Bedside diagnosis of mitochondrial dysfunction in aneurysmal subarachnoid hemorrhage.

OBJECTIVES: Aneurysmal subarachnoid hemorrhage (SAH) is frequently associated with delayed neurological deterioration (DND). Several studies have shown that DND is not always related to vasospasm and ischemia. Experimental and clinical studies have recently documented that it is possible to diagnose and separate cerebral ischemia and mitochondrial dysfunction bedside. The study explores whether cerebral biochemical variables in SAH patients most frequently exhibit a pattern indicating ischemia or mitochondrial dysfunction. METHODS: In 55 patients with severe SAH, intracerebral microdialysis was performed during neurocritical care with bedside analysis and display of glucose, pyruvate, lactate, glutamate, and glycerol. The biochemical patterns observed were compared to those previously described in animal studies of induced mitochondrial dysfunction as well as the pattern obtained in patients with recirculated cerebral infarcts. RESULTS: In 29 patients, the biochemical pattern indicated mitochondrial dysfunction while 10 patients showed a pattern of cerebral ischemia, six of which also exhibited periods of mitochondrial dysfunction. Mitochondrial dysfunction was observed during 5162 h. An ischemic pattern was obtained during 688 h. Four of the patients (40%) with biochemical signs of ischemia died at the neurosurgical department as compared with three patients (10%) in the group of mitochondrial dysfunction. CONCLUSIONS: The study documents that mitochondrial dysfunction is a common cause of disturbed cerebral energy metabolism in patients with SAH. Mitochondrial dysfunction may increase tissue sensitivity to secondary adverse events such as vasospasm and decreased cerebral blood flow. The separation of ischemia and mitochondrial dysfunction bedside by utilizing microdialysis offers a possibility to evaluate new therapies.

Bedside diagnosis of mitochondrial dysfunction after malignant middle cerebral artery infarction.

BACKGROUND: The study explores whether the cerebral biochemical pattern in patients treated with hemicraniectomy after large middle cerebral artery infarcts reflects ongoing ischemia or non-ischemic mitochondrial dysfunction. METHODS: The study includes 44 patients treated with decompressive hemicraniectomy (DCH) due to malignant middle cerebral artery infarctions. Chemical variables related to energy metabolism obtained by microdialysis were analyzed in the infarcted tissue and in the contralateral hemisphere from the time of DCH until 96 h after DCH. RESULTS: Reperfusion of the infarcted tissue was documented in a previous report. Cerebral lactate/pyruvate ratio (L/P) and lactate were significantly elevated in the infarcted tissue compared to the non-infarcted hemisphere (p < 0.05). From 12 to 96 h after DCH the pyruvate level was significantly higher in the infarcted tissue than in the non-infarcted hemisphere (p < 0.05). CONCLUSION: After a prolonged period of ischemia and subsequent reperfusion, cerebral tissue shows signs of protracted mitochondrial dysfunction, characterized by a marked increase in cerebral lactate level with a normal or increased cerebral pyruvate level resulting in an increased LP-ratio. This biochemical pattern contrasts to cerebral ischemia, which is characterized by a marked decrease in cerebral pyruvate. The study supports the hypothesis that it is possible to diagnose cerebral mitochondrial dysfunction and to separate it from cerebral ischemia by microdialysis and bed-side biochemical analysis.

Recirculation usually precedes malignant edema in middle cerebral artery infarcts.

