Respiratory depressant effects of fentanyl analogs are opioid receptor-mediated.

Opioid-related fatalities involving synthetic opioids have reached unprecedented levels. This study evaluated the respiratory depressant effects of seven fentanyl analogs that have either emerged in the illicit drug supply or been identified in toxicological analyses following fatal or non-fatal intoxications. Adult male Swiss Webster mice were administered fentanyl analogs (isobutyrylfentanyl, crotonylfentanyl, para-methoxyfentanyl, para-methoxybutyrylfentanyl, 3-furanylfentanyl, thiophenefentanyl, and benzodioxolefentanyl) and their effects on minute volume as compared to mu-opioid receptor (MOR) agonist standards (fentanyl, morphine, and buprenorphine) were measured using whole body plethysmography (WBP). All drugs elicited significant (p ≤ 0.05) hypoventilation relative to vehicle for at least one dose tested: morphine (1, 3.2, 10, 32 mg/kg), buprenorphine, (0.032, 0.1, 0.32, 1, 3.2 mg/kg), fentanyl (0.0032, 0.01, 0.032, 0.1, 1, 32 mg/kg), isobutyrylfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), crotonylfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), para-methoxyfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), para-methoxybutyrylfentanyl (0.32, 1, 3.2, 10 mg/kg), 3-furanylfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), thiophenefentanyl (1, 3.2, 10, 32, 100 mg/kg), and benzodioxolefentanyl (3.2, 10, 32, 100 mg/kg). The ED50 values for hypoventilation showed a rank order of potency as follows: fentanyl (ED50 = 0.96 mg/kg) > 3-furanylfentanyl (ED50 = 2.60 mg/kg) > crotonylfentanyl (ED50 = 2.72 mg/kg) > para-methoxyfentanyl (ED50 = 3.31 mg/kg) > buprenorphine (ED50 = 10.8 mg/kg) > isobutyrylfentanyl (ED50 = 13.5 mg/kg) > para-methoxybutyrylfentanyl (ED50 = 16.1 mg/kg) > thiophenefentanyl (ED50 = 18.0 mg/kg) > morphine (ED50 = 55.3 mg/kg) > benzodioxolefentanyl (ED50 = 10,168 mg/kg). A naloxone pretreatment (10 mg/kg) attenuated the hypoventilatory effects of all drugs. These results establish that the respiratory depressant effects of these fentanyl analogs are at least in part mediated by the MOR.

Eupnea and gasping in vivo are facilitated by the activation of 5-HT2A receptors.

Eupnea and gasping in infancy depend on central nervous system (CNS) serotonin (5-hydroxytryptamine; 5-HT). Although previous in vitro preparations have provided some evidence that 5-HT acts through type 2 A receptors (5-HT2A) to facilitate eupnea and gasping, here the hypothesis addressed is that 5-HT2A receptor activation is necessary for eupnea and the proper generation of gasping in vivo. To test this, we administered 2,5-dimethoxy-4-iodoamphetamine (DOI; 0.25 mg/kg i.p.), a 5-HT2A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.25 mg/kg i.p.), a 5-HT1A agonist, or vehicle (saline) to 7-9-day-old tryptophan hydroxylase 2 knockout (TPH2-/-) mice. A second experiment assessed the effect of MDL-11,939 (MDL; 10 mg/kg i.p.), the specific 5-HT2A antagonist, or vehicle (DMSO) on the gasping of wild-type (TPH2+/+) animals. Drugs were given 15 min prior to five episodes of severe hypoxia that elicited gasping. TPH2-/- breathed more slowly but had the same V̇e and V̇e/V̇o2 compared with TPH2+/+. As previously reported, the gasping of TPH2-/- was significantly delayed (P < 0.001) and occurred at a significantly lower frequency compared with TPH2+/+ (P = 0.04). For both genotypes, DOI hastened eupneic frequency but had no effect on V̇e or V̇e/V̇o2. The gasping of TPH2-/-, although unaffected by 8-OH-DPAT, was indistinguishable from the gasping of TPH2+/+ following DOI. In TPH2+/+, application of MDL led to hypoventilation (P = 0.01), a delay in the appearance of gasping (P = 0.005), and reduced gasp frequency (P = 0.05). These data show that, in vivo, 5-HT2A receptors facilitate both eupnea and gasping. As has been shown in vitro, 5-HT2A probably promotes gasping by exciting hypoxia-resistant pacemaker neurons.NEW & NOTEWORTHY Previous in vitro studies suggest that 5-HT2A receptors contribute to eupnea and are necessary for fictive gasping. The current study shows that the impaired gasping displayed by neonatal TPH2-/- mice, deficient in CNS serotonin, is restored by 5-HT2A receptor activation. Following 5-HT2A blockade, wild-type mice hypoventilated and their gasping resembled that of TPH2-/- mice. This study shows that both eupnea and gasping in vivo rely on the activation of 5-HT2A receptors.

