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Trial registered on ANZCTR


Registration number
ACTRN12614000207617
Ethics application status
Approved
Date submitted
9/02/2014
Date registered
26/02/2014
Date last updated
4/11/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
The effectiveness of cathodal electrical stimulation in pressure ulcer treatment
Scientific title
A randomized, controlled, clinical study on the effectiveness of cathodal high voltage pulsed current in treating pressure ulcers in geriatric patients
Secondary ID [1] 283984 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Physical therapy in wound healing 291012 0
Pressure ulcer treatment with cathodal high voltage pulsed current (HVPC) electrical stimulation 291013 0
Condition category
Condition code
Physical Medicine / Rehabilitation 291357 291357 0 0
Physiotherapy
Physical Medicine / Rehabilitation 291581 291581 0 0
Other physical medicine / rehabilitation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Aim of study.
The experiment sets out to determine whether cathodal high voltage pulsed current (HFPC) is effective in healing stage II, stage III, and III pressure ulcers in geriatric patients, whether it helps decrease the surface area of wounds and their linear dimensions, and whether it can significantly accelerate the rate of healing. In the experiment, healing progress is also assessed against wound shape.

The subjects are elderly people (over 60 years of age) suffering from conditions typical of geriatric age. Most of them are in poor health, bed-ridden and unable to change position without help; logical communication with the patients is either very difficult or impossible.

Intervention
Study enrollment. Patients with pressure ulcers that were screened for the study were the residents of nursing and care centers in Silesia (Poland).

The study eligibility of a patient was determined by their physician. The eligibility criteria were the following: 60 years of age and older, a stage II, III or IV pressure ulcer of at least 0.5 cm2 persisting for a minimum of 1 month but not longer than 6 months. In patients with two pressure ulcers both are evaluated for healing progress.
Patients with multiple (more than two) pressure ulcers were not eligible to participate in the experiment. Other excluding criteria included neoplasm, lymphatic system diseases, central nervous system demyelinating diseases and cirrhosis of the liver. Patients with deep, tunneling, necrotic wounds likely to involve osteomyelitis and requiring surgical intervention were also excluded from the study.

Allocation to main groups / randomization. After the selected patients, or their legal guardians, gave their consent to take part in the study, they were randomly divided between two main groups: a treatment group (TG) and a control group (CG).

The main investigator in charge of patients’ allocation to groups had 60 envelopes, each containing a piece of paper marked with A (a treatment group) or B (a control group). The envelopes were opened one by one in the presence of a physiotherapist and the pertinent patient was directed to the appropriate comparative group.

The demographic information on the subjects was obtained from standardized interviews, physical examinations, as well as from additional examinations of the subjects and their history of concomitant diseases available in medical documentation.

Wound severity at enrolment was assessed using the National and European Pressure Ulcer Advisory Panel criteria: partial-thickness loss of the dermis – stage II PUs; full-thickness tissue loss (fat visible) – stage III PUs; full-thickness tissue loss (muscle/bone visible) – stage IV PUs.

The protocol of the experiment requires healing progress to be observed for 6 weeks, but for ethical reasons observation will be extended beyond that deadline for all patients who wish so and electrical stimulation will be administered to all willing patients in the control group.

Treatment.
All patients receive treatment aimed to prevent the development of additional pressure ulcers. Pressure-redistribution surfaces, devices and pillows are applied as needed. A physiotherapist or a nurse reposition patients who are unable to move on their own at least every 2 hours. Those patients who can communicate logically and change their position have been requested to do so as often as they can in order to relieve the pressure affecting the ulcer area.

Wounds are assessed during the experiment to select topical treatments appropriately addressing moisture control, bacterial burden and debridement needs. Following a comprehensive, interdisciplinary assessment of the wounds an SWC program taking account of the specific requirements of each subject has been developed, which includes nutritional intervention, optimization of the wound dressing protocol, and continence management.

