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The Magnesium Web Site received the following email:

Dear Sir , You may be interested to know that we in Sri Lanka have figured out a way to use magnesium to manage tetanus patients without using a ventilator. Normally these patients have to be kept ventilated with a machine even for weeks. Please add this site to your list. This has been reported in international journals.

http://www.geocities.com/tetanus_tetanus/

thank you

pras

The page describing the use of magnesium sulphate infusions in the management of tetanus has been reproduced here. (http://www.geocities.com/tetanus_tetanus/magnesium.html)


Magnesium!

The use of magnesium sulphate infusions in the management of tetanus enables one to minimise sedation and reduce the need for mechanical ventilation, and thereby greatly simplifying the care of the tetanus patient. Magnesium is also able to minimise sympathetic overactivity associated with tetanus. Furthermore, magnesium sulphate is already a well-known entity due to its extensive use in the management of pregnancy induced hypertension.

The following article introduced this concept for the first time:

Attygalle D, Rodrigo N, Magnesium sulphate for control of spasms in severe tetanus. Can we avoid sedation and artificial ventilation? Anaesthesia 1997 Oct;52(10):956-62

The description below will give you a rough idea of the concept. However, when reading it, please note the following:

Summary

A prospective pilot study was undertaken to investigate the ability of magnesium sulphate to control the spasms of severe tetanus without the need for sedation and artificial ventilation. All eight patients admitted with severe tetanus to our intensive care unit within the last year were given magnesium sulphate 5 g i.v. as a loading dose followed by an infusion of 2-3 g/h. The infusion rate was increased to control spasms while retaining the patella tendon reflex, which proved an effective guide to overdose. Spasms were effectively controlled and serum magnesium concentrations were maintained within the therapeutic range. Spontaneous ventilation was adequate, ventilatory support being provided only for the management of lung pathology. There was no evidence of cardiovascular instability due to sympathetic over activity. No supplementary sedation was required for the control of spasms or autonomic dysfunction during magnesium therapy.

We conclude that magnesium sulphate can be used as the sole agent for the control of spasms in tetanus without the need for sedation and artificial ventilation.

Introduction

Tetanus has been aptly described as a third world disease the treatment of which requires first world technology1, as heavy sedation and ventilatory support (with or without muscle relaxants) are the mainstay of management, and these are not always available to tetanus patients in those developing countries in which the disease is prevalent. Even in the developed world the problems in the management of tetanus have yet to be solved. Reported mortality for severe tetanus ranges between 15-40%2, 3, 4, and depends on the availability and quality of intensive care. Deaths due to cardiovascular dysfunction have not been convincingly reduced by the various regimen of sedation, although with management guided by pulmonary artery catheterisation, mortality has been reduced to 6.5% in one study5. The complications resulting from long term heavy sedation and artificial ventilation (pulmonary sepsis, bronchospasm, atelectasis, pressure sores, deep vein thrombosis, pulmonary embolism and gastric haemorrhage) also contribute significantly to morbidity and mortality3, 4, 6, 7. This is exemplified in Edmondson's6 series in which 6 out of 10 deaths were attributable to respiratory complications. There is, therefore, a continuing search for drugs which can control the spasms and the autonomic dysfunction of tetanus without the need for heavy sedation and artificial ventilation8, 9, 10.

A role for magnesium in the management of tetanus has been postulated by many authors. As early as 1906 Blake11 described two cases of severe tetanus treated with intrathecal magnesium sulphate. James and Lipmann used it intravenously for the control of autonomic dysfunction12, 13, but its efficacy in the control of spasms has not been investigated. Magnesium is a physiological calcium antagonist and there is a significant correlation between depression of neuromuscular transmission and serum magnesium concentrations14. The fact that these effects are dose dependent and controllable is a great advantage over muscle relaxants. Magnesium is utilized in the control of spasms in eclampsia and the safety of the therapeutic range (2-4 mmols/l) has been well established15, 16 as areflexia only occurs at levels above 4 mmol/l and muscle paralysis above 6 mmol/l. It is therefore possible that would also control the tetanus without paralysis and the need for artificial ventilation.

