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January2011 Vol.48 Issue:      1 Table of Contents
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The Role of Magnesium Sulphate in Treatment of Subarachnoid Hemorrhage and its Effect on Outcome

Magdy Aidaros, Tarek Goda, Khaled A. M. El-Sharkawy

 

Department of Neurology, Zagazig University; Egypt



ABSTRACT

Background: High-dose magnesium sulphate (MgSO4) therapy is safe and reduces the incidence of delayed ischemic neurological deficit (DIND) and subsequent poor outcome after subarachnoid hemorrhage (SAH). Objective: The aim of the study was to assess the safety and efficacy of high-dose MgSO4 therapy after SAH in order to reduce incidence of DIND and to evaluate the impact on clinical outcome. Methods: The study was carried out on 20 patients with SAH in neurology critical care unit, Zagazig University Hospitals, from January 2007 to July 2010.  Our 20 patients were divided into eight patients who received placebo and 12 patients who received MgSO4.Magnesium sulphate (MgSO4) infusion was adjusted every 12 hours until day 10 according to the target serum magnesium level. The occurrence of DIND, secondary infarction, side effects, and the outcome after 3 and 12 months were assessed. Results: The difference in occurrence of DIND and secondary infarction was not significant. Treatment group showed a significantly better outcome after 3 months and after 1 year. Hypotension and hypocalcemia occurred more in the treatment group than placebo group but the difference was not statistically significant. In 42% of patients, the MgSO4 therapy had to be stopped before day 10 because of side effects. Conclusion: High-dose MgSO4 therapy might be effective as a prophylactic therapy after SAH to reduce the risk for poor outcome. However, because of the high frequency of the side effects, patients should be observed in an intensive care unit. [Egypt J Neurol Psychiat Neurosurg.  2011; 48(1): 79-83]

 

Key Words: Subarachnoid hemorrhage, Vasospasm, Magnesium sulfate.

 

Correspondence to Magdy A. Aidaros, Neurology Department, Zagazig University, Egypt.

Tel.: +0127419310      Email: aidarosaidaros66@yahoo.com




INTRODUCTION

 

Recent studies suggest that high-dose MgSO4 therapy is safe and reduces the incidence of delayed cerebral ischemia and subsequent poor outcome after SAH.1,2 However, optimal dosages are under discussion and results are not yet definitive. With early aneurysm clipping, delayed ischemic neurological deficit (DIND) due to cerebral vasospasm has become the most common cause of death and disability after aneurysmal SAH.3,4

The aim of the study was to evaluate efficacy of MgSO4 in preventing the occurrence of DIND and secondary ischemic infarction; to evaluate the impact on clinical outcome; and  to assess the safety and side effects of MgSO4 infusion at a given dosage and concomitant with other medication

 

PATIENTS AND METHODS

 

This prospective randomized placebo controlled study was carried out on 20 patients with SAH in neurology department, Zagazig  University Hospitals, from January 2007 to July 2010.

 

Inclusion criteria:  age above 18 years and were presenting within 3 days after SAH. Exclusion criteria were pregnancy, history of allergy, renal and neuromuscular diseases, heart disease, hypotension  or bradycardia.

The diagnosis of aneurysmal SAH was based on CT brain and angiography studies. The severity of SAH was assessed by the world federation of neurosurgery (WFNS) scale.15

All patients were managed according to a standardized treatment protocol for aneurysmal SAH and vasospasm5. The bleeding aneurysms were occluded with early surgery within 3 days. Patients received prophylactic antiepileptic treatment with intravenous phenytoin. Oral nimodipine 60 mg 4 hourly starting from third day after onset of SAH.

All patients were treated in the neurology critical care unit and were kept under close observation with continuous monitoring of the arterial blood pressure, ECG monitoring, and arterial oxygen saturation, until at least 10 days after SAH. Magnesium levels were measured every 12 hours. Patients were divided randomly into treatment group (were treated with MgSO4) and placebo group (were given Ringer's lactate).

