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The effects of intermittent hyperbaric oxygen on pain perception and eccentric strength in a human injury… Staples, James Robert 1996

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The effects of intermittent hyperbaric oxygen on pain perception and eccentric strength in a human injury model by JAMES ROBERT STAPLES B.Sc , The University of Waterloo, 1992 A THESIS SUBMITTED IN PARTIAL F U L F I L L M E N T OF THE REQUIREMENTS FOR THE D E G R E E OF MASTER OF SCIENCE in THE F A C U L T Y OF G R A D U A T E STUDIES School of Human Kinetics We accept this thesis as conforming to t^T£{qur^dr|tandard THE UNIVERSITY OF BRITISH C O L U M B I A January 8,1996 © James Robert Staples, 1996 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of The University of British Columbia Vancouver, Canada Date 31 T a n , mi DE-6 (2/88) ii A B S T R A C T In order to determine whether intermittent exposures to hyperbaric oxygen (HBO) enhance recovery from a model muscle injury, 70 subjects performed intense eccentric contractions on a leg dynamometer (300 repetitions in 30 minutes). They were then treated in a monoplace hyperbaric chamber in two separate phases of this study. In the first phase, there were 4 groups: control, HBO, delayed HBO, and sham. A 3-day HBO group, 5-day HBO group, and a sham group made up the second phase. The hyperbaric groups breathed 100% oxygen for 60 minutes at 2.0 atmospheres absolute (ATA). The sham group breathed 21% oxygen for 60 minutes at 1.2 A T A . Recovery was monitored by testing eccentric strength pre- and postexercise, 48h postexercise, and 96h postexercise and pain perception through daily pain scales (visual analogue scales). In phase I, a significant difference (p = 0.021) in recovery of eccentric torque was noted was noted in the HBO group compared to the delayed HBO, control, and sham groups (69.2 Nm vs. 44.9 Nm, 47.3 Nm, and 49.6 Nm. respectively). In phase II, significant differences were observed between the 5-day HBO and sham groups. From the raw strength data, the mean torque value of the HBO group was significantly greater than the sham group at 96 hours postexercise (p= 0.023; 191.9 Nm and 147.2 Nm, respectively). For strength recovery from postexercise to 96h postexercise, a significant difference was noted between the same groups at p = 0.005 (54.9 Nm versus 4.3 Nm). No significant differences were noted for pain perception in either phase or among combined data. These results are complicated by the lack of similarity between the 3-day and 5-day HBO groups in phase II. The 3-day group had 3 out of 10 anomalous sets of data for eccentric torque, which contributes to much of the group differences. The results Ill suggest that treatment with hyperbaric oxygen may enhance recovery of eccentric strength from a delayed onset muscle soreness injury. iv Table of Contents Abstract ii Table of Contents iv List of Tables vi List of Figures vii Acknowledgements viii Chapter 1- Introduction 1 Rationale 2 Assumptions 7 Delimitations 8 Limitations 8 Chapter 2- Review of Literature 9 Physiological Effects of Hyperbaric Oxygen 9 Oxygen Toxicity 13 Hyperbaric Oxygen and Burns 15 Hyperbaric Oxygen and Wound Healing 17 Hyperbaric Oxygen and Fracture Healing 19 Hyperbaric Oxygen and Crush Injuries/Orthopaedic Traumas 20 Hyperbaric Oxygen and Human Performance 24 Hyperbaric Oxygen and Sports Medicine 28 Chapter 3- Methodology 30 Subjects 30 Procedures 30 Statistical Analysis 36 Chapter 4- Results 37 Anthropometric data 37 Phase I data 37 Phase II data 42 Combination of Phase I and Phase n data 45 Chapter 5- Discussion 60 Pain 60 Eccentric Strength 62 Chapter 6- Conclusions and Recommendations 76 References 78 Appendix , 93 Appendix A : Visual Analogue Scale 94 vi List of Tables Tables: Table 1: A tabular representation of the HBO/DOMS study 32 Table 2: Time Course Design of the HBO/DOMS study 33 Table 3: A Comparison of Anthropometric Data 38 Table 4: Phase I Mean Pain Values (Units ± S.E.) 39 Table 5: Phase II Mean Pain Values (Units ± S.E.) 39 Table 6: Phase I and II Mean Pain Values (Units ± S.E.) 39 Table 7: Phase I Mean Eccentric Torque Values (Nm + S.E.) 40 Table 8: Phase II Mean Eccentric Torque Values (Nm + S.E.) 40 Table 9: Phase I and U Mean Eccentric Torque Values (Nm ± S.E.) 40 Table 10: Phase I and II Mean Eccentric Torque Values (Nm ± S.E.); (Outliers Removed) 40 Table 11: Strength Recovery (Gain Score) Means for Phase I Data (Nm±S.E.) 41 Table 12: Strength Recovery (Gain Score) Means for Phase n Data (Nm±S.E.) 41 Table 13: Strength Recovery (Gain Score) Means for Phase I and U Data (Nm±S.E.) 41 Table 14: Strength Recovery (Gain Score) Means for Phase I and n Data (Nm + S.E.); (Outliers Removed) 41 vii List of Figures Figures: Figure 1: Calculation of Ideal Alveolar Pressure at 2.0 A T A 12 Figure 2: Pain: Phase I Raw Data 46 Figure 3: Pain: Phase II Raw Data 47 Figure 4: Pain: Phase I and II Raw Data 48 Figure 5: Eccentric Strength: Phase I Raw Data 49 Figure 6: Eccentric Strength: Phase I Raw Data (an alternative look) 50 Figure 7: Eccentric Strength: Phase II Raw Data 51 Figure 8: Eccentric Strength: Phase II Raw Data (an alternative look) 52 Figure 9: Eccentric Strength: Phase I and II Raw Data 53 Figure 10: Eccentric Strength: Phase I and U Raw Data (an alternative look) 54 Figure 11: Eccentric Strength: Total Recovery-Phase I Data 55 Figure 12: Eccentric Strength: Total Recovery- Phase U Data 56 Figure 13: Eccentric Strength: Total Recovery- Combined Data 57 Figure 14: Eccentric Strength: Total Recovery- Combined Data (outliers removed) 58 ACKNOWLEDGEMENTS This author would like to thank the efforts and contributions of the following people, without whose assistance,this study would have never been completed; Diana Jespersen, Dr. Jim Potts, Dr. Andrew Stager, Terry Laurence, Karen Friesen, Daniel Ngui, A . William Sheel, Serge Soolsma, H Y O X Systems Inc., and OxyMed Systems. 1 CHAPTER 1: INTRODUCTION Hyperbaric oxygen therapy refers to the therapeutic procedure where patients inspire 100% oxygen while their entire bodies are subjected to pressure greater than ambient barometric pressure at sea level (110), that is, encounter pressures greater than one atmosphere absolute (ATA) or 760 mmHg. Proponents of oxygen therapy suggest several benefits from inspiring oxygen above 21 % to injured body tissue: • This therapy can offset the local tissue hypoxia by increasing the partial pressure of oxygen (18,45,46,53,81,82,84,86). • It may reduce the edema by vasoconstriction, and decrease blood flow to the area as result of hyperbaric compression (14,18,81,82,84,86,135). • Lastly, supplemental oxygen may promote healing, and prevent infection (45,78,81,82,84,86,135). Increasingly, evidence supports the efficacy of adjuvant use of hyperbaric oxygen (HBO) in healing soft tissue injuries if the trauma is adequately severe (110). Recent experimental evidence implies that pain may be decreased with intermittent to long-term exposure to hyperbaric oxygen. Vezzani and associates observed increased levels of p-endorphins and adrenocorticotrophic hormone (ACTH) (170). They attribute these increases to the stimulation of the precursor, proopiummalanocortine, after initial exposure and throughout the ten days of daily exposures (170). As well the results of an ischemic rat model suggest increased recovery of muscle strength after a period of insufficient blood flow (ischemia) and subsequent exposure to HBO (185). Therefore, the purpose of this study was to determine if hyperbaric oxygen decreased pain perception and hastened the return of eccentric strength in a human injury model (exercise induced muscle soreness). 2 The muscle soreness is more commonly referred to in the literature as delayed onset muscle soreness (DOMS). After three hundred eccentric contractions in thirty minutes, subjects were treated with daily exposures of hyperbaric oxygen and monitored for changes in the soreness and strength over a five-day period. The initial challenge, though, was to determine how and why hyperbaric oxygen would work on a soft tissue injury model. R A T I O N A L E Given the evidence of Vezzani and associates (170), and Zamboni and associates (186), plus the studies illustrating the efficacy of HBO in wound healing, burns, fractures, crush injuries, and other traumas, this author includes two hypotheses predicting the outcome for this endeavour: 1. It is proposed that hyperbaric oxygen therapy should reduce the subjective pain perception of exercise induced muscle soreness over the time course of the injury. 2. Secondly, hyperbaric oxygen therapy should accelerate the return of eccentric strength, reduced below maximal levels by exercise induced muscle soreness. To achieve an insult that caused painful and functional disturbances, a model was needed that was also acceptable to a research ethics committee and the subject population at large. Exercise induced muscle soreness or delayed-onset muscle soreness (DOMS) is serious enough to cause a local inflammatory response in the quadriceps in other studies and affect strength. Meanwhile, part of the pain caused by DOMS occurs because of the acute inflammatory response occurring in the eccentrically-exercised muscle or muscles (11,43,98,149). A convincing review by Smith (149) suggested that similarities in pain, swelling, and loss of function in acute inflammation and DOMS are due to a general response of the body to a stressful or traumatic insult. Since the body responds to all forms of tissue injury by activating 3 the inflammatory response, there is no reason to believe that a separate response has evolved to deal with injury incurred during unaccustomed eccentrically biased exercise (149). When examining pain, it appears that in both acute inflammation and DOMS a delay may occur before the onset of pain. The biochemical explanation for this event seems related to the delay in the macrophage entry into the injured area (11,149). The sensation of pain may be caused by the synthesis of prostaglandin-!^ (PGE2) from the macrophage (10,11). Smith (149) has also proposed that the pain begins with the release of large quantities of E series prostaglandins that sensitizes local nociceptors over the first twenty-four hours. An increase in the intramuscular pressure results and provides a stimulus for the prostaglandin E2-sensitized receptors. The pain itself follows, although predominantly during contraction or palpation of the damaged muscle. Similarly, the edema from the injured soft tissue and hyperemia accompanying an acute injury may cause localized pain from an increase in intramuscular pressure and/or pressure on local nociceptors. Smith conjectures that the pain of DOMS arises to encourage immobilization during critical period of healing. For an acute soft tissue injury, pain certainly encourages immobilization. However, studies observing DOMS and the effect of prostaglandin inhibiting drugs report ambiguous results when ascertaining whether NSAIDS (nonsteroidal anti-inflammatory drugs) like ibuprofen alleviate the perception of soreness (54,76,98). In acute soft tissue injuries, NSAIDS have much more success in pain relief. The similarities between the DOMS model and acute soft tissue injuries do not conclude with pain. Evidence from animal studies (11) and human models (149) suggest that a similar pattern of leukocyte infiltration into the damaged area exists. Macrophages are present at about the same 4 time at the site of injury at twenty-four and forty-eight hours in DOMS and acute inflammation (149). Most recently, Maclntyre et aL (108) has observed an acute inflammatory response in the twenty-four hours after exercise stimulus. That is, a significant number of labelled WBC was found in the exercised quadriceps muscles compared to the non-exercised leg. However, some authors believe that exercise induced muscle soreness is a result of mechanical damage to connective tissue, and/or the result of excessive Ca 2 + (calcium ion) in the sarcolemma or the extracellular environment (10,13,23). Most researchers have taken up a middle ground, where consensus has muscle damage from eccentric exercise resulting from a combination of factors or sequence of events. Kuipers (99) proposed that because similar features of structural damage are observed after ischemia and in patients with metabolic defects, it is likely that metabolic factors contribute to the induction of muscle damage. Additionally, compromised microcirculation leads to metabolic changes, and free radical formation, which may activate proteolytic enzymes. Armstrong and colleagues (12) contend that calcium plays a pivotal role for inducing the secondary changes. They assume that the mechanical overload induces an increase in intracellular calcium concentration that may trigger a chain of events after cessation of exercise including a cellular inflammatory response. Finally, animal and human studies imply that free radical formation contributes to the secondary changes (52,114,189). In summary, Rodenburg and co-workers (140) best state the conservative position on the cause of delayed-onset muscle soreness: "DOMS ultimately arises from a 'sequence of events' occurring after eccentric exercise, including myofibrillar disruption, increased permeability of the sarcolemma to muscle proteins, free radical release, and inflammatory 5 processes, with the latter possibly leading to DOMS. This 'sequence of events' is initiated by mechanical stress on the muscle fibres, metabolic overload or a combination of both." To maximize a model that induces pain, a valid instrument for assessing painful stimuli must be employed. The selection of the visual analogue scale to monitor pain intensity in this study was used because the pain literature suggests that this scale provides a simple and adequate measure of painful stimuli (143,190). Session-to-session (one day or more) reliability of visual analogue scale for experimental pain has been established at r= 0.97 (138). It was assumed that this investigator received accurate results from the subjects completing pain scales over consecutive days. However, the analysis of visual analogue scale data causes controversy. Some researchers suggest that