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Keywords:

  • tetanus;
  • costs;
  • incremental costs;
  • intrathecal injection;
  • immunoglobulin

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

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.

Objectif

Estimer le coût supplémentaire de l'administration intrathécale d'immunoglobulines antitétaniques par rapport à l'alternative intramusculaire.

Méthodes

Les coûts ont été estimés pour deux interventions en comparaison, en utilisant la méthodologie du coût standard. Les catégories de coûts étaient liées au personnel, aux frais généraux, aux consommables, aux antibiotiques pour traiter l'infection, aux gaz pour l'assistance respiratoire et aux immunoglobulines. Les patients atteints de tétanos, âgés de 12 ans ou plus, qui faisaient partie d'un essai clinique randomisé et contrôlé mené dans un hôpital de référence à Recife, au Brésil, ont été répartis en deux groupes: un groupe témoin (58) et un groupe d’étude (62). Les patients affectés au groupe témoin ont reçu 3000 unités internationales (UI) d'immunoglobulines humaines, contenant un agent conservateur, par voie intramusculaire. Le groupe d’étude a aussi reçu la même quantité d'immunoglobulines par voie intramusculaire, plus une dose de 1000 UI d'immunoglobulines humaines par voie intrathécale, sans agent conservateur, pour éviter l'irritation des méninges et le besoin de corticostéroïdes. Ainsi, la différence entre les deux groupes était l'usage exclusif des immunoglobulines par voie intrathécale. Les résultats mesurés étaient: la progression clinique, le séjour à l'hôpital, l'assistance respiratoire et les infections respiratoires.

Résultats

L'administration d'immunoglobulines par voie intrathécale chez les patients a permis d’économiser un total de 60.389 US$ dans un traitement en soins intensifs de 10 jours, en évitant une aggravation de la sévérité du tétanos (ex: passage du Stade I aux Stades II, III, IV). Une réduction importante des coûts a également été observée en termes de séjour à l'hôpital (173.104 US$).

Conclusions

Le traitement par voie intrathécale du tétanos permet des économies. Cette intervention mérite d’être considérée par les médecins et les décideurs comme un moyen d’économiser les ressources, tout en maintenant des résultats de santé de qualité.

Objetivo

Calcular el coste incremental de poner la inmunoglobulina antitetánica por vía intratecal, comparada con la opción intramuscular.

Métodos

Los costes se calcularon para dos intervenciones comparadas utilizando una metodología estándar de costes. Las categorías de costes fueron personal, costes indirectos, consumibles, antibióticos para tratar infecciones, gases para asistencia respiratoria e inmunoglobulina. Los pacientes con tétano, con 12 años o más, que eran parte de un ensayo clínico aleatorizado y controlado realizado en un hospital de referencia de Recife, Brasil, se asignaron a uno de dos grupos: un grupo control (58) y un grupo de estudio (62). Los pacientes asignados al grupo control recibieron 3000 unidades internacionales (IU) de inmunoglobulina humana, con preservativo, por vía intramuscular. El grupo de estudio recibió la misma cantidad de inmunoglobulina, también por vía intramuscular, y además una dosis intratecal de 1000 IU de inmunoglobulina humana, libre de preservativos, para prevenir la irritación de las meninges y evitar la necesidad de administrar corticosteroides. Por lo tanto, la diferencia entre los dos grupos era el uso de la inmunoglobulina intratecal. Los resultados medidos eran la progresión clínica, el ingreso hospitalario, la asistencia respiratoria y la infección respiratoria

Resultados

El dar inmunoglobulina intratecal a los pacientes ahorró un total de US$ 60,389, en un tratamiento de 10 días de cuidados intensivos, al prevenir un empeoramiento en la severidad del tétano (por ej. del Grado I a Grados II, III, IV). También se observó un ahorro sustancial en términos de ingreso hospitalario (US$173,104).

Conclusiones

El tratamiento intratecal del tétano ahorra costes. Esta intervención debería ser tenida en cuenta por doctores y legisladores como un medio para ahorrar recursos a la vez que se mantiene una alta calidad en los resultados sanitarios.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

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-analysis 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 following decades, two randomised clinical trials were published (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 suspected (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 central 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 individuals 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 intrathecal HTIG could reduce the costs of tetanus treatment by reducing the severity of the tetanus to a mild version of the disease in a large number of patients during 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 incremental cost of the treatment of tetanus with HTIG using the intrathecal route compared to the intramuscular option.

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

The randomised controlled trial (RCT) and study setting

Details of the randomised controlled trial have been published (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 (accidental 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 immunoglobulin, with preservative, intramuscularly. The study group (intervention 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 the intrathecal immunoglobulin.

Health outcomes

Different health outcomes were assessed for different periods of time. Tetanus severity was assessed for a period 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, present 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 classification 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 intramuscular 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 characterised as a change in tetanus severity in a specific period 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 classified 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 characteristic 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 infection. Rather than using the 10-day evaluation period, we took into account the entire period of the patient's hospitalisation, in number of days, until their discharge (including those who died during the period of evaluation) to define these outcomes (Miranda Filho et al. 2004). Table 1 summarises the health outcome measures in both groups.

