S/F Oranı NIV Başarı Oranın Ölçmedeki Yeri

S/F Oranı NIV Başarı Oranın Ölçmedeki Yeri

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J Crit Care. Author manuscript; available in PMC 2012 October 1.

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Published in final edited form as:

J Crit Care. 2011 October ; 26(5): 510–516. doi:10.1016/j.jcrc.2010.08.015.

Oxygen saturation/FiO2 ratio is a simple predictor of noninvasive positive pressure ventilation failure in critically ill patients

Carol Spada, RRT1, Rikesh Gandhi2, Sanjay R. Patel, MD, MS3, Paul Nuccio, MS, RRT, FAARC1, Gerald L. Weinhouse, MD4,5, and Po-Shun Lee, MD2,5,*

1 Respiratory Care Department, Brigham & Women’s Hospital, Boston, MA.

2 Translational Medicine Division, Brigham & Women’s Hospital, Boston, MA.

3 Division of Pulmonary, Critical Care and Sleep Medicine, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio.

4 Pulmonary & Critical Care Division, Brigham & Women’s Hospital, Boston, MA.

5 Harvard Medical School, Boston, MA.

Abstract

Purpose—Noninvasive positive pressure ventilation (NPPV) can improve outcomes of critically ill patients. Early and simple predictors of NPPV outcome could improve clinical management of patients with respiratory failure.

Materials and Methods—A prospective observational study was conducted in a medical intensive care unit (ICU) of a tertiary medical center. Patients requiring NPPV were included and followed. Clinical data including respiratory mechanics at the time of NPPV initiation, and clinical outcomes were recorded. Data were analyzed to identify variables that distinguished NPPV success or failure.

Results—A total of 133 patients were included in the study. NPPV success rate was 41%. Patients diagnosed with malignancy had only 29% NPPV success rate. Among patients without malignancy, higher oxygen saturation, oxygen saturation/FiO2 (SF) ratios, and SF/minute ventilation (MV) ratios were associated with NPPV success. Receiver operating curve analyses identify SF < 98.5 to be a specific (89% specificity, P=0.013) predictor of NPPV failure.

Furthermore, for patients requiring at least 24hr of NPPV support, tidal volume (TV)/predicted body weight (PBW) ratio inversely correlated with respiratory improvement.

Conclusions—For patients without malignancy, SF ratios at the time of NPPV initiation discriminated NPPV success and failure, and could be used to help guide the management of critically ill patients who require ventilatory support.

© 2010 Elsevier Inc. All rights reserved.

*Corresponding Author Po-Shun Lee, MD 1 Blackfan Circle Karp Research Building, 6th Floor Brigham & Women’s Hospital Boston, MA 02115 Tel# 617-355-9012 Fax# 617-355-9016 plee4@partners.org.

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Keywords

Mechanical ventilation; Respiratory Insufficiency; Non-Invasive Positive-Pressure Ventilation; Clinical Markers; Hypoxemia; Critical Care

Introduction

Mechanical ventilation is an essential component of critical care for patients suffering from acute respiratory failure. However, several aspects of invasive mechanical ventilation can detrimentally impact clinical outcomes. Complications of invasive mechanical ventilation include ventilator-associated pneumonia (VAP), increased sedation use, and mechanical trauma of the upper airway[1-3]. Noninvasive positive pressure ventilation (NPPV) has received increasing consideration in the intensive care unit (ICU) because of these potential benefits over invasive ventilatory support. Randomized controlled studies have offered support for the use of NPPV in chronic obstructive pulmonary disease (COPD) patients[4] and in the immunocompromised hosts[5]; however the use of NPPV in a more general population of patients with acute respiratory failure is less certain with several reports having suggested that patients with hypoxemic respiratory failure are less likely to benefit from NPPV [1,6,7]. Therefore, predictors of NPPV success would be valuable in selecting patients who would more likely benefit from NPPV. Other investigators have identified P/F (PaO2/FiO2) ratio, various injury severity scores, academia, and temporal changes of physiologic variables as predictors of NPPV outcomes[8-10]; however, these parameters require invasive and/or extended periods of monitoring and observations. We conducted a prospective observational study to identify noninvasive parameters at the time of NPPV institution that can serve as predictors of NPPV outcomes in the intensive care setting.

Methods

Study Design

All patients with respiratory failure receiving NPPV support in the medical ICUs at the Brigham & Women’s Hospital between May 2007 and March 2009 were included in the study. Routine practice in our ICU is that the respiratory therapists select the mask type or interface, and the initial NPPV settings aiming to provide adequate support. Subsequently, the therapist records respiratory mechanics, including exhaled tidal volumes, and ventilator settings from the ventilator (Vision BiPAP, Respironics, Murrysville, PA) every 4 hours. Then ventilator system was humidified by Fisher & Paykel 850 humidifier (Fisher & Paykel Healthcare, Irvine, CA) with heated wire. Initial data after NPPV initiation and stabilization (typical lasting several minutes) were used for this study. Patient demographics, vital signs, clinical data and outcomes were extracted from medical records. Clinical management of the patient was entirely made by the caring physicians without any influence by this observational study; therefore, the decisions to initiate NPPV or to intubate patients were entirely based on clinical judgments of the caring physicians. The study was approved by the Brigham & Women’s Hospital Institutional Review Board, Partners Human Research Comitttee with waived informed consents because the study was strictly observational without any impact to clinical care and in compliance with the Helsinki Declaration.

Classification

Diagnosis of COPD and malignancy were determined from medical records. Immunocompromised states were defined as active immunosuppressant therapy (e.g. prednisone at > 5mg/day), diagnosis of malignancy, or positive HIV test. NPPV success was

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defined as surviving ICU discharge without invasive mechanical ventilatory support. Cases not meeting these criteria were classified as NPPV failure.

Statistics

Pre-selected parameters for analysis were oxygen saturation% (O2 Sat), tidal volume in ml without and with predicted body weight in kg (PBW) correction (TV and TV/PBW), respiratory rate per minute (RR), minute ventilation in liters (MV), inspiratory and expiratory positive airway pressures in cmH2O (IPAP and EPAP). Pre-selected combination variables for analysis were O2 Sat /FiO2 ratio (SF), SF/MV ratio, RR/TV(L) ratio, and SF/ EPAP ratio. For patients with multiple ICU admissions and NPPV initiations, only the initial admission was considered.

Summary data are presented as mean ± SD where appropriate. Differences between groups were compared with the Chi square test for dichotomous variables and the Student t test for continuous variables. Logistic regression was performed to identify factors correlating NPPV outcomes in univariate and multivariate analyses (SAS version 8.0 ,SAS Institute, Cary, NC). Receiver operating curve (ROC) characteristics were performed using Prism 4 (Graphpad Software, La Jolla, CA). P<0.05 was considered significant.

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Results

Patient Characteristics

A total of 133 patients were included in the study. The general characteristics of these patients are summarized in Table 1.

Our study population spent almost half of the initial 24hr period on NPPV (average 13hr) and only 41% of our patients improved on NPPV compared to the 70% NPPV success rate reported by a large multicenter ICU study[9]. The high failure rate in our study was likely reflecting high severity of disease and the relatively high percentage of cancer patients (43%) in our medical ICU population.

The initial respiratory-related data are presented in Table 2. Our patients typically required high FiO2 support (average 0.75), resulting in an average SF ratio of 151, again reflecting a very ill patient population.

Variables associated with NPPV outcome

We then examined the relationship between NPPV success and demographic variables as well as underlying medical conditions and pre-defined initial respiratory mechanics using univariate regression analysis (Table 3).

Patients carrying the diagnosis of COPD were more likely to benefit from NPPV (71% of patients with COPD improved), consistent with published studies[11,12]. Patient without malignancy were 2.7 times more likely to improve compared to those with malignancy, with only 29% of cancer patients improving, demonstrating the poor outcomes of cancer patients in the ICU. Among the initial respiratory mechanics and NPPV setting variables, only O2 Sat and SF/MV ratio were found to be significant positive predictors of clinical improvement, while SF ratio showed a trend toward statistical significance. Other parameters, such as RR, TV, MV that have been reported to be NPPV success predictors were not significant discriminators of outcomes in our study[10].

When we re-examined each variable while controlling for COPD and malignancy status in multi-variable regression analysis, only oxygen saturation remained significant.

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Patients with or without malignancy

Because our population had a relatively high percentage of cancer patients and their outcomes appears to be dramatically different from those of non-cancer patients, we performed separate analyses stratifying on malignancy status. Table 4 shows the clinical data of patients with and without malignancy. Patients with malignancy were more likely to fail NPPV than those without malignancy. Cancer patients appeared to be much sicker at the time of NPPV initiation, as reflected by higher amounts of FiO2 and EPAP support, leading to higher lower SF, SF/MV, and SF/EPAP ratios. We further examined how respiratory mechanics and NPPV setting variables may be differentially associated with clinical improvement according to malignancy status. Table 5 shows that several variables incorporating respiratory mechanics, NPPV settings and oxygen saturation, including O2 Sat, SF and SF/MV ratios, were predictive of NPPV success in those without malignancy.

However, for patients with malignancy, no variables were found to be predictive of NPPV success.

Predictors of NPPV failure in non-cancer patients can be helpful in clinical decision-making and avoiding emergent intubation. We therefore performed ROC analysis on SF and SF/MV predicting non-cancer patients’ chance of failure on NPPV (Figure 1). SF (AUC=0.6875, P=0.005) and SF/MV (AUC=0.6571, P=0.019) were similar with only modest predictive ability. However, a cutoff of SF <98.5 is 40% sensitive and 89% specific in predicting NPPV failure with a likelihood ratio of 3.7. A cutoff of SF/MV <6.4 is 29% sensitive and 89% specific in predicting NPPV failure with a likelihood ratio of 2.57. Thus, while not sensitive, these easily calculated variables provide a fairly specific assessment of NPPV failure in patients without cancer presenting with acute respiratory failure.

Impact of tidal volume on respiratory status

Excessive TV can be injurious to ARDS patients receiving mechanical ventilation[13], and is reported to be associated with development of ARDS in respiratory compromised patients receiving mechanical ventilation[14-16]. While the initial TV and TV/PBW ratio did not correlate with NPPV outcomes (Table 3), we reasoned that total time exposed to NPPV may also be a factor. Examining only those patients (N=30) who were on NPPV for at least 24hr, we analyzed the relationship between the average TV/PBW and the changes of SF ratio at 24hr compared to initial, as reflected by SF(24hr)/SF(Initial) ratio. Figure 2 shows that average TV/PBW negatively correlated with changes in SF ratios (Pearson R=-0.372, p=0.0429), suggesting excessive TV may be injurious to spontaneously breathing patients receiving NPPV support, leading to worsen respiratory status as reflected by decreasing SF ratios. In addition we found average TV/PBW did not correlate with average MV, RR, IPAP, EPAP, FiO2, or O2Sat (p-values > 0.12, R2 < 0.07, Pearson’s Correlation), further supporting high TV having direct detrimental effect in NPPV patients, independent of respiratory demand or oxygenation status.

Discussion

NPPV can be an essential component for providing respiratory support to critically ill patients. Patient selection is critical in ensuring optimal use of NPPV[6]. We found that patient co-morbidity plays a significant role in predicting NPPV success; specifically, patients with malignancy had a dramatically lower chance of improvement on NPPV reflecting generally worse outcomes of critically ill cancer patients with respiratory failure[17,18]. Further, we did not find any respiratory mechanic variables predictive of NPPV success in cancer patients, suggesting that critically ill cancer patients with respiratory failure may require much higher levels of support compared to those non-cancer patients with similar respiratory impairment. This is in contrast to a recent report by Adda et

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al suggesting that high respiratory rate (RR) is an independent predictor of NPPV failure in cancer patients[19]. One possible explanation is the differences in the timing of RR measurement between the studies. In the study by Adda et al, while the RR was recorded when the patient was supported by NPPV, the exact timing is unclear. It is possible that Adda et al’s RR data were derived at later time points of NPPV support, and reflected diverging respiratory mechanics observed between patients who respond or fail NPPV support[9]. Furthermore, RR was specifically used as an indicator for NPPV failure and for instituting invasive ventilation in their ICU; therefore, it is perhaps not surprising that RR would prove to be predictive in that study.

It is important to note that our data do not necessarily suggest that NPPV should be avoided in cancer patients, because it is possible that cancer patients who received NPPV support still had better outcomes compared to those supported by invasive mechanical ventilation[18]. Our data suggest that it is perhaps more difficult to predict NPPV outcomes in cancer patients. Moreover, in our study, cancer patients had lower initial SF and SF/MV ratios, suggesting that at the time of NPPV, their respiratory status were worse compared to those of non-cancer patients. Based on this observation, we suggest that cancer patients with respiratory distress may deteriorate more rapidly than other patients, leading to a relative delay of NPPV initiation. This may explain the poorer outcomes and the lack of outcome predictors in cancer patients with respiratory failure. More vigilant monitoring and earlier institution of NPPV in cancer patients with respiratory symptoms may improve clinical outcome, and merit further investigation.

For patients without malignancy and requiring NPPV support in the ICU, we found that initial parameters incorporating the degree of hypoxemia and oxygen support with or without minute ventilation normalization correlated with NPPV success or failure. In particular, oxygen saturation (from pulse oximeter) to FiO2 ratio (SF) could potentially be used to identify patients at high risk of failing NPPV support. SF has first been reported to be associated with mortality in hematopoietic stem cell transplantation (HSCT) recipients with pulmonary infiltrates[20]. Subsequent studies have validated that SF ratios correlate with PaO2/FiO2(PF) ratios [21-23]. Because delay in intubation could adversely impact outcomes [24], and SF ratio can be quickly determined noninvasively, we suggest that in patients with respiratory failure requiring NPPV support, an initial SF ratio of less than 98.5 should prompt clinicians to consider invasive ventilation sooner.

In contrast to a previous study[10], we did not find parameters reflecting initial ventilatory demands, such as TV, or MV, to be associated with NPPV outcome. Our data suggest that patients with more significant hypoxemia were more likely to fail NPPV while the degree of ventilatory requirement had no predictive value. This may suggest that NPPV provided adequate ventilatory support in our patient population. It is interesting to note that despite having very poor SF ratios, our patients only received very modest EPAP support (6±2 cm H2O). Optimizing EPAP support in NPPV management thus deserves further consideration and investigation.

Lower PBW-normalized TV is protective in mechanically ventilated ARDS patients[13], and studies have suggested that in patients with respiratory failure requiring mechanical ventilation, higher tidal volume may increase the risk of subsequent ARDS development[14-16]. However, the impact of TV in spontaneously breathing patients requiring NPPV support is uncertain. While Rana et al described higher TV significantly associated with NPPV failure, the relationship is lost when TV is normalized to PBW, suggesting ventilatory demand as the underlying reason of the relationship instead of injurious tidal volume[10]. We report here for the first time that in patients managed with NPPV for at least 24hr, TV/PBW inversely correlated with changes in SF ratios, suggesting

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lower tidal volume may also be protective in patients supported by NPPV for extended amount of time. More study is required to confirm this possibility.

Our study has several limitations. First, our study had a fairly high number of cancer patients in this single institution study, and our findings may be not generalized. Second, our database lacks the specific diagnosis, such as pneumonia or ARDS, attributed to the respiratory failure. Third, we did not have information on the technical aspect of NPPV application, such as patient comfort and air leak. Fourth, this was a single institution study and results could be unduly influenced by institutional practice routines. Lastly, validation study was not performed to prospectively test proposed outcome predictors in NPPV patients. Additional studies are needed to confirm and extend our findings.

Conclusions

In conclusion, we propose that a simple index of oxygen saturation/FiO2 ratio (SF) at the time of NPPV initiation could be used to identify patients at high risk of NPPV failure. Avoiding delayed or emergent intubation could potentially improve outcomes of critically ill patients requiring respiratory support. Furthermore, our data suggest lower tidal volume may be protective in at risk patients who required more than 24hr of NPPV support.

Acknowledgments

We thank the tremendous respiratory therapists at the Brigham & Women’s Hospital for assisting in patient identification and data gathering which made this study possible. Part of the study has been presented by Carol Spada in abstract form at the International Respiratory Congress in Anaheim, CA on December 14, 2008.

This work was supported by American Heart Association Scientist Development Grant 0735620N (PSL) and National Institute of Health HL081385 (SRP). The funding agency played no role in the study or the manuscript. The authors have no conflicts of interest to declare.

References

    1. Ambrosino N, Vagheggini G. Noninvasive positive pressure ventilation in the acute care setting: where are we? Eur Respir J. 2008; 31:874–886. [PubMed: 18378782]
    2. Hess DR. Noninvasive positive-pressure ventilation and ventilator-associated pneumonia. Respir Care. 2005; 50:924–929. discussion 929-931. [PubMed: 15972113]
    3. Keenan SP, Sinuff T, Cook DJ, et al. Does noninvasive positive pressure ventilation improve outcome in acute hypoxemic respiratory failure? A systematic review. Crit Care Med. 2004; 32:2516–2523. [PubMed: 15599160]
    4. Brochard L, Mancebo J, Wysocki M, et al. Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med. 1995; 333:817–822. [PubMed: 7651472]
    5. Hilbert G, Gruson D, Vargas F, et al. Noninvasive ventilation in immunosuppressed patients with pulmonary infiltrates, fever, and acute respiratory failure. N Engl J Med. 2001; 344:481–487. [PubMed: 11172189]
    6. Garpestad E, Hill NS. Noninvasive ventilation for acute lung injury: how often should we try, how often should we fail? Crit Care. 2006; 10:147. [PubMed: 16879722]
    7. Hess DR. The evidence for noninvasive positive-pressure ventilation in the care of patients in acute respiratory failure: a systematic review of the literature. Respir Care. 2004; 49:810–829. [PubMed: 15222912]
    8. Antonelli M, Conti G, Esquinas A, et al. A multiple-center survey on the use in clinical practice of noninvasive ventilation as a first-line intervention for acute respiratory distress syndrome. Crit Care Med. 2007; 35:18–25. [PubMed: 17133177]
    9. Antonelli M, Conti G, Moro ML, et al. Predictors of failure of noninvasive positive pressure ventilation in patients with acute hypoxemic respiratory failure: a multi-center study. Intensive Care Med. 2001; 27:1718–1728. [PubMed: 11810114]

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    1. Rana S, Jenad H, Gay PC, et al. Failure of non-invasive ventilation in patients with acute lung injury: observational cohort study. Crit Care. 2006; 10:R79. [PubMed: 16696863]
    2. Agarwal R, Gupta R, Aggarwal AN, et al. Noninvasive positive pressure ventilation in acute respiratory failure due to COPD vs other causes: effectiveness and predictors of failure in a respiratory ICU in North India. Int J Chron Obstruct Pulmon Dis. 2008; 3:737–743. [PubMed: 19281088]
    3. Kramer N, Meyer TJ, Meharg J, et al. Randomized, prospective trial of noninvasive positive pressure ventilation in acute respiratory failure. Am J Respir Crit Care Med. 1995; 151:1799– 1806. [PubMed: 7767523]
    4. The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000; 342:1301–1308. [PubMed: 10793162]
    5. Gajic O, Dara SI, Mendez JL, et al. Ventilator-associated lung injury in patients without acute lung injury at the onset of mechanical ventilation. Crit Care Med. 2004; 32:1817–1824. [PubMed: 15343007]
    6. Gajic O, Frutos-Vivar F, Esteban A, et al. Ventilator settings as a risk factor for acute respiratory distress syndrome in mechanically ventilated patients. Intensive Care Med. 2005; 31:922–926. [PubMed: 15856172]
    7. Jia X, Malhotra A, Saeed M, et al. Risk factors for ARDS in patients receiving mechanical ventilation for > 48 h. Chest. 2008; 133:853–861. [PubMed: 18263691]
    8. Soares M, Salluh JI, Spector N, et al. Characteristics and outcomes of cancer patients requiring mechanical ventilatory support for >24 hrs. Crit Care Med. 2005; 33:520–526. [PubMed: 15753742]
    9. Depuydt PO, Benoit DD, Vandewoude KH, et al. Outcome in noninvasively and invasively ventilated hematologic patients with acute respiratory failure. Chest. 2004; 126:1299–1306. [PubMed: 15486396]
    10. Adda M, Coquet I, Darmon M, et al. Predictors of noninvasive ventilation failure in patients with hematologic malignancy and acute respiratory failure. Crit Care Med. 2008; 36:2766–2772. [PubMed: 18766110]
    11. Patel NR, Lee PS, Kim JH, et al. The influence of diagnostic bronchoscopy on clinical outcomes comparing adult autologous and allogeneic bone marrow transplant patients. Chest. 2005; 127:1388–1396. [PubMed: 15821221]
    12. Khemani RG, Patel NR, Bart RD 3rd, et al. Comparison of the pulse oximetric saturation/fraction of inspired oxygen ratio and the PaO2/fraction of inspired oxygen ratio in children. Chest. 2009; 135:662–668. [PubMed: 19029434]
    13. Pandharipande PP, Shintani AK, Hagerman HE, et al. Derivation and validation of Spo2/Fio2 ratio to impute for Pao2/Fio2 ratio in the respiratory component of the Sequential Organ Failure Assessment score. Crit Care Med. 2009; 37:1317–1321. [PubMed: 19242333]
    14. Rice TW, Wheeler AP, Bernard GR, et al. Comparison of the SpO2/FIO2 ratio and the PaO2/FIO2 ratio in patients with acute lung injury or ARDS. Chest. 2007; 132:410–417. [PubMed: 17573487]
    15. Esteban A, Frutos-Vivar F, Ferguson ND, et al. Noninvasive positive-pressure ventilation for respiratory failure after extubation. N Engl J Med. 2004; 350:2452–2460. [PubMed: 15190137]

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Figure 1. Receiver operating curves of SF and SF/MV in discriminating NPPV failures

SF (Oxygen saturation/FiO2) yielded an area under the curve (AUC) of 0.6710, P=0.013, and SF/MV had an AUC of 0.6464, P=0.033. A cutoff of SF <98.5 is 40% sensitive and 89% specific in predicting NPPV failure with a likelihood ratio of 3.7. A cutoff of SF/MV

<6.432 is 29% sensitive and 89% specific in predicting NPPV failure with a likelihood ratio of 2.57.

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Figure 2. Correlation of TV/PBW and 24hr changes in SF ratios

In 30 patients on NPPV for at least 24hr, the average tidal volume (TV)/ predicated body weight (PBW) inversely correlated with changes of SF (Oxygen saturation/FiO2) as reflected by SF(24hr)/SF(Initial), with a Pearson R=-0.372, p=0.0429.

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Table 1

Patient Characteristics

Category Number

Total 133

COPD 26 (20%)

Malignancy 55 (43%)

Immunocompromised 88 (68%)

Female 70 (53%)

Age (Yr) 62 ± 16

Hr on NPPV within 1st 24hr 13±8

NPPV Success 55 (41%)

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Initial respiratory data of the study population.

Table 2

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VariableMean ± Std
TV (ml)520±181
TV/PBW (ml/kg)8.6±2.7
MV (L)15±9
RR (per min)28±9
IPAP (cm H2O)12±3
EPAP (cm H2O)6±2
FiO20.75±0.27
O2Sat(%)97±3
SF151±69
SF/MV13±11
RR/TV(L)59±31
SF/EPAP27±15

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Predictors of NPPV success.

Table 3

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VariableORCI (95%)P-Value
Non-COPD0.310.126-0.7630.0108*
Non-Malignancy2.7161.297-5.690.0081*
Non-Immunocompromised1.930.911-4.0870.0859
Female0.8890.445-1.7740.7384
Age (Yr)1.0150.993-1.0380.1786
TV (ml)10.999-1.0020.6134
TV/PBW (ml/kg)1.0540.929-1.1960.41
MV (L)0.9870.945-1.0310.5578
RR (per min)0.9720.933-1.0130.1768
IPAP (cm H2O)0.9610.862-1.0720.4746
EPAP (cm H2O)1.0120.856-1.1960.886
FiO20.4980.138-1.7940.2862
O2Sat(%)1.1661.028-1.3220.0171*
SF1.0040.999-1.0090.1444
SF/MV1.0411.004-1.0780.0291*
RR/TV(L)0.9940.982-1.0060.3258
SF/EPAP1.0130.990-1.0370.2659

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Table 4

Comparisons between patients with or without malignancy.

Malignancy

VariableNOYESP-Value
NPPV Success/Total39/7416/550.0073*
Female/Total41/7425/550.2635
Hr on NPPV within 1st 24hr13±813±80.9778
Age (Yr)63±1758±140.11
TV (ml)522±178530±1840.8081
TV/PBW (ml/kg)8.9±2.98.3±2.50.2669
MV (L)14±1016±60.3224
RR (per min)26±829±90.1786
IPAP (cm H2O)12±312±30.7239
EPAP (cm H2O)6±17±30.0126*
FiO20.70±0.280.83±0.230.0066*
O2Sat(%)97±397±30.8071
SF163±74130±520.0062*
SF/MV16±1310±70.0025*
RR/TV(L)57±2861±320.4511
SF/EPAP30±1622±130.0031*

** Four patients with missing diagnosis information were excluded from this analysis.

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Table 5

Predictors of NPPV success in patients with or without malignancy.

No Malignancy (N=74) Malignancy (N=55)

VariableORCI (95%)P-ValueORCI (95%)P-Value
Female0.8750.349-2.1940.7760.9070.281-2.9270.8708
Age (Yr)1.0090.982-1.0360.52751.0350.989-1.0830.1413
TV (ml)1.0000.998-1.0030.94571.0000.997-1.0040.757
TV/PBW (ml/kg)1.0460.891-1.2290.58020.9850.779-1.2450.8983
MV (L)0.9920.949-1.0370.72580.9840.892-1.0850.7451
RR (per min)0.9710.918-1.0280.30910.9910.929-1.0570.7893
IPAP (cm H2O)0.9450.0822-1.0860.42510.9870.821-1.1850.8847
EPAP (cm H2O)1.0000.729-1.3720.99831.1380.908-1.4250.2623
FiO20.2060.039-1.0990.064416.2670.678-390.30.0854
O2Sat(%)1.2681.066-1.5080.0072*1.0870.890-1.3290.4136
SF1.0071.000-1.0140.0428*0.9890.974-1.0050.1629
SF/MV1.0641.009-1.1210.0209*0.9510.853-1.0600.3606
RR/TV(L)0.9980.982-1.0150.8280.9950.975-1.0150.6321
SF/EPAP1.0260.995-1.0580.10350.9580.904-1.0160.1538

** Four patients with missing diagnosis information were excluded from this analysis.

PDF olarak indirebilirsiniz. Oxygen Saturation FİO2 ratiois a simple predictor of NIV

S/F Oranı ve ROX Indexinin HFNC Başarı Belirlemedeki Rolü

S/F Oranı ve ROX Indexinin HFNC Başarı Belirlemedeki Rolü

European Journal of Pediatrics https://doi.org/10.1007/s00431-020-03847-6

ORIGINAL ARTICLE

Predicting nasal high-flow therapy failure by pediatric respiratory rate-oxygenation index and pediatric respiratory rate-oxygenation index variation in children

Dincer Yildizdas 1 & Ahmet Yontem1 & Gokce Iplik 1 & Ozden Ozgur Horoz 1 & Faruk Ekinci1

Received: 8 August 2020 / Revised: 7 October 2020 / Accepted: 13 October 2020

# Springer-Verlag GmbH Germany, part of Springer Nature 2020

Abstract

The primary objective of this study was to evaluate whether pediatric respiratory rate-oxygenation index (p-ROXI) and variation in p- ROXI (p-ROXV) can serve as objective markers in children with high-flow nasal cannula (HFNC) failure. In this prospective, single- center observational study, all patients who received HFNC therapy in the general pediatrics ward, pediatric intensive care unit, and the pediatric emergency department were included. High-flow nasal cannula success was achieved for 116 (88.5%) patients. At 24 h, if both p-ROXI and p-ROXV values were above the cutoff point (≥ 66.7 and ≥ 24.0, respectively), HFNC failure was 1.9% and 40.6% if both were below their values (p < 0.001). At 48 h of HFNC initiation, if both p-ROXI and p-ROXV values were above the cutoff point (≥ 65.1 and ≥ 24.6, respectively), HFNC failure was 0.0%; if both were below these values, HFNC failure was 100% (p < 0.001).

