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This study analyzed the predictable factors of outcome such as neuro-parameters and systemic complications to elucidate the indications for therapeutic hypothermia. In our institute, 35 patients with severe head injury (Glasgow Coma Scale 3-7) were treated with mild hypothermia therapy (33-35wC). Twenty-two of these 35 patients underwent complete neuromonitoring and outcome assessments by Glasgow Outcome Scale (GOS) at three months after injury. GOS of hypothermia group was significantly better than another patient group which was treated without mild hypothermia therapy. The hypothermia group was divided into two groups: good outcome (GOOD) (good recovery or moderate disability; n = 9, 40.9%) and poor outcome (POOR) (severe disability, vegetative state, or death; n = 13, 59.1 %). The mean age (mean 30.2 years, range 9-46) was significantly lower in GOOD than in POOR (mean 45.2 years, range 17-62). Patients aged over 50 years had poor outcome. CPP was significantly higher in GOOD during hypothermia. All patients with thrombocytopenia had poor outcome. Hypothermia therapy can improve outcome in patients with traumatic brain injury who are younger than 50 years old, without severe brain damage, and if improvement of cerebral perfusion is expected. Systemic complications must be prevented as far as possible by combination with other therapies. [Neurol Res 2002; 24: 789-795]

Keywords: Cerebral perfusion pressure; hypothermia; intracranial pressure; jugular venous blood oxygen saturation; prognosis; traumatic brain injury

INTRODUCTION

Hypothermia therapy is widely accepted as a useful therapeutic option for brain damage caused by trauma, ischemic stroke, and metabolic brain injury based on both laboratory and clinical studies1-7. Hypothermia clearly reduced the neuronal damage in traumatic brain injury models8-10. The beneficial effects of hypothermia are believed to occur via neuro-metabolic, neurochemical, and pathological processes. Such neuroprotective effects involve the temperature-dependent reduction of cerebral metabolic rate for oxygen, decreased excitatory amino acid release, attenuation of ionic disruption, suppression of free radical production, and limitation of blood-brain barrier disruption10-15.

Severe systemic complications are associated with hypothermia, including cardiac arrhythmia, coagulation disorder, and pneumonia 16-18. Mild and moderate hypothermia (32deg-34degC) have been used to treat patients with severe head injury to avoid systemic complication3,5. Prolonged induced hypothermia therapy is also a useful clinical method, as combined with mild hypothermia19,20. In contrast, a multicenter study showed that moderate hypothermia therapy (32deg-33degC) for 48h did not produce significant neurological improvement21. However, there was evidence of benefit in subgroups consisting of younger patients with normal systemic hydration, patients cooled before hospitalization, and others.

This study analyzed the factors predictive of outcome such as neuro-parameters and systemic complications to elucidate the indications for therapeutic hypothermia.

MATERIALS AND METHODS

Patient population

Eighty-four patients with severe traumatic brain injury, with a score 3 to 7 on the Glasgow Coma Scale (GCS), were admitted to the Department of Neurosurgery, Juntendo University, Izunagaoka Hospital from 1993 through 2000. Thirty-five of these 84 patients were treated by mild hypothermia therapy (33deg-35degC), since we had indicated mild hypothermia therapy in 1995. Twenty-two of these 35 patients were monitored using mean arterial blood pressure (ABP), intracranial pressure (ICP), jugular vein oxygen saturation (Sj02), arteriovenous jugular oxygen content difference (AVDO^sub 2^), and brain temperature, and were included in this study. In 49 patients without mild hypothermia therapy, 17 patients treated with Barbiturate were defined as nonhypothermia group, who were able to have three month outcome assessments by GOS.

Neuromonitoring

All patients were ventilated with arterial blood gas analysis monitoring under sedation with midazolam (0.05 mg kg^sup -1^ h^sup -1^) and vecuronium bromide (0.05 mg kg^sup -1^ h^sup -1^) during the hypothermia therapy. Brain temperature was maintained between 32degC and 35degC using a water-circulating cooling blanket (Gaymar Industries, Orchard Park, NY, USA). The mean ABP was continuously monitored through the radial artery. The ICP and the brain temperature were continuously measured using a fiberoptic transducer-tipped catheter (Integra Neurocare, San Diego, CA, USA). The cerebral perfusion pressure (CPP) was calculated as [CPP = mean ABP ICP]. The bladder temperature was also monitored as the body core temperature. The SjO^sub 2^ was continuously monitored via a fiberoptic catheter (Abbott Laboratories, North Chicago, IL, USA) and intermittently analyzed by jugular blood sampling. The AVDO2 was calculated as follows: [AVDO^sub 2^=(SaO^sub 2^ SvO^sub 2^) * Hb 1.34+(PaO^sub 2^ PvO^sub 2^) * 0.003] where SaO^sub 2^: arterial oxygen saturation, SvO^sub 2^: venous oxygen saturation, Hb: hemoglobin, PaO^sub 2^: arterial oxygen tension, and PvO^sub 2^: venous oxygen tension.

