Propofol, a short-acting hypnotic drug, is increasingly administered by a diverse group of specialists (e.g., by cardiologists, gastroenterologists) during diagnostic and therapeutic procedures to optimize patient well-being.1–3 The use of propofol by nonanesthesiologists in selected patients (ASA classes I–II) is referred to as nonanesthesiologist-administered propofol (NAAP). At the time of the study, applicable guidelines recommended continuous pulse oximetry with visual assessment of the patient’s breathing pattern as standard respiratory monitoring during sedation.1,4 Because undetected hypoventilation is a common pathway for many complications during such procedures, some authors have advocated monitoring of exhaled carbon dioxide (CO2) with capnography as an addition to pulse oximetry.5–7
Microstream capnography, a relatively new technology for CO2 monitoring in exhaled air, is capable of reliably monitoring respiratory patterns in spontaneously breathing patients.8,9 This technique provides more useful information on the frequency, effectiveness, and regularity of ventilation than visual assessment of the patient’s breathing pattern.10,11 A meta-analysis illustrated that capnography significantly increases the detection of abnormal respiration.11 Additional studies also indicated a decrease in sedation-associated hypoxemia by early identification of respiratory depression during capnographic monitoring.5,6,12,13 However, in these studies, an independent observer prompted the medical team in case of capnography abnormalities5,6,13 or supplemental oxygen was routinely administered.6,12,13 None of these studies investigated the additional value of capnography when monitored by the responsible medical team to prevent hypoxemia during deep sedation with propofol (administered as monotherapy without additional opioids or sedatives) if supplemental oxygen is not routinely administered.
The purpose of this study was to examine the effectiveness of microstream capnography by early detection and therapy of alveolar hypoventilation during deep sedation in comparison with standard monitoring with pulse oximetry only. In the current randomized trial, we tested the hypothesis that using microstream capnography in women undergoing deep sedation with propofol (monotherapy) without routinely administered supplemental oxygen reduces the incidence of hypoxemia.
Approval of the study protocol was obtained from the Medical Ethics Board of University Medical Centre Utrecht. Written informed consent was obtained from 438 patients older than 18 years undergoing minor gynecology procedures (mainly abortions) under deep sedation in an outpatient clinic (CASA clinic, Leiden, the Netherlands). We excluded patients with ASA classes III to V, a history of allergic reactions to propofol, soy bean or egg proteins, sleep apnea syndrome, and patients who refused participation or who were unable to give informed consent. The study was conducted in accordance with the moral, ethical, and scientific principles governing clinical research in the Declaration of Helsinki (2008) and Good Clinical Practice. The trial was registered at ClinicalTrials.gov under identifier NCT 01220765.
Randomization and Masking
This was an open, stratified, and randomized controlled trial. To best simulate normal clinical conditions, we took a pragmatic approach for monitoring of the capnograph by using the medical team providing sedation, instead of an independent observer. Patients were randomly assigned to 1 of the 2 parallel groups to receive either standard respiratory monitoring with pulse oximetry and visual observation of breathing (standard care) or standard respiratory monitoring combined with capnography (capnography group). Stratified block randomization was conducted using random block sizes of 4, 6, 8, and 10 to ensure equal distribution over physicians. Patients and physicians were aware of the treatment allocation by the time sedation was administered.
Microstream capnography was performed using a cannula under the nose (Smart CapnoLine; Oridion Capnography Inc., Needham, MA) connected to a capnograph (Capnostream™ 20; Oridion Medical 1987 Ltd., Jerusalem, Israel). The microstream technique is based on emission of selective infrared wavelengths exactly matching for CO2 absorption.14 Due to this efficient and selective emission process, only small samples of CO2 are necessary to be able to detect alveolar hypoventilation. The capnograph displays respiratory rate, end-tidal carbon dioxide (EtCO2) levels, and a continuous capnographic waveform. In both study groups, pulse oximetry was measured with the pulse oximeter integrated in the device. Both nurses and doctors were trained and certified in sedation management. In addition, both groups were trained in the assessment of capnographic waveforms and interpretation of EtCO2 values before the trial started. The training consisted of written study material, a theoretical lecture, practical training, and a written test. The course comprised physiologic understanding and assessment of capnographic traces, integrating multiple readings, and performing appropriate actions. All nurses passed the written test; overall, 80% of questions were correctly answered. Nurses responsible for the sedation were also primarily responsible for monitoring the capnograph. Inadequate ventilation on the capnograph was defined as high EtCO2 (EtCO2 ≥ 6.7 kPa), absent alveolar plateau, apnea (flat line on the capnograph >10 seconds), bradypnea (respiratory rate ≤8 breaths per minute), and tachypnea (respiratory rate ≥30 breaths per minute).