Perioperative Care and Medication-related Hypoventilation.

Cumulative evidence supports the association of adverse postoperative outcomes with obstructive sleep apnea (OSA) and obesity hypoventilation syndrome (OHS). Although current guidelines recommend preoperative screening for OSA and OHS, the best perioperative management pathways remain unknown. Interventions attempting to prevent complications in the postoperative period largely are consensus based and focused on enhanced monitoring, conservative measures, and specific OSA therapies, such as positive airway pressure. Until further research is available to improve the quality and strength of these recommendations, patients with known or suspected OSA and OHS should be considered at higher risk for perioperative cardiopulmonary complications.

Hypoventilation following oxygen administration associated with alfaxalone-dexmedetomidine-midazolam anesthesia in New Zealand White rabbits.

OBJECTIVE: To investigate the relationship between oxygen administration and ventilation in rabbits administered intramuscular alfaxalone-dexmedetomidine-midazolam. STUDY DESIGN: Prospective, randomized, blinded study. ANIMALS: A total of 25 New Zealand White rabbits, weighing 3.1-5.9 kg and aged 1 year. METHODS: Rabbits were anesthetized with intramuscular alfaxalone (4 mg kg-1), dexmedetomidine (0.1 mg kg-1) and midazolam (0.2 mg kg-1) and randomized to wait 5 (n = 8) or 10 (n = 8) minutes between drug injection and oxygen (100%) administration (facemask, 1 L minute-1). A control group (n = 9) was administered medical air 10 minutes after drug injection. Immediately before (PREoxy/air5/10) and 2 minutes after oxygen or medical air (POSToxy/air5/10), respiratory rate (fR), pH, PaCO2, PaO2, bicarbonate and base excess were recorded by an investigator blinded to treatment allocation. Data [median (range)] were analyzed with Wilcoxon, Mann-Whitney U and Kruskal-Wallis tests and p < 0.05 considered significant. RESULTS: Hypoxemia (PaO2 < 88 mmHg, 11.7 kPa) was observed at all PRE times: PREoxy5 [71 (61-81) mmHg, 9.5 (8.1-10.8) kPa], PREoxy10 [58 (36-80) mmHg, 7.7 (4.8-10.7) kPa] and PREair10 [48 (32-64) mmHg, 6.4 (4.3-8.5) kPa]. Hypoxemia persisted when breathing air: POSTair10 [49 (33-66) mmHg, 6.5 (4.4-8.8) kPa]. Oxygen administration corrected hypoxemia but was associated with decreased fR (>70%; p = 0.016, both groups) and hypercapnia (p = 0.016, both groups). Two rabbits (one per oxygen treatment group) were apneic (no thoracic movements for 2.0-2.5 minutes) following oxygen administration. fR was unchanged when breathing air (p = 0.5). PaCO2 was higher when breathing oxygen than air (p < 0.001). CONCLUSIONS AND CLINICAL RELEVANCE: Early oxygen administration resolved anesthesia-induced hypoxemia; however, fR decreased and PaCO2 increased indicating that hypoxemic respiratory drive is an important contributor to ventilation using the studied drug combination.

