Non‐invasive positive pressure ventilation (CPAP or bilevel NPPV) for cardiogenic pulmonary oedema

Nicolas Berbenetz; Yongjun Wang; James Brown; Charlotte Godfrey; Mahmood Ahmad; Flávia MR Vital; Pier Lambiase; Amitava Banerjee; Ameet Bakhai; Matthew Chong

doi:10.1002/14651858.CD005351.pub4

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Figure 1

PRISMA statement flow diagram for 2019 review update.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 4

Funnel plot of comparison: 1 NPPV vs SMC, outcome: 1.1 HOSPITAL MORTALITY.

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Figure 5

Funnel plot of comparison: 1 NPPV vs SMC, outcome: 1.8 ETI RATE.

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Figure 6

Funnel plot of comparison: 1 NPPV vs SMC, outcome: 1.17 HOSPITAL LENGTH OF STAY.

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Analysis 1.1

Comparison 1 NPPV vs SMC, Outcome 1 HOSPITAL MORTALITY.

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Analysis 1.2

Comparison 1 NPPV vs SMC, Outcome 2 Hospital mortality ‐ by NPPV.

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Analysis 1.3

Comparison 1 NPPV vs SMC, Outcome 3 Hospital mortality ‐ by location.

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Comparison 1 NPPV vs SMC, Outcome 4 Hospital mortality ‐ by baseline PaCO2.

Analysis 1.4

Comparison 1 NPPV vs SMC, Outcome 4 Hospital mortality ‐ by baseline PaCO₂.

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Analysis 1.5

Comparison 1 NPPV vs SMC, Outcome 5 Hospital mortality ‐ sensitivity analysis (low risk of bias).

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Analysis 1.6

Comparison 1 NPPV vs SMC, Outcome 6 Hospital mortality ‐ sensitivity analysis (missing data).

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Analysis 1.7

Comparison 1 NPPV vs SMC, Outcome 7 Hospital mortality ‐ sensitivity analysis (fixed‐effect).

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Analysis 1.8

Comparison 1 NPPV vs SMC, Outcome 8 ETI RATE.

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Analysis 1.9

Comparison 1 NPPV vs SMC, Outcome 9 ETI rate ‐ by NPPV.

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Analysis 1.10

Comparison 1 NPPV vs SMC, Outcome 10 ETI rate ‐ by location.

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Comparison 1 NPPV vs SMC, Outcome 11 ETI rate ‐ by baseline PaCO2.

Analysis 1.11

Comparison 1 NPPV vs SMC, Outcome 11 ETI rate ‐ by baseline PaCO₂.

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Analysis 1.12

Comparison 1 NPPV vs SMC, Outcome 12 ETI rate ‐ sensitivity analysis (low risk of bias).

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Analysis 1.13

Comparison 1 NPPV vs SMC, Outcome 13 ETI rate ‐ sensitivity analysis (missing data).

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Analysis 1.14

Comparison 1 NPPV vs SMC, Outcome 14 ETI rate ‐ by face mask type.

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Analysis 1.15

Comparison 1 NPPV vs SMC, Outcome 15 ACUTE MI INCIDENCE.

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Analysis 1.16

Comparison 1 NPPV vs SMC, Outcome 16 Acute MI incidence ‐ by NPPV.

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Analysis 1.17

Comparison 1 NPPV vs SMC, Outcome 17 HOSPITAL LENGTH OF STAY.

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Analysis 1.18

Comparison 1 NPPV vs SMC, Outcome 18 Hospital length of stay ‐ by NPPV.

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Analysis 1.19

Comparison 1 NPPV vs SMC, Outcome 19 Hospital length of stay ‐ by location.

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Comparison 1 NPPV vs SMC, Outcome 20 Hospital length of stay ‐ by baseline PaCO2.

Analysis 1.20

Comparison 1 NPPV vs SMC, Outcome 20 Hospital length of stay ‐ by baseline PaCO₂.

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Analysis 1.21

Comparison 1 NPPV vs SMC, Outcome 21 ICU LENGTH OF STAY.