Nurses qualified in patient sedation management performed sedation, following an approved standardized protocol supervised by a physician with similar sedation training. No anesthesiologist was in attendance. All patients received a peripheral IV catheter and were continuously monitored for heart rate, pulse oximetry, visual assessment of chest wall excursions, and periodic arterial blood pressure measurement. Supplemental oxygen was not administered routinely according to the institutional sedation protocol. Routinely administered supplemental oxygen is considered to reduce the additive value of pulse oximetry as a respiratory monitor.15,16
Patients were placed in the lithotomy position and deeply sedated (Ramsay sedation score 5, sluggish response to a loud verbal stimulus) with an initial dose of 100 mg propofol (monotherapy) IV followed by repeated bolus injections of 20 to 30 mg when lighter levels of sedation were noticed. Local anesthesia of the cervix was performed with 100 to 200 mg lidocaine. In 11 cases (2.7%), IV analgesia (a single bolus of alfentanil 0.5 mg IV) was administered off protocol and commissioned by the responsible physician in patients with discomfort that could not be redressed with propofol only. When inadequate ventilation or oxygenation was detected, nurses intervened according to the study protocol. They intervened by checking the position of the nasal cannula, refrained from additional propofol administration and aroused the patient by a verbal stimulus. If this was not sufficient to restore adequate ventilation, they performed an airway maneuver (chin-lift or jaw-thrust). When these actions did not improve respiration, supplemental oxygen was administered using a nonrebreathing mask until the abnormalities were normalized.
The primary outcome was the occurrence of hypoxemia, defined as oxygen saturation (SpO2) <91% of any duration. Recorded SpO2 values <91% were considered artifacts when loss of pulse occurred 0 to 20 seconds before and after the episode, or when SpO2 level decreased >10% within 5 seconds. Secondary outcomes were profound hypoxemia (SpO2 <81%), prolonged hypoxemia (≥60 seconds), administration of supplemental oxygen, airway interventions, arousal or movement of the patient that interfered with performing the procedure, and early termination of the procedure.
Data Collection and Processing
Demographic information was collected for eligible patients from a routinely performed health care questionnaire. Three trained research collaborators collected data. They recorded patient characteristics and medical observations (e.g., propofol dosage, airway interventions) in an Anesthesia Information Medical System via a customized entry screen, and a free text box to enter any relevant observations. Patients were randomized by a Web-based application according to a computer-generated randomization list (programmed by ATvRL) when entering the intervention area. The plethysmographic waveform from the pulse oximeter and the capnography waveform were stored in coupled text files with a 20 Hz sample frequency. SpO2 values were averaged every 5 to 7 seconds. After termination of the trial, electronic data were analyzed with a dedicated algorithm using LabView software (version 8; 2005 National Instruments, Austin, TX). The algorithm evaluates each text file separately and identifies episodes with a SpO2 level <91%. Point of time, number, and duration of episodes were displayed by the algorithm. A graph was then produced, with time on the x-axis and SpO2, and heart rate on the y-axis. Any hypoxemic event detected by the algorithm was manually verified by the researcher (KvL) who was kept blinded to the group allocation and classified as either a “true” desaturation or an artifact. In patients allocated to the capnography arm of the trial, CO2 and respiratory rate were also plotted versus time. Episodes of bradypnea, tachypnea, apnea, and hypercapnia were automatically identified by the algorithm and manually verified (KvL) to eliminate episodes with obvious artifacts. Afterwards, the SpO2 and capnography graphs were coupled to determine whether capnography changes preceded desaturations and the time interval between abnormalities.
The sample size calculation was based on preliminary observations in this study population where hypoxemia was recorded in 21 of 100 (21%) patients. Based on a comparison of 2 proportions, we needed 440 patients to demonstrate a significant decrease in the incidence of hypoxemia from 20% to 10% with a significance level of 0.05 and power of 0.80 with 10% lost to follow-up.
