Tetanus

Incremental costs of treating tetanus with intrathecal

antitetanus immunoglobulin

Dem�ocrito B. Miranda-Filho1, Ricardo A. A. Ximenes1,2, Noemia T. Siqueira-Filha3 and Andreia C. Santos4

1 Departamento de Cl�ınica M�edica, Faculdade de Ciencias M�edicas, Universidade de Pernambuco, Recife, Brazil2 Departamento de Medicina Tropical, Universidade Federal de Pernambuco, Recife, Brazil3 Instituto de Avaliac�~ao de Tecnologias em Sa�ude, Recife, Brazil4 London School of Hygiene and Tropical Medicine, UK

Abstract objective To estimate the incremental cost of delivering intrathecal tetanus immunoglobulin

compared to an intramuscular option.

methods To compare the two interventions, costs were estimated using standard cost methodology.

Cost categories were personnel, overhead, consumables, antibiotics to treat infection, gases for

respiratory assistance and immunoglobulin. Tetanus patients, aged 12 years or older, who were part

of a randomised controlled clinical trial conducted in a referral hospital in Recife, Brazil, were

allocated to two groups: a control group (58) and a study group (62). Patients allocated to the

control group received 3000 international units (IU) of human immunoglobulin, with preservative,

intramuscularly. The study group received the same quantity of immunoglobulin also intramuscularly

plus an intrathecal dose of 1000 IU of a human immunoglobulin, free of preservatives, to prevent

irritation of the meninges and avoid the need for corticosteroids. Thus, the difference between the

two groups was the exclusive use of intrathecal immunoglobulin. The outcome measurements were

clinical progression, hospital stay, respiratory assistance and respiratory infection.

results Delivering intrathecal immunoglobulin to patients saved a total of US$ 60 389, in a 10-day

intensive care treatment, by preventing a worsening of their tetanus severity (e.g. from Grade I to

Grades II, III, IV). Substantial cost saving was also observed in terms of hospital stay (US$ 173 104).

conclusions Intrathecal treatment of tetanus is cost saving. This intervention deserves

consideration by doctors and decision-makers as a mean of saving resources while maintaining

high-quality health outcomes.

keywords tetanus, costs, incremental costs, intrathecal injection, immunoglobulin

Introduction

In spite of the studies published in the 1970s and 1980s

on the use of antitetanus immunoglobulin (HTIG) by an

intrathecal route in the treatment of tetanus, a meta-anal-

ysis published in 1991 was inconclusive as to the efficacy

of this treatment. The authors suggested that this route

would be indicated only in the context of randomised

clinical trials (Abrutyn & Berlin 1991). In the two fol-

lowing decades, two randomised clinical trials were pub-

lished (Agarwal et al. 1998; Miranda Filho et al. 2004),

and a meta-analysis published in 2006 suggested that the

intrathecal route is more effective than the intramuscular

option and should be preferred whenever tetanus is sus-

pected (Kabura et al. 2006). A 2011 study also showed

the benefits of an intrathecal route with a significant

improvement in outcomes of neonatal tetanus in terms of

mortality and hospital stay (Ahmad et al. 2011).

Tetanus immunoglobulin for intrathecal use must be of

human origin and free of preservatives, which cause cen-

tral nervous system irritation. Its cost is higher because

the production process is more complex due to the

greater possibility of contamination. This formulation of

HTIG has a shorter life.

Although most patients with tetanus are admitted to

hospital with mild disease, some of them may progress

to severe forms and may need respiratory assistance

(Miranda-Filho et al. 2006). Given this evolutionary

potential, several authors recommend that these individ-

uals be treated from admission in intensive care units,

mainly in referral centres (Brauner et al. 2002; Attygalle

& Rodrigo 2004; Gouveia et al. 2009). The delivery of

© 2013 Blackwell Publishing Ltd 555

Tropical Medicine and International Health doi:10.1111/tmi.12091

volume 18 no 5 pp 555–563 may 2013

intrathecal HTIG could reduce the costs of tetanus treat-

ment by reducing the severity of the tetanus to a mild

version of the disease in a large number of patients dur-

ing treatment. Further and more importantly, it could

reduce the burden of disease on capacity-constrained

hospitals in poor countries, by saving limited resources.

