Factors Associated with Failure of Noninvasive ... - Wiley Online Library

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Factors Associated with Failure of Noninvasive Positive Pressure Ventilation in the Emergency Department Paolo G. Merlani, MD, Patrick Pasquina, RN, Jean Max Granier, RN, Miriam Treggiari, MD, MPH, Olivier Rutschmann, MD, Bara Ricou, MD Abstract Objectives: To determine the factors associated with failure of noninvasive positive pressure ventilation (NPPV) in patients presenting with acute respiratory failure to the emergency department (ED). Methods: The authors retrospectively analyzed patients admitted to the ED for acute respiratory failure (defined as a PaCO 2 level .45 mm Hg, and pH # 7.35 or a PaO 2/FiO2 ratio ,250 mm Hg) and who were treated with NPPV. NPPV was delivered routinely according to an institutional protocol. Failure of NPPV was defined as the requirement of endotracheal intubation at any time. Results: A total of 104 patients were included. NPPV failed in 31% (32/104), and the mortality was significantly higher in this group (12/32 [44%]) compared with patients who were not intubated (2/72 [3%]) (p , 0.0001). Factors associated with failure of NPPV were Glasgow Coma Scale score ,13 at ED admission (odds ratio

[OR], 3.67; 95% confidence interval [CI] ¼ 1.33 to 10.07), pH # 7.35 (OR, 3.23; 95% CI ¼ 1.25 to 8.31), and respiratory rate (RR) $20 min21 (OR, 3.86; 95% CI ¼ 1.33 to 11.17) after one hour of NPPV. The negative predictive value for NPPV failure was 86% (95% CI ¼ 70% to 95%) for RR $20 min21. In the multivariate analysis, pH # 7.35 and RR $20 min21 after one hour of NPPV were independently associated with NPPV failure (adjusted ORs, 3.51; 95% CI ¼ 1.29 to 9.62 and 3.55; 95% CI ¼ 1.13 to 11.20, respectively). Conclusions: Patients with pH # 7.35 and an RR $20 min21 after one hour of NPPV had an increased risk of subsequent endotracheal intubation. Key words: acute respiratory failure; hypoxemia; hypercapnia; endotracheal intubation; respiratory rate; critically ill. ACADEMIC EMERGENCY MEDICINE 2005; 12:1206–1215.

Ventilatory support is usually applied through an endotracheal tube in patients with hypoxemic and hypercapnic acute respiratory failure (ARF) to improve gas exchange and reduce the work of breathing. Noninvasive positive pressure ventilation (NPPV) is increasingly used as an alternative to endotracheal intubation in patients with ARF.1–5 NPPV with pressure support was shown to improve gas exchange, tidal volume, respiratory rate (RR), and diaphragmatic activity.6,7 In addition, NPPV was associated with reduced risk of nosocomial infection, shorter intensive care unit (ICU) and hospital stay, and decreased mortality compared with endotracheal

intubation.1,3,8–10 However, most of these findings were observed in critical care settings. Only limited information is available about the safety and efficacy of NPPV in patients with ARF in the emergency department (ED).11–15 In a recent review, Cross suggested that NPPV is safe and effective as a first-line treatment in the ED for patients presenting with ARF.16 Different predictors of short-term failure of NPPV, including pH, PaCO2 level, PaO2/FiO2 ratio, severity scores, age, the presence of acute respiratory distress syndrome or pneumonia, or the tolerance of NPPV or mask leaks, were previously identified in the ICU.1,10,17–19 Only one study in the emergency setting reported pH and PaCO2 level as factors associated with NPPV failure at the end of an NPPV trial.20 In the present study, we sought to identify factors present at ED admission or during the initial hour of NPPV in the ED independently associated with a subsequent NPPV failure, defined as the need of endotracheal intubation.

From the Division of Surgical Intensive Care, Department of Anesthesiology, Pharmacology, and Surgical Intensive Care (PGM, PP, JMG, MT, BR), and Division of Medical and Surgical Emergency, Department of Internal Medicine (OR), University of Geneva Hospital, Geneva, Switzerland. Received January 24, 2005; revisions received May 17, 2005, June 14, 2005, and July 14, 2005; accepted July 19, 2005. Preliminary study results were presented in poster and abstract form at the American Thoracic Society international conference, Seattle, WA, May 2003. Address for correspondence and reprints: Paolo G. Merlani, MD, Division des Soins Intensifs de Chirurgie, De´partement APSIC, Hoˆpitaux Universitaires de Ge`neve, Rue Micheli-du-Crest 24, 1211 Geneva 14, Switzerland. Fax: 41-22-382-74-70; e-mail: paolo.merlani@ hcuge.ch. doi:10.1197/j.aem.2005.07.018

