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Biomedical subjects

R G Grossman

Publications and source records attributed to R G Grossman.

At least 55 records · Page 3Linked to original sources

Adenovirus-mediated gene therapy in an experimental model of breast cancer metastatic to the brain.

We investigated the therapeutic efficacy of adenovirus-mediated gene therapy to treat malignant mammary tumors in vitro and in vivo in the brain. A mammary adenocarcinoma cell line derived from Fischer rats (13762 MAT B III; MAT-B) was used. In vitro studies demonstrated that the MAT-B cells could be efficiently transduced with a replication-defective adenovirus (ADV) vector that carried the herpes simplex virus gene for thymidine kinase (ADV-tk), and that ADV-tk transduction rendered the MAT-B cells sensitive to killing, in a dose-dependent manner, with ganciclovir (GCV). An animal model of a mammary tumor metastatic to the brain was produced by injecting MAT-B cells into the caudate nucleus of Fischer rats. Seven days after MAT-B cell injection, when the tumors were approximately 5 mm2 in cross-sectional size, the tumors were injected with ADV-tk or a control adenovirus vector containing the beta-galactosidase (beta-Gal) gene (ADV-beta gal). After vector injection the animals were treated with GCV or with saline for 6 days. Sixteen days after tumor cell injection, the brains were examined histologically. The rats that were injected with ADV-beta gal and treated with GCV or saline, and those that were injected with ADV-tk and treated with saline had large tumors, whereas the rats that were injected with ADV-tk and treated with GCV had no visible tumor tissue at the site of tumor cell injection. In survival studies animals treated with ADV-tk+GCV survived a significantly longer time than animals treated with ADV-beta gal+GCV. Our results demonstrate that the recombinant adenoviral vector containing the tk gene confers GCV cytotoxic sensitivity to mammary tumor cells in vitro and in the brain, and suggest that this treatment strategy may be useful in treating somatic tumors that metastasize to the brain.

Adenocarcinoma↗

Outcome after stereotactic thalamotomy for dystonia and hemiballismus.

The outcome after single or staged stereotactic thalamotomies in 17 patients with dystonia and 2 patients with hemiballismus is reviewed. All patients were severely disabled by their movement disorders despite optimal pharmacological therapies. Eight of the patients with dystonia (47%) showed moderate improvement immediately after the procedures. Six of these eight patients maintained their improvement, and two other patients with dystonia improved significantly, during the follow-up period (mean, 37.6 mo). The long-term outcome was better in patients with secondary dystonia (50% moderately or markedly improved at a mean of 41.0 mo) than in patients with primary dystonia (43% moderately or markedly improved at a mean of 32.9 mo). Excellent control was achieved in both of the patients who underwent thalamotomies for hemiballismus.

Adolescent↗

Clinical evaluation of a miniature strain-gauge transducer for monitoring intracranial pressure.

In 25 patients, we evaluated the accuracy of a new miniature strain-gauge transducer developed for the measurement of intracranial pressure (ICP). The ICP in each patient was measured with the intraventricular, miniature strain-gauge transducer, and that value was compared with the ICP measured with a ventriculostomy catheter coupled to an external strain-gauge transducer. From the two monitors, 2218 simultaneous measurements of ICP were obtained. The average ICP measured with the miniature strain-gauge transducer was 15.9 +/- 10.0 mm Hg (range, -3 to 104 mm Hg). The ICP measured with the ventriculostomy-catheter transducer averaged 15.4 +/- 10.1 mm Hg (range, -9 to 104 mm Hg). A highly significant correlation was found over the wide range of pressures observed (n = 2218, r = 0.97, P < 0.001). The average difference between the two measurements of the ICP was 0.5 +/- 2.6 mm Hg, and the differences were equally positive and negative, demonstrating no consistent bias. The two values for the ICP were within 2 mm Hg of each other on 63% of the measurements and within 4 mm Hg of each other on 89% of the measurements. The average zero drift of the miniature strain-gauge transducer, measured at ambient pressure after removal of the catheter, was 0.2 +/- 0.5 mm Hg. The results indicate that this miniature strain-gauge transducer is highly accurate and stable and that it is a reliable alternative to a ventriculostomy for monitoring the ICP.

Adult↗

Outcome after stereotactic thalamotomy for parkinsonian, essential, and other types of tremor.

