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Meta analysis of clinical efficacy of pulsed radio frequency

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  • 1. REVIEW AND META-ANALYSIS Meta-Analysis of Clinical Efficacy of Pulsed Radio Frequency Energy Treatment Lifei Guo, MD, PhD, FACS,∗ Nicole J. Kubat, PhD,† Teresa R. Nelson, MS,‡ and Richard A. Isenberg, MD† Objective: To statistically evaluate published clinical efficacy data related to the use of pulsed radio frequency energy (PRFE) therapy in 3 clinical applications. Background: Numerous clinical studies have reported efficacy outcomes for PRFE therapy use in the palliative treatment of both postoperative and non- postoperative pain and edema, and for its use as an adjunctive wound-healing (WH) therapeutic. Although diverse in design and endpoint, these studies are amenable to systematic review using both a vote-counting and P-value combination meta-analytic technique. Methods: A meta-analysis of efficacy outcomes reported in clinical trials was performed using a vote-counting procedure. In addition, when possible, the sum of logs method of P-value combination was used to determine a significance level for the combined evidence within each endpoint and clinical area. Results: Of the 186 clinical articles identified after application of selection criteria, there were 25 controlled trials that met criteria for inclusion in vote- counting and P-value combination methods and were used for formal statis- tical analysis. In total, 1332 patients receiving PRFE treatment were studied. Vote-counting procedure applied to clinical outcomes from controlled studies resulted in a greater number of positive outcomes than neutral outcomes, and zero negative outcomes, for each of the clinical application groups evaluated. The sum of logs P-value method found statistically significant improvement in pain, reduction in edema, and improvement in WH outcomes. Conclusions: On the basis of statistical evaluation of published clinical effi- cacy data, there is strong statistical evidence that PRFE therapy is effective in the treatment of postoperative and nonpostoperative pain and edema and in WH applications. (Ann Surg 2012;255:457–467) Pulsed radio frequency energy (PRFE) therapy involves the lo- cal delivery of pulsed, shortwave radio frequency (RF) energy at a carrier frequency between 13 and 27.12 MHza to a target tis- sue without the intended generation of deep heat. The treatment is noninvasive, relatively low cost, and easy to administer, providing it with a number of desirable advantages. Numerous clinical studies over the past several decades have investigated the efficacy of PRFE therapy for a number of clinical applications. Although diverse in design and endpoint, these studies are amenable to systematic review From the ∗ Department of Plastic Surgery, Lahey Clinic Medical Center, Burlington, MA; †Regenesis Biomedical, Inc, Scottsdale, AZ; and ‡Technomics Research, LLC, Minneapolis, MN. Dr. Kubat is an independent contract consultant. Received for publication October 27, 2010; revision April 28, 2011; accepted November 30, 2011. Disclosure: No support was received for this research article. Reprints: Lifei Guo, MD, PhD, FACS, Department of Plastic Surgery, La- hey Clinic Medical Center, 41 Mall Road, Burlington, MA 01805. E-mail: lifei.guo@lahey.org Copyright C 2012 by Lippincott Williams & Wilkins ISSN: 0003-4932/12/25503-0457 DOI: 10.1097/SLA.0b013e3182447b5d aIn general, PRFE treatment devices described in clinical articles use a carrier frequency of 27.12 MHz. using vote-counting and P-value combination techniquesb allowing for meaningful aggregation of study results. Pulsed RF energy therapy has been studied for use as a pal- liative treatment for both postoperative (PO) and nonpostoperative (NPO) pain and edema, and as a wound-healing (WH) therapeutic in soft tissue. Postoperative patient care is an important health care issue, and patient outcomes in the days immediately after surgery can have an important impact on long-term patient recovery. Greater pain reported days after surgery, for example, has been associated with poorer long-term outcomes, specifically with respect to long-term pain, physical functioning, and perceived recovery.1 Traumatic in- jury and certain degenerative disorders are also associated with pain and/or edema, and the effectiveness of PRFE therapy at treating these conditions arising from nonsurgical origins has been investigated as well. A third application for which there is a growing amount of clinical data is the use of PRFE therapy in the treatment of soft- tissue wounds such as pressure ulcers and surgical wounds. Pulsed RF energy therapy has been reported to promote healing of chronic wounds otherwise nonresponsive to standard of care treatment, such as chronic lower extremity wounds in patients with diabetes.2,3 Effec- tive wound therapeutics that obviate the need for surgical intervention are especially important in this particular population, which has a high incidence of nontraumatic lower limb amputation.4 An analysis of the available clinical data supporting the use of PRFE therapy in these 3 intended uses was performed to provide a statistical basis for efficacy of the treatment. In addition, variables related to pathology, anatomy, duration of symptoms, duration of therapy, and technology were also examined for relevance to efficacy outcomes. METHODS Literature Search and Selection Criteria The literature search utilized several electronic medical and academic bibliographic databases to ensure all available published literature was included in the review. The databases utilized included PubMed, Academic Search Premier, CINAHL, Wiley Interscience, and Medline. Key search terms included “pulsed electromagnetic field” or “PEMF,” “shortwave diathermy,” “electromagnetic energy,” “electromagnetic field” or “EMF,” “electromagnetic therapy,” “elec- tromagnetic radiation,” “pulsed radiofrequency” or “PRF,” “pulsed electrical energy, “electrotherapy,” “pulsing EMF,” “Diapulse,” and “high frequency.” Key words were used individually and in combi- nation. Publications as of June 2009 were included in the review. Results of the electronic search were then sorted by title for applica- bility to the subject, with titles referencing in vivo human application of electromagnetic energy included. Titles referencing industrial and bone-growth applications of RF were excluded, as were titles referenc- ing static magnetic (eg, not electromagnetic) fields. The title-sorted electronic search was further augmented by inclusion of relevant articles referenced within the articles generated from the search. bDue to the diversity of design and endpoint, the studies are not amenable to a meta-analysis that provides an overall estimate of effect size in a single scale for each endpoint. Copyright © 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Annals of Surgery r Volume 255, Number 3, March 2012 www.annalsofsurgery.com | 457