OBJECTIVES: In patients with large middle cerebral artery (MCA) infarcts, maximum brain swelling leading to cerebral herniation and death usually occurs 2-5 days after onset of stroke. The study aimed at exploring the pattern of compounds related to cerebral energy metabolism in infarcted brain tissue. METHODS: Forty-four patients with malignant MCA infarcts were included after decision to perform decompressive hemicraniectomy (DHC). Cerebral energy metabolism was in all patients monitored bedside by 1-3 microdialysis catheters inserted into the infarcted hemisphere during DHC. In 29 of the patients, one microdialysis catheter was also placed in the non-infarcted hemisphere. MCA blood-flow velocity was monitored bilaterally by transcranial Doppler ultrasound. RESULTS: The interstitial glucose levels were in both sides within normal limits throughout the monitoring period. Mean lactate/pyruvate (LP) ratio was very high in infarcted tissue immediately after DHC. The ratio slowly decreased but did not reach normal level during the study period. In the infarcted hemisphere, MCA blood-flow velocities increased from approximately 42 cm/s 1 day prior to DHC (nine of nine patients) to approximately 60 cm/s at day 4. CONCLUSIONS: Normal interstitial glucose level in the infarcted hemisphere in combination with substantial MCA blood-flow velocities bilaterally even before DHC was performed indicates that malignant brain swelling usually commences when the embolus/thrombosis has been largely resolved and recirculation of the infarcted area has started. The protracted increase of the LP ratio in infarcted tissue might indicate mitochondrial dysfunction.

Cerebral blood flow, vasoreactivity, and oxygen consumption during barbiturate therapy in severe traumatic brain lesions.

Mean hemispheric cerebral blood flow (CBF) and intracranial pressure (ICP) were measured in 19 severely head-injured patients treated with barbiturate coma. The CBF was calculated from the clearance of tracer substance monitored by extracranial scintillation detectors after intravenous administration of xenon-133. In 11 of the patients cerebral arteriovenous oxygen differences were measured simultaneously. In all patients the effects of pronounced hyperventilation were recorded prior to initiation of barbiturate treatment. A normal CBF response to hyperventilation (delta CBF/delta PaCO2 greater than or equal to 1) was obtained in eight patients. In these patients induction of barbiturate coma was accompanied by physiological decreases in CBF and in the calculated cerebral metabolic rate of oxygen (CMRO2); they also exhibited a rapid and lasting decrease in ICP. A decreased or an abolished CO2 reactivity was recorded (delta CBF/delta PaCO2 less than 1) in 11 patients. In 10 of these 11 patients the physiological decreases in CBF and CMRO2 were not obtained during barbiturate treatment and the decrease in ICP was transitory. This study demonstrates a correlation between cerebral vasoreactivity, physiological effects of barbiturate therapy, and clinical outcome.

Assessment of motor and process skills reflects brain-injured patients' ability to resume independent living better than neuropsychological tests.

OBJECTIVE: To compare recovery of cognitive functions and activities of daily living during the first year of rehabilitation after severe brain trauma. METHODS: Sixteen patients were evaluated by neuropsychological tests and occupational performance (assessment of motor and process skills, AMPS) on admission to the rehabilitation centre and 3, 6 and 12 months later. RESULTS: Cognitive functions improved continuously. Motor skills recovered rapidly and were relatively stable after 3 months. For process skills recovery was protracted. Six of 15 patients were still below the cut-off level after 12 months. Eleven of 13 patients deteriorated regarding process skills after leaving the rehabilitation centre. CONCLUSION: AMPS gives a different view of the patient's restitution than neuropsychological tests and may be a better indicator of the patients' ability to resume independent living. The deterioration of process skills post-rehabilitation suggests that lasting contact in an outpatient setting might facilitate return to social life.

Complications and side effects during thiopentone therapy in patients with severe head injuries.

This study reports all complications and side effects occurring in 38 patients with severe traumatic brain lesions treated with barbiturate coma because of a dangerous increase in intracranial pressure. The treatment was induced by intravenous infusion of thiopentone (5-11 mg.kg-1) followed by a continuous infusion of 4-8 mg.kg-1.h-1. The subsequent rate of thiopentone infusion was governed by the level of the intracranial pressure with the intention of keeping ICP below 20 mmHg (2.7 kPa). The duration of treatment was 1-15 days. Arterial hypotension occurred in 58%, hypokalemia in 82%, respiratory complications in 76%, infections in 55%, hepatic dysfunction in 87% and renal dysfunction in 47% of the patients. Twenty patients survived. Mortality in 17 patients was caused by an untreatable increase in intracranial pressure. In one patient complications due to barbiturate treatment may have contributed to the fatal outcome. In none of the other cases were the noted complications and side effects associated with any permanent symptoms or dysfunctions.

Bedside biochemical monitoring of the penumbra zone surrounding an evacuated acute subdural haematoma.

