An Unexpected Detrimental Effect on the Incidence of Heel Pressure Ulcers After Local 5% DMSO Cream Application: A Randomized, D

Pressure ulcers (PU) continue to be an enormous healthcare problem that affects large segments of the patient population. A PU is an area of localized damage to the skin and underlying tissues caused by pressure, shear, or friction.¹ Apart from relief of tissue loading there are no appropriate therapies for preventing PU.
The complete etiology of PU is not yet fully understood. However, some components of the injury are caused by ischemia followed by reperfusion.² Ischemia-reperfusion (I-R) injury has been defined as the injury, at the cellular level, resulting from the restoration of blood flow to tissue with previous ischemia. Reoxygenation promotes the generation of various reactive oxygen species (ROS) leading to the uncontrolled oxidation of vital cellular components. The hydroxyl radical (HO•), which is formed during the reaction between superoxide and hydrogen peroxide in the presence of iron, appears to be the critical oxidant and an important initiator of lipid-peroxidation during I-R injury.^3,4
Several defense mechanisms are present within tissues and cells for the protection against ROS. In addition, a number of drugs and antioxidants have been shown to prevent or scavenge damaging oxidants and free radicals. Studies in ischemia-reperfusion related PU animal studies showed a decrease of tissue necrosis after treatment with various systemically or locally applied antioxidants.^2,5–7
Dimethyl sulfoxide [DMSO (CH3)2SO] has a potentially complex mechanism of action due to its anti-ischemic, anti-inflammatory, and antioxidant properties. DMSO is widely used as antioxidant in both in-vivo and in-vitro I-R models for its ability to scavenge the highly cytotoxic hydroxyl radical and inhibit leukocyte adherence.^8,9 Topical application of DMSO, an organic liquid with excellent penetrating properties, has been shown to increase the survival of primarily ischemic island skin flaps.¹⁰ As I-R injury plays a role both in ischemic skin flaps and PU, topical DMSO could, likewise, be useful in the prevention of PU development.11 Local therapy to improve the outcome of I-R damage in PU development other than pressure relief may open a new therapeutic window for PU prevention.
Against this background, a double-blinded randomized study with a local antioxidant (DMSO) was conducted. This study is the first part of a more in-depth crossover investigation of the effect of DMSO on the buttocks versus the heel and ankle area.¹²
The objective of this study was to determine whether topically applied DMSO in a 5% concentration prevents or attenuates PU formation in a population prone to this condition.

Methods
A double blind, randomized, multicenter, placebo-controlled study to investigate the effect of a 5% DMSO cream on 2 separate locations (the buttocks and heel/ankle) in a population prone to PU development was conducted. Both buttocks and heel/ankle area are vulnerable for PU development. The heel and ankle region are particularly susceptible because of their relatively lower resting blood perfusion, higher surface pressure under load, and the extent of subcutaneous tissue covering the heel bone, or malleoli of the fibula and tibia. Due to similarities between heel and ankle they are taken together in the incidence rates.
Three intervention groups were compared: 1) a control group without a topical application (control); 2) a placebo cream group (placebo); and 3) a group with 5% DMSO cream. The control group received the same preventive measures as the other groups without a locally applied cream and was introduced as a third arm in the study to exclude a possible effect of massaging. All groups received treatment for the period of 4 weeks. All noted pressure ulcers were re-evaluated by 2 external experts who visited the ward every 2 days.
The study was performed in 8 nursing homes that were comparable in terms of guided PU policy. This type of institution is typical in the Dutch healthcare system. The patients referred to nursing homes in the Netherlands are those who would normally stay in regular hospitals in other countries. These are patients who have a high risk for developing PU due to their advanced age, do not sense the need or have a limited ability or inability to reposition themselves, or have a severe chronic illness. They have a high prevalence rate of PU and the population is rather stable over a long time.¹³ The Ethics Committee of the Academic Hospital Maastricht, The Netherlands, approved the study.
Patients. The following inclusion criteria were applied: 1) Written informed consent was obtained from each patient. If the mental capability of the patient to decide on participation was uncertain, the legal representative of the patient was asked for consent; 2) patients had to be able to participate for an evaluation for 4 weeks; 3) patients had to rest on an anti-pressure ulcer mattress; 4) patients had to be at high risk of developing PU according to the Braden scale using a cut-off point of 20.¹⁴
Exclusion criteria were: 1) patients who were treated with another, unrelated ointment or cream; 2) patients who were to undergo or had undergone surgery less than 2 weeks prior; 3) patients with existing PU; 4) patients with dark skin because of difficulty in assessment.
Interventions. For practical reasons, the 3 intervention groups were randomly assigned at the ward level and not at the patient-level. A control group of patients not receiving any treatment was not included for ethical reasons.
The 3 interventions were:
Control: 30-degree position change that was repeated every 6 hours for 4 weeks.
Placebo: prevention as control group, with 3-minute massage of the buttock, heel, and ankle regions with an indifferent cream (Vaseline-cetomacrogol) combined with a 30-degree position change. This procedure was repeated every 6 hours for 4 weeks.
DMSO: prevention as treatment placebo group with massage using a “DMSO-cream.” The DMSO-cream consisted of 5% dimethyl sulfoxide in Vaseline-cetomacrogol cream.
Instruments. The presence of PU was evaluated with the 4-grade system of the European Pressure Ulcer Advisory Panel.1 Special attention was given to grade I, nonblanchable redness. It is sometimes difficult to differentiate between blanchable redness and grade I nonblanchable redness. If local redness persisted after 10 minutes of pressure relief, a transparent convex lens (6.5-cm) was pushed against the skin. If the redness was still present after 4 hours of pressure relief, as confirmed by 2 external observers, they were recorded as grade 1 PU. When PU did occur, the location, but not the patient, was excluded from the study. The outcome measure of the study was the presence of PU.

