Received: 6 March 2002Accepted: 4 September 2002Published online: 4 October 2002© Springer-Verlag 2002

Abstract Objective: Therapeutichypothermia may improve outcomein patients with severe head injury,but clinical studies have producedconflicting results. We hypothesisedthat the severe side effects of artifi-cial cooling might have masked thepositive effects in earlier studies, andwe treated a large group of patientswith severe head injury with hypo-thermia using a strict protocol to pre-vent the occurrence of cooling-induced side effects. Design: Pro-spective clinical trial. Setting: Uni-versity teaching hospital. Patients: Hundred thirty-six consec-utive patients admitted to our hospi-tal with severe head injury (GlasgowComa Scale (GCS) ≤8). Measurements and results: Patientsincluded are the 136 patients with aGCS of 8 or less on admission inwhom intracranial pressure (ICP) re-mained above 20 mmHg in spite oftherapy according to a step-up proto-col. Those who responded to the laststep of our protocol (barbiturate co-ma) constituted the control group(n=72). Those who did not respondto barbiturate coma (n=64) weretreated with moderate hypothermia(32–34°C). Average APACHE IIscores were higher (28.9±14.4 vs25.2±12.1, p<0.01) and averageGCS at admission slightly lower(5.37±1.8 vs 5.9±2.1, p<0.05) in thehypothermia group, indicating great-er severity of illness and more severeneurological injury. Predicted mor-

tality was 86% for the hypothermiagroup versus 80% in controls(p<0.01). Actual mortality rates weresignificantly lower: 62% versus72%; the difference in mortality be-tween hypothermic patients and con-trols was significant (p<0.05). Thenumber of patients with good neuro-logical outcome was also higher inthe hypothermia group: 15.7% ver-sus 9.7% for hypothermic patientsversus controls, respectively(p<0.02). These differences were ex-plained almost entirely by the sub-group of patients with GCS of 5 or 6at admission (mortality 52% vs 76%,p<0.01; good neurological outcome29% vs 8%, p<0.01). Conclusions: Artificial cooling cansignificantly improve survival andneurological outcome in patientswith severe head injury when used ina protocol with great attention to theprevention of side effects. Becausethere is likely to have been biasagainst the hypothermia group in thisstudy, the positive effects of hypo-thermia might even have been under-estimated. In addition, our resultsconfirm the value of therapeutic hy-pothermia in treating refractory in-tracranial hypertension.

Keywords Head injury · Artificialcooling · Outcome · Intracranialpressure · Side effects · Therapeutichypothermia

Intensive Care Med (2002) 28:1563–1573DOI 10.1007/s00134-002-1511-3 O R I G I N A L

Kees H. PoldermanRudi Tjong Tjin JoeSaskia M. PeerdemanWilliam P. VandertopArmand R. J. Girbes

Effects of therapeutic hypothermia on intracranial pressure and outcome in patients with severe head injury

K.H. Polderman (✉) · A.R.J. GirbesDepartment of Intensive Care, VU University Medical Center PO Box 7057, 1007 MB Amsterdam, The Netherlandse-mail: k.polderman@tip.nlTel.: +31-20-4443912Fax: +31-20-6392125

R. Tjong Tjin Joe · S.M. PeerdemanW.P. VandertopDepartment of Neurosurgery, VU University Medical Center PO Box 7057, 1007 MB Amsterdam, The Netherlands

Introduction

Over the past 20 years the outcome of patients with se-vere head injury has steadily improved due to a combi-nation of various factors. These include more rapidtransportation of patients to emergency departments, theadvent of specialised trauma centres, improvements inmethods of resuscitation, aggressive and early treatmentof hypotension and hypoxia, early brain imaging, promptsurgical intervention and the guidance of treatmentthrough monitoring and controlling of intracranial pres-sure (ICP) [1]. However, mortality remains high, as doesthe number of patients with severe neurological impair-ment following head injury. The main goal of therapy inthese patients is the prevention of additional injury to thebrain in the period following trauma.

Various in vitro and animal studies have demonstratedthat mild hypothermia is effective in blocking deleteri-ous chemical cascades and reverses pathophysiologicalchanges such as cerebral thermo-pooling that can takeplace in the brain following neurological injury [2, 3]. Inaddition it may prevent re-perfusion injury and cellulardamage induced by free radical reactions. On this basis,several clinical trials have been carried out to assess theeffectiveness of artificial cooling in patients with severehead injury [4, 5, 6, 7, 8, 8, 10, 11, 12, 13, 14], various(usually cardiothoracic) surgical procedures [15, 16],post-anoxic coma following cardiopulmonary resuscita-tion [17, 18, 19, 20, 21, 22] and stroke [23, 24, 25]. Theinitial results in patients with head injury appeared high-ly promising [4, 5, 6, 7, 8, 9, 10], provided the artificialcooling was initiated shortly after admission [10, 12]. Incontrast, a recently published multi-centre study ob-served no benefits resulting from therapeutic hypother-mia and reported more ‘days with complications’ in pa-tients treated with artificial cooling [14]. The findings ofthis study, however, may have been influenced by thefact that the side effects of artificial cooling were insuffi-ciently taken into account, leading to a bias against thehypothermia group due to a higher prevalence of epi-sodes of hypovolaemia, hypotension and electrolyte dis-orders in the hypothermia group [26].

