Sedation with Dexmedetomidine or Propofol Impairs Hypoxic Control of Breathing in Healthy Male Volunteers: A Nonblinded, Randomized Crossover Study

RESPIRATORY depression is a common side effect of many general anesthetics. Propofol, being widely used for both sedation and anesthesia, impairs central and peripheral regulation of breathing and may in addition cause apnea during induction of anesthesia.^1–3  In contrast, the α₂-adrenoceptor agonist dexmedetomidine has been put forward as a novel anesthetic or sedative with minimal effect on respiration, thus serving as an attractive drug for sedation and anesthesia.⁴ 

Regulation of breathing is, in part, controlled by chemoreflexes: carbon dioxide dependent for the central chemoreceptors in the brain stem and oxygen dependent for peripheral receptors in the carotid body (CB).⁵  It is well recognized that many anesthetic drugs obtund these important reflexes in the postoperative setting; inhaled anesthetics and the intravenous anesthetic propofol obtund both reflexes, whereas opioids mainly depress central regulation of breathing.^1–3,6  In experimental volunteer studies, also α₂-adrenoceptor agonists such as dexmedetomidine have reduced hypercapnic ventilation.^7–9  Moreover, clonidine, another α₂-adrenoceptor agonist, when administered orally to healthy subjects reduces the hypoxic ventilatory response,¹⁰  indicating that α₂-adrenoceptor agonists potentially reduce not only hypercapnic ventilation but also hypoxic ventilation. However, there are conflicting findings from animal studies regarding the effects of α₂-adrenoceptor agonists on CB chemosensitivity to hypoxia.^11–14  There is a lack of information on the possible effect of dexmedetomidine on hypoxic ventilation in humans and hence a gap of knowledge as to whether sedation with dexmedetomidine interacts with human regulation of breathing during hypoxia.

The primary aim of this study was to investigate whether dexmedetomidine-induced sedation reduces hypoxic ventilation and to compare that to sedation with propofol. The secondary aims were to investigate and compare the effects of sedation with dexmedetomidine or propofol on the hypercapnic ventilation and analyze the effects of the drugs on the regulation of breathing with regard to depth of sedation as assessed with different sedation scales, Bispectral Index Score (BIS), and plasma concentrations of both study drugs.

This study conforms to the standard of the Declaration of Helsinki and was approved by the Regional Ethics Committee on Human Research at the Karolinska Institutet, Stockholm, Sweden, and the Swedish Medical Products Agency, Uppsala, Sweden. The trial was conducted according to Good Clinical Practice and the CONSORT guidelines (appendix 1). The study was registered at the European Clinical Trials Database, EudraCT 2012-005812-24 on January 23, 2013, and at ClinicalTrials.gov on May 29, 2013 (NCT01873612, principal investigator Dr. Jonsson Fagerlund).

The ventilatory tests and analysis of propofol concentrations were made at the Clinical Research Unit, Department of Anesthesia, Surgical Services and Intensive Care, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden. Analysis of dexmedetomidine was performed at the University of Turku, Turku, Finland.

Eleven healthy male volunteers (age, 18 to 40 yr) entered this nonblinded, randomized crossover study after oral and written consent. None of them used nicotine, and all had normal body weight. Exclusion criteria were use of any drugs, allergy to the study drugs, body mass index of more than 26 kg/m², or a history of snoring or obstructive sleep apnea. The study period was from June 2013 to February 2014.

The volunteers were randomized to start with dexmedetomidine or propofol in a crossover design, with each volunteer acting as his own control with a minimum interval of 2 days between treatments. Randomization was done in a first block of 10 volunteers followed by a second block of five volunteers on a Web site.¹⁵  All experiments were performed in the morning.

The subjects were placed supine in a bed with a 30° head-up tilt and with subdued lighting in the room. They were told to rest aiming to stay awake during control and recovery sessions of the protocol, i.e., they were allowed to sleep during sedation. We verbally assessed the level of sedation at regular intervals in-between tests, and a continuous BIS monitor was used.

