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Low Energy Laser as a Treatment for Refractory Diabetic Leg Ulcers

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Low Energy Laser as a Treatment for Refractory Diabetic Leg Ulcers

By Wendy Price
Wake Forest University
Department of Physician Assistant Studies
4/10/2009

I would like to thank everyone at Coy C. Carpenter library help and reference desks. To Ekatrina Zachry who translated the Russian research papers, thank you is the very least I can say for such an excellent job.
I would like to tell my girls how proud I am of them and thank them for their patience, pictures, and prayers. You make it all worth the while. I would also like to thank my mother for her support, coming to help with the girls while I have been in school, and her motherly faith in me that never waivers.
Most of all I want to thank my husband Clay Price for being an amazing pillar of strength, encouragement, patience, understanding, and love. I know I COULD NOT have done it without you. UA&F

Low Energy Laser as a Treatment for Refractory Diabetic Leg and Foot Ulcers

ABSTRACT

BACKGROUND: Diabetic leg and foot ulcers often lead to immobility, infection, and amputation, cost $7,000 to $40,000 per ulcer, and erode mental health and QOL. Lasers have been effectively utilized in medicine since the 60’s, from various surgical uses to the treatment of diseases. Although low-energy (also called low-power, low-level, and cold) laser therapy for “biostimulation” (or biomodulation) of ulcer healing has been studied extensively, quality data on diabetic wound healing is rare. This review seeks to evaluate the efficacy of laser therapy as an adjunct in healing of recalcitrant diabetic ulcers.
METHODS: Literature review and statistical analysis using RRR, NNT, d, t, r2, and fail-safe calculations.
RESULTS: Six studies with 6 probabilty scores met the inclusion and exclusion criteria. They showed an overall mean RRR of 86% (CI .21-.33). Four of the studies, totaling 8 effect sizes, were analyzed. The overall mean effect of laser therapy on diabetic ulcers from these studies was highly significant (d= 2.4). The studies analyzed for probability of healing resulted in an overall mean Numbers Needed to Treat (NNT) of 7.1. The studies analyzed for risk reduction yielded a Fail-Safe number of 44.
CONCLUSION: Low-level laser therapy reduces the risk of chronic ulceration and is a highly effective adjunctive treatment for healing recalcitrant diabetic leg and foot ulcers.

BACKGROUND: Diabetic lower extremity ulcers can lead to immobility, infection, and amputation, cost $7,000 to $45,000 per ulcer, and erode mental health and QOL. Lasers have been effectively utilized in medicine since the 60’s, from various surgical uses to the treatment of diseases like psoriasis. Although low-energy (also called low-power, low-level, and cold) laser therapy for biostimulation of ulcer healing has been studied extensively, quality data on diabetic wound healing is rare. This review seeks to evaluate the efficacy of laser therapy as an adjunct in healing of recalcitrant diabetic lower leg and foot ulcers.
METHODS: Literature review and general statistical analysis of RR (95% CI) and effect size (Cohen’s d), with NNT and fail-safe calculations reported to make the data more clinically applicable.
RESULTS: Six studies with 6 probabilty scores met the inclusion and exclusion criteria. They showed an overall mean RR of .27 (.21-.33) when examining the outcome of percent of the population healed with laser plus the standard of care as compared to just standard of care. These studies analyzing the probability of healing with laser plus standard of care resulted in an overall mean Numbers Needed to Treat (NNT) of 7.6. Four of the studies, totaling 8 effect sizes, were analyzed for mean healing time. The overall mean effect of laser therapy on diabetic ulcers from these studies was highly significant (d= 2.4, p<0.0001). . The studies analyzed for risk reduction yielded a Fail-Safe number of 44.
CONCLUSION: Low-level laser therapy reduces the risk of chronic ulceration and is a highly effective adjunctive treatment for healing recalcitrant diabetic leg and foot ulcers.

INTRODUCTION:
Case:
A 52 yo male schizophrenic with diabetic foot ulcer was transferred by a general surgeon of the VA hospital, where he was a psych ward resident, to a cardiovascular surgeon at a larger hospital. The patient had been scheduled for lower extremity revascularization on his left leg but had unstable vital signs and arrhythmias during preoperative evaluation before transfer. Patient has a history of DMII x 10 years, with prior incidence of foot and leg ulcers. Patient complained of 10/10 pain in surrounding area, which had been getting worse since its onset several months ago. He stated he hasn’t been staying off it as he was told. Admitted to numbness and tingling in his feet. Denied fever or chills. Patient admitted to occassional palpitations and shortness of breath. Patient stated he wakes 3 times at night to urinate. Meds: Metformin 200mg BID, Amaryl 4 mg BID, and is uncertain of psych meds. Patient had 25 pack-year history of smoking. BP on admission 148/98, HbA1c 8.5, and SBG 150. EKG showed pt. was in asymptomatic a fib. Doppler pulses confirmed weak pedal pulses on the left. ABI showed reduced pedal pressures. MRI revealed no osteomyelitis. A&P: Diabetic patient with neuropathy and PVD presented with advanced stage diabetic foot ulcer. Patient would benefit from revascularization but was a poor surgical candidate. Other options needed to be explored for healing his ulcer as quickly as possible to avoid infection and possible amputation.

