Effect of intrapulmonary percussive ventilation on intensive care unit length of stay, the incidence of pneumonia and gas exchange in critically ill patients: A systematic review

Anwar Hassan; William Lai; Jennifer Alison; Stephen Huang; Maree Milross

doi:10.1371/journal.pone.0255005

. 2021 Jul 28;16(7):e0255005. doi: 10.1371/journal.pone.0255005

Effect of intrapulmonary percussive ventilation on intensive care unit length of stay, the incidence of pneumonia and gas exchange in critically ill patients: A systematic review

Anwar Hassan ^1,^2,^*, William Lai ¹, Jennifer Alison ², Stephen Huang ^1,², Maree Milross ²

Editor: Shane Patman³

PMCID: PMC8318278 PMID: 34320018

Abstract

Background

Pulmonary complications such as pneumonia, pulmonary atelectasis, and subsequent respiratory failure leading to ventilatory support are a common occurrence in critically ill patients. Intrapulmonary percussive ventilation (IPV) is used to improve gas exchange and promote airway clearance in these patients. The current evidence regarding the effectiveness of intrapulmonary percussive ventilation in critical care settings remains unclear. This systematic review aims to summarise the evidence of the effectiveness of intrapulmonary percussive ventilation on intensive care unit length of stay (ICU-LOS) and respiratory outcomes in critically ill patients.

Research question

In critically ill patients, is intrapulmonary percussive ventilation effective in improving respiratory outcomes and reducing intensive care unit length of stay.

Methods

A systematic search of intrapulmonary percussive ventilation in intensive care unit (ICU) was performed on five databases from 1979 to 2021. Studies were considered for inclusion if they evaluated the effectiveness of IPV in patients aged ≥16 years receiving invasive or non-invasive ventilation or breathing spontaneously in critical care or high dependency units. Study titles and abstracts were screened, followed by data extraction by a full-text review. Due to a small number of studies and observed heterogeneities in the study methodology and patient population, a meta-analysis could not be included in this review. Outcomes of interest were summarised narratively.

Results

Out of 306 identified abstracts, seven studies (630 patients) met the eligibility criteria. Results of the included studies provide weak evidence to support the effectiveness of intrapulmonary percussive ventilation in reducing ICU-LOS, improving gas exchange, and reducing respiratory rate.

Interpretation

Based on the findings of this review, the evidence to support the role of IPV in reducing ICU-LOS, improving gas exchange, and reducing respiratory rate is weak. The therapeutic value of IPV in airway clearance, preventing pneumonia, and treating pulmonary atelectasis requires further investigation.

Introduction

The incidence of pulmonary complications such as pulmonary atelectasis, pneumonia (including ventilator-associated pneumonia), and acute respiratory failure is high in critical care patients [1, 2]. The incidence of ventilator-associated pneumonia can be as high as 27% amongst mechanically ventilated patients [3]. Studies have shown that 16% of critically ill patients have been reported to develop acute respiratory failure, which is associated with prolonged intensive care unit stay, resulting in significantly higher mortality than non-respiratory failure patients [2, 4–7]. Increased morbidity and mortality contribute to the burden on the health care system and lead to poor health-related outcomes [6–8]. Multimodal physiotherapy plays a role in the management of these critically ill patients [9]. Chest physiotherapy (CPT) interventions such as chest percussion & vibrations, postural drainage, positioning, thoracic expansion exercises, manual hyperinflation, ventilator hyperinflation, and airway suctioning aim to promote airway secretion clearance, increase alveolar recruitment, minimise pulmonary shunting, and optimise ventilation and perfusion (V/Q) matching [10, 11]. In addition to these CPT interventions, intrapulmonary percussive ventilation (IPV) is used in patients with underlying pulmonary atelectasis, excessive airway secretions, and respiratory failure [12–15].

IPV is a non-continuous form of high-frequency ventilation delivered by a pneumatic device that provides small bursts of sub-physiological tidal breaths at a frequency of 60–600 cycles/minute superimposed on a patient’s breathing cycle [16–18]. The high-frequency breaths create shear forces causing dislodgement of the airway secretions. Furthermore, the IPV breath cycle has an asymmetrical flow pattern characterised by larger expiratory flow rates, which may propel the airway secretions towards the central airway [18]. In addition, the applied positive pressure recruits the lung units, resulting in a more homogeneous distribution of ventilation and improved gas exchange [19]. In acute care and critical care settings, IPV intervention is used in a range of patients, from spontaneously breathing patients to those receiving invasive mechanical ventilation where IPV breaths can be superimposed on a patient’s breathing cycle or superimposed on breaths delivered by a mechanical ventilator. The most common indications for IPV use are reported as removal of excessive bronchial secretions, improving gas exchange, and recruitment of atelectatic lung segments [12–14, 18]. In the last two decades, studies have reported IPV in the critical care setting to be effective in improving outcomes in patients with an acute exacerbation of chronic obstructive pulmonary disease (COPD), burns, pulmonary atelectasis, and those with post-abdominal or thoracic surgery [14, 15, 20, 21]. Despite the available studies, the overall evidence regarding its effectiveness in critical care settings remains unclear. Recently, Reychler and colleagues (2018) [22] summarised the effectiveness of IPV in promoting airway clearance and gas exchange in chronic lung diseases such as COPD, cystic fibrosis, and bronchiectasis. The question regarding the role of IPV in preventing or reversing atelectasis and reducing the incidence of pneumonia in critically ill patients remains unanswered. Most of the studies reviewed by Reychler and colleagues (2018) included stable patients; hence the findings of their review are not applicable to critically ill patients [22]. The objective of this systematic review was to summarise the evidence for the effectiveness of IPV in improving outcomes such as intensive care unit length of stay (ICU-LOS), gas exchange, respiratory rate, the incidence of pneumonia, and reversing or preventing atelectasis in critical care patients.