Sedation was induced by a bolus infusion for 10 min of either dexmedetomidine (Dexdor^®; Orion Pharma, Finland) up to 1.1 μg/kg or propofol (Propofol-Lipuro^®; B. Braun Melsungen AG, Germany) up to 750 μg/kg, followed by continuous infusion of dexmedetomidine 0 to 1 μg kg⁻¹ h⁻¹ or propofol 0 to 75 μg kg⁻¹ min⁻¹, adjusted to target a value of 2 to 4 on the five-point composite Observer’s Assessment of Alertness/Sedation (OAA/S) scale with scores 1 for deep sedation, 2 to 4 for light to moderate sedation, and 5 for the alert state. Sedation was assessed with responsiveness to speech, and if no response was evoked by a loud call, by tactile stimulation.¹⁶  The infusions were administered using a standard syringe pump (Alaris TIVA; CareFusion Corporation, USA). In addition to OAA/S, the level of sedation was assessed with the Richmond Agitation Sedation Scale (RASS)¹⁷  every 3 min, or more often if a fluctuation in the level of sedation was observed. Continuous recording of BIS (BIS Vista Monitor; Covidien LLC, USA) was also performed as an objective measure of sedation. Adjustments of the infusion rate were made continuously according to the sedation-level scores. Directly after each of the three hypoxic challenges, blood samples were collected for measurement of plasma concentrations of dexmedetomidine or propofol.

Cardiorespiratory parameters (heart rate, noninvasive blood pressure, oxygen saturation measured by pulse oximetry [Spo₂], end-tidal carbon dioxide [ETco₂], fractional inspired oxygen tension [Fio₂], inspired carbon dioxide fraction, end-tidal oxygen [ETo₂], airway pressure, and airway flow) were monitored and recorded continuously (Datex-Ohmeda AS/3 and S/5 Collect; GE Medical Systems, USA). End-tidal pressure of carbon dioxide (Petco₂) was calculated based on ETco₂ in relation to daily atmospheric pressure. Respiratory movements were monitored by application of thoracic and abdominal impedance bands (Bio-Radio; Great Lakes NeuroTechnologies, USA).

Volunteers were allowed solid food until 6 h and liquids until 2 h before infusion start, but refrained from alcohol and caffeine for at least 24 h before start of study procedures. The volunteers were placed supine with a 30° elevated head. Intravenous cannulae were placed in cubital veins of both arms. A continuous infusion of buffered 2.5% glucose solution (B. Braun Melsungen AG) was administered via one cannula together with the intravenous sedative agent. The intravenous cannula in the contralateral arm was used for blood sampling.

The protocol included three sets of breathing tests: resting ventilation during normoxia (i.e., control), hypoxic ventilation—resting ventilation during normocapnia (i.e., control), and hypercapnic ventilation. These breathing tests were repeated at baseline, during sedation with dexmedetomidine or propofol at OAA/S 2 to 4, and finally after recovery at OAA/S 5 (fig. 1). Venous blood sampling for monitoring of drug concentrations in plasma was done immediately after each period of hypoxic ventilation, i.e., after switching to room air Fio₂, 0.21). Sedation was induced after the first breathing test sequence. After reaching steady state at a sedation level of OAA/S 2 to 4, the respiratory pattern was observed for a period of 15 min with special focus on central apnea and upper airway obstruction (UAO). Central apnea was defined as cessation of airflow for 10 s with no thoracic or abdominal respiratory movement. UAO was observed as snoring and a decrease in airflow with preserved respiratory effort measured by thoracic or abdominal impedance. After this period of observation of the respiratory pattern, the protocol was continued with the breathing tests during sedation and after recovery (fig. 1).

Discontinuation criteria during conductance of the protocol were respiratory or circulatory adverse effects that could not easily be corrected, for instance, by reducing the dose rate of the drug. These included bradycardia of less than 35 beats/min, mean arterial blood pressure of less than 50 mmHg, persistent UAO, or apnea.

