Ekkehard Kunze

Prophylactic intravenous magnesium sulfate for treatment of aneurysmal subarachnoid hemorrhage: A randomized, placebo-controlled, clinical study

Objective:To examine whether the maintenance of elevated magnesium serum concentrations by intravenous administration of magnesium sulfate can reduce the occurrence of cerebral ischemic events after aneurysmal subarachnoid hemorrhage. Design:Prospective, randomized, placebo-controlled study. Setting:Neurosurgical intensive care unit of a University hospital. Interventions:One hundred ten patients were randomized to receive intravenous magnesium sulfate or to serve as controls. Magnesium treatment was started with a bolus of 16 mmol, followed by continuous infusion of 8 mmol/hr. Serum concentrations were measured every 8 hrs, and infusion rates were adjusted to maintain target levels of 2.0–2.5 mmol/L. Intravenous administration was continued for 10 days or until signs of vasospasm had resolved. Thereafter, magnesium was administered orally and tapered over 12 days. Measurements and Main Results:Delayed ischemic infarction (primary end point) was assessed by analyzing serial computed tomography scans. Transcranial Doppler sonography and digital subtraction angiography were used to detect vasospasm. Delayed ischemic neurologic deficit was determined by continuous detailed neurologic examinations; clinical outcome after 6 months was assessed using the Glasgow outcome scale. Good outcome was defined as Glasgow outcome scale score 4 and 5. The incidence of delayed ischemic infarction was significantly lower in magnesium-treated patients (22% vs. 51%; p = .002); 34 of 54 magnesium patients and 27 of 53 control patients reached good outcome (p = .209). Delayed ischemic neurologic deficit was nonsignificantly reduced (9 of 54 vs. 15 of 53 patients; p = .149) and transcranial Doppler-detected/angiographic vasospasm was significantly reduced in the magnesium group (36 of 54 vs. 45 of 53 patients; p = .028). Fewer patients with signs of vasospasm had delayed cerebral infarction. Conclusion:These data indicate that high-dose intravenous magnesium can reduce cerebral ischemic events after aneurysmal subarachnoid hemorrhage by attenuating vasospasm and increasing the ischemic tolerance during critical hypoperfusion.

Decompressive Craniectomy in Patients with Uncontrollable Intracranial Hypertension

There has been controversial discussion about the benefits of decompressive craniectomy in patients with critically raised intracranial pressure (ICP) after severe head injury. The aim of this retrospective study was to analyze the results of secondary decompressive craniectomy in patients with uncontrollable raised ICP after maximum aggressive medical treatment. The data of 28 patients (mean age 22 years, range 8-44 years) with severe head injury and posttraumatic cerebral edema were analyzed retrospectively. Surgery was not indicated in patients with vast primary lesions, hypoxia, ischemic infarction, brainstem injuries and central herniation. The outcome was classified according to the Glascow Outcome Scale (GOS) after one year. The decompressive crainectomy was performed an average of 68 hours after trauma, and ICP (< 25 mm Hg) decreased always while cerebral perfusion pressure (CPP > 75 mm Hg) improved as well as cerebral blood flow and microcirculation to normal values. 15 patients (56%) had a good outcome after one year (GOS 4 + 5). 5 patients (18%) were severely disabled, 4 patients (14%) remained in vegetative state and 3 patients (11%) died. Decompressive craniectomy should be kept in mind as the last therapeutic step, especially in young patients with head injury and raised ICP, which is not controllable with conservative methods.

Monitoring of brain tissue oxygenation following severe subarachnoid hemorrhage.