We describe a penumbra zone with increased biochemical vulnerability in cerebral cortex underlying an evacuated acute subdural haematoma. Two microdialysis catheters were placed in this zone and one catheter was placed in the opposite, less injured hemisphere. The microdialysis perfusates were analysed bedside for glucose, pyruvate, lactate, glutamate, and glycerol. In the penumbra zone, but not in the opposite hemisphere, energy metabolism was seriously disturbed with signs of cell membrane degradation. During an adverse event (decrease in haemoglobin level, systemic blood pressure and cerebral perfusion pressure) the perturbation of energy metabolism increased in this zone. Energy metabolism recovered and the signs of cell membrane degradation disappeared after normalization of the physiological parameters. We use the term biochemical penumbra zone to describe an area with signs of energy failure and cell membrane degradation, which has a capacity to regain a normal metabolic pattern but also an increased vulnerability to secondary insults.

Economic aspects of capacity for work after severe traumatic brain lesions.

During 1981-84,310 patients with severe traumatic brain lesions were treated at the Department of Neurosurgery in Lund, Sweden. A total of 161 patients were treated after the introduction of a more aggressive management protocol in 1983. In this first part of a long-term follow-up study we concentrate on the economic aspects. Two questions were addressed: first, what was the vocational outcome after severe head injuries? and second, what were the long-term effects of the new protocol? Out of 147 patients classified as good recovery/moderate disability (GR/MD) 6-months after injury, 106 patients agreed to participate in the study. Five to 8 years after injury 70 patients were classified as capable of working: 57 of these patients were actually at work, nine were studying and four were unemployed. Twenty-two patients had received disability pension and 14 patients had retired because of old age. In the age groups up to 60 years, 70% of patients had returned to work or school. The number of patients who returned to work was significantly higher after introduction of the more aggressive management protocol: 38 of 57 patients who had returned to work were in the group treated between 1983 and 1984. Mean income for patients who had returned to work was close to the average for the corresponding age groups in Sweden. Mean sick leave 5-8 years after severe head injuries was only slightly higher than average in Sweden. Our data show that a majority of the patients classified as GR/MD 6 months after severe traumatic brain lesions have the capacity to return to work. The improvements in the primary management of patients with severe head injuries introduced in 1983 increased the number of patients who work and thus increased the number of patients who favourably contributed to the economy of the community.

Psychosocial outcome 5-8 years after severe traumatic brain lesions and the impact of rehabilitation services.

This study addresses three questions. First, what is the long-term psychosocial outcome for severely head-injured patients? Second, is an increased survival rate associated with an increase in the number of patients with a poor quality of life? Third, do rehabilitation services affect the final outcome? The long-term outcome was assessed by means of questionnaires for self-ratings, interviews with patients and relatives and neurophysical examinations. One hundred and six patients initially judged as good recovery/moderate disability (GR/MD) 6 months post-injury participated in the study. Forty to 50% of these patients showed co-ordination disturbances; more than 20% had speech disorders and cranial nerve deficits. Twenty-eight per cent had psychiatric symptom scores on the Hopkins Symptom Checklist (HSCL) indicating need of treatment. Social function according to the Social Adjustment Scale--Self-Report (SAS--SR) showed that 40% had problems concerning interpersonal relations and 20-30% had problems within the field of leisure activities, but few problems were reported on work activities and economy. The Comprehensive Psychopathological Rating Scale (CPRS) revealed that hostile feelings, failing memory and fatiguability were common symptoms and were reported by relatives in 71%, 52% and 48%, respectively, but the mean distress levels were moderate. A correlation was seen between quality of life reported by relatives and the degree of mental and social disability according to the Bond Outcome Scale, but the correlation to neurophysical handicap was rather weak. The majority of patients were able to return to a productive social life. The proportion of patients with a poor long-term outcome did not increase after introduction of an aggressive management protocol for head injuries. Data indicated that improvements in facilities for rehabilitation may positively affect psychosocial adjustment.

Cerebral vasoreactivity and the prediction of outcome in severe traumatic brain lesions.