We previously reported that artificial cooling is asso-ciated with significant side effects, including significantfluid loss through hypothermia-induced diuresis andelectrolyte depletion [25]. This is important becauseeven brief episodes of hypovolaemia can affect cerebralperfusion pressure (CPP) and cerebral blood flow and ithas been shown that even very short episodes of de-creased CPP can significantly affect neurological out-come [1, 27]. Electrolyte disorders are associated withvarious forms of cardiac arrhythmias, neuromuscular ir-ritability, vasoconstriction and increased mortality in theICU [28, 29, 30, 31] and may even negate any potentialbenefits of artificial cooling. Magnesium appears to beespecially important in this regard [28, 29, 30, 32, 33,

34, 35]. We therefore studied the outcome of patientswith severe head injury treated with moderate hypother-mia, according to a strict protocol in which great atten-tion was paid to the prevention of side effects.

Patients and methods

This study was conducted according to guidelines approved by thehospital ethics committee. All patients with a severe head injury(Glasgow Coma Scale score ≤8 on admission) admitted to our uni-versity teaching hospital, a tertiary neurosurgical referral centre,between July 1995 and July 2000 were treated according to a step-up protocol as described previously [32] and depicted schemati-cally in Fig. 1.

A smaller number of patients had GCS higher than 8 at admis-sion but subsequently suffered a deterioration in their neurologicalconditions; these patients were treated according to the same step-wise protocol and some of them were treated with artificial cool-ing according to this protocol. Data from these patients werepooled with data from the other patients; however, as this categoryof patients may represent a slightly different group (relatively highGCS at admission but deterioration shortly thereafter versus lowGCS already present at admission), sub-analyses for the two cate-gories of patients were also performed (shown in Table 4).

Standard treatment

A cranial probe (Camino, Integra LifeSciences, Plainsboro, N.J.,USA) was inserted in every patient to measure ICP. The primarygoals of therapy were stabilisation or improvement of the patient’sneurological condition, maintenance of an ICP of 20 mmHg orless (normal value in healthy subjects: ≤15 mmHg) and a mean ar-terial pressure (MAP) 90 or more with vasoactive mediators (do-pamine and norepinephrine) to maintain a cerebral perfusion pres-sure (CPP = MAP–ICP) of 70 mmHg or more. In patients withICP higher than 20 mmHg initial treatment included appropriatesedation with the benzodiazepine midazolam (dosage: bolus of10 mg, continuous dose of 14 (range 10–20) mg/h), the opiate fen-tanyl (dosage: bolus of 0.25 mg, continuous dose of 0.48 (range0.35–0.70) mg/h), and propofol (dosage: bolus 20 mg, continuousdose 94 (range 80–110) mg/h), as well as treatment with muscleparalysers (vecuronium bromide, bolus 8 mg, continuous dose10.4 (range 8–20) mg/h) and administration of mannitol (maxi-mum dose: 100 ml 20% intravenously 8 times daily). Neurosurgi-cal interventions were undertaken when necessary to evacuatesubdural lesions or large intracerebral lesions if this was deemedappropriate. Arterial partial pressure of carbon dioxide (PaCO2)concentrations were maintained at 34–40 mmHg; arterial partialpressure of oxygen (PaO2) levels were maintained above90 mmHg.

Study protocol

All patients in whom ICP remained higher than 20 mmHg in spiteof the above measures were subsequently treated with barbiturates(pentobarbital bolus 100–200 mg, followed by continuous infu-sion of 100–300 mg/h) until burst suppression, monitored by elec-troencephalography (EEG). If the ICP responded to this treatmentthe patient was included in our control group. Response was de-fined as a significant decrease (=20% from baseline value) in ICPwithin 30 min and a decrease to and stabilisation at levels below20 mmHg within 60 min after pentobarbital administration. Allpatients who did not meet these criteria (i.e., patients who failed torespond to barbiturate administration) were included in our hypo-

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thermia group. Barbiturate administration was continued in thesepatients. Previous sedation and muscle paralysis were discontin-ued in all patients when pentobarbital administration was initiated.Treatment with mannitol was continued in all patients.

