Hypothermia in acute blunt head injury

RESUSCITATION

ELSEVIER

Resuscitation

28

(I 994) 9- 19

Review article

Hypothermia

in acute blunt head injury

Leopold0 C. Cancio* a, William G. Worthamb, Frank Zimba” “General Surgery Service, bDepartment of Medicine, ‘Neurosurgery Service, Brooke Army Medical Center, Fort Sam Houston, Texas 78234, USA Received

20 September

1993; accepted

30 March

1994

Abstract Mild to moderate hypothermia has been employed since the 1940s in the treatment of acute blunt head trauma. The utility of hypothermia in ischemic injury has been confirmed, by both animal studies and clinical experience, in cardiovascular and neurological surgery. In blunt injury, though, only one prospective, randomized study has shown a statistically significant improvement in long term outcome. Clinical experience, animal data, proposed mechanisms, technical considerations, and potential risks are reviewed. Hypothermia remains controversial in the setting of blunt head injury but may prove to be a useful treatment modality. Keyword:

Head injuries, closed; Brain injuries; Hypothermia,

induced

1. Introduction

2. Clinical studies

Hypothermia has been utilized for cerebral protection since the 1930s [I]. Animal studies and clinical experience in both cardiovascular and neurological surgery confirm the beneficial role of hypothermia in ischemic injury, while there is a need for prospective, randomized studies to evaluate its role in blunt head injury. The mechanisms by which hypothermia protects the brain are also controversial. This article reviews the use of mild to moderate hypothermia in head injured patients, to include clinical and laboratory experience, techniques available, and potential complications.

In 1936 Temple Fay, a neurosurgeon, postulated that cancer cell growth might be inhibited by low temperatures. He treated a patient’s invasive cervical cancer with local refrigeration, and noted pain relief and tumor shrinkage [1,2]. In another case, he was faced with metastases to the brain, chest and spine; since these were not locally accessible, he decided to refrigerate the entire patient. He did so by sedating her and surrounding her with cracked ice [3]. He developed the cooling blanket for topical cooling, and a method for direct local cooling of the brain. Over a 4-year period he subjected 126 patients to local and/or general refrigeration [4]. Neurologic exams were performed on a series

* Corresponding author. 0300-9572/94/$07.00 0 1994 Elsevier Science Ireland SSDI 0300-9572(94)00766-Z

Ltd. All rights reserved

10

L.C. Cancio et al. /Resuscitation

of 42 patients while they were cooled as low as 23.4”C for 1-5 days; although neurologic function declined gradually with decreasing temperature, all patients emerged neurologically intact once warmed [5]. Noting that pre-terminal head injured patients occasionally became febrile to as high as 41-42”C, he then cooled two such patients to 33°C [5], with encouraging results. Fay’s work led to the use of hypothermia for cerebral protection in a variety of settings. A review of the literature disclosed that a total of 628 blunt head injured patients treated with hypothermia have been reported in the West; this experience is summarized in Table 1. Three studies evaluated outcome in a prospective, randomized fashion. Clifton [6] randomized 30 patients with low initial Glasgow Coma Scale (GCS) scores [7] to normothermia vs. hypothermia. The GCS score at 2 1 days was significantly higher in the hypother-

28 (1994) 9-19

mia group, but outcome data at 3 and 6 months showed only a strong trend in favor of hypothermia. Marion [S] similarly randomized 40 patients at initial presentation and also found a trend toward better outcome at 3 months. Shiozaki [9] enrolled 33 patients whose ICPs were uncontrolled despite conventional therapy and found a signiticant improvement in survival with a trend towards improved outcome at 6 months. Thus, aside from the effect on mortality observed by Shiozaki, no prospective study has shown long term statistically significant outcome benefit from hypothermia. Hypothermia has also been used for cerebral protection in cardiovascular surgery. In 1949 hypothermia was employed to decrease systemic oxygen demand during pediatric heart surgery [lo]. Hypothermic total circulatory arrest was developed to enable cardiac surgery without bypass [ 1l- 131. This technique has been employed in the

Table 1 Hypothermia in blunt head trauma: clinical experience, 1945-1993 Year

Author [reference]