Perinatal exposure to ethanol in rats induces permanent disturbances of breathing and chemosensitivity during adulthood.

Perinatal exposure to drugs of abuse, including alcohol (ethanol), is known to impinge the development of respiratory function. However, most studies described the short-term effects of these exposures, focusing mostly on the early postnatal life. After exposure to ethanol during gestation and lactation we have previously shown that 3-4 week-old rat exhibit chronic hypoventilation and an altered response to hypoxia at the end of ethanol exposure. However, whether these deficits are reversible following ethanol withdrawal remained unknown. Here, we investigated through whole-body plethysmography the respiratory activity of 2 months-old rats exposed to ethanol from gestation to weaning followed by one month of ethanol withdrawal. After ethanol withdrawal, rats persistently exhibited a significant reduction in respiratory frequency without change in tidal volume associated to a lower arterial blood oxygen content. In addition, the response to hypoxia in these rats was reduced whereas the response to hypercapnia remained unaltered. In conclusion perinatal exposure to ethanol in rats, unlike exposure to cocaine, morphine or nicotine, is characterized by selective alterations of basal respiratory activity and chemosensitivity that persist long after withdrawal.

Ventilatory response to CO2 in patients with epilepsy.

OBJECTIVE: Severe periictal respiratory depression is thought to be linked to risk of sudden unexpected death in epilepsy (SUDEP) but its determinants are largely unknown. Interindividual differences in the interictal ventilatory response to CO2 (hypercapnic ventilatory response [HCVR] or central respiratory CO2 chemosensitivity) may identify patients who are at increased risk for severe periictal hypoventilation. HCVR has not been studied previously in patients with epilepsy; therefore we evaluated a method to measure it at bedside in an epilepsy monitoring unit (EMU) and examined its relationship to postictal hypercapnia following generalized convulsive seizures (GCSs). METHODS: Interictal HCVR was measured by a respiratory gas analyzer using a modified rebreathing technique. Minute ventilation (VE ), tidal volume, respiratory rate, end tidal (ET) CO2 and O2 were recorded continuously. Dyspnea during the test was assessed using a validated scale. The HCVR slope (ΔVE /ΔETCO2 ) for each subject was determined by linear regression. During the video-electroencephalography (EEG) study, subjects underwent continuous respiratory monitoring, including measurement of chest and abdominal movement, oronasal airflow, transcutaneous (tc) CO2 , and capillary oxygen saturation (SPO2 ). RESULTS: Sixty-eight subjects completed HCVR testing in 151 ± (standard deviation) 58 seconds, without any serious adverse events. HCVR slope ranged from -0.94 to 5.39 (median 1.71) L/min/mm Hg. HCVR slope correlated with the degree of unpleasantness and intensity of dyspnea and was inversely related to baseline ETCO2 . Both the duration and magnitude of postictal tcCO2 rise following GCSs were inversely correlated with HCVR slope. SIGNIFICANCE: Measurement of the HCVR is well tolerated and can be performed rapidly and safely at the bedside in the EMU. A subset of individuals has a very low sensitivity to CO2 , and this group is more likely to have a prolonged increase in postictal CO2 after GCS. Low interictal HCVR may increase the risk of severe respiratory depression and SUDEP after GCS and warrants further study.

Inhalational Anesthetics Induce Neuronal Protein Aggregation and Affect ER Trafficking.

