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Over an extended period of time, this type of repetitive injury results in inflammation, focal tissue ischemia, necrosis, and ulceration. As lower-extremity protective sensation is compromised in diabetic patients with peripheral sensory neuropathy, this process usually develops and progresses unrecognized.
There is currently no effective treatment to reverse loss of protective sensation secondary to diabetic peripheral neuropathy, therefore, any treatment and prevention scheme must concentrate on alleviation of plantar foot pressure. Historically, this has been achieved using 2 basic methods—either externally or internally. External accommodation may take the form of orthoses, casting, prescriptive footwear, or padding. Internal accommodation may be achieved surgically by either removing foci of stress or altering vectors of force through osteotomies or tendon balancing.
Unfortunately, neither of these methods is ideal. External accommodation requires a high level of compliance by the patient to wear his/her protective device and by the physician to change the device as it loses its pressure-reducing properties. Surgical accommodation carries with it all of the potential complications of invasive care.
Although the previously discussed modalities are currently the most widely used in diabetic foot care, an additional invasive technique of pressure reduction has recently received some attention in the literature. Injected liquid silicone (ILS) has been used for nearly 4 decades at 1 center with a high level of anecdotal success and minimal side effects.
reported on the results of the first randomized controlled trial that corroborated past anecdotal reports, suggesting that peak plantar pressures and plantar tissue thickness could be favorably affected by the use of small amounts of ILS over the course of 1 year. However, to date, there are no reports in the literature describing the ability of ILS to reduce pressure and to augment tissue thickness over a longer period. Therefore, this study sought to assess these parameters in patients of the aforementioned study followed over a 24-month period.
The local ethics committee approved the study. All subjects received full information about the study before giving signed consent.
Most of these methods have been described in a previous, 12-month randomized controlled trial report of ILS.
Briefly, 28 diabetic patients attending the Manchester Diabetic Foot Clinic were enrolled for the study. Inclusion criteria were established neuropathy (vibration perception threshold [VPT] >25V or a Neuropathy Disability Score >6)
and the presence of callus under at least 1 metatarsal head. Patients with peripheral vascular disease (absence of more than 1 foot pulse in both feet or an Ankle Brachial Index score <0.9) and with an active or previous ulcer in the past 6 months were not selected for the study.
The patients were randomized to active (silicone) treatment (n=14) or to equal amounts of placebo (saline) treatment (n= 14). Areas of injection were chosen under metatarsal head sites with callus or widened skin striae (indicating a pressure area) or at sites with high plantar pressure. Eight subjects in the active treatment group and 7 patients in the placebo treatment group had a history of ulceration at the start of the study.
All subjects underwent a neuropathic and vascular baseline investigation using the aforementioned criteria. The plantar pressure and tissue thickness were assessed at the injection sites after callus was débrided.
Patients received 6 injections at 2 weekly intervals and were seen for follow-up assessments at 3, 6, and 12 months after first injection. At 24 months postinjection, 16 of the original group of 28 patients were seen again for another follow-up visit. Throughout the first year of the study, the patients were treated by the same study podiatrist, after which they went back to their local foot care clinic. All patients in the study continued to receive the same treatment as is offered to all patients at high risk of foot ulceration, including receiving specialist footwear and regular podiatry treatment. Patients were dispensed different footwear as per individual consultation.
Dynamic plantar pressures were measured during barefoot walking using the Optical Pedobarograph.
A minimum of 5 steps was measured for each foot, depending on the patients' balance. Any steps regarded as atypical or out of balance during data collection, as judged by the investigator, were not saved and thus not used for analysis. Peak pressures were analysed for each area of injection and were averaged over the number of steps measured. Although peak pressure is the only pressure parameter that has been reported to be predictive for foot ulceration,
peak pressure time integrals (PTIs) were also analyzed because this parameter incorporates the time that high pressure is applied to a site, which may be an even more important factor than the height of peak pressure alone. PTI was calculated as the area under the pressure build-up curve at each injected metatarsal head. This curve represents the maximum pressure within the area of interest at each point in time during stance. The pressure measurement was standardized for each patient in such a way that at each follow-up visit the pressure was measured during the same step after initiation of gait (second or third step for all subjects). Data from our laboratory showed a coefficient of variation (CV) for peak pressure between 8.0% at the first metatarsal head and 20.6% at the fifth metatarsal head.