  • 2. Guo et al Annals of Surgery r Volume 255, Number 3, March 2012 Only those publications that were reviews, standards, primary scien- tific reports, or primary clinical study reports, published in English, pertaining to PRFE were retained for further review. Editorials, per- sonal communications, and foreign language articles were excluded. Articles pertaining to electromagnetic field technologies operating in frequency bands other than the shortwave bandc were excluded. Clinical Application Categories Studies were categorized into groups based on broad categories of clinical application that included PO, NPO, and WH studies. The endpoints of interest within the PO and NPO clinical areas included direct measurements of pain and edema. The endpoints of interest for the statistical analysis within the WH application were those end- points that described the WH process. Studies within the PO, NPO, and WH categories were further categorized on the basis of the qual- ity of evidence provided. The majority of the studies were controlled studies that provided a within-study comparison to a concurrent con- trol group utilizing routine medical care with or without a “sham” device. Concurrently controlled studies compared with “sham” or standard of care in the PO, NPO, and WH categories with endpoint of interest information were considered evaluable for the statistical analysis. Studies that did not meet criteria were those that reported on patients outside the indicated population (eg, patients ≤18 years of age, treatment of deep tissue, or treatment of bone structures), were single-arm or case studies, were compared with another treatment modality, or those articles in which specific pain or edema results were not reported. Outcome Classification Each study that met criteria was reviewed and categorized as positive, neutral, or negative for PRFE efficacy, that is, a vote-counting procedure was used.5 Positive was defined as statistically and/or clin- ically significantly better results associated with PRFE therapy as compared with routine medical therapy. Neutral was defined as simi- lar results for both PRFE therapy as compared with routine medical therapy. Negative was defined as statistically and/or clinically signifi- cantly worse results associated with PRFE therapy as compared with routine medical therapy. Statistical Analysis For studies that were classified with respect to outcome that reported a P value or in which a P value could be calculated from the information provided using Fisher exact test (categorical outcome) or a Z test for 2 independent means (continuous outcome), the sum of logs method of P-value combination5 was used to determine a signifi- cance level for the combined evidence within each endpoint and clin- ical area. Where multiple comparisons were made within a study, the most conservative P value was used. When the text simply reported a nonsignificant comparison, P = 1.000 was used. The majority of the clinical trials reviewed were randomized placebo-controlled double- blind trials, the gold standard in clinical research. The vote-counting procedure and P-value combination were used because of the het- erogeneity of clinical applications, assessments used to measure the endpoints of interest, and follow-up time. An overall meta-analytic estimate of treatment effect would not be possible given the amount of heterogeneity observed.5 To overcome some of the shortcomings associated with vote-counting procedures, the within-study statisti- cal design, sample size, estimate of treatment effect, and statistical significance for the key comparison between treated group versus cElectromagnetic radiation in the frequency band 10 to 100 MHz is considered radio frequency. Only those articles defined as shortwave by 21 CFR 890.5290(b), that is, 13 to 27.12 MHz, were included in this analysis. routine medical therapy are tabulated and discussed along with the positive, neutral, or negative vote. RESULTS Literature Search Results A total of 186 relevant articles were identified for review after application of selection criteria. Within these articles, there were 25 controlled trials that met criteria for vote-counting analysis and were the subject of this review and analysis. In total, 1332 patients receiving PRFE therapy were studied, with no reported serious adverse events associated with the use of PRFE therapy (0/1332 patients). The 25 controlled trials consisted of 6 PO studies, 14 NPO stud- ies, and 5 WH studies. The PO studies consisted of patients treated with PRFE after various procedures including oral, foot, breast aug- mentation, and plastic (eye) surgeries. The NPO studies consisted of patients treated with PRFE for various soft-tissue disorders involving trauma, including sprains, lacerations, fractures, childbirth, whiplash and posttraumatic algoneurodystrophy, and neuromas, and degener- ative disorders including osteoarthritis and low back pain. The WH studies consisted primarily of patients treated for pressure ulcers and some surgical wounds and partial amputations. The follow-up time ranged from 1 to 7 days for the PO group, immediate to 10 years for the NPO group, and 5 days to 4 weeks for the WH group. The duration of symptoms before treatment for the NPO and WH groups ranged from less than 24 hours to 5 years, and immediate (upon suture removal) to more than 30 days, respectively. Technologies