Acta Neurochir (Wien) (2006) 148: 565–570

DOI 10.1007/s00701-006-0747-z

History of Neurosurgery
Cold as a therapeutic agent

H. Wang1 , W. Olivero1 , D. Wang2 , and G. Lanzino1

1
Department of Neurosurgery, Illinois Neurological Institute, University of Illinois College of Medicine at Peoria, Peoria, Illinois, USA
2
Department of Neurology, Illinois Neurological Institute, University of Illinois College of Medicine at Peoria, Peoria, Illinois, USA

Received February 1, 2005; accepted June 14, 2005; published online February 17, 2006
# Springer-Verlag 2006

Summary in a variety of neurological disorders. Yet, the use of

The use of cold as a therapeutic agent has a long and colorful history.
The Edwin Smith Papyrus, the most ancient medical text known, dated
3500 B.C., made numerous references to the use of cold as therapy.
Baron de Larrey, a French army surgeon during Napoleon’s Russian
campaign, packed the limbs in ice prior to amputations to render the
procedures painless. In the early twentieth century, a neurosurgeon,
Temple Fay, pioneered ‘‘human refrigeration’’ as a treatment for malig-
nancies and head injuries. In 1961, Irving Cooper developed the first
closed cryoprobe system and ushered in the modern era of cryogenic
surgery with his imperturbable convictions. Fay’s early work fell victim
to the disruptive sequel of the World War II. The Nazis confiscated his
data (presented before the Third International Cancer Congress in 1939)
forwarded to Belgium for publication and brutally applied his refrigera-
tion techniques experimentally without any benefit of anesthesia in the
concentration camps, especially Dachau. Hypothermia became asso-
ciated in the public mind with the atrocities exposed at the war trials
in N€urnberg. After lying dormant for decades, the interest was rekindled
in the late 80s when mild hypothermia was shown to confer dramatic
neuroprotection in a number of experimental models of brain injury.
With several large multi-center clinical studies currently under way, hy-
pothermia is receiving unprecedented attention from the medical and
scientific communities.
Keywords: Hypothermia; cold; history of medicine.
Sarah Parks . . . gave still-birth to a baby boy . . . A
young doctor assisting the Parks’ regular physician
begged for an opportunity to experiment with an idea
he had to rouse the lifeless infant. A tub of ice was
ordered and the young doctor plunged the baby into it.
Out came the screaming little Parks and he was named
Gordon after the doctor who prodded him to life.
Sir John Floyer, 1697
Increasing interest has centered in the past two decades
concerning the potential protective effects of hypothermia
cold as a therapeutic agent has a long and colorful history.
We review some of the critical historical steps and pio-
neering attempts eventually leading to today’s renewed
interest in this ancient therapeutic remedy.
Cold, an ancient remedy
Cold, as a simple and easily accessible element,
is among man’s earliest remedies. The Edwin Smith
Papyrus, the most ancient medical text known, dated
3500 B.C., made numerous references to the use of cold
as therapy [13]. The Hippocratic school of medicine
used total body cooling for tetanus treatment during
the fourth and fifth centuries B.C. [1]. The renowned
anatomist, surgeon and clinician, Claudius Galen advo-
cated cold affusion for tertian fever [13]. The famous
Chinese surgeon, Hua To (c. 200 A.D.) routinely im-
mersed forcibly his naked and febrile patient in a stone
trough in his garden until the vapor rose several feet
above the trough [29]. Both a physician and politician,
Jerome Mercurialis (1530–1606) of Forli, Italy, was
often found abruptly interrupting the civil ceremony in
the Court of Emperor Maximillian and dashing for the
River Arnus. He would then appear in a squatting figure
always in one particular spot in the Arnus where cold
springs entered and the chilling currents washed away
his agony from the unpredictable bouts of severe recur-
ring renal colic. Many of his patients, afflicted by the
same agony, also came to be known as the ‘‘squatting
figures of the River Arnus’’ [11].
566
In 1791, the French humanist physician, Philippe
Pinel recorded an interesting case of the effects of hy-
pothermia on mental illness [19]. A lunatic escaped from
the asylum in the Pyrenees and roamed about naked in
the wintry forest. After frolicking in the snow for some
time, he gradually became dispossessed of his mania
without other apparent ill effects. This recorded event
antedated John Talbot’s use of hypothermia for mental