Five milliliters of blood was drawn from the cubital vein of the arm contralateral to the one where drug infusion was given. The blood was drawn into EDTA-containing tubes that were chilled in wet ice and directly centrifuged at +4°C for 10 min at 1,500g. The plasma was immediately transferred to precooled polypropylene tubes and frozen at −20°C or colder.

Concentrations of dexmedetomidine in plasma were determined with reversed-phase high-performance liquid chromatography with tandem mass spectrometric detection (PE Sciex API4000; PE Sciex, USA) with deuterium-labeled medetomidine as the internal standard, as previously described.¹⁸  The lower limit of reliable quantitation was 0.02 ng/ml, and within- and between-run coefficients of variation were less than 10% at 0.02 ng/ml and less than or equal to 4% at higher concentrations.

Concentrations of propofol in plasma were determined according to Court et al.¹⁹  Briefly, the supernatant of the acetonitrile-treated and centrifuged plasma samples containing thymol as internal standard was subjected to high-performance liquid chromatography analysis using a Lichrospher^® (Merck, Germany) 100, 250 × 4 mm, RP-18.5-μm column. Excitation and emission wavelengths used for fluorescence detection were 270 and 310 nm, respectively. The amounts of propofol were determined using standard curves with a lower detection limit of 10 ng/ml.

A transparent tight-fitting face mask with a dead space of 160 to 200 ml, depending on the size of the face, was connected to a breathing circuit (Engström 2024, Sweden) with a one-way valve, not allowing for rebreathing. A fresh gas flow of 15 l/min was maintained. Airway flow and airway pressure were measured with a spirometer, and inspiratory tidal volumes were automatically calculated and recorded (D-lite, Datex-Ohmeda AS/3, and S/5 Collect; GE Medical Systems). The breathing system was calibrated before each experiment with 500- and 1,000-ml calibration syringes.

While breathing room air via the face mask, all volunteers rested for a minimum of 10 min to allow for adjusting to the equipment. This was followed by measurements of resting ventilation, Spo₂, and ETco₂.

The primary outcome measure in this study was the ventilatory response to hypoxia measured as increase in minute ventilation. Before testing the hypoxic ventilation, 0.2% CO₂ was added to inspired air at rest (approximately 0.2%) to ensure an adequate increase of 1 to 2 l/min and reproducible baseline minute ventilation. The same level of ETco₂ was then maintained during the entire hypoxic test by adding carbon dioxide to inspired air with a micro flowmeter in order to maintain isocapnia during hypoxic ventilation. Isocapnic hypoxic ventilation was induced by abruptly reducing the inspiratory Fio₂ to 0.08 to 0.12 in one step targeting an Spo₂ of 80% while keeping ETco₂ constant (fig. 1). An Spo₂ of 80% was reached after approximately 4 min in this system. The peak hypoxic ventilation was then averaged for 3 min after 3 min of hypoxia, i.e., 7 to 10 min after initiation of the hypoxic test (fig. 1). After the hypoxic test, the volunteers had a 14-min period of rest in order to resume resting ventilation.

The hypercapnic ventilation was assessed by a step addition of 5% CO₂ to inspired air (Fio₂, 0.21). The hypercapnic ventilation was presented as the increase in minute volume based on the control value at normocapnic ventilation and a mean of the last 3 min of the 8-min period of hypercapnia and was obtained under non–steady-state conditions.

Before study initiation, a power analysis of the two-treatment crossover study was designed to have a two-tailed alpha error of 0.05 and a beta error of 0.2 (power 80%) if the true difference between treatments was at least 0.15 units (increase in minute ventilation during hypoxic ventilation). Assuming that the SD of the difference in the treatment effects was 0.15 (d = 1), a sample size of 10 was suggested. Based on that, we arrived at a sample size of 15 volunteers to fulfill the protocol in order to compensate for possible dropouts. Since the effect of dexmedetomidine on hypoxic ventilation was unknown, before study initiation, we decided on an interim analysis after 10 volunteers completed study protocol in order to recalculate the power analysis based on actual values and SDs. Also, we included criteria for termination of the study if significant differences for the primary aims were to be found after that analysis. After 10 volunteers completed study protocol, we found a statistically significant reduction in hypoxic and hypercapnic ventilation for both drugs. Based on that, the study was terminated as specified in the original protocol. No P value adjustments were made for this interim analysis, but exact P values are reported to allow readers to adjust the inferences as they see fit.