included in the review were capable of delivering PRFE at a carrier frequency of 27.12 MHz resulting in nonthermal ap- plication. A summary of devices used and device-related parameters reported for each article is provided in Table 1. Efficacy Outcomes The measured efficacy outcomes that were most consistently reported were pain and edema within the PO and NPO studies, and rate of WH within the WH studies. However, although these out- comes were consistently reported, the manner in which they were reported was highly variable. Therefore, each outcome was evaluated individually as follows. Pain Focusing on the reported outcome of pain, the measures re- ported throughout the PO and NPO literature included patient assess- ments rated “none, mild, or considerable,” “reduced, no change, or worse,” or “no, mild, moderate, or severe.” Other measures included utilizing pain scales from 1 to 4 (4 being severe pain), 1 to 5 (5 being severe pain), visual analog scale score from 0 to 10, 0 to 15, or 0 to 100, and the Western Ontario and McMaster Universities Osteoarthri- tis Index pain scales (0–10). Therefore, by giving each study a vote and accumulating the within-study P values across the studies that report pain, it becomes clear that regardless of the measures utilized, the application of PRFE results in a reduction in pain when compared with a control. A total of 16 controlled trials included in this review reported pain outcomes (5 PO and 11 NPO) with a total of 936 patients actively treated with PRFE (350 PO and 586 NPO) and 962 patients in the control group (317 PO and 645 NPO).6–10,12–22 Of the 16 controlled studies, 11 were randomized controlled trials (4 PO and 7 NPO) and 11 were blinded studies (3 PO and 8 NPO). Fourteen of the 16 trials (4 PO and 10 NPO) were included in the P-value combination analysis. Table 2 outlines the reported pain information by article for the study design, number of patients enrolled, clinical area, duration of symptoms, minutes of therapy, vote, and study finding with the Copyright © 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 458 | www.annalsofsurgery.com C 2012 Lippincott Williams & Wilkins
  • 3. Annals of Surgery r Volume 255, Number 3, March 2012 PRFE Efficacy Meta-Analysis TABLE 1. Therapy Regimen Parameters by Article Device-Related Parameters (Reported) Time-Related Parameters Power Driving the Treatment Coil (W)b Author Devicea Pulse/ second (pps) Pulse Width (μs) Mean Peak Other Total Minutes of Therapy Total Minutes of Energy Exposure Kaplan and Weinstock6 Diapulsec 600 65 38d 975 90 3.51 Aronofsky7 Diapulse 600 65 38 975 40 and 55e 1.56 and 2.15 Rhodes8 Diapulse 400–600 65 7.6–38 293–975 50 0.46 Heden and Pilla9 SofPulsef 2 2000 NRg h 660 2.64 Hutchinson et al10 Diapulse 500 65 NR 30 0.98 Nicolle and Bentall11 Bentalli 1000 100 NR 1440 144 Wilson12 Diapulse 600 65 38d 975 180 7.02 Barclay et al13 Diapulse 600 65 11.4–38d 293–975 420 3.85 Foley-Nolan et al14 NR 450 60 NR j 10080 272.16 Comorosan et al15 Diapulse 80–600 65 1.5–38 293–975 300k 8.37 Foley-Nolan et al16 NR 450 60 NR j 40320 1088.64 Pennington et al17 Diapulse NR 65 NR 70 NDl Shandles et al18 Diapulse 400 and 600m 65 ND and 38d NRn and 975 Varied ND Barker et al19 Therafield Betao 640 65 NR 135 5.62 Grant et al20 Megapulsep 100 65 NR 30 0.2 Callaghan et al21 Megapulse 400 200 and 400q 10 and 20 125d 120 9.6 and 19.2 Laufer et al22 Curapuls 670r 110 and 300s 82 and 300 1.8 or 18 200 180 1.62 and 16.2 Jan et al23 Curapuls 419 NR NR NR 600 ND Pasila et al24 Diapulse and Curapuls NR NR 38 and 40t ND 60 ND Buzzard et al25 Curapuls 403 26 200 35u 150 0.78 Cameron26 Diapulse 400 65 NR 160 4.16 Goldin et al27 Diapulse 400 65 25.3 975 270 7.02 Salzberg et al28 Diapulse 80–600 65 1.5–38d 293–975 5040 111.4 Kloth et al29 NR 600 65 NR v 600 23.4 Muirhead et al30 Curapuls 20–46 400 8–18.4d 1000 116 1.5 a A carrier frequency of 27.12 MHz (or 27 MHz) was reported for all studies. b Does not reflect the power in the tissue target. It is possible to estimate such power if the actual electromagnetic field amplitude emitted by the device is known and if the magnetoelectric properties of the tissue can be estimated or measured. c Diapulse Corporation, USA. d Calculated based on values reported. e Two PRFE treatment groups: one group received therapy both pre- and postsurgery, the other group received postsurgery therapy only. f Ivivi Technologies, USA. g NR: not reported h Reported as corresponding to average induced electric field of 32±6 mV/cm in tissue target. i Proprietary j Approximate power per unit area reported as 1.5 mW/cm2 at skin surface. k Includes PRFE therapy administered locally and at sympathetic ganglia. l ND: not determined (could not be calculated on the basis of data reported). m Two target tissues: wound (600 pps) and epigastrium (400 pps). n Two power settings were used, with peak power reported for the highest setting only. o Therafield Beta, United Kingdom. p Electro-Medical Supplies, United Kingdom. q Two treatment groups. r Enraf Nonius, The Netherlands. s Two treatment groups: (110 pps/82 μs) and (300 pps/300 μs). t Two treatment groups: Diapulse (38 W) and Curapuls (40 W). u Did not state whether the value reported was mean or peak power. v Peak magnetic field in tissue reported as approximately 2 G, reported as corresponding to a peak induced electric field of 1V/cm and current density of 1 mA/cm2 in a typical wound target. associated P value that was used in the combination analysis. As seen in the table, there were 11 positive studies (4 PO and 7 NPO), 5 neu- tral studies (1 PO and 4 NPO), and 0 negative studies demonstrating a majority of applications resulted in significant reductions in pain. The overall vote-counting procedure and P-value combination for reported pain outcomes clearly demonstrates a clinically and statisti- cally significant improvement for patients receiving active treatment (PO: P < 0.0001, NPO: P < 0.0001). There was 1 study within the NPO category that had pain outcomes reported but was not included in the vote-counting and Copyright © 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. C 2012 Lippincott Williams & Wilkins www.annalsofsurgery.com | 459
