Comparison of the SpO 2 /FIO 2 Ratio and the PaO 2 /FIO 2 Ratio in Patients With Acute Lung Injury or ARDS*

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1 CHEST Original Research Comparison of the SpO 2 /FIO 2 Ratio and the PaO 2 /FIO 2 Ratio in Patients With Acute Lung Injury or ARDS* Todd W. Rice, MD, MSc; Arthur P. Wheeler, MD, FCCP; Gordon R. Bernard, MD, FCCP; Douglas L. Hayden, MA; David A. Schoenfeld, PhD; and Lorraine B. Ware, MD, FCCP; for the National Institutes of Health, National Heart, Lung, and Blood Institute ARDS Network CRITICAL CARE MEDICINE Background: The diagnostic criteria for acute lung injury (ALI) and ARDS utilize the PaO 2 / fraction of inspired oxygen (FIO 2 ) [P/F] ratio measured by arterial blood gas analysis to assess the degree of hypoxemia. We hypothesized that the pulse oximetric saturation (SpO 2 )/FIO 2 (S/F) ratio can be substituted for the P/F ratio in assessing the oxygenation criterion of ALI. Methods: Corresponding measurements of SpO 2 (values < 97%) and PaO 2 from patients enrolled in the ARDS Network trial of a lower tidal volume ventilator strategy (n 672) were compared to determine the relationship between S/F and P/F. S/F threshold values correlating with P/F ratios of 200 (ARDS) and 300 (ALI) were determined. Similar measurements from patients enrolled in the ARDS Network trial of lower vs higher positive end-expiratory pressure (n 402) were utilized for validation. Results: In the derivation data set (2,613 measurements), the relationship between S/F and P/F was described by the following equation: S/F (P/F) [p < ; r 0.89). An S/F ratio of 235 corresponded with a P/F ratio of 200, while an S/F ratio of 315 corresponded with a P/F ratio of 300. The validation database (2,031 measurements) produced a similar linear relationship. The S/F ratio threshold values of 235 and 315 resulted in 85% sensitivity with 85% specificity and 91% sensitivity with 56% specificity, respectively, for P/F ratios of 200 and 300. Conclusion: S/F ratios correlate with P/F ratios. S/F ratios of 235 and 315 correlate with P/F ratios of 200 and 300, respectively, for diagnosing and following up patients with ALI and ARDS. (CHEST 2007; 132: ) Key words: acute lung injury; ARDS; definition; Pao 2 /fraction of inspired oxygen ratio Abbreviations: AECC American European Consensus Conference; ALI acute lung injury; AUC area under the curve; CI confidence interval; Fio 2 fraction of inspired oxygen; PBW predicted body weight; PEEP positive end-expiratory pressure; P/F Pao 2 /fraction of inspired oxygen; ROC receiver operator characteristic; S/F pulse oximetric saturation/fraction of inspired oxygen; Spo 2 pulse oximetric saturation Acute lung injury (ALI) and the ARDS are devastating clinical syndromes with high morbidity and mortality. 1,2 Acute hypoxic respiratory failure, as defined by the Pao 2 /fraction of inspired oxygen (Fio 2 ) ratio (or P/F ratio) is one of the criteria for ALI/ARDS that was developed by an American European Consensus Conference (AECC) in A P/F ratio 300 and 200, respectively, are utilized to define ALI and ARDS. 3 Despite the straightforward nature of the AECC definition of ALI and ARDS, the requirement for arterial blood gas sampling may contribute to the underdiagnosis of these syndromes. 4 Concerns about anemia, excessive blood draws, and a movement to minimally invasive approaches have led to fewer arterial blood gas measurements in critically ill patients. 5 7 In healthy subjects, changes in Pao 2 correlate well with changes in pulse oximetric saturation (Spo 2 ) for oxygen saturation in the range of 80 to 100% However, studies in critically ill patients, especially those with ALI/ARDS, are lacking. Furthermore, threshold values for Spo 2 /Fio 2 (S/F) ratios could be used as noninvasive 410 Original Research

