Abstract
Increased “wasted” ventilation and heightened neural drive explains excess exercise ventilation in CTEPH http://ow.ly/Z4YBc
To the Editor:
Exercise intolerance due to excessive ventilation and dyspnoea are fundamental clinical features of patients with pulmonary vascular diseases [1]. Among these diseases, chronic thromboembolic pulmonary hypertension (CTEPH) is associated with the largest increase in exercise ventilation [2]. Understanding the mechanism(s) underlying excess exercise ventilation in CTEPH is clinically relevant when designing evidence-based therapeutic and rehabilitative strategies to improve patients' symptoms and quality of life.
Excess exercise ventilation in CTEPH has been traditionally ascribed to increased “wasted” ventilation, i.e. hypoperfusion of well-ventilated alveoli. In fact, the physiological dead space fraction of tidal volume (VD/VT ratio) at peak exercise not only predicts CTEPH after pulmonary embolism [3] but also improves after clinical [4] and surgical [5] treatment. As the end-tidal carbon dioxide tension (PETCO2) diminishes when ventilation is excessive relative to perfusion [6], increased VD/VT has been mechanistically linked to inordinately low PETCO2 in CTEPH [7]. A PETCO2 lower than arterial (a) carbon dioxide tension (PCO2) (i.e. a positive P(a-ET)CO2 gradient) [6] also suggests impaired pulmonary perfusion as a potential explanation for low exercise PETCO2in these patients [8].
Surprisingly, however, seminal studies comparing lung absorption of multiple inert gases showed no or a limited increase in VD/VT despite marked pulmonary arterial obstruction [9]. This prompts an alternative (or complementary) explanation for a low exercise PETCO2 in CTEPH: reduced alveolar PCO2 (hyperventilation) [10]. In fact, heightened neural drive has been found in pulmonary vascular diseases secondary to increased chemosensitivity [11] and/or higher afferent stimuli from “central” baro- and mechano-receptors [12]. Thus, alveolar hyperventilation under the stress of exercise may also explain the relatively lower PETCO2 in CTEPH. A hyperbolic correlation between increasing minute ventilation (V′E)/carbon dioxide production (V′CO2) and decreasing arterial carbon dioxide tension (PaCO2) in CTEPH is also suggestive of heightened neural drive and consistent with the alveolar equation [13].
There is another intriguing feature of the PETCO2 response that brings additional uncertainty about the meaning of a low exercise PETCO2 in CTEPH. Similar to pulmonary arterial hypertension (PAH) [9], PETCO2 paradoxically increases (instead of further decreasing as in normal subjects) as soon as CTEPH patients enter the recovery phase. In this context, evaluation of PaCO2 (or arterialised capillary (PcCO2) as its surrogate) [8] and P(c-ET)CO2 across the exercise-to-recovery transition might shed light on the mechanisms underlying the PETCO2 behaviour during recovery in CTEPH. Thus, we reasoned that during recovery: 1) if PcCO2 remains stable or further decreases despite higher PETCO2, a narrower P(c-ET)CO2 would suggest improved VD/VT (scenario 1); 2) conversely, if PcCO2 and PETCO2 increase proportionally leading to stable P(c-ET)CO2, lower neural drive would explain higher PETCO2 (scenario 2); 3) but if a narrower P(c-ET)CO2 develops as a consequence of PcCO2, increasing less than PETCO2, improved VD/VT plus lower neural drive would explain a higher PETCO2 (scenario 3).
