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CURRENT OPINION
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Nullius in Verba A Call for the Incorporation of Evidence-Based Practice into the Discipline of Exercise Science William E. Amonette,1 Kirk L. English1 and Kenneth J. Ottenbacher 2 1 Preventive Medicine and Community Health, Division of Rehabilitation Sciences, University of Texas Medical Branch, Galveston, Texas, USA 2 Division of Rehabilitation Sciences, University of Texas Medical Branch, Galveston, Texas, USA
Abstract
Evidence-based practice (EBP) is a concept that was popularized in the early 1990s by several physicians who recognized that medical practice should be based on the best and most current available evidence. Although this concept seems self-evident, much of medical practice was based on outdated textbooks and oral tradition passed down in medical school. Currently, exercise science is in a similar situation. Due to a lack of regulation within the exercise community, the discipline of exercise science is particularly prone to bias and misinformation, as evidenced by the plethora of available programmes with efficacy supported by anecdote alone. In this review, we provide a description of the five steps in EBP: (i) develop a question; (ii) find evidence; (iii) evaluate the evidence; (iv) incorporate evidence into practice; and (v) re-evaluate the evidence. Although objections have been raised to the EBP process, we believe that its incorporation into exercise science will improve the credibility of our discipline and will keep exercise practitioners and academics on the cutting edge of the most current research findings.
Beneath all physiological phenomena lie causal mechanisms. The purpose of the scientific process as it relates to human physiology is to uncover these mechanisms. Unfortunately, knowledge of a phenomenon is often buried deep beneath many partially understood or even misunderstood mechanisms, rendering what we currently know incomplete. Ideally, with each research experiment, we gain a more complete understanding of a given phenomenon; thus, knowledge is dynamic and continually evolves. The evolution of knowledge creates a unique challenge; instructors and practitioners must teach and practice with incomplete knowledge. Despite their best efforts to incorporate the latest scientific evidence, by the time a lecture is deliv-
ered, it is likely that science has already uncovered more of the story. Usually, discovery simply adds to the information that was presented to students, but sometimes advances in knowledge radically change scientific thought. In the 1930s and 1940s it was believed that muscle contractions were the result of folding and unfolding of long protein filaments located within skeletal muscle sarcomeres.[1] With the invention of a new, more powerful light microscope,[2] Huxley and Hanson were able to see two proteins, actin and myosin, that appeared to slide over each other during the shortening and lengthening of a muscle.[3,4] Now, 55 years later, the sliding filament theory of muscle contraction is taught to all physiology students as the basis of
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muscular contraction. While the teachers of the 1940s taught to the best of their ability based on contemporary knowledge, Huxley and Hanson’s discovery rendered what was taught incomplete and inaccurate. Evidence-based medicine is a term coined in the early 1990s to describe a paradigm in which clinical decisions are based on the highest available levels of research knowledge or evidence.[5,6] Although this idea seemed obvious, it was a novel approach to clinical practice. In fact, in 2000 it was estimated that only 15–40% of clinical decisions were based on research evidence.[7,8] The medical community’s call to evidence-based practice (EBP) argued that knowledge is dynamic and that clinicians should incorporate the latest evidence into practice to optimize clinical outcomes. EBP has since spread from the field of medicine to other health fields. Much has been written about the incorporation of EBP into nursing,[9,10] physical therapy[11-13] and various medical disciplines including orthopaedics.[14-16] Exercise science is susceptible to misinformation and bogus claims – perhaps more than any other field. This is evident from a cursory knowledge of the personal training industry. While organizations such as the National Strength and Conditioning Association (NSCA) and the American College of Sports Medicine (ACSM) have done much to legitimize the credentials of exercise scientists, the field is still full of misinformation. This misinformation is due, in part, to the lack of standardization among agencies that certify instructors in exercise and sports science. Many exercise certifications require minimal academic training. In fact, the only requirements of some certification agencies are to attend a weekend-long workshop and pass a written multiple choice exam. The result of such certifications are under-qualified exercise professionals equipped with minimal theoretical knowledge of training physiology and little or no ability to access the latest scientific research pertinent to their profession. These certified exercise professionals often base their practice on a flawed set of theoretical knowledge, personal experience or anecdotal hearsay, and non-peer-reviewed publications. Inevitably, misinformation leaks into the field ª 2010 Adis Data Information BV. All rights reserved.
Amonette et al.
and exercise specialists are poorly equipped to evaluate the legitimacy of information, resulting in a plethora of devices, nutritional supplements and programme theories that have little or no scientific merit. The intention of academia and practice should be to constantly evolve with the literature in a quest to create highly effective exercise programmes that are based on current knowledge. We propose that EBP be taught in undergraduate exercise science programmes as the foundation of all exercise programming. The purpose of this paper is to introduce the structural framework of EBP as it relates to exercise science and to present the advantages and limitations of EBP in the discipline of exercise science. 1. The Mechanics of Evidence-Based Practice (EBP) Sackett et al.[17] have suggested that EBP is applicable in three distinct facets of medicine: prognosis, diagnosis and intervention. While it might be argued that there are diagnostic and prognostic components of exercise science, the primary application of EBP in exercise is at the intervention or programming level. Thus, we focus solely on the programming aspect. 1.1 Step One: Develop a Question
The evaluation and interpretation of client or patient data should lead to the development of a focused, practical question.[17-20] The question should include information about the subject population, exercise parameters (e.g. duration, frequency, intensity) and desired adaptations. Questions that are too broad will yield enormous amounts of information, making interpretation of the literature difficult. Narrowing the population will result in a smaller and more focused list of abstracts. When considering the population, at least five questions should be addressed: (i) is the scenario sex specific; (ii) are there underlying clinical issues; (iii) what is the training experience of the client; (iv) what is the chronological age of the client; and (v) what is the desired outcome of the programme (e.g. increased strength, power, Sports Med 2010; 40 (6)
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cardiovascular fitness)? Each of these questions may be useful in narrowing the search and providing better evidence to construct the programme. 1.2 Step Two: Search for Evidence
Acquiring appropriate, reputable evidence has become increasingly easier with the availability of peer-reviewed research on the internet. The definition of ‘evidence’ has been a source of debate as some have mistakenly assumed that advocates of EBP believe that research alone constitutes evidence. Others have argued strongly for the value of clinical intuition and experience as important contributors to evidence.[21,22] We believe that there are three primary sources of evidence: professional experience, academic preparation and research knowledge. 1.2.1 Sources of Evidence
When evaluating the three sources of evidence, it is important to understand that each element of knowledge is incomplete, open to interpretation and therefore potentially biased. First, professional experience can be a valuable source of evidence. Lessons learned through field experience can reinforce academic knowledge. However, it is vital to understand that knowledge gained through professional experience is the least objective and most influenced by bias. For instance, in prescribing medicine, doctors may be influenced by relationships with drug companies, the preference of their mentors, and the static set of knowledge taught in medical school. While this information is often valid, it is important to understand that it may not represent the best treatment scenario. Exercise science practitioners are prone to these same biases. It is difficult to deviate from methodologies taught by mentors and well respected colleagues. While many of these methodologies are valid and effective, mentors were, at best, working from the best evidence available at that point in time. Second, academic preparation provides a valuable source of evidence. The best professors strive to incorporate recent research findings into courses teaching foundational scientific principles. Academic courses typically utilize textbooks ª 2010 Adis Data Information BV. All rights reserved.
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containing fundamental physiology knowledge that is needed to read scientific research. However, there are two inherent flaws to academic preparation: (i) the material delivered in academic lectures is often outdated by the time it is presented; and (ii) lecture material is subject to the personal bias and current knowledge of the professor. By the time a professor prepares and delivers a lecture, new evidence has already been added to the body of knowledge. It is estimated that by the time a new edition of a textbook is published, it is at least 1 year out of date;[23] similarly, with the time required to develop coursework, academic lectures are likely several months out of date by the time they are delivered – assuming they are updated each semester with the latest evidence. Like practitioners, instructors are prone to bias. There is a tendency for instructors to teach with a style similar to those who mentored them. Additionally, there is a propensity to teach the very material that one was taught. Thus, when information is presented to students it may be severely out of date; this underscores the need for the incorporation of less biased research evidence. Scientific research constitutes the level of evidence that is least prone to bias. The motto for the Royal Society of London is the Latin phrase ‘Nullius in verba’, which translates as ‘on no man’s word’. The best way to minimize bias is to remove the human element and let the data speak for itself. While the interpretation of research evidence can be biased, research evidence per se is less biased than personal experience, textbooks or academic lectures. It is our opinion that research evidence should provide the foundation for all practical programming decisions. Empirical data should exert the ultimate influence on exercise programming as it is a less biased form of evidence. 1.2.2 Gathering Evidence
In past generations, the collection of peerreviewed materials required travel to libraries, searching through card catalogues, retrieving materials from library shelves and extensive photocopying. Today, the internet enables easy access to quality resources including medical Sports Med 2010; 40 (6)
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databases and peer-reviewed journal articles online. Instead of travelling to the library, practitioners need only to search topics using publicly available databases such as PubMed and Google Scholar. The result is a vast availability of research, requiring minimal effort. 1.3 Step Three: Evaluate Evidence
The proponents of EBP argue that there is a hierarchy to evidence and that not all evidence (even scientific research) should be considered equal (table I).[20] The highest level of evidence is a systematic review of randomized controlled trials.[24] This type of research evidence is assigned a level 1a ranking, as it represents a series of replicated randomized controlled trials. Level 1b evidence is a single randomized controlled trial with narrow confidence intervals.[24] Systematic reviews of non-experimental studies (e.g. cohort studies), both single well designed cohort studies and poorly designed randomized controlled trials, and outcomes research are given rankings of 2a, 2b and 2c, respectively.[24] Systematic reviews of case-control studies (3a) and a single case-control study (3b) are given lower rankings
because of the greater potential for bias.[24] Finally, expert opinion, textbooks, decisions based on mechanistic research (basic science), and practical experience are given level 5 rankings.[24] In this system, the research that is least prone to bias, replicated randomized controlled trials (i.e. a systematic review), is recognized as the highest level of evidence while the information that is most prone to bias, expert opinion, is assigned the lowest level of evidence. This provides an impartial method of ranking evidence and determining its influence on practical decision making. 1.4 Step Four: Incorporate Evidence Into Practice
The highest available level of evidence should be used as the basis for exercise prescription. If practice is currently founded on reputable level 5 evidence, then it is likely that new evidence will only fine tune current exercise programmes. However, it is prudent for all individuals who prescribe exercise to understand the science upon which prescriptions are based. This may be especially important for exercise professionals who currently base their practice on non-peer-reviewed
Table I. Classic levels of evidence for rehabilitation practice (reproduced from Law and MacDermid,[24] with the permission of SLACK Inc.) Level
Classic ‘levels of evidence’ for therapy/prevention
Placement of additional types of clinical evidence
1a
Systematic review (with homogeneity) of RCTs
CPGs where recommendations are based on systematic reviews that contain multiple RCTs and the development includes supplemental data or expert opinion to make recommendations only where evidence is lacking
1b
Individual RCT (with narrow confidence interval)
1c
All or none
2a
Systematic review (with homogeneity) of cohort studies
2b
Individual cohort study (including low-quality RCT; e.g. <80% follow-up)
2c
‘Outcomes’ research
3a
Systematic review (with homogeneity) of case-control studies
3b
Individual case-control study
4
Case series (and poor-quality cohort and case-control studies)
Unstructured quantitative or qualitative expert consensus; large descriptive practice analysis/survey that defines common ground; critical appraisal/comprehensive systematic review or synthesis of biological studies, or first principles
5
Expert opinion without explicit critical appraisal, or based on physiology, bench research or ‘first principles’
CPGs that are not based on the use of evidence review or quantitative data; clinical protocols or rehabilitation theory
Lower quality CPGs that are based on informal evidence review and expert consensus, where few RCTs are identified
Structured consensus processes based on quantitative ratings of agreement and formal consensus processes using qualified experts
CPG = clinical practice guideline; RCT = randomized controlled trial.
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Evaluate client • identify chronological age • establish training goals • determine training experience • identify clinical pathologies • collect standardized baseline data
Publish case study protocol
Re-evaluate the evidence • re-evaluate the client • interpret results • compare results to research evidence and previously used protocols
Develop a question • specific to clients goals, pathology, etc. • narrow question
Incorporate the evidence • design programme • integrate EBP protocols
Search for evidence • PubMed 'clinical query' (systematic reviews) • search for single randomized controlled trials • search for other experimental studies • search for non-experimental studies • consult expert opinion and textbooks Evaluate the evidence • evaluate evidence giving greater weight to less biased designs and to peer-reviewed material
Fig. 1. The fundamental steps of evidence-based practice in the context of individual exercise prescription. Solid lines indicate the primary path in the evidence-based practice (EBP) process whereas dotted lines indicate alternative or additional steps that may arise from the original query.
material, professional experience, non-expert opinion or less reputable certification agencies. In medicine, EBP is incorporated at the individual level;[25] the patient has a voice in treatment options. EBP in exercise science should also include the input of the individual. Exercise scientists will increase their professional credibility by discussing the evidence behind programme development with their clients/patients. This is particularly important when research leads to a non-traditional training approach or goes against current trends. In the past, patients of medical doctors blindly followed their recommendations based on the authority of their office. Some in the medical community adamantly oppose the shift to medical practice based on the authority of research evidence, disregarding the fact that the science upon which recommendations are made is the ultimate authority, not a physician. The shift from authoritarian medicine ‘‘Do this because I say so’’ to authoritative medicine ‘‘Do this because research evidence says so’’ produces less ª 2010 Adis Data Information BV. All rights reserved.
biased medical prescription,[26] and will yield similar results in exercise prescription. 1.5 Step Five: Routinely Re-Evaluate the Evidence
The final step in EBP is a constant re-evaluation of practice. It is sensible for practitioners to continually read on particular subjects in order to stay abreast of new studies relevant to their field. However, it is impossible to keep up with every journal and thus it is necessary to routinely repeat searches on a particular topic. A diagram describing the process of EBP is provided in figure 1. 2. Potential Criticisms and Benefits of EBP in Exercise Science 2.1 Potential Criticisms of EBP in Exercise Science
A variety of arguments have been levelled against EBP in the field of medicine. While we Sports Med 2010; 40 (6)
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believe that EBP is both important and necessary to the advancement of exercise science, we recognize that similar contentions will be raised to its inclusion in our field. Some have suggested that the implementation of EBP minimizes the importance of the practitioner’s experience and intuition; this argument is certainly applicable to the prescription of exercise. We acknowledge that personal experience is a valuable source of evidence, and, in many cases, the only source of evidence to substantiate practice. However, the prudent search for additional information can only improve practice and add to the repertoire of experienced exercise professionals. In many cases, research validates what the practitioner has known for years through practical experience or intuition. However, at times research goes against popular thought. A second argument against EBP is that it removes the ‘art’ or creativity from practice. This is certainly a valid concern, as creativity in programme design can mitigate the monotony of exercise training. Some contend that focusing on evidence as the driving factor for practice could lead to a ‘cook book’ approach where every individual gets the same treatment.[27] While this is a valid concern, the current state of the exercise industry suggests a need for the re-evaluation of programmes based on evidence. Popular trends in exercise training including the use of new devices, dietary supplements, and novel programming techniques are often implemented based on the recommendation of expert or non-expert opinion alone (level 5 evidence). Faced with a dearth of evidence to substantiate such practice, exercise specialists argue that the use of these techniques constitutes the ‘art’ or creativity of training. However, exercise specialists must not violate the proven principles of training physiology for the sake of ‘art’. Music is a beautiful art; talented composers are able to carefully arrange notes to create beautiful expressions. Thousands of songs have been written from only 12 musical notes. Each song involves a unique arrangement of melodies, harmonies, rhythms, etc. It is the arrangement of these twelve notes that results in the creativity of each composition. Despite the limited number of notes, ª 2010 Adis Data Information BV. All rights reserved.
each song has a unique ‘sound’. The same can be said of the art of exercise training. While the proven concepts of training physiology may limit the strategies employed, it certainly does not limit creativity. Instead, the ability of exercise specialists to creatively order volume, intensity, rest periods, tempo and exercises, using established evidence, typifies the art of training. 2.2 Benefits of EBP in Exercise Science
We believe that there are two primary benefits to the inclusion of EBP into exercise prescription. First, EBP will improve the quality of exercise programming. The consuming desire of an exercise professional who wants to excel should be to provide the best exercise programme for every individual based on the current set of knowledge. The result of the continuous search for evidence is a better product for the client/patient. Second, the incorporation of EBP will enhance the legitimacy of our profession. Although there are many qualified and outstanding graduates of exercise science programmes employed as exercise specialists, the lack of licensure hurts our credibility with medical professionals and with the general public. The credibility crisis is worsened by a multitude of certifications requiring varying levels of competencies. Between certification agencies, there exist varying recommendations as to the appropriate exercise prescriptions and differing terminology to describe them. This creates problems when exercise specialists converse with each other and with medical professionals. Therefore, the incorporation of evidence will provide a common foundation upon which various groups can agree. Additionally, EBP gives authority to the exercise professional. Instead of standing behind agency recommendations, or answering questions based on academic knowledge, we can stand on the credibility of the latest research findings (figure 2). 3. Incorporation of EBP into Exercise Science There are two viable points of entry for EBP into the discipline of exercise science: undergraduate Sports Med 2010; 40 (6)
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a Accumulate articles for course lectures
Consensus of articles and implementation into lectures
Exercise science or certification course teaching general principles
Student knowledge of subject
Body of scientific knowledge with respect to time
b Accumulate articles for course lectures
Consensus of articles and implementation into lectures
Student knowledge of subject
Exercise science or certification course teaching general principles + EBP
Body of scientific knowledge with respect to time
Fig. 2. Theoretical knowledge base of students enrolled in (a) a traditional course or certification that teaches only general principles versus (b) a course or certification teaching both general principles and the philosophy of evidence-based practice (EBP).
programmes and national certification agencies. These two avenues will capture the majority of the new professionals who will fill leadership roles within the exercise community. There are several clear ways to incorporate EBP into undergraduate exercise science programmes. First, teach a mandatory class on EBP. This course would introduce the concepts of EBP and provide practical instruction in constructing answerable questions, searching for evidence (research), and evaluating research to reach practical conclusions. Most importantly, this course would emphasize the dynamic nature of scientific knowledge, i.e. that students should stay abreast of and search for current best evidence (especially those not in research positions) and not base their training and coaching entirely on information gained during an undergraduate education. Second, a more thorough approach would incorporate EBP as an undertone of the entire programme. Thus, in addition to standard lectures on basic physiological and physical principles, each class would involve searches for best evidence to answer specific questions. By graduation, students would have accumulated years of practice finding and evaluating research. Such repetitive exposure is particularly important for those who will not have careers generating reª 2010 Adis Data Information BV. All rights reserved.
search but who can and should be competent research consumers. Third, students could complete a senior EBP thesis, investigating a specific question. A project of this nature would necessitate the implementation of one or both of the previously discussed options so that students would have adequate familiarity with the concepts of EBP. The other readily accessible route by which EBP could be introduced to the exercise science community is through the certification process. The two most highly regarded certifying bodies in the exercise science field are the ACSM and the NSCA; not incidentally, both of these agencies require a bachelor’s degree in an exercise-related or allied health field to even test for their higherlevel certifications. However, both agencies also offer certifications for personal trainers that require only a high school diploma or its equivalent. Recognizing that commercial demand for personal trainers and coaches makes it practically impossible to require a college degree for all certifications, the inclusion of EBP as a fundamental component of these ‘lower-level’ certifications would serve to further elevate the profession in competency, prestige and, ultimately, public perception. As organizations, the ACSM and NSCA would benefit from both the increased prestige of their certifications and the increased Sports Med 2010; 40 (6)
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revenue from mandatory workshops necessary to teach the concepts of EBP. Although undergraduate programmes and national certifications will expose a large portion of incoming exercise professionals to the principles of EBP, admittedly, substandard organizations will continue to certify under-qualified trainers. However, strengthening the professional skills of those who obtain undergraduate degrees or upper-tier certifications will create a clear distinction between those who are truly competent to prescribe exercise and those who are not. 4. Conclusion In his President’s Address to the Royal Society of Medicine in 1965, Sir A. Bradford Hill stated, ‘‘All scientific work is incomplete – whether it is observational or experimental. All scientific work is liable to be upset or modified by advancing knowledge. That does not confer upon us a freedom to ignore the knowledge we already have, or to postpone the action that it appears to demand at a given time.’’[28] As exercise professionals, we are obligated to act based on the current state of scientific knowledge to develop the best possible programmes for our clients/patients. In doing so, we must recognize that the best programme in 2010 may not be the best programme in 2015. EBP is not a new concept; there are certainly exercise professionals who already employ its principles. In keeping with the motto of the Royal Society of London (Nullius in verba), we propose that the use of evidence be the driving component of exercise prescription. To implement this philosophy, the principles of EBP must be incorporated into the curriculum of exercise science programmes. Our appeal to exercise science instructors and practitioners is to teach and implement programmes founded on the most recent scientific evidence. This will improve the programmes provided to the individual and our credibility as a profession. Acknowledgements W. Amonette and K. English were partially supported by a National Center for Medical and Rehabilitation Research
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(NICHD) grant at the National Institute of Health (T32 HD007539). The authors have no conflicts of interest that are directly relevant to the content of this review.
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26. Davidoff F, Case K, Fried PW. Evidence-based medicine: why all the fuss [letter]? Ann Int Med 1995; 122 (9): 727 27. Sauerland S, Lefering R, Neugebauer EA. The pros and cons of evidence-based surgery. Langenbeck Arch Surg 1999; 384 (5): 423-31 28. Hill AB. The environment and disease: association or causation? Proc R Soc Med 1965; 58: 295-300
Correspondence: Mr William E. Amonette, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0411, USA. E-mail:
[email protected]
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REVIEW ARTICLE
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Arginine Vasopressin, Fluid Balance and Exercise Is Exercise-Associated Hyponatraemia a Disorder of Arginine Vasopressin Secretion? Tamara Hew-Butler Exercise Science Program, Oakland University, Rochester, Michigan, USA
Contents Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Arginine Vasopressin (AVP) and the Osmotic Regulation of Fluid Balance at Rest and during Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. The Possible Effects of Non-Osmotic AVP Secretion on Fluid Regulation. . . . . . . . . . . . . . . . . . . . . . . . 3. The Effect of Exercise on Plasma AVP Concentrations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 High Intensity Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Steady-State Exercise. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 Prolonged Endurance Exercise. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. AVP, Exercise and Changes in Urine Osmolality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. AVP and Changes in Sweat Osmolality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 Exogenous Administration of AVP. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 Endogenous Changes in AVP and Sweat Osmolality/Sodium Concentration . . . . . . . . . . . . . . . 6. Influence of Sex on AVP and Fluid Regulation during Exercise. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Influence of Training on the AVP Response to Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8. Performance, Thermoregulation and AVP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. Influence of Other Endocrine Mediators on AVP Secretion and Fluid Homeostasis . . . . . . . . . . . . . . 9.1 Classic Fluid Regulatory Hormones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.1.1 Aldosterone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.1.2 Atrial Natriuretic Peptide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.2 Potential Fluid Regulatory Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.2.1 Oxytocin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.2.2 Interleukin-6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10. Exercise-Associated Hyponatraemia (EAH) as a Potential Consequence of Exercise-Induced Non-Osmotic AVP Secretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Hypertonic Saline Administration in the Treatment of EAH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12. Conclusions and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Abstract
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The ability of the human body to regulate plasma osmolality (POsm) within a very narrow and well defined physiological range underscores the vital importance of preserving water and sodium balance at rest and during exercise. The principle endocrine regulator of whole body fluid homeostasis is the posterior pituitary hormone, arginine vasopressin (AVP). Inappropriate AVP secretion may perpetuate either slow or rapid violation of these biological boundaries, thereby promoting pathophysiology, morbidity and occasional
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mortality. In the resting state, AVP secretion is primarily regulated by changes in POsm (osmotic regulation). The osmotic regulation of AVP secretion during exercise, however, may possibly be enhanced or overridden by many potential non-osmotic factors concurrently stimulated during physical activity, particularly during competition. The prevalence of these highly volatile non-osmotic AVP stimuli during strenuous or prolonged physical activity may reflect a teleological mechanism to promote water conservation during exercise. However, non-osmotic AVP secretion, combined with high fluid availability plus sustained fluid intake (exceeding fluid output), has been hypothesized to lead to an increase in both the incidence and related deaths from exercise-associated hyponatraemia (EAH) in lay and military populations. Inappropriately, high plasma AVP concentrations ([AVP]p) associated with low blood sodium concentrations facilitate fluid retention and sodium loss, thereby possibly reconciling both the water intoxication and sodium loss theories of hyponatraemia that are currently under debate. Therefore, given the potential for a variety of exercise-induced non-osmotic stimuli for AVP secretion, hydration strategies must be flexible, individualized and open to change during competitive events to prevent the occurrence of rare, but lifethreatening, EAH. This review focuses on the potential osmotic and non-osmotic stimuli to AVP secretion that may affect fluid homeostasis during physical activity. Recent laboratory and field data support: (i) stimulatory effects of exercise intensity and duration on [AVP]p; (ii) possible relationships between changes in POsm with changes in both sweat and urinary osmolality; (iii) alterations in the AVP osmoregulatory set-point by sex steroid hormones; (iv) differences in [AVP]p in trained versus untrained athletes; and (v) potential inter-relationships between AVP and classical (aldosterone, atrial natriuretic peptide) and non-classical (oxytocin, interleukin-6) endocrine mediators. The review concludes with a hypothesis on how sustained fluid intakes beyond the capacity for fluid loss might possibly facilitate the development of hyponatraemia if exercise-induced non-osmotic stimuli override ‘normal’ osmotic suppression of AVP when hypo-osmolality exists.
1. Arginine Vasopressin (AVP) and the Osmotic Regulation of Fluid Balance at Rest and during Exercise Arginine vasopressin (AVP) is the body’s primary antidiuretic hormone. Arginine vasopressin is synthesized in the supraoptic and paraventricular nuclei of the hypothalamus and stored and secreted into the bloodstream by the posterior pituitary gland. AVP induces water retention through activation of vasopressin V2 receptors in the kidney and vasoconstriction V1a receptors in arterioles. Osmoreceptors located in the brain but outside of the blood-brain barrier ª 2010 Adis Data Information BV. All rights reserved.
(circumventricular organs) detect changes in plasma osmotic pressure and transmit electrochemical signals to activate the synthesis and release of AVP from the supraoptic nucleus and posterior pituitary, respectively.[1] Baroreceptors located in the heart detect changes in blood volume and send afferent signals to both the supraoptic and paraventricular nuclei to increase the synthesis and release of AVP.[1] The ancestral vasopressin gene has been calculated to be more than 500 million years old and present in virtually all vertebrate species.[2] This underscores the evolutionary importance of water conservation in times when water was scarce and hypernatraemia Sports Med 2010; 40 (6)
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(with or without dehydration) was the most common life-threatening dysnatraemia in both mammalian and non-mammalian vertebrates. The osmotic regulation of AVP secretion and the sensation of thirst synergistically maintain plasma osmolality (POsm) within a normal physiological range (~275–295 mOsmol/kg H2O). The precision and sensitivity of the osmoregulatory system is well documented in animals as well as in humans.[3] Pituitary AVP secretion is stimulated when POsm increases by only 1–2%, representing the body’s attempt to prevent dehydration by decreasing kidney water excretion. The threshold for AVP release is generally between ~280 and 285 mOsmol/kg H2O, although significant variation between individual set points exists.[4] After maximal antidiuresis is achieved, an osmotically driven thirst signal is stimulated to encourage the replacement of fluid losses that are now in excess of the ability of osmotically stimulated AVP antidiuresis to conserve body water. The threshold for the stimulation of osmotically stimulated thirst is generally set at 5–10 mOsmol/kg H2O higher than that of AVP secretion (~290–295 mOsmol/kg H2O) or when decreases in body water reach approximately 1.7–3.5%.[4-6] This evolutionary design liberates animals from constantly seeking water, as osmotically driven thirst is stimulated only when antidiuresis is maximal and extra fluid intake is necessary to offset increases in plasma tonicity and hypernatraemia. POsm is maintained within a narrow physiological range to protect intracellular volume. Plasma sodium concentrations ([Na+]p) mirror POsm[7] because sodium is the principal solute of extracellular fluid; thus [Na+]p and POsm are viewed as interchangeable in this review, although the appropriate calculation is: POsm = 2 · [Na+]p + [BUN] + [glucose] (all in mmol/L), where BUN is blood urea nitrogen.[6] The maintenance of intracellular volume is of vital importance for cell function and survival. A reduced intracellular volume induced by the hyperosmotic shift of water from the intracellular into the extracellular compartment can reduce the rates of glycogen and protein synthesis.[8] Additionally, hypertonicity beyond serum sodium concentraª 2010 Adis Data Information BV. All rights reserved.