subjective measures of pain are not suited for manipulation as averages or other statistical analysis (28,83,143). Also, they contend that subjective data should be treated as ordinal data, and analyzed by non-parametric statistical methods (28,83,143). The assumption of equal ratios of the V A S , and its subsequent analysis as parametric data, may be married with experimental pain, based on a modification of Stevens' psycho-physical law on estimated pain (151). This assumption facilitated analysis in the current study according to the ratio scale of measurement (33,151,153). The measurement of pain, though, was only half of the story. The functional changes of eccentric strength were also documented because objective outcomes of eccentric exercise have been more accurate parameters than pain scores in recovery studies (139). The work of Zamboni et al (185) provided the necessary support for enhanced strength in skeletal muscle after HBO treatments. Because of a lack of correlation between DOMS and other outcomes of eccentric exercise, many authors suggest 6 measurements of functional and biochemical variables are preferred above measurement of soreness or pain when investigating whether differences exist between groups (24,139). The change in eccentric strength begins shortly after commencing exercise. In their study, Newham et al. (122) illustrated the force loss was related to changes in the contractile elements of fully activated muscles. Those results provided evidence that an initial bout of exercise causes damage and destruction to a population of susceptible fibers, possibly those near the end of their life cycle (118). Unlike concentric exercise, where exhaustive exercise may result in short-term deficits due to fatigue, eccentric exercise may produce longer term losses. The slow return of functional strength is based on observations that immediately after exercise there is a dramatic loss in strength of over 50 % (24,43). Strength is gradually restored such that in six-to-seven days after unaccustomed eccentric exercise the eccentric strength has returned to baseline (12,24,43). However, pain alone does not cause the decrements in strength resulting from DOMS, since studies observed reduced strength of contractions even after electrical stimulation (128,149). Many investigators suggest that pain serves as protection to muscles, but not necessarily a limiting factor in strength (126,135,162). The literature suggests that trained subjects are less susceptible to DOMS, elevation of serum creatine phosphokinase (CK), and muscle disruption (115). Therefore, to demonstrate changes in DOMS variables untrained subjects had to be used for the best results. As well adaptation from one exposure seems to last at least 6 weeks for strength recovery, muscle shortening ability and soreness, and ten weeks for muscle contractures (40). These effects have been demonstrated by the ability of muscle to recover contractile function more quickly following subsequent bouts of strenuous eccentric exercise up to ten weeks later (40,115). As a 7 consequence, recent exposure to eccentrically biased activities by possible subjects was controlled for in this experiment. Although recruitment of subjects would have been easier had females been included, women were not for a specific physiological reason. Studies have demonstrated that after a comparable amount of eccentric work males have a higher plasma C K activity than females, suggesting that males may have more extensive muscle damage. Amelink and Bar conducted studies showing that androgenic steroids increase the C K efflux and that estrogen inhibits enzyme release (7,8,17,99). Therefore, fiber damage is not necessarily reflected in proportional increases in plasma C K activities. Also, the inclusion of female participants may have increased the variability in the torque measurements. Obviously, unlike an animal environment, some variables are beyond an experimenter's controL Certain assumptions are inherent for this study. Assumptions 1. Three hundred eccentric contractions caused a functional insult in all subjects used. 2. Subjects concerted their maximal effort during the exercise protocol and accurately reported their pain rating at the specified time. 3. Subjects did not exercise intensely before or immediately (up to twenty-four hours) after the DOMS protocol 4. The subjects responded honestly about the average amount exercise they performed in a week. Delimitations 1. To maximize the extent of the induced muscle soreness, sedentary or relatively sedentary subjects were used rather than more athletic subjects. 8 2. To ease the recruitment of subjects, the pool of male subjects who were attending university (acceptable limits-18 to 35 years of age) was targeted. 3. The use of delayed onset muscle soreness: (three hundred eccentric contractions) allowed the investigator to control the origin and the severity of the injury. Limitations 1. This study may not apply directly to soft tissue inflammatory injuries like contusions, lacerations, abrasions, and more serious injuries like sprains and fractures. 2. The severity of the soreness induced may be subject to inter-subject variability. 3. The power of the study was based on differences not directly determined in the literature. However, a difference of 25 % was approximated in strength or pain perception, with a fairly large variability of 20 %, Cohen's d for effect size was 1.2. Using the power tables for independent t-tests, since these tables were the best available, given a lack of A N O V A tables, the power of this study was at least 0.85 using 10 subjects per group at a significance level of p< 0.05. In fact, some of the HBO literature, (36,74,92) suggested that the observed effect size may be 1.5 or higher, which made this study potentially more powerfuL CHAPTER 2: REVIEW OF LITERATURE P H Y S I O L O G I C A L EFFECTS OF H Y P E R B A R I C O X Y G E N Although the interest in applying HBO to sports injuries is a recent phenomenon, the basic physiobgy of increased oxygen tensions in injury management has a rich history. Grounded in research due, in large part, to diving and undersea medicine, persuasive anecdotal evidence exists demonstrating the efficacy of hyperbaric healing. Residents living at high altitudes notice that wounds heal more slowly than at sea level while people living in undersea habitats at hyperbaric pressures observe wounds heal faster at the enhanced pressure environment as compared to sea level (82). Physicians and physiologists operated on that postulate and eventually formulated an explanation for the increased healing phenomenon (81). With a soft tissue injury, like a muscle contusion, the injury may cause disruption of cells and blood vessels at the injury site and a subsequent aggregation of platelets and collagen. This event causes the injured vessels to thrombose, and nearby vessels dilate especially venules. Leukocytes migrate between endothelial cells in the area of injury (86,149). Within hours, the edge of the area is infiltrated by granulocytes, polymorphonuclear cells (PMN) and macrophages (two to six hours) (86,149). As a consequence, the injured tissue is overloaded with rapidly metabolizing white cells. These cells are shortly replaced by metabolizing fibroblasts in area of damaged vasculature(86). Thus, at the time when the metabolic needs are at their greatest, the local circulation is least able to supply that need. Accordingly, a local energy crisis results and a hypoxic environment occurs (81,135,147). If macrophages and monocytes cannot reach the wound, delayed collagen formation ensues, followed by a consequent delay in the neovascularization (81,82,86). 10 The initial damage can lead to tissue edema, complications with blood flow, and eventually, tissue death (86). These complications may include ischemia (the decreased or non-flow of blood to an area) which affects normal and partially damaged tissue (45,63,86). The efflux of extracellular fluid impairs the oxygen delivery from the capillaries to the cells by increasing the diffusion distance (86). "When tissue oxygen (O2) tensions fall below 30 mmHg, the responses of cells to subdue infection and ischemias are compromised (81,136). Leukocyte-bactericidal efficacy becomes defective or non-existent (78). Host repair processes like fibroblast secretions of collagen are arrested (81). Therefore, without a collagen matrix in wound, and without new blood capillaries, wound healing cannot occur (81,135,136). Rapid application of HBO results in increased tissue oxygen tensions that make it possible for host responses to become functional (81,86). At 2.0 ATA, the blood O2 content is increased 2.5 % while plasma and tissue oxygen tensions increase tenfold (1000 %) (18,86). Sufficient oxygen becomes physically dissolved in plasma to keep tissues alive despite inability of hemoglobin-bound oxygen to reached the insulted area (4,51). Edema reduction secondary to the vasoconstriction is another effect. The reduction in blood flow with no change in stroke volume produces a subsequent 20 % reduction in post traumatic vasogenic edema (174). Essentially, HBO therapy maintains oxygen delivery while blood flow to microcirculation remains intact (86,131,148,184). Early application of HBO within the first 4-6 hours after injury achieves the best results provided a sufficient vascular supply exists (74,82,86). These consequences of HBO depend on the physiologically sound explanation of how the oxygen gets into plasma. Dalton's Law asserts that the total pressure exerted by a mixture of gases can be expressed as the sum of the partial pressures of each gas in the mixture. With the subject breathing 100 11 % oxygen, the partial pressure of oxygen comprises the entire mixture and thus exerts all the pressure. However, the delivery of partial pressure of a gas to the body differs from the pressure of the ambient air, especially in a hyperbaric environment (18,86). Henry's Law states that the degree to which a gas enters into physical solution in body fluids is directly proportional to the partial pressure of the gas to which the fluid is exposed (18,86). In this case, as the partial pressure of an inspired gas (oxygen) increases, the amount of physically dissolved oxygen in plasma increases proportionately. Gas dissolved in a liquid exerts partial pressure or tension equal to the force with which gas molecules move through the liquid (18,86). While Henry's Law describes relative quantities, the absolute amount of gas in physical solution is determined by its solubility coefficient, which is temperature dependent (18,86). The solubility of oxygen in plasma at 37°C is 0.0214 mL oxygen per mL plasma per atmosphere PO2, but it is more soluble in a hemoglobin-water solution (18). Therefore, one must adjust to estimate the overall physical solubility of oxygen in whole blood. Assuming an oxyhemoglobin capacity of 20 voL %; the solubility of oxygen in water of whole blood at 37 °C is 0.0236 mL O2 per mL blood per atm PaOi or 0.003 voL % Oi/mmHg PaCh (18,86). At 2.0 atmospheres absolute, breathing pure oxygen, the ideal alveolar pressure is 1433 mmHg (18). See Figure 1 for a sample calculation of the ideal alveolar pressure. Thus, the blood contains, theoretically, 4.44 vol % of dissolved oxygen (18,86). In reality, because of ventilation/perfusion imbalances (even in normal lungs), anatomical shunts, and diffusion barriers, the arterial partial pressures may be slightly lower than the alveolar values (18,81). 12 Figure 1: Calculation of the ideal alveolar oxygen pressure at 2.0 ATA Alveolar Gas Equation PAOZ = PTOZ - P A C C V R + [ P A C O J * F A * 1 - R / R ] , where P A C A = 4 0 mmHg and R = 0.8 (breathing air) and PACQS = 4 0 mmHg and R = 1.0 (breathing 100% oxygen), and P T 0 2 = ( P B - 47) * F A At 2.0 ATA: P A A = (1520 -47) * 1.0 - 40/1 + [(40) * 1 * 0] = 1473 - 4 0 = 1433 mmHg 13 One study measured the partial pressure of oxygen in blood at 2.0 A T A to be 1376 mmHg (174). No consensus exists concerning what constitutes tissue hypoxia in vigorous muscular work or in injured tissue. That is, some studies have reported that the tissue environment becomes hypoxic when exposed to a Pa0 2 less than 40 mmHg (175), 80 mmHg (116), or even as low as 2 mmHg (155). However, in work by Sheffield, he suggested that the optimal P 0 2 lies between 50-100 mmHg at the circulatory level (144). He further stated that hyperoxic treatment healed most effectively when the wound P A was greater than 30 mmHg (145). Despite the great quantity of work on the medical use of hyperbaric oxygen, this review referred only to topics of soft tissue damage and recovery: the effects of HBO on burns, wound healing, fracture healing, crush injuries and related orthopaedic traumas, human perfomance, and sports injuries. Nevertheless, because inspiring oxygen above ambient temperature and pressure is a drag and has the potential for tissue damage, a review of the toxic effects of oxygen must be considered. OXYGEN TOXICITY Like most drags, excess oxygen can be detrimental The threat to the central nervous system (Le., grand mal seizures) is more pronounced at 3.0 A T A (39,41,101), whereas independent of any CNS damage, pulmonary oxygen toxicity can occur at 2.0 A T A (4,5,39,40,58,102,152). In both cases, though, the toxic effects occur after prolonged exposure under pressure (Le., three hours or more) (39,40). Early effects of oxygen toxicity can be completely reversible, but prolonged exposure initially increase the recovery time, with repeated, extended sessions leading to irreversible damage (86). Certain drugs like aspirin, insulin, and adrenocortical steroids, hormones like epinephrine and norepinephrine, and 14 physical exercise may enhance the onset of oxygen toxicity (9,64,86). A study conducted at 2.0 A T A breathing pure oxygen with multiple bouts of exercise and rest, concluded no adverse effects on oxygen tolerance with exercise (152). Conversely, certain drugs have been used to prevent or delay the onset of toxicity: antioxidants like vitamin E, lithium, disulfiram, and magnesium. Money observed that protection against toxicity directly related to the level of vitamin E supplementation (118). Another