BACKGROUND: According to the World Health Organization the number of people suffering from Diabetes Mellitus (DM) will be about 250 million by the year 2050. Around 15% of this population will have a foot ulcer at some point and these patients have a 22-fold higher risk of getting a non-traumatic foot amputation. The baseline cost of each ulcer ranging from $7,000 to $45,000 per ulcer depending on the types of treatment. This variation in cost results from the fact that 15-25% of diabetics foot ulcers will not respond to the standard of wound care and require surgical intervention, including amputation. The overall cost of amputation, including the cost of invalidity were estimated at $1,000,000 per patient. Diabetics fear immobility, infection, and amputation. Diabetics with ulcers are more depressed than those without. When considering all these costs it seems worth investigating any therapies between the standard of care (SOC) and amputation.
To consider alternatives it is necessary to understand what must be affected in diabetic patients to improve on their healing. On the most basic level an ulcer is simply “a lesion through the skin or a mucous membrane resulting from loss of tissue, usually with inflammation. The Wound Healing Society defines a chronic wound as one that fails to go through “an orderly and timely reparative process to establish sustained anatomic and functional integrity”. A chronic ulcer is chronologically defined as one that has not healed in 30 days with treatment. However, a diabetic ulcer is not considered chronic until 20 weeks of non-healing with therapy. The difference in diabetics lies in the molecular mechanisms of healing, and impediments that occur in diabetics specifically. Healing usually occurs as a smooth transition between the stages of hemostasis, inflammation, proliferation, and remodeling.
Diabetics are prone to foot ulcers through multiple etiologies, including sensory, motor, and autonomic neuropathies, vascular insufficiencies, and immunocompromise. First, neuropathies result in loss of protective foot sensations that make them more apt for injury and less apt to properly respond to an injury. Yet, neuropathy is not just sensory, it can also be motor neuropathy and autonomic neuropathy. Motor neuropathy leads to inactivity and atrophy of muscles, resulting in foot deformities like clawed toes, bunions, and Charcot’s foot. These deformities lend themselves to minor trauma from increased pressures over bony prominences, hence pressure/decubitus ulcers form. Autonomic neuropathy leads to microneurovascular basal motor disturbances, endothelial dysfunction, and lack anhidrosis (leading to drying and cracking). Secondly, diabetics have a tendency toward vascular insufficiency, leading to poor circulation and ischemia. This may be part of the mechanisms described above or due to increased atherosclerosis in this population (PAD). Third, diabetics are immunocompromised leading to poor healing. Leukocyte/neutrophil function is impaired leading to impaired bacterial killing, phagocytosis of dead tissue, and chemotaxis of immune and healing factors. Diabetics have decreased amounts of growth factors needed for healing. Diabetics are also being studied for complications with chemotaxis and errors in migration of elements of healing like granulocytes, fibroblasts, and myofibroblasts. There is also an inability of collagen to accumulate or be broken down. The overall result is delayed wound contraction and closure. In addition, the high degree of glycosylation is theorized to limit joint mobility leading to irregular pressures as well. Diabetic foot wounds that do not respond to the standard of care within 20 weeks are generally considered refractory. Standard of care in the US, similar to other countries , for treating DM leg and foot ulcers is treatment of infection, offloading, protection through dressings and medications, debridement, managing comorbidities such as DM, and surgical interventions like revascularization or amputation. Other adjuncts are being explored because clearly the standard of care is not sufficient, when one considers the monetary as well as mental health costs. One of these adjuncts includes the use of light therapy known as low-level, low-power, low-intensity, or low-energy laser therapy.
The use of laser irradiation for ablative purposes is common in medicine in the US. The technological push is now for less ablative and less invasive technology, generally referred to as phototherapy. Unlike lasers used in surgery, low energy lasers are non-ablative, and do not cause a significant rise in temperature of the skin. Yet little is known in about the ability of lasers at lower intensities to biomodulate cellular function. In fact, biomodulation of cell function, or phototherapy, may sound like science fiction to most in the US. Yet, logically we know that cells, like retinal and epithelial cells, as well as other molecules in the body react to light forms of electromagnetic radiation with a photochemical response. This understanding has been applied to the treatment of sleep disorders, depression, acne, eczema, jaundice, Vitamin D deficiency and psoriasis. The exact effector molecules and pathways for many of these therapies are currently being described through human in vitro research. Some mechanisms for laser biostimulation being studied are increase in metabolic activity of cells by effecting ATP, DNA, or mitochondria (chromophores), and biostimulation of healing factors like monocytes and fibroblasts. Others studies have focused on keratinocytes, macrophages, RNA synthesis, granule release, membrane potential, neurotransmitter release, phagocytosis, and prostaglandin synthesis.

“The main absorbers in tissue are, as mentioned, nucleic acids, proteins and aromatic molecules in the UV, melanin and heme proteins in the visible range and water in the infrared range, i.e. that of Er-YAG or CO2 laser.” “Unlike the higher powered lasers employed in medicine, these low level lasers do not deliver enough power to damage tissue, but they do deliver enough energy to stimulate a response from the body tissues to initiate healing. Laser radiation has a wavelength-dependent capability to alter cellular behavior in the absence of significant heating. Light radiation must be absorbed to provide a biological response. The visible red and infrared portions of the spectrum have been shown to have highly absorbent and unique therapeutic effects in living tissues.”

Considering that laser is simply monochromatic light that is focused to have characteristics indicative of lasers, which are coherence and parallelity, brings the science fiction argument back to a reality. “Laser therapy” originated during a study by Mester in the 1960’s, where he noticed at low dosages (J/cm2) an increase hair growth occurred in mice. Laser is currently used around the world on a large variety of ailments for its biostimulatory effects , yet it is held at the level of science fiction in this country because of lack of strong clinical trials to prove its efficacy and safety. The difficulty lies in the plethora of laser types and parameters, as well as variety in pathogenesis of ulcers. Although HeNe lasers seem most commonly used nowadays, others include Nd:YAG, ruby, GaAs, CO2, and argon. Essential parameters of lasers that can be varied between studies include wavelength, frequency, power output, spot diameter, irradiation time, intensity, dose, and treatment intervals. With all this variability strong consistent data is hard to find surrounding one ulcer etiology such as diabetic foot ulcers. OBJECTIVE: Therefore the objective of this review paper is to assess the effectiveness of low-level laser therapy in healing diabetic leg and foot ulcers that have failed therapy with the standard of care alone.

METHODS: A literature review of original research was undertaken Cochrane Library (all Chochrane products), CINAHL (Citation Index for Nursing and Allied Health Literature) –through EBSCOhost, OVID, PUBMED, Inspec , ISI Web of Science, Academic Search Premier, and Health Source- Nursing and Academic Addition. Other search engines explored with no additional results were NLM Gateway, TRIP, Dynamed, Biomedcentral, EBM Reviews, SUMSearch, ACP Journal Club. Secondary sources of information were gathered by searching reference sections of the obtained studies and relevant review articles for further trials and reviews. The following words or phrases were used to search this topic: diabetes, diabetic, wound, ulcer, monochromatic , infrared, laser, irradiation, radiation, energy, phototherapy, light, low level, low intensity, low energy. Searches were limited to “humans” in the search engines when possible. (See APPENDIX A for detailed description of Boolean-type search terms used). Title, abstract, and full-text exhaustive searches were then undertaken using inclusion and exclusion criteria described below. Inclusion criteria were review articles, meta-analysis and clinical trials, that addressed the use of various lasers on diabetic wound healing . The primary outcome had to behealing as compared with need for surgical interventions, such amputation, to save the limb. The primary measures of this outcome needed to be objective, such as rate of change in ulcer area, time to complete healing, or the proportion of population with ulcers healed within the trial period. All dates of publication, languages, or ages of patients were included. Both type 1 and 2 diabetic (DM) patients were included. Patient had to have foot or lower leg “diabetic ulcers” and be treated with laser therapy with or without another adjunctive therapy. All low-level laser and treatment parameters were accepted for review. Exclusion criteria were pathophysiology and animal studies, as clinical relevance was key for this therapy question. Case studies were excluded as trials are most useful to answer this therapy question. Articles that did not clearly identify specific data for diabetic ulcers, although they may have been included in the study, were excluded. Non-patient oriented outcomes If data were missing no effort was made to contact authors for the missing info and these articles were excluded. Duplicate studies across all search engines were removed. See Appendix B for a summary of excluded articles. Relevance and Validity Assessment was then done with the final papers selected for review. The relevance of the studies was evaluated based on the conduct of the study and the characteristics of the patients (see Table 1). Conduct in terms of study type reported, population size, treatment type, and outcome(s) measures were compared. The validity of the studies (See Table 2) was evaluated two-fold; first with standardized study criteria for therapy research and secondly by use of Oxford Centre for Evidence-based Medicine Levels of Evidence (see Appendix E). The Level of Evidence (LOE) looks at the type of study and its quality, and gives a ranking based on a 1-5 scale with subdivisions a-c. An overall Grade of Recommendation was given for these studies, based on these levels in the range of A-D. Statistical analysis of the raw data for “percent of population healed” and “mean healing time”, measures consistently reported in all research, was undertaken to try to determine amputation risk reduction and effectiveness in terms of healing time reduction of laser therapy. The first analysis included calculations of Relative Risk (RR), with a 95% confidence (CI) interval, and Numbers Needed to Treat (NNT) for each study. RR = ER/CR
Where:
ER = Risk of non-healing in experimental group (=EC/EP)
CR = Risk of non-healing in control group (=CC/CP)
EC = Experimental Chronic Ulcer Group
EP = Experimental Population
CC = Control Chronic Ulcer Group
CP = Control Population

