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Article in International Journal of Research in Pharmaceutical Sciences • January 2021
DOI: 10.26452/jijps.v12i1.4164

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Pandit Bhagwat Dayal Sharma University of Health Sciences
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Article History:

Received on: 23 Nov 2020
Revised on: 24 Dec 2020
Accepted on: 02 Jan 2021
Keywords:

Complete Cervical SCI, Cough capacity in cervical injury, RIMT in Acute SCI, Spirometry in SCI

Name: Gitanjali Sikka
Phone: +917027192620
Email: gitanjali.sikka@gmail.com
ISSN: 0975-7538
DOI: https://doi.org/10.26452/ijrps.v12i1.4164
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There is an annual incidence of 3.6-195.4 patients per million of SCI in the world (Amanat et al., 2019). India is the second most populous country in the world (Mathur et al., 2015) and the average annual incidence of SCI is 15,000 new cases per year with a prevalence of 0.15 million (Mukherjee et al., 1999). Respiratory complications in tetraplegics patients like atelectasis, pneumonia, pulmonary emboli, septicemia (Vázquez et al., 2013) and ultimately ventilatory failure (Reid et al., 2010) are the most com-
mon reasons behind rehospitalizations, morbidity and mortality during first 6 months to one year after trauma (Berlowitz and Tamplin, 2013). The profile of pulmonary functional tests of individuals with complete tetraplegia is typically that of a restrictive ventilatory deficit with corresponding reduction in cough capacity (Liaw et al., 2000).
In the early phase, there is reduction in lung compliance as early as one week after injury, accompanied with atelectasis, pneumonia, and ventilatory failure that progress further in the first month of injury and does not change afterwards (Scanlon et al., 1989). The rate of motor recovery for cervical AIS grade A and B, is maximum in the first 04 weeks of injury, progressively decreases after 08 weeks and 16 weeks of injury and plateaus after 26 weeks. Therefore, it has been advocated that studies that focus on neuroprotective substances should begin at the earliest after a spinal injury since both the motor and sensory scores at baseline and their further recovery is maximum in first month after injury (Fawcett et al., 2007) .

Strength training of respiratory muscles is hypothesized to be similar to that of limb muscles, potentially resulting from neural adaptations in the form of increase motor unit excitability, enhanced coordination, more efficient motor programming and muscular adaptations like increased muscle diameter. Intensive training is believed to offer neuroprotection and slowdown the progression of disease through neurorestoration of compromised pathways of signaling (Hirsch and Farley, 2009). Therefore, there is need for implementation of early phase inspiratory muscle training (IMT) incomplete cervical cord injury patients.
There is dearth of evidence supporting use of RIMT in tetraplegics patients within the acute phase of SCI, because the majority of studies conducted upto now which have concluded that inspiratory muscle training improves lung functions in tetraplegic patients have included patients one month post-SCI (Postma et al., 2014) and those studies conducted on SCI subjects within the first month of injury have supported use of RIMT, but have advocated that further research needs to be carried out in this patient population because of pitfalls in these studies (McDonald and Stiller, 2019).

Thereby, in the present study motor complete cervical spinal cord injury patients with AIS grade A and $B$$B$BB, within the first seven days of spinal injury were recruited, to impart them resistive IMT training. Also, since it has been quoted that motor recovery is maximum in the first 04 weeks after injury, so 04 weeks of RIMT training protocol was
choosen in the present study. The 04 weeks RIMT protocol has previously been followed in a study that concludes improvement after 4 week in cervical spine injury patients, but it has limitations owing to small sample size and nature of study was case series type (Boswell-Ruys et al., 2015). Thereby, present study was designed to see whether RIMT programme of 4 weeks duration is effective in improving respiratory functions in tetraplegic patients during in-patient rehabilitation.

