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The effect of hypermagnesemic treatment on cerebrospinal fluid magnesium level in patients with aneurysmal subarachnoid hemorrh


Magnesium Research. Volume 22, Numéro 2, 60-5, June 2009, Original article

DOI : 10.1684/mrh.2009.0167

Summary  

Auteur(s) : George KC Wong, Christopher WK Lam, Mathew TV Chan, Tony Gin, Wai S Poon , Division of Neurosurgery, Department of Anesthesia and Intensive Care, Department of Chemical Pathology, The Chinese University of Hong Kong, China.

ARTICLE

Auteur(s) : George KC Wong1, Christopher WK Lam3, Mathew TV Chan2, Tony Gin2, Wai S Poon1

1Division of Neurosurgery
2Department of Anesthesia and Intensive Care
3Department of Chemical Pathology, The Chinese University of Hong Kong, China

Spontaneous subarachnoid haemorrhage accounts for only 3-5% of all strokes but the consequences can be devastating. Most are due to ruptured intracranial aneurysms. Advances in understanding of the disease, neuro-intensive care, endovascular treatment and refinement of microsurgical treatment have all led to improvement in management outcomes in the last decade. Nevertheless, its associated complications, such as delayed ischemic neurological deficit, remain a major cause of morbidity and mortality in this group of patients. Magnesium is a cerebral vasodilator [1-3] and a voltage-dependent calcium channel blocker [4, 5]. Furthermore, its antagonistic action on NMDA receptors in the brain attenuates glutamate stimulation and decreases calcium influx during ischemic injury [4-8]. Though results in animal models on cerebral ischemia have been conflicting [9], initial experimental results in humans demonstrated its safety and effectiveness as compared to control data [10-15].

In a study of brain availability of peripheral administered magnesium sulfate by McKee et al. [16], the authors measured the passage of intravenously administered Mg2+ into cerebrospinal fluid in patients with acute brain injury requiring ventricular drainage. During that experiment, total and ionized cerebrospinal fluid Mg2+ was maximally increased by 15% and 11% relative to baseline, respectively, during induced hypermagnesemia. Lampl et al. [17] studied cerebrospinal fluid magnesium levels as a prognostic factor in ischemic stroke and the results demonstrated a decrease in the severity of neurological deficits, as shown by the Matthew Neurological Score, with higher cerebrospinal fluid (CSF) Mg2+ levels. However, little is known about the bioavailability of hypermagnesemic treatment in aneurysmal subarachnoid haemorrhage patients, especially over an extended period of time, and its possible site of action in vivo. One important question is whether elevated plasma magnesium can result in elevated cerebrospinal fluid magnesium levels in aneurysmal subarachnoid hemorrhage patients, to a larger magnitude than in traumatic brain injury. If so, what is the magnitude of increase? With these questions in mind, we carried out the current study.

Patients and method

We concurrently recruited 22 IMASH-trial patients between March 2007 and October 2008 into the current study. Approval was obtained from the local clinical research and ethics committee. Informed consent was obtained from patients or next of kin as appropriate.

The intravenous magnesium sulfate after aneurysmal subarachnoid hemorrhage (IMASH) trial was a multi-center double-blinded randomized controlled clinical trial to study the effect of magnesium sulfate (MgSO4) infusion in patients after aneurysmal subarachnoid hemorrhage (SAH). The recruitment was closed on 31st December 2008 and six month follow-up results are awaited. The study protocol has been previously described [13]. All IMASH-trial patients were randomized to either the MgSO4 infusion group or the control group. For patients assigned for MgSO4 infusion, MgSO4 20 mmol was administered over 30 minutes; this was followed by a continuous infusion of magnesium sulfate 80 mmol/day for 10-14 days. Infusion was adjusted so that the plasma magnesium concentration was raised to approximately twice the baseline value and < 2.5 mmol/L. Patients in the control group received the equivalent volume of normal saline.

Patients recruited into the current study had daily blood and 24-hour urine collection for magnesium level measurements. In the 13 patients with external ventricular drains inserted for hydrocephalus, daily cerebrospinal fluid samples were collected under aseptic techniques and sent for magnesium level measurements. Blood and cerebrospinal fluid samples were sent at around 9am daily and 9am was also the cut-off for daily 24-hour urine measurement.