NNT = 1/ARR (Absolute Risk Reduction) Where: ARR = CR – ER Two assumptions were made in the Relative Risk analysis, which are based on the percent of the population healed. When the Control Population data is not available (in all but the Landau et al. 2001 study, which reported int control group size), the Control Population (PU) is calculated using insight from Mulder’s 2001 metanalysis which states,“15-20% of patients with chronic wounds do not respond to conventional therapy and may require the use of advanced therapy and may require the use of advanced technologies to stimulate and expedite tissue repair.” The original DM ulcer control population size had to be assumed based on a conservative 15% non-healing rate with SOC, as reported by Mulder 2001. The number of this control group that did not heal with SOC was then used for the next assumption of the therapy group population size. An independent measures t-test was needed to correctly determine how many would heal with SOC + laser. To do this the study group was conservatively assumed based on a 20% rate that didn’t heal with SOC for the therapy group. In both assumptions of population size (P and N) the most conservative number for SOC as supported by current data was used, either 15% or 20%. The relative risk data were then converted to NNT for each study and 95% confidence intervals for RR were calculated. In Landau et al. 2001, patients lost to follow up (14) or only treated with HBO were placed in the treatment failure group for a more conservative analysis of the effects of laser + SOC as compared with SOC alone. A second analysis was completed for the four studies (Kazemi-Khoo and 3 Landau studies) that reported “mean healing time” (as compared to the need for surgical intervention). Effect sizes (Cohen’s d) were calculated for all patients who healed with Laser + SOC + HBO as compared to just SOC.
Cohen’s d = M1 – M2 / p
Where:
M1 = Mean Healing Time of Control Group
M2 = Mean Healing Time of Experimental Group
p = Pooled Standard Deviations:pooled = [(1²+ ²) / 2]

Because the therapy group acted as their own control in these studies, the length of ulcer duration without healing was assumed as the “SOC healing time” for all studies. This assumption was conservative because it assumed healing occurred as soon as participation in the therapy group began, so the clock stopped on the “SOC healing time” early. Statistical Power and significance values (p, where  = 0.05) were also calculated for these studies. A power calculator from http://www.danielsoper.com/statcalc/calc49.aspx was used. Again the assumed population sizes were used, but according to Clay The mean rate of healing and associated standard deviations also allow for the calculation of the p-value and statistical power of each study. An overall Fail-Safe number with a statistical significance set at 0.05, was then calculated from the effect sizes. Nfs0.05 = N (d-dc)/ dc Where: N = number of studies d = average effect size of the studies dc= effect criterion value that equates to a small effect (0.2) Two studies (Schindle and Saltmarche) reported their healing times in medians and were therefore only used in the % population healed analysis, for calculations of RR (with CI) and NNT. An assumption in all calculations is that all treatment groups received standard of care. A confounding variable in some studies is that they received hyperbaric oxygen as an adjunct to laser therapy. The assumption is that, because these same studies report no significance between the effects of laser and HBO, then the effect of hyperbaric oxygen is insignificant, and there is not synergism.

RESULTS:
Literature Search strategies above yielded 169 articles. After applying the inclusion criteria to abstracts and full text, PubMed narrowed to 5, Cochrane 5, Ovid 8 , ISI 7, and EBSCOhost 7 (utilizing the “highly relevant” and “full text search” feature and reviewing the top 50 “most relevant”). Five additional articles were found from the 32 articles references as well as those of relevant review and meta-analyses articles. After applying the exclusion criteria 6 articles remained (see Appendix B for a table of excluded articles).
Article Summaries are given below. Note: Patients in these studies were not randomly assigned to treatment, rather they were referred based on relevance to the question of refractory ulcers. That is they were referred for the reason that their ulcer was refractory and needed advanced or experimental care to induce healing as compared to a population of ulcers that responded to SOC in a reasonable amount of time. This group served as its own control in the calculations, before and after laser therapy. The lack of randomization makes these “quasi-experimental” study designs. For the purpose of data analysis the population of DM patients with ulcers (PU1) was extrapolated as mentioned in Methods, from the given number of chronic ulcers (PCU) and conservative, current statistics on incidence of chronic diabetic foot ulcers after therapy with SOC. (15%) This chronic ulcer population (PCU) served as control in the analysis. A theoretical therapy population (PU2) was also extrapolated from the non-healing ulcer group in the manner described in Methods as well, this time using 20% to give more weight to SOC. The same PU value could have been used for both pretest and posttest analysis but it would not have yielded as conservative result towards laser. Using the chronic ulcer groups as their own controls (ie. By using their data on healing time and number healed before and after therapy), changed the studies into quasi-experimental “single group type” trials, known as a Nonequivalent Dependent Variables (NEDV) Design. No dosing parameters will be reported, as it was not relevant to the broad-based purpose of this paper.

