Phonophoretic delivery of 10% hydrocortisone through the epidermis of humans as determined by serum cortisol concentrations.

Background and Purpose. The purpose of this investigation was to determine whether application of hydrocortisone phonophoresis enhances transcutaneous delivery of topically applied hydrocortisone in humans, as determined by blood cortisol levels. Subjects. The subjects were 16 men and women, between the ages of 18 and 33 years (X=25, SD=2.74), without symptoms of any ongoing inflammatory condition. Methods. A gel coupling medium containing 10% hydrocortisone acetate was used. Ultrasound was delivered over a 50-[cm.sup.2] area for 5 minutes at an intensity of 1.0 W/[cm.sup.2] and a frequency of 1.0 MHz. Each subject received a control treatment (ultrasound alone) and an experimental treatment (hydrocortisone phonophoresis) on the volar aspect of the forearm 1 week apart. Blood was drawn, under both control and experimental conditions, from a cubital vein just proximal to the treatment site prior to each treatment and 0, 5, and 15 minutes posttreatment. Serum cortisol concentrations were measured using a fluorescence polarization immunoassay. Results. No rise in serum cortisol concentrations following hydrocortisone phonophoresis was detected. Conclusion and Discussion. These findings suggest that there was no penetration of hydrocortisone through the epidermis and into the underlying vasculature. Clinical implications regarding hydrocortisone levels within the subcutaneous tissues are discussed, and further research is suggested. [Bare AC, McAnaw MB, Pritchard AE, et al. Phonophoretic delivery of 10% hydrocortisone through the epidermis of humans as determined by serum cortisol concentrations. Phys Ther. 1996;76:738-749.]

Corticosteroids are commonly used to reduce inflammation associated with soft tissue musculoskeletal injuries and chronic periarticular conditions. Traditionally, these anti-inflammatory medications have been delivered locally via injection or systemically when taken orally. Physical therapists often combine the use of a drug-impregnated coupling medium with ultrasound to drive whole molecules of topically applied medication percutaneously into inflamed tissues. This technique, known as phonophoresis, is thought to act as a fast, painless, noninvasive alternative to local injection.[1,2]

Phonophoresis is often applied via continuous ultrasound with an intensity between 1.0 and 2.0 W/[cm.sup.2], at a frequency of 1 MHz, and with a treatment duration of 5 minutes.[1-3] Medications commonly used in phonophoresis include hydrocortisone, dexamethasone, salicylates, and lidocaine. Frequently, hydrocortisone is combined with a gel base to formulate a 10% hydrocortisone solution.[2,4] This coupling medium is easy to prepare in sufficient quantity simply by blending hydrocortisone powder into the gel. Pottenger[2] states that 86% of US Arm), physical therapy clinics surveyed used hydrocortisone as the phonophoretic drug of choice for the treatment of tendinitis, bursitis, and epicondylitis. Additionally, 74% of US Army clinics use a gel as a suspension base.[2]

The physical mechanism by which phonophoresis acts is not known. Several mechanisms, however, have been proposed: increasing tissue temperature and hydration, acoustic streaming, radiation pressure wave, increasing the drug's kinetic energy, and altering membrane potentials.[5-10]

Although research on phonophoresis has been ongoing since the 1960s, results have often been conflicting. Griffin and colleagues[11-13] conducted several studies using hydrocortisone phonophoresis on swine and reported increased subcutaneous cortisol levels in both muscle and nerve. Although Griffin and colleagues' work demonstrated--through serum and tissue analysis-enhanced transcutaneous penetration with the use of phonophoresis, its clinical applicability is limited. These researchers typically used ultrasound doses that far exceeded those used in clinical practice, one combination of which caused second-degree burns in the swine skin.

Levy et al[14] and Davick et al[15] conducted studies on rats and guinea pigs and on dogs, respectively, which demonstrated, through laboratory analysis, improved penetration of the phonophoretic drug. Brown,[5] however, stated that the most salient weakness of animal studies relating to traditional application of phonophoresis is that the anatomic and physiologic differences among species present a major limitation in generalizing these experiments to humans.