METHODS Study Design. This was a retrospective analysis of patients admitted to the ED with ARF and who were treated with NPPV. The following definition of ARF was used: severe dyspnea with a PaCO2 level .45

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mm Hg on arterial blood gas (ABG) analysis and one of the following two ABG criteria: pH # 7.35 or a PaO2/FiO2 ratio ,250 mm Hg.10,21 For each NPPV prescription, the respiratory team is called to administer the treatment and keep a record. This standard collection instrument was used for this study. The institutional ethical committee approved the study and waived explicit informed consent but required that all patients were informed about the retrospective study. Patients who refused to permit access to their medical files were excluded. Study Setting and Population. The ED of our tertiary 1,200-bed university hospital receives 50,000 visits annually, including 800–900 patients with severe respiratory distress, about 300 of whom have chronic obstructive pulmonary disease (COPD), 250 have cardiogenic pulmonary edema, and 250 have dyspnea of other origin. The great majority of patients are treated with oxygen and/or continuous positive airway pressure, which can be applied 24 hours per day by ED nurses. In our institution, NPPV is prescribed by emergency physicians. The NPPV prescriptions are limited to the daytime and are delivered only by dedicated respiratory therapists. When NPPV is necessary during nighttime, the patients are directly transferred to ICUs. These patients were not considered in our study. Study Protocol. NPPV: Institutional Protocol. NPPV is the administration of pressure support, volume, or pressurecontrolled ventilation applied through a face mask. Continuous positive airway pressure is not considered as a type of NPPV. Within five minutes of the prescription, in the absence of contraindications such as pneumothorax, facial deformities or lesions, hemodynamic instability, or life-threatening arrhythmia, NPPV is initiated after clinical assessment and ABG analysis. The head of the bed is maintained at least at 45° during the NPPV session to minimize the risk of gastric distention and/or bronchial aspiration. In the presence of clinical or radiologic evidence of gastric distention, a nasogastric tube is inserted. All patients are continuously monitored with continuous surface electrocardiography, percutaneous SaO2, and noninvasive blood pressure. An inflatable soft cushion seal facial mask (Vital Signs Inc, Totowa, NJ), adapted to the size of the patient and held in place by head straps (Ru¨sch AG, Waiblingen, Germany), is applied to the patient’s face. Humidification of inspired gases is provided by HME (Hydro-therm HME; Intersurgical Ltd., Wokingham, England). The ventilators used for NPPV are either Evita 2 or Evita 4 (Dra¨ger, Lu¨beck, Germany). The initial ventilatory settings are as follows: pressure support ventilation

1207 with the pressure adjusted to achieve an expiratory tidal volume of 8–10 mL/kg, a flow trigger sensitivity of 1 L/min, and an FiO2 level adjusted to achieve a percutaneous SaO2 level .90%. In the presence of respiratory efforts unable to trigger inspiration, extrinsic positive end-expiratory pressure is applied and increased gradually up to 8 cm H2O to unload the respiratory muscles by reducing intrinsic positive end-expiratory pressure.7 An extrinsic positive endexpiratory pressure of 5 cm H2O is applied also when the percutaneous SaO2 level is ,90% with a FiO2 level .50%. Ventilatory settings are adjusted considering the patient’s clinical status and breathing pattern, the ventilatory variables, and the resulting gas exchanges (ABG and percutaneous SaO2). The therapy aims in particular to reduce the RR, decrease the activity of the accessory muscles, minimize air leaks, and increase the patient’s comfort. If the patient shows an apnea longer than 20 seconds or an inadequate minute ventilation despite the optimization of ventilatory settings, the respiratory mode is switched to volumecontrolled mandatory ventilation with the following initial settings: expiratory tidal volume of 8–10 mL/kg, RR of 20 breaths/min, inspiratory/expiratory time of 1:2, trigger sensitivity of 1 L/min, and FiO2 level adjusted to achieve a percutaneous SaO2 level .90%. The NPPV trial is applied for one hour. Patients do not receive sedation during the one-hour NPPV trial. Short periods of disconnection to allow coughing are permitted. After one hour, clinical reassessment and an ABG analysis are performed. If the breathing pattern and the ABG values improve above the minimum criteria for NPPV, NPPV is discontinued and the patient maintained with supplemental oxygen by mask (Hospitak; Maersk Medical, Reynosa, Mexico) to maintain a percutaneous SaO2 level .90%. If any clinical or ABG signs of respiratory failure persist or resume within one hour, NPPV is continued and the patient admitted to the ICU. Otherwise, the decision of transfer to the ICU or general ward is left to the discretion of the attending physician. Physicians making triage decisions or the decision to intubate are all at least fellows in internal medicine, due to the fact that in Switzerland the emergency medicine specialty does not yet exist. NPPV is continued or reinstalled in the ICU according to ICU medical order. NPPV is not permitted in general wards at our institution. Indications for Endotracheal Intubation. Indications for endotracheal intubation are as follows: respiratory or cardiac arrest, hemodynamic instability, lifethreatening arrhythmia, inability to clear secretions, face mask intolerance, worsening of the level of consciousness, progressive worsening of dyspnea, or worsening of ABG values. Following intubation, patients are subsequently mechanically ventilated with Evita 2 or Evita 4 and transferred to the ICU.