So far, there is no publication in the literature on the

cost evaluation of treatment of patients with tetanus.

The objective of this article is thus to estimate the incre-

mental cost of the treatment of tetanus with HTIG using

the intrathecal route compared to the intramuscular

option.

Materials and methods

The randomised controlled trial (RCT) and study setting

Details of the randomised controlled trial have been pub-

lished (Miranda Filho et al. 2004). Briefly, it comprised

120 patients, aged 12 years or older, recruited from an

intensive care unit (ICU) in Oswaldo Cruz University

Hospital, in the city of Recife, state of Pernambuco,

north-east Brazil, between July 1997 and July 2001. This

is the referral hospital for patients with tetanus (acciden-

tal or neonatal) and admits virtually all cases of tetanus

in the state. Cases of tetanus were allocated to two

groups: a control group (62) and a study group (58);

placebo was not used, as it would be unethical. Patients

allocated to the control group (baseline intervention)

received 3000 international units (IU) of immunoglobu-

lin, with preservative, intramuscularly. The study group

(intervention group) received the same quantity of immu-

noglobulin also intramuscularly plus an intrathecal dose

of 1000 IU of a human immunoglobulin free of preserva-

tives to prevent irritation of the meninges and avoid the

need for corticosteroids. Thus, the difference between the

two groups was the exclusive use of the intrathecal

immunoglobulin.

Health outcomes

Different health outcomes were assessed for different

periods of time. Tetanus severity was assessed for a per-

iod of 10 days, in both arms of the trial. The decision

to limit the follow-up and classification of patients

according to their tetanus severity to a 10-day period

was for convenience and took into consideration the

heavy workload faced by medical doctors working at

the referral hospital. The 10-day period, however, was

enough to capture fluctuations in the clinical severity of

tetanus per patient in the control and study groups,

showing clearly the health benefits of both interventions.

Tetanus severity was classified as one of four levels:

Grade I (trismus + dysphasia + generalised rigidity, pres-

ent in more than one segment of the body [head, trunk,

arms or legs], - with no spasms); Grade II (mild and

occasional spasms, generally after stimulus), Grade III

(severe and recurrent spasms, usually triggered by minor

stimulus or imperceptible stimuli) and Grade IV (the

same features as Grade III + sympathetic nervous system

hyperactivity syndrome) (Miranda-Filho et al. 2006).

Patients were assessed and classified according to their

tetanus severity level at day 0, day 2, day 4, day 6, day 8

and day 10. The assessment was conducted by medical

experts working at the hospital and involved in the study.

To minimise observation bias, we used a standardised

form to collect information that would allow classifica-

tion according to the levels of tetanus severity; rotated

among the doctors involved in the clinical classification

of patients; recorded the clinical classification on separate

forms which contained no information on the patient’s

treatment or on previous classifications performed by

other doctors; and held periodic meetings with the team

to discuss doubts. To compare intrathecal and intramus-

cular therapies by tetanus severity level as a measure of

health benefit, we estimated the number of patients that

had clinical progression (improvement or deterioration)

during the 10-day period. Clinical progression was char-

acterised as a change in tetanus severity in a specific per-

iod of time (0–10 days). It was also expected that

fluctuations would occur during the 10-day period

regarding tetanus severity: a patient could have been clas-

sified as Grade IV on day 2, then as Grade II on day 4,

Grade III on day 6, Grade II on day 8 and finally Grade I

on day 10. These fluctuations were expected as a charac-

teristic of the disease and were captured every two days

by clinical assessment.

Other assessed health outcomes for both arms were

hospital stay, respiratory assistance and respiratory infec-

tion. Rather than using the 10-day evaluation period, we

took into account the entire period of the patient’s hospi-

talisation, in number of days, until their discharge

(including those who died during the period of evalua-

tion) to define these outcomes (Miranda Filho et al.

2004). Table 1 summarises the health outcome measures

in both groups.