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Analysis 1.22

Comparison 1 NPPV vs SMC, Outcome 22 SYSTOLIC BP AFTER ONE HOUR.

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Analysis 1.23

Comparison 1 NPPV vs SMC, Outcome 23 Systolic BP after one hour ‐ by NPPV.

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Analysis 1.24

Comparison 1 NPPV vs SMC, Outcome 24 DIASTOLIC BP AFTER ONE HOUR.

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Analysis 1.25

Comparison 1 NPPV vs SMC, Outcome 25 Diastolic BP after one hour ‐ by NPPV.

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Analysis 1.26

Comparison 1 NPPV vs SMC, Outcome 26 MEAN BP AFTER ONE HOUR.

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Analysis 1.27

Comparison 1 NPPV vs SMC, Outcome 27 RESPIRATORY RATE AFTER ONE HOUR.

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Analysis 1.28

Comparison 1 NPPV vs SMC, Outcome 28 Respiratory rate after one hour ‐ by NPPV.

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Comparison 1 NPPV vs SMC, Outcome 29 PaO2 (mmHg) AFTER ONE HOUR.

Analysis 1.29

Comparison 1 NPPV vs SMC, Outcome 29 PaO₂ (mmHg) AFTER ONE HOUR.

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Comparison 1 NPPV vs SMC, Outcome 30 PaO2 (mmHg) after one hour ‐ by NPPV.

Analysis 1.30

Comparison 1 NPPV vs SMC, Outcome 30 PaO₂ (mmHg) after one hour ‐ by NPPV.

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Analysis 1.31

Comparison 1 NPPV vs SMC, Outcome 31 ADVERSE EVENTS.

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Summary of findings for the main comparison. NPPV compared to SMC for cardiogenic pulmonary oedema