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Measurements. Data collected in the standard respiratory therapy records are as follows: 1) at admission to the ED, demographic data, patient diagnosis, medical history of respiratory disease, heart rate, systolic and diastolic blood pressure, Glasgow Coma Scale (GCS) score, RR (measured during 30 seconds), ABG values, and FiO2 level required; 2) after one hour and while receiving NPPV, heart rate, systolic and diastolic blood pressure, RR, ventilator settings, and ABG values. The requirement for maintaining NPPV after ED discharge, admission to the ICU, reason and the time of endotracheal intubation, duration of mechanical ventilation, and length of ICU and hospital stay were also collected from the patients’ charts. Mortality in the ED, ICU, and hospital at 28 days was assessed. The occurrence of an acute myocardial infarction during the first 24 hours of hospitalization was determined by review of the medical files, based on the criteria of the Joint Committee of the European Society of Cardiology and the American College of Cardiology.22 The primary study end point was failure of NPPV, defined as the need for endotracheal intubation and mechanical ventilation at any time during the study. Data Analysis. For the statistical analysis, Stata statistical software (release 8.0; Stata Corp., College Station, TX) was used. The univariate analysis was performed in all patients (N ¼ 104) and in two subgroups: patients with COPD (n ¼ 68) and patients without COPD (n ¼ 36). In the univariate analyses, risk factors for NPPV failure were evaluated with two-tailed

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Fisher’s exact test for dichotomous variables, unpaired t-test, or Mann-Whitney U test for continuous variables, as appropriate. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated considering all patients (N ¼ 104) to estimate the effect size of risk factors associated with failure of NPPV. Continuous variables were dichotomized according to a priori defined clinical thresholds as follows: GCS score of 13, pH 7.35, and RR of 20 min21, referring to normal values. Multiple logistic regression was then performed considering all patients to obtain adjusted estimates of the ORs and to identify factors independently associated with failure of NPPV. All significant predictors at a 0.05 a level in the univariate analysis were entered into the model of the multivariate analysis. To evaluate model calibration, we performed the Hosmer–Lemeshow goodness-of-fit test. The predictive accuracy of the multivariate model was expressed as area under the receiver operating characteristic curve. The curve represents the relationship between corresponding values of sensitivity and specificity with all possible values of probabilities as a cutoff point to predict the failure of NPPV. Variables are expressed as mean (6SD) if not specified otherwise. A p-value less than 0.05 was considered statistically significant.

RESULTS Between October 1997 and September 2001, 121 patients underwent NPPV in the ED. Twelve patients

TABLE 1. Admission Characteristics in Patients Who Did and Patients Who Did Not Require Endotracheal Intubation

Age (yr) Male/female Admission diagnosis, n (%) COPD exacerbation COPD exacerbation and cardiogenic pulmonary edema Cardiogenic pulmonary edema Community-acquired pneumonia Others Glasgow Coma Scale score Respiratory rate (breaths/min) pH PaCO2 (mm Hg) PaO2 (mm Hg) HCO32 (mmol/L) PaO2/FiO2 (mm Hg) Heart rate (beats/min) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg)

Required Intubation (n ¼ 32)

No Intubation (n ¼ 72)

p-value

72.0 6 10.9 16/16

71.3 6 10.4 40/32

0.76* 0.67y

20 (62.5)

41 (56.9)

0.67y

1 (3.1) 5 (15.6) 4 (12.5) 2 (6.3)z 13 6 3 30.8 6 8.5 7.29 6 0.08 74 6 14 61 6 21 36 6 7 168 6 71 105 6 15 145 6 20 81 6 15

6 (8.3) 21 (29.2) 2 (2.8) 2 (2.8)§ 14 6 2 30.5 6 8.0 7.30 6 0.08 73 6 14 66 6 40 36 6 7 189 6 68 106 616 148 6 23 82 6 16

0.43y 0.22y 0.07y 0.58y 0.02k 0.87* 0.64* 0.87* 0.44* 0.93* 0.15* 0.77* 0.45* 0.68*

COPD ¼ chronic obstructive pulmonary disease. *Student’s t-test. yFisher’s exact test. zOthers included septic shock (1) and peripheral neuropathy (1). §Others included intoxication (1) and central hypoventilation (1). kMann-Whitney U test.