  • 4. Guo et al Annals of Surgery r Volume 255, Number 3, March 2012 TABLE 2. Articles That Met Criteria for and Were Included in Vote Counting and P-Value Combination With Reported Pain Outcomes Author Study Design (T: n, C: n) Clinical Area Duration of Symptoms Minutes of Therapya Measure Follow-Up Time Statistical Result (P) Vote PO Kaplan and Weinstock6 Randomized/ blinded (T: 50, C: 50) Various foot surgeries PO Minimum of 90 Grades 1–4 (1 being no pain) >3 d Less grade 3 & 4 in T (T: 30% vs C: 60%, (P = 0.0046) + Aronofsky7 Randomized (T1: 30, T2: 30, C: 30) Various oral surgeries PO T1: 55 T2: 40 None, moderate, considerable 72 h Higher proportion of no pain associated with treatment (T1: 63%, T2: 40%, vs C: 7%, (P ≤ 0.0057) + Rhodesb8 Controlled case series (T: 189, C: 188) Dental problems requiring surgery PO 50 Days until pain resolved NA Observed 10.04-day reduction in average time until pain resolved in T compared with C (T: 0.97 vs C: 11.01, no P value available) + Heden and Pilla9 Randomized/ blinded (T: 14, C: 12) Breast augmentation PO 660 VAS (0–100) 7 d Faster rate of improvement associated with T (Slope for T is 1.8X greater than for C, P < 0.001c) + Hutchinson et al10 Randomized/ blinded (T: 37, C: 37) Oral surgery PO 30 None, mild, moderate, severe 5 d No significant differences were found (P = 1.000) o NPO Wilson12 Matched case control, blinded (T: 20, C: 20) Ankle inversion injuries <72 h 180 0–4 (4 being severe) 3 d Positive (T patient progress better than matched pair) = 13, Negative (T patient progress worse than matched pair) = 1, None (no clear preference) = 6, P = 0.002c + Barclay et al13 Controlled case series (T: 114, C: 116) Hand/thumb injuries <36 h 420 1–5 (5 being severe) 7 d Shows more average improvement associated with T vs C (T: 1.79 grade change vs C: 0.84 grade change (no P value available)) + Foley-Nolan et al14 Randomized/ blinded (T: 10, C: 10) Neck pain >8 wk 10,080 VAS (0–10) 3 wk Shows more improvement associated with T vs C (T: 3.00 score change vs C: 1.25 score change, P < 0.023c) + Comorosan et al15 Matched case control (T: 45, C: 20) Posttraumatic algoneurodys- trophy after contusions or fractures 2–6 wk NR None, mild, moderate, severe 15 d 82% of patients reported none or mild pain in T vs 15% in C (P < 0.0001) + Foley-Nolan et al16 Randomized/ blinded (T: 20, C: 20) Acute whiplash injuries <72 h 40,320 VAS (0–10) 2, 4, and 12 wk T shows more improvement by 2 wk (p < 0.05c) and 4 wk (P < 0.05c), but by 12 wk groups are the same +d (Continues) Copyright © 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 460 | www.annalsofsurgery.com C 2012 Lippincott Williams & Wilkins
  • 5. Annals of Surgery r Volume 255, Number 3, March 2012 PRFE Efficacy Meta-Analysis TABLE 2. Articles That Met Criteria for and Were Included in Vote Counting and P-Value Combination With Reported Pain Outcomes (Continued ) Author Study Design (T: n, C: n) Clinical Area Duration of Symptoms Minutes of Therapya Measure Follow-Up Time Statistical Result (P) Vote Pennington et al17 Randomized/ blinded (T: 25, C: 25) Grades I and II acute sprains <72 h 70 Reduced, no change, worse Same day 64% T have reduced pain vs 33% in C, (P = 0.0465) + Shandles et al18 Controlled case series (T: 101, C: 216) Heel neuroma 5 yr Minimum of 40 Cure without surgery (y/n) 1–10 yr The rate of cure for T (95%) is higher than C (75%), (P < 0.0001) + Barker et al19 Randomized/ blinded (T: 34, C: 39) Lateral ligament sprains of the ankle <36 h 135 VAS (0–10) 15 d Groups show no difference in pain at follow-up (T: 0.1 vs C: 0.2, P = 0.5090) o Grant et al20 Randomized/ blinded (T: 135, C: 139) Operative vaginal deliveries or sustained perineal trauma or severe perineal edema, bruising, or hematomas <24 h 30 VAS (0–100) 36 h Same improvement in VAS reported at 36 he (T: 21.6 vs C: 21.1 (P = 0.8599) o Callaghan et al21 Randomized/ blinded (T1: 9f, T2: 9, C: 9) Knee osteoarthritis NR 120 VAS (0–10) 2 wk Groups were comparable at follow-up (T1: 5.5, T2: 5.0 vs C: 6.3) (P ≥ 0.4673) o Laufer et al22 Randomized/ blinded (T1: 27g, T2: 37, C: 31) Grades II or III knee osteoarthritis >3 mo 180 WOMAC (0–10) 3 wk The improvement is comparable among groups (T1: 0.4, T2: 0.4 vs C: 0.5, P = 1.000c) o a Calculated by reported minutes of treatment × number of treatments per day × number of days treated. b Reported subset of patients age 21 years and older. c P value as reported in publication. d Earlier pain relief is a positive outcome for acute whiplash even though pain relief was achieved at 12 weeks in both treated and control groups. e The most relevant comparison is at 36 hours because treatment with PRFE was given for up to 3 treatments within the first 36 hours. f T1 = pulse width of 200 μs and T2 = pulse width of 400 μs, all other technological parameters were consistent. g T1 = pulse width of 300 μs and pulse frequency of 300 Hz, T2 = 82 μs and pulse frequency of 110 Hz. C indicates control group; o, neutral; T, treatment group; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index; VAS, visual analog scale. P-value combination analysis. The reason for exclusion was a poten- tial study bias present at baseline because patients were allowed to choose their therapy (treatment vs control).23 Edema Focusing on the reported outcome of edema, the measures re- ported throughout the PO and NPO literature included patient assess- ments rated as “none, mild, moderate, or severe,” “none, moderate, or considerable,” “no swelling, just-visible swelling, moderate swelling, severe swelling,” “improved, same, or worse,” or a scale of 1 to 4 (1 being least amount of edema). Other measures included using volumetric displacement methods, circumferential measurements, or days until all edema was gone. Again, it becomes clear that the appli- cation of PRFE results in a reduction in edema when compared with a control, regardless of the type of measures utilized. A total of 14 studies included in this review reported edema outcomes (5 PO and 9 NPO) with a total of 958 patients actively treated (355 PO and 603 NPO) and 803 patients in the control group (324 PO and 479 NPO).6–8,10–13,15,17,19,20,23–25 Of the 14 controlled studies, 8 were