Looking Into the Plateau of Oxygen Uptake

Sport scientists have been studying adaptations to maximal cardiorespiratory effort for decades. A plateau of the oxygen uptake (2plVO•) nearby the maximal effort, which means that the 2VO• stops to increase despite the workload progress, is one of these interesting physiological responses. Although the 2plVO• raises a great interest, this phenomenon is not observed in a large number of Graduate Exercise Tests. It might occur because of the 2VO• kinetics, biological characteristic of the tested individuals, exercise protocols and 2plVO• cutoff criteria. Therefore, this lack of methodological standards has provoked a non-consensual approaching about the plateau occurrence. Thus, new studies in which a better control of those variables occurs must be done, in order to understand this complex phenomenon.

Keywords: Aerobic capacity; Maximal oxygen consumption; Cardiovascular health; 2maxVO

Abbreviations: FR: Front Row; SR: Second Row; BR: Back Row; HB: Half Back; C: Centre; B3: Back Three; D: Distance per Minute; HSR: High Speed Running per Minute; MV: Maximum Velocity; AZ4, AZ5 AZ6, DZ4, DZ5, DZ6: Accelerations/Decelerations in Zones 4, 5 and 6; COL: Collisions; SP: Sprints; BC: Total Ball Carries; PASS: Passes; TA: Tackle Attempts; RUCK: Ruck Involvements; MAUL: Maul Involvements; PEN: Penalties; WCSD: Worst Case Scenario Distance; WCSHSR: Worst Case Scenario High-Speed Running

Chronic Exertional Compartment Syndrome (CECS) is a disabling condition that effects the lower leg, which was first described in 1945 [1]. CECS is characterized by lower leg pain after exertional activities, which is usually alleviated with rest [2]. If an individual continues exertional activity after the onset of pain, other symptoms may progress including increased intramuscular pressure, tightness, numbness, tingling, paresthesia, and muscular weakness [2]. While CECS is a relatively uncommon condition, researchers and healthcare providers believe it is likely under-reported [3]. A study of the US military population yielded an estimated average annual incidence of 0.49 per 1,000 person-years during the period of 2006 to 2011 [4]. Researchers consider this to be the best estimate of incidence for CECS in the absence of more accurate patient reported occurrence [5].

The majority of healthcare providers elect for conservative management of CECS initially [1]. Conservative treatment measures include oral nonsteroidal anti-inflammatory drugs, stretching, physical therapy, and activity modification [1]. However, it has been noted that activity modification may not be possible in populations such as competitive athletes and military service members [1]. Unfortunately, a systematic review of managing CECS patients revealed a 94% failure rate that resulted in patients opting for surgical intervention [6]. Since 1956, surgical fascial release has been the gold standard surgical intervention for CECS patients who have field non-operative treatment [7-9]. Despite being the gold standard, a study of US military personnel who had undergone fascial release for CECS revealed a 45% recurrence rate, a 28% chance of being unable to return to full duty, a 6% chance of requiring revision surgery, and a 16% chance of complications [10]. The same study reported that 17% of fascial release patients ultimately required a medical discharge even after surgery [10].

Given the ineffectiveness of conservative measures as well as the high recurrence rate following surgery in physically active populations, it is imperative to develop additional management strategies for CECS. Previous case reports and preliminary studies have reported promising results for treating CECS with botulinum toxin-A injections [2,3,11-13]. Within the preliminary study of 25 anterior compartments and 17 lateral compartments, intramuscular pressure decreased by 63% ± 21% in the anterior compartment, and 68% ± 21% in the lateral compartment at follow up (range, 3-9 months) [11]. While these results have shown the potential for botulinum toxin-A to be a safe and effective alternative to surgical intervention, the researchers reporting their findings all stressed the need for more research [2,3,11-13]. Researchers have also stressed the need for providers to have a full understanding of the implications behind using botulinum toxin-A [2,3,11-13]. Therefore, the purpose of this review was to describe the currently available literature related to managing CECS patients with botulinum toxin-A injections.

Management of Chronic Exertional Compartment Syndrome with Botulinum Toxin-A

Presently, there are four commercially available preparations of botulinum toxin, each of which as its own potency and list of FDA approvals [14]. While traditionally used for aesthetic procedures such as treating wrinkles, a growing body of evidence suggests botulinum toxin may have a therapeutic role in treating musculoskeletal conditions [15]. In fact, the use of botulinum toxin has been described in treating neuropathic pain, popliteal artery entrapment, sternocleidomastoid fibrosis, and post-surgical abdominal wall musculature [16-19]. As with the previously mentioned studies on CECS patients, these authors also noted the need for further research on how to best utilize botulinum toxin for treatment musculoskeletal conditions.