A majority of research involving human subjects has been based on patient-reported decreases in pain and dysfunction rather than direct tissue or serum analysis. Several clinical studies[10,16-18] that were subjectively based had numerous extraneous variables (ie, based on patients who were receiving a wide array of treatments, to include cortisol injections in some cases) and little or no experimental control. Furthermore, only indirect evidence is provided by McElnay et al,[19] who assessed the phonophoretic delivery of 25% lignocaine by pricking the skin with a hypodermic needle to determine loss of sensation following treatment with the anesthetic. McElnay and colleagues suggested that because no local anesthesia occurred, ultrasound did not increase the percutaneous absorption of lignocaine. In contrast, the preponderance of research involving human subjects has supported the efficacy of phonophoresis. McElnay et also used an experimenter-interpreted blanching test to indirectly assess the absorption of fluocinolone acetonide, and Griffin et al[10] reported a marked decrease in pain and an increase in range of motion (as determined by experimenter measure) in patients treated with 10% hydrocortisone phonophoresis. Klinekort and Wood[16] have demonstrated that patients needed fewer treatments and had greater relief of pain and greater increases in range of motion when treated with 10% versus 1% hydrocortisone cream.

Two case studies of hydrocortisone phonophoresis have been reported on patients with temporomandibular joint dysfunction. Wing[17] and Kahn,[18] using hydrocortisone phonophoresis, reported increases in range of motion and reduced complaints of pain.

Research on humans involving laboratory analysis of cortisol values has failed to demonstrate any transdermal penetration via phonophoretic technique. Benson et al[21] used a surface recovery method to assess absorption of benzydamine and found no transdermal penetration. Oziomek et al[22] achieved similar results using tralamine salicylate, as measured by serum analysis.

Due to limitations of past research, conflicting results, poor generalizability, and lack of experimental controls, the efficacy of hydrocortisone phonophoresis has yet to be established. This study attempted to demonstrate the transdermal delivery of 10% hydrocortisone by direct measurement of serum cortisol following phonophoresis as it is clinically applied to humans. As ultrasound was thought to increase intracellular permeability, it is assumed that hydrocortisone penetrating the stratum corneum and epidermis would enter the underlying vasculature as it proceeds to the target tissue. We hypothesized that hydrocortisone phonophoresis would produce an increase in serum cortisol levels following treatment.

Method

Preliminary Study

Prior to conducting this study, a preliminary investigation was performed to determine the effect of catheterization on blood cortisol levels. Eight volunteers (3 male, 5 female) were recruited from the active-duty population at Fort Sam Houston, Texas. The volunteers ranged in age between tiff and 45 years (X=29, SD=7.8). Each volunteer was placed in a semirecumbent position, and a 23-gauge catheter was inserted into a cubital fossa vein. Immediately following catheterization, a 5-cc sample of blood was drawn and the line was flushed with 2 cc of saline to maintain patency. Prior to each successive blood sample, saline within the catheter was drawn off and discarded to prevent any dilution of the blood sample. Samples were drawn 5 minutes, 10 minutes, 15 minutes, 22 minutes 40 seconds, 27 minutes 40 seconds, 30 minutes following catheterization.

Blood samples were allowed to clot at room temperature. The samples were centrifuged within 2 hours at a relative centrifugal force of 2,400g in a Fisher Centrific[TM] tabletop centrifuge* for 20 minutes. Serum was pipetted, placed in a 5-cc aliquot tube, and immediately frozen at -50 degrees C for later analysis. Serum cortisol concentrations were determined by the Brooke Army Medical Center Area Laboratory (Fort Sam Houston, Tex) using the Abbott TDx cortisol assay,t which combines competitive binding immunoassay with fluorescence polarization immunoassay technology.[23] The sensitivity of this assay to cortisol is 0.45 mg/L in serum.[23] Reliability was determined using 18 repeated low and medium controls, producing a standard deviation of 0.6 mg/dL or less. This standard deviation indicates a measurement error of approximately 1.2 mg/dL. In this study 3,000 mg of hydrocortisone was placed on the skin (methods to be described later). If only 5% (150 mg) of this amount was absorbed into the blood, a systemic serum cortisol change of approximately 4 mg/dL would be detected.