useful experimental antioxidant includes an exogenous supply of superoxide dismutase, which is an antioxidant defense chemical normally found in the body (162). The simplest way to prevent oxygen toxicity is through interrupted exposure to pure oxygen by periodically breathing normal air (21% oxygen) (42). Most of these studies involved animals and/or humans exposed to HBO for durations and depths not normally employed in soft tissue injuries. Of greater interest is literature examining toxic effects of hyperbaric oxygen at therapeutic 'doses'. A prospective study exposed patients to pure oxygen (100%) in 2.0, 2.2, and 2.4 A T A hyperbaric environments and detailed no oxygen related complications or seizures at 2.0 A T A in 12,468 cases during a five year continuing study (77). The only complication at this pressure was mild aural barotrauma (77). Other complications sometimes observed at this pressure can include nausea, tooth and sinus pain, and blurred vision (86). The suggestion is that intermittent HBO exposure for 60 minutes at 2.0 A T A poses no toxic risk (18,32,40,86). The only contraindications for HBO therapy in otherwise healthy people appear to be upper respiratory tract infections, fever, and claustrophobia. The former contraindications prevent patients from undergoing HBO until the symptoms are resolved. Claustrophobia can be 15 overcome with familiarity and patience by both the subject and the chamber operator (60,86,100). Carbon dioxide retention theoretically presents a problem. Considering that hemoglobin normally transports 20% of the excess CO2 and that HBO completely saturates hemoglobin, the excess is disposed of by the plasma (venous side) in a dissolved form, and by the bicarbonate buffer system (H2CO3-HCO3). A consequent minor rise in PCO2 of approximately 5-6 mmHg (18,86) follows. Carbon dioxide does not rise continuously in the blood and tissues as long as the blood flow remains constant, which is not a problem in healthy subjects (86). Even with the mild increase in CO2, the effects are transitory and disappear within one to three hours post exposure (18,85). Therefore, as long as subjects avoid prolonged exercise in a hyperbaric environment, excess carbon dioxide poses no physiological threat (86,100,102). H Y P E R B A R I C O X Y G E N A N D BURNS A great deal of research has gone into the effect of HBO on burns, especially thermal burns. In almost all cases, the HBO treatment was used as adjunctive therapy. Animal studies examining second degree burns report faster epithelialization, decreased fluid requirements, less conversion of partial to full thickness injury, a reduction in edema, and a reduced inflammatory response when treated with HBO (29,97). In a model scald burn, Nylander and associates demonstrated a decrease in global edema following an ear burn, which they credited to marked vasoconstriction (130). More recently, Stewart and associates examined the effect of HBO therapy on ATP, phosphocreatine, and collagen synthesis in burn wounds in rats (154). They established that adjunctive HBO can preserve or enhance energy rich phosphate compounds and collagen synthesis in model burn wounds (154). 16 In controlled human studies, adjunctive HBO therapy has had definite clinical benefits: decreased mortality (71), marked improvement in morbidity (34,35,179,182), and a decrease in length of hospital stay with matching of patients for severity of burns (67,179). In comparative studies with patients of second and third degree burns, results demonstrated faster epithelialization, and a decrease in healing time in the patients whose treatment included HBO. The mortality rates were not affected (127,178). Also, no attempt was made to match patients based on severity of the bum or age (127,178). A human study dealing with severe burns reported fewer deaths, reduced length of hospitalization, reduced need for surgery, and decreased cost of care in the adjunctive HBO group (36). A criticism of this study is the small sample size used (37). In severely burned hands, Cianci and associates discovered that HBO adjunctive therapy reduced by half the number of patients that needed surgical grafting. They concluded that HBO gave excellent cosmetic and functional results (35). While few double blind studies with human subjects have been done with HBO treatment under any circumstances, one of the most influential bum experiments is the study by Hart and associates (74). They observed a difference of 21 days between control and HBO-treated groups in mean healing time while pairing for bum severity (74). In a double blind study using a human bum model, HBO had beneficial effects on superficial dermal lesions, and caused reductions in edema, exudation, and hyperemia, but failed to accelerate the rate of epithelialization on a u.v. irradiated suction blister (70). This volume of research suggests increased healing and possible beneficial effects on epithelialization when HBO was used with conventional therapy. However, evidence from other controlled randomized human studies contradicts the majority of the literature. These results suggest HBO alone or as an adjuvant is 17 not effective in healing severe burns (130,136), or increasing vascular proliferation in granulation tissue formation in full-thickness burns (136). In a small series study, with paired control groups in severe burns, Waisbren et aL found no deleterious nor beneficial HBO effects on mortality, with some impairment of renal function (188). Perhaps the delay before initiating adjunctive HBO treatment, (twenty-four to forty-eight hours post injury) is responsible for the discrepancies in the literature. H Y P E R B A R I C O X Y G E N A N D W O U N D H E A L I N G A host of studies has been conducted into the healing powers of hyperbaric oxygen. The majority of studies have investigated chronically non-healing open wounds (57,68,85,160). Collagen synthesis, necessary for tissue repair and growth, requires oxygen as does enzymatic hydroxylation of the collagen molecule (necessary for scar formation) (81,82). Without oxygen, production of intracellular ATP is likewise affected (100). For the HBO therapy to be most beneficial, investigations indicate the compromised or injured area must have intact regional blood flow (81,82,84,103,136). Exposure to hyperbaric oxygenation substantially increases arterial PO2, causing significant increases in wound oxygen tension in previously hypoxic wounds, as measured by invasive polarographic electrode (144). Consequently, healing appears to be stimulated by hyperoxic and hyperbaric exposures in animal and tissue cultures (9,47,48,63,82,155). In general, HBO promotes granulation tissue formation (103,135), revascularization (103,135), epithelialization (103,135), while stimulating increased fibroblastic activity with collagen production (124), fibroblast migration (116), and capillary budding (81,136). Hunt and Pai tested rabbits breathing hypoxic, normal, and hyperoxic (12%, 21%, and 45% oxygen) and observed collagen synthesis above normal in the hyperoxic group (82). They 18 proposed that collagen accumulation is related to partial pressure of arterial oxygen, although they could not explain the cellular mechanisms involved (82). Another animal study detected greater survival rates of rat skin flaps treated with HBO than skin flaps receiving no treatment (62). A more recent study demonstrates that HBO therapy effectively enhances healing of hypoxic wounds [tissue cultures in low (< 40 mmHg PO2) oxygen environments], but does not amplify healing in normoxic wounds (9). Generally, HBO appears to have little role in healing clean, normal, incised wounds (81,104,141). At the same time, daily HBO over five days does not increase the severity of inflammation in a human inflammatory model (2). The study used a shorter than recommended exposure (30 minutes) (176), plus the authors admitted their results could not predict how long-term exposures (10 days and longer) affect this model (1,2,29). In light of these shortcomings, the aforementioned studies provided helpful but not unequivocal predictions concerning the success or failure of this current study. Clinical studies suggest that in hypoxic wounds (PO2 = 5-20 mmHg), tissue healing occurs with sufficient tissue oxygenation and that response is enhanced by HBO (144,145,146). Also, an improvement in healing in uncontrolled trials has been demonstrated even in the presence of ischemia, infection, or neutrophilic changes (96,103,110). In a prospective, controlled study with chronic diabetic foot lesions, Doctor et aL found better control of infection and less need for amputation in the group treated with conventional management and four sessions of HBO (53). Not all studies have been positive (75,95). An animal study determined that long-term HBO at 2.0 A T A had no effect of the healing rate in open wounds with the circulation left intact (95). When the wound edges were devascularized, however, HBO enhanced the wound closure rate in the final stages of healing (95). Other experiments suggest human cell samples 19 receive no benefit from HBO sessions in prolonging full thickness, partial thickness, or cryo-preserved skin graft survival nor any improved immune response (120,161). An experiment involving HBO in combination with fibrin sealant suggests hyperbaric oxygen has no effect on enhancing early wound strength in axial rat incisions (75). In fact, the authors submit that HBO may have deleterious effects on early wound strength (75). Therefore, HBO seems to be a useful adjuvant to conventional treatments in wound healing and control of infection in humans, whereas in vitro and animal studies are not as definitive. The lack of positive results in the animal and the in vitro models may be due to the mildness of the imposed injury and/or an insufficient vascular supply. H Y P E R B A R I C O X Y G E N A N D F R A C T U R E H E A L I N G Hyperbaric oxygenation has been used on many occasions to attempt to heal non-union and complicated fractures where the chance of infection is increased (125,126). The rationale seems to be that healing is retarded or does not occur in hypoxic environments, especially those susceptible to anaerobic infection (125), like open and multifragmentary fractures and high energy injuries with soft tissue insult (68,133,164). HBO exposure appears to increase the rate of bone mineralization (171,177), and of hematoma formation (177). HBO generally alters the homeostatic environment by affecting bone cells and/or bone mineralization (65,169,177). In animal studies, researchers have found reductions in osteoblast formation (46,177), increased healing in infected and hypoxic tibial fractures due to systemic hyperbaric oxygen exposure (133), stimulated repair of non-inflamed mandibular fractures at 2.0 A T A (92), and in cases of significant inflammation of mandibular fractures, stimulated repair at 2.5 A T A (92). With clinical trials, several studies have used HBO as an adjunct to conventional therapy and found reductions in healing time for the HBO-treated groups (158,169,188). In one series, 20 investigators recorded a difference of two weeks from what was normally expected (188). Other clinical studies with open fractures did not observe decreased healing time (57,95). These poor reactions may be related to a late start in HBO treatment (Le., twelve hours or more after the injury). Little attention has been paid to accelerating bone healing in uncomplicated fractures by HBO therapy because most bones heal safely on their own. Studies with fractured rat tibias demonstrate that expedited development of callus tissue was achieved from intermittent hyperbaric treatment compared with atmospheric controls (81,125). However, no significant differences in mechanical strength were observed (81,125). Studies of faster healing in uncomplicated fractures in humans would be of the most interest to athletes and sports medicine practitioners. At present, these studies do not exist. HYPERBARIC O X Y G E N AND CRUSH INJURIES/ ORTHOPAEDIC T R A U M A S Given the reputed benefits of HBO therapy, the reduction of swelling, edema, and enhanced healing capacities proves advantageous in a traumatic injury situation. Such traumatic insults include severe injuries to the limbs with vascular damage (156,171), extensive skin loss (171), anaerobic infections associated with open fractures (45,46,84,85,171), real or artificial ischemia (113,133,142), and compartment syndromes (72,120,157,159). In crush injuries the blood loss is diffuse, resulting in tissue hypoxia (156). With the hypoxia, the cells do not die but their function can be severely affected. That is, the abilities to resist infection and repair themselves are partially or entirely compromised (89,151). Of secondary consequence to tissue hypoxia, and increased blood flow, edema can accompany any injury, resulting in stagnation of extravasated blood and serum (9,156). The edema often causes an increased diffusion distance for oxygen from the capillaries (86). As a result, external pressures of the swollen tissue 21 collapse the microcirculation and exacerbate the perfusion problems (86,148). In a closed crush wound, all circulation to the injured area is effectively stopped (133). HBO therapy can cause a 20% reduction in blood flow almost immediately (19). Additionally, the increase in the arterial content and plasma content of the blood can provide a sufficient environment necessary for macrophages to kill efficiently (a PO2 of at least forty mmHg) (78,96,113). Several practitioners have realized this potential and recorded their experiences. Initial experiences treating patients with HBO had mixed results. Bird and Teller suggest that in grossly ischemic limbs, the hyperbaric oxygen might not ever reach the limb (19). Consequently, reduced blood flow to a distally ischemic wound would have little recuperative benefit (19). That recommendation is based on their observation of virtually no difference in the oxygen content provided to normal limbs (19). In clinical trials, researchers have demonstrated beneficial results from adjuvant HBO therapy, like combatting wound infections accompanying open traumas of their extremities (84), accelerating the recovery of neutrophil phagocytic activity (45,92), saving limbs from amputation (156), and healing the open fracture without suppuration (dead skin with a distinct line of demarcation) (84,85). Unfortunately, they neglected to compare these results with patients treated more conservatively to illustrate a clear difference in healing. Holt sums up the use of HBO in trauma, suggesting that adjuvant use of HBO with normal aggressive treatment can stimulate repair following trauma (80). The effects of tissue edema and ischemia on injury have drawn the attention of many researchers. They have simulated ischemias with animal models to check the efficacy of HBO therapy in treating these disorders. Nylander and associates subjected rat hind limbs to three hours of temporary ischemia, then forty-five minutes of HBO at 2.5 A T A (129). The 22 treatment caused a significant reduction in post ischemic edema of the tourniqued leg for up to 48 hours after restoration of circulation. They concluded that HBO was a useful adjuvant in the treatment of acute ischemic conditions when surgical repair could not be attempted or failed to reverse ischemia (129,131,132). To simulate compartment syndromes (increased pressure in skeletal muscle compartments causing reduced capillary perfusion, and leading to ischemia, nonfunction, and necrosis of tissues), Hargens and associates imposed 100 mmHg of pressure for eight hours on the lower legs of selected dogs. They waited two hours, and then subjected the animals to three intermittent HBO exposures (72). The HBO treatment, even delayed for two hours, reduced muscular necrosis to almost nil compared to the controls (72). From the histological assessment of the muscular necrosis, the HBO-treated dogs had near normal muscle morphology in relation to the control dogs. Intramuscular edema is also significantly less in the HBO-treated dogs (approximately 20 %) (72). Skyhar and associates in experimental animal models illustrated reduction in edema and skeletal muscle necrosis connected with hemorrhagic hypotension (148). The clinical relevance of this finding is that patients with borderline compartment syndrome and hemorrhagic hypotension may benefit from HBO as an adjuvant to normal therapy (148). In the only human (prospective) study, Strauss and associates (159) reported resolutions of neuropathies, arrest of tissue necrosis, an absence of secondary infections in two thirds of the 38 patients treated with HBO following surgical intervention to relieve the pressure. The other third received HBO upon onset of symptoms and signs like an increase in intracompartmental pressure. None of this group required surgery and all recovered completely (159). 23 Finally, using animal models, Zamboni and his associates have completed several experiments examining the effect of hyperbaric oxygen on ischemic muscle (183,184,185,186,187). In injured ischemic tissue, blood flow is reduced because of the partial collapse of the microcirculation. Hypoxia-induced rigid RBCs have been found to obstruct capillaries blocking other RBCs which might be deformable. As a consequence, local hypoxia can be self-reinforcing (112). Also, the cellular elements are more impeded in their flow through the compromised microcirculation than the plasma. Therefore, with the increased oxygen content, tissue oxygenation is maintained in the presence of hypoxic, partially collapsed microcirculation (185). Zamboni and colleagues found no evidence of arteriolar vasoconstriction in rat muscle microcirculation following four hours of ischemia and one HBO treatment at 2.5 A T A compared to non-ischemic and non-HBO controls (183,184). In the follow-up study, Zamboni and associates examined the acute effects of hyperbaric oxygen in ischemic axial flaps in rats (185) . They observed that HBO treatment improves distal microvascular perfusion as measured by laser Doppler flowmetry in the skin flaps whether given during or post global ischemia (185). The results suggested that HBO-induced vasoconstriction did not occur in the microcirculation of ischemic rat skin flaps (185). Most recently, this same research group, using a rabbit hind limb ischemia-reperfusion model noted that HBO treatments on ischemic muscle reduce edema and improve strength (186) . Zamboni suggest that these beneficial effects can only be achieved at the high oxygen tensions provided under hyperbaric conditions and that this result tends to corroborate this research group's previous microcirculation results (186). Thus, this body of the literature 24 suggests experimental beneficial effects that require further scrutiny in human controlled, double-blind studies. HYPERBARIC OXYGEN AND HUMAN PERFORMANCE Oxygen has been singled out as a possible limitation to exhaustive exercise (26,49,50,102). Using hypoxic gases or hypoxic (high altitude) environments, subjects suffer a reduction in their maximal oxygen consumption (175). They also produce greater lactate levels for moderate to severe hypoxic conditions (fraction of inspired oxygen [FTO2] < 16%) compared to performance under normoxic conditions (6,175). This information suggests that a lack of oxygen degrades performance. To that end, a great deal of research has explored if oxygen has any capacity of augmenting performance. Oxygen-enriched performance studies have been conducted under normobaric conditions (1 ATA) while breathing 100% oxygen and also under hyperbaric conditions (> 1.0 ATA) while inspiring pure oxygen. For both conditions, some general physiological responses occur. The cardiovascular system responds with bradycardia and decreased blood flow to an exercising limb to offset the increase in oxygen tension (86). Pulmonary function changes with decreased pulmonary ventilation and a decrease in oxygen consumption compared to exercise under normal conditions (86). Biochemically, there are increases in concentration of the hydronium ion [H 4], a reduction in excess lactate and a diminished rate of glucose utilization (86). Because lactate has been identified as a culprit in fatigue and subsequent recovery (50), a plethora of research has examined the link between lactate metabolism and hyperbaric oxygenation. Studies have illustrated lower lactate levels in exercising muscles after exposure to hyperbaric and hyperoxic conditions (16,26,49). Several theories have been proposed to explain this phenomenon: 25 • the oxygen to exercising muscles during HBO is sufficient to decrease lactate formation by counteracting hypoxia and subsequent lactate production (174); • HBO stimulates the oxidative the oxidative enzymatic process to cause a rise in the removal of lactate (174); • HBO inhibits glycolytic sulfhydryl enzymes and thus impairs glycolysis and decreases lactate (174). The inhibition appears to last for forty-five minutes following exercise. This phenomenon would explain the continual decrement of lactate after HBO exposure and subsequent exercise under normobaric conditions (6,174,175). In a study comparing the blood chemistry in healthy adults exercising while breathing air under normal pressure and pure oxygen at 1.5 A T A (59), the lactate levels immediately following exercise (1-20 minutes) were lower for the HBO condition than for the normobaric condition (59). More studies have been conducted using hyperoxic rather than hyperbaric conditions, probably due to the problems experienced exercising above 1.5 ATA: increased respiratory resistance because of the denser inspired gas; the heightened energy cost of ventilation; carbon dioxide retention; dyspnea; bradycardia. Therefore, the increased pressure may cancel the beneficial effects of the increased oxygen content. In performance, several studies have demonstrated a benefit from HBO. One study concluded that while breathing pure oxygen at 2.0 ATA, ventilation decreased, arterial pH and PCO2 were restored towards resting levels, and fixed blood acid was reduced (102). No oxygen toxicity occurred during the exercise. Linnarsson et a l (105) found that with submaximal exercise oxygen deficit, phosphagen depletion, and muscle lactate production were inversely proportional to inspired PO2. This information was based on one 4-minute 26 submaximal bicycle test at 50% of the subject's maximal oxygen consumption (VO2 max) and a 4-minute maximal test. The authors also suggested that tissue hypoxia may have accounted for lactate formation at the onset of exercise and the hyperoxia seemed to slow the formation of lactate. This observation was based on the decrease in lactate formation and the other decreased glycolytic enzymes (glucose-6-phosphate, pyruvate) during submaximal exercise at 1.4 ATA, compared to the results under normoxic conditions. Unfortunately, due to the poor statistical analysis of this article (multiple t-tests, which increases the chance of a false positive result), the use of a submaximal aerobic tests to predict maximal performance, and hyperbaric exposures of less than sixty minutes which may not properly perfuse the working muscles, the results and conclusions should be interpreted cautiously. Another study exploring performance under hyperbaric conditions discovered that maximal aerobic performance is not enhanced by HBO exposure. Specifically, the maximal oxygen consumption in an active muscle was not increased when the content of arterial oxygen was increased, via percutaneous catheter sampling of arterial and deep venous blood (90). The study did demonstrate a significant difference between the control and experimental conditions (HBO at 3.0 ATA) in terms of maximal exercise lactate concentration (90). The problem with this experiment was that the maximal work performed did not adequately tax the aerobic system in terras of duration of exercise [6 minutes]. The author did not consider the increased work of breathing in a hyperbaric environment due to an increase in the density of the inspired gas as a possibility in explaining the lack of an increase in muscular performance during HBO exposure. Therefore, the conclusions of this study should be interpreted cautiously. With animal studies, Loduto exercised dogs under hyperoxic and submaximal conditions, and found evidence that the metabolic rate and cardiac output were decreased with 27 implications for metabolic regulation of oxygen utilization (106). In an interesting study by Nelson and associates (121), the researchers attempted to determine if intermittent doses of hyperbaric oxygen stimulate or otherwise alter skeletal muscle metabolites like citrate synthase, adenylate kinase, and a-glycerophosphate dehydrogenase (121). Over eight weeks they examined post-mortem the presence or activity of the aforementioned enzymes in soleus, tibialis anterior, and planteris muscle samples of rabbits. In the soleus muscle, the researchers found increases in cc-GDPH and citrate synthase for the tissues exposed to 100% oxygen at two atmospheres for ninety minutes per day, five times a week compared to the control group tissues (50% and 36% greater, respectively) (121). They concluded that intermittent hyperbaric exposures, like acute exercise, may cause adaptation to occur by inhibiting certain enzymes like nucleotide adenosine dehydrogenase (NADH). HBO may also influence certain other enzymes in the same pathway (glycolytic or citric acid cycle) to increase (121). The indication was that adaptation only occurs in slow twitch fibres, like the soleus (121). However, the authors suggest that repeated intermittent exposures to HBO may cause repeated enzyme inactivation. This systematic manipulation may provide a stimulus, like aerobic training, for inducing an augmentation in enzyme activity (121). A paucity of studies have considered the prophylactic effect of hyperoxia or hyperbaric oxygenation, although a hyperoxic study suggested a six per cent increase in oxygen consumption if the exercise proceeds within five minutes of hyperoxic exposure (6,180). In a randomized study examining cardiorespiratory parameters in athletes (made up of rowers and judo wrestlers) (107), two weeks of intermittent hyperbaric exposures at 2.2 A T A (ten sessions) appeared to show significant reductions in heart rate and oxygen consumption at submaximal levels in the HBO-treated group compared to the control group (104). A study by 28 Cabric et aL (27) suggested that HBO at 2.8 A T A improved maximal oxygen consumption and time to fatigue by 10-18% (27). They also reported that the beneficial effects lasted up to three hours post-exposure (27). However, given the technique used to quantify oxygen consumption (a Douglas bag technique), these results should be interpreted prudently. Hoffman and associates (79) performed a study similar to the Cabric study. This protocol employed an exhaustive bicycle test (speed-independent) initially, and two bicycle tests to exhaustion at seventy per cent of the maximum power based on the initial test (79). The authors observed no difference in the time to exhaustion or work capacity between the HBO group (pure oxygen) and the control group (normal oxygen) after treatments at 1.5 A T A (79). Confounding issues of this study included no absolute control group (no hyperbaric exposure at all) and the use of older subjects whose minimum age was forty years. Thus, very little valid, objective proof currently exists suggesting that HBO improves human performance, since it does appear to alleviate factors that cause fatigue. Hyperbaric oxygen does not provide a reservoir of oxygen that can be tapped into after exposure. It is possible that the time to recover may be lessened with hyperbaric oxygen (86), although further research needs to be conducted into exhaustive aerobic and anaerobic work and recovery. H Y P E R B A R I C O X Y G E N A N D SPORTS MEDICINE At this time, a scarcity of research exists in this domain. The only completed study, in part supported by a company that produces monoplace chambers (HYOX), with professional soccer players in Scotland claimed up to a 70 % reduction in days lost to injury (87). The results compared a physiotherapist's estimation of the time course for the injury and the actual number of days missed as a result of routine therapy and daily (1 hour) sessions of HBO at 2.0 A T A (87). This study required a control group, input from an objective third party (physician), 29 and greater homogeneity of injuries, to have more persuasive data. As exciting as the possibility of cutting injury time in half especially for professional sports teams, the claims by the group from the United Kingdom must be substantiated by randomized, controlled, and double blind studies with quantifiable injuries (Le., ankle sprains). Currently, a study of ankle sprains recently concluded at Temple University. The preliminary analysis of the patient data suggests subjects treated with HBO returned approximately 30% faster than the control group (R. Peterson, personal communication). Given the large amount of variability in the study, the result was non-significant. The authors of the study stated that the difficulty in quantifying the severity of ankle sprains created much of the observed variability. The initial human trial had inconclusive results. An animal study using a downhill running model to initiate damage showed significant changes in the myeloperoxidase levels in rats treated with hyperbaric oxygen compared to untreated rats. This study was suggestive of an inhibitory effect of HBO on the inflammatory process or the ability of HBO to actually modulate the injury to the tissue (150). To document the latter suggestion, another study involving muscle histology is in the planning stages. The objectives and design of this study met most of the requirements for stringent scientific research. This study utilized a randomized, double-blind design with a quantifiable injury with a controlled start and end point. 