A better understanding of the mechanisms underlying movement disorders, coupled with refinements in surgical technique, has led to a resurgence of interest in the surgical treatment of patients with tremor. We retrospectively analyzed the outcomes of 60 patients (62 patient sides) with medically intractable tremor who underwent stereotactic thalamotomy. Of these 60 patients, 42 had Parkinson's disease (of whom 2 patients underwent bilateral surgery for a total of 44 patient sides), 6 had essential tremor, 6 had cerebellar tremor, and 6 had post-traumatic tremor. The patients received follow-up for as long as 13 years (mean, 53.4 mo) after their operations. At the most recent follow-up visit, 86% of the patients with Parkinson's disease, 83% of the patients with essential tremor, 67% of the patients with cerebellar tremor, and 50% of the patients with post-traumatic tremor had cessation of or moderate-to-marked improvement in their contralateral tremor, with a concomitant improvement in function. The mean daily dose of levodopa for those patients preoperatively taking levodopa (n = 35) was reduced by approximately 156 mg at a mean of 53.4 months after thalamotomy. Immediate postoperative complications were common, occurring in 58% of patients. The most common complications were contralateral weakness (34%), dysarthria (29%), and confusion (23%). These complications generally resolved rapidly during the postoperative period.

Adult↗

Early detection of delayed traumatic intracranial hematomas using near-infrared spectroscopy.

Delayed intracranial hematomas are an important treatable cause of secondary brain injury in patients with head trauma. Early identification and treatment of these lesions, which appear or enlarge after the initial computerized tomography (CT) scan, may improve neurological outcome. Serial examinations using near-infrared spectroscopy (NIRS) to detect the development of delayed hematomas were performed in 167 patients. The difference in absorbance of light (delta OD) at 760 nm between the normal and the hematoma side was measured serially during the first 3 days after injury. Twenty-seven (16%) of the patients developed a type of late hematoma: intracerebral hematoma in eight, extracerebral hematoma in six, and postoperative hematoma in 13 patients. Eighteen of the delayed hematomas caused significant mass effect and required surgical evacuation. The hematomas appeared between 2 and 72 hours after admission. In 24 of the 27 patients, a significant increase (> 0.3) in the delta OD occurred prior to an increase in intracranial pressure, a change in the neurological examination, or a change on CT scan. A favorable outcome occurred in 67% of the patients with delayed hematomas, which suggests that early diagnosis using NIRS may allow early treatment and reduce secondary injury caused by delayed hematomas.

Adolescent↗

Adenovirus-mediated gene therapy of experimental gliomas.

The efficacy of adenovirus (ADV)-mediated gene therapy to treat brain tumors was tested in a syngeneic glioma model. Tumor cells were transduced in situ with a replication-defective ADV carrying the herpes simplex virus thymidine kinase (HSV-tk) gene controlled by the Rous sarcoma virus promoter. Expression of the HSV-tk gene enables the transduced cell to convert the drug ganciclovir to a form that is cytotoxic to dividing cells. Tumors were generated in Fischer 344 rats by stereotaxic implantation of 9L gliosarcoma cells into the caudate nucleus. Eight days later, the tumors were injected either with the ADV carrying the HSV-tk (ADV-tk) gene or a control ADV vector containing the beta-galactosidase (ADV-beta gal) gene and the rats were treated with either ganciclovir or saline. Tumor size was measured 20 days after implantation of 9L cells or at death. Rats treated with ADV-beta gal and ganciclovir or with ADV-tk and saline had large tumors. No tumors were detected in animals treated with ADV-tk and with ganciclovir at doses > or = 80 mg/kg. An infiltrate of macrophages and lymphocytes at the injection site in animals treated with ADV-tk and ganciclovir indicated an active local immune reaction. In survival studies, all animals treated with ADV-tk and ganciclovir have remained alive longer than 80 and up to 120 days after tumor induction whereas all untreated animals died by 22 days. These results demonstrate that ADV-mediated transfer of HSV-tk to glioma cells in vivo confers sensitivity to ganciclovir, and represents a potential method of treatment of brain tumors.

Adenoviridae↗

Gene therapy for brain tumors: regression of experimental gliomas by adenovirus-mediated gene transfer in vivo.