Table 1. Health outcome measures in the two intervention groups
Health outcomesControl groupStudy groupP-value
Clinical progressionN = 60N = 58 
Improvement23 (38%)36 (62%) 
Deterioration37 (62%)22 (38%)0.005
Hospital stay in number of days (average)N = 52N = 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 of days (average)N = 30N = 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 infectionN = 62N = 58 
Yes42 (68%)29 (50%) 
No20 (32%)29 (50%)0.07

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 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 overheads and personnel.

Table 2. Cost items included in the two treatment scenarios
Control groupStudy group
OverheadOverhead
PersonnelPersonnel
Antibiotics to treat respiratory infectionsAntibiotics to treat respiratory infections
Antibiotics to treat urinary infectionAntibiotics to treat urinary infection
Other drugsOther drugs
ConsumablesConsumables
TestsTests
Gases (respiratory assistance)Gases (respiratory assistance)
Mechanical ventilation (depreciation)Mechanical ventilation (depreciation)
3000 IU immunoglobulin3000 IU immunoglobulin
1000 IU immunoglobulin
Training for intrathecal administration of immunoglobulin

The perspective of the analysis was that of the public health sector. All recurrent and capital costs were calculated. 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 frequency 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 converted 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 administrative 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 equipment 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 differences. However, as this exercise of weighting productions 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 activities. We also added the cost of meals served to tetanus patients during their hospital stay to the cost of overheads. 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 admitted 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 respiratory assistance to patients in treatment. As an alternative, we used the average market price of gases per hour, delivered by different types of private company to hospitals and clinics, and multiplied this by 24 to estimate the average cost of gases per day. This information was 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.) multiplied by the dosage, per level of tetanus severity, during the period of hospitalisation. The cost per day was estimated 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 consumables and tests.

The average cost of an application of 3000 IU immunoglobulin was estimated as the cost of the immunoglobulin 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 application 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 immunoglobulin 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 intervention 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 professionals (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 average 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 covering 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 multiplied 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 depreciation 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 intrathecal 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%.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

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.

Table 3. Number of patients per severity level of tetanus and period of evaluation
Period of evaluationGrade IGrade IIGrade IIIGrade IVTotal
Day 0
Control242315062
Study212313158
Day 2
Control151319855
Study202213156
Day 4
Control1013201053
Study19239253
Day 6
Control1112171252
Study18217046
Day 8
Control91617951
Study23165044
Day 10
Control91117643
Study22105239

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 infection, but had costs of US$ 10.94 and US$ 17.50, per day, for the treatment of respiratory infection (Table 4).

Table 4. Unit costs by tetanus severity, in 2010 US$ prices
 Grade IGrade IIGrade IIIGrade IVAverage cost per item
Cost item per day
Overhead2.412.412.412.412.41
Personnel1.091.091.091.091.09
Antibiotics to treat respiratory infection010.9417.5019.2111.91
Antibiotics to treat urinary infection00026.896.72
Other drugs13.6622.8838.3346.3030.29
Consumables68.24108.68200.73381.11189.69
Tests15.4038.05102.35248.53101.08
Respiratory assistance (gases)156.62183.54231.61252.13205.98
Cost items per patient
Respiratory assistance (gases: depreciation of equipment)64.9564.9564.9564.9564.95
3000 IU immunoglobulin for intramuscular use (control and study groups)197.84197.84197.84197.84197.84
1000 IU immunoglobulin for intrathecal use (study group only)605.02605.02605.02605.02605.02
Training for intrathecal application of immunoglobulin (study group only)13.6713.6713.6713.6713.67

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 assistance was the main cost item related to tetanus treatment. 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 5. Average cost of tetanus treatment per severity level, per day and per patient, in 2010 US$ prices
Grades of severityCost per day*Average number of days for treatmentCost per patient in the control group**Cost per patient in the study group**
  1. *Includes only costs per day, not per patient; **Includes costs per day multiplied by the average number of days for treatment plus 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).

Grade I257.43154124.234742.92
Grade II367.59249084.989703.67
Grade III594.023018 083.4418 702.13
Grade IV977.654140 346.6340 965.32
All Grades549.172715 090.4915 709.18

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 consistently observed. The total cumulative cost saving for the period between day 0 and day 10 was US$ 60 389.

Table 6. Total and incremental cost for a 10-days period of evaluation by tetanus severity level, in 2010 US$ costsa
Period of evaluationGrade IGrade IIGrade IIIGrade IVTotalIncremental cost
  1. a

    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.

Day 0
Control12 48514 49912 852039 836 
Study23 91728 72919 182185973 68733 850
Day 2
Control7723955722 57315 64255 496 
Study10 29716 17415 445195543 871−11 624
Day 4
Control5149955723 76119 55358 020 
Study978216 90910 692391141 294−16 725
Day 6
Control5663882220 19723 46458 146 
Study926715 4398316033 023−25 123
Day 8
Control463411 76320 19717 59854 191 
Study11 84211 7635940029 545−24 646
Day 10
Control4634808720 19711 73244 649 
Study11 32773525940391128 530−16 120
Incremental cumulative cost (from day 0 to day 10)     −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 respiratory assistance and US$ 62 192 for respiratory infection (Table 7).