NPPV compared to standard medical care for cardiogenic pulmonary oedema
Patient or population: People with cardiogenic pulmonary oedema Setting: Pre‐hospital intensive care, emergency department, coronary care unit, or intensive care unit Intervention: NPPV Comparison: Standard medical care (SMC)
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with SMC	Risk with NPPV
HOSPITAL MORTALITY follow‐up: median 13 days; range 1 day ‐ 41 days	Study population		RR 0.65 (0.51 to 0.82)	2484 (21 RCTs)	⊕⊕⊝⊝ LOW^a,b	‐
	176 per 1000	114 per 1000 (90 to 144)
ETI RATE follow‐up: median 1 day; range 0.1 day ‐ 30 days	Study population		RR 0.49 (0.38 to 0.62)	2449 (20 RCTs)	⊕⊕⊕⊝ MODERATE^c	‐
	154 per 1000	75 per 1000 (58 to 95)
ACUTE MI INCIDENCE follow‐up: median 3 days; range 1 day ‐ 41 days	Study population		RR 1.03 (0.91 to 1.16)	1313 (5 RCTs)	⊕⊕⊕⊝ MODERATE^d	‐
	421 per 1000	433 per 1000 (383 to 488)
HOSPITAL LENGTH OF STAY	The mean HOSPITAL LENGTH OF STAY was 9.65 days	MD 0.31 days lower (1.23 lower to 0.61 higher)	‐	1714 (11 RCTs)	⊕⊝⊝⊝ VERY LOW^e,f,g	‐
ICU LENGTH OF STAY	This outcome could not be pooled due to high heterogeneity. There was no evidence of a difference between NPPV and SMC in 4 RCTs, and 2 RCTs reported a shorter length of stay for NPPV (1 day shorter (95% CI −1.79 to −0.21); n = 30; 4 days shorter (95% CI −4.36 to −3.64); n = 120)		‐	587 (6 RCTs)	⊕⊝⊝⊝ VERY LOW^h,i,j	Data were not pooled due to high heterogeneity with an I² of 99%
INTOLERANCE TO ALLOCATED TREATMENT ‐ not reported	‐	‐	‐	‐	‐	Outcome was not reported
ADVERSE EVENTS	Reported adverse events included skin damage, pneumonia, gastrointestinal bleeding, gastric distention, vomiting, pneumothorax, sinusitis, mask discomfort, hypotension, arrhythmia, cardiorespiratory arrest, gastric aspiration, stroke, seizures, claustrophobia, and hypercapnia. There was no evidence of a difference between groups for most of these events. However, there was an increase in discomfort with mask reported with NPPV (35/658) compared with SMC (0/442); RR 12.59 (95% CI 2.39 to 66.28). One small study (n = 83) reported a higher incidence of gastric distention in the NPPV group (13/56 in NPPV group, 0/27 in SMC group; RR 13.26 (95% CI 0.82 to 215.12)), but the number of events was low and the confidence interval wide. There was also some weak evidence of a lower incidence of cardiorespiratory arrest in the NPPV group (24/836 (NPPV) vs 26/516 (SMC); RR 0.60 (95% CI 0.34 to 1.05)		‐	2038 (11 RCTs)	⊕⊕⊝⊝ LOW^k,l	‐
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
^aDowngraded by one level for risk of bias. Most trials providing hospital mortality evidence were at unclear or high risk of bias for key domains, including: randomisation sequence, allocation concealment, selective reporting bias, and other significant bias. ^bDowngraded by one level for imprecision. Most trials had few participants and few mortality events, with a confidence interval crossing a RR of 0.75. ^cDowngraded by one level for risk of bias. Most trials providing ETI evidence were rated as having unclear or high risk of bias for key domains, which included randomisation sequence generation, allocation concealment, selective reporting bias, and other significant bias. ^dDowngraded by one level for imprecision. Most trials had few participants and few acute MI events, with a confidence interval crossing a RR of 1.0. In addition, the definition of acute MI varied between trials, with some trials using creatinine kinase and others using troponin. ^eDowngraded by one level for risk of bias. Most trials were at low or unclear risk of bias. Potential limitations from lack of blinding are likely to lower confidence in hospital length of stay. ^fDowngraded by one level for inconsistency. Hospital length of stay was heterogeneous, with an I² of 58% and visually‐evident heterogeneity. ^gDowngraded by one level for imprecision. Most trials had few participants, with a confidence interval crossing a MD of 0. ^hDowngraded by one level for risk of bias. Most information was from studies at low or unclear risk of bias. Potential limitations from lack of blinding are likely to lower confidence in ICU length of stay. ⁱDowngraded by one level for imprecision. Most trials had few participants, with a confidence interval crossing a MD of 0. ^jDowngraded by one level for inconsistency. ICU length of stay was heterogeneous, with an I² of 99% and visually‐evident heterogeneity. ^kDowngraded by one level for risk of bias. Most studies had at least one domain at high or unclear risk of bias. ^lDowngraded by one level for imprecision, as confidence intervals included both directions of effect for many of the adverse events.

Summary of findings for the main comparison. NPPV compared to SMC for cardiogenic pulmonary oedema

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Table 1. NPPV intervention summary: EPAP, IPAP, and PEEP settings, duration of therapy.