Patients in both groups receive similar topical SWC selected to meet their individual needs and to promote moist interactive healing. Wounds are first cleansed with Octenidinum dihydrochloridum + Phenoxyethanolum antiseptic agents and then a moisture retentive dressing is placed on the ulcer base. Dressings in all comparative groups consist of non-adherent gauze pads moistened with 0.9% sodium chloride, octenilin gel, hydrogel and calcium alginiate. When wound debridement is required or infection is suspected, octenilin, fibrinolysin/deoxyribonuclease, octenidinum dihydrochloridum + phenoxyethanolum, and sulfadiazinum argentum are additionally administered before ES or sham ES is applied.

All immobile patients receive low-molecular-weight heparin (enoxaparin) as a standard therapy. Patients with elevated leukocyte levels are treated with antibiotics selected following the microbiological culture and sensitivity testing of pressure ulcers.


Electrical stimulation group (ES group).
The patients in the ES group additionally receive electrical stimulation with HVPC, the parameters of which are selected as per previously published protocols of clinical studies.
The device used for this purpose is the Intelect Advanced Combo (Chattanooga, USA). The voltage applied exceeds 50 V. Twin monophasic triangular pulses of 50 microseconds and a frequency of 100 pps are used. The amperage used during HVPC procedures evokes a tingling sensation in the patients, without inducing any motor effects.
The electrodes are made of conductive carbon rubber and each patient has their own set of the electrodes. The treatment electrode is placed on an aseptic gauze pad saturated with physiological saline that overlies the wound site. The dispersive electrode (closing the electric circuit) is positioned at least 20 cm from the PU (proximally or distally, depending on where the PU developed). The electrodes are sterilized after each procedure in a disinfectant solution. The cathode has been introduced as the only treatment electrode.
The patients are applied five 50-minute procedures per week (one procedure per day). Treatment will continue until PUs heal or for a maximum of 6 weeks.
Patients’ pressure ulcers are thoroughly cleansed with 0.9% sodium chloride solution before ES is applied. As soon as the procedure is complete, the wounds are covered with the dressings described above.
Intervention code [1] 288669 0
Treatment: Devices
Intervention code [2] 288670 0
Treatment: Other
Intervention code [3] 288671 0
Rehabilitation
Comparator / control treatment
Patients in the control group are treated to prevent the development of new pressure ulcers. Pressure-redistribution surfaces, devices and pillows are administered as needed. A physiotherapist or a nurse repositions patients who cannot move unaided at least every 2 hours. Patients who can communicate logically and change position are requested to do so as often as they can to relieve pressure affecting the ulcer area.

Wounds are assessed during the experiment to select topical treatments appropriately addressing moisture control, bacterial burden and debridement needs. After a comprehensive, interdisciplinary assessment of the wounds, an SWC program addressing special requirements
of each subject has been developed. It includes nutritional intervention, optimization of the wound dressing protocol, and continence management.

The patients in the control group receive standard topical care selected to meet the needs of individual subjects and to promote moist interactive healing.

All patients receive topical SWC selected to meet their individual needs and to promote moist interactive healing. Wounds are first cleansed with Octenidinum dihydrochloridum + Phenoxyethanolum antiseptic agents and then a moisture retentive dressing is placed on the ulcer base. Dressings in all comparative groups consist of non-adherent gauze pads moistened with 0.9% sodium chloride, octenilin gel, hydrogel and calcium alginiate. When wound debridement is required or infection is suspected, octenilin, fibrinolysin/deoxyribonuclease, octenidinum dihydrochloridum + phenoxyethanolum, and sulfadiazinum argentum are additionally administered before ES or sham ES is applied.

All immobile patients receive low-molecular-weight heparin (enoxaparin) as a standard therapy. Patients with elevated leukocyte levels are treated with antibiotics selected following the microbiological culture and sensitivity testing of pressure ulcers.

