the remora studyscripties.umcg.eldoc.ub.rug.nl/files/root/geneeskunde/... · 2015-07-07 · nellcor...

M.H. Verheul – respiratory rate monitoring during procedural sedation and analgesia – study report 1

The REMORA study

Respiratory Rate Monitoring In Patients Receiving Procedural Sedation And Analgesia For Upper Gastrointestinal Endoscopy

Milou Verheul s1807889 Faculty supervisor: Drs. C. Bles, anesthetist-intensivist, Deventer Ziekenhuis External supervisors: Drs. Hugo Touw, specialty registrar in Anesthesia, VUmc Amsterdam Dr. C. Boer, associate professor research acute & perioperative care, VUmc Amsterdam Location: VU University Medical Centre, Amsterdam, Department of Anesthesiology


Index Nederlandse samenvatting..................................................................................................... 3 English summary................................................................................................................... 4 Background........................................................................................................................... 5

Respiratory changes during sedation.................................................................................. 6 Ventilation ........................................................................................................................ 6 Oxygenation...................................................................................................................... 7 Monitoring of respiratory function in gastrointestinal endoscopy....................................... 8

Material and method............................................................................................................ 12 Patients............................................................................................................................ 12 The endoscopic procedure ............................................................................................... 12 Monitoring ...................................................................................................................... 12 Respiratory variables....................................................................................................... 13 Statistical analysis ........................................................................................................... 14

Results ................................................................................................................................ 15 Patient characteristics ...................................................................................................... 15 Respiratory monitoring.................................................................................................... 16 Analysis of the agreement between RROXI and RRETCO2................................................... 16 Detection of abnormal breathing patterns ........................................................................ 18

Discussion........................................................................................................................... 21 Conclusion .......................................................................................................................... 23 Acknowledgments............................................................................................................... 24 References .......................................................................................................................... 25


Nederlandse samenvatting ACHTERGROND De Nellcor 2.0 is een nieuwe monitor die via een vinger sensor de saturatie meet en de ademhalingsfrequentie (AH/min) berekent op basis van het toepassen van een algoritme op het plethysmogram, een curve die de mate van vulling van het vaatbed weerspiegelt. Doel van deze studie was om de klinische toepasbaarheid vast te stellen van implementatie van de Nellcor 2.0 bij orale gastro-intestinale endoscopieën onder procedurele sedatie en analgesie (PSA). Daarmede werd de mate van overeenstemming bepaald tussen de Nellcor 2.0 en de goud standaard; de via capnografie verkregen ademhalingsfrequentie (RRETCO2). METHODE Vierentwintig patiënten werden gemonitord gedurende de toediening van PSA bij orale gastro-intestinale endoscopieën. De gemeten ademhalingsfrequenties van de Nellcor 2.0 (RRoxi) werden vergeleken met de simultaan verkregen referentie ademhalingsfrequenties van de capnometer (RRETCO2, gebaseerd op end-tidal CO2 metingen). RESULTATEN Een totaal van 1054 minuten aan respiratoire data werd verkregen en geanalyseerd. Het mediane percentage van de procedure tijd dat de Nellcor 2.0 geen ademhalingsfrequentie kon weergeven was 15,5 % (8,6 – 27,7 %), resulterend in 885 gepaarde ademhalingsfrequentie metingen. De gemiddelde RRETCO2 was 12,4 AH/min, variërend tussen de 0 en 36 AH/min. Het gemiddelde verschil ± standaard deviatie tussen de ademhalingsfrequentie metingen was 5,78 ± 8,58 AH/min, met 95 % - grenzen van overeenkomst van – 11,03 tot 22,59 AH/min. De lineaire correlatie coëfficiënt van de regressie analyse tussen het gemiddelde en het verschil van de door beide monitoren gemeten ademhalingsfrequentie was – 0,55 (p < 0,0001). Additionele analyse werd uitgevoerd, daarbij onderscheid makend tussen lage ademhalingsfrequenties (4 – 11 AH/min) en hogere ademhalingsfrequenties (≥ 12 AH/min). Het gemiddelde verschil tussen de metingen was voor de lagere frequenties 1,71 ± 3,00 AH/min, met 95 % - grenzen van overeenkomst van – 4,17 tot 7,60 AH/min. Voor de hogere frequenties was het gemiddelde verschil – 0,50 ± 3,18 AH/min, met 95 % - grenzen van overeenkomst van – 5,72 tot 6,73 AH/min. CONCLUSIE De resultaten van deze studie suggereren dat de Nellcor 2.0 niet klinisch toepasbaar is in de setting van orale gastro-intestinale endoscopieën onder procedurele sedatie en analgesie. Bij lagere ademhalingsfrequenties verminderde de mate van overeenstemming tussen RRoxi en RRETCO2.


English summary BACKGROUND The Nellcor 2.0 is a new non-invasive monitor, which measures the oxygen saturation using a finger sensor and calculates the respiratory rate (RRoxi) based on the plethysmogram, a curve which reflects the amount of vascular filling. The aim of this study was to investigate the clinical feasibility of implementation of the Nellcor 2.0 in patients receiving procedural sedation and analgesia (PSA) for upper gastrointestinal endoscopy, and to determine the level of agreement with the capnography waveform based respiratory rate as gold standard. METHOD Twenty-four patients undergoing upper gastrointestinal endoscopy were monitored during the administration of PSA. The acquired respiratory data of the Nellcor 2.0 (RRoxi) were compared to the simultaneously acquired end-tidal CO2 reference rate (RRETCO2). RESULTS A total of 1054 minutes of respiratory data were collected. The median percentage of monitored procedure time the Nellcor 2.0 did not report respiratory rate was 15.5 % (8.6 – 27.7 %), yielding a total of 885 paired observations. The mean measured respiratory rate for the reference method was 12.4 brpm, ranging from 0 to 36 brpm. Mean difference between respiratory rate measurements ± standard deviation was 5.78 ± 8.58 brpm, with 95 % limits of agreement from – 11.03 to 22.59 brpm. The linear correlation coefficient of the regression analysis between the average of measured respiratory rate of both monitors and the difference was – 0.55 (p < 0.0001). Additional analyses were performed, distinguishing between respiratory rates from 4 to 11 brpm and respiratory rates above 12 brpm. The mean difference between measurements of respiratory rates from 4 to 11 brpm was 1.71 ± 3.00 brpm, with 95 % limits of agreement from – 4.17 to 7.60 brpm. For higher respiratory rates the mean difference was – 0.50 ± 3.18 brpm, with 95 % limits of agreement from – 5.72 to 6.73 brpm. CONCLUSION The results of this study suggest that the Nellcor 2.0 is not clinical feasible in the setting of patients receiving procedural sedation and analgesia for upper gastrointestinal endoscopies. The agreement between RRoxi and RRETCO2 decreased along with decreasing respiratory rates.