Anesthetic agents have been implicated in the causation of neurological and cognitive deficits after surgery, the exacerbation of chronic neurodegenerative disease, and were recently reported to promote the onset of the neurologic respiratory disease Congenital Central Hypoventilation Syndrome (CCHS), related to misfolding of the transcription factor Phox2B. To study how anesthetic agents could affect neuronal function through alterations to protein folding, we created neuronal cell models emulating the graded disease severity of CCHS. We found that the gas anesthetic isoflurane and the opiate morphine potentiated aggregation and mislocalization of Phox2B variants, similar to that seen in CCHS, and observed transcript and protein level changes consistent with activation of the endoplasmic reticulum (ER) unfolded protein response. Attenuation of ER stress pathways did not result in a correction of Phox2B misfolding, indicating a primary effect of isoflurane on protein structure. We also observed that isoflurane hindered the folding and activity of proteins that rely heavily on ER function, like the CFTR channel. Our results show how anesthetic drugs can alter protein folding and induce ER stress, indicating a mechanism by which these agents may affect neuronal function after surgery.

Respiratory Volume Monitoring Reduces Hypoventilation and Apnea in Subjects Undergoing Procedural Sedation.

INTRODUCTION: The use of monitored anesthesia care for endoscopic procedures increases the risk of respiratory depression, necessitating careful monitoring of patient ventilation. We examined the effectiveness of an impedance-based respiratory volume monitor (RVM) in improving the safety of patients undergoing upper and lower gastrointestinal endoscopies under total intravenous anesthesia. We hypothesized that feedback from the RVM would allow anesthesiologists to maintain adequate ventilation, which would reduce the duration of respiratory depression (ie, hypoventilation and apnea) compared to a blinded control group. METHODS: Sixty-five subjects were enrolled in a randomized controlled trial and monitored with a noninvasive impedance-based RVM, which displayed respiratory traces and calculated expiratory minute ventilation (V̇E), tidal volume (VT), and breathing frequency (f) measurements. Prior to induction of anesthesia, a baseline V̇E measurement (V̇E-baseline) was taken as a measurement of normal breathing. V̇E was monitored throughout the procedure for signs of hypoventilation and apnea. Hypoventilation was defined as V̇E < 40% V̇E-baseline, and apneas were defined as V̇E = 0 for > 15 s. RESULTS: Sixty-five subjects were randomly assigned to either a control (n = 38) or RVM intervention group (n = 27). Subjects in the intervention group had a higher V̇E% for the entire procedure (P = .045), as well as the third and fourth quartile of the procedure compared to the control group (P = .01). Likewise, subjects in the RVM intervention group spent significantly less time below 40% V̇E-baseline compared to the control group throughout the entire procedure (12 ± 15% vs 32 ± 24%, respectively) (P < .001). The median number of apneas per subject was greater in the control group (median 2, interquartile range 1-2, maximum 4) compared to the RVM intervention group (median 1, interquartile range 1-2, maximum 3) (P = .037). CONCLUSIONS: The control group had a higher incidence of hypoventilation and apnea compared to the RVM intervention group. Respiratory monitoring using the RVM can potentially be a useful tool for identifying early signs of respiratory depression and for titrating anesthetics to maintain adequate ventilation while minimizing patient risk.

Progressive hypoventilation due to mixed CD8+ and CD4+ lymphocytic polymyositis following tremelimumab - durvalumab treatment.

BACKGROUND: The combination of CTLA-4 and PD-L1 inhibitors has a manageable adverse effect profile, although rare immune-related adverse events (irAE) can occur. CASE PRESENTATION: We describe an autoimmune polymyositis following a partial response to combination tremelimumab and durvalumab for the treatment of recurrent lung adenocarcinoma. Radiography revealed significant reduction in all metastases; however, the patient developed progressive neuromuscular hypoventilation due to lymphocytic destruction of the diaphragmatic musculature. Serologic testing revealed a low level of de novo circulating antibodies against striated muscle fiber. Immunohistochemistry revealed type II muscle fiber atrophy with a mixed CD8+ and CD4+ lymphocyte infiltrate, indicative of inflammatory myopathy. CONCLUSIONS: This case supports the hypothesis that muscle tissue is a target for lymphocytic infiltration in immune checkpoint inhibitor-associated polymyositis. Further insights into the autoimmune mechanism of PM will hopefully contribute to the prevention and treatment of this phenomenon.