illness by a century and a half. Napoleon’s surgeon to
the Grand Army, Baron Larrey described the use of ice
and snow in the performance of painless amputations
and other operations upon soldiers in the field [13]. In
the late 1700’s, John Hunter devised a mercurial thermom-
eter. Soon afterwards, James Currie of Liverpool carried
out the first purposeful human experimentation to deter-
mine the effects of various methods of cooling upon the
body temperature, pulse, respiration, and other param-
eters. Currie subsequently employed cooling techniques
for the treatment of numerous clinical disorders and
documented the first records of human temperatures in
health, disease, and experimental conditions [13]. Using
a body cooling regimen, William Osler brought the
average mortality from typhoid at the Johns Hopkins
Hospital from 24.2% down to 7.1% [13].
Despite the exploration and investigation of hypo-
thermia in the nineteenth century by Currie, Barnard,
Edwards, Walther, Horvath, Arnott, and Langendorff, to
mention but a sampling, clinical hypothermia never ac-
quired the due recognition of the profession or the public.
Temple Fay on November 28, 1938
On November 28, 1938, Temple Fay, a neurosurgeon,
first introduced whole body hypothermia as a treatment
H. Wang et al.
for malignancies and head injuries [10]. A young woman
with intractable pain from metastatic breast carcinoma
was referred to Fay’s service for possible cordotomy.
After several weeks of deliberate delay from ‘‘fear of
the unknown possibilities and the physiologic teachings
of the past, which had indicated that human beings could
not long survive at temperatures below 95 F’’, Fay finally
reached the determination to carry out the plan. It was a
cool crisp wintry day in Philadelphia. After shutting off
the heat and closing the door to the hall, Fay opened all
the windows allowing Nature herself to supply the cold
air that aided the 150 pounds of cracked ice amongst
which his patient lay. A laboratory thermometer was used
for rectal temperature recording because clinical thermom-
eters were not calibrated below 94 F in those days. The
patient’s rectal temperature was rapidly lowered to 90 F
and remained in that state for 18 hours. The patient was
then rewarmed by heat applied to the body surface and a
hot coffee enema. ‘‘Within a few hours the patient had
returned again to conscious levels and was not aware of
the experience through which she had been taken’’.
However, the nursing staff was unwilling to participate
in this type of ‘‘radical’’ therapy because of undesirable
working environment, difficulty in monitoring vital
signs, and poor temperature control. No nurse wanted
the ‘‘Refrigeration Service’’, and a state of mutiny was
prevailing. Fay subsequently developed a special cooling
blanket (Fig. 1). He conducted 169 episodes of total
human refrigeration on patients desiring a respite from
intractable chronic pain associated with metastatic
malignancy. An amazingly low mortality (11.2%) and
a high success of pain relief (95.7%) were observed [10].
Through direct irrigation and intracranial implanta-
tion of a metal capsule (Fig. 2), Fay delivered localized
Fig. 1. Special insulated mattress is between the bed
and the ‘‘zipper’’ blanket containing rubber tubing for
continuous circulation of chilled solution. The addi-
tion of hood allows full application of cold to the head
Cold as a therapeutic agent
Fig. 2. Pneumoencephalogram showing large postoperative decompressive craniotomy with refrigeration capsule in place
Fig. 3. Instruments devised for application of local refrigeration
hypothermia in the post-craniotomy tumor bed. Local-
ized refrigeration delivered through various ingeniously
devised instruments (Fig. 3) was also routinely applied
to patients with cerebritis, brain abscess, and osteomye-
litis of the skull before the advent of antibiotics. For
patients with severe head injuries, Fay developed a
deliberate hypothermia program. The lowest rectal tem-
perature achieved was 75 F for 3 days and the patient
recovered fully. Although Fay’s data were presented at
the Third International Cancer Congress in 1939, the
manuscript forwarded to Belgium for publication was
567
confiscated by the Nazis. In Nazi concentration camps,
especially Dachau, these techniques were brutally ap-
plied without any benefit of anesthesia. Such atrocities
were exposed in part at the N€urnberg trials. The benefits
of clinical hypothermia were set back for decades by
association with Nazis’ infamous abuse of such a po-