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tions of 160 mmol/L can cause encephalopathy from cell shrinkage and death.[9] Conversely, acute hypotonicity causes intracellular expansion via the hypo-osmotic shift of fluid from the extracellular into the intracellular space. Although such increases in cell volume can stimulate glycogen and protein synthesis, excessive and acute cellular swelling from serum sodium levels below 125 mmol/L can lead to hyponatraemic encephalopathy, non-cardiogenic pulmonary oedema and death.[10] A linear relationship between AVP and POsm is well documented during exercise regardless of baseline hydration status,[11] changes in body temperature,[11] degree of fluid replacement during prolonged (>2 hours) exercise[12] or from dehydration (-2.8%) induced by passive heating or intermittent exercise[13] in well controlled settings. The increase in AVP appears to be intensity dependent, from the proportional movement of hypotonic fluid from the intravascular into the interstitial space.[14] The increase in AVP per unit rise in POsm during exercise, however, tends to be higher than the per unit rise in AVP seen after infusion of hypertonic saline, suggesting that other factors may be involved in the stimulation of AVP secretion during exercise.[14] 2. The Possible Effects of Non-Osmotic AVP Secretion on Fluid Regulation Non-osmotic or non-suppressed AVP secretion for a given level of hypo-osmolality at rest or during exercise may potentially lead to inappropriate fluid retention and hyponatraemia. The pathophysiological consequence of inappropriate AVP secretion at rest in clinical scenarios was first described in 1967 as the ‘‘syndrome of inappropriate anti-diuretic hormone secretion.’’[15] It is thereby hypothesized in this review that nonsuppressed exercise-induced AVP secretion may be one potential cause of hyponatraemia in exercise settings, primarily due to inappropriate fluid retention and secondarily to concomitant pressure natriuresis.[16-22] During exercise, especially long-distance competitive exercise, limited descriptive evidence Sports Med 2010; 40 (6)
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suggests the possibility that non-osmotic stimuli to AVP secretion may override the osmotic regulation of AVP resulting in life-threatening fluid overload during vigorous physical activity.[17-22] Possible non-osmotic AVP stimuli during exercise include plasma volume contraction,[17,23,24] elevated body temperature,[25] nausea with or without vomiting,[26] hypoglycaemia[27,28] or other yet to be identified factors.[29] Circulating endocrine factors, which have recently been implicated as potential non-osmotic stimuli to AVP secretion in animals and humans during exercise, include interleukin (IL)-6,[30] angiotensin II,[31,32] corticosterone, oxytocin and brain natriuretic peptide.[17,33] It must be emphasized that plasma concentrations of AVP ([AVP]p) do not have to be abnormally high or even out of the ‘normal’ range to cause fluid dysregulation, morbidity or death.[18,20,34,35] AVP secretion that is simply inappropriate for the current state of plasma hypo-osmolality can lead to pathological fluid retention and dilutional hyponatraemia.[15,36] More simply described, if [Na+]p fall below 135 mmol/L (or below ~280 mOsmol/kg H2O for POsm), pituitary AVP secretion and the corresponding [AVP]p should be maximally suppressed (i.e. under the detectable range for the assay, which in most cases is <0.5 pg/mL). Maximal suppression of AVP would then allow for maximal kidney free water excretion rates of between 800 and 1000 mL/h[37] to effectively normalize [Na+]p via a sodium concentrating effect. Thus, [AVP]p does not have to be abnormally high – or even elevated from baseline – to contribute to fluid retention. The detectable presence of AVP will limit the maximal rate of urinary free water excretion necessary to normalize low blood sodium levels if and when hyponatraemia occurs. Any osmotically inappropriate (non-osmotic) AVP secretion during exercise would thereby result in increased urine osmolality and decreased urine volume when [Na+]p are below the normal range. Accordingly, high urine osmolalities have been measured in athletes hospitalized with critical hyponatraemia and inappropriate [AVP]p levels have been documented in exerciseassociated hyponatraemia (EAH).[38-43] Thus, a ª 2010 Adis Data Information BV. All rights reserved.
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lower rate of urine production has been shown to correlate significantly with a higher rate of [Na+]p decrease in athletes drinking excessively during exercise,[44] which may facilitate the development of EAH in scenarios where drinking rates far exceed the capacity for fluid loss. While [AVP]p normally fluctuates between 0–7 pg/mL, at ~4 pg/mL, antidiuresis and urineconcentrating ability are maximal in most healthy individuals although wide inter-individual (but not intra-individual) variability exists.[3] More importantly, [AVP]p within the lowest detectable range (0.5–2 pg/mL) promote urinary free water (<100 mOsmol/kg H2O) excretion rates, which cover a very broad range (2–20 L/day),[45] whereas for every 1 mOsmol/kg H2O decrease in POsm, urine osmolality decreases by 96 mOsmol/kg H2O (a gain in sensitivity of ~100) and vice versa.[3] Thus, the sensitivity of the osmoregulatory system appears exquisitely tuned. This documented sensitivity at rest further suggests the potential for adverse physiological consequences if nonosmotic AVP stimulation occurs in conjunction with hypo-osmolality plus sustained fluid intakes during exercise. 3. The Effect of Exercise on Plasma AVP Concentrations Both a threshold exercise intensity and duration have been identified for the stimulation of many endocrine factors above baseline levels,[46] including AVP.[33] For the purpose of this review, ‘high intensity’ exercise is defined as maximal intensity exercise (>90% of maximal oxygen . consumption [VO2max]) to volitional exhaustion. ‘Steady-state’ exercise is defined as submaximal exercise maintained at a set intensity and duration. Both high intensity and steady-state exercise tests are generally conducted in well controlled and largely replicable laboratory scenarios. ‘Prolonged endurance’ exercise refers to continuous endurance exercise generally lasting beyond 1 hour and conducted at self-selected speeds, which vary over time and distance. Investigations of prolonged endurance exercise are typically conducted in field settings and refer to both competitive and non-competitive events. Sports Med 2010; 40 (6)
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3.1 High Intensity Exercise
(i) a resistance to glucocorticoid suppression by the administration of dexamethasone; (ii) an ACTH response following exercise; (iii) an enhancement of AVP secretion with administration of dexamethasone; and (iv) a higher plasma ACTH response after AVP infusion.[53] It has been further hypothesized that high responders have an enhanced hypothalamic drive for AVP,[53] with the wide variability in the response of the HPA-axis primarily related to the magnitude of AVP release.[47] Additionally, the temporal relationship between [AVP]ppeak (20 minutes), ACTH (30 minutes) and cortisol (40 minutes) have been documented in female subjects participating in short duration (20 minutes) high intensity exercise.[56,57] Hence, these collective findings support a direct stimulatory role for AVP on ACTH stimulation that would suggest that AVP – and not corticotrophin releasing hormone (CRH) – acts as the primary stress hormone in response to maximal high intensity exercise.[54]
During maximal exercise to volitional exhaustion, there appears to be a clear and significant increase in [AVP]p, which far exceeds predicted levels concurrent with increases in POsm or volume.[33,47,48] Administration of g-aminobutyric acid (GABA) agonists (valproic acid [sodium valproate][49] or alprazolam[50]) has been shown to abolish the AVP response to high intensity exercise in humans while administration of GABA antagonist (dehydroepiandrosterone)[50] has been shown to increase the AVP – adrenocorticotropic hormone (ACTH)-cortisol response. These findings suggest that an osmotic/hypovolaemic stimulus indeed controls AVP release during exercise.[49,50] However, the apparent gain in the relationship between POsm and [AVP]p at maximal exercise intensities seems to exceed the mathematical slope previously documented in healthy individuals at rest.[3] Recent evidence suggests that the ~4-fold increase[33,51] in [AVP]p following short duration (<15 minute) high intensity exercise can be significantly reduced by prior administration of somatostatin.[51] However, if the opioid antagonist naloxone is administered with somatostatin prior to exercise, the somatostatin-induced reduction in [AVP]p following maximal intensity exercise is abolished.[51] Therefore, naloxone-sensitive endogenous opioids appear to play a role in the mechanism underlying somatostatin-induced reduction in maximal [AVP]p, while naloxonesensitive endogenous opioids alone do not appear to mediate an increase in [AVP]p following high intensity exercise.[51] Ambient temperature or subject age do not appear to influence the significant rise in [AVP]p following maximal intensity exercise.[52] The highly variable and substantial increase in AVP immediately following high intensity exercise is hypothesized to stimulate the hypothalamicpituitary axis during acute episodes of vigorous activity.[47,53,54] Individual sensitivity to the hypothesized AVP-ACTH-cortisol axis has prompted researchers to classify athletes into either ‘non’[55] or ‘high’[53] responder categories. Accordingly, ‘high-responders’ have been characterized by: ª 2010 Adis Data Information BV. All rights reserved.
3.2 Steady-State Exercise
A statistically significant increase in [AVP]p generally occurs above a sustained submaximal exercise intensity threshold between 40%[58] and . [11,59] of VO2max. Although it appears that the 65% parallel increase in [AVP]p with exercise intensity most likely results from plasma hyper-osmolality produced by a proportional hypotonic efflux out of the vascular space,[14,58] other factors may be involved.[60] The osmotic regulation of [AVP]p during steady-state laboratory exercise can persist independent of hydration level,[11,12,29] composition of beverage ingested,[61] exercise intensity <65%,[11] changes in core body temperature[11] and plasma volume changes[12,13,58,61] below maximum intensity exercise.[47] However, these data conflict with findings from different investigations whereas [AVP]p is more responsive to plasma volume change[23] particularly during periods of de-training.[24] Other laboratory investigations have suggested modulation of the osmotic regulation of [AVP]p by small increases in core body temperature,[25] while other studies Sports Med 2010; 40 (6)
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have documented an exercise-induced increase in [AVP]p unrelated to changes in POsm.[29,60,62-64] It is noteworthy to mention that ingestion of 300 mL of tap water 60 minutes prior to exercise suppresses the exercise-induced increase in [AVP]p,[60] as does ingestion of a beverage containing carbohydrate versus plain water.[64] However, the latter conclusion has been negated in a similar study performed at higher ambient temperatures.[65] Therefore, although the osmotic regulation of [AVP]p is well documented in a variety of hydration, training and ambient conditions during sustained physical activity, the potential for non-osmotic stimuli to influence osmotic regulation of AVP may be greater during exercise compared with resting conditions, especially during competitive exercise where heightened stress and environmental factors are often unpredictable. 3.3 Prolonged Endurance Exercise
The measurement of [AVP]p following longdistance particularly competitive-endurance exercise has been characterized by statistically significant increases in [AVP]p with[66-69] or without[17,22,70] statistically significant increases in [Na+]p or osmolality. However, most of the available fieldbased data has been evaluated in small (n < 10) groups[71-73] under varying states of hydration[67] and with considerable time delays in blood sampling that often exceed the half-lives of many of the regulatory hormones evaluated.[68-70,73] The exercise-induced increase in [AVP]p has been shown to persist for 2 hours following completion of a 24-hour competitive track run[70] and for 31 hours following completion of a 38 km non-competitive marathon run,[74] although significant variation in the return to baseline levels has been reported.[66,67,70] As demonstrated during steady-state exercise, it appears that an intensity-dependent effect on [AVP]p during prolonged endurance exercise similarly exists. This assumption is based upon a collective comparison of independent data that illustrates this apparent dose dependency: 5 days of hill walking did not illicit any change in [AVP]p or POsm when sampled twice daily;[75] a 24-hour ª 2010 Adis Data Information BV. All rights reserved.
track run at a calculated walk-run intensity between 45% and 50% induced a moderate (133%) increase in [AVP]p;[70] a cohort of well trained marathon runners completing a 42.2 km test run (mean finishing time 2 hours 44 minutes 30 seconds) experienced a 4-fold (9 pg/mL) increase in [AVP]p,[66] while the fittest and fastest runner of a cohort of nine runners completing a 42.2 km marathon run posted the highest post-race [AVP]p (45.6 ng/L) of all runners tested.[73] Whether the same basic mechanism that currently explains the intensity-dependent increase in [AVP]p documented during steady-state exercise (progressive increase in hydrostatic forces) similarly applies to exercise of long duration cannot be fully evaluated from these data. However, the ingestion of fluids during field exercise,[67] as well as ingestion of beverages containing glucose polymers, further reduces exercise-induced increases in [AVP]p[76] as similarly documented in steady-state controlled laboratory exercise of comparable duration.[64] Observational investigations involving 82 runners completing a 56 km marathon and 33 cyclists completing a 109 km cycle race support the likelihood of sustained or more frequent non-osmotic AVP secretion occurring during competitive exercise.[17,22] However, differential mechanisms seem to underlie the suspected non-osmotic increase in [AVP]p. The mean ~4-fold increase in [AVP]p documented following completion of an ultramarathon footrace was associated with a statistically significant decrease in plasma volume (-9%) and non-significant decrease (-1 mmol/L) in plasma [Na+]p.[17] The mathematically significant plasma volume decrease appears physiologically significant, as demonstrated by the linear correlation between plasma volume versus aldosterone plasma concentration [aldosterone]p, which would infer exercise-associated stimulation of volume-sensing baroreceptors. This data supports the possibility that plasma volume contraction may serve as a non-osmotic stimulus to AVP secretion in this cohort of well trained marathon runners, although a dose-dependent relationship between changes in [AVP]p versus plasma volume was not apparent. Additionally, recursive mathematical pathway models (involving Sports Med 2010; 40 (6)
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15 measured endocrine secretions) suggests the possibility that brain natriuretic peptide, corticosterone and oxytocin may have contributed to 47% of the variance noted in post-race [AVP]p in this cohort of runners.[17] However, during cycling a similar ~4-fold increase in [AVP]p was associated with decreases in both plasma volume (-5%) and plasma [Na+]p (-2 mmol/L).[22] This more modest plasma volume contraction did not appear to be the main non-osmotic stimulus to [AVP]p, as inferred by a comparative analysis of four athletes who participated in both the ultradistance cycling and running trials. Since cycling exercise involves concentric rather than eccentric muscle contractions[77] and requires a sitting posture,[78] it is not surprising these cycling data do not support plasma volume contraction as a unifying nonosmotic stimulus to AVP secretion during endurance exercise.[22]
water excretion has been verified in well controlled laboratory settings.[13,59,60,63] This consistent, but seemingly paradoxical, finding may reflect either a decrease in the renal sensitivity of AVP V2 receptors during exercise, exercise-induced changes in renal function[59] or increased kidney sodium absorption induced by a simultaneous increase in [aldosterone]p.[13,59,63] These highly dynamic exercise-associated relationships between AVP, POsm and urine osmolality are quite tenuous, which only fuels the controversy of whether or not urine indices[79,80] or plasma indices[81] represent reliable surrogates of realtime hydration status.[82] At rest, it is apparent that urine colour and specific gravity are accurate representatives of hydration status.[83,84] However, during or immediately following exercise, urinary indices may lag behind plasma indices as the kidney acts as an effector organ in the acute maintenance of plasma tonicity.[85,86]
4. AVP, Exercise and Changes in Urine Osmolality
5. AVP and Changes in Sweat Osmolality . Above ~40% of VO2max, sweat production predominates as the primary source of water and electrolyte loss during exercise.[87] Ninety-two percent of all water[88] and 87% of all sodium lost[89] during exercise has been shown to be derived from sweat, verifying the potentially large impact sweating has on fluid and electrolyte balance. Sweat glands play an active role in thermoregulation while the kidneys act to maintain fluid and solute homeostasis.[90] Despite these functional and structural differences, regulatory mechanisms that govern the concentration of sweat may serve important physiological roles in water and sodium balance when renal excretion is suppressed. The parallel response of sweat rate and urine production to changes in POsm cautiously supports AVP as a potential endocrine mediator of both secretions.[91] Sweat glands possess all of the essential elements required for acute fluid and sodium regulation including: aquaporins (AQP5),[92] Na+/H+ exchangers,[93] adrenergic nerve terminals, b-adrenergic receptors, and cyclic adenosine monophosphate (cAMP) regulatory components that activate or inactivate cystic fibrosis
AVP causes anti-diuresis by activating kidney V2 receptors. Activation of V2 receptors stimulates the insertion of aquaporin-2 water channels into the collecting tubules, which induces water reabsorption. Water re-absorption at the kidney will produce more concentrated urine. Osmotic or nonosmotic stimulation of pituitary AVP secretion should therefore be accompanied by a decrease in free water secretion while AVP suppression should promote a maximal free water diuresis. Significant linear relationships between the preto post-race change (D) in [AVP]p versus urine osmolality D in endurance cyclists[22] and between [AVP]p D versus post-race urine [Na+]p D in endurance runners[17] suggests that the renal response to AVP may be appropriate in athletes participating in competitive prolonged endurance exercise. However, in shorter duration laboratory investigations similar relationships between AVP versus urine osmolality have not been reproduced.[47] Regardless of whether the exercise-induced increase in AVP is produced by osmotic or nonosmotic stimuli, a concomitant increase in free ª 2010 Adis Data Information BV. All rights reserved.
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transmembrane conductance regulator (CFTR)Cl channels within the sweat duct.[94] Sweat sodium concentration is neither ‘fixed’ over time nor identical over different regions of the body;[95] with inter- and intra-subject variability[90] supporting the plausible role that sweat glands may play in fluid and electrolyte balance. Although the activation,[90,96,97] anatomy[90,93] and function[90,98] of the sweat glands are morphologically distinct from those of the renal tubules, similar responses to perturbations in both salt intake[98-100] and plasma chloride concentration (as a surrogate for sodium chloride)[101] suggest that sweat glands may perform parallel functions to those the kidneys perform in the acute regulation of serum [Na+]p. 5.1 Exogenous Administration of AVP
AVP may affect sweat rate and composition via two possible mechanisms: (i) vasoconstriction of cutaneous blood flow (V1 receptors); or (ii) water re-absorption (V2 receptors). Injections of either vasopressin or felypressin provide strong evidence against V1a receptors acting as the principal mechanism of AVP on sweat output. Fifty mUnits of felypressin contains 2.5 times the amount of pressor activity as 20 mUnits of vasopressin; yet sweat rates remain indistinguishable when the two analogues are compared.[102] Furthermore, local injections of bradykinin have similar effects on sweating rate to local injections of AVP, although bradykinin stimulates concurrent vasodilation, not vasoconstriction, of skin blood flow.[103] Dissociations between [AVP]P and skin blood flow[104] plus documentation that sweat production continues after arterial occlusion[105] therefore suggests that any affect AVP might have on sweat rate or composition would likely result from AVP stimulation of V2 rather than V1 receptors. Previous studies are mixed with regard to the influence of exogenous AVP administration on sweat rate and sodium concentration. Investigations that support a positive relationship between AVP administration and sweat [Na+]p utilized local injections of vasopressin.[102,103] Rats receiving vasopressin or felypressin injecª 2010 Adis Data Information BV. All rights reserved.
tions into the plantar aspect of the foot – as well as humans receiving sub-dermal injections of 0.16–80 mUmL vasopressin into the forearm, abdomen and thigh - display significant increases in sweat [Na+]p. The increase in sweat [Na+]p is accompanied by a 50% reduction in sweat rate within the first treatment hour.[102,103] Although sweat [Na+]p is significantly elevated, the total amount of sodium excreted is less than control values.[102,103] Therefore, both studies confirm that local concentrations of AVP may stimulate both sodium and water re-absorption in the sweat gland in response to cholinergic and thermal stimulation. The only other study to document a significant increase in sweat [Na+]p, with a concomitant decrease in sweat volume, involved a male with diabetes insipidus receiving 3–4 units of vasopressin subcutaneously.[106] In contrast, other investigations document either an increase[91,107,108] or no change[109,110] in sweat rate and composition following systemic vasopressin administration. Three studies document an increase in sweat rate following subcutaneous or intramuscular injections of 5–10 units of vasopressin, with[91,107] or without[108] exercise as an additional thermal stimulus. It is interesting to note, however, that the increases in sweat rate were only noted in ‘light sweaters’[107] and in temperatures exceeding 29C.[107,108] Other studies that do not document changes in sweat rate or composition following vasopressin administration show clear methodological differences pertaining to the timing of collection (>60 minutes),[105] inadequate dosing (no change in urinary indices)[110] or hyperhydration in extreme heat (maximal sweating rates achieved).[109] 5.2 Endogenous Changes in AVP and Sweat Osmolality/Sodium Concentration
To date, only two studies have investigated the role of endogenous [AVP]p on sweat [Na+]p. The first study did not document a significant relationship between these two variables but failed to collect sweat and blood samples on the same ‘testing’ day.[111] The second study documented significant linear relationships between both sweat and urine [Na+]p versus serum [Na+]p following Sports Med 2010; 40 (6)
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steady-state treadmill exercise.[48] A similar increase in sweat [Na+]p in response to dehydrationinduced hypernatraemia has been previously documented in one study involving eight cyclists riding for 2 hours in the heat.[112] These very preliminary data suggest that the maintenance of fluid and thermoregulatory balance may be simultaneously affected by changes in AVP secretion. 6. Influence of Sex on AVP and Fluid Regulation during Exercise The vast majority of investigations detailing AVP and exercise involve exclusively male cohorts. A few notable exceptions involve female cohorts investigating physical stress and menstrual phase,[56] physical stress and lactation,[57] and fluid balance during pregnancy.[32] Fluctuations in plasma levels of estrogen and progesterone during the menstrual cycle make comparisons among women and between women and men difficult to interpret. Ideally, female subjects should be investigated during the same phase of their menstrual cycle (luteal, follicular) or separations made between pre- and post-menopausal women in order to make valid physiological conclusions.[56,113] However, in field competitions the timing of such events in combination with fewer female participants makes the inclusion and interpretation of collective female data most challenging.[17,22,69,73] A series of elegant and well controlled laboratory investigations sought to delineate sex and female sex-steroid differences in the response of [AVP]p to acute fluid and hypertonic challenges. These studies conducted at rest (steady state) revealed the following: (i) neither sex nor menstrual phase affect basal levels of [AVP]p; (ii) men display greater sensitivity of the [AVP]p in response to POsm; (iii) the osmotic threshold for AVP release was lowest during the luteal phase of the menstrual cycle whereas [estrogens]p were highest; (iv) the estrogen-associated increase in [AVP]p did not contribute to fluid retention; and (v) estrogens and progesterone alone or in combination likely alter the operating osmotic set-point but not overall water and sodium balance.[114,115] A recent prospective study in women ª 2010 Adis Data Information BV. All rights reserved.
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with or without a previous history of hyponatraemia revealed that sex hormone manipulation did not contribute to the fall in blood sodium levels during 3 hours of cycling.[36] However, those women susceptible to hyponatraemia retained more fluid and lost more sodium when both estradiol and progesterone were elevated.[36] Limited exercise investigations (20 . minutes of incremental exercise up to 90% VO2max) performed in women during both the follicular and luteal phases of their menstrual cycle revealed that relatively low levels of estradiol and progesterone (early follicular phase) significantly reduced the stress-induced increase in [AVP]p compared with when plasma gonadal steroid levels were relatively high (mid-luteal phase).[56] Furthermore, this response was replicated in non-lactating (high relative [estradiol]p) versus lactating (low relative [estradiol]p) women utilizing the same protocol.[57] Although measures of fluid balance were not directly assessed in the two studies of high intensity exercise, modulation of AVP by alterations in female sex steroids seemed clearly apparent. Taken together, women with a history of hyponatraemia and/or in the luteal phase of the menstrual cycle should be especially attentive to water weight gain and acute fluid balance changes during exercise. High intensity, steady-state and field investigations not controlling for menstrual phase in female athletes did not reveal statistically significant sex differences in the AVP response to exercise.[17,48] A sex difference did appear, however, in a mathematically derived association between [AVP]p and [oxytocin]p following prolonged endurance running.[17] Further investigations are therefore necessary to more critically assess potential sex differences in AVP and fluid regulation, particularly during prolonged endurance exercise where fatal hyponatraemic encephalopathy is disproportionately higher in females.[10,16] 7. Influence of Training on the AVP Response to Exercise Exercise training appears to modulate the relationship between AVP and POsm before,[67] Sports Med 2010; 40 (6)
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during[116] and after[117] exercise. Data suggest that a short-term training stimulus (<8 days) induces a hypervolaemia characterized by a greater AVP (and plasma renin) response ([AVP]p D) to an exercise challenge on the initial training day,[118] a 5-fold increase in resting plasma protein content[119] and a subsequent decrease in absolute [AVP]p D to a repeat exercise challenge.[87,118] However, when normalized to relative exercise intensity the [AVP]p D to short-term training was not different from pre-training.[87] Therefore, in short-term intraindividual investigations of training and detraining, the exercise-induced increases in [AVP]p were either associated with subsequent changes in POsm[87] and/or plasma volume,[24] although some of the variance was unexplained by either fluid variable.[24] An increase in baseline [AVP]p was documented in 24 male soldiers following 30 days of field training in the heat (40C).[67] Conversely, a decrease in baseline [AVP]p has been documented in four previously untrained males following 5 months of endurance training[117] and in nine female basketball players before and after a 5-month basketball season.[120] In the separate male and female cohorts, the 5-month training period augmented the [AVP]p D response to a standardized pre- and post-exercise challenge.[117,120] This augmented AVP response to training is of unknown physiological significance, as POsm was not simultaneously measured. Furthermore, the disparate changes in baseline [AVP]p between the soldiers training in the heat versus the other two cohorts may likely reflect a difference in activity level, heat acclimatization, timeline or other methodological differences too numerous to describe. Two inter-individual investigations comparing trained versus untrained males documented an altered [AVP]p/POsm response to exercise[116] and to a water load[121] without any statistically significant alteration in baseline [AVP]p.[116,121] Trained subjects exposed to an exercise challenge showed a blunted [AVP]p POsm relationship compared with untrained subjects without differences in the thirst-POsm relationship or drinking behaviour when euhydrated or hypohydrated.[116] ª 2010 Adis Data Information BV. All rights reserved.
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Conversely, trained athletes given a water load at rest demonstrated an augmented [AVP]p/POsm response combined with a blunted diuresis compared with untrained athletes.[121] Together, these studies suggest that training adaptations may: (i) increase the renal sensitivity of V2 receptors[116] during exercise; and (ii) promote water conservation at rest by blunting the oropharyngeal inhibition of AVP.[121] 8. Performance, Thermoregulation and AVP The effect of AVP on performance has been evaluated in two investigations using desmopressin; a vasopressin analogue highly selective for the renal (V2) receptor. The hypothesis for both experiments was that fluid retention would increase exercise performance. A cycling trial of . 60 minutes at 70% VO2max followed by an incremental increase in workload to exhaustion conducted in an ambient temperature of 22C demonstrated no performance enhancement with 20 mg of intranasal desmopressin administered 30 minutes prior to exercise.[122] In contrast, a treadmill trial of 40 minutes at 60% oxygen uptake followed by an incremental run until exhaustion performed in a rubberized tracksuit (to induce hyperthermia) demonstrated a 5–8% performance enhancement with 30 mg of intranasal desmopressin administered 60 minutes prior to exercise.[123] Furthermore, in this running trial, tympanic temperature and heart rate were lower in the desmopressin trial compared with the trial without desmopressin.[123] Although the data from these conflicting trials have many methodological disparities, it has been demonstrated elsewhere that cycling performance is impaired with 3% dehydration at an ambient temperature of 20C but not at 2C.[124] Taken together, it may be suggested that low ambient and endogenous temperature may have favourable effects on exercise performance. There is limited data, particularly in animals, which also suggest that AVP acts as an antipyretic[125] and, when injected both centrally and systemically, may induce hypothermia.[126] Recent evidence supporting the possibility that exercise Sports Med 2010; 40 (6)
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itself is pyrogenic – activating prostaglandin E2 (PGE2)-mediated inflammatory processes[127] – would cautiously support a potential role for AVP in the restraint of exercise-induced hyperthermia. However, more conclusive evidence is necessary to establish a role for AVP in both thermoregulation and exercise performance. 9. Influence of Other Endocrine Mediators on AVP Secretion and Fluid Homeostasis AVP, aldosterone and atrial natriuretic peptide (ANP) are classically identified as the principal hormones regulating overall fluid balance in humans.[23] During exercise, however, the relationships between these hormones with common markers of fluid balance[81] become less predictable. The dissociations that are evident between the established steady-state relationships of AVP with POsm,[14,24] aldosterone with plasma volume[13,24] and ANP with volume overload[13] suggest that other endocrine factors may assist in the regulation of fluid homeostasis during periods of heightened physical stress. Alternatively, fluid regulatory hormones may be stimulated by perturbations from other regulatory systems when homeostasis is acutely disrupted.[25,26,128] 9.1 Classic Fluid Regulatory Hormones 9.1.1 Aldosterone
Aldosterone is the principal mineralocorticoid hormone promoting both sodium conservation and blood pressure maintenance. The significant increase in [aldosterone]p, following high intensity, steady-state and prolonged endurance exercise is a well documented physiological response.[129,130] Potential stimuli to aldosterone secretion during exercise include changes in plasma volume,[17,23] POsm,[24] sympathetic nerve activity,[13] renin and angiotensin secretion,[29] hydration status,[11] ambient temperature,[131] sodium status[132] and potassium levels.[133] The increase in plasma aldosterone concentrations following short, intense bouts of exercise likely result from fast ‘non-genomic’ actions of aldosterone, which can influence sodium channels within 2 minutes.[134] The probable stimuli to ª 2010 Adis Data Information BV. All rights reserved.