2 criteria for diagnosing ALI/ARDS. In this study, we sought to derive and validate the relationship between S/F and P/F ratios in critically ill patients with ALI/ ARDS. We hypothesize that the continuously available S/F ratio can be used as a surrogate for the P/F ratio in the diagnosis of ALI/ARDS. The use of the S/F ratio may better facilitate the screening and rapid identification of patients with ALI/ARDS while avoiding the blood use and cost for blood gas determinations. Derivation Data Set Materials and Methods Corresponding measurements of Spo 2 and Pao 2 from patients enrolled in the National Heart, Lung, and Blood Institute ARDS Network trial 11 comparing tidal volumes of 6 ml/kg predicted body weight (PBW) with those of 12 ml/kg were utilized to establish the relationship between S/F and P/F ratios. Each ARDS Network site received approval from local institutional review boards to conduct the studies. The inclusion and exclusion criteria for the ARDS Network tidal volume study 11 have been reported elsewhere. All patients underwent measurements of Spo 2 and Pao 2 with documentation of inhaled concentrations of oxygen at study enrollment and as clinically indicated prior to study day 28 or achieving unassisted breathing. Research personnel were instructed to document Spo 2 values at the time of arterial blood gas sampling. In rare cases when this was not possible, the Pao 2 measurement closest to the Spo 2 value was utilized. The following measures were employed to improve the accuracy of the Spo 2 measurements: optimal position and cleanliness of the sensor; satisfactory waveforms; no position changes or endobronchial suctioning for at least 10 min prior to the measurement; and no invasive procedures or ventilator changes for at least 30 min prior to the measurement. 12 Spo 2 was observed for a minimum of 1 min before the value was recorded. Because the P/F ratio cutoffs used to diagnosis ALI/ARDS differ at lower barometric pressures, patients who were enrolled in the study at centers located 1,000 m in altitude (eg, Salt Lake City and Denver) were excluded from the data sets. Measurements *From the Division of Allergy, Pulmonary, and Critical Care Medicine (Drs. Rice, Wheeler, Bernard, and Ware), Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN; ARDS Network Clinical Coordinating Center (Mr. Hayden and Dr. Schoenfeld), Massachusetts General Hospital, Boston, MA. This research was funded by National Institutes of Health grants N01-HR (to Drs. Rice, Wheeler, and Bernard), N01-HR (to Mr. Hayden and Dr. Schoenfeld), HL07123 (to Dr. Rice), HL70521 (to Dr. Ware), and HL81332 (to Dr. Ware) from the National Heart, Lung, and Blood Institute. The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Manuscript received March 20, 2007; revision accepted May 2, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( org/misc/reprints.shtml). Correspondence to: Todd W. Rice, MD, MSc, Division of Allergy, Pulmonary, and Critical Care Medicine, T-1218 MCN, Nashville, TN ; todd.rice@vanderbilt.edu DOI: /chest with Spo 2 values of 97% were also excluded from analysis because the oxyhemoglobin dissociation curve is flat above these levels. Analysis of the Derivation Data Set A scatterplot of S/F vs P/F ratios was utilized to determine the linear relationship between the two measurements. Generalized estimating equations 13 were then utilized to quantify the best regression line. The equation for this regression line was employed to determine threshold values for S/F ratios that correlate with P/F ratios of 300 and 200, respectively, for ALI and ARDS. The S/F ratio divided by the P/F ratio was plotted against Fio 2, positive end-expiratory pressure (PEEP), and Spo 2 to assess the effect that each had on the relationship. Linear mixed-effect modeling was undertaken to determine the effect that PEEP exerted on the S/F threshold values for defining either ALI or ARDS, as defined by the P/F ratio oxygenation criterion. Arterial ph and Paco 2 might also affect the relationship between S/F and P/F ratios but were not included in the model because both require arterial blood sampling. In these situations, the availability of the P/F ratio would obviate the need for a noninvasive measurement defining ALI. An interaction term was included in the model to assess the effect modification by PEEP on the relationship between the P/F and S/F ratios. Receiver operator characteristic (ROC) curves were plotted to assess the degree of discrimination between S/F and P/F ratios and to slightly adjust the S/F ratio threshold values for both ALI and ARDS to optimize the sensitivity and specificity. Validation Data Set The relationship of S/F vs P/F ratio was externally validated using similarly matched data for S/F and P/F ratios from patients enrolled in another ARDS Network trial comparing lower vs higher PEEP. 14 This study utilized inclusion and exclusion criteria that were similar to those of the derivation data set study. 