Background Since the beginning of the twentieth century, sedatives and analgesics are used to relieve anxiety and pain. Sedation for this purpose was first used by Ralph Walters (1883 - 1979), a dental surgeon, who sedated children to make the unpleasant dental procedure more tolerable. Anesthesiologists filled the role of sedation experts. In 1960 there became an increasing interest for using shorter-acting anesthetic strategies with a more rapid return to normal awareness. The use of these sedation strategies extended to the medical diagnostic scene of computed tomography (1974), magnetic resonance imaging (1974), interventional radiology procedures, cardiac catheterization, gastrointestinal and pulmonary endoscopy.1 In the last decades, the number of noninvasive and minimal invasive procedures that are performed outside the operating room are growing exponentially. These procedures can be interventional or diagnostic. Often sedation and/or analgesia is needed, mostly because the procedures can be unpleasant, painful or frightening. The use of sedation and analgesia in the aforementioned settings is called procedural sedation and analgesia (PSA). During PSA, sedatives or dissociative agents with or without analgesics are administered to provide decreased awareness. Thereby, it is of importance that the patients remain able to independently maintain their oxygenation.2 Gastrointestinal endoscopies are frequently performed under PSA. For instance, when the procedure is considered intolerable beforehand or patient preference. Nevertheless, the administration of PSA is not without risks. The use of PSA is an independent risk factor for morbidity and mortality in addition to the procedure itself.3 Side effects include a depressive effect on breathing and circulation. The depressive effect on breathing is associated with the provision of analgesia, which is acquired by activation of µ- and κ-receptors, whereby activation of the µ-receptor also induces respiratory depression. The effect on circulation mainly consists of a decrease in cardiac output and bradycardia.4 These sedation-related cardiorespiratory effects form a major proportion of the endoscopy-associated complications. The incidences of cardiorespiratory unwanted events are associated with patient age, higher risk classification, inpatient status, trainee participation and the routine use of supplemental oxygen during procedures.5 During endoscopy, hypoxia is the most common cardiorespiratory complication with an incidence of 1.5% - 70%. Typically, hypoxia occurs within 5 minutes of medication administration or endoscope intubation.6 The risk of developing hypoxia is related to the level of sedation, the state of health and the type of procedure. The state of health is defined by the American Society of Anesthesiologists (ASA) classification, a widely used grading system for physical status of the patient. The depth of sedation is divided into various sedation levels.7 The following definitions of sedation levels are used for PSA. Minimal sedation (anxiolysis): There is a normal response to verbal stimulation. The cognitive function and coordination may be impaired. Ventilatory and cardiovascular functions are unaffected. Moderate sedation/analgesia: The depression of consciousness is drug-induced. The patient responds purposefully to verbal commands. The airway is patent. Spontaneous ventilation is adequate. The cardiovascular function is usually unaffected.


Deep sedation/analgesia: The depression of consciousness is drug-induced. The patient is not easily aroused, but responds purposefully following repeated or painful stimulation. The maintenance of ventilatory function may be impaired. Patient may require assistance in maintaining a patent airway. Spontaneous ventilation may be inadequate. The cardiovascular function is usually maintained. Understanding the risks associated with these levels of sedation is essential for the PSA to be safe and effective.8 In recent years, further education in the administering of PSA has arisen for anesthesiology assistants. These sedation specialists are qualified and trained for administering moderate to deep sedation, thereby being responsible for the vital functions of the patient and able to provide adequate care in the acute setting with anesthesiologist consultation immediately available. When mild (or in some cases moderate sedation) is targeted, non-anesthesiologists are allowed to administer the sedatives. During PSA, the level of sedation is mostly moderate, although very painful procedures may require deep sedation.8 To prevent complications and to decrease the risks related to sedation, it is important to monitor the patient properly. The availability of noninvasive monitoring of the vital functions, together with ability of PSA administration with maintenance of cardiorespiratory function whereas the drugs are short acting and specific reversal agents for both opioids and benzodiazepines are available makes the administering of PSA more safe.

Respiratory changes during sedation Since mainly respiratory changes can occur during the administering of PSA, the respiratory system should be closely monitored. In addition, respiratory rate monitoring is a clinically important parameter, whereas a change in respiratory rate is one of the earliest and most important indicators of preceding major respiratory complications, such as respiratory tract infections, respiratory depression associated with opioid administration, anesthesia and sedation, as well as respiratory failure.9 The respiratory system consists of ventilation and oxygenation. These are two different things and shall be discussed below.

Ventilation Ventilation is the process of inhaling and exhaling. Ventilation is primarily driven by arterial carbon dioxide (CO2) tension, which is not detected by pulseoximetry.10 Clinical signs to evaluate the adequacy are for instance chest exercises and the manual assessment of respiratory rate. Capnography can also be used to assess ventilation and has become the gold standard. Capnography measures CO2 by using infrared spectography to continuously and quantitatively track a characteristic absorption peak of CO2 at 4200 nanometers, which can be translated into a real-time graphic assessment of respiratory activity. This is accomplished through continuous sampling with a modified nasal cannula.11 In capnography, the measured CO2 is analyzed to detect the presence or absence of ventilation. The depth of the ventilation can also be measured by analyzing the end-tidal CO2, which is the concentration of CO2 at the end of the expiration.