The aim of this study was to investigate the efficacy and safety of magnesium sulphate i.v. in controlling the spasms of severe tetanus without the need for sedation and ventilatory support; efficacy to be assessed by the ability to control spasms and safety, by monitoring cardiovascular and respiratory function and serum magnesium concentrations.

Patients and methods

The investigation took the form of a prospective study which was approved by the institutional ethical committee. Informed consent was obtained from the patient or relatives.

All eight patients with severe tetanus admitted to the Anaesthetic Intensive Care Unit (ICU) of the National Hospital of Sri Lanka between March 1996 and 1997 were included in the study. The presence of severe trismus and dysphagia, generalized muscle rigidity, opisthotonus, an frequent spontaneous spasms embarrassing respiration on admission qualified them for inclusion to Grade III A of Ablett's classification17. Exclusion criteria were defined as compromised renal function on the basis of blood urea > 6 mmol/l or urine output < 50 ml/hour and no patient qualified for exclusion.

Patients had been initially treated in the ward with antitoxin, toxoid, surgical debridement if the wound could be identified, and i.v. metronidazole and diazepam. Tracheostomy was performed in all eight patients as they had spasms sufficiently frequently and severe enough to interfere with respiration.

On admission to the ICU i.v. diazepam was omitted and magnesium sulphate therapy commenced within 24 hours, after ensuring adequate urine output, and obtaining serum magnesium concentrations and assessing the intensity of the patellar tendon reflex (knee jerk). A loading dose of i.v. magnesium sulphate 5 g over 20 minutes, was followed by an infusion of 2 g /hour via an infusion pump. The rate of infusion was increased by 0.25-0.5 g every 8 hours till control of spasms was achieved, as long as the patellar reflex could be elicited. The patellar reflex was assessed every half-hour in the first 4 hours after commencing the infusion, whenever the dose was increased, and then less frequently thereafter. Serum magnesium concentrations were measured 12 hours after the infusion was commenced, whenever the dose was increased, and at regular intervals thereafter. Once the dose was stabilized, regular attempts were made to reduce the infusion rate to ensure that the minimum required dose was administered. Evidence of hypocalcaemia was sought using clinical signs (Chvostek’s and Trousseau’s) and the measurement of total serum calcium concentrations.

Presence of increased sweating, salivation and bronchial secretions were noted. Monitoring included continuous electrocardiography and pulse oximetry, half-hourly measurement of non-invasive blood pressure measurements, and hourly measurements of urine volume, tidal volumes and respiratory rate. End tidal carbon dioxide was monitored at intervals and arterial blood gases measured when indicated.

The clinical features, circulatory, respiratory and other parameters were charted and chest radiography, and bacteriological and haematological investigations were performed according to our usual intensive care protocol. Incidental complications (e.g. urinary tract infections) were treated appropriately. Enteral feeding was given via nasogastric tube on the basis of 2500 kcals/day with sufficient fluids to maintain a urinary output of > 50 ml/kg /day. Serum sodium and potassium were maintained within normal limits.

General management included chest and limb physiotherapy, tracheal suction, skin and mouth care. Fentanyl 50 mcg was given before chest physiotherapy 3-4 times a day. Low dose subcutaneous heparin was given to the first two patients only.

Indications for supplementary therapy were laid down in the event of uncontrollable spasms and autonomic dysfunction and complications of magnesium therapy.

  1. i.v. diazepam, and vecuronium (ortubocurarine) were to be given. If control of spasms could not be achieved without loss of the patella reflex and within therapeutic serum magnesium concentrations of 2-4 mmol/l.

  2. i.v. morphine was to be given if unacceptable autonomic dysfunction occurred (systolic hypertension > 160 mm or tachycardia > 120/minute sustained for over one hour).

  3. If signs of magnesium overdose occurred (muscle flaccidity with loss of the patella reflex, respiratory depression or prolonged PR interval on the ECG); magnesium therapy was to be temporarily discontinued, diuresis enforced, and calcium gluconate given if necessary. Once the signs of overdosage disappeared the infusion was to be recommenced at a lower dosage.

  4. Ventilatory support was to be given if the tidal volume was < 5 ml/kg or respiratory rate > 30/minute with PaCO2 > 6kPa.

  5. 10 ml of 10% calcium gluconate were to be given i.v. if clinical signs of hypocalcaemia were evident.