1945 1954 1957 1958 1958 1958 1958 1959 1962 1963 1963 1966 1967 1974 1977 1984 1985 I992 1992 1993 1993 1993 1993 I994 TOTAL

Woringer [I351 Mosca [I361 Lazorthes 11371 Sedzimir [ 1381 Borri [I391 Tonso [140] Hendrick [I411 Drake [133] Morando [142) Kavazarakis [143] Bouzarth [I441 Ciofti [I451 Shapiro [I461 James [I471 Nordby [148] Legros [ 1491 Elias-Jones [ 1SO] Clifton (ISI] Clifton [6] Vise [I521 Marion [S] Shiozaki (91 Resnick [ 13I]

Pay 111

NA, not available

Patients (n) 2 19 43 47 30 26 18

21 61 31 16 100 3 15 16 27 39 IO 16 31 20 16 20 628

Temperature (“C)

Mortality (%)

33 na 34.5-35 30-37 34 34-35 36.8 31-32 28-36 34-35 34-37 31-35 ~29 30-32 27-36 32-35 32 32 30-32 32-33 30 32-33 33.5-34.5 32-33

16 (84) 21 (49) 34 (72) 4 (13) 11 (42) 0 (0) IO (56) 9 (43) 18 (30) 13 (42) 3 (19) NA 2 (67) NA 6 (38) 19 (70) 9 (23) 1 (JO) 4 (25) 7 (23) 0 (0) 8 (50) NA

Comments

0 (0)

Children

Barbituates; ICP monitor

Children Prospective Prospective Historical controls Prospective Prospective Coagulation study

L.C. Cancio et al. /Resuscitation

surgery of pediatric congenital heart lesions [ 14- 171;and of difficult thoracic aortic aneurysms [18-201. In 1955 hypothermia was first applied in nontrauma neurological surgery. Two patients were cooled to 26°C and underwent successful resection of otherwise inoperable intracranial lesions [2 I]. This entailed partial or complete occlusion of both carotid and vertebral arteries for up to 14 min. Others carried out neurosurgical operations under hypotension and hypothermia without vascular occlusion [22,23]; and then under hypothermic cardiac arrest [24]. The development of cardiopulmonary bypass facilitated hypothermic circulatory arrest in the treatment of intracranial aneurysms during the 1960s; temperatures of 12-18°C allowed arrest times of up to 1 h. Subsequently, bypassrelated complications, development of the operating microscope, and anesthesic advances made circulatory arrest obsolete for all but the most difficult cases [25,26]. Moderate hypothermia to 32°C without arrest has also recently been used for cerebral protection in neurosurgery [27]. Hypothermia has been advocated for cerebral resuscitation following cardiac arrest [28]. Benefit

Table 2 Animal models of hypothermia Author [reference]

Animal

Method

Temperature

of injury

dura dura

25 25

Cat

Cold to exposed

brain

25-28

Mullan [42] Rosomoff [75] Bouzarth [4l]

Dog Dog Dois

28-30 25

Clifton

pt I [38]

Rat

Clifton

pt 2 1381

Rat

Piston blow to skull Cold to exposed dura Blasting caps to both zygomata Epidural saline injection Epidural saline injection Epidural balloon inflation Epidural balloon inflation

Ebmeyer Pomeranz

has been shown in controlled canine studies for mild to moderate hypothermia induced immediately following arrest; no controlled clinical trials have been performed [29-321. Hypothermia has been used in the treatment of non-traumatic encephalopathies with elevated intracranial pressure in children. Results have been mixed [33-351.

3. Animal studies Animal studies have sought to corroborate clinical findings and to elucidate the mechanisms by which hypothermia confers a protective effect. Animal simulations of closed head injury have yielded mixed results, with some in favor of hypothermia [36-401, and others showing no benefit or a detrimental effect [41,42]. These results are summarized in Table 2. Note that among the early models of closed head trauma were cold injury models, in which a cylinder containing dry ice, liquid air, or liquid nitrogen was applied to exposed dura or brain in order to cause a reproducible injury. Advantages and disadvantages of various

Delay

Outcome

for cooled group

Prior Prior vs. l-12 h Prior vs. 6h I5 min Prior

Decreased No deaths if cooled Decreased

15 min Prior

No change in mortality Decreased mortality in 30°C group

Prior

Improved

beam-balance

I5 min

Decreased

volume of injured

brain

I5 min

Decreased

volume of injured

brain

(“C) Cold to exposed Cold to exposed

Laskowski

II

in blunt head injury

Dog Dog

Rosomoff Rosomoff

28 (1994) 9-19

[44] [36] [37]

[40] [39]

Dog

Dog

All studies used surface

cooling.