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TABLE 2. Patient Characteristics and Effect of the One-Hour NPPV Trial in Patients Who Did and Patients Who Did Not Require Endotracheal Intubation Required Intubation (n ¼ 32)


p-value

Ventilatory variables Mode, n (%) Pressure support ventilation Volume-assisted/controlled mandatory ventilation Pressure support level (cm H2O) Extrinsic positive end expiratory pressure (cm H2O) Expiratory tidal volume (L) Minute volume (L) Duration of trial (min) Respiratory rate (breaths/min)

23 (72) 9 (28) 24.8 6 4.9 2.5 6 2.5 0.62 6 0.14 12.9 6 3.8 87 6 45 23.3 6 5.1

59 (82) 1 (18) 23.4 6 4.5 2.6 6 2.4 0.66 6 0.14 13.6 6 3.8 76 6 51 20.6 6 5.2

0.30* 0.30* 0.20y 0.76y 0.12y 0.37y 0.31y 0.03y

ABG values after 1-hour NPPV trial pH PaCO2 (mm Hg) PaO2 (mm Hg) HCO32 (mmol/L) PaO2/FiO2 (mm Hg)

7.35 62 71 35 229

6 6 6 6 6

0.06 12 11 6 57

7.38 56 73 34 249

6 6 6 6 6

0.06 13 16 7 63

0.04y 0.06y 0.72y 0.47y 0.16y

27.7 0.05 212.5 65

6 6 6 6

8.4 0.05 10.3 60

29.8 0.09 217.1 59

6 6 6 6

7.0 0.07 12.6 66

0.19y 0.004y 0.52y 0.69y

Change from baselinez Respiratory rate (breaths/min) pH PaCO2 (mm Hg) PaO2/FiO2 (mm Hg) Hemodynamic variables Heart rate (beats/min) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg)

98 6 13 128 6 18 73 6 12

95 6 12 129 6 19 75 6 13

0.30y 0.67y 0.28y

ABG ¼ arterial blood gases; NPPV ¼ noninvasive positive pressure ventilation. *Fisher’s exact test. yStudent’s t-test. zValue after 1-hour NPPV trial minus value before NPPV.

were excluded from the analysis because they did not meet the ARF criteria, one patient was excluded for incomplete data, one patient refused consent, and in three patients the decision to withhold intubation was the reason for use of NPPV. Those patients were not considered in this study, leaving 104 patients available for the analysis. Overall, a total of 32 of 104 patients (31%) required subsequent endotracheal intubation during their whole hospitalization (i.e., failure of NPPV). The clinical and laboratory characteristics at ED admission were similar in patients who required, or did not require, endotracheal intubation, with the exception of the GCS score, which was significantly lower in patients requiring intubation (Table 1). We did observe a particularly high proportion of patients with ARF due to community-acquired pneumonia that required intubation (Table 1). There was no difference between the two groups in the NPPV delivery regarding the ventilation mode, pressure support level, extrinsic positive end-expiratory pressure, tidal volume, minute ventilation, and NPPV trial duration (Table 2). Risk Factors for Intubation (NPPV Failure). After a one-hour NPPV trial, both groups showed an increase

in pH and PaO2/FiO2 ratios and a decrease in PaCO2 levels and RR compared with the admission values (p , 0.01) (Tables 1 and 2). Patients who required intubation had a lower pH (p ¼ 0.03) and a significantly higher RR (p ¼ 0.03) after the one-hour NPPV trial. The analysis of patients ventilated only with pressure support mode showed a similar result (RR in patients who required intubation was 23.6 [6 6.0] breaths/min vs. 20.7 [6 5.7] breaths/min in patients who did not require intubation, p ¼ 0.04). The univariate analysis indicated that there was a significant association between NPPV failure and a GCS score ,13 at ED admission and pH # 7.35 and RR $20 min21 after one hour of NPPV. The sensitivity, specificity, positive predictive value, and negative predictive value of these elements are displayed in Table 3. In the multivariate analysis, only pH # 7.35 (adjusted OR, 3.51; 95% CI ¼ 1.29 to 9.62) and RR $20 min21 (adjusted OR, 3.55; 95% CI ¼ 1.13 to 11.20) were independently associated with NPPV failure (Table 4). The performance of the final multivariate model was satisfactory (Hosmer–Lemeshow goodnessof-fit test; p ¼ 0.42) and discriminated reasonably well between patients who required intubation (NPPV failure) and patients who did not. The area under the receiver operating characteristic curve for the

