Comparing Nasal End-Tidal Carbon Dioxide Measurement Variation and Agreement While Delivering Pulsed and Continuous Flow Oxygen in Volunteers and Patients.

BACKGROUND: Supplemental oxygen is administered during procedural sedation to prevent hypoxemia. Continuous flow oxygen, the most widespread method, is generally adequate but distorts capnography. Pulsed flow oxygen is novel and ideally will not distort capnography. We have developed a prototype oxygen administration system designed to try to facilitate end-tidal carbon dioxide (ETCO2) measurement. We conducted a volunteer study (ClinicalTrials.gov, NCT02886312) to determine how much nasal ETCO2 measurements vary with oxygen flow rate. We also conducted a clinical study (NCT02962570) to determine the median difference and limits of agreement between ETCO2 measurements made with and without administering oxygen. METHODS: Both studies were conducted at the University of Utah and participants acted as their own control. Inclusion criteria were age 18 years and older with an American Society of Anesthesiologists physical status of I-III. Exclusion criteria included acute respiratory distress syndrome, pneumonia, lung or cardiovascular disease, nasal/bronchial congestion, pregnancy, oxygen saturation measured by pulse oximetry <93%, and a procedure scheduled for <20 minutes. For the volunteer study, pulsed and continuous flow was administered at rates from 2 to 10 L/min using a single sequence of technique and flow. The median absolute deviation from the median value was analyzed for the primary outcome of ETCO2. For the clinical study, ETCO2 measurements (the primary outcome) were collected while administering pulsed and continuous flow at rates between 1 and 5 L/min and were compared to measurements without oxygen flow. Due to institutional review board requirements for patient safety, this study was not randomized. After completing the study, measurements with and without administering oxygen were analyzed to determine median differences and 95% limits of agreement for each administration technique. RESULTS: Thirty volunteers and 60 patients participated in these studies which ended after enrolling the predetermined number of participants. In volunteers, the median absolute deviation for ETCO2 measurements made while administering pulsed flow oxygen (0.89; 25%-75% quantiles: 0.3-1.2) was smaller than while administering continuous flow oxygen (3.93; 25%-75% quantiles: 2.2-6.2). In sedated patients, the median difference was larger during continuous flow oxygen (-6.8 mm Hg; 25%-75% quantiles: -12.5 to -2.1) than during pulsed flow oxygen (0.1 mm Hg; 25%-75% quantiles: -0.5 to 1.5). The 95% limits of agreement were also narrower during pulsed flow oxygen (-2.4 to 4.5 vs -30.5 to 2.4 mm Hg). CONCLUSIONS: We have shown that nasal ETCO2 measurements while administering pulsed flow have little deviation and agree well with measurements made without administering oxygen. We have also demonstrated that ETCO2 measurements during continuous flow oxygen have large deviation and wide limits of agreement when compared with measurements made without administering oxygen.

A comparison of controlled ventilation with a noninvasive ventilator versus traditional mask ventilation.

After induction, but before intubation, many general anesthesia patients are manually bag-mask ventilated. The objective of this study was to determine the efficacy of bag-mask ventilation (MkV) of an anesthetized patient versus mask ventilation using a noninvasive ventilator (NIV). We hypothesized that feedback-controlled, mask ventilation via NIV is more efficacious and safer. This critical short period of time in the operating room was chosen to compare MkV versus NIV. 30 ASA I-III patients, aged 18-74, presenting for elective surgery under general anesthesia were enrolled in the study. Patients were ventilated first with MkV and then with NIV. One minute of ventilation data was collected for each method. Respiratory inductance plethysmography (RIP) bands around the chest and abdomen were used to measure tidal volumes and breath rates for each method of ventilation. The NIV was set to deliver 10 breaths per minute with 12 cmH2O of pressure support. A non-inferiority test was used to compare MkV and NIV. MkV breaths had an average of 13 breaths and tidal volume of 364 mL (SD 145 mL). NIV resulted in an average of 10 breaths and tidal volume of 552 mL, i.e., 188 mL more than MkV (lower bound of the 95% confidence interval equal to 120 mL). The hypothesis of non-inferiority at the - 100 mL level and the superiority hypothesis at the + 100 mL level was accepted. NIV also resulted in much more consistent ventilation rates (zero variation since it is controlled by the ventilator) when compared to manual ventilation while maintaining safe airway pressures (8 cmH2O EPAP and 20 cmH2O IPAP). Feedback controlled mask ventilation via a NIV is a viable alternative to MkV. It can deliver more optimal tidal volumes with the operator utilizing only one hand. The airway pressures are fixed at safe limits during a period where the goal is to reach a maximal level of oxygenation prior to intubation. Over-ventilation or over-pressurization of the airway is not a concern with NIV since the pressures are maintained well within safe thresholds to avoid injury.