Conclusion: We observed that these parameters can be used as good markers in pediatric clinics to predict the risk of HFNC

failure in patients with acute respiratory failure.

What is Known:

  • Optimal timing for transitions between invasive and noninvasive ventilation strategies is of significant importance.
  • The complexity of data requires an objective marker that can be evaluated quickly and easily at the patients bedside for predicting HFNC failure in children with acute respiratory failure.

What is New:

  • Our data showed that combining p-ROXI and p-ROXV can be successful in predicting HFNC failure at 24 and 48 h of therapy.

Keywords High-flow nasal cannula . Children . Acute respiratory failure . P-ROXI . P-ROXV

Abbreviations p-ROXI Pediatric respiratory rate-oxygenation index

AUROC Area under the ROC curve HFNC High-flow nasal cannula

p – ROXV

Variation in pediatric respiratory rate-oxygenation index

IMV Invasive mechanical ventilation NIMV Noninvasive mechanical ventilation

SpO2 Pulse oximetry

Communicated by Peter de Winter Communicated by Peter de Winter

Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00431-020-03847-6) contains supplementary material, which is available to authorized users.

* Ahmet Yontem drayontem@gmail.com

Dincer Yildizdas dyildizdas@gmail.com

Gokce Iplik gokceiplik@gmail.com

Ozden Ozgur Horoz oozgurhoroz@yahoo.com

Faruk Ekinci farukekinci83@gmail.com

1 Faculty of Medicine, Division of Pediatric Intensive Care Unit, Çukurova University, Sarıçam, Adana, Turkey

Introduction

While high-flow nasal cannula (HFNC) therapy is most commonly applied for infants with respiratory failure due to bronchiolitis [1, 2], studies have demonstrated its effectiveness in various cases including respiratory diseases such as acute respiratory failure [3, 4], post- extubation [5], and cardiogenic pulmonary edema [6]. Recent studies evaluating the efficacy and safety of HFNC in reducing the need for invasive mechanical ventilation (IMV) in pediatric patients with acute respi- ratory failure are ongoing. Although these studies are growing in number, the increasing use of HFNC brings with it the risk of delay in cases where intubation is required [7]. A predictor that accurately identifies pa- tients at high risk of HFNC failure may be helpful to consider escalation of the respiratory support at the right time.

In an observational study evaluating adult patients receiv- ing HFNC therapy for severe pneumonia, Roca et al. de- scribed respiratory rate-oxygenation (ROX) index as the ratio of SpO2/FiO2 to respiratory rate [8]. The results indicated a ROX index (ROXI) ≥ 4.88 after 12 h of HFNC therapy to be associated with a lower need for IMV. The researchers then conducted a study to validate the diagnostic accuracy of the ROXI in which five centers participated [9]. These studies showed that ROXI could be used to predict HFNC outcomes in adult patients. Studies evaluating the factors associated with HFNC failure are increasing daily. While there are many pa- rameters to be considered in predicting HFNC failure in pedi- atric patients, a marker that can be used has not been proven yet. Considering changes in respiratory rate based on age in children, we used respiratory rate z-score instead of respirato- ry rate in the calculation and defined as pediatric respiratory rate-oxygenation index (p-ROXI).

Accordingly, this study aimed to evaluate whether p-ROXI and variations in p-ROXI (p-ROXV) could be used as objec- tive markers in children with HFNC failure.

Materials and methods

Study design

This research was a prospective, single-center, observa- tional study that included 131 patients between 1 month and 18 years of age, who received HFNC therapy be- tween March 2018 and December 2019. It was ap- proved by the Çukurova University Faculty of Medicine Non-Interventional Clinical Research Ethics Committee. The parents of the included patients were informed about the study and provided their informed consent for inclusion.

Patients and definitions

All patients between 1 month and 18 years of age and treated in the general pediatrics ward, pediatric intensive care unit, and the pediatric emergency department and who received HFNC therapy were included in the study. Patients requiring urgent intubation within the first hour of HFNC and elective intubation for diagnostic or therapeutic reasons were exclud- ed. HFNC failure was defined as follows: (1) the need for noninvasive mechanical ventilation (NIMV) or IMV support due to unstable condition and (2) providing HFNC support again within 24 h after HFNC termination. The patients with apnea, altered mental status, poor perfusion (cool extremities, capillary refill > 3 s), or bradycardia were considered unstable. The p-ROXI describes the ratio of SpO2/FiO2 to the respira- tory rate z-score. The p-ROXV describes the percentage changes in p-ROXI for the first, second, fourth, sixth, 24th, and 48th hours of HFNC initiation.

Example of p-ROXI calculation: SpO2=FiO2=Respiratory rate z−score Example of p-ROXV calculation:

First hour p−ROXV

¼ ðfirst hour p−ROXI–0−hour p−ROXIÞ x 100=0−hour p−ROXI

Device description and management

In the Çukurova University Faculty of Medicine, Department of Child Health and Diseases, HFNC therapy is carried out using two devices. The first is a Vapotherm Precision Flow, and the second is a Fisher and Paykel Airvo 2 Optiflow. The nasal cannula and set connected to the patient were the same brands as the device used and were adjusted based on the age of the patient.

Support for HFNC was provided to patients who could not maintain pulse oximetry (SpO2) > 92%, despite a 15 L/min oxygen supplement with a non-rebreather mask, and whose respiratory rate was > 2 SD above the normal respiratory rate based on the age [10]. HFNC was initiated with a minimum flow rate of 1 L/kg/min and FiO2 = 0.6. In the first hour, flow rate and FiO2 were titrated to maintain pulse oximetry SpO2 > 92%. If the respiratory rate or SpO2 could not be maintained at the target values, the flow rate was gradually increased 0.5 L/ kg/min every 15 min to the highest rate the patient could tolerate (maximum of 2.5 L/kg/min). FiO2 was titrated by attending physician. FiO2 was weaned at any time to provide the lowest possible oxygen percentage to maintain an oxygen saturation level of at least 92% and after 6 h of receiving an

Fio2 of 0.21, and HFNC therapy was stopped. There was no modification in the treatment modality according to patients’ p-ROXI. Attending physicians were not informed about the p- ROXI.

Patients’ sex, age, weight, the primary disease requiring HFNC, comorbidities, medical treatments, whether HFNC therapy had been successful, length of hospital stay, compli- cations, and mortality during treatment were recorded. At the outset, the first, second, fourth, sixth, 24th, and 48th hours of HFNC initiation, respiratory rate and heart rate z-score [10], flow rate and FiO2, blood gas parameters, SpO2/FiO2, p- ROXI, and p-ROXV values were recorded.

Statistical analysis

Categorical measurements were given as numbers and per- centages, and numerical measurements were given as median (25th and 75th percentile) values. Chi-square or Fisher’s exact test was used to compare categorical variables. In comparison with numerical measurements between groups, Student’s t test or the Mann-Whitney U test was used, as appropriate. To assess the accuracy of different variables for correctly classi- fying patients who would succeed or failed HFNC, the receiv- er operating characteristic (ROC) curve was performed, and the area under the ROC curve (AUROC) was calculated. According to the ROC analysis, the best cutoff points were calculated using Youden’s index. To compare the changes in numerical measurements over time for the same individual, one-way ANOVA or Friedman test was performed, as appro- priate. The statistical significance level was taken as 0.05 in all tests. The IBM SPSS Statistics v. 20.0 software package was used to conduct statistical analysis of the data.

Results

General characteristics of the cohort

Our study included 131 patients who were treated with HFNC. The median age of patients was 23.0 (IQR, 9.0– 92.0) months, and 65 of the patients were male (49.6%). Among the patients, 85.5% (n = 112) had an underlying chronic disease; the most common chronic disease was con- genital heart disease (22.9%, n = 30), and 19 (14.5%) did not have any comorbidity. The most common reason for requiring HFNC therapy was pneumonia in 75 patients (57.3%) and bronchiolitis in 17 patients (12.9%). Sixty-seven of 75 (90%) patients with pneumonia had underlying disease. The median duration of HFNC therapy was 3.25 (IQR, 2.0–5.0) days. The general characteristics of the patients and the treat- ments are given in Table 1.

High-flow nasal cannula success and failure

Successful HFNC was achieved in 116 (88.5%) patients. There was no difference between HFNC success and failure patients in terms of primary disease, comorbidity, and the site of HFNC therapy. There was no difference between success and failure groups in terms of vital signs and blood gas pa- rameters at HFNC initiation (Table 1). In all of the patients with HFNC failure, tachypnea continued after the initiation of HFNC; in 14 patients (93.3%), the need for FiO2 did not decrease, and in one patient (6.6%), respiratory acidosis was observed in the blood gas analysis.

In the entire cohort, one (0.7%) patient failed within the first 2 h, and eight (6.1%) patients failed within the first 48 h. Among HFNC failure patients, the maximum duration of HFNC therapy was 5 days. There was a significant difference between HFNC success and failure patients in terms of the duration of HFNC therapy (3.4 and 0.8 days, respectively, p < 0.001). Eight of HFNC failure patients were transferred to another hospital after the initiation of advanced respiratory support. Thirteen (86.7%) of HFNC failure patients received IMV and two (13.3%) received NIMV. Four patients with IMV and one with NIMV died during these treatments. The mortality rate of the entire cohort was 3.8%. No deaths oc- curred among patients where HFNC had been a success (p < 0.001). The length of hospitalization was 15.0 days for successful treatments. Statistical analysis did not carry out due to the deaths and the transfers in patients with HFNC failure. Comparisons of flow rate and FiO2 provided by HFNC, respiratory rate z-score, and SpO2/FiO2 for successful and failed therapies are given in Online Resource 1. While there was no significant difference between the two groups at the initiation of therapy regarding SpO2/FiO2 (p = 0.072), SpO2/ FiO2 significantly improved in patients where HFNC therapy had been successful as the treatment progressed (p < 0.001). While there was no flow rate difference between the groups at the initiation of HFNC (p = 0.143), the need for flow support in successful HFNC therapies was significantly lower at the 24th hour after HFNC initiation (p = 0.014). There was no improvement in respiratory rate z-score among patients for whom HFNC therapy failed, despite the presence of high-

flow support (p = 0.223).

Pediatric respiratory rate-oxygenation index and rate- oxygenation variation

While the increase in p-ROXI was significant for patients with HFNC success (p = 0.001), there was no significant change in p-ROXI for patients with HFNC failure (p = 0.471). During HFNC therapy, the increase in percentage change in p-ROXI (p-ROXV) was also associated with success (p < 0.001), while there was no significant change in p-ROXV for patients where

Table 1 Characteristics of high- flow nasal cannula success and failure patients

Cohort (n = 131)

Median (25p- 75p)

HFNC success (n = 116)

Median (25p-75p)

HFNC failure p

(n = 15)

Median (25p-75p)

Sex (male) n (%)65 (49.6)59 (50.8)6 (40)0.428
Age (months)23.0 (9.0–92.0)24.0 (11.0–95.0)15.0 (5.0–26.0)0.136
Primer diagnosis n (%)0.294
Pneumonia75 (57.3)66 (56.9)9 (60.0)
Bronchiolitis18 (13.7)18 (15.5)
Bronchopneumonia9 (6.9)8 (6.9)1 (6.7)
Post-extubation9 (6.9)9 (7.8)
Heart failure6 (4.6)5 (4.3)1 (6.7)
Fluid overload5 (3.8)4 (3.4)1 (6.7)
Sepsis5 (3.8)3 (2.6)2 (13.3)
Asthma1 (0.8)1 (0.9)
Others3 (2.3)2 (1.7)1 (6.7)
Comorbidities n (%)*
Cardiac30 (22.9)25 (21.6)5 (33.3)
Renal-metabolic26 (19.8)22 (18.9)4 (26.7)
Neurologic22 (16.8)17 (14.7)5 (33.3)
Hematologic-oncologic16 (12.2)14 (12.1)2 (13.3)
Pulmonary11 (8.4)11 ((9.5)
Immunocompromised9 (6.9)7 (6.0)2 (13.3)
Others3 (2.3)3 (2.6)
None19 (14.5)19 (16.4)
Site of HFNC therapy n (%)0.401
General ward80 (61.1)69 (59.5)11 (73.3)
Emergency department41 (31.3)37 (31.9)4 (26.7)
PICU10 (7.6)10 (8.6)0 (0)
Heart rate (bpm)144 (126–160)142 (124–160)151 (138–160)0.450
Heart rate (z-score)0.8 (0.3–1.5)0.8 (0.3–1.5)0.8 (0.0–1.3)0.888
Systolic blood pressure100 (90–100)100 (90–102)92 (90–100)0.451
(mmHg)
Diastolic blood pressure60 (50–60)60 (50–60)60 (50–60)0.747
(mmHg)
pH7.37 (7.32–7.44)7.37 (7.32–7.44)7.38 (7.33–7.44)0.997
PaCO2 (mmHg)39 (34–47)39 (34–48)40 (35–47)0.842
Lactate** (mmol/L)1.8 (0.9–2.8)1.7 (0.9–2.8)2.6 (1.3–3.2)0.452
Duration of HFNC therapy3.3 (2.0–5.0)3.4 (2.3–5.2)0.8 (0.3–2.6)< 0.001
(days)

HFNC high-flow nasal cannula, PICU pediatric intensive care unit

*Statistical analysis did not carry out due to some patients with multiple comorbidities

**41 of HFNC success and 4 in HFNC failure group had lactate results were included in analysis

HFNC therapy failed (p = 0.455). p-ROXV was associated with HFNC success at the 24th and 48th hours (Table 2).

Predicting high-flow nasal cannula failure

The area under the ROC analysis was performed to evaluate the accuracy of p-ROXI and p-ROXV to pre- dict HFNC failure at various time points during therapy

(Table 3). At the 24th hour of HFNC therapy, the ac- curacy of p-ROXI and p-ROXV could successfully pre- dict HFNC failure (AUROC, 0.79 and 0.72, respective- ly). The best predictive accuracy was observed at the 48th hour after HFNC initiation. The accuracy of p- ROXI and p-ROXV for predicting HFNC failure at the 48th hour after HFNC initiation had AUROC results of

0.88 and 0.88, respectively. In addition, the cutoff

Table 2 Pediatric respiratory rate-oxygenation index and pediatric respiratory rate-oxygenation index variation of high-flow nasal cannula therapy success and failure patients

TimeHFNCHFNCp
SuccessFailure
p-ROXI0 h68.0 (55.5–89.5)63.5 (40.4–85.0)0.191
1 h79.2 (62.9–102.2)66.3 (44.4–80.7)0.077
2 h79.9 (61.6–107.8)66.4 (42.5–79.3)0.055
4 h88.0 (67.0–125.4)55.3 (37.1–124.6)0.054
6 h94.1 (68.9–138.9)66.7 (37.9–132.4)0.103
24 h104.7 (74.6–178.4)50.9 (44.3–66.4)0.008
48 h130.0 (80.7–208.1)52.9 (47.2–64.7)0.001
p< 0.0010.471
p-ROXV (%)0 h
1 h8.9 (1.3–22.1)3.5 (−0.6–14.1)0.102
2 h10.0 (0.0–26.5)0.0 (−3.7–14.1)0.066
4 h16.9 (3.7–35.8)0.6 (−2.6–32.1)0.254
6 h27.1 (6.0–47.7)17.0 (−1.8–39.4)0.269
24 h37.2 (9.4–65.4)14.4 (−12.5–23.6)0.035
48 h47.9 (26.3–78.4)11.3 (−35.2–17.6)0.001
p< 0.0010.455

p-ROXI pediatric respiratory rate-oxygenation index, p-ROXV pediatric respiratory rate-oxygenation index variation

points for sensitivity and specificity values above 90% at various time points are given in Online Resource 2. When the best cutoff point for ROC curve was evaluated,

p-ROXI ≤ 66.7 at the 24th of HFNC therapy predicted HFNC

Table 3 AUROC analysis of pediatric respiratory rate-oxygenation index and pediatric respiratory rate-oxygenation index variation at different time points of high-flow nasal cannula therapy

failure with 86% sensitivity and 79% specificity (Table 4). At the 48th hour of HFNC initiation, the best cutoff point for p- ROXI was 65.1, and its specificity had increased to 88%. The best cutoff points for p-ROXV at 24 and 48 h were 24.0 and 24.6, respectively.

Kaplan-Meier analysis was performed to compare HFNC failure according to high and low values from the best cutoff points determined for p-ROXI and p- ROXV. HFNC failure was found to be higher in pa- tients who were below the cutoff points for p-ROXI and p-ROXV at 24 h of HFNC therapy (p < 0.001 and p < 0.001, respectively). In patients who were below the cutoff points, HFNC failure was also found to be higher for p-ROXI and p-ROXV at 48 h of HFNC therapy (p = 0.016 and p < 0.001, respectively). Kaplan-Meier analyses were also performed by combining cutoff points for p-ROXI and p-ROXV. At 24 h, if both p- ROXI and p-ROXV values were above the cutoff point (≥ 66.7 and ≥ 24.0, respectively), HFNC failure was 1.9% and 40.6% if both were below these values (p < 0.001). At 48 h after HFNC initiation, if both p- ROXI and p-ROXV values were above the cutoff point (≥ 65.1and ≥ 24.6, respectively), HFNC failure was 0.0%; and if both were below these values, HFNC fail- ure was 100% (p < 0.001).

Discussion

Optimal timing for transitions between invasive and noninvasive ventilation strategies is of significant impor- tance. Accordingly, the decision to continue HFNC ther- apy or advanced respiratory support, which may affect mortality and morbidity in pediatric patients with acute respiratory failure, remains an important challenge for clinicians.

Although HFNC failure rate varies according to de- mographic and clinical features such as age, HFNC

Table 4 Predicting power of high-flow nasal cannula failure by the pediatric respiratory rate-oxygenation index and pediatric respiratory rate-oxygenation index variation at 24 and 48 h of high-flow nasal cannula therapy

Cutoff Sensibility Specificity PPV NPV

HFNC failure/success (n)VariableAUROC95% CIp
0 h15/116p-ROXI0.640.40–0.880.223
p-ROXV
1 h15/116p-ROXI0.690.47–0.900.102
p-ROXV0.660.48–0.840.161
2 h14/116p-ROXI0.670.43–0.910.132
p-ROXV0.620.42–0.820.294
4 h13/116p-ROXI0.760.53–1.000.021
p-ROXV0.700.50–0.890.077
6 h13/115p-ROXI0.690.41–0.960.099
p-ROXV0.590.35–0.820.451

 

24 h7/105p-ROXI0.790.59–0.990.010p-ROXI24 h66.7867923.198.8
p-ROXV0.720.56–0.880.05448 h65.1868835.398.8
48 h7/92p-ROXI0.880.78–0.980.001p-ROXV24 h24.0866514.698.6
p-ROXV0.880.80–0.960.00148 h24.61007725.0100

AUROC area under the ROC curve, CI confidence interval, HFNC high- flow nasal cannula, p-ROXI pediatric respiratory rate-oxygenation index, p-ROXV pediatric respiratory rate-oxygenation index variation

HFNC high-flow nasal cannula, NPV negative predictive value, PPV positive predictive value, p-ROXI pediatric respiratory rate-oxygenation index, p-ROXV pediatric respiratory rate-oxygenation index variation

indication, and underlying disease, it was reported that this rate may reach up to 50% among children experiencing acute respiratory failure [1114]. In retro- spective studies conducted by Betters et al., the relation- ship between high FiO2, history of intubation, cardiac comorbidity, and HFNC failure was demonstrated [14]. The Pediatric Risk of Mortality score > 4.5, PaCO2/ PaO2 > 0.64, and high PCO2 were also found to be associated with HFNC failure [15, 16]. The complexity of data requires an objective marker that can be evalu- ated quickly and easily at the patient’s bedside for predicting HFNC failure in children with acute respira- tory failure. However, studies on this subject remain limited.

No study was found in the literature that evaluated the effectiveness of ROXI in pediatric patients. However, as is known, the respiratory physiology of adults and children differ in some respects, and the age and respiratory rate in children change inversely. Therefore, it will not be appropriate to simply establish a ROXI value for children of all ages. We modified ROXI and evaluated the relationship of p-ROXI with outcomes in children receiving HFNC therapy due to acute respiratory failure. We also calculated the percent- age variation in the p-ROXI between the initiation and different therapy hours. We evaluated p-ROXI and p- ROXV individually and in combination.

In our study, we evaluated changes in p-ROXI and p- ROXV in patients from the initiation to the 48th hour of HFNC therapy. While the increase in p-ROXI and p- ROXV values was significant among HFNC success pa- tients, we did not find any improvement in HFNC fail- ure patients. With the improvement of the patients’ clin- ical condition, a decrease in the flow rate they needed was observed by the 24th hour; this situation was not observed in HFNC failure group. Similar relationships existed in patients’ FiO2 requirements and SpO2 values. In the ROC analysis, the best cutoff points for p-

ROXI and p-ROXV at 24th hour were 66.7 and 24.0, respectively. When both were evaluated in combination, if both values were above the cutoff points, HFNC fail- ure was 1.9%, and it was 40.6% if both were below the cutoff points. In HFNC failure patients, 47% of patients still received HFNC support after 48 h, and the best predictive values for HFNC failure were denoted at the 48th hour. When p-ROXI and p-ROXV values were evaluated in combination, HFNC failure was 0.0% after

48 h of therapy if both values were above the cutoff points; all patients where both values presented under the cutoff points failed.

The findings of this study are promising for predicting early HFNC failure. According to these re- sults, considering that approximately one in two patients

whose values were below the cutoff points after 24 h failed, it is suggested that these patients be followed closely in terms of HFNC failure and that healthcare staff working together be informed in the event this occurs and to have the required materials ready for ur- gent intubation. Data at the 48th hour of HFNC initia- tion revealed that the combined use of p-ROXI and p- ROXV enabled predicting HFNC failure with high sen- sibility. Providing the necessary conditions can thus help to prevent delays in cases where intubation is needed and reduce the risk of intubation-related complications.

After Roca et al. suggested that ROXI could be used to predict HFNC failure [8], several clinicians published articles regarding their concerns about the reliability of ROXI and its clinical use. Karim and Esquinas sug- gested that ROXI will be more reliable when modified with PaO2/FiO2 and various hemoglobin concentrations, considering the oxyhemoglobin association–dissociation curve [17]. However, if the purpose was to establish a marker that could be employed easily and quickly at the patient’s bedside, it will be more appropriate to consider SpO2 in the foreground because of the difficulty concerning blood sampling and the risk of an arterial puncture in children. Mauri et al. reinterpreted data from their existing prospective studies in which they demonstrated that flow rate affected oxygenation, respi- ratory rate, and ROXI [18, 19]. They suggested that the cutoff values of ROXI be determined according to di- verse flow rates and that variations in ROXI would be more successful in terms of predicting outcomes. As in adults, there is no consensus regarding children in terms of how flow rate should be adjusted based on patient groups. In addition, since lung capacity varies greatly according to age, different opinions exist on the current rate that requires adjustment. Additional issues include whether the mouth is open or closed, effective humidi- fication, cannula diameter/nostril diameter ratio, and how patient comfort may affect the physiological effec- tiveness of HFNC [20]. Considering the reasons noted here, it will be difficult to carry out strong randomized controlled studies evaluating the effectiveness of ROXI in children with HFNC. At this stage, we believe that ROXI and ROXV can be used as markers for identify- ing children who may be at the risk of HFNC failure, rather than using invasive ventilation approaches.

Our study includes some limitations. While evalua- tions within the research were generalized to children with acute respiratory failure, no additional analysis was conducted for etiological causes, due to an insuffi- cient number of patients. As this was an observational study, FiO2 supports were adjusted by clinicians. The advanced respiratory support timing was decided by the

clinical care team. Despite of definitions, unstable con- dition criteria are prone for subjective interpretation.

Conclusions

In conclusion, this research represents the first pediatric study in which p-ROXI and p-ROXV were used in combination. Our data showed that combining p-ROXI and p-ROXV can be suc- cessful in predicting HFNC failure at 24 and 48 h of therapy. We believe that these parameters can be used as useful markers in pediatric clinics to help predict the risk of HFNC failure in pa- tients experiencing acute respiratory failure. However, further research is needed in this regard.

Authors’ contribution DY conceived and designed the study and critical- ly reviewed the manuscript.

AY collected and analyzed the data and wrote the first draft of the manuscript.

GI collected the data and wrote a part of the first draft of the manuscript.

OOH acquired the data and critically reviewed the manuscript. FE acquired the data and critically reviewed the manuscript.

Compliance with ethical standards

Conflict of interest The authors declare that they have no conflict of interest.

Ethical approval This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Çukurova University Faculty of Medicine Non-Interventional Clinical Research Ethics Committee.

Informed consent Informed consent was obtained from legal guardians.