The plantar tissue thickness was measured with weight bearing at each injected site using the Planscan.
The Planscan is a scanning platform, which holds a high-resolution probe. The ATL Utramark 9 Ultrasound scannerb with a 5-MHz linear array transducer was used for the assessment. The subjects stood barefoot on the plastic barrier of the scanning platform with an ultrasound probe located underneath the upper surface. The metatarsal head of interest was positioned directly above the transducer, and the distance between the most prominent part of the metatarsal head and the skin was determined as the plantar tissue thickness. Three measurements were obtained and averaged for subsequent analysis. The Planscan CV for measuring plantar tissue thickness was less than 8%, which indicates, on average, a variation of less than 0.7mm. (The average plantar tissue baseline thickness of the placebo group was 8.46mm.)
All outcome measurements during the first year of the study were performed completely blinded to the treatment regimen. All follow-up measurements, including the 24-month visit were carried out without knowledge of results from previous visits.
Patients were randomized according to a random number sequence. All investigators and patients were blinded to the treatment regimen throughout the study, with the exception of the podiatrist administering the injections, who did not participate in any of the assessments or analyses. A total of 6 injections were given per site at 2 weekly intervals. Between 1 and 5 sites were selected for injection, depending on the number of callus sites. Thus, each patient received a total of between 6 and 30 injections. The volume of silicone or saline per injection was 0.2mL for each site; the total maximum volume injected was 1.2mL per injection site. The total volume injected was divided into 6 injections to increase the cushioning effect of silicone and to decrease the possibility of fluid migration by allowing the tissue to respond to the injection by imbedding the silicone in a web of collagen fibers.
An area with previous ulceration was only chosen for injection when it had been healed for a minimum of 6 months. Before injection, all areas to be injected were débrided of callus and were cleaned using a 70% isopropyl alcohol wipe. A skin refrigerant (fluroethyl) was sprayed over the site of injection for 2 to 3 seconds before injection. Local anaesthesia (mepivicaine 3%) was used if needed. A disposable luer-lock syringe and a 25-gauge 1- or 1.5-in needle were used for injection. A needle guide was attached to the syringe to assist in a more precise injection. The liquid silicone or saline was implanted subcutaneously in equal amounts beneath and within 1 to 2mm of the central point of callus.
After injections, the sites were covered with a sterile adhesive bandage, and the patient was advised to keep the area dry for 24 hours and to check the site for any signs of inflammation or infection. Patients were allowed to resume regular activities immediately after injection.
Calculations and statistical analysis
The change from baseline was used for data analysis of the plantar tissue thickness and pressures to eliminate the effect of natural differences in baseline plantar thickness and pressure at different sites. Data are presented as mean ± standard deviation (SD). The change in the plantar pressure variables (peak pressure, PTI) and tissue thickness per injected site was averaged over the total of number of injected sites per patient, as treatment was randomized per patient and not per injection site. The average change per patient was then used for further analysis by using the Wilcoxon nonparametric test for paired samples to assess differences from baseline in both treatment groups at each follow-up visit, using each patient as his/her own control.
Twelve patients were not available for follow-up at the 2-year interval. These included 9 placebo and 3 silicone patients. Reasons for inability to follow-up included death of the patient (n=1), inability or unwillingness to travel to the gait laboratory (n=4), active ulcers (n=3), patient unwell at time of follow-up (n=2), and lost to follow-up (n=2). This left a total of 16 patients (11 active, 5 placebo) to evaluate at the 2-year interval. By using a repeat-measures design, a difference of 25% in peak plantar pressure could be detected with a sample size of 4 in 1 arm and 7 in the other, with a power exceeding 84%. The sample size was therefore adequate to continue with analysis.