The therapeutic efficacy of adenovirus-mediated herpes simplex virus thymidine kinase (HSV-tk) gene transduction of rat C6 glioma cells followed by ganciclovir (GCV) administration was studied in tumors generated in the brains of nude mice. C6 glioma cells were efficiently transduced in vitro by a replicative-defective recombinant adenovirus carrying the HSV-tk gene (ADV/RSV-tk) that rendered them sensitive to GCV in a dose-dependent manner. Tumors were generated by stereotaxic intracerebral injection of 1 x 10(4) C6 cells in nude mice. After 8 days of tumor growth, 3 x 10(8) ADV/RSV-tk viral particles were injected into the tumors and the mice subsequently were treated with GCV for 6 days. Tumor size in untreated and treated animals was compared 20 days after tumor implantation. The mean cross-sectional area of the tumors in the treated animals was 23-fold smaller than in control animals and the tumor volume was reduced by > 500-fold. These results demonstrate that the recombinant adenoviral vector can function as an efficient gene delivery vehicle for the treatment of gliomas by in vivo gene therapy.

Adenoviridae↗

Development of a model for Parkinson's disease in sheep using unilateral intracarotid injection of MPTP via slow continuous infusion.

The effects of unilateral intracarotid administration of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in sheep were studied with the goal of producing a non-primate, large animal model of Parkinson's Disease. Adult female sheep were given an acute (over 30 min) or chronic (over 1 week) injection of MPTP (0.4-5.0 mg/kg) via the common carotid artery. Both methods produced parkinsonian-like behavior. Turning contralateral to the side of injection was induced by apomorphine (APO) in both groups. However, amphetamine (AMP) induced ipsilateral turning only in the chronic treatment group. Acute and chronic MPTP treatment resulted in a loss of substantia nigra tyrosine hydroxylase immunoreactive (THIR) neurons with a significantly greater loss ipsilateral to the injection in each treatment group (acute p < 0.05; chronic p < 0.01). Caudate dopamine (DA) was depleted in both treatment groups, although the difference between ipsilateral and contralateral DA content was significant only in the chronic treatment group (p < 0.05). The best results were seen in those animals with chronic infusion with the occipital artery occluded to prevent entry of drug into the posterior circulation with subsequent bilateral distribution. Use of slow and continuous intracarotid administration of MPTP with the ipsilateral occipital artery occluded can prevent some of the bilateral effects of acute treatment, and results in statistically significant ipsilateral reduction of THIR neurons in the substantia nigra and reduction of tissue levels of DA in the caudate nucleus. Such treatment produces appropriate turning responses to both AMP and APO challenge not seen in the acute treatment group, and appears to be an effective method of producing parkinsonian-like behavior in a large animal.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

Glial cell nuclear hypertrophy in complex partial seizures.

The white matter of resected temporal lobes from patients with intractable complex partial seizures shows increased cellularity which appears to be related to glia and neurons. This study, using quantitative methods, defines an increase in glial cell numbers and a significant increase in glial nuclear size within a defined area of white matter in the lateral temporal lobe. Evaluation was made on specimens from ten patients with complex partial seizures compared with two patients with non-epileptic brain lesions and five autopsy patients with no neurologic disease. The importance of recognizing these alterations in glia and the possible relevance to the pathoetiology of epilepsy are discussed.

Adolescent↗

Jugular venous desaturation and outcome after head injury.

Early experience with continuous monitoring of jugular venous oxygen saturation (SjvO2) suggested that this technology might allow early identification of global cerebral ischaemia in patients with severe head injury. The purpose of the present study was to examine the relationship between episodes of jugular venous desaturation and neurological outcome. One hundred and sixteen severely head-injured patients had continuous monitoring of SjvO2 during days 1-5 after injury. Episodes of jugular venous desaturation (SjvO2 < 50% for more than 10 minutes) were prospectively identified, and the incidence of desaturation was correlated with neurological outcome: 77 episodes of desaturation occurred in 46 of the 116 patients; 27 had one episode and 19 had multiple episodes of desaturation. The causes of these episodes were systemic (n = 36), cerebral (n = 35), or both (n = 6). Most of the episodes were less than 1 hour in duration, and it is probable that many of them would not have been detected without continuous measurement of SjvO2. Episodes of desaturation were most common on day 1 after injury, and were twice as common in patients with a reduced cerebral blood flow as in patients with a normal or elevated cerebral blood flow. The occurrence of jugular venous desaturation was strongly associated with a poor neurological outcome. The percentage of patients with a poor neurological outcome was 90% with multiple episodes of desaturation and 74% in patients with one desaturation, compared to 55% in patients with no episodes of desaturation. When adjusted for all co-variates that were found to be significant, including age, Glasgow coma score, papillary reactivity, type of injury, lowest recorded cerebral perfusion pressure, and highest recorded temperature, the incidence of desaturation remained significantly associated with a poor outcome. Although a cause and effect relationship with outcome cannot be established in this study, the data suggest that monitoring SvO2 might allow early identification and therefore treatment of many types of secondary injury to the brain.

