Magnesium! The use of magnesium sulphate infusions in the management of tetanus enables one 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 introduces this concept:

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:

· since the study was published , many more cases have been managed and the treatment protocol has been refined.

· the best and easiest way for you to get the latest information and to get your queries answered is to join the  email based discussion group. The authors of the paper are also members of the discussion group and have considerable experience in managing tetanus patients. Whatever your level of expertise or interest, you are welcome to join this unique discussion group. Alternatively, you are welcome to  send an email to us at our address: dattygalle@mail.ewisl.net

· Keeping the above points in mind , please read the following  description of the study :

· 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 5g i.v. as a  loading dose followed by an infusion of 2-3g/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 mortality,3,4,6,7.  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 intra thecal magnesium sulphate. James and Lipmann used it intravenously  for  the  control of autonomic dysfunction 12,13,, 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 the  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 established 15,16 as areflexia only occurs at levels above 4mmol/l and muscle paralysis above 6mmol/l. It is  therefore possible  that  magnesium would also  control the spasms of 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,  and 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  >6mmol/l or urine output < 50ml/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   5g over 20 minutes,  was followed by an infusion of 2g / hour  via an infusion pump. The rate of infusion was increased by  0.25 - 0.5g 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, when  ever 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  >50ml/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 50mcg 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 (or tubocurarine)  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  > 160mm 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 < 5ml/kg or  respiratory rate  >30/minute with PaCO2 >6kPa;               . 

5.      10ml 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 I. 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

-

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 semi solid 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 7.5mg,  and tubocurarine 3mg  to control spasms, and morphine 5mg  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  2000ml and 1000ml  respectively which fell further  during  the second week of therapy. (Table 3). Patient 7  had a vital capacity  of  1000ml after the commencement of  therapy.

                Table 3 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 of 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

 

 

 

 

 

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

 

 

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 to pyrexia 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 patients enteral 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 documented 18,19. 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 regimes.21,22.  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 neurotransmitters 24,25   Magnesium sulphate has been previously  used in the control of sympathetic over activity of tetanus12,13 and phaeochromocytoma 23.  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 acetyl choline at the ganglia26 and vagal nerve terminals 27,  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. Muller 8 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 8mmol/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 4low cost and ease of administration are major advantages in  developing countries.

 

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