Artificial cooling

Artificial cooling was initiated immediately when the above-men-tioned steps had failed to control ICP, using water-circulating blan-kets (Blanketrol II hyper-hypothermia, Cincinnati Sub-Zero, Cin-cinnati, USA; blanket temperature 4°C). The aim was to lower the

body temperature to 32°C as quickly as possible. Once the targetcore temperature had been achieved, temperatures were maintainedby keeping the water-circulating blankets at or slightly below32°C. If ICP remained at 20 mmHg or less for 24 h, the patient wasslowly re-warmed (1°C per 12 h). If ICP rose above 20 mmHg,cooling was re-initiated until ICP decreased to below 20 mmHg.

Preventive measures

All patients (i.e., controls and hypothermia patients) were treatedwith large volumes of intravenous fluids, initiated at the start of

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Fig. 1 Protocol for the treat-ment of patients with severehead injury (CT computed to-mography, GCS Glasgow Co-ma Scale, MAP mean arterialpressure, PaO2 arterial partialpressure of oxygen, PaCO2 ar-terial partial pressure of carbondioxide, CPP cerebral perfu-sion pressure, ICP intracranialpressure, EEG electroencepha-lography)

pentobarbital administration. Upon inclusion in our hypothermiagroup, patients received an additional dose of fluid (500–1000 mlof saline in 30 min) upon initiation of cooling. Central venouspressure and urine production were monitored continuously in allpatients and fluid management was based on these parameters aswell as changes in heart rate, wedge pressure in patients in whoma pulmonary artery catheter had been inserted, etc. Every effortwas made to maintain CPP at 70 mmHg or higher using intravas-

cular filling and vasoactive medication. Electrolyte levels weremeasured frequently (at 60min intervals or more frequently whennecessary) using a rapid lab device installed in the ICU (RapidLab855, Chiron Diagnostics, Emeryville, Calif.). This allowed us tocorrect any electrolyte disorders immediately. The goal of therapywas to maintain high-normal electrolyte levels [Mg ≥1.1 mmol/l,K ≥4.0, P ≥1.0 mmol/l, Ca (corrected for albumin) ≥2.3 mmol/l,free (ionised) Ca ≥1.2 mmol/l].

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Table 1 Patient characteristics, clinical parameters, medication and outcome. Student’s unpaired t-test used for statistical comparisons(APACHE II Acute Physiology And Chronic Health Evaluation II, GCS Glasgow Coma Scale)

Patient characteristics Hypothermia group Controls p value

Number of patients 64 72Age (years) 39.2±24.2 34.2±29.6 <0.02

(range 16–73) (range 17–72)APACHE II score 28.9±14.4 25.2±12.1 <0.01

(range 14–38) (range 11–38)

GCS at admission8 or higher 10 16 <0.017 6 10 NS6 11 15 NS5 14 10 0.094 10 11 NS3 13 10 0.08

Computed tomography based assessment of severity of injurya

Class I (no significant abnormalities visible on CT scan) 0 0 NSClass II (small visible lesions, shift 0–5 mm, cisterns open) 14 (22%) 22 (31%) NSClass III (As class II but with compressed cisterns) 13 (20%) 14 (19%) NSClass IV (as class III but with shift >5 mm) 10 (16%) 12 (17%) NSClass V (surgically evacuated lesion) 15 (23%) 18 (2%) NSClass VI (large lesions (>25 cc) not surgically evacuated) 12 (19%) 6 (8%) <0.05

Head injury as sole significant lesion 21 (33%) 27 (38%) NSPolytraumatised 43 (67%) 45 (62%) NSCraniotomy (apart from probe insertion) 58 61 NSAverage dose of dopamine (mg/h) before cooling 17.4±14 16.7±13 NSAverage dose of dopamine (mg/h) during cooling 19.2±12 15.8±12 <0.02Average dose of nor-epinephrine (mg/h) before cooling 0.88±0.32 0.62±0.26 <0.01Average dose of nor-epinephrine (mg/h)during cooling 1.01±0.24 0.61±0.22Number of patients treated with anti-arrhythmic medication 48 32 <0.01Average amount of mannitol (ml) received in first 3 h of hospital admission 122 126 NS

(before cooling)Average amount of mannitol (ml) received in subsequent 6 h period 84 89 NS

Average amounts of electrolytes administered in first 6 hMagnesium (g) 4.2±1.4 1.8±0.5 <0.01

(range 3.0–6.2) (range 0–4.0)Potassium (mmol) 83±14 41±22 <0.01

(range 56–130) (range 12–60)Phosphorus (mmol) 7.8±2.2 1.4±2.4 mmol <0.01

(range 5.6–10.2) (range 0.0–6.8)Average amount of filling in first 6 h of admission (ml) 5389±1857 4135±964 <0.01Core temperature (°C) before cooling (t=0) 37.5 37.2 NSCore temperature (°C) during cooling 32.8 37.4 <0.01

Time (h) elapsed until temperature ≤34°CFrom start of cooling 2.8 –

(range 1.1–4.5) –From hospital admission 5.2 –

(range 1.3–17) –

a Marshall classification [37]

Outcome

The primary outcome measure was the assessment of patients ac-cording to the five-category Glasgow Outcome Scale [36], whichwas conducted 6 months after hospital discharge by examinerswho were unaware of the patients’ treatment group assignments.Good recovery (GOS 5) and moderate disability (GOS 4) weredesignated as favourable outcomes; severe disability GOS 3), avegetative state (GOS 2) and death (GOS 1) were designated aspoor outcomes.

