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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