Study	Mask type	IPAP level (cmH2O) ± SD	EPAP in bilevel NPPV (cmH2O) ± SD	PEEP in CPAP (cmH2O) ± SD	Time of bilevel NPPV (h) ± SD	Time of CPAP (h) ± SD
Agmy 2008	Face mask	NA	NA	NA	NA	NA
Austin 2013	Face mask	NA	NA	10	NA	0.583333
Crane 2004	Face mask	15	5	10	NA	NA
Ducros 2011	Face mask	NA	NA	10	NA	3
El‐Refay 2016	Face mask	15	10	10	1	‐
Frontin 2011	Face mask	NA	NA	10	NA	NA
Gray 2008	Face mask	14±5	7 ± 3	10 ± 4	2 ± 1.3	2.2 ± 1.5
Hao 2002	Face mask	NA	NA	6 to 10	NA	4.6 ± 2.8
Kelly 2002	Face mask	NA	NA	7.5	NA	NA
L'Her 2004	Face mask	NA	NA	7.5	NA	NA
Levitt 2001	Face mask selected for mouth breathers Nasal available	NA	NA	NA	2	2
Li 2005	Face mask	15 to 18	5 to 8	NA	2	NA
Lin 1991	Face mask	NA	NA	12.5	NA	6
Lin 1995	Face mask	NA	NA	12.5	NA	6
Masip 2000	Face mask	15.2 ± 2.4	5	NA	4.2 ± 1.5	NA
Moritz 2003	Face mask	NA	NA	9.3 ± 0.3	0.5	NA
Nava 2003	Face mask	14.5 ± 21.1	6.1 ± 3.2	NA	11.4 ± 3.6	NA
Park 2001	Nasal bilevel and face mask for CPAP	12	4	7.5	2.6 ± 0.6	2.8 ± 1.5
Park 2004	Face mask	17 ± 2	11 ± 2	11 ± 2	2.1 ± 1	1.7 ± 0.7
Räsänen 1985	Face mask	NA	NA	10	NA	NA
Takeda 1997	Nasal	NA	NA	4 to 10	11.9 ± 8.4	NA
Takeda 1998	Nasal	NA	NA	4 to 10	NA	NA
Thys 2002	Face mask	16.5 ± 3.3	6.1 ± 1.5	NA	1.3 ± 0.3	NA
Zokaei 2016	Face mask 1st, nasal 2nd	10 to 20	4 to 7	NA	1	NA
Not all papers provided a mean and standard deviation. Where unavailable, the range represents the IPAP/EPAP/CPAP settings described in the Methods. NA: not applicable

Table 1. NPPV intervention summary: EPAP, IPAP, and PEEP settings, duration of therapy.

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Table 2. Standard medical therapy for each trial

Study	Lasix	Lasix dose	Nitrate	FiO₂ mask and %FiO₂	Other	Additional differences between SMC received in treatment group
Agmy 2008	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Austin 2013	yes	40 mg	Sublingual 400 ‐ 1600 mcg q5min	Yes, 8 ‐ 15 Lpm	Morphine 1 ‐ 2 mg IV	None
Crane 2004	yes	Unclear	nitrates	Yes, 10 Lpm	diamorphine	None
Ducros 2011	yes	Lasix 40 mg ‐ 120 mg IV or 1 ‐ 3 mg bumetanide	nitroglycerin (1 mg per 3 min) and a continuous IV infusion unless systolic BP < 110 mmHg	15 Lpm	NA	None
El‐Refay 2016	yes	Lasix 40 mg IV	nitroglycerin 0.4 mg sublingual	15 Lpm	Morphine 2 mg IV	None