As shown in Figure 1, blood cortisol levels declined over the 30-minute period in which they were drawn. Because a decrease in blood cortisol levels was observed following catheterization, any elevation detected in the actual study could not be attributed to the insertion of the catheter.

Subjects

Twenty-four volunteers (14 male, 10 female) without symptoms of any ongoing inflammatory condition were recruited from the active-duty population at Fort Sam Houston. The subjects ranged in age between 18 and 33 years (X=25, SD=2.74).

Procedure

Each subject signed an informed consent agreement and underwent a medical screening including taking of a medical history, a blood pressure assessment, and a musculoskeletal evaluation of the cervical spine and upper extremities to exclude those individuals with conditions that would medically preclude them from receiving hydrocortisone phonophoresis.

Each subject in the study received two ultrasound treatments 1 week apart. In the control treatment, 30 mE of Aquasonic[TM] gel++ was used as the coupling medium. The experimental treatment utilized 30 mL of 10% hydrocortisone gel as prepared in the Brooke Army Medical Center Pharmaceutical Laboratory by blending 100 g of micronized hydrocortisone acetate into 1 L of Aquasonic[TM] gel. Subjects were randomly assigned a treatment time later than 12 PM. The first treatment each subject received was randomly determined by allowing the subject to blindly select a precoded vial from a collection of blood vials. One week later, the subject returned at the same appointed time to receive the alternate treatment.

Each subject was placed in a semirecumbent position with the treatment arm resting on a pillow. The subject's vision was obscured by placing an 85 x 60-cm cardboard shield over the treatment arm just distal to the axilla. A registered nurse used aseptic techniques to insert a 23-gauge butterfly catheter into a cubital fossa vein proximal to the treatment area. A 5-cc pretreatment blood sample was drawn, followed by a 2-cc saline flush to keep the line open. A clear plastic template with a 50-[cm.sup.2] opening was then placed on the distal, volar aspect of the subject's arm. The treatment site was selected in order to place it within the catheterized vein's field and in close proximity to the catheter to maximize detection of phonophoretically driven hydrocortisone prior to systemic dilution.

Five minutes following insertion of the catheter, the line was again flushed with 2 cc of normal saline to maintain its patency. Ten minutes following the insertion of the catheter, the preselected continuous-wave ultrasound treatment was administered for a period of 5 minutes at 1.0 W/[cm.sup.2] using a 1.0-MHz Mettler Electronics Sonicatar[TM] 706 [sections] with a 5-[cm.sup.2] sound head. This ultrasound unit was calibrated prior to beginning the 2-week study and was checked at the conclusion of the study by the Biomedical Engineering Department at Fort Sam Houston. Immediately following treatment, the saline was withdrawn from the catheterized line and discarded. Once the line was cleared of saline, a 5-cc sample of blood was withdrawn for analysis. The line was then flushed with 2 cc of normal saline to maintain patency. The hydrocortisone gel was then removed with a dry terry-cloth towel as is done following clinical application. Five minutes after treatment, the line was again cleared of saline and a third 5-cc sample of blood was withdrawn, followed by a 2-cc normal saline flush of the line. The same procedure was followed at 15 minutes posttreatment to obtain a fourth sample. After the last sample was drawn, the catheter was removed.

All blood samples were centrifuged, frozen, and analyzed using the same procedures that were used in the preliminary investigation. All blood samples were coded to blind the laboratory personnel to the treatment conditions of each of the samples.

Twenty-four volunteers participated in this study, but statistical analysis was performed only on data obtained from 16 of the 24 subjects. Because 1 subject did not show up for the second treatment, this subject's data collection was incomplete. Clotting in the catheter resulted in incomplete data collection for 4 more subjects. Retrospective analysis showed greatly elevated cortisol levels in 3 subjects. Further investigation determined that those subjects were taking oral contraceptives, which had altered assay results. Data from these 3 subjects were excluded from the final statistical analysis due to the effects of the oral contraceptives on assayed serum cortisol levels.