We therefore measured PcCO2 (arterialised ear lobe blood), P(c-ET)CO2 and plasma lactate 1 min before peak incremental exercise, at peak and in recovery at every minute up to the fifth minute of unloaded cycling. Responses from 10 patients (age 54–78 years, five males, mean±se pulmonary arterial pressure 51.5±9.7 mmHg, pulmonary wedge pressure 9.2±3.4 mmHg, stable segmental perfusion defects after 6 months of anticoagulation) were contrasted with those from eight age- and sex-matched healthy subjects. As expected, patients had a lower peak oxygen uptake, V′CO2 and arterial oxygen saturation measured by pulse oximetry (SpO2) (p<0.05). Lactate corrected for peak work rate was higher in patients (0.14±0.05 versus 0.08±0.04 mEq·L−1·W−1; p<0.01). These findings were associated with lower peak PETCO2 and positive P(c-ET)CO2 (figure 1b).
In line with our previous observations, whereas recovery PETCO2 consistently increased throughout recovery in patients, it remained lower than peak exercise in controls (figure 1b). This increased PETCO2 was associated with a faster decline in V′E compared with V′CO2 in patients; conversely, V′E recovered at a slower rate than V′CO2 in controls (figure 1a). Lactate remained similarly increased in both groups; conversely, SpO2 was lower in patients up to the third minute of recovery (91.1±3.5% versus 96.4±2.0%; p<0.05). In controls, PcCO2 further decreased up to the second minute and remained stable thereafter, i.e. a negative P(c-ET)CO2 was found for most of recovery. In patients, PcCO2 increased throughout recovery; however, as it increased less than PETCO2, P(c-ET)CO2 systematically decreased in CTEPH (figure 1c). Under the logical assumption that recovery reversed the abnormalities seen during exercise, scenario 3 seems in line with the suggestions of Delcroix et al. [10] and Naeije and van de Borne [11] that both high VD/VT and heightened neural drive are related to excess exercise ventilation in CTEPH.
As pointed out by the late eminent physiologist Brian J. Whipp, the transition between different rates of metabolic demand (e.g. exercise–recovery) provides a unique window to understand the complexities linking tissue gas exchange to pulmonary ventilation [14]. Thus, when V′CO2 slowly decreased after exercise in our patients, V′E did not lag behind as in normal subjects. Conversely, V′E decreased consistently faster than V′CO2 in patients (figure 1a). The sudden decrease in V′E and resulting elevation in PcCO2 (figure 1b) suggest an abrupt reduction in neural drive in these patients. Sluggish muscle gas exchange kinetics due to a slower rate of phosphocreatine replenishment and/or slower cardiocirculatory dynamics during recovery may have contributed to a more protracted V′CO2 in patients [14]. It is also conceivable that carbon dioxide released during exercise has been slowly washed-out from carbon dioxide reservoirs, which are likely to be larger in chronically hypocapnic patients [15]. In fact, resting PaCO2 and exercise-induced decrements in PcCO2 were closely related to V′CO2 kinetics in patients (r=0.85 and r=0.88, respectively; p<0.001). Although additional studies are needed to clarify the underlying mechanism(s), it is clear that V′E did not “wait” for V′CO2, which resulted in post-exercise decreases in the V′E/V′CO2 ratio, thereby contributing to increase PETCO2 in CTEPH.
Another key finding relates to a P(c-ET)CO2 decrease after exercise in patients, which seems consistent with post-exercise improvement in VD, likely to be secondary to enhanced pulmonary perfusion and ventilation/perfusion matching [6, 7]. Zhai et al. [13] found that while V′E/V′CO2 (assumed as an index of VD/VT behaviour) for a given PaCO2 was increased in CTEPH compared with PAH, the difference disappeared when V′E/V′CO2 was expressed as a function of PETCO2. This suggests a greater contribution of increased VD to the excessive exercise ventilation (and low PETCO2) in CTEPH compared with PAH during exercise.
In conclusion, increased “wasted” ventilation (high VD/VT) is not the only explanation for excess exercise ventilation in CTEPH: heightened neural drive also contributes to these abnormalities. Interventions able to decrease both VD/VT and neural drive might prove particularly valuable in this patient population.
Footnotes
Conflict of interest: None declared.
- Received November 21, 2015.
- Accepted February 28, 2016.
- Copyright ©ERS 2016