30 CHAPTER 3: METHODOLOGY Subjects Relatively sedentary or untrained male subjects of university age (18-35) were included in this study. The term "untrained" for the purposes of the study referred to subjects who did not regularly participate in physical activity more than four hours a week on average. To satisfy the power requirements, seventy subjects were recruited. Forty volunteers participated in phase I of this study. Thirty volunteers participated in phase II of this study. The segment of the student population excluded from participating in this investigation encompassed athletes who were actively weight training, running, training for most team sports (basketball, volleyball, football, soccer, etc.), and skiing, because these activities had some eccentrically-biased component in training. Also, subjects who had experienced delayed onset muscle soreness in the last three months were excluded. If a preliminary examination by their physician indicated an incompatibility to hyperbaric exposure, (Le., pneumothorax, idiopathic lung cyst, hyperinflation, any other lung abnormality, unresolved upper respiratory tract infection, or fever at the time of exposure), these potential subjects did not participate in our study. Also, since the non-dominant leg was used as the exercise leg, subjects who had recent knee ligament injuries and/or surgery, or had chronic knee pain to their non-dominant leg were excluded. For any inconvenience that occurred as a result of participation in this study, subjects received an honorarium of $100 for phase I and $75 for phase II, upon successful completion of the protocoL Procedures The first phase of the experiment involved four groups of ten subjects to determine the efficacy of HBO on strength recovery and pain perception as well as a placebo effect and the 31 effect of delayed treatment. The second phase involved a closer examination of treating DOMS with HBO using a longer treatment window (five versus three hyperbaric treatments). In addition, from the results of the two phases, the data from sham and HBO groups was combined and compared over the first three days of treatment, to elucidate the short-term efficacy of hyperbaric oxygen on delayed onset muscle soreness. See Table 1 and Table 2 for an alternative representation of the experimental design. Subjects accepted into the study were instructed to appear with a water bottle, and wearing T-shirt and shorts. Subjects gave informed consent in accordance with the standards of the University of British Columbia Clinical Screening Committee for Research Involving Human Subjects. A l l subjects were exercised on a KinCom Dynamometer (Chattecx, Chattanooga, Tennessee) either at the unit located on the third floor of the School of Rehabilitation Medicine or at the Allan McGavin Sports Medicine Centre. In addition to the seventy subjects who completed the protocol, five other subjects began but did not finish the protocol because their physical status contraindicated further participation (either recent upper respiratory infection or claustrophobia). Subjects were asked to perform four deep knee bends; and subsequently filled out a visual analogue scale (VAS), given a the range of 'no pain' to 'worst pain ever experienced'. (See appendix A). The subjects were instructed to repeat these steps following the exercise bout and report any feelings of pain (not fatigue) in the exercised leg. This investigator set the KinCom dynamometer arm to proper distance for each subject and lined up the center of the subject's right knee with the middle of the rotational axis of the KinCom. To account for the effect of gravity on eccentric torque, the leg was weighed. To prevent unwanted movement, H 03 cr CD 03 cr c_ —* TO - i CD C/3 CD a 03 I—* o" 3 CD I 00 O D o CO C/3 i—»• c C L < CO 3 CD cn l ro co ct> 3 C O O co C O I o o O CO 0 3 ro • ro O co CD 3 m x D CD 3' CD 3 O c a O o 3 g-ZJ" 03 o" 13 o ^ CO "0 =r 03 C/3 CD CD O CO — L 03 Q. s cr CD H CD 03 3 CD 3 CO 03 C/3 CD ro co 3 o co • a. <^ JL CD O • ro O CO CD 3 cn l o o er-o co CD 3 CO I o o O CO CD 3 ro ro CO CD 13 m x a CD I' CD 3 Q o c D c 3 cr CD CD O i— CO T J ZT 03 C/3 CD ro c 3 cr CD o —i -n CD 03 3 CD 3 CO CO 03 3 cn • ro CO CD 3 5 ST o ro i ro O co CD P. 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Following the baseline test, subjects were instructed to use the first five or six sets as a warm-up, (Le., exert submaximal effort through the range of motion). For the remainder of the exercise, subjects were instructed to resist maximally the downward force of the dynamometer arm through the range of motion for a total of thirty sets of ten repetitions or three hundred eccentric contractions. Each set lasted about forty seconds with a fifteen second recovery. Subject had biofeedback available to them to let them know with how much force they were resisting, either through the force/velocity curve display or the resistive force display at the bottom of the screen of the KinCom display unit. Upon completion of the exercise, there was a brief break, followed by a repeat of the mean torque test. The post-test torque measurement was followed by a repeat analysis of the pain perception with a VAS. If not already there, subjects then travelled to the Allan McGavin Sports Medicine Centre Physiology Laboratory, where the subject began the first of five hyperbaric treatments in the H Y O X monoplace hyperbaric chamber. They either received a hyperbaric oxygen treatment (100 % oxygen @ 2.0 ATA) or a sham treatment (21 % oxygen @ 1.2 ATA). See Figure 2 for a breakdown of treatments for each group. In the case of the 35 control group in phase I, these subjects were required to complete their pain scales in front of the blinded investigator at the Allan McGavin Sports Medicine Centre daily at approximately twenty-four, forty-eight, seventy-two, and ninety-six hours postexercise. Prior to compression in the chamber, subjects were instructed to try on the mask, to ensure a comfortable fit. Clearing techniques were explained, (Le., swallowing, valsalva manoeuvre, etc.). Emergency equipment was explained. That is, subjects were instructed on how they could decompress chamber on their own and let themselves out if necessary. The microphone, which was always open, was pointed out to all subjects. This situation allowed them to communicate any problems they experienced during compression, such as difficulty in clearing their ears. To begin the treatment phase, subjects were seated in the semi-recline chair and pushed into the machine, and the door panel closed so that there was a tight seal Subjects were also advised not to put the mask on until the treatment pressure (2.0 ATA, for experimental condition and 1.2 ATA, for the sham condition) was reached. The delay in putting on the gas mask was to allow the mask to become operational and to allow the subjects to breathe freely. The actual compression in the experimental group lasted about eight minutes or so depending on the size of the subject (more volume, less time to pressurize). During compression, the subjects were closely monitored to insure that they had no problems equalizing their ears with the pressure changes. In cases with patients who struggled to clear their ears, compression was briefly interrupted to allow equalization. The sham group needed approximately six minutes to pressurize, in an attempt to lengthen the compression process. This procedure involved running the compressor and the vent simultaneously. To effectively blind the subjects, it was 36 necessary to keep the subjects guessing as to which group they had been assigned. Thus, in hyperbaric and sham conditions, subjects experienced some pressure. A curtain was draped over the air distribution panel to prevent subjects from seeing which gas they receiving. The tanks and regulators were connected in series to a three-way valve so that a flip of a switch provided the subjects with either air (21 % oxygen) or 100 % oxygen. This set-up was also necessary in the unlikely event of a seizure during exposure. Essentially, the method just described was used for all five treatments. The only difference was that subsequent instructions to the subjects before compression were brief, given the initial instructions. Subjects did not complete a VAS following the first hyperbaric treatment because, theoretically, subjects should not have felt any pain in first two-to-four hours. On subsequent visits for treatments, subjects were treated approximately twenty-four, forty-eight, seventy-two, and ninety-six hours post exercise. Following each subsequent hyperbaric exposure, the subject marked another VAS after four deep knee bends to indicate the current intensity of pain and discomfort in the quadriceps. To clarify, visual analogue scales were completed before and after treatment in phase I and following treatment in phase n. In addition, each subject's eccentric strength was measured on the third day of the study (forty-eight hours post exercise) prior to the chamber exposure and on the fifth day (ninety-six hours post exercise) after the chamber exposure. Statistical Analysis The pain data was analyzed by a means of a two factor mixed design [(2 X 6) group by time] A N O V A with repeated measures on the time factor. The strength data was analyzed by a two factor [(2 X 4) group by test] A N O V A with repeated measures on the test factor. Comparisons were made according to previously planned contrasts. Significance level was set at p< 0.05. 37 CHAPTER 4: RESULTS Anthropometric data No statistical differences existed between subjects in terms of height, weight, and age. This fact was true for both Phase I and Phase II subjects. See Table 3 for a comparison of the groups in terms of anthropometric data. Phase I Data Because of the anomalous subject data, one set of scores from each group in phase I was removed. In each case, the subjects were rejected because of an abnormal response to eccentric exercise. Their eccentric strength after intense exercise increased rather than decreasing. Therefore, analyses of these results were based on the pain scores and mean eccentric torque values for nine subjects per group. As presented in Table 4, the overall pain scores (raw) demonstrated no significant differences over time. In fact, the subjects from the non-treatment groups scored lower pain than those from HBO-treated groups (the immediate HBO and delayed H B O groups). (See Figure 2). For example, on the second and third days of treatment, 24h post and 48h post, the control and sham groups averaged 4.79 and 4.49, and 3.97 and 3.79, respectively, while the HBO groups marked their pain at 4.87 and 4.94, and 4.87 and 4.66, respectively. These differences, like all others, were not significant. The overall mean torque raw scores for each experimental group (group effect) were not significantly different from each other. (Consult Table 7). However, given the appearance of the eccentric data (Figure 5 and Figure 6), this author checked the difference between the immediate HBO group and sham, delayed H B O , and control groups. Of interest were the differences between the groups over time: pre- and Table 3: A Comparison of Anthropometric Data Phase I Data (±S.D.) Group Height (cm) Weight (ka) Age (years) Control (n=9) 178.60 ± 6 . 4 8 77.48 ± 6 . 2 6 24.20 ± 2 . 7 0 HBO [3-day] (n=9) 180.97 ±7 .14 77.48 ± 7 . 7 2 26.20 ± 3 . 5 8 Delayed HBO (n=9) 178.65 ±7 .83 75.76 ± 8 . 3 2 24.50 ± 3 . 4 7 Sham(n=9) 181.80 ±5 .65 78.35 ± 5 . 3 6 24.80 ± 4 . 6 6 Phase II Data (± S.D.) Group Height (cm) Weight (Kg) Age (years) 3-day HBO (n=10) 182.35 ±3 .93 77.93 ± 8.92 26.50 ± 5 . 9 5 5-day HBO (n=10) 180.10±7.31 78.70± 5.56 22 .00±3 .23 Sham (n=10) 178.02 ± 8.33 74.60 ± 10.59 23.50 ± 3.63 39 Table 4: Phase I Mean Pain Values (Units ± S.E.) Group Pre-exercise Post Exercise 24h Post 48h Post 72h Post 96h Post (VAS1) (VAS2) (VAS3) (VAS4) (VAS5) (VAS6) Control (n=9) 0.58 ± 0 . 1 0 2.17 ±0 .39 4.79 ± 0.44 3.97 ± 0.45 2.17 ± 0 . 3 7 1.34 ± 0 . 1 9 HBO (n=9) 0.29 ± 0 . 1 0 2.71 ± 0.39 4.87 ± 0 . 4 4 4.87 ± 0.45 3.21 ± 0.37 1.36 ± 0 . 1 9 Delayed HBO (n=9) 0.59 ± 0.10 1.88 ±0 .39 4.94 ± 0 . 4 4 4.66 ± 0.45 3.38 ± 0 . 3 7 1.38 ± 0 . 1 9 Sham (n=9) 0.40 ± 0 . 1 0 2.30 ± 0.39 4.49 ± 0.44 3.79 ± 0.45 2.17 ± 0 . 3 7 1.25 ± 0 . 1 9 Table 5: Phase II Mean Pain Values (Units ± S.E.) Group Pre-exercise Post Exercise 24h Post 48h Post 72h Post 96h Post (VAS1) (VAS2) (VAS3) (VAS4) (VAS5) (VAS6) Sham(n=10) 0.51 ± 0 . 2 4 3.12 ± 0.73 3.81 ± 0 . 8 0 2.98 ± 0.83 1.44 ± 0 . 5 4 0.72 ± 0 . 3 1 3-day HBO (n=10) 0.82 ± 0 . 2 4 2.60 ±0 .73 3.87 ± 0 . 8 0 3.40 ± 0 . 8 3 1.53 ± 0 . 