A comparison of ventilation with a non-invasive ventilator versus standard O2 with a nasal cannula for colonoscopy with moderate sedation using propofol.

The aim of this study was to test the effects of CPAP on moderately sedated patients undergoing colonoscopy. Our hypothesis was that CPAP can reduce the incidence and duration of obstructive apnea and hemoglobin oxygen desaturation in patients undergoing procedural sedation for colonoscopy. Two groups of consenting adult patients scheduled to undergo routine colonoscopy procedures and sedated with propofol and fentanyl were monitored in this study: control and intervention. Patients in the intervention group were connected via a facemask to a ventilator that delivered supplemental oxygen (100%) through a standard air-cushion mask. The mask had a built-in leak to facilitate CO2 clearance during CPAP. Patients in the control group received 2-10 L/min of oxygen via nasal cannula or non-rebreather mask. Subjects in the control group were collected in a prior study and used as historical controls. The primary outcome measures were the number of apneic events and the cumulative duration of apneic events. An apneic event was defined as a period longer than 10 s without respiration. The secondary outcome was the area under the curve (AUC) for the arterial oxygen saturation less than 90% versus time during sedative and analgesic administration (time (s) below threshold multiplied by percent below threshold). A desaturation event was defined as a period of time during which arterial oxygen saturation was less than 90%. 29 patients were enrolled in the intervention group and 156 patients were previously enrolled in the control group as part of an earlier study. The median number of apneic events in the control group was 7 compared to 0 in the intervention group. The intervention group experienced apnea less than 1% of the total procedure time compared to 17% in the control group (p < 0.001). There were no desaturation events observed in the 29 patients in the intervention group. In contrast, 27 out of 156 patients in the control group experienced a desaturation event. Average AUC of patients in the control group was 70%-s (time (s) * oxygen saturation below < 90%) (95% CI 32.34-108.60%) whereas the average AUC in intervention group patients was 0%-s (% time (s) * oxygen saturation < 90%) (95% CI 0-0%), p = 0.01. This preliminary study found that CPAP via a tight-fitting mask may be an effective tool to reduce the incidence and duration of obstructive apneic events as well as hemoglobin oxygen desaturation during lower endoscopy procedures that use propofol and fentanyl for sedation.Clinical Trial Registration ClinicalTrials.gov ID: NCT02623270. https://clinicaltrials.gov/ct2/show/NCT02623270 .

Propofol for Treatment-Resistant Depression: A Pilot Study.

Background: We hypothesized that propofol, a unique general anesthetic that engages N-methyl-D-aspartate and gamma-aminobutyric acid receptors, has antidepressant properties. This open-label trial was designed to collect preliminary data regarding the feasibility, tolerability, and efficacy of deep propofol anesthesia for treatment-resistant depression. Methods: Ten participants with moderate-to-severe medication-resistant depression (age 18-45 years and otherwise healthy) each received a series of 10 propofol infusions. Propofol was dosed to strongly suppress electroencephalographic activity for 15 minutes. The primary depression outcome was the 24-item Hamilton Depression Rating Scale. Self-rated depression scores were compared with a group of 20 patients who received electroconvulsive therapy. Results: Propofol treatments were well tolerated by all subjects. No serious adverse events occurred. Montreal Cognitive Assessment scores remained stable. Hamilton scores decreased by a mean of 20 points (range 0-45 points), corresponding to a mean 58% improvement from baseline (range 0-100%). Six of the 10 subjects met the criteria for response (>50% improvement). Self-rated depression improved similarly in the propofol group and electroconvulsive therapy group. Five of the 6 propofol responders remained well for at least 3 months. In posthoc analyses, electroencephalographic measures predicted clinical response to propofol. Conclusions: These findings demonstrate that high-dose propofol treatment is feasible and well tolerated by individuals with treatment-resistant depression who are otherwise healthy. Propofol may trigger rapid, durable antidepressant effects similar to electroconvulsive therapy but with fewer side effects. Controlled studies are warranted to further evaluate propofol's antidepressant efficacy and mechanisms of action. ClinicalTrials.gov: NCT02935647.

Inhaled Remimazolam Potentiates Inhaled Remifentanil in Rodents.

