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Michael G. Dolan, MA, ATC, CSCS; Paul Graves; Chika Nakazawa, BS; Teresa Delano, BS, ATC; Alan Hutson, PhD; and Frank C. Mendel, PhD, contributed to conception and design; analysis and interpretation of the data; and drafting, critical revision, and final approval of the article.
Context: Ibuprofen is widely used to manage pain and inflammation after orthopaedic trauma, but its effect on acute swelling has not been investigated. Cathodal high-voltage pulsed current (CHVPC) at 120 pulses per second and 90% of visible motor threshold is known to curb edema formation after blunt trauma to the hind limbs of rats.
Objective: To examine the effects of ibuprofen, continuous CHVPC, and simultaneous ibuprofen and CHVPC on acute edema formation after blunt trauma to the hind limbs of rats.
Design: Randomized, parallel-group, repeated-measures design.
Setting: Laboratory animal facility.
Participants: A total of 21 3-month-old Zucker Lean rats (mass = 288 ± 55 g) were studied.
Intervention(s): We assessed the effects of ibuprofen, continuous CHVPC, and simultaneous ibuprofen and CHVPC on acute edema formation after blunt trauma to the hind limbs of rats.
Main Outcome Measure(s): Limb volumes were measured immediately before and after trauma and every 30 minutes over the 4 hours of the experiment.
Results: Volumes of treated limbs of all 3 experimental groups were smaller (P < .05) than those of untreated limbs, but no treatment was more effective than another.
Conclusions: Ibuprofen, CHVPC, and simultaneous ibuprofen and CHVPC effectively curbed edema after blunt injury by roughly 50% relative to untreated but similarly injured control limbs of rats.
Management of acute orthopaedic injuries is a role that delineates certified athletic trainers from almost all other health care professionals. From the inception of the profession in 1950, athletic trainers have nearly universally treated acute orthopaedic injuries with rest, ice, compression and elevation (RICE). More than 50 years later, RICE is still widely believed to be effective in managing pain and edema and reducing time to recovery after athletic injuries.1 Unfortunately, little evidence from controlled research supports that belief,2,3 and good support is lacking for other therapies commonly used to manage acute pain and edema and reduce recovery time, such as electric stimulation,4 contrast baths,5 and nonsteroidal anti-inflammatory drugs (NSAIDs).6 Ibuprofen (IBU), available by prescription and over the counter, is a commonly used NSAID in the management of soft tissue injuries.6,7 We were interested in examining the effects of IBU as a first-aid intervention, that is, using it within minutes of injury. Others have examined the effects of NSAIDs on soft tissue injuries but not when treatment was initiated immediately after the injury.8–10 High-voltage electric stimulation is another clinically unproven “therapy” commonly applied to control edema after orthopaedic injuries. However, cathodal high-voltage pulsed current (CHVPC) at 120 pulses per second and 90% of motor threshold is effective in curbing acute edema formation in laboratory animals.11–15 This animal research indicates that extended or continuous treatments are more effective in curbing edema than the shorter intervals typically used by clinicians.12
Athletic trainers, physical therapists, and other health care professionals often apply various clinical treatments simultaneously in hope of increasing the treatment effect. Ibuprofen and other NSAIDs are thought to reduce the inflammatory process by inhibiting prostaglandin synthesis.6,9 High-voltage pulsed current decreases the permeability of microvessels, although the exact mechanism is unknown.16,17 We hypothesized that if the 2 treatments curbed edema formation by different root mechanisms, then an additive treatment effect might occur. Our purpose was to examine the effects on acute edema formation of continuous treatment with IBU, CHVPC, and simultaneous application of IBU + CHVPC after blunt trauma to the limbs of rats.
Because clinical trials are difficult to control, we have designed mock clinical trials using rats as subjects. Using rats rather than humans allows us to control age, sex, size, and degree and locale of injury. In addition, the effects of noncompliance and placebo are eliminated.