This study was a prospective randomized control trial conducted in a single SCI rehabilitation centre conducted between March 2017 and March 2020; approved by the institutional ethics committee. Participants who met the inclusion criteria were randomly allocated using computer generated randomization list by the principal investigator to RIMT and Control group with written informed consent. Inclusion criteria: patients 18-70 years old, within first week of traumatic cervical spinal cord injury between C4-C7 level and with ASIA scale grade A and B. Exclusion criteria: Patients who were clinically diagnosed with medical instability, chronic pulmonary and/or cardiac disease (s) (COPD, interstitial lung disease, coronary artery disease, congestive cardiac failure, uncontrolled hypertension, had history of any cardiothoracic surgery), head injuries, chest injuries and/or deformities, required tracheostomy/ventilator dependency, smoking history and psychiatric illness. The enrollment, follow up and analysis of participants are shown in the CONSORT (Consolidated Standards of Reporting Trials) flow diagram (Figure 1). Sample size calculation was done using Cohen effect size’s (pre vs post training " d " values) observed in the research study for various outcome measures with $\mathrm{d}=0.8$$\mathrm{d}=0.8$d=0.8\mathrm{d}=0.8 (large); Tail(s) = Two; Allocation ratio N2/N1 = 1; $\alpha$$\alpha$alpha\alpha err prob. $=0.05$$=0.05$=0.05=0.05 and power ( $1-\beta$$1-\beta$1-beta1-\beta err prob.) $=0.95$$=0.95$=0.95=0.95. The number needed to treat was 84 with 42 subjects in each group.

Patients were positioned within the supine lying position with the bed flat. All patients had normal Chest X-rays before entering the training programme. Monitoring of physiological parameters including blood pressure and heart rate was also done for all subjects, during and after each training session to ensure hemodynamic stability. Patients within the RIMT group were given inspiratory muscle training for four weeks with an IMT Threshold trainer (commercially referred to as Threshold

IMT, Respironics Inc, Parsippany, New Jersey, USA). Training intensity began at $30\mathrm{\%}$$30\mathrm{\%}$30%30 \% maximal inspiratory pressure (MIP) and 30% maximal expiratory pressure (MEP); was increased on alternate days by $10\mathrm{\%}$$10\mathrm{\%}$10%10 \%, if tolerated and was capped at $70\mathrm{\%}$$70\mathrm{\%}$70%70 \% of the very best weekly MIP or MEP. Training frequency was twice daily, 5 days per week, with 3 sets of 12 inspirations and then 3 sets of 12 expirations and continued for four weeks. Conventional intervention, including deep breathing exercises, huffing and cough assisting, postural drainage, percussion, vibration and other rehabilitative programs like passive range of motion exercises, MAT exercise, sitting balance and upper limb functional training administered. Persons allocated to the control group were given only the conventional intervention, similar to RIMT group.

Measurements of dependent variables were obtained before commencement of intervention (PRE); repeated after two weeks (POST-1) and after four weeks (POST-2) of intervention. The subsequent tests were performed:-

Pulmonary function testing /Spirometry: Flowvolume curves were repeatedly performed for three to five times and best trials with highest values were used for analysis. Measurements were performed in accordance with the standards modified for people with SCI by American Thoracic Society (Postma et al., 2014) parameters including FVC (Forced vital capacity), FEV1 (Forced expiratory volume in 1s of exhalation), PEFR (Peak expiratory flow rate), SVC (Slow vital capacity) and MVV (Minute ventilation volume) were recorded within the supine position (Katz et al., 2018) with RMS portable spirometer, HELIOS 702.

Respiratory Muscle strength: - MIP and MEP were measured using hand-held Capsule sensing pressure gauge meter (commercially known as CSPG-V; designed, tested and calibrated by an ISO 9001 certified company; namely General Instruments Consortium Company, Mumbai, India), with pressure range of -200 to $+200\mathrm{cm}{\mathrm{H}}_2\mathrm{O}$$+200\mathrm{cm}{\mathrm{H}}_2\mathrm{O}$+200cmH_(2)O+200 \mathrm{~cm} \mathrm{H}_{2} \mathrm{O}, markings at every 5 cm ${\mathrm{H}}_2\mathrm{O}$${\mathrm{H}}_2\mathrm{O}$H_(2)O\mathrm{H}_{2} \mathrm{O} and accuracy rated as $\pm 2\mathrm{\%}\mathrm{FSD}$$\pm 2\mathrm{\%}\mathrm{FSD}$+-2%FSD\pm 2 \% \mathrm{FSD} (Jalan et al., 2015). A nose clip was applied to avoid nasal air leak and the investigator held CSPG-V gauge with the dial facing patient positioned in supine lying for visual feedback. The gauge piece was attached with unidirectional valve system together with plastic rigid flanged mouthpiece for alternate inspiration and expiration (Grams et al., 2015). MIP was measured after full expiration near residual volume (RV) and MEP was measured after maximal inspiration near total lung capacity (TLC). The subject was
asked to close his/her lips firmly around the flanged mouthpiece and strong verbal encouragement was given during the test. Eight such maneuvers were performed, with each effort being sustained for a minimum of one second and with a rest interval of roughly one minute between each effort. Highest value which had a variation of less than $5\mathrm{\%}$$5\mathrm{\%}$5%5 \% of the following value was recorded and used for analysis (Postma et al., 2014) . Before the start of the testing session, instructions about the procedure were given in a standardized manner and all measurements were performed by the researcher.