BACKGROUND: Remimazolam is an ester-based short-acting benzodiazepine currently in clinical trials for IV administration. This study explored the feasibility of delivering remimazolam alone and as an adjunct to remifentanil via inhalation in rodent models. METHODS: Mice were exposed to remimazolam via inhalation; sedation was assessed using time to movement outside a set perimeter. Rats were also exposed to remimazolam aerosol alone and in combination with inhaled remifentanil, and analgesia was quantified by using a tail flick meter. Pulmonary injury was assessed in mice using mechanics measurements. RESULTS: Mice showed significantly increased time to movement outside a set perimeter after 5-minute exposure to increasing concentrations (10-25 mg/mL solutions) of inhaled remimazolam aerosols. Differences in mean (95% confidence interval) time to movement from pretest baseline group (0.05 [0.01-0.09] minutes) were 11 (4-18), 15 (5-26), 30 (19-41), and 109 (103-115) minutes after exposure to remimazolam aerosol of 10, 15, 20, and 25 mg/mL, respectively (P = .007 - P < .0001). Exposure of rats to remimazolam aerosols alone failed to produce sedation or analgesia after a 5-minute exposure. When remimazolam (10 or 25 mg/mL) was administered in combination with 250 µg/mL remifentanil, there was a significant difference in time to tail flick (P < .0001) consistent with a strong analgesic effect. Mean (95% confidence interval) differences in time to tail flick from the pretest baseline group (3.2 [2.5-3.9] seconds) were 14 (10-18) seconds when 250 µg/mL remifentanil was administered with either 10 or 25 mg/mL remimazolam. Remimazolam alone or in combination with remifentanil did not cause lung irritation, bronchospasm, or other adverse pulmonary events to the respiratory tract of mice as assessed by Flexi-Vent pulmonary function tests. CONCLUSIONS: Remimazolam can significantly potentiate the analgesic effect of remifentanil when concurrently delivered via inhalation.

Inhaled Remifentanil in Rodents.

BACKGROUND: Remifentanil is an injectable opioid that is metabolized rapidly at a constant rate by plasma esterases. This supports its use as an analgesic for short-term, but painful, procedures in a wide range of patients. The aim of this study was to explore the feasibility and safety of administering remifentanil via inhalation. Our hypothesis was that inhaled remifentanil would be absorbed rapidly, pharmacologically active, rapidly cleared, and noninjurious to rodent airways and lungs. METHODS: Rats were exposed to remifentanil aerosol (100-2000 µg/mL) for varying times (1-5 minutes). Analgesia was quantified as a function of dose and time by measuring time to tail flick in response to a painful stimulus. Remifentanil was measured in blood using liquid chromatography-tandem mass spectrometry. Pulmonary mechanics and histology were assessed in mice for the evidence of adverse effects after acute and repeated (subacute) dosing. RESULTS: Exposure of rats to remifentanil aerosols produced dose-dependent analgesia within 2 minutes, which was sustained for the exposure period. Subsequently, the rats experienced rapid and complete recovery with a return to baseline tail flick response to a painful stimulus within 5 minutes. Analgesia mirrored the concentration profile of remifentanil in blood, and the animals were not affected adversely by repeated dosing. Pulmonary mechanics measurements in mice indicated that remifentanil was nonirritating and that the nasal and respiratory tissues of rats were free of significant morphological changes. CONCLUSIONS: Remifentanil delivered by inhalation is rapidly absorbed, pharmacologically active, rapidly cleared, and noninjurious to respiratory tissues in rodents.

Flow-through versus sidestream capnometry for detection of end tidal carbon dioxide in the sedated patient.

