Magnesium in subarachnoid hemorrhage

Abstract

The main objective of this thesis was to determine the role of serum magnesium in the pathophysiology after subarachnoid hemorrhage (SAH) and to assess the effect of magnesium treatment in reducing cerebral ischemia in experimental SAH and in improving clinical outcome in patients with aneurysmal SAH. In Chapter 2 we reviewed the potentials of magnesium treatment in subarachnoid hemorrhage by describing the pathophysiology of ischemia after SAH and the many ways magnesium may interfere with this. In Chapter 3 we described a study in which cortical spreading depressions (CSDs) are induced by topical administration of potassium chloride in rat brain. We demonstrated that intravenous magnesium administration reduced CSDs and delayed anoxic depolarization in intact rat brain. Therefore we hypothesized that the neuroprotective role of magnesium in cerebral ischemia is partly due to effective suppression of ischemia-induced depolarization. In Chapter 4 we induced an experimental subarachnoid hemorrhage in the rat by means of the endovascular filament model. MRI measurements were performed on a 4.7T NMR spectrometer 1 and 48 hours after SAH and 9 days thereafter. We showed that it is feasible to detect alterations of in-vivo vessel diameter and blood flow velocities and their consequences for brain damage after experimental SAH in the rat. The increase of the infarct and the concomitant vasoconstriction suggest that delayed cerebral ischemia after SAH occurs in rats and that vasoconstriction may play an important role. In the study described in Chapter 5 we also used the endovascular filament method to induce SAH in the rat. Extracellular direct current potentials were continuously recorded from 6 Ag/AgCl electrodes, before and up to 90 minutes following SAH. Next, animals were transferred to the 4.7T NMR spectrometer. We demonstrated that prolonged depolarizations occur immediately after SAH and that the duration of these depolarizations is related to the extent of ischemic lesions observed on MRI. Moreover, we found that pretreatment with magnesium sulfate reduces the duration of the depolarizations and the extent of the ischemic lesions. Cortical spreading depressions play a minor role, if any, in the acute pathophysiology of SAH. In Chapter 6 a clinical study is described in which we measured serum magnesium in 107 consecutive patients admitted within 48 hours after SAH. Hypomagnesemia is frequently present after SAH (38%) and is associated with the amount of subarachnoid blood (cisternal blood p=0.006; ventricular blood p=0.005), a longer duration of unconsciousness (p=0.007), and a worse clinical condition at admission (p=0.001). Hypomagnesemia occurring between days 2 and 12 after SAH predicts DCI (HR 3.2; 95% CI 1.1-8.9). In Chapter 7 we describe the relation between hypomagnesemia and ECG abnormalities after SAH. Lower serum magnesium levels were related to less pronounced increase in the QTc interval and a long PR interval. Although the direction of the relation was unexpected, decreased serum magnesium might be the missing link between SAH and ECG abnormalities. In Chapter 8 we describe the results of our dose-finding study, preceding our randomized controlled trial. We found that with a continuous intravenous dosage of 64 mmol per day, serum magnesium levels after SAH maintained within the pursued range of 1.0-2.0 mmol/l for 14 days. In Chapter 9 we confirmed that with the dosage schedule found in Chapter 7 serum magnesium levels of 1.0-2.0 mmol/l can easily be maintained without severe side effects in a vast majority of patients. In Chapter 10 we describe the results of our randomized controlled trial performed with the above mentioned dosage regime in 283 patients. Magnesium treatment reduced the risk of DCI by 34% (HR 0.66; 95% CI 0.38-1.14). The risk reduction for poor outcome after 3 months was 23% (RR 0.77; 95% CI 0.54-1.09). At that time 18 patients in the treatment group and 6 in the placebo group had an excellent outcome (RR for non-excellent outcome 0.91; 95% CI 0.84-0.98). This study shows that there is a strong tendency towards a reduction of DCI and subsequent poor outcome in patients treated with magnesium, but as yet, the evidence for the introduction of magnesium treatment in clinical practice is inconclusive. A large phase III trial with functional recovery as the primary measure of outcome should provide final evidence for the effect of magnesium therapy in addition to the standard therapy.