Statistical analysis was performed with the software package SPSS statistical software (SPSS IBM Version 25) for windows version. The significance of difference in proportions of qualitative demographic variables expressed as proportions and percentage was inferred by Chi-square test ( $\mathrm{P}<0.05$$\mathrm{P}<0.05$P < 0.05\mathrm{P}<0.05 ) and significance of differences in mean values of quantitative data expressed as mean $\pm$$\pm$+-\pm SD was inferred by unpaired " t " test ( $\mathrm{P}<0.05$$\mathrm{P}<0.05$P < 0.05\mathrm{P}<0.05 ). Tests of normality were done to evaluate the normal distribution of various outcome measures and all variables were normally distributed. Comparison for within group differences in RIMT and Control group was done using One-way ANOVA ( $\mathrm{P}<0.01$$\mathrm{P}<0.01$P < 0.01\mathrm{P}<0.01 ) and post hoc analysis of mean values was done with Duncan’s multiple range test ( $\mathrm{P}<0.05$$\mathrm{P}<0.05$P < 0.05\mathrm{P}<0.05 ). Comparison of differences between RIMT and Control group was done using unpaired " t " test ( $\mathrm{P}<0.05$$\mathrm{P}<0.05$P < 0.05\mathrm{P}<0.05 ). The " t -values" and degree of freedom ( $\mathrm{df}=94$$\mathrm{df}=94$df=94\mathrm{df}=94 ) were further used for calculating the clinical significance of changes in outcome measures; namely Cohen’s “D” effect size. The effect size value was calculated at POST-1 and POST-2 time intervals. Effect size of $<0.5$$<0.5$< 0.5<0.5 represents small effect, 0.5-0.8 a medium effect, and $>0.8$$>0.8$> 0.8>0.8 a large, clinically significant effect.

There were no significant differences between the two groups for any of the physical characteristics (Table 1). The pre-training and post-training mean values of all outcome measures revealed highly significant differences within both the groups with one way ANOVA ( $\mathrm{P}<0.01$$\mathrm{P}<0.01$P < 0.01\mathrm{P}<0.01 ) and with post hoc analysis using Duncan’s multiple range test ( $\mathrm{P}<0.05$$\mathrm{P}<0.05$P < 0.05\mathrm{P}<0.05 ) (Table 2). RIMT as compared to the conventional treatment with unpaired " t " test, resulted in a highly significant positive effect on all measures of pulmonary functions and respiratory strength, recorded after 2 and 4 weeks of training ( $\mathrm{P}<0.01$$\mathrm{P}<0.01$P < 0.01\mathrm{P}<0.01 ) (Table 3). The effect size difference between RIMT and control group, for all the outcome measures was
falling in the large effect size zone and effect sizes for RIMT vs. Control group are presented in Figure 2.

The general improvement observed in all the measures in comparison to basal values within both the groups of patients in the present study can be considered related to change from muscle flaccidity associated with the initial phase of spinal shock to trained accessory muscle status and slowly developing hypertonicity of the paralyzed intercostals and abdominal muscles (Ledsome and Sharp, 1981). The results of present study are comparable to the results quoted by previous studies done on patients with acute cervical spinal cord injury by (Ledsome and Sharp, 1981), which also observed that in patients with complete transections of the spinal cord at levels C4, C5, and C6 there is significant increase in vital capacity within the first five weeks of injury and approximately twice its value after 3 months of injury

The majority of studies conducted till date have included patients at least two months post-SCI, with this lag period included to regulate for the effect of natural recovery on outcomes. In the setting of SCI, with respect to IMT specifically (rather than respiratory muscle training), a systematic review concluded that there was level 1a evidence that IMT significantly increased inspiratory muscle strength in acute SCI subjects as quoted by two randomized controlled trials, one by (Van Houtte et al., 2008) and second one by (Derrickson et al., 1992) and level 5 evidence from one case report by Hornstein and Ledsome, that IMT improved inspiratory muscle strength and decreased the number of respiratory infections (McDonald and Stiller, 2019).
The randomized controlled trials done by (Van Houtte et al., 2008), delivered normocapnic hyperpnoea training to 14 patients who were at least two months post complete SCI and the study concluded that there was significant improvement in respiratory muscle strength and endurance in patients who underwent training program as compared to the control group. However, the study had limitations owing to the method of IMT being used for training, being time consuming, poses increased physical demands on patients and was associated with increase in muscle spasm/spasticity.