For descriptive analyses, we computed frequencies for categorical variables and mean with standard deviation (SD) or median with interquartile range for continuous variables. We addressed the null hypothesis that equal proportions of intervention and control subjects would experience hypoxemia using the χ2 test. Confidence intervals (CIs) for absolute risk differences were calculated with the Newcombe-Wilson method without continuity correction. A per-protocol analysis was also performed without cases that received alfentanil. Analyses were performed with SPSS version 15.0.1 (SPSS Inc., Chicago, IL).
From April 2010 to January 2011, we screened 1210 patients for possible study participation (main reasons for not participating: the patient chose not to participate, was underage or ASA class >2), of whom 427 were randomized (Fig. 1). Eleven patients gave their informed consent but were excluded because one of the randomization strata was depleted; therefore, they were not randomized and received standard care. Four hundred fifteen patients had the primary outcome registered and were thus available for intention-to-treat analysis. In 12 patients, data were lost due to technical (device) failure. The number of patients treated per group was 209 for standard care and 206 for capnography. Baseline characteristics of patients were similar in both study groups (Table 1). Duration of the procedure (18.9 vs 19.3 minutes, P = 0.685) and propofol dose did not differ between standard care and capnography, respectively. Propofol was administered in bolus injections consistent with an average infusion rate of 15.3 (SD 5.3) vs 14.9 (SD 3.2) mg·kg−1·h−1 (P = 0.326). The average total propofol dose was 4.6 (SD 2.2) mg·kg−1 for both groups.
Primary Outcome: Incidence of Hypoxemia
The number of patients with hypoxemia (SpO2 <91%) at any time during NAAP sedation was 53 (25.7%) in the capnography group and 52 (24.9%) in the standard care group (P = 0.843), resulting in an absolute risk difference of 0.8% (95% CI, −7.5% to 9.2%) (Table 2).
Secondary Analysis of the Primary Outcome
The number of patients with profound hypoxemia (SpO2 <81%) was equally distributed between groups (3.4% vs 2.9%). Also, the number of patients with a prolonged hypoxemic episode (hypoxemic episode ≥60 seconds) did not differ significantly (3.9% vs 1.4%, P = 0.121). In the capnography group, 86 hypoxemic episodes were detected by pulse oximetry vs 81 in the standard care group. The duration of the hypoxemic periods differed slightly between groups. Most hypoxemic episodes were very brief (hypoxemic episode ≤15 seconds) in both the capnography and standard care groups (42 vs 39 episodes), but more prolonged hypoxemic episodes were present in the capnography group (12 vs 3 episodes). “Off protocol” administration of alfentanil in 11 patients resulted in a higher incidence of hypoxemia (73%), but did not influence the primary outcome of the study. In the per-protocol analysis, the number of patients with hypoxemia was 48 (24.0%) in the capnography group and 49 (24.0%) in the standard care group (P = 0.996).
The incidence of airway interventions performed was significantly higher in the capnography group. One hundred two (49.5%) patients in the capnography group and 67 (32.1%) in the standard care group underwent a chin-lift or jaw-thrust at least once during the procedure (P < 0.001). Supplemental oxygen was administered in 26 (12.6%) patients in the capnography group and 17 (8.1%) in the standard care group (P = 0.134). Three patients from the capnography group had their sedation prematurely terminated, because in 1 patient, the gynecology procedure could not be performed due to technical difficulties, and in 2 patients, respiratory function was seriously compromised during sedation. In these 2 patients, the procedure was continued under local anesthesia. The occurrence of agitation and restlessness was almost similar; 35 patients in the capnography group (17%) and 42 (20.1%) in the standard care group had an episode of inadequate sedation causing suboptimal conditions for the physician performing the procedure. The pulse oximetry signal was distorted (artifacts) in 189 (45.5%) patients during on average 2.1% of total monitoring time. In 9 patients (4.4%), capnography traces showed a brief period of artifacts.
In the capnography group, the respiratory pattern was characterized by tachypnea. Average respiratory rate at baseline (20 breaths per minute) significantly increased to 25 breaths per minute during the remainder of the procedure (mean difference +5.34; 95% CI, 4.46–6.23). Capnographic changes preceded the period of hypoxemia (SpO2 <91%) in 63% of the desaturation episodes (Table 3). In most cases, capnography showed an absent alveolar plateau (25.6%) before hypoxemia occurred. Furthermore, an apneic period preceding the occurrence of hypoxemia was recorded in 18.6% of patients who experienced a hypoxemic episode (Table 3). None of the hypoxemic periods was preceded by high EtCO2 values suggestive of persistent hypoventilation. The median time between the start of the capnography abnormalities and hypoxemia was 32 seconds (range, 0–117 seconds).