31 36 vs. 36 vs. 31

vs. 33 30 vs. 33 30

31 x 5 min. 35 x 5-62 h

edema & WBC response if cooled before 3 h; no protection after 7 h edema in prior group

Increased mortality Faster transition to reparative

phase of injury

performance

12

L.C. Cancio et al. /Resuscitation 28 (1994) 9-19

animal models of blunt head injury have been reviewed [43]. Other animal studies have examined various models of ischemic injury as opposed to blunt trauma. Most studies support the use of hypothermia in ischemic injury [44-591, whereas others do not [60-621. These studies have been extensively reviewed [63]. Their application to blunt trauma is based on the observation that ischemia may play a prominent role in the pathophysiology of blunt injury. Ninety percent of patients dying of blunt head injury showed ischemic changes at autopsy [64]. Xenon-133 cerebral blood flow studies conducted during the initial computerized tomography scan demonstrated a 3 1% incidence of ischemia in blunt head injured patients [65]. Some animal models of blunt injury, however, have failed to demonstrate regional blood flow decrements or histopathological evidence of ischemia [66]. The mechanism of action of hypothermia has been evaluated at metabolic, cellular, and molecular levels. At the metabolic level, hypothermia may improve substrate supply to, and reduce demand from, marginal ischemic neurons. Rosomoff measured cerebral oxygen consumption (CMRo2) in uninjured hypothermic dogs, and found that it decreases proportionately with temperature. Cerebral blood flow (CBF) also varied proportionately with temperature to the same extent as CMRO, [67]. He also showed that hypothermia causes a decrease in the brain volume (BV) and CSF pressure of hypothermic dogs [68]. Other workers confirmed that hypothermia reduces CMRo2 [69-721. As has been observed clinically, hypothermia reduces ICP in head injured animals as well [39, 401. These effects - decreased CMRO,, CBF, BV, and ICP - may in turn exert a beneficial effect in head injury, although the mechanism is unclear. In part, the survival of neurons in a marginal ischemic penumbra may be increased [26,73]. These mechanisms may be analagous to those proposed for barbituates, which may improve neuronal survival by decreasing metabolic demand; or by decreasing CBF, cerebral blood volume, and ICP, thus improving global perfusion [74]. There is no clear-cut evidence, however, that the mechanism of hypothermia and barbituates is the same; and the concept

of an improved supply/demand relationship in hypothermia is not fully supported by recent molecular evidence (see below). At the cellular level, hypothermia may modulate the inflammatory response to injury. In a cold injury model of closed head trauma, Rosomoff found histological evidence of decreased cellular damage, interstitial edema, hemorrhage, and neutrophilic infiltration in dogs pretreated with hypothermia to 25°C [44]. He then found that dogs injured during hypothermia appeared to progress more rapidly through the various phases of wound healing [75]. Hypothermia also reduces blood-brain barrier disruption in traumatic [76], ischemic [77], and cold injury [37], although control of post-injury hypertension may play a role in reducing tracer leakage [76]. Recent efforts have examined the effect of hypothermia at the molecular level. It has been proposed that blunt head injury involves a massive release of excitatory neurotransmitters such as glutamate and dopamine. These in turn result in transient or permanent cell dysfunction [66]. Improved histopathologic outcome with hypothermia in temporary global ischemic injury of the rat was not due to a decrease in the severity of the initial insult, as measured by ATP, glucose, glycogen, and pyruvate depletion and by lactate accumulation [49,78]. Rather, hypothermia decreases dopamine and glutamate release [78]. It also decreases levels of acetylcholine [79] and glycine [80]. On the one hand, these changes may reflect a decrease in endogenous neurotransmitter production; release of neurotransmitters from synaptic vesicles has been shown in some animals to decrease with hypothermia [81,82]. On the other hand, there may also be a decrease in exogenous entry of neurotransmitters due to blood-brain barrier stabilization [66]. Hypothermia modulates a variety of other molecular processes. It decreases the early postischemic production of leukotriene B4, a membrane breakdown product which causes cerebral edema [50]. It may stabilize cell membranes by an effect on the Na-K pump [73]. On the other hand, mild hypothermia does not alter the accumulation in ischemia of free fatty acids, which are a cell membrane breakdown product [78]. Hypothermia