14 Arterial blood gas measurements and Spo 2 data were collected at similar time points using methods that were similar to those of the derivation data set. Analysis of the Validation Data Set Generalized estimating equations 13 was utilized to quantify the relationship between S/F and P/F ratios in the validation data set. ROC curves were plotted to determine the sensitivity and specificity of the threshold values derived from the derivation data set for both ALI and ARDS, with the area under the curve (AUC) calculated to assess the degree of discrimination between S/F and P/F ratios. Statistical Analysis Normally distributed continuous variables are expressed as the means and SD. Nonnormally distributed continuous variables are reported as the median and interquartile range. The correlation between P/F and S/F ratios was analyzed using Spearman correlation analysis. Linear regression modeling was utilized to compare the relationship between P/F and S/F ratios with adjustment for levels of PEEP as a potential confounder and effect modifier. A fixed effect with parametric compound symmetry structure was utilized to account for multiple measurements obtained from the same patient. PEEP, P/F ratio, and the interaction term PEEP*P/F were included in the model as continuous variables. Statistical software packages (SPSS, version 14.0; SPSS; Chicago, IL; and SAS, version 9.1; SAS Institute Inc; CHEST / 132 / 2/ AUGUST,

3 Cary, NC) were utilized to perform analyses, graph scatterplots and ROC curves, and calculate the AUC of the ROC. Likelihood ratios were calculated using appropriate software (Confidence Interval Analysis, version 2.1.0) [available at: soton.ac.uk/cia]. Two thousand bootstrap samples were computed by resampling patients with replacement to determine 95% CI for the likelihood ratios. Results Of the 861 patients enrolled in the study comparing tidal volumes of 6 and 12 ml/kg PBW, 189 were enrolled at sites located at 1,000 m in altitude (Fig 1). The remaining 672 patients provided 3,384 Pao 2 and Spo 2 measurements at known Fio 2 values. Spo 2 exceeded 97% in 711 patients, leaving 2,673 data points for analysis in the derivation data set. Of the 549 patients who were enrolled in the trial comparing high and low PEEP, 146 were enrolled at centers that were at altitudes of 1,000 m, and 1 patient had no matched measurements for Spo 2 and Pao 2. The remaining 402 patients provided 2,031 measurements with Spo 2 values of 97% for the validation data set (Fig 1). Patients enrolled in both studies had similar baseline demographics, which have been previously detailed elsewhere 11,14 and are briefly summarized in Table 1 Baseline Demographics of the Patients Enrolled in the Studies for Both Data Sets Variables Derivation Data Set (n 672) Validation Data Set (n 402) Age, yr Female sex Etiology of ALI Pneumonia Sepsis Trauma 10 9 Aspiration Baseline P/F ratio Minute ventilation, L/min APACHE III score Nonpulmonary organ failures, No *Values are given as the mean SD or %. APACHE acute physiology and chronic health evaluation. 43 Table 1. The respiratory parameters from the time of the measurements for both data sets are depicted in Table 2. In the derivation data set, the minimum Spo 2 measurement was 56%, with 94% of the measurements being between 88% and 97%. Likewise, the minimum Spo 2 measurement in the validation data set was 62%, with 95% of the measurements Figure 1. Flow diagram for the data points utilized in the derivation and validation data sets. The derivation set was derived from the ARDS Network trial 11 of 6 vs 12 ml/kg tidal volume ventilation. The validation set was derived from the ARDS Network trial 14 of higher vs lower PEEP. 412 Original Research

4 being between 88% and 97%. The majority of P/F ratio measurements met the AECC oxygenation criterion for ARDS (P/F ratio 200) in both the derivation data set (2,130 of 2,673 measurements; 79.7%) and the validation data set (1,475 of 2,031 measurements; 72.6%), while 96.9% of measurements for the derivation data set (2,590 of 2,673 measurements) and 96.1% of measurements for the validation data set (n 1952/2031) met the criterion for ALI (P/F ratio 300). Derivation Data Set S/F and P/F ratios demonstrated a linear correlation. This relationship, which did not differ between the two tidal volume strategies (ie, 6 vs 12 ml/kg PBW) is described by the following regression equation: S/F (P/F) [95% CI, S/F (58 