Kazemi-Khoo 2006 (Iran):
OBJECTIVES: To compare low-level laser therapy (LLLT) to conventional conservative medical management on the healing of refractory diabetic foot ulcers. METHODS: Non-randomized, non-blinded, prospective case series of 7 patients with Braden Scale grades II and III diabetic foot ulcers. Ulcers had been present on average 6.9 + 0.9 months. Treatment was bed irradiation, IV irradiation with fiber optics, and acupuncture infrared irradiation at 6 points. Wavelengths, power, and dosage were given for the tri-laser therapies. Frequency of treatment was every other day for 2 weeks then twice weekly to healing. Twenty minute sessions were reported for IV therapy. Primary outcome was complete healing. Post study follow-up for ulcer reoccurrences was approximately 6 months. RESULTS: 100% healed in average of 19 treatments or 1.4 + 0.7 months. This is equivalent to a RR of 0, NNT of 7, and large effect size (d) of 6.6. Adverse events were 0. CONCLUSIONS: LLLT could be a safe and effective method for treatment of diabetic foot ulcers. Quality of study = poor, LOE = 2b.
Landau et al. 2006
OBJECTIVES: To evaluate the effects of concommitant total hyperbaric oxygen (THBO) and low-energy laser (LLLT) irradiation on refractory diabetic foot ulcer healing (and make a comparison to chronic venous ulcers). METHODS: Un-blinded, prospective, quasi-experimental (non-random) study of first 218 consecutive patients referred with Wagner Scale grades I and IV diabetic foot ulcers. Ulcers had been around an on average 2.9 + 2.0 months (chronic defined as more than 1 month). Treatment was SOC, ulcer bed irradiation, IV irradiation with fiber optics, acupuncture infrared irradiation at 6 points, and THBO. Wavelength and powers reported were reported but were unclear as to not be replicable without clarification. Dosage was reported. Frequency of treatment was 2-3 per week for 20 minutes. Primary outcome was complete healing (vs. amputation). Post study follow-up not mentioned. RESULTS: 78% healed in average of 31.4 + 20 treatments or 3.7 + 1.3 months. This is equivalent to a RR of 0.294, NNT of 9, and large effect size (d) of 0.88. Adverse events were not mentioned. CONCLUSIONS: THBO and LLLT are promising techniques for diabetic foot ulcers. Quality of study = poor, LOE = 2b.
Landau 2001
OBJECTIVES: To evaluate the effects of adjunctive total hyperbaric oxygen (THBO) and low-energy laser (LEL) irradiation on resistant diabetic foot ulcer healing. METHODS: Un-blinded, prospective, quasi-experimental study of first 114 consecutive patients referred with chronic diabetic foot ulcers. Ulcers had been around an on average 4.5 + 1.2 months (14 no shows not included). Treatment was SOC (as necessary), THBO, and LLLT (in 89 patients). Wavelength, power and dosage were reported. Frequency of treatment was 2-3 per week for 10-20 minutes. Primary outcome was complete healing (vs. amputation). Post study follow-up recorded as a median of 18 months. RESULTS: 80% healed in average of 25 + 13 treatments or 3.2 + 1.7 months. This is equivalent to a RR of 0.289 (when adjusted so the 11 patients receiving only THBO as an adjunct and the 14 not accounted for at the conclusion were calculated as a “laser treatment failure”), NNT of 4, and large effect size (d) of 0.88. Adverse events were 0. CONCLUSIONS: THBO/LLLT may be a safe, simple, and inexpensive early adjunctive treatment for patients with chronic diabetic foot ulcers. Quality of study = poor, LOE = 2b.
Landau 1998
OBJECTIVES: To evaluate the effects of adjunctive total hyperbaric oxygen (THBO) in conjunction with low-energy laser (LEL) irradiation on chronic diabetic foot ulcer healing (with an arm also receiving only the THBO adjunct). METHODS: Un-blinded, prospective, quasi-experimental study of first 35 patients referred with Wagner Scale grades I and IV diabetic foot ulcers. Ulcers had been around an on average 9 + 6.6 months. Treatment was SOC (medical management as necessary), THBO, and LLLT (in 35 patients). Wavelength, power, and dosage were reported. Frequency of treatment was 2-3 per week for 20 minutes. Primary outcome was complete healing (vs. amputation). Post study follow-up recorded as 12 months. RESULTS: 80% healed in average of 25 + 13 treatments or 3.1 + 1.8 months. This is equivalent to a RR of 0.266, NNT of 9, and large effect size (d) of 1.24. Adverse events were 0. CONCLUSIONS: THBO combined with LLLT (or THBO alone) is an attractive modality that should be considered in the treatment of chronic diabetic foot ulcers. Quality of study = poor, LOE = 2b.
Schindle et al. 1999
OBJECTIVES: To evaluate the effects of adjunctive low-energy laser (LLLT) irradiation on refractory diabetic foot ulcer healing as compared to other ulcer types, and determine what factors correlate with healing. METHODS: Modified control-designed study of 8 recalcitrant diabetic foot ulcer patients. Ulcers had been around for a median of 9.9 (2.1-10.3) months. Treatment was SOC and wound edge irradiation. Wavelength, power, and dosage were reported. Frequency of treatment was 3 per week. Primary outcome was complete healing (vs. amputation). Post study follow-up not mentioned. RESULTS: 100% healed in median of 43 (32.0-123.0) treatments or 3.7 (2.1-10.3) months. This is equivalent to a RR of 0, NNT of 7, but no effect size could be calculated. Adverse events were 0. CONCLUSIONS: LLLT could be a valuable non-invasive, inexpensive, safe, tool for the induction of wound healing in recalcitrant diabetic foot ulcers as compared to other more invasive and costly treatment modailites. Also reported was that healing time correlated to ulcer cause and size, and that overall median healing time was comparable to treatment with homologous platelet-derived wound healing factors. Quality of study = poor, LOE = 2b.
Saltmarche 2008
OBJECTIVES: To assess the effectiveness and feasibility of adjunctive low-energy laser (LLLT) irradiation on refractory diabetic foot ulcers. METHODS: Pretest-posttest comparison study of 6 recalcitrant (chronic defined as > 3 months) diabetic foot ulcers of nursing home resident. Ulcers had been around an average of 5.1 months. Treatment was SOC plus wound ulcer and edge irradiation. Wavelength, power, and dosage are reported. Frequency of treatments was reported as either 1-2 times daily. Primary outcome was % healing as measured by tracings and photographs (and PUSH scores for other ulcer types), where healing was defined as complete epithelization and no drainage. Post study follow-up not mentioned. RESULTS: 33% healed in 9 weeks This is equivalent to a RR of .889, NNT of 60 (where all other wounds were counted as laser treatment failures even if they did decrease in size in the short 9 week study), but no effect size could be calculated. Cost savings analysis for a subset of reimbursable ulcers showed a savings of $3,280/month is time and supplies. Laser treatment added 2 to 8 minutes to dressing changes (depending on wound size). Adverse events were 0. CONCLUSIONS: LLLT is a safe, less costly, effective adjunctive tool for the induction of wound healing in recalcitrant diabetic foot ulcers, with an additional potential benefit of pain reduction. Quality of study = poor, LOE = 2b.