Model design, data collection and costing analysis

Costs were primarily calculated as per level of severity of

tetanus, as defined in the health outcomes section above.

The incremental cost was estimated by comparing the

costs by tetanus severity level when patients received the

immunoglobulin intramuscularly or intrathecally. Cost

556 © 2013 Blackwell Publishing Ltd

Tropical Medicine and International Health volume 18 no 5 pp 555–563 may 2013

D. B. Miranda-Filho et al. Incremental costs of treating tetanus

items included in the two scenarios are summarised in

Table 2. Costs for hospitalisation, respiratory assistance

and respiratory infection were calculated as the average

cost per tetanus severity level, for the entire period of

hospitalisation. All listed costs are likely to be affected by

the intrathecal intervention, including the costs for over-

heads and personnel.

The perspective of the analysis was that of the public

health sector. All recurrent and capital costs were calcu-

lated. The use of resources for both interventions was

based on the results of the RCT published in 2004 and

reflected the patient’s use of hospital resources (in fre-

quency and quantity) as described in Table 2 (Miranda

Filho et al. 2004). Costs, however, were estimated in

2010 local currency prices (Brazilian Real) and then con-

verted to USD values, with an average exchange rate to

the USD of 0.5663 Brazilian Real (www.oanda.com).

All cost data were collected from the hospital adminis-

trative records. Interviews with medical and non-medical

professionals were conducted to determine the frequency

and use of resources, when information was not available

from the RCT.

Overhead costs were estimated taking into account the

value of all contracts of service supplied to the hospital

including waste collection, cleaning, building and equip-

ment maintenance, water, telephone and electricity and

administrative costs, in a year. As a proxy, we allocated

40% of these contract costs to outpatient activities and

60% for inpatient activities, based on hospital production

and the opinion of the hospital’s administrative staff. We

then divided the cost allocated to inpatients by the total

annual hospital patient-days, including hospitalisations

due to tetanus. We recognise this is a rough approach, as

outpatient and inpatient treatments have different levels

of complexity and cost allocation should reflect these dif-

ferences. However, as this exercise of weighting produc-

tions by their level of complexity would require close

monitoring of hospital activities for a considerable

amount of time, we opted for the simple approach of

allocating the total cost by outpatient and inpatient activ-

ities. We also added the cost of meals served to tetanus

patients during their hospital stay to the cost of over-

heads. This cost was estimated as the total cost of meals,

in a year, divided by total annual hospital patient-days

(Drummond et al. 2005). The overhead cost parameter

was tested in the sensitivity analysis.

To estimate the cost of personnel per day, we took the

amount paid in salaries per year to doctors and nurses

working in the referral ICU and then multiplied this

amount by the proportion of tetanus patient-days admit-

ted to the ICU (total tetanus patient-days at the ICU

divided by the total annual patient- days at the ICU)

(Drummond et al. 2005).

The hospital kept records for the annual cost of gases,

but did not keep information about the cost of gases by

any level of use, for example, per patient or hospital unit.

Thus, it was difficult to allocate the gases used for respi-

ratory assistance to patients in treatment. As an alterna-

tive, we used the average market price of gases per hour,

delivered by different types of private company to hospi-

tals and clinics, and multiplied this by 24 to estimate the

average cost of gases per day. This information was

Table 2 Cost items included in the two treatment scenarios

Control group Study group

Overhead OverheadPersonnel Personnel

Antibiotics to treat

respiratory infections

Antibiotics to treat respiratory

infections

Antibiotics to treaturinary infection

Antibiotics to treat urinaryinfection

Other drugs Other drugs

Consumables Consumables

Tests TestsGases (respiratory assistance) Gases (respiratory assistance)

Mechanical ventilation

(depreciation)

Mechanical ventilation

(depreciation)3000 IU immunoglobulin 3000 IU immunoglobulin

1000 IU immunoglobulin

Training for intrathecal

administration ofimmunoglobulin

Table 1 Health outcome measures in the two interventiongroups

Health outcomes Control group Study group P-value

Clinical progression N = 60 N = 58Improvement 23 (38%) 36 (62%)

Deterioration 37 (62%) 22 (38%) 0.005

Hospital stay

in number of

days (average)

