Carbon dioxide for neurogenic orthostatic hypotension in adults: a novel therapy

Neurogenic orthostatic hypotension (nOH) is a hallmark feature of autonomic nervous system failure.1 On standing, people with nOH experience large reductions in blood pressure (≥20/10 mmHg) and debilitating symptoms (e.g. light-headedness, blurred vision, and syncope).1 Current blood pressure therapies have limited efficacy and potentially serious side effects, including supine hypertension,2 creating a strong clinical need for new therapeutic approaches. Previous studies examining the effects of hypocapnia [i.e. low arterial carbon dioxide (CO2)] on blood pressure have shown that hyperventilation-induced hypocapnia decreases supine blood pressure in nOH patients and can be readily prevented with exogenous CO2.3,4 Whether exogenous CO2 can prevent OH in these patients is unknown. In this proof-of-concept study, we tested the hypothesis that increased inspired CO2 increases standing blood pressure in patients with nOH. We performed a randomized, unblinded study in male and female nOH patients.1 All participants provided written informed consent prior to participating. Respired end-tidal CO2 (ETCO2) and ETO2 were controlled using prospective gas targeting. Breath-by-breath ETO2, ETCO2, and ventilation were measured. Participants were instrumented with a non-invasive beat-to-beat finger blood pressure cuff (Finapres Nova, FMS, the Netherlands), and a three-lead electrocardiogram. Beat-to-beat blood pressure was analysed using Modelflow Waveform Analysis to obtain estimates of stroke volume, cardiac output, and systemic vascular resistance. Participants completed three sit-to-stand tests breathing: (i) 0 mmHg CO2 relative to baseline (0CO2: ETCO2 clamped at baseline), (ii) +5 mmHg CO2 relative to baseline (+5CO2), and (iii) +10 mmHg CO2 relative to baseline (+10CO2). Interventions were randomized using a computer-generated randomizer. Each condition consisted of a minimum 5-min seated baseline followed by a 5-min stand (as tolerated). Stands were separated by a seated 10-min rest to allow cardiorespiratory parameters to normalize. Data were acquired at a sampling frequency of 1000 Hz (WinDaq, DATAQ Corp) for off-line analysis (LabChart Pro 8, ADInstruments, New Zealand). Average baseline cardiorespiratory data were calculated over the final 2 min of seated baseline preceding each stand. Standing cardiorespiratory data were averaged across each minute. Delta (Δ) values were calculated as the average final minute of stand-average baseline. Data are presented as mean ± standard deviation unless indicated otherwise. A Shapiro–Wilk test was used to determine normality. The primary endpoint was the elevation in systolic blood pressure (SBP) in response to CO2 (0CO2 vs. +10CO2). Using a paired t-test and our own preliminary data, we estimated 15 patients would have 80% power to detect a difference with an α = 0.05. Secondary analyses compared cardiorespiratory changes across CO2 condition using repeated measures analysis of variance with Bonferroni corrections for multiple comparisons or a mixed-effects model if values were missing. Two-factor mixed-effects models with Bonferroni corrections were used to evaluate interactions between CO2 and time. A proportion of patients meeting OH criteria between 0CO2 and +10CO2 were compared using a paired McNemar test. Statistical significance was set at P < .05. Statistical analyses were performed using GraphPad Prism (v.9.4.1, GraphPad, USA). Figures were created using GraphPad Prism, and Adobe Illustrator (Adobe Systems Inc., USA). Seventeen patients participated in this study (Figure 1A). Compared with 0CO2, +10CO2 increased SBP (0CO2: −44 ± 25 mmHg; +10CO2: −4 ± 30 mmHg; P < .001). Systolic blood pressure also showed a robust dose-dependent increase across each CO2 condition (0CO2: 100 ± 23 mmHg; +5CO2: 123 ± 21 mmHg; +10CO2: 135 ± 29 mmHg; P < .001) and as a function of time (Figure 1B and C). Changes in SBP were predominantly facilitated by dose-dependent increases in stroke volume and cardiac output (Figure 1B). In contrast, neither the change in heart rate (0CO2: 10 ± 5 b.p.m.; +5CO2: 11 ± 5 b.p.m.; +10CO2: 13 ± 7 b.p.m.; P = .16) nor systemic vascular resistance (0CO2: −703 ± 639 dynes/s/cm5; +5CO2: −602 ± 604 dynes/s/cm5; +10CO2: −567 ± 551 dynes/s/cm5; P = .61) were different across conditions. Cardiorespiratory changes associated with increased inspired CO2 in patients with neurogenic orthostatic hypotension. (A) In 17 patients with neurogenic orthostatic hypotension, (B) systolic blood pressure (P < .001), stroke volume (P < .001), and cardiac output (P > .001) each showed a robust dose-dependent increase across each CO2 condition. (C) CO2 increased systolic blood pressure as a function of time (P < .001) and reduced the duration of orthostatic hypotension (P < .001). A mixed-effects model with a Bonferroni correction for multiple comparisons was used to compare the changes in cardiorespiratory parameters and to compare duration of OH between CO2 conditions. A two-factor