BACKGROUND: End tidal carbon dioxide (ETCO(2)) in non-intubated patients can be monitored using either sidestream or flow-through capnometry [Yamamori et al., J Clin Monit Comput 22(3):209-220, 2008]. The hypothesis of this validation study is that, flow-through capnometry will yield a more accurate estimate of ETCO(2) than sidestream capnometry when evaluated in a bench study during low tidal volumes and high oxygen administration via nasal cannula. Secondarily, when ETCO(2) from each is compared to arterial CO(2) (PaCO(2)) during a study in which healthy, non-intubated volunteers are tested under normocapnic, hypocapnic and hypercapnic conditions, the flow-through capnometer will resemble PaCO(2) more closely than the sidestream capnometer. This will be especially true during periods of lower minute ventilation and high oxygen flow rates via mask in non-intubated, remifentanil sedated, healthy volunteers whose physiologic deadspace is small. METHODS: The performance of a flow-through (cap-ONE, Nihon Kohden, Tokyo, Japan) and a sidestream (Microcap Smart CapnoLine Plus, Oridion Inc., Needham, MA) capnometer were compared in a bench study and a volunteer trial. A bench study evaluated ETCO(2) accuracy using waveforms generated via mechanical lungs during low tidal volumes and high oxygen flow rates. A volunteer study compared the ETCO(2) for each capnometer against PaCO(2) during sedation in which 8 l O(2) was delivered via mask rather than the nasal cannula. RESULTS: In the bench study, the flow-through capnometer gave slightly higher values of ETCO(2) during high-flow oxygen and no discernable differences during variable tidal volumes. Bland and Altman plots comparing ETCO(2) to PaCO(2) showed essentially equal performance between the two capnometers in the volunteers. CONCLUSIONS: Within a wide limit of agreement between the volunteer and bench study, flow-through and sidestream capnometry performed equally well during bench testing and in non-intubated, sedated patients.

Hypercapnic hyperventilation shortens emergence time from isoflurane anesthesia.

BACKGROUND: To shorten emergence time after a procedure using volatile anesthesia, 78% of anesthesiologists recently surveyed used hyperventilation to rapidly clear the anesthetic from the lungs. Hyperventilation has not been universally adapted into clinical practice because it also decreases the Paco2, which decreases cerebral bloodflow and depresses respiratory drive. Adding deadspace to the patient's airway may be a simple and safe method of maintaining a normal or slightly increased Paco2 during hyperventilation. METHODS: We evaluated the differences in emergence time in 20 surgical patients undergoing 1 MAC of isoflurane under mild hypocapnia (ETco2 approximately 28 mmHg) and mild hypercapnia (ETco2 approximately 55 mmHg). The minute ventilation in half the patients was doubled during emergence, and hypercapnia was maintained by insertion of additional airway deadspace to keep the ETco2 close to 55 mmHg during hyperventilation. A charcoal canister adsorbed the volatile anesthetic from the deadspace. Fresh gas flows were increased to 10 L/min during emergence in all patients. RESULTS: The time between turning off the vaporizer and the time when the patients opened their eyes and mouths, the time of tracheal extubation, and the time for normalized bispectral index to increase to 0.95 were faster whenever hypercapnic hyperventilation was maintained using rebreathing and anesthetic adsorption (P < 0.001). The time to tracheal extubation was shortened by an average of 59%. CONCLUSIONS: The emergence time after isoflurane anesthesia can be shortened significantly by using hyperventilation to rapidly clear the anesthetic from the lungs and CO2 rebreathing to induce hypercapnia during hyperventilation. The device should be considered when it is important to provide a rapid emergence, especially after surgical procedures where a high concentration of the volatile anesthetic was maintained right up to the end of the procedure, or where surgery ends abruptly and without warning.

Hypercapnia shortens emergence time from inhaled anesthesia in pigs.

BACKGROUND: Anesthetic clearance from the lungs and the circle rebreathing system can be maximized using hyperventilation and high fresh gas flows. However, the concomitant clearance of CO2 decreases PAco2, thereby decreasing cerebral blood flow and slowing the clearance of anesthetic from the brain. This study shows that in addition to hyperventilation, hypercapnia (CO2 infusion or rebreathing) is a significant factor in decreasing emergence time from inhaled anesthesia. METHODS: We anesthetized seven pigs with 2 MACPIG of isoflurane and four with 2 MACPIG of sevoflurane. After 2 h, anesthesia was discontinued, and the animals were hyperventilated. The time to movement of multiple limbs was measured under hypocapnic (end-tidal CO2 = 22 mm Hg) and hypercapnic (end-tidal CO2 = 55 mm Hg) conditions. RESULTS: The time between turning off the vaporizer and to movement of multiple limbs was faster with hypercapnia during hyperventilation. Emergence time from isoflurane and sevoflurane anesthesia was shortened by an average of 65% with rebreathing or with the use of a CO2 controller (P < 0.05). CONCLUSIONS: Hypercapnia, along with hyperventilation, may be used clinically to decrease emergence time from inhaled anesthesia. These time savings might reduce drug costs. In addition, higher PAco2 during emergence may enhance respiratory drive and airway protection after tracheal extubation.

Rapid recovery from sevoflurane and desflurane with hypercapnia and hyperventilation.

