The broad implication of our study is that patients with heart failure and comorbid hypocapnia have worse long-term prognosis and poor clinical outcome.
Importantly, we have shown that low pCO2 was not associated with conventional clinical and laboratory triggers. The results presented here suggest that hypoperfusion was a key factor in the development of hypocapnia.
Dyspnea is the most common symptom among patients with HF and tends to be inevitably more severe as the disease progresses. The term itself refers to the subjective experience of breathing discomfort and is frequently described by patients as an inability to take a deep breath or a chest tightness. This symptom is complex in its etiology as there is a wide spectrum of pathophysiological triggers and mechanisms (cardiac/metabolic/neurogenic/pulmonary/haematological) involved in its development. Even though this phenomenon is widely studied, the diagnostic accuracy of dyspnea assessment seems to be limited due to lack of objective measures. The dyspnea in AHF might be related to hyperventilation (expressed by an increase in tidal volume and/or respiratory rate), but it may also be dependent on the subjective perception of unsatisfied inspiration caused by respiratory muscle weakness or dynamic lung hyperinflation10. Clinicians seldom precisely assess the specific physiological variables like respiratory rate, tidal volume or the minute ventilation in AHF patients. Therefore, there is a persistent unmet need for an objective identification of the patient’s ventilatory status. A growing body of evidence suggests that hyperventilation may contribute to the development of physiological derangements that result in HF progression.
Here, we used pCO2 as surrogate of hyperventilation. We believe that the results of this study provide an insight into heart failure pathophysiology, relations of low pCO2 with potential clinical triggers of hyperventilation and prognostic significance of hypocapnia in AHF.
First, the results of our study reveal that there were discrepancies between pCO2 level/ hyperventilation and patient self-reported dyspnea. The level of pCO2 did not affect the sensation of dyspnea reported by AHF patients. Therefore, it can be assumed that subjective dyspnea measures have inadequate diagnostic accuracy for identification of patients with disturbed breathing patterns and pCO2 seems to be more reliable indicator for detecting hyperventilation.
Second, hyperventilation was not contingent on evident and expected potential triggers such as anaemia (expressed by haemoglobin, haematocrit), infection (expressed by WBC, CRP, IL-6, IL-22), hypoxemia (expressed by pO2 and sO2) or pulmonary congestion on physical examination. However, hyperventilating patients had some markers of more advanced disease phenotypes and more severe multi-organ dysfunction. On the other hand, alternative markers of disease progression such as RAAS, iron status or spot urine sodium were comparable between the two groups.
Both groups differed in relation to markers of hypoperfusion and hypoxemia/hypoxia. A higher lactate level on admission was observed in the group with low pCO2. Lactate as a product of an anaerobic metabolism corresponds to impaired tissue perfusion. In response to energetic stress (as during AHF episode) energy demand increases and the sympathetic nervous system hyperactivates, all of which result in an increased glycolysis and lactate accumulation. Under conditions of insufficient tissue perfusion, persistent energy debt exceeds the buffering capacity of the body what consecutively leads to the development of hyperlacticaemia and metabolic acidosis. This goes also with agreement with the occurrence of metabolic acidosis (the lower bicarbonate levels) observed in the hyperventilating group. The metabolic acidosis may also be a surrogate of inadequate peripheral perfusion in AHF. As a result of bicarbonate depletion, ventilatory compensation (in the form of hyperventilation) emerges to maintain acid-base balance.
Therefore, it can be inferred that one of the mechanisms underlying hypocapnia in AHF is related to response to peripheral hypoperfusion. Thus, we may speculate that hypoperfusion (rather than direct hypoxemia) contributed to hyperventilation in an attempt to buffer the developing acidosis at the expense of CO2 loss11–14.
As elegantly shown by Torres-Torrelo et al. peripheral chemoreceptors are also lactate sensors15. Thus, overactivation of the chemoreflex arc may be seen as hypothetical link between diminished tissue perfusion and increased ventilatory effort resulting in hypocapnia. It is also worth noting that HF individuals with hypersensitive peripheral chemoreceptors (~ 30% of HF patients) are characterized by worse prognosis. Therefore, it may be speculated that poor outcomes seen in our study in low pCO2 group might have been partly related to that fact. Assessment of peripheral chemosensitivity would definitely shed more light on the matter.
The association between hemodynamic impairment, enhanced sensitivity to carbon dioxide and Cheyne-Stokes respiration (CSR) among patients with HF is an additional contributing factor that should be taken under consideration16. Hyperventilation induced hypocapnia contributes to the ventilatory instability and the development of a periodic breathing with central sleep apnoea (CSA)16. Indeed, as it was presented by Naughton et al., patients with CSR-CSA had significantly lower values of pCO2 in comparison to patients who did not present this breathing pattern17.
It should be noted that, Cheyne-Stokes ventilation is a marker of a poor prognosis in HF and the central sleep apnoea is related to higher mortality risk in HF population18. Consequently, it can be assumed, that this aspect could have partially contributed to the poor clinical outcome observed in a group with hypocapnia. This assumption should be addressed in future studies.
It should be emphasized that hypocapnia on admission for AHF might not be a simple function of hyperventilation. It is well possible that in some patients it was present even before the acute event.
This could potentially be related to chronic renal disease with concomitant metabolic acidosis, the presence of periodic breathing or other unidentified factors – which by themselves may affect the survival.
In conclusion, hypocapnia is relatively frequent among patients admitted to the hospital with AHF and related with poor prognosis. Low pCO2 was not contingent on evident and expected potential clinical and laboratory triggers, while tissue hypoperfusion seemed to play an important role in its’ development.