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aldosterone secretion during high intensity exercise include plasma volume contraction,[33] which is a strong stimulus of the renin-angiotensinaldosterone system,[135] and ACTH stimulation of the adrenal cortex in response to heightened physical stress.[136,137] If exercise progresses to lower, more sustainable exercise intensities, ‘genomic’ mediation of aldosterone secretion possibly overrides non-genomic stimulation, which then dynamically regulates sodium re-absorption at the kidney to maintain blood volume and pressure. Plasma aldosterone levels have been shown to increase 3- to 8-fold following endurance races lasting between 2 and 27 hours.[17,66,68,70,74,138] The variation in the magnitude of increase between these field studies is likely to be dependent on the degree of plasma volume contraction,[17] thermal exposure,[131] level of dehydration before and during the race,[29] tonicity of the rehydration beverage[61] and/or exercise intensity.[11] Higher aldosterone levels are generally found in faster runners competing in shorter distances,[66] while lower aldosterone levels are documented in slower runners competing in longer distances.[70] Aldosterone concentrations have been shown to increase 2-fold 10 km into a 42 km run[68] and remain elevated for up to 2 days following a 24-hour run.[70] The initial increase in aldosterone levels are most likely due to ACTH stimulation[137] combined with the coupling between sympathetic nerve activity and the renin-angiotensin system that has been described elsewhere during exercise.[13,63] The sustained elevation in aldosterone levels 1 to 2 days post-race may facilitate the isotonic return or even expansion of plasma volume over pre-race levels in response to prolonged endurance exercise.[132] Therefore, these collective data suggest that aldosterone secretion is rapid, predictable and consistent following exercise and confirms that aldosterone participates in the regulation of fluid balance during periods of physical stress.[11,13,129,130,139] 9.1.2 Atrial Natriuretic Peptide
ANP is secreted by granules located in the atria primarily in response to volume receptor stimulation by an increase in central blood volume.[52,140] Sports Med 2010; 40 (6)
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ANP stimulation typically elicits a diuresis and a natriuresis at the kidney by inhibiting AVP, angiotensin II and aldosterone, thereby restoring cardiovascular function and fluid homeostasis.[140] However, during exercise either a disassociation or a blunting of the diuretic and natriuretic response to ANP secretion occurs.[13,63] A significant increase in [ANP]p has been noted following high intensity,[52] low intensity,[141] steady-state[62,63,142] and prolonged endurance exercise.[68,74,143] Exercise lasting for 24 hours, however, results in a 68% decrease in [ANP]p from baseline.[70] Acclimatization to long-term (30 days) field training in the heat has been documented to lower baseline [ANP]p[67] as does a diuretic-induced isotonic hypovolaemia of ~14% pre-exercise.[62] Conversely, an isotonic plasma volume expansion of >14% increased baseline [ANP]p[23] while fluid ingestion after an exercise challenge further increased [ANP]p during the rehydration period, particularly if the fluid replacement beverage contained a carbohydrate and electrolyte mix.[67] These data support the well described volume-reducing role of natriuretic peptides whereas changes in plasma volume directly impact baseline [ANP]p at rest. In contrast to these baseline conditions, an increase in [ANP]p has been shown to occur in conjunction with an exercise-induced decrease in plasma volume.[12,62,74,141] The exerciseinduced increase in [ANP]p is also typically associated with concomitant increases in both [AVP]p[13,63,67,74,141] and [aldosterone]p,[12,13,63,74,142] which would physiologically oppose the diuretic and natriuretic effects of an elevated [ANP]p. The statistically significant increase in [ANP]p is documented after only 10 minutes of cycling at . 60% of peak oxygen uptake (VO2peak).[144] The exercise-induced rise in [ANP]p in this study was linearly related to the degree of atrial distension at the onset of exercise.[144] However, the rise in [ANP]p continued during the next 20 minutes of steady-state cycling, while the rate of atrial pressure steadily declined after only 5 minutes of riding. Therefore, other factors such as an increase in core body temperature, increase in catecholamines and/or an increase in heart rate may serve as an additional stimulus to ANP after ª 2010 Adis Data Information BV. All rights reserved.
endurance exercise.[144] Thus, since the kidney, adrenal gland, lung, gonad and lymphoid tissue contain significant amounts of ANP and its mRNA,[140] the possibility that ANP is stimulated by other overriding factors such as cytokines,[145] lipolysis,[146] renal blood flow[147] or vascular permeability[148] during exercise, necessitates further scientific inquiry. 9.2 Potential Fluid Regulatory Hormones 9.2.1 Oxytocin
Of the two posterior pituitary hormones, AVP is the primary endocrine or whole body fluid homeostasis regulator, whereas oxytocin is better known for its role in pregnancy and lactation. Osmotic stimulation of oxytocin and its role in stimulating natriuresis and inhibiting sodium appetite has been well described in rats[149,150] but is equivocal in human studies.[151,152] Oxytocin, like AVP, can cause an antidiuresis in humans[153] that is likely to be mediated by V2 receptors in the collecting duct of the kidney.[154] However, the dosage of oxytocin required to stimulate an equivalent antidiuresis is 100 times the amount of AVP.[155] Accordingly, very few studies have measured oxytocin in humans during exercise. Only three studies have documented an increase in [oxytocin]p following exercise.[17,33,48,156] Plasma concentrations of oxytocin did not change following high intensity exercise in male cyclists exercising for 20–25 minutes until exhaustion[157] or in healthy females during 20 minutes of graded ex. ercise up to 90% VO2max.[56,57] In contrast, two studies documented an increase in [oxytocin]p following ~60 minutes of . treadmill running at 60%[48] and 80%[156] of VO2peak. Additionally, a ~2-fold increase in [oxytocin]p has also been documented following ~6 hours of continuous running.[17] These cumulative findings suggest that oxytocin may not be stimulated by short duration high intensity exercise but may be stimulated by continuous exercise activity lasting ‡60 minutes. Oxytocin secretion may, of course, be stimulated by factors unrelated to fluid homeostasis during prolonged endurance exercise as oxytocin has been shown to enhance Sports Med 2010; 40 (6)
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glucose production and metabolism,[158] as well as restrict exercise-associated tachycardia in rats.[159] A robust positive correlation has recently been documented between AVP versus oxytocin following prolonged endurance exercise.[17] A similar positive association has been documented in rats[160,161] and dogs[162] and shown to remain robust under dissimilar stimuli such as hypovolaemia, hyperosmolality, hypotension, uraemia and nausea.[160] However, when data from seven well trained runners participating in high intensity, steady-state and prolonged endurance running were separated by running condition, an independent secretion pattern was noted between AVP and oxytocin whereas [AVP]p was highest after the high intensity condition and [oxytocin]p was highest after prolonged endurance running.[33] Such independent secretion of AVP and oxytocin has been previously recorded in humans after chronic dehydration and sodium loading,[151] and in assessments of diurnal variation.[156] Thus, although different mechanisms may stimulate AVP and oxytocin during exercise, both posterior pituitary hormones may possibly be associated with the maintenance of fluid homeostasis during sustained endurance exercise. 9.2.2 Interleukin-6
IL-6 has been shown to stimulate AVP production in non-exercising humans[163,164] and hypothesized to play a role in the development of exercise-induced hyponatraemia via non-osmotic AVP stimulation.[30] Circulating levels of IL-6 have been documented to increase following prolonged endurance[17,165,166] but not high intensity or short duration steady-state exercise.[33] Plasma concentrations of IL-6 have been shown to increase 12-fold following a 56 km footrace,[17] 100-fold following a competitive, higher intensity marathon[166] and 8000-fold after a 245 km mountain run.[165] However, a direct stimulatory role of IL-6 on AVP has yet to be convincingly confirmed during prolonged endurance exercise.[33] Active muscles produce IL-6 during exercise[167,168] and although the exact physiological function of these marked increases in IL-6 production is unclear, possible metabolic roles in ª 2010 Adis Data Information BV. All rights reserved.
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the stimulation of lipolysis[169,170] and in the augmentation of endogenous glucose production and clearance[171] are postulated. Mice deficient in IL-6 have a reduced energy expenditure and exercise capacity, further suggesting that IL-6 is necessary for normal exercise capacity,[172] albeit unrelated to fluid homeostasis. 10. Exercise-Associated Hyponatraemia (EAH) as a Potential Consequence of Exercise-Induced Non-Osmotic AVP Secretion EAH was first described in the literature in 1985[40] and since that time five deaths have been reported in marathon runners[16] and four in military personnel.[173-175] An incidence of between 0% and 44% in athletic sampling cohorts have since been reported, which represents an increase in the reported incidence of EAH over the past 25 years.[176-179] EAH is described as the occurrence of hyponatraemia during or up to 24 hours after prolonged physical activity and is defined by a serum or [Na+]p below the normal reference range of the laboratory performing the test.[16] For most laboratories, this is a [Na+]p less than 135 mmol/L.[16] Exercise-associated hyponatraemia may result from dilution, depletion or a likely combination of both water retention and sodium loss. Dilutional hyponatraemia is caused by an increase in total body water relative to the amount of total body exchangeable Na+ in events and is more frequent in competitive endurance events lasting <20 hours.[17-22] Depletional hyponatraemia is caused by overt sodium losses, particularly sweat sodium losses, and appears to play a greater role in the pathogenesis of EAH in longer distance events (>20 hours), races held in warmer climates[180] and in individuals with high sweat sodium content as demonstrated in mathematical modelling techniques.[181,182] While a negative fluid balance results primarily from under-replacement of sodium and water losses, a positive fluid balance during exercise may occur from either the overconsumption of fluid and/or impaired renal water clearance. Hyponatraemia caused solely by the overconsumption Sports Med 2010; 40 (6)
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of fluids has been demonstrated at rest in athletes with and without a history of EAH.[183-185] Although some cases of EAH may be due to pure water intoxication from overconsumption of fluids, recent descriptive data suggest that AVP secretion may be an exacerbating factor in the development of EAH.[17-22] During exercise, plasma AVP levels may not be maximally suppressed, highly suggestive of the presence of non-osmotic AVP secretion.[17,18,22,38,184] Small increases in circulating AVP markedly reduce maximal kidney excretory capacity,[6] thus increasing the likelihood of retaining all ingested fluids even if rates of drinking do not exceed previously recommended drinking rates of 800–1200 mL/h. Thus, the risk of developing fluid overload with previously ‘normal’ or excessive fluid intakes is enhanced when AVP is secreted inappropriately during prolonged exercise, resulting in increased urine osmolality and decreased urine volume. A strikingly parallel or related entity is hyponatraemia associated with ingestion of the recreational drug ecstasy (methylenedioxymetamfetamine) at ‘rave’ parties. First described in 1993, at least 15 deaths from ecstasy-associated hyponatraemia have been reported in the literature from more than 25 separate case reports.[186] The overall incidence of symptomatic hyponatraemia is 0.4% in a 28-month study period of enquiries to the London Centre of National Poisons Information Service,[187] with 59–94% of symptomatic cases reported in females.[186-189] Ecstasy-associated hyponatraemia is currently considered a dilutional hyponatraemia resulting from a likely combination of three events: ecstasy-induced AVP secretion; ecstasy-induced thirst; and the ready availability and consumption of fluids.[186] Methylenedioxymetamfetamine and its metabolites have clearly been demonstrated as potent non-osmotic stimuli to AVP release in both humans and animals,[190] with concomitant effects on the serotonergic system well described.[186,190] Clinical findings do not appear to reflect the magnitude of hyponatraemia, with vomiting, altered mental status and seizures reflecting the clinical picture of both ecstasy-associated hyponatraemia and EAH.[187] ª 2010 Adis Data Information BV. All rights reserved.
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Inappropriate antidiuretic hormone secretion induces a concomitant natriuresis.[191,192] Thus, the hypothesis that non-osmotic AVP secretion may possibly contribute to the pathogenesis of exercise- and ecstasy-associated hyponatraemia potentially reconciles both the fluid retention and sodium depletion theories currently under debate. Only the degree of salt loss versus water retention would vary depending on each individual situation, with a salt-loss-induced volume contraction a likely non-osmotic stimulus to AVP secretion during prolonged endurance exercise, corresponding water retention diluting blood sodium levels and then pressure natriuresis contributing to an even greater sodium loss when hyponatraemia develops. 11. Hypertonic Saline Administration in the Treatment of EAH The administration of intravenous hypertonic saline solutions has been shown to rapidly reduce non-osmotic AVP stimuli in all hypo-osmolar conditions where inappropriate AVP secretion appears to be the primary pathophysiological mechanism in clinical scenarios.[193] Accordingly, the administration of hypertonic saline solutions appears to be the most efficacious treatment of life-threatening EAH, regardless of the underlying pathophysiological mechanism.[10,18,194-197] Exercise-associated hyponatraemia with or without osmotically inappropriate [AVP]p is an acute hyponatraemia. Therefore, concern regarding osmotic demyelination should not be an impediment to rapidly correcting hyponatraemia in symptomatic EAH.[10,18,38,39,41,42,195,197-200] Prompt administration of a bolus of hypertonic saline solution to athletes with hyponatraemic encephalopathy has been shown to be reliable, safe and life saving.[10,18,196,201,202] Although the total amount of sodium administered in a small dose of hypertonic saline is modest (51 mmol in a 100 mL bolus of 3% saline solution), the 1–2% reduction in cerebral oedema will reverse most neurological symptoms.[194] Hypertonic saline administration induces a robust plasma volume expansion, which would effectively treat both hypovolaemic hyponatraemia Sports Med 2010; 40 (6)
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caused by exuberant sweat sodium losses and hypervolaemic hyponatraemia caused by nonosmotically stimulated AVP, thereby stimulating a free water diuresis, which further corrects abnormally low serum [Na+]p.[203] 12. Conclusions and Future Directions This review served to: (i) create a more thorough understanding of both osmotic and non-osmotic regulation of AVP secretion during exercise; and (ii) identify potential non-osmotic stimuli, which may override osmotic regulation of AVP secretion. The hypothesis that EAH may develop when non-osmotic stimuli override ‘regulatory’ osmotic AVP stimulation during competitive endurance exercise, is thereby presented as a pathophysiological possibility if: (i) hypoosmolality exists; and (ii) sustained fluid intake continues to exceed output over a significant (>4 hours) period of time. Specific areas that require further investigation to clarify the role of AVP and fluid balance during exercise include but are not limited to: 1. carefully controlled interventional studies, which would clearly demonstrate a causal link between non-osmotic AVP secretion and EAH; 2. studies that clarify the role of AVP on sweat rate and osmolality during sustained endurance exercise; 3. studies that clarify the role of AVP in thermoregulation during exercise; 4. investigations that identify specific nonosmotic AVP stimuli during exercise; 5. studies that clarify the role of sex and training on AVP secretion during exercise to potentially explain the increased incidence of EAH in females and under-fit marathon populations. Acknowledgements I wish to thank Joseph G. Verbalis, MD, for inspiring my passion for hormones, Timothy D. Noakes, DSc, for inspiring my passion for science, Arthur J. Siegel, MD, for his unrelenting support, the EAH Consensus Group for their commitment to eradicating EAH, the reviewers of this paper for ensuring this review presented all viewpoints, and Sports Medicine Assistant Editor, Roger Olney, MBChB,
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who mediated a long and windy debate that finally ended in reconciliation. No sources of funding were used to assist in the preparation of this review. The author has no conflicts of interest that are directly relevant to the content of this review.
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180. Hiller WDB. Dehydration and hyponatraemia during triathlons. Med Sci Sports Exerc 1989; 21 Suppl.: 219-21 181. Montain SJ, Cheuvront SN, Sawka MN. Exercise associated hyponatraemia: quantitative analysis to understand the aetiology. Br J Sports Med 2006; 40: 98-105 182. Montain SJ, Sawka MN, Wenger CB. Hyponatraemia associated with exercise: risk factors and pathogenesis. Exerc Sport Sci Rev 2001; 29: 113-7 183. Noakes TD, Wilson G, Gray DA, et al. Peak rates of diuresis in healthy humans during oral fluid overload. S Afr Med J 2001; 91: 852-7 184. Galun E, Tur-Kaspa I, Assia E, et al. Hyponatraemia induced by exercise: a 24-hour endurance march study. Miner Electrolyte Metab 1991; 17: 315-20 185. Speedy DB, Noakes TD, Boswell T, et al. Response to a fluid load in athletes with a history of exercise induced hyponatraemia. Med Sci Sports Exerc 2001; 33: 1434-42 186. Campbell GA, Rosner MH. The agony of ecstasy: MDMA (3,4-methylenedioxymethamphetamine) and the kidney. Clin J Am Soc Nephrol 2008; 3: 1852-60 187. Hartung TK, Schofield E, Short AI, et al. Hyponatraemic states following 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) ingestion. QJM 2002; 95: 431-7 188. Rosenson J, Smollin C, Sporer KA, et al. Patterns of ecstasy-associated hyponatraemia in California. Ann Emerg Med 2007; 49: 164-71, 171 189. Budisavljevic MN, Stewart L, Sahn SA, et al. Hyponatraemia associated with 3,4-methylenedioxymethylamp hetamine (‘‘Ecstasy’’) abuse. Am J Med Sci 2003; 326: 89-93 190. Fallon JK, Shah D, Kicman AT, et al. Action of MDMA (ecstasy) and its metabolites on arginine vasopressin release. Ann N Y Acad Sci 2002; 965: 399-409 191. Schwartz WB, Bennett W, Curelop S, et al. A syndrome of renal sodium loss and hyponatraemia probably resulting from inappropriate secretion of antidiuretic hormone. 1957. J Am Soc Nephrol 2001; 12: 2860-70 192. Verbalis JG. Pathogenesis of hyponatraemia in an experimental model of the syndrome of inappropriate antidiuresis. Am J Physiol 1994; 267: R1617-25 193. Kamoi K, Ishibashi M, Yamaji T. Interaction of osmotic and nonosmotic stimuli in regulation of vasopressin secretion in hypoosmolar state of man. Endocr J 1997; 44: 311-7 194. Hew-Butler T, Noakes TD, Siegel AJ. Practical management of exercise-associated hyponatremic encephalopathy: the sodium paradox of non-osmotic vasopressin secretion. Clin J Sport Med 2008; 18: 350-4 195. Davis DP, Videen JS, Marino A, et al. Exercise-associated hyponatraemia in marathon runners: a two-year experience. J Emerg Med 2001; 21: 47-57 196. Hew-Butler T, Anley C, Schwartz P, et al. The treatment of symptomatic hyponatraemia with hypertonic saline in an Ironman triathlete. Clin J Sport Med 2007; 17: 68-9 197. Siegel AJ. Hypertonic (3%) sodium chloride for emergent treatment of exercise-associated hypotonic encephalopathy. Sports Med 2007; 37: 459-62
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198. Armstrong LE, Curtis WC, Hubbard RW, et al. Symptomatic hyponatraemia during prolonged exercise in heat. Med Sci Sports Exerc 1993; 25: 543-9 199. Frizzell RT, Lang GH, Lowance DC, et al. Hyponatraemia and ultramarathon running. JAMA 1986; 255: 772-4 200. Surgenor S, Uphold RE. Acute hyponatraemia in ultraendurance athletes. Am J Emerg Med 1994; 12: 441-4 201. Siegel AJ, d’Hemecourt P, Adner MM, et al. Exertional dysnatremia in collapsed marathon runners: a critical role for point-of-care testing to guide appropriate therapy. Am J Clin Pathol 2009; 132: 336-40 202. Stefanko G, Lancashire B, Coombes JS, et al. Learning from errors: Pulmonary oedema and hyponatraemia
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after an ironman triathlon. BMJ Case Reports 2009 [online]. Available from URL: http://casereports.bmj.com/ content/2009/bcr.04.2009.1764.full [Accessed 2010 May 25] 203. Moritz ML, Ayus JC. Hospital-acquired hyponatraemia: why are hypotonic parenteral fluids still being used? Nat Clin Pract Nephrol 2007; 3: 374-82
Correspondence: Dr Tamara Hew-Butler, Assistant Professor, Exercise Science Program, School of Health Sciences, Oakland University, 363 Hannah Hall, Rochester, MI 48309, USA. E-mail:
[email protected],
[email protected]
Sports Med 2010; 40 (6)
Sports Med 2010; 40 (6): 481-492 0112-1642/10/0006-0481/$49.95/0
REVIEW ARTICLE
ª 2010 Adis Data Information BV. All rights reserved.
Arterial Prehabilitation Can Exercise Induce Changes in Artery Size and Function that Decrease Complications of Catheterization? Amr Alkarmi,1 Dick H.J. Thijssen,2,3 Khalled Albouaini,1 N. Timothy Cable,2 D. Jay Wright,1,2 Daniel J. Green2,4 and Ellen A. Dawson2 1 2 3 4
Liverpool Heart and Chest Hospital, Liverpool, UK Research Institute for Sport and Exercise Science, Liverpool John Moores University, Liverpool, UK Department of Physiology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands School of Sport Science, Exercise and Health, The University of Western Australia, Crawley, Western Australia, Australia
Contents Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Introducing the Concept of Arterial ‘Prehabilitation’ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Does Arterial Catheterization Cause Vascular Damage? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Does Exercise Training Enhance Conduit Artery Function in Humans? . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Localized Effects of Small Muscle Group Exercise Training . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Whole Body or Large Muscle Group Exercise Training Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Effects of Exercise Training on Conduit Artery Remodelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Interaction between Functional Change and Structural Change Following Training . . . . . . . . . . . . . 6. Relevance of Functional and Structural Arterial Adaptation to ‘Prehabilitation’ . . . . . . . . . . . . . . . . . 7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Abstract
481 482 482 483 483 483 484 486 486 487
Coronary angiography and angioplasty are common invasive procedures in cardiovascular medicine, which involve placement of a sheath inside peripheral conduit arteries. Sheath placement and catheterization can be associated with arterial thrombosis, spasm and occlusion. In this paper we review the literature pertaining to the possible benefits of arterial ‘prehabilitation’ – the concept that interventions aimed at enhancing arterial function and size (i.e. remodelling) should be undertaken prior to cardiac catheterization or artery harvest during bypass graft surgery. The incidence of artery spasm, occlusion and damage is lower in larger arteries with preserved endothelial function. We conclude that the beneficial effects of exercise training on both artery size and function, which are particularly evident in individuals who possess cardiovascular diseases or risk factors, infer that exercise training may reduce complication rates following catheterization and enhance the success of arteries harvested as bypass grafts. Future research efforts should focus directly on examination of the ‘prehabilitation’ hypothesis and the efficacy of different interventions aimed at reducing clinical complications of common interventional procedures.
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1. Introducing the Concept of Arterial ‘Prehabilitation’ Whilst the benefits of exercise in healthy individuals and patients with ischaemic heart disease and cardiovascular disease risk factors are well established[1] and include significant reduction in cardiovascular mortality,[2-4] the effects of exercise on traditional cardiovascular risk factors are relatively modest.[2] Indeed, a recent analysis of 27 000 subjects[5] demonstrated that risk factor modification is responsible for only ~50% of the cardiovascular benefit of exercise.[6] A potential explanation for the ‘missing’ cardioprotective benefits of exercise may relate to direct impacts of training on arterial function and size (i.e. remodelling).[6] In this article we review evidence relating to the direct impact of different forms of exercise training on arterial function and structure. We propose that these benefits may be particularly important in decreasing complications of arterial catheter and sheath insertion, and in optimizing arteries used as bypass grafts. 2. Does Arterial Catheterization Cause Vascular Damage? The vascular endothelium performs an array of homeostatic functions in normal blood vessels.[7] At the interface between the blood and vascular smooth muscle cells, the endothelium is a monolayer of cells capable of transuding bloodborne and haemodynamic signals. It senses mechanical forces within the lumen and regulates vascular tone through the production of vasoactive autacoids. Of these substances, nitric oxide (NO) is the most comprehensively studied. NO is a labile, lipid-soluble gas synthesized in endothelial cells from its precursor L-arginine, by the action of NO synthase (NOS).[7] The physiological stimulus to endothelial NO production is an increase in blood flow and shear stress,[8,9] subsequently leading to NO diffusion into smooth muscle cells and activation of intracellular cyclic guanosine monophosphate (GMP). This leads to decreased intracellular calcium, smooth muscle relaxation and consequent vasoª 2010 Adis Data Information BV. All rights reserved.
dilatation. Basal and stimulated production of NO tends to normalize the vascular shear stress via vasodilatation. Impaired endothelial NOmediated vasodilator function predicts prognosis[10-14] and, enhancing endothelial function, decreases cardiovascular events.[15,16] Endothelial injury due to sheath insertion during cardiac catheterization or percutaneous transluminal coronary angioplasty (PTCA) has been documented.[17-19] Although rare, this endothelial and artery wall damage can be associated with more serious complications, such as thrombosis and total or subtotal occlusion.[20-24] Such complications are more frequent in females, possibly due to their smaller arteries, which are predisposed to injury from sheath insertion. Burstein et al.[17] demonstrated a significant loss of flow-mediated dilatation (FMD), a measure of endothelium-dependent NO function, in the radial artery following cardiac catheterization. Endothelial dysfunction persisted for 9 weeks post-procedure. Whilst it is possible that artery function recovers after a longer period, this study indicates that catheter and sheath placement is associated with damage to the artery wall. The authors suggested that the decreased FMD was due to direct endothelial damage during sheath insertion, resulting in impaired vasodilatation in response to a shear stimulus and severe vasomotor dysfunction. Sanmartin et al.[18] also concluded that transradial catheterization was associated with impaired vasoreactivity, although recovery was reported after 1 month. These studies indicated that immediately after catheterization, baseline artery diameter was significantly increased. This suggests that small arteries such as the radial are physically stretched and distorted by sheath placement. Other studies have indicated that the long-term effect of sheath placement in small arteries involves arterial wall thickening and concentric remodelling.[17,25-27] Collectively, these studies indicate that sheath insertion is associated with structural damage in smaller arteries, which triggers intimal hyperplasia, vascular remodelling[28] and a pro-atherogenic inflammatory cascade. Indeed, Sports Med 2010; 40 (6)
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assessment of the radial artery after it has been harvested has demonstrated that prior transradial catheterization induces intimal hyperplasia, medial inflammation and tissue necrosis at the puncture site.[29] The studies described above indicate that arterial catheterization and sheath insertion can have a detrimental impact on arterial health, which may compromise the future use of such arteries as bypass grafts, particularly if the patient has undergone repeat catheterization of the artery. Specifically, catheter and sheath placement are associated with the immediate endothelial dysfunction, which may predispose the artery to spasm, thrombus formation, occlusion and the future development of focal atherosclerotic lesions. Increasing the size and function of conduit arteries prior to catheterization would, logically, help to minimize these complications. Although little research has directly addressed the efficacy of such ‘arterial prehabilitation’, we review evidence in the next section, which suggests that exercise training can enhance vascular function and increase the circumferential size of conduit arteries in humans.
3. Does Exercise Training Enhance Conduit Artery Function in Humans? 3.1 Localized Effects of Small Muscle Group Exercise Training
Although there have been few studies of the impact of small muscle group exercise on conduit artery function or structure in healthy volunteers (figure 1), all studies in patients with evidence of pre-existing endothelial dysfunction and/or cardiovascular disease have reported improved FMD (figure 2). Increases in endothelial function have been found following 4 weeks[44,65] and 8 weeks[41] of handgrip, or 10 weeks of localized leg training[43] with no changes in indices of smooth muscle function.[43,65] Taken together, these studies strongly suggest that subjects with impaired conduit artery vasodilator function can derive benefit from localized ª 2010 Adis Data Information BV. All rights reserved.