Frontin 2011	yes	1 mg/kg IV	isosorbide dinitrate IV 2 mg if SBP > 180 mmHg	15 Lpm	NA	None
Gray 2008	yes	50 mg above usual dose to max 100 mg IV	Buccal nitrates 2 ‐ 5 mg	15 Lpm	Opiates	None
Hao 2002	yes	20 ‐ 40 mg IV	Buccal nitrates 0.5 mg to 1 mg IV	6 Lpm	Morphine 2 mg IV	None
Kelly 2002	yes	50 ‐ 100 mg IV	buccal nitrate 5 mg if systolic BP > 90 mmHg	oxygen 60% by venturi mask	morphine IV 2.5 ‐ 10 mg	None
Li 2005	yes	Unclear	nitroglycerin	Mask high concentration	Unclear	None
Levitt 2001	yes	Unclear	nitroglycerin IV	Mask high flow	Morphine	None
L'Her 2004	yes	80 mg IV	nitroglycerin IV infusion 1 mg/hour	8 Lpm	Morphine 2 ‐ 10 mg IV	None
Lin 1991	Unclear	Unclear	Unclear	FiO₂ 100%	Unclear	Unclear
Lin 1995	yes	40 mg IV or double home dose	nitroglycerin sublingual 0.6 mg or isosorbide 10 ‐ 20 mg, or nitro infusion 10 ‐ 50 mcg/min	FiO₂ 100%	Morphine 2 ‐ 10 mg IV	None
Masip 2000	yes	40 mg IV	IV glyceryl trinitrate 1mg if systolic BP > 180 mmHg	FiO₂ 50%	Morphine 4 mg IV	None
Moritz 2003	yes	40 mg IV or double home dose	IV nitroglycerin infusion 0.125 ‐ 0.25 mcg/kg/min	FiO₂ 100%	Unclear	None
Nava 2003	yes	40 mg IV or double usual dose, repeated, if necessary, every 20 mins, up to 320 mg	continuous glyceryl trinitrate at an initial rate of 1.5 mg/hour. A bolus dose of 1 mg IV was added if systolic BP > 180 mmHg	10 Lpm	morphine sulphate up to 4 mg	None
Park 2001	Unclear	Unclear	5 mg isosorbide dinitrite if systolic BP > 100 mm Hg	15 Lpm	Unclear	Unclear
Park 2004	Unclear	Unclear	5 mg isosorbide dinitrate was given sublingually and if necessary titrated up to 15 mg	FiO₂ 50%	Unclear	Unclear
Räsänen 1985	yes	40 ‐ 80 mg IV	Nitroprusside, nitroglycerine	FiO₂ 30%	Morphine	Unclear
Takeda 1997	yes	Unclear	Nitroglycerin infusion	FiO2 50%	Morphine	Unclear
Takeda 1998	yes	Unclear	Nitroglycerin infusion	FiO₂ 70%	Morphine	Unclear
Thys 2002	yes	40 mg IV	isosorbide dinitrate 2 mg/hour	Unclear	Unclear	Unclear
Zokaei 2016	yes	40 ‐ 320 mg	IV nitroglycerin 5 ‐ 50 mcg/kg/min	10 Lpm	morphine 5 ‐ 10 mg	Unclear
BP: blood pressure; FiO₂: fraction of inspired oxygen; IV: intravenous; Lpm: litres per minute; NA: not available; mcg: micrograms; mcg/kg/min: micrograms per kilogram per minute; mg: milligrams; min: minutes; mmHg = millimetres of mercury