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TABLE 3. Sensitivity, Specificity, Positive Predictive Value, and Negative Predictive Value for NPPV Failure NPPV Failure

Sensitivity

Specificity

Positive Predictive Value

Negative Predictive Value

Variables at ED admission Glasgow Coma Scale score ,13

0.34 (0.19, 0.53)

0.87 (0.78, 0.94)

0.55 (0.32, 0.77)

0.75 (0.64, 0.84)

Variables after 1 hour of NPPV pH # 7.35 Respiratory rate $20 breaths/min

0.58 (0.37, 0.77) 0.84 (0.67, 0.95)

0.70 (0.58, 0.81) 0.42 (0.30, 0.54)

0.44 (0.27, 0.62) 0.39 (0.28, 0.52)

0.80 (0.68, 0.90) 0.86 (0.70, 0.95)

95% CIs are listed in parentheses. NPPV ¼ noninvasive positive pressure ventilation.

cohort was 0.72, predicting NPPV failure correctly in 77% of patients. ICU and Hospital Outcomes of NPPV Failure. A flowchart illustrating patients’ course after ED discharge is presented in Figure 1. After ED discharge, 24 patients required neither intubation nor further NPPV therapy. Nineteen patients were directly transferred to the ward. Among the 32 patients requiring intubation, eight were intubated in the ED and 24 in the ICU. Timing and reasons for intubation are shown in Figure 2. Intubated patients were mechanically ventilated for a median duration of seven days (1–24 days, 5th to 95th percentile). Outcome variables in patients are shown in Table 5. Patients who required intubation stayed longer in the ICU (p , 0.01). The hospital length of stay did not differ in the two groups (p ¼ 0.09). There was 44% mortality in patients who required intubation, compared with 3% in patients who did not require intubation (p , 0.0001). The causes of death are described in Table 5. Nine of 104 patients (9%) had a confirmed diagnosis of acute myocardial infarction during their hospital stay. Myocardial infarction was more frequent in patients with cardiogenic pulmonary edema (n ¼ 7)

compared with those with COPD (n ¼ 2) (p , 0.01). Seven of them presented to the ED with already-established infarction criteria before initiation of NPPV. Only two patients in the cardiogenic pulmonary edema group showed those criteria secondarily. Predictors of NPPV Failure and Outcomes in Patients with COPD and Patients without COPD. In patients with COPD, the PaO2/FiO2 ratio at ED admission and the pH after one hour of NPPV were lower in patients requiring intubation (Table 6). Although not significantly, the GCS score was lower in patients requiring intubation (Table 6). In patients without COPD, the respiratory rate and the PaCO2 level were higher one hour after NPPV than in patients requiring intubation, and the increase in pH after one hour of NPPV was lower in patients requiring intubation (Table 6). Although not significantly, the increase in PaO2/FiO2 ratio after one hour of NPPV was lower in patients requiring intubation, as was pH (Table 6). Patients with COPD and patients without COPD were comparable regarding the intubation rate, mortality, the decision to withhold or withdraw therapy, and the length of ICU or hospital stay. Patients with COPD were more often transferred to the ICU (61/68

TABLE 4. Univariate and Multivariate Analysis of the Risk Factors for NPPV Failure at ED Admission and One Hour after NPPV

Variables at ED admission Glasgow Coma Scale score $13 ,13 Variables after 1 hour of NPPV* pH .7.35 #7.35 Respiratory rate (breaths/min) ,20 $20

Univariate Analysis

Multivariate Analysis

No. of Intubations/Total (%)

OR

95% CI

21/84 (25) 11/20 (55)

1.00 3.67

— 1.33, 10.07

11/56 (20) 15/34 (44)

1.00 3.23

— 1.25, 8.31

3.51

1.29, 9.62

5/35 (14) 27/69 (39)

1.00 3.86

— 1.33, 11.17

3.55

1.13, 11.20

NPPV ¼ noninvasive positive pressure ventilation. *Values were taken 1 hour after the beginning of NPPV, while on NPPV.

OR

95% CI

NS

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Figure 1. Flowchart of patients admitted for ARF to our ED and treated with NPPV in the ED. White boxes ¼ patients who were intubated; dark gray boxes ¼ patients who needed NPPV after ED presentation; light gray boxes ¼ patients who did not need further NPPV sessions after ED presentation; ARF ¼ acute respiratory failure; ED ¼ emergency department; ICU ¼ intensive care unit; NPPV ¼ noninvasive positive pressure ventilation.

[90%]) compared with patients without COPD (24/36 [67%]; p ¼ 0.007).