At the day of admission, patients of the treatment group (12 patients) received MgSO4 with a bolus of 16 mmol in a 150-mL solution of Ringer's lactate administered over 15 minutes, followed by a continuous, intravenous infusion of 64 mmol per day. To maintain the serum magnesium at the level of twice the baseline, with a maximum of 2.0 mmol/L, until day 10 after SAH, subsequent dosage adjustments of the MgSO4 infusion were made every 12 hours.

Patients of the placebo group (8 patients) were treated with a corresponding amount of plain Ringer’s lactate. The administration of MgSO4 was discontinued if bradycardia (heart rate 45 beat /min) or hypotension (systolic blood pressure below 110 mm Hg, unresponsive to intravenous administration of fluids) occurred. Hypocalcemia was considered when serum ionized calcium was below 1 mmol/L.

Further indications to end the MgSO4 therapy were heart block, respiratory failure (suspected of being MgSO4 related), oliguria, and/or severe fluid and electrolyte imbalance.

Daily transcranial Doppler (TCD) measurements were performed between day 4 and 10 by a neuroradiologist. The incidence of TCD-detected vasospasm, DIND, occurrence of infarction attributed to vasospasm, and outcome after 3 months and 1 year were prospectively analyzed according to Glasgow outcome scale (GOS).

New ischemic lesions in CT scans that could not be attributed to other causes were considered as vasospasm-induced infarctions. Delayed ischemic neurologic deficit (DIND) was defined as new focal neurologic deficits after exclusion of seizures, hydrocephalus, electrolyte disturbance, or infection. The presence of ischemic lesion in CT scans was not mandatory for diagnosis of  DIND .

 

Statistical Analysis:

Data were analyzed using statistical package for social science (SPSS), version 10 software. Statistical significance between variables were calculated by using mean ± standard deviation, student t test, P value. P is significant when >0.05.

 

RESULTS

 

There was no difference between the baseline Mg2+ and Ca2+ levels of the treatment and placebo groups. The other baseline characters did not differ (Table 1).

The mean Mg2+ levels during treatment were significantly higher and the mean Ca+2 levels were significantly lower in the treatment group than in the placebo group. The overall incidence of TCD-detected vasospasm and vasospasm-induced infarctions occurred less often in the treatment group although without reaching statistical significance. There was significantly better outcome after 3 months and after 1 year. Patients of the treatment group showed more adverse effects than placebo group, but the difference was not statistically significant (Table 2).

In the treatment group, MgSO4 was discontinued in 42% of patients. The difference in baseline characteristics of continued and discontinued group was not statistically significant (Table 3).


 

Table 1. Baseline characteristics of treatment and placebo group of SAH.

 

 

Treatment group

(n=12)

Placebo group

(n=8)

P value

Sex (male:female)

7:5

5:3

NS

Mean age (±SD)

50.5±10.2

52.3±11.4

NS

History of hypertension

7(58%)

5(62.5%)

NS

Concomitant medications:

                     Phenytoin

                     Nimodipine

 

8(66.6%)

9(75%)

 

7(87.5%)

5(62.5%)

 

NS

NS

Mean Ca +2 baseline level (±SD, mmol/d)

1.16±0.05

1.15±0.09

NS

Mean Mg+2  baseline level (±SD, mmol/d)

0.75±0.09

0.76±0.06

NS

MgSO4 dose:

           Mean (± SD,mmol/d)

           Range (mmol/d)

 

75±18

(40-94)

 

0

0

 

Ca +2 Calcium, mmol Millimol, MgSO4 Magnesium sulphate, SD standard deviation

Table 2. Outcome and adverse events in treatment and placebo group of SAH.

 

 

Treatment group

(n=12)

Placebo group

(n=8)

P value

Mean Mg+2 level (during treatment) (± SD, mmol/l)

1.5±0.07

0.76±0.06

P=0.000

Mean Ca+2 level (during treatment) (± SD, mmol/l)

1.04±0.09

1.3±0.07

P=0.000

Vasospasm:

- TCD-detected vasospasm

- New infarct  in CT brain

- DIND

 

5(42%)

2(16.7%)

2(16.7%)(16.7%

 

6(75%)

3(37.5%)

4(50%)

 

NS

NS

NS

Adverse effects:

- Hypotension

- Bradycardia

- Respiratory depression

- Hypocalcemia

 

6(50%)

2(16.7%)

1(8.3%)

3(25%)

 

1(12.5%)

0

0

0

 

NS

NS

NS

NS

Outcome after 3 months:

- Death

- Vegetative

- Severely and moderately disabled

- Good recovery

 

2(16.7%)

1   (8.3%)

3(25%)

6(50%)

 

2(25%)

2(25%)

4(50%)

0

P=0.04*

Outcome after 1 year:

- Death

- Vegetative

- Severely and moderately disabled

- Good recovery

 

3(25%)

1(8.3%)

2(16.7%)

6(50%)

 

3(37.5%)

2(25%)

3(37.5%)

0

P=0.04*

Ca +2 Calcium, CT computerized tomography, DIND Delayed ischemic neurologic deficit, mmol Millimol, Mg+2 Magnesium, SD standard deviation, TCD transcranial Doppler

NS=non-significant *significant at p<0.05

 

Table 3. Baseline characteristics of continued and discontinued group of patients with SAH.

 

 

Continued  (n=7)

Discontinued  (n=5)

P value

Sex(male:female)

5:2

4:1

NS

Mean age(±SD)

50.2±10.2

55±8.3

NS

History of hypertension

4(57%)

3(60%)

NS

Concomitant medications:

                    Phenytoin

                    Nimodipine

 

6(86%)

3(43%)

 

4(80%)

3(60%)

 

NS

NS

Mean Ca+2  baseline level (±SD, mmol/d)

1.15(±0.08)

1.16(±0.09)

NS

Mean Mg+2  baseline level (±SD, mmol/d)

0.75(±0.05)

0.76(±0.08)

NS

Ca +2 Calcium, mmol Millimol, Mg+2 Magnesium, SD standard deviation

NS=non-significant

 

 


DISCUSSION

 

After SAH, activation of NMDA-receptors facilitates pain transmission in the central nervous system, which can lead to hyperalgesia.7 Usual analgesics are not effective and may even exaggerate hyperalgesia. This facilitation of the NMDA-receptor may be ameliorated by an NMDA-receptor antagonist such as magnesium6. Furthermore, the anti-nociceptic effect of opioids may be potentiated by magnesium.

Intravenous magnesium therapy, besides a supposed beneficial effect on outcome, also provides pain relief for SAH patients, for whom it might also improve functional outcome.8

In our study, patients received the substantially higher daily dose of 16 g (64 mmol) magnesium sulphate for a sustained period, which may be more effective than smaller single doses. We did not administer bolus injections, because a bolus injection led to more side effects in a previous study.17

In the present study, there was a fewer evidence of severe vasospasm detected by transcranial Doppler, there was also fewer CT-detected ischemia in treated group compared with placebo group. However, the difference in CT detected ischemia and vasospasm in both groups was not statistically significant. On the other hand, there was a statistically significant better outcome after 3 months and after 1 year.

 

In contrast to all other studies2,3, we were faced with more cardiovascular side effects. Based on our criteria for termination of MgSO4 infusion, the therapy had to be discontinued in (42%) of  patients in treatment group. Cardiovascular side effects  as well as hypocalcemia occurred more in treatment than placebo group. However, this difference was not statistically significant.

Although the average MgSO4 dose in patients of the discontinued group was higher than those of the continued group, the difference in mean magnesium level between both groups was not statistically significant. The broad range of MgSO4 doses needed to reach the target values indicates that monitoring of serum magnesium level is needed for appropriate dose optimization.

Although TCD is a sensitive tool for screening, the test is nonspecific for vasospasm. However, TCD remains the only noninvasive and well established technique to assess early signs of vasospasm, and further diagnostic steps and therapy often depend on its findings. Therefore, it was assumed that the assessment of TCD values in magnesium therapy is of interest, although ultrasonographic evidence of vasospasm does not always lead to DIND.

Baseline magnesium levels were at the lower end of the reference range. This observation supports the findings that serum  magnesium levels are lower early after SAH, as previously described.9

It is of interest that baseline  calcium levels were  also at the lower end of the reference range because 25% of the patients treated with MgSO4 developed hypocalcemia. An inverse correlation between serum  magnesium and calcium levels was found during treatment.