Statistical analysis

Data are expressed as means ± SD. Comparisons between patientstreated with hypothermia and controls were carried out using chi-square tests or Fisher’s exact test. Comparisons for some simplecontinuous variables were performed with two-sided t-tests. Anal-ysis of variance for repeated measurements (ANOVA) was usedfor comparison of fluid and electrolyte administration and of se-rum electrolyte levels within groups (before and during artificialcooling and/or barbiturate administration). Student’s t-test for un-paired results and, where necessary, Fisher’s exact test were usedfor comparison between pooled measurements of electrolyte levelsand amounts of electrolytes administered between hypothermiapatients and controls. We considered p less than 0.05 to be statisti-cally significant. Data from patients with GCS above 8 at admis-sion but with a subsequent deterioration in neurological conditionwere analysed both separately and as pooled data.

Results

Patient inclusion and baseline characteristics

Baseline characteristics of the study patients are shownin Table 1. Most of the patients included in our studywere men (group 1: 48/64, group 2: 51/72) and the mostcommon cause of head injury was a motorcycle or caraccident. Other causes included assault, bicycle acci-dents and falls from heights. Causes of injury were even-ly matched in the hypothermia patients and controls,with no preponderance of any particular cause in eithergroup (data not shown). Mean APACHE II scores, ageand average ICP were slightly higher in the hypothermiagroup (Table 1). The two groups did not differ signifi-cantly in terms of numbers of patients with severe addi-tional injuries, such as abdominal or chest injuries orpelvic fractures.

Mean GCS at admission was slightly lower in group 1,possibly reflecting more severe head injuries in thisgroup; however, the CT-based classification of the sever-ity of the injury (using the modified Marshall scale) [37]did not differ between the groups.

Barbiturates and artificial cooling

Hundred thirty-six patients met the study inclusion crite-ria and were treated with barbiturates. Within 30 minICP decreased to below 20 mmHg in 52 patients; these

were included in the control group. Barbiturate adminis-tration was continued in 29 patients in whom a decreaseof 20% or more was observed. After 60 min, ICP had de-creased below 20 mmHg in 20 of these 29 remaining pa-tients, who were then also included in the control group(group 2, n=72). Patients who did not respond to barbitu-rate administration within 30 or 60 min, 55 and 9, re-spectively, were assigned to the hypothermia group(group 1, n=64). Core temperatures of 34°C or less werereached after an average period of 3.4 h (range1.5–5.5 h). Temperatures were maintained at 34°C infive patients because of massive diuresis and resultingdifficulties in maintaining euvolemia in these patientswhile their body temperatures were decreasing. This wasdeemed acceptable because, at 34°C, ICP had decreasedto below 20 mmHg in four of these patients and to23 mmHg in the fifth. Core temperatures of 32–33°Cwere reached in all the other 59 patients, on averagewithin 4.1 h after initiation of cooling.

Hypothermia was continued until ICP was 20 mmHgor less for 24 h or more, after which the temperature wasincreased slowly (1°C/12 h). If ICP increased to20 mmHg or more, the temperature was again decreaseduntil ICP decreased to below 20 mmHg (protocol flowchart shown in Fig. 1). The average duration of hypo-thermia was 4.8 days (range 24 h–21 days).

Electrolytes and anti-arrhythmic medication

All patients were treated with high doses of electrolytesto prevent electrolyte disorders. The amounts required toachieve this aim were higher in group 1, especially dur-ing cooling; when target core temperatures wereachieved the amounts of electrolytes required decreasedand remained comparable in the two groups (Table 1).Anti-arrhythmic medications (mostly amiodarone; rarelysotalol, flecainide or lidocaine) were used to treat anyform of arrhythmia occurring in our patients, except forisolated ventricular or supraventricular premature ven-tricular contractions (PVCs); when more than four ofthese occurred per minute anti-arrhythmic medicationwas also started. Anti-arrhythmic medication accordingto these criteria was required significantly more fre-quently in the hypothermia patients. Sodium levels weremonitored frequently; levels remained normal in bothgroups (141±7.4 in group 1, 139.7±6.4 in group 2;p=NS).