Mechanism of action

Botulinum toxin-A is one of seven toxins produced by the bacterium Clostridum botulinum [15]. Although there are different preparations of botulinum toxin A, the mechanism of action is the same. When acting on motor neurons, botulinum toxin-A reduces muscle activity by binding to the motor endplate presynaptic receptors, thereby inhibiting the release of acetylcholine [20]. When acting on sensory neurons, botulinum toxin-A inhibits the release of pain modulating chemical mediators, including substance P, glutamate, capsaicin-induced duration of anesthesia, TRPV1 pathway, and calcitonin gene-related peptide at both the peripheral and central neuron level [20]. The muscle weakness and effects on voluntary muscle contraction following botulinum toxin-A treatment last approximately three months, and the autonomic pain modular effects are reported to last around six months [20]. While the effect of botulinum toxin-A on pain is fairly well understood, this does not account for any changes in compartmental pressure that have been observed when treating CECS patients.

Other hypotheses about the mechanism of action of botulinum toxin-A in CECS patients include the resulting muscle hypotonia following botulinum toxin-A injection [11,21,22]. This reduction in hypertrophy of the muscles within the affected lower leg compartment, would theoretically help reduce the symptoms of CECS [11]. Another plausible hypothesis is related to the muscle relaxation effects of botulinum toxin-A [11,23]. This reduction in muscle spasm would increase the length of time the muscle was relaxed, and subsequently improve blood flow to the muscles of the compartment [11]. Such an increase in blood flow would have potential modulary effects for any ischemic pain symptoms. It should be noted that all three of these theoretical modes of action may play a role in reducing the symptoms of CECS [11].

CECS recurrence rates following Botulinum Toxin-A treatment

To date, the majority of research on length of efficacy of treating CECS with botulinum toxin-A comes from case reports. These case reports show promising evidence for long-term impact on symptoms, with reports showing symptom alleviation for up to 36 months [2,12]. In spite of these findings, the authors of these case reports also noted that more extensive research needs to be conducted in order to produce a more definitive statement on the long-term efficacy of botulinum toxin-A for treating CECS. One retrospective study that assessed the efficacy of botulinum toxin-A on CECS examined the cases of 16 patients (median age: 25.5) [24]. The study reported 68.75% efficacy, with seven patients experiencing complete relief of symptoms, and four patients experiencing partial relief of symptoms [24]. Patients with initial partial efficacy experienced a recurrence of pain at a median time of 2.25 months, while 57.1% of patients with complete relief of symptoms experienced recurrence of pain at a median time of 5 months [24]. Although there was a recurrence of symptoms in several patients, the authors did note that botulinum toxin showed at least moderate efficacy while patients suffered no major adverse effects [24].

Adverse effects

The most reported side effects from botulinum toxin-A injections appear to be injection site related [25]. These effects include soreness, edema, and ecchymosis [25]. Fortunately, true allergic reactions to botulinum toxin-A injections are a rare event [26,27]. There is some evidence to suggest that botulinum toxin-A injection increases the risk of granulomatous reactions at the injection site [28,29]. However, the authors noted that these infections may have been the result of a foreign body being introduced to the injection site from a botulinum toxin-A diluent or lubricant material from the syringe [28,29].

Another extremely rare complication of botulinum toxin-A dosing is botulism. Botulism is characterized by systemic muscle weakness, fatigue, difficulty speaking, vomiting, abdominal swelling, and diarrhea, and can potentially be fatal [25]. Most authors agree that botulism toxicity generally results from the use of an unlicensed botulinum toxin product, or an overdose [25,30]. A systematic review of 63 cases of the systemic muscle weakness related to botulism found that, on average, the doses in affected patients were over three times the recommended dose for the preparation being used [31]. The same review suggested the most practical solution for reducing the risk of botulism is to use botulinum toxin-A preparations that are approved by the United States Food and Drug Administration (FDA) at recommended doses [31]. Regarding localized decreases in muscle strength, authors noted that these decreases did not result in functional impairment and patients were overall satisfied with the outcomes of their treatments [2,3,12]. A localized decrease in muscle strength in the lower leg compartments is clinically meaningful, as patients need to be counseled on the implications of potential changes to their strength, proprioception, and balance. However, these changes in muscle strength appear to be transient in nature [20].

Dosing

As previously mentioned, appropriate dosing in accordance with FDA recommendations is crucial for reducing the risk of adverse effects of botulinum toxin-A injection [31]. The protocol from the Uniformed Services University of the Health Sciences recommends delivering 25 units of onabotulinum toxin A into proximal and distal locations in each compartment for a total of 50 units per compartment [15]. The one exception within this protocol is for the superficial posterior compartment, for which 50 units is injected into the medial and lateral heads of the gastrocnemius and 50 units is injected into the soleus muscle [15]. The authors recommend that all injections be done under ultrasound guidance into the muscle belly [15]. Other protocols within case studies have used similar dosing schedules that have had similar results [2,12,13].

The purpose of this review was to describe the currently available literature related to the treatment of CECS with botulinum toxin-A.

While current studies do admit the need for further research to support the use of botulinum toxin-A for the treatment of CECS, the available literature does show promise [2,3,11,12]. Several case reports and a preliminary study have shown that botulinum toxin-A may be a safe and effective non-surgical alternative for the treatment of CECS [2,3,11,12]. Given that proper dosing and use of FDA-approved preparations significantly limits the risk of severe adverse outcomes, the use of botulinum toxin-A may be considered a relatively safe treatment option for CECS.