References

  1. Hough JL, Pham TM, Schibler A (2014) Physiologic effect of high- flow nasal cannula in infants with bronchiolitis. Pediatr Crit Care Med 15:214 – 219. https://doi.org/10.1097/PCC. 0000000000000112
  2. Moreel L, Proesmans M (2020) High flow nasal cannula as respi- ratory support in treating infant bronchiolitis: a systematic review. Eur J Pediatr 179:711–718. https://doi.org/10.1007/s00431-020- 03637-0
  3. Shioji N, Iwasaki T, Kanazawa T, Shimizu K, Suemori T, Sugimoto K, Kuroe Y, Morimatsu H (2017) Physiological impact of high-flow nasal cannula therapy on postextubation acute respi- ratory failure after pediatric cardiac surgery: a prospective observa- tional study. J Intensive Care 5:35. https://doi.org/10.1186/s40560- 017-0226-z
  4. Richter RP, Alten JA, King RW, Gans AD, Rahman AF, Kalra Y, Borasino S (2019) Positive airway pressure versus high-flow nasal cannula for prevention of extubation failure in infants after congen- ital heart surgery. Pediatr Crit Care Med 20:149–157. https://doi. org/10.1097/PCC.0000000000001783
  5. Colleti Junior J, Azevedo R, Araujo O, Carvalho WB (2020) High- flow nasal cannula as a post-extubation respiratory support strategy

in preterm infants: a systematic review and meta-analysis. J Pediatr 96:422–431. https://doi.org/10.1016/j.jped.2019.11.004

  1. Marjanovic N, Flacher A, Drouet L, Le Gouhinec A, Said H, Vigneau JF, Chollet B, Lefebvre S, Sebbane M (2020) High-flow nasal cannula in early emergency department management of acute hypercapnic respiratory failure due to cardiogenic pulmonary ede- ma. Respir Care 65:1241–1249. https://doi.org/10.4187/respcare. 07278
  2. Helviz Y, Einav S (2018) A systematic review of the high-flow nasal cannula for adult patients. Critical Care (London, England) 22:71. https://doi.org/10.1186/s13054-018-1990-4
  3. Roca O, Messika J, Caralt B, García-de-Acilu M, Sztrymf B, Ricard JD, Masclans JR (2016) Predicting success of high-flow nasal can- nula in pneumonia patients with hypoxemic respiratory failure: the utility of the ROX index. J Crit Care 35:200–205. https://doi.org/ 10.1016/j.jcrc.2016.05.022
  4. Roca O, Caralt B, Messika J, Samper M, Sztrymf B, Hernández G, García-de-Acilu M, Frat JP, Masclans JR, Ricard JD (2019) An index combining respiratory rate and oxygenation to predict out- come of nasal high-flow therapy. Am J Respir Crit Care Med 199: 1368–1376. https://doi.org/10.1164/rccm.201803-0589OC
  5. Sepanski RJ, Godambe SA, Zaritsky AL (2018) Pediatric vital sign distribution derived from a multi-centered emergency department data- base. Front Pediatr 6:66. https://doi.org/10.3389/fped.2018.00066
  6. Vásquez-Hoyos P, Jiménez-Chaves A, Tovar-Velásquez M, Albor- Ortega R, Palencia M, Redondo-Pastrana D, Díaz P, Roa-Giraldo JD (2019) Factors associated to high-flow nasal cannula treatment failure in pediatric patients with respiratory failure in two pediatric intensive care units at high altitude. Factores asociados al fracaso de la terapia con cánulas nasales de alto flujo en pacientes pediátricos con insuficiencia respiratoria en dos unidades de cuidados críticos pediátricos a gran altitud. Medicina intensiva. https://doi.org/10. 1016/j.medin.2019.10.005
  7. Milési C, Essouri S, Pouyau R, Liet JM, Afanetti M, Portefaix A, Baleine J, Durand S, Combes C, Douillard A et al (2017) High flow nasal cannula (HFNC) versus nasal continuous positive airway pressure (nCPAP) for the initial respiratory management of acute viral bronchiolitis in young infants: a multicenter randomized con- trolled trial (TRAMONTANE study). Intensive Care Med 43:209– 216. https://doi.org/10.1007/s00134-016-4617-8
  8. Lee WY, Choi EK, Shin J, Lee EH, Choi BM, Hong YS (2020) Risk factors for treatment failure of heated humidified high-flow nasal cannula as an initial respiratory support in newborn infants with respiratory distress. Pediatr Neonatol 61:174–179. https://doi. org/10.1016/j.pedneo.2019.09.004
  9. Betters KA, Gillespie SE, Miller J, Kotzbauer D, Hebbar KB (2017) High flow nasal cannula use outside of the ICU; factors associated with failure. Pediatr Pulmonol 52:806–812. https://doi.org/10.1002/ ppul.23626
  10. Liu J, Li DY, Liu ZQ, Lu GY, Li XQ, Qiao LN (2019) High-risk factors for early failure of high-flow nasal cannula oxygen therapy in children. Zhongguo dang dai er ke za zhi = Chinese J Contemp Pediatr 21:650–655
  11. Guillot C, Le Reun C, Behal H, Labreuche J, Recher M, Duhamel A, Leteurtre S (2018) First-line treatment using high-flow nasal cannula for children with severe bronchiolitis: applicability and risk factors for failure. Arch de Pediatr 25:213–218. https://doi.org/10. 1016/j.arcped.2018.01.003
  12. Karim H, Esquinas AM (2019) Success or failure of high-flow nasal oxygen therapy: the ROX index is good, but a modified ROX index may be better. Am J Respir Crit Care Med 200:116–117. https://doi. org/10.1164/rccm.201902-0419LE
  13. Mauri T, Alban L, Turrini C, Cambiaghi B, Carlesso E, Taccone P, Bottino N, Lissoni A, Spadaro S, Volta CA, Gattinoni L, Pesenti A, Grasselli G (2017) Optimum support by high-flow nasal cannula in acute hypoxemic respiratory failure: effects of increasing flow rates.

Intensive Care Med 43:1453–1463. https://doi.org/10.1007/ s00134-017-4890-1

  1. Mauri T, Carlesso E, Spinelli E, Turrini C, Corte FD, Russo R, Ricard JD, Pesenti A, Roca O, Grasselli G (2019) Increasing sup- port by nasal high flow acutely modifies the ROX index in hypox- emic patients: a physiologic study. J Crit Care 53:183–185. https:// doi.org/10.1016/j.jcrc.2019.06.020
  2. Mauri T, Galazzi A, Binda F, Masciopinto L, Corcione N, Carlesso E, Lazzeri M, Spinelli E, Tubiolo D, Volta CA et al (2018) Impact

of flow and temperature on patient comfort during respiratory sup- port by high-flow nasal cannula. Critical Care (London, England) 22:120. https://doi.org/10.1186/s13054-018-2039-4

Publisher’s note Springer Nature remains neutral with regard to jurisdic- tional claims in published maps and institutional affiliations.

PDF olarak indirebilirsiniz. Yıldızdas 2020 Article

HFNC ile Aerosolizasyon Kullanımı

HFNC ile Aerosolizasyon Kullanımı

pharmaceutics

Article

Impact of Gas Flow and Humidity on Trans-Nasal Aerosol Deposition via Nasal Cannula in Adults: A Randomized Cross-Over Study

Luciana Alcoforado 1, Arzu Ari 2 , Jacqueline de Melo Barcelar 1, Simone Cristina S. Brandão 3, James B. Fink 2,4 and Armele Dornelas de Andrade 1,5,*

  1. Department of Physical Therapy, Universidade Federal de Pernambuco, Recife 50740-560, PE, Brazil
  2. Department of Respiratory Therapy, Texas State University, Round Rock, TX 78665, USA
  3. Medicine Nuclear Department, Universidade Federal de Pernambuco, Recife 50670-901, PE, Brazil
  4. Aerogen Pharma Corp, San Mateo, CA 94402, USA
  5. Avenida Jornalista Aníbal Fernandes, SN—Cidade Universitária, CEP, Recife 50740-560, PE, Brazil

* Correspondence: armele@ufpe.br; Tel.: +55-81-21268496

Received: 27 May 2019; Accepted: 4 July 2019; Published: 7 July 2019

check for

updates

Abstract: Background: Trans-nasal pulmonary aerosol delivery using high flow nasal cannula (HFNC) devices is described with the administration of high gas flows exceeding patient inspiratory flow (HF) and with lower flows (LF). The aim of this pilot clinical trial was to compare deposition and distribution of radiolabeled aerosol via nasal cannula in healthy adults across three rates of gas flow delivered with active heated humidification, and to further identify the impact of aerosol administration without heated humidity. Methods: Twenty-three (23) healthy adults (16F) were randomized to receive aerosol with active heated humidification or unheated oxygen at gas flows of 10 L/min (n = 8), 30 L/min (n = 7), or 50 L/min (n = 8). Diethylenetriaminepentaacetic acid labeled with 1 millicurie (37 MBq) of Technetium-99m (DTPA-Tc99m) was mixed with NaCl to a fill volume of 1 mL, and administered via mesh nebulizer placed at the inlet of the humidifier. Radioactivity counts were performed using a gamma camera and the regions of interest (ROIs) were delimited with counts from the lungs, upper airways, stomach, nebulizer, circuit, and expiratory filter. A mass balance was calculated and each compartment was expressed as a percentage of the total. Results: Lung deposition (mean ± SD) with heated humidified gas was greater at 10 L/min than 30 L/min or 50 L/min (17.2 ± 6.8%, 5.71 ± 2.04%, and 3.46 ± 1.24%, respectively; p = 0.0001). Using unheated carrier gas, a lung dose of aerosol was similar to the active heated humidification condition at 10 L/min, but greater at 30 and 50 L/min (p = 0.011). Administered gas flow and lung deposition were negatively correlated (r = −0.880, p < 0.001). Conclusions: Both flow and active heated humidity inversely impact aerosol delivery through HFNC. Nevertheless, aerosol administration across the range of commonly used flows can provide measurable levels of lung deposition in healthy adult subjects (NCT 02519465).

Keywords: nasal cannula; humidity; aerosol; scintigraphy; oxygen and nebulizer

Introduction

Oxygen administration via high flow nasal cannula (HFNC) supports acute and critically ill patients with respiratory failure [15]. HFNC therapy promotes oxygenation, generation of positive airway pressure, reduced rebreathing of carbon dioxide, and increased comfort when compared to other methods [49]. Patients receiving HFNC may benefit from inhaled medications. Trans-nasal pulmonary administration of medical aerosols using HFNC devices has been reported with gas flow exceeding patient inspiratory demand (high flow) and gas delivery lower than patient inspiratory flow (LF) [10].

Pharmaceutics 2019, 11, 320; doi:10.3390/pharmaceutics11070320 www.mdpi.com/journal/pharmaceutics

Administration of oxygen via HFNC presents a variety of challenges for efficient aerosol delivery. High gas flow dilutes aerosol, and generates transitional and turbulent flows in narrow circuits and cannula, thus increasing impacting losses of aerosol and reducing the amount of aerosol available to be inhaled. Additionally, the nasopharynx filters aerosols, thereby increasing deposition in the upper airways and reducing the therapeutic dose in the lungs [5,9,11,12].

In vitro studies have reported a reduction of inhaled dose as system delivery flow increases [6,13,14] and the diameter of the nasal cannula decreases [15]. Aerosol deposition reported with different systems have varied by an order of magnitude based on the type of humidifier, nebulizer, adapter, and placement used.

In vitro testing of aerosol delivery during mechanical ventilation commonly report inhaled dosage with unheated versus heated humidified gas, favoring unheated delivery by >60% [16]. More recently, the use of models simulating active heated humidified exhalation have reported smaller differences of the inhaled dose between unheated and heated humidified gas than models which do not heat and humidify exhaled gas. The implication is that models without active heated exhalation may overestimate the inhaled dose with unheated gas compared to in vivo delivery [17]. Although clinical administration of anhydrous unheated oxygen at flows greater than 6 L/min (American College of Chest Physicians) is not recommended, we aimed to assess the aerosol delivery with heated humidified and unheated gas in vivo to better understand the relevance of those in vitro observations.

In vitro studies [6,9,1315] differ as to whether aerosol administered via HFNC can provide clinically relevant therapeutic levels of aerosols to the lungs; however, an in vivo study of radiolabeled aerosol by Dugernier et al. [18] observed low deposition (3.6%) of aerosol from a mesh nebulizer via high-flow nasal cannula at a single flow of 30 L/min; however, it remains unknown if the higher deposition observed with lower flow rates on the bench translates to greater lung delivery in humans. Thus, the behavior of trans-nasal pulmonary deposition of aerosol at both lower and elevated flows, as well as the influence of unheated vs. active heated humidification using HFNC devices in humans is not yet known [4,5]. Clinical studies to quantify pulmonary deposition of aerosol via HFNC devices are necessary to provide guidance on the use of administrating high and low gas flows in

clinical practice.

Our hypothesis was that trans-nasal pulmonary aerosol delivery using a HFNC device:

  1. can deliver measurable quantities of aerosol to the lungs;
  2. has greater delivery efficiency with lower system gas flow; and
  3. varies when administered with active heated humidification rather than unheated gas.

Therefore, the aim of this study was to compare the effect of gas flow and active heated humidification on the deposition and distribution of radiolabeled aerosol from a vibrating mesh nebulizer (VMN) during administration via HFNC setup in healthy adult subjects.

Methods

    1. In Vivo Study Design and Sample

A randomized, cross-over pilot clinical study of healthy volunteers was performed at the Nuclear Medicine Department of the Hospital das Clínicas/Universidade Federal de Pernambuco in Recife, Brazil, and was approved by the Research and Ethics Committee on Humans (no. 54705616700005208 with Clinical Trials Registry (no. NCT 02519465). Informed consent was obtained from all individual participants included in the study.

Consenting volunteers were randomly allocated to receive radiolabeled aerosol via HFNC with heated humidified and unheated gas (crossover) at gas flows of 10, 30 or 50 L/min, with ≥7-day washout between administrations (Figure 1).

Figure 1. Study flow chart.

Two researchers were involved. The first generated random tables (http://www.randomization. com) and managed sealed envelopes, while the second administered inhalation and image acquisition. Subjects were blinded to administered flow and active heated humidification.

Healthy volunteers of both genders between 18–65 years, without a history of lung disease, with forced vital capacity (FVC) or forced expiratory volume in the first second (FEV1) ≥ 80% of predicted values [19] were included. Exclusion criteria were a history of smoking, diagnosed lung disease, active rhinitis, sinusitis, or pregnant women.

    1. Procedures and Measurements
      1. Initial Clinical Evaluation

The initial evaluation included age, gender, body mass index (BMI), respiratory rate (RR), blood pressure (AP0316, CBEMED, BIC, São Paulo, Brazil) with oxygen saturation (SpO2) and heart rate (HR) (pulse oximeter, Onyx® Vantage 9590, Plymouth, MN, USA). Spirometry (Micro Loop 8/Cardinal Health, England, UK) followed the American Thoracic Society [20] guidelines.

      1. Aerosol Administration

Diethylenetriaminepentaacetic acid labeled with 1 millicurie (37 MBq) of Technetium-99m (DTPA-Tc99m) in 0.9% saline to a total volume of 1 mL was administered via vibrating mesh nebulizer (VMN: Aerogen Solo, Aerogen Ltd., Galway, Ireland) placed at the inlet of a passover humidifier filled with sterile water and attached to a corrugated heated wire tubing and medium-sized adult nasal cannula (OptiflowTM; Fisher&Paykel Healthcare, Auckland, New Zealand) (Figure 2).

Figure 2. High flow nasal cannula system consisting of compressed oxygen cylinder with regulator and pressure compensated flowmeter, connecting to a T-piece with vibrating mesh nebulizer attached to the inlet of the humidifier chamber, with the outlet connected to a heated wire circuit attached to a nasal cannula and placed in the nares of the subject. A mask with a collecting filter was placed over the face and cannula to collect exhaled and escaped aerosol.

Oxygen was dispensed from a calibrated back pressure compensated flowmeter at 10, 30, and 50 L/min. Gas passed through the nebulizer connector, carrying aerosol into the inlet of the humidifier filled with water. For heated humidity, the water in the humidifier and circuit were heated to 34–36 ◦C. For unheated conditions, water in the humidifier was room temperature (20–22 ◦C) and the circuit was unheated.

After device setup and temperature stabilization, subjects were seated and nasal cannula prongs were placed in the nostrils. An orofacial mask with filter (Vital Signs, San Diego, California, USA) was placed over the cannula and lightly sealed to the face. Subjects were instructed to breathe normally and allotted 2 min to acclimate to the setup prior to dosing. The 1 mL dose was placed in the nebulizer reservoir and administered to completion.

      1. Lung Scintigraphy

To sample the posterior thorax, subjects were seated close to the gamma camera detector (Starcam 3200 AC/T GE Medical Systems, Little Chalfont, Buckinghamshire, UK) with an acquisition of 300 s with a matrix of 256 × 256 pixel. The scanner was repositioned to scan the anterior upper airway/face, followed by a scan of device components (nebulizer, humidifier chamber, tubing, cannula, mask, and filter) [21].

Both pulmonary and extrapulmonary regions of interest (ROI) were delimited using the Xeleris 3 Functional Imaging Workstation (GE Healthcare, Milwaukee, WI, USA). The radiation count of each compartment (lungs, upper respiratory tract, stomach, device, and filter) was determined for each ROI, with a mass balance expressed as a percentage of the sum of the counts (primary outcomes) [22]. Attenuation and tissue absorption correction factors for lungs, stomach, and oropharynx were applied as described by Lee [23]. Correction factors of 2.27 were specifically applied to the lung and stomach counts, and 2.37 for the upper airway, with no correction applied to device components and filters.

      1. Particle Size Characterization

The mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of aerosol exiting the HFNC under conditions described above were determined by a cascade impactor (Andersen Cascade Impactor; Thermo, Atlanta, GA, USA) operated at 28.3 L/min. Radiolabeled aerosol with gas rates of 10, 30, and 50 L/min was sampled for 2 min with throat and impactor stages scanned using 2D scintigraphy for 300 s, with each stage counted as ROI. Counts were used to calculate MMAD and GSD with software (http://www.mmadcalculator.com).

    1. Statistical Analysis

The study sample size was calculated after a pilot study with five volunteers in each group (10, 30, and 50 L/min) using (http://hedwig.mgh.harvard.edu/sample_size/size.html). The sample size calculation was made as a superiority study with primary endpoint of pulmonary deposition at flows of 10 L/min (49,522 ± 18,693), 30 L/min (42,953 ± 21,529), and 50 L/min (32,872 ± 12,227). A total of 15

individuals with allocation of 5 volunteers in each group was estimated based on the alpha level and power set to 0.05 and 80%, respectively.

Sample distribution was analyzed using the Shapiro–Wilk and Levene tests. The non-categorical variable was evaluated with Fisher’s exact test. We used the one-way analysis of variance (ANOVA) to compare flow rates with the Tukey post-hoc test for parametric variables and the Kruskal–Wallis test for non-parametric variables. Comparisons in aerosol deposition between heated humidified and unheated systems were performed using the paired sample t-test for parametric variables and Mann–Whitney U test for non-parametric variables. The Pearson and Spearman correlation were used to assess correlation between variables. Data were processed with SPSS 18.0 statistical software (SPSS Inc., Chicago, IL, USA) (p < 0.05). Aerosol deposition was expressed as percentage (mean ± SD%) of nominal dose placed in the nebulizer [22].

Results

Of the 27 subjects screened, 23 participated in the study with 8 allocated to receive a flow of 10 L/min, 7 of 30 L/min, and 8 of 50 L/min. (Figure 1). Anthropometric characteristics and spirometric measures were similar for all three groups (Table 1). The dosing time ranged from 2–4 min.

Table 1. Anthropometric characteristics and spirometric measures of participants who received inhalation therapy through HFNC at 10 L/min, 30 L/min, and 50 L/min.

Parameter 10 L/min

(n 8)

=

30 L/min

(n = 7)

50 L/min

(n = 8)

p-Value

AGE (years) 30.88 8.34 24.00 3.05 26.63 5.4 0.115

± ± ±

Gender 2 M/6 F 2 M/5 F 3 M/5 F 0.856

BMI (Kg/m2) 22.24 ± 2.25 25.62 ± 1.48 24.64 ± 3.60 0.058

HR (bpm) 78.57 ± 6.21 88.33 ± 5.39 77.00 ± 9.41 0.099

RR (ipm) 13.57 ± 4.07 15.33 ± 2.73 13.83 ± 3.65 0.650

SpO2 (%) 98.14 ± 0.69 97.83 ± 1.16 98.14 ± 0.69 0.765

IC (L) 2.27 ± 0.34 2.44 ± 0.45 2.52 ± 0.59 0.646

Tidal Volume (L) 0.91 ± 0.33 0.77 ± 0.15 0.70 ± 0.52 0.599

FEV1 (%pred) 94.00 ± 10.11 90.67 ± 8.31 89.00 ± 6.57 0.594

FVC (%pred) 93.33 ± 9.00 89.33 ± 6.77 89.33 ± 6.12 0.570

PEF (%pred) 82.20 ± 18.95 82.40 ± 6.46 81.40 ± 4.61 0.990

FEV1/FVC (%pred) 100.0 ± 5.17 100.17 ± 6.85 98.17 ± 7.38 0.843

±

Data is expressed as mean standard deviation. One-way Anova, p < 0.05. BMI = body mass index, HR = heart rate, RR = respiratory rate, SpO2 = oxygen saturation, IC = inspiratory capacity, FEV1 (%pred) = percentage of predicted for forced expiratory volume in 1 s, FVC (%pred) = percentage of predicted forced vital capacity, PEF (%pred) = percentage of predicted for peak expiratory flow, FEV1/FVC (%pred) = percent predicted for the ratio of forced expiratory volume in 1 s and forced vital capacity.

    1. Lung Deposition

Table 2 shows percentage of aerosol deposition (mean ± SD) during HFNC with active heated humidification.

Table 2. Percentage of mass aerosol deposition across compartments with different flow rates using the heated/humidified HFNC system.

Compartment 10 L/min

(n 8)

=

30 L/min

(n = 7)

50 L/min

(n = 8)

p-Value

Lung (%) 17.23 ± 6.78 5.71 ± 2.04 * 3.46 ± 1.24 ** <0.001 #

Upper airway (%) 34.48 ± 10.25 42.10 ± 13.92 46.07 ± 8.45 0.213

Stomach (%) 0.37 ± 0.15 1.05 ± 1.12 0.35 ± 0.49 0.116

Nebulizer (%) 13.57 ± 7.42 9.43 ± 6.30 10.30 ± 7.12 0.437

Cannula (%) 8.78 ± 3.63 13.18 ± 3.32 *** 18.40 ± 3.48 ** <0.001

Tubing (%) 21.93 ± 4.90 24.99 ± 9.31 23.41 ± 7.17 0.720

Humidifier (%) 12.21 ± 5.47 16.79 ± 9.68 10.95 ± 1.87 0.201 #

Exp Filter (%) 11.40 ± 3.65 5.68 ± 3.17 * 6.82 ± 4.00 0.014

Data is expressed as percentage (mean ± standard deviation). One-way ANOVA and # Kruskal–Wallis Test. p < 0.05.

* 10 L/min × 30 L/min, ** 10 L/min × 50 L/min, *** 30 L/min × 50 L/min.

A negative correlation of lung deposition and flow rate was observed with and without active heated humidification (r = −0.874/p < 0.001 and r = −0.572/p < 0.001, respectively). Representative scintigraphy images of pulmonary deposition with active heated humidified condition at 10, 30, and 50 L/min are shown in Figure 3.

Figure 3. Representative images of pulmonary deposition with heated humidified LFNC at 10 L/min and HFNC at 30 L/min and 50 L/min.

Lung delivery of aerosol with unheated gas via HFNC was greater than with active heated humidification at 30 L/min (13.16 ± 6.78% vs. 5.71 ± 2.04%, respectively; p = 0.015) and 50 L/min

(8.59 ± 2.54% vs. 3.46 ± 1.24%, p < 0.001). However, at 10 L/min lung deposition with active heated

humidification (17.23 ± 6.78%) and without (18.86 ± 10.01) were similar (p = 0.531) (Figure 4).

 

010 L/min H10 L/min U30 L/min H30 L/min U50 L/min H50 L/min U
LUNG17.218.95.713.23.58.6
UPPER AIRWAY32.828.540.739.145.041.5
FILTER11.412.15.79.66.810.3
DEVICE40.939.648.238.146.138.9

Figure 4. Aerosol distribution across compartments with LF and HFNC during heated humidified (H) and unheated (U) at flows of 10, 30, and 50 L/min.

      1. Aerosol Deposition in the Device

A positive correlation was observed between deposition in the nasal cannula and flow with (r = 0.778, p < 0.001) and without active heated humidification (r = 0.597, p < 0.001) conditions, respectively. There was a negative correlation between the amount of drug deposited in the nasal cannula and lung dose with active heated humidification using HFNC (r = −0.665, p < 0.001), and with unheated gas (r = −0.606, p < 0.01).

      1. Aerosol Deposition in the Expiratory Filter and Mask

Expiratory filter deposition was lower at 30 and 50 than 10 L/min (p = 0.014) (Table 2). A negative correlation was found between flow rate and drug deposition in the expiratory filter with active heated humidification conditions (r = −0.456, p = 0.029).

    1. MMAD Results

MMAD of aerosol exiting the cannula at 10, 30, and 50 L/min was greater with active heated humidification than unheated gas (2.29 ± 0.22 µm vs. 1.29 ± 0.22 µm; p = 0.038) with no trend in particle size change across flows. In contrast, GSD with heated humidification was similar to unheated gas (1.45 ± 0.18 vs. 1.6 ± 0.25, respectively), independent of flow.

Discussion

To our knowledge, this is the first study to quantify pulmonary delivery of radiolabeled aerosol administered via HFNC to adult subjects across a range of flows, confirming that flow and heated humidity impact lung dose.

Our lung dose at 30 L/min with active heated humidity (5.71 ± 2.04) is consistent with that reported by Dugernier et al. [18], who observed a lung deposition of 3.6% with a 4 mL (4 miC) fill volume using the same model of VMN at 30 L/min with heated humidity, as determined by single photon emission computed tomography (SPECT). It should be noted that the difference in fill volume used (1 and 4 mL) was not associated with differences in lung delivery efficiency. They reported 2.6% dose retention in the VMN compared to our 6%. The retention in the jet nebulizer which they used was 45.0%, which could partly account for the lower deposition in comparison with VMN. The authors [18] estimated loss of exhaled and escaped aerosols trickling from the nose at 20.5% in contrast to our measured losses of 4.3% in the expiratory filter and mask. In contrast, we report an upper airway deposition (42.1%) which was similar to their combined upper airway and nasopharyngeal compartments of 35.5%.

    1. Influence of Flow Rate on Pulmonary Deposition

The inverse correlation of administered gas flow to inhaled lung dose are consistent with in vitro reports. Using a casting of an adult airway, Reminiac et al. [6] reported reductions of aerosol delivery efficiency distal to the trachea with flows of 30, 45, and 60 L/min (6.7%, 3.5%, and 3%, respectively). Measuring the dose distal to the cannula at flows of 10, 30, and 50 L/min, Dailey et al. [17] reported inhaled dose efficiency of 26.7%, 11.6%, and 3.5%, respectively. Differences between the two models may be due to the collection point, with higher delivery efficiency in the simulated nose than distal to the trachea.

In contrast and using the same VMN with a different humidifier system (Vapotherm), adapter and nebulizer position, Perry et al. [14] reported lower deposition by >10 fold than other models at flows of 5 (2.5%), 10 (0.8%), 20 (0.4%), and 40 L/min (0.2%), respectively. The authors concluded that the low delivery efficiency of aerosol with HFNC would not be suitable for effective therapeutic drug delivery to adults. Our findings are more consistent with the in vitro reports of Ari, Dailey, and Reminiac, and suggest that a measurable and potentially therapeutic lung dose can be achieved with HFNC.

    1. Particle Size Distribution

The particle size distribution of aerosol exiting the VMN was measured as 3.9 µm MMAD with

2.1 GSD. We found that aerosol exiting the cannula during HFNC was larger with active heated humidity as carrier gas, with no emitted particles greater than 2.6 µm. We observed a trend to larger aerosol particle size distribution with active heated humidified versus unheated gas; however, the difference in aerosol MMAD exiting the cannula in both conditions was not flow dependent, and likely not of clinical significance. This suggests that much of the impacted loss of generated aerosol occurs en route through the circuit before reaching the cannula.

Bhashyam et al. [15] reported volume median diameter of aerosol particles emitted by the VMN to be 5 µm, with a reduction to 1.9–2.2 µm exiting the cannula at 3 L/min, with variations dependent on the size of cannula. Reminiac et al. [6] reported a MMAD of 1.8 µm with a GSD of 1.9. In contrast, Perry et al. [14] reported MMAD of 0.61 µm with GSD of 9.6 at 10 L/min, and 4.8 µm with GSD of 9.5 at 40 L/min. The greater variability in range of MMAD across the two flows and the higher GSDs could be attributed to the adapter used and placement with the implemented Vapotherm HFNC system, as well as condensation droplets accumulating and spraying from the cannula outlet.