N = 52 N = 54

�15 (8.5) 14 (27%) 23 (43%)16–30 (23) 17 (33%) 19 (35%)

>30 (55.5) 21 (40%) 12 (22%) 0.03

Respiratory assistance

in number ofdays (average)

N = 30 N = 20

�10 (5.5) 4 (13%) 9 (45%)

11–20 (15.5) 12 (40%) 7 (35%)>20 (41) 14 947%) 4 (20%) 0.01

Respiratory infection N = 62 N = 58

Yes 42 (68%) 29 (50%)No 20 (32%) 29 (50%) 0.07




supplied by private companies. In Brazil, the price of

gases for respiratory assistance in the private and public

sector is similar. To calculate the cost of gases, we added

the cost per day of a straight-line depreciation for the

equipment used for mechanical ventilation, taking into

account the life expectancy of the equipment.

The use of antibiotics for the treatment of respiratory

and urinary infections, use of other drugs for clinical

treatment, consumables and tests were estimated on the

basis of the expert opinion of the first author when this

information was missing from patients’ records. The

average cost of drugs per type of treatment was estimated

as the cost of drug (in millilitres, milligrams, etc.) multi-

plied by the dosage, per level of tetanus severity, during

the period of hospitalisation. The cost per day was esti-

mated as the total cost of drugs for a specific treatment

divided by the average number of days of drugs usage.

A similar approach was used to estimate the cost of con-

sumables and tests.

The average cost of an application of 3000 IU immu-

noglobulin was estimated as the cost of the immunoglob-

ulin plus the cost of one syringe and needle needed for

the intramuscular injection of 3000 IU immunoglobulin.

The cost of 1000 IU immunoglobulin was estimated as

the cost of the immunoglobulin plus the cost of two

syringes, a spinal needle 23G appropriate for the applica-

tion of 1000 IU immunoglobulin, gloves and gauze.

A 5% wastage rate for the immunoglobulin, syringes and

needles was assumed in the cost calculation (Griffiths

et al. 2011). The estimates related to 3000 IU immuno-

globulin were made for the control and study groups

while those related to 1000 IU immunoglobulin were

made just for the study group.

Training was required only for the intrathecal interven-

tion with 1000 IU immunoglobulin, as the 3000 IU is

delivered on a routine basis, and no additional training

was required. Medical doctors accredited by the Brazilian

Unified Health System (SUS) performed the training. We

took into account the gross salary paid to these profes-

sionals (including productivity bonuses) and divided this

amount by the average number of hours they worked in

a year. The resulting amount was multiplied by the aver-

age number of hours the doctors spent on preparation

and delivery of training sessions at the hospital in a year.

That amount was divided by the number of tetanus

patients in a year, to derive the average cost of training

per patient. A total of six training sessions were held,

each one lasting, on average, for 60 min, and the average

time for the immunoglobulin application was 15 min.

To estimate the total and incremental cost per hospital

stay, respiratory assistance and respiratory infection cov-

ering the entire period of hospitalisation (shown in

Table 7), we adopted the following strategy: hospital stay

was calculated as average cost for tetanus for all grades

as in Table 5 multiplied by the number of patients multi-

plied by the average number of days of hospital stay, all

summed to the average cost of 3000 UI immunoglobulin

for intramuscular use per patient and cost with deprecia-

tion of gas equipment per patient; respiratory assistance

was calculated as average cost for respiratory assistance

for all grades as in Table 4 multiplied by the number of

patients multiplied by the average number of days of use

of respiratory assistance, all summed to the average cost

of 3000 UI immunoglobulin for intramuscular use per

patient and cost with depreciation of gas equipment per

patient; respiratory infection was calculated as average

cost for respiratory assistance plus the average cost to

treat respiratory infection for all grades as in Table 4

multiplied by the number of patients multiplied by the

average number of days for the treatment of respiratory

infection, all summed to the average cost of 3000 UI

immunoglobulin for intramuscular use per patient and

cost with depreciation of gas equipment per patient. For

the study group, for the calculations above described, we

added the cost of 1000 UI immunoglobulin for intrathe-

cal use per patient and costs with training per patient.