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exercise training programmes aimed at improving vascular endothelial function.[44] 3.2 Whole Body or Large Muscle Group Exercise Training Effects
To date, only a few studies have demonstrated an improvement in FMD in conduit arteries after whole body exercise in healthy subjects (figure 1). Whilst an increase in endothelial function has been demonstrated after 10 weeks of daily running,[38] other studies in healthy volunteers have found no change,[34,35] or slight and non-significant increases in FMD post-training.[36,37] In a recent study, 8 weeks of cycling exercise generated significant increases in FMD over the first 4 weeks of exercise, which returned to near baseline at the end of week 8.[33] This time course effect of training may resolve some of the previous disparity in the literature regarding the impact of whole body training in healthy volunteers. It suggests that initial changes in arterial function as a consequence of the shear stress increases associated with repeated bouts of exercise are ultimately superseded by shear-mediated increases in arterial size (i.e. remodelling), which consequently enable a normalization of artery function (see section 5). Studies involving large muscle group exercise in subjects with evidence of endothelial dysfunction (e.g. existing cardiovascular disease or risk factors) have generally demonstrated improvement in endothelium-dependent function posttraining (figure 2). In subjects with coronary artery disease, significant improvements in FMD (endotheliumdependent function) were noted after exercise training.[39,43,56,57] Similarly, in patients with chronic cardiac failure, most of the studies that have examined the relationship between large muscle group exercise and endothelial function have demonstrated an improvement in vascular function.[58-60,66] This has also been found in patients with hypertension,[34,58] hypercholesterolaemia[56] and peripheral vascular disease.[42,47] In summary, a beneficial effect of exercise training on NO-mediated endothelial function is Sports Med 2010; 40 (6)
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+
−1
0
4 5 6 7 8 1 2 3 Change in function with training (%)
9
Whole body exercise
⎫ ⎪ ⎬ ⎪ ⎭ ⎫ ⎪ ⎪ ⎪ ⎬ ⎪ ⎪ ⎪ ⎭
Localized exercise
484
Study
No.
Duration (wk)
Allen et al. 2003
14
4
McGowan et al. 2007
16
8
Wray et al. 2007
11
6
Tinken et al. 2008
13
8
Moriguchi et al. 2005
10
12
Thijssen et al. 2007
8
8
Rakobowchuck et al. 2005
28
12
Pullin et al. 2004
17
4
Clarkson et al. 1999
25
10
Mean ± SE
Mean ± SE
10
Fig. 1. Changes in flow-mediated dilatation (FMD) in the brachial or the femoral artery in healthy volunteers following local and whole body exercise. The number of volunteers, duration of exercise and the change in FMD post-exercise are identified next to each study. The absolute change in all studies is calculated and marked in the black square.[30-38] SE = standard error.
evident in individuals with impaired endothelial function a priori.[67] 4. Effects of Exercise Training on Conduit Artery Remodelling In a classic study, Langille and O’Donnell[68] demonstrated that ligation of one carotid artery in rabbits led to a 70% reduction in flow and a subsequent decrease in arterial size over 2 weeks. This change in arterial size was dependent upon the presence of an intact and functional endothelial layer. Subsequent elegant studies further elucidated this finding. Tronc et al.[69] produced a chronic increase in blood flow and consequent shear stress through the common carotid artery in rabbits via an arteriovenous fistula with the external jugular vein. The diameter of the artery increased in order to restore the baseline shear rate in the experimental compared with the control group. Furthermore, they established that the arterial remodelling was, at least partially, NO-dependent as the increase in vessel calibre was attenuated in a subgroup treated with the ª 2010 Adis Data Information BV. All rights reserved.
NO synthesis inhibitor NG-nitro-L-argininemethyl ester (L-NAME). Later, Tuttle and colleagues[70] examined the correlation between the rate of arterial size expansion and blood flow/ shear rate in Wistar rats (resistance) arteries by either increasing or decreasing the number of supply arteries to a given vessel. As expected, a reduction in shear rate and consequently a diminished expansion resulted in a reduced arterial luminal size, and vice versa. The increase in arterial lumen was associated with increased intimal and adventitial cell densities in arteries with the highest increase in shear rate. There was also an increased endothelial NOS (eNOS) expression in the arteries with increased flow, which led them to highlight the significant role of NO in this mechanism.[70] In summary, the study demonstrated that the rate of arterial size remodelling, arterial wall remodelling and gene expression is correlated with shear rate in the resistance arteries.[70] In humans, cross-sectional studies in healthy volunteers have suggested that localized exercise of small muscle groups can induce structural vascular enlargement. For example, a demonstrable Sports Med 2010; 40 (6)
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resistance vessel[75,76] and conduit artery diameter[35,71,77-79] following endurance training in healthy subjects. Taken together, these studies strongly suggest that conduit arteries adapt rapidly to chronic exercise training via structural enlargement, possibly to accommodate increased shear stress and flows associated with the repeated exercise bouts.[67] Vascular remodelling as a consequence of exercise may play an important role in enhancing vessel function and enlarging diameter prior to cardiac catheterization, potentially leading to a reduction in site complication rate. However, data pertaining to conduit remodelling are limited in patients with cardiovascular risk factors or diseases, and further research is required in this area.
⎫ ⎪ ⎪ ⎪ ⎪ ⎪ ⎬ ⎪ ⎪ ⎪ ⎪ ⎪ ⎭
+ −
−
+
+ −
−1
0
1
2 3 4 5 6 7 Change in function with training (%)
8
9
Recent MI Hypertension PAD CAD CHF
Study
No.
Duration (wk)
Vona et al. 2004 McGowan et al. 2007 McDermott et al. 2009 Gocke et al. 2002 Hornig et al. 1996 Hambrecht et al. 2000
52 16 36 40 12 10
4 8 24 10 4 4
Mean ± SE Vona et al. 2009 Vona et al. 2004 Brendle et al. 2001 PAD McDermott et al. 2009 PVD Andreozzi et al. 2007 Lavrencic et al. 2002 Fuchsjager-Mayrl et al. 2002 Diabetes Maiorana et al. 2001 Meyer et al. 2006 Hamdy et al. 2003 Obesity Watts et al. 2004 Watts et al. 2004 Hypertension Moriguchi et al. 2005 Paul et al. 2007 CAD Walsh et al. 2003 Edwards et al. 2004 Wisloff et al. 2007 Belardinelli et al. 2006 CHF Linke et al. 2001 Guazzi et al. 2004 Belardinelli et al. 2007 Kobayashi et al. 2003 IHD Blumenthal et al. 2005 Recent MI
Whole body exercise
⎫ ⎪ ⎬ ⎪ ⎭
Localized exercise
increase in the capacity for peak blood flow, indicative of resistance arterial remodelling,[71] and a larger baseline artery diameter[72] have been reported in the preferred versus nonpreferred limb of elite tennis players.[73,74] The adaptation of the vessels to specific and localized training is demonstrated by the finding of a larger subclavian artery in tennis players compared with road cyclists and untrained subjects, and a larger resting diameter of the common femoral artery in cyclists compared with tennis players and untrained subjects.[72] The ‘trainability’ of conduit arteries has been demonstrated even in athletes with prior evidence of vascular enlargement.[71] Data from longitudinal training studies have also demonstrated an increase in
52 52 19 51 22 14 18 16 33 24 14 19 15 40 10 9 18 30 11 16 59 14 48
4 12 24 24 6 12 16 8 24 24 8 8 12 12 8 12 12 8 4 8 8 12 16
Mean ± SE 10
Fig. 2. Change in flow-mediated dilatation (FMD) in the brachial or the femoral artery in patients with recent myocardial infarction (MI), peripheral artery disease (PAD), peripheral vascular disease (PVD), diabetes mellitus, obesity, hypertension, coronary artery disease (CAD), ischaemic heart disease (IHD) and congestive heart failure (CHF) following local and whole body exercise. The number of volunteers, duration of exercise and the change in FMD are identified next to each study. The absolute change in all studies is calculated and marked in the black square.[34,39-64] SE = standard error. ª 2010 Adis Data Information BV. All rights reserved.
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5. Interaction between Functional Change and Structural Change Following Training Evidence suggests that enhancement of function in conduit arteries with normal or abnormal endothelial function occurs rapidly following exercise training.[45,50,65,80-84] Laughlin and colleagues[85,86] have demonstrated, in animals, that adaptations in conduit artery structure occur subsequent to improved function following exercise training. This group was the first to suggest that arterial remodelling, which may be NOmediated, decreases arterial shear levels, thereby resulting in normalization of NO-mediated endothelial function. Hence, structural remodelling supersedes functional adaptation. This proposal may explain some of the disparity in the human exercise training literature, since some studies that have employed longer durations of exercise training have not demonstrated enhanced NO endothelium-dependent vasodilatation.[87-89] Whilst some indirect evidence has supported the notion of functional adaptation preceding structural change,[67] no study had directly tested this hypothesis until recently. In a study of 20 healthy males (13 who undertook 8-week cycling exercise training and seven who were controls), both brachial and popliteal arteries were examined every 2 weeks throughout the 8-week period. Improvement in arterial endothelium-dependent NO function (i.e. FMD) was observed in both arteries in the first 4 weeks of exercise training, but thereafter these values returned to baseline levels. Interestingly, the conduit dilator capacity (an index of conduit artery remodelling) followed the converse pattern, with an improvement in structure in the latter part of the exercise training programme. Therefore, this finding in humans reinforces the proposal of Laughlin et al.,[86] in that it appears that the initial improvement in function is followed by an outward remodelling of the arteries in humans. 6. Relevance of Functional and Structural Arterial Adaptation to ‘Prehabilitation’ The studies above suggest that exercise training improves both artery function and structure. ª 2010 Adis Data Information BV. All rights reserved.
‘Prehabilitative’ exercise may therefore be beneficial both before arterial cannulation and before removal of the artery as a bypass graft. The aim of ‘prehabilitation’ would be to reduce arterial injury and spasm and thereby improve success rates of transradial catheterization. Arterial spasm is more likely to occur in smaller arteries,[90,91] and an exercise training programme that triggers vascular remodelling would be beneficial to the patient by reducing painful arterial spasms as well as improving procedural success rates. If the artery is to be used as a graft then it is possible that ‘prehabilitation’ could increase artery size and thereby reduce damage induced by the catheter sheath insertion, which, in turn, could improve graft patency and potentially even improve clinical outcomes. In the context of ‘prehabilitation’ before coronary artery bypass surgery, a final paper by the Hambrecht group deserves mention.[80] They examined male patients with stable coronary artery disease and preserved left ventricular function who were waiting for coronary artery bypass grafting surgery, during which the left internal mammary artery (LIMA) was employed as a graft. Patients were randomized into either a control or an exercise trained group. The exercise group completed a 4-week exercise programme prior to surgery, which included daily supervised exercise for 30 minutes on a rowing ergometer and 30 minutes on a bicycle ergometer. Exercise was set to the maximum intensity that could be tolerated in the absence of angina symptoms. An invasive in vivo assessment of the LIMA was carried out before and 4 weeks after the randomization. A small tissue sample was also obtained from the LIMA at the time of surgery. The group demonstrated that exercise training led to significantly enhanced endothelium-dependent vasodilatation (as assessed by an increase in mean peak flow velocity) following acetylcholine infusion, which was not evident in the control group. There was no significant change in endotheliumindependent vasodilatation induced by glyceryl trinitrate (nitroglycerin) infusion. Furthermore, the exercise trained group had increased eNOS expression in the LIMA biopsy, which was correlated with the improved in vivo endothelial Sports Med 2010; 40 (6)
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function. The authors therefore concluded that exercise training resulted in enhanced endothelial function and that the mechanism behind this was associated with increased eNOS expression, which leads to an increase of NO activity.[80] The above study demonstrates that an endurance exercise training programme can be undertaken in patients with stable coronary artery disease; however, this type of whole body exercise may not be suitable for all populations (figure 3). Localized exercise, such as handgrip training, has been shown to improve the function and structure of radial and brachial arteries (figure 2 and section 4). Interestingly, this mode of exercise, if submaximal values are employed, does not increase central blood pressure, and as such represents a low risk to patients with cardiovascular disease. Furthermore, localized training, in particular handgrip exercise, is a cheap mode of exercise training that could be carried out by the patients at home. In contrast, whole body exercise presents a higher risk and would require expert supervision. Whilst we cannot give exact times required for prehabilitative exercise to be effective, improvements in arterial function have been found after as little as 4 weeks of training,[44] and increases in artery size have been reported after 4–8 weeks.[33,35,78] Within the authors’ hospital, the current waiting time for coronary artery bypass graft surgery is 6 weeks and the waiting time for coronary angioplasty in patients with stable angina is approximately 4 weeks. Given the previous literature, this may be sufficient time to produce improvements in both arterial function and structure. As there are no data on improved outcomes from either transradial catheterizations or longterm graft survival with ‘prehabilitation’, we cannot conclusively comment on cost-benefits. However, Hambrecht and colleagues[15] reported that exercise training was more cost effective (over half the cost) over 12 months compared with PTCA. This was related to the cost of angioplasty and also to the higher number of re-hospitalizations and coronary re-interventions that were required in the PTCA (non-exercise trained) group. If exercise training is able to imª 2010 Adis Data Information BV. All rights reserved.
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prove artery function and size prior to catheterization or removal of the artery as a graft, then this may reduce arterial spasm, improve success rates of transradial catheterization or positively affect graft longevity following bypass surgery. If this is the case, then it may be a viable option for patients awaiting these procedures. There are limitations with our proposed model of ‘prehabilitation’. First, exercise training, particularly whole body exercise training, is contraindicated in some populations (figure 3). This type of training is obviously not viable in patients who require immediate angiography or coronary artery bypass surgery. Nor do we suggest that it is undertaken by patients with unstable angina, since an acute bout of exercise in untrained individuals might result in plaque rupture, myocardial infarction and arrhythmias. Second, we do not propose delaying necessary interventional procedures in favour of prehabilitative exercise, although the data of Hambrecht et al.[15] suggest relative benefits of exercise compared with PTCA in some patients. Rather, we propose to make use of redundant waiting time in patients with stable coronary disease. 7. Conclusions This review of the literature pertaining to vascular adaptation to exercise reveals that: 1. Exercise training is associated with decreased cardiovascular risk, in large part due to the direct beneficial impact of repeated acute bouts of exercise on endothelial function and arterial remodelling. 2. Endothelial cells possess antiatherogenic and antithrombotic properties. Endothelial dysfunction predisposes to increases cardiovascular events, and improvement in endothelial function is cardioprotective. 3. Percutaneous coronary interventional procedures involve placement of a sheath inside peripheral conduit arteries and this procedure is associated with entry site complications and predisposition to endothelial damage, denudation and dysfunction. 4. Exercise training is a potent stimulus to arterial adaptation and repair. Both localized Sports Med 2010; 40 (6)
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Is prehabilitation contraindicated? Contraindications (ACSM criteria): Unstable angina Resting systolic blood pressure >200 or resting diastolic blood pressure >110 mmHg should be evaluated on a case-by-case basis Orthostatic blood pressure drop of >20 mmHg with symptoms Critical aortic stenosis (peak systolic gradient of >20 mmHg with aortic valve orifice area <0.75 cm2 in average size adult) Acute systemic illness or fever Uncontrolled atrial or ventricular arrhythmias Uncontrolled sinus tachycardia (>120 beats/min) Third-degree AV heart block (without pacemaker) Active pericarditis or myocarditis Recent embolism Thrombophlebitis Resting ST-segment displacement (>2 mm) Uncontrolled diabetes mellitus (resting blood glucose >400 mg/dL) Severe orthopaedics that would prohibit exercise Other metabolic problems, such as acute thyroiditis, hypo- or hyperkalaemia, hypovolaemia, etc. No
Yes Is immediate intervention indicated? Yes
Further cardiological consultation and medical assessment
No Prehabilitation Systemic exercise: if moderate or high intensity then GXT required
Localized exercise: no medical GXT required
Adverse symptoms during exercise? Examples of systemic exercise
n
tio
Duration: 30 min at target intensity or four sets at 20 min each (4 min rest between sets)
Endothelium Smooth muscle
nc
Intensity: 30−50% or maximal voluntary contraction or 70% maximal work at 30 contractions/min for 30 min
Fu
Duration: Start at 15 min at target exercise intensity, advance to 60 min (within patient tolerence)
Activities such as handgrip exercise 2−7 d/wk
Duration of training
Intensity: Exercise intensity below myocardial ischaemic threshold RPE 11−14, or 40−75% of HRpeak
Artery function and structure
Artery remodelling
Aerobic training: Activities such as walking/running, cycling and swimming 4−7 d/wk
Examples of localized exercise
Resistance (weight) training: Activities such as circuit weight training, theraband exercise and bodyweight exercise 2−3 d/wk Intensity: RPE 11−15 Six to 15 repetitions per set Commence at one set per exercise, progressing to up to three sets Four to eight different exercises for the major muscle groups
−ve
+ve
CABG or PTCA
Fig. 3. Risk stratification, examples of exercise training . and changes in vascular function with proposed ‘arterial prehabilitation’. Moderate exercise: 40–50% of maximal oxygen consumption (VO2max); 3–6 metabolic equivalents (METs); ‘‘an intensity well within the individuals . capacity, one which can be comfortably sustained for a prolonged period of time (~45 minutes).’’[92] High intensity exercise: >60% of VO2max; >6 METs; ‘‘exercise intensity enough to represent a substantial cardiorespiratory challenge.’’[92] Examples of systemic exercise[15,80,93-95] and localized[30,41,44] exercise in patient populations in the literature. ACSM = American College of Sports Medicine; AV = atrioventricular; CABG = coronary artery bypass graft; GXT = graded exercise test; HRpeak = peak heart rate; PTCA = percutaneous transluminal coronary angioplasty; RPE = rating of perceived exertion; ST = ECG derived ST segment; -ve = negative; +ve = positive.
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Sports Med 2010; 40 (6)
Prehabilitation: Exercise to Enhance CV Outcomes
small muscle group exercise and whole body exercise can enhance endothelial function, enlarge conduit arteries and modulate endothelial progenitor cell number and function. 5. Based on the above evidence, we propose ‘arterial prehabilitation’, the concept that interventions aimed at enhancing arterial function, remodelling and repair should be undertaken prior to cardiac catheterization, or artery harvest for bypass graft surgery, in order to optimize subsequent outcomes and minimize complications such as artery spasm and occlusion or graft patency post-bypass surgery. 6. Future research effort should focus directly on examination of the hypothesis that beneficial effects of exercise training may be evident prior to routine procedures and that ‘prehabilitation’ may serve as an effective strategy in reducing clinical complications of common interventional procedures.
489
8.
9.
10.
11.
12.
13. 14.
15.
Acknowledgements 16.
Daniel Green was supported by the National Heart Foundation of Australia. Dick Thijssen was supported by the Netherlands Organisation for Scientific Research (NWOgrant 82507010) and is a recipient of the E. Dekker-stipend from the Dutch Heart Foundation. The authors have no conflicts of interest that are directly relevant to the content of this review.
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58. Wisloff U, Stoylen A, Loennechen JP, et al. Superior cardiovascular effect of aerobic interval training versus moderate continuous training in heart failure patients: a randomized study. Circulation 2007; 115 (24): 3086-94 59. Belardinelli R, Capestro F, Misiani A, et al. Moderate exercise training improves functional capacity, quality of life, and endothelium-dependent vasodilation in chronic heart failure patients with implantable cardioverter defibrillators and cardiac resynchronization therapy. Eur J Cardiovasc Prev Rehabil 2006; 13 (5): 818-25 60. Linke A, Schoene N, Gielen S, et al. Endothelial dysfunction in patients with chronic heart failure: systemic effects of lower-limb exercise training. J Am Coll Cardiol 2001; 37 (2): 392-7 61. Guazzi M, Reina G, Tumminello G, et al. Improvement of alveolar-capillary membrane diffusing capacity with exercise training in chronic heart failure. J Appl Physiol 2004; 97 (5): 1866-73 62. Belardinelli R. Exercise training in chronic heart failure: how to harmonize oxidative stress, sympathetic outflow, and angiotensin II. Circulation 2007; 115 (24): 3042-4 63. Kobayashi N, Tsuruya Y, Iwasawa T, et al. Exercise training in patients with chronic heart failure improves endothelial function predominantly in the trained extremities. Circ J 2003; 67 (6): 505-10 64. Blumenthal JA, Sherwood A, Babyak MA, et al. Effects of exercise and stress management training on markers of cardiovascular risk in patients with ischemic heart disease: a randomized controlled trial. JAMA 2005; 293 (13): 1626-34 65. Hambrecht R, Hilbrich L, Erbs S, et al. Correction of endothelial dysfunction in chronic heart failure: additional effects of exercise training and oral L-arginine supplementation. J Am Coll Cardiol 2000; 35 (3): 706-13 66. Hambrecht R, Fiehn E, Weigl C, et al. Regular physical exercise corrects endothelial dysfunction and improves exercise capacity in patients with chronic heart failure. Circulation 1998; 98 (24): 2709-15 67. Green DJ, Maiorana A, O’Driscoll G, et al. Effect of exercise training on endothelium-derived nitric oxide function in humans. J Physiol 2004; 561 (Pt 1): 1-25 68. Langille BL, O’Donnell F. Reductions in arterial diameter produced by chronic decreases in blood flow are endothelium-dependent. Science 1986; 231 (4736): 405-7 69. Tronc F, Wassef M, Esposito B, et al. Role of NO in flowinduced remodeling of the rabbit common carotid artery. Arterioscler Thromb Vasc Biol 1996; 16 (10): 1256-62 70. Tuttle JL, Nachreiner RD, Bhuller AS, et al. Shear level influences resistance artery remodeling: wall dimensions, cell density, and eNOS expression. Am J Physiol Heart Circ Physiol 2001; 281 (3): H1380-9 71. Naylor LH, O’Driscoll G, Fitzsimons M, et al. Effects of training resumption on conduit arterial diameter in elite rowers. Med Sci Sports Exerc 2006; 38 (1): 86-92 72. Huonker M, Schmid A, Schmidt-Trucksass A, et al. Size and blood flow of central and peripheral arteries in highly trained able-bodied and disabled athletes. J Appl Physiol 2003; 95 (2): 685-91 73. Green DJ, Fowler DT, O’Driscoll JG, et al. Endotheliumderived nitric oxide activity in forearm vessels of tennis players. J Appl Physiol 1996; 81 (2): 943-8
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74. Sinoway LI, Musch TI, Minotti JR, et al. Enhanced maximal metabolic vasodilatation in the dominant forearms of tennis players. J Appl Physiol 1986; 61 (2): 673-8 75. Martin 3rd WH, Kohrt WM, Malley MT, et al. Exercise training enhances leg vasodilatory capacity of 65-yr-old men and women. J Appl Physiol 1990; 69 (5): 1804-9 76. Green DJ, Cable NT, Fox C, et al. Modification of forearm resistance vessels by exercise training in young men. J Appl Physiol 1994; 77 (4): 1829-33 77. Dinenno FA, Tanaka H, Monahan KD, et al. Regular endurance exercise induces expansive arterial remodelling in the trained limbs of healthy men. J Physiol 2001; 534 (Pt 1): 287-95 78. Miyachi M, Tanaka H, Yamamoto K, et al. Effects of onelegged endurance training on femoral arterial and venous size in healthy humans. J Appl Physiol 2001; 90 (6): 2439-44 79. Miyachi M, Iemitsu M, Okutsu M, et al. Effects of endurance training on the size and blood flow of the arterial conductance vessels in humans. Acta Physiol Scand 1998; 163 (1): 13-6 80. Hambrecht R, Adams V, Erbs S, et al. Regular physical activity improves endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase. Circulation 2003; 107 (25): 3152-8 81. Gielen S, Erbs S, Linke A, et al. Home-based versus hospital-based exercise programs in patients with coronary artery disease: effects on coronary vasomotion. Am Heart J 2003; 145 (1): E3 82. Higashi Y, Sasaki S, Kurisu S, et al. Regular aerobic exercise augments endothelium-dependent vascular relaxation in normotensive as well as hypertensive subjects: role of endothelium-derived nitric oxide. Circulation 1999; 100 (11): 1194-202 83. Higashi Y, Sasaki S, Sasaki N, et al. Daily aerobic exercise improves reactive hyperemia in patients with essential hypertension. Hypertension 1999; 33 (1 Pt 2): 591-7 84. Radegran G, Saltin B. Nitric oxide in the regulation of vasomotor tone in human skeletal muscle. Am J Physiol 1999; 276 (6 Pt 2): H1951-60 85. Laughlin MH, Overholser KA, Bhatte MJ. Exercise training increases coronary transport reserve in miniature swine. J Appl Physiol 1989; 67 (3): 1140-9 86. Laughlin MH, Rubin LJ, Rush JW, et al. Short-term training enhances endothelium-dependent dilation of coronary arteries, not arterioles. J Appl Physiol 2003; 94 (1): 234-44 87. Kingwell BA, Arnold PJ, Jennings GL, et al. Spontaneous running increases aortic compliance in Wistar-Kyoto rats. Cardiovasc Res 1997; 35 (1): 132-7 88. McAllister RM, Laughlin MH. Short-term exercise training alters responses of porcine femoral and brachial arteries. J Appl Physiol 1997; 82 (5): 1438-44 89. McAllister RM, Kimani JK, Webster JL, et al. Effects of exercise training on responses of peripheral and visceral arteries in swine. J Appl Physiol 1996; 80 (1): 216-25 90. Ruiz-Salmeron RJ, Mora R, Velez-Gimon M, et al. Radial artery spasm in transradial cardiac catheterization: assessment of factors related to its occurrence, and of its consequences during follow-up. Rev Espan Cardiol 2005; 58 (5): 504-11
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91. Fukuda N, Iwahara S, Harada A, et al. Vasospasms of the radial artery after the transradial approach for coronary angiography and angioplasty. Jpn Heart J 2004; 45 (5): 723-31 92. American College of Sports Medicine. ACSM’s guidelines for exercise testing and prescription. 6th ed. Philadelphia (PA): Lippincott Williams & Wilkins, 2000 93. Maiorana A, O’Driscoll G, Cheetham C, et al. Combined aerobic and resistance exercise training improves functional capacity and strength in CHF. J Appl Physiol 2000; 88 (5): 1565-70 94. Maiorana A, O’Driscoll G, Dembo L, et al. Effect of aerobic and resistance exercise training on vascular function in
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Correspondence: Dr Ellen A. Dawson, Research Fellow, Research Institute for Sport and Exercise Science, Liverpool John Moores University, Tom Reilly Building, Byrom Street, Liverpool L3 3AF, UK. E-mail:
[email protected]
Sports Med 2010; 40 (6)
Sports Med 2010; 40 (6): 493-507 0112-1642/10/0006-0493/$49.95/0
REVIEW ARTICLE
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Physical Activity and Pregnancy Cardiovascular Adaptations, Recommendations and Pregnancy Outcomes Katarina Melzer,1,2 Yves Schutz,3 Michel Boulvain2 and Bengt Kayser1 1 Institute of Movement Sciences and Sports Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland 2 Department of Obstetrics and Gynaecology, University Hospitals of Geneva, Faculty of Medicine, University of Geneva, Geneva, Switzerland 3 Department of Physiology, University of Lausanne, Lausanne, Switzerland
Contents Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Cardiovascular Adaptations to Training and Detraining in Pregnant and Nonpregnant States . . . . 1.1 Cardiovascular Adaptations to Training . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2 Cardiovascular Adaptations to Detraining. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Cardiovascular Changes due to Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Cardiovascular Changes during Labour and Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Postpartum Cardiovascular Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Physical Activity and Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Submaximal Aerobic Capacity during Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Work Efficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 Maximum Aerobic Capacity during Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4 Maximal Heart Rate during Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Physical Activity Recommendations during Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Recommended Heart Rate Target Zones for Aerobic Exercise in Pregnancy . . . . . . . . . . . . . . . . 5. Compliance with Physical Activity Recommendations during Pregnancy . . . . . . . . . . . . . . . . . . . . . . 6. Effects of Physical Activity on Pregnancy Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Abstract
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Regular physical activity is associated with improved physiological, metabolic and psychological parameters, and with reduced risk of morbidity and mortality. Current recommendations aimed at improving the health and wellbeing of nonpregnant subjects advise that an accumulation of ‡30 minutes of moderate physical activity should occur on most, if not all, days of the week. Regardless of the specific physiological changes induced by pregnancy, which are primarily developed to meet the increased metabolic demands of mother and fetus, pregnant women benefit from regular physical activity the same way as nonpregnant subjects. . Changes in submaximal oxygen uptake (VO2) during pregnancy depend on the type of exercise performed. During maternal rest or submaximal weight-bearing exercise (e.g. walking, stepping, treadmill exercise), absolute
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. maternal VO2 is significantly increased compared with the nonpregnant state. The magnitude of change is approximately proportional to maternal weight gain. When pregnant women perform submaximal weight-supported exercise on land (e.g. level cycling), the findings are . contradictory. Some studies remany others reported ported significantly increased absolute VO2, while . unchanged or only slightly increased absolute VO2 compared with the nonpregnant state. The latter findings may be explained by the fact that the metabolic demand of cycle exercise .is largely independent of the maternal body mass, resulting in no absolute VO2 alteration. . . Few studies that directly measured changes . in maternal maximal VO2 (VO2max) showed no difference in the absolute VO2max between pregnant and nonpregnant subjects in cycling, swimming or weight-bearing exercise. Efficiency of work during exercise appears to be unchanged during pregnancy in non-weight-bearing exercise. During weight-bearing exercise, the work efficiency was shown to be improved in athletic women who continue exercising and those who stop exercising during pregnancy. When adjusted for weight gain, the increased efficiency is maintained throughout the pregnancy, with the improvement being greater in exercising women. Regular physical activity has been proven to result in marked benefits for mother and fetus. Maternal benefits include improved cardiovascular function, limited pregnancy weight gain, decreased musculoskeletal discomfort, reduced incidence of muscle cramps and lower limb oedema, mood stability, attenuation of gestational diabetes mellitus and gestational hypertension. Fetal benefits include decreased fat mass, improved stress tolerance, and advanced neurobehavioural maturation. In addition, few studies that have directly examined the effects of physical activity on labour and delivery indicate that, for women with normal pregnancies, physical activity is accompanied with shorter labour and decreased incidence of operative delivery. However, a substantial proportion of women stop exercising after they discover they are pregnant, and only few begin participating in exercise activities during pregnancy. The adoption or continuation of a sedentary lifestyle during pregnancy may contribute to the development of certain disorders such as hypertension, maternal and childhood obesity, gestational diabetes, dyspnoea, and pre-eclampsia. In view of the global epidemic of sedentary behaviour and obesity-related pathology, prenatal physical activity was shown to be useful for the prevention and treatment of these conditions. Further studies with larger sample sizes are required to confirm the association between physical activity and outcomes of labour and delivery.