A VMN producing 3.9 µm particles at the inlet of the humidifier results in larger particles impacting in the humidifier and connecting tubing prior to entering the cannula, thereby reducing the volume of particles impacting in the cannula. This reduces liquid incidence building up in the cannula and the frequency of spraying larger droplets into the nose.

The decrease in inhaled aerosol with increasing flows during HFNC is related to two factors:

(1) increased transitional flows and turbulence promoting greater inertial particle impaction within the device and airways, reducing the mass of aerosol available for inhalation; and (2) dilution of aerosol as gas flows exceed the inspiratory flow of the subject, reducing the concentration of inhaled aerosol, decreasing the inhaled aerosol mass/L.

    1. Heating and Humidifying Influence Pulmonary Deposition

Heated humidification is commonly used during nasal oxygen greater than low flows of 4–6 L/min [24]. High flow rates of anhydrous gas can cause dryness in the nose, mouth, and throat and irritate mucosa, increasing nasal resistance and bronchial hyper-responsiveness. Consequently, providing heat and humidity is considered essential, even at the risk of reduced pulmonary aerosol delivery [2527]. The use of active heated humidity with HFNC has been associated with greater comfort, tolerance, and lower respiratory rate [12,24]. This is consistent with our findings.

Pulmonary deposition of the aerosol with lower flow (10 L/min) was similar in comparing deposition with and without active heated humidified gas. This may be partly due to the function of the upper airway in heating and humidifying gas on inspiration so that change in particle size occurred prior to passing through the lower airways.

Aerosol administered with active heated humidity during ventilator support is associated with lower aerosol delivery efficiency attributed to hygroscopic particle growth [27] in transit, with subsequent greater impacting losses in circuit components and airways. However, it appears that particle size changes in response to high absolute humidity may occur secondary to the subject’s exhaled humidity, resulting in similar lung deposition efficiency at 10 L/min with and without active heated humidification condition, but not at higher flows. It is possible that the capacity of the nose to heat and humidify inhaled gas is exceeded in the presence of higher flows, and the isothermal saturation boundary (the point at which high absolute humidity is achieved) moves lower in the airways [24]. As administered gas flow increases, the volume passing through the cannula exceeds the ability of the upper airways to provide sufficient absolute humidity, it is likely that the particle size does not increase as much with the unheated condition, resulting in a higher lung dose.

Previous studies [24,25,2830] have reported that the deposition of aerosol using pressurized metered-dose inhalers (pMDI) and nebulizers can be reduced by 50% when delivered gas is heated and humidified versus dry. Miller et al. [31] confirmed reduced delivery with heated humidification via ETT in vivo. Our findings of reduced aerosol delivery at higher flows (30 and 50 L/min) with active heated humidity compared to unheated gas are consistent with Miller et al. [31].

    1. Aerosol Therapy and HFNC

We demonstrated pulmonary aerosol delivery ranging from 3.5% to 17.2%. Lower deposition at high flow may be sufficient for administration of drugs like bronchodilators, but not necessarily sufficient for therapeutic dosing with other drug classes. MacIntyre et al. [32] reported lung doses of 2–3% in ventilated subjects, with Fuller et al. [33] reporting even lower deposition from jet nebulizers

during mechanical ventilation. Duarte et al. [34] reported bronchodilator response in ventilated patients with jet nebulizers under similar conditions, while Dugernier et al. [18] reported lower lung dose with JN (1%) than VMN (3.6%) with similar flows, albeit the placement of nebulizers were different. Bräunlich and Wirtz [35] compared administration of a standard dose of short acting bronchodilator via jet nebulizer via HFNC at gas flow of 35 L/min compared to nebulizer with mouthpiece, reporting similar pre and post bronchodilator response in both arms. Similarly, in a randomized control trial of 25 subjects with obstructive airways disease, they received 2.5 mg of albuterol via VMN during HFNC at 30 L/min and by jet nebulizer with a facemask. Furthermore, Reminac et al. [36] reported that albuterol vibrating mesh nebulization within a nasal high-flow circuit induced similar bronchodilation to standard facial mask jet nebulization. They concluded that beyond pharmacological bronchodilation, nasal high flow by itself may induce small but significant bronchodilation.

    1. Clinical Implications

Nasal cannula over any flow range from low to high may be a useful way to deliver aerosols in general, thus representing another tool available to the clinician. Compared to oral delivery, nasal delivery may have some advantages, particularly at higher flow where oral aerosol delivery may interrupt the benefits in oxygenation, CO2 reductions, and positive airway pressure associated with HFNC. Administering aerosol via oral routes while the subject receives HFNC greatly reduces the inhaled dose [37]. However, any possible clinical advantages at this stage of development are remain speculative. Our findings demonstrate that it is possible to achieve measurable transnasal pulmonary delivery under the conditions tested, and that further work in acutely ill patients is required to demonstrate whether these levels of delivery can achieve desired clinical endpoints for aerosol administration of specific agents to the lung via HFNC. The low flow of 10 L/min provided greater aerosol to the lung (17%) than would be expected with standard jet nebulizer using a mouthpiece or mask (8–12%) [32], representing the range of lung dose associated with the jet nebulizers commonly used in the clinical trials for many of the approved nebulizer formulations for inhalation. For prolonged administration masks (for oxygen or aerosol) tend to be problematic as they are difficult to seal properly, can be uncomfortable and difficult for patient to speak or take nourishment. Standard oxygen masks at 10 L/min typically deliver FIO2 in the range of 30–40%, but only when firmly and securely seated on the face. Not all patients require the higher range of gas flow to support oxygenation. For patients with lower FIO2 requirements, flows of 10 L/min or less are common. Most adults have peak inspiratory flows of 30 L/min and mean inspiratory flows of 14 L/min at rest, but peak inspiratory flow may increase to 45 or 60 L/min when patients are in respiratory distress. For severely hypoxic patients, the higher flows are common to achieve FIO2 of 0.7 or greater, so not all patients on HFNC would be

expected to tolerate the lower 10 L/min flow.

Limitations

This study was conducted in normal healthy adult volunteers with relatively consistent non-stressed respiratory rate, tidal volume, and inspiratory capacity. Our findings may underestimate pulmonary delivery for patients with distressed breathing patterns as shown in vitro [6,18]. In contrast, using a mask with a filter to collect exhaled and fugitive aerosols allowed us to quantify a key compartment comprising the mass balance; however, the mechanical dead space of the mask may have had a reservoir effect, thereby slightly increasing the inhaled upper airway and lung dose.

There is inherent variability in the emitted dose rate and particle size distribution of the commercial ‘off the shelf’ vibrating mesh nebulizer used in this study, Aerosol output ranges from 0.2–0.5 mL/min resulting in administration times of a 1.0 mL dose ranging from 2–4 min. Our reported particle size distribution of aerosol exiting the VMN of 3.9 µm MMAD is greater than the range of 2.0–3.2 µm reported by the manufacturer (FDA 510(k) K133360). Device variability and the different analytic methods (assay of albuterol sulfate with UV/VIS vs. 2D scintigraphy of radiolabeled aerosol) may

explain these differences. Nevertheless, the reduction of aerosol MMAD exiting the cannula is consistent with other reports [6,15].

We only reported placement of the VMN at the inlet of the humidifier, consequently HFNC with nebulizer placed elsewhere in the circuit may change inhaled delivery efficiency. Placement of aerosol devices between humidifier and patient results in greater rainout of aerosol particles in the tubing with more frequent occlusion of the nasal prongs.

Deposition results for radiolabeled aerosol delivery are very sensitive to attenuation correction and it has been well documented that attenuation corrections vary between individuals. Due to the limitation of available technology on site, we did not measure these effects for each subject, but rather applied a ‘representative’ factor across subjects. These representative values may result in potential errors compared to individual values. In addition, the systemic and clinical consequences of relatively high nasopharyngeal deposition of aerosol of specific medications were not addressed in this study. Future clinical work should assess the side effects of associated systemic exposure with specific inhaled medications.

Conclusions

Both flow and active heated humidity inversely impact aerosol delivery through HFNC. Nevertheless, aerosol administration across the range of commonly used flows can provide measurable levels of lung deposition in healthy adult subjects. Further studies in acutely ill patients are warranted to evaluate dosing strategies for effective drug delivery via HFNC across flows.

Author Contributions: Conceptualization, L.A., A.A., J.B.F., and A.D.d.A.; Methodology, L.A., A.A., J.d.M.B., S.C.S.B., J.B.F., and A.D.d.A.; Formal Analysis, L.A., S.C.S.B., J.d.M.B., J.B.F., and A.D.d.A.; Investigation, L.A.,

A.A., J.d.M.B., S.C.S.B., J.B.F., and A.D.d.A.; Writing—Original Draft Preparation, L.A., J.B.F., and A.D.d.A.; Writing—Review & Editing, L.A., J.B.F., and A.D.d.A.

Funding: This study was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (grant number PVE 400801/13-2 and PDJ grant number 150454/2018-0) and FACEPE–APQ (grant number 0154-4.08/15).

Acknowledgments: The authors thank all the volunteers in this study, and the Medicine department and Fisher & Paykel Healthcare teams.

Conflicts of Interest: The authors declare no conflict of interest. The co-author James B. Fink is CSO of Aerogen Pharma Corp. The company had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

References

  1. Parke, R.L.; McGuinness, S.P.; Dixon, R.; Jull, A. Protocol for a randomised controlled trial of nasal high flow oxygen therapy compared to standard care in patients following cardiac surgery: The HOT-AS study. Int. J. Nurs. Stud. 2012, 49, 338–344. [CrossRef] [PubMed]
  2. Frat, J.P.; Thille, A.W.; Mercat, A.; Girault, C.; Ragot, S.; Perbet, S.; Prat, G.; Boulain, T.; Morawiec, E.; Cottereau, A.; et al. High-Flow Oxygen through Nasal Cannula in Acute Hypoxemic Respiratory Failure. N. Engl. J. Med. 2015, 372, 2185–2196. [CrossRef] [PubMed]
  3. Masclans, J.R.; Pérez-Terán, P.; Roca, O. The role of high-flow oxygen therapy in acute respiratory failure.

Med. Intensive 2015, 39, 505–515. [CrossRef] [PubMed]

  1. Hess, D.R. Aerosol therapy during noninvasive ventilation or high-flow nasal cannula. Respir. Care 2015, 60, 880–891. [CrossRef] [PubMed]
  2. Papazian, L.; Corley, A.; Hess, D.; Fraser, J.F.; Frat, J.P.; Guitton, C.; Jaber, S.; Maggiore, S.M.; Nava, S.; Rello, J.; et al. Use of high-flow nasal cannulaoxygenation in ICU adults: A narrative review. Intensive Care Med. 2016, 42, 1336–1349. [CrossRef] [PubMed]
  3. Réminiac, F.; Vecellio, L.; Heuzé-Vourc’h, N.; Petitcollin, A.; Respaud, R.; Cabrera, M.; Pennec, D.L.; Diot, P.; Ehrmann, S. Aerosol Therapy in Adults Receiving High Flow Nasal Cannula Oxygen. Ther. J. Aerosol Med. Pulm. Drug Deliv. 2016, 29, 134–141. [CrossRef] [PubMed]
  4. Dysart, K.; Miller, T.L.; Wolfson, M.R.; Shaffer, T.H. Research in high flow therapy: Mechanisms of action.

Respir. Med. 2009, 103, 1400–1405. [CrossRef] [PubMed]

  1. Ward, J.J. High-flow oxygen administration by nasal cannula for adult and perinatal patients. Respir. Care

2013, 58, 98–122. [CrossRef]

  1. Longest, P.W.; Walenga, R.L.; Son, Y.J.; Hindle, M. High-efficiency generation and delivery of aerosols through nasal cannula during noninvasive ventilation. J. Aerosol Med. Pulm. Drug Deliv. 2013, 26, 266–279. [CrossRef]
  2. Elmi-Sarabi, M.; Deschamps, A.; Delisle, S.; Ased, H.; Haddad, F.; Lamarche, Y.; Perrault, L.P.; Lambert, J.; Turgeon, A.F.; Denault, A.Y. Aerosolized vasodilators for the treatment of pulmonary hypertension in cardiac surgical patients: A systematic review and meta-analysis. Anesth. Analg. 2017, 125, 393–402. [CrossRef]
  3. Heyder, J.; Gebhart, J.; Rudolf, G.; Schiller, C.F.; Stahlhofen, W. Deposition of particles in the human respiratory tract in the size range 0.005–15 µm. J. Aerosol Sci. 1986, 17, 811–825. [CrossRef]
  4. Lee, J.H.; Rehder, K.J.; Williford, L.; Cheifetz, I.M.; Turner, D.A. Use of high flow nasal cannula in critically

ill infants, children, and adults: A critical review of the literature. Intensive Care Med. 2013, 39, 247–257. [CrossRef] [PubMed]

  1. Ari, A.; Harwood, R.; Sheard, M.; Dailey, P.; Fink, J.B. In vitro comparison of heliox and oxygen in aerosol delivery using pediatric high flow nasal cannula. Pediatr. Pulmonol. 2011, 46, 795–801. [CrossRef]
  2. Perry, S.A.; Kesser, K.C.; Geller, D.E.; Selhorst, D.M.; Rendle, J.K.; Hertzog, J.H. Influences of cannula size and flow rate on aerosol drug delivery through the Vapotherm humidified high-flow nasal cannula system. Pediatr. Crit. Care Med. 2013, 14, e250–e256. [CrossRef]
  3. Bhashyam, A.R.; Wolf, M.T.; Marcinkowski, A.L.; Saville, A.; Thomas, K.; Carcillo, J.A.; Corcoran, T.E. Aerosol delivery through nasal cannulas: An in vitro study. J. Aerosol Med. Pulm. Drug Deliv. 2008, 21, 181–188. [CrossRef] [PubMed]
  4. Fink, J.; Ari, A. Aerosol delivery to intubated patients. Expert Opin. Drug Deliv. 2013, 10, 1077–1093. [CrossRef]
  5. Dailey, P.A.; Harwood, R.; Walsh, K.; Fink, J.B.; Thayer, T.; Gagnon, G.; Ari, A. Aerosol delivery through high flow nasal cannula with heliox and oxygen. Respir. Care 2017, 62, 1186–1192. [CrossRef]
  6. Dugernier, J.; Hesse, M.; Jumetz, T.; Bialais, E.; Roeseler, J.; Depoortere, V.; Michotte, J.B.; Wittebole, X.; Ehrmann, S.; Laterre, P.F.; et al. Aerosol delivery with two nebulizers through high-flow Nasal Cannula: A Randomized Cross-over Single-Photon Emission Computed Tomography Study. J. Aerosol Med. Pulm. Drug 2017, 30, 349–358. [CrossRef]
  7. Pereira, C.A.D.C.; Barreto, S.D.P.; Simões, J.G.; Pereira, F.W.L.; Gerstler, J.G.; Nakatani, J. Valores de referência para a espirometria em uma amostra da população brasileira adulta. J. Pneumol. 1992, 18, 10–22.
  8. Celli, B.R.; Decramer, M.; Wedzicha, J.A.; Wilson, K.C.; Agustí, A.; Criner, G.J.; MacNee, W.; Make, B.J.; Rennard, S.I.; Stockley, R.A.; et al. An Official American Thoracic Society/European Respiratory Society Statement: Research questions in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2015, 191, e4–e27. [CrossRef]
  9. Galindo-Filho, V.C.; Ramos, M.E.; Rattes, C.S.; Barbosa, A.K.; Brandão, D.C.; Brandão, S.C.; Fink, J.B.; De Andrade, A.D. Radioaerosol pulmonary deposition using mesh and jet nebulizers during noninvasive ventilation in healthy subjects. Respir. Care 2015, 60, 1238–1246. [CrossRef] [PubMed]
  10. Dubus, J.C.; Vecellio, L.; De Monte, M.; Fink, J.B.; Grimbert, D.; Montharu, J.; Valat, C.; Behan, N.; Diot, P. Aerosol deposition in neonatal ventilation. Pediatr. Res. 2005, 58, 10–14. [CrossRef] [PubMed]
  11. Lee, Z.; Berridge, M.S.; Nelson, A.D.; Heald, D.L. The effect of scatter and attenuation on aerosol deposition as determined by gamma scintigraphy. J. Aerosol Med. 2001, 14, 167–183. [CrossRef] [PubMed]
  12. Chanques, G.; Constantin, J.M.; Sauter, M. Discomfort associated with underhumidified high-flow oxygen therapy in critically ill patients. Intensive Care Med. 2009, 35, 996–1003. [CrossRef] [PubMed]
  13. Dhand, R. Aerosol Therapy in Patients Receiving Noninvasive Positive Pressure Ventilation. J. Aerosol Med. Pulm. Drug Deliv. 2012, 25, 63–78. [CrossRef]
  14. Fink, J.B.; Dhand, R. Aerosol therapy in mechanically ventilated patients: Recent advances and new techniques. Semin. Respir. Crit. Care Med. 2000, 21, 183–201. [CrossRef] [PubMed]
  15. Lange, C.F.; Finlay, W.H. Overcoming the adverse effect of humidity in aerosol delivery via pressurized metered-dose inhalers during mechanical ventilation. Am. J. Respir. Crit. Care Med. 2000, 161, 1614–1618. [CrossRef]
  16. Lin, H.L.; Harwood, R.J.; Fink, J.B.; Goodfellow, L.T.; Ari, A. In Vitro Comparison of Aerosol Delivery Using Different Face Masks and Flow Rates With a High-Flow Humidity System. Respir. Care 2015, 60, 1215–1219. [CrossRef]
  17. Ari, A.; Fink, J.B.; Dhand, R. Inhalation Therapy in Patients Receiving Mechanical Ventilation: An Update.

J. Aerosol Med. Pulm. Drug Deliv. 2012, 25, 319–332. [CrossRef]

  1. Dhand, R. Aerosol delivery during mechanical ventilation: From basic techniques to new devices. J. Aerosol Med. Pulm. Drug Deliv. 2008, 21, 45–60. [CrossRef]
  2. Miller, D.D.; Amin, M.M.; Palmer, L.B.; Shah, A.R.; Smaldone, G.C. Aerosol Delivery and Modern Mechanical Ventilation: In Vitro/In Vivo Evaluation. Am. J. Respir. Crit. Care Med. 2003, 168, 1205–1209. [CrossRef] [PubMed]
  3. MacIntyre, N.R.; Silver, R.M.; Miller, C.W.; Schuler, F.; Coleman, R.E. Aerosol delivery in intubated, mechanically ventilated patients. Crit. Care Med. 1985, 13, 81–84. [CrossRef] [PubMed]
  4. Fuller, H.D.; Dolovich, M.B.; Posmituck, G.; Pack, W.W.; Newhouse, M.T. Pressurized aerosol versus jet aerosol delivery to mechanically ventilated patients. Comparison of dose to the lungs. Am. Rev. Respir. Dis. 1990, 141, 440–444. [CrossRef] [PubMed]
  5. Duarte, A.G.; Mobii, K.; Bidani, A. Bronchodilator therapy with metered-dose inhaler and spacer versus nebulizer in mechanically ventilated patients: Comparison of magnitude and duration of response. Respir. Care 2000, 45, 817–823. [PubMed]
  6. Bräunlich, J.; Wirtz, H. Oral versus nasal high-flow bronchodilator inhalation in chronic obstructive pulmonary disease. J. Aerosol Med. Pulm. Drug Deliv. 2017, 31, 1–7.
  7. Reminiac, F.; Vecellio, L.; Bodet-Contentin, L.; Gissot, V.; Le Penec, D.; Gandonniere, C.S.; Cabrera, M.; Dequin, P.; Plantier, L.; Ehrmann, S. Nasal hifgh-flow bronchodilator nebulization: A randomized cross-over study. Ann. Intensive Care 2018, 8, 128. [CrossRef] [PubMed]
  8. Bennett, G.; Joyce, M.; Fernandez, E.F.; MacLoughin, R. Comparison of aerosol delivery across combinations of drug delivery of interfaces with and without concurrent high-flow nasal therapy. Intensive Care Med. Exp. 2019, 7, 20. [CrossRef]

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons

 

PDF olarak indirebilirsiniz. Pharmaceutics

HFNC ve NIV Kullanımının Weaning’e Etkisi

HFNC ve NIV Kullanımının Weaning’e Etkisi

Open access Protocol

High-flow nasal cannula oxygen therapy alone or with non-invasive ventilation during the weaning period after extubation in ICU: the prospective randomised controlled HIGH-

WEAN protocol

Arnaud W Thille,1,2 Grégoire Muller,3 Arnaud Gacouin,4 Rémi Coudroy,1,2 Alexandre Demoule,5 Romain Sonneville,6 François Beloncle,7 Christophe Girault,8 Laurence Dangers,9 Alexandre Lautrette,10 Séverin Cabasson,11 Anahita Rouzé,12 Emmanuel Vivier,13 Anthony Le Meur,14 Jean-Damien Ricard,15 Keyvan Razazi,16 Guillaume Barberet,17 Christine Lebert,18 Stephan Ehrmann,19 Walter Picard,20 Jeremy Bourenne,21 Gael Pradel,22 Pierre Bailly,23 Nicolas Terzi,24

Matthieu Buscot,25 Guillaume Lacave,26 Pierre-Eric Danin,27

Hodanou Nanadoumgar,28 Aude Gibelin,29 Lassane Zanre,30 Nicolas Deye,31 Stéphanie Ragot,2 Jean-Pierre Frat,1,2 For the REVA research network

To cite: Thille AW, Muller G, Gacouin A, et al. High-flow nasal cannula oxygen therapy alone or with non-invasive ventilation during the weaning period after extubation

in ICU: the prospective randomised controlled HIGH- WEAN protocol. BMJ Open 2018;8:e023772. doi:10.1136/

bmjopen-2018-023772

Received 25 April 2018

Revised 12 July 2018

Accepted 20 July 2018

© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

For numbered affiliations see end of article.

Correspondence to Professor Arnaud W Thille; aw.thille@gmail.com

Abstract

Introduction Recent practice guidelines suggest applying non-invasive ventilation (NIV) to prevent postextubation respiratory failure in patients at high risk of extubation failure in intensive care unit (ICU). However, such prophylactic

NIV has been only a conditional recommendation given the low certainty of evidence. Likewise, high-flow nasal cannula (HFNC) oxygen therapy has been shown to reduce reintubation rates as compared with standard oxygen and to be as efficient as NIV in patients at high risk. Whereas HFNC may be considered as an optimal therapy during the postextubation period, HFNC associated with NIV could be

an additional means of preventing postextubation respiratory failure. We are hypothesising that treatment associating NIV with HFNC between NIV sessions may be more effective than HFNC alone and may reduce the reintubation rate in patients at high risk.

Methods and analysis This study is an investigator- initiated, multicentre randomised controlled trial comparing HFNC alone or with NIV sessions during the postextubation period in patients at high risk of extubation failure in the ICU. Six hundred patients will be randomised with a 1:1 ratio in two groups according to the strategy of oxygenation after extubation. The primary outcome is the reintubation rate within the 7 days following planned extubation. Secondary outcomes include the number of patients who meet the criteria for moderate/severe respiratory failure, ICU length of stay and mortality up to day 90.

Ethics and dissemination The study has been approved by the ethics committee and patients will be included after informed consent. The results will be submitted for publication in peer-reviewed journals.

trial registration number NCT03121482.

  • High-flow nasal cannula (HFNC) oxygen therapy had never previously been used as a reference therapy. When administered to a control group, this treat- ment seemed highly innovative and in agreement with the recent literature. Likewise, the ventilatory strategy used in the interventional group associating non-invasive ventilation (NIV) and HFNC had never previously been assessed.
  • This study will be the largest randomised controlled trial never conducted on the use of NIV during the postextubation period and may help to establish strong recommendations on weaning strategy with a high level of evidence.
  • A large population of patients considered to be at high risk for reintubation will be included. Patients older than 65 years or those with an underlying chronic cardiac or respiratory disease are easy to identify in clinical practice and represent nearly half of the patients who are extubated in the intensive care unit.
  • The individual study assignments of the patients will not be masked. Given the characteristics of the two strategies under evaluation, a double-blind trial is not possible.

strengths and limitations of this study

IntroductIon Background and Rationale

The day of extubation is a critical time during an intensive care unit (ICU) stay because in case of extubation failure, mortality can

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Thille AW, et al. BMJ Open 2018;8:e023772. doi:10.1136/bmjopen-2018-023772 1

Open access

Table 1 Main randomised controlled trials having assessed the use of prophylactic NIV to prevent postextubation respiratory failure in ICU
Randomised controlled trials No of centres/inclusion criteriaMain results: NIV versus standard oxygen (O2)
Nava et al3

3 centres: NIV (n=48) vs O2 (n=49)

Patients considered at high risk for reintubation

Reintubation: n=4 (8%) vs n=12 (24%), p=0.027* In-ICU mortality: n=3 (6%) vs n=9 (18%), p=0.064
Ferrer et al5

2 centres: NIV (n=79) vs O2 (n=83)

Age>65, APACHE II>12 or intubation for cardiac heart failure

Respiratory failure after extubation: n=13 (16%) vs n=27 (33%), p=0.029*

Reintubation: n=9 (11%) vs n=18 (22%), p=0.12 Nosocomial Infections: 18 (23%) vs 27 (33%), p=NS

In-ICU mortality: NIV n=2 (3%) vs. n=12 (14%), p=0.015

Ferrer et al6

3 centres: NIV (n=54) vs O2 (n=52)

PCO2 >45 mm Hg at the end of the spontaneous breathing trial

Respiratory failure after extubation: n=8 (15%) vs n=25 (48%), p<0.0001*

Reintubation: n=6 (11%) vs n=10 (19%), p=0.37 Pneumonias: 3 (6%) vs 9 (17%), p=0.12

In-ICU mortality: n=3 (6%) vs n=4 (8%), p=0.71 Mortality at day 90: n=6 (11%) vs n=16 (31%), p=0.024

Khilnani et al26

1 single centre: NIV (n=20) vs O2 (n=20) Patients with COPD

Reintubation: n=5 (25%) vs n=3 (15%), p=0.44* Length of ICU stay: 18.3±7.9 j vs 16.1±6.3, p=0.34
Su et al27

3 centres: NIV (n=202) vs O2 (n=204) Intubation≥48 hours

Extubation failure: n=30 (15%) vs n=27 (13%), p=0.62* Reintubation: n=21 (10%) vs n=16 (8%), p=0.37

In-ICU mortality: n=3 (1.5%) vs n=2 (1%), p=0.64

Ornico et al4

1 single centre: NIV (n=20) vs O2 (n=18) Intubation ≥3 days for respiratory failure

Reintubation: n=1 (5%) vs n=7 (39%), p=0.016* In-hospital mortality: 0% vs n=4 (22%), p=0.041
Vargas et al28

6 centres: NIV (n=71) vs O2 (n=72) Patients with chronic lung disorders

Respiratory failure after extubation: n=6 (8%) vs n=20 (28%), p=0.002*

Reintubation: n=6 (8%) vs n=13 (18%), p=0.09 In-ICU mortality: n=2 (3%) vs n=6 (8%), p=0.28

Mortality at day 90: n=7 (10%) vs n=11 (15%), p=0.33

*Main end point.