Cardiorespiratory data from each experimental period were averaged over the last 3 min, i.e., during steady state. Most of the electronically charted monitoring data are continuous data (i.e., respiratory rate, tidal volume, Fio₂, inspired carbon dioxide fraction, ETo₂, Petco₂, Spo₂, heart rate, blood pressure, and BIS). These results are presented as mean ± SD, and preplanned comparisons were analyzed using planned comparison: baseline dexmedetomidine versus sedation dexmedetomidine, baseline propofol versus sedation propofol, and sedation dexmedetomidine versus sedation propofol for change in minute ventilation during hypoxic or hypercapnic challenges. Other relevant data were explored using two-way repeated-measures ANOVA with two within factors: TIME and TREATMENT. TIME was defined as “baseline before sedation,” “during sedation,” and “recovery from sedation” and TREATMENT being the two study drugs: dexmedetomidine and propofol. If significant differences were revealed by ANOVA, pairwise comparisons were made. Before the analysis, sphericity was checked with Mauchly sphericity test using Statistica 13 (StatSoft, Sweden). When only two parameters were compared between drug challenges (i.e., fluid volume and drug infusion times), unpaired or paired Student’s t tests were used as appropriate. Categorical data (i.e., OAA/S and RASS) are presented as medians and ranges, and differences were analyzed using Mann–Whitney U test. Correlations were explored using Spearman regression analysis. Statistical analysis and graphs were made using Prism 6.0 (GraphPad; Software Inc., USA) or Statistica 13 (StatSoft). P value of less than 0.05 was considered statistically significant.

Ten out of 11 volunteers completed the study protocol (appendix 2). One volunteer chose not to participate on the second occasion and was therefore excluded from the analysis. The mean age of the 10 volunteers included was 28 ± 6 yr, and their body mass index was 23.5 ± 2.5 kg/m². They were examined on two separate days with an average of 50 (15 to 92) days between the two occasions. Although all 10 volunteers completed the periods of hypoxic ventilation, one volunteer was excluded from the analysis of hypoxic ventilation due to repetitive UAO and irregular breathing during the dexmedetomidine infusion. Therefore, in the hypoxic ventilation data presented, the number of subjects is nine, and for all other data, the number of subjects is 10. The data presented are free from interference by UAO or apneas unless otherwise stated.

In order to obtain an OAA/S scale levels of 2 to 4, dexmedetomidine was given as a mean bolus dose of 0.59 ± 0.25 μg/kg during 10 min followed by an infusion of 0.53 ± 0.21 μg kg⁻¹ h⁻¹ during 75 ± 13 min. Propofol was given as a bolus of 74.5 ± 1.6 μg kg⁻¹ min⁻¹ for 10 min followed by an infusion of 48.6 ± 10.0 μg kg⁻¹ min⁻¹ for a total time of 75 ± 10 min. Stable sedation at OAA/S 2 to 4 was reached after 24 ± 7 min for both drugs (P = 0.83). BIS was 82 ± 8 and 75 ± 3 for dexmedetomidine and propofol, respectively (fig. 2A). The volunteers were awake during the initial baseline period and thereafter sedated to OAA/S 3 (fig. 2A; table 1). The plasma concentrations of dexmedetomidine and propofol and OAA/S, RASS, and BIS values are presented in table 1 and figure 2, A and B.

The time to recovery from sedation at OAA/S 2 to 4 to recovery at OAA/S 5 was longer for dexmedetomidine than for propofol, 40 ± 11 and 26 ± 2 min (P = 0.005), respectively.