To test the robustness of the estimates, we used a one-

way sensitivity analysis (one parameter is changed at a

time), which indicates how the estimates would react to

percentage changes in the value of the cost parameters of

the model. Using our estimate as a baseline, we varied

our cost estimates by plus/minus 10, 20 and 50%.

Table 3 Number of patients per severity level of tetanus andperiod of evaluation

Period of

evaluation Grade I Grade II Grade III Grade IV Total

Day 0

Control 24 23 15 0 62

Study 21 23 13 1 58

Day 2Control 15 13 19 8 55

Study 20 22 13 1 56

Day 4Control 10 13 20 10 53

Study 19 23 9 2 53

Day 6

Control 11 12 17 12 52Study 18 21 7 0 46

Day 8

Control 9 16 17 9 51

Study 23 16 5 0 44Day 10

Control 9 11 17 6 43

Study 22 10 5 2 39




Results

The number of patients per level of severity of tetanus

and per period of evaluation is shown in Table 3. On

day 0, the distribution of patients by degree of severity

was similar in the control and in the study groups. From

day 2 onwards, Grades I and II predominated in the

study group and Grades III and IV predominated in the

control group. Such differences may be attributed to

intrathecal therapy. Variations in the number of patients

over the period of evaluation are explained by hospital

discharge and patient death.

Tetanus severity had a direct impact on cost items

related to treatment. The cost of antibiotics varied

depending on the grade of tetanus severity. While for

Grade I there were no antibiotic costs in either group, for

Grade IV the cost per patient per day was US$ 19.21 and

US$ 26.89 to treat respiratory and urinary infections,

respectively. Patients with Grade II or III had no costs

related to antibiotics for the treatment of urinary infec-

tion, but had costs of US$ 10.94 and US$ 17.50, per day,

for the treatment of respiratory infection (Table 4).

Respiratory assistance may or may not be related to

respiratory infection. Recurrent spasms of the larynx and

respiratory muscles are the main reasons for the use of

gases and the need for respiratory assistance for patients

at all levels of tetanus severity. In fact, respiratory assis-

tance was the main cost item related to tetanus treat-

ment. Costs varied from US$ 157 for Grade I to US$ 252

for Grade IV (Table 4).

Costs for other drugs, consumables and tests varied

considerably among different grades of severity. Other

drug costs for patients with Grade IV were three times

more than for patients with Grade I (US$ 13.66 against

US$ 46.30). Costs for consumables were five times more

for patients with Grade IV than for patients with Grade

I. Costs for tests were 16 times more for patients with

Grade IV than Grade I. (Table 4).

The average costs per severity level, per day, were US$

257.43 for Grade I, US$ 367.59 for Grade II, US$

594.02 for Grade III and US$ 977.65 for Grade IV. On

average, the cost for all grades of tetanus was US$

549.17. The average cost per severity grade of tetanus for

all grades for the entire period of hospitalisation,

perpatient, was US$ 15 090.49 in the control group and

US$ 15 709.18 in the study group (Table 5).

Table 4 Unit costs by tetanus severity, in 2010 US$ prices

Grade I Grade II Grade III Grade IV Average cost per item

Cost item per day

Overhead 2.41 2.41 2.41 2.41 2.41Personnel 1.09 1.09 1.09 1.09 1.09

Antibiotics to treat respiratory infection 0 10.94 17.50 19.21 11.91

Antibiotics to treat urinary infection 0 0 0 26.89 6.72Other drugs 13.66 22.88 38.33 46.30 30.29

Consumables 68.24 108.68 200.73 381.11 189.69

Tests 15.40 38.05 102.35 248.53 101.08

Respiratory assistance (gases) 156.62 183.54 231.61 252.13 205.98Cost items per patient

Respiratory assistance (gases: depreciation of equipment) 64.95 64.95 64.95 64.95 64.95

3000 IU immunoglobulin for intramuscular use

(control and study groups)