Intracranial pressure and cerebral perfusion pressure

Upon inclusion in our study, the average ICP in the 136patients was 38.4 mmHg (range 24–68). Due to the na-ture of our protocol, in which hypothermia was used as alast resort, patients in the hypothermia group had signifi-

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cantly longer periods of time with high ICP. However,using inotropic medication and large volumes of fluidadministration, we were able to maintain CPP above70 mmHg in most patients after ICU admission, evenwhile ICP levels were still (too) high (Tables 1 and 2).Artificial cooling was started in most patients (n=54)soon after admission. In a smaller number of patients inrelatively good neurological condition and with highGCS at admission (Tables 3 and 4), barbiturate adminis-tration and/or cooling were initiated later, when theirneurological condition deteriorated within 12 h of hospi-tal admission, with GCS decreasing below 8 points. Forthis reason the time period elapsing between admissionand initiation of cooling was somewhat longer in thesepatients. In other aspects they were comparable and thereaction of these patients’ ICPs to artificial cooling wassimilar to the response in patients in whom cooling had

been initiated earlier. The data shown in Tables 1, 2 and3 reflect overall results (i.e., pooled data); Table 4 de-picts separate data for the patients in whom cooling wasstarted soon after admission and those in whom it wasinitiated somewhat later.

Intracranial pressure decreased markedly in all pa-tients during cooling, to 14±8 mmHg (range 5–24). ICPvalues of 20 or less were achieved within 2 h in 39/64patients, within 3 h in 55/64 patients and within 4 h in62/64 patients. ICP levels remained above 20 but below25 mmHg in two patients, one of whom was maintainedat a slightly higher temperature because of severe sideeffects during the induction of hypothermia (describedabove). The amount of time from the moment of injuryuntil ICP 20 mmHg or lower and the elapsed time fromcranial probe insertion until ICP normalisation is pre-sented in Table 3.

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Table 2 Effect on intracranialpressure (ICP), overall mortali-ty and neurological outcome.Student’s unpaired t-test usedfor statistical comparisons(CPP cerebral perfusion pres-sure, GCS Glasgow ComaScale, GOS Glasgow OutcomeScale, SDD selective bowel de-contamination)

Patient characteristics Hypothermia Controls p valuegroup (n=64) (n=72)

ICP before barbiturate administration 41±15 36±18 NSICP before cooling (mmHg 37±20 <20 <0.01ICP during cooling (mmHg) 14±8 17±6.2 <0.05Average time elapsed before normalisation 5.1±3.3 3.7±2.6 <0.01

of ICP from moment of injury (h)Average time (h) elapsed before normalisation 3.1±2.1 1.8±1.4 <0.01

of ICP from time of cranial probe insertion (h)Total amount of time (min) with CPP 60 mmHg 22±8 17±11 NS

in 6h period from moment of probe insertionTotal amount of time (min) with CPP 70 mmHg 39±20 28±20 <0.01

in 6h period from moment of probe insertion

Late complicationsDelayed intracranial haematomas 4.7% (n=3) 5.5% (n=4) NSAcute renal failurea 1.5% (n=1) 2.8% (n=2) NSPersistent renal failure 0.0% 0.0% NSCardiac complicationsb 1.5% (n=1) 1.4% (n=1) NSPulmonary complicationsc 9.4% (n=6) 12.5% (n=9) NSDeep venous thrombosis 1.5% (n=1) 0.0% NS

ICU mortality 62.5% (n=40) 72.2% (n=52) <0.05Survivors with GCS ≥12 upon leaving the ICU 23.4% (n=15) 20.8% (n=15) NSSurvivors with good or excellent neurological outcome 15.6% (n=10) 9.7% (n=7) <0.02

(GOS 4 or 5) 6 months after hospital discharge

a Defined as a rise in serum ofcreatinine ≥100 µmol/lb Apart from brief and easilytreatable arrhythmias with nosignificant haemodynamic ef-fectsc Infections, pneumothorax andbleeding. The hypothermiagroup was treated with SDD

Table 3 Mortality and neurological outcome: subgroup analysis by Glasgow Coma Scale (GCS) at admission. Fisher’s exact test usedfor statistical comparison (GOS Glasgow Outcome Scale)

GCS at admission Hospital mortality Good/excellent outcome (GOS 4 or 5)

Group 1 Group 2 p value Group 1 Group 2 p valueHypothermia Barbiturates Hypothermia Barbiturates

≥7 9/16 (56%) 16/26 (61.5%) NS 1/16 (5.9%) 3/26 (11.5%) NS5–6 13/25 (52%) 19/25 (76%) <0.01 8/25(32.0%) 3/25 (12.0%) <0.023–4 18/23 (78.3%) 17/21 (80.9%) NS 1/23 (4.3%) 1/21 (4.8%) NSTotal 40/64 (62.5%) 52/72 (72.2%) <0.05 10/64 (15.6%) 7/72 (9.7%) <0.02

