Introduction
Spinal cord injury (SCI) is one of the serious health challenges and has many side effects [1]. In scientific literature, SCI is defined as a consequence of natural damage to the area of the spinal cord that results in disorders in the nerve fiber [2]. SCIs can be divided into two categories based on the damage: direct damage and indirect damage. Evidence suggests that most SCIs result from direct damage [3]. SCI can have various side effects for the patient. Chronic side effects of SCI include pressure ulcers in different body parts, atherosclerotic cardiovascular diseases, kidney, and urinary tract disorders, respiratory disorders, pain syndrome, muscle spasms, neurological gastrointestinal disorders, osteoporosis, and bone fractures. Pressure ulcers are among the most common side effect of SCI [4]. 
The worldwide prevalence of SCI is around 50 to 1298 cases in 1 million people, rising during the last decade [2]. According to the studies, 3.8% of all trauma patients from 1999 to 2004 were related to bone fractures of the spinal cord, among of these, 5.8% had SCI complication [5]. 
SCI is a harmful event that not only affects the life of the patient and their family but also has a heavy impact on society and the health care system. Such effects include hospitalization, frequent visits for rehabilitation, and medical care in daily activities for a lifetime [6, 7]. SCI is a heavy burden for the health care system. According to a study in Canada, the net life expenses of an individual with SCI are around 336000 dollars [8]. 
A specialized rehabilitation program for SCI includes inpatient care, ambulatory care, and follow-up care aimed at rehabilitating SCI patients and their families to reach a desired quality of life, increase their self-confidence, and attain individual independence for returning to society [9].
SCI patients require compact rehabilitation services after fixation and initial treatment [9]. These services can have significant effects on improving the patient’s status. The efficacy of these interventions has been reported in various studies. These services have been evaluated in terms of different metrics, such as quality of life, functional independence in daily activities, and neurological indices, along with reducing future side effects [10, 11, 12].
Despite the evidence on the efficacy of early rehabilitation interventions in SCI patients, and considering that such interventions have great pressure on the healthcare system, it is necessary to evaluate the cost-effectiveness of these interventions for service providers of countries. This aim becomes more crucial, considering that few studies have been conducted on this issue. 
Accordingly, and given the increasing trend of SCI patients in Iran and various aspects of rehabilitation for this issue, this economic evaluation study examines the net monetary benefit (NMB) of rehabilitation services of inpatient and ambulatory care in SCI patients in Iran. 
Materials and Methods 
The present study is a comprehensive economic evaluation conducted in 2019. It compares the rehabilitation strategies for SCI patients without any rehabilitation protocol. Accordingly, the cost evaluation of rehabilitation services for SCI patients was done, and then the cost analysis of the efficacy of the two strategies was performed. Finally, NMB was extracted.
Costs of spinal cord injury rehabilitation
We used the bottom-up approach to calculate the average cost of each patient and the total cost of rehabilitation services. First, according to the available evidence and using the standard ID of rehabilitation services for SCI patients in Iran, we extracted the list of rehabilitation services, their abundance categorized based on different stages of the disease (paraplegia and tetraplegia from sub-acute to severe stages), along with the type of rehabilitation service. Then, by multiplying the number of rehabilitation services per patient for that specific service, we calculated the average cost of rehabilitation services per patient for each stage of the disease. The costs of rehabilitation included the cost of 7-day hospitalization, the cost of 3- to 8-day rehabilitation services for acute stages, and 6- to 12-month ambulatory rehabilitation services. These numbers were calculated based on the cost unit for each intervention. 
Markov model
We performed the first modeling for economic evaluation in this study.
The model was based on the disease types, the normal process of the disease, the manner and details of conducted rehabilitation services for SCI patients in different groups of the disease, clinical implications, the probability of implications, and related costs.
To evaluate the clinical implication of the efficacy of SCI rehabilitation in this study, based on the available evidence and reviewing the literature on the clinical efficacy of rehabilitation services for SCI patients, we selected the functional independence measure (FIM) as the base index.
The designed model for economic evaluation is shown in Figure 1. The structure of this model is designed in a way that every strategy is based on a Markov model. To design the model, according to the objectives of the study and available evidence regarding the efficacy of interventions, we selected two groups of patients (paraplegia and tetraplegia), and each group was divided into 4 subgroups in terms of the intensity of the damage (subacute, mild, acute, severe). Considering that no evidence was found regarding the 4 groups for the severity of the disease, they were divided into incomplete and complete damage in the modeling (these two groups can be considered subacute-mild damage and acute-severe damage).
According to the natural process of the disease, rehabilitation protocols for SCI patients, and opinions of clinical specialists, the efficacy and cost of SCI rehabilitation were considered in only one cycle, and no changes regarding the health status were considered in the following cycles. Patients remain in that status in the following cycles with the previous quality of life until they pass away. 
Model assumptions
This study was conducted from a social perspective, and the time horizon in the base case analysis was considered a lifetime. Eventually, the model of 50 cycles was investigated, and costs and implications were extracted accordingly. 
According to the evidence on the efficacy of SCI rehabilitation, the duration of each cycle and the inpatient and ambulatory care interventions were considered one year. The efficacy of rehabilitation interventions was based on the increase in the score of FIM in the four groups of patients. We used the evidence related to mapping for these two indices to equate the scores of FIM in each health status with the quality of life related to health and the measure of quality-adjusted life years. Then, the values of the quality-adjusted life-year (QALY) in each health status were extracted [13].
Also, in each health status, in addition to the costs of rehabilitation interventions, the cost of care, nursing the patient at home (based on the disease group and the dependence degree for doing daily activities of life in each health status), and the cost of the inability to work (based on the absent days in each month) were considered as well.
Considering the various side effects of SCI and the efficacy of rehabilitation interventions in reducing such side effects, reducing the costs of these side effects was considered another variable in this study to demonstrate the rehabilitation implications. Based on the conducted search, the incidence of pressure ulcers (degree of 1 to 4) in SCI patients is considered the most important side effect, and the amount of cost reduction for this side effect is another variable related to the efficacy of rehabilitation.
In the study model, the costs of rehabilitation and treating pressure ulcers are only considered in the first cycle; however, the cost of guarding, care, and inability to work were considered in all cycles based on the health status. The annual discount rate of costs and implications in this study was considered to be 5%. 
Based on the domestic studies conducted on SCI patients, the average age of 35 years was considered for patients in the initial phase of the Markov model.
Sensitivity analysis
Given the uncertainty regarding some of the parameters in the model, we used probabilistic sensitivity analysis using the Monte Carlo simulation, along with considering the probabilistic distribution of the values of indefinite variables. The distributions used for indefinite parameters in the probabilistic sensitivity analysis are provided in Table 1. 