Treatment protocol

All patients were admitted to our institution within 3 h after head injury. Intracranial hematomas and hemorrhagic contusions were evacuated immediately after diagnosis based on CT. External decompression was performed if conditions leading to high ICP such as acute brain swelling were expected. In several cases, an additional surgical approach was taken to maintain ICP during hypothermia. The mild hypothermia therapy was started rapidly after hospitalization or during surgery, and was maintained for at least 36 h to seven days maximum, according to the severity of brain injury. During hypothermia, arterial carbon dioxide tension (PaC02) was maintained between 30 and 35 mmHg to reduce ICP as mild hyperventilation therapy. CPP was maintained higher than 70 mmHg at all times by administering osmotic agents to decrease ICP and/or catecholamines to induce hypertension. The period of re-warming was determined by findings of normalized ICP or by follow-up CT findings showing improvement of cerebral swelling, mid-line shift, or mass effects. The patients were passively rewarmed to 36.5deg-37.0degC at a rate no greater than 0.5degC/12 h. General blood laboratory examinations were performed every day. Any abnormal finding was corrected if possible in each case.

In nonhypothermia group, thiopental sodium was continuously given by 3 to 5 mg kg^sup -1^ h^sup -1^ for two or three days. The neuro-monitoring, ICP management and other patient care was given to them as well as the hypothermia group.

Assessment of neurological outcome

The neurological outcome was scored according to the Glasgow Outcome Scale at three months after injury. The patients were divided into two groups: Good outcome with good recovery or moderate disability, and poor outcome with severe disability, vegetative state, and death.

The base-line characteristics, CT findings, and complications were compared between these groups. Neuromonitoring parameters of ICP, CPP, cerebral blood flow, and cerebral metabolism were statistically analyzed as prognostic factors.

RESULTS

The hypothermia group had significantly better outcome than nonhypothermia group in this study (Figure 1). The mortality rate in hypothermia group (18.2%) also was radically improved against nonhypothermia group (52.9%: rho

The clinical profiles of the 22 patients are shown in Table 1. There were significantly more males than females among the presented cases. The initial GCS was similar in the good outcome group and poor outcome group. A few patients with lower GCS (3-4 scores) had a good outcome. The mean age (30.2 years, range 9-46) in the good outcome group was significantly lower than in the poor outcome group (47.7 years, range 17-62). All patients over 50 years old had a poor outcome (Figure 2). Mean ABP, body temperature, pH, PaO^sub 2^, and PaCO^sub 2^ on admission were not significantly different in the two groups. Two patients with hyperthermia (>38degC) on admission had a poor outcome, but the difference was not significant (Table 2).

The mean time ( +/- standard error) after injury before the bladder or brain temperature reached 35degC was 6.9 +/- 1.2 h in the good outcome group, and 8.0 +/- 1.6 h in the poor outcome group. There was no correlation between the time to reach the target temperature and the outcome. Duration of hypothermia therapy in the poor outcome group tended to be longer than in the good outcome group but not significantly. Overall, 17 patients (77.3%) underwent evacuation of mass and external decompression with extended dural plasty. The requirement for surgical decompression was not different in the two groups (Table 2).

The CT classification in hypothermia group is shown in Table 3. Fifteen patients had acute subdural hematoma (SDH), six in the good outcome group and nine in the poor outcome group. There was no significant difference. However, the number of patients with both SDH and cerebral contusion was greater in the poor outcome group. Cerebral contusion injury was more severe in the poor outcome group, but there was no significant difference between the two groups.