Haemodynamic parameters

Arrhythmias occurred in many hypothermia patients, butin most cases these were not serious. Most patients weretreated with the above-mentioned anti-arrhythmic agentsduring the study period; five patients were treated withisoprenaline because of severe sinus bradycardia. All pa-tients received dopamine and norepinephrine to maintainCPP at 70 mmHg or more (Table 1). We were able tokeep the patients haemodynamically stable and thereforemaintain CPP during cooling. Measurements of cardiacoutput (CO) carried out in 17 of our patients using a pul-monary artery catheter established a 28% decrease in COcompared to baseline when core temperatures of 33°C orbelow were achieved, as expected in view of the de-crease in metabolism induced by cooling (data notshown).

Mortality and neurological outcome

These data are summarised in Tables 2 and 3. In the hy-pothermia group, hospital mortality was lower (62.5 vs72.2%, p<0.05), and the number of patients with goodneurological outcome higher (15.6 vs 9.7%, p<0.02) than

in the control group. Average predicted mortality accord-ing to the APACHE II scores at ICU admission was 86%versus 80% (p<0.01). The mean stay in the ICU and inthe hospital was similar in the two groups. The rates oflate complications such as delayed post-traumatic intra-cranial haematomas, infections, deep venous thrombosisand pulmonary, renal and cardiac complications weresimilar in the two groups (Table 2). In particular, nobleeding complications related to hypothermia were ob-served.

The differences in outcome between the hypothermiagroup and controls are explained entirely by the sub-group of patients with GCS of 5 or 6 at admission. Inthis subgroup 12/25 patients (48%) in the hypothermiagroup survived, versus 6/25 (24%) in controls (24%)(p<0.01). Six months after hospital discharge, 8/26 hypo-thermia patients (30.7%) had a score on the GlasgowOutcome Scale of 4 or 5, as compared with 3/26 patients(7.7%) in controls (p<0.02). In contrast, patients withinitial coma scores of 3 or 4 did not benefit from hypo-thermia (mortality 78.3 vs 80.9%, good neurological out-come 4.3 vs 4.8%). Patients with relatively good comascores (≥7) upon admission also did not appear to benefitfrom hypothermia (mortality 60 vs 61.5%, good neuro-logical outcome 5.9 vs 11.5%).

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Table 4 Subgroup analysis: comparison of hypothermia patients cooled soon after admission and those in whom cooling was initiatedlater because of deterioration in Glasgow Coma Scale (GCS): mortality and outcome. Chi square test was used for statistical comparison

Hypothermia Barbiturates

Number Time elapsed until Outcome Number Outcomerectal temperature ≤34°C

From start From hospital Mortality Good or Mortality Good or of cooling admission excellent excellent

outcome outcome

Barbiturates 54 2.8 h 4.7 h 61% 17% 56 75% 13%and/or cooling (range 1.1–4.5) (range 1.3–5.8) (n=33) (n=9) (n=42) (n=7)initiated immediately after admissionSubgroup: 6 3.2 h 4.9 h 33% 0% 10 60% 30%patients with (range 1.7–4.5) (range 3.6–5.4) (n=2) (n=0) (n=6) (n=3)GCS of 7 at admissionBarbiturates 10 3.2 h 10.8 h 70% 10% 16 63% 0%and/or cooling (range 1.9–4.2) (range 3.8–17) (n=7) (n=1) (n=10) (n=0)initiated in later phase because of deterioration in clinical parameters and GCSOverall 64 2.8 h 5.2 h 62.5% 15.6% 72 72% 10%

(range 1.1–4.5) (range 1.3–17) (n=40) (n=10) (n=52) (n=7)

Discussion

In this study we observed clear benefits in survival andneurological outcome in patients with severe head inju-ry and GCS of 5 or 6 at admission who were treatedwith artificial cooling according to a strict protocol inwhich great attention was paid to the prevention of sideeffects. Although overall mortality was high in bothtreatment groups, it was significantly lower than thepredicted mortality according to APACHE II scores atadmission, corrected for underlying disease using theappendix from the original APACHE II study [38].Thus, although crude mortality rates were also high inthe hypothermia group, this was to be expected on thebasis of their severe injury and high APACHE II scores,and overall outcome was better than expected. In thesubgroup of patients with GCS 5–6 the difference be-tween predicted and actual outcome was significantlymore pronounced.