Results

Details of age, sex, approximate weight, incubation period, onset times, and site of wound are given in Table 1. No patient gave a history of immunisation to tetanus. All eight patients were admitted to the ICU within 48 hours of the onset of spasms, three patients (1, 2 & 6) having suffered pulmonary aspiration previously in the ward.

Table 1. Patient characteristics

Patient No.

Sex

Age (yrs)

Weight (kg)

Incubation period (days)

Onset time (h)

Site of Wound

1

M

25

45

3

< 72

foot

2

F

32

50

7

< 48

foot

3

M

45

55

7

< 72

scalp

4

F

28

50

?

< 24

no history

5

M

58

70

10

< 24

foot

6

M

69

70

7

18

foot + # femur

7

M

54

70

18

< 48

foot

8

M

31

60

4

< 96

foot

 

Control of spasms and rigidity

The intensity and frequency of spasms were reduced within 2-3 hours of the commencement of magnesium sulphate therapy and was suppressed within 24 hours. The rate of infusion had to be progressively increased with increasing severity of spasms in the first week but required only minimal adjustments in the second week and could be reduced in the third week (Table 2).

Table 2. Data on Magnesium (Mg) therapy

Patient No.
 

Mg dose g/h
1st week

Mg dose g/h
2nd week

Mg dose g/h
3rd week

Mg dose g/h
4th week

Mg Conc. mmol./l
 

Mg therapy (days)
 

1

1.5 - 2.0

1.5 - 2.0

1.5 - 1.0

-

2.0 - 2.2

20

2

2.0 - 3.0

2.0 - 2.5

2.5 - 1.5

-

2.2 - 2.4

20

3

2.0 - 2.5

2.25- 2.5

2.0 - 0.5

-

2.4 - 3.2

19 + 4**

4

2.0 - 3.0

3.0

-*

-*

3.1 - 3.5

14*

5

2.0 -

2.0 - 1.5

1.0

-

2.0 - 2.6

17

6

2.0 - 2.5

2.5 - 2.75

2.5 - 2.25

2.5 -1.0

2.5 - 3.0

21+ 6**

7

2.0 - 3.0

2.5 - 3.0

2.5 - 2.0

-

2.5 - 3.0

16

8

2.0 - 3.5

3.0 - 3.5

3.0 - 1.0

-

2.6 - 3.3

17

     Mg conc. refers to the range of serum magnesium concentrations at which spasms were controlled.

*   No stocks of magnesium sulphate

** Refers to the days during which magnesium was given for control of tachycardia after spasms subsided.

 

Magnesium therapy had to be continued for a few days after the cessation of spasms as attempts at withdrawal resulted in unacceptable rigidity in some patients and sustained tachycardia (> 120/min.) in others. The serum magnesium concentrations were found to be within the therapeutic range (2-4 mmol/l) throughout therapy. No patient needed supplementary therapy.

Rigidity was not completely abolished but reduced sufficiently in all patients to suppress trismus which allowed easy mouth care. Dysphagia was reduced and all but one patient could swallow saliva, three of them being able to swallow small quantities of semisolid diet. Lung and limb physiotherapy could be performed without difficulty.

Continuous magnesium therapy was interrupted in the following two patients. Patient 4 had magnesium therapy for the first 14 days but due to inability to obtain further stocks of magnesium sulphate sedation and paralysis (hourly diazepam 7.5 mg, and tubocurarine 3 mg to control spasms, and morphine 5 mg to control autonomic dysfunction) were introduced for the next 12 days. Patient 6 whose spasms were well controlled on the first two days was taken off magnesium therapy on the 3rd day, as he needed CMV for worsening aspiration pneumonia. He was given i.v. midazolam morphine and vecuronium for 60 hours. On the 6th day all drugs were discontinued and two hours later when spasms recurred magnesium therapy was recommenced. Spasms were then controlled but ventilatory support with SIMV and pressure support had to be continued for 21 days till the pneumonia resolved.