We studied 21 3-month-old Zucker Lean rats (Harlan Sprague Dawley, Inc, Indianapolis, IN) with mass of 288 ± 55 g. Animals were provided food and water ad libitum until the experiment began. The Institutional Laboratory Animal Care Committee approved anesthesia and handling procedures, including mode of traumatizing hind limbs and sacrifice.
Impact injury was induced by a procedure similar to that described by Dolan et al.12 This consisted of dropping a steel rod weighing 85.5 g through a vertical tube from a height of 30 cm onto the plantar aspect of each hind foot just distal to the malleoli. A rectangular piece of plastic (2 × 2 × 0.5 cm) was interposed between the foot and the tube to distribute the force of impact. Postmortem dissections after an earlier study14 confirmed that this method of inducing trauma resulted in changes in limb volume that were attributable to edema formation and not frank bleeding; that is, it caused tissue damage without rupturing major vessels.
Limb volumes were determined by immersing hind limbs and measuring the amount of water displaced using equipment and techniques we previously described and illustrated in the Journal of Athletic Training.12 The immersion vessel was 2 cm in diameter and 6 cm long. The inferior end of the vessel was tapered and an additional 6 cm long. A 3-way stopcock was attached so that the vessel could be rapidly filled through the tapered end of the vessel. A 23-gauge stainless-steel tube, 3 cm long with a 90° bend in the middle, was affixed with epoxy to the inside wall so that 1.5 cm of the tube extended into the immersion vessel. The end of the tube outside the vessel was attached via polyethylene tubing and a 23-gauge needle to a 5-cc syringe. Using this tubing complex as a siphon, the water level in the immersion vessel could be brought to the same level repeatedly. At the exact level as the tip of stainless-steel tube in the vessel, a 3-cm piece of 2-O thread was affixed with white plastic tape to the outside surface. We prepared animals, suspended in cloth slings, for volume measurement by painting lines at the level of their malleoli. Animals were then lowered by motorized booms until lines painted on hind limbs lined up with the threads affixed to immersion vessels (at the level of the tips of the stainless-steel tubes). Water displaced was collected in 5-cc syringes by siphoning and weighed on an S-300D Microbalance (Fisher Scientific, Pittsburgh, PA). The weight of the fluid collected was equivalent to the animal's limb volume (1 mL = 1 mg). Published work from our laboratory has repeatedly established that the limb volume measurement system is reliable and valid within ±1%.12–14
Immersion of traumatized limbs was accomplished by lowering an animal via a motorized boom until its hind limbs were immersed to painted lines in 100-mL beakers of water. Water in all beakers was maintained at room temperature, 23°C (75°F). We selected this temperature because Matsen et al18 reported that it had no therapeutic effect. Injured but untreated limbs of the CHVPC group served as controls because only this group received limb-specific treatment and not systemic treatment (ie, IBU).
Because anesthesia can cause body temperature to fall,19 body temperature was regulated throughout these experiments. A rectal probe was inserted 2 to 3 cm and connected to a YSI Tele-thermometer (Yellow Springs Instruments Co, Yellow Springs, OH), and body temperature was monitored and recorded every 30 minutes throughout an experiment. Body temperature was regulated between 35°C and 37.5°C by directing a 60-W lamp on an animal throughout an experiment. Temperature of the beaker water was also monitored continuously with a YSI Tele-thermometer and probe. Shaved ice chips were added to beakers to maintain the desired temperature.
Each rat was anesthetized by an intraperitoneal injection of sodium pentobarbital (60 mg/kg of body weight) and supplemented over the course of a 4-hour experiment as needed with doses one half the original (consistent with our previous work12,13). Boosters were provided when any motion was observed. Animals in the IBU group needed an average of 1.8 boosters during the experiment (range = 1–3), animals receiving CHVPC needed an average of 1.9 boosters (range = 1–3), and those in the IBU + CHVPC group needed an average of 1.7 boosters (range = 1–3). After the animals were anesthetized, their legs, feet, and abdomens were shaved. Animals were then placed in cloth slings and suspended at 45° (caudal end down) with both hind limbs fully exposed and in dependent position. Lines were painted at the level of malleoli and rectal probes inserted.