Table 7. Total and incremental cost per hospital stay, respiratory assistance and respiratory infection covering the entire period of hospitalisation, in 2010 US$ costs
Effectiveness measureControl 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 stay933 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 assistance168 546 (30)83 027 (20)−85 518
Respiratory infection: 13–41 (27)
Total cost respiratory infection258 896 (42)196 703 (29)−62 192

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).

Table 8. Univariate sensitivity analysis
Cost itemControl group
−10%−20%−50%Baseline estimate10%20%50%
Overhead per day310 202310 066309 6492.41310 476310 613311 023
Personnel per day310 274310 211310 0281.09310 399310 462310 650
Antibiotics to treat respiratory infection per day309 657308 976306 93211.91311 020311 701313 747
Antibiotics to treat urinary infection per day310 096309 854309 1286.72310 581310 823311 548
Other drugs per day308 644306 950301 86730.29312 034313 726317 561
Consumables per day300 432290 522260 800189.69320 246330 154359 878
Tests per day305 318300 302285 246101.08315 355320 374335 428
Respiratory assistance per day298 678287 017252 030205.98322 000333 660368 644
Respiratory assistance per patient309 936309 533308 32564.95310 741311 144312 352
3000 IU immunoglobulin for intramuscular use per patient309 112307 885304 205197.84311 565312 792316 471
1000 IU immunoglobulin for intrathecal use per patient310 338310 338310 338605.02310 338310 338310 338
Training for intrathecal application of immunoglobulin per patient310 338310 338310 33813.67310 338310 338310 338
Cost itemStudy Group
−10%−20%−50%Baseline estimate10%20%50%
Overhead per day249 822249 694249 3042.41250 078250 206250 591
Personnel per day249 888249 830249 6591.09250 006250 065250 241
Antibiotics to treat respiratory infection per day249 542249 136247 91611.91250 356250 762251 984
Antibiotics to treat urinary infection per day249 920249 890249 8016.72249 979250 008250 097
Other drugs per day248 768247 588244 04630.29251 132252 309255 701
Consumables per day243 919237 886219 795189.69255 980262 011280 105
Tests per day247 608245 271238 253101.08252 286254 626261 644
Respiratory assistance per day240 240230 533201 405205.98259 658269 365298 492
Respiratory assistance per patient249 572249 195248 06664.95250 326250 703251 833
3000 IU immunoglobulin for intramuscular use per patient248 802247 654244 212197.84251 096252 244255 687
1000 IU immunoglobulin for intrathecal use per patient246 440242 931232 404605.02253 458256 967267 495
Training for intrathecal application of immunoglobulin per patient249 870249 791249 55213.67250 029250 108250 345
Cost itemComparing the two groups
−10%−20%−50%Baseline estimate10%20%50%
Overhead per day−60 380−60 372−60 3452.41−60 398−60 407−60 432
Personnel per day−60 386−60 381−60 3691.09−60 393−60 397−60 409
Antibiotics to treat respiratory infection per day−60 115−59 840−59 01611.91−60 664−60 939−61 763
Antibiotics to treat urinary infection per day−60 176−59 964−59 3276.72−60 602−60 815−61 451
Other drugs per day−59 876−59 362−57 82130.29−60 902−61 417−61 860
Consumables per day−56 513−52 636−41 005189.69−64 266−68 143−79 773
Tests per day−57 710−55 031−46 993101.08−63 069−65 748−73 784
Respiratory assistance per day−58 438−56 484−50 625205.98−62 342−64 295−70 152
Respiratory assistance per patient−60 364−60 338−60 25964.95−60 415−60 441−60 519
3000 IU immunoglobulin per patient−60 310−60 231−59 993197.84−60 469−60 548−60 784
1000 IU immunoglobulin for intrathecal use per patient−63 898−67 407−77 934605.02−56 880−53 371−42 843
Training for intrathecal application of immunoglobulin per patient−60 468−60 547−60 78613.67−60 309−60 230−59 993

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

This is the first time the incremental costs of intramuscular 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.

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 respiratory assistance compared with the control group. Respiratory 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 overestimation of the costs of hospitalisation. Some aspects of the study design, however, may have minimised this possible 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 underestimated. 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. However, 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 intervention 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 information 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 assistance. Thus, our results may only be extrapolated to other referral centres with expertise in treating the disease. 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 reference or for replication for decision-making on adopting 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 preservatives 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 contamination. 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

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

Our study shows that the use of human immunoglobulin by an intrathecal route for tetanus treatment is cost saving and that this intervention deserves consideration by doctors and decision-makers as a means of saving resources while maintaining high-quality health outcomes.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

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 Científico e Tecnológico – CNPq and Instituto Nacional de Ciência e Tecnologia para Avaliação de Tecnologia em Saúde/Conselho Nacional de Desenvolvimento Científico e Tecnológico do Ministério da Ciência e Tecnologia.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References
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