APACHE, Acute Physiology and Chronic Health Evaluation; COPD, chronic obstructive pulmonary disease; ICU, intensive care unit; NIV, non- invasive ventilation; PCO2, partial pressure of carbon dioxide.

reach 30%–50%.1 2 The overall rate of extubation failure is around 10%–15%, but it may exceed 20% in patients at high risk.1 2 Several studies suggest that prophylactic non-invasive ventilation (NIV) applied within the first 24–48 hours after extubation could reduce the risk of respiratory failure in patients at high risk table 1.3–8 Recent European/American clinical practice guidelines have suggested that NIV be used to prevent postextuba- tion respiratory failure in patients at high risk.9 These guidelines specified that for most of these studies, patients at high risk of extubation failure included those >65 years or with underlying cardiac or respiratory disease.3 5–8 In a before–after study assessing the imple- mentation of a specific prophylactic NIV programme, we observed a significant reduction in the reintubation rate when prophylactic NIV was systematically applied after extubation in this population at high risk.8 A meta-anal- ysis of randomised controlled trials also suggests that prophylactic NIV may decrease reintubation rates in this population.10 However, that has not been demonstrated in large randomised controlled trials and only two small randomised controlled studies have shown that NIV

decreased reintubation rates as compared with standard oxygen.3 4 Therefore, use of prophylactic NIV was a condi- tional recommendation in recent international guide- lines, given the low certainty of evidence.9

Up until now, the majority of patients have been treated with standard oxygen after extubation.11 High-flow nasal cannula oxygen therapy (HFNC) is an alternative device for oxygenation that improves gas exchange and reduces the work of breathing.12–14 Two randomised controlled trials have shown a significant reduction in the reintuba- tion rate for patients treated with HFNC as compared with standard oxygen.15 16 In another large-scale randomised controlled trial, HFNC was equivalent to NIV in patients at high risk of extubation failure.17 Therefore, HFNC may be considered as the reference therapy during the postextubation period. In order to further improve gas exchange and the work of breathing, HFNC may be asso- ciated with NIV.

Objectives

We aim to conduct a prospective multicentre randomised controlled trial comparing HFNC alone or with NIV

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2 Thille AW, et al. BMJ Open 2018;8:e023772. doi:10.1136/bmjopen-2018-023772

Open access

sessions during the postextubation period in patients at high risk of extubation failure in the ICU, with the hypothesis that treatment associating HFNC with NIV may reduce the reintubation rate as compared with HFNC alone.

Primary Objective

To compare the reintubation rate within the 7 days following planned extubation between HFNC alone and HFNC with NIV in patients at high risk of extubation failure in the ICU.

Secondary Objectives

To compare the number of patients who meet the criteria for moderate/severe respiratory failure within the 7 days following extubation, and the rates of reintubation at 48 hours, 72 hours and up to ICU discharge.

To compare the number of ventilator-free days within the 14 days following extubation, length of stay in ICU and in the hospital and, mortality in ICU, in hospital, at day 28 and up to day 90 between the two groups.

Trial Design

The HIGH-FLOW for WEANING (HIGH-WEAN) study

is an investigator-initiated, prospective, multicentre, randomised, control, open trial comparing a strategy of oxygenation during the postextubation period with HFNC alone or with NIV in patients at high risk of extuba- tion failure in the ICU. Patients will be randomly assigned to the NIV group or HFNC group, with a 1:1 ratio.

Methods: Participants, Interventions And Outcomes Study Setting

The HIGH-WEAN study is taking place in 30 ICUs in France.

Eligibility Criteria

Inclusion criteria

Adult patients intubated more than 24 hours in ICU and at high risk of extubation failure will be eligible if consid- ered ready for extubation by the physician in charge and after success of a spontaneous breathing trial performed according to the international conference consensus on weaning (figure 1).18

Patients will be considered at high risk of extubation failure according to the following criteria19: patients older than 65 years, or those having any underlying chronic cardiac or lung disease. Underlying chronic cardiac diseases include left ventricular dysfunction whatever the cause defined by left ventricular ejection fraction 45%, history of cardiogenic pulmonary oedema, documented ischaemic heart disease or permanent atrial fibrillation. Chronic lung diseases include the existence of any under- lying chronic obstructive pulmonary disease (COPD), obesity hypoventilation syndrome (OHS) or restrictive pulmonary disease. The underlying lung disease will be either documented or highly suspected by the physician in a patient intubated for acute hypercapnic respiratory

failure and having (1) a history of smoking with intrinsic positive end-expiratory pressure (PEEP) during mechan- ical ventilation and/or emphysema on chest X-ray or scanner suggesting underlying COPD, (2) obesity body mass index (>30 kg/m2) with alveolar hypoventilation arterial carbon dioxide tension (PaCO2 >45 mm Hg) suggesting OHS or (3) rib cage deformation suggesting restrictive pulmonary disease.

Exclusion criteria

Patients fulfilling one of the following criteria will not be included: patients admitted for traumatic brain injury or with any underlying chronic neuromuscular disease (myopathy or myasthenia gravis), patients with NIV or continuous positive airway pressure at home, or with a contraindication to NIV, and patients with do-not-reintu- bate order at time of extubation or unplanned extuba- tion (accidental or self extubation).

Intervention

Oxygenation strategy during the postextubation period

Patients eligible for inclusion will be randomised at time of decision of planned extubation and assigned to one of the two following groups: (1) The patients assigned to control group will receive continuously HFNC alone and

(2) The patients assigned to interventional group will receive NIV during at least 12 hours a day with HFNC between NIV sessions.

As NIV may be more effective in hypercapnic patients, blood gas will be systematically assessed at the end of the spontaneous breathing trial prior to extubation in order to stratify the randomisation for PaCO2 level and to include the same number of hypercapnic patients (PaCO2 >45 mm Hg) in the two groups.

Control group: HFNC alone

Immediately after planned extubation, the patients assigned to the control group will be continuously treated by HFNC for at least 48 hours with a flow of 50 L/min and fractional inspired oxygen (FiO2) adjusted to obtain adequate oxygenation (Pulse Oximetry (SpO2)92%). To provide sufficient humidification the temperature of the heated humidifier will be set as during invasive mechan- ical ventilation, that is, at 37°C.

Interventional group: HFNC and NIV

NIV will be immediately initiated after planned extuba- tion with a first session of at least 4 hours and then by sessions of at least 2 hours for a minimal duration of at least 12 hours a day during the 48 hours following extu- bation. Continuous application of NIV will be promoted throughout the entire night period (between 22:00 and 6:00 hours). NIV will be carried out with a ventilator dedicated for NIV (ICU ventilator with NIV mode or NIV ventilator) in pressure-support ventilation with a minimal PS level of 5 cm H2O targeting a tidal volume around 6–8 mL/kg, a PEEP level between 5 and 10 cm H2O and FiO2 adjusted to obtain adequate oxygen- ation (SpO2 92%). Between NIV sessions, HFNC

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Figure 1 Flow chart of the patients and study design. Patients extubated after at least 24 hours of mechanical ventilation and without do-not-reintubate order will be eligible if they are considered at high risk of extubation failure, that is, more than 65 years old or with underlying chronic cardiac or respiratory disease. Patients will be randomised and treated either with

high-flow nasal cannula (HFNC) oxygen therapy alone or with sessions of non-invasive ventilation (NIV) with at least 12 hours a day of NIV. Forty-eight hours after planned extubation, treatment will be stopped or continued according to patient respiratory status. CPAP, continuous positive airway pressure; FiO2, fractional inspired oxygen; ICU, intensive care unit; PaO2, arterial oxygen tension; PACO2, arterial carbon dioxide tension.

will be delivered as in the control group with a flow of 50 L/min and a FiO2 to achieve adequate oxygenation (SpO2 92%).

In both groups, therapeutic NIV used to treat postextu- bation respiratory failure will be discouraged given that it has no proven benefit20 and can even increase the risk of death by delaying reintubation.21

Duration of treatment

In the two groups, patients will be treated for a minimal duration of 48 hours. After that, continuation of the treat- ment will be decided according to the patient respiratory status (figure 1).

If none of the criteria for moderate respiratory failure are present 48 hours after extubation (see criteria below),

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treatment will be stopped and switched to standard oxygen therapy. If at least one criterion for moderate respiratory failure appears or persists 48 hours after extubation, the allocated treatment will be continued for periods of 24 hours until complete disappearance of these respiratory criteria.

Criteria for moderate respiratory failure include the following: (1) Respiratory rate >25/min persistent at least 2 hours, (2) Clinical signs suggesting respiratory distress with increase in the work of breathing and/or respira- tory fatigue including activation of accessory respiratory muscles, (3) Respiratory acidosis defined as pH <7.35 units and PaCO2 >45 mm Hg, (4) Hypoxaemia defined as a need for FiO2 50% to maintain SpO2 92% or arterial oxygen tension (PaO2)/FiO2 150 mm Hg.

An episode of moderate acute respiratory failure during

the postextubation period will be defined by the presence of at least two criteria for moderate respiratory failure.

Outcomes

Primary outcome

The primary outcome is reintubation within the 7 days following planned extubation.

Patients will be reintubated only if one of the following criteria occurs:

  1. Severe acute respiratory failure defined by the pres- ence of at least two criteria for severe respiratory failure among the following: (1) Respiratory rate >35/min,

(2) Clinical signs suggesting respiratory distress with increase in the work of breathing and/or respiratory fatigue including activation of accessory respiratory muscles, (3) Respiratory acidosis defined as pH <7.25 units and PaCO2 >45 mm Hg, (4) Hypoxaemia defined

as a need for FiO2 80% to maintain SpO2 92% or PaO2/FiO2 100 mm Hg.

  1. Haemodynamic failure defined as systolic arterial pres- sure <90 mm Hg or mean arterial pressure <65 mm Hg with a need for vasopressors.
  2. Neurological failure: altered consciousness (Glasgow <12) or agitation.
  3. Cardiac or respiratory arrest.

Secondary outcomes

Secondary outcome variables include the following:

  1. Reintubation at 48 hours, 72 hours and up until ICU discharge.
  2. An episode of moderate acute respiratory failure with- in the 7 days following extubation.
  3. An episode of severe acute respiratory failure within the 7 days following extubation.
  4. Number of ventilator-free days within the 14 days fol- lowing extubation.
  5. Length of stays in ICU and in hospital.
  6. Mortality in ICU, in hospital, at day 28 and at day 90.

Sample size

We determined that enrolment of 590 patients would provide a power of 80% to show an absolute difference

of 8% in the rate of reintubation between the control group using HFNC alone (rate of reintubation estimated to 18%) as compared with the interventional group using HFNC and NIV (rate of reintubation estimated to 10%) at a two-sided alpha level of 0.05. As NIV may be more effective in hypercapnic patients, stratification will be performed in order to include the same number of hyper- capnic patients (PaCO2 >45 mm Hg) in the two groups.

Expected Rate of Reintubation in the two groups

The expected rates of reintubation in the two groups are based on the recent literature using HFNC in the postex- tubation period15–17 and on our preliminary studies assessing NIV in patients at high risk.8 19 22

In our preliminary studies, the reintubation rate in patients at high risk treated with NIV was 15% within the 7 days following extubation. Although no study to date has evaluated a ventilatory strategy combining NIV and HFNC, we can expect an additionally decreased reintuba- tion rate (around 10%) in the interventional group.

Several studies have assessed HFNC alone during the postextubation period.15–17 The rates of reintubation reached 19% in the subset of patients at high risk.17 Although these rates could be underestimated (first, because the rate of reintubation was assessed within the first 48 or 72 hours following extubation and not at day 7 as in our study, and second because hypercapnic patients considered at high risk for reintubation were excluded), we expect a rate of reintubation at day 7 of around 15%–20% in the control group treated by HFNC alone.

Recruitment

The initial duration of patient enrolment expected is 2 years, starting in April 2017.

  • End of 2015: national grant award.
  • 2016: approval by an independent ethics committee.
  • 2017: inclusion of patients.
  • 2018–2019: end of inclusions, monitoring of partici- pating centres and queries to investigators; overseen by the steering committee at the REVA Network meetings every 4 months; blind review to determine protocol violation, to define intention-to-treat and per-protocol analysis populations; new queries to investigators, cleaning and closure of the database.
  • 2019: data analysis, writing of the manuscript and submission for publication.

Methods: Assignment of Intervention, Data Collection, Management And Analysis

Allocation and sequence intervention

A computer-generated randomisation is performed with stratification according to centre and PaCO2 45 or

>45 mm Hg measured at the end of the spontaneous breathing trial in a 1:1 ratio, using a centralised web-based management system (Clinfile). After randomisation, the strategy assigned to the patient (HFNC alone or with NIV) will be initiated immediately after extubation.

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Figure 2 Flow chart of the study showing timing collection of different variables. ICU, intensive care unit; HFNC, high-flow nasal cannula; NIV, non-invasive ventilation.

Data Collection and Management

Data will be collected on an Case Report Form (e-CRF) by a trained investigator or research assistant at each centre (figure 2). At time of inclusion, the following data on weaning procedure will be collected: type of spontaneous breathing trial performed before extubation (T-tube or pressure-support trial), vital parameters at the end of the spontaneous breathing trial and classification according to weaning difficulty.18 We will also collect qualitative assessment of cough strength and amount of secretions, and the use of steroids before extubation.

Ventilatory settings (gas flow and FiO2 using HFNC, pressure-support, PEEP, FiO2 and expiratory tidal volume with NIV), and blood gas will be collected 1 hour after extubation and then at H6, between H12 and H24, and between H24 and H48. During the first 48 hours after extubation, we will collect the number and duration of NIV sessions and HFNC, criteria for moderate/severe acute respiratory failure and need for reintubation. All these parameters will be collected each day from day 3 to ICU discharge. Informed consent, intubation or trache- otomy, ventilator-free days at day 14 and length of ICU stay will be collected at ICU discharge while death will be collected by phone at day 90.

Statistical Methods

All the analyses will be performed by the study statisti- cian according to a predefined statistical analysis plan and using statistical software (SAS, V.9.3; SAS Institute). A two-tailed p<0.05 will be considered as indicating statis- tical significance.

Descriptive analysis of patient groups at baseline

The analysis will be performed on an intention-to-treat basis after validation by a blind review committee of the inclusion and exclusion criteria for each patient. Wrongly

included subjects as well as those lost to follow-up will be described. Deviations from the protocol will be described and analysed on a case-by-case basis.

Analysis pertaining to the main criteria of evaluation

Kaplan-Meier curves will be plotted to assess time from enrolment to reintubation and will be compared by means of the log-rank test at day 7. The variables asso- ciated with reintubation with a p<0.20 will be assessed by means of a Cox proportional hazard regression anal- ysis applying a backward-selection procedure. The final model will include variables significantly associated with reintubation with a p<0.05 and will be expressed using adjusted relative risk and HR with 95% CI. The percentages of patients having needed reintubation within the 7 days following planned extubation will be compared between the two groups by means of the

2test. The analysis will subsequently be completed

by multivariate logistic regression after testing for interactions.

Analysis pertaining to the secondary criteria of evaluation Reintubation rates at the various predefined times and moderate or severe acute respiratory failure rates will be compared between the two groups according to the same statistical methodology as the main outcome. Number of ventilator-free days and lengths of stay be compared between the two treatment groups by means of the Student’s t-test. Regarding mortality criteria (at day 28 and at day 90), Kaplan-Meier curves will be plotted to assess the time from enrolment to death and will be compared between the two treatment groups by means of the log-rank test. A Cox proportional hazard regression analysis will be performed using a back- ward-manual procedure.

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Predetermined subgroup analysis

Randomisation will be stratified according to the PaCO2 value before extubation in order to obtain the same propor- tion of hypercapnic patients defined as a PaCO2 >45 mm Hg at the end of the spontaneous breathing trial. A subgroup analysis will consequently be performed for the main and secondary criteria of evaluation in hypercapnic patients with PaCO2 >45 mm Hg before extubation and in non-hypercapnic patients, as well. Prior to adjustment, an interaction test will be carried out to detect heterogeneity of treatment effect between hypercapnic and non-hyper- capnic patients. If the interaction test is positive, results will be given in two different subgroups.

We will also perform a subgroup analysis according to the existence of any underlying cardiac or lung disease, age, severity scores, type of spontaneous breathing trial, clinical parameters at the end of the spontaneous breathing trial, cough assessment, amount of secretions, use of steroids and weaning difficulty (simple, difficult or prolonged). As the duration of NIV may have an impact on outcome, we will also perform a subgroup analysis among patients having actually received at least 12 hours of NIV during the first 24 hours (dose recommended by the study protocol).

Data monitoring

An investigator at each centre will be responsible for daily patient screening, enrolling patients in the study, ensuring adherence to the protocol and completing the e-CRF. Research assistants will regularly monitor all the centres on site to check adherence to the protocol and the accuracy of the data recorded.

Ethics And Dissemination Consent or Assent

The patient will be included after having provided a written informed consent to the investigator according to the decision of the central ethics committee. If the patient is not able to understand the information given, he/she can be included if the same procedure is completed with a next of kin. After the patient’s recovery, he/she will be asked if he/she agrees to continue the trial.

Confidentiality

Data will be handled according to French law. All orig- inal records will be archived at trial sites for 15 years. The clean database file will be anonymised and kept for 15 years.

Declaration of Interest

The HIGH-WEAN study is an investigator-initiated trial supported by the French Ministry of Health with funds obtained in 2015 from a national hospital clin- ical research programme (Programme Hospitalier de Recherche Clinique National 2015). The European research network REVA has endorsed the study project. The study is promoted by the University Hospital of

Poitiers. The firm Fisher & Paykel Healthcare provides high-flow oxygen therapy equipment and face masks for NIV to all the participating centres but has no other involvement in the study.

Access to Data

All investigators will have access to the final data set. Participant-level data sets will be made accessible on a controlled access basis.

Dissemination Policy

Findings will be published in peer-reviewed journals and presented at local, national and international meetings and conferences to publicise and explain the research to clinicians, commissioners and service users.

Patient and Public Involvement

Patients and public were not involved in the study

Discussion

Several studies have suggested that prophylactic NIV could reduce the risk of postextubation respiratory failure in ICU patients at high risk of extubation failure (table 1).3–8 NIV was started immediately after extubation and applied either continuously (at least 18 hours/day) during the first 24 hours4 or by sessions of 1–2 hours for a total duration of at least 8 hours a day during the first 48 hours.3 4 8 Only three of these studies (two randomised controlled trials and one before–after study), all performed in single centre and including a small patient sample, have observed that reintubation rates were lower with NIV than with standard oxygen.3 4 8 The HIGH-WEAN study will be the largest randomised controlled trial ever conducted on the use of NIV during the postextubation period and may help to establish strong recommenda- tions on weaning strategy with a high level of evidence.

Whereas previous studies have included a high propor- tion of hypercapnic patients,3 5–7 we decided to include a larger population of patients at high risk including patients older than 65 years or with an underlying chronic cardiac or respiratory disease. In a preliminary study, we found that prophylactic NIV systematically applied for 24 hours or more according to respiratory status reduced the reintubation rate in this population, from 28% to 15% (p=0.03)8 and enabled us to calculate the sample size of the present study. However, as NIV may be more effective in case of hypercapnia, we decided to stratify according to this variable at time of randomisation in order to have the same number of hypercapnic patients in the two groups and to plan subgroup analysis.

Although the international consensus conference on weaning defined extubation success as absence of ventilatory support during the first 48 hours after extu- bation,18 several studies have used a more prolonged time interval to assess extubation failure and reintuba- tion.22–25 As prophylactic NIV may delay reintubation, the time interval needed to assess extubation failure

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should probably be longer than 48 hours in order to avoid underestimating extubation failure rates. We therefore decided to consider extubation failure in case of reintubation within the 7 days following planned extubation.

In our previous study, NIV was prolonged beyond the first 24 hours in more than 20% of the cases because of patients’ respiratory status.8 Therefore, whatever the group of randomisation, all patients will receive HFNC alone or NIV interspaced with HFNC during at least 48 hours while this strategy may be continued beyond the first 48 hours in the absence of complete recovery.

The usual treatment after planned extubation includes standard oxygen alone through a facemask or nasal cannula. However, it has recently been shown that the use of HFNC after planned extubation decreased the rate of reintubation as compared with standard oxygen.15 16 In another study, the rate of reintubation was similar in high-risk patients treated with HFNC alone and in those treated with prophylactic NIV interspaced by standard oxygen.17 Therefore, HFNC may be an alternative to stan- dard oxygen during the postextubation period. According to clinical practice in participating centres, the use of standard oxygen alone would have been considered as a suboptimal strategy for patients at high risk. The clini- cian must offer at any time the best possible treatment for the patient. If a clinician is convinced of the superiority of one treatment over another, then he has no reason to propose a randomised study comparing these two treat- ments. To promote equipoise and facilitate inclusions in different centres, we decided to use HFNC as ventilatory support in the control group.

In conclusion, the HIGH-WEAN trial is an investi-

gator-initiated pragmatic randomised controlled trial empowered to test the hypothesis that NIV with HFNC may decrease reintubation rates after planned extubation of patients at high risk in ICU in comparison with HFNC alone. This study presents several innovative aspects. First, HFNC had never previously been used as a reference therapy although this treatment seems highly innovative and is in agreement with the recent literature. Likewise, the ventilatory strategy used in the interventional group associating NIV and HFNC had never previously been assessed.

Author affiliations

1Department of Réanimation Médicale, CHU de Poitiers, Poitiers, France

2Université de Poitiers, INSERM CIC 1402 ALIVE, Poitiers, France

3Médecine Intensive Réanimation, Groupe Hospitalier Régional d’Orléans, Orléans, France

4Service des Maladies Infectieuses et Réanimation Médicale, CHU de Rennes, Hôpital Ponchaillou, Rennes, France

5Service de Pneumologie et Réanimation Médicale du Département R3S, AP-HP, INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, Sorbonne Université, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Paris, France 6Hôpital Bichat – Claude Bernard, Médecine Intensive Réanimation, AP-HP, Université Paris Diderot, Paris, France

7Département de Médecine Intensive – Réanimation, Université d’Angers, CHU d’Angers, Angers, France

8Département de Réanimation Médicale, Normandie Université, UNIROUEN, EA3830-GRHV, Institute for Research and Innovation in Biomedicine (IRIB), CHU de Rouen, Hôpital Charles Nicolle, Rouen, France

9Service de Réanimation Polyvalente, CHU Félix Guyon, Saint Denis de la Réunion, France

10Service de Réanimation Médicale, CHU de Clermont-Ferrand, Hôpital Gabriel Montpied, Clermont-Ferrand, France

11Service de Réanimation, Centre hospitalier de la Rochelle, La Rochelle, Nouvelle- Aquitaine, France

12Centre de Réanimation, Université de Lille, CHU de Lille, Lille, France 13Reanimation Polyvalente, Hôpital Saint Joseph Saint Luc, Lyon, France 14Médecine Intensive Réanimation, CHU de Nantes, Nantes, France

15Réanimation Médico-Chirurgicale, AP-HP, INSERM, Université Paris Diderot, UMR IAME 1137, Sorbonne Paris Cité, Hopital Louis-Mourier, Colombes, France 16Service de Réanimation Médicale DHU A-TVB, AP-HP, Hopitaux Universitaires Henri Mondor, Creteil, Île-de-France, France

17Service de Réanimation Médicale, Groupe Hospitalier Régional Mulhouse Sud Alsace, Site Emile Muller, Mulhouse, France

18Service de Médecine Intensive et Réanimation, Centre Hospitalier Départemental de Vendée, La Roche-sur-Yon, France

19CHU de Tours, Médecin Intensive Réanimation, CIC 1415, CRICS-TriggerSEP, Centre d’étude des pathologies respiratoires, INSERM U1100, Université de Tours, Tours, France

20Service de Réanimation, Centre Hospitalier de Pau, Pau, France

21CHU La Timone 2, Médecine Intensive Réanimation, Réanimation des Urgences, Aix-Marseille Université, Marseille, France

22Service de Réanimation, Centre Hospitalier Henri Mondor d’Aurillac, Aurillac, France

23Médecine Intensive Réanimation, CHU de Brest, Brest, France

24Médecine Intensive Réanimation, INSERM, Université Grenoble-Alpes, U1042, HP2, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France 25Réanimation Médicale Archet 1, Université Cote d’Azur, CHU de Nice, Nice, France 26Service de Réanimation Médico-Chirurgicale, Centre Hospitalier de Versailles, Le Chesnay, France

27Réanimation Médico-Chirurgicale Archet 2, INSERM U 1065, CHU de Nice, Nice, France

28Réanimation Chirurgicale, CHU de Poitiers, Poitiers, France

29Réanimation et USC médico-chirurgicale, CARMAS, AP-HP, Faculté de Médecine Sorbonne Université, Collegium Galilée, Hopital Tenon, Paris, France

30Service de Réanimation, Centre Hospitalier Emile Roux, Le Puy-en-Velay, France 31Réanimation Médicale et Toxicologique, AP-HP, INSERM UMR-S 942, Hopital Lariboisiere, Paris, France

Contributors J-PF and AWT (the REVA Network), in collaboration with all authors designed the study and wrote the manuscript together. SR provided substantial contributions to the conception and design of the study, and wrote the statistical analysis plan and estimated the sample size with AWT. AWT, GM, AG, RC, AD, RS, FB, CG, LD, AL, SC, AR, EV, ALM, J-DR, KR, GB, CL, SE, WP, JB, GP, PB, NT, MB, GL,

P-ED, HN, AG, LZ, ND and J-PF contributed for drafting the work, revising it critically for important intellectual content and approved the final version of the manuscript. All authors gave their agreement to be accountable for all aspects of the work, and ensure the accuracy and integrity of any part of the work.

funding The study was funded by the ‘Programme Hospitalier de Recherche Clinique National 2015’ of the French Ministry of Health. The study promoter is the University Hospital of Poitiers, Poitiers, France.

disclaimer The firm Fisher & Paykel provided the high-flow oxygen therapy equipment and masks for non-invasive ventilation to all the participating centres but has no other involvement in the study.

Competing interests AWT and J-DR report travel expenses coverage to attend scientific meetings by Fisher & Paykel. AD and SE received research grants from Fisher & Paykel. J-PF reports consulting fees from Fisher & Paykel.

Patient consent Obtained.

Ethics approval The study has been approved by the central ethics committee (Ethics Committee Ouest III, Poitiers, France) with the registration number 2016- A01078-43 (20 July 2016).

Provenance and peer review Not commissioned; externally peer reviewed.

