TITLE PAGE

WORD COUNT FOR ABSTRACT- 250

WORD COUNT FOR TEXT- 2871 ( Including Introduction, Material and Methods,

Results, Conclusions, Aknowledgements, References)

CORRESPONDING AUTHOR- Professor (Dr) Nilkanth T. Awad, M.D,

Head of Department of Pulmonary Medicine, L.T.M.M.C & L.T.M.G.H, Sion,

Mumbai-22

ADDRESS-

TEL NO- 02224044644

FAX- 02224044644

EMAIL – nta1960@gmail.com

Co-author- Dr. Unnati D. Desai, M.D,

Registrar, Department of Pulmonary Medicine, L.T.M.M.C & L.T.M.G.H, Sion,

Mumbai-22

ADDRESS-

TEL NO-02224044644

FAX- 02224044644

EMAIL- unnati_desai82@yahoo.co.in

For both author’s there are no conflicts of interest , no financial disclosures, funded

by none

1
KEYWORDS- Magnesium sulphate, Outcome, Tetanus, Diazepam

KEY MESSAGES- Management of tetanus and use of adjunctive medications in

tetanus and its outcome2

2
 ABSTRACT PAGE

TITLE – MANAGEMENT OF TETANUS IN INTENSIVE RESPIRATORY CARE UNIT

- OUTCOME WITH MAGNESIUM SULPHATE

ABSTRACT-

Background and Aims- Tetanus is not eradicated in developing world. Standard

tetanus treatment consists of sedation, prompt ventilation, paralytics, treating

autonomic dysfunction, antibiotics, immunoglobulin. We studied newer adjunctive

medication, intravenous magnesium sulphate in outcome of tetanus and parameters

affecting outcome.

Subjects and Methods-Ours is an observational study in 61 patients admitted to

tertiary hospital intensive respiratory care unit. After noting vitals intrathecal tetanus

immunoglobulin, antibiotics, oral diazepam and need based intravenous sedation

and paralysis were given. A subset received magnesium sulphate. Outcome was

discharge or death.24 received magnesium sulphate with diazepam. 37 received

only diazepam

Results- 93.40% were males, 57%unskilled labourers. 7 (11.5%) were earlier

immunised. In 28(45.9%) incubation period was unknown. 45(73.8%) had period of

onset within 2 days. Mean diazepam dose in those received magnesium sulphate

was 6898.33mg and not received was 9147.10mg. Severe group mean diazepam

dose was 6562.50mg in those receiving and 11236.92mg in not receiving

magnesium sulphate. Mild tetanus required 364.67gm magnesium sulphate and

severe 546.67gm. Of 55(90%) tracheostomised 39(71%) tracheostomised by 2 days.

Mean total stay was 26.75 days in those receiving magnesium sulphate; in others

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29.11 days, increasing to 33.83(+/-11.8) days in very severe. 28(46%) required

ventilator. Overall death 24.5%. 4 deaths (16.7%) occurred in 24 patients receiving

magnesium sulphate while 11(29.7%) deaths in 37 not receiving. 8 discharged of 12

ventilated receiving magnesium sulphate. 6 discharged of 16 ventilated not receiving

magnesium sulphate.

Conclusion-Magnesium sulphate did not influence need for tracheostomy, ventilator,

stay and mortality except decreased sedative dosage in severe tetanus.

4
 TEXT

INTRODUCTION-

Tetanus is important cause of hospital admission and deaths in developing world,

characterized by prolonged, lock jaw, muscle spasms, sometimes autonomic

instability. Antitoxin, antibiotics improve outcome but optimum management of

respiratory compromise that characterize severe form remains uncertain.

Supportive management aims at controlling muscle spasms, maintaining patent

upper airway, providing adequate ventilation, treating autonomic complications.

Benzodiazepines in high doses are mainstay for relaxing muscles and controlling

spasms. Severe spasms require nondepolarizing neuromuscular agents. Magnesium

sulphate is nowadays used for control of spasms and autonomic dysfunction.