197.84 197.84 197.84 197.84 197.84

1000 IU immunoglobulin for intrathecal use (study group only) 605.02 605.02 605.02 605.02 605.02

Training for intrathecal application of immunoglobulin

(study group only)

13.67 13.67 13.67 13.67 13.67

Table 5 Average cost of tetanus treatment per severity level, perday and per patient, in 2010 US$ prices

Grades ofseverity

Costper day*

Average

number

of days fortreatment

Cost per

patient in

the controlgroup**

Cost per

patient

in the studygroup**

Grade I 257.43 15 4124.23 4742.92Grade II 367.59 24 9084.98 9703.67

Grade III 594.02 30 18 083.44 18 702.13

Grade IV 977.65 41 40 346.63 40 965.32

All Grades 549.17 27 15 090.49 15 709.18

*Includes only costs per day, not per patient; **Includes costsper day multiplied by the average number of days for treatmentplus the cost of depreciation of respiratory assistance equipment

and the 3000 UI immunoglobulin for the control and study

groups and the cost of 1000 UI immunoglobulin plus the cost of

training for the study group (all from Table 4).




The incremental cost regarding the treatment of tetanus

by different severity levels is shown in Table 6. After two

days of intrathecal treatment, cost savings were consis-

tently observed. The total cumulative cost saving for the

period between day 0 and day 10 was US$ 60 389.

When the total and incremental costs by other health

outcomes, for the entire period of hospitalisation, are

assessed, there are cost savings of US$ 173 104, when

the outcome is a hospital stay, US$ 85 518 for respira-

tory assistance and US$ 62 192 for respiratory infection

(Table 7).

The sensitivity analysis assessing all parameters of cost

shows there are costs savings even when costs are

increased or decreased by 10%, 20% and 50%

(Table 8).

Discussion

This is the first time the incremental costs of intramuscu-

lar HTIG delivery have been compared to those for an

intrathecal alternative. Our results show that treatment

of tetanus patients by the intrathecal route saves costs.

Table 6 Total and incremental cost for a 10-days period of evaluation by tetanus severity level, in 2010 US$ costs*

Period of evaluation Grade I Grade II Grade III Grade IV Total Incremental cost

Day 0

Control 12 485 14 499 12 852 0 39 836Study 23 917 28 729 19 182 1859 73 687 33 850

Day 2

Control 7723 9557 22 573 15 642 55 496Study 10 297 16 174 15 445 1955 43 871 �11 624

Day 4

Control 5149 9557 23 761 19 553 58 020

Study 9782 16 909 10 692 3911 41 294 �16 725Day 6

Control 5663 8822 20 197 23 464 58 146

Study 9267 15 439 8316 0 33 023 �25 123

Day 8Control 4634 11 763 20 197 17 598 54 191

Study 11 842 11 763 5940 0 29 545 �24 646

Day 10Control 4634 8087 20 197 11 732 44 649

Study 11 327 7352 5940 3911 28 530 �16 120

Incremental cumulative cost (from day 0 to day 10) �60 389

*For day 0, we included costs per day per tetanus severity level as in Table 5, cost with depreciation of gas equipment and costs with

3000 UI immunoglobulin for intramuscular use per patient (study and control groups) and costs with 1000 UI immunoglobulin for

intrathecal use per patient and costs with training (study group); from day 2, costs with immunoglobulin were excluded.

Table 7 Total and incremental cost per hospital stay, respiratory assistance and respiratory infection covering the entire period ofhospitalisation, in 2010 US$ costs

Effectiveness measure Control group US$ (n) Study group US$ (n) Incremental cumulative cost US$

Hospital stay in number of days (average)

�15 (8.5) 69 031 (14) 127 638 (23)

16–30 (23) 219 195 (17) 256 737 (19)

>30 (55.5) 645 581 (21) 376 328 (12)Total cost hospital stay 933 806 (52) 760 703 (54) �173 104

Respiratory assistance in number of days (average)

�10 (5.5) 5171 (4) 17 202 (9)

11–20 (15.5) 41 465 (12) 28 519 (7)>20 (41) 121 910 (14) 37 306 (4)