We studied the effect of adding capnography to pulse oximetry monitoring during NAAP without routine oxygen supplementation and did not observe a decreased incidence of hypoxemia during sedation. The overall incidence of hypoxemia (SpO2 <91% of any duration) was 25%. This incidence matches the reported incidences in reasonably comparable study populations (12%–53%), while we held the more stringent definition for hypoxemia.5,12,13,16,17 Most hypoxemic episodes were brief and could be considered as “mild” hypoxemia (91% < SpO2 ≤ 81%). Off protocol administration of alfentanil did not influence the study outcome. In contrast to our a priori hypothesis, capnography also did not decrease the incidence of profound (SpO2 <81%) and prolonged (hypoxemia episode ≥60 seconds) hypoxemia. The number of prolonged hypoxemic episodes in patients additionally monitored with capnography was slightly higher, although this difference was not statistically significant. Nurses did respond to abnormal capnography traces with significantly more airway interventions and were also more likely to administer supplemental oxygen. Nevertheless, these maneuvers could not prevent patients from developing hypoxemia. Off-line analysis of capnographic traces revealed that hypoxemic episodes were preceded by evident capnographic changes in only two-thirds of patients. The most frequent capnographic abnormality before hypoxemia was an absent alveolar plateau indicating shallow breathing resulting in larger dead-space fraction ventilation.
There are various possible explanations for these unexpected findings. First, propofol was used as the sole sedative drug. Infusion of propofol induces a marked tidal volume reduction and a 20% to 30% increase in respiratory rate.18 The latter is also supported by our data. Propofol-induced respiratory changes limit the respiratory reserve, which would explain the short time interval between the onset of capnographic abnormalities and the occurrence of desaturations. This effect is even more pronounced because oxygen was not routinely administered. Therefore, the time available to interpret altered capnographic traces and take proper therapeutic action may be too short to prevent hypoxemia. Second, hypoxemic episodes were not always preceded by overt capnographic abnormalities. This was also observed by Sivilotti et al.19 in a randomized clinical trial comparing titrated propofol with fentanyl to propofol with low-dose ketamine for procedural sedation in the emergency room. Third, apneas, defined as an episode without breathing for at least 15 seconds, occur either as a result of upper airway obstruction or depression of the central respiratory drive system. The latter is not preventable or treatable with an airway intervention such as chin-lift or oxygen supply. The medical team was very reluctant to use bag-mask ventilation in such situations, because it may result in stomach insufflation, vomiting, and aspiration. Given the transient nature of these apneas, as rapid recovery is seen after terminating the propofol infusion, one might argue that this practice is defensible, provided that recovery to normal respiratory function is closely monitored.
None of our study participants received supplemental oxygen routinely. According to the institutional and study protocol, supplemental oxygen was only temporarily administered in case of disturbed oxygenation or ventilation. At the time of the study, applicable guidelines recommended only pulse oximetry, and not capnography, as part of standard monitoring equipment during sedation.1,4 Routine supplemental oxygen administration diminishes the value of pulse oximetry as a ventilatory monitor, since hypoxemia becomes a late sign of respiratory depression. It was confirmed by Deitch et al.16 that supplemental oxygen was related to a higher incidence of respiratory depression. Adding capnography in the specific setting with propofol monotherapy sedation in the absence of routinely administered supplemental oxygen did not decrease the incidence of hypoxemia. Our study findings do not discount the possibility that the value of capnography monitoring might be more pronounced in patients receiving routine supplemental oxygen or receiving different sedation regimens.
A final possible explanation for the observed lack of effectiveness of capnography for reducing the incidence of hypoxemia in this specific setting is incorrect or late execution of appropriate airway interventions. The nurses and physicians in this study, however, had received theoretical and practical training by anesthesiologists, and it is unlikely that other nonanesthesiologists in a similar setting would perform better. Still, it is counterintuitive that more extensively monitored patients had more episodes of prolonged hypoxemia. In 3 of 8 patients with prolonged hypoxemia, no overt capnographic changes could be observed; in 2 patients, respiratory abnormalities preceded the hypoxemic episode, but these had normalized during the actual hypoxemic episode; and in 3 patients, ventilation was consistently abnormal (2 patients with an absent alveolar plateau and 1 patient with repeated apneic episodes). Possibly, caregivers were reassured by the presence of a normal capnography waveform, which may have induced them to accept the low SpO2 values. Integrating the results from 2 different monitors is a difficult task and probably requires more experienced personnel and specific training. The potential explanation that caregivers increased the propofol dose because they were reassured by the presence of a capnographic waveform did not hold, as the propofol dose did not differ between patients with or without a hypoxemic episode in the randomization groups.