Spontaneous tidal volumes were adequate to maintain normocarbia. However patients 1, 2, 3 and 6 required ventilatory support, for the management of lung pathology (Table 3). Bronchial secretions were markedly increased but often responded to nebulisation with ipratropium bromide. Cough was not sufficiently effective in the presence of increased bronchial secretions and patients required frequent tracheal suction. Vital capacity was low in all patients during therapy. (Table 3) Patients 5, 7, and 8 were sufficiently cooperative and able to enable us to measure vital capacity without stimulating spasms prior to magnesium therapy. Patient 5 & 7 had vital capacities of 2000 ml and 1000 ml respectively which fell further during the second week of therapy. (Table 3). Patient 7 had a vital capacity of 1000 ml after the commencement of therapy.

Table 3. Pulmonary function during the course of the disease

Patient No. Vt (ml/kg) f (bpm) V. C. (ml) Ventilatory support (days)
1 6 20 - 28 700 1st - 5th
2 7 22 - 26 800 1st - 3rd
3 6 20 - 22 700 11th - 12th
4 7 22 - 26 - 15th - 26th *
5 8 16 - 20 1000 None
6 6 22 - 24 600 2nd - 21st
7 8 16 - 20 1500 None
8 6 22 - 24 700 None

Clinical variables Vt, f & VC measured during spontaneous ventilation on magnesium therapy without ventilatory support (CMV, SIMV or pressure support).

 

Vt = Lowest spontaneous tidal volumes
f = range of respiratory rates
VC = Lowest vital capacity
* on relaxants and IPPV due to shortage off magnesium sulphate.

No patient had clinical signs of hypocalcaemia at any time but total serum calcium concentrations were reduced (range 2.72 to 3 mmol/l). Concentrations were restored to normal within 2-3 days of stopping magnesium therapy.

 

Autonomic dysfunction

Continuous ECG monitoring and 12 lead ECG records showed no dysrhythmias or heart block in any of the patients. During magnesium therapy there was no hypertension or tachycardia and the variability in heart rates and blood pressures were minimal (Table 4) even during tracheal suction. Occasional episodes of bradycardia (45 bpm) which occurred in patient 6 were by stimulation of the patient and i.v. atropine. During the periods off magnesium, patients 4 and 6 showed some cardiac instability. In patient 4 during the 12 days of sedation there were periods of sustained tachycardia (> 120 /min) with a greater variability when compared with the two weeks on magnesium therapy. In patient 6 during the three days off magnesium the variability in blood pressures and more so in heart rates (SD in Table 4) was greater and episodes of bradycardia more frequent when compared with that of the period on magnesium therapy.

Table 4. Blood pressures and heart rates during the first 3 weeks tetanus.

Patient No.
 
 
Mean BP (mm Hg)
Mean Heart rate
(beat min-1)
1st week
 
 
2nd week
 
 
3rd week
 
 
1
 
Mean BP
Mean HR
81 (10.2)
96 (13.3)
91 (5.5)
85 (10.8)
89 (7.3)
87 (14.1)
2
 
Mean BP
Mean HR
87 (12.1)
99 (10.5)
86 (11.2)
87 (6.3)
87 (11.2)
86 (8.5)
3
 
Mean BP
Mean HR
94 (8.1)
92 (9.01)
85 (6.1)
97 (8.7)
86 (7.5)
100 (10.8)
4
 
Mean BP
Mean HR
80 (6.4)
86 (7.2)
79 (4.5)
88 (7.3)
*83 (6.1)
*109 (10.7)
5
 
Mean BP
Mean HR
95 (6.8)
64 (7.09)
96.95 (8.0)
67.46 (6.1)
 
6
 
Mean BP
Mean HR
*95 (16.6), **83 (11.6)
*94 (29.0), **77 (9.1)
80 (12.8)
70 (9.4)
74 (12.8)
71 (9.1)
7
 
Mean BP
Mean HR
101 (7.3)
71 (9.4)
91 (6.6)
74 (7.5)
 
 
8
 
Mean BP
Mean HR
84 (8.2)
75 (14.2)
63 (8.3)
79 (6.0)
87 (5.6)
67 (12.0)

Mean (SD) of hourly of blood pressures and heart rates are given for each of the 3 weeks.