Adolescent↗

Calorie sources and recovery from central nervous system ischemia.

OBJECTIVES: Glucose is the primary substrate for the energy requirements of the nervous system. Nevertheless, administration of glucose to critically ill patients with central nervous system trauma may have adverse effects on their neurologic recovery. The purpose of this study was to evaluate the effects of other sources of nonprotein calories on spinal cord lactate accumulation and on electrophysiologic recovery after a period of severe spinal cord ischemia. DESIGN: Two randomized, blinded studies were performed: one of glycolytic energy substrates (fructose, xylitol, sorbitol, glycerol) and one of ketogenic energy substrates (beta-hydroxybutyrate, acetate, butyrate). SETTING: College teaching hospital laboratory. SUBJECTS: New Zealand albino rabbits (weight 3.5 to 4.5 kg). INTERVENTIONS: After infusion of the randomly assigned treatment, temporary ischemia was produced in the lumbosacral spinal cord by occluding the abdominal aorta with a balloon catheter. MEASUREMENTS AND MAIN RESULTS: Blood concentrations of glucose, lactate, pyruvate, and ketone bodies and spinal cord dialysate concentration of lactate were measured before and after infusion of the assigned treatment, and during ischemia and during the first 2 hrs after reperfusion. Spinal somatosensory evoked potentials were recorded during ischemia to assure a similar severity of ischemia in all animals and during the first 2 hrs after reperfusion as a measure of electrophysiologic recovery. Infusion of the glycolytic nutrients xylitol and fructose increased blood glucose and lactate concentrations, and resulted in increased lactate accumulation in the spinal cord during ischemia and resulted in a significantly poorer recovery of the spinal somatosensory evoked potential than infusion of saline. Infusion of sorbitol and glycerol did not have these adverse effects in the doses administered. None of the ketogenic nutrients increased blood glucose concentration or increased lactate accumulation in the spinal cord during ischemia when compared with infusion of saline. Infusion of butyrate and acetate caused arterial hypotension and resulted in a poorer recovery of the spinal somatosensory evoked potential than saline. Infusion of beta-hydroxybutyrate did not have an adverse effect on blood pressure or on evoked potential recovery. CONCLUSIONS: Glycerol, sorbitol, and beta-hydroxybutyrate deserve further evaluation as potential nonprotein calorie sources in patients with neurologic injury. Xylitol and fructose are not suitable since these substrates resulted in hyperglycemia and increased lactate accumulation in the central nervous system, and had detrimental effects on electrophysiologic recovery after ischemia. The short-chain fatty acids (acetate and butyrate) also had adverse effects on electrophysiologic recovery after ischemia, probably because of their hypotensive effects when given intravenously, rather than from the effects of their metabolism.

Analysis of Variance↗

Evaluation of a microsensor intracranial pressure transducer.

This report describes the results of a laboratory evaluation of a new device for monitoring intracranial pressure (ICP), consisting of a miniature pressure transducer mounted on a pressure sensing diaphragm. In in vitro tests, 6 microsensor transducers were monitored for drift at pressures of 10 mmHg and 20 mmHg. The maximal drift of any of the transducers was 1 mmHg over 9 days. In in vivo tests, the ICP measurement obtained with the microsensor transducer correlated well with pressures recorded from a catheter in the cisternal magna with a Statham transducer over a wide range of ICP values (n = 511, r = 0.998, P < 0.001). If these laboratory findings can be duplicated in clinical studies, this microsensor transducer may be a useful alternative to the ventriculostomy catheter and other currently used devices for monitoring ICP.