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open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

References

  1. Thille AW, Richard JC, Brochard L. The decision to extubate in the intensive care unit. Am J Respir Crit Care Med 2013;187:1294–302.
  2. Thille AW, Cortés-Puch I, Esteban A. Weaning from the ventilator and extubation in ICU. Curr Opin Crit Care 2013;19:57–64.
  3. Nava S, Gregoretti C, Fanfulla F, et al. Noninvasive ventilation to prevent respiratory failure after extubation in high-risk patients. Crit Care Med 2005;33:2465–70.
  4. Ornico SR, Lobo SM, Sanches HS, et al. Noninvasive ventilation immediately after extubation improves weaning outcome after acute respiratory failure: a randomized controlled trial. Crit Care 2013;17:R39.
  5. Ferrer M, Valencia M, Nicolas JM, et al. Early noninvasive ventilation averts extubation failure in patients at risk: a randomized trial. Am J Respir Crit Care Med 2006;173:164–70.
  6. Ferrer M, Sellarés J, Valencia M, et al. Non-invasive ventilation after extubation in hypercapnic patients with chronic respiratory disorders: randomised controlled trial. Lancet 2009;374:1082–8.
  7. Vargas F, Clavel M, Sanchez-Verlan P, et al. Intermittent noninvasive ventilation after extubation in patients with chronic respiratory disorders: a multicenter randomized controlled trial (VHYPER). Intensive Care Med 2017;43:1626–36.
  8. Thille AW, Boissier F, Ben-Ghezala H, et al. Easily identified at- risk patients for extubation failure may benefit from noninvasive ventilation: a prospective before-after study. Crit Care 2016;20:48.
  9. Rochwerg B, Brochard L, Elliott MW, et al. Official ERS/ATS clinical practice guidelines: noninvasive ventilation for acute respiratory failure. Eur Respir J 2017;50:1602426.
  10. Bajaj A, Rathor P, Sehgal V, et al. Efficacy of noninvasive ventilation after planned extubation: a systematic review and meta-analysis of randomized controlled trials. Heart Lung 2015;44:150–7.
  11. Peñuelas O, Frutos-Vivar F, Fernández C, et al. Characteristics and outcomes of ventilated patients according to time to liberation from mechanical ventilation. Am J Respir Crit Care Med 2011;184:430–7.
  12. Mauri T, Turrini C, Eronia N, et al. PHysiologic effects of high-flow nasal cannula in acute hypoxemic respiratory failure. Am J Respir Crit Care Med 2017;195:1207–15.
  13. Mauri T, Alban L, Turrini C, et al. Optimum support by high-flow nasal cannula in acute hypoxemic respiratory failure: effects of increasing flow rates. Intensive Care Med 2017;43:1453–63.
  14. Delorme M, Bouchard PA, Simon M, et al. Effects of high-flow nasal cannula on the work of breathing in patients recovering from acute respiratory failure. Crit Care Med 2017;45:1981–8.
  15. Maggiore SM, Idone FA, Vaschetto R, et al. Nasal high-flow versus Venturi mask oxygen therapy after extubation. Effects on oxygenation, comfort, and clinical outcome. Am J Respir Crit Care Med 2014;190:282–8.
  16. Hernández G, Vaquero C, González P, et al. Effect of postextubation high-flow nasal cannula vs conventional oxygen therapy on reintubation in low-risk patients: A randomized clinical trial. JAMA 2016;315:1354–61.
  17. Hernández G, Vaquero C, Colinas L, et al. Effect of postextubation high-flow nasal cannula vs noninvasive ventilation on reintubation and postextubation respiratory failure in high-risk patients: a randomized clinical trial. JAMA 2016;316:1565–74.
  18. Boles JM, Bion J, Connors A, et al. Weaning from mechanical ventilation. Eur Respir J 2007;29:1033–56.
  19. Thille AW, Harrois A, Schortgen F, et al. Outcomes of extubation failure in medical intensive care unit patients. Crit Care Med 2011;39:2612–8.
  20. Keenan SP, Powers C, McCormack DG, et al. Noninvasive positive- pressure ventilation for postextubation respiratory distress: a randomized controlled trial. JAMA 2002;287:3238–44.
  21. Esteban A, Frutos-Vivar F, Ferguson ND, et al. Noninvasive positive- pressure ventilation for respiratory failure after extubation. N Engl J Med 2004;350:2452–60.
  22. Thille AW, Boissier F, Ben Ghezala H, et al. Risk factors for and prediction by caregivers of extubation failure in ICU patients: a prospective study. Crit Care Med 2015;43:613–20.
  23. Demling RH, Read T, Lind LJ, et al. Incidence and morbidity of extubation failure in surgical intensive care patients. Crit Care Med 1988;16:573–7.
  24. Epstein SK, Ciubotaru RL, Wong JB. Effect of failed extubation on the outcome of mechanical ventilation. Chest 1997;112:186–92.
  25. Girault C, Bubenheim M, Abroug F, et al. Noninvasive ventilation and weaning in patients with chronic hypercapnic respiratory failure: a randomized multicenter trial. Am J Respir Crit Care Med 2011;184:672-9.
  26. Khilnani GC, Galle AD, Hadda V, et al. Non-invasive ventilation after extubation in patients with chronic obstructive airways disease: a randomised controlled trial. Anaesth Intensive Care 2011;39:217–23.
  27. Su CL, Chiang LL, Yang SH, et al. Preventive use of noninvasive ventilation after extubation: a prospective, multicenter randomized controlled trial. Respir Care 2012;57:204–10.
  28. Vargas F, Saint-Leger M, Boyer A, et al. Physiologic Effects of High- Flow Nasal Cannula Oxygen in Critical Care Subjects. Respir Care 2015;60:1369–76.

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Thille AW, et al. BMJ Open 2018;8:e023772. doi:10.1136/bmjopen-2018-023772 9

 

PDF olarak indirebilirsiniz. HFNC&NIV together

HFNC ve NIV’ın Birlikte Kullanımının Reentubasyona Etkisi

HFNC ve NIV’ın Birlikte Kullanımının Reentubasyona Etkisi

JAMA | Original Investigation | CARING FOR THE CRITICALLY ILL PATIENT

Effect of Postextubation High-Flow Nasal Oxygen With Noninvasive Ventilation vs High-Flow Nasal Oxygen Alone

on Reintubation Among Patients at High Risk of Extubation Failure

A Randomized Clinical Trial

Arnaud W. Thille, MD, PhD; Grégoire Muller, MD; Arnaud Gacouin, MD; Rémi Coudroy, MD; Maxens Decavèle, MD; Romain Sonneville, MD, PhD; François Beloncle, MD; Christophe Girault, MD; Laurence Dangers, MD; Alexandre Lautrette, MD, PhD; Séverin Cabasson, MD; Anahita Rouzé, MD; Emmanuel Vivier, MD; Anthony Le Meur, MD; Jean-Damien Ricard, MD, PhD; Keyvan Razazi, MD; Guillaume Barberet, MD; Christine Lebert, MD; Stephan Ehrmann, MD, PhD; Caroline Sabatier, MD; Jeremy Bourenne, MD; Gael Pradel, MD; Pierre Bailly, MD; Nicolas Terzi, MD, PhD;

Jean Dellamonica, MD, PhD; Guillaume Lacave, MD; Pierre-Éric Danin, MD; Hodanou Nanadoumgar, MD; Aude Gibelin, MD; Lassane Zanre, MD; Nicolas Deye, MD, PhD; Alexandre Demoule, MD, PhD; Adel Maamar, MD; Mai-Anh Nay, MD; René Robert, MD, PhD; Stéphanie Ragot, PharmD, PhD; Jean-Pierre Frat, MD; for the HIGH-WEAN Study Group and the REVA Research Network

IMPORTANCE High-flow nasal oxygen may prevent postextubation respiratory failure in the intensive care unit (ICU). The combination of high-flow nasal oxygen with noninvasive ventilation (NIV) may be an optimal strategy of ventilation to avoid reintubation.

OBJECTIVE To determine whether high-flow nasal oxygen with prophylactic NIV applied immediately after extubation could reduce the rate of reintubation, compared with high-flow nasal oxygen alone, in patients at high risk of extubation failure in the ICU.

DESIGN, SETTING, AND PARTICIPANTS Multicenter randomized clinical trial conducted from April 2017 to January 2018 among 641 patients at high risk of extubation failure (ie, older than 65 years or with an underlying cardiac or respiratory disease) at 30 ICUs in France; follow-up was until April 2018.

INTERVENTIONS Patients were randomly assigned to high-flow nasal oxygen alone (n = 306) or high-flow nasal oxygen with NIV (n = 342) immediately after extubation.

MAIN OUTCOMES AND MEASURES The primary outcome was the proportion of patients reintubated at day 7; secondary outcomes included postextubation respiratory failure at day 7, reintubation rates up until ICU discharge, and ICU mortality.

RESULTS Among 648 patients who were randomized (mean [SD] age, 70 [10] years; 219 women [34%]), 641 patients completed the trial. The reintubation rate at day 7 was 11.8% (95% CI, 8.4%-15.2%) (40/339) with high-flow nasal oxygen and NIV and 18.2% (95% CI, 13.9%-22.6%) (55/302) with high-flow nasal oxygen alone (difference, −6.4% [95% CI,

−12.0% to −0.9%]; P = .02). Among the 11 prespecified secondary outcomes, 6 showed no significant difference. The proportion of patients with postextubation respiratory failure at day 7 (21% vs 29%; difference, −8.7% [95% CI, −15.2% to −1.8%]; P = .01) and reintubation

rates up until ICU discharge (12% vs 20%, difference −7.4% [95% CI, −13.2% to −1.8%];

P = .009) were significantly lower with high-flow nasal oxygen and NIV than with high-flow nasal oxygen alone. ICU mortality rates were not significantly different: 6% with high-flow nasal oxygen and NIV and 9% with high-flow nasal oxygen alone (difference, −2.4% [95% CI,

−6.7% to 1.7%]; P = .25).

CONCLUSIONS AND RELEVANCE In mechanically ventilated patients at high risk of extubation failure, the use of high-flow nasal oxygen with NIV immediately after extubation significantly decreased the risk of reintubation compared with high-flow nasal oxygen alone.

TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03121482

JAMA. doi:10.1001/jama.2019.14901

Published online October 2, 2019.

Visual Abstract Editorial Supplemental content

Author Affiliations: Author affiliations are listed at the end of this article.

Group Information: The

HIGH-WEAN Study Group and REVA Research Network members are listed at the end of the article.

Corresponding Author: Arnaud W. Thille, MD, PhD, Médecine Intensive Réanimation, CHU de Poitiers, 2 rue la Milétrie, 86021 Poitiers Cedex, France (aw.thille@gmail.com).

Section Editor: Derek C. Angus, MD, MPH, Associate Editor, JAMA (angusdc@upmc.edu).

E1

© 2019 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ on 10/02/2019

n intensive care units (ICUs), approximately 10% to 15% of patients ready to be separated from a ventilator experi- ence extubation failure leading to reintubation.1 In pa- tients considered at high risk, these rates can even exceed 20%.1,2 Because reintubation is associated with particularly high mortality,3,4 a strategy of oxygenation aimed at avoiding reintubation deserves consideration. Although noninvasive ventilation may prevent postextubation respiratory failure in patients at high risk,5-9 only 2 small-scale randomized clini- cal trials (RCTs) have shown decreased reintubation rates com- pared with standard oxygen.5,6 The most recent international clinical practice guidelines recommend the use of noninva- sive ventilation to prevent postextubation respiratory failure in patients at high risk of extubation failure.10 However, up un- til now, no large-scale RCT has demonstrated a significant re- duction of reintubation rates with noninvasive ventilation com- pared with standard oxygen. Thereby, most patients are treated with standard oxygen in clinical practice and only 10% of them receive noninvasive ventilation after extubation in the ICU.2,11 High-flow nasal oxygen is an alternative strategy that may reduce the risk of reintubation in the ICU compared with stan- dard oxygen.12,13 A large-scale RCT has reported that high- flow nasal oxygen was noninferior to noninvasive ventilation in preventing reintubation in patients at high risk.14 Whereas high-flow nasal oxygen could be considered as a reference treat- ment after extubation, using high-flow nasal oxygen with non- invasive ventilation may further improve gas exchange and the work of breathing,15 thereby avoiding reintubation.

This multicenter RCT involving patients at high risk of ex- tubation failure in the ICU was conducted to determine whether high-flow nasal oxygen with noninvasive ventilation, com- pared with high-flow nasal oxygen alone, after extubation could reduce the rate of reintubation.

Key Points

Question Among mechanically ventilated patients at high risk of extubation failure, does the use of high-flow nasal oxygen with noninvasive ventilation after extubation reduce the risk of reintubation compared with high-flow nasal oxygen alone?

Findings In this randomized clinical trial that included 641 patients, high-flow nasal oxygen with noninvasive ventilation, compared with high-flow nasal oxygen alone, significantly decreased the rate of reintubation within the first 7 days after extubation (11.8% vs 18.2%).

Meaning In patients at high risk of extubation failure, the use of high-flow nasal oxygen with noninvasive ventilation after extubation significantly decreased the risk of reintubation compared with high-flow nasal oxygen alone.

sure at home, contraindication to noninvasive ventilation, un- derlying chronic neuromuscular disease (myopathy or myas- thenia gravis), or traumatic brain injury leading to intubation, as well as patients who underwent unplanned extubation (ac- cidental or self-extubation) or with a do-not-reintubate order at time of extubation.

The trial was overseen by a steering committee that pre- sented information regarding the progression and monitor- ing of the study at REVA (Réseau Européen de Recherche en Ventilation Artificielle) Network meetings every 6 months. No safety committee was required because the interventions used in the study were strategies of oxygenation typically used in clinical practice. Research assistants regularly monitored all the centers on site to check adherence to the protocol and the accuracy of the data recorded. An investigator at each center was responsible for daily patient screening, enrolling pa- tients in the study, ensuring adherence to the protocol, and completing the electronic case-report form. Although the in-dividual study assignments of the patients could not be

Methods

The study was conducted in 30 ICUs in France. For all the cen- ters, the study protocol (Supplement 1) was approved by the central ethics committee (Ethics Committee Ouest III, Poitiers, France; registration No. 2016-A01078-43). Written informed consent was obtained from all patients or next of kin before inclusion in the study.

Adult patients intubated more than 24 hours in the ICU and ready for extubation, after a successful spontaneous breath- ing trial performed according to the international conference consensus on weaning,16 were enrolled if they were at high risk of extubation failure (ie, older than 65 years or had any un- derlying chronic cardiac or lung disease).10 Underlying chronic cardiac diseases included left ventricular dysfunction, what- ever the cause, defined by left ventricular ejection fraction equal to or below 45%; history of cardiogenic pulmonary edema; documented ischemic heart disease; or permanent atrial fibrillation. Underlying chronic lung diseases included chronic obstructive pulmonary disease, obesity-hypoventila- tion syndrome, or restrictive pulmonary disease.

The main exclusion criteria were long-term treatment with noninvasive ventilation or continuous positive airway pres-

masked, the coordinating center and all the investigators re- mained unaware of the study group outcomes until the data were locked in January 2019.

Randomization

Randomization was computer-generated using a centralized web-based management system in permuted blocks of 4 par- ticipants (unknown to investigators), with stratification ac- cording to the center and arterial partial pressure of carbon di- oxide (PaCO2) level (≤45 or >45 mm Hg) measured at the end of the spontaneous breathing trial (or under mechanical ven- tilation before the trial if this latter was not measured). Strati- fication was performed on PaCO2 level to include the same num- ber of hypercapnic patients in the 2 groups because noninvasive ventilation may be more effective in these patients.7,8 Pa- tients were randomly assigned in a 1:1 ratio to receive high- flow nasal oxygen alone (control group) or with noninvasive ventilation (intervention group) immediately after extuba- tion (Figure 1).

Interventions

Patients assigned to the control group were continuously treated by high-flow nasal oxygen alone for at least 48 hours

E2 JAMA Published online October 2, 2019 jama.com

Figure 1. Flow of Patients in the HIGH-Wean Trial of High-Flow Nasal Oxygen With or Without Noninvasive Ventilation

1661 At high risk of reintubation were extubated after at least 24 h of mechanical ventilationa

3121 Patients extubated in the 30 participating intensive care units during the study period (April 2017-January 2018)

1460 Excluded

927 At low risk of extubation failure

414 Intubated <24 h

101 Under law protection or nonaffiliated to health system

18 Minor

692 Excluded

274 Do-not-reintubate order at time of extubation

182 Long-term treatment with noninvasive ventilation or continuous positive airway pressure at home

119 Unplanned extubation (accidental or self-extubation)

41 Contraindication to noninvasive ventilation 39 Underlying chronic neuromuscular disease 37 Traumatic brain injury

648 Randomized

342 Randomized to receive high-flow oxygen with noninvasive ventilation 339 Received intervention as

randomized

3 Did not receive intervention

1 Under law protection

1 Died before being extubated

1 Missing data

306 Randomized to receive high-flow oxygen alone

302 Received intervention as randomized

4 Did not receive intervention

2 Under law protection

2 Missing data

969 Eligible for inclusion

321 Not included

270 No staff available or logistic issues

51 Declined to participate

a Those at high risk of reintubation were older than 65 years or had an underlying chronic cardiac

or lung disease.

339 Included in the intention-to-treat analysis and in the 90-d follow-up

302 Included in the intention-to-treat analysis and in the 90-d follow-up

with a flow of 50 L/min and fraction of inspired oxygen (FIO2) adjusted to obtain adequate oxygenation, with an oxygen satu- ration as measured by pulse oximetry (SpO2) of at least 92%. To provide sufficient humidification, the temperature of the heated humidifier was set at 37°C as during invasive mechani- cal ventilation.

Patients assigned to the intervention group (referred to here as the noninvasive ventilation group) were treated with high-flow nasal oxygen with noninvasive ventilation. Nonin- vasive ventilation was initiated immediately after extubation with a first session of at least 4 hours and minimal duration of at least 12 hours a day during the 48 hours following extuba- tion. Continuous application of noninvasive ventilation was promoted throughout the entire night period. Noninvasive ven- tilation was carried out with an ICU ventilator with noninva- sive ventilation mode or dedicated bilevel ventilator in pressure-support mode with a minimal pressure-support level of 5 cm H2O targeting a tidal volume around 6 to 8 mL/kg of

predicted body weight, a positive end-expiratory pressure level between 5 and 10 cm H2O, and a FIO2 adjusted to obtain ad- equate oxygenation (SpO2 ≥92%). Between noninvasive ven- tilation sessions, high-flow nasal oxygen was delivered as in the control group. Blood gases were performed 1 hour after treatment initiation under high-flow oxygen in the high-flow nasal oxygen alone group and under noninvasive ventilation in the noninvasive ventilation group. In the 2 groups, pa- tients were treated for a minimum of 48 hours. When there were no signs of respiratory failure 48 hours after extubation, treatment was stopped and switched to standard oxygen. According to patient respiratory status, treatment could be con- tinued until complete respiratory recovery. In case of estab- lished postextubation respiratory failure, the use of noninva- sive ventilation was discouraged in accordance with the most recent international clinical practice guidelines,10 given that it has no proven benefit17 and can even increase the risk of death by delaying reintubation.18

 

Outcomes

The primary outcome was the proportion of patients who required reintubation within the 7 days following extubation. To ensure the consistency of indications across sites and reduce the risk of delayed intubation, patients were immedi- ately reintubated if 1 of the following criteria was fulfilled: severe respiratory failure, hemodynamic failure with the need for vasopressors, neurological failure (altered con- sciousness with a Glasgow Coma Scale score <12), or cardiac or respiratory arrest. Severe respiratory failure leading to reintubation was defined by the presence of at least 2 criteria among the following: a respiratory rate greater than 35 breaths per minute, clinical signs suggesting respiratory dis- tress with activation of accessory respiratory muscles, respi- ratory acidosis defined as a pH level below 7.25 units and PaCO2 greater than 45 mm Hg, hypoxemia defined as a need for FIO2 at 80% or more to maintain an SpO2 level at 92% or more, or a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (PaO2:FIO2) equal to or below 100 mm Hg.

Secondary outcomes included reintubation at 48 hours, 72 hours, and up until ICU discharge; an episode of postextu- bation respiratory failure within 7 days following extubation; the proportion of patients in whom the treatment was con- tinued beyond the first 48 hours following extubation; length of stay in the ICU and in the hospital; and mortality in the ICU, in the hospital, at day 28, and at day 90. An episode of postextubation respiratory failure was defined by the pres- ence of at least 2 criteria among the following: a respiratory rate greater than 25 breaths per minute, clinical signs sug- gesting respiratory distress, respiratory acidosis defined as a pH level less than 7.35 units and PaCO2 level greater than 45 mm Hg, hypoxemia defined as a need for FIO2 at least 50% to maintain SpO2 level of at least 92%, or a PaO2:FIO2 ratio equal to or below 150 mm Hg.

Exploratory outcomes included blood gases 1 hour after treatment initiation, time to reintubation, the proportion of pa- tients who met criteria for reintubation, reasons for reintuba- tion, use of noninvasive ventilation as rescue therapy, the pro- portion of patients who were reintubated or died in the ICU, and mortality of reintubated patients.

Statistical Analysis

Enrollment of 590 patients was determined to provide a power of 80% and to show an absolute difference of 8% in the rate of reintubation between the control group using high-flow nasal oxygen alone (rate of reintubation estimated to 18%) compared with the intervention group using high- flow nasal oxygen and noninvasive ventilation (rate of reintu- bation estimated to 10%) at a 2-sided α level of .05 (ie, exactly the same difference as that planned in a previous RCT com- paring high-flow nasal oxygen vs standard oxygen on reintu- bation among patients at low risk of extubation failure13). To allow for the potential secondary exclusions, the number of patients to be enrolled was then inflated to 650 patients (increased by 10%).

All the analyses were performed by the study statistician according to a predefined statistical analysis plan. The analy-

sis was performed on all randomized patients who were ex- tubated and for whom the primary outcome was completed. Patients were analyzed according to their randomization group regardless of the treatment applied. The proportions of pa- tients having needed reintubation within the 7 days follow- ing planned extubation were compared between the 2 groups by means of the χ2 test.

Kaplan-Meier curves were plotted to assess time from ex- tubation to reintubation and were compared by means of the log-rank test at day 7. Reintubation rates at the various pre- defined times, postextubation respiratory failure rates at day 7, and mortality rates in the ICU and hospital were compared between the 2 groups by means of the χ2 test. Kaplan-Meier curves were plotted to assess the time from extubation to death and were compared by means of the log-rank test at day 90.

A multiple logistic regression analysis was performed for the primary outcome to adjust on the stratification variable (PaCO2 level) and on potential baseline unbalanced variables. Lack of balance was defined as P < .05, and the only variable ultimately included in the model was underlying chronic lung disease. The results were presented as odds ratios with 95% CIs. A post hoc random-effects multilevel logistic regres- sion model was used to take into account the effect of the hospital. Treatment group was introduced in the model as a fixed effect and hospital was introduced in the model as a random effect. A subgroup analysis was performed for the primary and secondary outcomes according to the PaCO2 level (≤45 or >45 mm Hg) prior to extubation after an interac- tion test carried out to detect heterogeneity of treatment effect between hypercapnic and nonhypercapnic patients. Because of the potential for type I error due to multiple com- parisons, findings for analyses of secondary end points should be interpreted as exploratory. A 2-tailed P value of less than .05 was considered to indicate statistical signifi- cance. We used SAS software version 9.4 (SAS Institute) for all analyses.

Results

Study Participants

From April 2017 through January 2018, 3121 patients were extubated in the 30 participating units, 969 were eligible for inclusion in the study, and 648 underwent randomization (mean [SD] age, 70 [10] years; 219 women [34%]) (Figure 1). Seven patients were secondarily excluded because they were protected under French law, which was not known at ran- domization (n = 3), died before extubation (n = 1), or were missing data for the primary outcome (n = 3), leaving 641 patients included in the analysis: 302 patients were assigned to high-flow nasal oxygen alone and 339 to high-flow nasal oxygen with non-invasive ventilation.

The characteristics of the patients at inclusion were similar in the 2 groups except for a higher proportion of patients with underlying chronic lung disease in the noninva- sive ventilation group (Table 1). The median duration of mechanical ventilation prior to extubation was 5 days (interquartile range [IQR], 3-10), and weaning was considered

E4 JAMA Published online October 2, 2019 jama.com

Table 1. Baseline Patient Characteristicsa

CharacteristicNo. (%)
High-Flow Nasal Oxygen Alone High-Flow Nasal Oxygen With NIV (n = 302) (n = 339)

Characteristics of the patients at admission

Age, mean (SD), y 70 (10) 69 (10)

Sex
Men 195 (65) 230 (68)
Women107 (35)109 (32)
Body mass index, mean (SD)b28 (6)28 (7)
SAPS II score at admission, mean (SD)c55 (17)55 (20)
Main reason for intubation
Acute respiratory failure158 (52)167 (49)
Coma55 (18)57 (17)
Shock30 (10)37 (11)
Cardiac arrest26 (9)35 (10)
Surgery28 (9)35 (10)
Other reason5 (2)8 (2)

Risk factors of extubation failure

Age >65 y 223 (74) 237 (70)

Underlying chronic cardiac diseased145 (48)161 (47)
Ischemic heart disease78 (26)88 (26)
Atrial fibrillation58 (19)45 (13)
Left ventricular dysfunction39 (13)52 (15)
History of cardiogenic pulmonary edema21 (7)25 (7)
Underlying chronic lung diseased87 (29)126 (37)

Chronic restrictive pulmonary disease 12 (4) 24 (7)

Chronic obstructive pulmonary disease64 (21)86 (25)
Obesity-hypoventilation syndrome16 (5)20 (6)

Characteristics of the patients the day of extubation

SOFA score, mean (SD)e4.2 (2.5)4.4 (2.7)
Duration of mechanical ventilation,5 (3-9)6 (3-11)
median (IQR), d
Weaning difficultyf

Prolonged 7 (2) 14 (4)

Simple203 (67)232 (68)
Difficult92 (31)93 (27)

Ventilator settings before the spontaneous breathing trial

Assist-control ventilation42 (14)49 (14)
Pressure-support ventilation260 (86)290 (86)
Pressure-support level, mean (SD), cm H2O9.6 (2.8)9.3 (2.9)
Positive end-expiratory pressure,5.7 (1.6)5.9 (1.6)
mean (SD), cm H2O
Tidal volume, mean (SD)
mL/kg7.7 (2.4)7.9 (2.5)
Respiratory rate, mean (SD), breaths/min22 (7)22 (6)

Median (IQR) 30 (30-40) 30 (30-40)

mL 468 (125) 479 (144)
FIO2, mean (SD), % 35 (10) 35 (11)

PaO2:FIO2, mean (SD), mm Hg 274 (93) 275 (89)

pH, mean (SD), units 7.45 (0.06) 7.45 (0.05)

PaCO2 mean (SD), mm Hg 40 (8) 40 (8)

(continued)

jama.com JAMA Published online October 2, 2019 E5

Table 1. Baseline Patient Characteristicsa (continued)

Arterial pressure, mean (SD), mm Hg
Systolic 136 (21) 136 (22)
CharacteristicNo. (%)
High-Flow Nasal Oxygen Alone High-Flow Nasal Oxygen With NIV (n = 302) (n = 339)
breathing trial
T-piece trial188 (62)206 (61)
Low level of pressure support114 (38)133 (39)
Duration of the trial, median (IQR), min60 (30-60)60 (30-60)
Diastolic67 (14)68 (16)
Heart rate, mean (SD), bpm92 (17)92 (18)
Respiratory rate, mean (SD), breaths/min23 (6)23 (6)
SpO2, mean (SD), %96 (3)96 (3)
PaO2, mm Hg
Mean (SD) [No.]39 (8) [221]40 (9) [241]
Administration of steroids before extubation42 (14)53 (16)
Ineffective cough, No./No. (%)65/284 (23)86/322 (27)
Abundant secretions, No./No. (%)121/288 (42)114/326 (35)
Participating centers (n = 30)
No. of centers that participated30 (100)30 (100)
No. of patients per center, median (IQR)10 (9-25)13 (9-23)

Abbreviations: bpm, beats per minute; FIO2, fraction of inspired oxygen; IQR, interquartile range; NIV, noninvasive ventilation; PaCO2, arterial partial pressure of carbon dioxide; PaO2, partial pressure of arterial oxygen;

Characteristics at the end of the spontaneous

Mean (SD) [No.] pH, units

Mean (SD) [No.]

