Phenylephrine alters phase synchronization between cerebral blood velocity and blood pressure in ME/CFS with orthostatic intolerance

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with orthostatic intolerance (OI) is characterized by neurocognitive deficits perhaps related to upright hypocapnia and loss of cerebral autoregulation (CA). We performed N-back neurocognition testing and calculated the phase synchronization index (PhSI) between arterial pressure (AP) and cerebral blood velocity (CB_V) as a time-dependent measurement of cerebral autoregulation in 11 control (mean age = 24.1 yr) and 15 patients with ME/CFS (mean age = 21.8 yr). All patients with ME/CFS had postural tachycardia syndrome (POTS). A 10-min 60° head-up tilt (HUT) significantly increased heart rate (109.4 ± 3.9 vs. 77.2 ± 1.6 beats/min, P < 0.05) and respiratory rate (20.9 ± 1.7 vs. 14.2 ± 1.2 breaths/min, P < 0.05) and decreased end-tidal CO₂ (ETCO₂; 33.9 ± 1.1 vs. 42.8 ± 1.2 Torr, P < 0.05) in ME/CFS versus control. In ME/CFS, HUT significantly decreased CB_V compared with control (-22.5% vs. -8.7%, P < 0.005). To mitigate the orthostatic CB_V reduction, we administered supplemental CO₂, phenylephrine, and acetazolamide and performed N-back testing supine and during HUT. Only phenylephrine corrected the orthostatic decrease in neurocognition by reverting % correct n = 4 N-back during HUT in ME/CFS similar to control (ME/CFS = 38.5 ± 5.5 vs. ME/CFS + PE= 65.6 ± 5.7 vs. Control 56.9 ± 7.5). HUT in ME/CFS resulted in increased PhSI values indicating decreased CA. Although CO₂ and acetazolamide had no effect on PhSI in ME/CFS, phenylephrine caused a significant reduction in PhSI (ME/CFS = 0.80 ± 0.03 vs. ME/CFS + PE= 0.69 ± 0.04, P < 0.05) and improved cerebral autoregulation. Thus, PE improved neurocognitive function in patients with ME/CFS, perhaps related to improved neurovascular coupling, cerebral autoregulation, and maintenance of CB_V.NEW & NOTEWORTHY We evaluated cognitive function before and after CO₂, acetazolamide, and phenylephrine, which mitigate orthostatic reductions in cerebral blood velocity. Neither CO₂ nor acetazolamide affected N-back testing (% correct answers) during an orthostatic challenge. Only phenylephrine improved upright N-back performance in ME/CFS, as it both blocked hyperventilation and increased CO₂ significantly compared with those untreated. And only phenylephrine resulted in improved PSI values in both ME/CFS and control while upright, suggesting improved cerebral autoregulation.

Keywords: N-back testing; myalgic encephalomyelitis/chronic fatigue syndrome; phase synchronization; phenylephrine.

Graphical abstract

Figure 1.

Comparison of baseline-supine (left bars), baseline-supine treatment (middle bars), and 60° head-up tilt (HUT, right bars) cerebral blood velocity in control and ME/CFS subjects comparing no Treatment with acetazolamide, CO₂, and phenylephrine. Data are shown as means ± SE. *Significantly different comparing Baseline-Supine with HUT (P < 0.05); ‡significantly different comparing control with ME/CFS (P < 0.05). ME/CFS, myalgic encephalomyelitis/chronic fatigue syndrome.

Figure 2.

Neurocognitive function evaluated by N-back testing comparing %correct measured in control and ME/CFS subjects SUPINE (top) and during 60° head-up tilt (HUT, bottom). *Significantly different, comparing responses measured in ME/CFS supine with those during HUT (P < 0.05) at N-back 3 and 4. ME/CFS, myalgic encephalomyelitis/chronic fatigue syndrome.

Figure 3.

Effect of acetazolamide, CO₂ compared with no treatment in ME/CFS subjects (top) and phenylephrine (bottom) on neurocognitive function evaluated by N-back testing comparing %correct measured during 60° head-up tilt (HUT). Results of similar testing in control subjects are shown in bottom for comparison. *Significantly different, comparing responses measured in ME/CFS plus phenylephrine at N-back 3 and 4 with ME/CFS untreated (P < 0.05). ME/CFS, myalgic encephalomyelitis/chronic fatigue syndrome.

Figure 4.

Phase synchronization index during performance of neurocognitive testing (N=Back) comparing results measured SUPINE (top) and during 60° head-up tilt (HUT, bottom) in untreated Control and ME/CFS subjects. *Significantly different, comparing responses measured in Control and ME/CFS during HUT (P < 0.05) at N-back 4. ME/CFS, myalgic encephalomyelitis/chronic fatigue syndrome.

Figure 5.

Phase synchronization index during performance of neurocognitive testing (N-back) comparing results measured during 60° head-up tilt (HUT, bottom) in control (top) and ME/CFS subjects (bottom) comparing no treatment (No Tx) to that measured following acetazolamide and CO₂ (left) and with phenylephrine (right). *Significantly different comparing responses measured in with and without phenylephrine in control at N-back 0 and 1 and in ME/CFS at N-back 0–4. (P < 0.05) at N-back 4. ME/CFS, myalgic encephalomyelitis/chronic fatigue syndrome.