In this observational study clinical course, effect, outcome of tetanus patients

referred to a tertiary hospital by using magnesium sulphate and sedatives vs only

sedation in controlling spasms, autonomic instability and need for sedation and

paralytics was studied.

MATERIAL AND METHODS-

The study was conducted in intensive respiratory care unit of tertiary university

hospital after IRB approval (IEC-HR/DISS/94(11/07) IEC, L.T.M.GENERAL

HOSPITAL). Tetanus patients above 12 years of age, admitted from January 2004 to

September 2009 were enrolled. All patients presenting to casualty with acute onset

generalized muscle spasms, rigidity, ophisthotonus, trismus, spatula test positive

leading to clinical diagnosis of tetanus were included in the study. Pulse,Blood

Pressure, Respiratory Rate, Temperature recorded, General and Systemic

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Examination done. Ablett’s score was used to grade tetanus severity. Patients with

drug poisoning, seizures, meningitis, encephalitis, dental pathology, hypocalcemic

tetany, papilloedema were excluded.

Patients were kept in calm atmosphere without external stimulus, oxygen

administered if required, antibiotics Ciprofloxacin, Metronidazole, antihelminthics

given, injection Tetanus Toxoid given intramuscularly, oral diazepam given through

Ryle’s tube. Intravenous sedatives and paralytics given if needed. Intravenous

magnesium sulphate was given in a subset of patients comparing previous without

magnesium sulphate.

Patients on magnesium sulphate were monitored with electrocardiogram, knee jerk

suppression, Chvostek sign, Trousseau sign, respiratory depression, serum calcium.

Oral and intravenous calcium was supplemented.

Tracheostomy was done if conducted sounds, secretions, laryngospasm causing

desaturation < 90% and finally on physicians opinion.

Patients were ventilated with mechanical ventilator if uncontrolled spasms caused

respiratory failure and if spasm control required paralytics on top of sedatives and

baclofen. Complete hemogram, renal and liver function tests, random blood sugar,

serum calcium, Chest X ray, electrocardiogram, Cerebrospinal fluid, Urine for

myoglobinuria were done.

Outcome measured as discharge from hospital or death.

Statistical Analysis done using the chi square test, Annova test.

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RESULTS-

61 patients were studied. 24 received magnesium sulphate and sedatives, 37

without magnesium sulphate. Their age groups ranged from 14 to 80 years. Mean

age 29.67 years. Distribution is as in table 1.

Outcome Total
Discharge Death

Age <=20
grou 17 6 23
p

21-
9 2 11
25

26-
7 3 10
30

31-
1 1 2
35

36-
2 2 4
40

41-
1 0 1
45

46-
4 0 4
50

7
 51+ 5 1 6

Total 46 15 61

Table1

57(93.4%) were males, 4(6.6%) females.

Cases with mild severity were 5, moderate 12, severe 21, very severe 23.

Distribution is as in table 2

Received
magnesium
sulphate Total

Yes No

Abletts Mild Count 3 2 5

score
% 12.5% 5.4% 8.2%

Moderate Count 6 6 12

% 25.0% 16.2% 19.7%

Severe Count 6 15 21

% 25.0% 40.5% 34.4%

Very Count 9 14 23
Severe
% 37.5% 37.8% 37.7%

Total Count 24 37 61

% 100.0% 100.0% 100.0%

Table 2

As severity increased more deaths were observed. It was statistically significant.

( Chi-Square Test p= 0.010 ).15 deaths occurred in the study. 4 deaths(16.7%)

occured in 24 patients receiving magnesium sulphate, all in the very severe group.

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11 deaths occured in 37(29.7%) not receiving magnesium sulphate, 1death in

moderate, 3 in severe and 7 in very severe group.Though not statistically significant

there was increase in total deaths in patients not receiving magnesium sulphate.

Outcome in each group is as in table 3

Abletts score Received magnesium sulphate Outcome Total

discharge Death

Mild Yes 3 0 3

No 2 0 2

Total 5 0 5

Moderate Yes 6 0 6

No 5 1 6

Total 11 1 12

Severe Yes 6 0 6

No 12 3 15

Total 18 3 21

Very Severe Yes 5 4 9

No 7 7 14

9
 Total 12 11 23

Table 3

Nine patients died due to sepsis , one died due to ARDS, one due to autonomic

dysfunction, one due to cardiac arrest, in three the cause was unknown.