Table 2. Standard medical therapy for each trial

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Table 3. In‐hospital mortality duration of follow‐up

Study	Follow‐up (days)
Agmy 2008	Unclear
Austin 2013	7.2^a
Crane 2004	41^b
Ducros 2011	> 7
El‐Refay 2016	1
Frontin 2011	30
Gray 2008	30
Hao 2002	NA
Kelly 2002	15^a
Li 2005	NA
Levitt 2001	38^b
L'Her 2004	12^a
Lin 1991	1
Lin 1995	9
Masip 2000	14^a
Moritz 2003	NA
Nava 2003	5.4^a
Park 2001	3^b
Park 2004	15
Räsänen 1985	Unclear
Takeda 1997	7.7^a
Takeda 1998	Unclear
Thys 2002	17.6^a
Zokaei 2016	7
^aEstimated based on longest reported mean hospital length of stay; ^bBased on latest death reported in trial

Table 3. In‐hospital mortality duration of follow‐up

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Table 4. Intubation criteria for trials reporting endotracheal intubation rates

Study	Intubation Criteria
Agmy 2008	Unclear
Austin 2013	Unclear
Crane 2004	RR > 40, RR < 10, altered level of consciousness, arterial pH < 7.2
Ducros 2011	SpO₂ < 85% after 30 mins of 15 Lpm or FiO₂ 60% CPAP, respiratory arrest, psychomotor agitation, SBP < 80 mmHg
El‐Refay 2016	Unclear
Frontin 2011	Worsening SpO₂ despite effective treatment, loss of airway protective reflexes (cough, swallow), decreased level of consciousness, haemodynamic instability, intolerance/poor fit of face mask for the CPAP group, medical clinical impression of deterioration, or participant request
Gray 2008	At discretion of treating clinician
L'Her 2004	Cardiac or respiratory arrest, severe haemodynamic instability (SBP < 80), administration of epinephrine/norepinephrine, refractory hypoxaemia SaO₂ < 92% despite face mask, clinical signs of respiratory exhaustion (accessory muscle use with paradoxical abdominal motion), coma or seizures, agitation requiring sedation
Levitt 2001	Clinical or arterial blood gas findings. Severe respiratory distress, deterioration in mental status, or further deterioration in vital signs with increasing HR, RR, or a decrease in BP. Decrease in pO₂ < 60 or rise in pCO₂ > 50 along with signs of clinical deterioration warranted intubation
Lin 1991	Clinician discretion. Loss of consciousness or airway obstruction were indications for intubation
Lin 1995	Cardiopulmonary resuscitation or clinical deterioration with any 2 of the following: (1) a rise in arterial carbon dioxide tension to more than 55 mm Hg; (2) arterial blood oxygen partial pressure divided by fraction of inspired oxygen content less than 200 mm Hg; and (3) respiratory rate over 35 breaths/min.
Masip 2000	Patients were intubated when the criteria for treatment failure were met. Details not specified.
Nava 2003	Unclear
Park 2001	Clinical judgement
Park 2004	Clinical judgement
Räsänen 1985	Clinical judgement. Loss of consciousness or airway obstruction were indications for intubation at any time.
Takeda 1997	Clinical deterioration and either a decrease in the PaO₂/FiO₂ < 100 with an FIO₂ ≥ 70% or a increase in the PaCO₂ > 55 mmHg
Takeda 1998	Clinical deterioration and either a fall in PaO₂/FiO₂ < 100 with an FiO₂ of 70% or a rise in PaCO₂ to > 55 mmHg.
Thys 2002	Deterioration in clinical status including all of the following: dyspnoea, respiratory or heart frequency or both, sweating and agitation or deterioration in blood gases or in haemodynamic status or both
Zokaei 2016	RR after 1 hour of bilevel NPPV > 30, persistent hypoxaemia, haemodynamic instability (systolic BP < 70), agitation, or worsened neurologic status, inability to tolerate mask or aspiration of gastric content
BP: blood pressure; CPAP: continuous positive airway pressure; FiO₂: fraction of inspired oxygen; HR: heart rate; Lpm: litres per minute; PaCO₂: arterial partial pressure of carbon dioxide; PaO₂: arterial partial pressure of oxygen; RR: respiratory rate; SBP: systolic blood pressure

Table 4. Intubation criteria for trials reporting endotracheal intubation rates

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Comparison 1. NPPV vs SMC

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 HOSPITAL MORTALITY Show forest plot	21	2484	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.51, 0.82]

2 Hospital mortality ‐ by NPPV Show forest plot	21	2484	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.58, 0.87]

2.1 CPAP vs SMC	16	1454	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.48, 0.88]
2.2 bilevel NPPV vs SMC	11	1030	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.53, 0.98]
3 Hospital mortality ‐ by location Show forest plot	21	2484	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.51, 0.82]

3.1 ER	10	1596	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.47, 0.93]
3.2 ICU	10	862	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.35, 0.77]
3.3 unclear	1	26	Risk Ratio (M‐H, Random, 95% CI)	1.94 [0.09, 43.50]
4 Hospital mortality ‐ by baseline PaCO₂ Show forest plot	21	2484	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.51, 0.82]

4.1 PaCO2 <= 45mmHg	10	581	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.27, 0.63]
4.2 PaCO2 > 45mmHg	11	1903	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.65, 1.03]
5 Hospital mortality ‐ sensitivity analysis (low risk of bias) Show forest plot	7	1505	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.61, 1.06]

6 Hospital mortality ‐ sensitivity analysis (missing data) Show forest plot	18	2283	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.54, 0.86]

7 Hospital mortality ‐ sensitivity analysis (fixed‐effect) Show forest plot	21	2484	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.55, 0.81]

8 ETI RATE Show forest plot	20	2449	Risk Ratio (M‐H, Random, 95% CI)	0.49 [0.38, 0.62]

9 ETI rate ‐ by NPPV Show forest plot	20	2449	Risk Ratio (M‐H, Random, 95% CI)	0.49 [0.39, 0.63]

9.1 CPAP vs SMC	15	1413	Risk Ratio (M‐H, Random, 95% CI)	0.46 [0.34, 0.62]
9.2 Bilevel NPPV vs SMC	11	1036	Risk Ratio (M‐H, Random, 95% CI)	0.50 [0.31, 0.81]
10 ETI rate ‐ by location Show forest plot	20	2449	Risk Ratio (M‐H, Random, 95% CI)	0.49 [0.38, 0.62]