* Refers to periods off magnesium therapy

The mean (SD) for patient 6 in the first week is given separately for the * 3 days off magnesium and ** 3 days on magnesium

 

Excessive sweating unrelated topyrexia was noted in all except patient 7 after about the fifth day and was more profuse in patients 4 and 6 when off magnesium. Increased salivation was not a problem because patients were able to swallow saliva. In all parenteral feeding was well tolerated but constipation was a problem till they were mobilized out of bed. There were no indications for supplementary therapy during the period on magnesium therapy.

Patients were conscious, rational and cooperative and were able to communicate with staff and relatives which simplified nursing care. They were comfortable during the day but were given 5-10 mg. oral diazepam to promote sleep at night.

Mobilization and discharge from ICU were delayed in patient 4 who was on sedation and paralysis and in patient 6 who had a fracture neck of femur and remained in the ICU till surgery was performed. In the others the mean (range) period to mobilization out of bed was 15.8 day (8-21) and mean (range) duration of ICU stay was 21 days (18-31).

Discussion

The efficacy of magnesium sulphate was clearly demonstrated in all eight patients as spasms were controlled without the need for benzodiazepines, opiates, muscle relaxants or ventilatory support. The safety of our regime was shown by the fact that control of spasms was achieved with serum magnesium concentrations within the therapeutic range. Since areflexia occurs only at serum magnesium concentrations above 4 mmols, the presence of the patellar reflex proved a valid end point to ensure that the therapeutic range was not exceeded. We were successful in using this simple clinical guide as our patients were not paralysed and the patellar reflex was retained at concentrations which controlled spasms. James12 who titrated the dose to serum magnesium concentrations (for the control of autonomic dysfunction in paralysed patients) was not always successful in keeping within the therapeutic range. The patellar reflex should in fact prove a more valid index of muscle tone in the presence of hypocalcaemia (which occurs during magnesium therapy), since the depression of neuromuscular transmission has a better correlation with the serum Mg/Ca ratio than with serum magnesium concentrations14. The development of hypocalcaemia seen in our patients in response to hypermagnesaemia has been well documented18, 19. and the absence of clinical signs in spite of low serum calcium concentrations is similar to the findings of Cholst20. Its return to normal within 2-3 days of stopping magnesium therapy indicates that hypocalcaemia was only temporary. The main advantage of magnesium therapy namely the avoidance of ventilatory support is lost if aspiration occurs, as was the case in three of our patients. Aspiration however could have been prevented by timely tracheostomy at the stage of severe dysphagia before the onset of severe spasms.

Though ventilation was adequate, vital capacity was reduced in all patients. Magnesium in the therapeutic range has been reported to produce a small but significant reduction of vital capacity in obstetric patients receiving similar regimes21, 22. Such a reduction would assume a greater clinical significance in tetanus in view of the reduction in vital capacity that is already present due to rigidity as was seen in patients 5, 7 and 8. Whatever the cause, reduced vital capacity and ineffective cough in the presence of profuse secretions required frequent tracheal suction. The tracheostomy which was originally performed to prevent aspiration during spasms was essential to clear the lungs of secretions and could only be closed when the secretions subsided. The reduction in vital capacity also probably compromises the ability of patients to cope with severe infections without respiratory support as seen in patient 6.

If respiratory complications are avoided or managed successfully deaths occur due to sympathetic over activity. The physiological basis of the effects of magnesium on SOA is its ability to reduce catecholamine concentrations to normal13, 23 by inhibiting their release and also reducing the sensitivity of receptors to these neurotransmitters24, 25. Magnesium sulphate has been previously used in the control of sympathetic over activity of tetanus12, 13 and phaeochromocytoma23. In these reports12, 13, magnesium therapy was given after SOA occurred. In our study magnesium therapy was commenced before autonomic dysfunction could set in but evidence for the prevention of SOA was seen in patients 4 and 6, who during the periods of sedation and paralysis acted as their own controls.

In all our patients cardiovascular stability was maintained during magnesium therapy without the need for sedatives. This is contrary to the findings in the case report by Lipman13 who questioned the ability of magnesium sulphate to control autonomic dysfunction in the absence of sedation.

Parasympathetic over activity also plays an important role in the autonomic dysfunction of tetanus. Although magnesium is said to suppress acetylcholine at the ganglia26 and vagal nerve terminals27, all our patients except patient 7 had increased salivation and bronchial secretions which were not suppressed by magnesium therapy.