7 received injection tetanus toxoid in past. Immunisation rate was 11.5%. Everyone

received tetanus toxoid after admission.

Incubation period was unknown in 28 (45.9%).In others it ranged from 2 to 90 days.

Mean period of onset was 2.38 days, ranging from 1 to 10 days. In 45( 73.8%)

patients it was within 48 hours. As the period of onset increased disease severity

decreased significantly ( chi square , p= 0.006).

55 patients required tracheostomy. As severity increased need for trachoestomy

increased and was statistically significant (table4)

Abletts score

Mil
d Moderate Severe Very Severe

Tracheo- NO
5 1 0 0
stomy

YES 0 11 21 23
Table 4 Chi-Square Tests p=0.000

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Patients tracheostomised earlier on admission had significantly severe disease .

Tracheostomy was required for minimum 7 to maximum 47 days in surviving

patients. Mean 20.41 days

6 did not require tracheostomy and 2 patients data on day of tracheostomy was

unavailable.

60 received diazepam. 5 patients data on diazepam required was insufficient. Mean

diazepam dose received was 8165.82mg. In patients receiving magnesium sulphate

it was 6898.33mg.In patients not receiving magnesium sulphate it was 9147.10mg.

As severity increased mean diazepam dose increased and was statistically

significant (table 5) ANOVA test p= 0.025

Mean diazepam

Abletts score (mg) N

Mild 690.00 4
Moderate 3351.25 12
Severe 9760.79 19
Very Severe 11034.50 20
Total 8165.82 55

Table 5

Maximum total diazepam required was 39810mg and minimum total dose of

180mg.Average diazepam dose ranged from 81mg to 1440mg/day. Mean diazepam

dose was 6562.50mg in patients receiving and 11236.92mg in patients not receiving

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magnesium sulphate in severe group. In other groups there was no difference

(table6)

Abletts score Received magnesium sulphate Mean diazepam (mg)

Mild Yes 676.67

No 730.00

Moderate Yes 3367.50

No 3335.00

Severe Yes 6562.50

No 11236.9

Very Severe Yes 11550.0

No 10612.7
Table 6

24 patients received magnesium sulphate for minimum 2 to maximum 13 days.

Mean for 9 days. Mean magnesium sulphate dose increased with severity, was

statistically significant p=0.047(Anova test) (table 7). Three patients in very severe

group received low doses of magnesium sulphate due to severe hypocalcemia

inspite of calcium supplementation

Abletts score Mean magnesium sulphate dose ( gms)

Mild 364.67

12
Moderate 325.67
Severe 548.67
Very Severe 272.22
Total 366.25

Table-7

33 did not require ventilator and 28 required ventilator. Ventilated patients consisted

of 1 in moderate, 9 in severe, 18 in very severe group. Ventilated group had more

deaths, was statistically significant (table8). 12 of 24 receiving magnesium sulphate

and 16 of 37 not receiving required ventilation.

outcome Total

discharge Death

Ventilation NO Count 32 1 33

YES Count 14 14 28

Total Count 46 15 61

Table 8 Chi-square test, p= 0.000,

In ventilated patients receiving magnesium sulphate in severe group 4 discharged

,none died. Very severe 4 died and 4 discharged. Whereas ventilated patients not

receiving magnesium sulphate in moderate group one died,in severe 3 discharged

and 2 died,in very severe 3 discharged and 7 died.

In survived, total stay ranged from minimum 7 to maximum 64 days. As severity

increased, stay increased, was statistically significant ANOVA test, p=0.003. Mean

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stay in those receiving magnesium sulphate was 26.75 days and those not receiving

was 29.11 days.

Hypocalcemia occurred in 20 patients receiving magnesium sulphate.Two patients

on magnesium sulphate therapy had apneas and required short term ventilation for

same.