Thus, up to 1-year follow-up data will be presented of all 28 patients included in the study and 2-year data of the 16 patients who were available at that time.
Descriptive characteristics of the study population are detailed in table 1.
1Table 1: Characteristics of the subjects assessed at the 24-month follow-up
There was no significant difference in age, duration of diabetes, level of glucose control, or severity of neuropathy (VPT) between the groups evaluated. There was a nonsignificant difference in average baseline plantar tissue thickness between the silicone-treated group (6.7±2.1mm) compared with the placebo group (8.5±2.6mm) (P=.06). The different number of first and fifth metatarsal heads chosen as injection sites caused the difference in thickness, because the tissue thickness decreases toward the lateral metatarsal heads.
The ratio of first to fifth metatarsal head injection sites was 7/12 for the silicone group and 11/7 for the placebo group. This tissue thickness difference did not influence the results, because the change from baseline was used for all analyses.
At 12 months, the plantar tissue thickness had increased by a mean of 1.6±0.9mm (P=.001) in the silicone group compared with baseline. The placebo group showed no significant change in thickness (.30±.70mm, P=.22) (fig 1).Peak plantar pressures remained significantly lower (compared with baseline) at 1 year after injection in the silicone group (−165.0±253.5kPa, P=.03). There was, however, no difference in plantar pressures in the placebo group 1 year postinjection (76.6±183.5kPa, P=.14) (fig 2).
At 24 months, 16 patients were reassessed. The plantar tissue thickness was still increased in the silicone patients (1.1±0.7mm, P=.003) and there was no difference from baseline in the placebo group (−0.1±0.6mm, P=.34) (fig 1). However, no significant change was realized in plantar pressure in either the silicone- (−23.5±51.7kPa, P=.86) or placebo-treated patients (36.9±275.2kPa, P=.89) (fig 2).
The PTI had decreased at 12 months postinjection by −.71±1.17kPa/s (P=.055) in the silicone-treated patients, whereas there was a nonsignificant increase of .44±.72kPa/s in the placebo-treated group (P=.086). At 24 months, the PTI did not differ from baseline in the silicone-treated patients (−.24±1.22kPa/s, P=.859), whereas there was a significant increase in the placebo-treated patients (.64±.37kPa/s, P= .043). Figure 3 shows the change in PTI from baseline averaged per patient for the silicone- and placebo-treated group.The greatest reduction from baseline for the silicone-treated group was observed at the 3-month follow-up. In addition, the graphs clearly show a continuous increase of PTI after the 3-month follow-up visit for both treatment groups.
Seven patients developed foot ulcers during the first year of the study. Three placebo- and 3 silicone-treated patients developed ulcers at noninjected sites (at toes, interdigital, toenail, heel, Achilles' tendon), while 1 placebo-treated patient developed an ulcer at an injection site. Two patients from the placebo group developed unrelated diseases (cerebrovascular accident, malignancy). In the second year of the study, 11 patients developed 23 ulcers. Nine placebo patients developed 2 ulcers at injected sites and 13 at noninjected sites (all at toes). Two silicone-treated patients developed 3 ulcers at injection sites, of which 1 was caused by a nail puncture through the sole of the shoe, and 5 at noninjected sites (toes, metatarsal heads). No clinical evidence of any migration of injected silicone was observed throughout the study. All patients included in this trial were at high risk of foot ulceration as defined in the Methods section, therefore, ulcer development during the study had been anticipated.
The results of this study suggest that ILS may reduce peak plantar pressure and increase plantar tissue thickness over at least a 1-year period after initial administration. However, after 2 years, the ability of silicone to sustain its optimal plantar pressure reduction capacity appears to deteriorate. This would suggest that booster injections of liquid silicone might be required periodically to improve subcutaneous tissue cushioning in certain high-risk feet.
No significant side effects were reported, and only minimal side effects have been reported by Balkin and Kaplan.
however, this was only observed in early cases when larger volumes were injected per single callus (>3.0mL): no such migration was seen in any of our study patients. For a lasting effect of the increased subcutaneous cushioning and prevention of migration of the ILS, it has been advised to inject small amounts of the silicone repeatedly, as opposed to larger amounts less frequently.