DISCUSSION To our knowledge, the present work is the largest study investigating factors associated with failure of NPPV in the emergency setting in patients presenting with ARF. NPPV improved gas exchanges, and 69% of patients did not require subsequent endotracheal intubation. A GCS score of ,13 at ED admission, pH # 7.35, or RR $20 min21 after one hour of NPPV were identified as factors associated with NPPV failure, defined as requirement for intubation at any time during the study. Multivariate analysis identified pH # 7.35 and RR $20 min21 after one hour of NPPV as independently associated with NPPV failure. In addition, patients who did not require intubation had a shorter duration of ICU stay and lower mortality. Previous studies have shown a similar beneficial effect of NPPV in the ED in improving gas exchanges

and suggested a decrease in the need for intubation.11,13,20,23 Two randomized trials assessed specifically the efficacy of NPPV in avoiding endotracheal intubation.21,24 Both studies included patients with heterogeneous causes of ARF. One study showed an intubation rate (after crossover of patients in the placebo group) of 15%.24 The other study showed a higher rate of 44%.21 However, this finding should be interpreted in the context of the use of nasal masks. The use of facial masks in our study could explain the higher efficacy observed. Poponick et al. investigated factors associated with NPPV failure in the emergency setting in 58 patients receiving a 30-minute trial of bilevel pressure ventilation.20 Lack of improvement of pH and PaCO2 level were identified as indicators for the need of endotracheal intubation. Our data extend these findings, identifying the pH after one hour of NPPV as an independent predictor of subsequent endotracheal intubation. In our study, PaCO2 level did not appear to be a significant independent predictor in a multivariate

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Figure 2. Distribution over time (first 72 hours) of clinical indications for endotracheal intubation among patients who required such intubation.

model. The GCS score of ,13 at ED admission was also associated with NPPV failure in our study. Similar findings were reported by Carlucci et al. in the critical care setting. The investigators found that a high encephalopathy score predicted NPPV failure.18 Interestingly, our findings show that the RR at the end of the NPPV trial was an independent predictor of subsequent endotracheal intubation and a good predictor to identify patients who will not require intubation. Indeed, NPPV is known to reduce the respiratory rate,6,7 and it is therefore not surprising when patients who respond well to the NPPV trial improve their RR. This finding is clinically relevant, because RR can be easily assessed at the bedside without laboratory testing. RR monitoring could potentially help identify patients who may not need intubation, with a good negative predictive value for NPPV failure for patients with a RR $20 min21 after one hour of NPPV. In the ED setting, we did not identify other predictors of NPPV failure previously reported in the critical care setting, such as severity scores,17–19 age,17 the presence of acute respiratory distress syndrome or pneumonia,17 or the tolerance of NPPV or mask leaks.17,19 The reason why the RR may be a better predictor of NPPV failure than the PaCO2 level can be explained. Indeed, the severity of the respiratory failure can be associated with the absolute PaCO2 value only when the underlying pathology and the level of bicarbonates are known, whereas the absolute value of the RR is probably more directly associated with the severity of the respiratory failure and/or the respiratory reserve. This is especially true in patients with COPD, as seen in our study. In patients without COPD, the RR and PaCO2 level did correlate better. In several clinical situations, the PaCO2 level can decrease while the RR increases. For example, in asthma, the PaCO2

level can first decrease, then normalize, and finally increase the PaCO2 level again. The importance of the RR, more than the PaCO2 level, is already recognized for the prediction of successful extubation.25 An exception is patients with impairment of the respiratory drive who remain at a low RR while the respiration fails and the PaCO2 level increases. Such patients were very rare in our patient population (n ¼ 2). The pH was another good predictor of NPPV failure, better than the PaCO2 level. In patients with COPD, the absolute value of PaCO2 does not reflect TABLE 5. Outcomes Variables, Mortality, and Mortality-related Complications Required Intubation (n ¼ 32) Transferred to ICU, n (%) 30 (94) Median length of ICU stay, days (range) 10 (1–40) Median length of hospital stay, days (range) 19.5 (1–78) Decision to withhold or withdraw therapy, n (%) 5 (29) Mortality, n (%) 12 (44)z Causes of death, n (% of death) Ventricular fibrillation/ cardiac arrest 3 (25) Cardiogenic shock 1 (8) Septic shock 2 (17) Multiple organ failure 3 (25) Ventilator-associated pneumonia 2 (17) Hemoptysis 1 (8) Status asthmaticus 0 (0)

No Intubation (n ¼ 72) 55 (76)

p-value 0.05*

3 (1–10)

,0.0001y

13 (1–32)

0.12y

0 (0) 2 (3)

0 1 0 0

0.002* ,0.0001*

(0) (50) (0) (0)

0.02* 0.47* 0.07* 0.02*

0 (0) 0 (0) 1 (50)

0.07* 0.27* 1.00*

*Fisher’s exact test. yMann-Whitney U test. zThe percentage does not take account of the patients with decision to withhold or withdraw therapy.