mixed-effects model with Bonferroni corrections were used to evaluate CO2 condition and time interactions. Circles = 0 CO2, Triangles = +5 CO2, and Diamonds = +10 CO2. Purple shading represents threshold for orthostatic hypotension (systolic drop ≥ 20 mmHg). Data for minute-by-minute changes are presented as mean ± SEM. BMI, body mass index; CO, cardiac output; CO2, carbon dioxide; OH, orthostatic hypotension; SBP, systolic blood pressure; SV, stroke volume At 0CO2, 12/17 (71%) patients met the SBP criteria for OH.1 During +5CO2, 8/17 (47%) patients met OH criteria, while only 4/16 (25%) met OH criteria during +10CO2. Further, +10CO2 reduced the proportion of patients meeting OH criteria compared with 0CO2 (P = .02). Importantly, increased inspired CO2 reduced the duration of OH while patients were standing (Figure 1C). Here, we show for the first time that increased inspired CO2 powerfully elevates standing blood pressure in patients with nOH and reduces the duration of OH. Rather than through changes in heart rate or systematic vascular resistance, this response was primarily driven by an increase in stroke volume and cardiac output. This haemodynamic profile strongly suggests that inspired CO2 increases blood pressure via enhanced cardiac venous return. While the precise mechanisms remain unknown, residual sympathetic nerve activity, which has been postulated in the pathogenesis of supine hypertension in nOH patients;5 a direct constrictor effect of CO2 on blood vessels;3,4 and increased ventilation/ventilatory effort to produce a negative inspiratory pressure6 are all potential mechanisms underlying the observed pressor response. As OH is associated with an increased risk of injurious falls and OH-related hospitalizations,7–10 identifying an effective pressor therapy could have a broader clinical benefits beyond mere blood pressure elevation including reduced fall risk, OH-related hospitalizations, and associated healthcare costs. Other acute benefits could include improved orthostatic tolerance and enhanced ability to perform daily activities. Despite these findings, the following limitations warrant consideration, including the use of a sit-to-stand manoeuvre, which may elicit smaller haemodynamic changes compared with a standard head-up tilt or supine-to-stand test; the short exposure to CO2, which precludes us from understanding the long-term implications of this intervention; the relatively smaller sample size; and the absence of detailed mechanistic insights into CO2-mediated pressor effects. Lastly, we evaluated patients with neurogenic OH and, therefore, cannot comment on the efficacy of CO2 in other forms of OH. However, the observed dose–response suggests that, with appropriate titration, CO2 therapy could potentially benefit patients with mild, moderate, or severe OH. Addressing these limitations in future research could provide a more comprehensive understanding of the therapeutic potential of CO2 in nOH management. Increased inspired CO2 elevates standing blood pressure in patients with nOH and reduces the duration of OH. These findings support further exploration of CO2 delivery interventions as an acute blood pressure therapy in nOH, potentially improving orthostatic tolerance and preventing syncope, traumatic falls, and, in turn, OH-related hospitalizations. The authors would like to acknowledge the patients who took the time to participate in this study. S.R.R.: consultant for Theravance Biopharma and Amneal Pharma related to neurogenic orthostatic hypotension and consultant to Servier Affaires Medicales, Regeneron, argenx BV, and Antag Pharma related to postural orthostatic tachycardia syndrome. A.A.P.: consultant and shareholder in ONWARD Medical. The remaining authors have nothing to disclose. S.R.R. takes responsibility for the integrity of the data and the accuracy of the data analysis. Please contact the corresponding author to discuss access to the data used in these analyses. This work was supported by a University of Calgary Seed Funding (S.R.R.). J.R.B. is supported by a Canadian Institutes of Health Research (CIHR) Fellowship, a Libin Cardiovascular Institute Post-Doctoral Fellowship in Women’s Cardiovascular Health, the Natural Sciences and Engineering Research Council of Canada (NSERC) Brain CREATE Program, and a Canadian Cardiovascular Society Fellowship. S.I.R. is supported by the NSERC Brain CREATE Program, an Alberta Graduate Excellence Scholarship, and an Alberta Strategy for Patient-Oriented SUPPORT Unit scholarship. A.V.I. is supported by a CIHR Fellowship and an Achievers in Medical Science Postdoctoral Fellowship. R.J.A.W. supported this work through a CIHR Project Grant. A.A.P. supported this work through a Canadian Foundation for Innovation (CFI) John R. Evans Leaders Fund, NSERC Discovery Grant, and a CIHR Project Grant. Ethical approval for this study was obtained from the Conjoint Health Research Ethics Board (REB20-1322) at the University of Calgary, Calgary, AB, Canada. NCT05295810.

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