Impact of hypocapnia and cerebral perfusion on orthostatic tolerance

Abstract

We examined two novel hypotheses: (1) that orthostatic tolerance (OT) would be prolonged when hyperventilatory-induced hypocapnia (and hence cerebral hypoperfusion) was prevented; and (2) that pharmacological reductions in cerebral blood flow (CBF) at baseline would lower the 'CBF reserve', and ultimately reduce OT. In study 1 (n = 24; aged 25 ± 4 years) participants underwent progressive lower-body negative pressure (LBNP) until pre-syncope; end-tidal carbon dioxide (P ET , CO 2) was clamped at baseline levels (isocapnic trial) or uncontrolled. In study 2 (n = 10; aged 25 ± 4 years), CBF was pharmacologically reduced by administration of indomethacin (INDO; 1.2 mg kg(-1)) or unaltered (placebo) followed by LBNP to pre-syncope. Beat-by-beat measurements of middle cerebral artery blood flow velocity (MCAv; transcranial Doppler), heart rate (ECG), blood pressure (BP; Finometer) and end-tidal gases were obtained continuously. In a subset of subjects' arterial-to-jugular venous differences were obtained to examine the independent impact of hypocapnia or cerebral hypoperfusion (following INDO) on cerebral oxygen delivery and extraction. In study 1, during the isocapnic trial, P ET , CO 2 was successfully clamped at baseline levels at pre-syncope (38.3 ± 2.7 vs. 38.5 ± 2.5 mmHg respectively; P = 0.50). In the uncontrolled trial, P ET , CO 2 at pre-syncope was reduced by 10.9 ± 3.9 mmHg (P ≤ 0.001). Compared to the isocapnic trial, the decline in mean MCAv was 15 ± 4 cm s(-1) (35%; P ≤ 0.001) greater in the uncontrolled trial, yet the time to pre-syncope was comparable between trials (544 ± 130 vs. 572 ± 180 s; P = 0.30). In study 2, compared to placebo, INDO reduced resting MCAv by 19 ± 4 cm s(-1) (31%; P ≤ 0.001), but time to pre-syncope remained similar between trials (placebo: 1123 ± 138 s vs. INDO: 1175 ± 212 s; P = 0.53). The brain extracted more oxygen in face of hypocapnia (34% to 53%) or cerebral hypoperfusion (34% to 57%) to compensate for reductions in delivery. In summary, cerebral hypoperfusion either at rest or induced by hypocapnia at pre-syncope does not impact OT, probably due to a compensatory increase in oxygen extraction.

Figure 1. Mean tolerance time to pre-syncope in study 1

Mean tolerance time to pre-syncope in the unclamped (uncontrolled) and clamped (normocapnic) trials (A), and comparison between sexes (B). *Significant main effect for sex; females significantly lower than males (P = 0.001).

Figure 2. Mean change in cardiorespiratory variables and cerebral blood flow velocity with pre-syncope in study 1

Mean change in mean middle cerebral artery (MCAv) and posterior cerebral artery (PCAv) blood flow velocity, end-tidal carbon dioxide (), minute ventilation, mean arterial blood pressure (MAP) and cardiac output (CO) from baseline to pre-syncope in study 1. *Main effect for time, independent of experimental trial; baseline significantly different from pre-syncope (P < 0.0001). ^†Main effect for experimental trial, independent of time point; clamped trial significantly different from unclamped trial (P < 0.0001). ^‡Significant interaction between time point and experimental trial; mean PCAv in the clamped trial significantly different from the unclamped trial at baseline; mean PCAv, mean MCAv and in the clamped trial were significantly different from the unclamped trial at pre-syncope (P < 0.0001).

Figure 3. Sex differences in the mean change in cardiorespiratory variables and cerebral blood flow velocity with pre-syncope in study 1

Mean change in mean middle cerebral artery blood flow velocity (MCAv), end-tidal carbon dioxide (), minute ventilation, mean arterial blood pressure (MAP), heart rate. Stroke volume (SV) and cardiac output (CO) from baseline to pre-syncope in study 1. *Females significantly different from males.

Figure 4. Mean change in cardiorespiratory variables and cerebral blood flow, cerebral delivery of oxygen and cerebral oxygen extraction at rest with hypocapnia in study 1B

Mean ± SD (continuous line) and individual change (dotted lines) in global cerebral blood flow (gCBF), cerebral delivery of oxygen (CDO₂), arterial carbon dioxide (), cerebral oxygen (O₂) extraction and mean arterial blood pressure (MAP) from normocapnia to hypocapnia in study 1B. *Hypocapnia significantly different from normocapnia (P < 0.001).

Figure 5. Mean change in cardiorespiratory variables and cerebral blood flow velocity with pre-syncope in study 2

Mean change in mean middle cerebral artery blood flow velocity (MCAv), end-tidal carbon dioxide (), minute ventilation, mean arterial blood pressure (MAP) and cardiac output (CO) from baseline to pre-syncope in study 2. *Main effect for time, independent of experimental trial; baseline significantly different from pre-syncope (P < 0.0001). ^†Main effect for experimental trial, independent of time point, clamped trial significantly different from unclamped trial (P < 0.0001). ^‡Significant interaction between time point and experimental trial; mean MCAv in the clamped trial was significantly different from the unclamped trial at baseline (P < 0.0001).

Figure 6. Mean change in cardiorespiratory variables and cerebral blood flow, cerebral delivery of oxygen and cerebral oxygen extraction at rest following indomethacin in study 2B

Mean ± SD (continuous line) and individual (dotted lines) baseline change in global cerebral blood flow (gCBF), cerebral delivery of oxygen (CDO₂), arterial carbon dioxide (), cerebral oxygen (O₂) extraction and mean arterial blood pressure (MAP) following administration of indomethacin (NDO); study 2A. *Post-INDO significantly difference from pre-INDO (P < 0.001).