Figure 1. Normal capnogram. Phase I (A-B) is the inspiratory baseline. Phase II (B-C) is the expiratory upstroke. Phase III (C-D) is the expiratory plateau, outflow alveolar gas. Phase IV (D-E) is the inspiratory down stroke, as fresh gas replaces alveolar gas at the sampling site. C: End-Tidal CO2.12 When apnea or airway obstruction occurs in the patient, the end-tidal CO2 drops immediately. The capnograph will show a flat line, which provides an immediate detection of apnea and/or airway obstruction and allows medical staff to anticipate. When supplemental oxygen is used, capnographic monitoring is still reliable because the CO2 is measured at the end of the exhalation and therefore CO2 sampling is not influenced by the extra flow of oxygen.14 As mentioned above, prior to hypoxia, seen on the monitor as a decrease in oxygen saturation, changes in the respiratory rate can be noticed. This supports the use of capnographic monitoring as an early detector of respiratory changes. Consequently, during PSA, the capnographic monitoring of ventilatory status of the patient is of great value. And so, with a quicker notification of respiratory depression, hypoxia can be prevented.

Oxygenation Oxygenation is the process of taking oxygen from inspired air and using this for the aerobic cellular mechanism. Oxygen diffuses passively from the alveolus to the pulmonary capillaries. From there it binds to hemoglobin or it dissolves in the plasma. The arterial oxygen saturation (SaO2) is the proportion of red blood cells whose hemoglobin is bound to oxygen. The arterial oxygen tension (PaO2) is the amount of oxygen that is dissolved in the plasma. Oxygenation is measured via the peripheral oxygen saturation, using pulseoximetry. Pulseoximetry is a noninvasive method to measure the oxygen saturation, using a sensor device, which includes a two wavelengths light and a photo detector, in which the finger can be placed in between. Subsequently it measures the oxygen saturation by utilizing the light absorptive characteristics of hemoglobin and the pulsatile blood flow. The principle of pulseoximetry is that it measures oxyhemoglobin saturation rather than PaO2. In the blood, oxygen is carried out in two forms; dissolved in the plasma and oxygen bound to hemoglobin. The oxygen dissolved in the plasma is only a small fraction of the total oxygen. This is reflected by the PaO2 value. The bigger fraction is the oxygen bound to hemoglobin, and reflected by the SaO2, the hemoglobin saturation. The hemoglobin molecule is capable of binding four oxygen molecules in total. When an oxygen molecule binds, the shape of the hemoglobin changes and thereby also the affinity for the next oxygen molecule changes. This is showed in the S-curved oxyhemoglobin dissociation curve, and reflects that the PaO2 and SaO2 are not linearly related.


Figure 2. The oxyhemoglobin dissociation curve. 13 This S-curve is important for the physiological uptake and delivery of oxygen in the body. The steep slope of the curve shows that a drop in saturation can occur very quickly with only a small drop in PaO2. Changes in oxygenation, measured by the pulseoximetry, are not noticed until the PaO2 drops to the 70 - 80 millimeters of mercury (mmHg) range, where oxygen desaturation occurs and the steep part of the curve is easily approached. However, a drop of approximately 60 - 100 mmHg in PaO2

has to occur before the saturation of 96% will drop to 90%. In procedures where supplemental oxygen is administered patients have a higher PaO2. So, in these patients the PaO2 has to fall even more drastically before any changes in SaO2 will be detected by pulseoximetry.14 In case of supplemental oxygen use, the detection of these changes can be delayed up to 30-60 seconds while hypoventilation or apnea is already present.15,16 A fall in SpO2 is a good indicator for impending respiratory failure, however, due to the nonlinear relationship between SaO2 and PaO2, pulseoximetry can stay behind in the notification of impending respiratory failure.17 This emphasizes the benefit of respiratory monitoring to provide earlier indication of impending respiratory depression. In conclusion, pulseoximetry gives a good reflection of the oxygenation, but not the ventilation.

Monitoring of respiratory function in gastrointestinal endoscopy The use of PSA during gastrointestinal endoscopies goes together with close monitoring of the vital functions of the patient, whereby respiratory function is monitored using capnography along with clinical assessment and peripheral measurements of saturation. However, it seems that capnographic monitoring during oral gastrointestinal endoscopy is not completely reliable since the respiratory function is measured in the same area and influenced by the oral procedure. Qadeer et al. described periods of flat line monitoring (no waveform activity is visible on the capnometer representing apnea) occurred in 13 % of the patients receiving PSA for endoscopic cholangiopancreatography (ERCP) and ultrasonography (EUS), although on clinical exam the patient was breathing effectively.6 Possibly, this low specificity (referred to as a false alarm) can be ascribed to obesity, a narrow oropharyngeal entrance accompanied by reduced air flow due to presence of the oral scope, the suction pump for endoscopic aspiration sucks away the CO2 whereby no CO2 can be detected, or blockage of the nasal cannula by residual moisture accumulation.18 Moreover, it can also occur that the capnometer is failing to register respiratory activity while in the meantime respiratory function is deteriorating, with that the progressive signs of impending respiratory depression staying unnoticed. By not recognizing this respiratory depression on time, due to the measuring error, hypoxia can develop. During oral gastrointestinal endoscopy it is of benefit to diminish, or even prevent, these measuring errors since periods of hypoxia can be prevented. This reflects the need for a monitor that is not influenced by the factors as mentioned above and on that account making the measurements a more reliable representation of the respiratory activity.