DISCUSSION-

In present study majority are young mean age being 29.67 years. In Thwaites’ study

it was 47 years (1). Present study had 57(93.4%) males and 4 females. This could

be due to higher exposure to injuries in men. In studies conducted by Edmonson( 4),

Onwuchekwa(2) , Thwaites(1) males were 75% , 58.1% and 72% respectively.

In present study 57% patients were unskilled labourers , 20% skilled labourers , 7%

farmers , 7% students , 1.5% civil servant , 4.5% traders , 3% unemployed. In

Onwuchekwa’s study 6% were unskilled labourers , 26% skilled labourers , 4%

farmers , 26% students , 18% civil servants , 6% traders , unemployed 6% ( 2 ).

Unskilled labourers are at increased risk of tetanus in our study followed by skilled

labourers. Onwuchekwa’s study reveals similar results except skilled labourers and

students in their study were at higher risk to develop tetanus, probably due to

ignorance of immunisation( 2 ).

All patients in our study received intrathecal tetanus immunoglobulin. Geeta’s study

states it reduces mortality, morbidity, in mild and moderate tetanus( 5 ). Agarwal

states in mild tetanus it reduces mortality, retards progression of disease ,reduces

stay, need for tracheostomy, sedative dose in mild tetanus( 6 ). Kabura concluded

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that intrathecal administration of TIG is more beneficial than intramuscular

administration(7 ).

Only 7 (11.5%) of 61 were earlier immunised. In Lee’s study 20% and Pawar’s study

4.2% received tetanus toxoid in past(8)(9). In study from kasturba hospital 20% were

previously immunised(10). This is more or less common in Indian studies.

In 28(45.9%) incubation period was unknown as history of antecedent event was not

elicited. In Edmonson’s study it was unknown in 45%(4).

In 73.8% the period of onset was within 48 hours and more than 48 hours in 26.2%.

In Onwuchekwa’s study period of onset was within 48 hours in 41.9% and more than

48 hours in 58.1%(1) . In L.Ramchandra ‘s study 60% had period of onset within 48

hrs (10). In this study of the 15 deaths, all had period of onset within 3 days and 13

within 2 days. As period of onset increased, severity decreased and mortality

decreased, is established in the universally accepted Gallais’ score( 11 ). Mortality

was 87% in patients having period of onset within 48 hours in current study . In

Yodh’ s study it was 61.1%(12) and in Bhatt’s study 65.5%( 13).

Various scores are used to grade severity of tetanus. We used the Ablett’s score

(14). Patel and Joag suggested classifying tetanus cases into five grades( 15 ).

In present study 5(8.2%) belonged to mild, 12(19.7%) to moderate, 21(34.4 %) to

severe and 23(37.7%) to very severe group. Edmonson’s study distribution in the

mild, moderate, severe, very severe group was 7% , 3% , 69% , 21% respectively(4).

Trujillo’s study had 13.4% patients in mild, moderate group and 86.6% patients in

severe, very severe group(16).

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Patients tracheostomised earlier on admission had statistically significant severe

disease . Tracheostomy was required for minimum 7 to maximum 47 days in

surviving patients. Mean of 20.41 days. 39 were tracheostomised in first 48 hours

and 14 later on.

Femi- pearse used 2.4 mg/kg/day of diazepam in mild, 4.3 mg/kg/day in moderate

and 9.4 mg/kg/day in severe and very severe tetanus. Maximum diazepam dose

used was 40 mg/kg/day. In present study maximum total diazepam required was

39810mg, minimum total diazepam was180mg.Average diazepam dose ranged from

81mg/day to 1440mg/day in patients not receiving magnesium sulphate,it ranged

from 53 mg/day to 1380 mg/day for patients receiving magnesium sulphate, not

statistically significant.

Mean diazepam dose was 6562.50mg in patients receiving and 11236.92mg in

patients not receiving magnesium sulphate in severe group. In other groups there

was no much difference. In Thwaites’ study (1) average diazepam dose in mg/kg/day

was 40 and 47.1 in those receiving and not receiving magnesium sulphate

respectively, their average midazolam dose in mg/kg/day was 7.1 and 1.4

respectively. The total sedative dose was 47.1 and 48.5 not showing much

significance. We did not use midazolam.