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TABLE 6. Characteristics at ED Admission or after the NPPV Trial of Patients Who Did and Patients Who Did Not Require Endotracheal Intubation, According to Their Admission Group (COPD versus Non-COPD) COPD (n ¼ 68)

Admission characteristics in the ED Glasgow Coma Scale score PaCO2 (mm Hg) PaO2/FiO2 (mm Hg) ABG values after 1 hour of NPPV Respiratory rate (breaths/min) pH PaCO2 (mm Hg) Change from baselinez Respiratory rate (breaths/min) pH PaCO2 (mm Hg) PaO2/FiO2 (mm Hg)

Non-COPD (n ¼ 36)



13 6 3 75 6 14 174 6 73 22.2 6 4.4 7.36 6 0.07 63 6 13 27.3 0.05 212.2 74

6 6 6 6

9.5 0.05 8.9 63

p-value



p-value

15 6 1 76 6 13 209 6 58

0.07* 0.83* 0.04y

12 6 3 71 6 14 156 6 70

13.5 6 3 68 6 15 152 6 70

0.13* 0.60* 0.89y

20.7 6 5.4 7.39 6 0.05 61 6 11

0.25y 0.03y 0.47y

24.6 6 6.1 7.32 6 0.04 57 6 7

20.3 6 4.8 7.36 6 0.08 48 610

0.03y 0.06y 0.04y

5.8 0.06 12.2 68

0.45y 0.14y 0.38y 0.10y

28.7 0.07 214.9 42

6 6 6 6

28.5 0.05 222.0 42

6 6 6 6

6.4 0.04 27.8 47

211.9 0.12 220.9 87

6 6 6 6

8.5 0.06 12.6 53

0.23y 0.005y 0.87y 0.06y

*Mann-Whitney U test. yStudent’s t-test. zValue after 1-hour NPPV trial minus value before NPPV.

the respiratory deterioration, while the pH reflects the acute failure. In patients without COPD, changes in PaCO2 level and pH did correlate better. However, even in these patients, the pH was a better predictor. The pH probably reflects the respiratory and metabolic clinical degradation better. Very high levels of PaCO2 may impact on the state of consciousness and therefore require intubation. Also in these cases, the absolute value of PaCO2 seems less predictive for the need of intubation than other parameters, such as the GCS score. For all of these reasons, we understand that the RR, pH, and GCS score were better predictors of intubation than the PaCO2 level. The fact that the great majority of patients without COPD had cardiogenic pulmonary edema can explain the tendency of the PaO2/FiO2 ratio to increase more in patients not requiring intubation after one hour of NPPV. Some of these patients can recover rapidly and almost completely due to the application of positive airway pressure. This is underscored by the fact that patients without COPD were transferred less frequently than patients with COPD to the ICU. Mehta et al. found that patients with cardiogenic pulmonary edema treated with NPPV, as compared with continuous positive airway pressure, had a higher rate of myocardial infarction (71% vs. 31%, respectively), questioning the safety of NPPV in patients with cardiogenic ARF.26 In our cohort, as well as in other studies,15,27 we did not observe an important incidence of myocardial infarction attributable to NPPV. Only seven patients with cardiogenic pulmonary edema (27%) were diagnosed with acute myocardial infarction during the hospital stay. All seven patients were admitted to the ED with cardiogenic pulmonary edema, thoracic pain, and electrocardiographic changes. Only two (8%) of them had,

at ED admission, a normal troponin level that increased only after the initiation of NPPV. Our results are in agreement with previous reports in the emergency and critical care settings with regard to the association of NPPV failure with prolonged length of ICU stay and increased mortality in patients with ARF.3,10,17,20

LIMITATIONS We acknowledge that our study has several limitations. First, this is a retrospective study. However, randomized trials or rigorous prospective evaluations with more than 100 patients analyzing NPPV in the ED setting are lacking. Second, we analyzed only patients treated by NPPV during the daytime, when a dedicated respiratory therapist was available to perform NPPV. This might create a bias in patients’ selection. There is no evidence that the population of patients presenting with ARF is different between day and night. Third, the adjustment for the severity of ARF was crude, and we cannot exclude the possibility that some residual confounding factors may interfere. Fourth, because NPPV was not assigned by randomization, we cannot infer that the use of NPPV in the ED influenced the subsequent clinical events. Because of the retrospective nature of our study, this question cannot be answered and should be investigated in the future. Fifth, we did not account for the total duration of NPPV. However, the ‘‘late NPPV failure’’ (.48 hours after NPPV initiation) rate was very low in our study (6/107 [6%]). Sixth, the decision to intubate was taken following ‘‘usual practice’’ described in Methods and not following explicit criteria. We did not measure adherence to usual practice. Seventh, six of 32 patients were intubated more than 48 hours after ED admission. Due to the