70) ( ) P/F] (p ; r 0.89) [Fig 2]. The relationship between S/F and P/F ratios did not change across varying levels of Fio 2 (Fig 3, top, A) or PEEP (Fig 3, middle, B). Since the Fio 2 delivered to patients was protocol-driven with a goal Spo 2 between 88% and 92%, the inverse of the Fio 2 correlates similarly with P/F ratio (r 0.83) [Fig 3, bottom, C]. ROC curves (Fig 4) demonstrated that S/F ratios had excellent ability to discriminate between patients with and without ARDS (ie, P/F ratio 200; AUC 0.929) and ALI (P/F 300; AUC 0.920). Linear mixed-effect analysis of the derivation data set demonstrated that PEEP had a significant effect on S/F ratios (p 0.001) and slightly modified the effect of the P/F ratio on S/F ratios (p 0.001) as described by the following equation: S/F (P/F) 4.0 (PEEP) (PEEP) (P/F) [95% CI: S/F ( ) ( ) P/F ( ) PEEP ( ) (PEEP) (P/F)] (p 0.001; r 0.87). The linear regression equation utilized in conjunction with the mixed-effect model and ROC curves predicted that S/F ratios of 235 and 315 would correspond with P/F ratios of 200 (ARDS) and 300 (ALI), respectively. Validation Data Set S/F and P/F ratios demonstrated a similar linear relationship in the validation data set, described by the following equation: S/F (P/F) [95% CI, S/F (60 77) ( ) P/F] (p ; r 0.82) [Fig 5]. S/F ratios also demonstrated discriminatory ability for P/F ratio values of both 200 and 300 in the validation data set as shown by AUC values of and 0.878, respectively, for ROC curves. The S/F ratio threshold of 235 from the derivation data set accurately identified 1,257 of the 1,475 cases of ARDS in the validation data set (P/F ratio 200), yielding a sensitivity of 85%. The same threshold value also correctly discriminated 472 of the 556 cases in which the P/F ratio was 200, for a specificity of 85%. The positive and negative likelihood ratios for the S/F ratio value of 235 discriminating P/F ratio values of 200 (ie, the oxygenation criterion for ARDS in the AECC definition) were 5.64 (95% CI, 4.69 to 7.08) and 0.17 (95% CI, 0.15 to 0.20), respectively. Similarly, the S/F threshold of 315 demonstrated 91% sensitivity (accurately identifying 1,778 of the 1,952 cases) for discriminating ALI (P/F ratio 300) with 56% specificity (correctly discriminating 44 of the 79 cases in which the P/F ratio was 300). The positive and negative likelihood ratios for the S/F ratio of 315 for ALI (P/F ratio 300) were 2.06 (95% CI, 1.64 to 2.76) and 0.16 (95% CI, 0.12 to 0.21), respectively. Discussion We hypothesized that the continuously available S/F ratio can serve as a surrogate for P/F ratio in the diagnostic criteria for ALI/ARDS. Using data from patients with ALI and ARDS who were enrolled in two large clinical trials, 11,14 we found that S/F ratio correlates well with a simultaneously obtained P/F ratio. The correlation improves slightly if PEEP is included in the regression model. S/F ratios of 235 Table 2 Respiratory Parameters at the Time of the Corresponding S/F and P/F Ratio Measurements in Both Data Sets* Variables Derivation Data Set Measurements (n 2,673) Validation Data Set Measurements (n 2,031) S/F ratio (188; ) (194; ) P/F ratio (146; ) (157.5; ) Tidal volume, ml/kg PBW Total respiratory rate, breaths/min Minute ventilation, L/min (12.7; ) (11.8; ) PEEP, cm H 2 O Paco 2,mmHg (39; ) (41; 35 47) Arterial ph *Values are given as the mean SD (median; interquartile range for variables that are not normally distributed ). CHEST / 132 / 2/ AUGUST,

5 Figure 2. S/F ratio vs P/F ratio scatterplot for the derivation data set. The line represents the best fit linear relationship (S/F ratio [P/F]) [p ; r 0.89]. and 315, were found to correspond to P/F ratios of 200 and 300, respectively, which are the oxygenation criteria defining ARDS and ALI, respectively. 3 These threshold S/F ratios demonstrated excellent sensitivity and good specificity in predicting the corresponding P/F ratios in a validation data set. To our knowledge, these findings represent the first large study of the relationship between Spo 2 and Pao 2 in critically ill patients. The noninvasive and continuously available Spo 2 is standard monitoring in most ICUs. 15 Although Spo 2 reliably predicts Pao 2 measured by blood gas analysis in healthy subjects, 8,9,15 17 patient race, oximeter location, and disease states, like low cardiac output or methemoglobinemia, may reduce the accuracy. 