Although the levels of sedation were the same for propofol and dexmedetomidine, sedation with dexmedetomidine was perceived by the subjects as more profound than sedation with propofol.

During sedation with dexmedetomidine, heart rate was reduced compared with baseline. In contrast, heart rate increased during sedation with propofol (fig. 2C). During both drug infusions, heart rate was increased in response to hypoxia and hypercapnia (fig. 2C).

Blood pressure was reduced during sedation with both drugs, with a tendency toward a larger reduction for dexmedetomidine (fig. 2C). After recovery (OAA/S 5), the propofol-induced reduction of blood pressure was reversed, whereas the reduction in blood pressure by dexmedetomidine persisted. Because of this, the volunteers received more fluids during the dexmedetomidine experiment, i.e., 735 ± 186 ml compared with 492 ± 237 ml during the propofol session (P = 0.02, unpaired Student’s t test).

Basal ventilation was stable throughout the study period (tables 2 and 3). In order to describe basal ventilation in more detail, we extracted values for resting ventilation before each test of hypercapnic ventilation (i.e., during baseline, sedation, and at recovery), since Petco₂ was kept constant during resting ventilation before each hypoxic challenge (table 4). Sedation with dexmedetomidine or propofol did not change basal minute ventilation or respiratory rate (table 4). The reduction in tidal volume during sedation with dexmedetomidine or propofol did not reach statistical significance (table 4). Resting Spo₂ was reduced to the same extent by sedation with dexmedetomidine and propofol (table 4).

Typical changes in ventilation and gases during the 10-min isocapnic hypoxic ventilation in one subject before dexmedetomidine-induced sedation are presented in figure 3. An Spo₂ of 80% was reached after approximately 4 min in this system, while maintaining isocapnic conditions. Note that breath-by-breath changes of the tidal volume and respiratory rate progressively increased during the initial decrease of Spo₂ but remained relatively constant during the last 3 min. An example of a breath-by-breath plots of the Spo₂versus minute ventilation before, during, and after dexmedetomidine and propofol-induced sedation in the same subject is displayed in figure 4.

Figures 5 and 6 summarize results of effect of sedation with dexmedetomidine or propofol on hypoxia-induced increase in minute ventilation in all nine subjects, demonstrating that dexmedetomidine- and propofol-induced sedation reduced hypoxic ventilation to a similar extent. The hypoxia-induced increase in minute ventilation was reduced to 59 and 53% of baseline for dexmedetomidine and propofol, respectively (P = 0.11; fig. 6; table 2). After recovery from sedation, hypoxic ventilation returned to 97 and 94% of baseline for dexmedetomidine and propofol, respectively (fig. 6). Data on hypoxic ventilation at baseline, during sedation with dexmedetomidine or propofol, and after recovery are summarized in figure 6 and table 2. Petco₂ was kept constant throughout the periods of hypoxic ventilation (table 2). Spo₂ was reduced similarly during hypoxic ventilation carried out before, during, and after the drug infusions, by 15 to 18%, with no differences between the sessions (table 2; fig. 5A).

A typical time course of the hypercapnic challenge in 1 individual is displayed in figure 7. Summarized data for the hypercapnic ventilation at baseline, during sedation with dexmedetomidine or propofol, and after recovery are presented in table 2. Addition of 5% CO₂ increased the minute ventilation at baseline, whereas the response was reduced during sedation with dexmedetomidine or propofol and normalized after recovery from sedation (table 3). As demonstrated in table 3, sedation with dexmedetomidine and propofol reduced the increase in minute ventilation by 18 and 14%, respectively, compared to baseline. The responses were normalized after recovery from sedation (table 3).