Propofol or Ketofol for Procedural Sedation and Analgesia in Emergency Medicine-The POKER Study: A Randomized Double-Blind Clinical Trial.

STUDY OBJECTIVE: We determine whether emergency physician-provided deep sedation with 1:1 ketofol versus propofol results in fewer adverse respiratory events requiring physician intervention when used for procedural sedation and analgesia. METHODS: Consenting patients requiring deep sedation were randomized to receive either ketofol or propofol in a double-blind fashion according to a weight-based dosing schedule. The primary outcome was the occurrence of a respiratory adverse event (desaturation, apnea, or hypoventilation) requiring an intervention by the sedating physician. Secondary outcomes included hypotension and patient satisfaction. RESULTS: Five hundred seventy-three patients were enrolled and randomized, 292 in the propofol group and 281 in the ketofol group. Five percent in the propofol group and 3% in the ketofol group met the primary outcome, an absolute difference of 2% (95% confidence interval [CI] -2% to 5%). Patients receiving propofol were more likely to become hypotensive (8 versus 1%; difference 7%; 95% CI 4% to 10%). Patient satisfaction was very high in both groups (10/10; interquartile range 10 to 10/10), and although the ketofol group was more likely to experience severe emergence delirium (5% versus 2%; difference 3%; 95% CI 0.4% to 6%), they had lower pain scores at 30 minutes postprocedure. Other secondary outcomes were similar between groups. CONCLUSION: Ketofol and propofol resulted in a similar incidence of adverse respiratory events requiring the intervention of the sedating physician. Although propofol resulted in more hypotension, the clinical relevance of this is questionable, and both agents are associated with high levels of patient satisfaction.

Hypoxia following etorphine administration in goats (Capra hircus) results more from pulmonary hypertension than from hypoventilation.

BACKGROUND: Etorphine, a potent opioid agonist, causes pulmonary hypertension and respiratory depression. Whether etorphine-induced pulmonary hypertension negatively influences pulmonary gas exchange and exacerbates the effects of ventilator depression and the resultant hypoxemia is unknown. To determine if these effects occurred we instrumented twelve goats with peripheral and pulmonary arterial catheters to measure systemic and pulmonary pressures before and after etorphine administration. Concurrent cardiopulmonary and arterial blood gas variables were also measured. RESULTS: Etorphine induced hypoventilation (55% reduction to 7.6 ± 2.7 L.min(-1), F(11,44) = 15.2 P < 0.0001), hypoxia (<45 mmHg, F(11,44) = 8.6 P < 0.0001), hypercapnia (>40 mmHg, F(11,44) = 5.6 P < 0.0001) and pulmonary hypertension (mean 23 ± 6 mmHg, F(11,44) = 8.2 P < 0.0001). Within 6 min of etorphine administration hypoxia was twice (F(11,22) = 3.0 P < 0.05) as poor than that expected from etorphine-induced hypoventilation alone. This disparity appeared to result from a decrease in the movement of oxygen (gas exchange) across the alveoli membrane, as revealed by an increase in the P(A-a)O2 gradient (F(11,44) = 7.9 P < 0.0001). The P(A-a)O2 gradient was not correlated with global changes in the ventilation perfusion ratio (P = 0.28) but was correlated positively with the mean pulmonary artery pressure (P = 0.017, r(2) = 0.97), indicating that pulmonary pressure played a significant role in altering pulmonary gas exchange. CONCLUSION: Attempts to alleviate etorphine-induced hypoxia therefore should focus not only on reversing the opioid-induced respiratory depression, but also on improving gas exchange by preventing etorphine-induced pulmonary hypertension.