randomized controlled trials (3 PO and 5 NPO) and 7 were blinded studies (2 PO and 5 NPO). Eleven of the 14 controlled clinical trials were evaluable for the P-value combination analysis (3 PO and 8 NPO). Table 3 outlines the reported edema information by article for the study design, number of patients enrolled, clinical area, duration of symptoms, minutes of therapy, vote, and study finding with the associated P value that was used in the combination analysis. As seen in the table, there were 9 positive studies (4 PO and 5 NPO), 5 neutral studies (1 PO and 4 NPO), and 0 negative studies demonstrating a majority of applications resulted in significant reductions in edema. Like the reported pain outcomes, the overall vote-counting proce- dure and P-value combination for reported edema outcomes clearly demonstrates a clinically and statistically significant improvement for patients receiving active treatment (PO: P < 0.0001, NPO: P < 0.0001). Wound Healing The same vote-counting procedure and P-value combination analysis was conducted for the WH category of articles as was used for PO and NPO articles. Again, on the basis of the results of the review, regardless of the type of measures used within the study, it becomes obvious that the application of PRFE results in improved healing Copyright © 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. C 2012 Lippincott Williams & Wilkins www.annalsofsurgery.com | 461
  • 6. Guo et al Annals of Surgery r Volume 255, Number 3, March 2012 TABLE 3. Articles That Met Criteria for Vote Counting and P-Value Combination With Reported Edema Outcomes Author Study Design (T: n, C: n) Clinical Area Duration of Symptoms Minutes of Therapya Measure Follow-Up Time Statistical Result (P) Vote PO Kaplan and Weinstock6 Randomized/ blinded (T: 50, C: 50) Various foot surgeries PO Minimum 90 Grades 1–4 (4 being severe) >3 d Less grade 3 & 4 in T vs C (T: 19%, vs C: 54%) (P = 0.0008) + Aronofsky7 Randomized (T1: 30, T2: 30, C: 30) Various oral surgeries PO T1 = 55, T2 = 40 None, moderate, considerable 72 h Higher proportion of no edema associated with T (T1: 77%, T2 53% vs C: 7%, P < 0.0001) + Rhodes8 Controlled case series (T: 189, C: 188) Dental problems requiring surgery PO 50 Days until edema resolved NA Observed 8.93d reduction in average time until edema resolved when T compared with C (T: 2.61 vs C: 11.54, no P-value available) + Nicolle and Bentall11 Within patient controlled comparison (T: 19 eyes, C: 19 eyes) Blepharoplasty PO 1,440 Improved, same, worse as nontreated eye 24 h, 3 d, 6 d Improved: 11 (58%) Same: 6 (32%) Worse: 2 (11%) (no P-value available) + Hutchinson et al10 Randomized/ blinded (T: 37, C: 37) Oral surgery PO 30 No swelling, just visible swelling, moderate, or severe 3 d, 5 d No significant differences were found (P = 1.0000b) o NPO Wilson12 Matched case control, blinded (T: 20, C: 20) Ankle inversion injuries <72 h 180 0–4 (4 being >1.5 in increase in diameter over uninjured ankle) 3 d Positive (T progress better than matched pair) = 9, Negative (T progress worse than matched pair) = 2, None (no clear preference) = 9, P = 0.033b. + Barclay et al13 Controlled case series (T: 114, C: 116) Hand/thumb injuries <36 h 420 1–5 (5: circumference greater than normal by 2.0 cm) 7 d Shows more average improvement associated with T vs C (T: 1.35 vs C: 0.000, no P-value available) + Comorosan et al15 Matched case control (T: 45, C: 20) Posttraumatic algoneurodys- trophy after contusions or fractures 2–6 wk NR None, mild, moderate, severe 15 d 89% of patients reported none or mild edema in T vs 30% in C (P < 0.0001) + Pennington et al17 Randomized/ blinded (T: 25, C: 25) Grades I and II acute sprains <72 h 70 Volume Same day On average, T had 33 mL more reduction compared with C (T: 44 mL vs C: 11 mL [P = 0.0001]) +c,d (Continues) Copyright © 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 462 | www.annalsofsurgery.com C 2012 Lippincott Williams & Wilkins
  • 7. Annals of Surgery r Volume 255, Number 3, March 2012 PRFE Efficacy Meta-Analysis TABLE 3. Articles That Met Criteria for Vote Counting and P-Value Combination With Reported Edema Outcomes (Continued) Author Study Design (T: n, C: n) Clinical Area Duration of Symptoms Minutes of Therapya Measure Follow-Up Time Statistical Result (P) Vote Jan et al23 Patient chose therapy or no therapy (T15: 11, T25: 10, C: 9) Degenerative osteoarthritic knee of grade 3 or less NR 600 Synovial sac thickness After 30 session Decreased thickness in T groups as compared with C (T1 and T2: 28%–33% vs C: no change P < 0.0001b) +d,f Pasila et al24 Randomized/ blinded (T1g: 100, T2g: 100, C: 100) Foot/ankle sprains <4 d 60 Circumference of ankle and volume of foot 3 d Curapuls group provided a significant reduction in ankle circumference (mm) as compared with control, Diapulse did not. (T1: 4.5, T2 5.0, C: 2.6). There were no statistically significant differences between groups for the reduction in volume (mL) of the foot (T1: 30, T2: 40, C: 36) (P = 1.000h) o Barker et al19 Randomized/ blinded (T: 34, C: 39) Lateral ligament sprains of the ankle <36 h 135 Volume (ratio of injured/ noninjured) 15 d Groups are comparable at follow-up (P = 0.7644) o Grant et al20 Randomized/ blinded (T: 135, C: 139) Operative vaginal deliveries or sustained perineal trauma or severe perineal edema, bruising, or hematomas <24 h 30 Edema free (y/n) 36 h Groups are comparable at 36 h (P = 0.5549) o Buzzard et al25 Randomized (T: 9, C: 11) Acute calcaneal fractures 16–18 h 150 Measured circumference 5 d No statistical difference for any of the changes between day 1 and day 5 (P = 0.22b) o a Calculated by reported minutes of treatment × number of treatments per day × number of days treated. b P value as reported in publication. c “We conclude that nonthermal, pulsed, electromagnetic energy as delivered by Diapulse can be used to decrease swelling and pain in the acutely sprained ankle. This can be important in a population which is required to wear restrictive footwear and is expected to return to continue active training as rapidly as possible.” (Pennington et al, 1993.) d Pennington et al, 1993, and Jan et al, 2006, were removed from the P-value combination