Sedation with both study drugs impaired upper airway patency during resting ventilation. During sedation with dexmedetomidine, we observed repetitive episodes of snoring and UAO in 9 of the 10 subjects, measured as decreased air flow with preserved respiratory efforts (fig. 8). Signs of airway obstruction typically started 15 to 20 min after infusion start and lasted in four of the subjects for less than 12 min, and thereafter resolved while the level of sedation was kept constant. In five of the subjects, signs of intermittent airway obstruction were seen for 15 to 52 min along with frequent or periodically continuous snoring. During propofol sedation, 4 of the 10 volunteers had signs of UAO and snoring at resting ventilation during a maximum of 12 min except for one individual with partial obstruction that lasted 30 min.

Interestingly, 2 of the 10 volunteers displayed clinically significant central apnea episodes during both dexmedetomidine and propofol sedation, with apnea durations of 10 to 30 s, starting within 8 to 10 min after the initiation of sedation and lasting for a period of 5 to 10 min (fig. 8). All episodes of airway obstruction and apnea resolved to verbal or physical stimulation. Two subjects responded with both airway obstruction and central apnea during both drug infusions.

The current randomized crossover trial in healthy male volunteers demonstrates that sedation with dexmedetomidine reduces hypoxic ventilation by half and to a similar extent as propofol sedation. In addition, we confirm previous observations that sedation with dexmedetomidine or propofol impairs hypercapnic regulation of breathing.

A comprehensive understanding of the impact of dexmedetomidine on regulation of breathing during hypoxia is lacking. It has been demonstrated that the α₂-adrenoceptor agonist clonidine at an oral dose of 3.5 μg/kg reduces the hypoxic ventilatory response in healthy male volunteers by approximately 50%.¹⁰  Thus, α₂-adrenoceptor agonists have the potential to reduce the hypoxic ventilatory response.

While previously it has been shown that dexmedetomidine reduces both slope and minute ventilation during hypercapnic challenge,⁷  a recent study could not find a reduction in hypercapnic ventilation.⁴  In that study,⁴  hypercapnic stimulation caused an arousal phenomenon mirrored by increased BIS values corresponding to increased minute ventilation during hypercapnia, whereas in the current study and others, there was no arousal and a reduction in hypercapnic ventilation.⁷  Thus, dexmedetomidine seems to depress hypercapnic ventilation in the absence of carbon dioxide–induced arousal.

Propofol is a well-described respiratory depressant that markedly reduces acute hypoxic and hypercapnic ventilation, and the degree of respiratory depression observed in previous studies are in line with the results of the current study.^1,2,20  During dexmedetomidine sedation, resting ventilation was minimally affected with a slight reduction of Spo₂ and a tendency to decreased minute ventilation and tidal volume while Petco₂ remained largely unchanged, confirming previous studies in healthy volunteers and patients.^4,7,21,22  In these studies, there was only a minor increase in Petco₂ over a wide range of dexmedetomidine dose and concentration levels.^4,7,21,22  In summary, our results regarding resting ventilation are in line with previous studies, but we have uncovered that sedation with dexmedetomidine can significantly impair the hypoxic control of breathing.

The measures of sedation provided by the two different sedation scales and BIS showed good agreement, which also has been demonstrated earlier.^23,24  In order to have an objective assessment of the drug exposure in each individual, plasma concentrations of dexmedetomidine and propofol were measured. They were in good agreement with observations of light to moderate sedation from previous studies.^3,4,21,25 

The findings of frequent periods of UAO and apnea during dexmedetomidine sedation are supported by an array of studies reporting episodes of UAO after intravenous dexmedetomidine^4,7  and intravenous, epidural, or intrathecal clonidine.^8,26,27  In the clonidine hypoxic ventilation study, two volunteers were excluded from data analysis because of clonidine-induced UAO.¹⁰ 

To compensate for large interindividual variation in hypoxic ventilation, we applied a randomized crossover study design. We also stabilized the hypoxic ventilation by conducting the experiments under strictly standardized conditions, that is, allocation to the same time of the day and by investigating only male subjects because it is known that the hypoxic ventilatory response varies with circadian rhythm and female sex hormones.²⁸  Since propofol is widely used as an anesthetic or sedative and is known to depress ventilation,^1,2,20  we used propofol as a comparator in order to validate data and the experimental setup. The targeted level of sedation was based on a clinical sedation scale and thus represented an individual and clinically relevant level of sedation rather than a fixed dosage or BIS value for all subjects. We believe that this approach makes the results clinically more meaningful although testing with a sedation scale includes interaction with the subjects and thus a risk for arousal and interference with sedation. In addition, the clinical sedation scales were combined with objective measurements of plasma drug concentrations and BIS. With this combined study design, we found good agreement between the different sedation monitoring modalities.