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retrospective nature of the study, the therapy that patients were given during this period could not be standardized. Therefore, the association between the factors assessed during the first hour in the ED predicting intubation and the intubation occurring more than 48 hours afterward could be biased by other, nonidentified, confounding elements. Eighth, the choice of NPPV criteria (e.g., considering only clinical signs and not ABG values) might have an impact on the factors associated with NPPV failure. Finally, our patient population is heterogeneous, including COPD, cardiogenic pulmonary edema, community-acquired pneumonia, or other ARF etiologies. The analysis of subgroups was not possible due to the small sample size of each group. Despite these limitations, in the general ED population in whom the cause of ARF is rarely established within the first hour of admission, simple indicators that are not linked with the specific cause of ARF and that indicate the risk of subsequent intubation might be most useful. Similarly, previous studies included heterogeneous populations presenting to the ED.11,13,20,21,24

CONCLUSIONS In conclusion, this study showed that a large majority of patients presenting with ARF in the ED did not require intubation once NPPV was applied. Patients with an admission GCS score of ,13, pH # 7.35, or RR $20 min21 after one hour of NPPV had an increased risk of subsequent endotracheal intubation. RR $20 min21 after one hour of NPPV had a good sensitivity (85%; 95% CI ¼ 67% to 95%) for predicting subsequent intubation. Whether these factors can be used in clinical practice in deciding patient destination after the ED should be further investigated in a randomized, prospective study across the spectrum of presenting times.

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18. The authors thank Dr. B. Vermeulen for his active participation in this study.

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REFLECTIONS Is That Me Looking—Reflecting—Back at Me? Our professional life, and our personal life, is a continuum of decisions: some bad, some good, bad becomes good, and vice versa. Toward the end of one’s career, an individual looks back and is either happy or sad, content or restless, wondering ‘‘what if,’’ or fulfilled. Those of us who chose health care as a profession are no different. Certainly, my own life has had all the above-mentioned emotions. In the local high school from which I graduated, I now volunteer to help teach five classes in the curriculum titled ‘‘Health and Medical Careers.’’ My teenage years in this same high school were influenced by four people: 1) my geometry teacher, who changed my name from ‘‘Joey’’ to Joe, 2) my chemistry teacher, who saw something special in a student on the ‘‘outside’’ of the high school ‘‘in crowd,’’ 3) the high school and junior high basketball coaches keeping a ‘‘kid off the streets’’ by being his ‘‘basketball manager,’’ and 4) a neighbor who became a ‘‘father figure/mentor’’ to a child without a dad. I graduated from high school barely knowing how to spell ‘‘doctor,’’ let alone knowing what being a physician encompassed (hopefully I have learned over the past 40 years). Somewhere along the path of life, I decided to ‘‘give back’’ in order to try to help others realize the reward and options of health care. Our present high school class curriculum is a three-year endeavor directed by a high school teacher with 37 years of experience. During the first year, students are introduced to health care and its various fields of interest by several outside guest instructors from the community and from Washington University School of Medicine/Barnes-Jewish Hospital in St. Louis, Missouri, where I also work as an attending physician in the emergency department. Areas of trauma, obstetrics and gynecology, research, pediatrics, primary care, internal medicine, surgery, pastoral care, HIPPA, pharmacy, respiratory therapy, ethics, nursing, veterinary medicine, dentistry, chiropractic medicine, and paramedics/ emergency medical services are just some of the many areas explored and amplified by the outside guest instructors. Students in the second and third years participate in job-shadowing externships, write focused essays about themselves and their life goals, and are given more in-depth talks on nutrition, psychiatry, death and dying, the pros and cons of national health insurance, malpractice, and a ‘‘job-shadow day’’ in their particular area of interest at the Washington University School of Medicine/Barnes-Jewish Hospital in St. Louis. Only time will tell—long after my myocardium stops—if I have helped these students make good decisions about their future professional life, but I believe we are all here to ‘‘pass on’’ and ‘‘pay back’’ with interest what we have learned and taken from those who came and taught before us. There are many days in the classroom when I see the students’ faces and eyes and watch them absorb what is being taught, and I ask myself, ‘‘Is that me looking back at me?’’ Joseph Mueri Primrose, MD, FACS, FACEP Division of Emergency Medicine Washington University School of Medicine in St. Louis St. Louis, Missouri