The volume (pretrauma) of each hind limb was determined at least twice and averaged to determine the measurement. Both hind limbs of each rat were then injured by dropping a steel rod onto the plantar aspect of each foot just distal to the malleoli. Volumes of both hind limbs were again measured, and within 5 minutes after injury, the limbs were immersed in separate 100-mL beakers. Animals were randomly assigned to 1 of 3 treatment groups. Seven animals in group 1 received 15 mg/kg IBU (Wegman's Food Market Inc, Rochester, NY) in oral suspension (100 mg of IBU per 5 mL). Individual dosages were calculated for each animal to equate to an 800-mg dose20 in an adult human and administered via gavage. That is, a thin plastic tube was inserted into the stomach via the esophagus. A 1-cm3 syringe was then attached to the tube, and the IBU was injected into the stomach. After the medication was administered, the plunger of the syringe was retracted slightly, and a small amount of air was pushed through the tubing to ensure that the entire dose was inserted in the stomach. Both hind limbs were placed and maintained in beakers of water (23°C), except during volume measurements. Right hind limbs of 7 animals in group 2 received 3 continuous hours of CHVPC at 120 pulses per second and 90% of motor threshold in water (immersion technique) maintained at 23°C.12–14 The CHVPC was delivered via an Intelect 500S stimulator (Chattanooga Corp, Chattanooga, TN). Output consisted of twin spiked monophasic pulsed current. Spikes of 5 and 8 microseconds were separated by an interpulse interval of 75 microseconds. Each cloth sling used to suspend an animal was lined with a 9 × 3.6-cm carbon-rubber electrode (1 per sling) that functioned as an anode; the electrode was coated with electrode gel and applied to the shaved abdominal wall. Carbon-rubber electrodes were immersed in treatment beakers, 1 per beaker, so that water in the beakers served as cathodes. Injured but untreated left hind limbs of group 2 served as control limbs for the experiment because groups 1 and 3 received systemic treatment (ie, ibuprofen). Control limbs were also placed in water maintained at 23°C, except during volume measurements. The third group of 7 animals received the simultaneous application of IBU and CHVPC as described previously. Volumes of treated and control limbs (group 2 only) were measured every 30 minutes for the 4-hour experiment. Throughout treatments, rests, and measurements, animals remained hanging in slings with their limbs in dependent position. After removal from water beakers and before volume measurement, feet were dabbed with tissue paper to remove adherent water and to minimize evaporative cooling. At no time were limbs rubbed or squeezed during drying. At the conclusion of an experiment, animals were sacrificed by exposure to carbon dioxide.
To standardize the results to body size, data were expressed as changes from pretrauma hind limb volumes per kilogram of body weight. The primary outcome variable was volume. Data were analyzed using a repeated-measures analysis-of-variance model with factors for treatment (IBU, CHVPC, IBU + CHVPC, control/untreated limb) and time (0–240 minutes in 30-minute intervals), using SPSS statistical software (version 10.1; SPSS Inc, Chicago, IL). Special consideration was given to the variance-covariance structure in terms of measuring the appropriate intra- and interexperimental rat correlation; that is, control volumes were correlated within rat for a respective treatment assignment, whereas volumes were correlated across time. Appropriate pairwise contrasts were then made at 30-minute intervals using a Bonferroni-corrected alpha level of .05/9.
Volumes of treated limbs were smaller than those of untreated control limbs for all treatment conditions after 30 minutes and remained so throughout the 4-hour experiment (F1,26 = 60.7, P = .001; Figure 1). No one treatment (IBU, CHVPC, or IBU + CHVPC) was more effective than another in curbing acute edema formation (F2,18 = 1.024, P = .378; Figure 2). The Table presents the calculated effect size of the treatment at each time interval from 30 to 240 minutes. Continuous treatment maintained limb volumes at 50% or less of those of control limbs.