In addition to standard wound care described above, the control group receives sham ES. The arrangement of the electrodes is similar to that in the ES groups and all current parameters are displayed on the monitor too, but the current is not applied. Five 50-minute sessions of sham ES are held a week (one a day). Sham ES is applied over a period of 6 weeks
Control group
Active

Outcomes
Primary outcome [1] 291353 0
Each subject's wound surface area (WSA; cm2), wound longest lengths (wound length; WL; cm), and wound longest (perpendicular) widths (wound width; WW; cm) will be determined immediately before the experiment and then at the completion of each of the 6 weeks of treatment. In total, each subject's pressure ulcers will be measured 7 times.

Wound sizes will be recorded by transferring their homothetic, congruent images onto transparent film sheets. The images show wound perimeters and allow wound lengths and widths to be measured with a centimeter ruler.

In order to determine pressure ulcer surface area the images will be measured with a planimeter. Pressure ulcer area and perimeter will be e calculated with a digital set consisting of a digitizer (Mutoh Kurta XGT, Altek, USA) wired to a personal computer (C-GEO v. 4.0 Nadowski, PL), which is also used for storing the results. Pressure ulcers are additionally photographed.
Timepoint [1] 291353 0
At baseline, week 1, week 2,week 3, week 4, week 5, and week 6
Secondary outcome [1] 306579 0
After 6 weeks of treatment, percentage changes in wound surface area and linear dimensions will be calculated in both groups according to formulas:

1) Change in WSA (%): S% is equal to (Si – Sf) * 100% /Si
S% - change in wound size area (%),
Si – initial WSA (cm2)
Sf – final WSA (cm2);

2) Change in WL (%): L% is equal to (Li – Lf ) *100% /Li
L% - change in wound’s longest length (%),
Li – initial longest length (cm)
Lf – final longest length (cm)

3) Change in WW (%): W% is equal to (Wi – Wf ) *100% /Wi
W% - change in wound’s longest width (%),
Wi – initial longest width (cm)
Wf – final longest width (cm)

4) Gilman parameter: D is equal to S/p
D – the Gilman parameter
S = (Si – Sf)
Si , Sf - initial and final wound areas
p = (pi + pf) / 2
pi , pf - initial and final wound perimeters

The proportions of stage II and stage III PUs that will significantly improve (decrease by at least 50%), close or worsen (their WSA exceed its initial value) at the end of the intervention (at 6 week) will be determined for each group.
Timepoint [1] 306579 0
At baseline and week 6

Eligibility
Key inclusion criteria
The study eligibility of a patient is determined by their physician. The eligibility criteria are the following: older than 70 years of age, a stage II or III pressure ulcer of at least 1.0 cm2 located on the trunk or buttock region, persisting for a minimum of 1 month but not longer than 6 months. If a patient has two pressure ulcers, both are evaluated for healing progress.
Minimum age
60 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients with more than two pressure ulcers are not eligible to participate in the experiment. Other excluding criteria are neoplasm, lymphatic system diseases, central nervous system demyelinating diseases and cirrhosis of the liver. Patients with deep, tunneling, necrotic wounds likely to involve osteomyelitis and requiring surgical intervention are also excluded from the study.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The study eligibility of a patient was determined by their physician. After the selected patients, or their legal guardians, gave their consent to take part in the study, they were randomly divided between two main groups: a treatment group (HVPC group) and a control group (C group).
The main investigator in charge of patients’ allocation to groups had 60 envelopes, each containing a piece of paper marked with A (a treatment group) or B (a control group). The envelopes were opened one by one in the presence of a physiotherapist and the pertinent patient was directed to the appropriate comparative group.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Single randomisation using numbered envelopes
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
In both groups, the patients will be assessed for the homogeneity of distribution of their characteristics. The relative and percentage changes in wound area, longest length and longest width will be calculated. Mean wound areas, lengths, and widths were calculated in each group before treatment and will be calculated again at its completion. The healing rates of stage II, III and IV wounds that have significantly improved (decreasing by at least 50%), closed or worsened (WSA exceeding its initial value) will be calculated at the end of intervention (at 6 week).