Plasma, cerebrospinal fluid and urinary magnesium concentrations were measured by colorimetry using a dye-binding method on the Roche D & P Modular Analyzer (Roche Diagnostics GmBH, Mannheim, Germany). Patient characteristics, clinical and radiological severity of subarachnoid hemorrhage, as well as biochemical data were recorded.

All patients were treated according to a standard protocol in the neurosurgical high dependency unit or intensive care unit if mechanical ventilation was required. Normotension, defined as systolic arterial pressure between 120 mmHg and 160 mmHg, was maintained except during episodes of vasospasm when hemodynamic therapy was induced. The intracranial aneurysm was either occluded by endovascular coils or clipped microsurgically. Endovascular coiling or microsurgical clipping was usually performed within 48 hours after admission. Patients also received nimodipine infusion 0.5 to 2 mg/hr and prophylactic anticonvulsant, sodium valproate 400 mg intravenously every 8 hours, switching to enteral administration after aneurysm treatment, typically within 96 hours after ictus.

Statistical analysis

Data were analyzed according to the day(s) of IMASH-study-drug infusion, comparing the hypermagnesemic treatment group to the control group using ANOVA. Statistical significances were taken as p < 0.05 and trends were described for p between 0.10 and 0.05. Statistical analysis was carried out with SPSS for Windows Version 15.0.

Results

Twenty-two patients were recruited into the current study with plasma and urine magnesium levels measured. Thirteen (59%) patients had, in addition, cerebrospinal fluid levels measured. A total of 304 plasma magnesium samples, 194 cerebrospinal fluid magnesium samples, and 258 24-hour urine magnesium samples were processed. Age (mean ± SD) was 58.4 ± 10.2 years. Male to female ratio was 3:2. WFNS grades on admission were: I in 5 (23%) patients, II in 7 (32%) patients, III in 2 (9%) patients, and IV in 8 (36%) patients. Aneurysm distribution was: anterior cerebral artery in 2 (9%) patients, anterior communicating artery in 9 (41%) patients, internal carotid artery in 4 (18%) patients, middle cerebral artery in 4 (18%) patients, and vertebrobasilar system in 3 (14%) patients. Embolization was done in 15 (68%) patients and microsurgical clipping was done in 7 (32%) patients. Fifteen patients received magnesium sulfate infusion (treatment group) and 7 patients received saline infusion (control group). Thirteen patients had cerebrospinal fluid samples available, of which 9 patients received magnesium sulfate infusions and 4 patients received saline infusions. Clinical outcome was not included in the current report as they will be included in the IMASH report subsequently.

Data on serum levels are described in table 1. The mean plasma levels of the hypermagnesemic treatment group ranged from 1.59 mmol/L to 1.84 mmol/L and the mean plasma levels of control group ranged from 0.85 mmol/L to 1.02 mmol/L. Throughout the period of the drug infusion study, the hypermagnesemic treatment group had significantly higher plasma magnesium levels than the control group, as described in the protocol.

Data on the cerebrospinal fluid magnesium levels are described in table 2. Day 1, and day 10-13 were not included for statistical analysis due to the small number (less than 10) of patients. Otherwise, from day 2 to day 9, cerebrospinal fluid levels of magnesium were higher for the hypermagnesemic treatment group as compared to the control group, with statistically significant differences reached on day 2, day 5 to day 8, and trends were observed on day 3, day 4, and day 9. The mean plasma levels of the hypermagnesemic treatment group ranged from 1.22 mmol/L to 1.28 mmol/L, and the mean plasma levels of the control group ranged from 1.09 mmol/L to 1.10 mmol/L, with a percentage increase ranging from 10.5% to 21.3%.

Data on urinary magnesium levels are described in table 3. 24-hour urine levels of magnesium were significantly higher for the hypermagnesemic treatment group as compared to the control group. The mean 24-hour urine levels of the hypermagnesemic treatment group ranged from 47.9 mmol to 77.3 mmol and the mean 24-hour urine levels of the control group ranged from 2.7 mmol to 3.5 mmol, suggesting that most of the magnesium sulfate infused was excreted on the same day.
Table 1 Plasma magnesium levels (mean ± SD, number of patients with plasma samples).