Incremental Net Monetary Benefit of Spinal Cord Injury Rehabilitation in Iran 
For the calculation of NMB, according to the designed model for economic evaluation, the average incremental NMB (INMB) of rehabilitation for each patient was measured: 
INMB12=[(QALY rehab-QALYno rehab)*k]-(COST rehab-COSTno rehab)]
Where K is a constant that shows the gross domestic product per capita as the tendency of a society to pay for each unit of QALY. In this study, this measure is equal to 300 million Iranian Rials (IRR).
All stages of the study are performed with the TreeAge 2011 software.
Results
Spinal cord injury rehabilitation cost
Table 2 and Table 3 present the calculations of cost evaluation for SCI rehabilitation services according to public and private tariffs, respectively.


Based on the public tariffs, the average annual cost of rehabilitation for each patient in the paraplegia group ranges from 94276000 to 114857000 IRR for subacute to severe stages of the disease. This measure ranges from 169841 to 174127 thousand rials for the tetraplegia group.
Considering the whole population of patients in each group, the total annual costs of SCI rehabilitation in Iran in the paraplegia group ranges from 32 to 40 billion IRR and 25 to 26 billion IRR in the tetraplegia group for subacute to severe stages of the disease. Accordingly, the total cost of rehabilitation for SCI patients, based on the public tariffs, is 256 billion IRR annually. 
Similarly, the findings of this study based on the private sector tariffs are provided in Table 3.


Accordingly, the total annual cost of SCI rehabilitation in Iran in the paraplegia group ranges from 86 to 103 billion IRR and 67 to 68 billion IRR for the tetraplegia group for subacute to severe stages of the disease. Hence, the total cost of rehabilitation for SCI patients based on the private sector tariffs is 668 billion IRR annually. 
Economic evaluation
Base case analysis
Table 4 presents the cost evaluation analysis of efficacy based on public and private tariffs.


Accordingly, the rehabilitation of SCI patients has lower costs of average living years and, on the other hand, higher efficacy (higher QALY measure) compared to the non-rehab group, showing the dominancy of the rehabilitation cost strategy. The incremental cost-effectiveness ratio in this state based on the public tariffs equals 647 million IRR and 629 million IRR for the private sector tariffs for each unit of QALY. According to the gross domestic product per capita, which is 300 million IRR (the value of QALY in 2019), the INMB of lifetime rehabilitation for each SCI patient based on public and private tariffs equal 4.4 and 4.2 billion IRR, respectively. 
Sensitivity analysis
Considering the function of the distribution of indefinite parameters of the model, the probabilistic sensitivity analysis using the Monte Carlo simulation was performed for both models according to the public and private tariffs.
Figure 2 demonstrates the optimal probability, or the probability of effectiveness cost of each strategy, by considering the effectiveness cost threshold of 300 million IRR and 1000 repetition frequency of Monte Carlo based on the distribution of the value of indefinite parameters for both models according to public and private tariffs. Hence, the probability of the effective cost of a rehabilitation strategy for SCI patients according to the changes in parameters and various simulations is similar and equal to 100% in both groups. Accordingly, the initial analysis results are proved with high probability and show the robustness of the model and initial results.
Incremental net monetary benefit
According to the number of patients under rehabilitation in the public and private tariffs, the INMB of SCI patient rehabilitation in Iran is calculated based on estimating the number of SCIs in Iran annually. Accordingly, based on the public sector tariffs, the INMB equaled 8991 billion IRR. These measures based on the private sector tariffs equaled 8579 billion Iranian IRR (Table 5). 