Recently, two large studies have demonstrated thattherapeutic hypothermia can improve outcome in pa-tients with post-anoxic brain injury following cardiac ar-rest [21, 22]. However, this treatment remains highlycontroversial, especially in patients with severe traumat-ic head injury. In the 1990s a number of papers werepublished describing beneficial effects of artificial cool-ing as a means of controlling ICP [3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13] and outcome [10]. In contrast, a recently pub-lished multi-centre trial by Clifton and associates report-ed no survival benefit and more “days with complica-tions” in patients treated with hypothermia [14]. Howev-er, this particular study may have been influenced by thelarge number of participating hospitals, with resultingdifferences in treatment protocols, ICU procedures andvarious other factors. Moreover, treatment with hypo-thermia is associated with a number of potentially seri-ous, but preventable, side effects including electrolytedepletion, arrhythmias, hypovolaemia and hypotensiveepisodes [26, 32]. These side effects appear to be causedin part by hypothermia-associated diuresis [26], as alsoobserved in a previous study by our group [32].

These side effects are especially important in thebrain-injured patient, in whom it is of vital importance tomaintain euvolemia and “to squeeze [sufficient amountsof] blood through the swollen brain” [1]. It has beenshown that even very brief episodes of mild hypotensionand/or hypovolaemia can adversely affect outcome [27].Therefore, in our opinion it is of the utmost importancethat physicians using therapeutic hypothermia in any cat-egory of patients be aware of the risk of hypothermia-induced polyuria and take appropriate precautions andcountermeasures [26, 32].

In addition, various animal experiments and clinicalstudies have demonstrated the important role of magne-sium in the injured brain [33, 34, 39]. Thus, the induc-tion of magnesium depletion by hypothermia is likely to

have significant adverse effects on outcome in patientswith severe head injury. Moreover, as demonstrated pre-viously by our research group, patients with severe headinjury often have hypomagnesemia and depletion of oth-er electrolytes at admission [40]. Thus, potential benefi-cial effects of hypothermia are highly likely to be ob-scured by side effects if sufficient precautions are nottaken to prevent these from occurring.

In our treatment protocol, great care was taken toavoid all the potentially harmful effects of hypothermia.Large amounts of electrolytes were given to all patientsand great care was taken to prevent even the briefest epi-sodes of hypovolaemia and hypotension. As shown inTables 1 and 2 we were quite successful in achieving thisobjective. For the reasons set out above, we feel that thisis a vital prerequisite to being able to assess the effectsof artificial cooling adequately. We observed that fluidand electrolyte requirements were especially high in theinitial phase of cooling, while body temperatures de-creased. Fluid and electrolyte requirements decreasedonce the target temperatures had been reached.

As hypothermia-induced hypokalaemia is due to acombination of increased urinary loss and intracellularshift [32], there is a risk for hyperkalaemia during re-warming due to reversal of the intracellular shift, i.e.mobilisation of potassium from the cells. Thus potassi-um administration should be decreased in this phase andpotassium levels should be monitored frequently. Ourprotocol prescribed slow re-warming and decrease inpotassium administration during re-warming; we ob-served no cases of rebound hyperkalaemia in any of ourpatients.

The swift induction of hypothermia, pre-empting orcorrecting the resulting side effects while maintainingeuvolemia and adequate CPP at all times, in combinationwith all the other forms of treatment simultaneously re-quired in brain-injured patients, is a highly complex anddifficult procedure. Thus it is hard to control all thesevariables in a multi-centre research setting. Variations intreatment protocol, monitoring, fluid infusions, surgicalprocedures, timing of probe insertion, vasoactive medi-cation and other treatments between various centres arehighly likely to occur. For this reason we feel that oursingle-centre results may more adequately reflect the po-tential benefits of artificial cooling than a multi-centreeffort would.

It should be emphasised that artificial cooling, as anexperimental form of treatment, was used only as anoption of last resort in our protocol. Therefore only pa-tients with refractory ICP elevation, in whom all othertherapeutic options had been tried, were included in ourprotocol. Obviously this category of patients had an ex-tremely poor prognosis and this explains the high over-all mortality rate in our study group. However, predict-ed mortality according to the average APACHE IIscores at ICU admission was significantly higher than

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observed mortality (predicted: 86% vs 80%; observed:62.5% vs 72.2% for groups 1 and 2, respectively). Wealso wish to underscore that the fact that hypothermiawas used only as a measure of last resort in our proto-col almost certainly induced substantial bias against thehypothermia group. The reason for this is that the con-trol group was comprised of patients in whom earliertreatments (barbiturate coma and mannitol administra-tion) were successful, while hypothermia was used onlyin patients who failed to respond to these treatments.Therefore, the average time period during which pa-tients had elevated ICP was longer in group 1 than ingroup 2. This alone implies that any benefits in group 1are likely to have been underestimated. In addition, thefact that ICP failed to respond to earlier steps in ourprotocol (including barbiturate administration) may initself signify a more grave neurological situation in thepatients in group 1. However, in spite of the gravity ofour patients’ neurological conditions and the inherentbias against the hypothermia group, we were still ableto demonstrate clear benefits of artificial cooling. Inour opinion this makes our observations extra poignantand underscores the potential benefits of this form oftreatment.