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/02/2013
Actual
1/11/2013
Date of last participant enrolment
Anticipated
30/08/2014
Actual
17/11/2014
Date of last data collection
Anticipated
Actual
30/12/2014
Sample size
Target
60
Accrual to date
Final
49
Recruitment outside Australia
Country [1] 5775 0
Poland
State/province [1] 5775 0
Silesia

Funding & Sponsors
Funding source category [1] 288608 0
University
Name [1] 288608 0
Academy of Physical Education
Country [1] 288608 0
Poland
Primary sponsor type
University
Name
Academy of Physical Education
Address
Academy of Physical Education, Department of Physical Therapy, Mikolowska 72A, street
40-065 Katowice, Poland
Country
Poland
Secondary sponsor category [1] 287318 0
None
Name [1] 287318 0
Address [1] 287318 0
Country [1] 287318 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290469 0
The Research Ethics Committee from the Academy of Physical Education in Katowice, Poland
Ethics committee address [1] 290469 0
Mikolowska 72A street
40-065 Katowice
Ethics committee country [1] 290469 0
Poland
Date submitted for ethics approval [1] 290469 0
27/01/2010
Approval date [1] 290469 0
11/03/2010
Ethics approval number [1] 290469 0
10/2010 of 11 March 2010

Summary
Brief summary
Pressure ulcers are a serious condition that is particularly common among frail elderly people, hence the development and implementation of effective therapies is a pressing issue. Concerning pressure ulcers that resist standard wound care (SWC), the National and European Pressure Ulcer Advisory Panel guidelines (2009y) recommend using electrical stimulation (ES).
According to various authors, ES can be applied at different stages of wound healing: 1) to promote autolysis and/or reactivate the early inflammatory phase, 2) to promote the antibacterial effect, 3) to reactivate the anti-inflammatory effect, 4) to stimulate granulation tissue growth, and 5) to promote re-epithelialization. However, the precise rules for treating wounds with ES still need to be developed and confirmed in clinical research.
The authors of in vitro and in vivo studies point to the migration of cells involved in tissue repair toward the anode or cathode created by an electrical field delivered into a tissue culture. In cell cultures, the anode enhances the motility of macrophages and neutrophils, but human keratinocytes, fibroblasts and bovine corneal epithelial cells migrate directionally toward the cathode. As regards in vivo studies, it has been shown that the application of electric current significantly increases the synthesis of adenosine triphosphate (five-fold) and protein (by 70%). ES of fibroblasts improves collagen synthesis. Studies have also shown that ES stimulates angiogenesis and improves blood flow. It is commonly recognized that cells involved in tissue repair require oxygen to function more efficiently. The results of studies in diabetic patients and in individuals with spinal cord injury (SPI) indicate that ES facilitates a temporary increase in local tissue oxygen tension.
The National and European Pressure Ulcer Advisory Panels recommend using electrical therapy for treating chronic and/or recurrent stage II, III and IV pressure ulcers. In his literature review of 2005, Kloth, too, justifies the use of electric charges for wound healing, particularly in the case of chronic wounds in which the natural low of bioelectric currents may be disturbed by tissue desiccation, residue from heavy metals (e.g. iodine, silver), the presence of nonconductive petrolatum in some impregnated dressings, and debriding enzymes. In those cases, ES can restore natural electric potentials and intensify healing processes.
Electrical stimulation with high-voltage pulsed current (HVPC) appears to be a particularly promising method of wound treatment. However, even though studies show HVPC as an efficacious wound treatment modality, the methodology of its application has not been established to date.
Clinical studies are not unanimous about what polarity the treatment electrode should have. Some authors use only one polarity of the treatment electrode for the length of treatment, more frequently choosing the cathode, than the anode. In other studies, both these electrodes were used over the period of treatment. Franek et al. applied the cathode for the first 2 weeks on average and then replaced it with the anode until the end of treatment. In the study by Houghton et al., cathodal stimulation was applied for the length of the first week and then the polarity of the electrodes was reversed weekly.
The series of in vivo studies with animals that Brown et al. conducted in the years 1987-1995 has demonstrated that the negative electrode was effective in the early stages of wound healing. In the first 4 days of treatment, cathodal stimulation considerably accelerated the healing of new incisions made in rabbits. Seven days after the experiment commenced the cathode was found to inhibit the healing process. Anodal simulation was not found to be effective during the first four days of treatment, but in the later period it considerably accelerated the re-epithelialization of wounds.
In both Mertz et al. and Brown et al. studies the authors have demonstrated that the anode is effective at later stages of wound treatment, that it can promote the re-epithelialization of wounds, and that ES is the most effective when first the cathode and then the anode are used.
An in vivo study conducted by Zhao et al. has made him conclude, though, that as epithelial cells are attracted to the cathode it is the negative electrode that can effectively promote epithelialization.
Mehmandoust et al. who have investigated the effects of anodal and cathodal ES on acute wound healing have concluded that ES can significantly decrease wound surface area and make wounds close faster regardless of the treatment electrode polarity, however anodal stimulation applied for the first 3 days and then replaced by cathodal stimulation for the remainder of treatment may strengthen tissue repair.
The conclusion of the Talebi et al. study has been that anodal ES is capable of improving the healing of acute skin wounds, because it causes the wound surface to close and the wound potential to return faster to the preinjury level.
In their randomized in vivo study with rats, Borba et al. have demonstrated that anodal stimulation has positive effect on neoangiogenesis in the early stage of acute experimental wound healing. According to their trial, preoperative anodal stimulation can be instrumental in treating early/acute stages of wounds.
The results of Bourguignon et al. in vitro study with human fibroblasts indicate that the maximum stimulation of protein and DNA synthesis is obtained at 50 V and 75 V at cells located to the negative electrode.
In the clinical study conducted by Franek et al., cathodal stimulation was observed to promote the growth of granulation tissue in venous leg ulcers.
The study by Asadi et al. has showed that cathodal sensory ES increases the release of vascular endothelial growth factor (VEGF) in skin.
Clear guidelines on how anode and cathode should be best used to treat wounds in humans are still to be developed. The results of in vitro and in vivo studies indicate, though, that both the electrodes promote wound healing and that the polarity of the treatment electrode should be matched to the wound healing stage.
Therefore, more experimental and clinical research is needed to provide evidence giving a better insight into how cell migration is affected by a sequence of polarities or other factors. Until this knowledge is acquired, the polarity of the treatment electrode will have to be selected based on the outcomes of experimental and clinical studies and best practice.
Trial website
Trial related presentations / publications
Evaluation of the Healing Progress of Pressure Ulcers Treated with Cathodal High-Voltage Monophasic Pulsed Current: Results of a Prospective, Double-blind, Randomized Clinical Trial