Regular physical activity is associated with improved physiological, metabolic and psychological parameters, and with reduced risk of morbidity and mortality from diseases such as cardiovascular disease, hypertension, diabetes mellitus, obesity, osteoporosis, sarcopenia, cognitive disorders and some forms of cancer.[1] Current recommendations aimed at improving ª 2010 Adis Data Information BV. All rights reserved.
the health and well-being of nonpregnant subjects advise that an accumulation of 30 minutes or more of moderate physical activity should occur on most, if not all, days of the week.[2] Regardless of the specific physiological changes induced by pregnancy, which are primarily developed to meet increased metabolic demands of mother and fetus, pregnant women benefit Sports Med 2010; 40 (6)
Physical Activity and Pregnancy
from regular physical activity the same way as nonpregnant subjects.[3] However, a substantial proportion of women stop exercising and decrease their general physical activity level after they discover they are pregnant, and only few begin participating in exercise or sport activities during pregnancy.[4] The adoption or continuation of a sedentary lifestyle during pregnancy may contribute to development of certain disorders such as hypertension, maternal and childhood obesity, gestational diabetes, dyspnoea and pre-eclampsia.[3] In view of the global epidemic of sedentary behaviour and obesity-related pathology, prenatal physical activity has been shown to be useful for the prevention and treatment of these conditions.[5] A systematic literature review was conducted on physical activity and pregnancy. The search included articles published in MEDLINE and ISI Web of Science databases. Keywords used were: ‘physical activity’ OR ‘physical exercise’, ‘pregnancy’ OR ‘gestation’, ‘pregnancy outcomes’, ‘labour’, ‘cardiovascular adaptations’, ‘heart rate’, ‘training’, ‘detraining’, ‘physical activity recommendations’ AND ‘pregnancy’. In a first round, there were no restrictions to certain years of publication. In a second round, publications published between 2007 and 2009 were specifically reviewed to assure inclusion of any relevant new publication. The aim of this article was to review the current state of knowledge on (i) the cardiovascular adaptations to physical activity in the pregnant and nonpregnant states; (ii) the compliance of pregnant women with current physical activity recommendations; and (iii) the effects of physical activity on pregnancy outcomes. 1. Cardiovascular Adaptations to Training and Detraining in Pregnant and Nonpregnant States 1.1 Cardiovascular Adaptations to Training
Repeated episodes of physical activity performed over a longer period (i.e. training) cause adaptations in the respiratory, cardiovascular and neuromuscular systems that enable physiª 2010 Adis Data Information BV. All rights reserved.
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cally trained persons to exercise for longer at a given absolute exercise intensity, or to exercise at a higher exercise intensity for a given duration.[6] The adaptations in metabolic and physiological systems depend on the type of exercise overload imposed. Short duration activities demanding high levels of anaerobic metabolism favour the adaptation of the immediate and short-term energy systems, with limited impact on the aerobic system. Regular endurance training, on the other hand, improves overall aerobic capacity.[7-9] For public health concerns and in contrast to training for sports-specific improvement, current interest in physical activity participation arises largely from a desire to improve health-related fitness components, primarily cardiorespiratory fitness.[10] Aerobic training produces significant changes to the cardiovascular system: enlarged left ventricular cavity of the heart; enhanced blood and stroke volume; increased maximum ˙ ); and decreased resting and subcardiac output (Q maximal exercise heart rate.[6] The lower resting and sub-maximum exercise heart rate generally reflect an improved submaximal and maximal . oxygen uptake (VO2max) and a correspondingly higher level of cardiovascular fitness. 1.2 Cardiovascular Adaptations to Detraining
While regular physical activity is accompanied by better cardiovascular fitness, a reduction or cessation of physical activity leads to partial or complete reversal of the physiological adaptations. Inactivity is accompanied by a rapid . decline in VO2max and blood volume. Consequently, submaximal exercise heart rate increases but insufficiently to counterbalance decreased stroke volume, thus resulting in a reduction of ˙ .[11] Measurable alterations in physiomaximal Q logical functions take place after only a week or two of detraining.[8] Total loss of training improvements occurs within several months.[8] As a result, any sudden physical effort imposed on the detrained subjects leads to physiological and metabolic stress, as they are not able to respond to imposed physical exertion as efficiently as trained subjects. Sports Med 2010; 40 (6)
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2. Cardiovascular Changes due to Pregnancy Regardless of training status, women who become pregnant undergo profound cardiovascular system alterations (figure 1). The first haemodynamic change during pregnancy is a rise in heart rate, both at rest and during submaximal workout. It starts between 2 and 5 weeks of pregnancy and continues well into the third trimester.[12] On average, the resting heart rate raises 8 beats/min by the eighth week, and reaches an increase of 16 beats/min by the end of pregnancy.[13] The effect is less evident in supine or lateral positions and more evident during sitting.[14] The mechanism of the increased heart rate is not yet clearly identified. It may be attributed to chorionic gonadotropin, or to sympathetic reflex adjustments to maintain arterial blood pressure despite reduced peripheral vascular resistance.[15] Between 10 and 20 weeks of pregnancy, a notable increase in blood volume takes place due to an increase in both plasma and erythrocytes.[16,17] This represents a rise of approximately 1500 mL,[16] of which 1000 mL is plasma volume and 500 mL is erythrocytes.[18] Since plasma volume amplifies more than red blood cell volume, a relative dilutional anaemia occurs.[19] Blood volume expansion may be even greater in multifetal gestations.[18] ˙ is increased as early as the fifth week Resting Q of pregnancy as a result of the increased heart
Increase in. resting and sub-VO2max
Descrease in blood pressure
rate, stroke volume and blood volume.[12,17,20] ˙ increases by 1 L/min at 8 weeks of gestResting Q ation, which represents >50% of the overall change in pregnancy.[20] During the third trime˙ increases only minimally, primarster, resting Q ily because of the increase in heart rate as term approaches.[21] In multifetal pregnancies, resting ˙ is greater by approximately 20% maternal Q ˙ is also compared with singleton pregnancies.[19] Q affected by the positional changes of the women.[14] After 20 weeks of gestation, the gravid uterus may obstruct the aorta and inferior vena cava, causing a decrease in uteroplacental blood flow and venous return to the heart,[9] especially when the woman is in the supine position. The left lateral position quickly relieves compression of the inferior vena cava.[21] Left uterine displacement also tends to prevent aortocaval compression, although it is less optimal than the left lateral position.[19] Blood pressure is not increased in normal pregnancy due to decreased peripheral vascular resistance.[19] In fact, systolic pressure remains quite stable, whereas diastolic pressure decreases up to 15 mmHg in mid-pregnancy.[22] 2.1 Cardiovascular Changes during Labour and Delivery
˙ remains relatively constant in the Although Q latter half of pregnancy, there is a significant
Increase in resting and sub-maximal heart rate
Pregnancy-induced cardiovascular changes
. Increase in Q
Increase in plasma and red blood cell mass
Increase in blood volume Increase in stroke volume
. ˙ = cardiac output; VO2max = maximal oxygen uptake. Fig. 1. Pregnancy-induced cardiovascular changes. Q
ª 2010 Adis Data Information BV. All rights reserved.
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increase during active labour and immediately after delivery. A study[12] of normal labour in women without epidural anaesthesia reported an increase ˙ of 12% and 34% between contractions and at in Q ˙ full dilatation, respectively. The increase in Q seems to be caused by an increase in heart rate and stroke volume. Such changes are thought to be sympathetically mediated and are likely due to the combined effects of pain, increased metabolic demand and increased venous return during uterine contractions.[23] Circulating blood volume also increases during contractions by an additional 300–500 mL due to blood autotransfusion from the placenta.[24] The physical effort of normal labour does not impose high energy demands on the parturient. The energy requirement is affected more by the frequency and duration of uterine contractions than by the total duration of labour.[25] Katz et al. measured energy expenditure of la[25] bour in 23 healthy . women. The results showed oxygen uptake (VO2) of 0.255 L/min during uterine relaxation (at 4 cm dilatation), 0.338 L/min during contractions (at 4 cm dilatation), and . 0.510 L/min at delivery. Thus, the VO2, which increases ~20% during normal pregnancy, may increase an additional 60% during the contractions, but remains rather low when compared with the increase observed during physical activity (walking, running, cycling). It is higher in multiparous women than in nulliparous women and is highest in those women with the shortest labour.[25] If the process of expulsion is prolonged (>30 minutes), the increased demand for oxygen is partially met by anaerobic metabolism causing an increase in maternal blood lactate levels.[25] The haemodynamic changes seen during labour and delivery are influenced by anaesthetic and analgesic techniques.[21] Lumbar epidural anaesthesia during labour reduces maternal [26] and decreases adrenaline (epinephrine) levels, . the work of breathing, VO2,[27,28] fetal heart ˙ and blood pressure.[30-32] The rate,[29] maternal Q haemodynamic changes are also influenced by the ˙ and position of the parturient. For example, Q stroke volume are significantly decreased in the supine, compared with the lateral, position.[33] ª 2010 Adis Data Information BV. All rights reserved.
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2.2 Postpartum Cardiovascular Changes
Within the first 15–20 minutes after delivery of the fetus and placenta there is a substantial ˙ , as the blood is no longer diverted increase in Q to the uteroplacental vascular bed, but rather redirected to the maternal circulation.[21] By ˙ is no longer signifi24 hours after delivery, Q cantly different from pre-labour values,[34] and fully returns to pre-pregnant values by 2 weeks after delivery. Stroke volume also decreases within 2 weeks, although there is a further small reduction up to 6 months after delivery.[12] 3. Physical Activity and Pregnancy ˙, Although pregnancy induces an increase in Q stroke volume and heart rate, women who continue aerobic exercise training during pregnancy have lower resting heart rate and higher stroke volume than matched sedentary controls.[35,36]. In addition, aerobically fit women have greater VO2 response at a given heart rate compared with their sedentary counterparts.[36] 3.1 Submaximal Aerobic Capacity during Pregnancy
. Changes in submaximal VO2 during pregnancy depend on the type of exercise performed. During maternal rest or submaximal weightbearing exercise (e.g. walking,. stepping, treadmill exercise), absolute maternal VO2 (L/min) is significantly increased compared with the nonpregnant state.[37,38] The magnitude of change is approximately proportional to maternal weight gain. At the same speed . or grade of walking or running, the values for VO2 expressed in mL/kg/min are thus similar or only slightly higher during pregnancy compared with the nonpregnant state.[37,39-41] When pregnant women perform submaximal weight-supported exercise on land (e.g. level cycling), where the energy cost of locomotion is not altered by maternal morphological changes, the findings are contradictory. Some studies . reported significantly increased absolute VO2,[37,40,42] while many others[15,35,38,40,43-47] reported .unchanged or only slightly increased absolute VO2 Sports Med 2010; 40 (6)
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compared with the nonpregnant state. The latter findings may be explained by the fact that the metabolic demand of cycle exercise is largely independent of the . maternal body mass, resulting in no absolute VO2 alteration. 3.2 Work Efficiency
Net efficiency of work during exercise, i.e. the . slope of the relationship between VO2 and work rate, appears to be unchanged during pregnancy in non-weight-bearing exercise (e.g. cycle ergometer testing).[38,44,48] The efficiency of weightbearing exercise (e.g. treadmill testing), on the other hand, was shown to be improved in early pregnancy in athletic women who continue exercising and those who stop exercising during pregnancy.[49,50] The increase in exercise efficiency is obscured after the fifteenth week of pregnancy by pregnancy-associated increases in maternal weight. When adjusted for weight gain, the increased efficiency is maintained throughout the pregnancy, with the improvement being greater in women who continue exercising during pregnancy.[49] 3.3 Maximum Aerobic Capacity during Pregnancy
. VO2max, as a criterion measure of cardiovascular fitness, is . poorly documented in pregnancy. Measuring VO2max during gestation holds a theoretical risk of inducing fetal stress due to blood distribution favouring maternal skeletal muscle at the expense of uterine blood flow. For ethical reasons, most studies report estimated values obtained by extrapolating individual sub. maximal heart rate-VO2 curves rather than actual measured values at peak exercise intensity. The few studies (table I). that directly measured changes in .maternal VO2max showed no difference in the VO2max (L/min) between pregnant and nonpregnant subjects in cycling,[44-47,50-53] swimming or weight-bearing exercise.[47,50,51,54] Well conditioned women or athletes who maintain a moderate to high level of exercise during and after pregnancy have even shown a small but . significant increase in VO2max following pregnancy.[53,54] Thus, pregnancy may have an added ª 2010 Adis Data Information BV. All rights reserved.
training effect in well conditioned, recreational sports women. 3.4 Maximal Heart Rate during Pregnancy
. Although the VO2max values do not seem to differ significantly in the pregnant compared with the nonpregnant state, maximal heart rate was reported to be approximately 4 beats/min lower in pregnancy compared with post partum.[50] The blunted heart rate responses to maximal exercise may be due to reduced sympathoadrenal responses to heavy exertion during pregnancy.[43] As a result of the increased resting heart rate and decreased maximal heart rate, heart rate reserve is reduced and . heart rate rises to a lesser extent with increasing VO 2, lowering the slope of the heart rate. VO2 relationship during pregnancy compared with the nonpregnant state.[15,51] However, with the exception . of resting heart rate, the change in the heart rate-VO2 relationship appears not to be affected significantly by a woman’s habitual exercise behaviour throughout pregnancy.[55] 4. Physical Activity Recommendations during Pregnancy In the past, recommendations for physical activity were based on cultural and traditional mores rather than scientific evidence. In the 1950s, continuation of household chores and a 1.6 km (1 mile) walk per day, preferably divided into several short sessions, was advised, whereas sports and exercise were discouraged.[5] In 1985, the American College of Obstetricians and Gynecologists (ACOG) formulated one of the first recommendations for exercising during pregnancy. It was advised that the intensity of exercise should not induce an increase in heart rate above 140 beats/min and that strenuous exercise should not last more than 15 minutes.[5] Since then, evidence has accumulated on the type, intensity, duration and frequency of exercise beneficial for mother and offspring,[56] leading to the revision of the guidelines. Present ACOG recommendations,[57] and those jointly published by the Society of Obstetricians and Gynecologists of Canada (SOGC) and the Sports Med 2010; 40 (6)
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. Table I. Studies reporting actual measured maximal oxygen uptake (VO2max) in pregnant women Study (year)
No. of subjects
Heenan et al.[44] (2001)
14
Lotgering et al.[50,51] (1991, 1992)
33
McMurray et al.[52] (1991)
10
Sady et al.[45] (1988)
45
Sady et al.[46] (1989)
45
Spinnewijn et al.[47] (1996)
11
. VO2 = oxygen uptake.
Measurements
Findings
. VO2 (L/min) measurements in pregnant women (35 – 0.4 wk) and age-matched nonpregnant control group (n = 14) while cycling maximally. Low agespecific aerobic capacity levels . VO2 measurements (L/min) at 16, 25 and 35 wk of pregnancy and 7 wk post partum at increasing levels of cycling and treadmill exercise until maximum aerobic power was reached. Average age-specific aerobic capacity levels . VO2 measurements (L/min) at 25–35 wk of pregnancy and 9–11 wk post partum during cycling and swimming maximally. Average age-specific aerobic capacity levels . VO2 (L/min) measurements in pregnant women (26 – 3 wk) and a nonpregnant control group (n = 10) while cycling maximally. Low age-specific aerobic capacity levels . VO2 (L/min) measurements at 26 – 3 wk of pregnancy and 8 – 2 wk post partum while cycling maximally. Low age-specific aerobic capacity levels . VO2 measurements (L/min) at 30–34 wk of pregnancy and 8–12 wk post partum during cycling and swimming maximally. Average age-specific aerobic capacity levels
. No significant differences in VO2max in pregnant vs control group
Canadian Society of Exercise Physiology (CSEP),[58] advise that pregnant women who are free of medical or obstetric complications follow the American College of Sports Medicine– Centers of Disease Control and Prevention (ACSM-CDC) guidelines for physical activity and exercise. According to these guidelines, pregnant women may safely engage in ‡30 minutes of moderate physical activity on most, if not all, days of the week.[57] Moderate physical activity is defined as an activity performed at an intensity of three to six metabolic equivalents (METs), which corresponds to brisk walking at ~5–7 km/h (3–4 mph).[59] Previously sedentary women should start with 15 minutes of continuous exercise three times a week, increasing gradually to 30-minute sessions four times a week.[58] The aim of exercising during pregnancy is to maintain a good condition without trying to reach a peak fitness level.[58] Because of the potential risk of certain activities, healthcare professionals should adapt the exercise prescriptions accordingly, prescribing ª 2010 Adis Data Information BV. All rights reserved.
. No significant differences in VO2max in pregnancy period vs post partum during cycling and treadmill exercise
. No significant differences in VO2max in pregnancy period vs post partum during cycling. . The swim VO2max was significantly greater post partum than in the 35th swim trials . No significant differences in VO2max in pregnant vs control group
. No significant differences in VO2max in pregnancy period vs post partum . No significant differences in VO2max in pregnancy period vs post partum during bicycle and swimming
activities such as walking, swimming, stationary cycling and aquafit rather than gymnastics, horseback riding, skiing, racquet sports or contact sports. The risks of injury associated with falling are increased in latter activities due to increased levels of oestrogen and relaxin, which augment ligamentous laxity and hypermobility.[54,60] Pelvic support belts and core stability exercise can be used to enable women to remain active in spite of these changes. In addition, muscle conditioning (light weight-lifting in moderate repetitions) is suggested to maintain flexibility and muscle tone, prevent gestational lower back pain, and promote general conditioning.[61] Abdominal strengthening is difficult to perform due to the development of diastasis recti and associated abdominal muscle weakness.[58] For that reason, pregnant women should avoid exercising in the supine position after ~16 weeks of gestation. Scuba diving is also to be avoided throughout pregnancy, as the fetus is not protected from decompression sickness and gas embolism.[58] Sports Med 2010; 40 (6)
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Exertion at altitudes above 2500 m (8250 feet) is advised only after 4–5 days of exposure and acclimatization to such high altitudes.[62] Metabolic responses during exercise in pregnancy are related to the duration and intensity of exercise. Blood glucose of pregnant women decreases at a faster rate and to a significantly lower level post-exercise than in nonpregnant women.[63] This decrease does not seem to cause hypoglycaemia, even after 40 minutes of moderate walking or aerobic dancing.[64,65] However, consuming adequate calories and limiting exercise sessions to <45 minutes is advisable. During the course of pregnancy, thermoregulation improves as a result of increased blood circulation and sweating. Prolonged exercise in hot, humid conditions should nevertheless be avoided and adequate hydration maintained knowing that maternal core temperature above 39.2C during the first trimester may be potentially teratogenic (neural tube defects).[66] At present, the limited data that are available from studies on exercising pregnant women suggest that women do generally not exercise at levels that cause significant hyperthermia.[67,68] 4.1 Recommended Heart Rate Target Zones for Aerobic Exercise in Pregnancy
As a result of the reduced maximal heart rate reserve during pregnancy, modified heart rate target zones for aerobic exercise are proposed for each age decade (table II). The proposed modification is based on lowering the top end of the zone by 5 beats/min, thus reducing its range from 20 to 15 beats/min.[61] The heart rate target range represents ~60–80% of aerobic capacity of a pregnant woman. Table II. Modified heart rate target zones for aerobic exercise in pregnancy (reproduced from Davies et al.,[58] with permission from the Society of Obstetricians and Gynaecologists of Canada) Maternal age (years)
Heart rate target zone (beats/min)
Heart rate target zone (beats/10 sec)
<20
140–155
23–26
20–29
135–150
22–25
30–39
130–145
21–24
‡40
125–140
20–23
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If the heart rate is chosen to be used solely as an indicator of exercise intensity during pregnancy, ratings of perceived exertion (RPE) is recommended to be used in addition to heart rate (table III).[58] RPE consists of numerical ratings from 6–20.[69] When multiplied by 10, the RPE ratings would roughly correspond to heart rate observed in healthy young adults. The conventional prescriptive zone for fitness training of healthy adults is 12–16. Pivarnik et al.[40] have shown that this zone is not significantly altered in pregnancy during weight-supported exercise (e.g. cycling). By contrast, the RPE rises in pregnancy during weight-bearing exercise (e.g. walking) proportionally to increased energy expenditure due to maternal weight gain. For that reason, a target zone of 12–14 is identified as the recommended RPE range in pregnancy. 5. Compliance with Physical Activity Recommendations during Pregnancy Individual physical activity varies greatly during pregnancy, and is determined by socioeconomic and cultural factors specific to the population. Activity-induced energy expenditure is generally low in gestation[70-75] and tends to decrease as pregnancy advances.[76-83] The decrease in physical activity during pregnancy is probably attributed to difficulties of movement related to larger body mass and discomfort from pregnancyinduced morphological and physiological changes. Reductions also occur as a result of behaviour changes with respect to the type of activity and in the pace or intensity at which it is carried out.[84,85] Studies reviewing retrospective and prospective data on physical activity during pregnancy concluded that women decrease physical activity intensity and duration as pregnancy progresses and shift toward performing less intense, more comfortable modes of activity with lower risks of maternal and fetal injury.[83,86-88] Pregnant women who ran or jogged before pregnancy were reported to be no longer involved in these modes of exercise but to have shifted toward swimming, walking or gardening. A similar trend can be observed regarding occupational activities. Women Sports Med 2010; 40 (6)
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Table III. Borg’s rating of perceived exertiona (reproduced from Davies et al.,[58] with permission from the Society of Obstetricians and Gynaecologists of Canada) Borg’s rating of perceived exertion 6 7
Very, very light
8 9
Somewhat light
10 11
Fairly light
12 13
Somewhat hard
14 15
Hard
16 17
Very hard
18 19
Very, very hard
20 a
A rating of 12–14 is appropriate for most pregnant women.
with physically strenuous professions are more likely to stop working during the last trimester of pregnancy than women working in less physically demanding occupations.[83] The decrease in activity-related energy expenditure during pregnancy can be observed in both the developed and the developing world. Compared with nonpregnant women, energy expended on physical activity during pregnancy is decreasing, on average, by 233 kcal/day (20%) at 30 weeks in Sweden,[76] 201 kcal/day (22%) at 25 weeks and 240 kcal/day (23%) at 35 weeks in Colombia,[89] and 103 kcal/day (13%) at 38 weeks in Switzerland.[90] As a result, few women reach the recommended physical activity (‡30 minutes of moderate physical activity on most, if not all, days of the week) during pregnancy. In the US, only 16% of pregnant women comply with the physical activity recommendations, compared with 26% of nonpregnant women.[91] Even healthy, otherwise active women decrease physical activity due to pregnancy. For example, 70% of women living in Switzerland complied with the recommendations during pregnancy compared with 89% in the nonpregnant state.[92] ª 2010 Adis Data Information BV. All rights reserved.
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6. Effects of Physical Activity on Pregnancy Outcomes The influence of physical activity on pregnancy outcomes is widely debated. Traditionally, pregnant women were advised to reduce their levels of physical activity. This advice was based on concerns that exercise would affect pregnancy outcomes by raising core body temperature, by increasing the risk of maternal musculoskeletal injury due to changes in posture, centre of gravity and ligamentous laxity, and by moving transport of oxygen and nutrients to maternal skeletal muscle rather than to the developing fetus.[58] In the meantime, research has provided a significant amount of new information about how a pregnant woman and her fetus respond to regular engagement in moderate physical activity.[93] New investigations have shown no adverse maternal or neonatal outcomes, no abnormal fetal growth and no increase in early pregnancy loss or late pregnancy complications.[58] On the contrary, regular physical activity has proven to result in marked benefits for mother and fetus. Maternal benefits include improved cardiovascular function, limited pregnancy weight gain,[94] decreased musculoskeletal discomfort,[5] reduced incidence of muscle cramps and lower limb oedema,[60] mood stability[83,95] and attenuation of gestational diabetes and gestational hypertension.[96] Fetal benefits include decreased fat mass, improved stress tolerance, and advanced neurobehavioural maturation.[97] The most common fetal response to maternal exercise is alteration in fetal heart rate. The fetal heart rate was reported to increase in the immediate post-exercise period, and to be correlated with both duration and intensity of maternal exercise.[15,98] Increases in maternal core temperature and maternal-fetal transfer of catecholamines have been reported as causes of post-exercise fetal tachycardia.[99] Transient decrease in fetal heart rate was also reported during mild or moderate intensity exercise or in studies involving high intensity maternal exertion.[98,99] Reduced uterine blood flow caused by a rapid post˙ was postulated as a cause of the exercise fall in Q bradycardia, although firm physiological bases Sports Med 2010; 40 (6)
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for these changes are still lacking.[99] Despite the overall alterations of fetal heart rate due to maternal exercise, no abnormal birth outcomes have been noted in healthy women undergoing a normal pregnancy.[99] Only a few studies so far have directly examined the effects of physical activity on labour and delivery. One of them was performed by Clapp[100] on 131 well conditioned recreational athletes. Those who continued to exercise at or above 50% of their pre-pregnancy performance level throughout pregnancy had a lower incidence of operative abdominal and vaginal deliveries and fewer fetuses with acute fetal distress in labour. Erdelyi[101] reported that among 172 Hungarian athletes, the frequency of caesarean section was almost 50% lower than in a control group of 184 non-athletes. Even sporadic exercisers, who participated in a structured exercise programme for at least 1 hour, twice weekly for a minimum of 12 weeks during pregnancy, were more likely to have a spontaneous vaginal delivery than their nonexercising counterparts.[102] Hall and Kaufmann[103] studied 845 pregnant women who were given the option to participate in exercise programmes designed specifically for pregnant women. They reported that the incidence of caesarean delivery was 6.7% in the high-exercise group (women who completed 64 exercise sessions [range 60–99] during pregnancy), compared with 28.1% in the sedentary group (0.8 sessions [range 0–10] during pregnancy) [p < 0.0001]. Melzer et al.[92] studied the effects the recommended levels of ‡30 minutes of moderate physical activity per day on pregnancy outcomes in 44 healthy Swiss women. Active women had a lower risk of operative delivery compared with inactive women (odds ratio = 3.67; 95% CI 1.02, 13.1). Adjustment for parity, maternal weight gain and infant weight strengthened the association between lack of physical activity and operative delivery (adjusted odds ratio = 7.65; 95% CI 1.27, 45.84). Prior studies showed a strong correlation between length of labour and physical fitness.[100-102,104,105] Penttinen and Erkkola,[106] on the other hand, found no significant differences in labour parameters between athletes and controls. Many other studies[103,106-108] also reported ª 2010 Adis Data Information BV. All rights reserved.
