Overview of research design
A randomised controlled trial was designed to study the effects of the intervention. Patients diagnosed with DPN are recruited from the University hospital and referred to a physiotherapist, who performs the initial blind assessment.
The design and flowchart of the steps of the protocol are presented in Figure .
Flowchart of the protocol steps.
The patients allocated to the intervention group receive the treatment for 12 weeks, twice a week, 40-60 min per session. They are assessed at baseline condition (A1), after 12 weeks (A2-intervention period), and after 24 weeks (A3-follow-up period).
The patients allocated to the control group represent the crossover arm of the study. They also are assessed at baseline condition (A1) and after 12 weeks (A2). During this period, they continue to receive the usual recommended medical care at the hospital, which includes pharmacological treatment and self-care instructions. After the end of the second evaluation, they receive physiotherapy intervention for 12 weeks and are then assessed after intervention (A2'-24 weeks after baseline) and after the follow-up period (A3'-36 weeks after baseline). This design was chosen in order to increase the number of patients receiving the intervention, as we can expect losses to the follow-up evaluation due to the longer period of time required to complete all the protocol procedures (intervention and follow-up period).
Participants and recruitment
This study is currently recruiting patients (study start date: August 2010).
The eligibility criteria are:
- patients 45 to 65 years of age
- diabetes mellitus type 1 or 2, diagnosed for at least seven years
- body mass index ranging between 18.5 and 29.9 kg/m2 (normal and overweight groups)
- presence of DPN previously diagnosed by the medical care centre
- score higher than 2 out of 13 in the questionnaire of the Michigan Neuropathy Screening Instrument [64
], indicating the presence of at least two DPN symptoms
- score higher than 1 out of 10 for physical assessment of the same instrument, but always including at least impaired vibration perception
- ability to walk independently in the laboratory space
- any plantar ulceration should be healed for at least six months
- not having partial or total foot amputation
- not receiving any physical therapy intervention
Patients are not selected if they have other neurological or orthopaedic impairments (such as stroke, cerebral palsy, poliomyelitis, rheumatoid arthritis, prosthesis, or moderate or severe osteoarthritis), major vascular complications (venous or arterial ulcers), severe retinopathy, or severe nephropathy that causes edema or requires haemodialysis.
The participants are recruited from three settings: (a) diabetes mellitus ambulatory medical care located in a regional hospital, (b) National Association of Diabetes Mellitus (ANAD), and (c) patients from a primary care centre at the School of Medicine of the University. The potential patients are interviewed by telephone and, when selected, are assessed in the laboratory to confirm all the eligible criteria. This first laboratory assessment represents the baseline condition (blind assessment).
The patients allocated to the intervention group are treated in the Physical Therapy Department, in an ambulatory setting that assists all the physical therapy treatments of the Department, providing a real environment for the intervention.
Randomisation and blinding
The randomisation schedule was prepared by an independent researcher who was not aware of the numeric code for the control and intervention groups, using Clinstat software [66
]. A numeric block randomisation sequence is kept in opaque envelopes.
After the patients' agreement to participate in the research, the allocation into the groups is made by another independent researcher, who is also unaware of the codes. Only the physiotherapist knows who is receiving the intervention.
All the assessments are performed by a physiotherapist who is blind to group allocation of the patients. Each assessment consists of anamnesis for personal details, diabetes history, and any other health issue of interest. The Michigan Neuropathy Screening Instrument questionnaire and physical assessment are used [64
] to characterise the signs and symptoms, and to monitor the disease status.
To assess the patients' confidence in performing daily locomotor skills, we chose to use the Activities-Specific Balance Confidence Scale (ABC) [67
We also measure passive and active ankle ROM and first metatarsophalangeal joints in the sagittal plane. For the ankle measurement, we use an electrogoniometer (model SG110/A and SG 150, Biometrics, Gwent, England). For measuring the first metatarsophalangeal joint, we use a manual goniometer.