PaCO2, mm Hg

87 (28) [221]

86 (27) [241]

7.45 (0.06) [221]

7.45 (0.05) [241]

SAPS, Simplified Acute Physiology Score; SOFA, Sequential (Sepsis-Related)

Organ Failure Assessment; SpO2, oxygen saturation as measured by pulse oximetry.

a The only significant differences in baseline characteristics between the 2 trial groups were the proportion of patients with underlying chronic lung disease (P = .02).

b Calculated as weight in kilograms divided by height in meters squared.

c The SAPS II score was calculated from 17 variables at admission. Scores range from 0 to 163, with higher scores indicating more severe disease and higher

mortality risk. Patients with a SAPS II score of 55 at admission have a predicted mean 43% chance of survival.

d Patients could have more than 1 underlying chronic cardiac or lung disease.

e The SOFA score was calculated from 6 variables the day of extubation. Scores range from 0 to 24, with higher scores indicating more severe organ failure and higher mortality risk. Patients with a SOFA score between 4 and 5 have a predicted mean chance of survival >90%.

f Weaning difficulty was defined as follows: simple weaning included patients extubated after success of the first spontaneous breathing trial, difficult weaning included patients who failed the first spontaneous breathing trial and were extubated within the 7 following days, and prolonged weaning included patients extubated more than 7 days after the first spontaneous breathing trial.

difficult or prolonged in 32% of patients (206 of 641 patients). At the time of extubation, 111 patients (17%) had hypercapnia (PaCO2 >45 mm Hg).

Initial mean (SD) settings were as follows: in the high-flow nasal oxygen alone group, the gas flow rate was 50 (5) L/min with FIO2 of 0.41 (0.13); in the noninvasive ventilation group, the pres- sure-support level was 7.8 (2.5) cm H2O, PEEP was 5.3 (1.1) cm H2O, and FIO2 was 0.34 (0.10), resulting in a tidal volume of 8.6 (2.9) mL/kg of predicted body weight.

In the noninvasive ventilation group, noninvasive venti- lation was delivered for a mean (SD) of 22 (9) hours within the first 48 hours following extubation (mean of 13 hours within the first 24 hours) and was delivered for 4 hours or less due to intolerance in 20 patients (6%). In the high-flow nasal oxy- gen alone group, high flow nasal oxygen was delivered for a mean (SD) of 42 (11) hours within the first 48 hours.

Primary Outcome

The reintubation rate at day 7 was 11.8% (95% CI, 8.4%-

15.2%) with noninvasive ventilation and 18.2% (95% CI, 13.9%- 22.6%) with high-flow nasal oxygen alone (difference, −6.4% [95% CI, −12.0 to −0.9]; P = .02) (Figure 2).

Secondary Outcomes

Reintubation rates were also significantly lower with nonin- vasive ventilation than with high-flow nasal oxygen alone at 48 hours, 72 hours, and until ICU discharge (Table 2). The pro- portion of patients with postextubation respiratory failure at day 7 was significantly lower with noninvasive ventilation than with high-flow nasal oxygen alone (21% vs 29%; difference,

−8.7% [95% CI, −15.2% to −1.8%]; P = .01). In the noninvasive ventilation group, noninvasive ventilation was continued be- yond the first 48 hours for incomplete recovery of respiratory

E6 JAMA Published online October 2, 2019 jama.com

status in 86 patients (25%), whereas in the high-flow nasal oxy- gen alone group, high-flow nasal oxygen was continued in 106 patients (35%) (difference, −9.7% [95% CI, −16.8% to −2.6%]; P < .01). Mortality in the ICU, in the hospital, and at day 90 were not significantly different between groups (Table 2; eFigure in Supplement 2).

Exploratory Outcomes

One hour after treatment initiation, PaO2:FiO2 was higher with noninvasive ventilation than with high-flow nasal oxygen alone (mean [SD], 291 [97] mm Hg vs 254 [113] mm Hg; difference,

37.0 [95% CI, 19.7 to 54.3]; P < .001), whereas the proportion of patients with hypercapnia did not differ (21% vs 19%, re- spectively; difference, 1.2% [95% CI, −5.4% to 7.7%]; P = .72).

Figure 2. Kaplan-Meier Analysis of Time From Extubation to Reintubation for the Overall Study Population

25

High-flow nasal oxygen alone

High-flow nasal oxygen with noninvasive ventilation

Log-rank P = .02

Patients Requiring Reintubation, %

20

15

10

5

0

0 1 2 3 4 5 6 7

The median time to reintubation was not significantly dif- ferent between groups: 33 hours (IQR, 7-81) with noninvasive ventilation and 39 hours (IQR, 12-67) with high-flow nasal oxy- gen alone (difference, −5.0 [95% CI, −42.0 to 32.0]; P = .76).

Among the 100 patients who were reintubated in the ICU,

96% met prespecified criteria for reintubation: 95% (39/41) in

No. at risk

High-flow nasal oxygen

Alone 302265253248246244 243
With 339 321314308305294292 291

276

noninvasive ventilation

Time Since Intubation, d

the noninvasive ventilation group vs 97% (57/59) in the high- flow nasal oxygen alone group (difference, −1.5% [95% CI,

−13.0% to 7.4%]; P = .99). The reason for reintubation was se- vere respiratory failure in 88 patients, neurological failure in 37 patients, hemodynamic failure in 16 patients, and respiratory or cardiac arrest in 10 patients (eTable 1 in Supplement 2).

Among the 70 patients who had postextubation respira- tory failure with high-flow nasal oxygen alone, 20 patients (29%) were treated with noninvasive ventilation as rescue therapy delivered for a mean (SD) of 7 (6) hours, of which 10 patients (50%) needed reintubation. Results for additional ex- ploratory outcomes are shown in Table 2.

Subgroup Analysis and Additional Analyses

No significant interaction was noted between PaCO2 at enroll- ment and treatment group with respect to the primary out- come (P for interaction = .25). Among the 111 patients with PaCO2 greater than 45 mm Hg before extubation, the reintubation rate at day 7 was significantly lower with noninvasive ventilation than with high-flow nasal oxygen alone (8% vs 21%; differ- ence, −12.9% [95% CI, −27.1% to −0.1%]; P = .049) (Figure 3).

Among the 530 patients with PaCO2 of 45 mm Hg or less, rein- tubation rates at day 7 were not significantly different be- tween groups (13% with noninvasive ventilation vs 18% with high-flow nasal oxygen alone; difference, −5.0% [95% CI, −11.2%

to 1.1%]; P = .10) (eTables 2, 3, and 4 in Supplement 2).

After adjustment for PaCO2 level at enrollment (≤45 or

>45 mm Hg, stratification randomization variable) and under- lying chronic lung disease (variable unbalanced between both groups indicated in Table 1), the odds ratio for reintubation at day 7 was significantly lower with noninvasive ventilation than with high-flow nasal oxygen alone (adjusted odds ratio, 0.60 [95% CI, 0.38-0.93]; P = .02). The post hoc analysis showed a lower reintubation rate with noninvasive ventilation than with high-flow nasal oxygen alone after adjustment for the hospi- tal random effect (P = .02 without hospital random effect, and P = .02 after adjustment for the hospital random effect) (eTable 5 in Supplement 2).

The median observation time was 7 days (interquartile range, 7-7) in both treatment groups.

During the study, there were no severe adverse events at- tributable to the randomization group.

Discussion

In this multicenter, randomized, open-label trial, high-flow na- sal oxygen with noninvasive ventilation, compared with high- flow nasal oxygen alone, decreased the rate of reintubation within the first 7 days after extubation in the ICU.

This study was designed to assess noninvasive ventila- tion in a large population of patients who are particularly easy to identify and extubated daily in the different ICUs. Al- though noninvasive ventilation may be beneficial on out- comes of hypercapnic patients,7,8 these patients account for only about 20% to 30% of patients at high risk of extubation failure in the ICU.7,19 Patients older than 65 years or with un- derlying chronic cardiac or respiratory disease are also at high risk of reintubation20 and could benefit from noninvasive ventilation.21

To our knowledge, the combination of high-flow nasal oxy- gen with noninvasive ventilation had not been previously as- sessed after extubation in the ICU. A preliminary study ob- served a reintubation rate of 15% at day 7 with noninvasive ventilation and standard oxygen in exactly the same population.21 Therefore, the study hypothesized that a new strategy combining high-flow nasal oxygen with noninvasive ventilation could further reduce the rate of reintubation, whereas the estimated rate would exceed 15% in the control group.13,14 For an overall reintubation rate around 15% in the ICU,22 an absolute difference of at least 5% (relative reduc-

tion of one-third) would be considered clinically significant and in the range of previous large multicenter RCTs assessing re- intubation as the main outcome.13,23 Reintubation rates were

jama.com JAMA Published online October 2, 2019 E7

Table 2. Primary, Secondary, and Exploratory Outcomes

No. (%)

High-Flow Nasal High-Flow Nasal

Oxygen Alone Oxygen With NIV Absolute Difference,

(n = 302)(n = 339)% (95% CI)P Value
Primary Outcome
Reintubation at day 755 (18)40 (12)−6.4 (−12.0 to −0.9).02
Secondary Outcomes
Postextubation respiratory failure at day 788 (29)70 (21)−8.5 (−15.2 to −1.8).01
Reintubation
At 48 h36 (12)24 (7)−4.8 (−9.6 to −0.3).04
At 72 h47 (16)30 (9)−6.7 (−11.9 to −1.7).009
Up until ICU discharge59 (20)41 (12)−7.4 (−13.2 to −1.8).009
Length of stay, median (IQR), days
In ICU11 (7 to 19)12 (7 to 19)0.5 (−1.6 to 2.6).55
In hospital23 (15 to 39)25 (15 to 42)2.3 (−1.4 to 6.1).31
In ICU26 (9)21 (6)−2.4 (−6.7 to 1.7).25
In hospital46 (15)54 (16)0.7 (−5.0 to 6.3).80
At day 2833 (11)39 (12)0.6 (−4.4 to 5.5).82
At day 9065 (21)62 (18)−3.2 (−9.5 to 2.9).30
Exploratory Outcomes
Patients meeting reintubation criteria during ICU stay65 (22)49 (14)−7.1 (−13.1 to −1.1).02
Mortality or reintubation in ICU64 (21)51 (15)−6.2 (−12.2 to −0.2).04
Mortality of reintubated patients21/59 (36)11/41 (27)−8.8 (−25.7 to 9.9).35

Abbreviations: ICU, intensive care unit, IQR, interquartile range; NIV, noninvasive ventilation.

Mortality

Figure 3. Kaplan-Meier Analysis of Time From Extubation to Reintubation According to Predefined Strata

Hypercapnic patients (PaCO2 >45 mm Hg)

A

25

High-flow nasal oxygen alone

High-flow nasal oxygen with noninvasive ventilation

Log-rank P = .049

Nonhypercapnic patients (PaCO2 ≤45 mm Hg)

25

B

20 20

Patients Requiring Reintubation, %

Patients Requiring Reintubation, %

High-flow nasal oxygen alone

15 15

10 10

High-flow nasal oxygen with noninvasive ventilation

5 5

Log-rank P = .11

0 0

0 1 2 3 4 5 6 7

0 1 2 3

4 5 6 7

No. at risk

High-flow nasal oxygen

Time Since Intubation, d

No. at risk

High-flow nasal oxygen

Time Since Intubation, d

Alone 4844443938373737 Alone 254 232221214210209207206
With 6363615958585858 With 276 258253249247236234233
noninvasivenoninvasive
ventilationventilation

Results in hypercapnic patients with arterial partial pressure of carbon dioxide (PaCO2) greater than 45 mm Hg (A) and in nonhypercapnic patients with PaCO2 of 45 mm Hg or less (B) are shown. The median observation time was 7 days (interquartile range, 7-7) in both treatment groups.

almost exactly the expected rates in the 2 groups (18.2% and 11.8%), reinforcing the external validity of the study.

To date, only 2 RCTs have observed lower reintubation rates with noninvasive ventilation than with standard oxygen.5,6 To our knowledge, the present study is the largest RCT showing a reduced risk of reintubation after extubation in the ICU with noninvasive ventilation. Unlike a previous RCT

that reported similar reintubation rates between noninvasive ventilation and high-flow nasal oxygen applied 24 hours af- ter extubation in nonhypercapnic patients,14 this study com- bined noninvasive ventilation and high-flow nasal oxygen for at least 48 hours and treatment was prolonged if necessary. Al- though the beneficial effects of noninvasive ventilation on oxy- genation, alveolar ventilation, and work of breathing are well

E8 JAMA Published online October 2, 2019 jama.com

demonstrated,24,25 continuation of high-flow nasal oxygen be- tween sessions of noninvasive ventilation may further pro- vide clinical improvement by decreasing work of breathing.15,26 Approximately one-third of patients treated with high- flow nasal oxygen alone received noninvasive ventilation as rescue therapy in case of postextubation respiratory failure. Although noninvasive ventilation as rescue therapy may avoid reintubation in a number of cases, it has been shown to possibly be deleterious and increase mortality in this setting.18 Moreover, international clinical practice guidelines suggest that noninvasive ventilation should not be used in the treatment of patients with established postextubation

respiratory failure.10

Limitations

This study has several limitations. First, high-flow nasal oxy- gen rather than standard oxygen was used in the control group. However, it has been shown that reintubation rates with high- flow nasal oxygen were reduced as compared with standard oxygen.12,13 According to clinical practice in participating cen- ters, the use of standard oxygen alone would have been consid- ered a suboptimal strategy for patients at high risk. Therefore, high-flow nasal oxygen was used in the control group to pro- mote equipoise and facilitate inclusions in different centers.

Second, attending physicians could not be blinded to the study group and this could have modified the decision of re- intubation by promoting early reintubation in patients treated with high-flow nasal oxygen alone. However, almost all rein- tubated patients met prespecified criteria for reintubation, and they had particularly high mortality (exceeding 30%), con- firming high severity of patients who were reintubated.

Third, the weaning protocol and the type of spontaneous breathing trial performed before extubation may have influ- enced the results.27 In addition, inclusion criteria identifying patients at high risk were different from previous studies.6,13,14 However, international clinical practice guidelines specify that patients at high risk who may benefit from noninvasive ven- tilation are those older than 65 years or who have any under- lying cardiac or respiratory disease.10

Conclusions

In mechanically ventilated patients at high risk of extubation failure, the use of high-flow nasal oxygen with noninvasive ventilation immediately after extubation significantly de- creased the risk of reintubation compared with high-flow na- sal oxygen alone.

ARTICLE INFORMATION

Accepted for Publication: September 9, 2019.

Published Online: October 2, 2019. doi:10.1001/jama.2019.14901

Author Affiliations: Centre Hospitalier Universitaire de Poitiers, Médecine Intensive Réanimation, Poitiers, France (Thille, Coudroy, Robert, Frat); INSERM Centre d’Investigation Clinique 1402 ALIVE, Université de Poitiers, Poitiers, France (Thille, Coudroy, Robert, Ragot, Frat); Groupe Hospitalier Régional d’Orléans, Médecine Intensive Réanimation, Orléans, France (Muller, Nay); Centre Hospitalier Universitaire de Rennes, Hôpital Ponchaillou, Service des Maladies Infectieuses et Réanimation Médicale, Rennes, France (Gacouin, Maamar); Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Service de Pneumologie, Médecine Intensive et Réanimation (Département R3S), AP-HP, INSERM, UMRS1158

Neurophysiologie Respiratoire Expérimentale et Clinique, Sorbonne Université, Paris, France (Decavèle, Demoule); Hôpital Bichat–Claude Bernard, Médecine Intensive Réanimation, AP-HP, Université Paris Diderot, Paris, France (Sonneville); Centre Hospitalier Universitaire d’Angers, Département de Médecine Intensive Réanimation, Université d’Angers, Angers, France (Beloncle); Centre Hospitalier Universitaire de Rouen, Hôpital Charles Nicolle, Département de Réanimation Médicale, Normandie Université, UNIROUEN, EA3830-GRHV, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France (Girault); Centre Hospitalier Universitaire Félix Guyon, Service de Réanimation Polyvalente, Saint Denis de la Réunion, France (Dangers); Centre Hospitalier Universitaire de Clermont-Ferrand, Hôpital Gabriel Montpied, Service de Réanimation Médicale, Clermont-Ferrand, France (Lautrette); Centre Hospitalier de La Rochelle, Service de Réanimation, La Rochelle, France (Cabasson);

Centre Hospitalier Universitaire de Lille, Centre de Réanimation, Université de Lille, Lille, France (Rouzé); Hôpital Saint-Joseph Saint-Luc, Réanimation Polyvalente, Lyon, France (Vivier); Centre Hospitalier Universitaire de Nantes, Médecine Intensive Réanimation, Nantes, France (Le Meur); Hôpital Louis Mourier, Réanimation Médico-Chirurgicale, AP-HP, INSERM, Université Paris Diderot, UMR IAME 1137, Sorbonne Paris Cité, Colombes, France (Ricard); Hôpitaux universitaires Henri Mondor, Service de Réanimation Médicale DHU A-TVB, AP-HP, Créteil, France (Razazi); Groupe Hospitalier Régional Mulhouse Sud Alsace, site Emile Muller, Service de Réanimation Médicale, Mulhouse, France (Barberet); Centre Hospitalier Départemental de Vendée, Service de Médecine Intensive Réanimation, La Roche Sur Yon, France (Lebert); Centre Hospitalier Régional Universitaire de Tours, Médecine Intensive Réanimation, CIC 1415, Réseau CRICS-Trigger SEP, Centre d’étude des pathologies respiratoires, INSERM U1100, Université de Tours, Tours, France (Ehrmann); Centre Hospitalier de Pau, Service de Réanimation, Pau, France (Sabatier); Centre Hospitalier Universitaire La Timone 2, Médecine Intensive Réanimation, Réanimation des Urgences,

Aix-Marseille Université, Marseille, France (Bourenne); Centre Hospitalier Henri Mondor d’Aurillac, Service de Réanimation, Aurillac, France (Pradel); Centre Hospitalier Universitaire de Brest, Médecine Intensive Réanimation, Brest, France (Bailly); Centre Hospitalier Universitaire Grenoble Alpes, Médecine Intensive Réanimation, INSERM, Université Grenoble-Alpes, U1042, HP2, Grenoble, France (Terzi); Centre Hospitalier Universitaire de Nice, Médecine Intensive Réanimation, Archet 1, Université Cote d’Azur, Nice, France (Dellamonica); Centre Hospitalier de Versailles, Service de Réanimation Médico-Chirurgicale, Le Chesnay, France (Lacave); Centre Hospitalier Universitaire de Nice, Réanimation Médico-Chirurgicale Archet 2,

INSERM U 1065, Nice, France (Danin); Centre Hospitalier Universitaire de Poitiers, Réanimation Chirurgicale, Poitiers, France (Nanadoumgar);

Hôpital Tenon, Réanimation et USC

médico-chirurgicale, CARMAS, AP-HP, Faculté de médecine Sorbonne Université, Collegium Galilée, Paris, France (Gibelin); Centre Hospitalier Emile Roux, Service de Réanimation, Le Puy en Velay, France (Zanre); Hôpital Lariboisière, Réanimation Médicale et Toxicologique, AP-HP, INSERM UMR-S 942, Paris, France (Deye).

Author Contributions: Dr Thille had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors give their agreement to be accountable for all aspects of the work, and ensure the accuracy and integrity of any part of the work. Concept and design: Thille, Girault, Dellamonica, Lacave, Zanre, Ragot, Frat.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Thille, Coudroy, Girault, Cabasson, Nanadoumgar, Zanre, Demoule, Ragot, Frat.

Critical revision of the manuscript for important intellectual content: Thille, Muller, Gacouin, Coudroy, Decavèle, Sonneville, Beloncle, Girault, Dangers, Lautrette, Rouzé, Vivier, Le Meur, Ricard, Razazi, Barberet, Lebert, Ehrmann, Sabatier, Bourenne, Pradel, Bailly, Terzi, Dellamonica, Lacave, Danin, Gibelin, Zanre, Deye, Demoule, Maamar, Nay, Robert, Ragot, Frat.

Statistical analysis: Thille, Zanre, Ragot.

Obtained funding: Thille, Pradel, Zanre. Administrative, technical, or material support: Thille, Gacouin, Dangers, Rouzé, Le Meur, Razazi, Lebert, Lacave, Zanre, Demoule, Robert.

Supervision: Thille, Zanre, Robert, Ragot.

Conflict of Interest Disclosures: Dr Thille reported receiving grants from the French Ministry of Health

jama.com JAMA Published online October 2, 2019 E9

and personal fees and nonfinancial support from Fisher & Paykel Healthcare during the conduct of the study and personal fees from Maquet-Getinge, GE Healthcare, and Covidien outside the submitted work. Dr Sonneville reported receiving grants from the French Ministry of Health, the European Society of Intensive Care Medicine, and the French Society of Intensive Care Medicine and personal fees from Baxter outside the submitted work. Dr Beloncle reported receiving personal fees from Lowenstein Medical and nonfinancial support from GE Healthcare, Getinge Group, and Covidien outside the submitted work. Dr Girault reported receiving grants, personal fees, and nonfinancial support from Fisher & Paykel Healthcare during the conduct of the study and grants and nonfinancial support from ResMed outside the submitted work.

Dr Ricard reported receiving travel and accommodation expenses from Fisher & Paykel Healthcare outside the submitted work.

Dr Ehrmann reported receiving grants, nonfinancial support, and other funding from Fisher & Paykel Healthcare during the conduct of the study; grants, personal fees, nonfinancial support, and other funding from Aerogen; grants from Hamilton; personal fees from La Diffusion Technique Française; and personal fees from Baxter outside the submitted work. In addition, Dr Ehrmann had a patent to EP17305015 issued. Dr Terzi reported receiving personal fees from Boehringer Ingelheim and Pfizer outside the submitted work. Dr Danin reported receiving fees for lectures from Fisher and Paykel during the conduct of the study. Dr Deye reported receiving lecture and travel fees from Zoll and Bard outside the submitted work. Dr Demoule reported receiving personal fees from Medtronic, Baxter, Hamilton, and Getinge; grants, personal fees, and nonfinancial support from Philips and Lungpacer; personal fees and nonfinancial support from Fisher & Paykel Healthcare; and grants from the French Ministry of Health and Respinor outside the submitted work. Dr Frat reported receiving personal fees and nonfinancial support from Fisher & Paykel Healthcare during the conduct of the study and personal fees and nonfinancial support from SOS Oxygen outside the submitted work.

No other disclosures were reported.

Funding/Support: The study was funded by the “Programme Hospitalier de Recherche Clinique National 2015” of the French Ministry of Health through the University Hospital of Poitiers, Poitiers, France.

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Fisher & Paykel provided to all the participating centers the

high-flow nasal oxygen equipment and masks for noninvasive ventilation but had no other involvement in the study.

Group Information: Members of the HIGH-WEAN Study Group and REVA Research Network include the following: Florence Boissier (Centre Hospitalier Universitaire de Poitiers, Médecine Intensive Réanimation, Poitiers), Delphine Chatellier (Centre Hospitalier Universitaire de Poitiers, Médecine Intensive Réanimation, Poitiers), Céline Deletage (Centre Hospitalier Universitaire de Poitiers, Médecine Intensive Réanimation, Poitiers), Carole Guignon (Centre Hospitalier Universitaire de

Poitiers, Médecine Intensive Réanimation, Poitiers), Florent Joly (Centre Hospitalier Universitaire de Poitiers, Médecine Intensive Réanimation, Poitiers), Morgane Olivry (Centre Hospitalier Universitaire de Poitiers, Médecine Intensive Réanimation, Poitiers), Anne Veinstein (Centre Hospitalier Universitaire de Poitiers, Médecine Intensive Réanimation, Poitiers), Dalila Benzekri-Lefevre (Groupe Hospitalier Régional d’Orléans, Médecine Intensive Réanimation, Orléans), Thierry Boulain (Groupe Hospitalier Régional d’Orléans, Médecine Intensive Réanimation, Orléans), Yves Le Tulzo (Centre Hospitalier Universitaire de Rennes, Hôpital Ponchaillou, Service des Maladies Infectieuses et Réanimation Médicale, Rennes), Jean-Marc Tadié (Centre Hospitalier Universitaire de Rennes, Hôpital Ponchaillou, Service des Maladies Infectieuses et Réanimation Médicale, Rennes), Suela Demiri (Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Service de Pneumologie et Réanimation Médicale, AP-HP, Paris), Julien Mayaux (Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Service de Pneumologie et Réanimation Médicale, Paris), Lila Bouadma (Hôpital Bichat–Claude Bernard, Médecine Intensive Réanimation, Paris), Claire Dupuis (Hôpital Bichat–Claude Bernard, Médecine Intensive Réanimation, Paris), Pierre Asfar (Centre Hospitalier Universitaire d’Angers, Département de Médecine Intensive Réanimation, Angers), Marc Pierrot (Centre Hospitalier Universitaire d’Angers, Département de Médecine Intensive Réanimation, Angers), Gaëtan Béduneau (Centre Hospitalier Universitaire de Rouen, Hôpital Charles Nicolle, Département de Réanimation Médicale, Rouen), Déborah Boyer (Centre Hospitalier Universitaire de Rouen, Hôpital Charles Nicolle, Département de Réanimation Médicale, Rouen), Benjamin Delmas (Centre Hospitalier Universitaire Félix Guyon, Service de Réanimation Polyvalente, Saint Denis de la Réunion), Bérénice Puech (Centre Hospitalier Universitaire Félix Guyon, Service de Réanimation Polyvalente, Saint Denis de la Réunion), Konstantinos Bachoumas (Centre Hospitalier Universitaire de Clermont-Ferrand, Hôpital Gabriel Montpied, Clermont-Ferrand), Edouard Soum (Centre Hospitalier Universitaire de Clermont– Ferrand, Hôpital Gabriel Montpied,

Clermont-Ferrand), Marie-Anne Hoppe (Centre Hospitalier de La Rochelle, Service de Réanimation, La Rochelle), Quentin Levrat (Centre Hospitalier de La Rochelle, Service de Réanimation, La Rochelle), Saad Nseir (Centre Hospitalier Universitaire de Lille, Center de Réanimation, Lille), Olivier Pouly (Centre Hospitalier Universitaire de Lille, Center de Réanimation, Lille), Gaël Bourdin (Hôpital

Saint-Joseph Saint-Luc, Réanimation Polyvalente, Lyon), Sylvène Rosselli (Hôpital Saint-Joseph Saint-Luc, Réanimation Polyvalente, Lyon), Charlotte Garret (Centre Hospitalier Universitaire de Nantes, Médecine Intensive Réanimation, Nantes), Maelle Martin (Centre Hospitalier Universitaire de Nantes, Médecine Intensive

Réanimation, Nantes), Guillaume Berquier (Hôpital Louis Mourier, Réanimation Médico-Chirurgicale, Colombes) Abirami Thiagarajah (Hôpital Louis Mourier, Réanimation Médico-Chirurgicale, Colombes), Guillaume Carteaux (Hôpitaux Universitaires Henri Mondor, Service de Réanimation Médicale, Créteil), Armand

Mekontso-Dessap (Hôpitaux Universitaires Henri Mondor, Service de Réanimation Médicale, Créteil), Antoine Poidevin (Groupe Hospitalier Régional Mulhouse Sud Alsace, site Emile Muller, Service de

Réanimation Médicale, Mulhouse), Anne-Florence Dureau (Groupe Hospitalier Régional Mulhouse Sud Alsace, site Emile Muller, Service de Réanimation Médicale, Mulhouse), Marie-Ange Azais (Centre Hospitalier Départemental de Vendée, Service de Médecine Intensive Réanimation, La Roche Sur Yon), Gwenhaël Colin (Centre Hospitalier Départemental de Vendée, Service de Médecine Intensive Réanimation, La Roche Sur Yon), Emmanuelle Mercier (Centre Hospitalier Régional Universitaire de Tours, Médecine Intensive Réanimation, Tours), Marlène Morisseau (Centre Hospitalier Régional Universitaire de Tours, Médecine Intensive Réanimation, Tours), Alexandre Massri (Centre Hospitalier de Pau, Service de Réanimation, Pau), Walter Picard (Centre Hospitalier de Pau, Service de Réanimation, Pau), Marc Gainnier (CHU La Timone 2, Médecine Intensive Réanimation, Marseille), Thi-My-Hue Nguyen (Centre Hospitalier Henri Mondor d’Aurillac, Service de Réanimation, Aurillac), Gwenaël Prat (Centre Hospitalier Universitaire de Brest, Médecine Intensive Réanimation, Brest), Carole Schwebel (Centre Hospitalier Universitaire Grenoble Alpes, Médecine Intensive Réanimation, Grenoble), and Matthieu Buscot (Centre Hospitalier Universitaire de Nice, Réanimation Médicale

Archet 1, Université Cote d’Azur, Nice).