analysis to assess the sensitivity of the statistical significance of the P-value combination analysis to their inclusion. Pennington et al were removed because baseline difference in the foot volume observed between the control and treated groups was larger (143 mL) than the observed difference in improvement between the groups (33 mL). Jan et al were conservatively removed because of the selection bias evident in pain. Upon removal of both studies, the significance of the P-value combination analysis was 0.0028. In addition, Pennington et al were included as a nonsignificant study (P = 1.000) with Jan et al removed. The significance of the P-value combination was 0.0077. The observation of statistically significant effect on edema across studies due to nonthermal shortwave diathermy is unchanged and does not depend on the inclusion of these 2 studies. e T1 = treatment alone, T2 = treatment plus nonsteroidal anti-inflammatory drugs. f Included because the study groups were comparable at baseline with respect to the edema measurement; average synovial sac thickness; short-wave diathermy alone 1.66, short-wave diathermy in combination with nonsteroidal anti-inflammatory drugs, 2.11, versus no treatment (1.94, P > 0.05∗ as reported in the publication). g T1 = treatment with Diapulse, T2 = treatment with Curapuls. h Conservatively, a P = 1.000 used in the P-value combination analysis because 3 of the 4 comparisons between treated and control in regard to edema measurements were not found to be statistically significant. The P-value associated with the Curapuls comparison with control for ankle circumference was reported as P < 0.01 in the publication. Copyright © 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. C 2012 Lippincott Williams & Wilkins www.annalsofsurgery.com | 463
  • 8. Guo et al Annals of Surgery r Volume 255, Number 3, March 2012 TABLE 4. Articles That Met Criteria for Vote Counting and P-Value Combination With Reported WH Outcomes Author Study Design (T: n, C: n) Clinical Area Duration of Symptoms Minutes of Therapya Measure Follow-Up Time Statistical Result (P) Vote Cameron26 Randomized, blinded (T: 50, C: 50) Surgical wound Immediate 160 Suture removal (y/n) 5 d 48% sutures removed by day 5 in T vs 18% in C, P = 0.0026b + Goldin et al27 Randomized, blinded (T: 29, C: 38) Surgical wound Immediate 270 % >90% healed 7 d Proportion of wounds healed >90% at 7 d was 59% for T vs 29% for C, P = 0.0239c + Salzberg et al28 Randomized, blinded Stage II: (T: 10, C: 10) Stage IIId: (T:5, C:5) Stages II and III pressure ulcers in spinal cord–injured patients NR 5,040 Wound area, % healed, days to heal 1 wk and until healed Greater % of wound healed at 1 wk for T (84%) vs C (40%), P = 0.015e,f and lower number of days to heal for T (13.0) vs C (31.5), P < 0.001f + Kloth et al29 Randomized, blinded (T: 5, C: 5) Pressure ulcers in spinal cord–injured patients >30 d 600 % wound closure 4 wk 64% wound closure for T and no change for C (−8%), P = 0.016f + Muirhead et al30 Randomized (T: 48, C: 48) Pretibial lacerations Immediate 116 Wound area, healing time, healing rate Time until healed Time to heal and rate of healing was not statistically different (P = 0.43f and P > 0.80e,f) o a Calculated by (reported minutes of treatment × number of treatments per day × number of days treated). b Conservatively used P-value associated with overall comparison. This action is conservative because the publication reported an 81-patient single-arm study that validated the results seen in the all but abdominal surgery subgroup. The analysis for the all but abdominal surgeries subgroup in the double-blind study reported the following proportion of treated patients with suture removal as compared with control (T: 89%, C: 13%, P < 0.0001). Within the subgroup with abdominal surgery, the proportion with their sutures removed by 5 days was not found to differ between groups (T: 28%, C: 21%, P = 0.5704). The lack of a significant effect in the abdominal surgery subgroup as reported in the publication is due to conservative behavior on the part of the surgeon to avoid possible wound dehiscence. The 81-patient single-arm study results reported 86% of patients with sutures removed by day 5. c P value reported in publication is in error and is reported to be between 0.05 and 0.25. d Statistical comparisons between treated and control not performed on stage III ulcers. Three of the 5 healed in treated group versus 0 of the 5 in control. Seventy percent decrease in wound size in treated group as compared with 21% in control. e Conservatively, maximum P value used in P-value combination analysis. f P value as reported in publication. characteristics (time, % wound closure, etc) when compared with a control. A total of 5 randomized, controlled studies reported WH outcomes with a total of 147 patients actively treated with PRFE and 156 patients in the control group.26–30 Of the 5 randomized studies, 4 were blinded studies and all were included in the P-value combination analysis. Table 4 outlines the reported information by article for the study design, number of patients enrolled, clinical area, duration of symptoms, minutes of therapy, vote, and study finding with the asso- ciated P value that was used in the combination analysis. As seen in the table, there were 4 positive studies, 1 neutral study, and 0 nega- tive studies demonstrating that a majority of applications resulted in significant reductions in WH time. Similar to the reported outcomes for pain and edema, the overall vote-counting procedure and P-value combination for reported WH outcomes also demonstrate a clinically and statistically significant improvement for patients receiving active treatment (P < 0.0001). DISCUSSION Statistical Evidence of PRFE Therapy Efficacy in Multiple Clinical Settings In evaluating articles that were considered to be scientifically valid research (randomized studies or controlled case series), with pertinent technological compatibilities (ie, equivalent carrier frequen- cies of 27.12 MHz) within the specified patient population (>18 years of age), it was possible to draw clear conclusions regarding the effi- cacy of PRFE therapy in multiple clinical