Abstract The purpose of this prospective observational study was to investigate the relation between the frequency of critical neuromonitoring parameters (brain tissue pO2, (PtiO2) ≤ 10 mmHg, intracranial pressure (ICP) > 20 mmHg, cerebral perfusion pressure (CPP) ≤ 70 mmHg) and outcome after severe aneurysmal subarachnoid hemorrhage (SAH). In a prospective study on 42 patients monitoring of ICP, CPP, and PtiO2 (in the area at risk for vasospasm) was performed. All patients were primarily classified as Hunt and Hess grade 4 or with secondary deterioration to this grade. Relative proportions of PtiO2 ≤ 10 mmHg (n = 42), ICP > 20 mmHg (n = 25) and CPP ≤ 70 mmHg (n = 23) were derived from multimodal neuromonitoring data sets for different time intervals, i.e. 1. the total monitoring time; 2. the total monitoring time without the last two monitoring days; 3. the second last monitoring day; and 4. the last monitoring day. Patients were divided into nonsurvivors (GOS = 1) and survivors (GOS = 3-5). For the total monitoring time, significant differences in the relative proportion of critical values were found for all neuromonitoring parameters (p < 0.05). The detailed analysis of consecutive time intervals revealed significantly increased proportions of critical values in nonsurvivors for all neuromonitoring parameters during the last day only. Additionally, ICP > 20 mmHg was significantly more frequent during the second last day (p < 0.01). For other time periods no differences were observed. We conclude, that critical neuromonitoring values are not early predictors of nonsurvival in patients suffering from severe SAH.

Clinical cerebral microdialysis: brain metabolism and brain tissue oxygenation after acute brain injury.

Abstract While continuous monitoring of brain tissue oxygenation (ptiO2) is known as a practicable, safe and reliable monitoring technology supplementing traditional ICP-CPP-monitoring, the impact of cerebral microdialysis, now available bedside, is not proven extensively. Therefore our studies focused on the practicability, complications and clinical impact of microdialysis during long term monitoring after acute brain injury, especially the analysis of the correlation between changes of local brain oxygenation and metabolism. Advanced neuromonitoring including ICP-CPP-ptiO2 was performed in 20 patients suffering from acute brain injury. Analysis of the extracellular fluid metabolites (glucose, lactate, pyruvate, glutamate) were performed bedside hourly. No catheter associated complications, like infection and bleeding, occurred. However, longterm monitoring was limited in 5 out of 20 patients caused by obliteration of the microdialysis catheter after 3-4 days. In the individual patients partly a correlation between increased lactate levels as well as lactate pyruvate ratios and hypoxic brain tissue oxygenation could be found. Analysing the data sets of all patients only a low correlation was detected indicating physiological and increased lactate and lactate/pyruvate ratio during sufficient brain oxygenation. Additionally, concentrations of excitatory amino acid glutamate were found in normal and elevated range during periods of hypoxic oxygenation (ptiO2 < 10 mmHg) and intracranial hypertension. Our data strongly suggest partly evidence of correlation between hypoxic oxygenation and metabolic disturbances after brain injury. On the other hand brain metabolism is altered without changes of cerebral oxygenation. Further studies are indicated to improve our pathophysiological knowledge before microdialysis is routinely useful in neurointensive care. [Neurol Res 2001; 23: 801-806]

THE IMPACT OF BALLOON ANGIOPLASTY ON THE EVOLUTION OF VASOSPASM-RELATED INFARCTION AFTER ANEURYSMAL SUBARACHNOID HEMORRHAGE

OBJECTIVEVasospasm of the cerebral vessels remains a major source for morbidity and mortality after aneurysmal subarachnoid hemorrhage. The purpose of this study was to evaluate the frequency of infarction after transluminal balloon angioplasty (TBA) in patients with severe subarachnoid hemorrhage-related vasospasm. METHODSWe studied 38 patients (median Hunt and Hess Grade II and median Fisher Grade 4) with angiographically confirmed severe vasospasm (>70% vessel narrowing). A total of 118 vessels with severe vasospasm in the anterior circulation were analyzed. Only the middle cerebral artery, including the terminal internal carotid artery, was treated with TBA (n = 57 vessel segments), whereas the anterior cerebral artery was not treated (n = 61 vessel segments). For both the treated and the untreated vessel territories, infarction on unenhanced computed tomographic scan was assessed as a marker for adverse outcome. RESULTSInfarction after TBA occurred in four middle cerebral artery territories (four out of 57 [7%]), whereas the infarction rate was 23 out of 61 (38%) in the anterior cerebral artery territories not subjected to TBA (P < 0.001, Fisher exact test). Three procedure-related complications occurred during TBA (dissection, n = 1; temporary vessel occlusions, n = 2). One of these remained asymptomatic, whereas this may have contributed to the development of infarction on follow-up computed tomographic scans in two cases. CONCLUSIONIn a population of patients with a high risk of infarction resulting from vasospasm after subarachnoid hemorrhage, the frequency of infarction in the distribution of vessels undergoing TBA amounts to 7% and is significantly lower than in vessels not undergoing TBA despite some risk inherent to the procedure.