Meeting Presentation: Presented at the annual congress of the European Society of Intensive Care Medicine, October 2, 2019, Berlin, Germany.

Additional Contributions: We thank Jeffrey Arsham (a translator employed by CHU de Poitiers, Poitiers, France) for reviewing and editing the original English-language manuscript.

Data Sharing Statement: See Supplement 3.

REFERENCES

  1. Thille AW, Richard J-CM, Brochard L. The decision to extubate in the intensive care unit. Am J Respir Crit Care Med. 2013;187(12):1294-1302. doi: 10.1164/rccm.201208-1523CI
  2. Esteban A, Frutos-Vivar F, Muriel A, et al. Evolution of mortality over time in patients receiving mechanical ventilation. Am J Respir Crit Care Med. 2013;188(2):220-230. doi:10.1164/rccm. 201212-2169OC
  3. Epstein SK, Ciubotaru RL, Wong JB. Effect of failed extubation on the outcome of mechanical ventilation. Chest. 1997;112(1):186-192. doi:10.1378/ chest.112.1.186
  4. Frutos-Vivar F, Esteban A, Apezteguia C, et al. Outcome of reintubated patients after scheduled extubation. J Crit Care. 2011;26(5):502-509. doi:10. 1016/j.jcrc.2010.12.015
  5. Ornico SR, Lobo SM, Sanches HS, et al. Noninvasive ventilation immediately after extubation improves weaning outcome after acute respiratory failure: a randomized controlled trial. Crit Care. 2013;17(2):R39. doi:10.1186/cc12549
  6. Nava S, Gregoretti C, Fanfulla F, et al. Noninvasive ventilation to prevent respiratory failure after extubation in high-risk patients. Crit Care Med. 2005;33(11):2465-2470. doi:10.1097/01. CCM.0000186416.44752.72
  7. Ferrer M, Valencia M, Nicolas JM, Bernadich O, Badia JR, Torres A. Early noninvasive ventilation averts extubation failure in patients at risk:

a randomized trial. Am J Respir Crit Care Med.

E10 JAMA Published online October 2, 2019 jama.com

2006;173(2):164-170. doi:10.1164/rccm.200505-

718OC

  1. Ferrer M, Sellarés J, Valencia M, et al.

Non-invasive ventilation after extubation in hypercapnic patients with chronic respiratory disorders: randomised controlled trial. Lancet. 2009;374(9695):1082-1088. doi:10.1016/S0140-

6736(09)61038-2

  1. Vargas F, Clavel M, Sanchez-Verlan P, et al. Intermittent noninvasive ventilation after extubation in patients with chronic respiratory disorders: a multicenter randomized controlled trial (VHYPER). Intensive Care Med. 2017;43(11):1626- 1636. doi:10.1007/s00134-017-4785-1
  2. Rochwerg B, Brochard L, Elliott MW, et al. Official ERS/ATS clinical practice guidelines: noninvasive ventilation for acute respiratory failure. Eur Respir J. 2017;50(2):1602426. doi:10.1183/ 13993003.02426-2016
  3. Demoule A, Chevret S, Carlucci A, et al; oVNI Study Group; REVA Network (Research

Network in Mechanical Ventilation). Changing use of noninvasive ventilation in critically ill patients: trends over 15 years in francophone countries.

Intensive Care Med. 2016;42(1):82-92. doi:10.1007/ s00134-015-4087-4

  1. Maggiore SM, Idone FA, Vaschetto R, et al. Nasal high-flow versus Venturi mask oxygen therapy after extubation. Effects on oxygenation, comfort, and clinical outcome. Am J Respir Crit Care Med. 2014;190(3):282-288. doi:10.1164/rccm. 201402-0364OC
  2. Hernández G, Vaquero C, González P, et al. Effect of postextubation high-flow nasal cannula vs conventional oxygen therapy on reintubation in low-risk patients: a randomized clinical trial. JAMA.

2016;315(13):1354-1361. doi:10.1001/jama.2016.2711

  1. Hernández G, Vaquero C, Colinas L, et al. Effect of postextubation high-flow nasal cannula vs noninvasive ventilation on reintubation and postextubation respiratory failure in high-risk patients: a randomized clinical trial. JAMA. 2016;316 (15):1565-1574. doi:10.1001/jama.2016.14194
  2. Di Mussi R, Spadaro S, Stripoli T, et al. High-flow nasal cannula oxygen therapy decreases postextubation neuroventilatory drive and work of breathing in patients with chronic obstructive pulmonary disease. Crit Care. 2018;22(1):180. doi: 10.1186/s13054-018-2107-9
  3. Boles JM, Bion J, Connors A, et al. Weaning from mechanical ventilation. Eur Respir J. 2007;29 (5):1033-1056. doi:10.1183/09031936.00010206
  4. Keenan SP, Powers C, McCormack DG, Block G. Noninvasive positive-pressure ventilation for postextubation respiratory distress: a randomized controlled trial. JAMA. 2002;287(24):3238-3244. doi:10.1001/jama.287.24.3238
  5. Esteban A, Frutos-Vivar F, Ferguson ND, et al. Noninvasive positive-pressure ventilation for respiratory failure after extubation. N Engl J Med. 2004;350(24):2452-2460. doi:10.1056/ NEJMoa032736
  6. Thille AW, Boissier F, Ben Ghezala H, Razazi K, Mekontso-Dessap A, Brun-Buisson C. Risk factors for and prediction by caregivers of extubation failure in ICU patients: a prospective study. Crit Care Med. 2015;43(3):613-620. doi:10.1097/CCM. 0000000000000748
  7. Thille AW, Harrois A, Schortgen F, Brun-Buisson C, Brochard L. Outcomes of extubation failure in medical intensive care unit patients. Crit Care Med. 2011;39(12):2612-2618. doi:10.1097/CCM. 0b013e3182282a5a
  8. Thille AW, Boissier F, Ben-Ghezala H, et al. Easily identified at-risk patients for extubation failure may

benefit from noninvasive ventilation: a prospective before-after study. Crit Care. 2016;20(1):48. doi:10. 1186/s13054-016-1228-2

  1. Thille AW, Cortés-Puch I, Esteban A. Weaning from the ventilator and extubation in ICU. Curr Opin Crit Care. 2013;19(1):57-64. doi:10.1097/MCC. 0b013e32835c5095
  2. François B, Bellissant E, Gissot V, et al; Association des Réanimateurs du Centre-Ouest (ARCO). 12-H pretreatment with methylpred- nisolone versus placebo for prevention of postextubation laryngeal oedema: a randomised double-blind trial. Lancet. 2007;369(9567):1083- 1089. doi:10.1016/S0140-6736(07)60526-1
  3. Brochard L, Mancebo J, Wysocki M, et al. Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med. 1995;333(13):817-822. doi:10.1056/ NEJM199509283331301
  4. Vitacca M, Ambrosino N, Clini E, et al. Physiological response to pressure support ventilation delivered before and after extubation in patients not capable of totally spontaneous autonomous breathing. Am J Respir Crit Care Med. 2001;164(4):638-641. doi:10.1164/ajrccm.164.4. 2010046
  5. Pisani L, Fasano L, Corcione N, et al. Change in pulmonary mechanics and the effect on breathing pattern of high flow oxygen therapy in stable hypercapnic COPD. Thorax. 2017;72(4):373-375. doi:10.1136/thoraxjnl-2016-209673
  6. Subirà C, Hernández G, Vázquez A, et al. Effect of pressure support vs T-piece ventilation strategies during spontaneous breathing trials on successful extubation among patients receiving mechanical ventilation: a randomized clinical trial. JAMA. 2019; 321(22):2175-2182. doi:10.1001/jama.2019.7234

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S/F Oranı ile P/F Oranının Korelasyonu

S/F Oranı ile P/F Oranının Korelasyonu

  J Cardiovasc Thorac Res, 2015, 7(1), 28-31 doi: 10.15171/jcvtr.2014.06 http://journals.tbzmed.ac.ir/jcvtr

Publishing Group TUOMS Original Article

Comparison of the Spo2/Fio2 Ratio and the Pao2/Fio2 Ratio in Patients With Acute Lung Injury or Acute Respiratory Distress Syndrome

Nemat Bilan, Azar Dastranji*, Afshin Ghalehgolab Behbahani

Pediatric Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

Article info

Article History:

Received: 2 August 2014

Accepted: 12 February 2015

Keywords: ARDS ALI

Pao2/Fio2

Pulse Oximetry

Abstract

Introduction: Diagnostic criteria for acute lung injury (ALI) and Acute Respiratory Distress syndrome (ARDS) includes acute onset of disease, chest radiograph demonstrating bilateral pulmonary infiltrates, lack of significant left ventricular dysfunction and Pao2/Fio2 (PF) ratio ≤300 for ALI or ≤200 for ARDS. Recent criteria require invasive arterial sampling. The pulse oximetric saturation Spo2/Fio2 (SF) ratio may be a reliable non-invasive alternative to the PF ratio.

Methods: In this cross-sectional study, we enrolled 70 patients with ALI or ARDS who were admitted in Tabriz children’s hospital pediatrics intensive care unit (PICU). Spo2, Fio2, Pao2, charted within 5 minutes of each other and calculated SF and PF were recorded to determine the relationship between SF and PF ratio. SF values were examined as a substitute of PF ratio for diagnosis ARDS and ALI.

Results: The relationship between SF and PF ratio was described by the following regression equation: SF=57+0.61 PF (P<0.001). SF ratios of 181 and 235 corresponded of PF ratio 300 and 200. The SF cutoff of 235 had 57% sensitivity and 100% specificity for diagnosis of ALI. The SF cutoff of 181 had 71% sensitivity and 82% specificity for diagnosis of ARDS.

Conclusion: SF ratio is a reliable noninvasive surrogate for PF ratio to identify children with ALI or ARDS with the advantage of replacing invasive arterial blood sampling by non-invasive pulse oximetry.

Introduction

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are grave syndromes associated with high mortality and morbidity.1,2 It is estimated that 30% to 60% of all patients admitted to pediatric intensive care unit (PICU) require mechanical ventilation, and of these patients up to 25% suffer ALI and 5% to 10% have ARDS. With the implementation of lung-protective ventilation strategies, overall morbidity and mortality have improved significantly for both adult and children with ALI and ARDS.3,4 Based on American European Consensus Conference (AECC) in 1994, diagnostic criteria for ALI and ARDS require acute onset of disease, chest radiograph demonstrating bilateral pulmonary infiltrates, lack of significant left ventricular dysfunction and arterial partial pressure of carbon dioxid/Fraction of inspiratory oxygen (Pao2/Fio2) (PF) ratio ≤300 for ALI or ≤200 for ARDS.5

The first three components can be established with clinical history or noninvasively tools such as chest radiograph or echocardiography. However PF criteria require arterial blood sampling.6,7 Concerns about anemia following repeated blood sampling and tendency to implement less

invasive approaches have led to less frequent blood gas measurements in critically ill patients.8-9 However studies in ARDS and ALI patients are lacking. Furthermore SF threshold values could be used for diagnosing ARDS and ALI.6-10

Pulse oximetry is the most commonly utilized technique to monitor oxygenation which is non-invasive and safe. In this method arterial hemoglobin O2 saturation is measured by differentiating oxy hemoglobin form deoxygenated hemoglobin using their respective light absorption at wave lengths of 660 nm (red) and 940 nm (infra red).11,12 Pulse oximetry is used for detection of hypoxia, prevention of hyperoxia, weaning from mechanical ventilation, and for titration of Fio2.9-13

In most PICUs daily arterial blood sampling to calculate the PF ratio is not feasible. Calculation of SF ratio as a surrogate for PF ratio for diagnose ARDS or ALI, which is less-invasive, is desirable.14 SF ratio determines the degree of hypoxemia non invasively without the need for arterial blood sampling.7

In this study, we examined the relationship between SF and PF ratio in critically ill patients with ALI and ARDS.

*Corresponding author: Azar Dastranji, Email: dastranji61@gmail.com

© 2015 The Author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons. org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Acute lung injury and Spo2/Fio2 Ratio

It is presumed that the more available and less invasive SF ratio measurement can replace PF ratio measurement in the diagnosis of ALI and ARDS.

Materials and methods

In this cross-sectional study 70 children with ARDS or ALI who were admitted in Tabriz children’s hospital PICU, Iran between 2012 and 2013 were enrolled. In patients with ARDS or ALI who were intubated and under mechanical ventilation with same Fio2; Pao2 was measured with arterial blood sampling and Spo2 was measured with pulse oximetry and charted within 5 min. SF and PF ratio were then calculated.

Inclusion criteria were children with ARDS or ALI and acute onset of disease and chest radiograph demonstrating bilateral pulmonary infiltrates , consistent with pulmonary edema.

Exclusion criteria were children with pulmonary edema due to heart failure and congenital heart disease and anatomic anomalies of lung or air ways and hypotension and weak pulses.

Statistical analysis

Statistical analyses were performed using the Statistical Package for Social Sciences, version 17.0 (SPSS, Chicago, Illinois). Quantitative data were presented as mean ± standard deviation (SD), while qualitative data were demonstrated as frequency and percent (%). The categorical parameters were compared by χ2 tests, and the continuous variables were compared by independent

 

Results

Of 70 children enrolled in this study, 38 patients were female (54.3%) and 32 patients were male (45.7%) . Mean age of study population was 32+ 5 months (minimum 2 and maximum 144 months).

A total of 70 data pairs 56 (80%) met the PF ratio criteria for ARDS and 14 (20%) met the PF criteria for ALI. The median time difference between charted values of Spo2 and Pao2 pairs was 5 minutes.

Table 1 demonstrates baseline findings of the patients enrolled in the study.

Age had no significant relationship with either SF ratio (P = 0.81) or PF ratio (P =0.99). Similarly, gender did not have a significant relationship with either SF ratio (P = 0.77) or PF ratio (P =0.06).

In general, SF ratio could be predicted well from PF ratio, described by the linear regression equation (SF =57+0.61 PF). Based on this equation a PF ratio of 300 corresponds to an SF ratio of 235 and PF ratio of 200 to an SF ratio of 181 [P <0.001 (Figure 1)]. The SF cut off of 235 had 57% sensitivity and 100% specificity for the diagnosis of ALI and cut off of 181 had 71% sensitivity and 82% specificity for the diagnosis of ARDS. SF ratio had excellent discrimination ability for ARDS (AUC=0.86) (Figure 2) and good discrimination ability for ALI and ARDS (AUC=0.89) (Figure 3).

 

Discussion

ALI and ARDS are major contributors to morbidity and mortality for patients admitted to PICU.15 The routine use of pulse oximetry and capnography have led to less frequent arterial blood gas sampling. In most PICUs, pulse oximetry is readily available and is being used routinely for continuous monitoring of oxygenation status.16-18 Pulse

Table 1. Base line findings of the patients

Max-MinMean±SD
Pao2/ Fio2298-46155±61
Spo2/Fio2248-77152±47
Spo299-7194±4
Fio2100-4067±18
Pao2176-4196±25
Age144-232±5

300

250     200

t test. A P <0.05 was considered statistically significant. Relationship between SF and PF, described by linear regression equation. ROC curves were plotted to determine the sensitivity and specificity of the SF threshold values correlating with PF of 200 (ARDS) and 300 (ALI).

Figure 1. S/F ratio vs P/F ratio scatter plot for the derivation data set. The line represents the best fit linear relationship SF=57+0.61PF (P<0.001).

Figure 2. ROC curves for S/F vs P/F ratios of ≤200 (ARDS).

Ethical issues

Figure 3. ROC curves for S/F vs. P/F ratios of ≤ 200 (ARDS) and
S/F vs. P/F ratios of ≤ 300 (ALI) for the derivation data set

oximetry circumvents the harms and costs of arterial blood sampling.19 Using SF ratio for diagnosing ALI and ARDS leads to identification of undiagnosed cases of aforementioned syndromes.20
SF ratio may be useful in many organ failure scores, such as lung injury scores21, multi organ dysfunction score22, sequential organ failure assessment23, as an alternative to PF ratio to estimate the degree of hypoxemia.  In this study we enrolled 70 patients with ALI or ARDS. Pao2 and Spo2 were measured with the same Fio2 and SF and PF ratio were calculated. The relationship between SF and PF ratio was described with the following equation: SF=57+0.61 PF. SF ratio threshold values for ALI was 235 and for ARDS was 181 corresponding to PF ratio
300 and 200. A similar study was conducted by Khemani et al.24 on pediatric population. They report that a cut-off of 201 for  SF could predict PF for ARDS with 84% sensitivity and 78% specificity and a cut-off of 263 for SF could predict ALI with 93% sensitivity and 43% specificity. However, they didn’t have age limitation. Also the time interval between pulse oximetry and arterial blood sampling was 15 minutes which is longer that our study. They did not examine the relationship between SF and PF ratio with sex and gender. In adult patients, Rice et al.25 report that a cut-off 235 for SF could predict ARDS with 85% sensitivity and 85% specificity and cut-off of 315 for SF could predict ALI with 91% sensitivity and 56 % specificity. In this study, we  examined the relationship between age and gender with PF and SF ratio. We measured Pao2 and Spo2 in maximum 5 minutes apart. The SF ratio thresholds determined in this study were based on the PF ratio which is proposed by the AECC. There are limitations to this study. First, ABG and pulse oximetry measurements were not simultaneous. Given that changes in Spo2 and Pao2 can take place quickly, this could affect our results. In addition we did not control for PH, hemoglobin, Paco2 , body temperature, ventilator set up. These factors also could influence the relationship
between Spo2 and Pao2.
.

Competing interests

Authors declare no conflict of interests in this study.

Conclusion

According to this study SF ratio is a reliable non invasive and readily available marker for PF ratio for the diagnosis of children with ALI or ARDS which replaces arterial blood sampling by pulse oximetry. Considering complications of arterial blood sampling such as anemia, and bleeding in critical care patients, pulse oximetry is a

Figure 3. ROC curves for S/F vs. P/F ratios of ≤ 200 (ARDS) and S/F vs. P/F ratios of ≤ 300 (ALI) for the derivation data set.

oximetry circumvents the harms and costs of arterial blood sampling.19 Using SF ratio for diagnosing ALI and ARDS leads to identification of undiagnosed cases of aforementioned syndromes.20

SF ratio may be useful in many organ failure scores, such as lung injury scores21, multi organ dysfunction score22, sequential organ failure assessment23, as an alternative to PF ratio to estimate the degree of hypoxemia.

In this study we enrolled 70 patients with ALI or ARDS. Pao2 and Spo2 were measured with the same Fio2 and SF and PF ratio were calculated. The relationship between SF and PF ratio was described with the following equation: SF=57+0.61 PF. SF ratio threshold values for ALI was

235 and for ARDS was 181 corresponding to PF ratio 300 and 200.

A similar study was conducted by Khemani et al.24 on pediatric population. They report that a cut-off of 201 for SF could predict PF for ARDS with 84% sensitivity and 78% specificity and a cut-off of 263 for SF could predict ALI with 93% sensitivity and 43% specificity. However, they didn’t have age limitation. Also the time interval between pulse oximetry and arterial blood sampling was 15 minutes which is longer that our study. They did not examine the relationship between SF and PF ratio with sex and gender.

In adult patients, Rice et al.25 report that a cut-off 235 for SF could predict ARDS with 85% sensitivity and 85% specificity and cut-off of 315 for SF could predict ALI with 91% sensitivity and 56 % specificity. In this study, we examined the relationship between age and gender with PF and SF ratio. We measured Pao2 and Spo2 in maximum 5 minutes apart. The SF ratio thresholds determined in this study were based on the PF ratio which is proposed by the AECC.

There are limitations to this study. First, ABG and pulse oximetry measurements were not simultaneous. Given that changes in Spo2 and Pao2 can take place quickly, this could affect our results. In addition we did not control for PH, hemoglobin, Paco2, body temperature, ventilator set up. These factors also could influence the relationship between Spo2and Pao2.

desirable replacement for arterial blood sampling.

References

  1. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000; 342:1334–1349. doi: 10.1056/NEJM200005043421806.
  2. Rubenfeld GD, Caldwell E, Peabody E. Incidence and outcomes of acute lung injury. N Engl J Med 2005; 353:1685–1693. doi: 10.1089/jamp.2009.0775
  3. Bernard GR, Artigas A, Brigham KL. The American-European Consensus Conference on ARDS: definitions,mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149:818–824. doi: 10.1164/ ajrccm.149.3.7509706
  4. Merlani P, Garnerin P, Diby M, Ferring M. Quality improvement report: linking guideline to regular feedback to increase appropriate requests for clinical test; blood gas analysis in intensive care. BMJ 2001; 323:620–62. doi: 10.1371/journal.pone.0078962
  5. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, et al. Thoracic SoG-The American European Consensus Conference on ARDS efinitions, mechanisms. Am J Respir Crit Care Med 1994; 149: 818-24. doi: 10.1164/ajrccm.149.3.7509706
  6. Pilon CS, Leathley DM, London R. Practice guideline for arterial blood gas measurement in the intensive care unit decreases numbers and increases appropriateness of tests. Crit Care Med 1997; 25:1308–1313. doi: 10.1016/j.jcrc.2007.11.013
  7. Jensen LA, Onyskiw JE, Prasad NG. Meta-analysis of arterial oxygen saturation monitoring by pulse oximetry in adults. Heart Lung 1998; 27:387–40. doi: 10.1016/S0147-9563(98)90086-3
  8. Ferguson ND, Frutos-Vivar F, Esteban A, Fernández- Segoviano P, Aramburu JA, Nájera L, et al. Acute respiratory distress syndrome: underrecognition by clinicians and diagnostic accuracy of three clinical definitions. Crit Care Med 2005; 33:2228–223. doi: 10.1007/978-3-319-03746-2
  9. Roberts D, Ostryzniuk P, Loewen E, Shanks A, Wasyluk T, Pronger L, et al. Control of blood gas measurements in intensive-care units. Lancet 1991; 337: 1580–1582. doi: 10.1016/0140-6736(91)93271-A
  10. Perkins GD, McAuley DF, Giles S. Do changes in

30 J Cardiovasc Thorac Res, 2015, 7(1), 28-31

Acute lung injury and Spo2/Fio2 Ratio

pulse oximeter oxygen saturation predict equivalent changes in arterial oxygen saturation? Crit Care 2003; 7:R67. doi: 10.1186/cc2339

  1. Ms Mortz. US patent 714,803,2004 pulse oximeter probe off detection system.
  2. Kliegman RM, Stanton BM, Geme JS, Schor N, Behrman RE. Nelson Textbook of Pediatrics.19 th ed. Elsevier; 2011. p.318
  3. Slutsky AS. Mechanical ventilation. American College of Chest Physicians’ Consensus Conference. Chest 1993;104(6):1833-59. doi: 10.1378/chest.104.6.1833
  4. Pandharipande PP1, Shintani AK, Hagerman HE, St Jacques PJ, Rice TW, Sanders NW, et al. Derivation and validation of Spo2/Fio2 ratio to impute for Pao2/Fio2 ratio in the respiratory component of the Sequential Organ Failure Assessment score. Crit Care Med 2009;37(4):1317-21. doi: 10.1097/ CCM.0b013e31819cefa9
  5. Khemani RG, Markovitz BP, Curley MAQ. Epidemiologic factors of mechanically ventilated PICU patients in the United States [abstract]. Pediatr Crit Care Med 2007;8(suppl):A39. doi: 10.1001/ jama.293.4.470
  6. Numa AH, Newth CJ. Assessment of lung function in the intensive care unit. Pediatr Pulmonol 1995; 19:118–128. doi: 10.1378/chest.09-0207
  7. Montgomery AB, Stager MA, Carrico CJ. Causes of mortality in patients with the adult respiratory distress syndrome. Am Rev Respir Dis 1985; 132:485–489. doi: 10.1001/jama.1995.03520280052
  8. Jubran A. Pulse oximetry. Intensive Care Med 2004; 30:2017–2020. doi: 10.1007/soo134-004-2399-x
  9. Jubran A, Tobin MJ. Reliability of pulse oximetry in titrating supplemental oxygen therapy in ventilator- dependent patients. Chest 1990; 97:1420–1425. doi: 10.1378/chest.97.6.1420
  10. 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; 342:1301–130. doi: 10.1056/NEJM 200005043421801.
  11. Murray JF, Matthay MA, Luce JM, Flick MR. An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis 1988; 138:720–723.
  12. Marshall JC, Cook DJ, Christou NV, Bernard GR, Sprung CL, Sibbald WJ. Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome. Crit Care Med 1995; 23:1638–1652.
  13. Le Gall JR, Lemeshow S, Saulnier F. A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. JAMA 1993; 270:2957–2963. doi:10.1001/ jama.1993.03510240069035.
  14. Khemani RG, Patel NR, Bart RD 3rd, Newth CJ. Comparison of the pulse oximetric saturation/ fraction of inspired oxygen ratio and the PaO2/ fraction of inspired oxygen ratio in children. Chest 2008;135(3):662-8. doi: 10.1378/chest.08-2239
  15. Rice TW, Wheeler AP, Bernard GR, Hayden DL, Schoenfeld DA, Ware LB. Comparison of the SpO2/ FIO2 ratio and the PaO2/FIO2 ratio in patients with acute lung injury or ARDS. Chest 2007; 132(2):410- 7. doi: 10.1378/chest.07-0617

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