This study confirms our previous work: electric stimulation is shown again to be effective in curbing acute edema formation in laboratory animals.11–14,21 Previous work has shown that CHVPC is as effective as cool-water immersions (12.8°C) in curbing edema formation in laboratory animals.13 Earlier work has also shown that extended treatments are more effective than the traditional 20- to 30-minute treatments typically recommended by health care professionals.12 When we applied CHVPC for 3 continuous hours12 or for 4 continuous hours, as we did here, swelling was limited to 50% of that observed in injured but untreated control limbs. When we applied CHVPC for 30 minutes on, 30 minutes off, for 4 hours, we observed a significant (P < .05) but much less profound effect.13 Interestingly, cold and CHVPC, when applied continuously for 3 or more hours, had nearly identical treatment effects on acute edema formation.
To mimic what a physician might prescribe after an acute injury, we administered the equivalent of an 800-mg dose of IBU immediately after injury. This dose limited swelling in treated limbs to about half that observed in injured but untreated control limbs. Interestingly, combining IBU and CHVPC produced no greater effect than either treatment applied individually. This outcome at least suggests that both treatments may be affecting the same mechanism of action. We hypothesized that if the 2 treatments curbed edema formation by different root mechanisms, then an additive treatment effect might occur. No such effect was apparent. We speculate, therefore, that the treatments we applied may be affecting the same physiologic mechanism. The primary cause of acute edema after trauma is increased permeability of microvessels.22,23 Cryotherapy (cool-water immersions at 10°C– 15°C),24 high-voltage electric stimulation,16,17 and NSAIDs25 are all known to reduce permeability of microvessels. We hypothesize that both IBU and CHVPC affect permeability of microvessels but seemingly not any better in combination than when applied separately.
Previously, we demonstrated that immersion in cool water (12.8°C) is as effective as but no more so than CHVPC in curbing edema when applied immediately postinjury and continuously throughout most of the acute inflammatory period.12,26 Here we observed that IBU was as effective as CHVPC when similarly applied. Although not strictly comparable, results of these studies suggest that cool-water immersion (12.8°C), CHVPC (at 90% of motor threshold), and now IBU (800-mg equivalent) are roughly comparable in their capacity to curb acute edema. The clinical implications are important, assuming, of course, that these findings can be replicated in humans and that curbing edema reduces recovery time (an assumption as yet unproven). It is possible that IBU, perhaps other NSAIDs, and some time-honored first-aid and therapeutic modalities, such as cryotherapy and CHVPC, may be equally effective in controlling edema. If so, then it seems to us that compliance and cost should be the next important considerations in choosing among proven therapies. Certainly maintaining therapeutic levels of IBU is relatively safe, simple, and inexpensive and, therefore, seems to be, under many circumstances, the preferred treatment for contusions and perhaps sprains. Alternately, IBU is known to have serious side effects, especially if taken for long periods.6,10 Some27 have suggested that administration of NSAIDs may result in reduced strength of healed tendons and ligaments and may, therefore, make those structures more liable to future injuries. And some clinicians and patients prefer not to use drugs, so alternative therapies such as high-voltage pulsed current may present welcome alternatives. Key to making such options available are carefully controlled large-scale clinical trials in which putative therapies are tested and compared for efficacy in treating symptoms (eg, pain, edema) and speed of recovery of normal function. Only then will clinicians have the necessary information to confidently apply proven therapies tailored to circumstance and patient preferences. This study is a small step toward fashioning such trials.
We conclude that use of IBU at doses roughly equivalent to 800 mg for adult humans or CHVPC (at 120 pulses per second and 90% of motor threshold) or IBU and simultaneous application of CHVPC applied immediately after injury for 4 continuous hours curbs acute edema formation by roughly 50% relative to untreated but similarly injured control limbs of rats.
This study was partially funded by the Eastern Athletic Trainers' Association and the New York State Athletic Trainers' Association.