10.1 ER	9	1561	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.37, 0.96]
10.2 ICU	10	862	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.29, 0.56]
10.3 unclear	1	26	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.13, 1.67]
11 ETI rate ‐ by baseline PaCO₂ Show forest plot	20	2449	Risk Ratio (M‐H, Random, 95% CI)	0.49 [0.38, 0.62]

11.1 PaCO2 <= 45mmHg	9	523	Risk Ratio (M‐H, Random, 95% CI)	0.37 [0.26, 0.52]
11.2 PaCO2 > 45mmHg	11	1926	Risk Ratio (M‐H, Random, 95% CI)	0.64 [0.46, 0.91]
12 ETI rate ‐ sensitivity analysis (low risk of bias) Show forest plot	6	1491	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.55, 1.32]

13 ETI rate ‐ sensitivity analysis (missing data) Show forest plot	17	2248	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.40, 0.69]

14 ETI rate ‐ by face mask type Show forest plot	20	2449	Risk Ratio (M‐H, Random, 95% CI)	0.49 [0.38, 0.62]

14.1 Exclusive full face mask use	15	2213	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.40, 0.69]
14.2 Exclusive or permissive nasal mask use	5	236	Risk Ratio (M‐H, Random, 95% CI)	0.35 [0.20, 0.62]
15 ACUTE MI INCIDENCE Show forest plot	5	1313	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.91, 1.16]

16 Acute MI incidence ‐ by NPPV Show forest plot	5	1313	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.91, 1.16]

16.1 CPAP vs SMC	3	569	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.80, 1.14]
16.2 bilevel NPPV vs SMC	5	744	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.92, 1.29]
17 HOSPITAL LENGTH OF STAY Show forest plot	11	1714	Mean Difference (IV, Random, 95% CI)	‐0.31 [‐1.23, 0.61]

18 Hospital length of stay ‐ by NPPV Show forest plot	11	1714	Mean Difference (IV, Random, 95% CI)	‐0.19 [‐1.02, 0.64]

18.1 CPAP vs SMC	7	943	Mean Difference (IV, Random, 95% CI)	‐0.52 [‐1.77, 0.72]
18.2 bilevel NPPV vs SMC	6	771	Mean Difference (IV, Random, 95% CI)	0.39 [‐0.35, 1.13]
19 Hospital length of stay ‐ by location Show forest plot	11	1714	Mean Difference (IV, Random, 95% CI)	‐0.30 [‐1.21, 0.61]

19.1 ER	8	1455	Mean Difference (IV, Random, 95% CI)	‐0.38 [‐1.70, 0.93]
19.2 ICU	3	259	Mean Difference (IV, Random, 95% CI)	‐0.21 [‐1.30, 0.89]
20 Hospital length of stay ‐ by baseline PaCO₂ Show forest plot	11	1714	Mean Difference (IV, Random, 95% CI)	‐0.30 [‐1.21, 0.61]

20.1 PaCO2 <= 45mmHg	5	397	Mean Difference (IV, Random, 95% CI)	‐1.18 [‐2.33, ‐0.04]
20.2 PaCO2 > 45mmHg	6	1317	Mean Difference (IV, Random, 95% CI)	0.60 [‐0.15, 1.34]
21 ICU LENGTH OF STAY Show forest plot	6		Mean Difference (IV, Random, 95% CI)	Totals not selected

22 SYSTOLIC BP AFTER ONE HOUR Show forest plot	7	1408	Mean Difference (IV, Random, 95% CI)	‐1.72 [‐5.03, 1.58]

23 Systolic BP after one hour ‐ by NPPV Show forest plot	7	1408	Mean Difference (IV, Random, 95% CI)	‐1.72 [‐5.03, 1.59]

23.1 CPAP vs SMC	7	866	Mean Difference (IV, Random, 95% CI)	‐1.65 [‐5.58, 2.28]
23.2 bilevel NPPV vs SMC	3	542	Mean Difference (IV, Random, 95% CI)	‐1.89 [‐8.01, 4.23]
24 DIASTOLIC BP AFTER ONE HOUR Show forest plot	6	1361	Mean Difference (IV, Random, 95% CI)	1.46 [‐1.86, 4.78]