During the study, 4 of the 16 subjects requested that the intensity of the ultrasound be reduced because of excessive heating. Three of the 4 subjects made this request while receiving the experimental treatment, and 1 subject made this request when receiving the control treatment. The intensity of the ultrasound was subsequently reduced to a tolerable setting of 0.85 W/[cm.sup.2] for the duration of the 5-minute treatment.

Data Analysis

A two-factor repeated-measures analysis of variance was used to analyze differences between control and experimental treatments over the 30-minute time period. The criterion for significance was set at P[less than or equal to .05].

Results

The mean cortisol levels and variance for both control and experimental treatment groups across all datacollection times are shown in Table 1 and Figure 2. There was a gradual decline in cortisol levels over 30-minute period of approximately 2 mg/dL in both the experimental group and the control group, corresponding to known in vivo cortisol diurnal variation? The summary table for the two-factor repeated-measures analysis of variance in blood cortisol levels is presented in Table 2. There were no differences in cortisol levels between the groups over time. With current sample size, alpha level, and variability of data, this study had a power of .90 to detect a serum cortisol change of 3 to 4 mg/dL.

Discussion

The results of this study indicate that no difference in blood cortisol levels existed between those subjects who received 10% hydrocortisone phonophoresis and those who received ultrasound with the gel. The results of this study concur with the findings of the preliminary study in which serum cortisol levels were found to decrease during the 30-minute period following catheterization. The results obtained also concur with those of other researchers.[19-22]

McElnay and colleagues conducted two studies of phonophoresis using lignocaine[19] and fluocinolone acetonide[20] on human subjects. Attempting to optimize study success, McElnay and colleagues deviated from clinical practice by applying a posttreatment dressing. Assessment of drug penetration, however, showed that there was no difference between the treatment group and the control group in either study.

Benson et al[21] conducted a study of benzydamine phonophoresis with 10 subjects. These researchers used phonophoresis at several frequencies (0, 0.75, 1.5, and 3.0 MHz) and intensities (1.0 and 1.5 W/[cm.sup.2]). In spite of these adaptations, Benson et al still failed to find a phonophoretic effect via analysis of the remaining coupling medium after applying a surface recovery procedure.

Oziomek et al[22] conducted a study on human subjects with trolamine salicylate. This study's methods were similar to ours in that serum analysis was used to determine whether the drug was effectively delivered, and both studies were unable to detect a phonophoretic effect.

Two powerful commonalities exist among our study and the works of Benson et al,[21] Oziomek et al,[22] and McElnay and colleagues. [19,20] All of these studies involved phonophoresis on human subjects, and all failed to demonstrate penetration of the drug.

Work has been done demonstrating a positive ultrasonic effect of transcutaneous drug penetration. Byl et al,[9] Griffin and colleagues,[11-13,25] Levy et al,[14] and Davick et al,[15] have all documented drug penetration with phonophoresis; however, all of their studies involved animal models.

Griffin and colleagues conducted extensive hydrocortisone phonophoretic research using a swine model. In an effort to optimize transcutaneous drug penetration, these researchers used some ultrasonic settings that are not commonly used in clinical practice. They used intensities of between 0.1 and 3.0 W/[cm.sup.2],[11-13] frequencies of 0.09, 0.95, 0.50, 1.0, and 3.6 MHz,[25] and durations of 5 to 51 minutes.[11] Griffin and colleagues[12,13,24] found that hydrocortisone phonophoresis increases tissue cortisol levels in the paravertebral musculature and lumbosacral plexus. The extreme intensities and frequencies that Griffin and colleagues[11-13] used, combined with a stationary sound head and continuous-wave ultrasound, also caused considerable thermal damage to the swine skin, and would be inappropriate for clinical use.