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no significant difference in labour duration between recreationally active women and their controls. Lastly, maternal exercise has been reported to increase,[103,109,110] decrease[100] or have no effect[88,102,111,112] on newborn birthweight. The inconsistent results on the effects of exercise on the newborn’s birthweight may be due to the differences in type, timing, frequency and duration of the exercise regimen imposed (table IV). Clapp et al.[113] demonstrated that women who begin a regular, moderate regimen of weight-bearing exercise (treadmill, step aerobic or stair stepper) in early pregnancy (for 20 minutes 3–5 times per week) gave birth to larger newborn birthweights compared with non-exercising mothers. Other studies further indicated that women who stayed active throughout the pregnancy also experienced improved fetal growth.[103,109,110] Physical activity during pregnancy may thus be an important mechanism for improving placental functional capacity, circulation and gas exchange, which in turn increases nutrient delivery and overall growth rate of the fetus.[109,113] Nevertheless, weight-bearing exercise was shown to influence fetal growth in both a timedependent and exercise volume-dependent fashion.[114] Women who increased the volume of their moderate weight-bearing exercise (treadmill, step aerobic or stair stepper) in late pregnancy (20 minutes 3–5 times per week through week 20, gradually increasing to 60 minutes 5 days per week by week 24 and maintaining that regimen until delivery) experienced a significantly lower newborn birthweight than those women who maintained the high volume of exercise in early pregnancy and then decreased it by twothirds in late pregnancy.[114] For women who exercised to term, the drop in infant weight was attributed mainly to differences in newborn fat mass. Clapp and Capeless[115] concluded that most of the variability in birthweight (40%) can be explained by the relative level of weightsupported exercise performance in the last 5 months of pregnancy. Other studies have been unable to demonstrate decreased birthweight in women who continue exercising but at reduced levels, or in those performing weight-supported exercise (cycling) and/or weight-lifting exercise.[103,107] Sports Med 2010; 40 (6)
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Table IV. Effect of a structured exercise programme during pregnancy on a newborn’s birthweight Study (year)
Number of subjects
Exercise mode
Newborn birthweight
Beckmann and Beckmann[102] (1990)
50 exercise group; 50 control group
Exercise group participated in a nonendurance strength training programme for at least 1 h, 2·/wk, for a minimum of 12 wk during pregnancy
No statistical difference in birthweight between exercise and control group (3.69 – 0.3 vs 3.65 – 0.3 kg)
Clapp[100] (1990)
87 exercise group (runners, aerobic dancers); 44 control group (runners, aerobic dancers who stopped exercising during pregnancy)
Exercise at ‡50% of preconception level (preconception level: running, . 14–68 km/wk, 51–83% VO2max; aerobics, 3–11 sessions/wk, 25–30 min at 54–90% . VO2max)
Exercise group had heavier babies than those born to control group women (3.78 – 0.4 vs 3.37 – 0.3 kg; p = 0.01)
Clapp et al.[97] (1999)
34 exercise group; 31 control group
Throughout pregnancy: running, aerobics, swimming or stair-climbing, . 3·/wk, >20 min, >55% VO2max
Control group had heavier babies than those born to exercise group women (3.64 – 0.05 vs 3.44 – 0.1 kg; p = 0.01)
Clapp et al.[113] (2000)
22 exercise group; 24 control group
Weight-bearing exercise (treadmill, step aerobics or stair stepper) from the 8th wk of pregnancy, 20 min, 3–5·/wk at . 55–60% pre-pregnancy VO2max
Exercising mothers had heavier babies than those born to control women (3.75 – 0.8 vs 3.49 – 0.7 kg; p = 0.05)
Clapp et al.[114] (2002)
26 L-H; 24 M-M; 25 H-L
From the 8th wk of pregnancy, at . 55–60% VO2max: L-H, 20 min, 5·/wk through wk 20, increasing to 60 min 5·/wk by wk 24 and maintaining that level until delivery; M-M, 40 min, 5·/wk; H-L, 60 min, 5·/wk through wk 20, decreasing to 20 min, 5·/wk by wk 24 and maintaining that level until delivery
H-L group had heavier babies compared with the M-M and H-L groups (3.90 – 0.1 vs 3.44 – 0.1 vs 3.34 – 0.1 kg; p < 0.001)
Collings et al.[107] (1983)
20 exercise group; 12 control group
During the 2nd and 3rd trimester of pregnancy: aerobic exercise 3·/wk, . >25 min, 65–70% VO2max
Exercise group had no significantly heavier babies from those born to control group women (3.60 – 0.4 vs 3.35 – 0.4 kg)
Hall and Kaufmann[103] (1987)
393 control group (average 0.8 sessions); 82 low level exercise group (15 sessions); 309 medium level exercise group (32 sessions); 61 high level exercise group (64 sessions)
Throughout pregnancy, exercise session consisted of 3 components: warm-up (5 min treadmill at 5–6 km/h, or 5 min bicycle at 50 W) + 5·/wk, 45 min weightlifting + bicycle ergometer (~85% of maximal HR but <140 beats/min)
High exercise group had 151 g heavier babies than those born to control group women (3510 vs 3359 g; p = 0.06)
Kardel and Kase[112] (1998)
21 MEG; 21 HEG
From 20th wk of pregnancy, 3-part programme: 1. Muscle strength: MEG and HEG: 5·/wk, 72 min 2. Interval aerobic (HR = 170–180 beats/min): MEG, 1st day 15 sec exercise, 15 sec rest for 10 min, 2 times with 5 min break between; HEG, the same as MEG with 15 min rest 3. Endurance aerobic (HR 120–140 beats/min): MEG and HEG, 2·/wk, 90 min
No statistical difference in birthweight between MEG and HEG group (3.59 – 0.5 vs 3.65 – 0.5 kg)
HEG = high intensity exercise group; H-L = high-low exercise. group; HR = heart rate; L-H = low-high exercise group; MEG = medium intensity exercise group; M-M = moderate-moderate exercise group; VO2max = maximal oxygen uptake.
7. Conclusions Various physiological modifications arise during pregnancy, labour and delivery in order to ª 2010 Adis Data Information BV. All rights reserved.
meet the increased metabolic demands of mother and fetus. Despite the pregnancy-induced physiological changes, moderate physical activity during normal pregnancy appears to be beneficial Sports Med 2010; 40 (6)
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and should be encouraged. Unfortunately, energy expended on physical activity often decreases as pregnancy advances, which may have negative consequences on mother and infant, including maternal cardiovascular fitness and capacity to sustain efforts required during labour and delivery. Further studies with larger sample sizes are required to confirm the association between physical activity and outcomes of labour and delivery. Acknowledgements The study was supported in part by a competitive grant attributed to Drs Boulvain and Kayser by the Clinical Research Centre, Faculty of Medicine, University of Geneva, and was further supported by the Faculty of Medicine of the University of Geneva, and the University Hospitals of Geneva, Switzerland. The SOGC guideline has been provided free of charge courtesy of the Society of Obstetricians and Gynecologists of Canada. The authors have no conflicts of interest that are directly relevant to the content of this review.
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52. McMurray RG, Hackney AC, Katz VL, et al. Pregnancyinduced changes in the maximal physiological responses during swimming. J Appl Physiol 1991; 71: 1454-9 53. Kardel KR. Effects of intense training during and after pregnancy in top-level athletes. Scand J Med Sci Sports 2005; 15: 79-86 54. Clapp III JF, Capeless E. The VO2max of recreational athletes before and after pregnancy. Med Sci Sports Exerc 1991; 23: 1128-33 55. Pivarnik JM, Stein AD, Rivera JM. Effect of pregnancy on heart rate/oxygen consumption calibration curves. Med Sci Sports Exerc 2002; 34: 750-5 56. McMurray RG, Mottola MF, Wolfe LA, et al. Recent advances in understanding maternal and fetal responses to exercise. Med Sci Sports Exerc 1993; 25: 1305-21 57. Artal R, O’Toole M. Guidelines of the American College of Obstetricians and Gynecologists for exercise during pregnancy and the postpartum period. Br J Sports Med 2003; 37: 6-12 58. Davies GA, Wolfe LA, Mottola MF, et al. Joint SOGC/CSEP clinical practice guideline: exercise in pregnancy and the postpartum period. J Obstet Gynaecol Can 2003; 25: 516-29 59. Pate RR, Pratt M, Blair SN, et al. Physical activity and public health: a recommendation from the centers for disease control and prevention and the American College of Sports Medicine. JAMA 1995; 273: 402-7 60. Arena B, Maffulli N. Exercise in pregnancy: how safe is it? Sports Med Arthroscop Rev 2002; 10: 15-22 61. Wolfe LA, Davies GA. Canadian guidelines for exercise in pregnancy. Clin Obstet Gynecol 2003; 46: 488-95 62. Huch R. Physical activity at altitude in pregnancy. Semin Perinatol 1996; 20: 303-14 63. Soultanakis HN, Artal R, Wiswell RA. Prolonged exercise in pregnancy: glucose homeostasis, ventilatory and cardiovascular responses. Semin Perinatol 1996; 20: 315-27 64. Lokey EA, Tran ZV, Wells CL, et al. Effects of physical exercise on pregnancy outcomes: a meta-analytic review. Med Sci Sports Exerc 1991; 23: 1234-9 65. McMurray RG, Hackney AC, Guion WK, et al. Metabolic and hormonal responses to low-impact aerobic dance during pregnancy. Med Sci Sports Exerc 1996; 28: 41-6 66. Milunsky A, Ulcickas M, Rothman KJ, et al. Maternal heat exposure and neural tube defects. JAMA 1992; 268: 882-5 67. Jones RL, Botti JJ, Anderson WM, et al. Thermoregulation during aerobic exercise in pregnancy. Obstet Gynecol 1985; 65: 340-5 68. McMurray RG, Katz VL. Thermoregulation in pregnancy: implications for exercise. Sports Med 1990; 10: 146-58 69. Borg G. Borg’s perceived exertion and pain scales. Champaign (IL): Human Kinetics, 1998 70. Butte NF, Wong WW, Treuth MS, et al. Energy requirements during pregnancy based on total energy expenditure and energy deposition. Am J Clin Nutr 2004; 79: 1078-87 71. Clarke PE, Rousham EK, Gross H, et al. Activity patterns and time allocation during pregnancy: a longitudinal study of British women. Ann Hum Biol 2005; 32: 247-58
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72. Lawrence M, Whitehead RG. Physical activity and total energy expenditure of child-bearing Gambian village women. Eur J Clin Nutr 1988; 42: 145-60 73. Lof M, Forsum E. Activity pattern and energy expenditure due to physical activity before and during pregnancy in healthy Swedish women. Br J Nutr 2006; 95: 296-302 74. Rousham EK, Clarke PE, Gross H. Significant changes in physical activity among pregnant women in the UK as assessed by accelerometry and self-reported activity. Eur J Clin Nutr 2006; 60: 393-400 75. Haakstad LA, Voldner N, Henriksen T, et al. Physical activity level and weight gain in a cohort of pregnant Norwegian women. Acta Obstet Gynecol Scand 2007; 86: 559-64 76. Forsum E, Kabir N, Sadurskis A, et al. Total energy expenditure of healthy Swedish women during pregnancy and lactation. Am J Clin Nutr 1992; 56: 334-42 77. Heini A, Schutz Y, Diaz E, et al. Free-living energy expenditure measured by two independent techniques in pregnant and nonpregnant Gambian women. Am J Physiol 1991; 261: E9-17 78. Lawrence M, Singh J, Lawrence F, et al. The energy cost of common daily activities in African women: increased expenditure in pregnancy? Am J Clin Nutr 1985; 42: 753-63 79. Singh J, Prentice AM, Diaz E, et al. Energy expenditure of Gambian women during peak agricultural activity measured by the doubly-labelled water method. Br J Nutr 1989; 62: 315-29 80. Borodulin KM, Evenson KR, Wen F, et al. Physical activity patterns during pregnancy. Med Sci Sports Exerc 2008; 40: 1901-8 81. Gawade P, Pekow P, Markenson G, et al. Physical activity before and during pregnancy and duration of second stage of labor among Hispanic women. J Reprod Med 2009; 54: 429-35 82. van Raaij JM, Schonk CM, Vermaat-Miedema SH, et al. Body fat mass and basal metabolic rate in Dutch women before, during, and after pregnancy: a reappraisal of energy cost of pregnancy. Am J Clin Nutr 1989; 49: 765-72 83. Poudevigne MS, O’Connor PJ. A review of physical activity patterns in pregnant women and their relationship to psychological health. Sports Med 2006; 36: 19-38 84. DiNallo JM, Le Masurier GC, Williams NI, et al. Walking for health in pregnancy: assessment by indirect calorimetry and accelerometry. Res Q Exerc Sport 2008; 79: 28-35 85. Nagy LE, King JC. Energy expenditure of pregnant women at rest or walking self-paced. Am J Clin Nutr 1983; 38: 369-76 86. Chasan-Taber L, Schmidt MD, Pekow P, et al. Correlates of physical activity in pregnancy among Latina women. Matern Child Health J 2007; 11: 353-63 87. Pereira MA, Rifas-Shiman SL, Kleinman KP, et al. Predictors of change in physical activity during and after pregnancy: Project Viva. Am J Prev Med 2007; 32: 312-9 88. Jarrett JC, Spellacy WN. Jogging during pregnancy: an improved outcome? Obstet Gynecol 1983; 61: 705-9 89. Dufour DL, Reina JC, Spurr G. Energy intake and expenditure of free-living, pregnant Colombian women in an urban setting. Am J Clin Nutr 1999; 70: 269-76 90. Melzer K, Schutz Y, Boulvain M, et al. Pregnancyrelated changes in activity energy expenditure and resting
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Correspondence: Professor Bengt Kayser, Director, Institute of Movement Sciences and Sports Medicine, Faculte´ de Medecine, Universite´ de Gene`ve, 10 rue du Conseil Ge´ne´ral, 1205 Gene`ve, Switzerland. E-mail:
[email protected]
Sports Med 2010; 40 (6)
Sports Med 2010; doi: 10.2165/11531940-000000000-00000 0112-1642/10/0000-0000/$49.95/0
REVIEW ARTICLE
ª 2010 Adis Data Information BV. All rights reserved.
Whole-Body Cryotherapy in Athletes Giuseppe Banfi, Giovanni Lombardi, Alessandra Colombini and Gianluca Melegati IRCCS Galeazzi, Milan, Italy
Contents Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Haematology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Antioxidant Capacity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Immunology and Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Muscular Enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Cardiac Markers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Abstract
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Cold therapy is commonly used as a procedure to relieve pain symptoms, particularly in inflammatory diseases, injuries and overuse symptoms. A peculiar form of cold therapy (or stimulation) was proposed 30 years ago for the treatment of rheumatic diseases. The therapy, called whole-body cryotherapy (WBC), consists of exposure to very cold air that is maintained at -110C to -140C in special temperature-controlled cryochambers, generally for 2 minutes. WBC is used to relieve pain and inflammatory symptoms caused by numerous disorders, particularly those associated with rheumatic conditions, and is recommended for the treatment of arthritis, fibromyalgia and ankylosing spondylitis. In sports medicine, WBC has gained wider acceptance as a method to improve recovery from muscle injury. Unfortunately, there are few papers concerning the application of the treatment on athletes. The study of possible enhancement of recovery from injuries and possible modification of physiological parameters, taking into consideration the limits imposed by antidoping rules, is crucial for athletes and sports physicians for judging the real benefits and/or limits of WBC. According to the available literature, WBC is not harmful or detrimental in healthy subjects. The treatment does not enhance bone marrow production and could reduce the sport-induced haemolysis. WBC induces oxidative stress, but at a low level. Repeated treatments are apparently not able to induce cumulative effects; on the contrary, adaptive changes on antioxidant status are elicited – the adaptation is evident where WBC precedes or accompanies intense training. WBC is not characterized by modifications of immunological markers and leukocytes, and it seems to not be harmful to the immunological system. The WBC effect is probably linked to the modifications of immunological molecules having paracrine effects, and not to systemic immunological functions. In fact, there is an increase in antiinflammatory cytokine interleukin (IL)-10, and a decrease in proinflammatory
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cytokine IL-2 and chemokine IL-8. Moreover, the decrease in intercellular adhesion molecule-1 supported the anti-inflammatory response. Lysosomal membranes are stabilized by WBC, reducing potential negative effects on proteins of lysosomal enzymes. The cold stimulation shows positive effects on the muscular enzymes creatine kinase and lactate dehydrogenase, and it should be considered a procedure that facilitates athletes’ recovery. Cardiac markers troponin I and high-sensitivity C-reactive protein, parameters linked to damage and necrosis of cardiac muscular tissue, but also to tissue repair, were unchanged, demonstrating that there was no damage, even minimal, in the heart during the treatment. N-Terminal pro B-type natriuretic peptide (NT-proBNP), a parameter linked to heart failure and ventricular power decrease, showed an increase, due to cold stress. However, the NT-proBNP concentrations observed after WBC were lower than those measured after a heavy training session, suggesting that the treatment limits the increase of the parameter that is typical of physical exercise. WBC did not stimulate the pituitary-adrenal cortex axis: the hormonal modifications are linked mainly to the body’s adaptation to the stress, shown by an increase of noradrenaline (norepinephrine). We conclude that WBC is not harmful and does not induce general or specific negative effects in athletes. The treatment does not induce modifications of biochemical and haematological parameters, which could be suspected in athletes who may be cheating. The published data are generally not controversial, but further studies are necessary to confirm the present observations.
Local cold therapy or cryotherapy is commonly used as a procedure to relieve pain symptoms, particularly in inflammatory diseases, injuries and overuse symptoms. A peculiar form of cold therapy or stimulation was proposed 30 years ago[1] for the treatment of rheumatic diseases. The therapy consists of the brief exposure to very cold air in special temperature-controlled cryochambers, where the air is maintained at -110C to -140C. The treatment was named whole-body cryotherapy (WBC). Exposure to WBC is usually for 2 minutes, but in some protocols it lasts 3 minutes. Exposure can be performed with a single subject, but entry of a small group of subjects, up to four, in the same chamber is permitted. Each participant’s entry to the cryochamber is preceded by 30 seconds of temperature adaptation in a vestibule at a temperature of -60C. During the exposure, the subjects have minimal clothing and to avoid frostbite they wear shorts (bathing suit), socks, clogs or shoes, surgical mask, gloves, and a hat (or headband) covering the auricles. Any sweat is removed from ª 2010 Adis Data Information BV. All rights reserved.
the subjects before entering the cryochamber, where the air is clear and dry. While in the cryochamber, the subjects have to move their fingers and legs and avoid holding their breath. The system is automatically controlled, but safety personnel are always present (figure 1). The treatment is applied to relieve pain and inflammatory symptoms caused by numerous disorders, particularly those associated with rheumatic conditions, and it is recommended for the treatment of arthritis, fibromyalgia and ankylosing spondylitis. WBC has been shown to be not deleterious to lung function;[2] a sudden exposure to cold water or air may elicit several effects on the respiratory system, such as a gasp response, increase in ventilation and bronchoconstriction, but repeated treatments are not harmful to local reactions and do not impair the local immunological barrier. Despite the wealth of literature on rehabilitation techniques, published data on WBC in physiology or rehabilitation programmes are scarce. The scientific information is based on pilot studies, Sports Med 2010
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Subject
Medical examination: There are no specific contraindications, with the exception of claustrophobia and cold hypersensitivity (Raynaud’s phenomenon). There are some aspecific contraindications, such as heart diseases
Before entry: dry the eventual sweat The subject goes into the cryochamber wearing minimal clothing: bathing suit, socks, clogs or shoes, surgical mask, gloves, hat or headband
The subject goes in vestibule where they stay for 60 seconds at −60°C
From the vestibule the subject passes to the cryochamber where they stay for 2−3 minutes at temperatures of −110°C to −140°C Fig. 1. Preparation of patients and treatment with whole-body cryotherapy.
abstracts of congresses and reports in journals, but are not generally in the English language. In sports medicine, WBC has gained wider acceptance as a method to improve recovery from muscle injury. The enhancing effects of WBC are anecdotally widely used for recovering from traumas and for preventing overtraining symptoms. The enhancement of the cardiovascular system, amelioration of muscular activation, limitation of sport-induced haemolysis, potent anti-inflammatory effect and additional potentially beneficial effects of WBC could be useful for athletes. The study of WBC effects can have a practical value not only for many physiological and clinical purposes, but also for determining clinical significance in the context of antidoping testing, since techniques that accelerate recovery may be classified as prohibited. Furthermore, post-WBC treatment changes in biochemical and haematological parameters could lie outside the threshold range imposed by sports federations and official control agencies for athletes classified as being doped, or they could be interpreted as an attempt to mask changes caused by illicit treatment. There are few studies on the effects of WBC on athletes, but it is interesting to review the data ª 2010 Adis Data Information BV. All rights reserved.
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observed to date in physically-active subjects to describe WBC effects and possible modifications of physiological parameters in order to stimulate further studies in the field. We evaluated the medical literature available on PubMed using the keywords ‘‘whole body cryotherapy’’ and ‘‘whole body cryostimulation’’. Papers concerning only patients were not evaluated. Those involving healthy subjects and sportsmen were evaluated. Additional references were identified from the reference lists of published articles selected in the PubMed search. Only papers concerning a treatment involving a cryochamber, and which described the protocol treatment and ethical assessment, were evaluated. 1. Haematology The haematological parameters before and after 1 week of WBC treatment have been evaluated in top-level rugby players.[3] Originally, the aim of the study was to determine the potential risk of bone marrow-boosting, which could be induced by WBC treatment, as suggested in the media. From 30 rugby players who underwent WBC treatment, 10 athletes from the Italian national team were randomly selected to be studied before and after a WBC treatment cycle performed at Spa"a, Poland. The treatment was applied once a day for 5 days; during this period, the athletes trained regularly and following the same protocol used during the previous weeks. The analyses were performed with a Coulter LH 750 haematology analyser and showed no modifications of leukocytes, platelets and reticulocytes. As far as erythrocytes are concerned, their cell count did not show modifications, but a significant decrease of haemoglobinization appeared. Haemoglobin decreased from a mean of 15.8 g/dL to 15.5 g/dL, and mean corpuscular haemoglobin and mean corpuscular haemoglobin concentration parameters were also reduced. The effect, probably due to the relatively short period of treatment, did not influence the mean corpuscular volume, and the significant decrease in mean reticulocyte volume did not affect erythrocyte volume or reticulocyte counts. Sports Med 2010
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Thus, this treatment does not accelerate erythrocyte maturation or haemoglobin production. Conversely, a slight decrease of haemoglobinization was found.[3] These results are similar to those described in 11 professional field hockey players from the Polish national team. WBC was administered twice a day for a total of 18 procedures. The athletes regularly trained after treatment. Blood was drawn before the treatment cycle and after the series of treatments. A decrease of erythrocytes, haemoglobin and haematocrit was shown; however, the decrease was transient. Subjects recovered their basal levels after 1 week for erythrocytes and haematocrit, and overwhelmed the baseline concentration of haemoglobin.[4] An interesting result of WBC is the reduction of haemolysis, which usually accompanies intense physical exercise and possibly induces a decrease in haemoglobin, a condition universally known as sports anaemia. A specific effect of cold temperatures in reducing haemolysis after intense exercise has already been described where cold water immersion of the legs was used in 30 toplevel rugby players.[5] The difference between mean corpuscular volume, which remains stable, and mean sphered corpuscular volume (MSCV), which decreases when haemolysis occurs, was statistically significant in the whole group of athletes and in the subgroup who performed passive recovery after an intense bout of training. Conversely, in the other two subgroups, who performed active recovery (i.e. cycling at maximal power followed by leg immersion in iced water or vice versa), the difference was not significant.[5] After the 1 week of WBC treatment, the rugby players had a significant increase in haptoglobin mean values, from 56.6 mg/L to 75.2 mg/L. Haptoglobin is a protein that blocks the free haemoglobin released by broken erythrocytes; its increase is linked to a decrease in haemolysis. The MSCV values also increased from a mean of 84.6 fL to 87.6 fL, whilst the difference between mean corpuscular volume and MSCV also decreased, confirming the reduction of sportinduced haemolysis, usually linked to an increase of membrane peroxidation from reactive oxygen ª 2010 Adis Data Information BV. All rights reserved.
species, which are produced in high amounts during exercise.[6] In conclusion: 1. WBC does not enhance bone marrow production. 2. WBC could reduce the sport-induced haemolysis. 2. Antioxidant Capacity Physical exercise leads to increased production and release of reactive oxygen species, which induce oxidative stress mainly as lipid peroxidation and, consequently, membrane damage. The body responds to this via the antioxidant system, including non-enzymatic scavengers and some enzymes, which reduce the potentially dangerous effect of oxidant molecules. The WBC effect on pro-oxidant-antioxidant balance was studied in 20 top-level kayakers from the Polish Olympic team and in 10 untrained men.[7] The kayakers completed a 10-day programme with training sessions twice a day. The first training session each day was preceded by one WBC treatment, and the second by two WBC treatments, whereas controls received only one WBC treatment. Blood samples were taken before training, and after 6 and 10 days of training with WBC. Blood samples for the controls were taken 3 days before and immediately after the treatment. The athletes also performed an identical training cycle that was not accompanied by WBC treatment. In non-athletes, some oxidant reagents, such as conjugated dienes in plasma and erythrocytes, increased, whereas other oxidant species, such as thiobarbituric acid-reactive substances (TBARs), did not. Conversely, the activity of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx) increased, whereas that of catalase did not. A similar scenario appeared in athletes on days 6 and 10 of training without WBC treatment (i.e. there was an increase in plasma and erythrocyte conjugate dienes, and an increase in SOD and GPx). Moreover, plasma and erythrocyte TBARs were also increased in athletes as a result of intensified lipid peroxidation, but probably also because of a Sports Med 2010
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different rate of metabolization of these products during intensive physical exercise. However, the differences between the results observed during training cycles, with and without WBC, were the relative decrease in conjugated dienes in plasma and erythrocytes, and the relative increase of TBARs. After training without WBC, the activity of SOD and GPx significantly increased. Conversely, after training that is preceded by WBC, only GPx activity significantly increased. When comparing the two training models, the SOD activity was 47% lower after the 6th day with WBC and the GPx activity more than halved after the 10th day. The WBC treatment induced reactive oxygen species generation, probably by muscle shivering or metabolism of intensified oxidation of catecholamines released by cold stress. A single application of WBC induced an increase in conjugated diene concentration, and SOD and GPx activity in sedentary subjects. However, the lower activity of antioxidant enzymes during training accompanied by WBC, at the same time as a lower concentration of lipid peroxidation molecules, indicates a decrease in the generation of reactive oxygen species. The low temperatures induced adaptation of the body to ensure a correct balance between pro-oxidantantioxidant reactants during intense training. WBC preceding kayakers’ training induced positive adaptive changes in cells protecting organisms from pro-oxidative-antioxidative equilibrium disturbances.[7-9] WBC influences the equilibrium between oxidant and antioxidant species. Some experiments have been conducted in healthy, but nonphysically active, individuals. Lubkowska et al.[10] showed that one WBC session causes disturbances of the oxidant-antioxidant balance. The concentration of peroxides, a sign of total oxidant status, was decreased 30 minutes after leaving the cryochamber in 15 young men (mean age 21 years), and it remained low after 24 hours, whereas the level of total antioxidant status decreased immediately after cold exposure, but had increased after 24 hours. Siems and Brenke[11] observed that acute cold stimulation (winter swimming) induced a decrease in plasma antioxidants (ascorbic acid, uric ª 2010 Adis Data Information BV. All rights reserved.
