Hyperventilation during rest and exercise in orthostatic intolerance and Spiky-Leaky Syndrome

Abstract

Background: Orthostatic intolerance, with or without postural orthostatic tachycardia syndrome (POTS), is collectively referred to as orthostatic intolerance dysautonomia syndromes (OIDS). This condition often presents with daytime hyperventilation, which is considered to be secondary to sympathetic hyperactivity. This hyperventilation appears to be a key characteristic in a newly described subset of patients with OIDS who also exhibit craniocervical instability, mast cell activation syndrome (MCAS), hypermobility spectrum disorder (HSD), and the phenomenon of alternating intracranial hypertension with hypotension due to cerebrospinal fluid (CSF) leaks, collectively termed Spiky-Leaky Syndrome (SLS).

Methods: We performed a retrospective review of clinical metabolic exercise data in young patients with SLS, comparing them to matched patients with OIDS and healthy controls (CTL). We assessed metabolic parameters at rest, at the anaerobic threshold (AT), and at maximal oxygen consumption (VO₂max). The parameters included end-tidal CO₂ (ETCO₂), end-tidal O₂ (ETO₂), peak oxygen pulse, total work performed, and peak oxygen uptake efficiency slope (OUESp).

Results: Of 323 reviewed exercise stress tests, 44 were conducted on patients with SLS, 210 on those with OIDS, and 53 on healthy controls. VO₂max, AT, peak oxygen pulse, total work performed, and OUESp were all significantly reduced in patients with OIDS and were further reduced in those with SLS. ETCO₂ levels were notably lower at rest, at the time of the anaerobic threshold, and at the time of maximal oxygen uptake in the OIDS group, and even more so in the SLS group. These lower levels of ETCO₂ persisted throughout exercise. In contrast, ETO₂ demonstrated a similarly strong but opposite trend.

Conclusion: Compared to the control group, patients with OIDS-and especially those with SLS-exhibited reduced metabolic parameters, particularly a decrease in peak oxygen pulse and ETCO₂ levels during both rest and exercise. These findings suggest a reduction in ventricular preload and chronic daytime hyperventilation. These exercise parameters may serve as markers for POTS physiology and sympathetic hyperactivity, both of which could play a role in the pathophysiology of SLS.

Keywords: Ehlers-Danlos syndrome; POTS; Spiky-Leaky Syndrome; dysautonomia; end-tidal CO2; exercise stress testing; hypermobility spectrum disorder; mast cell activation syndrome.

Figure 1

VO₂ measures of the controls (CTL), patients with orthostatic intolerance dysautonomia syndromes (OIDS), and patients with Spiky-Leaky Syndrome (SLS) at three stages of the exercise—rest and at the times of anaerobic threshold (AT) and VO₂max (VO₂max_t). Significance levels are indicated as follows: ^*p ≤ 0.05.

Figure 2

Peak oxygen uptake efficiency slope (OUESp) of the controls (CTL), patients with orthostatic dysautonomia intolerance syndromes (OIDS), and patients with Spiky-Leaky Syndrome (SLS). Significance levels are indicated as follows: ^*p ≤ 0.05, ^***p ≤ 0.001.

Figure 3

End-tidal O₂ (ETO₂) measures of the controls (CTL), patients with orthostatic intolerance dysautonomia syndromes (OIDS), and patients with Spiky-Leaky Syndrome (SLS) at three stages of the exercise—rest and at the times of anaerobic threshold and VO₂max. Significance levels are indicated as follows: ^*p ≤ 0.05, ^**p ≤ 0.01, ^***p ≤ 0.001.

Figure 4

End-tidal CO₂ (ETCO₂) measures of the controls (CTL), patients with orthostatic intolerance dysautonomia syndromes (OIDS), and patients with Spiky-Leaky Syndrome (SLS) at three stages of the exercise—rest and at the times of anaerobic threshold and VO₂max. Significance levels are indicated as follows: ^*p ≤ 0.05, ^**p ≤ 0.01, ^***p ≤ 0.001.

Figure 5

Peak oxygen pulse measures of the controls (CTL), patients with orthostatic intolerance dysautonomia syndromes (OIDS), and patients with Spiky-Leaky Syndrome (SLS) at three stages of the exercise—rest and at the times of anaerobic threshold and VO₂max. Significance levels are indicated as follows: ^*p ≤ 0.05, ^**p ≤ 0.01, ^***p ≤ 0.001. The lower oxygen pulse values during rest are a consequence of the higher baseline heart rates in the OIDS and SLS groups.

Figure 6

Total work performed of the controls (CTL), patients with orthostatic intolerance dysautonomia syndromes (OIDS), and patients with Spiky-Leaky Syndrome (SLS). Significance levels are indicated as follows: ^*p ≤ 0.05.

Figure 7

Oxygen pulse curves of the patients through the course of the exercise, showing those of a control with average fitness, (Average CTL), a control with athletic fitness (Athletic CTL), and a patient with Spiky-Leaky Syndrome (SLS). The curve rises to peak exercise, with a peak oxygen pulse of approximately 11 mlO2/beat in a healthy person with average fitness. It rises to 22 in a person who is aerobically trained, and it is depressed at all levels of exercise in a person with POTS physiology.

Figure 8

Oxygen Uptake Efficiency Slopes of two extremes from this study; (a) that of a control patient with athletic fitness (Athletic CTL), and (b) of a patient with Spiky-Leaky Syndrome (SLS). x axis: Minute Ventilation VE at BTPS (body temperature (37C, ambient pressure and gas saturated with water vapor), y axis: Oxygen consumption normalized to BSA. Note that the scales of the two Y axes are quite different resulting are much different slopes. Normal values for OUESp is 1,400 to 2,000 ml O2/min/m²BSA. An aerobically-trained healthy athlete can approach 4,000 while those with cardiovascular compromise may fall below 1,400 ml O2/min/m²BSA. Normal values for OUESp is 1,000 to 2,200 mL O2/min/m²BSA (31, 32).