The Impact of HbA1c Levels on Diabetic Foot Ulcers Using Fish Skin Grafts
Abstract Introduction
This is a retrospective review that explores the effect of hemoglobin A1C (HbA1c) levels on diabetic foot ulcer (DFU) healing in type II diabetes mellitus (DMII) patients. There is currently conflicting evidence as to whether HbA1c levels influence wound healing rate and there are no studies on the association of HbA1c levels with acellular fish skin (AFS) treatment for DFU.
Methods
This study reviewed 20 cases of chronic DFUs (defined as DFUs that did not show improvement after 30 days of standard of care (SOC) treatment). Patients were treated with AFS once a week for 4 weeks, and the wound size was recorded at the beginning and end of this process. Patients were broken into two groups, each consisting of 10 patients. One group were patients with HbA1c levels between 6 - 8, while the other group consisted of patients with HbA1c levels between 8 - 10.
Results
The group with HbA1c 6 - 8 showed an average of -41.30% decrease in wound size. The HbA1c 8-10 group had an average of -30.41% decrease. After performing an independent t-test, t-value: -0.56, p-value: 0.299, p>0.05. HbA1c levels do not have a statistically significant effect on wound healing time.
Conclusion
This study confirms that fish skin grafts are an effective form of wound care treatment. It further proves that despite uncontrolled HbA1c, fish skin treatment remains effective, as HbA1c is not a factor in healing rate.
Introduction
According to the Centers for Disease Control and Prevention (CDC) more than 37 million Americans have diabetes, and 90 - 95% of them have type II diabetes mellitus (DMII). One of the key areas of morbidity associated with diabetes mellitus is the diabetic foot. 15 - 25% of patients with diabetes will develop a diabetic foot ulcer (DFU) within their lifetime, accounting for a total of 9.1 to 26.1 million DFU cases worldwide.1 DFU has become one of the leading causes of limb loss as it is associated with more than 80% of diabetes-related lower extremity amputations. Additionally, the combination of high blood sugar, poor blood circulation and immune system deficiencies that diabetic patients experience increase the risk for wounds and subsequently poor wound healing.2
Hemoglobin A1C (HbA1C) measures the blood glucose levels in diabetic patients and is a standard test to monitor glycemia. Hb1AC reflects glycemia over 2 - 3 months. When hemoglobin is
Shenmei Wu University of Nevada, Las Vegas Las Vegas NV, United States Dr Ryan Huang Teaching Faculty, Valley Hospital Medical Center Residency Program Adjunct Professor, Touro University Nevada Las Vegas NV, United Statesglycated, there is the formation of advanced glycation end products (AGEs).3 AGEs have a high affinity for RAGE (receptor for advanced glycation end products), which have been shown to induce proinflammatory pathways.4 However, there has been conflicting evidence whether HbA1c levels affect wound healing rate in diabetic wounds. While some studies claim that the increase in HbA1c decreases healing time,5 others said the association remained unclear.6
We define a chronic DFU as one that did not show improvement after 30 days of standard of care (SOC) treatment. Once the ulcers are not healed, they may become infected and lead to amputation. Current SOC for DFU includes five principles:
1. Pressure relief 2. Debridement 3. Dressing to facilitate moist wound environment
4. Infection management
5. Treatment of arterial insufficiency7,8,9
In addition to those principles, the Society for Vascular Surgery has recommended adequate glycemic control of Hb1AC less than 7% to reduce the incidence of DFU and infections.10
The use of skin substitutes has been considered as advanced treatment for chronic, nonhealing DFU. Skin substitutes are used to cover the open chronic ulcers, create an optimal environment for the patient’s own cells to migrate into, proliferate, revascularize and promote wound healing. Among many commercially available skin substitutes originated from highly processed human and animal tissues, AFS is a recent, innovative addition. AFS is made from North Atlantic cod fish that are wildly caught in the pristine waters of Iceland. Since there is no disease transmission risk from cod fish to humans, the graft is subjected to a gentle, minimally processed manufacturing procedure
to remove cellular components while still retaining the structural integrity and bioactive compounds of the fish skin. Particularly, AFS contains a rich amount of Omega3 fatty acids that are uniquely high in docosahexaenoic acid (DHA) and eicosatetraenoic acid (EPA).11
AFS has been proven to be more effective at healing DFUs compared to the standard of treatment;12,13,14 the authors concluded that AFS was able to drive the DFU from a chronic phase into an acute wound due to its porous, homologous structure to human skin and rich omega-3 fatty acids source.
The application of advanced treatments for chronic DFU such as skin substitutes is often delayed until patients get their HbA1C level under control, as required by insurance companies to receive coverage. This process can be lengthy as blood glucose takes time to improve. It involves diet, exercise, weight loss, medication and stress management. For patients with open DFU, the delay in treatment until adequate HbA1C levels are reached can worsen the wound and expose it to a higher risk of infection. There is no evidence as to whether HbA1C interferes with a skin substitute treatment for DFU, especially with AFS. Our objective is to identify the impact of HbA1C levels in chronic DFU treated with AFS in the lower extremities, in patients with DMII.