Mean hemispheric blood flow (CBF) was studied in 38 comatose, severely brain-injured patients following intravenous administration of xenon-133. Repeated measurements were performed in order to evaluate cerebral vasoreactivity following a decrease in PaCO2. Simultaneously, arterial-venous oxygen differences (AVDO2) and intracranial pressure (ICP) were measured. An impaired CBF response to hyperventilation (delta CBF/delta PaCO2 less than 1.0) was obtained in 22 patients. Three of 16 patients with preserved CO2-reactivity died because of their brain injuries and 12 patients reached good recovery/moderate disability. In the group of patients with impaired vasoreactivity 11 of 22 patients died and only three patients reached good recovery/moderate disability. The study documents that in patients with severe traumatic brain lesions measurements of cerebral vasoreactivity to hyperventilation give prognostic information that is not obtained by clinical observations or CT-scanning.

Severe traumatic brain lesions in Sweden. Part 2: Impact of aggressive neurosurgical intensive care.

During a 6 year period (1977-1982), 425 patients were treated in the Department of Neurosurgery, University Hospital of Lund, for severe traumatic brain lesions (coma greater than 6 hours). From 1983 a more aggressive management protocol was introduced including early recording of intracranial pressure (ICP) and 162 patients were included in the study 1983-1984. A dangerous increase in ICP in spite of adequate surgical treatment and moderately controlled hyperventilation was the incentive for barbiturate coma therapy in selected patients. In the first part of the study overall mortality was 48% whereas 39% of the patients reached good recovery/moderate disability 6 months after injury. During the second part of the study the corresponding figures were 35% and 54%, respectively (in both cases p less than or equal to 0.01). In the group of patients with focal intracranial mass lesions mortality decreased from 59% to 46% (p less than or equal to 0.05) and good recovery/moderate disability increased from 30% to 42% (p less than or equal to 0.05). Improvement in outcome was even more pronounced in patients with no-mass lesions, mortality decreased from 30% to 12% and good recovery/moderate disability increased from 56% to 80% (p less than or equal to 0.05 and p less than or equal to 0.01, respectively). No change occurred in age distribution or in the types of intracranial lesions that could explain these improvements. It is concluded that aggressive neurosurgical intensive care significantly improves outcome in patients with severe traumatic brain lesions.

Clinical outcome and cognitive impairment in patients with severe head injuries treated with barbiturate coma.

This study reports on clinical outcome in 38 patients with severe head injuries (posttraumatic coma for 6 hours or more) treated with barbiturate coma because of intracranial hypertension. Eighteen patients died, 4 patients remained in a severely disabled or a chronic vegetative state, and 16 patients reached the levels good recovery/moderate disability. Six of these patients returned to work or school full time, 4 for half time and 3 were in a rehabilitation program. Fourteen patients were subjected to a comprehensive neuropsychological assessment. All patients except one exhibited varying degrees of cognitive dysfunction and 6 patients had signs of personality change. The quality of life for the majority of surviving patients was relatively good but the positive effects of barbiturate coma therapy in the age groups over 40 years appeared to be limited.

Improved outcome after severe head injury with a new therapy based on principles for brain volume regulation and preserved microcirculation.

OBJECTIVE: To assess the new "Lund therapy" of posttraumatic brain edema, based on principles for brain-volume regulation and improved microcirculation. DESIGN: A prospective, nonrandomized outcome study over a 5-yr period on severely head-injured patients with increased intracranial pressure, comparing the results with a historical control group with the same selection criteria for patients who were treated according to conventional principles. SETTING: General intensive care unit of a university hospital. PATIENTS: Fifty-three consecutive head-injured patients with a Glasgow Coma Score of <8, and with increased intracranial pressure (>25 mm Hg), despite conventional treatment. INTERVENTIONS: Interstitial fluid resorption was obtained by lowering intracapillary hydrostatic pressure, by preserving normal colloid osmotic pressure, and by maintaining a normovolemic (normal albumin/serum and hemoglobin/serum), not overtransfused patient. Intracapillary pressure was reduced by the combination of precapillary vasoconstriction (low-dose thiopental, dihydroergotamine) and reduction of mean arterial pressure, the latter attained with a beta1-antagonist (metoprolol 0.2 to 0.3 mg/kg/24 hrs iv) and an alpha2-agonist (clonidine 0.4 to 0.8 microg/kg x 4 to 6 iv). Clonidine, in combination with normovolemia, also improves microcirculation by reducing catecholamines in plasma. Intracranial blood volume was reduced by arterial (low-dose thiopental sodium and dihydroergotamine) and large-vein (dihydroergotamine) vasoconstriction. The start dose of dihydroergotamine (maximum 0.9 microg/kg/hr) was successively reduced toward discontinuation within 4 to 5 days. MEASUREMENTS AND MAIN RESULTS: There were 8% of patients who died and the neurologic conditions of 13% remained severely damaged, compared with 47% and 11%, respectively, for the control group. CONCLUSIONS: The low mortality compared with previous outcome studies strongly indicates that this therapy improves outcome for severe head injuries. However, a randomized, controlled study is needed to reach general acceptance of this new therapy.