tential therapeutic aid. Although World War II inter-
rupted the ‘‘Human Refrigeration Program’’, Fay sent his
equipment and apparatus to Claude Beck and Charles
Bailey to facilitate the pioneer work of hypothermia in
cardiac surgery [10].
Irving Cooper and cryogenic surgery
In 1961, neurosurgeon Irving Cooper developed the
first closed cryoprobe system cooled by liquid nitrogen
( 196  C) and ushered in the modern era of cryogenic
surgery [8]. Although the apparatus was designed to
produce a cryogenic lesion in the brain for the treatment
of parkinsonism, interest in clinical cryosurgery bur-
geoned after its development. Cooper’s pioneer work
in employing this technique in the treatment of extra-
pyramidal disorders, intracranial tumors, cancer of the
rectum, and ophthalmological disorders stimulated the
interest of his associates in other specialties. Cryosur-
gery began to be used in treating advanced malignancies
in diverse sites [12].
In 1963, Cooper attempted the destruction of the pitu-
itary gland with the cryoprobe through a transfrontal
approach. Rand et al. subsequently described a tech-
nique for stereotactic cryohypophysectomy via a trans-
sphenoidal approach. Wilson and associates reported on
stereotactic cryohypophysectomy for functioning pi-
tuitary tumors [12]. Between 1963 and 1970, Cooper
and his associates performed stereotactic cryosurgery
568
of the basal ganglia in approximately 8,000 patients with
parkinsonism. Benefits were evident in 85–90% of these
patients [27]. However, when L-dopa came into use in
1968, cryosurgery fell into disfavor.
The development of intraoperative ultrasound and its
use to monitor the process of tissue freezing revived the
interest in cryosurgery in the 1990s. Such renaissance of
interest was most evident in the treatment of prostatic
and hepatic cancers by freezing. The rapid advance-
ments made in the intracranial imaging techniques may
warrant a reappraisal of the cryosurgical treatment of
brain tumors [12].
Further development of hypothermia
In 1958, James Miller from New Orleans and Bjorn
Westin from Stockholm conducted a striking clinical
study involving 10 severely depressed term infants who
had failed conventional resuscitation methods available
at the time [28]. The apneic infants were immersed in a
specially constructed cold water bath. Cooling was stopped
when spontaneous respirations commenced or when
the rectal temperature approached 27  C. The infants
were then dried and allowed to rewarm spontaneously.
Minimum core temperature was between 23  C and
30  C and periods of apnea ranged from 8 to 79 minutes.
At follow-up 10 years later, none of the survived nine
infants showed neurological impairment or cerebral palsy.
Also in 1958, extracorporeal cooling with a pump
oxygenator was used successfully for open-heart surgery
[22]. Pioneering work in the 1950s on profound whole-
body hypothermia for neuroprotection during cardiovas-
cular and neurosurgical procedures [5, 9, 20] introduced
deep hypothermia into modern clinical neurosurgical
practice [24–26].
It was initially believed that only moderate to deep
hypothermia could be therapeutic as a form of cerebral
resuscitation. Although many centers employed hypo-
thermia in the 1950s and 60s, it was largely abandoned
thereafter because of the significant side effects and
associated management problems of moderate hypother-
mia (life-threatening arrhythmia, infection, coagulopa-
thy, etc.). After lying dormant for decades, the interest
in hypothermia was rekindled in the late 80s when even
mild hypothermia was shown to confer dramatic neuro-
protection in a number of experimental models of brain
injury [6, 14, 21]. Since then, improved neurological
outcome with induced hypothermia was demonstrated
in two prospective, randomized, controlled trials in
patients with anoxic brain injury from prehospital car-
H. Wang et al.
diac arrest [4, 18]. Prospective, randomized, controlled
trials have also been conducted in patients with severe
head injury and results have been mixed [3]. Encourag-
ing preliminary results are becoming available in pa-
tients with severe stroke, newborn hypoxic-ischemic
encephalopathy, meningitis=encephalitis, and hepatic
encephalopathy [3]. Several large multi-center clinical
studies of hypothermia are currently under way [3].
Mechanisms of hypothermic neuroprotection
The mechanisms of hypothermic neuroprotection are
not completely understood, but most likely depend to
some degree on the type of hypothermia. Whole body
hypothermia changes the core temperature and initiates