Animals↗

The relationship between hormonal mediators and systemic hypermetabolism after severe head injury.

The relationships of hormonal mediators to the systemic hypermetabolism and catabolism of head injury were studied in 15 patients with severe head injuries. Resting energy expenditure (REE), urinary nitrogen balance, and plasma glucose concentration were measured daily for the first 2 weeks after injury as the major indicators of hypermetabolism. These dependent variables were correlated with daily measurements of urinary epinephrine, norepinephrine, metanephrine, normetanephrine, dopamine, and cortisol, and with plasma levels of insulin, glucagon, and C-reactive protein. Urinary catecholamine and cortisol excretion were markedly elevated in these patients throughout the 2 weeks of study. Catecholamine excretion peaked between days 7 and 10, whereas cortisol excretion tended to be highest on day 5 after injury. Urinary levels of norepinephrine, normetanephrine, and cortisol were highest in the two patients with Glasgow Coma Scale scores of 4. Plasma insulin and glucagon concentrations were elevated on day 1 after injury and tended to increase throughout the 2-week period of study. The variables significantly associated with REE were the severity of injury, reflected by the GCS score, the urinary excretion of norepinephrine during the first 2 days after injury, and the urinary excretion of epinephrine and norepinephrine during days 3 to 7 after injury. A negative nitrogen balance was associated with the urinary excretion of epinephrine and norepinephrine, with caloric balance, and with plasma C-reactive protein during days 1 and 2 after injury. During days 3 to 7, a negative nitrogen balance was associated with the urinary excretion of epinephrine and norepinephrine and with caloric balance, and during days 8 to 14, a negative nitrogen balance was associated primarily with urinary cortisol excretion.

Adult↗

Near-infrared spectroscopic localization of intracranial hematomas.

Near-infrared spectroscopy (NIRS) of the cerebral hemispheres, applied transcranially through the intact scalp and skull, was evaluated for its ability to detect the presence of an intracranial hematoma in 46 head-injured patients. In 40 patients intracranial hematomas (22 subdural, 10 epidural, eight intracerebral) were identified on computerized tomography (CT); in all 40 cases, NIRS demonstrated greater absorption of light at 760 nm on the side of the hematoma. The mean difference in optical density (OD) between the hemisphere with the hematoma and the normal hemisphere was 0.99 +/- 0.30 for epidural hematomas, 0.87 +/- 0.31 for subdural hematomas, but only 0.41 +/- 0.11 for intracerebral hematomas. In 36 patients, the asymmetry in OD resolved after surgical evacuation of the hematoma or with spontaneous resorption of the hematoma. Four patients who developed postoperative or delayed hematomas exhibited persistence of the asymmetry in OD. Six patients had only diffuse injuries and exhibited only minor differences in OD between the hemispheres, similar to 10 patients in the control group with no head injury. It appears that NIRS is useful in the initial examination of the head-injured patient, as an adjunct to CT, and in following patients postoperatively in the intensive care unit.

Adolescent↗

Uncovering ocular pseudomyasthenia.

A 61-year-old woman who presented with unilateral ptosis and subsequently a lateral rectus weakness was followed for 2.5 years with the diagnosis of ocular myasthenia. Signs then developed that led to the discovery of a cavernous sinus meningioma. When ruling out ocular myasthenia, the importance of checking for diminished corneal sensation, an anisocoria that increases in the light, and aberrant regeneration of the third cranial nerve is pointed out.

Blepharoptosis↗

Cerebral blood flow, arteriovenous oxygen difference, and outcome in head injured patients.