L.C. Cancio et al. / Re&imiion 28 (1994) 9-19

abolishes the ischemic inhibition of protein kinase C; this is a calcium dependent enzyme involved in neurotransmitter release [83]. Hypothermia also reduces ischemic inhibition of calcium/calmodulin-dependent protein kinase II, another critical mediator [78]. Hypothermia may also alter the expression of the immediate-early genes involved in the cell death process [54]. Other proposed mechanisms have been reviewed [63,77].

4. Technique Head injured patients may be treated by general hypothermia and/or by selective brain cooling. Most studies of general hypothermia in humans have employed topical cooling methods similar to those first developed by Dr Fay, with the occasional addition of chilled intravenous fluid [30] or iced gastric lavage [38, 84-881. Other methods include continous arterio-venous shunt cooling [89], veno-venous shunt cooling [90], instillation of cold fluid into the chest [91], and cardiopulmonary bypass [92]. Peritoneal lavage or dialysis is effective; it can be performed intermittently with one tube, or continuously using two tubes [93-951. Intermittent peritoneal dialysis with refrigerated fluid has been used by us in head injured patients where topical cooling failed (961. In a canine heatstroke model, peritoneal lavage (6- 1O’C) cooled faster than external application of bags of ice slush [94]. But, in a similar model, continous peritoneal lavage (6°C) was no faster than spraying the dogs with 15°C water through a hose with a large fan [951. Antipyretics such as indomethacin [97,98] and acetominophen [99] have been used to lower core temperature in head injured patients, and indomethacin has also been noted to decrease cerebral blood flow via cerebral vasoconstriction [98]. Sedation and occasionally paralysis have been a part of most regimens of general hypothermia, as shivering must be avoided. Selective head cooling has been advocated on the theory that it avoids the systemic complications of generalized cooling. Topical head cooling has been accomplished in animals with ice [29,100,101], with a copper cooling helmet [53], or

13

with nasopharyngeal lavage [30,51]. Topical head cooling has been less successful in humans. Wrapping blocks of frozen liquid around the head, using a cooling helmet, and blowing cool oxygen into the nasopharynx were all ineffective [99]. On the other hand, pumping cooled Ringer’s lactate [57] or cooled blood from the femoral [ 102,103] or carotid arteries [ 104,105] into the cerebral circulation has been successful. Direct cooling of exposed brain was described by Fay [3]. Infusion of cold normal saline into the ventricles has been performed [103]. How soon after injury should hypothermia be instituted? Several animal studies have demonstrated decreased benefit with delays in treatment. Waiting more than 7-8 h post injury caused the mortality rate of treated dogs to equal that of normothermic dogs [36]. Rats treated with hypothermia at the time of ischemic injury had less damage than those in whom hypothermia was delayed by only 30 min [ 1061.Initiation of hypothermia in the field has been proposed [39]. The duration of hypothermia is controversial, with some studies showing an increase in complications with prolonged treatment (see below). On the other hand, the rewarming phase may be particularly dangerous [39]; 17 of the 19 patients who died in Fay’s series of 124 neurosurgical patients did so during rewarming or shortly thereafter [3], suggesting that slow rewarming may be beneficial. What temperature range should be sought? Whereas temperatures of lo-20°C enable a patient to withstand total circulatory arrest, and might be useful in head injury as well, the cardiovascular and hemostatic complications noted below 28°C are prohibitive. In dogs subjected to cardiac arrest, hypothermia to 15°C produced a worse neurological and myocardial outcome than did 34°C for unclear reasons [32]. Furthermore, animal studies have shown that mild hypothermia of 30-35°C provides significant neurological protection over normothermia [29,41,49,52,55]. As a minimum, avoidance of fever may be critical [41,49,63,107]. Brain temperature (as tympanic membrane, nasopharyngeal, or ICP probe temperature) and core temperature (as pulmonary arterial, central venous, or esophageal temperature) should be