The results of the neuromonitoring study are shown in Table 4. The highest ICP during hypothermia, and the mean ICP during hypothermia were not significantly different between the two groups. The lowest CPP during hypothermia was lower in the poor outcome group than in the good outcome group. Mean CPP during hypothermia in the poor outcome group was significantly lower than in the good outcome group. SjO2 and AVD02 showed no significant difference between the outcome groups. The trend of SjO^sub 2^ during hypothermia in each patient is shown in Table 5. Hyperemia was defined as SjO^sub 2^> 80%. Ischemia was defined as SjO^sub 2^

The complication rate during and after hypothermia therapy is shown in Table 1. Cerebral swelling during rewarming occurred in four patients (Table 3). All four patients were in the poor outcome group (rho = 0.07). All six patients with thrombocytopenia had poor outcome. There was no significant difference in pneumonia and liver dysfunction between the two groups.

ILLUSTRATIVE CASES

Case 1

A 23-year-old woman injured in a motor vehicle accident suffered bruising in the right temporal region. The initial GCS was 5 (E1, V1, M3). CT showed an acute SDH, traumatic subarachnoid hemorrhage, and cerebral contusion in the left temporal region (Figure 3A). Acute hematoma was immediately evacuated and external decompression was performed. Systemic hypothermia was started during surgery. The changes in ICP, brain temperature, SjO^sub 2^, and AVDO^sub 2^ are shown in Figure 4A. ICP was maintained by decompression surgery and hypothermia therapy combined with standard treatment. In monitoring of cerebral blood flow and metabolism, hyperemic cerebral perfusion with SjO^sub 2^ of 82.6% was observed after surgery, which was improved during hypothermia therapy. Three months after injury, the patient had recovered to moderate disability.

Case 2

A 43-year-old man fell from a 2 m height and presented with anisocoria greater on the right than the left. GCS on admission was 5t (E1, V1t, M3). CT revealed an acute SDH and cerebral contusion in the right occipital region. Initial CT showed frontal base fracture with pneumocephalus (Figure 38). Monitoring of cerebral perfusion after surgery found ischemia with SjO^sub 2^ of 53.2% (Figure 48). SjO^sub 2^ returned to normal after hypothermia combined with standard therapy. Three months after injury he had moderate disability.

DISCUSSION

The control of brain temperature is one of the most important factors which influence the severities of neuronal damage. Hyperthermia would accelerate the neuronal damage, and hypothermia could be neuroprotective in traumatic brain injurys-5,22. Clinically, the patients with hyperthermia at hospitalization, generally have poor outcome21. In contrast, hypothermia before hospitalization can be a good prediction factor3-5. In our study, the hypothermia protocol has improved the survival ratio to severe traumatic brain injury patients by contrast with barbiturates treatment.

On the other hand, it is a fact that a side effect becomes severe as much as body temperature is low, and as long as that period. The side effects become a major negative factor for the treatment of the brain damage, which the period of hypothermia should be necessary at least for 48 h. As a side effect of hypothermia, the most important factors are repression of an immunity function and coagulation disorder, and occur in serious infection disease or in DIC18,23,24. It experimentally confirms that enough brain protection action is obtained, through the hypothermia therapy being done at present, which maintains brain temperature between 33deg to 35degC9,25.

In the present study, when attempting to evaluate side effects of severe head injury patients which were treated with mild hypothermia therapy, pneumonia was admitted by 72.7% and coagulapathy was admitted by 27.2%. Most pneumonia cases were improved by the strict respiratory management and use of antibiotics. All six patients with thrombocytopenia had poor outcome. Scrupulous management is necessary so as not to cause these complications.

For severe head injury patients, the clinical characteristics including the patient's age, the initial GCS score, and the CT diagnosis are the important factors influencing the outcome26. The present series showed the prognosis was better in younger patients. Conversely, all patients who were over fifty years old, were affected by convalescence defects. Systemic complications such as pneumonia and platelet dysfunction were considered to be a negative factor24,27. Elderly patients easily suffer fatal complications such as cardiac failure, renal failure, or septic infection.

Initial GCS which is correlated with the severity of the brain damage, is also one of the important factors in predicting the outcome28. Several previous studies reported that hypothermia therapy was not effective in patients with initial GCS of 3 or 4. However, three of our younger patients with lower GCS scores of 3 or 4 showed good improvement. The CT findings are another important factor as an index to show the severity of brain damage. CT showed that these patients did not have very severe brain damage; two patients had an SDH with focal cerebral contusion on the nondominant side, and the other had only SDH. For these patients, direct brain injury might not be the major factor, as the lower GCS could be caused by secondary insults such as hypoxia or hypotension. In a younger patient, the possibility that the hypothermia therapy treatment is effective is shown, even if GCS is lowest. Evidence of minimum initial cerebral injury and focal damage, and expected improvement of GCS by correction of secondary insults can indicate hypothermia therapy as a therapeutic option. An experimental study proved that hypothermia protected against neuronal damage due to traumatic brain injury from secondary insult10.