The Nellcor 2.0 is a new CE-marked monitor that is able to monitor respiratory rate, as well as the arterial oxygen saturation and pulse rate. The ability to monitor these three parameters by only using a single finger sensor is unique and clinically useful, with the additional advantage of measurements not being influenced by the oral procedure. It provides a continuous monitoring of the arterial oxygen saturation, pulse rate and respiratory rate. An indication of the central ventilatory drive is provided by the respiratory rate. The respiratory rate is processed and interpreted by the photoplethysmogram. The photoplethysmogram is a noninvasive circulatory signal that is related to the pulsatile tissue volume of blood. The changes in volume are detected by using a light emitting diode attached to the finger sensor, where reductions in light intensity indicate relative increases in blood volume and vice versa.19

Figure 3. The NellcorTM Bedside Respiratory Patient Monitoring System Respiration Rate Version 2.0. The photoplethysmogram signal is used to measure the arterial oxygen saturation. A classic pleth pattern consists of a regular cardiac pulse waveform with a constant baseline

component (figure 4a). The cardiac pulse and the baseline can vary over time, for instance as a result of physiological changes. In the pulseoximetry these changes are filtered out to provide accurate arterial oxygen saturation. The Nellcor 2.0, on contrary, uses these subtle changes. The respiratory rate is based on tracking three types of changes, which are associated with the respiratory cycle. These three components include;

Baseline variation During the respiratory cycle the intrathoracic pressure changes. These changes influence the venous return to the heart. During inspiration, the decrease in intrathoracic pressure results in a small decrease in central venous pressure increasing venous return. The opposite occurs during expiration. This results in cyclically filling and draining of the venous bed at the probe site, causing the baseline variation in the pleth (figure 4b).

Pulse amplitude variation Due to the changes in intrathoracic pressure, the cardiac stroke volume varies during the respiratory cycle. During inspiration there is a decreased left ventricular stroke volume, leading to decreased pulse amplitude. The opposite occurs during expiration. This results in pulse amplitude variation in the pleth (figure 4c).

Respiratory sinus arrhythmia During inspiration the heart rate generally increases, and decreases during expiration. This respiratory sinus arrhythmia (RSA) results in pulse frequency variations. The presence of RSA is influenced by several factors including age, health status and physical fitness. The precise mechanisms of RSA remain controversial, but it is generally assumed that RSA is a result of autonomic nervous system activity fluctuation during respiration (figure 4d).20


Figure 4. Variations of the pleth due to respiration.20 These three subtle changes are used to base the respiratory rate upon. The respiratory rate provided by the Nellcor 2.0 (RRoxi) therefore gives a reflection of the central ventilatory drive, and is not a direct measure of ventilation.20 Measurement of respiratory rate based upon this algorithm has proven to be a viable technology. The accuracy of the Nellcor 2.0 algorithm has been demonstrated in various patient groups (table 1).

Table 1. Determining the accuracy of the Nellcor 2.0, compared to capnography data. Number of

patients Mean measured respiratory rate

± SD

Agreement between RRoxi and RRETCO2*,

mean difference ± SD Healthy volunteers 9 139 14.49 ± 4.36 -0.23 ± 1.14 General care floor patients 17 63 16.3 ± 4.7 -0.48 ± 1.77 High respiratory rate at onset monitoring 21

17 22.7 ± 2.4

0.94 ± 1.55

Congestive heart failure patients** 22

12 16.7 ± 3.0

0.4 ± 1.5

Chronic obstructive pulmonary disease patients 23

22 17.6 ± 4.4

0.7 ± 1.6

Note: SD standard deviation, brpm breaths per minute; RRETCO2 respiratory rate based upon measurements of end tidal CO2. *Agreement measured by Bland-Altman analysis. **Congestive heart failure was thought to negatively influence the Nellcor 2.0 algorithm, but this research showed that is was not of influence, and measurements were still accurate. The algorithm has furthermore proven to be viable to detect changes in respiratory rate that occurred due to opioid induced respiratory depression, with a mean drop in respiratory rate from 13.11 ± 3.07 to 6.77 ± 0.76 brpm.24 This feature is important for reason that having accurate and reliable notification of a decrease in respiratory rate, which is a precursor of a decrease in oxygen saturation, gives the medical staff the opportunity to support the patients breathing more quickly and thereby preventing respiratory complications. These data suggest that the Nellcor 2.0 is a clinically acceptable technology for measuring respiratory rate in a range of respiration between 14.8 and 22.7 breaths per minute (brpm).9,17,21,22,23,24 To broaden the use of the Nellcor 2.0, taking in account the importance of performance of the algorithm at the extremes, the algorithm has to be evaluated upon patients with low respiratory rates (and low arterial oxygen saturation levels) to determine whether the Nellcor 2.0 is accurate in those conditions. Due to the administering of procedural sedation and


analgesia, during upper gastrointestinal endoscopy, respiratory rate and the arterial oxygen saturation can vary over time making this an interesting patient population to evaluate the Nellcor 2.0 algorithm upon. The aim of our study was to investigate the clinical feasibility of implementation of the Nellcor 2.0 in patients receiving PSA for upper gastrointestinal endoscopy and to determine the level of agreement with the capnography waveform based respiratory rate as gold standard. We hypothesized that the Nellcor 2.0 is able to provide accurate and reliable notification of (decreasing) respiratory rate. The subsidiary objectives included: (1) to measure the respiratory rate using the Nellcor 2.0 and the capnometer in patients receiving PSA for upper gastrointestinal endoscopy; (2) to determine the elapsed time between occurrence of a respiratory depression and the signaling of a decrease in oxygen.


Material and method This study was approved by the Medical Ethical Committee (METc) and it was confirmed that it is non-WMO (Medical Research involving Human Subjects Act). The study design is a prospective observational study with the use of clinical non-invasive measurements.

Patients Patients receiving PSA for upper gastrointestinal endoscopy were enrolled if they met all of the following inclusion criteria: (1) age 18 years or older and (2) able to give written informed consent. Patients were excluded from enrollment if they met any of the following criteria: (1) mechanical ventilation, (2) atrial fibrillation and (3) presence of implanted pacemaker. Prior to the endoscopic procedure, data on patient characteristics, comorbidity, medical history, ASA classification and type of procedure were collected from hospital records and pre-operative screening reports.