25 Diastolic BP after one hour ‐ by NPPV Show forest plot	6	1361	Mean Difference (IV, Random, 95% CI)	1.05 [‐2.15, 4.25]

25.1 CPAP vs SMC	6	823	Mean Difference (IV, Random, 95% CI)	0.92 [‐3.92, 5.75]
25.2 bilevel NPPV vs SMC	3	538	Mean Difference (IV, Random, 95% CI)	1.08 [‐2.88, 5.04]
26 MEAN BP AFTER ONE HOUR Show forest plot	3	251	Mean Difference (IV, Random, 95% CI)	‐2.50 [‐8.29, 3.30]

27 RESPIRATORY RATE AFTER ONE HOUR Show forest plot	10	1636	Mean Difference (IV, Random, 95% CI)	‐1.87 [‐2.70, ‐1.03]

28 Respiratory rate after one hour ‐ by NPPV Show forest plot	10	1636	Mean Difference (IV, Random, 95% CI)	‐1.58 [‐2.22, ‐0.94]

28.1 CPAP vs SMC	10	1107	Mean Difference (IV, Random, 95% CI)	‐1.64 [‐2.41, ‐0.87]
28.2 bilevel NPPV vs SMC	3	529	Mean Difference (IV, Random, 95% CI)	‐2.17 [‐4.69, 0.35]
29 PaO₂ (mmHg) AFTER ONE HOUR Show forest plot	10	1428	Mean Difference (IV, Random, 95% CI)	16.19 [3.54, 28.84]

30 PaO₂ (mmHg) after one hour ‐ by NPPV Show forest plot	10	1428	Mean Difference (IV, Random, 95% CI)	13.74 [2.72, 24.76]

30.1 CPAP vs SMC	8	761	Mean Difference (IV, Random, 95% CI)	9.55 [‐9.10, 28.19]
30.2 bilevel NPPV vs SMC	6	667	Mean Difference (IV, Random, 95% CI)	19.50 [4.29, 34.71]
31 ADVERSE EVENTS Show forest plot	11	9570	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.73, 1.50]

31.1 Skin damage	2	190	Risk Ratio (M‐H, Random, 95% CI)	9.09 [0.74, 111.09]
31.2 Pneumonia	1	130	Risk Ratio (M‐H, Random, 95% CI)	0.5 [0.05, 5.38]
31.3 Gastrointestinal bleeding	2	170	Risk Ratio (M‐H, Random, 95% CI)	2.32 [0.35, 15.42]
31.4 Gastric distention	1	83	Risk Ratio (M‐H, Random, 95% CI)	13.26 [0.82, 215.12]
31.5 Vomiting	5	1467	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.49, 2.17]
31.6 Pneumothorax	2	1165	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.08, 6.89]
31.7 Sinusitis	1	130	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.12, 72.31]
31.8 Discomfort with mask	3	1100	Risk Ratio (M‐H, Random, 95% CI)	12.59 [2.39, 66.28]
31.9 Hypotension	1	1030	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.58, 1.16]
31.10 Arrhythmia	1	1027	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.50, 1.38]
31.11 Cardiorespiratory arrest	4	1352	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.34, 1.05]
31.12 Gastric aspiration	1	1037	Risk Ratio (M‐H, Random, 95% CI)	1.58 [0.06, 38.61]
31.13 Stroke	1	130	Risk Ratio (M‐H, Random, 95% CI)	0.2 [0.01, 4.09]
31.14 Seizures	1	130	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 8.03]
31.15 Claustrophobia	1	130	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.12, 72.31]
31.16 Hypercapnia	3	299	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.16, 3.62]

Comparison 1. NPPV vs SMC

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