Methods
Patients or Study Population
Patient charts from Professional Wound Specialists (PWS) reviewed data from 20152021. The place of care varies from facilities, to office, to home health care. This study reviewed de-identified data of patients with DMII and chronic DFU treated by practitioners from PWS, that were treated with AFS. Exclusion criteria included patients whose wounds healed prior to four applications, expired patients, and non-compliant patients. With a total population
“With a total population of 20 patients, we created two groups of patients. One with relatively controlled HbA1c levels. between 6-8. The other group consisted of patients with HbA1c levels between 8-10. Each group consisted of 10 patients.”
of 20 patients, we created two groups of patients; one with relatively controlled HbA1c levels between 6 - 8, the other with HbA1c levels between 8 - 10. Each group consisted of 10 patients.
Clinical Information/ Data Gathered
Patients’ HbA1c levels were measured within the first 3 months of their first treatment. If the levels was not obtained from the primary care physician, then they were obtained by PWS prior to the study. The patient’s chronic DFU was treated once a week using the PWS treatment standard (see next section). Wound sizes were measured before the first treatment and after 4 treatments, over a 4-week time period. Demographic information recorded includes gender and age.
Treatment
The DFU wound bed was first prepared with a wound cleanser. Afterwards, a curette was used to stimulate the wound bed, as well as removing any bioburden. AFS was then rehydrated with normal saline and placed on the wound bed with the scale side facing away from the wound bed. A mesh was then placed and secured with steristrips. Finally, an outer dressing was placed over the wound. Treatment was performed on a weekly basis.
Results
“The average age was 77 years old in HbA1C 6-8 patient group with 6 females and 4 males. For HbA1C >8 patient group, the average age was 70 years old with 3 females and 7 males.” Table 1: Patient demographics. Wound Masterclass - Vol 1 - September 2022 65
The Impact of HbA1c Levels on Diabetic Foot Ulcers Using Fish Skin Grafts
The average starting size for HbA1C 6 - 8 was 15.33 cm2 and was reduced to 8.46 cm2, which is a 41.3% reduction in wound size. The HbA1C average was 6.86. For the HbA1C >8 patient group, the average week 1 size was 12.17 cm2 and was reduced to 7.6 cm2, with a 30.4% reduction rate.
Table 2: Wound size change.
The average HbA1C level in this group was 8.92. Overall, the combined average wound size was 16.81 cm2 and was reduced to 10.96 cm2. This was a 36% reduction in size with an average HgA1C of 7.9. See Table 2.
Patient Week 1 Week 5 HbA1c % size change
1 8 7.41 6.2 -7 2 16.66 13.2 6.3 -21 3 20 3 6.5 -85 4 6.72 1.56 6.6 -77 5 10 7.92 6.8 -21 6 72.25 64 7.1 -11 7 40 24.57 7.2 -39 8 15.75 8.68 7.3 -45 9 16 7.56 7.4 -53 10 4.84 2.25 7.4 -54 Average 15.33 8.46 6.86 -41.30% SD 10.6 7.07 0.48 26.00% HbA1c >8
HbA1C 6-8
11 15 10.14 8.2 -32 12 4.5 2.1 8.4 -53 13 28 2.86 8.5 -90 14 9 1 8.8 -89 15 21.6 9.3 8.8 -57 16 17.48 29.07 8.9 66 17 2.25 0.9 9.1 -60 18 4 3.6 9.1 -10 19 14.88 9 9.6 -40 20 5 8.06 9.9 61 Average 12.17 7.6 8.92 -30.40 SD 8.62 8.39 0.53 55.01 Total Average 16.81 10.96 7.9 -36.00 Total SD 15.64 14.27 1.98 44%
The Impact of HbA1c Levels on Diabetic Foot Ulcers
“The average wound size reduction rate was at 41.3% for the lower HbA1c level group and 30.4% for the higher HbA1c level group... The study findings support that AFS is an effective treatment for chronic DFU regardless of HbA1c level.”
Figure 1: Comparison of HbA1c levels between the two groups. Comparing the two group’s wound size reduction rate (41.3% vs 30.4%), there is no statistical significance between them.
Discussion
Our study reviewed 20 patients with DFU who received treatment with AFS. According to our analysis, there is no correlation between HbA1c levels from two groups with their wound size reduction rate. The baseline HbA1c levels were not associated with ulcer healing. The average wound size reduction rate was at 41.3% for the lower HbA1c level group and 30.4% for the higher HbA1c level group.
This result is consistent with previous literature indicating that baseline HbA1c is not associated with lower extremity wound healing in patients with diabetes. Fesseha et al. proposed a model in which HbA1c was divided into <6.5%, 6.5-8% and >8%, and found no relationship between initial blood glucose level and healing rate.15 Margolis et al. pooled over 586 patients with DMII who had neuropathic DFUs, to predict the risk factors that affect the healing rate, and found HbA1c levels measured at the start of the study were not associated with the probability of wound healing.16 Xiang et al. also found similar results where there were no differences in wound healing rate among groups with different baselines HbA1c levels.17
Conclusion
Advanced biologic therapeutics for DFUs is often delayed while HbA1c levels are corrected because it is believed that the wound will not respond while the HbA1c is elevated. This delay in treatment can lead to deterioration in the wound for several weeks and leave the open wound at risk of infection. The study findings support that AFS is an effective treatment for chronic DFU, regardless of HbA1c level. The use of skin substitutes, especially those that are proven to respond to the ulcers, should be recommended as the primary treatment for DFU.
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September - October 2022
