Sleep is a vulnerable period during which blunted respiratory drive and low airway muscle
tone can cause dangerous breathing disorders. Obstructive sleep apnea (OSA) describes the
intermittent collapse of the upper airway that induces O2 desaturations and arousals from
sleep, placing patients at risk for cardiovascular disease, stroke, and death. In some
obese patients, sleep causes carbon dioxide (CO2) accumulation progressing to daytime
hypercapnia, a condition called obesity hypoventilation syndrome (OHS). Continuous
positive airway pressure (CPAP) treats OSA and OHS, but is poorly tolerated, and may not
fully correct sleep dysfunction.
Changes in metabolism may help to control OSA or OHS. The investigators recently
published results from the Ketogenic Diet for OHS clinical trial (KETOHS, NCT04108819)
showing that a 2-week ketogenic diet (high fat, low carbohydrate) for patients with OSA
and OHS lowered reduced CO2, serum bicarbonate (HCO3), respiratory quotient, nocturnal
hypoxemia(2). KD also significantly improved OSA. After participants resumed their prior
diet, CO2 returned to baseline. The mechanisms by which KD improves sleep in this
population could be related to reduced CO2 production (through fat oxidation), lowering
of body weight, or direct effects of ketone bodies on sleep and breathing.
It is difficult to adhere long-term to KD, and there are multiple effects of this diet
that make it challenging to understand mechanistic impacts on respiration. The
investigators hypothesize that increasing ketone levels in the body, without having to
adhere to a ketogenic diet, may be another method to improve breathing during sleep.
Indeed, some drugs affecting acid-base status (e.g. acetazolamide or sulthiame) improve
OSA, presumably through increasing and stabilizing respiratory drive. In this pilot
study, the investigators will examine the pharmacokinetics, tolerability, and impacts of
ingesting exogenous ketones (which are commercially available products) on sleep and
breathing.
The specific ketone product to be tested for its impact on sleep and breathing is 1,3
butanediol (1,3BD) in a commercially available formulation called "Ketone IQ". 1,3BD is
generally recognized as safe (GRAS approved) by the FDA. 1,3BD is converted by liver
metabolism into the ketone body beta-hydroxybutyrate (BHB) and has been utilized in
multiple studies.
This project will be conducted in two studies, KETO-SLEEP 1 (KS1), and KETO-SLEEP 2
(KS2).
KETO-SLEEP 1: Examine the pharmacokinetics, tolerability, and sleep impacts of ingesting
exogenous ketones (EK) before sleep (n=20, 10 men, 10 women). KS1 will lay the foundation
for KS2 and other studies that administer exogenous ketones at bedtime, through
dose-finding and assessment of tolerability. Patients with moderate-severe OSA
(apnea-hypopnea index (AHI) >15)) adherent to CPAP will ingest EK or placebo 30 minutes
before sleep. They will measure capillary BHB levels before ingestion and at 1, 3, 5,
hours post-ingestion as well as upon awakening. CPAP use will be maintained on all nights
and sleep architecture will be monitored with portable EEG. Questionnaires will solicit
feedback about EK palatability, GI side effects, and sleep quality. Two doses (20 g and
40 g) of Ketone-IQ will be tested each for two nights, with one night used to measure BHB
levels and separate night to allow for uninterrupted sleep.
[KETO-SLEEP 2: Examine the preliminary efficacy of ingesting exogenous ketones before
sleep on OSA (n=20, 10 men, 10 women). KS2 will examine the respiratory effects of
exogenous ketones taken before sleep. Patients with known OSA will be asked to
temporarily discontinue CPAP, a technique used in our laboratory to temporarily elicit
OSA(10). To account for night-to-night variability in OSA severity the investigators will
use portable sleep monitoring to collect sleep and respiratory data two nights under each
condition. The dose of Ketone-IQ to be administered each night will vary from 20 to 40 g,
depending upon results of KS-1.