Veyna et al.10, described the phenomenon of hypocalcemia in which calcium was substituted. In some case reports, hypocalcemia induced by therapeutic hypermagnesemia and the possible role of parathyroid hormone have been mentioned11,12. Whether low  calcium levels in patients with SAH should be treated or not, is not  well established. In our study, no patient with hypocalcemia showed obvious symptoms of increased neuromuscular irritability with characteristic Chvostek and Trousseau signs.

Mild mental status changes such as irritability, perioral numbness, paresthesias, and muscle cramps are already described as being related to hypocalcemia13. These symptoms might be confused with secondary neurologic deficits induced by vasospasm. Ca2+ is essential for homeostasis and the function of multiple organ systems, so Ca2+ levels have to be closely monitored during MgSO4 infusion. Particularly, in patients with SAH, the importance of sustaining hemodynamic, temperature, and metabolic homeostasis is well recognized.14

Several pilot studies have been reported to assess the effectiveness and safety of MgSO4 therapy in patients with SAH.1-4. The most promising study, with which we agree, was reported by Van den Bergh et al.9. This study included a total of 283 patients with SAH. Magnesium treatment reduced the risk of developing new infarctions detected in CT scans, by 34%. After 3 months, the reduction of poor outcome (defined as modified Rankin score N3) was 23%.

Our study also agrees with results of other studies8 that found that elevated serum magnesium levels are associated with slightly less severe headache and less frequent use of opioids. These data imply that intravenous magnesium therapy, besides a supposed beneficial effect on outcome, also provides pain relief for SAH patients, for whom it might also improve functional outcome. On the other hand, we disagree with results of other studies16 that did not show any beneficial effect of magnesium sulphate on SAH outcome.

 

Conclusion

High-dose MgSO4 therapy might be effective as a prophylactic therapy in patients with SAH to reduce the risk of poor outcome. High-dose MgSO4, at least in combination with nimodipine and phenytoin, may be associated with cardiovascular side effects. Therefore, patients should be carefully observed in an intensive care unit.

 

[Disclosure: Authors report no conflicts of interest]

 

REFERENCES

 

1.      Prevedello DM-S, Cordeiro JG, de Morais AL, Saucedo NS, Chen IB, Araujo JC. Magnesium sulfate: role as possible attenuating factor in vasospasm morbidity. Surg Neurol. 2006; 65(Suppl 1): S1: 14-21.

2.      Schmid-Elsaesser R, Kunz M, Zausinger S, Prueckner S, Briegel J, Steiger HJ. Intravenous magnesium versus nimodipine in the treatment of patients with aneurysmal subarachnoid hemorrhage: a randomized study. Neurosurgery. 2006; 58: 1054-65.

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

4.      Yahia AM, Kirmani JF, Qureshi AI, Guterman LR, Hopkins LN. The safety and feasibility of continuous intravenous magnesium sulfate for prevention of cerebral vasospasm in subarachnoid hemorrhage. Neurocrit Care. 2005; 3: 16-23.

5.      Keller E, Krayenbuhl N, Bjeljac M, Yonekawa Y. Cerebral vasospasm: Results of a structured multimodal treatment. Acta Neurochir (Wien) 2005; 94(suppl): 65-73.

6.      Van den Bergh WM, Dijkhuizen RM, Rinkel GJ. Potentials of magnesium treatment in subarachnoid haemorrhage. Magnes Res. 2004; 17(4): 301-13.

7.      Woolf CJ, Thompson SW. The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation: implications for the treatment of post-injury pain hypersensitivity states. Pain. 1991 March; 44(3): 293-9.

8.      Dorhout SM,  Bertens DH, Van der Worp HB, Gabriel JE. Magnesium and headache after subarachnoid hemorrhage. J Neurol Neurosurg Psychiatry. 2010 May;81(5):490-3.

9.      Van den Bergh WM, Algra A, Van Kooten F, Dirven CM, Van Gijn J, Vermeulen M, et al.: Magnesium sulfate in aneurysmal subarachnoid hemorrhage: a randomized controlled trial. Stroke. 2005; 36: 1011-105.