Potential limitations include lack of blinding of the study drugs evoking a risk for bias. Since the study drugs have large differences in pharmacokinetics, i.e., longer elimination halftime for dexmedetomidine, we did not blind for drug due to safety reasons. Although the study subjects were the same for both drugs, baseline hypoxic ventilation was slightly higher before dexmedetomidine sedation than before propofol. Day-to-day variability of the hypoxic ventilatory response can amount to 20 to 50%, where our data are in the lower range.²⁹  Hypoxic ventilation after recovery was similar to baseline after both drugs, thus indicating stable experimental settings.

The golden standard for maintaining the carbon dioxide levels is computerized dynamic end-tidal forcing, but we chose to manually adjust the carbon dioxide levels. However, the stable carbon dioxide levels maintained during the hypoxic ventilation demonstrate that we managed to control the carbon dioxide levels. No differences were noted between the two drugs in terms of reduction of the hypoxic or the hypercapnic ventilation. The current study was obviously underpowered to exclude possible small differences between drugs.

We report a hitherto unknown high incidence of UAO during sedation with dexmedetomidine in these volunteers who had not undergone sleep studies before inclusion. However, the exclusion criteria snoring and overweight, in addition to old age, are predictors of obstructive sleep apnea.²⁹  Despite this, since sleep in a susceptible individual could cause UAO, overnight polysomnography might have been of value. Another limitation of the study is that we only investigated one level of sedation, i.e., light to moderate, and we can therefore not display a dose–response relationship. It would be of interest to investigate the effects of other levels of sedation on regulation of breathing, and novel insights into mechanistic data for dexmedetomidine pinpoint a stepwise approach considering specific targets for various levels of sedation and anesthesia.³⁰ 

The CB is the peripheral regulator of breathing during hypoxia initiating the hypoxic ventilatory response as sensed by CB chemoreceptor cells, ultimately leading to increased efferent output via the phrenic nerve.⁵  Although there are conflicting reports regarding the effects of α₂-adrenoceptor agonists on CB chemoreception, some well-controlled animal studies demonstrate inhibitory actions of α₂-agonists.^11–14  α₂-adrenoceptors are present in the cat CB, and α₂-agonists inhibit hypoxia-induced chemoreceptor responses in vivo.¹²  Using a combination of an in vitro rabbit CB preparation and isolated chemoreceptor cells, the presence of α₂-adrenoceptors at the chemoreceptor cell and at the sympathetic nerve endings surrounding the CB was demonstrated.¹⁴  More importantly, α₂-agonists inhibit hypoxia-induced catecholamine release from the chemoreceptor cells, subsequently reducing the afferent carotid sinus nerve activity.¹⁴  Recently, in a more limited study, Nakatani et al.¹³  demonstrated a slight increase in chemoreceptor activity with a low dose of dexmedetomidine and no change during higher doses in an in vitro rabbit preparation. There are no experimental data on a molecular level addressing the effect of α₂-agonists in the human CB, but we have preliminary results in our laboratory suggesting expression of the α_2A- and α_2C-adrenoceptor genes in human CB from surgical patients (unpublished microarray data: Souren Mkrtchian, M.D., Ph.D., Stockholm, Sweden, January 15, 2015). α₂-adrenoceptors are widespread in the central nervous system including important sites for central control of breathing.³¹  Several animal studies demonstrate that activation of presynaptic α₂-adrenoceptors causes inhibition of neurons in the locus coeruleus, dorsal motor nucleus of the vagus, the hypoglossal nucleus, and preganglionic sympathetic neurons. α₂-Adrenoceptor agonists such as clonidine have been identified to inhibit breathing in various animal species and in humans.³¹ 