Cerebral blood flow (CBF) and other physiological variables were measured repeatedly for up to 10 days after severe head injury in 102 patients, and CBF levels were related to outcome. Twenty five of the patients had a reduced CBF [mean (SD) 0.29 (0.05) ml/g/min]; 47 had a normal CBF, (0.41 (0.10) ml/g/min); and 30 had a raised CBF (0.62 (0.14) ml/g/min). Cerebral arteriovenous oxygen differences were inversely related to CBF and averaged 2.1 (0.7) mumol/ml in the group with reduced CBF, 1.9 (0.5) mumol/ml in the group with normal CBF, and 1.6 (0.4) mumol/ml in the group with raised CBF. Patients with a reduced CBF had a poorer outcome than patients with a normal or raised CBF. Mortality was highest in patients with a reduced CBF, and was 32% at three months after injury, whereas only 21% of the patients with a normal CBF and 20% of the patients with a raised CBF died. There were no differences in the type of injury, initial score on the Glasgow Coma Scale, mean intracranial pressure (ICP), highest ICP, or the amount of medical treatment required to keep the ICP less than 20 mm Hg in each group. Systemic factors did not significantly contribute to the differences in CBF among the three groups. A logistic regression model of the effect of CBF on neurological outcome was developed. When adjusted for variables which were found to be significant confounders, including age, initial Glasgow Coma Score, haemoglobin concentration, cerebral perfusion pressure and cerebral metabolic rate of oxygen, a reduced CBF remained significantly associated with an unfavourable neurological outcome.

Adult↗

Dietary nonprotein calories and cerebral infarction size in rats.

BACKGROUND AND PURPOSE: Conventional diets may cause hyperglycemia in patients with neurological injuries. The purpose of this study was to examine the effect on the severity of cerebral infarction of replacing carbohydrates as the primary dietary source of nonprotein calories. METHODS: Sixty-nine Long-Evans rats were either fasted for 24 hours, fed isocaloric amounts of a control diet containing 51.5% of the calories as carbohydrates, or fed one of five experimental diets before middle cerebral artery occlusion for 45 minutes. In the experimental diets, 60% of the carbohydrate calories were replaced with one or more of the following substrates: 1,3-butanediol, triacetin, tributyrin, and long- and medium-chain triglycerides. RESULTS: The plasma glucose concentration in the fasted animals was 6.4 +/- 1.1 mumol/ml. In the animals receiving the control diet, which contained the greatest number of carbohydrate calories, plasma glucose was 9.1 +/- 1.4 mumol/ml. The 1,3-butanediol diet resulted in an intermediate plasma glucose concentration averaging 7.8 +/- 1.3 mumol/ml. Plasma beta-hydroxybutyrate levels were elevated in the fasted group and with the 1,3-butanediol diet. Plasma acetate levels were increased with the diets supplemented with triacetin. The smallest infarct volume (53 +/- 43 mm3) was found in the fasted group and the largest (162 +/- 56 mm3) in the control diet group. Infarct volumes that were significantly smaller were found with the 1,3-butanediol diet (98 +/- 41 mm3) and with the triacetin/tributyrin diet (105 +/- 53 mm3). The volume of the infarct was directly related to the plasma glucose concentration before ischemia (n = 69, r = 0.47, p less than 0.01), but not to plasma lactate, ketone body, or acetate levels. CONCLUSIONS: It may be possible to develop a diet for patients with neurological injuries using noncarbohydrate calorie sources, such as 1,3-butanediol, triacetin, or tributyrin, that would supply systemic caloric and protein requirements without the adverse effect of conventional diets.

Animals↗

Effect of head elevation on intracranial pressure, cerebral perfusion pressure, and cerebral blood flow in head-injured patients.

The traditional practice of elevating the head in order to lower intracranial pressure (ICP) in head-injured patients has been challenged in recent years. Some investigators argue that patients with intracranial hypertension should be placed in a horizontal position, the rationale being that this will increase the cerebral perfusion pressure (CPP) and thereby improve cerebral blood flow (CBF). However, ICP is generally significantly higher when the patient is in the horizontal position. This study was undertaken to clarify the issue of optimal head position in the care of head-injured patients. The effect of 0 degree and 30 degrees head elevation on ICP, CPP, CBF, mean carotid pressure, and other cerebral and systemic physiological parameters was studied in 22 head-injured patients. The mean carotid pressure was significantly lower when the patient's head was elevated at 30 degrees than at 0 degrees (84.3 +/- 14.5 mm Hg vs. 89.5 +/- 14.6 mm Hg), as was the mean ICP (14.1 +/- 6.7 mm Hg vs. 19.7 +/- 8.3 mm Hg). There was no statistically significant change in CPP, CBF, cerebral metabolic rate of oxygen, arteriovenous difference of lactate, or cerebrovascular resistance associated with the change in head position. The data indicate that head elevation to 30 degrees significantly reduced ICP in the majority of the 22 patients without reducing CPP or CBF.

Adult↗