Intrinsic and extrinsic foot and ankle muscle functions are assessed through manual testing [68
], as there is not currently an instrument available that is capable of measuring the function of this group of muscles. Other authors also use manual testing and consider it a useful tool [45
]. The assessed muscles are triceps surae, tibialis anterior, interosseous, lumbrical, flexor hallucis brevis, flexor digitorum brevis, extensor hallucis longus and brevis, and extensor digitorum longus and brevis.
Foot function is assessed based on a test protocol designed by Palmer and Epler [69
], which consists of asking the patient to perform, as quickly as possible, the following tasks, while seated: (a) grab a cotton piece with the toes, keeping the heel on the floor, and (b) raise only the toes, keeping the heel and forefoot on the floor. Then, in a standing position, the patient is asked to (a) raise the forefoot and (b) raise the heel. These tests are very practical and easily reproducible. Each test has a scale relating to the number of movement repetitions: 'absent functionality' (zero repetitions), 'little functionality' (1 to 4 repetitions), 'reasonable functionality' (5 to 9 repetitions), and 'normal functionality' (10 to 15 repetitions).
Plantar pressure is recorded using the Pedar-X system (Novel, Munich, Germany) at 100 Hz. The patient walks barefoot on a 10 m flat walkway at a self-selected cadence (controlled between subject's trials within 96-116 steps/min), with the insole placed and fixed, using an anti-skid sock and a stripe at the ankle. Four valid trials are recorded, and we discard the first and last steps from the analysis. The foot is divided into six areas (heel, midfoot, lateral forefoot, middle forefoot, medial forefoot, hallux, and toes), using the same software for data acquisition. A time-series analysis will be performed to compare the pressure curve in each area, over the stance duration, intending to describe changes in plantar pressure distribution. Values of contact area and peak pressure will be compared in these six areas.
Kinematic gait parameters are acquired using three-dimensional displacement of passive reflective markers (20 mm in diameter) tracked with six infrared cameras (OptiTrack FLEX: V100, Natural Point, Corvallis, OR, USA) (Trombini-Souza et al., 2011). The markers are placed on the subject using a standard Cleveland Clinic marker set (iliac spine antero-superior, superior aspect of the greater trochanter, lateral knee joint line, lateral malleolus, calcaneus, and head of the fifth metatarsal) [70
]. Extra markers are placed bilaterally at the medial knee joint line, medial malleolus, and first metatarsal joint for the static standing trial, in order to determine relative joint centres of rotation for the knee, ankle, and longitudinal axis of the foot. These extra markers are removed in the gait trial. In addition, three non-collinear reflective markers are fixed at two squares, forming sets of technique cluster. One of these is placed in the lateral thigh and the other over the shank. Theses landmarks are determined by the same physiotherapist who performs the blind assessment. The laboratory coordinate system is established at one corner of the force plate, and all initial calculations are based on this coordinate system. Each lower limb segment (foot, shank, and thigh), based on surface markers, is modelled as a rigid body with a local coordinate system that coincides with the anatomical axes, and translations and rotations of each segment are reported relative to neutral positions defined during the initial standing static trial.
Ground reaction forces are acquired by a force plate (AMTI OR-6-1000, Watertown, MA, USA) embedded in the centre of the walkway.
Force and kinematic data acquisition are synchronized and sampled by an A/D card (AMTI, DT 3002, 12 bits) at 100 Hz. Mathematical analysis of the kinematic data will be performed using Visual3D software (C-motion, Kingston, ON, Canada), and the ground reaction force analysis will be performed using a custom-written Matlab function (MathWorks, Natick, MA, USA). The variables to be analysed are: (1) joint angles and (2) net ankle moments in the sagittal and frontal planes; and (3) step length and (4) duration. These variables will contribute to discussion of the possible changes in plantar pressure distribution, especially the ankle position in the initial and terminal stance phases.