The endoscopic procedure Gastroenterologists performed the upper gastrointestinal endoscopies. The sedation specialist was responsible for the PSA administration and the monitoring of the vital functions of the patient. PSA was administered according to the national guideline for the administration of PSA outside the operating rooms, and the VU Medical Center protocol for PSA during endoscopy.25,26 Propofol (10 milligram per milliliter) was administered via a target-controlled infusion (TCI) system. TCI combines a real-time pharmacokinetic model with an infusion pump. It allows the administration and maintenance of a constant blood concentration of the drug, and thereby the sedation can be maintained. TCI for propofol has several benefits including rapid recovery with a low incidence of nausea and vomiting.27

Monitoring All patients were monitored continuously using pulseoximetry (saturation), capnography via a nasal cannula (respiratory rate monitoring), ECG (heart frequency) and intermittent blood pressure measurements. For study purpose the Nellcor 2.0 finger sensor was attached to the patient, on the opposite side of where the blood pressure cuff was located, to register the respiratory rate. In all procedures supplemental oxygen (100% oxygen, liters per minute set up according to the sedation specialists) was administered via the nasal cannula. Monitoring started when the first gift of PSA was given and continued until removal of the endoscope at the end of the procedure. The NellcorTM Bedside Respiratory Patient Monitoring System Respiration Rate Version 2.0 (Covidien, Mansfield, MA, USA) was used for measuring respiratory rate (RRoxi). It reproduces a respiratory rate every second, and is able to measure respiratory rate from 4 to 40 brpm. No alarms were set on the Nellcor 2.0 whereas this research is purely observational.


Figure 5. The IntelliVue MX450 – Philips The IntelliVue MX450 – Philips capnometer together with the Microstream CO2 filterline (Koninklijke Philips NV, Böblingen, Germany) were used for measuring respiratory rate, RRETCO2. The IntelliVue MX450 is a small portable monitor, which is often used for sedations outside the operating rooms. The use of the capnometer is standard during these procedures. The capnometer shows a capnography waveform on the monitor that represents the exhaled carbon dioxide. Alarms were set so that when no exhaled carbon dioxide is detected, the alarm went off.

After removal of the endoscopic device, the total amount of TCI administered propofol was noted, as well as the total dosages of other used sedatives and analgesics. Respiratory data were extracted from both monitors. The capnometer converts the capnography waveform data into a respiratory rate for every twelve seconds. The Nellcor 2.0 provides a respiratory rate every second, whereby the displayed respiratory rate the average is of measurements done in the past (approximately) 45 seconds, which is time needed for the algorithm analysis.

Respiratory variables For each monitor, the Nellcor 2.0 and capnometer, respiratory rate alone and in conjunction with oxygen saturation were closely examined and evaluated as follows:

Bradypnea Bradypnea was defined as a respiratory rate from 1 to 7 breaths per minute. The amount of detected bradypnea episodes, and the average length, was calculated for both monitors. Furthermore the amount of bradypnea episodes followed by desaturation was calculated.

Oxygen desaturation Oxygen desaturation was defined as SpO2 below 92%. The amount of episodes of desaturation, and the average length, was calculated. The period prior to desaturation was evaluated for both monitors, and categorized into desaturation following a period of non-registration, a respiratory rate above 8 brpm, bradypnea, or (for the capnometer) apnea. In the case desaturation preceded by an episode of bradypnea, the elapsed time between the occurrence of bradypnea and the signaling of a decrease in oxygen was calculated for both monitors.

Apnea Episodes of apnea captured by the capnometer were defined as > 36 seconds no detection of exhaled carbon dioxide. Episodes of apnea that required basic life support, including airway maneuvers (head-tilt chin-lift, jaw-thrust) and ventilation support with the manual resuscitator (Ambu bag), were recorded. Since it is known that the capnometer has a tendency of registering episodes of apnea, while during clinical exam the contrary is observed, all these (possibly false) apnea alarms were closely examined and compared to the simultaneous performance of the Nellcor 2.0 and if it corresponded with the clinical examined apnea.

Non-registration The performance of monitoring was observed, calculating the percentage and average duration of non-registration during the procedure, defined as the inability to calculate respiratory rate for at least once a minute.


Primary outcomes were respiratory rate and oxygen saturation. Endpoints were bradypnoea and oxygen desaturation.

Statistical analysis Statistical analyses were done using IBM SPSS version 19.0 and GraphPad Prism 6. Standard descriptive statistics were used to describe the characteristics and respiratory data. Nominal variables were expressed as frequencies and percentages, ordinal variables as median and interquartile range, continuous variables as mean and standard deviation. Statistical difference was defined as p < 0.05. The capnometer data consisted of respiratory rates for every twelve seconds, the Nellcor 2.0 for every second. For each patient, acquired data were repeatedly converted into mean respiratory rate per minute for both the capnometer and the Nellcor 2.0 (the average of 5 measurements and 60 measurements, respectively). These converted data were subsequently used for further analysis. Thereby simultaneous measured respiratory rates were compared. Bland-Altman plotting was used to analyze the agreement between the different monitors. Regression analysis was used to quantify whether the difference between measurements for both monitors was related to the average measured respiratory rate.


Results

Patient characteristics A total of twenty-four patients who met the inclusion and exclusion criteria were enrolled in this study. One patient was excluded due to atrial fibrillation, since the Nellcor 2.0 algorithm cannot be performed in the presence of arrhythmia. The study was conducted as expected without protocol deviations and no adverse events occurred. The study population consisted of 16 males and 8 females, with a mean age of 75 ± 16 years and a mean Body Mass Index (BMI) of 23.8 ± 4.9. Median ASA classification for the study population was ASA 2, ranging from 1 to 3. Baseline characteristics of the study population are detailed in Table 2. Table 2. Patient characteristics Patients (n = 24) Demographics - Males / females 16 / 8 - Age, mean 75 ± 16 - BMI, mean 23.8 ± 4.9 Comorbidity - ASA score, median (IQR) 2 (1 – 3) - Alcohol use, n (%) 7 (29) - History of smoking, n (%) 8 (33) Medical condition Respiratory

- Chronic obstructive pulmonary disease, n (%) 2 (8) - Obstructive sleep apnea, n (%) 1 (4)

Cardiovascular - Hypertension, n (%) 7 (29) - Cardiomyopathy, n (%) 1 (4) - Heart failure, n (%) 1 (4)

Renal - Renal failure, n (%) 1 (4)

Hepatic - Cirrhosis, n (%) 1 (4)

Metabolic - Diabetes mellitus, n (%) 2 (8)