Total cost respiratory assistance 168 546 (30) 83 027 (20) �85 518

Respiratory infection: 13–41 (27)Total cost respiratory infection 258 896 (42) 196 703 (29) �62 192




Table 8 Univariate sensitivity analysis

Cost item

Control group

�10% �20% �50% Baseline estimate 10% 20% 50%

Overhead per day 310 202 310 066 309 649 2.41 310 476 310 613 311 023

Personnel per day 310 274 310 211 310 028 1.09 310 399 310 462 310 650Antibiotics to treat respiratory infection per day 309 657 308 976 306 932 11.91 311 020 311 701 313 747

Antibiotics to treat urinary infection per day 310 096 309 854 309 128 6.72 310 581 310 823 311 548

Other drugs per day 308 644 306 950 301 867 30.29 312 034 313 726 317 561

Consumables per day 300 432 290 522 260 800 189.69 320 246 330 154 359 878Tests per day 305 318 300 302 285 246 101.08 315 355 320 374 335 428

Respiratory assistance per day 298 678 287 017 252 030 205.98 322 000 333 660 368 644

Respiratory assistance per patient 309 936 309 533 308 325 64.95 310 741 311 144 312 352

3000 IU immunoglobulin forintramuscular use per patient

309 112 307 885 304 205 197.84 311 565 312 792 316 471

1000 IU immunoglobulin for

intrathecal use per patient

310 338 310 338 310 338 605.02 310 338 310 338 310 338

Training for intrathecal application of

immunoglobulin per patient

310 338 310 338 310 338 13.67 310 338 310 338 310 338

Cost item

Study Group


Overhead per day 249 822 249 694 249 304 2.41 250 078 250 206 250 591

Personnel per day 249 888 249 830 249 659 1.09 250 006 250 065 250 241Antibiotics to treat respiratory infection per day 249 542 249 136 247 916 11.91 250 356 250 762 251 984

Antibiotics to treat urinary infection per day 249 920 249 890 249 801 6.72 249 979 250 008 250 097

Other drugs per day 248 768 247 588 244 046 30.29 251 132 252 309 255 701Consumables per day 243 919 237 886 219 795 189.69 255 980 262 011 280 105

Tests per day 247 608 245 271 238 253 101.08 252 286 254 626 261 644

Respiratory assistance per day 240 240 230 533 201 405 205.98 259 658 269 365 298 492

Respiratory assistance per patient 249 572 249 195 248 066 64.95 250 326 250 703 251 8333000 IU immunoglobulin for

intramuscular use per patient

248 802 247 654 244 212 197.84 251 096 252 244 255 687



246 440 242 931 232 404 605.02 253 458 256 967 267 495

Training for intrathecal application of

immunoglobulin per patient

249 870 249 791 249 552 13.67 250 029 250 108 250 345

Cost item

Comparing the two groups


Overhead per day �60 380 �60 372 �60 345 2.41 �60 398 �60 407 �60 432

Personnel per day �60 386 �60 381 �60 369 1.09 �60 393 �60 397 �60 409Antibiotics to treat respiratory infection per day �60 115 �59 840 �59 016 11.91 �60 664 �60 939 �61 763

Antibiotics to treat urinary infection per day �60 176 �59 964 �59 327 6.72 �60 602 �60 815 �61 451

Other drugs per day �59 876 �59 362 �57 821 30.29 �60 902 �61 417 �61 860Consumables per day �56 513 �52 636 �41 005 189.69 �64 266 �68 143 �79 773

Tests per day �57 710 �55 031 �46 993 101.08 �63 069 �65 748 �73 784

Respiratory assistance per day �58 438 �56 484 �50 625 205.98 �62 342 �64 295 �70 152

Respiratory assistance per patient �60 364 �60 338 �60 259 64.95 �60 415 �60 441 �60 5193000 IU immunoglobulin per patient �60 310 �60 231 �59 993 197.84 �60 469 �60 548 �60 784



�63 898 �67 407 �77 934 605.02 �56 880 �53 371 �42 843

Training for intrathecal application ofimmunoglobulin per patient

�60 468 �60 547 �60 786 13.67 �60 309 �60 230 �59 993




The selected outcomes were those that showed the

health benefits of intrathecal treatment and the resultant

impact on costs. The study group showed better clinical

progression, shorter duration of hospital stay and respira-

tory assistance compared with the control group. Respi-

ratory infection was also less frequent in the study group.