The second RCT by (Derrickson et al., 1992), was actually the foremost study identified where IMT was commenced in the acute phase post-SCI. This
was a RCT with level 2 evidence, a study on eleven tetraplegics patients where the mean time postinjury was 12 days for an IMT group and 25 days for an abdominal weights group (range 2-74 days). Flaws in this study included lack of a control group, small sample size and non-standardized training programme with a very basic IMT resistor. Nevertheless, no adverse effects associated with IMT were reported.

Another recent study by (McDonald and Stiller, 2019), also supported the very fact that a highresistance, low-repetition program of the IMT was both feasible and safe in an earlier stage post-SCI than has previously been documented and quoted that further study is required to demonstrate the efficacy of IMT when instituted during the acute phase post-SCI. The main limitations of this study were the small sample size and uncontrolled design clearly limiting the generalizability of the results.

In the present study, it’s been best tried to overcome the lacunae of previous randomized control trials (Derrickson et al., 1992) and case studies (McDonald and Stiller, 2019) conducted on acute phase tetraplegia individuals, by conducting a randomized control trial, on an outsized homogenous patient population of ninety-six patients within the acute phase of motor complete cervical spine injury and by incorporating standardized IMT protocol for the use of threshold IMT resistor device.

The pre-training and post-training mean values of MIP, FVC, PEFR and MVV within the RIMT and Control group observed in the present study are comparable to the mean values quoted within the previous studies on acute phase tetraplegics patients (Derrickson et al., 1992). The results observed in the RIMT group are in accordance with results from other studies that also quoted significant improvement in pulmonary functions and respiratory muscle strength post IMT in patients with tetraplegia (Derrickson et al., 1992). Also, the overcoming of limitations in the present study as observed in earlier studies on acute phase tetraplegic subjects (McDonald and Stiller, 2019) could explain the reason for significant differences observed between RIMT and control group in the present study.

The rate of motor recovery for cervical AIS grade $A$$A$AA and $B$$B$BB, is maximum in the first 04 weeks of injury, progressively decreases after 08 weeks and 16 weeks of injury and plateaus after 26 weeks. Therefore, it has been advocated that studies that focus on neuroprotective substances should begin at the earliest after a spinal injury since both the motor and sensory scores at baseline and their further recovery is maximum in first month after injury,

Figure 1: CONSORT (Consolidated standards of ReportingTrails) flow diagram of study participants from enrolment to analysis

Table 1: Comparison of baseline characteristics of RIMT Group and Control Group

Table 2: Pre-training and post-training mean values (Mean $\pm$$\pm$+-\pm S.D.) within RIMT and Control Group

** Highly significant difference ( $\mathrm{P}<0.01$$\mathrm{P}<0.01$P < 0.01\mathrm{P}<0.01 ) of One-way ANOVA between pre-and post-training values within group; Post - hoc analysis shown by superscripts, means with different superscripts in a row differ significantly ( $\mathrm{P}<0.05$$\mathrm{P}<0.05$P < 0.05\mathrm{P}<0.05 ). PRE (baseline measurement), POST1 (after two weeks training), POST-2 (after four weeks of training).

Table 3: Comparison between RIMT and Control Group for pre- and post-training changes

${}^{\mathrm{\S }}$${}^{\mathrm{\S }}$^(§){ }^{\S} Highly significant difference ( $\mathrm{P}<0.01$$\mathrm{P}<0.01$P < 0.01\mathrm{P}<0.01 ) of unpaired $t$$t$tt test between RIMT andControl group after 02 weeks of training (POST-1 time interval). ${}^{\ast \ast }$${}^{\ast \ast }$^(****){ }^{* *} Highly significant difference ( $\mathrm{P}<0.01$$\mathrm{P}<0.01$P < 0.01\mathrm{P}<0.01 ) of unpaired t-test between RIMT and Control group after 04 weeks of training (POST-2 time interval). PRE (baseline measurement), POST-1 (after two weekstraining), POST-2 (after four weeks of training).
trial of a regeneration/ repair-inducing treatment might begin within 1-4 weeks and finally, a trial of a neural plasticity-inducing intervention might begin at almost any time, including during the chronic state of SCI (e.g. 12 months after injury) (Fawcett et al., 2007). The recruitment of patients in the immediate post traumatic phase of cervical spinal cord injury in the present study and initiation of neuroprotective therapy in the form of RIMT in the first week of injury could also be one of the possible reasons for differences in pulmonary functions between RIMT and Control group.