8,10,16,18 Despite the ubiquity of Spo 2,Pao 2 is the accepted gold standard for determining arterial oxygenation. The measurement of Pao 2 may also significantly vary in patients over short periods of time despite constant Fio 2 due to factors such as positioning, agitation, and endotracheal suctioning. 19,20 Institutions, in an effort to contain costs, conserve blood, and reduce inappropriate use, 5 7 have vastly reduced the number of arterial blood gas samples obtained in mechanically ventilated patients. 21 The sensitivity and specificity of the threshold S/F ratios of 235 and 315 derived in this study suggest that they are appropriate surrogates for P/F ratios of 200 and 300. The use of the S/F ratio in the diagnostic definitions for ALI/ARDS has several potential clinical applications. First, the use of these values will allow the recognition of patients who likely have ALI/ARDS but have not undergone arterial blood gas sampling, facilitating early enrollment into clinical trials and early diagnosis and treatment in clinical practice. Second, the S/F ratio threshold of 315 can be utilized as a continuously available screening tool to identify which patients should undergo arterial blood gas analysis to determine whether they meet the oxygenation criterion for ALI. For example, a ventilated patient receiving 30% Fio 2 with 94% Spo 2 (S/F ratio 313) who meets the other criteria for ALI has a high likelihood of also meeting the P/F ratio oxygenation criterion. Utilizing S/F ratios to facilitate the clinical diagnosis of ALI/ARDS should help to address the underdiagnosis of these syndromes. A volume-limited and pressure-limited ventilation strategy is the only therapeutic intervention that has been shown to significantly reduce mortality in patients with ALI. 11 Despite being inexpensive and easy to use, this intervention has not been widely adopted One explanation may be that ALI and ARDS are often not recognized, 4,26 likely contributing to the failure to implement treatment strategies such as lung-protective ventilation and conservative fluid management. 11,27 S/F ratios may be useful in other important clinical applications. Many organ failure scores, such as lung injury score, 28 sequential organ failure assessment, 29 simplified acute physiology score II, 30 or multiorgan dysfunction score, 31 utilize P/F ratios to quantify hypoxemia. In instances in which these scores are calculated frequently, the respiratory component is often omitted due to the lack of repeated arterial blood gas analyses. Using S/F ratio as a surrogate measure of hypoxemia would allow these scores to be calculated in the absence of arterial blood gas sampling. It should be noted, however, that, except for the lung injury score, these scoring systems are often used for widely heterogeneous groups of critically ill patients and not just those with ALI/ARDS requiring mechanical ventilation. Since a diagnosis of ALI or ARDS was required for enrollment in both of the trials utilized in our analysis, 95% of the measurements in both the derivation and validation data sets met the oxygenation criteria for ALI. The relatively few patients with a P/F ratio of 300 in our data sets and the exclusion of patients enrolled at sites located at altitudes of 1,000 m renders extrapolation of our results to these populations uncertain. Furthermore, the majority of the patients were nonsurgical, with medical conditions causing ALI/ARDS. Our results should be prospectively validated in other patient populations, including patients not requiring mechanical ventilation and patients without lung 414 Original Research

6 Figure 4. ROC curves for (top, A) S/F vs P/F ratios of 200 and (bottom, B) S/F vs P/F ratios of 300 for the derivation data set. Figure 3. Relationship of S/F vs P/F ratio across varying levels of (top, A) Fio 2 (r 0.14), (middle, B) PEEP (r 0.18), and (bottom, C) P/F vs 1/F ratio (P/F /Fio 2 ; r 0.83) for the derivation data set. The line in all panels represents the best-fit linear relationship. injury, to ensure that they remain accurate in these heterogeneous populations. There are some additional limitations of this study. First, although the vast majority of the Spo 2 and Pao 2 measurements were made simultaneously, the protocols allowed separation by a few hours, which could contribute to discrepancies between measure- CHEST / 132 / 2/ AUGUST,