Acute vasoconstriction: decrease and recovery of cerebral blood flow after various intensities of experimental subarachnoid hemorrhage in rats

OBJECT Immediate vasoconstriction after subarachnoid hemorrhage (SAH) has been observed in a number of experimental studies. However, it has not yet been examined which pattern this acute-type vascular reaction follows and whether it correlates with the intensity of SAH. It was the purpose of the present study to vary the extent of SAH using the endovascular filament model of SAH with increasing filament sizes and to compare the course of intracranial pressure (ICP), cerebral perfusion pressure (CPP), and regional cerebral blood flow (rCBF). METHODS Male Sprague-Dawley rats were subjected to SAH using the endovascular filament model. Subarachnoid hemorrhage was induced using a 3-0, 4-0, or 5-0 Prolene monofilament (8 rats in each group). Eight animals served as controls. Bilateral rCBF (laser Doppler flowmetry), mean arterial blood pressure, and ICP were continuously monitored. Thereafter, the rats were allowed to wake up. Twenty-four hours later, the animals were killed, their brains were removed, and the extent of SAH was determined. RESULTS After induction of SAH, ICP steeply increased while CPP and rCBF rapidly declined in all groups. With increasing size of the filament, the increase of ICP and the decrease of CPP were more pronounced. However, the decline of rCBF exceeded the decline of CPP in all SAH groups. In a number of animals with minor SAH, an oscillating pattern of rCBF was observed during induction of SAH and during early recovery. CONCLUSIONS The disparity between the decline and recovery of CPP and rCBF suggests that acute vasoconstriction occurs even in SAH of a minor extent. Acute vasoconstriction may contribute significantly to a perfusion deficit in the acute stage after SAH. The oscillating pattern of rCBF in the period of early recovery after SAH resembles the pattern of synchronized vasomotion, which has been thoroughly examined for other vascular territories and may yield therapeutic potential.

Therapeutic aspects of brain tissue pO2 monitoring after subarachnoid hemorrhage.

Prolonged phases of brain tissue hypoxia (ptiO2 < 10 mmHg) lead to cerebral infarction. Therefore, the present study investigates the role of ptiO2--monitoring to guide hypervolemic hypertensive therapy in patients suffering from severe subarachnoid hemorrhage (SAH). Besides transcranial doppler, neuromonitoring of ICP/CPP was supplemented by ptiO2 monitoring. The ptiO2 catheter was inserted into viable tissue in the vascular territory with the highest risk for vasospasm. Patients were divided in an infarction (n = 21) and a non-infarction group (n = 11). Critical CPP (< 70 mmHg) as well as hypoxic ptiO2 (< 10 mmHg) was significantly more frequent in the infarction group (CPP: 25 vs 13%, p < 0.001; ptiO2: 16 vs 7%, p < 0.001). In both groups, over 25% of the critical ptiO2 values occurred at a CPP > 90 mmHg. In the infarction group, 13 patients showed transient phases of hypoxia which normalized under induced hypervolemic hypertension and 5 patients developed persistent hypoxia. In the non-infarction group 6 patients showed transient hypoxia and in 5 patients no hypoxic values could be found. In conclusion, monitoring of ptiO2 provides an additional independent parameter to detect hypoxic events and to guide therapy.

Time-course of cerebral perfusion and tissue oxygenation in the first 6 h after experimental subarachnoid hemorrhage in rats.