In terms of protocol of IMT in the present study, there was incorporation of a standardized IMT protocol of 4 week duration as being done in a previous study that recorded improvement after 4 week

IMT training in cervical spine injury patients, but had limitations owing to small sample size, patients included were with both acute and chronic SCI and nature of study was case series type (Boswell-Ruys et al., 2015).

In the present study, the effect size (Mueller et al., 2013) was calculated between RIMT and Control group using the " $t$$t$tt-values" and degree of freedom at two time intervals namely: after two weeks of treatment (POST-1) (Ledsome and Sharp, 1981) and after four weeks of treatment (POST-2) (BoswellRuys et al., 2015). Both at POST-1 AND POST-2 time intervals, the effect size difference between RIMT and control group for all the outcome measures was falling in the large effect size zone i.e. greater than

Effect size, " $\mathrm{d}\ge 0.8$$\mathrm{d}\ge 0.8$d >= 0.8\mathrm{d} \geq 0.8 " indicates a large clinically significant effect. POST-1 (after two weeks training), POST-2(after four weeks of training).
Figure 2: Comparison of Effect Sizes (“Cohen -d values”) for pre to post training changes between RIMT and Control Group
or equal to 0.8 . This lead to the conclusion that there were clinically significant differences ( $\mathrm{d}>0.8$$\mathrm{d}>0.8$d > 0.8\mathrm{d}>0.8 ) for measures of all pulmonary functions and respiratory strength in patients who underwent RIMT as compared to those patients who received conventional treatment.

The sample size was calculated using the G-Power Software in order to generate number of patients needed to be treated for yielding clinically significant results. Effect size d $=0.8$$=0.8$=0.8=0.8 (large), with Tail(s) = Two; Allocation ratio $\mathrm{N}2/\mathrm{N}1=1$$\mathrm{N}2/\mathrm{N}1=1$N2//N1=1\mathrm{N} 2 / \mathrm{N} 1=1; $\alpha$$\alpha$alpha\alpha err prob $=$$=$== 0.05 ; Tail(s) = Two; Power (1- $\beta$$\beta$beta\beta err prob) = 0.95; Output: Sample size RIMT group = 42; Sample size Control group $=42$$=42$=42=42; Total sample size $=84$$=84$=84=84. Thereby, the number needed to treat i.e. to yield clinically significant difference between the two groups was recorded as eighty four. But, the number of patients already analyzed in the study since the time of study initiation was ninety-six. So, the number of patients enrolled in the present study, treated and analyzed for differences between RIMT and control group, hereby prove to be the desired sample size for observing statistical and clinical difference between the two study groups.
In previous studies by (Postma et al., 2014) and that by (Derrickson et al., 1992), the power analysis conducted for the mean difference between the two treatment groups for continuous variables was carried out with a beta level of $0.20(80\mathrm{\%})$$0.20(80\mathrm{\%})$0.20(80%)0.20(80 \%) and an alpha level of .05 to determine the sample size needed to minimize Type II errors. However, in the present
study the sample size needed to minimize Type II errors was carried out with beta level of 0.05 ( 95%) and also with effect size, $d$$d$dd value of large difference ie.0.8. Thereby, the results of the present study could be relied upon to be generalizable to a patient population with acute cervical spine injury.

The patients were not followed up for long term changes post intervention and the development of respiratory complications after discharge from the hospital. Future research should be carried out to find out if prolonged the intervention of RIMT beyond the time duration of 4 weeks has additional benefit and/or similar pattern of improvement in pulmonary functions and respiratory strength, or it has a ceiling effect.

The findings of the present study show a beneficial effect of RIMT on respiratory functions (FVC, FEV1, PEFR, SVC and MVV) and strength (MIP and MEP) in patients with motor complete cervical cord injury in the first month after injury. Furthermore, in light of the outcome of the present research, we propose that RIMT should be included early in the acute phase rehabilitation protocol of patients with cervical spine injury to improve their respiratory function.

The authors declare that they have no conflict of interest for this study.

The authors declare that they have no funding support for this study.

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