Anna Polak, Luther C Kloth, Edward Blaszczak, Jakub Taradaj, Agnieszka Nawrat-Szotysik, Anna Walczak, Lidia Bialek, Malgorzata Paczula, Andrzej Franek, Cezary Kucio.

Adv Skin Wound Care 2016; 29: 447-459.
Public notes

Contacts
Principal investigator
Name 45858 0
Dr Anna Polak
Address 45858 0
Department of Physical Therapy, Academy of Pysical Education,
Mikolwska 72A street
40-065 Katowice
Country 45858 0
Poland
Phone 45858 0
+48608519262
Fax 45858 0
Email 45858 0
a.polak@awf.katowice.pl; polanna@op.pl
Contact person for public queries
Name 45859 0
Dr Anna Polak
Address 45859 0
Department of Physical Therapy, Academy of Pysical Education,
Mikolwska 72A street
40-065 Katowice
Country 45859 0
Poland
Phone 45859 0
+48608519262
Fax 45859 0
Email 45859 0
a.polak@awf.katowice.pl; polanna@op.pl
Contact person for scientific queries
Name 45860 0
Dr Anna Polak
Address 45860 0
Department of Physical Therapy, Academy of Pysical Education,
Mikolwska 72A street
40-065 Katowice
Country 45860 0
Poland
Phone 45860 0
+48608519262
Fax 45860 0
Email 45860 0
a.polak@awf.katowice.pl; polanna@op.pl

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