We did not distinguish the costs for the time that the

patient spent in an ICU from the time they spent on a

ward. We have assumed that all tetanus patients were

hospitalised in an ICU. This proxy may suggest an over-

estimation of the costs of hospitalisation. Some aspects of

the study design, however, may have minimised this pos-

sible overestimation in costs. First, all patients were

admitted to an ICU, spending only few days on a ward

before their discharge. Second, the main cost item in our

analysis, respiratory assistance, is provided exclusively in

the ICU. Finally, the sensitivity analysis showed that our

results were robust for the range of variations applied.

In fact, our calculations are likely to be underesti-

mated. For instance, while assessing the use of drugs for

a case of respiratory infection, we calculated that the

patient had, on average, one episode of infection. How-

ever, these episodes can be recurrent, particularly if the

length of hospitalisation is longer and if the patient needs

respiratory assistance.

We also observed a reduction in cost savings when

assessing the tetanus severity level from day 8 (Table 6),

which may suggest the savings for the intrathecal inter-

vention could be substantially reduced when taking into

account the entire period of hospitalisation. However,

when we assessed other health outcomes, such as hospital

stay, respiratory assistance and respiratory infection that

cover the entire period of hospitalisation until cure or

patient death, we can see the costs savings are consistent,

which reduces the uncertainties surrounding the 10-days

evaluation for tetanus severity level.

This study was based on a clinical trial conducted in

a referral centre for tetanus treatment, in which infor-

mation regarding the current costs of treating patients

with tetanus was also collected (Miranda Filho et al.

2004). We are aware that cost analyses of treatment of

tetanus patients may vary in different contexts of assis-

tance. Thus, our results may only be extrapolated to

other referral centres with expertise in treating the dis-

ease. Our data on the health benefits of intrathecal

treatment may also not represent exactly what occurs

under natural conditions. However, considering that

few studies have been published in recent years and

that there is a small likelihood that other RCTs will be

developed on this issue, it is reasonable to assume that

the cost analysis presented here may be useful as a ref-

erence or for replication for decision-making on adopt-

ing this intervention (Thwaites & Farrar 2003;

Miranda-Filho et al. 2004; Kabura et al. 2006).

Tetanus immunoglobulin suitable for intrathecal use

is not readily available. Its production is complex, its

cost is relatively high, compared to products with pre-

servatives for intramuscular use, and it may not be

attractive to the pharmaceutical industry in countries

where the incidence of tetanus is low and falling. On

the other hand, it is the final product in a chain of the

hemoderivates industry, which, in some countries, is

supported (subsidised) with public resources. Some

technical adjustments would allow the safe handling of

the product, so there would be no risk of contamina-

tion. Production in a single country could meet the

demand of several others and help to deal with the

disease in a more cost-saving way.

Conclusion

Our study shows that the use of human immunoglobulin

by an intrathecal route for tetanus treatment is cost sav-

ing and that this intervention deserves consideration by

doctors and decision-makers as a means of saving

resources while maintaining high-quality health out-

comes.

Acknowledgements

The authors thank the two anonymous reviewers for their

comments, which helped to improve the article. The

authors were partially funded by Conselho Nacional de

Desenvolvimento Cient�ıfico e Tecnol�ogico – CNPq and

Instituto Nacional de Ciencia e Tecnologia para

Avaliac�~ao de Tecnologia em Sa�ude/Conselho Nacional

de Desenvolvimento Cient�ıfico e Tecnol�ogico do

Minist�erio da Ciencia e Tecnologia.

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Corresponding Author Dem�ocrito B Miranda-Filho, N�ucleo de P�os-Graduac�~ao da Faculdade de Ciencias M�edicas, Universidade

de Pernambuco, Rua Arn�obio Marques, 310, Santo Amaro, Recife 50100.130, Pernambuco, Brazil. Email: [email protected]




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