Present study showed no significant difference in paralytic requirement in patients

receiving and not receiving magnesium sulphate. Thwaites study had significant

decrease in need for paralysis in patients receiving magnesium sulphate. This may

be in contrast because Thwaites probably used more midazolam in addition to

diazepam administration and put more patients(80%) on ventilation. Whereas in our

study only 46% needed ventilation. Of 28 ventilated patients 12 received and 16 did

16
not receive magnesium sulphate. Magnesium sulphate therapy did not affect

ventilator requirement. Severity at presentation is responsible for ventilator therapy.

Attygalle and Rodrigo(17)(18) state, need for mechanical ventilation and

tracheostomy decreases in those receiving magnesium sulphate. Thwaites

demonstrated magnesium infusions did not affect requirement of mechanical

ventilation. Our study shows more or less same results as Thwaites.(1)

Present study had more deaths in ventilated patients and was statistically significant.

Because we had more patients 44 (72.1%) in severe and very severe group. In

survived patients total stay ranged from minimum 7 to maximum 64 days. As severity

increased, stay increased, was statistically significant (p= 0.003).Mean total stay in

those receiving and not receiving magnesium sulphate was 26.75 days and 29.11

days respectively, not statistically significant. Thwaites and Attygalle found no

significant difference on hospital stay due to magnesium sulphate

There were 15 deaths( 24.5%) none in mild, 1(6.7%) in moderate, 3 (20%) in severe

and 11 (73.3%) in very severe group. As severity increased more deaths occurred

and was statistically significant (p=0.01).The mortality rate was 47.7% , 49.9%,

15.3% , 8%, 12.5% , 48% in studies done by Bhatt (13), Yodh(12) , Trujillo(16) ,

Edmonson(4) , A.C.Shah(19) , Patel(15) respectively

4 deaths occurred in 24 patients receiving magnesium sulphate. All in very severe

group. Thwaites reported mortality of 13% in magnesium sulphate severe group ,in

our study it was 16.7% in very severe group and 0% in mild, moderate, severe

groups in patients receiving magnesium sulphate. We had no death in severe group

receiving magnesium sulphate.

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11 deaths occurred in 37 patients not receiving magnesium sulphate, 1 in

moderate,3 in severe, 7 in very severe groups. Thwaites reported mortality of 16% in

severe group not receiving magnesium sulphate, our study it was 0% in mild, 2.7% in

moderate,8.1% in severe, 18.9% in very severe group. Death rate in Thwaites study

was confined to only severe group as per Ablett’s score. Death rate in our study was

confined to very severe group. Though not statistically significant there was increase

in deaths in patients not receiving magnesium sulphate

Thwaites stated, preventilator era deaths in tetanus occurred due to laryngospasm,

asphyxia while now hospital infections and autonomic dysfunction are major causes

of death. In our study 9 of 15 deaths were due to sepsis. Other causes were ARDS ,

autonomic dysfunction , cardiac arrest. Sepsis related deaths are similar to Trujillo’s

study(16)

Magnesium sulphate infusion led to fall in serum calcium levels below 7mg and

bradycardia. Two in magnesium sulphate group had apneas on magnesium sulphate

and one died due to cardiac arrest.

CONCLUSIONS-

In this study males predominantly affected and unskilled labourers commonest to

suffer.Magnesium sulphate did not influence need for tracheostomy, ventilator, stay

and mortality. Though not significant it showed overall decreased trend for mortality

with magnesium sulphate and decreased sedative dosage in severe tetanus. As

18
severity increased dosages of magnesium sulphate and diazepam increased

significantly.

ACKNOWLEDGEMENTS-

Both authors have no conflicts of interest. Funded by none, financial disclosure

none. This study is done under personal and close supervision of

Professor(Dr.)N.T.Awad and data collection, analysis done by Dr.Unnati Desai. We

thank the Dean of L.T.M.Medical College for permission and other staff members

involved in management of tetanus patients in IRCU.

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randomised control trial” Lancet 2006;368:1436-43

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