BACKGROUND: Hypercapnia with hyperventilation shortens the time between turning off the vaporizer (1 MAC) and when patients open their eyes after isoflurane anesthesia by 62%. METHODS: In the present study we tested whether a proportional shortening occurs with sevoflurane and desflurane. RESULTS: Consistent with a proportional shortening, we found that hypercapnia with hyperventilation decreased recovery times by 52% for sevoflurane and 64% for desflurane (when compared with normal ventilation with normocapnia). CONCLUSION: Concurrent hyperventilation to rapidly remove the anesthetic from the lungs and rebreathing to induce hypercapnia can significantly shorten recovery times and produce the same proportionate decrease for anesthetics that differ in solubility.

A Turbine-Driven Ventilator Improves Adherence to Advanced Cardiac Life Support Guidelines During a Cardiopulmonary Resuscitation Simulation.

BACKGROUND: Research has shown that increased breathing frequency during cardiopulmonary resuscitation is inversely correlated with systolic blood pressure. Rescuers often hyperventilate during cardiopulmonary resuscitation (CPR). Current American Heart Association advanced cardiac life support recommends a ventilation rate of 8-10 breaths/min. We hypothesized that a small, turbine-driven ventilator would allow rescuers to adhere more closely to advanced cardiac life support (ACLS) guidelines. METHODS: Twenty-four ACLS-certified health-care professionals were paired into groups of 2. Each team performed 4 randomized rounds of 2-min cycles of CPR on an intubated mannikin, with individuals altering between compressions and breaths. Two rounds of CPR were performed with a self-inflating bag, and 2 rounds were with the ventilator. The ventilator was set to deliver 8 breaths/min, pressure limit 22 cm H2O. Frequency, tidal volume (VT), peak inspiratory pressure, and compression interruptions (hands-off time) were recorded. Data were analyzed with a linear mixed model and Welch 2-sample t test. RESULTS: The median (interquartile range [IQR]) frequency with the ventilator was 7.98 (7.98-7.99) breaths/min. Median (IQR) frequency with the self-inflating bag was 9.5 (8.2-10.7) breaths/min. Median (IQR) ventilator VT was 0.5 (0.5-0.5) L. Median (IQR) self-inflating bag VT was 0.6 (0.5-0.7) L. Median (IQR) ventilator peak inspiratory pressure was 22 (22-22) cm H2O. Median (IQR) self-inflating bag peak inspiratory pressure was 30 (27-35) cm H2O. Mean ± SD hands-off times for ventilator and self-inflating bag were 5.25 ± 2.11 and 6.41 ± 1.45 s, respectively. CONCLUSIONS: When compared with a ventilator, volunteers ventilated with a self-inflating bag within ACLS guidelines. However, volunteers ventilated with increased variation, at higher VT levels, and at higher peak pressures with the self-inflating bag. Hands-off time was also significantly lower with the ventilator. (ClinicalTrials.gov registration NCT02743299.).

Correction: Antidepressant and Neurocognitive Effects of Isoflurane Anesthesia versus Electroconvulsive Therapy in Refractory Depression.

[This corrects the article DOI: 10.1371/journal.pone.0069809.].

Antidepressant and neurocognitive effects of isoflurane anesthesia versus electroconvulsive therapy in refractory depression.

BACKGROUND: Many patients have serious depression that is nonresponsive to medications, but refuse electroconvulsive therapy (ECT). Early research suggested that isoflurane anesthesia may be an effective alternative to ECT. Subsequent studies altered drug, dose or number of treatments, and failed to replicate this success, halting research on isoflurane's antidepressant effects for a decade. Our aim was to re-examine whether isoflurane has antidepressant effects comparable to ECT, with less adverse effects on cognition. METHOD: Patients with medication-refractory depression received an average of 10 treatments of bifrontal ECT (n = 20) or isoflurane (n = 8) over 3 weeks. Depression severity (Hamilton Rating Scale for Depression-24) and neurocognitive responses (anterograde and retrograde memory, processing speed and verbal fluency) were assessed at Pretreatment, Post all treatments and 4-week Follow-up. RESULTS: Both treatments produced significant reductions in depression scores at Post-treatment and 4-week Follow-up; however, ECT had modestly better antidepressant effect at follow-up in severity-matched patients. Immediately Post-treatment, ECT (but not isoflurane) patients showed declines in memory, fluency, and processing speed. At Follow-up, only autobiographical memory remained below Pretreatment level for ECT patients, but isoflurane patients had greater test-retest neurocognitive score improvement. CONCLUSIONS: Our data reconfirm that isoflurane has an antidepressant effect approaching ECT with less adverse neurocognitive effects, and reinforce the need for a larger clinical trial.