Day of study drug infusion

Magnesium group

Control group

p-value

1

1.59 ± 0.47 mmol/L, 15

0.85 ± 0.09 mmol/L, 7

< 0.001

2

1.76 ± 0.30 mmol/L, 15

0.89 ± 0.09 mmol/L, 7

< 0.001

3

1.76 ± 0.29 mmol/L, 15

0.89 ± 0.06 mmol/L, 7

< 0.001

4

1.70 ± 0.30 mmol/L, 15

0.89 ± 0.08 mmol/L, 7

< 0.001

5

1.76 ± 0.28 mmol/L, 15

0.90 ± 0.07 mmol/L, 7

< 0.001

6

1.70 ± 0.16 mmol/L, 15

0.90 ± 0.09 mmol/L, 7

< 0.001

7

1.72 ± 0.17 mmol/L, 15

0.88 ± 0.10 mmol/L, 7

< 0.001

8

1.73 ± 0.19 mmol/L, 15

0.87 ± 0.10 mmol/L, 7

< 0.001

9

1.80 ± 0.29 mmol/L, 15

0.88 ± 0.10 mmol/L, 7

< 0.001

10

1.79 ± 0.30 mmol/L, 15

0.88 ± 0.10 mmol/L, 7

< 0.001

11

1.80 ± 0.23 mmol/L, 15

0.91 ± 0.06 mmol/L, 7

< 0.001

12

1.84 ± 0.20 mmol/L, 15

0.91 ± 0.07 mmol/L, 5

< 0.001

13

1.80 ± 0.27 mmol/L, 15

0.89 ± 0.06 mmol/L, 3

< 0.001


Table 2 Cerebrospinal fluid magnesium levels (mean ± SD, number of patients with cerebrospinal fluid samples).

Day of study drug infusion

Magnesium group

Control group

p-value

2

1.22 ± 0.06 mmol/L, 7

1.10 ± 0.05 mmol/L, 4

0.013

3

1.27 ± 0.15 mmol/L, 9

1.10 ± 0.04 mmol/L, 4

0.058

4

1.28 ± 0.18 mmol/L, 9

1.09 ± 0.07 mmol/L, 4

0.064

5

1.28 ± 0.14 mmol/L, 8

1.10 ± 0.03 mmol/L, 4

0.029

6

1.27 ± 0.13 mmol/L, 7

1.10 ± 0.05 mmol/L, 4

0.035

7

1.26 ± 0.10 mmol/L, 7

1.05 ± 0.06 mmol/L, 4

0.015

8

1.26 ± 0.11 mmol/L, 7

1.04 ± 0.07 mmol/L, 4

0.007

9

1.25 ± 0.13 mmol/L, 7

1.09 ± 0.10 mmol/L, 4

0.065


Table 3 24-urine magnesium levels (mean ± SD, number of patients with 24-hour urine samples).