Propofol is a chemodepressant in the CB in vivo³²  and in vitro,³³  and the underlying mechanisms might involve inhibition of nicotinic transmission in the CB, rather than interaction with γ-aminobutyric acid receptor type A receptors.³³  The human CB contains both γ-aminobutyric acid receptor type A and nicotinic acetylcholine receptors, and thus, there seems to be prerequisites for the direct actions of propofol.³⁴  In order to further elucidate the underlying mechanisms behind the respiratory-depressant effect of both dexmedetomidine and propofol on peripheral chemoreception, a study simultaneously investigating both drugs on glomus cells and the afferent nerve endings is needed.

The results from this study demonstrate a marked effect of sedation with dexmedetomidine on regulation of breathing at both hypoxia and hypercapnia. This highlights the importance of adequate clinical monitoring of respiration when using dexmedetomidine for sedation. It should be noted that this study was carried out in nonstimulated volunteers, i.e., without surgical stimulation or need for sedation. Patients with discomfort and anxiety may react differently in terms of regulation of breathing. Since this study is limited to healthy volunteers, there is an obvious need to investigate the effect of dexmedetomidine sedation on control of breathing in the clinical setting and furthermore in high-risk patients. It would also be of interest to compare the effect on hypoxic ventilation for the two different α₂-adrenoceptor agonists, clonidine and dexmedetomidine, in equipotent dosage in the same study. Based on the findings of UAO and apnea episodes induced by dexmedetomidine sedation, the impact on upper airway patency needs to be explored.

Sedation with dexmedetomidine reduces both hypoxic and hypercapnic regulation of breathing to a similar extent as sedation with propofol. In addition, dexmedetomidine-induced sedation causes UAO and episodes of apnea to the same degree as propofol-induced sedation, underscoring the need for continuous respiratory monitoring during dexmedetomidine and propofol sedation.

We thank Anna Granström, R.N.A., Anna Schening, R.N.A., and Elisabeth Hellgren, R.N.A., from the Department of Anesthesiology, Surgical Services and Intensive Care, Karolinska University Hospital, Stockholm, Sweden, for practical assistance in conduction of the trial.

Supported by the departments and institutions involved and by grants from the Stockholm County Council (ALF 20130035), the Swedish Society of Medicine, Stockholm, Sweden, Tore Nilsons Funds, Stockholm, Sweden, Jaensens Funds, Stockholm, Sweden, and Karolinska Institutet Funds, Stockholm, Sweden, and ESA Maquet Anesthesia grant (to Dr. Jonsson Fagerlund).

Dr. Hårdemark Cedborg is employed by AGA Gas AB (Stockholm, Sweden), member of the Linde group (Stockholm, Sweden) since January 2014, and has received lecture fees from AbbVie AB (Stockholm, Sweden) and Fresenius Kabi (Uppsala, Sweden). Dr. Scheinin has contract research relationships with Orion Corporation (Espoo, Finland), AstraZeneca (Espoo, Finland), Hoffmann-La Roche (Espoo, Finland), H. Lundbeck (Turku, Finland), and Pfizer (Helsinki, Finland), and has received speaker’s fees and research support from Orion Corporation and speaker’s fees from Fresenius Kabi (Helsinki, Finland). Dr. Eriksson has received lecture fees from Merck Inc. (Stockholm, Sweden) and is a board member of Alteco Medical AB (Lund, Sweden). Dr. Jonsson Fagerlund has received lecture fees from Fresenius Kabi (Uppsala, Sweden). The other authors declare no competing interests.

Full protocol available from Dr. Jonsson Fagerlund: malin.jonsson.fagerlund@ki.se. Raw data available from Dr. Jonsson Fagerlund: malin.jonsson.fagerlund@ki.se.