Davick et al [15] used tritiated cortisol phonophoresis over a 12-[cm.sup.2] area at a frequency of 0.87 MHz on dogs for 8 minutes. These researchers found increased levels of cortisol subcutaneously using a typical clinical approach, but they deviated from common clinical practice by shaving and washing the dogs' skin.

Levy et al[14] performed phonophoresis using mannitol, inulin, and physostigmine on rats and guinea pigs and then monitored urine metabolite output. They were able to demonstrate a significant phonophoretic effect. Levy et al also utilized a clinically used approach, with a frequency of 1 MHz and either a continuous-wave intensity of 1.5 W/[cm.sup.2] for 3 minutes or a pulsed-wave intensity of 3.0 W/[cm.sup.2] for 5 minutes. This approach may not have been appropriate due to the small size of the animals used.

Byl et al[9] recently studied the effects of phonophoresis on Yucatan swine, adhering to a clinical protocol with a 1-MHz frequency, a 5-minute treatment, and an intensity of 1.5 W/[cm.sup.2]). These researchers used ePTFE (polytetrafluroethylene) tubing inserted subcutaneously. This tubing is sensitive to a by-product of collagen synthesis, which is decreased by cortisol. Byl et al performed phonophoresis using both dexamethasone and hydrocortisone, but only the dexamethasone treatment was found to decrease collagen synthesis.

Some research has promoted the use of phonophoresis. This research, however; is based on animal models and cannot be assumed to be valid for humans. The skin of animals differs greatly from human skin due to its large number of hair follicles.[5] Brown[5] stated that hair follicles offer another route of passage through the stratum corneum (the proposed rate-limiting barrier to transcutaneous drug penetration).s Another weakness of animal research is its deviation from common clinical practice. Ultrasonic protocols utilized on animals would generally not have been tolerated by humans.

We attempted to measure cortisol absorption following a clinical phonophoresis treatment in human subjects using common clinical ultrasound procedures. The preliminary study clearly demonstrated that cortisol levels declined following insertion of a catheter, and our study design controlled for the effect of ultrasound alone. Nevertheless, phonophoresis with hydrocortisone, as it is applied to patients in the clinical setting, failed to improve absorption into the blood.

Several aspects of our methodology, however, may have influenced our findings. Although we optimized recovery of cortisol in the blood sample, using a systemic measure of cortisol may not necessarily reflect the cortisol within subcutaneous tissue. Griffin and colleagues[12,13] stated that tissues that are more sensitive to ultrasound due to their high protein content (ie, nerve and muscle) have been shown to contain more cortisol following phonophoresis than tissues that are low in protein, such as serum. Additionally, Brown[5] suggested that corticosteroids may be transferred intracellularly after penetration of the stratum corneum. Serum cortisol levels, therefore, might be normal while a therapeutic dosage of the drug is active in the subject's tissues. Cortisol is also highly soluble in lipids and may be stored in the subcutaneous fat prior to release into tissues. In future research to determine the effect of hydrocortisone phonophoresis, the use of tissue samples would be desirable. This is an invasive procedure, however, and has yet to be performed on humans. Griffin and colleagues[11-13] and Davick et al[15] found phonophoretic penetration using swine and dog tissue samples, respectively.

Our study deviated from common clinical practice in two ways. First, we did not administer consecutive hydrocortisone phonophoresis treatments, as is normally performed on a patient in a clinical setting. Consecutive treatments may allow saturation of the stratum corneum, facilitating drug release to the underlying tissues. Second, our study was based on the assumption that phonophoresis operates equally as well on the epidermis of healthy subjects as it would on the epidermis of actual patients with an ongoing inflammatory condition. Even though tendinitis, bursitis, and so on are rarely associated with actual epidermal inflammation, the affinity of hydrocortisone may differ between healthy and inflamed tissues, and generalizations to patient populations should be made with caution.

Lastly, we should consider a possible latent release of cortisol into the serum. Brown[5] suggested that there may be a 72-hour reservoir effect of the stratum corneum for corticosteroids. The influence of diurnal variation is another concern with any serum analysis that might last longer than 24 hours. We attempted to minimize the confounding effect of diurnal variation by treating the subjects at the same time of day on two consecutive Saturdays.