The main outcome measure is foot rollover, which will be described by time-series analysis of plantar pressure distribution during gait. This variable was chosen because it reflects the alterations of kinematics, kinetics, and muscle function in the dynamic task of gait.
The secondary outcomes are foot and ankle kinetics and kinematics during gait, neuropathy signs and symptoms, foot and ankle ROM, function and muscle strength, and Activities-Specific Balance Confidence Scale [67
This intervention protocol is based on evidence that shows that:
(1) Foot rigidity is associated with increasing local loads and predisposes to plantar ulceration [12
]. The increase in ROM of these segments could contribute to restoring foot rollover during gait.
(2) The weakness of the intrinsic foot muscles and ankle flexors and extensors represents an independent risk factor for the development of plantar ulcers, leading to a less effective plantar load distribution [14
]. The strengthening and recovery of their function also could be reflected in foot rollover during gait.
(3) There is evidence that shows that patients with DPN can improve gait and confidence, suggesting a possible recovery of motor control functions at some level [58
]. A more comprehensive exercise therapy should integrate the peripheral gains (increase in ROM and muscle function and strength) into motor tasks, such as gait. It could be achieved when requiring these gains during the execution of walking skills and simple balance exercises.
(4) The patients should perform the exercises independently at home, and the exercises should be simple enough to allow that.
The complete description of the intervention can be found in Additional file 1
: Table S1.
We divided the therapeutic sessions into four blocks of exercises, characterised by the main objective of each exercise group. They are: (a) gain of foot and ankle ROM, (b) foot and ankle muscle strengthening, (c) foot and ankle functional exercises, and (d) walking skills and foot rollover training. Each session is composed of some of the exercises from the four groups. Gradual and progressive difficulty is offered to the patient, respecting any limitation due to pain and/or decrease in performance during execution. In addition, in each session, the exercises are performed following an order that starts with the passive exercises, progresses to active, and finishes with walking and functional skills. Therefore, we can promote the motor integration of peripheral gains into functional movements in every session. Although this intervention is focused only on foot and ankle exercises, we have a complete approach to the rehabilitation process that depends on the association between the afferent and efferent peripheral system and the central system to perform tasks of daily living, such as walking. Previous studies do not accomplish that specificity of selecting the segments most impaired by DPN to recover, nor do they integrate the musculoskeletal gains in the foot rollover process during gait.
During all exercises, the physiotherapist focuses on proper alignment of the segments, especially if the patient has difficulty in maintaining it, in a way that no movement compensations are allowed. During weight-bearing exercises, additional care is taken to maintain proper foot support: the toes should always touch the floor, avoiding hammering or clawing when possible, and the ankle should not be laterally tilted (with lateral deviations). Thus, self-perception of the foot and ankle position is stimulated even during the most challenging tasks.
The discontinuation criteria for the exercises during one session are cramps, moderate to intense pain, fatigue, dizziness, fear, or any other condition that exposes the patient to any kind of risk or discomfort.
Sample size and statistical analysis
The sample size calculation was made using an effect size of 0.36 (moderate effect size), considering the primary outcome measure of peak plantar pressure. We took the SD estimates from a study we completed, wherein we recruited a similar patient cohort [71
]. A sample size of 46 subjects is needed to provide 81% power to detect a moderate effect difference between the highest and lowest group pressure means, assuming an alpha level of 0.05 and an statistical design of F test of repeated measures (between and within effects), and assuming a 10% loss to follow-up. The statistical analysis will be based on intention-to-treat analysis, and general linear models of analysis of variance for repeated measure will be used to detect treatment-time interactions. The outcome measures will be compared among baseline, 12 weeks, and 24 weeks. Cross-correlation analysis will also be provided between primary and secondary variables if it shows any relevance.
Ethics and data security
This trial was approved by the Ethics Committee of the School of Medicine of the University of São Paulo (Protocol number 054/10). All the patients will be asked for written informed consent according to the standard forms.