Several studies have addressed the potential additional value of capnography during procedural sedation in different settings (emergency department, elective sedation for several procedures) and different hypnotic regimes (propofol or midazolam with or without opioids). In previous studies, capnography reduced the incidence of hypoxemia during elective procedural sedation.5,6,12,13 In contrast to these studies, we evaluated daily practice, and no independent observer was used to interpret the capnogram and prompt the medical team when respiratory depression was detected. In a randomized controlled trial that evaluated procedural propofol sedation at an emergency department, capnography detected respiratory depression in all patients developing hypoxemia and the incidence of hypoxemia was also reduced by this intervention.12 Conversely, in a small observational study with 2 sedation regimens evaluating whether capnography or pulse oximetry first detected respiratory events during procedural sedation in adults breathing room air, pulse oximetry detected hypoxemia well before overt capnographic changes were identified.19 Our findings are in agreement with the study by Sivilotti et al.,19 because we were unable to demonstrate a benefit of adding capnography to pulse oximetry for preventing hypoxemia in this particular setting. In both our study and in Sivilotti et al.’s study,19 oxygen was not routinely administered. This is in contrast to the study by Deitch et al.12 who administered supplemental oxygen routinely and found a reduction of hypoxemia after introduction of capnography. From this study, it is unclear whether the reduced hypoxemia incidence was due to a positive effect of capnography or because supplemental oxygen decreased the ability of pulse oximetry to detect ventilatory depression.
When interpreting the findings of this study, some limitations should be considered. First, we chose hypoxemia as the primary outcome measure, which is a surrogate end point for patient outcome. Although this may be perceived as a limitation, the incidence of serious adverse events during procedural sedation in healthy patients is extremely low, which multiplies the amount of patients needed to study the effect of capnography on serious adverse events rates. Second, whether a patient experienced an episode of hypoxemia was based on off-line classification of recorded SpO2 values. Obvious artifacts were eliminated using a computer algorithm and visual inspection; nevertheless, it is possible that there was residual misclassification of hypoxemia as a result of artifacts. However, it is unlikely that the number of false positives differs between the capnography and standard care group because it was analyzed using a computer algorithm and treatment allocation was blinded during manual validation. The same applies to the number of false negatives for which no information is available because the diagnostic accuracy of pulse oximetry is not under research. Third, the results of this study can only be applied to situations in which propofol is administered as the sole drug for procedural sedation. It is conceivable that the added value of capnography will be much more obvious when opioid analgesics are used in combination with hypnotic/sedative drugs, because such regimens typically cause more respiratory depression.
We were unable to confirm an additive role for capnography in preventing hypoxemia during elective NAAP (monotherapy) sedation in healthy women in whom supplemental oxygen is not routinely administered. Based on the CI, the benefit of adding capnography is at most an absolute hypoxemia reduction of 7.5%, suggesting that adding it in this practice setting to the routine monitoring strategy does not necessarily improve patient safety in daily practice. This randomized controlled trial thereby emphasizes the importance of evaluating monitoring strategies for sedation.
Name: Kim van Loon, MD.
Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.
Attestation: Kim van Loon has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Aart T. van Rheineck Leyssius, MD.
Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.
Attestation: Aart T. van Rheineck Leyssius has seen the original study data and approved the final manuscript.
Name: Bas van Zaane, MD, PhD.
Contribution: This author helped analyze the data and write the manuscript.
Attestation: Bas van Zaane reviewed the analysis of the data and approved the final manuscript.
Name: Mirjam Denteneer, MD.
Contribution: This author helped design and conduct the study and write the manuscript.
Attestation: Mirjam Denteneer approved the final manuscript.
Name: Cor J. Kalkman, MD, PhD.
Contribution: This author helped design and conduct the study and write the manuscript.
Attestation: Cor J. Kalkman has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
This manuscript was handled by: Peter S. A. Glass, MB, ChB.
W. Beekhuizen, MD, and Professor J. T. A. Knape, MD, were involved in the early stages of designing the study and laid the foundation for cooperation between the University Medical Centre Utrecht and CASA clinic Leiden in this research project.
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