There is a possibility that our study did not demonstrate a positive phonophoretic effect because hydrocortisone molecules contained in the coupling medium or air bubbles trapped during the blending of our 10% hydrocortisone mixture may have reduced the transmissivity of the ultrasound. Cameron and Monroe[4] have reported zero transmissivity of ultrasonic energy using a similar 10% hydrocortisone preparation. They deviated from common clinical practice, however, when they measured transmission through a 5-mm-thick layer of coupling medium. We estimate a gel layer between the sound head and the skin in our study (and during clinical applications) to be at least one order of magnitude less titan the thickness used by Cameron and Monroe4 (less than 0.5 mm).

In contrast, Warren et al[26] reported only about 50% loss of transmissivity with hydrocortisone phonophoresis under clinical conditions when transmission was measured through a thickness layer that appropriately approximated clinical conditions. However, if greater than 90% of the ultrasonic energy is absorbed by the hydrocortisone cream, then all proposed ultrasonic mechanisms[6,8] (thermal agents, cavitation, acoustic streaming, and so on) are merely heating the coupling medium.[27-28]

Physical blocking of the ultrasonic energy by the hydrocortisone molecules may be responsible for the increased warmth reported by patients.[4,9] This warming effect was evident in our study. However, only 3 of 16 subjects receiving ultrasound with hydrocortisone gel requested that the intensity be reduced due to a hot sensation beneath the sound head. In addition, there is evidence that 10% hydrocortisone phonophoresis is an effective treatment.[10,16,-18] We believe it is unlikely that clinical benefits would be observed if 10% hydrocortisone agents did not transmit ultrasound. Although we did not measure the transmissivity of hydrocortisone gel, we believe that the scientific and clinical evidence supporting sufficient transmission through similar coupling media outweighs evidence to the contrary. Nevertheless, without a direct measure of transmission, we were not able to quantify, this effect and cannot eliminate the possibility that it influenced our results. Future research might focus on using a drug such as dexamethasone, for which transmissivity is known to be 95% to 98%.[9]

Future Research

Future research may investigate the effect of pulsed-wave ultrasound, which possesses several possible benefits over continuous-wave ultrasound. Continuous-wave ultrasound has a powerful tissue-heating effect that pulsed-wave ultrasound does not exhibit? This heating effect may have a deleterious effect on phonophoresis. Tissue heating can become very painful, necessitating continuous motion of the ultrasound head, which diffuses the ultrasonic energy over a larger area. With pulsed-wave ultrasound, patients can tolerate a virtually stationary sound head, ensuring a more concentrated ultrasound dosage at the treatment site. Furthermore, acoustic streaming, a proposed phonophoretic mechanism,[6,8] is more prevalent with pulsed-wave ultrasound.[6]

Griffin and Touchstone[25] found that the greatest and safest phonophoretic effect was achieved using a frequency of 3.6 MHz. Recently, Bommannan et al,[29] using guinea pigs, have shown that frequencies of 10 and 16 MHz facilitate transcutaneous movement of lanthanum hydroxide via an intercellular mechanism, as verified by electron microscopy. Perhaps future research should investigate the effect of higher frequencies on transcutaneous drug penetration in humans.

Furthermore, if the rate-limiting barrier to phonophoresis is the stratum corneum, as literature suggests, any procedure that reduces this barrier might facilitate the success of phonophoresis.[2,6] Cleaning, lightly abrading, or shaving the treatment area would theoretically reduce the barrier effect.

Conclusion

We conclude that 5 minutes of hydrocortisone phonophoresis with 10% hydrocortisone prepared by blending hydrocortisone acetate with Aquasonic[TM] gel using continuous ultrasound at 1.0 W/[cm.sup.2] does not result in an increase in human serum cortisol levels. We acknowledge that our data may not represent the cortisol in inflamed tissues, and this study did not address changes in symptomatic patients. However, the results of our study suggest that phonophoresis did not result in drug penetration.