Note: IQR interquartile range; BMI Body Mass Index; ASA American Society of Anesthesiologists classification. Different types of procedures were observed, with the majority being oral double balloon enteroscopy (33%), endoscopic retrograde cholangiopancreatograpy (29%) and gastroscopy (21%). The mean duration of the procedure was 44 ± 30 minutes. Every patient received supplemental oxygen with mean administration of 3 ± 0.6 liters of 100% oxygen per minute. One patient received ventilation support for a short time with the manual resuscitator. The procedural sedation and analgesia consisted of a target controlled infusion system with propofol for all patients, with a mean dosage of 392 ± 185 milligram. Bolus doses of alfentanil were administered in 21 patients (88%) with a mean dosage of 244 ± 215 microgram. Bolus doses of S-ketamine were administered in 20 patients (83%) with a mean dosage of 17 ± 11 milligram. The procedure characteristics are detailed in Table 3.


Table 3. Procedure characteristics Patients (n = 24) Type of procedure - Oral double balloon enteroscopy, n (%) 8 (33) - Endoscopic retrograde cholangiopancreatography, n (%)

7 (29)

- Gastroscopy, n (%) 5 (21) - Esophageal dilatation, n (%) 1 (4) - Upper endoscopic ultrasound, n (%) 1 (4) - Percutaneous endoscopic gastrostomy, n (%) 1 (4) Procedure characteristics - Mean duration, minutes 44 ± 30 - Mean supplemental oxygen, L/min 3.0 ± 0.6 - Manual resuscitation, n (%) 1 (4) - Mean heart rate during procedure, bpm 81 ± 15 - Mean saturation during procedure, SpO2 97 ± 3 Procedural sedation and analgesia - TCI propofol, mg 392 ± 185 - Alfentanil use, n (%) 21 (88) - Mean alfentanil use, mcg 244 ± 215 - S-ketamine use, n (%) 20 (83) - Mean S-ketamine use, mg 17 ± 11 Note: bpm beats per minute; mg milligram; mcg microgram; TCI Target Controlled Infusion.

Respiratory monitoring A total of 1054 minutes of respiratory data were analyzed. The mean measured respiratory rate for the reference method (RRETCO2) was 12.4 ± 7.6 brpm. RRETCO2 ranged from a lowest recorded value of 0 brpm (apnea) to a highest value of 36 brpm. RRoxi ranged from 4 brpm, the lowest measurable value for the Nellcor 2.0, to 32 brpm. The capnometer did not report a rate at the upmost 36 seconds, due to the machine recalibrating, but was able to report RRETCO2 at least once a minute during the procedures. The Nellcor 2.0 needed approximately 45 seconds for machine recalibrating, but showed longer periods of not being able to report respiratory rate, with a median of 15.5 % (interquartile range, 8.6 – 27.7) of the monitored procedure time. The Nellcor 2.0 was able to calculate respiratory rate when the SpO2 value ranged between 90 and 100 %. When SpO2 decreased below 90 %, or in case SpO2 dropped more than 3 points, the Nellcor 2.0 was programmed to blank out respiratory rate, because the measurements based on the photoplethysmogram algorithm were not considered trustworthy anymore.

Analysis of the agreement between RROXI and RRETCO2

The Nellcor 2.0 algorithm based respiratory rate was compared to the reference method, the capnographic waveform based respiratory rate. The respiratory rates (brpm) of both Nellcor 2.0 and capnometer were analyzed using Bland-Altman plotting.


First, all obtained respiratory rate measurements of both monitors were compared and analyzed. A total of 885-paired observations of respiratory rate are displayed in the plot, representing all patients. The Bland-Altman plot revealed a bias of 5.78 ± 8.58 brpm, with 95% limits of agreement from – 11.03 to 22.59 brpm, which are shown as a solid and dotted horizontal lines, respectively (figure 6A).

Figure 6. Bland Altman plots between respiratory rate (RR) measured by the capnometer (RRETCO2) and RR simultaneously obtained by the Nellcor 2.0 (RRoxi) in 24 patients receiving PSA for upper gastrointestinal endoscopy. The solid line represents the mean difference (bias). The 95% limits of agreement (LOA) are shown as two dotted lines. A all obtained respiratory rate measurements; B respiratory rate measurements of 4 brpm and higher; C respiratory rate measurements from 4 to 11 brpm; D respiratory rate measurements of 12 brpm and higher. Next, regression analysis was performed, to answer the question whether the difference between measurements was related to the average measured respiratory rate (figure 7). The correlation coefficient of the linear regression analysis was – 0.55 (p < 0.0001). Performed analysis implies that the difference between measurements decreases as the average respiratory rate increases.


Figure 7. Linear regression analysis of all obtained respiratory rate measurements. Taking into account that the Nellcor 2.0 cannot measure respiratory rate below 4 brpm, an additional Bland Altman plot was performed thereby excluding respiratory rates below 4 brpm as measured by the capnometer (figure 6B). This adjusted Bland Altman, representing 690-paired observations, revealed a bias of 2.25 ± 5.41 brpm, with 95% limits of agreement from – 8.35 to 12.84 brpm. In order to interpret the correlation among the difference between measurements and the average measured respiratory rate more closely, Bland Altman analysis was performed again to distinguish between respiratory rates above and below 12 brpm (figure 6C and 6D), whereby normal respiratory rate was considered as 12 brpm.28 In order to improve interpretation, once again rates from 0 to 3 brpm were excluded. These plots point out that the difference between measurements is greater for low respiratory rates as compared to higher rates, revealing a bias of 1.71 ± 3.00 brpm and 95% limits of agreement from – 4.17 to 7.60 brpm, and a bias of 0.50 ± 3.18 brpm with 95% limits of agreement from – 5.72 to 6.73 brpm, respectively.