Table [ 1 ] Relevance Assessment: Summary of Included Studies Study | Study Design (Population Size,N) | Inclusion Criteria | Gender (male) | Mean age (yrs) | A1c(mg/dL) | Therapy (SOC vs.) | Outcome(s) | Kazemi-Khoo 2006 (Iran) 20 | Prospective, case series(7) | Grade II & III ulcers(Braden) | 57% | 61(+ 12.1) | 8.1 + 1.93 | Tri-LLLT | Mean healing time&% Pop healed | Landau et al. 2006 (Israel)21 | Prospective, open, unblinded, non-randomized,observational study (218) | Consecutive, no gangrene, ABI >0.3 | 54 % | 67.7 | 8.2 + 2.3 | SOC +THBO +LLLT | Same as above | Landau et al. 2001 (Israel)22 | Prospective, open, unblinded, non-randomized,observational study (114) | Consecutive, no gangrene, failed > 14 wks of SOC | 51% | 64(+ 10) | >7.5 | SOC +THBO +LLLT | Same as above | Landau 1998 (Israel) 23 | Prospective, open, unblinded, non-randomized,observational study (35) | Failed > 8 wks of SOC | 56% | 59(+ 11) | ? | SOC +THBO +LLLT | Same as above | Schindl et al. 1999 (Austria) 24 | Modified control-designed study(8) | Venous insuff.< grade II, failed > 3 wks of SOC | 75% | <40,40-60, >60 | ? | SOC +LLLT | % Pop healed | Saltmarche et al. 2008 (Canada) 25 | Pre/posttest study(6) | Not pregnant, no infection, measurable | 100% | 76 - 97(one pt) | ? | SOC +LLLT | % Pop healed in 9 weeks |

Table [ 2 ] Validity Assessment: Standard Study Criteria and Level of Evidence Study | Clear In/Ex-clusion Criteria | Randomized& Concealed Allocation | Blinded | Controlled* | Adequate Timeline | Patient Accounting | ITT | LOE | Kazemi-Khoo 2006 | A | I | I | I | A | A | A | 2b | Landau et al. 2006 | A | I | I | I | A | A | A | 2b | Landau et al. 2001 | A | I | I | I | A | A | I | 2b | Landau 1998 | A | I | I | I | A | A | I | 2b | Schindl et al. 1999 | A | I | I | I | A | A | A | 2b | Saltmarche et al. 2008 | A | I | I | I | I | A | I | 2b- |

Table [ 3 ] Data Analysis: % of Population Healed % Population Healed | Study | Control Chronic Ulcer Group (CC) | Experimental Chronic Ulcer Group (EC) | ControlPop. (CP) | Experimental Pop. (EP) | Relative Risk(CI) | NNT | Kazemi-Khoo. 2006* | 7 | 0 | 47Extrapolated | 35Extrapolated | 0.000 (100% healed) | 7 | Landau et al. 2006 | 218 | 48 | 1453Extrapolated | 1090Extrapolated | 0.294 (.217-.397) | 9 | Landau et al. 2001 | 114 | 33 | 347Reported | 347Reported | 0.289 (.202-.414) | 4 | Landau1998 | 35 | 7 | 233Extrapolated | 175Extrapolated | 0.266 (.122-.583) | 9 | Schindl et al. 1999 | 8 | 0 | 53Extrapolated | 40Extrapolated | 0.000 (100% healed) | 7 | Saltmarche et al. 2008 | 6 | 4 | 40Extrapolated | 30Extrapolated | 0.889 (.279-2.834) | 60 | TOTALS | | | 2173 | 1717 | 0.29 (.23-.36) | 8 |

Table [ 4 ] Relative Risk Confidence Intervals

Table [ 5 ] Data Analysis: Mean Healing Time Mean Healing Time | Study | Control Mean, M1 (months) | Experimental Mean, M2 (months) | Cohen’s d | p-value | Power | Kazemi-Khoo. 2006 | 6.9 + 0.9** | 1.4 + 0.7 | 6.60 | <0.0001 | >0.99 | Landau et al. 2006 | 2.9 + 2** | 3.7 + 3 | 0.88 | <0.0001 | >0.99 | Landau et al. 2001 | 4.5 + 1.2 | 3.2 + 1.7 | 0.88 | <0.0001 | >0.99 | Landau et al. 1998 | 9 + 6.6 ** | 3.1 + 1.8 | 1.24 | <0.0001 | >0.99 | AVERAGES | | | 2.40 | <0.0001 | >0.99 | Fail-Safe Number* | | | | | 44 |