In our study the benefits of hypothermia were limitedto patients with GCS of 5 or 6 at admission. The generalgoal of therapy in all patients with severe head injury isto prevent secondary (additional) damage to the brain. Itseems likely that the initial injury was so severe in pa-tients with GCS of 3–4 at admission that they were un-able to benefit from treatment (“beyond repair”). Our ob-servations are in agreement with an earlier trial by Mari-on and associates [10], who also observed the best re-sults in improving neurological outcome in patients witha GCS between 5 and 7 at admission, with no clear bene-fits in patients with GCS of 3–4.

The group of patients with GCS of 8 or higher at ad-mission who were treated with hypothermia in our studyalso did not appear to benefit from this treatment. How-ever, this group contained a substantial number of pa-tients (10/16) whose neurological condition deterioratedduring ICU stay; they developed refractory rises in ICP,were treated according to our protocol and finally weretreated with hypothermia as an option of last resort. In-deed, this subgroup contained all patients in whom hypo-thermia was induced in a somewhat later phase of theirstay. Although hypothermia was effective in controllingICP in these patients, it seems likely that the events lead-ing to the deterioration in their clinical situation and theconcomitant rises in ICP also induced a situation wherethe patients’ brain damage progressed to a level “beyondrepair”. Thus, although survival was relatively high inthis group, good neurological outcome was rare, proba-bly because irreversible brain damage had already oc-curred at the moment of inclusion in our study. Thereforewe cannot rule out that artificial cooling might also be

effective in patients with GCS of 7 or more at admissionprovided it is initiated soon after admission. For what itis worth, the only patient in this group with a good neu-rological outcome was one of those who had been treat-ed with hypothermia.

Our observations show that therapeutic hypothermiacan play an important part in decreasing ICP in patientswith severe head injury and improve outcome at least inpatients with GCS of 5–6 at admission. However, physi-cians using this mode of treatment should be aware ofthe various potentially deleterious side effects and takeappropriate preventive measures. In our opinion, the lackof attention to these side effects (including hypomagne-semia, hypovolaemia, brief episodes of arrhythmias andhypotension) may explain the fact that some previousstudies were unable to demonstrate the effectiveness ofhypothermia.

The mechanism by which hypothermia can preventbrain damage has not yet been fully elucidated. It is like-ly that more than one mechanism plays a role. Thesemay include decreased brain swelling and lowering ofICP and a decrease in the metabolic rate and oxygen de-mand in the brain (it has been shown that during moder-ate hypothermia cerebral metabolism is reduced 5–7%for each centigrade degree reduction in body temperature[41, 42]). Other potential mechanisms are the inhibitionof deleterious chemical cascades in injured brain cells,decreases in unfavourable pathophysiological changessuch as cerebral thermo-pooling occurring in the brainfollowing neurological trauma, reductions in extracellu-lar concentrations of free radicals and excitatory neuro-transmitters such as glutamate, modulation of cytokineproduction (especially IL-10) and inhibition of leucocyteinfiltration into injured brain areas [43, 44].

In most previous studies cooling was discontinued af-ter an arbitrary period of time (usually 24–48 h). Wemaintained hypothermia for longer periods of time,slowly increasing body temperature after 24 h of ICPless than 20 mmHg and re-initiating artificial cooling ifICP rose above 20 mmHg during re-warming. In addi-tion, we were able to induce hypothermia relativelyquickly in our patients, with a shorter time interval thanhas been reported in most previous studies.

In conclusion, we observed that mortality was signifi-cantly lower and neurological outcome significantly bet-ter in patients treated with hypothermia and barbituratecoma compared to barbiturate coma alone. Moreover, theresults of our study confirm that artificial cooling is ahighly effective method to control high ICP in all cate-gories of patients with severe head injury. When used ina strict protocol with great attention to the prevention ofside effects, in a specialised neurosurgical centre, surviv-al and neurological outcome can be improved by artifi-cial cooling, at least in patients with GCS of 5 or 6 at ad-mission. It is doubtful whether patients with GCS of 3–4and persistent refractory high ICP will also benefit from

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therapeutic hypothermia; it seems likely that brain dam-age resulting from the initial trauma is too great in thesepatients, although hypothermia is effective in controllingICP even in this category of patients. We were unable todemonstrate long-term benefits from therapeutic hypo-thermia in patients undergoing neurological deterioration

while in hospital (i.e., some time after the initial trauma),although (as in all other categories) hypothermia was ef-fective in lowering ICP. The side effects of hypothermia,although potentially serious, are preventable and/or con-trollable, and thus should not deter us from using thisform of treatment.

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