systemic effects. Localized or regional hypothermia pro-
duces focal cooling in the tissue of injury without signif-
icantly affecting the body temperature, while cryogenic
lesioning results in focal tissue destruction to render its
therapeutic effects.
Hypothermia most likely affects a multitude of poten-
tial pathways highly relevant to tissue injuries from ische-
mia and reperfusion [2, 7, 15–17, 23]. Ischemic injury
results in membrane depolarization, calcium influx, gluta-
mate release, acidosis, and activation of lipases, proteases,
and nucleases. Cascades involving iron, free radicals,
nitric oxide, catecholamines, renewed excitatory amino
acid release, and renewed calcium shifts are initiated and
eventually lead to mitochondrial damage, DNA frag-
mentation, and scattered cell death. Mild hypothermia,
in addition to reducing oxygen demand, may mitigate
exitotoxicity, free radical reactions, edema, intracranial
pressure, cell destructive enzymes, and other deleterious
cascades. Because neurologic damage during ischemia
and reperfusion is a multifactorial process, hypothermia
with its potential global effects involving multiple mech-
anisms may be a more successful intervention than any
single pharmacologic intervention. This may also explain
why hypothermic neuroprotection is evident in a large
number of injury models with different pathologies.
Conclusion
The use of cold as a therapeutic agent has a long and
colorful history. Although the potentials of various types
of hypothermia offering great therapeutic effects have
been well reported, relatively few studies of high sci-
entific merits have demonstrated sustained success.
Furthermore, despite of encouraging preliminary results
in many areas of medicine, there are few well establish-
ed indications for resuscitative (post-injury) hypother-
Cold as a therapeutic agent
mia. Future attempts may continue to be challenged by a
currently poorly defined but most likely very brief ‘‘ther-
apeutic window’’ within which hypothermia must be
instituted to render its post-injury therapeutic effects.
However, improved neurological outcome with induced
hypothermia was recently demonstrated in two prospec-
tive, randomized, controlled trials in patients with anox-
ic brain injury from prehospital cardiac arrest [4, 18].
Hypothermia as a potentially important clinical therapy
continues to be heavily pursued in patients with se-
vere stroke, traumatic brain injury, newborn hypoxic-
ischemic encephalopathy, meningitis=encephalitis, and
hepatic encephalopathy [3]. Several large multi-center
clinical studies of hypothermia are currently under way
[3]. Will this tortuous historical pathway finally arrive at
its destination in the twenty-first century? Will therapeu-
tic hypothermia become the latest child of a marvelous
age for neurosurgery? Temple Fay and Irving Cooper
threw out the torch still awaiting to be re-claimed by
the succeeding generations of neurosurgeons.
Acknowledgment
The authors wish to acknowledge the secretarial assistance of Mrs.
JoAnna Gass in the preparation of this manuscript.
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Comments
The authors present a historical account of the use of hypothermia as a
special type of treatment for special disorders. As there are only a few
studies demonstrating long-lasting success from hypothermia, the
authors conclude future studies should try to define the ‘‘therapeutic
window’’ of cold after injury.
A historical appraisal of hypothermia can never claim to be complete.
A few additions may be suggested.
It may be added here that the idea of cold as a major therapeutic tool
had been supported by Laborit and Huguenard after the second world
war (Laborit, H. et Huguenard, P.: Tratique de l’hibernotherapie en
570
chirurgie et en medecine. Paris, Masson & Co, 1954). While the pro-
tective effect of cold against hypoxia is well known it should be dis-
cussed that there has been no evidence of benefit from cold after an
injury had been inflicted. As cold severely depresses immunoreactivity,
cold could also delay repair of lesions of the nervous system. Recent
studies on hypothermia in head injury had been terminated because of
the severe side effects, especially pneumonia.
Raimund Firsching
Magdeburg
H. Wang et al.: Cold as a therapeutic agent
An extremely well-written paper which was both interesting and
educational. I am sure the majority of readers have not considered the
historical aspects of cryotherapy.
Jake Timothy
Leeds
Correspondence: Giuseppe Lanzino, UICOMP, PO Box 1649, Peoria,
IL 61656, USA. e-mail: lanzino@uic.edu