The effect of ketamine on hypoventilation during deep sedation with midazolam and propofol: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Hypoventilation is a major cause of morbidity and mortality in patients having procedures under sedation. Few clinical strategies have been evaluated to reduce intraoperative hypoventilation during surgical procedures under deep sedation. OBJECTIVE: The primary objective of this investigation was to examine the effect of ketamine on hypoventilation in patients receiving deep sedation for surgery with midazolam and propofol. DESIGN: The study was a randomised, placebo-controlled, double-blind clinical trial. SETTING: Intraoperative. PATIENTS: Healthy women undergoing breast surgery. INTERVENTION: Randomised to receive ketamine (0.5 mg kg bolus, followed by an infusion of 1.5 µg kg min) or isotonic saline. MAIN OUTCOME MEASURE: Duration of hypercapnia measured continuously with a transcutaneous carbon dioxide (TCO2) monitor. RESULTS: Fifty-four participants were recruited. Patient and surgical characteristics were similar between the study groups. The median percentage of the sedation time with TCO2 more than 6.7 kPa in participants in the ketamine group, 1.2% (95% confidence interval, CI, 0 to 83), was less than that in the isotonic saline group (65%, 95% CI, 0 to 88; P = 0.01). Severe hypoventilation (TCO2 >8.0 kPa) was also less in the ketamine group, median 0% (95% CI, 0 to 11.7) compared with 28% (95% CI, 0 to 79.3; P = 0.0002) for the isotonic saline group. The ketamine group required less airway manoeuvres (chin lift) to keep the SaO2 greater than 95% median (95% CI) [0 (0 to 3) compared with 3 (0 to 16) in the isotonic saline group] (P = 0.004). CONCLUSION: Ketamine decreased the duration and severity of hypercapnia in patients undergoing deep sedation with propofol. The addition of ketamine may reduce hypoventilation and adverse effects in patients having procedures under sedation. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01535976.

A simple and novel method to monitor breathing and heart rate in awake and urethane-anesthetized newborn rodents.

Rodents are most useful models to study physiological and pathophysiological processes in early development, because they are born in a relatively immature state. However, only few techniques are available to monitor non-invasively heart frequency and respiratory rate in neonatal rodents without restraining or hindering access to the animal. Here we describe experimental procedures that allow monitoring of heart frequency by electrocardiography (ECG) and breathing rate with a piezoelectric transducer (PZT) element without hindering access to the animal. These techniques can be easily installed and are used in the present study in unrestrained awake and anesthetized neonatal C57/Bl6 mice and Wistar rats between postnatal day 0 and 7. In line with previous reports from awake rodents we demonstrate that heart rate in rats and mice increases during the first postnatal week. Respiratory frequency did not differ between both species, but heart rate was significantly higher in mice than in rats. Further our data indicate that urethane, an agent that is widely used for anesthesia, induces a hypoventilation in neonates whilst heart rate remains unaffected at a dose of 1 g per kg body weight. Of note, hypoventilation induced by urethane was not detected in rats at postnatal 0/1. To verify the detected hypoventilation we performed blood gas analyses. We detected a respiratory acidosis reflected by a lower pH and elevated level in CO2 tension (pCO2) in both species upon urethane treatment. Furthermore we found that metabolism of urethane is different in P0/1 mice and rats and between P0/1 and P6/7 in both species. Our findings underline the usefulness of monitoring basic cardio-respiratory parameters in neonates during anesthesia. In addition our study gives information on developmental changes in heart and breathing frequency in newborn mice and rats and the effects of urethane in both species during the first postnatal week.

Effect of transpleural perfusion with oxygenated perfluorocarbon in a rat model of acute lung injury.