5 4 0.76 ±0 .31 5-day HBO (n=10) 0.17 ± 0 . 2 4 1.74 ± 0.73 3.78 ± 0 . 8 0 3.65 ± 0 . 8 3 1.62 ± 0 . 5 4 0.49 ±0 .31 Table 6: Phase I and II Mean Pain Values (Units ± S.E.) Group Pre-exercise Post Exercise 24h Post 48h Post 72h Post 96h Post (VAS1) (VAS2) (VAS3) (VAS4) (VAS5) (VAS6) 3-day HBO (n=19) 0.51 ± 0 . 1 2 2 .65±0 .40 4 .18±0.41 4 .09±0.41 2 .34±0 .32 1 .05±0.19 Sham(n=19) 0 .46±0.12 2 .73±0 .40 4 .13±0.41 3 .36±0.41 1 .78±0.32 0 .97±0 .19 40 Table 7: Phase I Mean Eccentric Torque Values (Nm ± S.E.) Group Pre-exercise (MT1) Post Exercise (MT2) 48h Post (MT3) 96h Post (MT4) Control (n=9) 167.0 ±13 .2 123.9 ± 9 . 5 157.3 ± 1 0 . 0 171 .2±9 .6 HBO [3-day] (n=9) 184.2 ±13 .2 111.4±9.5 156.1 ± 1 0 . 0 174.2 ± 9 . 6 Delayed HBO (n=9) 168.7 ±13 .2 129.3 ± 9 . 5 151.4±10.0 180.7 ± 9 . 6 Sham (n=9) 167.0 ±13 .2 116.8 ± 9 . 5 144.2 ± 1 0 . 0 166.3 ± 9 . 6 Table 8 : Phase II Mean Eccentric Torque Values (Nm ± S.E.) Group Pre-exercise Post Exercise 48h Post (MT1) (MT2) (MT3) 96h Post (MT4) 3-day HBO (n=10) 151.5±12.9 140.6 ±12 .4 136.0 ± 1 3 . 2 156.6 ±13 .1 5-day HBO (n=10) 193.9 ±12 .9 137.0 ±12.4 165.7 ± 1 3 . 2 1 9 1 . 9 ± 1 3 . 1 ' Sham (n=10) 168.6 ±12 .9 142.9 ±12 .4 137.1 ± 1 3 . 2 147.2 ± 1 3 . 1 * p= 0.023; 5-day HBO vs. Sham Table 9 : Phase I and I Group Mean Eccentric Torque Values (Nm ± S.E.) Pre-exercise Post Exercise 48h Post (MT1) (MT2) (MT3) 96h Post (MT4) 3-day HBO (n=19) 167.0 ± 9 . 5 126.8 ± 8 . 1 145.5 ± 8 . 1 168.0 ± 8 . 2 Sham (n=19) 169.5 ± 9 . 5 130.5 ± 8 . 1 137.1 ± 8 . 1 156.3 ± 8 . 2 Table 1 0 : Phase I and Group II Mean Eccentric Torque Values (Nm ± S.E.); Outliers Removed Pre-exercise Post Exercise 48h Post 96h Post (MT1) (MT2) (MT3) (MT4) 3-day HBO (n=15) 178.0 ± 9 . 8 120.0 ± 9 . 0 147.3 ± 8 . 9 170.7 ± 8 . 8 Sham (n=18) 174.2 ± 8 . 9 132.2 ± 8 . 3 144.1 ± 8 . 1 160.4 ± 8 . 1 41 Table 11: Strength Recovery (Gain Score) Means for Phase I Data (Nm ± S.E.) Group Postexercise to 96 h Post (MT4 - MT2) Control (n=9) 47.3 ± 7.8 HBO (n=9) 69.2 ± 7.8* Delayed HBO (n=9) 44.9 ± 7.8 Sham (n=9) 49.6 ± 7.8 * p= 0.021; HBO (3-day) vs. Control, Delayed HBO, and Sham Table 12: Strength Recovery (Gain Score) Means for Phase II Data (Nm ± S.E.) Group Postexercise to 96 h Post (MT4 - MT2) 3-day HBO (n=10) 16.0± 11.8 5-day HBO (n=10) 54.9 ± 11.8* Sham(n=10) 4.3 ± 1 1 . 8 * p= 0.005; 5-day HBO vs. Sham Table 13: Strength Recovery (Gain Score) Means for Phase I and II Data (Nm ± S.E.) Group Postexercise to 96 h Post (MT4 - MT2) 3-day HBO (n=19) 41.2 ± 9.0 Sham(n=19) 25.7 ± 9 . 0 Table 14: Strength Recovery (Gain Score) Means for Phase I and II Data (Nm ± S.E.); Outliers Removed GrQMP Postexercise to 96 h Post (MT4 - MT2) 3-day HBO (n=15) 50.7 ± 8.9 Sham (n=18) 28.3 ± 8 . 1 42 postexercise, postexercise to 48 hours, and postexercise to 96 hours. These comparisons were set up as pre-planned contrasts. In the phase I data, the comparisons were made in the absence of a significant interaction effect. No differences in strength were noted between the HBO group and the amalgamation of the other three groups (sham, control, and delayed HBO group) at any of the times specified. This pattern was not true when controlling for some of the variability. The total recovery (gain) scores were compared (Table 11); that is, MT4 - MT2 [96 hours postexercise value - the postexercise value]. When examining the total recovery scores as a one-way A N O V A , the group effect suggested a trend might exist. Similar to the pre-planned contrasts performed on the raw data, a comparison of recovery scores for the HBO group (69.2 Nm change) and the sham, delayed HBO, and control groups (49.6 Nm, 44.9 Nm, and 47.3 Nm change, respectively) was made (Figure 11). This post hoc test revealed a significant difference between the HBO group and the other three groups at p= 0.021 for the recovery of eccentric strength from immediately postexercise to 96 hours postexercise. Based on these data, a second set of data was collected to determine if a treatment schedule more similar to a protocol used for soft tissue sports-related injuries would have greater functional effects. Phase II Data The pain data showed a similar pattern to the phase I data: the group main effect was not significant; the pain main effect was significantly different (p< 0.001); the interaction effect was, however, non significant. (Please refer to Table 5). That is, at no period where subjects marked their pain did a significant difference occur between any of the groups. Interestingly enough, though, on the fifth (last) day of the study, the average pain 43 score for the 5-day HBO group was lower than the averages for the other groups: 0.49 as compared to 0.72 for the sham group and 0.76 for the 3-day HBO group, with the standard error of the mean (SEM) equal to ± 0.31 units (Figure 3). The eccentric torque data communicated a different story. When reviewing the phase II mean torque data, the analysis revealed no significant differences for the groups main effect (Table 8 and Figure 7). The torque main effect showed a significant difference (p< 0.001) as expected. However, there was a significant interaction effect of the group by time effect (p= 0.025). This finding suggested that at least one of the four times eccentric strength was measured, a difference or differences existed among the three groups. Contrasts were conducted on the data to identify some of the differences between the groups. When comparing the raw torque means for the sham and 5-day HBO groups, a significant difference (p= 0.023) was detected at the final test of eccentric torque. (Refer to Figure 7). The 5-day HBO groups had a value of 191.9 Nm while the sham group had an average of 147.2 Nm with a standard error of 13.1 Nm. Consequently, the change from the post exercise value to the ninety-six hour postexercise value would also be significant (Figure 8). To check out the veracity of the previous statement additional statistical analyses were conducted. From Table 12 and Figure 12, when total recovery scores were calculated and evaluated as a one way A N O V A (analysis of variance), the 5-day HBO group, 3-day HBO group, and the sham group were significantly different than each other (p= 0.014; 54.9 Nm (5-day), 16.0 Nm (3-day), and 4.3 Nm (sham), respectively). Once again, contrasts were conducted to break down which groups were different. Of most interest in these 44 pre-planned tests, given the experience from phase I, was the difference between the sham group and the five-day group. The 5-day group was vastly different from the sham group in terms of recovery of eccentric strength at p= 0.005. An unfortunate consequence of the phase II data was the relationship between the other groups or other comparisons. To whit: the sham and 3-day H B O group were similar over the five days of the study (p> 0.05), while the 3-day HBO and 5-day HBO groups are statistically different initially and after 96 hours for torque. (See Figure 7). As well, the three groups did not decrease at the same rate during the initial exercise. Using the raw data once more, if the sham and 3-day torque data were combined and compared to the 5-day group, the initial drop in mean torque was significantly different (p= 0.041). Therefore, the data suggests some inequality in the severity of DOMS between groups, detracting from some of the further analysis. This fact also casts some doubt about any claims that can be made from this data. Part of the problem in the analyses was the large number of outliers in the groups, the 3-day HBO group especially. The outliers in this case were subjects who increased rather than decreased their mean torque measurements after the protocol. However, if the outliers were removed, the 3-day HBO group more closely resembled the 5-day H B O group. Similarly, the 3-day group also had a difference in the total recovery over the 96 hours post exercise period compared to the sham group (28.0 Nm versus 7.0 Nm) [Figure not shown]. Because of the high variability of the mean torque values, this difference was not significant 45 Combination of Phase I and Phase II Data As outlined in the proposal, some of the data from the two phases were combined and analyzed. A total of nineteen sham subjects and nineteen 3-day H B O subjects made up the comparative groups. The same result that had been noted in the phase I and phase II data individually was determined for the pain data (p> 0.10). No significant differences existed between the two groups at any time during the testing protocol (Table 6 and Figure 4). In contrast, the evaluation of the mean torque data illustrated some interesting trends. The raw data showed no significant differences (Table 9 and Figures 9 and 10). The analysis of the total recovery scores yielded no statistically different values (3-day HBO: 41.2 Nm; Sham: 25.7 Nm; and a standard error of the mean equal to ± 9.0 Nm) [See Table 13 and Figure 13]. However, when the outliers were removed, leaving 15 H B O and 18 sham subjects, some interesting tendencies materialized in the data. Once more, with the raw data, no significant group or interaction effects were noted. Please refer to Table 10. Comparing the groups on the basis of their total recovery scores rendered a different outcome. A trend towards significance between the two groups was noted for the overall recovery period, from immediately postexercise to 96 hours postexercise (Table 14 and Figure 14). The one way analysis of variance produced a near significant result (p= 0.072) based on the difference between the sham group mean of 28.3 Nm and the (3-day) HBO group mean (50.7 Nm). 46 47 VAS Score (units) _i o -» ro OJ ^ 01 8 8 8 8 '8 8 8 48 49 50 51 Mean Torque (Nm) o 8 8 8 H 8 I 8 8 '8 8 8 8 8 o o 52 Mean Torque (Nm) CO cn * 3 II §§ 5 u 53 Mean Torque (Nm) 8 8 8 § 8 § 8 8 8 8 8 8 54 Mean Torque (Nm) £ 8 8 8 8 8 8 8 8 8 8 8 55 56 Torque Change (Nm) o o o c 3 o o S § o 8 8 '8 8 8 8 8 8 8 57 Torque Change (Nm) o cn o 01 8 Si 8 8 £ £ 8 8 8 8 '8 8 8 8 8 - 8 8 8 X 58 Torque Change (Nm) o o 8 8 t 8 8 8 8 8 8 8 8 8 59 CHAPTER 5: DISCUSSION Pain The appeal of this study was the control this model offered in causing a quantifiable injury. Delayed-onset muscle soreness has been studied intensely for ten years, and as such, has several variables that can be compared, including pain perception and eccentric strength. The work of Maclntyre et al. (108) determined a significant negative correlation between the DOMS pain and eccentric torque over time. In almost all studies, the peak of DOMS pain perception occurred between twenty-four and forty-eight hours post exercise, as was observed in this study. For all groups in both phases, the subjects documented peak pain at twenty-four hours. It was hypothesized that pain would have been reduced by hyperbaric exposure. The results of the study suggest otherwise. Pain was not significantly affected by exposure to HBO, delayed exposure to HBO, or by simply being in the chamber (placebo effect). Studies observing the effect of HBO on plasma levels of adrenocorticotrophic hormone (ACTH) and beta-endorphins (fJ-endorphins, self-produced painkillers) reported significant increases acutely (after one treatment) and after five days of intermittent treatment (30,170). These studies, however, used a higher pressure (2.8 A T A ) for their treatments. Perhaps no pain attenuation occurred because the HBO treatments were administered for only three days. The lack of pain modification is a surprise in terms of the HBO but not in terms of the delayed onset muscle soreness. Several studies suggest an increased release of endorphins from H B O exposure (30,70,170). However, with the pain of DOMS, most studies using many different modalities and drug therapies, like ultrasound and NSAIDS (ibuprofen), 60 tended not to indicate any significant pain reduction (54,76). In that respect, the lack of pain relief mirrors previous research. This occurrence agrees with previous research on DOMS, where the peak soreness arises between twenty-four and forty-eight hours (44,108). The lack in pain relief reflects other studies where stretching before and after exercise, ultrasound, ibuprofen, and massage had little or no effect on the subjective variable of pain (38,54,98,139). At no point did a difference exist between the groups in pain perception in phase I or phase II. For the combination data, this investigator determined a similar lack of differences between the expanded groups in terms of pain perception. The lack of evidence of pain attenuation is in contrast to anecdotal experience. In some cases, pain relief occurred rapidly, even in the first twenty-four to forty-eight hours postinjury. Several explanations exist to rationalize the disparity. Objective parameters may be more sensitive to detect changes due to treatment. Its simplicity cannot be overstated. Pain is a highly subjective variable. It is possible that no demonstrable pain relief occurred in this model because of too frequent sampling of pain. Patients actually filled out pain scales subsequent to and immediately following their treatments, except for the control group subjects who scored pain once a day. Although not significantly different, the control group in phase I tended to have the lowest mean pain score at each monitoring period after the initiation of the injury. By surveying the subjects directly after their treatment, this investigator may have sampled at the wrong time. Because the subjects were often stiff after sitting in one place for an hour, they may not have experienced the full benefit of HBO immediately. Since the therapeutic effect of HBO appears to last for up to four hours after the treatment, (R. 61 Peterson, personal communication) perhaps the subjects' pain should have been monitored two to four hours after HBO. Problems with the Hawthorne effect may also have occurred. The Hawthorne effect generally refers to a subject's attempt to please the experimenter. In this case, because each subject had knowledge that they were supposed to become sore pain after exercise protocol, each subject anticipated pain immediately after exercise. By definition, a DOMS stimulus should cause very little or no pain immediately afterward. Despite suggestions to reconsider the pain, some subjects