DISCUSSION: * Literature Relevance: character of patients and conduct of study- include POEMS * Character of patients was very typical in terms of age, gender and A1c (where reported), however other characteristics that may have had an effect on the treatment outcome should have been reported, like history of previous ulcers which is a predictor of ulcers leading to amputation * Outcomes were very patient oriented * Treatment type was reasonable and based on previous research results in terms of type of laser, treatment time, frequency, power, and dosage * Literature Validity: Strengths and Weaknesses of studies -Standardized therapy study criteria and LOE (Individual cohort study or low quality randomized controlled trials (<80% follow-up)= 2b, - if wide CI) * Methodologic quality assessment: Type of study, controlled study with comparable demographics and wound character, clear inclusion and exclusion criteria, length of study, sample size, adequacy of allocation concealment, similarity on treatment groups, use of intension to treat analysis, extent of loss to outcome, and blinded outcome assessment * At least one "poor" quality RCT (PEDro < 4) or well-designed non-experimental study (non-randomized controlled trial, quasi-experimental studies, cohort studies with multiple baselines, single subject series with multiple baselines, etc.)- http://www.medicine.mcgill.ca/Strokengine/rating-en.html * Data Analysis and Validity: of POEMS (POEMs are healing time, less cost of treatment, less pain due to faster healing, less risk of infection/amputation , less trips to clinic or PT, and less pain, less swelling, (?risk of ulcerous cancer)), include CI, and assumptions and confounding variables * What does data mean and is it valid based on assumptions and confounding variables * Discord among laser type, parameters, and patient type. * It is also important to note that because of this study design, broad variety in laser types and parameters were used but were not deemed necessary for the purpose of this paper, which is speaking specif * The value of being able to compare the studies made it necessary to compare the studies despite the lack of homogeneity in therapy treatment. In addition this type of analysis and single group non-controlled experimental design lends itself, with high degree of external validity, to many applications and populations. Whether the effect is due to singular or synergistic laser therapy awaits to be determined by future trials that place laser alone in the ring against well accepted therapies, including SOC. * An assumption in all calculations is that all treatment groups received standard of care. A confounding variable in some studies is that they received hyperbaric oxygen as an adjunct to laser therapy. The assumption is that, because these same studies report no significance between the effects of laser and HBO, then the effect of hyperbaric oxygen is insignificant, and there is not synergism. * Discuss limitations and assumptions in this study design. Need to consider validity: Is there bias (anything that distorts the study findings), or confounding variables (the relationship could be duet to a third or unknown variable). Is it reliable data: consider size of the effect and precision of the effect? * No randomization: Randomization produces groups that are not systematically different with regard to known and unknown prognostic factors * Non-Assignment or “Natural Assignment” * participant is already “in” conditions before they arrive at the study -- “causal variable” is really a subject variable * Problem with all of these? * For each of these there is a “reason” for why participants are in a particular condition/order -- that reason, and anything associated with it produces a confounding of initial equivalence * How do they quantify the surface area of the open wound? 100% closure can be subjective * Some confounding variables to consider: age, race, gender, ulcer duration, initial ulcer size, initial hemoglobin (HgbA1c), average HgbA1c, change in HgbA1c, diabetes type, average hours of weight-bearing, study ulcer infection, history of smoking or alcohol use, and laboratory values. * We ignored the THBO in Landau and assumed its effects were insignificant. We aslo acted in Landau as if everyone continued with SOC and it said that is was given when necessary in 2001. * Maturation or healing that would have occurred anyway as part of the natural maturation of the ulcer, regression towards the mean, or the tendency for extreme measures to revert back to the average. (http://faculty.chass.ncsu.edu/garson/PA765/design.htm#quasi ) * In mean healing time calculations the ulcers that didn’t heal were not used in calulations of mean healing time, only the ones that did heal. This would show that there was a decrease in mean healing time that was skewed towards laser because it didn’t include the non-healers, because they got amputations and therefore could not be assessed any further. Their healing time could not be assumed as infinity. * According to Schindle ? age, race, diabetes type, ulcer duration, initial HgbA1c, average hours of weight-bearing, a history of smoking or alcohol use, creatinine, magnesium, and albumin levels did not seem to have a significant effect on healing, initial ulcer size, gender, and infection were found to affect time to healing and proportion of ulcers healed; change in HgbA1c was found to increase the likelihood of healing after 12 weeks, especially in HDF-managed wounds * Healing time is significantly effected by type and size of ulcer (See Schindle). Duration of previous treatment and depth seemed insignificant (see Schindle). * Some studies clearly got SOC before and others just mention the length the ulcers have been present on average. Landau 2001 and Schindle clearly state SOC conventional treatment times. Landau 98 just said the pts failed atleast 2 months SOC, with a range of 2-70 months the ulcers were present, and a mean ulcer duration of 9.9. Kazemi says average time ulcers were present. Landau 06 states time ulcers were present. Saltmarche says how long ulcers were present individually from which an average duration of ulcers could be calculated, but we don’t know the data for how long it took each ulcer to heal because it was ended prematurely at 9 weeks. * One-Group Pretest-Posttest Design: This is a common but flawed design in social science. It is subject to such threats to validity as history (events intervening between pretest and posttest), maturation (changes in the subjects that would have occurred anyway), regression toward the mean (the tendency of extremes to revert toward averages), testing (the learning effect on the posttest of having taken the pretest), and most challenges discussed in the separate section on validity. Sometimes the pretest data is collected at the same time as the posttest data, as when the researcher asks for recollection data of the "before" state. This is know as a proxy pretest-posttest design and has additional validity problems since the pretest data are usually significantly less reliable.- http://faculty.chass.ncsu.edu/garson/PA765/design.htm#quasi * Grade of Recommendation (further research is likely to have important impact on our confidence in the estimate of effect and may change the estimate- one high quality and several studies with limitations= B or Moderate Quality of Evidence) and AHRQ (fair evidence to support=B) * Clinical Significance: include risks and benefits, applicability (external vs. internal validity), why this study may change the SOC. * Were the results applicable and generalizable to my population? * If LLLT could be used in place of SOC as suggested by Kazemi-Khoo costs in staff time, expensive, dressings, medications, and supportive surfaces would be saved as per Saltmarche.

Saltmarche: Teaches us that even in the same person there are different mechanisms for each ulcer, and that their needs to be a variety of treatment options to match the variety of ulcer etiologies.

Kazemi-Khoo: Did not even use SOC in his therapy group, yet we lump his results together with the other studies that do. This may balance the effects that Landau gets when he adds an additional HBO to his therapy groups. One of them says that there is no statistical sign difference between treatment with laser/HBO and just HBO.

Landau et 2001: SOC was done by the unblinded study personnel who may have not put forth a complete effort to heal the wounds if they wanted SOC to fail and laser to succeed. 14 lost to follow up. Some patients received just THBO + SOC for logistic reasons and not laser at all. SOC was continued as necessary. Median follow-up was 18 months. Full compliance and no adverse events. SOC did include vascular surgery in some cases. HeNe and infrared at 632.8 nm/5mW and 904 nm/60W respectively. Dose 4 J/cm2. 20 minutes. + neuropathy. Attributed failure to lower ABI. SOC defined pg 96. 67 % healed with SOC. Patients served as their own controls. Patients failed 4.5 months of SOC. It is not possible to tell which modality caused the wound healing, but there was no significant diff in effect between the combo and HBO alone.

CONCLUSION:
Summary of conclusion: * This study tends to show good evidence but is based on questionable study designs and analysis * There is a fair research-based evidence* with moderately strong/weak data suggesting a large effectiveness in healing and reduction in the risk of amputation for chronic diabetic foot ulcers through the use of low-level laser therapy. * There are many reasons to try laser therapy and few reasons not to * Large potential: * Reduction of healing time * Reduction of amputation risk * Lower cost * Very low risk * This review should spark interest in studies to evaluate the use of laser therapy versus the SOC in treating diabetic foot ulcers that will not heal through the standard of care.
Implications for practice: S * Should be viewed cautiously but with hopeful anticipation of future trials that are designed better, multicenter, large, RCT, with various patient qualities but control of other confounding variables amongst pts, and lasers parameters.
Some suggestions for future research: * RCT’s, true control, laser vs. sham, clear description of SOC used, blinded, concealed allocation, published in international journals

For a standard of reference, s good article for testing the effects of laser therapy on healing recalcitrant diabetic foot ulcers would be a randomized control trial. The study would include diabetics with foot or leg ulcers that did not heal with traditional standard therapy in a reasonable amount of time. Typically 20 weeks is considered a reasonable standard healing time of a diabetic lower extremity ulcer. The outcomes specific to healing those ulcers would be objective measures that were clearly stated. The study would have at least 100 people randomly selected and randomly assigned to a control and a laser therapy group. The study should be double blinded with good patient follow-up, and intention-to-treat analysis of the data. This study should have the possibility to change clinical practice. During the last 40 years data has accumulated about laser wound healing, but only a small portion of studies has specifically published data on diabetics, even though many of the studies included diabetics in the study populations.