Mild and moderate hypothermia therapy is well known to significantly improve ICP, cerebral blood flow, and other physiological parameters1,4,25,29. Hypothermia suppressed reactive hyperemia after ICP was decreased based on cerebral metabolic rate for oxygen and SjO^sub 2^9,30. Post-ischemic hypoperfusion due to uncoupling of the cerebral metabolism might show no improvements with hypothermia therapy. In our study, ICP in most of the patients was maintained at less than 20 mmHg by decompression surgery, osmotic agents, mild hyperventilation, and hypothermia therapy. We found that the CPP in the good outcome group was significantly higher than in the poor outcome group. In Illustrative Case 1, hyperemia was improved by hypothermia. In Illustrative Case 2, ischemia recovered to normal perfusion. We usually combined various therapeutic options to maintain ICP and CPP, including osmotic agents for reduction of ICP (20% mannitol or 10% glycerin solution), induced hypertension by hydration and catecholamine for preservation of CPP, and mild hyperventilation (PaCO^sub 2^ 30-35 mmHg). However, patients who could not maintain CPP at the critical level might have poor outcome. Among the patients with high ICP due to hyperemia, control of ICP by combination therapy resulted in good outcome. Therefore, reserve CPP and oxygen metabolism during hypothermia are good prognostic factors25. On the other hand, patients with huge mass lesion, severe cerebral contusion, brain stem injury, or many hours delay before surgery will not benefit from hypothermia therapy.

The period of hypothermia therapy is still inconsistent between trauma centers. Some institutes insist that the length of hypothermia should be shorter than 48 h to prevent complications3,21,23. In contrast, prolonged hypothermia therapy is recommended for patients with severe head injury to a maximum of 14 days19,20. We decide the period of hypothermia according to the severity of brain injury, ICP elevation, SjO^sub 2^, or CT findings. The mean period of hypothermia was 85 h overall, which was greater than the multicenter study finding of 48 h. We consider that the optimum period of hypothermia therapy should produce good results, as well as an adequate re-warming procedure.

Diffuse cerebral swelling is known to be a negative factor4. We observed severe diffuse cerebral swelling in four patients, which occurred during or after re-warming. Brain swelling during re-warming may be associated with ischemic neuronal injury due to vasospasm. Preservation of CPP and sufficient hydration during rewarming are important to prevent ischemic injury.

We found that higher age, severe brain injury, diffuse brain swelling during re-warming, and thrombocytopenia were unfavorable prognostic factors. Especially, hypothermia therapy may have no advantage as a conventional therapy for patients older than 50 years. Hypothermia therapy should improve outcome in patients with traumatic brain injury, but is not effective in all patients21. If the brain protection effect of the mild hypothermia therapy is expected, it is necessary to start cooling before brain injury receives an irreversible damage. In our opinion, the hypothermia treatment should be applied to the restricted cases which could reach the target temperature within 6 h after injury, which would not have diffuse brain damage on CT diagnosis, and which would accept the improvement of cerebral perfusion and metabolism by neuromonitoring. Moreover, it is considered that the patients over 50 years old, and the case where the occurrence of major systemic complication would be expected such as thrombocytopenia, should be excepted. We suggest that hypothermia therapy combined with conventional treatment methods is useful for the treatment of patients with traumatic brain injury, if vasomotor response in cerebral perfusion is not completely impaired. Neuromonitoring such as continuous measurement of both ICP and CPP, brain temperature recording, AVDO^sub 2^ based on SjO^sub 2^ sampling, and general laboratory examinations can be another important part of the management in the hypothermic treatment. Further study of this modality is indicated.

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Takuji Yamamoto, Kentaro Mori and Minoru Maeda

Department of Neurosurgery, Juntendo University, Izunagaoka Hospital, Shizuoka, Japan

Correspondence and reprint requests to: Takuji Yamamoto, MD, Department of Neurosurgery, Juntendo University, Izunagaoka Hospital, 1129 Nagaoka, Izunagaoka-cho, Tagata-gun, Shizuoka 410-2295, Japan. [yamajr@mb.kcom.ne.jpl Accepted for publication July 2002.

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