Present knowledge about hemodynamic and metabolic changes after subarachnoid hemorrhage (SAH) originates from neuromonitoring usually starting with aneurysm surgery and animal studies that have been focusing on the first 1 to 3 h after SAH. Most patients, however, are referred to treatment several hours after the insult. We examined the course of hemodynamic parameters, cerebral blood flow, and tissue oxygenation (ptiO2) in the first 6 h after experimental SAH. Sixteen Sprague–Dawley rats were subjected to SAH using the endovascular filament model or served as controls (n = 8). Bilateral local cortical blood flow, intracranial pressure, cerebral perfusion pressure, and ptiO2 were followed for 6 h after SAH. After induction of SAH, local cortical blood flow rapidly declined to 22% of baseline and returned to 80% after 6 h. The decline of local cortical blood flow markedly exceeded the decline of cerebral perfusion pressure. ptiO2 declined to 57%, recovered after 2 h, and reached ≥140% of baseline after 6 h. Acute vasoconstriction after SAH is indicated by the marked discrepancy of cerebral perfusion pressure and local cortical blood flow. The excess tissue oxygenation several hours after SAH suggests disturbed oxygen utilization and cerebral metabolic depression. Aside from the sudden increase of intracranial pressure at the time of hemorrhage and delayed cerebral vasospasm, the occurrence of acute vasoconstriction and disturbed oxygen utilization may be additional factors contributing to secondary brain damage after SAH.

Magnesium treatment for neuroprotection in ischemic diseases of the brain.

This article reviews experimental and clinical data on the use of magnesium as a neuroprotective agent in various conditions of cerebral ischemia. Whereas magnesium has shown neuroprotective properties in animal models of global and focal cerebral ischemia, this effect could not be reproduced in a large human stroke trial. These conflicting results may be explained by the timing of treatment. While treatment can be started before or early after ischemia in experimental studies, there is an inevitable delay of treatment in human stroke. Magnesium administration to women at risk for preterm birth has been investigated in several randomized controlled trials and was found to reduce the risk of neurological deficits for the premature infant. Postnatal administration of magnesium to babies after perinatal asphyxia has been studied in a number of controlled clinical trials. The results are promising but the trials have, so far, been underpowered. In aneurysmal subarachnoid hemorrhage (SAH), cerebral ischemia arises with the onset of delayed cerebral vasospasm several days after aneurysm rupture. Similar to perinatal asphyxia in impending preterm delivery, treatment can be started prior to ischemia. The results of clinical trials are conflicting. Several clinical trials did not show an additive effect of magnesium with nimodipine, another calcium antagonist which is routinely administered to SAH patients in many centers. Other trials found a protective effect after magnesium therapy. Thus, it may still be a promising substance in the treatment of secondary cerebral ischemia after aneurysmal SAH. Future prospects of magnesium therapy are discussed.

The Temporal Profile of Cerebral Blood Flow and Tissue Metabolites Indicates Sustained Metabolic Depression After Experimental Subarachnoid Hemorrhage in Rats

BACKGROUND:Derangement of cerebral metabolism occurs after various insults such as ischemia, traumatic brain injury, and subarachnoid hemorrhage (SAH). OBJECTIVE:To investigate the course of cerebral blood flow and metabolic parameters in the first hours after experimental SAH. METHODS:Sixteen Sprague-Dawley rats were subjected to SAH using the endovascular filament model or served as controls (8 rats in each group). Local cerebral blood flow and intracranial pressure were measured continuously. Microdialysis samples were acquired in 30-minute intervals for 6 hours after SAH. Concentrations of glucose, lactate, pyruvate, and glutamate were determined. RESULTS:After induction of SAH, cerebral perfusion pressure and local cerebral blood flow sharply decreased. The decrease in local cerebral blood flow exceeded the decrease in cerebral perfusion pressure throughout the observation period. Glutamate concentrations in microdialysis samples increased sixfold and recovered to baseline levels. Lactate concentrations immediately increased after SAH, recovered incompletely, and remained above the levels of control animals until the end of the sampling period. Pyruvate concentrations showed a delayed increase starting 2 hours after SAH. CONCLUSION:The course of cerebral blood flow after SAH resembles global ischemia followed by a continuous low-flow state caused by a sudden decrease in cerebral perfusion pressure and acute vasoconstriction. The courses of lactate and pyruvate concentrations indicate a persistently deranged aerobic metabolism.