No infection, rejection, inflammation, or allergic reaction has been reported. Histopathology has shown that the silicone fluid is well retained where injected by essential noninflammatory tissue responses and has confirmed that medical-quality ILS in the foot is a safe procedure.
One potential problem with the present protocol involves the volume of silicone injected. As is mentioned in the Methods, a very small, standardized amount (maximum total volume per injection site, 1.2mL) of ILS was used. Previous surveys of patients receiving this modality have injected differing volumes based on parameters requiring clinical judgment (eg, site and severity of deformity, patient morphology, amount of pretreatment callus).
It may be postulated that not tailoring the amount injected (within certain volumetric parameters) may have adversely effected the follow-up at 2 years. Clearly, this is a subject that calls for further investigation.
The observation that PTI continued to rise in both the silicone- and placebo-treated group after the 3-month follow-up visit raises some interesting questions. Comparison of Fig. 2, Fig. 3 indicates that while peak pressure did not change from baseline for the placebo group, this is clearly not the case for the PTI. Although the PTI continued to rise after the first follow-up visit in the silicone-treated group, it never increased above baseline values. Whereas in the placebo-treated group, the PTI kept increasing from baseline measurements until it reached significance at the 2-year follow-up, suggesting that at this time the injected silicone was still exhibiting some cushioning properties. In addition, the continuous rise in PTI over time suggests that this is an important pressure variable to measure in high-risk patients.
Although plantar tissue thickness was increased even at 24 months in the silicone-treated group, there was clearly some reduction of the plantar tissue thickness augmentation immediately postinjection (ie, at 3- and 6-mo follow-up). This implies some movement of some of the small amount of silicone away from the area beneath the weight-bearing metatarsal. Although not noted macroscopically, it is possible that tiny silicone droplets, which are phagocytized and take up residence within phagolysosomes of macrophages, may migrate some distance away from the area, asymptomatically taking up residence either in the deeper tissues or in regional lymph nodes.
In this case, it is also possible that some of the injected silicone diffused over a wider area under the metatarsal head.
The mechanical etiology of tissue breakdown in the neuropathic foot can be divided into 3 main mechanisms. All 3 have in common the main offending factor—excessive or repetitive pressure—but differ in the duration, frequency, and amount of pressure applied to the tissue. The mechanisms include a single, high-force that acts for a short time period, causing direct mechanical disruption of tissue (eg, a nail puncturing the skin); increased duration of relatively low pressure caused by foot deformities and/or tight fitting shoes resulting in focal ischemia and skin breakdown; and, third, repetitive moderate pressure leading to inflammation and ulceration (eg, walking on an unprotected neuropathic foot leading to skin break down beneath a prominent metatarsal head). This mechanism is directly equivalent to any other type of materials testing, because cyclic loading is the most common precipitating factor in failure of materials. This phenomenon, called mechanical fatigue in engineering terms, is defined as a failure of a structure or biologic tissue at a submaximal level to maintain integrity because of repeated cycles of loading. Both the second and third mechanisms of tissue injury described previously are probably the most common etiology of the plantar diabetic foot ulcer.
These mechanisms are related to a few other factors, including foot deformity, severe limited joint mobility, reduced plantar tissue thickness, and altered soft tissue characteristics; this in turn leads to increased plantar foot pressures and increased susceptibility to tissue breakdown.
It would stand to reason that reducing peak plantar pressure by using ILS would increase the cycles of stress it would take to cause diabetic foot ulceration.
It appears that, although ILS is helpful in reducing pressures and increasing protective plantar tissue thickness, repeat injections might be necessary on an annual basis to maximize protection of high-pressure areas. Larger, multicenter studies are now required to confirm this observation and to answer whether ILS can reduce foot ulceration. In addition, using a more individualized approach to the volume of ILS at each treatment site may improve outcomes further and potentially reduce risk factors associated with ulceration and, ultimately, amputation.