Reduced mortality after severe head injury will increase the demands for rehabilitation services.

PRIMARY OBJECTIVE: In 1989, a new therapy to reduce intracranial pressure in severely head-injured patients was introduced in Lund. The new treatment reduced mortality significantly. The present study describes the quality of life for the survivors. METHODS AND PROCEDURES: The study includes 53 patients treated during 1989-1994, according to a new treatment protocol for increased intracranial pressure ('Lund concept' group). During 1982-1986, 38 patients were managed according to a protocol including high dose thiopentone ('Thiopentone' group). The two groups are compared regarding neurophysical and psychiatric symptoms as well as aspects regarding the patient's role, performance, interpersonal relationship, frictions, feelings and satisfaction in work, areas of social and leisure activities, and extended family. RESULTS: Mortality was reduced from 47% to 8%, but the number of patients with a persistent vegetative state and/or remaining severe disability did not increase. However, the number of patients with persisting emotional and intellectual deficits increased significantly. CONCLUSION: The new treatment regime has dramatically increased the number of survivors after severe head trauma. Although most patients have a favourable outcome, there are more patients with remaining sequelae and disabilities, and the demand for qualified rehabilitation has increased.

Neuropsychological assessments in relation to CBF after severe head injuries.

OBJECTIVE: To determine whether neuropsychological outcome is related to cerebral blood flow (CBF) early in the recovery phase. MATERIAL AND METHODS: Twelve consecutive patients (mean age of 30 years, range 15-48 years) with severe traumatic brain injuries were subjected to a neuropsychological test battery at admission to the rehabilitation unit and after 3, 6 and 12 months. CBF measurements were performed at admission and 6 and 12 months later with a high-resolution, two-dimensional regional cerebral blood flow system with 254 stationary detectors after 1 min of (133)Xe inhalation (70-100 MBq/l). RESULTS AND CONCLUSION: Mean CBF values were within normal range already in the early post-acute phase and remained virtually unchanged during the first year of rehabilitation. A correlation was found between the individual CBF level and neuropsychological outcome 1 year after injury, particularly with regard to verbal memory capacity, reasoning capacity, and information processing speed.

Volumes of chronic traumatic frontal brain lesions measured by MR imaging and CBF tomography.

The volumes (ml) of chronic traumatic frontal brain lesions were compared measured "morphologically" with MR imaging (T1 and T2 weighted images) and "functionally" with a tomographic rCBF technique (SPECT with 133Xe i.v.). The T1 volumes varied between 11 and 220 ml. The correlation between T1 and T2 volumes was 0.95, the T2 volumes being 33% larger than T1 volumes (p less than 0.001). The functional SPECT volumes were considerably larger (range 16-324 ml) than the MR volumes. The mean volume difference was 81% between T1 and SPECT images (p less than 0.001), and 35% between T2 and SPECT images (p less than 0.001). Correlations between the MR and SPECT volumes were also higher for T2 than T1 volumes. The volume difference is most likely explained by a functional decrease in regions around the lesion in which no morphologic change visible on MR images had taken place. MR and SPECT volume measurements were positively related to persistent lack of energy and personality changes, but only moderately related to duration of impaired consciousness and neuropsychologic outcome.