10.    Veyna RS, Seyfried D, Burke DG, Zimmerman C, Mlynarek M, Nichols V, et al.: Magnesium sulfate therapy after aneurysmal subarachnoid hemorrhage. J Neurosurg. 2002; 96: 510-4.

11.    Koontz SL, Friedman SA, Schwartz ML. Symptomatic hypocalcemia after tocolytic therapy with magnesium sulfate and nifedipine. Am J Obstet Gynecol. 2004; 90: 1773-6.

12.    Mayan H, Hourvitz A, Schiff E, Zvi F. Symptomatic hypocalcaemia in hypermagnesaemia-induced hypoparathyroidism, during magnesium tocolytic therapy—possible involvement of the calcium-sensing receptor. Nephrol Dial Transplant. 1999; 14: 1764-6.

13.    Ariyan CE, Sosa JA.: Assessment and management of patients with abnormal calcium. Crit Care Med 2004; 32(Suppl 4): S146-54.

14.    Wartenberg KE, Mayer SA.: Medical complications after subarachnoid hemorrhage: new strategies for prevention and management. Curr Opin Crit Care 2006; 12: 78-84.

15.    Report of World Federation of Neurological Surgeons Committee on a Universal Subarachnoid Hemorrhage Grading Scale. J Neurosurg. 1988 June; 68(6): 985-6.

16.    Van den Bergh WM. Magnesium Sulfate in Aneurysmal Subarachnoid Hemorrhage. A Randomized Controlled Trial. Stroke. 2005; 36: 1011-5

17.    Van den Bergh WM, Albrecht KW, Berkelbach van der Sprenkel JW, Rinkel GJ. Magnesium therapy after aneurysmal subarachnoid haemorrhage. A dose-finding study for long term treatment. Acta Neurochir (Wien). 2003 March; 145(3): 195-9.


 

 

 

الملخص العربي

 

دور كبريتات الماغنيسيوم في علاج نزيف تحت العنكبوتية و مدى تأثير ذلك على مصير المرضى

 

أجريت هذه الدراسة على عشرين مريضا بنزيف تحت العنكبوتية  في وحدة العناية المركزة بقسم الأعصاب بمستشفيات جامعة الزقازيق  في الفترة من يناير2007 حتى يوليو 2009  وكان الهدف من الدراسة هو معرفة مدى فعالية التنقيط الوريدي لجرعات كبيرة من كبريتات الماغنيسيوم في تقليل مضاعفات نزيف تحت العنكبوتية (تقلص الشرايين الدماغية) ومعرفة مدى تأثير ذلك على مصير المرضى. وقد تم ضبط جرعة كبريتات الماغنيسيوم كل 12 ساعة للوصول الى مستوى الماغنيسيوم المطلوب، وذلك حتى اليوم العاشر من حدوث النزيف. وقد أعطيت كبريتات الماغنيسيوم لأثنى عشر مريضا (المجموعة المعالجة) بينما أعطي الثمانية الباقون محلول لبنات الرينجر (المجموعة الضابطة). وتمت دراسة نسبة حدوث  تقلص الشرايين الدماغية، والأعراض الجانبية لكبريتات الماغنيسيوم، ومصير المرضى في كلتا المجموعتين وذلك بعد ثلاثة شهور واثني عشر شهرا من حدوث النزيف. وقد وجد أن الفرق في حدوث تقلص الشرايين الدماغية اقل فى المجموعة المعالجة،ولكنه عير ذو قيمه احصائيه. بينما كانت الأعراض الجانبية لكبريتات الماغنيسيوم أعلى في المجموعة المعالجة، ولكنه عير ذو قيمه احصائيه أيضا. وقد وجد أن مصير مرضى المجموعة المعالجة أفضل من المجموعة الضابطة، وذلك بعد ثلاثة شهور وأثنى عشر شهرا من حدوث النزيف. ولذلك ينصح باستخدام  كبريتات الماغنيسيوم كعلاج  مساعد لمرضى نزيف تحت العنكبوتية.



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