To get FDA “approval” it must have a multicenter randomized trial and manufacturing site inspection. “Approval” is for new techn with no legally marketed predicate, given for devices that are unique or high risk. Low risk devices or ones similar to products already on the market get an FDA “clearance”. A 510k application for clearance must give a technical comparison and proof of safety, but not necessarily a randomized placebo controlled trial. If a device is not very similar to one already cleared or if the use is different, a new clinical trial must be performed.
Even if a clinician uses an LLLT device for an FDA-cleared application, an insurance company may decide not to cover the procedure. Regulatorily, these devices are not considered experimental or investigational if used for the specifically approved indication. However, reimbursement is by "standard of care", not just safety and efficacy.- see Amer Soc of Photobiology website bookmarked.

Photomedicine and Laser Surgery
Volume 26, Number 5, 2008
© Mary Ann Liebert, Inc.
P. 411
DOI: 10.1089/pho.2008.9770
Editorial
Standard Parameters in Laser Phototherapy
“a detailed description of treatment as well as the device used in performing such treatment. A description of the device should include the name of the manufacturer, the manufacturer’s geographical location, the equipment model, power output, the wavelength of the light source, including a description of the source, e.g., solid state, gas, laser diode, light-emitting diode, etc., and the shape, size and type of treatment applicator used in delivering treatment. Similarly, a detailed description of treatment parameters is necessary; and should include: (1) the irradiance or power density measured in W cm_2, (2) the dose in the form of energy density or fluence measured in J cm_2, (3) the duration of each treatment session, preferably measured in seconds, (4) the frequency of treatment (i.e., the number of times treatment was done per week), and (5) the cumulative dose given, i.e., the individual doses multiplied by the number of treatment sessions.
Such reporting would yield the uniform standard profoundly needed to permit an objective comparison of studies in the literature.
Chukuka S. Enwemeka, Ph.D., FACSM
Co-Editor-in-Chief

BIBLIOGRAPHY OR REFERENCES:
MLA Citation: example Dunning, Thad. "Improving Causal Inference: Strengths and Limitations of Natural Experiments" Paper presented at the annual meeting of the American Political Science Association, Marriott Wardman Park, Omni Shoreham, Washington Hilton, Washington, DC, Sep 01, 2005 <Not Available>. 2009-02-05 <http://www.allacademic.com/meta/p41968_index.html> |

APA Citation: example Dunning, T. , 2005-09-01 "Improving Causal Inference: Strengths and Limitations of Natural Experiments" Paper presented at the annual meeting of the American Political Science Association, Marriott Wardman Park, Omni Shoreham, Washington Hilton, Washington, DC Online <APPLICATION/PDF>. 2009-02-05 from http://www.allacademic.com/meta/p41968_index.html |

* Posten W, Wrone D, Dover J, Arndt K, Silapunt S, Alam M. Low-Level Laser Therapy for Wound Healing: Mechanism and Efficacy. Dermatologic Surgery [serial online]. March 2005;31(3):334-340. Available from: Academic Search Premier, Ipswich, MA. Accessed February 7, 2009. * Houreld N, Abrahamse H. Low-level laser therapy for diabetic foot wound healing. Diabetic Foot [serial online]. December 2005;8(4):182. (Available from: CINAHL with Full Text, Ipswich, MA. Accessed February 8, 2009.) * . Enwemeka CS, Parker JC, Dowdy DS, Harkness EE, Sanford LE, Woodruff LD (2004). The effect of laser phototherapy on tissue repair and pain control: A meta-analysis of the literature. Photomed Laser Surg 22,323–329. * Woodruff LD, Bounkeo JM, Brannon WM, Dawes Jr. KS; Barham CD, Waddell DL, Enwemeka CS ( * The Braden scale was found at www. Bradenscale.com * The scoring system for the braden scale was taken from: "By the Numbers: Braden Score Interventions". Advances in Skin & Wound Care. FindArticles.com. 08 Mar, 2009. http://findarticles.com/p/articles/mi_qa3977/is_200404/ai_n9377170 * The wagner scale came from this article: Wagner FW. The dysvascular foot : a system of diagnosis and treatment. Foot Ankle 1981;2:64-122. (Or see http://www.doncasterpct.nhs.uk/documents/Wagnerscale.pdf)

APPENDIX A: Databases searched and search strategies
APPENDIX B: Summary of excluded studies

APPENDIX C: Summary of Included studies results (RR of not healing and Effectiveness of laser therapy) | % Population Healed | Mean Healing Time | Study | Relative Risk | CI | NNT | Cohen’s d (effect) | p-value | Power | Kazemi-Khoo 2006* | 0.000 | 0 (100% healed) | 7 | 6.60 | <0.0001 | >0.99 | Landau et al 2006 | 0.294 | (.217-.397) | 9 | 0.88 | <0.0001 | >0.99 | Landau et al 2001 | 0.289 | (.202-.414) | 4 | 0.88 | <0.0001 | >0.99 | Landau 1998 | 0.266 | (.122-.583) | 9 | 1.24 | <0.0001 | >0.99 | Schindl et al 1999 | 0.000 | 0 (100% healed) | 7 | | | | Saltmarche et al. 2008 | 0.889 | (.279-2.834) | 60 | | | | TOTALS | 0.27 | (.21-.33) | 7.6 | | | | AVERAGES | | | | 2.40 | <0.0001 | >0.99 | Fail-Safe Number | | | | | | 44 |

APPENDIX D: Abbreviations LLLT- a form of phototherapy; between 500 and 1100 nm at 1-4J/cm2 at output, powers of 10-90 mW. Or 3-4 J/cm2 on edge and .5 on wound; monochromatic and coherent light used to induce wound healing, through various biochemical events.