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acid) and an increase in the concentrations of a molecule that is a marker of lipid peroxidation, hydroxynonenal. Dugue´ et al.[12] observed a significant increase in total peroxyl radical trapping antioxidant capacity of plasma 2 minutes after cold stress in healthy women in the first 4 weeks over a 12-week treatment period. Thirty-five minutes after the application of cold stress, the effect was not apparent. The 20 women underwent either winter swimming or WBC, which included three exposures per week for 3 months. The authors remarked that the increase of trapping antioxidant capacity of plasma was unexpected and, moreover, that interindividual biological variation of this marker was high, as also outlined for total antioxidant status in another study.[13] The WBC effect resulted in immediate and significant increase in peroxidase and glutathione reductase activities, and a decrease in catalase and glutathione transferase in erythrocytes in healthy subjects. A single treatment induced oxidation stress, but the level of the oxidative stress was not high.[13] In conclusion: 1. WBC induces oxidative stress. 2. A single treatment can induce oxidative stress, but at low level. 3. Repeated treatments are not apparently able to induce cumulative effects; on the contrary, adaptive changes of antioxidant status are elicited. 4. WBC is not harmful for oxidative stress in healthy subjects. 5. The adaptation is evident where WBC precedes or accompanies intense training. 3. Immunology and Inflammation Classical immunological markers such as immunoglobulins and C-reactive protein (CRP) were measured in athletes before and after a treatment cycle. These markers are both regularly and easily evaluated in the general population and also in athletes as markers of acute or chronic infection and/or inflammation. Moreover, these parameters are universally available in clinical laboratories. In effect, lymphocyte and monocyte counts and plasma IL-6 concentration were Sports Med 2010
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higher in habitual winter swimmers than in inexperienced winter swimmers; the difference was probably due to the long-lasting exercise performed in the cold environment by experienced subjects.[14] Immunoglobulins were slightly, but not significantly, increased, and CRP showed a slight, but also not significant, decrease in rugby players who underwent WBC treatment The lymphocyte and monocyte counts did not change: 44.7% (SD 8.2) for lymphocytes before WBC and 37.8% (SD 10.6) after (p-value not significant), and 9.6% for monocytes in both the blood drawings (SD 1.7 before, 3.5 after; p-value not significant).[15] Thus, WBC is not characterized by modifications of immunological markers and it does not seem to be harmful to the immunological system. Data suggest that WBC does not have a detrimental effect on immunological parameters, although the period of observation, in this study, was too short to evaluate modifications of lymphocyte involvement and function. In fact, longterm cold water immersions of healthy males resulted in slight elevations in plasma tumour necrosis factor-a, and lymphocyte and monocyte counts.[16] Cold exposure has an immunostimulating effect possibly related to the enhanced noradrenaline (norepinephrine) response to cold. In effect, there is, in general, limited evidence of immunosuppression from short- or long-term cold exposure. On the contrary, a stimulating effect of cold exposure could be argued, which is dependent on the relationship between core temperature decrease and duration of exposure.[17] The WBC effect is probably linked to the modifications of immunological molecules having paracrine effects, rather than effects to systemic immunological functions. In fact, there is an increase in the antiinflammatory cytokine interleukin (IL)-10, and a decrease in the pro-inflammatory cytokine IL-2 and chemokine IL-8. Moreover, the decrease in intercellular adhesion molecule 1 (ICAM-1) supported the anti-inflammatory response. The contemporary decrease in prostaglandin E2, which is widely synthesized at sites of inflammation where it induces vasodilation and the ª 2010 Adis Data Information BV. All rights reserved.
Banfi et al.
increase of vascular permeability, confirmed that the treatment induces an anti-inflammatory protection.[15] The cytokine IL-1b did not show modification after 18 WBC exposures during a 9-day cycle in professional field hockey players.[4] The observed values of cytokines confirm the positive effect of WBC on immunological stimulation and/or protection. Some studies were performed to investigate the possible influence of WBC on inflammatory mechanisms. WBC effects on lysosomal enzymes were studied in 21 kayakers from the Polish Olympic team compared with 10 untrained men. The athletes were submitted to a 10-day training cycle where training sessions were preceded by WBC treatment three times a day. The athletes were also examined during a training cycle without WBC. Blood was taken before training and at days 6 and 10 of the cycle. The authors studied lysosomal enzymes because these molecules are involved in the hydrolysis of proteins from the injured muscle fibres. The increased muscle activity induced increases in levels of enzyme activity in blood and also enzyme release from monocytes and macrophages, which are involved in tissue repair. WBC does not induce increases in lysosomal enzymes: a single treatment with nonathletes did not change the levels of enzyme activities. Thus, WBC is not harmful to the lysosomal membrane and it does not facilitate the release of lysosomal enzymes. On the contrary, WBC seems to stabilize lysosomal membranes. In fact, the activity of acid phosphatase, arylsolphatase and cathepsin D was lower after the 6th day of training preceded by WBC, than after the 6th day of training without treatment.[18] An anti-inflammatory effect of WBC was found in rugby players who were treated for 1 week, where an increase in the anti-inflammatory cytokine IL-10, and a decrease in the proinflammatory cytokine IL-2 and chemokine IL-8 was seen. Moreover, the decrease in ICAM-1 supported the anti-inflammatory response.[15] Plasma IL-1b, IL-6 and tumour necrosis factor-a (signals of inflammation) did not show changes after cold exposure during 12 weeks of exposure to winter swimming or WBC in Sports Med 2010
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20 healthy females.[19] The reduction of inflammation could be proposed as the principal effect of WBC, enhancing and influencing the positive effects on various pathways of metabolism. In conclusion: 1. WBC has no detrimental effect on immunological parameters. 2. WBC has an immunostimulating effect. 3. WBC induces an increase in anti-inflammatory cytokine IL-10 and a decrease in proinflammatory cytokine IL-2 and chemokine IL-8, and also in prostaglandin E2. 4. WBC does not induce the release of lysosomal enzymes and stabilizes the lysosomal membranes. 4. Muscular Enzymes An increase in serum creatine kinase (CK) is the most typical sign of exertional rhabdomyolysis, and it could be used as a measure to predict physical workload, recovery and possible overtraining. The beneficial effects of active recovery have been described in top-level rugby players after training, where the immersion of legs in cold water resulted in a decrease in serum total CK concentration compared with passive recovery.[20] This confirmed the results of Gill et al.,[21] who also observed CK in interstitial muscular fluid of rugby players. WBC induced a clear and significant decrease in the mean values of CK and lactate dehydrogenase (LDH) after 1 week of treatment in professional rugby players.[15] It seems that short-time cold air exposure induces an enhancement of muscle fibre repair, reducing the breakdown of the cell membrane or reducing its increased permeability, which is generally caused by oxidant agents produced by physical exercise. Since the athletes did not change their training scheme or load during the period of WBC treatment, the significant decrease of serum total CK and LDH concentrations resulted in proper and rapid recovery of muscular damage.[16] The mechanism inducing the decrease of muscular enzymes could also be related to a thyroid response via the decreased sensitivity of mitochondria to adenosine diphosphate, creatine and mitochondrial CK, which influences the entire CK metabolism. In addition, membrane staª 2010 Adis Data Information BV. All rights reserved.
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bilization could explain the limited increase of muscular enzyme in the plasma. The reduction of microinjuries to muscle fibres caused by exercise (shown by a decrease in CK serum concentration) was confirmed in 21 kayakers performing two 10-day training cycles, one cycle without treatment and the other with WBC preceding each training session. The CK values in both groups were higher than those before training, as expected. The values during training with WBC were significantly lower than those observed during training without WBC. For example, the activity of CK after the 6th day of training with WBC was 34% lower than after training without treatment.[18] In conclusion: 1. WBC shows positive effects on muscular enzymes CK and LDH (i.e. a limitation of their increase), which are typical indicators of muscular involvement during physical exercise. 2. WBC is a procedure that facilitates athletic recovery. 5. Cardiac Markers WBC and acute cooling induce an increase in high frequency power and an increase in cardiac parasympathetic modulation. However, after 3 months of repeated WBC, the increase in parasympathetic tone in healthy females was limited as a result of adaptation.[22] Thus, the treatment should not be harmful to cardiac function in healthy people. A study was conducted in top-level athletes who were treated once a day for 1 week with WBC. Measurement was taken of the cardiac markers troponin I and high sensitivity C-reactive protein (hsCRP) [parameters linked to damage and necrosis of cardiac muscular tissue, but also to tissue repair] and N-terminal pro B-type natriuretic peptide (NTproBNP) [a parameter linked to heart failure and ventricular power decrease]. Troponin I and hsCRP were unchanged, demonstrating that there was no damage, even minimal, in the heart during the treatment. NT-proBNP increased from a mean of 19.7 pg/mL before WBC treatment to a mean of 31.3 pg/mL after treatment. The training workload was the same as that administered in Sports Med 2010
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the weeks preceding the treatment; therefore, the increase in NT-proBNP was due to cold stress. However, the NT-proBNP concentrations observed after WBC were lower than those measured after a heavy training session in the same group of athletes. WBC possibly limits the NTproBNP increase, which is a typical indicator of physical exercise.[23,24] In conclusion: 1. WBC does not appear to be deleterious for athletes’ cardiac function. 6. Hormones Hormonal homeostasis was studied in 22 elite soccer players who completed ten WBC sessions accompanied by kinesitherapy following each WBC session. Blood was collected before and 2 days after the treatment. After the treatment, a significant decrease in the concentration of testosterone and estradiol was found, whereas dehydroepiandrosterone sulphate and luteinizing hormone were unchanged. A possible influence of WBC on aromatization could be suggested.[25] No changes in serum concentration of growth hormone, thyroid stimulating hormone, prolactin or free thyroid hormones were found during 12 weeks of WBC treatment (three treatments per week) in six healthy females.[26] In another study, cortisol levels did not change after a single WBC treatment in untrained men. The concentration of cortisol increased by 23% after the first 6 days of training without treatment and remained at that level after the 10th day, whereas changes in the concentration after training with WBC were not significant.[18] WBC did not stimulate the pituitary-adrenal cortex axis during a 12-week treatment period in 20 healthy females who underwent winter swimming or WBC three times a week. Plasma adrenocorticotrophic hormone and cortisol concentrations in weeks 4–12 were significantly lower than in week 1 as a result of to habituation.[19] It is not possible to argue potential hormonal modifications by WBC from the limited published data. However, it seems that it does not directly influence pituitary function. Possible hormone modifications are linked to habituation ª 2010 Adis Data Information BV. All rights reserved.
and adaptation of the body to cold stress; plasma adrenaline was unchanged, but noradrenaline increased 2- or 3-fold at each exposure to cold temperatures in healthy females undergoing 12 weeks of treatment.[19] In conclusion: 1. WBC does not induce modifications of pituitary and thyroid hormones. 2. WBC induces a decrease in testosterone and estradiol. 3. WBC does not stimulate the pituitary-adrenal cortex axis or cortisol release. 4. WBC stimulates the release of noradrenaline. 7. Conclusions WBC is not harmful and does not induce negative general and specific effects in athletes. The published studies concentrate on physiological, biochemical and haematological parameters, which are not negatively modified; however, specific studies on physical parameters and the effects on recovery from injuries should be performed. WBC reduces proinflammatory responses, decreases pro-oxidant molecular species and stabilizes membranes, resulting in high potential beneficial effects on sports-induced haemolysis, and cell and tissue damage, which is characteristic of heavy physical exercise. Conversely, it does not influence immunological or hormonal responses, with the exception of testosterone and estradiol, or myocardial cell metabolism. Interleukin concentrations are modified by WBC, which induces an anti-inflammatory response. The treatment does not induce modifications of biochemical or haematological parameters that would be suspected in cheating athletes. The published data are generally not controversial, but further studies are necessary to confirm the present observations. Standardization of exposure times and the number of treatments during each cycle could improve data comparison. Intensities and frequencies of treatments are quite similar in the different studies, but a specific effort to standardize protocols in patients with various pathologies, and especially in athletes, should be encouraged. Standardization Sports Med 2010
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could further reduce the possible discrepancies among results from different studies. 13.
Acknowledgements 14.
We are indebted to Mrs Valentina Diani, who reviewed the language. We are also indebted to Dr Johanna Nowakowska, born in Poland and now working in IRCCS Galeazzi, who assisted us in translating Polish papers. No funding was used in the preparation of this review. The authors have no conflicts of interest directly relevant to the content of this review.
15.
16.
17.
References 1. Fricke R. Ganzokorpekaltetherapie in einer Kaltekammer mit Temperaturen um -110C. Z Phys Med Baln Med Klim 1989; 18: 1-10 2. Smolander J, Westerlund T, Uusitalo A, et al. Lung function after acute and repeated exposures to extremely cold air (-110 degrees C) during whole-body cryotherapy. Clin Physiol Funct Imaging 2006; 26: 232-4 3. Banfi G, Krajewska M, Melegati G, et al. Effects of the whole body cryotherapy on haematological values in athletes [letter]. Br J Sports Med 2008; 42: 558 4. Straburzynska-Lupa A, Konarska A, Nowak A, et al. Effect of whole-body cryotherapy on selected blood chemistry parameters in professional field hockey players [in Polish]. Fizjoterapia Polska 2007; 7: 15-201 5. Banfi G, Melegati G. Effect on sport hemolysis of cold water leg immersion in athletes after training sessions. Lab Hematol 2008; 14: 15-8 6. Banfi G, Melegati G, Barassi A, et al. Beneficial effects of whole-body cryotherapy on sport hemolysis. J Hum Sport Exerc 2009; 4: 189-93 7. Wozniak A, Wozniak B, Drewa G, et al. The effect of wholebody cryostimulation on the prooxidant-antioxidant balance in blood of elite kayakers during training. Eur J Appl Physiol 2007; 101: 533-7 8. Wozniak A, Wozniak B, Drewa G, et al. Lipid peroxidation in blood of kayakers after whole-body cryostimulation and training [in Polish]. Medycyna Sport 2007; 1: 15-221 9. Wozniak A, Wozniak B, Drewa G, et al. The influence of whole-body cryostimulation on blood enzymatic antioxidant barrier of kayakers during training [in Polish]. Medycyna Sport 2007; 4: 207-14 10. Lubkowska A, Chudecka M, Klimek A, et al. Acute effect of a single whole-body cryostimulation on prooxidantantioxidant balance in blood of healthy, young men. J Thermal Biol 2008; 33: 464-7 11. Siems W, Brenke R. Uric acid and glutathione levels during short-term whole body cold exposure. Free Radical Biol Med 1994; 16: 299-305 12. Dugue´ B, Smolander J, Westerlund T, et al. Acute and longterm effects of winter swimming and whole-body cryo-
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therapy on plasma antioxidative capacity in healthy women. Scand J Clin Lab Invest 2005; 65: 395-402 Lubkowska A, Dolegowska B, Szygula Z, et al. Activity of selected enzymes in erythrocytes and level of plasma antioxidants in response to single whole-body cryostimulation in humans. Scand J Clin Lab Invest 2009; 69: 387-94 Dugue´ B, Leppa¨nen E. Adaptation related to cytokines in man: effects of regular swimming in ice-cold water. Clin Physiol 2000; 20: 114-21 Banfi G, Melegati G, Barassi A, et al. Effects of whole-body cryotherapy on serum mediators of inflammation and serum muscle enzymes in athletes. J Thermal Biol 2009; 34: 55-9 Jansky L, Pospisilova´ D, Honzova´ H, et al. Immune system of cold-exposed and cold-adapted humans. Eur J Appl Physiol 1996; 72: 445-50 Walsh NP, Whitham M. Exercising in environmental extremes: a greater threat to immune function? Sports Med 2006; 36: 941-76 Wozniak A, Wozniak B, Drewa G, et al. The effect of wholebody cryostimulation on lysosomal enzyme activity in kayakers during training. Eur J Appl Physiol 2007; 100: 137-42 Leppa¨luoto J, Westerlund T, Huttunen P, et al. Effects of long-term whole-body cold exposures on plasma concentrations of ACTH, beta-endorphin, cortisol, catecholamines and cytokines in healthy females. Scand J Clin Lab Invest 2008; 68: 145-53 Banfi G, Melegati G, Valentini P. Effects of cold-water immersion of legs after training session on serum creatine kinase concentration in rugby players [letter]. Br J Sports Med 2007; 41: 339 Gill ND, Beaven CM, Cook C. Effectiveness of post-match recovery strategies in rugby players. Br J Sports Med 2006; 40: 260-3 Westerlund T, Uusitalo A, Smolander J, et al. Heart rate variability in women exposed to very cold air (-110C) during whole-body cryotherapy. J Thermal Biol 2006; 31: 342-6 Banfi G, Melegati G, Barassi A, et al. Effects of the wholebody cryotherapy on NTproBNP, hsCRP and troponin I in athletes. J Sci Med Sport 2009; 12 (6): 609-10 Banfi G, Melzi d’Eril G, Barassi A, et al. NT-proBNP concentrations in elite rugby players at rest and after active and passive recovery following strenuous training sessions. Clin Chem Lab Med 2008; 46: 247-9 Korzonek-Szlacheta I, Wielkoszynski T, Stanek A, et al. Influence of whole body cryotherapy on the levels of some hormones in professional footballers [in Polish]. Pol J Endocrinol 2007; 1: 27-32 Smolander J, Leppa¨luoto J, Westerlund T, et al. Effects of repeated whole-body exposures on serum concentrations of growth hormone, thyrotropin, prolactin and thyroid hormones in healthy women. Cryobiology 2009; 58: 275-8
Correspondence: Professor Giuseppe Banfi, IRCCS Galeazzi, School of Medicine, University of Milan, Via R Galeazzi, 4 - 20161 Milan, Italy. E-mail:
[email protected]
Sports Med 2010
CORRESPONDENCE
Sports Med 2010; 40 (6): 519-523 0112-1642/10/0006-0519/$49.95/0
ª 2010 Adis Data Information BV. All rights reserved.
‘Combining Hypoxic Methods for Peak Performance’: a Biomedical Engineering Perspective The review ‘Combining Hypoxic Methods for Peak Performance’[1] recently published in Sports Medicine, attempts to formulate practical proposals for leading athletes to peak fitness. Its format suggests that it is intended as a practical guide for sports practitioners. The objective of simplifying the task for the coach is laudable; however, we are concerned that the conclusions and recommendations of this review are too narrow. This may adversely influence the training practices of the sporting community and misguide further research into athletic health and performance. The review promotes the idea that the most expensive and cumbersome methods of hypoxia training (e.g. constructing real altitude camps and constant changing altitudes for training and living) are the only valid approaches for athletic performance enhancement. This encourages the misuse of economic resources, leads to using mega-budgets for training a few privileged athletes and justifies the construction of extremely expensive structures (i.e. altitude houses and altitude domes). Noticeably, the review is not systematic or comprehensive, as research that contravenes the main idea of the review is often omitted from citations. For example, early research on intermittent hypoxic training (IHT) is quoted and criticized as being non-controlled;[2] however, a later, properly designed placebo-controlled study by the same group[3] who demonstrated the same extent of performance enhancement, is not mentioned. Similarly, a recent meta-analysis of various hypoxic training modalities[4] presenting substantially different conclusions to the review was also not quoted. In concluding that ‘‘it is known that IHE is inefficient for performance
enhancement,’’[1] the review completely ignores the substantial amount of data that strongly suggests the opposite.[5-7] The terminology that is used in the review does not have a sound physiological basis and may confuse the reader. In addition to already confusing terms such as LHTL (live high-train low), LHTH (live high-train high), IHE (intermittent hypoxic exposure during rest) and IHT, an additional, baffling abbreviation LHTLHi (living high-training low and high, interspersed) is introduced. This bias in sources and confusion in terminology needs to be addressed. Dr Millet and colleagues state that ‘‘The underlying mechanisms behind the effects of hypoxic training are widely debated.’’ The origin of this debate, while not explicitly cited, is possibly the erythropoietin (EPO) paradigm of altitude training first suggested in the mid 1990s (LHTL),[8] which has been more recently criticized as incomplete and inconclusive.[9] This EPO paradigm of LHTL is itself based on another paradigm, which suggests that the maximal oxygen uptake . (VO2max) is an accurate predictor of enhanced aerobic performance in highly trained athletes. This hypothesis is questioned by some research[10-13] and it is now being scrutinized.[14] It is problematic to select best training practices based on a misleading end-marker. However, commitment to disproving all alternative altitude training methodology, which is based on the.fact that such a method ‘‘does not improve VO2max,’’[15,16] might provide an interesting hypothesis; because of the improved economy resulting from the . hypoxic training, the VO2max could be decreased in highly trained athletes. This data could serve as an indicator of improved performance. 1. What is Being Stressed? It is now well established that reduced oxygen partial pressure (pO2), which is monitored by hypoxia inducible factor (HIF)-1a[17] and by mitochondria,[18-20] induces the chain reaction at the cellular level. Only a significant or long-lasting drop in pO2 provokes detectable response to the altitude training. The reason that passive residing at altitudes of 1800 m fails to increase the
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performance markedly, is correctly pointed out in the review, which identifies that the sigmoid oxygenhaemoglobin dissociation curve does not allow much pO2 reduction until pulse oximeter arterial oxygen saturation (SpO2) levels decrease below 90%. Simply speaking, no stress results in no stress response. Thanks to simple, newer technology (i.e. the pulse oximeter), the arterial pO2 can now be monitored non-invasively and the ‘training dosage’ can be measured more directly and precisely. The optimal levels of SpO2 required to achieve an optimal result are not yet established, although empirically identified values of 76–83% of SpO2 demonstrably perform well,[3] provided that this range is tolerated by the individual. Prior to pulse oximeters, the only altitude training dosage was the elevation (meters) above sea level and duration of exposure (minutes and hours). Nowadays, technology for direct measurement of physiological parameters such as SpO2 is readily available, but the authors of this review still recommend using the old-fashioned approach ‘meters above sea level versus days of exposure’. It is generally conceded that there is wide individual variability for exposure to the same altitude.[21] The review[1] mentions this but offers no insight on how this problem could be practically solved, ignoring 20 years of fruitful research. It is time to acknowledge that there is no such thing as the ‘optimal altitude’ nor an ‘optimal dose of altitude’, as each person is different and any training regimen must be individually adjusted. To produce a meaningful stress response, arterial oxygen saturation should fall below 90% (SpO2 <90%).[22] The question remains about the required time a stressor should continue to trigger and fulfill transcription of the responsible genes. Research data indicates that physiological responses are evident at both systemic and cellular levels, even after only a few minutes of hypoxia, and are facilitated by HIF-1a release.[23] The rationale behind short term intermittent hypoxia/reoxygenation is that it is possible to produce a hypoxia challenge that is sufficiently strong and long, while avoiding any damage. Repetition of such intervention several times has a cumulative effect. A new, more objective measure of delivery to the individual was introduced recently; the ª 2010 Adis Data Information BV. All rights reserved.
Letter to the Editor
Hypoxic Training index (HTi).[22] Knowledge of HTi can be used to alter the training regimen for different athletes compensating for individual variability. It also ensures that the hypoxic exposure is correctly controlled for each subject. 2. Solution-Based Research If the aim of sport science is to find new costeffective methods and technologies for enhancing the performance and health of athletes without the adverse effects that are associated with drug use, then further research in therapeutic hypoxia must be worthwhile, since it has no reported physiological adverse effects and is drug-free. This goal embraces all hypoxia training protocols or technology without bias. Oleg Bassovitch Biomedtech Australia (GO2Altitude) Pty Ltd, Melbourne, Victoria, Australia
Acknowledgements The author is grateful for valuable comments and critique provided by Dr Rod Westerman (Associate Professor, PhD, MD, FRACGP) and Dr John Hellemans (FRNZCGP) during the drafting of this letter. No sources of funding were used to assist in the preparation of this letter. The author has no conflicts of interest that are directly relevant to the content of this letter.
References 1. Millet GP, Roels B, Schmitt L, et al. Combining hypoxic methods for peak performance. Sports Med 2010; 40 (1): 1-25 2. Hellemans J. Intermittent hypoxic training: a pilot study. Proceedings of the Second Annual International Altitude Training Symposium; 1999 Feb 18-20; Flagstaff (AZ); 145-54 3. Hamlin MJ, Hellemans J. Effect of intermittent normobaric hypoxic exposure at rest on haematological, physiological, and performance parameters in multi-sport athletes. J Sports Sci 2007 Feb; 25 (4): 431-41 4. Bonetti DL, Hopkins WG. Sea-level exercise performance following adaptation to hypoxia: a meta-analysis. Sports Med 2009; 39 (2): 107-27 5. Katayama K, Matsuo H, Ishida K, et al. Intermittent hypoxia improves endurance performance and submaximal exercise efficiency. High Alt Med Biol 2003 Fall; 4 (3): 291-304
Sports Med 2010; 40 (6)
Letter to the Editor
6. Shatilo VB, Korkushko OV, Ischuk VA, et al. Effects of intermittent hypoxia training on exercise performance, hemodynamics, and ventilation in healthy senior men. High Alt Med Biol 2008 Spring; 9 (1): 43-52 7. Hamlin MJ, Marshall HC, Hellemans J, et al. Effect of intermittent hypoxic training on 20km time trial and 30 s anaerobic performance. Scand J Med Sci Sports. Epub 2009 Sep 28 8. Levine BD, Stray-Gunderson J. ‘‘Living high-training low’’: effect of moderate altitude acclimatization with low-altitude training on performance. J Appl Physiol 1997; 83 (1): 102-12 9. Gore CJ, Clark SA, Saunders PU. Nonhematological mechanisms of improved sea-level performance after hypoxic exposure. Med Sci Sports Exerc 2007 Sep; 39 (9): 1600-9 10. Hahn AG, Gore CJ, Martin DT, et al. An evaluation of the concept of living at moderate altitude and training at sea level. Comp Biochem Physiol A Mol Integr Physiol 2001 Apr; 128 (4): 777-89 11. Gore CJ, Hopkins WG. Counterpoint: positive effects of intermittent hypoxia (live high: train low) on exercise performance are not mediated primarily by augmented red cell volume. J Appl Physiol 2005 Nov; 99 (5): 2055-7; discussion 2057-8 12. Hahn AG, Gore CJ. The effect of altitude on cycling performance: a challenge to traditional concepts. Sports Med 2001; 31 (7): 533-57 13. Jensen K, Nielsen TS, Fiskestrand A, et al. High-altitude training does not increase maximal oxygen uptake or work capacity at sea level in rowers. Scand J Med Sci Sports 1993; 3: 256-62 14. Vollaard NBJ, Constantin-Teodosiu D, Fredriksson K, et al. Systematic analysis of adaptations in aerobic capacity and submaximal energy metabolism provides a unique insight into determinants of human aerobic performance. J Appl Physiol 2009; 106: 1479-86 15. Julian CG, Gore CJ, Wilber RL, et al. Intermittent normobaric hypoxia does not alter performance or erythropoietic markers in highly trained distance runners. J Appl Physiol 2004 May; 96 (5): 1800-7 16. Tadibi V, Dehnert C, Menold E, et al. Unchanged anaerobic and aerobic performance after short-term intermittent hypoxia. Med Sci Sports Exerc 2007 May; 39 (5): 858-64 17. Webb JD, Coleman ML, Pugh CW. Hypoxia, hypoxiainducible factors (HIF), HIF hydroxylases and oxygen sensing. Cell Mol Life Sci 2009 Nov; 66 (22): 3539-54 18. Renshaw GMC, Nikinmaa M. Oxygen sensors of the peripheral and central nervous systems. In: Lajtha A, Johnson D, editors. Handbook of neurochemistry and molecular neurobiology. 3rd Ed. New York: Springer, 2007: 272-88 19. Prabhakar NR. Oxygen sensing during intermittent hypoxia: cellular and molecular mechanisms. J Appl Physiol 2001; 90: 1986-94 20. Nanduri J, Nanduri RP. Cellular mechanisms associated with intermittent hypoxia. Essays Biochem 2007; 43: 91-104 21. Chapman RF, Stray-Gundersen J, Levine BD. Individual variation in response to altitude training. J Appl Physiol 1998 Oct; 85 (4): 1448-56 22. Bassovitch O, Serebrovskaya TV. Equipment and regimes for intermittent hypoxia therapy. In: Xi L, Serebrovskaya TV, editors. Intermittent hypoxia: from molecular mechanisms
ª 2010 Adis Data Information BV. All rights reserved.