BACKGROUND: Despite advances in critical care, more effective methods of systemic oxygenation in patients with acute lung injury or acute respiratory distress syndrome are needed. The goal of this study was to determine if it is possible to increase systemic oxygenation by transpleural perfusion with oxygenated perfluorocarbon in animals with induced acute lung injury. METHODS: Eighteen Sprague-Dawley rats were intubated, and acute lung injury was induced by aspiration of 0.1N HCl (1 mL/kg) through the tracheal tube. Inflow and outflow tubes were placed in the thoracic cavity and connected to a perfusion circuit containing a roller pump, warmer, and oxygenator. Rats in group I were not treated after aspiration of HCl, those in group II were perfused with oxygenated saline, and those in group III were perfused with oxygenated perfluorocarbon. Arterial blood gases were collected every 30 minutes for 180 minutes. At the last step of the experiments, pathological examination of the lungs and parietal pleura was performed. RESULTS: PaO(2) in group III was significantly higher than that in group I or II. PaCO(2) in group III was significantly lower than that in the other two groups. Histological examination showed relatively well-delineated zones of inflammation-free coagulative necrosis of lung parenchyma in all groups. CONCLUSIONS: Transpleural perfusion with oxygenated perfluorocarbon in an animal model of induced acute lung injury resulted in a significant increase in systemic oxygenation and depletion of systemic carbon dioxide, and might be a useful method for improving systemic oxygenation in patients with acute lung injury.

Carbon dioxide accumulation during analgosedated colonoscopy: comparison of propofol and midazolam.

AIM: To characterize the profiles of alveolar hypoventilation during colonoscopies performed under sedoanalgesia with a combination of alfentanil and either midazolam or propofol. METHODS: Consecutive patients undergoing routine colonoscopy were randomly assigned to sedation with either propofol or midazolam in an open-labeled design using a titration scheme. All patients received 4 µg/kg per body weight alfentanil for analgesia and 3 L of supplemental oxygen. Oxygen saturation (SpO2) was measured by pulse oximetry (POX), and capnography (PcCO2) was continuously measured using a combined dedicated sensor at the ear lobe. Instances of apnea resulting in measures such as stimulation of the patient, a chin lift, a mask maneuver, or withholding of sedation were recorded. PcCO2 values (as a parameter of sedation-induced hypoventilation) were compared between groups at the following distinct time points: baseline, maximal rise, termination of the procedure and 5 min after termination of the procedure. The number of patients in both study groups who regained baseline PcCO2 values (± 1.5 mmHg) five minutes after the procedure was determined. RESULTS: A total of 97 patients entered this study. The data from 14 patients were subsequently excluded for clinical procedure-related reasons or for technical problems. Therefore, 83 patients (mean age 62 ± 13 years) were successfully randomized to receive propofol (n = 42) or midazolam (n = 41) for sedation. Most of the patients were classified as American Society of Anesthesiologists (ASA) II [16 (38%) in the midazolam group and 15 (32%) in the propofol group] and ASA III [14 (33%) and 13 (32%) in the midazolam and propofol groups, respectively]. A mean dose of 5 (4-7) mg of IV midazolam and 131 (70-260) mg of IV propofol was used during the procedure in the corresponding study arms. The mean SpO2 at baseline (%) was 99 ± 1 for the midazolam group and 99 ± 1 for the propofol group. No cases of hypoxemia (SpO2 < 85%) or apnea were recorded. However, an increase in PcCO2 that indicated alveolar hypoventilation occurred in both groups after administration of the first drug and was not detected with pulse oximetry alone. The mean interval between the initiation of sedation and the time when the PcCO2 value increased to more than 2 mmHg was 2.8 ± 1.3 min for midazolam and 2.8 ± 1.1 min for propofol. The mean maximal rise was similar for both drugs: 8.6 ± 3.7 mmHg for midazolam and 7.4 ± 3.2 mmHg for propofol. Five minutes after the end of the procedure, the mean difference from the baseline values was significantly lower for the propofol treatment compared with midazolam (0.9 ± 3.0 mmHg vs 4.3 ± 3.7 mmHg, P = 0.0000169), and significantly more patients in the propofol group had regained their baseline value ± 1.5 mmHg (32 of 41 vs 12 of 42, P = 0.0004). CONCLUSION: A significantly higher number of patients sedated with propofol had normalized PcCO2 values five minutes after sedation when compared with patients sedated with midazolam.