References

1 Quillen WS. Phonophoresis: a review of the literature and technique. Athletic Training. 1980;15:109-110.

2 Pottenger FJ. Utilization of hydrocortisone phonophoresis in US Army physical therapy clinics. Mil Med. 1989;154:355-358.

3 Quillen WS. Ultrasonic phonophoresis. The Physician and Sportsmedicine. 1982;10:211.

4 Cameron MH, Monroe LG. Relative transmission of ultrasound by media customarily used for phonophoresis. Phys Ther. 1992;72:142148.

5 Brown SA. Transdermal delivery of drugs, 1: relationship between drug agents and carriers in skin preparation. Dermatology Reports. 1987;6:1-8.

6 Newman JT, Nellermore MD, Carnett JL. Hydrocortisone phonophoresis: a literature review. J Am Podiatr Med Assoc. 1992;8:432-435.

7 Tyle P, Agrawala P. Drug delivery by phonophoresis. Pharm Res. 1989;6:355-361.

8 Michlovitz SL. Thermal Agents in Rehabilitation. Philadelphia, Pa: FA Davis Co; 1990.

9 Byl NN, McDenzie A, Halliday B, et al. The effects of phonophoresis with corticosteroids: a controlled pilot study. J Orthop Sports Phys Ther. 1993;18:590-600.

10 Griffin JE, Echternach JL, Price RE, Touchstone JC. Patients treated with ultrasonic-driven hydrocortisone and with ultrasound alone. Phys Ther. 1967;47:594-601.

11 Griffin JE, Touchstone JC. Low-intensity phonophoresis of cortisol in swine. Phys Ther. 1968;48:1336-1344.

12 Griffin JE, Touchstone JC. Ultrasonic movement of cortisol into pig tissues, I: movement into skeletal muscle. Am J Phys Med. 1963;42:7785.

13 Griffin JE, Touchstone JC, Liu ACY. Ultrasonic movement of cortisol into pig tissues, II: movement into paravertebral nerve. Am J Phys Med. 1965;44:20-25.

14 Levy D, Kost J, Meshulam Y, Langer R. Effect of ultrasound on transdermal drug delivery to rats and guinea pigs. J Clin Invest. 1989;83:2074-2078.

15 Davick JP, Martin Ag, Albright JP. Distribution and deposition of tritiated cortisol using phonophoresis. Phys Ther. 1988;68:1672-1675.

16 Kleinkort JA, Wood F. Phonophoresis with 1 percent versus 10 percent hydrocortisone. Phys Ther. 1975;55:1320-1324.

17 Wing M. Phonophoresis with hydrocortisone in the treatment of temporomandibular dysfunction. Phys Ther. 1982;62;32-33.

18 Kahn J. Iontophoresis and ultrasound for postsurgical temporomandibular trismus and paresthesia. Phys Ther. 1980;60:307-308.

19 McElnay JC, Matthews MP, Harland R, McCafferty DF. The effect of ultrasound on percutaneous absorption of lignocaine. Br J Clin Pharmacol. 1985;20:421-424.

20 McElnay JC, Kennedy TA, Harland R. The influence of ultrasound on the percutaneous absorption of fluocinolone acetonide. International Journal of Pharmaceutics. 1987;40:105-110.

21 Benson HA.E, McElnay JC, Harland R. Use of ultrasound to enhance percutaneous absorption of benzydamine. Phys Ther. 1989;69:113-118.

22 Oziomek AS, Perrin DH, Herold DA, Denegar CA. Effect of phonophoresis on serum salicylate levels. Med Sci Sports Exerc. 1991;23: 397-401.

23 TDX Assay Manual. North Chicago, Ill: Abbott Laboratories; 1985.

24 Berne RM, Levy MN. Physiology. St Louis, Mo: CV Mosby Co; 1983:957-958.

25 Griffin JE, Touchstone JC. Effects of ultrasound frequency on phonophoresis of cortisol into swine tissues. Am J Phys Med. 1972;51: 62-78.