settings. Although the liter- ature regarding the use of PRFE does not report outcome measures, especially in regard to pain, edema, and WH, in any standard measure, the application of a well-documented vote-counting procedure and P-value combination analysis allows for meaningful accumulation of results across all studies. By applying the vote-counting procedure and the sum of logs P-value combination method, strong statistical evidence is provided that demonstrates the efficacy of PRFE in the treatment of PO and NPO pain and edema and in WH applications. Additional clinical evidence outside the scope of this analysisd also supports the findings reported here. Subsequent to the conduct of this meta-analysis, a double-blind, placebo-controlled study by Rohde et al31 found a statistically significant reduction in pain, con- current with a significant reduction in interleukin-1ß levels in wound dThat is, data published after the meta-analysis was performed, in a format not identified with the search criteria used (eg, textbook format), or as a study that did not include a control group (eg, single-arm studies and case studies). Copyright © 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 464 | www.annalsofsurgery.com C 2012 Lippincott Williams & Wilkins
  • 9. Annals of Surgery r Volume 255, Number 3, March 2012 PRFE Efficacy Meta-Analysis exudates, in patients receiving PO PRFE therapy compared with con- trol patients, further supporting efficacy of PRFE therapy in PO pain management. In regard to edema outcome, Pilla32 reported on a ran- domized, controlled, multicenter prospective study of 395 patients with grade 2 lateral ankle sprains treated with PRFE. Edema reduc- tion in the PRFE-treated group was 7-times that of the sham control group (P < 0.05).e Finally, the efficacy of PRFE therapy in WH ap- plications, particularly for the treatment of recalcitrant wounds, is supported by numerous case studies in the literature as well.2,3,33–39 Efficacy Outcomes Related to Study Variables In analyzing the various degrees of efficacy reported in the literature associated with the application of PRFE, variables related to pathology, anatomy, duration of symptoms, duration of therapy, and technology were examined for relevance to study outcome. As discussed later, among the various potential predictors of efficacy, the most plausible from the medical perspective is duration of therapy. In addition, the observation that the treated populations did no better than the control populations in the neutral studies of PRFE may be explained as consequent to insufficient energy dosing. Anatomical and Pathological Variables It is interesting to note that all of the 8 positive studies in the NPO category are regarding the treatment of patients with pain and edema arising from soft-tissue trauma (either primary trauma such as lacerations, whiplash, or sprains or posttraumatic trauma arising from algoneurodystrophy or heel neuromas). This finding is consistent with the supposition that traumatic injury and surgical injury are compa- rable in terms of the body’s inflammatory response and suggests that the response to PRFE therapy is comparable as well. In contrast, 2 of the 6 neutral studies in the NPO category are studies related to the treatment of pain and edema associated with degenerative disease (such as osteoarthritis) rather than trauma, and there is a higher pro- portion of positive trials associated with trauma and WH as opposed to degenerative disease (P = 0.0254). An alternate explanation for the observed neutral response in osteoarthritis relates to anatomy rather than pathology. In these articles, PRFE was applied to a joint space, a region that likely behaves differently than other soft tissues because of its closed space and limited blood supply. Thus, in general, there is not yet enough evidence to draw conclusions regarding the efficacy of PRFE in the treatment of degenerative diseases. Duration of Symptoms Excluding the surgical studies (all PO studies and a portion of WH studies) in which treatment was initiated immediately after surgery, there is a similarity in regard to durations of symptoms with respect to positive and neutral studies. The duration of symptoms for positive studies ranged from less than 36 hours to up to 5 years with half of the studies (4/8) reporting less than 72-hour (3-day) symptom duration. Similarly, the neutral studies reported from 16 to 18 hours up to more than 3 months, with 5 of 7 reporting less than 4-day (84-hour) symptom duration. This suggests that the cellular response to PRFE is independent of the duration of the symptoms before treatment. Therapy Duration and Device Type Used Although the technologies included in the review were all of the shortwave diathermy device classification,f the regimen associ- ated with each treatment was highly variable. There is statistical eData published in textbook format (ie, not identified with the search criteria used in this study). fUS Food and Drug Administration, Code of Federal Regulations, Title 21, Part 890, Section 890.5290. evidence that the propensity for a positive study score is associated with the technology used in the evaluations (P = 0.00056). However, within each technology, it is not clear that a strong correlation can be associated with the reported pulse widths, pulse frequencies, or calcu- lated duty cycles alone. However, a strong correlation is drawn when evaluating the minutes of therapy applied (and associated calculated total energy delivered). Therefore, it is not clear whether the technol- ogy utilized or minutes of therapy applied are the driving factor in achieving a positive study result. In evaluating all of the studies that obtained a positive score in comparison with the studies that were scored neutral, there is a statistically significant difference in the minutes of therapy applied (positive = median 300 minutes, neutral = median 120 minutes; P = 0.0210). The positive studies did not have statistically more total energy exposure (calculated by [minutes of therapy × duty cycle]/100, where duty cycle equals pulse width × [pulse frequency/10,000]) as compared with neutral studies (P = 0.1360); nevertheless, the