One of the most effective non-surgical interventions for CECS is relative rest or activity modification [1]. However, authors have noted that this is not a practical intervention for populations such as military service personnel and competitive athletes [1]. The surgical gold standard for treating CECS, fascial release, still has relatively high rates of decreased function and recurrence of symptoms. It is reasonable for clinicians to exhaust as many nonsurgical interventions as possible [10]. Even with the potential for recurring symptoms after botulinum toxin-A injection, the relief of symptoms may allow an individual to achieve career or competitive goals prior to having to modify activity or elect for surgery. As with any medical procedure, informed patient consent is critical [32]. Patients should have a clear understanding of the benefits and risks of all management options for CECS. This allows patients to make the best possible decision according to their values.

In conclusion, the currently available evidence suggest that botulinum toxin-A injections may be a safe and effective nonoperative treatment option for CECS. The risk of severe adverse effects is minimal when clinicians use appropriate dosing and FDAapproved preparations. Patient education, and communication before, during, and after treatment are critical for ensuring that patients’ individual values have the best chance of being met by the chosen treatment option.

1. Bassett DR, Howley ET (2000) Limiting factors for maximum oxygen uptake and determinants of endurance performance. Med Sci Sports Exerc 32(1): 70-84.
2. Noakes TD (1998) Maximal oxygen uptake: "classical" versus "contemporary" viewpoints: a rebuttal. Med Sci Sports Exerc 30(9): 1381-1398.
3. Costill DL (1967) The relationship between selected physiological variables and distance running performance. J Sports Med Phys Fitness 7(2): 61-66.
4. Saltin B, Astrand PO (1967) Maximal oxygen uptake in athletes. J Appl Physiol 23(3): 353-358.
5. Poole DC, Jones AM (2017) Measurement of the maximum oxygen uptake V̇O_2max: V̇O_2peak is no longer acceptable. J Appl Physiol 122(4): 997-1002.
6. Niemeyer M, Knaier R, Beneke R (2021) The oxygen uptake plateau-A critical review of the frequently misunderstood phenomenon. Sports Med 51(9): 1815-1834.
7. Taylor HL, Buskirk E, Henschel A (1955) Maximal oxygen intake as an objective measure of cardio-respiratory performance. J Appl Physiol 8(1): 73-80.
8. Astrand I (1960) Aerobic work capacity in men and women with special reference to age. Acta Physiol Scand Suppl 49(169): 1-92.
9. Astorino TA, Willey J, Kinnahan J, Larsson SM, Welch H, et al. (2005) Elucidating determinants of the plateau in oxygen consumption at VO2max. Br J Sports Med 39(9): 655-660.
10. Niemeyer M, Leithaeuser R, Beneke R (2019) Oxygen uptake plateau occurrence depends on oxygen kinetics and oxygen deficit accumulation. Scand J Med Sci Sports 29(10): 1466-1472.
11. Duffield R, Edge J, Bishop D, Goodman C (2007) The relationship between the VO₂ slow component, muscle metabolites and performance during very-heavy exhaustive exercise. J Sci Med Sport10(3): 127-134.
12. Doncaster G, Marwood S, Iga J, Unnithan V (2016) Influence of oxygen uptake kinetics on physical performance in youth soccer. Eur J Appl Physiol 116(9): 1781-1794.
13. Robergs RA, Dwyer D, Astorino T (2010) Recommendations for improved data processing from expired gas analysis indirect calorimetry. Sports Med 40(2): 95-111.
14. Astorino TA, Robergs RA, Ghiasvand F, Marks D, Burns S (2000) Incidence of the oxygen plateau at VO_2max during exercise testing to volitional fatigue. JEPonline 3(4):1-12.
15. Myers J, Walsh D, Sullivan M, Froelicher V (1990) Effect of sampling on variability and plateau in oxygen uptake. J Appl Physiol (1985) 68(1): 404-410.
16. Duncan GE, Howley ET, Johnson BN (1997) Applicability of VO_2max criteria: discontinuous versus continuous protocols. Med Sci Sports Exerc 29(2): 273-278.
17. Niemeyer M, Bergmann TGJ, Beneke R (2020) Oxygen uptake plateau: calculation artifact or physiological reality? Eur J Appl Physiol 120(1): 231-242.
18. Lucía A, Rabadán M, Hoyos J, Hernández-Capilla M, Pérez M, et al. (2006) Frequency of the VO_2max plateau phenomenon in world-class cyclists. Int J Sports Med 27(12): 984-992.
19. Noakes TD (2008) How did A V Hill understand the VO_2max and the "plateau phenomenon"? Still no clarity? Br J Sports Med 42(7): 574-580.
20. Pompeu FA (2022) Why Pheidippides could not believe in the ‘Central Governor Model’: Popper's philosophy applied to choose between two exercise physiology theories. Sports Med Health Sci 4(1): 1-7.
21. Pompeu F (2018) A little bit more about Popper's philosophy. BMJ Open Sport Exerc Med 4(1): e000401.
22. Midgley AW, Carroll S (2009) Emergence of the verification phase procedure for confirming 'true' VO_2max. Scand J Med Sci Sports 19(3): 313-322.