Detection of abnormal breathing patterns The amount of detected bradypnea episodes, as well as their length and whether it resulted in a period of desaturation, was recorded for both monitors and are detailed in table 4. Only 2 episodes of bradypnea were detected by the Nellcor 2.0, compared to 69 episodes as detected by the capnometer. For each of these episodes it was looked up if they led to desaturation. For the capnometer, only 1 out of 69 episodes of bradypnea resulted in a period of desaturation, 25 seconds after onset of bradypnea. The two detected episodes of bradypnea by the Nellcor 2.0 both led to desaturation, with a mean elapsed time of 33 ± 11 seconds. Besides, these detected episodes did not overlap each other and occurred at different times for both monitors.

Legend figure 7 Pearson R – 0.55 R square 0.30 y = – 1.026 x + 21.06 y intercept 21.06 ± 0.83


Table 4. Bradypnea detection Capnometer Nellcor 2.0 Total detected episodes of bradypnea, n 69 2

- Mean episode length, minutes 1.5 ± 0.5 2.0 ± 1.4 Bradypnea episodes leading to desaturation, n (%) 1 (1) 2 (100)

- Mean elapsed time between bradypnea and desaturation, seconds

25 33 ± 11

Note: bradypnea defined as respiratory rate from 1 to 7 breaths per minute. Desaturation defined as SpO2 < 92 %. A total of 42 episodes of desaturation (SpO2 < 92%) were captured, with a median episode length of 34 seconds (interquartile range, 19 – 141). The breathing patterns prior to the occurrence of desaturation were evaluated separately for each monitor and are detailed in table 5. For both the capnometer and Nellcor 2.0, the majority of desaturations occurred without being proceded by a disturbed breathing pattern (64% and 71%, respectively), followed by apnea (33%) for the capnometer, and by non-registration (24%) for the Nellcor 2.0. Table 5. Episodes of desaturation Total Capnometer Nellcor 2.0 Amount of episodes, n (%) 42 (100) Episode length in seconds, median (IQR) 34 (19 – 141)

- Preceded by apnea, n (%) 14 (33) - Preceded by bradypnea, n (%) 1 (2) 2 (5) - Preceded by respiratory rate ≥ 8, n (%) 27 (64) 30 (71) - Preceded by non-registration, n (%) 10 (24)

Elapsed time between respiratory depression and desaturation, seconds

25 33 ± 11

Note: desaturation defined as SpO2 <92%. Apnea defined as >36 seconds respiratory rate (RRETCO2) = 0, only able to be detected by capnometer. Bradypnea defined as RR from 1 to 7 brpm. Only the capnometer was able to detect episodes of apnea (no exhaled carbon dioxide was measured). During an episode of apnea, together with an impending desaturation, the sedation specialists supported the patients breathing by applying the head-tilt/chin-lift maneuver, or even in one case ventilatory support with use of the manual resuscitator was needed. But, since periods of false alarms occured on the capnometer, it also happened that the capnometer was ignored and subsequently only clinical assessment of patients breathing was relied on. These detected episodes of (false) apnea and the simultaneous registration of the Nellcor 2.0 were evaluated and are detailed in table 6.


Table 6. Apnea detection by capnometer Apnea episodes Total detected episodes 63 - Nellcor 2.0 able to reproduce respiratory rate (> 4) during episode, n (% of total detected apnea episodes)

50 (79)

Mean episode length, seconds 129 ± 95 Episodes of apnea resulting in desaturation, n (%) 14 (22) Elapsed time until desaturation, seconds 57 ± 34 Note: apnea defined as > 36 seconds respiratory rate = 0. Desaturation defined as SpO2 < 92 %. NB. Nellcor 2.0 unable to measure respiratory rate < 4. In 79% of the apnea episodes as detected by the capnometer, the Nellcor 2.0 was able to register respiratory rate. Thereby it was noticed that the Nellcor 2.0 occasionally registered respiratory rate while the patient was truly not breathing (as assessed by clinical observation). An example of this event is shown in figure 11, representing the monitoring period of an included patient.

Figure 8. The curve of monitored respiratory rate and saturation. The courses of SpO2, RRETCO2 and RRoxi during the procedure are demonstrated, in which a period of desaturation developed. Right before desaturation, the RRETCO2 drops to zero, while the RRoxi at first even increases before blanking out, conform expectations during an apnea.

Legend figure 8 The lines represent the course of measurements, described as follows; SpO2 % RROXI (brpm) RRETCO2 (brpm)


Discussion Our study is the first to investigate the clinical feasibility of implementation of the Nellcor 2.0 in patients receiving PSA for upper gastrointestinal endoscopy, whereby the level of agreement was determined with the capnography waveform based respiratory rate. When all obtained respiratory rate measurements were analyzed, a large mean difference between the measurements (the bias) was revealed. This bias, however, is considered to be too great when measuring respiratory rate. The bias favorably dropped when the data were adjusted for the inability of the Nellcor 2.0 to measure respiratory rate below 4 brpm. But, the newly revealed bias is still considered not to be completely accurate. Finally when respiratory rates were divided into lower and higher rates, a beneficial bias was revealed for respiratory rates above 12 brpm. This bias is considered clinically acceptable when measuring respiratory rate. To sum up, in our study the Nellcor 2.0 showed to be only accurate in case of breathing at higher respiratory rates. When patients were breathing at lower respiratory rates the accuracy of the Nellcor 2.0 decreased. However, only 22-paired observations remained for the lower respiratory rates leading to a less reliable interpretation of the Nellcor 2.0 performance at lower rates. The accuracy at higher respiratory rates is in conformity with previous research, but the decrease in accuracy at decreasing respiratory rates has not been described before, yet mean measured respiratory rate of this study is lower than previous research.9,17,21,22,23 For respiratory system monitoring, it is of great value to be able to provide a continuous representative monitoring of respiratory rate, whereas respiratory rate can fluctuate very rapidly and respiratory complications can develop. In order to comment on this, we focused on the performance of monitoring and capturing of disordered breathing patterns. When focusing on the performance of monitoring, it was found that the Nellcor 2.0 occasionally showed periods of interference thereby not being able to monitor respiratory rate. This was thought to be mainly due to excessive patient movement, poor peripheral perfusion (cold hands) or in some cases disruption of monitoring system performance due to the sensor being surrounded by electrical noises of the endoscopic devices. Also, the Nellcor 2.0 did not report respiratory rate due to being programmed to blank out in cases where the SpO2 dropped more than 3 points or below a SpO2 value of 90 %.20 This presumably contributed to the 24% of the episodes of desaturation being preceded by non-registration of the Nellcor 2.0. For described setting these findings are unfavorable and contribute to a diminished applicability. In order to focus on the ability to capture disordered breathing patterns, detection of bradypnea episodes by the Nellcor 2.0 were closely examined. Compared to the capnometer, the Nellcor 2.0 hardly detected any bradypnea episodes. In previous research the Nellcor 2.0 was able to detect episodes of opioid-induced respiratory depression, however, those events occurred in the course of a mean SpO2 value of 98.9 ± 1.8 % and mainly without a decrease in SpO2 of more than 3 % during the respiratory depression.24 Therefore, the low detection rate of bradypnea in this research perhaps can be explained by the bradypnea episodes occurring during instable SpO2 situations (periods in which no respiratory rate can be provided due to the algorithm blanking out according to configuration) and with this inability to capture them. In view of this, the instable SpO2 situations contribute to the decreasing accuracy at lower respiratory rates.