14

L.C. Cancio et al. /Resuscitation

monitored separately [31], since these may differ significantly [63]. 5. Complications Several complications of hypothermia may also affect its clinical utility; these have been comprehensively reviewed [ 1081. Neurologically, even extreme hypothermia may be well tolerated - dogs have safely sustained total circulatory arrest with complete blood substitution for 3 h at 1.7”C [log]. On the other hand, one report found that cultured spinal neurons suffered significant damage at temperatures below 17°C [ 1lo]. Rewarming may be associated increased intracranial pressures [39,40]. The impact of hypothermia on the cardiovascular system is controversial. Sinus bradycardia is common. Cardiac contractility, measured in a variety of ways, increases down to about 25°C [ 1111. Thus, stroke volume may increase and cardiac output may be maintained [112]. On the other hand, some have reported decreased ejection fraction and cardiac output [ 1131, particularly with hypothermic times of lo-24 h or more [ 114,115]. Ventricular irritability and fibrillation is increasingly common below 2528°C [111,116,117]. During external rewarming, patients may be vulnerable to rewarming shock due to peripheral vasodilation [ 1181. Hematologic effects include increased blood viscocity [ 119,120] and coagulopathy. Hypothermia may cause coagulopathy by inhibiting coagulation cascade enzymes [121], by increasing fibrinolysis, and by interfering with platelet availability and function [93,122]. Several studies of multiple trauma victims have noted the association between hypothermia, acidosis, coagulopathy, and exsanguination [ 123- 1271. Post-operative bleeding was felt to be a troublesome problem in neurosurgical cases performed with hypothermic cardiopulmonary bypass [26]. Disseminated intravascular coagulation is well known in patients who sustain serious brain injury, particularly when massive tissue destruction, as opposed to extraaxial compression, is present [ 128- 1301. However, a prospective randomized study of hypothermia in 36 head injured patients noted no statistically sig-

28 (1994) 9-19

nificant difference in prothrombin time, partial thromboplastin time, incidence of thrombocytopenia, or incidence of delayed post-traumatic hemorrhage between normothermic patients and those intentionally cooled to 32-33°C for 24 h [131]. Admission hypothermia was not an independent predictor of adverse outcome in multiple trauma patients [ 1321.Thus hypothermia may be less likely to cause coagulopathy in the absence of systemic inflammatory processes such as bypass, systemic hypoperfusion, or massive brain tissue destruction. Clearly, though, careful patient selection and coagulation study monitoring is warranted in therapeutic hypothermia. Several authors have commented on an increased incidence of pneumonia in head injured patients treated with hypothermia [6, 133). This may reflect inhibition of neutrophil release [134] or other factors. 6. Conclusions Hypothermia has been used in the treatment of acute blunt head injury since the 1940s. It is of proven utility for cerebral protection during cardiovascular and neurological surgery. Prospective, randomized clinical studies of its efficacy in head injured patients are needed; several are ongoing. The mechanism by which hypothermia exerts its protective effect is unclear but probably multifactorial. Animal studies have focused on the ischemic brain, with several closed head injury models now available. Hypothermia to 30°C in the patient with isolated head injuries is well-tolerated, and may be adequate to confer cerebral protection without significant risk. It may worsen coagulopathy in multiple trauma victims. The sooner cooling begins after injury, the more likely it is to be beneficial. Acknowledgements

The authors gratefully acknowledge the tireless efforts of librarians Martin Perez Jr. and Geraldine Trumble; the helpful comments of Russell R. Martin, MD; and the linguistic assistance of Dr Michael Dechert and MS Renee Gamm.

L. C. Cancio et al. / Resuscitation 28 (I 994) 9- I9

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