scored their pain as equivalent to a fracture or ligament rupture. Another possible explanation for lack of significant pain data was that the stimulus did not cause significant damage, given the subject population used. The subjects may have been participating in eccentrically-biased sports or activities (team sports like volleyball, soccer, and soccer; activities like skiing, running especially downhill running, hiking, etc.) and misrepresented their activity levels and habits. By participating in the aforementioned activities, these subjects could have conditioned their quadriceps to the type of exercise they were performing. As a consequence, these subjects would not become as sore nor lose as much strength as the more sedentary subjects, as has been reported in the literature (15,24,109). Although not reaching significance, the non-treated subjects (sham and control) demonstrated lower pain scores for most of the postexercise measurements. This manifestation may represent a real placebo effect obscured by inter-subject variability or a reflection of an imprecise instrument for measuring pain. The best way to describe any effects on pain may be that the treatments did not affect the initial overload, but instead 62 affected individual phenomena of the 'sequence of events' (140). The lack of significant changes in pain may reflect that the effects of the treatments are only small, and just on the verge of being significant. To answer succinctly whether HBO provides effective pain relief, another study needs to be attempted with pain and pain relief the only variables. Casti and colleagues (30) suggest that A C T H reduction may relate to pain relief. A C T H reduction may also represent a stress response of reduced intensity. It is important to recognize the wide variation of the values related to plasma levels of A C T H . It seems likely that oxidoreductive processes, determined by the administration of H B O , can modify the function of opioid receptors. This modification may increase their affinity with endogenous opiates and create the analgesia. The lack of significant pain relief in the DOMS model should not inhibit other studies from examining pain relief proffered by HBO in other models. Eccentric Strength The reason for monitoring eccentric torque was to determine if subjects derived any benefit from hyperbaric treatment over five days. Unlike the pain data, the statistical analysis of the mean torque data documented some significant results. However, to state that the strength data provides a resounding demonstration of the efficacy of hyperbaric oxygen would be misleading. In terms of strength recovery, several studies (44,56,76,149) have found eccentric strength had not returned to normal for the time period being studied, usually the first forty-eight hours. This study illustrated a gradual return of strength in the subjects over five days. In two studies where eccentric strength was measured for longer than two days (61,99), eccentric strength did not return to baseline (peak) performance for six and seven 63 days, respectively. In that regard, the data behaved as expected with a couple of exceptions. By not testing on all five days, however, significant changes especially in the first 24 hours postexercise may have been missed. The examination of the raw torque data for the phase 1 data and the combination data illustrated a lack of significance. Although the HBO groups displayed no significant differences, they were greater values in the two postexercise measurements. The large variability between subjects would partially explain why significant differences were not observed. Also, from the first phase of the experiment, in two of the experimental groups (the control and delayed HBO groups), the final torque value (MT4) was higher than the baseline (and supposedly maximal) value. A learning effect may have occurred, wherein the subjects became more comfortable and more proficient at performing the novel movement (resisting against an external force while the muscle was lengthening rather than shortening). Given their apprehension and possible lack of coordination initially, the subjects may not have been able to produce their maximum effort for the initial torque test (MT1). To avoid this problem in the future, orientation sessions to familiarize subjects with the torque protocol prior to actual testing are suggested. For the combination data, groups that had the same protocol- the sham and 3-day H B O groups, further explanations of their variability exist. These groups were compared in the hope that the significant result in enhanced strength recovery in the H B O group determined in phase I would continue and become more significant (p< 0.01) with greater numbers. Due to the high variability in the phase II data, especially in the 3-day HBO group, any difference was obscured. Another part of the problem may have been that the two groups were not statistically different in phase I. Greater numbers only confirm this 64 fact. The initial post hoc comparison determined that the 3-day H B O group was different from the control, sham, and delayed HBO groups, though not necessarily different from the sham group alone. A review of the phase II data revealed a disparate relationship. The phase II data was clearly different because of the significant differences in the raw data. Firstly, the significant interaction verified a difference between the groups over time. As part of pre-selected contrasts, the difference between the sham and 5-day groups at the final torque measurement (MT4 or 96 hours postexercise) became a key to further interpretation. Essentially, this comparison suggested that the difference between the second torque test (MT2 or immediately postexercise) and the last torque test was statistically significant Using the same logic, the difference between the third and fourth torque (48 hours postexercise to 96 hours postexercise) measurements was also significant. These comparisons were important because of non-significant differences at the other measurement times. Therefore, recovery over ninety-six hours was enhanced at least in part by exposure to five days of hyperbaric oxygen therapy. The scope of this finding is limited to the comparison of the sham and 5-day HBO groups. To further strengthen the case for the efficacy for HBO, the significant results obtained for the recovery of torque production over the test period deserve comment. The striking thing about the recovery in phase I compared to phase II is the way the significant results complement each other. The highly significant figure in phase II (p= 0.005) may be linked to the two extra days of hyperbaric oxygen. Removal of outliers in the combination data provides more compelling evidence. Although this manipulation does not provide significance, the trend towards enhanced recovery seems more clear in the 3-day HBO group in both phase I and II (p= 0.072). 65 The recovery value for the 3-day HBO group was 50.7 Nm, while the mean for the sham group was 28.3 Nm. As well, the corrected data suggests greater similarity between the hyperbaric groups in phase U across all times and in terms of recovery scores. Several possibilities exist to explain the increase in strength recovery during the five days subjects were monitored. The first supposes that subjects were able to recruit other muscle motor units to produce force. If this differential recruitment occurred, why did this phenomenon happen only in one group? This investigator believes that hyperbaric oxygen was part of the reason underlying the increase in recovery in the 5-day HBO group. The results do not allow one to state explicitly whether the explanation was because of enhanced healing of the cellular damage caused by DOMS, or an attenuation of the injury that occurred. Perhaps, though, an augmentation of collagen deposition and vessel growth processes contributed to the enhanced strength recovery observed in this study. The sluggishness in healing in all other groups, save the 3-day HBO (immediate) group in phase I and the 5-day HBO group in phase II, tend to rule out unusually aberrant recovery in the other groups. The main problem of the phase II mean torque data was the variability of strength recovery. The third group, the 3-day HBO group, became a marker of internal validity, although that was not the original purpose for its inclusion. As chance would have it, the 3-day HBO subjects more closely resembled the sham group than the 5-day HBO group. In theory, given the same number of hyperbaric treatments for the HBO groups over the first three days, the subjects in each group should have reacted more analogously -if one accepts that hyperbaric oxygen does enhance healing in soft tissue injuries. 66 This result may complicate significance seen in the sham and 5-day HBO differences. Because the two hyperbaric groups do not drop similarly, any comparison after this point may be nullified. This initial inequality weakens the validity of these suggestions, and perhaps invalidates these arguments altogether. Several explanations exist to rationalize the differences determined between the 3-day and 5-day HBO groups in phase II. In the 3-day HBO group, three of the subjects had abnormal responses to eccentric exercise. Normally, intense eccentric exercise, like three hundred eccentric contractions of quadriceps, causes a drop from baseline or initial strength levels. In these three cases, the mean torque value increased after exercise. This rise could have been due to a true maximal effort on the post exercise strength trials, a submaximal effort during the three hundred repetitions, or a learning effect The first two suppositions have little merit. Subjects were encouraged to produce a maximal effort throughout the exercise and their appearance was monitored for physical manifestations of effort (i.e.- perspiration). As well, each dynamometer had a visual display that allowed the subjects and investigator to monitor the progress of their torque output during the exercise. Subjects were encouraged to resist with greater effort if the torque level dropped significantly and abruptly from their pre-exercise values. The more likely interpretation was that a learning effect transpired because subjects, with three hundred repetitions worth of practice, acquired a better motor program. This enhanced motor program allowed them to better recruit their quadricep motor units, with greater force production as a result. Part of the blame falls squarely on this investigator, who had to make a judgment on whether to offer subjects an additional set to practice before performing their baseline (maximal) torque test. Practice time had to be limited 67 because of time constraints and the reduction in maximal eccentric strength due to fatigue with continued attempts at submaximal and maximal efforts (i.e.-more than two or three attempts). The most efficient method of eliminating learning bias would require subjects to perform the exercise protocol twice and thus take part in a cross-over study. Unfortunately, that solution adds three months between trials to allow a 'wash-out' period for the quadriceps. Studies with repeated bouts demonstrate that twelve weeks or more are necessary to facilitate full recovery of the damaged tissue (15,55,122). Subsequent bouts of eccentric exercise prior to twelve weeks post-exercise have shown blunted responses to pain, plasma creatine kinase levels, and strength loss (15,55,122). This change in the protocol would require subjects to maintain the same level of unfitness and activity pattern for three months. It would also be a logistical challenge for the investigators. Given the increased probability of subject drop-out for such a protocol and the increased likelihood of activity levels changing during the wash-out period, this solution is not practical. More objective tests, like biochemical changes at the cellular level, would have been helpful. Unfortunately, no direct markers of damage were studied such as creatine kinase (CK) for skeletal muscle and malondialdehyde for evidence of lipid peroxidation. Physiological assays were not attempted on these or any other metabolites partially due to the additional expense and the great variability in measuring these markers. There was another reason for not examining C K levels. Plasma C K response after a similar bout of exercise may differ widely between individuals. To control for this inter-subject variability, Clarkson and Ebbeling have suggested discriminating between low, 68 medium, and high responders (42). A doctoral study might be a more appropriate setting for attempting such a human study. Another possible explanation for the increased recovery must be considered. Given the potential for raised expectations from the publicity and the anecdotal evidence concerning hyperbaric oxygen treatments, the act of sitting in the chamber under relatively normal atmospheric conditions (the sham treatment) could be enough stimulus to provide a placebo effect. From the analysis, there is no evidence linking better strength recovery to simply being exposed to the chamber. In each phase, the 'shammed' subjects performed no better than their counterparts in the other groups, and actually performed significantly more poorly when compared directly to the 5-day HBO group. Wells and co-workers (176) found that tissue P 0 2 in muscle tissue needed approximately thirty minutes to reach a plateau, but only remained at an elevated level for thirty minutes after the cessation of treatment. The suggestion that oxygen tissue levels remained above normal for an extended period after hyperbaric exposure may be important to the efficacy of H B O in soft tissue injuries (176). Therefore, better results for pain attenuation and strength recovery may have been realized with more or longer treatments (i.e.