Two other drugs, baclofen and dantrolene, have been used for the control of spasms without the need for sedation and artificial ventilation but have their own limitations. Baclofen a gaba B agonist has been used intrathecally in tetanus both as an adjunct to sedation and paralysis 28, 29 and also as the sole therapy8, 9. Muller8 using continuous infusions was able to control spasms without causing sedation or ventilatory compromise in two patients. The practical considerations are however the technical difficulties and the risk of infection with an external infusion device, and the high cost of the implantable variety. Due to these constraints in developing countries Saissy9 administered baclofen as intermittent intrathecal injections to ten patients but he failed to control spasms in two of them and five patients developed coma and ventilatory depression. The ability of baclofen to control cardiovascular dysfunction demonstrated by Muller was not confirmed by Saissy. Dantrolene has been used in two patients9 but sedation is required to control autonomic dysfunction. Disadvantages of dantrolene are its potential hepatotoxicity and prohibitive cost.

In comparison magnesium sulphate effectively controlled the spasms of severe tetanus with no failures, no need for additional sedation and no need for ventilatory support except when indicated for lung pathology. The fact that magnesium does not cause sedation at serum concentrations less than 8 mmol/l as long as ventilation is adequate (as it does not easily cross the blood brain barrier)30 was confirmed in all eight patients. Their ability to communicate, open the mouth, swallow saliva and move about in bed helped considerably in nursing. The ease of nursing care in conscious cooperative patients was in marked contrast to the authors’ personal experience of 60 patients previously managed with sedation and paralysis.

We conclude that magnesium sulphate in a dosage titrated to the preservation of the patellar reflex and maintaining serum concentrations within the therapeutic range could be used as the sole drug to control the spasms of severe tetanus. Spontaneous ventilation in this dose range is adequate and ventilatory support will be needed only for those patients who develop pulmonary complications. Tracheostomy is required both to protect the airway till spasms are brought under control and for the clearance of profuse secretions when cough is not effective. Magnesium therapy could possibly prevent SOA in the majority of patients, but is not effective in preventing parasympathetic effects.

The avoidance of ventilatory support and sedation would be cost effective, simplify nursing care and reduce the complications of deep vein thrombosis, barotrauma and respiratory infections. In addition its low cost and ease of administration are major advantages in developing countries.

References

1. Delport SD. Neonatal tetanus--an opportunity for prevention. South African Medical Journal 1990; 77: 78-9.

2. Trujillo MH, Castillo A, Espana J, Manzo A, Zerpa R. Impact of intensive care management on the prognosis of tetanus. Analysis of 641 cases. Chest 1987; 92:(1)63-5.

3. Sun KO, Chan YW, Cheung RTF, So PC, Yu YL, Li PCK. Management of tetanus: A review of 18 cases. Journal of the Royal Society of Medicine. 1994; 87: 135-37.

4. Reis E, Freire E, Alexandrino S. Tetanus in an ICU in Portugal. International Journal of Intensive Care 1994/95; 1 (4): 120-21.

5. Udwadia FE, Sunavala JD, Jain MC, D’Costa R, Jain PK, Lall A, Sekhar M, Udwadia ZF, Kapadia F, Kapur KC, Mehta SK, Kharas RJ. Haemodynamic studies during the management of severe tetanus. Quarterly Journal of Medicine, New Series. 1992; 83: No. 302: 449-60.

6. Edmondson RS, Flowers MW. Intensive care in tetanus: management, complications, and mortality in 100 cases. British Medical Journal. 1979; 1:1401-4.

7. Kerr JH, Corbett JL, Prys-Roberts C, Crampton Smith A, Spalding JMK. Involvement of the sympathetic nervous system in tetanus. Studies on 82 cases. The Lancet 1968; 2: 236-41.

8. Muller H, Borner U, Zierski J, Hempelmann G. Intrathecal baclofen for treatment of tetanus induced spasticity. Anaesthesiology 1987; 66,No 1: 76-79.

9. Saissy JM, Demaziere J, Vitris M, Seck M, Marcoux L, Gaye M, Ndiaye M. Treatment of severe tetanus by intrathecal injections of baclofen without artificial ventilation. Intensive Care Medicine 1992;18: 241-244.

