significant
adverse events reported in 9 patients reflect the serious Site 03
medical conditions of the enrolled patients, and only 2 Helmi Lutsep, MD
significant adverse events were attributed to the hypo- Susie Fisher, RN
thermia protocol. However, without a control group, no Oregon Health Sciences University
conclusions can be drawn about the safety profile of this Portland, OR
protocol, and a further safety trial is necessary, including
Site 04
controls, to ensure safety. The 3 hemorrhagic transforma-
Fahmi Al-Sanani, MD
tions are particularly worrisome, although the incidence
Robin Saiki, RN
(3/18; 17%) is consistent with the natural history of
University of Texas, Houston Medical School
ischemic stroke, especially if rt-PA used. A larger safety
Houston, TX
study of endovascular cooling combined with rt-PA is
needed to ensure the safety of this combination. Site 05
Numerous drugs alter thermoregulatory control, in- Ken Ng, MD
cluding most anesthetics and narcotics. Meperidine, Melissa Holycross, BS
which decreases the shivering threshold twice as fast as Ocala Neurodiagnostic Center
the vasoconstriction threshold through an unknown Ocala, FL
mechanism, is the most important and clinically relevant
Coordinating Center
drug for inhibiting thermoregulatory responses.17 A me-
Patrick Lyden, MD
peridine dose of 25 mg IV decreased the shivering thresh-
Karen Rapp, RN
old by 2°C, with no effect on alertness or respiratory
UCSD Clinical Trial Coordinating Center
function. To prevent substantial sedation and respiratory
San Diego, CA
depression associated with high-dose meperidine, other
agents may be combined with meperidine to produce a Study Safety and Monitoring
greater antishivering effect. Buspirone reduced the shiv- Justin Zivin, MD, PhD
ering threshold to 35.0°C ⫾ 0.8°C, whereas high-dose Julie Jurf, RN
meperidine reduced the shivering threshold to 33.4°C ⫾ IND Inc.
0.3°C.13 The combination of small doses of these 2 drugs Dallas, TX
reduced the shivering threshold to 33.4°C ⫾ 0.7°C with
Study Sponsor
only minimal sedation. The mechanism of the synergistic
John Dobak, MD
effects of buspirone and meperidine is unknown. We
Robin Allgren, MD, PhD
found that the combination of buspirone, meperidine,
INNERCOOL Therapies, Inc.
and modest surface warming with a forced-air warming
San Diego, CA
blanket produced the optimal shivering suppression.
The ICTuS study has enabled the derivation of an
endovascular cooling protocol that may be safe in elderly References
stroke victims. Using the final version of the protocol, 1. Bernard SA, Buist MD, Jones BM, et al. Treatment of
including a proactive antishivering regimen, we were comatose survivors of out-of-hospital cardiac arrest with
able to induce, maintain, and reverse mild hypothermia induced hypothermia. New Engl J Med 2002;346:557-563.
114
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