One of our objectives was to determine the elapsed time between the occurrence of a respiratory depression and the signaling of a decrease in oxygen. In order to do so, the breathing patterns prior to desaturation were evaluated. Interestingly, this revealed that the majority of desaturation episodes were not preceded by a disordered breathing pattern, but mostly by respiratory rates of 8 brpm and higher. For gastrointestinal endoscopies, periods of desaturation occurring while the patient is breathing at a normal rate have been described before, whereby it is thought that this might be due to changes in the oxygen exchange mechanism or subtle reduction in chest wall movements.6,29,30 These suddenly occurring desaturations leads to a difficulty in preventing them. Desaturation following bradypnea, though, might be prevented by proper monitoring of the respiratory system and the ability of the monitor to quickly detect decreasing respiratory rate. The two signaled bradypnea episodes by the Nellcor 2.0 during this study both led to desaturation, whereby the decreasing respiratory rate was properly detected prior to desaturation. This finding conforms previous research in the Nellcor 2.0 being able to adequately detect respiratory changes.24 The capnometer detected multiple episodes of apnea. However, it was of difficulty to exactly distinguishing between the presence of a false alarm on the capnometer and a short transient period of true apnea. Specifically, it occurred that the capnometer measurements were negatively influenced by the oral procedure, resulting in a misrepresentation of respiratory rate. As a result, the capnometer monitored a respiratory rate of zero, while the patient was effectively breathing. To gain further insight, the simultaneous performance of the Nellcor 2.0 was evaluated and showed that in the majority of the apneic events the Nellcor 2.0 was able to register respiratory activity. On the occasion of signaling false alarms by the capnometer, the Nellcor 2.0 is of benefit since it is not influenced by the oral procedure. This finding suggests, in relation to the discussed before, that the Nellcor 2.0 could be used complementary to the capnometer to overcome these false alarms, thereby ensuring continuous accurate monitoring of respiratory rate during oral procedures. Nevertheless, against expectations it occasionally happened that during periods of true apnea the Nellcor 2.0 monitored a respiratory rate of at least 4 brpm. This finding may be a result of interference of the Nellcor 2.0 algorithm. The Nellcor 2.0 algorithm is based on the photoplethysmogram and correlates with the changes in intrathoracic pressure. Due to the administration of sedatives and analgesics, weakening of the muscles of respiration can evolve leading to upper airway obstruction, called an obstructive apnea. During these events the effort to breath remains together with concomitant intrathoracic pressure changes, while due to the obstruction effective breathing cannot be established, confounding the Nellcor 2.0 algorithm and resulting in a misrepresentation of respiratory rate. These findings give rise to a difficulty in interpreting the Nellcor 2.0 measurements whereby interpretation cannot be achieved without clinical observation. Also, this might cause a delay in the notification of apnea, which is unfavorable since respiratory complications can further develop, with all the consequences that could entail. There were certain limitations in this study. The capnography waveform was not evaluated; only the capnography waveform based respiratory rate values. Analyzing the waveform would have given useful information in emphasizing the presence of an obstructive apnea. The same applies for, the now omitted, etCO2 measurements prior to the apneic event. This would have given a more complete overview and results could be easier placed in context.


This study once more confirmed that at normal to higher respiratory rates the Nellcor 2.0 is accurate and reliable. Taking this in regard, as well as the non-invasive easy application and the ability of the Nellcor 2.0 monitor to combine respiratory rate with oxygen saturation and pulse rate, the Nellcor 2.0 would be recommended in stable general care settings, mainly settings where deeper desaturations are not expected. In further research it would be recommended to involve bioimpendance sensors measuring thorax excursions during apneic events to address the concerns.

Conclusion This study suggests that the Nellcor 2.0 is not clinical feasible in the setting of patients receiving procedural sedation and analgesia for upper gastrointestinal endoscopies. For respiratory rates above 12 breaths per minute, the Nellcor 2.0 was considered accurate. Yet, the accuracy decreased along with decreasing respiratory rate. The Nellcor 2.0 was easily used and not influenced by the oral procedure, but on the contrary influenced by other factors leading to a diminished applicability. The elapsed time between the occurrence of a respiratory depression and the signaling of a decrease in oxygen was on average 33 seconds, although only two of these events were captured by the Nellcor 2.0. Episodes of desaturation occurred commonly, but were mostly not preceded by a disordered breathing pattern. Furthermore, it was occasionally observed that the Nellcor 2.0 gave a false representation of respiratory rate during apneic events, possibly arising from the Nellcor 2.0 algorithm that is based upon intrathoracic changes.


Acknowledgments I would like to thank my supervisors Hugo Touw and Christa Boer, for guiding me through this clerkship, for motivating me and because they have taught me a lot. My faculty supervisor Carmen Bles. The sedation specialists and the staff of the endoscopic unit, where I was warmly welcomed for the patient inclusions. The physics and medical technology department of the VU medical center and the product managers of Covidien and Philips, for helping me along with understanding the various specifications of the monitors.


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