Results

Seventy-nine persons were included in the study. Eighteen patients underwent position changes only (control); 32 patients were massaged with the placebo cream (placebo); 29 patients received the DMSO-cream (DMSO). There were no significant differences in patient characteristics (Table 1). No patients were lost during the study. An incidence rate of 44% was found for all locations. The heel/ankle location was especially susceptible to PU (Table 2). Only superficial forms of PU grade 1 and grade 2 were seen.
Massage with placebo cream neither showed a positive nor negative effect on PU incidence in comparison with the control group, for all 3 locations. Massage with a 5% DMSO cream, however, demonstrated a higher incidence of PU development compared to the control and to the placebo group (Table 2). This was caused by a significantly higher incidence of PU for the heel/ankle location (OR 8.80, 95% CI 2.61–29.6). No difference was found for the buttocks.

Since there is no difference between the control group and the placebo treatment group, a negative effect due to massage could be excluded. The statistically significant increase of the PU incidence on heel/ankle location must, therefore, be a result of the DMSO application.

Discussion
In the present study, nearly half of the included patients suffered from PU formation despite the extensively protocolized preventive measures. This confirms that PUs remain a major problem in daily patient care where preventive measures are often suboptimal. This study was intended to investigate the preventive effect of a 5% DMSO cream on PU formation in a high risk patient population. Surprisingly, there was no effect on the buttocks and furthermore, a statistically significant worsening effect on PU risk for heel/ankle compared to the placebo cream.
Reactive oxygen species (ROS), such as superoxide, hydrogen peroxide, and the hydroxyl radical, play a major role in the inflammation seen in PU formation.^2,5–7 DMSO has a potentially complex mechanism of action because of its anti-ischemic, anti-inflammatory, and antioxidant properties. Widely used as home remedy, systemically and topically, it is a safe and well-tolerated anti-inflammatory drug.⁹ As a potent scavenger of the hydroxyl radical, and by inhibiting leukocyte adherence, there is a rational basis for the use of DMSO to diminish tissue necrosis in pressure ulcers.¹¹ However, more tissue damage was found with the DMSO in the heel and ankle location.
A negative effect due to massage could be excluded since there was no difference between the control group and the placebo group. When used topically, 5% DMSO is a safe and well-tolerated drug. In concentrations from 50%–100%, it is known to cause irritation in the form of temporary erythema with scaling. Skin changes observed in this study, such as nonblanchable erythema and partial skin loss (grade I and II PU), are not known to be side effects of DMSO, not even in high concentrations.^9,11 The conclusion, therefore, is that topical 5% DMSO cream in combination with tissue loading by pressure, shearing, and/or friction must have been responsible for this unexpected effect.
Although, the detrimental effect on the heel and ankle that is opposite to a neutral effect on the area of the buttocks is difficult to explain, the authors speculate on 3 possibilities for this unexpected finding. It is unlikely that the penetration is different for the locations, as DMSO has excellent penetrating properties. The thickness of buttock and heel epidermis are comparable, as a thick hyperkeratotic layer of heels is often absent in elderly, immobile patients.
1) An explanation could be a different pathophysiologic mechanism of PU formation for the buttocks and heel. The response of mechanical loading in heel compared to the skin of the buttocks will vary greatly. Anatomical differences, such as the thickness of the subcutaneous tissue layer and absence of muscle between skin and the bony prominence, will cause high pressure points in the heel and ankle in the supine position. Mayrovitz et al¹⁵ showed that the effects of occlusion of blood flow by direct tissue loading, or by an inflated vascular cuff placed above the ankle are different. Consequently, ischemia followed by reperfusion is probably not the only pathophysiological explanation for PU formation in heels; tissue loading appears to be a necessary contributory factor. The role of I-R injury is just one of the pathophysiological mechanisms in the pathophysiology of PU. Impaired interstitial fluid flow and deformation of cells can also contribute to the development of PU.¹⁶
The influences of DMSO on the pathophysiologic mechanisms other than I-R injury are unknown, as DMSO is a relatively nonspecific compound that influences a variety of biological processes.¹⁷
2) The worsening of heel PU incidence can be the result of a paradoxical antioxidant effect of DMSO. Scavengers can be an antioxidant, neutral, or pro-oxidant. An antioxidant could be harmful because of preventing the cell response to stress by up-regulating its antioxidants defence. A negative effect of an antioxidant, in contrast to what could be expected, is called a pro-oxidant effect. Other studies also have shown that antioxidant therapy could have adverse effects.^18–20
3) The protective effect of antioxidants in oxygen stress related disease is concentration-dependant. High concentrations have been proven to provide protection; low DMSO concentrations could affect intact cells by producing a submaximal but biologically effective stimulation of a tyrosine kinase.^8,17 In the present study, a 5% DMSO cream was used for its low toxicity and the absence of garlic odor to facilitate a double-blind study design. A highly concentrated DMSO cream would probably have been more appropriate.

Conclusion
Insight in the pathophysiological processes in PU formation provides the opportunity for therapeutical approaches other than pressure relief. Interventions concerning the process of oxidative stress open a therapeutic window to treatment and prevention. However, antioxidants can have an opposite effect, as shown in this study. Further studies will be required to fully understand and characterize the critical role of oxidants and the pharmacologic properties of the antioxidant in I-R injury.
Double-blind randomized studies in humans are necessary, as discrepancies have been found in studies on the effect of antioxidants—orally or locally applied in animals and humans.¹⁹ Much remains to be learned about the uptake, biotransformation, and tissue distribution of molecules regularly thought of as antioxidants before one can reliably indicate that they have such functions in vivo.