median total energy exposure was higher in the positive articles (7.0 minutes) compared with the neutral articles (1.6 minutes). Figure 1 illustrates the correlation of minutes of therapy and total energy exposure for the positive and neutral studies included in this review. Of the positive studies that overlap in the region of neutral stud- ies, it is important to note the studies were all PO studies utilizing the Diapulse technology. Three of the studies were regarding oral surgery treatments. Recognizing the rich blood supply of the oral cavity and the typically small surgical field, it is conceivable that oral disorders may require less PRFE exposure to achieve the desired outcomes. Notably, the minutes of exposure were greater in the positive oral studies than in the neutral oral surgery study. The fourth study was the only study to include the treatment of the epigastrium along with the PO site, with the theory that treatment of the epigastrium would increase peripheral blood flow and improve the resulting pain and edema. As illustrated in the figure, within each clinical application (ie, PO, NPO, WH), the neutral votes are associated with lower en- ergy use and the positive votes are associated with higher energy use. Therefore, the relationship is consistent within clinical application. Finally, it is also interesting to note there is some evidence to suggest that the positive studies were more likely to involve a device using a solitary antenna (eg, Diapulse, SofPulse, Bentall) as opposed to an antenna plus surface electrodes (eg, Curapuls), whereas the neutral studies were roughly evenly split between devices with and without contact electrodes (P = 0.0561). Concluding Remarks A meta-analysis performed to evaluate the efficacy of PRFE therapy in 3 intended uses found statistically significant improvement in pain, reduction in edema, and improvement in WH outcomes as- sociated with PRFE therapy use. Overall, duration of therapy was the most plausible predictor of efficacy in the combined set of clinical studies evaluated in this analysis. Basic science research aimed at fur- ther understanding mechanisms underlying the therapeutic effects of PRFE treatment would be invaluable for further treatment optimiza- tion. Future clinical studies aimed at defining an optimized therapy regimen for each clinical application would also be a beneficial direc- tion for future studies. Along these lines, though not always easy to measure, data related to biophysical parameters, such as induced elec- tric field in situ and target tissue impedance, would make it possible to examine the contribution that such parameters have on therapy effi- cacy as well. In particular, providing information regarding the actual power that is delivered to the target tissue, a value that is lacking in most clinical studies, would be highly useful, and should be possible to estimate knowing the time-varying property of the wave (carrier frequency, repetition rate, pulse width), if the actual strength of the electromagnetic field would be known at the output of the device, Copyright © 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. C 2012 Lippincott Williams & Wilkins www.annalsofsurgery.com | 465
  • 10. Guo et al Annals of Surgery r Volume 255, Number 3, March 2012 FIGURE 1. Correlation between total minutes of therapy applied and aggregate energy exposure reported for positive and neutral studies included in this analysis for PO (A), NPO (B), and WH (C) studies. In the figure, filled circles denote positive studies, and nonfilled circles denote neutral studies, with clinical application denoted by color. Aggregate energy exposure was calculated by (minutes of therapy × duty cycle)/100, where duty cycle equals pulse width × (pulse frequency/10,000). and if a good estimate of the magnetoelectric property of the target tissue is known (ie, how the wave is attenuated in the target tissue). Although the latter, in particular, can be difficult to estimate, it is nevertheless recommended that such information be provided when possible in future clinical studies, which would make it possible to evaluate the effect of each of these parameters in relation to treatment efficiency. ACKNOWLEDGMENTS The authors thank Jill Munsinger for analysis, writing, and editing contributions. REFERENCES 1. Peters ML, Sommer M, van Kleef M, et al. Predictors of physical and emotional recovery 6 and 12 months after surgery. Br J Surg. 2010;97:1518–1527. 2. Porreca EG, Giordano-Jablon GM. Treatment of severe (stage III and IV) chronic pressure ulcers using pulsed radio frequency energy in a quadriplegic patient. Eplasty. 2008;8:e49. 3. Frykberg R, Tierney E, Tallis A, et al. Cell proliferation induction: healing chronic wounds through low-energy pulsed radiofrequency. Int J Low Extrem Wounds. 2009;8:45–51. 4. Reiber GE, Boyko EJ, Smith DG. Chapter 18: Lower extremity foot ulcers and amputations in diabetes. In: Diabetes in America 2nd ed. NIH Publication No. 95-1468. National Diabetes Data Group, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Bethesda, MD; 1995. Available at: http://diabetes.niddk.nih.gov/dm/pubs/America/contents. htm. 5. Sutton AJ, Abrams KR, Jones DR, et al. Methods for Meta-Analysis in Medical Research. West Sussex, England: John Wiley and Sons, Ltd; 2000. 6. Kaplan EG, Weinstock RE. Clinical evaluation of diapulse as adjunctive therapy following foot surgery. J Am Podiatry Assoc. 1968;58:218–221. 7. Aronofsky DH. Reduction of dental postsurgical symptoms using nonthermal pulsed high-peak-power electromagnetic energy. Oral Surg Oral Med Oral Pathol. 1971;32:688–696. 8. Rhodes LC. The adjunctive utilization of Diapulse therapy (pulse high peak power electromagnetic energy) in accelerating tissue healing in oral surgery. The Quarterly, NDA. 1981;39:166–175. 9. Heden P, Pilla AA. Effects of pulsed electromagnetic fields on postoperative pain: a double-blind randomized pilot study in breast augmentation patients. Aesthetic Plast Surg. 2008;32:660–666. Copyright © 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 466 | www.annalsofsurgery.com C 2012 Lippincott Williams & Wilkins
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