7 appropriate therapies such as lung-protective ventilation and conservative fluid management strategies. Future studies are needed to validate the relationship between S/F and P/F ratio in more heterogeneous populations of critically ill patients. Figure 5. S/F vs P/F ratio scatterplot for the validation data set. The line in both panels represents the best-fit linear relationship (S/F [P/F]) [p ; r 0.82]. ments. Despite this, S/F and P/F ratios remained highly correlated. Second, measurements made with an Spo 2 of 97% were excluded from analysis. At these saturations, the slope of the relationship between Spo 2 and Pao 2 becomes almost zero, and large changes in Pao 2 may result in little or no change in Spo 2. We believe that this limitation is acceptable because routine ICU care titrates Fio 2 to maintain saturations of 92 to 95%. 16 Finally, numerous studies have reported low specificity and sensitivity of the AECC definitions for ALI and ARDS, 4,32 38 with many studies criticizing the definition of hypoxemia Our proposal to utilize S/F ratio as a surrogate is not meant to alleviate these concerns. The S/F ratio thresholds determined in this study were based on P/F ratios proposed by the AECC. 3 Although using an S/F ratio will allow the degree of hypoxemia to be assessed noninvasively, the optimal definition of hypoxemia for the diagnosis of ALI/ARDS and whether measurements should be obtained on standardized PEEP and ventilator settings remains controversial. 4,39 42 Furthermore, S/F ratio does not allow the evaluation of acid-base status or Paco 2 levels, two other potentially important clinical reasons for performing blood gas analysis. In summary, we have derived and validated threshold values for S/F ratio that can be used as surrogates to diagnose ALI/ARDS when a P/F ratio is unavailable. Utilizing the noninvasive and continuously available S/F ratio may facilitate an earlier diagnosis of ALI/ARDS, allowing the application of References 1 Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000; 342: Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury. N Engl J Med 2005; 353: Bernard GR, Artigas A, Brigham KL, et al. The American- European Consensus Conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149: Ferguson ND, Frutos-Vivar F, Esteban A, et al. Acute respiratory distress syndrome: underrecognition by clinicians and diagnostic accuracy of three clinical definitions. Crit Care Med 2005; 33: Merlani P, Garnerin P, Diby M, et al. Quality improvement report: linking guideline to regular feedback to increase appropriate requests for clinical test; blood gas analysis in intensive care. BMJ 2001; 323: Pilon CS, Leathley M, London R, et al. Practice guideline for arterial blood gas measurement in the intensive care unit decreases numbers and increases appropriateness of tests. Crit Care Med 1997; 25: Roberts D, Ostryzniuk P, Loewen E, et al. Control of blood gas measurements in intensive-care units. Lancet 1991; 337: Jensen LA, Onyskiw JE, Prasad NG. Meta-analysis of arterial oxygen saturation monitoring by pulse oximetry in adults. Heart Lung 1998; 27: Perkins GD, McAuley DF, Giles S, et al. Do changes in pulse oximeter oxygen saturation predict equivalent changes in arterial oxygen saturation? Crit Care 2003; 7:R67 10 Webb RK, Ralston AC, Runciman WB. Potential errors in pulse oximetry: II. Effects of changes in saturation and signal quality. Anaesthesia 1991; 46: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome: the Acute Respiratory Distress Syndrome Network. N Engl J Med 2000; 342: Sasse SA, Jaffe MB, Chen PA, et al. Arterial oxygenation time after an Fio 2 increase in mechanically ventilated patients. Am J Respir Crit Care Med 1995; 152: Zeger SL, Liang KY. Longitudinal data analysis for discrete and continuous outcomes. Biometrics 1986; 42: Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 2004; 351: Jubran A. Pulse oximetry. Intensive Care Med 2004; 30: Jubran A, Tobin MJ. Reliability of pulse oximetry in titrating supplemental oxygen therapy in ventilator-dependent patients. Chest 1990; 97: Yamaya Y, Bogaard HJ, Wagner PD, et al. Validity of pulse oximetry during maximal exercise in normoxia, hypoxia, and hyperoxia. J Appl Physiol 2002; 92: Smatlak P, Knebel AR. Clinical evaluation of noninvasive monitoring of oxygen saturation in critically ill patients. Am J Crit Care 1998; 7: Original Research

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