521
to clinical applications. New York: Nova Science Publishers, 2009 561-72 23. Jewell UR, Kvietikova I, Scheid A, et al. Induction of HIF1a in response to hypoxia is instantaneous. FASEB J 2001 Mar; 15 (7): 1312-4
The Author’s Reply Hypoxic Training Terminology: Time for Consensus? We thank Mr Bassovitch for his interest in our work.[1] In his letter, he stated that: (a) the recommendations of our review were too narrow and ‘‘promoted the most expensive methods of hypoxia training;’’ (b) we ignored the substantial amount of data supporting the efficiency of intermittent hypoxic exposure (IHE); (c) the terminology used had no sound physiological basis and was confusing. Finally, Mr Bassovitch criticized: . (d) VO2max as a misleading end-marker to select hypoxic methods; (e) the notion of an ‘‘optimal dose of altitude.’’ In response to these points raised by Mr Bassovitch, I have the following reply: (a) 1. Our review[1] is the first one to suggest some innovative combinations of different hypoxic training methods (e.g. living high-training low and high, interspersed; LHTLHi) and their incorporation into the yearly training programme. We made clear in the conclusions that it requires further investigations to better understand their outcomes and mechanisms. These proposals were based on the belief that (i) a large ‘hypoxic dose’ is required for significantly ‘‘stimulating the erythropoietic pathway to the point that it enhances post-altitude sea-level endurance performance;’’[2] and (ii) intermittent hypoxic training (IHT) induces different responses than passive IH exposure (IHE). Recent publications confirm that exercising in hypoxia results in specific structural and functional adaptation in muscle tissue (see Lundby et al.[3] and Schmutz et al.[4] for details regarding transcripts Sports Med 2010; 40 (6)
522
and protein activation), whereas, passive exposure induces modest responses.[3] Hypoxia complement during exercise (IHT) leads to ‘‘a specific effect on metabolic processes and transcriptome in exercised muscley in contrast to the augmented oxygen transport capacity via erythropoiesisyin a different manner from normoxia.[4]’’ In addition, a high intensity of exercise in hypoxia induces greater muscle adaptations to compensate the decreased O2 availability.[5] 2. However, for at least two reasons, we agree that the recommendations of our review were too narrow and will evolve in the future with the advancement of knowledge described as follows: (i) Despite the molecular mechanisms emerging in favour of IHT, the optimal characteristics of exercise (during IHT or in the various combinations) are unclear. In other words, it is unknown how interval training in hypoxia has to be amended, when compared with normoxic interval training and by looking to the large number of studies dedicated to aerobic training,[6] definitely, we are far from an exhaustive view on IHT. (ii) Our review did not mention another emerging point that might have practical application for selecting hypoxic methods; the debated effect of barometric pressure on nitric oxide uptake by the blood[7] with potential differences in systemic responses.[8] Our review aimed to discuss the pros and cons of the various hypoxic methods on the basis of scientific findings and did not promote any of them for commercial reasons; in contrast with the position of Mr Bassovitch. (b) Our conclusions that ‘‘IHE is inefficient for performance enhancement’’[1] are in line with a recent review reporting ‘‘no direct or indirect evidence for any significant physiological changes that might be associated with improving athletic performance at sea level.’’[9] Five of the six IHE randomized blind studies reported no additional benefit of IHE for sea-level performance.[9] More specifically, the study[10] proposed by Mr Bassovitch as showing performance enhancement with IHE, reported a 3000 metre running time improvement in 7 of 12 IHE subjects versus 6 of 10 subjects in the control group and has been criticized.[9] We have to acknowledge that the excellent recent meta-analysis[11] ª 2010 Adis Data Information BV. All rights reserved.
Letter to the Editor
(not included in our review as a result of the publication delays), report of a 2.6% increase in mean power output with IHE (called ‘‘intermittent <1.5 hours/day intermittent train low’’) in sub-elite (but not in elite) athletes is not in line with our view. However, when looking to the ‘enhanced protocols’ (e.g. predicted means adjusted to – 1 SD away from the mean for selected study variables[11]) in sub-elite athletes, it appears that IHE is the less efficient method and that LHTLHi is worthy of interest since live hightrain low (LHTL) [terrestrial +4.6%; or artificial +4.8%] and IHT (+6.8%) show greater improvement in performance than IHE (+3.6%). (c) In our review,[1] the abbreviations (LHTH [live high-train high], LHTL, IHT, IHE) are those commonly used by various international research groups.[2,9,11,12] Interestingly, one can also find a distinction between prolonged HE (PHE) and IHE.[9] In fact, Mr Bassovitch seems to use IHT and IHE indifferently, although these two methods have different physiological basis (see reply a1). He mentioned ‘‘research on IHT’’ while quoting a study on intermittent normobaric hypoxic exposure at rest.[10] However, it raises the point that there is no consensus on the terminology. A previous consensus group[13] defined the level (e.g. low, moderate, high, extreme) of altitude and some consensus exists, for example, on the efficiency and characteristics of LHTL; since then, several reviews[1,14-16] have released similar recommendations. However, to date, there is no international consensus on how to name the different hypoxic methods. It is now time for a consensus statement to bridge this gap with the leading scientists[13-18] before any additional complex issue emerges (e.g. normobaric vs hypobaric, combination of methods, training characteristics, periodizationy). (d) We agree with Mr Bassovitch regarding . economy and the misuse of VO2max as a valid performance-related descriptor. In the debate discussing the effects of hypoxic training on economy,[19,20] we reported improved economy after LHTL.[21] (e) Finally, Mr Bassovitch stated that there is ‘‘no optimal dose of altitude, as each person is different and any training regimen must be inSports Med 2010; 40 (6)
Letter to the Editor
523
dividually adjusted’’ but suggested, on the basis of an IHE study[10] with pulse oximeter arterial oxygen saturation (SpO2) of 76–83% and unclear (see reply b) beneficial results, to use a SpO2 threshold of 90% (Hypoxic Training index). We agree that the ‘stressor’ (e.g. hypoxic dose = altitude level · exposure duration) has variable effects on the individual responses[22] and that hypoxic training, as in any training component, requires an individualized setting. However, prescription of hypoxic training based on SpO2 in general, and on SpO2 <90% specifically, is lacking experimental validation. However, this proposal is of interest and deserves further investigation. To summarize, in this reply, we took the opportunity to introduce the complexity of future questions (from molecular to applied levels) in natural and artificial hypoxic training methods and to call for a consensus statement on terminology. Gre´goire P. Millet
7.
8. 9.
10.
11.
12.
13.
14.
15.
ISSUL, Institute of Sport Sciences – Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
17.
References
18.
1. Millet GP, Roels B, Schmitt L, et al. Combining hypoxic methods for peak performance. Sports Medicine 40 (1): 1-25 2. Wilber RL, Stray-Gundersen J, Levine BD. Effect of hypoxic ‘‘dose’’ on physiological responses and sea-level performance. Med Sci Sports Exerc 2007 Sep; 39 (9): 1590-9 3. Lundby C, Calbet JA, Robach P. The response of human skeletal muscle tissue to hypoxia. Cell Mol Life Sci 2009 Sep 10; 66 (22) E3615-23 4. Schmutz S, Dapp C, Wittwer M, et al. A hypoxia complement differentiates the muscle response to endurance exercise. Exp Physiol. Epub 2010 Feb 22 5. Vogt M, Puntschart A, Geiser J, et al. Molecular adaptations in human skeletal muscle to endurance training under simulated hypoxic conditions. J Appl Physiol 2001 Jul; 91 (1): 173-82 6. Laursen PB, Jenkins DG. The scientific basis for highintensity interval training: optimising training programmes
ª 2010 Adis Data Information BV. All rights reserved.
16.
19.
20.
21.
22.
and maximising performance in highly trained endurance athletes. Sports Medicine 2002; 32 (1): 53-73 Hemmingsson T, Linnarsson D. Lower exhaled nitric oxide in hypobaric than in normobaric acute hypoxia. Respir Physiol Neurobiol 2009 Oct 31; 169 (1): 74-7 Kayser B. Disentangling hypoxia and hypobaria. Respir Physiol Neurobiol 2009 Dec 31; 169 (3): 338-9 Bartsch P, Dehnert C, Friedmann-Bette B, et al. Intermittent hypoxia at rest for improvement of athletic performance. Scand J Med Sci Sports 2008 Aug; 18 Suppl. 1: 50-6 Hamlin MJ, Hellemans J. Effect of intermittent normobaric hypoxic exposure at rest on haematological, physiological, and performance parameters in multi-sport athletes. J Sports Sci 2007 Feb 15; 25 (4): 431-41 Bonetti DL, Hopkins WG. Sea-level exercise performance following adaptation to hypoxia: a meta-analysis. Sports Med 2009; 39 (2): 107-27 Roels B, Millet GP, Marcoux CJ, et al. Effects of hypoxic interval training on cycling performance. Med Sci Sports Exerc 2005 Jan; 37 (1): 138-46 Bartsch P, Saltin B, Dvorak J. Consensus statement on playing football at different altitude. Scand J Med Sci Sports 2008 Aug; 18 Suppl. 1: 96-9 Richalet JP, Gore CJ. Live and/or sleep high:train low, using normobaric hypoxia. Scand J Med Sci Sports 2008 Aug; 18 Suppl. 1: 29-37 Stray-Gundersen J, Levine BD. Live high, train low at natural altitude. Scand J Med Sci Sports 2008 Aug; 18 Suppl. 1: 21-8 Wilber RL. Application of altitude/hypoxic training by elite athletes. Med Sci Sports Exerc 2007 Sep; 39 (9): 1610-24 Gore CJ, Hopkins WG. Counterpoint: positive effects of intermittent hypoxia (live high:train low) on exercise performance are not mediated primarily by augmented red cell volume. J Appl Physiol 2005 Nov; 99 (5): 2055-7; discussion 2057-8 Hoppeler H, Vogt M, Weibel ER, et al. Response of skeletal muscle mitochondria to hypoxia. Exp Physiol 2003 Jan; 88 (1): 109-19 Lundby C, Calbet JA, Sander M, et al. Exercise economy does not change after acclimatization to moderate to very high altitude. Scand J Med Sci Sports 2007 Jun; 17 (3): 281-91 Saunders PU, Telford RD, Pyne DB, et al. Improved running economy in elite runners after 20 days of simulated moderate-altitude exposure. J Appl Physiol 2004 Mar; 96 (3): 931-7 Schmitt L, Millet G, Robach P, et al. Influence of ‘‘living high-training low’’ on aerobic performance and economy of work in elite athletes. Eur J Appl Physiol 2006 Jul; 97 (5): 627-36 Chapman RF, Stray-Gundersen J, Levine BD. Individual variation in response to altitude training. J Appl Physiol 1998 Oct; 85 (4): 1448-56
Sports Med 2010; 40 (6)
CORRESPONDENCE
Sports Med 2010; 40 (6): 519-523 0112-1642/10/0006-0519/$49.95/0
ª 2010 Adis Data Information BV. All rights reserved.
‘Combining Hypoxic Methods for Peak Performance’: a Biomedical Engineering Perspective The review ‘Combining Hypoxic Methods for Peak Performance’[1] recently published in Sports Medicine, attempts to formulate practical proposals for leading athletes to peak fitness. Its format suggests that it is intended as a practical guide for sports practitioners. The objective of simplifying the task for the coach is laudable; however, we are concerned that the conclusions and recommendations of this review are too narrow. This may adversely influence the training practices of the sporting community and misguide further research into athletic health and performance. The review promotes the idea that the most expensive and cumbersome methods of hypoxia training (e.g. constructing real altitude camps and constant changing altitudes for training and living) are the only valid approaches for athletic performance enhancement. This encourages the misuse of economic resources, leads to using mega-budgets for training a few privileged athletes and justifies the construction of extremely expensive structures (i.e. altitude houses and altitude domes). Noticeably, the review is not systematic or comprehensive, as research that contravenes the main idea of the review is often omitted from citations. For example, early research on intermittent hypoxic training (IHT) is quoted and criticized as being non-controlled;[2] however, a later, properly designed placebo-controlled study by the same group[3] who demonstrated the same extent of performance enhancement, is not mentioned. Similarly, a recent meta-analysis of various hypoxic training modalities[4] presenting substantially different conclusions to the review was also not quoted. In concluding that ‘‘it is known that IHE is inefficient for performance
enhancement,’’[1] the review completely ignores the substantial amount of data that strongly suggests the opposite.[5-7] The terminology that is used in the review does not have a sound physiological basis and may confuse the reader. In addition to already confusing terms such as LHTL (live high-train low), LHTH (live high-train high), IHE (intermittent hypoxic exposure during rest) and IHT, an additional, baffling abbreviation LHTLHi (living high-training low and high, interspersed) is introduced. This bias in sources and confusion in terminology needs to be addressed. Dr Millet and colleagues state that ‘‘The underlying mechanisms behind the effects of hypoxic training are widely debated.’’ The origin of this debate, while not explicitly cited, is possibly the erythropoietin (EPO) paradigm of altitude training first suggested in the mid 1990s (LHTL),[8] which has been more recently criticized as incomplete and inconclusive.[9] This EPO paradigm of LHTL is itself based on another paradigm, which suggests that the maximal oxygen uptake . (VO2max) is an accurate predictor of enhanced aerobic performance in highly trained athletes. This hypothesis is questioned by some research[10-13] and it is now being scrutinized.[14] It is problematic to select best training practices based on a misleading end-marker. However, commitment to disproving all alternative altitude training methodology, which is based on the.fact that such a method ‘‘does not improve VO2max,’’[15,16] might provide an interesting hypothesis; because of the improved economy resulting from the . hypoxic training, the VO2max could be decreased in highly trained athletes. This data could serve as an indicator of improved performance. 1. What is Being Stressed? It is now well established that reduced oxygen partial pressure (pO2), which is monitored by hypoxia inducible factor (HIF)-1a[17] and by mitochondria,[18-20] induces the chain reaction at the cellular level. Only a significant or long-lasting drop in pO2 provokes detectable response to the altitude training. The reason that passive residing at altitudes of 1800 m fails to increase the
520
performance markedly, is correctly pointed out in the review, which identifies that the sigmoid oxygenhaemoglobin dissociation curve does not allow much pO2 reduction until pulse oximeter arterial oxygen saturation (SpO2) levels decrease below 90%. Simply speaking, no stress results in no stress response. Thanks to simple, newer technology (i.e. the pulse oximeter), the arterial pO2 can now be monitored non-invasively and the ‘training dosage’ can be measured more directly and precisely. The optimal levels of SpO2 required to achieve an optimal result are not yet established, although empirically identified values of 76–83% of SpO2 demonstrably perform well,[3] provided that this range is tolerated by the individual. Prior to pulse oximeters, the only altitude training dosage was the elevation (meters) above sea level and duration of exposure (minutes and hours). Nowadays, technology for direct measurement of physiological parameters such as SpO2 is readily available, but the authors of this review still recommend using the old-fashioned approach ‘meters above sea level versus days of exposure’. It is generally conceded that there is wide individual variability for exposure to the same altitude.[21] The review[1] mentions this but offers no insight on how this problem could be practically solved, ignoring 20 years of fruitful research. It is time to acknowledge that there is no such thing as the ‘optimal altitude’ nor an ‘optimal dose of altitude’, as each person is different and any training regimen must be individually adjusted. To produce a meaningful stress response, arterial oxygen saturation should fall below 90% (SpO2 <90%).[22] The question remains about the required time a stressor should continue to trigger and fulfill transcription of the responsible genes. Research data indicates that physiological responses are evident at both systemic and cellular levels, even after only a few minutes of hypoxia, and are facilitated by HIF-1a release.[23] The rationale behind short term intermittent hypoxia/reoxygenation is that it is possible to produce a hypoxia challenge that is sufficiently strong and long, while avoiding any damage. Repetition of such intervention several times has a cumulative effect. A new, more objective measure of delivery to the individual was introduced recently; the ª 2010 Adis Data Information BV. All rights reserved.
Letter to the Editor
Hypoxic Training index (HTi).[22] Knowledge of HTi can be used to alter the training regimen for different athletes compensating for individual variability. It also ensures that the hypoxic exposure is correctly controlled for each subject. 2. Solution-Based Research If the aim of sport science is to find new costeffective methods and technologies for enhancing the performance and health of athletes without the adverse effects that are associated with drug use, then further research in therapeutic hypoxia must be worthwhile, since it has no reported physiological adverse effects and is drug-free. This goal embraces all hypoxia training protocols or technology without bias. Oleg Bassovitch Biomedtech Australia (GO2Altitude) Pty Ltd, Melbourne, Victoria, Australia
Acknowledgements The author is grateful for valuable comments and critique provided by Dr Rod Westerman (Associate Professor, PhD, MD, FRACGP) and Dr John Hellemans (FRNZCGP) during the drafting of this letter. No sources of funding were used to assist in the preparation of this letter. The author has no conflicts of interest that are directly relevant to the content of this letter.
References 1. Millet GP, Roels B, Schmitt L, et al. Combining hypoxic methods for peak performance. Sports Med 2010; 40 (1): 1-25 2. Hellemans J. Intermittent hypoxic training: a pilot study. Proceedings of the Second Annual International Altitude Training Symposium; 1999 Feb 18-20; Flagstaff (AZ); 145-54 3. Hamlin MJ, Hellemans J. Effect of intermittent normobaric hypoxic exposure at rest on haematological, physiological, and performance parameters in multi-sport athletes. J Sports Sci 2007 Feb; 25 (4): 431-41 4. Bonetti DL, Hopkins WG. Sea-level exercise performance following adaptation to hypoxia: a meta-analysis. Sports Med 2009; 39 (2): 107-27 5. Katayama K, Matsuo H, Ishida K, et al. Intermittent hypoxia improves endurance performance and submaximal exercise efficiency. High Alt Med Biol 2003 Fall; 4 (3): 291-304
Sports Med 2010; 40 (6)
Letter to the Editor
6. Shatilo VB, Korkushko OV, Ischuk VA, et al. Effects of intermittent hypoxia training on exercise performance, hemodynamics, and ventilation in healthy senior men. High Alt Med Biol 2008 Spring; 9 (1): 43-52 7. Hamlin MJ, Marshall HC, Hellemans J, et al. Effect of intermittent hypoxic training on 20km time trial and 30 s anaerobic performance. Scand J Med Sci Sports. Epub 2009 Sep 28 8. Levine BD, Stray-Gunderson J. ‘‘Living high-training low’’: effect of moderate altitude acclimatization with low-altitude training on performance. J Appl Physiol 1997; 83 (1): 102-12 9. Gore CJ, Clark SA, Saunders PU. Nonhematological mechanisms of improved sea-level performance after hypoxic exposure. Med Sci Sports Exerc 2007 Sep; 39 (9): 1600-9 10. Hahn AG, Gore CJ, Martin DT, et al. An evaluation of the concept of living at moderate altitude and training at sea level. Comp Biochem Physiol A Mol Integr Physiol 2001 Apr; 128 (4): 777-89 11. Gore CJ, Hopkins WG. Counterpoint: positive effects of intermittent hypoxia (live high: train low) on exercise performance are not mediated primarily by augmented red cell volume. J Appl Physiol 2005 Nov; 99 (5): 2055-7; discussion 2057-8 12. Hahn AG, Gore CJ. The effect of altitude on cycling performance: a challenge to traditional concepts. Sports Med 2001; 31 (7): 533-57 13. Jensen K, Nielsen TS, Fiskestrand A, et al. High-altitude training does not increase maximal oxygen uptake or work capacity at sea level in rowers. Scand J Med Sci Sports 1993; 3: 256-62 14. Vollaard NBJ, Constantin-Teodosiu D, Fredriksson K, et al. Systematic analysis of adaptations in aerobic capacity and submaximal energy metabolism provides a unique insight into determinants of human aerobic performance. J Appl Physiol 2009; 106: 1479-86 15. Julian CG, Gore CJ, Wilber RL, et al. Intermittent normobaric hypoxia does not alter performance or erythropoietic markers in highly trained distance runners. J Appl Physiol 2004 May; 96 (5): 1800-7 16. Tadibi V, Dehnert C, Menold E, et al. Unchanged anaerobic and aerobic performance after short-term intermittent hypoxia. Med Sci Sports Exerc 2007 May; 39 (5): 858-64 17. Webb JD, Coleman ML, Pugh CW. Hypoxia, hypoxiainducible factors (HIF), HIF hydroxylases and oxygen sensing. Cell Mol Life Sci 2009 Nov; 66 (22): 3539-54 18. Renshaw GMC, Nikinmaa M. Oxygen sensors of the peripheral and central nervous systems. In: Lajtha A, Johnson D, editors. Handbook of neurochemistry and molecular neurobiology. 3rd Ed. New York: Springer, 2007: 272-88 19. Prabhakar NR. Oxygen sensing during intermittent hypoxia: cellular and molecular mechanisms. J Appl Physiol 2001; 90: 1986-94 20. Nanduri J, Nanduri RP. Cellular mechanisms associated with intermittent hypoxia. Essays Biochem 2007; 43: 91-104 21. Chapman RF, Stray-Gundersen J, Levine BD. Individual variation in response to altitude training. J Appl Physiol 1998 Oct; 85 (4): 1448-56 22. Bassovitch O, Serebrovskaya TV. Equipment and regimes for intermittent hypoxia therapy. In: Xi L, Serebrovskaya TV, editors. Intermittent hypoxia: from molecular mechanisms
ª 2010 Adis Data Information BV. All rights reserved.
521
to clinical applications. New York: Nova Science Publishers, 2009 561-72 23. Jewell UR, Kvietikova I, Scheid A, et al. Induction of HIF1a in response to hypoxia is instantaneous. FASEB J 2001 Mar; 15 (7): 1312-4
The Author’s Reply Hypoxic Training Terminology: Time for Consensus? We thank Mr Bassovitch for his interest in our work.[1] In his letter, he stated that: (a) the recommendations of our review were too narrow and ‘‘promoted the most expensive methods of hypoxia training;’’ (b) we ignored the substantial amount of data supporting the efficiency of intermittent hypoxic exposure (IHE); (c) the terminology used had no sound physiological basis and was confusing. Finally, Mr Bassovitch criticized: . (d) VO2max as a misleading end-marker to select hypoxic methods; (e) the notion of an ‘‘optimal dose of altitude.’’ In response to these points raised by Mr Bassovitch, I have the following reply: (a) 1. Our review[1] is the first one to suggest some innovative combinations of different hypoxic training methods (e.g. living high-training low and high, interspersed; LHTLHi) and their incorporation into the yearly training programme. We made clear in the conclusions that it requires further investigations to better understand their outcomes and mechanisms. These proposals were based on the belief that (i) a large ‘hypoxic dose’ is required for significantly ‘‘stimulating the erythropoietic pathway to the point that it enhances post-altitude sea-level endurance performance;’’[2] and (ii) intermittent hypoxic training (IHT) induces different responses than passive IH exposure (IHE). Recent publications confirm that exercising in hypoxia results in specific structural and functional adaptation in muscle tissue (see Lundby et al.[3] and Schmutz et al.[4] for details regarding transcripts Sports Med 2010; 40 (6)
522
and protein activation), whereas, passive exposure induces modest responses.[3] Hypoxia complement during exercise (IHT) leads to ‘‘a specific effect on metabolic processes and transcriptome in exercised muscley in contrast to the augmented oxygen transport capacity via erythropoiesisyin a different manner from normoxia.[4]’’ In addition, a high intensity of exercise in hypoxia induces greater muscle adaptations to compensate the decreased O2 availability.[5] 2. However, for at least two reasons, we agree that the recommendations of our review were too narrow and will evolve in the future with the advancement of knowledge described as follows: (i) Despite the molecular mechanisms emerging in favour of IHT, the optimal characteristics of exercise (during IHT or in the various combinations) are unclear. In other words, it is unknown how interval training in hypoxia has to be amended, when compared with normoxic interval training and by looking to the large number of studies dedicated to aerobic training,[6] definitely, we are far from an exhaustive view on IHT. (ii) Our review did not mention another emerging point that might have practical application for selecting hypoxic methods; the debated effect of barometric pressure on nitric oxide uptake by the blood[7] with potential differences in systemic responses.[8] Our review aimed to discuss the pros and cons of the various hypoxic methods on the basis of scientific findings and did not promote any of them for commercial reasons; in contrast with the position of Mr Bassovitch. (b) Our conclusions that ‘‘IHE is inefficient for performance enhancement’’[1] are in line with a recent review reporting ‘‘no direct or indirect evidence for any significant physiological changes that might be associated with improving athletic performance at sea level.’’[9] Five of the six IHE randomized blind studies reported no additional benefit of IHE for sea-level performance.[9] More specifically, the study[10] proposed by Mr Bassovitch as showing performance enhancement with IHE, reported a 3000 metre running time improvement in 7 of 12 IHE subjects versus 6 of 10 subjects in the control group and has been criticized.[9] We have to acknowledge that the excellent recent meta-analysis[11] ª 2010 Adis Data Information BV. All rights reserved.
Letter to the Editor
(not included in our review as a result of the publication delays), report of a 2.6% increase in mean power output with IHE (called ‘‘intermittent <1.5 hours/day intermittent train low’’) in sub-elite (but not in elite) athletes is not in line with our view. However, when looking to the ‘enhanced protocols’ (e.g. predicted means adjusted to – 1 SD away from the mean for selected study variables[11]) in sub-elite athletes, it appears that IHE is the less efficient method and that LHTLHi is worthy of interest since live hightrain low (LHTL) [terrestrial +4.6%; or artificial +4.8%] and IHT (+6.8%) show greater improvement in performance than IHE (+3.6%). (c) In our review,[1] the abbreviations (LHTH [live high-train high], LHTL, IHT, IHE) are those commonly used by various international research groups.[2,9,11,12] Interestingly, one can also find a distinction between prolonged HE (PHE) and IHE.[9] In fact, Mr Bassovitch seems to use IHT and IHE indifferently, although these two methods have different physiological basis (see reply a1). He mentioned ‘‘research on IHT’’ while quoting a study on intermittent normobaric hypoxic exposure at rest.[10] However, it raises the point that there is no consensus on the terminology. A previous consensus group[13] defined the level (e.g. low, moderate, high, extreme) of altitude and some consensus exists, for example, on the efficiency and characteristics of LHTL; since then, several reviews[1,14-16] have released similar recommendations. However, to date, there is no international consensus on how to name the different hypoxic methods. It is now time for a consensus statement to bridge this gap with the leading scientists[13-18] before any additional complex issue emerges (e.g. normobaric vs hypobaric, combination of methods, training characteristics, periodizationy). (d) We agree with Mr Bassovitch regarding . economy and the misuse of VO2max as a valid performance-related descriptor. In the debate discussing the effects of hypoxic training on economy,[19,20] we reported improved economy after LHTL.[21] (e) Finally, Mr Bassovitch stated that there is ‘‘no optimal dose of altitude, as each person is different and any training regimen must be inSports Med 2010; 40 (6)
Letter to the Editor
523
dividually adjusted’’ but suggested, on the basis of an IHE study[10] with pulse oximeter arterial oxygen saturation (SpO2) of 76–83% and unclear (see reply b) beneficial results, to use a SpO2 threshold of 90% (Hypoxic Training index). We agree that the ‘stressor’ (e.g. hypoxic dose = altitude level · exposure duration) has variable effects on the individual responses[22] and that hypoxic training, as in any training component, requires an individualized setting. However, prescription of hypoxic training based on SpO2 in general, and on SpO2 <90% specifically, is lacking experimental validation. However, this proposal is of interest and deserves further investigation. To summarize, in this reply, we took the opportunity to introduce the complexity of future questions (from molecular to applied levels) in natural and artificial hypoxic training methods and to call for a consensus statement on terminology. Gre´goire P. Millet
7.
8. 9.
10.
11.
12.
13.
14.
15.
ISSUL, Institute of Sport Sciences – Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
17.
References
18.
1. Millet GP, Roels B, Schmitt L, et al. Combining hypoxic methods for peak performance. Sports Medicine 40 (1): 1-25 2. Wilber RL, Stray-Gundersen J, Levine BD. Effect of hypoxic ‘‘dose’’ on physiological responses and sea-level performance. Med Sci Sports Exerc 2007 Sep; 39 (9): 1590-9 3. Lundby C, Calbet JA, Robach P. The response of human skeletal muscle tissue to hypoxia. Cell Mol Life Sci 2009 Sep 10; 66 (22) E3615-23 4. Schmutz S, Dapp C, Wittwer M, et al. A hypoxia complement differentiates the muscle response to endurance exercise. Exp Physiol. Epub 2010 Feb 22 5. Vogt M, Puntschart A, Geiser J, et al. Molecular adaptations in human skeletal muscle to endurance training under simulated hypoxic conditions. J Appl Physiol 2001 Jul; 91 (1): 173-82 6. Laursen PB, Jenkins DG. The scientific basis for highintensity interval training: optimising training programmes
ª 2010 Adis Data Information BV. All rights reserved.
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