Day of study drug infusion

Magnesium group

Control group

p-value

1

48.0 ± 10.5 mmol, 9

3.0 ± 3.6 mmol, 7

< 0.001

2

58.6 ± 12.6 mmol, 13

2.7 ± 1.4 mmol, 7

< 0.001

3

61.3 ± 9.6 mmol, 14

2.8 ± 1.0 mmol, 7

< 0.001

4

60.8 ± 15.5 mmol, 15

2.8 ± 0.7 mmol, 6

< 0.001

5

66.0 ± 24.5 mmol, 15

3.4 ± 1.4 mmol, 7

< 0.001

6

67.6 ± 21.7 mmol, 15

2.9 ± 1.0 mmol, 7

< 0.001

7

68.2 ± 17.3 mmol, 15

2.8 ± 1.2 mmol, 7

< 0.001

8

69.7 ± 20.3 mmol, 15

3.0 ± 1.2 mmol, 7

< 0.001

9

69.5 ± 21.0 mmol, 15

3.2 ± 1.6 mmol, 7

< 0.001

10

77.3 ± 24.6 mmol, 15

3.2 ± 1.4 mmol, 6

< 0.001

11

74.7 ± 25.0 mmol, 14

3.5 ± 1.7 mmol, 3

< 0.001

12

75.0 ± 29.0 mmol, 13

3.4 ± 1.9 mmol, 3

0.001

13

69.2 ± 25.1 mmol, 10

2.8 ± 0.4 mmol, 2

0.005

Discussion

One of the proposed mechanisms for magnesium sulfate infusion to improve outcome after aneurysmal subarachnoid hemorrhage is through neuroprotection. In order for this mechanism to be plausible, magnesium sulfate infusion must permeate through the blood-brain barrier and be sustained throughout the at risk period. Mg2+ is actively transported into the cerebrospinal fluid by an adenosine triphosphate-dependent mechanism in the choroid plexus. We have shown that hypermagnesemic treatment will certainly bring an increase in cerebrospinal fluid but the magnitude was modest. The more important observation was that it could be sustained for at least nine days. In fact, the 11-21% increase in cerebrospinal fluid magnesium was at the same magnitude as in the previous studies of other clinical conditions. Thuraut et al. [18] reported on 21 patients in whom spinal anesthesia was used for delivery. Ten patients with preeclampsia with therapeutic serum magnesium levels made up the study group and 11 term normotensive gravid women served as controls. At the time of spinal anaesthesia, a 1 mL aliquot of cerebrospinal fluid was obtained from each patient. Induced hypermagnesemia was administered by intravenous magnesium sulfate in the following manner: a 24 mmol loading dose was given over 15 to 20 minutes, followed by an 8 mmol/hour maintenance dose. Induced hypermagnesemia in parturients generated cerebrospinal fluid magnesium levels 15% higher than in untreated patients. Fuchs-Buder et al. [19] recruited 20 patients undergoing general anesthesia for neurosurgery and needing cerebrospinal fluid drainage. In this study, a single intraoperative intravenous bolus of 60 mg/kg magnesium sulfate increased cerebrospinal fluid magnesium levels by 19% and led to a significant increase at least for 90 minutes. McKee et al. [16] investigated 30 patients with acute brain injury secondary to subarachnoid hemorrhage, traumatic brain injury, primary intracerebral hemorrhage, subdural haematoma, brain tumour, central nervous system infection or ischemic stroke. First, a bolus of 20 mmol magnesium sulfate was given over 30 minutes. This was immediately followed by adjustment of the infusion rate to 8 mmol/hour. Induced hypermagnesemia increased the total cerebrospinal fluid magnesium level by 15% maximally. Although they also included aneurysmal subarachnoid hemorrhage patients, the authors acknowledged the hetereogeneity of their study population to assess the differential effect on different clinical entities. Moreover, these studies focused on cerebrospinal fluid magnesium levels within the first 24 hours.

In terms of dosage, it should be noted that our study used a higher level of hypermagnesemia that most other studies [11, 20]. Given the modest increase in cerebrospinal fluid magnesium in our study, it is possible that the regimen used in other studies may not obtain sufficient hypermagnesemia to bring an increase in cerebrospinal fluid magnesium. Although there was a suggestion that higher cerebrospinal fluid magnesium levels were associated with better clinical outcome in ischemic strokes [17], the exact level required in the human central nervous system remains unknown.

The mean 24-hour urine levels of the hypermagnesemic treatment group ranged from 47.9 mmol to 77.3 mmol, suggesting most of the infused magnesium sulfate was excreted on the same day. It concurred with a previous study in preeclamtic women that 75% of the infused magnesium was excreted during infusion and 90% within 24 hours [21].

The limitations of the current study included the small sample size and no clinical outcome data (as a participating centre for a phase III clinical trial). Nevertheless, this is an important contribution to elucidate that peripheral magnesium infusion significantly increases cerebrospinal fluid magnesium for an extended period of time and that the site of action of peripheral magnesium infusion may indeed be the central nervous system rather than on cerebral vasculature.

Conclusion

In patients with aneurysmal subarachnoid hemorrhages, magnesium sulfate infusion to double the baseline plasma magnesium level brought an 11% to 21% increase in cerebrospinal fluid magnesium in a sustained fashion for at least nine days. Whether this mild elevation in cerebrospinal fluid magnesium levels was adequate for neuroprotection awaits the results of ongoing clinical trials.

References

1 Perales AJ, Torregrosa G, Salom JB. In vivo and in vitro effects of magnesium sulfate in the cerebrovascular bed of the goat. Am J Obstet Gynecol 1991; 165: 1534-8.

2 Alborch E, Salom HB, Perales AJ. Comparison of the anticonstrictor action of dipyridines (nimodipine and nicardipine) and Mg2+ in isolated human cerebral arteries. Eur J Pharmacol 1992; 229: 83-9.