Discussion
The present study was a comprehensive economic evaluation for comparing the rehabilitation strategy for SCI patients versus the non-rehabilitation strategy. This comparison was conducted based on two scenarios according to private and public tariffs. Considering the chronic nature of the disease and the relative dependency of patients, along with the given economic evaluation perspective, a wider range of costs and implications were considered in this study. In terms of the costs, besides the direct medical costs, direct non-medical costs to the patient’s family and society were also taken into account.
The findings of this study showed that in both scenarios (based on public and private tariffs of rehabilitation for SCI patients), the dominant choice was the option of effective costs compared to the non-rehabilitation strategy, in a way that, along with the increase in QALY in rehabilitation, a considerable cost providence exists as well. The difference in results in the second scenario based on the private sector tariffs only pointed out the reduced measure of negative incremental cost-effectiveness ratio (ICER) because of increased costs of rehabilitation interventions based on private tariffs. In both scenarios, the results of the sensitivity analysis confirmed the results of the initial analysis with 100% probability.
The findings regarding NMB showed that according to public tariffs in 50 years study, the rehabilitation of SCI patients, on average for each patient, provides 4.4 billion IRR in financial benefit. This figure equals the considerable amount of 8991 billion IRR for 2000 patient incidences annually. These calculations were estimated relatively lower based on private tariffs. Hence, this figure equals 4.2 billion IRR for each patient and 8579 billion IRR for annual incidence.
To the best of our knowledge, this was the first study for a comprehensive economic evaluation of rehabilitation interventions for SCI patients; however, numerous studies have proven the efficacy of rehabilitation interventions for SCI patients [10, 12]. Based on studies, the biggest driver of total costs for medical care for SCI patients is the cost of rehabilitation interventions [21]. However, it is noteworthy to mention that considering the effectiveness of early rehabilitation interventions in these patients, a considerable reduction of costs occurs in the social costs of a patient’s lifetime [22]. This reduction can be in hospitalization costs and period, maintenance costs, nursing at home, costs of inability to work, and costs of different side effects.
As mentioned, in addition to reducing the medical costs and costs related to dependency on doing daily activities, these services increase the quality of life and decrease future costs in the patient’s lifetime, including the cost of absence from work. Because of lacking the support from the healthcare system and insufficient medical insurance coverage, after completing the first stage of medical care, many patients avoid the services of rehabilitation. Accordingly, the patient and their family may face numerous problems in the future. The findings of this study showed that providing rehabilitation services to SCI patients, considering the public and private tariffs, has positive NMB. Hence, providing these interventions to SCI patients is economically sound. Along with increasing the availability of these services, investment and full medical insurance coverage can have tremendous social benefits.
The present study has many limitations. In this study, the costs of pressure ulcers, as a variable showing the implication of rehabilitation, were considered in only one cycle because of insufficient evidence. Also, the reduction of costs in other side effects as the result of rehabilitation was not considered in the model because of insufficient meaningful evidence. 
Conclusion
Overall, the finding of this economic evaluation showed that the rehabilitation of SCI patients in Iran, based on public and private tariffs, has considerable positive NMB and efficacy costs. The results of sensitivity analysis in this study prove these findings. Hence, increasing the coverage of these services and expanding their availability is economical for patients.   

Ethical Considerations
Compliance with ethical guidelines
This study was approved by the ethics committee of University of Social Welfare and Rehabilitation Sciences (Code: IR.USWR.REC.1398.004).

Funding
This study was extracted from a research project and funded by Ministry of Health and Medical Education and University of Social Health and Rehabilitation Sciences.

Authors' contributions
Conceptualization: Mirtaher Mousavi, Rajabali Daroudi, Marzieh Shirazikhah, Mehdi Alizadeh Zarei, Hamidreza Hendi, Ali Darvishi; Methodology, validation: Mirtaher Mousavi, Rajabali Daroudi, Ali Darvishi, Hamidreza Hendi; data analysis: Mirtaher Mousavi, Rajabali Daroudi, Ali Darvishi, Hamidreza Hendi; Marzieh Shirazikhah; investigation: Mirtaher Mousavi, Rajabali Daroudi, Ali Darvishi, Marzieh Shirazikhah, Mehdi Alizadeh Zarei, Hamidreza Hendi, Faezeh Joghataei; resources: Hamidreza Hendi, Faezeh Joghataei, Ali Darvishi; initial draft preparation, editing & review: Mirtaher Mousavi, Hamidreza Hendi, Faezeh Joghataei, Ali Darvishi; supervision, project administration, funding acquisition: Mirtaher Mousavi, Rajabali Daroudi 

Conflict of interest
The authors declared no conflict of interest.

Acknowledgments
The authors would like to thank. Mohhammad Taghi Joghataei (Rehabilitation consultant, Ministry of Health and Medical Education) for his support.
 

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