26 Warren CG, Koblanski JN, Segelman RA. Ultrasound coupling media: their relative transmissivity. Arch Phys Med Rehabil. 1976;57:218222.

27 Griffin JE. Transmissiveness of ultrasound through tap water, glycerine, and mineral oil. Phys' Ther. 1980;60:1010-1016.

28 Benson HAE, McElnay JC. Transmission of ultrasound energy through topical pharmaceutical products. Physiotherapy. 1988;74:11-13.

29 Bommannan D, Menon GK, Okuyama H, et al. Sonophoresis, II: examination of the mechanism (s) of ultrasound-inhanced transdermal drug delivery. Pharm Res. 1992;9:1043-1047.

Key Words: Hydrocortisone, Phonophoresis, Serum analysis, Ultrasound.

AG Bare, 1LT, PT, ATC, Blanchfield Army Community Hospital, Ft Campbell, KY 42223 (USA). Address all correspondence to 1LT Bare.

MB McAnaw, 1LT, PT, Eisenhower Army Medical Center, Augusta, GA 30905.

AE Pritchard, 1LT, PT, ATC, Winn Army Community Hospital, Ft Stewart, GA 31314.

JG Struebing, LT, PT, Branch Medical Clinic, Marine Corps Recruit Depot, Parris Island, SC 29905.

MA Smutok, COL, PhD, PT, is Chief, Occupational Medicine Division, US Army Research Institute of Environmental Medicine, Natick, MA 01760-5007.

MA Domenech, MAJ, PhD, PT, is Physical Therapy Instructor, US Army-Baylor University Graduate Program in Physical Therapy, AMEDD Center and School, Fort Sam Houston, TX 78234-6100.

DS Christie, PhD, is Associate Professor of Anatomy and Physiology, AMEDD Center and School.

MA Bare, CPT, RN, BSN, CCRN, is ICU Nurse, Blanchfield Army Community Hospital.

ML Bloodworth, MAJ, PhD, is Chief, Chemical Section, Brooke Army Medical Center, Fort Sam Houston, TX 78234-6100.

LA Seal, LTC, PhD, is Chief, Microbiology Branch, AMEDD Center and School.

The research protocol for this study was approved by the Clinical Investigations Committee and the Institutional Review Board at Ft Sam Houston, Tex.

The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the US Department of the Army or the Department of Defense.

* Fisher Scientific, 711 Forbes Ave, Pittsburgh, PA 15219.

+ Abbott Laboratories, 1 Abbott Park Rd, Abbott Park, IL 60064.

++Parker Laboratories Inc, 307 Washington St, Orange, NJ 07050.

Table 1.
    Serum Cortisol Levels (in Micrograms per Deciliter)
    With Respect to Time

    Control Group
(Ultrasound Alone)                     Experimental Group
                                       (Hydrocortisone
                                        Phonophoresis)

[Time.-sup.a]

           X      SD     Range        X       SD     Range

1         9.7    4.1    2.5-35.4      10.1    2.9    5.0-36.0
2         8.2    4.2    1.8-28.3      8.8     3.5    3.9-30.1
3         8.2    3.8    1.8-28.6      9.4     3.5    4.6-35.1
4         7.6    3.6    2.0-27.0      8.0     2.3    4.2-31.3

"1=pretreatment blood sample, 2=immediate posttreatment blood sample, 3=5-minute posttreatment blood sample, 4=15-minute posttreatment blood sample.

  Table 2.
    Summary Table for Two-Factor Repeated-Measures Analysis of
Variance: Serum Cortisol Levels With Ultrasound Versus
Hydrocortisone Phonophoresis

Source              df       SS            MS           F

Drug                1        12.62         12.62        0.374
Error               15       506.16        33.74
Time                3        74.74         24.91        8.712[a]
Error               45       128.69        2.86
Drug x time         3        3.54          1.18         0.380
Error               45       140.09        3.11

P<.001.

[Sections] Mettler Electronics Corp, 1333 S Claudina St, Anaheim, CA 92805.

[FIGURES HAVE BEEN OMITTED]