- two-sixty minute sessions or ninety minute instead of sixty minute sessions). Ten treatments over a week accomplishes very little if hyperbaric oxygen is not administered in a timely fashion. In terms of the optimal time for applying this therapy, the results demonstrated no apparent benefit to late (forty-eight hours post-injury) HBO treatment, in terms of strength gain and pain modulation. From previous HBO studies, the most beneficial results occur when hyperbaric treatments are commenced in first eight hours. The strength outcomes in 69 this study are supported by the timely application of HBO in burn therapy, reperfusion of ischemic skeletal muscle, and spinal cord injuries (37,181,187). Conversely, no evidence exists to suggest that prior exposure to HBO provides a prophylactic or protective function. Any capacity to store oxygen in tissues quickly dissipates upon initiation of exercise. As a result, one can only speculate as to why statistical differences were observed in the recovery of strength at ninety-six hours between the sham and 5-day H B O groups. If one assumes that the HBO must have caused an increase in the healing from the initial insult, this study only provides indirect evidence as to the underlying explanation. Therefore, one can only speculate about the enhanced strength recovery in H B O treated subjects. Lactate synthesized by macrophages is the fundamental trigger for healing; specifically lactate stimulates fibroblasts to make collagen (103). Fibroblasts cannot synthesize collagen without a reasonable amount of oxygen, required for the post-translational processing of collagen necessary for its cross-Unking space (103). Vessel growth and collagen deposition have a delicate balance that is easily upset when host circulatory and nutritional support fail. This situation would exist in a muscle damaged by intense eccentric exercise or other traumatic wound. Because macrophages release lactate, even while well oxygenated, some stimulus to collagen synthesis remains even during hyperoxygenation. That stimulus would help explain how recovery could continue in a seemingly well perfused wound. Perhaps, then, an augmentation of collagen deposition and vessel growth processes contributed to the enhanced strength recovery observed. 70 Inflammatory response following injury greatly increases oxygen demand at the wound site. Leukocytes need large amounts of oxygen to meet demands for metabolism and free radical production intermediates for phagocytosis. In traumatic injury physical damage impairs oxygen delivery to circulatory systems and/or cause disruption of the local microcirculation (3). HBO is reputed to decrease the inflammatory response while significantly improving the microvasculature in bums (3,20). Edema extends the distance for diffusion of oxygen from capillaries to the injured tissues. Even when circulation is intact, increased oxygen demand resulting from the inflammatory response, added to the effects of edema, prevent maintenance of tissue oxygen levels despite the hyperemia caused by inflammation (3). If one concedes that all of detrimental effects are not caused solely by inflammation, Byrd (23) suggested another mode by which HBO may still combat effectively. In tissues that are highly active, oxygen free radicals are produced as a common metabolic intermediate. Oxidation of sulfhydryl groups of the ATPase pump was highly correlated with a reduction in the rate of calcium ion [Ca 2 +] uptake by the sarcoplasmic reticulum (SR) (23). Prolonged exercise at moderate intensity does not significantly alter high energy phosphates or muscle pH, yet temperature increases, glycogen content, and free radical formation by the muscle could play a role in SR dysfunction and thus muscle function. In high intensity exercise, temperature, pH, and high energy phosphates are significantly altered, but glycogen stores are not depleted. Therefore, a combination of effects may occur to alter SR function and structure (23) and consequently, muscle function. 71 Activated neutrophils are known to be a major source of oxygen free radicals such as superoxide and hypochlorous acid (HOC1) via N A D P H dehydrogenase and myeloperoxidase (MPO) enzymes, respectively (86). Studies suggest that neutrophil rather than xanthine oxidase production of free radicals may be more important in leading to the tissue-destructive events occurring from ischemia/reperfusion (93,165,166). However, it is likely that these two free radical-generating systems are somehow interrelated. Hyperbaric oxygen treatment has experimentally demonstrated an ability to decrease the amount of neutrophil adhesion in reperfusion injury (163,185). The mechanism by which HBO achieves this decrease is unknown, although at least two possibilities exist. Zamboni and colleagues (187) have suggested that exposure to hyperbaric oxygen modifies the glycoprotein adherence complex molecule (CD 18) responsible for firmly bonding to the endothelial surface of an injured blood vessel or cell. Thorn (166) has submitted that exposure to HBO (3 ATA) for forty-five minutes inhibited carbon monoxide (CO)-mediated lipid peroxidation the brains of rats. He proposed that HBO prevents the conversion of xanthine dehydrogenase to oxidase, a conversion process known to be due to the action of leukocytes (165). Xanthine oxidase-derived superoxide may play an important role in initiating the activity of some chemotactic substances, particularly the arachidonic acid metabolites (165). The inability of a neutrophil to securely fasten to a vessel surface retards the cascade of events that follow: the neutrophil cannot release its respiratory burst of phagocytic vacuoles and oxidative particles that commence the removal of debris (166). An accompanying chemotactic release that promotes the arrival of more neutrophils and other cells like platelets, thromboxane (from platelet reaction with injured endothelium), and leukotrienes (LTB4) does not occur 72 (166). These activating substances do not increase neutrophil hydrogen peroxide production. Consequently, buffered peroxide production does not activate more arachidonic acid metabolites, thus avoiding the vicious cycle of neutrophil adhesion and continued endothelial disruption (186). If all neutrophils were unable to stick to the walls of injured vessels, HBO therapy would have no beneficial effects. Had that scenario arisen, HBO would have disturbed normal healing and exacerbated not mitigated injury time. This author contends that the ability of HBO to prevent excess neutrophils and other particles from cluttering the injured area may explain the enhanced healing. This hypothesis has some scientific support. The results of a recent animal HBO/DOMS study completed at the University of British Columbia indicated that significant reductions were found in indices of muscle damage (lactate and myeloperoxidase activity) between control and HBO-treated rats (150). The reduction in myeloperoxidase activity may be related to an attenuated inflammatory response since the levels were reduced in the first forty-eight hours following downhill treadmill running. As stated by Friden and co-workers (61), eccentric exercise can lead to increased intramuscular pressure, which may cause transient localized interruptions in blood flow. This disruption could in the whole muscle (i.e.-quadriceps) cause some local hypoxia. The case could be made for a quasi-ischemia-reperfusion injury which would result in reduced function and increased histological evidence of cellular damage. This fact supports oxygen free radicals as an explanation of the injury as well as the potential place for the HBO treatment to act. Also, Zerba and co-workers found that isometric strength did not fall as severely when superoxide dismutase (SOD) was injected into animals (189). A 73 benefit of HBO may be an increase in SOD levels and a quenching of free radicals. This extinguishing would decrease the damage caused in DOMS by these reactive oxygen species. How HBO bolsters the viability of the vessels and tissues deserves further comment. One hypothesis for this beneficial effect is hyperoxia-induced vasoconstriction theoretically decreases edema by reducing capillary pressure. Although hyperoxia-induced vasoconstriction may be marked in cerebral arterioles, reducing blood flow 40 percent, the effect on the limb blood flow reduction is minimal (12-19 %) (19). Therefore, vasoconstriction is unlikely as the primary mechanism in skeletal muscle edema reduction. Indirect evidence suggests that the vasoconstriction that occurs in arterioles adjacent to venules is leukocyte-dependent (186). Only arterioles in close proximity to venules demonstrated this vasoconstriction (185,186). The local environment created by the leukocyte-damaged venule is responsible for this arteriole response. Local dilatation of the blood vessels exists and it appears to moderate the vasoconstrictive effect of oxygen (119). The beneficial effects of hyperbaric oxygen on ischemic tissue, however, are systemic and not local (186). The systemic mechanism by which H B O decreases neutrophil adhesion during reperfusion is not yet known. Perhaps the normal response to injury is too general; that is, the body does not have specific enzymes to halt the response to cell injury, at least in the initial stages. The blunting of adhesion of neutrophils may stop the release of oxygen free radicals, which are particularly damaging to tissue. If the oxygen free radicals are not neutralized, their continued activation may explain chronic inflammation, that is, protracted inflammation as a direct result of free radical attack on previously normal cells. Acute inflammation, this 74 author conjectures, has some free radical component that, even during a normal cellular injury, destroys indiscriminately to impede the healing process. Experimental evidence supports this hypothesis. According to McCord (115), the most likely physiological source of superoxide radical in the extracellular fluids appears to be metabolically activated polymorphonuclear leukocytes (PMN). The release of the superoxide radical into the surrounding medium is probably an unfortunate and potentially detrimental occurrence (115). Furthermore, the quantity of superoxide generated by phagocytes under physiological conditions is by no means trivial or insignificant (115). This mechanism in vivo accounts for synovial fluid deterioration in inflammatory arthritic conditions (115). By extension, a similar mechanism may be at work in acute inflammation, i.e.-'over-zealous leukocytes.' Hyperbaric oxygen as a scavenger of free radicals also has some scientific support. Aerobic bacteria respond to increased superoxide by producing more superoxide dismutase (SOD), for detoxification of superoxide under hyperoxic conditions (66). Kaelin et al. (89) found a significant increase in the activity of the free radical scavenger superoxide dismutase in rats with ischemic skin flaps treated with HBO. Thom and Elbuken studied lipid peroxidation in vitro and demonstrated that hyperoxia alters the free radical pathway in favor of hydroperoxyl radical formation (164). In Haapaniemi et al. (71), the loss of total glutathione, another endogenous antioxidant, was less in HBO-treated animals than in untreated ones. These quenching radicals react with lipid radicals to form nonradical products. In general, larger quantity of antioxidants and pathway alterations may explain why, in relatively small doses or treatments, H B O does not generate oxygen free radicals. 75 Of course, an acute but otherwise normal injury does not accumulate the same degree of damage as in a chronic situation. Moreover, to imply that the neutalizing effect of HBO on oxygen free radicals is the only mechanism at work would be misleading and probably wrong. A combination of HBO's vasoconstrictive properties, free radical-quenching ability, reduced neutrophil adhesion feature, and enhancement of leukocyte killing and hydroxyproline formation probably best explain the beneficial effects noted in these studies. 76 CHAPTER 6: CONCLUSIONS AND RECOMMENDATIONS In an injury model inducing delayed-onset muscle soreness, subjects treated with intermittent hyperbaric oxygen treatments over three and five days had augmented recovery of eccentric strength as compared to subjects who did not receive hyperbaric treatments. Subjects recover strength more quickly when hyperbaric treatment is initiated immediately following injury as opposed to waiting for forty-eight hours. Evidence supporting the timely application of HBO is the ability of the subjects treated with HBO immediately following exercise to increase their mean torque production more expeditiously than the other groups from the time immediately postexercise to ninety-six hours postexercise. This fact is true for the immediate (3-day) HBO group in phase I and the 5-day group in phase II (p= 0.021 and p= 0.005, respectively). Pain perception is not effectively reduced when treated over five days. Several options are available for future research. The significant results almost demand it. The problems of this study must be overcome. To elucidate the underlying mechanism of H B O in humans, further research should examine objective biochemical markers, like malondialdehyde for a measure of lipid peroxidation (oxygen free radical damage) and muscle myeloperoxidase from muscle biopsies to measure the inflammatory response. Serial measurements over twenty-four hours of the white blood cells in the exercised muscle, before and after hyperbaric exposure, should be considered via the nuclear medicine technique outlined in Maclntyre et al. (108). Following the biochemical markers suggested as well as examining markers for collagen synthesis and/or polyamines may help differentiate whether the benefits of hyperbaric oxygen stem from a reduction of the damage caused after injury or an actual enhacement in the healing capacity of the body. 77 The pain variable should be revisited. To aid in the objectification, other pain scales like the McGil l Pain Questionnaire should be considered. Alternatively, a technique described in Hasson et al. (76), to mechanically depress the sore areas of the muscle, may more Objectively measure pain. Other research should include the veracity of applying hyperbaric oxygenation to other acute soft tissue injuries in clinical models. Chronic inflammatory injuries may also respond to H B O and deserve investigation. Also, this DOMS study may have important implications for overtraining. 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