3 Ram Z, Sadeh M, Shacked I. Magnesium sulfate reverses experimental delayed vasospasm after subarachnoid hemorrhage in rats. Stroke 1991; 22: 922-7.

4 Zhang L, Rzigalinski BA, Ellis EF, Satin LS. Reduction of voltage dependent Mg2+ blockade of NMDA current in mechanically injured neurons. Science 1996; 274: 1921-3.

5 Muir KW. New experimental and clinical data on the efficacy of pharmacological magnesium sulfate infusions in cerebral infarct. Magnes Res 1998; 11: 43-56.

6 Nowak L, Bregestovski P, Ascher P. Magnesium gates glutamate-activated channels in mouse central neurons. Nature 1984; 307: 462-5.

7 Lin JY, Chung SY, Lin MC. Effects of magnesium sulfate on energy metabolites and glutamate in the cortex during focal cerebral ischemia and reperfusion in the gerbil monitored by a dual-probe microdialysis technique. Life Sci 2002; 71: 803-11.

8 van den Bergh WM, Dijkhuizen RM, Rinkel GJ. Potentials of magnesium treatment in subarachnoid haemorrhage. Magnes Res 2004; 17: 301-13.

9 Meloni BP, Zhu H, Knuckey NW. Is magnesium neuroprotective following global and focal ischaemia? A review of published studies. Magnes Res 2006; 19: 123-37.

10 Boet R, Mee E. Magnesium sulfate in the management of patients with Fisher grade 3 subarachnoid hemorrhage: a pilot study. Neurosurgery 2000; 47: 602-7.

11 Chia RY, Hughes RS, Morgan MK. Magnesium: a useful adjunct in the prevention of cerebral vasospasm following aneurysmal subarachnoid haemorrhage. J Clin Neurosci 2002; 9: 279-81.

12 van den Bergh WM. on behalf of the MASH study group. Magnesium sulfate in aneurysmal subarachnoid hemorrhage. Stroke 2005; 36: 1011-5.

13 Veyna RS, Seyfried D, Burke DG, Zimmerman C, Mlynarek M, Nichols V, Marrocco A, Thomas AJ, Mitsias PD. Magnesium sulfate therapy after aneurysmal subarachnoid hemorrhage. J Neurosurg 2002; 96: 510-4.

14 Wong GK, Chan MT, Boet R, Poon WS, Gin T. Intravenous magnesium sulfate after aneurysmal subarachnoid hemorrhage: a prospective randomized pilot study. J Neurosurg Anesthesiol 2006; 18: 142-8.

15 Wong GK, Chan MT, Poon WS, Boet R, Gin T. Magnesium within 48 hours of an aneurysmal SAH: neuropanacea. Neurological Res 2006; 28: 431-5.

16 McKee JA, Brewer RP, Macy GE, Phillips-Bute B, Campell KA, Borel CO, Reynolds JD, Warner DS. Analysis of the peripheral brain bioavailability of peripheral administered magnesium sulfate: A study in humans with acute brain injury undergoing prolonged induced hypermagnesemia. Crit Care Med 2005; 33: 661-6.

17 Lampl Y, Geva D, Gilad R, Eshel Y, Ronen L, Sarova-Pinhas I. Cerebrospinal fluid magnesium level as a prognostic factor in ischemic stroke. J Neurol 1998; 245: 584-8.

18 Thurnau GR, Kemp DB, Jarvis A. Cerebrospinal fluid levels of magnesium in patients with pre-eclampsia after treatment with intravenous magnesium sulfate: a preliminary report. Am J Obstet Gynecol 1987; 157: 1435-8.

19 Fuchs-Buder T, Tramer MR, Tassonvi E. Cerebrospinal fluid passage of intravenous magnesium sulfate in neurosurgical patients. J Neurosurg Anesthesiol 1997; 9: 324-8.

20 Investigators IMAGES. Magnesium for acute stroke (Intravenous Magnesium Efficacy in Stroke Trial): Randomized controlled trial. Lancet 2004; 363: 439-49.

21 Cruikshank DP, Pitkin RM, Donnelly E, Reynolds WA. Urinary magnesium, calcium, and phosphate excretion during magnesium sulfate infusion. Obstet Gynecol 1981; 58: 430-4.


 

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