Phototherapy-

Photostimulation-

Photobiostimulation

Coherence

Parallelity
Laser-

Monochromatic
Biomodulation
LED: Light Emitting Diode
Diabetic ulcer
THBO: Total Hyperbaric oxygen
LELT: Low Energy Laser Therapy
LLLT: Low Level Laser Therapy

Appendix E (http://www.cebm.net/index.aspx?o=1025)

Level | Therapy/Prevention, Aetiology/Harm | Prognosis | Diagnosis | Differential diagnosis/symptom prevalence study | Economic and decision analyses | 1a | SR (with homogeneity*) of RCTs | SR (with homogeneity*) of inception cohort studies; CDR† validated in different populations | SR (with homogeneity*) of Level 1 diagnostic studies; CDR† with 1b studies from different clinical centres | SR (with homogeneity*) of prospective cohort studies | SR (with homogeneity*) of Level 1 economic studies | 1b | Individual RCT (with narrow Confidence Interval‡) | Individual inception cohort study with > 80% follow-up; CDR† validated in a single population | Validating** cohort study with good††† reference standards; or CDR† tested within one clinical centre | Prospective cohort study with good follow-up**** | Analysis based on clinically sensible costs or alternatives; systematic review(s) of the evidence; and including multi-way sensitivity analyses | 1c | All or none§ | All or none case-series | Absolute SpPins and SnNouts†† | All or none case-series | Absolute better-value or worse-value analyses †††† | 2a | SR (with homogeneity*) of cohort studies | SR (with homogeneity*) of either retrospective cohort studies or untreated control groups in RCTs | SR (with homogeneity*) of Level >2 diagnostic studies | SR (with homogeneity*) of 2b and better studies | SR (with homogeneity*) of Level >2 economic studies | 2b | Individual cohort study (including low quality RCT; e.g., <80% follow-up) | Retrospective cohort study or follow-up of untreated control patients in an RCT; Derivation of CDR† or validated on split-sample§§§ only | Exploratory** cohort study with good†††reference standards; CDR† after derivation, or validated only on split-sample§§§ or databases | Retrospective cohort study, or poor follow-up | Analysis based on clinically sensible costs or alternatives; limited review(s) of the evidence, or single studies; and including multi-way sensitivity analyses | 2c | "Outcomes" Research; Ecological studies | "Outcomes" Research | | Ecological studies | Audit or outcomes research | 3a | SR (with homogeneity*) of case-control studies | | SR (with homogeneity*) of 3b and better studies | SR (with homogeneity*) of 3b and better studies | SR (with homogeneity*) of 3b and better studies | 3b | Individual Case-Control Study | | Non-consecutive study; or without consistently applied reference standards | Non-consecutive cohort study, or very limited population | Analysis based on limited alternatives or costs, poor quality estimates of data, but including sensitivity analyses incorporating clinically sensible variations. | 4 | Case-series (and poor quality cohort and case-control studies§§) | Case-series (and poor quality prognostic cohort studies***) | Case-control study, poor or non-independent reference standard | Case-series or superseded reference standards | Analysis with no sensitivity analysis | 5 | Expert opinion without explicit critical appraisal, or based on physiology, bench research or "first principles" | Expert opinion without explicit critical appraisal, or based on physiology, bench research or "first principles" | Expert opinion without explicit critical appraisal, or based on physiology, bench research or "first principles" | Expert opinion without explicit critical appraisal, or based on physiology, bench research or "first principles" | Expert opinion without explicit critical appraisal, or based on economic theory or "first principles" | 04/05/05 Adapted from JAMA Users’ Guides (21-22)

Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001)

Produced by Bob Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes since November 1998.

Notes
Users can add a minus-sign "-" to denote the level of that fails to provide a conclusive answer because of: * EITHER a single result with a wide Confidence Interval (such that, for example, an ARR in an RCT is not statistically significant but whose confidence intervals fail to exclude clinically important benefit or harm) * | By homogeneity we mean a systematic review that is free of worrisome variations (heterogeneity) in the directions and degrees of results between individual studies. Not all systematic reviews with statistically significant heterogeneity need be worrisome, and not all worrisome heterogeneity need be statistically significant. As noted above, studies displaying worrisome heterogeneity should be tagged with a "-" at the end of their designated level. | † | Clinical Decision Rule. (These are algorithms or scoring systems which lead to a prognostic estimation or a diagnostic category. ) | ‡ | See note #2 for advice on how to understand, rate and use trials or other studies with wide confidence intervals. | § | Met when all patients died before the Rx became available, but some now survive on it; or when some patients died before the Rx became available, but none now die on it. | §§ | By poor quality cohort study we mean one that failed to clearly define comparison groups and/or failed to measure exposures and outcomes in the same (preferably blinded), objective way in both exposed and non-exposed individuals and/or failed to identify or appropriately control known confounders and/or failed to carry out a sufficiently long and complete follow-up of patients. By poor quality case-control study we mean one that failed to clearly define comparison groups and/or failed to measure exposures and outcomes in the same (preferably blinded), objective way in both cases and controls and/or failed to identify or appropriately control known confounders. | §§§ | Split-sample validation is achieved by collecting all the information in a single tranche, then artificially dividing this into "derivation" and "validation" samples. | †† | An "Absolute SpPin" is a diagnostic finding whose Specificity is so high that a Positive result rules-in the diagnosis. An "Absolute SnNout" is a diagnostic finding whose Sensitivity is so high that a Negative result rules-out the diagnosis. | ‡‡ | Good, better, bad and worse refer to the comparisons between treatments in terms of their clinical risks and benefits. | ††† | Good reference standards are independent of the test, and applied blindly or objectively to applied to all patients. Poor reference standards are haphazardly applied, but still independent of the test. Use of a non-independent reference standard (where the 'test' is included in the 'reference', or where the 'testing' affects the 'reference') implies a level 4 study. | †††† | Better-value treatments are clearly as good but cheaper, or better at the same or reduced cost. Worse-value treatments are as good and more expensive, or worse and the equally or more expensive. | ** | Validating studies test the quality of a specific diagnostic test, based on prior evidence. An exploratory study collects information and trawls the data (e.g. using a regression analysis) to find which factors are 'significant'. | *** | By poor quality prognostic cohort study we mean one in which sampling was biased in favour of patients who already had the target outcome, or the measurement of outcomes was accomplished in <80% of study patients, or outcomes were determined in an unblinded, non-objective way, or there was no correction for confounding factors. | **** | Good follow-up in a differential diagnosis study is >80%, with adequate time for alternative diagnoses to emerge (eg 1-6 months acute, 1 - 5 years chronic) | * OR a Systematic Review with troublesome (and statistically significant) heterogeneity. * Such evidence is inconclusive, and therefore can only generate Grade D recommendations.

Grades of Recommendation

A | consistent level 1 studies | B | consistent level 2 or 3 studies or extrapolations from level 1 studies | C | level 4 studies or extrapolations from level 2 or 3 studies | D | level 5 evidence or troublingly inconsistent or inconclusive studies of any level |

"Extrapolations" are where data is used in a situation which has potentially clinically important differences than the original study situation.

Appendix F: Wagners’s Scale for diabetic ulcer evaluation

Appendix G: Braden’s scale for diabetic ulcer risk evaluation

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