10. Checketts MR, White RJ. Avoidance of intermittent positive pressure ventilation in tetanus with dantrolene therapy. Anaesthesia1993; 48: 969-71.

11. Blake JA. The use of magnesium sulphate in the production of anaesthesia and in the treatment of tetanus. Surgery, Gynaecology and Obstetrics 1906; 2: 541-550.

12. James MFM, Manson EDM. The use of magnesium sulphate infusions in the management of very severe tetanus. Intensive Care Medicine 1985; 11:5-12.

13. Lipman J, James MFM, Erskine J, Plit ML, Eidelman J, Esser JD. Autonomic dysfunction in severe tetanus: magnesium sulphate as an adjunct to deep sedation. Critical Care Medicine 1987; 15: (10):987-88.

14. Ramanathan J, Sibai BM, Pillai R, Angel JJ. Neuromuscular transmission studies in pre-eclamptic women receiving magnesium sulfate. American Journal of Obstetrics & Gynaecology 1988; 158: (1) 40-6.

15. Pritchard JA, Pritchard SA. Standardised treatment of 154 consecutive cases of eclampsia. American Journal of Obstetrics & Gynaecology 1975; 123: 543-552.

16. Pritchard JA, Cunningham G, Pritchard SA. The Parkland Memorial Hospital protocol for treatment of eclampsia. Evaluation of 245 cases. American Journal of Obstetrics & Gynaecology 1978; 148: 951-963.

17. Ablett JL. Symposium on tetanus in Great Britain. Leeds 1967.

18. Cruikshank DP, Pitkin RM, Reynolds WA, Williams GA, Hargis GK. Effects of magnesium sulphate treatment on perinatal calcium metabolism. American Journal of Obstetrics & Gynaecology 1979; 134: No 3 243-9.

19. Monif GRG, Savory J. Iatrogenic maternal hypocalcaemia following magnesium sulfate therapy. JAMA 1972; 219: (11) 1469-70.

20. Cholst IN, Steinberg SF, Tropper PJ, Fox HE, Segre GV, Bilezikian JP. The influence of hypermagnesemia on serum calcium and parathyroid hormone levels in human subjects. New England Journal of Medicine 1984; 310 No 19: 1221-25.

21. Ramanathan J, Sibai BM, Duggirala V, Maduska AL . Pulmonary function in pre eclamptic women receiving MgSO4. Journal of Reproductive Medicine 1988; 33 No. 5: 432-35.

22. Herpolsheimer A, Brady K, Yancey MK, Pandian M, Duff P. Pulmonary function of pre eclamptic women receiving intravenous magnesium sulfate seizure prophylaxis. Obstetrics & Gynaecology 1991; 78 (2): 241-53.

23. James MFM. Use of magnesium sulphate in the anaesthetic management of phaeochromocytoma: a review of 17 anaesthetics. British Journal of Anaesthesia 1989; 62:616-23.

24. Euler USv, Lishajko F. Effects of Mg2+and Ca2+ on noradrenaline release and uptake in adrenergic nerve granules in different media. Acta Physioligica Scandinavica 1973; 89: 415-22.

25. Lishajko F. Releasing effect of calcium and phosphate on catecholamines, ATP, and protein from chromaffin cell granules. Acta Physiologica Scandinavica 1970; 79:575-84.

26. Hutter OF, Kostial K. Effect of magnesium and calcium ions on the release of acetylcholine. Journal of Physiology 1954; 124: 234-41.

27. Somjen GG, Baskerville EN. Effect of excess magnesium on vagal inhibition and acetylcholine sensitivity of the mammalian heart in situ and in vitro. Nature 1968; 217: 679-80.

28. Brock H, Moosbauerk W, Gabriel C. Treatment of severe tetanus by continuous intrathecal infusion of baclofen. Journal of Neurology, Neurosurgery and Psychiatry. 1995; 59: 192-199.

29. Demaziere J, Saissey JM, Vitris M, Seck M, Marcoux L, Ndiaye M. Intermittent intrathecal baclofen for severe tetanus (letter). Lancet 1991; 1:427.

30. Somjen G, Hilly M, Stephen CR. Failure to anaesthetize human subjects by intravenous administration of magnesium sulfate. Journal of Pharmacology 1966; 154:652-9.


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