Hypocapnic cerebral hypoperfusion: A biomarker of orthostatic intolerance

Abstract

The objective of the study was to identify markers of hypocapnic cerebral hypoperfusion (HYCH) in patients with orthostatic intolerance (OI) without tachycardia and without orthostatic hypotension. This single center, retrospective study included OI patients referred for autonomic evaluation with the 10 min tilt test. Heart rate, end-tidal CO2 (ET-CO2), blood pressure, and cerebral blood flow velocity (CBFv) from middle cerebral artery were monitored. HYCH was defined by: (1) Symptoms of OI; (2) Orthostatic hypocapnia (low ET-CO2); (3) Abnormal decline in orthostatic CBFv due to hypocapnia; 4) Absence of tachycardia, orthostatic hypotension, or other causes of low CBFv or hypocapnia. Sixteen subjects met HYCH criteria (15/1 women/men, age 38.5±8.0 years) and were matched by age and gender to postural tachycardia patients (POTS, n = 16) and healthy controls (n = 16). During the tilt, CBFv decreased more in HYCH (-22.4±7.7%, p<0.0001) and POTS (-19.0±10.3%, p<0.0001) compared to controls (-3.0±5.0%). Orthostatic ET-CO2 was lower in HYCH (26.4±4.2 (mmHg), p<0.0001) and POTS (28.6±4.3, p<0.0001) compared to controls (36.9 ± 2.1 mmHg). Orthostatic heart rate was normal in HYCH (89.0±10.9 (BPM), p<0.08) and controls (80.8 ±11.2), but was higher in POTS (123.7±11.2, p<0.0001). Blood pressure was normal and similar in all groups. It is concluded that both HYCH and POTS patients have comparable decrease in CBFv which is due to vasoconstrictive effect of hypocapnia. Blood flow velocity monitoring can provide an objective biomarker for HYCH in OI patients without tachycardia.

Fig 1. Example of continuous raw data.

From top to bottom: electrocardiogram, beat-to-beat blood pressure, end tidal CO₂ and cerebral blood flow velocity.

Fig 2. Representative examples of control, HYCH and POTS.

Fig 3. Case of severe HYCH.

21 y/o woman presented with a sudden onset of shortness of breath, chest pain, fatigue and dizziness 2 years ago. Previously highly functioning women is on disability. Heart rate and blood pressure responses to tilt were normal (A). Patient was hypocapnic even at supine with end tidal CO₂ < 35 mmHg. End tidal CO₂ declined to 15 mmHg during the tilt which was associated with a drop of mean cerebral blood flow velocity (CBFv) about 50%. Just before the tilt the end tidal CO₂ increased to 35 mmHg that temporarily normalized CBFv demonstrating that the decline in CBFv was due to hypocapnia.

Fig 4. Superimposed end tidal CO₂ and mean cerebral blood flow velocity from the same patient as in Fig 3.

Fig 5. Comparison of HYCH, POTS and controls.

The hemodynamic variables were analyzed during supine position and at the minute 1, 5 and 10 of the tilt. Red circle shows significance difference compared to controls. A. CBFv = mean blood flow velocity, B. CBFv difference = percent difference in CBFv compared to supine baseline; C. ET = end tidal CO₂; D. HR = heart rate, E. CVR = cerebrovascular resistance, F. MBP = mean blood pressure;, G. RF = respiratory frequency.