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Loop gain response to increased cerebral blood flow at high altitude

  • Sleep Breathing Physiology and Disorders • Original Article
  • Published:
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Abstract

Purpose

To compare loop gain (LG) before and during pharmacological increases in cerebral blood flow (CBF) at high altitude (HA). Loop gain (LG) describes stability of a negative-feedback control system; defining the magnitude of response to a disturbance, such as hyperpnea to an apnea in periodic breathing (PB). “Controller-gain” sensitivity from afferent peripheral (PCR) and central-chemoreceptors (CCR) plays a key role in perpetuating PB. Changes in CBF may have a critical role via effects on central chemo-sensitivity during sleep.

Methods

Polysomnography (PSG) was performed on volunteers after administration of I.V. Acetazolamide (ACZ-10mg/kg) + Dobutamine (DOB-2–5 μg/kg/min) to increase CBF (via Duplex-ultrasound). Central sleep apnea (CSA) was measured from NREM sleep. The duty ratio (DR) was calculated as ventilatory duration (s) divided by cycle duration (s) (hyperpnea/hyperpnea + apnea), LG = 2π/(2πDR-sin2πDR).

Results

A total of 11 volunteers were studied. Compared to placebo-control, ACZ/DOB showed a significant increase in the DR (0.79 ± 0.21 vs 0.52 ± 0.03, P = 0.002) and reduction in LG (1.90 ± 0.23 vs 1.29 ± 0.35, P = 0.0004). ACZ/DOB increased cardiac output (CO) (8.19 ± 2.06 vs 6.58 ± 1.56L/min, P = 0.02) and CBF (718 ± 120 vs 526 ± 110ml/min, P < 0.001). There was no significant change in arterial blood gases, minute ventilation (VE), or hypoxic ventilatory response (HVR). However, there was a reduction of hypercapnic ventilatory response (HCVR) by 29% (5.9 ± 2.7 vs 4.2 ± 2.8 L/min, P = 0.1).

Conclusion

Pharmacological elevation in CBF significantly reduced LG and severity of CSA. We speculate the effect was on HCVR “controller gain,” rather than “plant gain,” because PaCO2 and VE were unchanged. An effect via reduced circulation time is unlikely, as the respiratory-cycle length did not change.

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Data availability

All data that support the findings of this study are available within the paper.

Abbreviations

ABG:

Arterial blood gas

ACZ:

Acetazolamide

AHI:

Apnea-hypopnea index

AMS:

Acute mountain sickness

BC:

British Columbia

BMI:

Body mass index

CA:

Carbonic anhydrase

CBF:

Cerebral blood flow

CBFv:

Cerebral blood flow velocity

CCR:

Central chemoreceptors

CO2:

Carbon dioxide

CO:

Cardiac output

CSA:

Central sleep apnea

CSF:

Cerebrospinal fluid

DOB:

Dobutamine

DR:

Duty ratio

EEG:

Electroencephalogram

EMG:

Electromyography

EOG:

Electrooculography

HA:

High altitude

HVR:

Hypoxic ventilatory response

HCVR:

Hypercapnic ventilatory response

HR:

Heart rate

I.V.:

Intravenous

LG:

Loop gain

PB:

Periodic breathing

PCR:

Peripheral chemoreceptors

PSG:

Polysomnography

VA:

Vertebral artery

VE:

Minute ventilation

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Acknowledgements

This study was carried out within the framework of the Ev-K2-CNR Project in collaboration with the Nepal Academy of Science and Technology as foreseen by the Memorandum of Understanding between Nepal and Italy. Thanks to contributions from the Italian National Research Council and the Italian Ministry of Foreign Affairs. We extend thanks to ADInstruments and Compumedics Ltd. for the use of their laboratory equipment.

Funding

The Peninsula Health Care p/l provided non-financial support on the form of equipment loan. NSERC provided financial support of in the form of a grant. CRC provided financial support in the form of funding for travel and consumables. Lottery Health NZ and the University of Otago provided financial support in the form of travel funding and salary (SJEL). The sponsors had no role in the design or conduct of the research.

Author information

Authors and Affiliations

  1. Canberra Sleep Clinic, Canberra, Australian Capital Territory, Australia

    Andrew Burgess

  2. Peninsula Sleep Clinic, Sydney, NSW, Australia

    Gareth Andrews, Katie M. E. Colby, Kate Sprecher & Keith R. Burgess

  3. University of Birmingham, Birmingham, UK

    Samuel J. E. Lucas

  4. University of Auckland, Auckland, New Zealand

    Joseph Donnelly

  5. University of British Columbia Okanagan, Kelowna, BC, Canada

    Philip N. Ainslie

  6. Banner University Medical Centre, Phoenix, AZ, USA

    Aparna S. Basnet

  7. Macquarie University, Sydney, NSW, Australia

    Keith R. Burgess

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  1. Andrew Burgess
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Correspondence to Keith R. Burgess.

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Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee (University of British Columbia Ethics Committee and the Nepal Health Medical Research Council) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in this study.

Disclosure of the presence or absence of financial support and off-label or investigational use

Intravenous acetazolamide use was off-label.

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The authors declare no competing interests.

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Summary at a glance

Intravenous administration of Acetazolamide and Dobutamine significantly reduced loop gain and the severity of central sleep apnea. The effect was most likely on the “controller gain.”.

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Burgess, A., Andrews, G., Colby, K.M.E. et al. Loop gain response to increased cerebral blood flow at high altitude. Sleep Breath (2023). https://doi.org/10.1007/s11325-023-02956-4

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