Methods

This systematic review followed recommendations from the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) [23]. The review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) before conducting the database search (Registration ID: CRD42018115517).

Search strategy

A systematic search of the literature was conducted in two stages. The first stage included database searches on MEDLINE, EMBASE, CINAHL, Web of Science, and PEDro, from 1979 (when IPV was first introduced) to February 2021. The details of the search strategy and keywords used are presented in S1 Table. The second stage included searching the relevant clinical trial registries (including ClinicalTrials.gov, ANZCTR, WHO, EUCTR, ATS, PROSPERO). A manual search of the reference lists of the included studies was also conducted.

Inclusion and exclusion criteria

Studies were considered for inclusion if they evaluated the effectiveness of IPV in patients aged ≥16 years receiving invasive or non-invasive ventilation (NIV) or breathing spontaneously in critical care units for acute or acute on chronic impairment of respiratory function. Studies that included stable patients in the inpatient, outpatient, or community-based settings were excluded.

Due to the limited number of studies, randomised controlled trials (RCT), quasi-randomised trials, randomised crossover studies, observational studies, comparative studies, experimental designs with random allocation, and retrospective studies were all considered. Studies that reported the effects of IPV, high-frequency ventilation, and high-frequency oscillation where these interventions were primarily used intermittently for a short duration to promote airway clearance, reverse, or treat pulmonary atelectasis, or to improve gas exchange were included, whereas the studies that used these interventions to provide continuous mechanical ventilation were excluded.

Studies that measured ICU-LOS and examined the physiological variables such as changes in the saturation of peripheral oxygen (SpO₂) and partial pressure of arterial oxygen (PaO₂), partial pressure of arterial carbon dioxide (PaCO₂) measured by arterial blood gas analysis and airway clearance were included. Other reported outcomes, such as pulmonary atelectasis and respiratory rate, were also included.

Study review and data extraction

Duplicates were removed using Covidence® software, followed by a manual search for duplicates. The remaining articles were screened independently by two authors (AH and WL) by reviewing the study titles and abstracts (inter-rater reliability, Kappa 0.84). Authors of the eligible studies with published abstracts only or papers with missing or insufficient data were contacted via email for the full-text article or raw data; the study was excluded if no response was obtained within four weeks. A full-text review was conducted by two authors (AH and WL), and ineligible studies were excluded (Fig 1). In case of disagreement, a third reviewer (MM) independently reviewed the study. Included studies were then used for data extraction and quality assessment for the risk of bias.

Assessment of quality and risk of bias

The quality and risk of bias for the studies that used random allocation were assessed according to the Cochrane Collaboration assessment tool during the data extraction phase using the Covidence® software [24]. For the included literature, the following risk of bias domains was assessed: random sequence generation, allocation sequence concealment, blinding of participants, blinding of the therapist, blinding of outcome assessors, incomplete outcome data, selective outcome reporting, and overall risk of bias (Table 1). The level of risk of bias was assessed under three categories: 1) high, 2) low, and 3) unclear. In addition, the Physiotherapy Evidence Database (PEDro) scale was also used to assess and summarise the study quality for all the included studies (Table 2) [25]. The PEDro scale allows assessment on ten different domains to determine the study quality. Based on the total PEDro score, studies can be categorised into; “poor” (score 0–3), “fair” (score 4–5), “good” (score 6–8), and “excellent” (score 9–10). Overall, based on the Cochrane assessment tool, three out of four studies appear to have a low risk of bias whereas, in one study [26], the risk of bias was high. On the PEDro scale, the quality of the studies ranged from “poor” to “good.”

Table 1. Cochrane assessment of the risk of bias.

Study	Random sequence generation	Allocation concealment	Blinding of participants and personnel	Blinding of outcome assessors	Incomplete outcome data	Selective reporting	Other bias
Antonaglia et al. (2006) [13]	Low	Low	High	High	Low	Low	Low
Vargas et al. (2005) [15]	Low	Low	High	High	Unclear	Unclear	Low
Clini et al. (2006) [12]	Low	Low	High	Low	Low	Low	Low
Dimassi et al. (2011) [26]	Low	High	High	Unclear	Low	High	High

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Table 2. Quality assessment using PEDro scale [25].

Study	Eligibility criteria	Random allocation	Concealed allocation	Groups similar at baseline	Subject blinding	Therapist blinding	Assessor blinding	< 15% dropouts	Intention to treat analysis	Statistical comparison in groups	Measure of variability	Total score
Antonaglia 2006 [13]	Y	Y	Y	Y	N	N	N	N	N	Y	Y	5/10
Vargas 2005 [15]	Y	Y	Y	Y	N	N	N	Y	N	Y	Y	6/10
Huynh 2019 [21]	Y	N	N	N	N	N	N	Y	Y	Y	Y	4/10
Clini 2006 [12]	Y	Y	Y	Y	N	N	Y	Y	N	Y	Y	7/10
Dimassi 2011 [26]	Y	Y	N	Y	N	N	N	Y	N	Y	Y	5/10
Vargas 2009 [27]	Y	N	N	N	N	N	N	Y	N	N	Y	2/10
Tsuruta 2006 [14]	Y	N	N	N	Y	N	N	Y	N	N	Y	3/10

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Y = Yes, N = No. PEDro score (0–3 = poor, 4–5 = fair, 6–8 = good, 9–10 = excellent)

Outcome measures

The primary outcome of interest was ICU-LOS. Secondary outcomes included PaO₂, the ratio of the partial pressure of arterial oxygen and fraction of inspired oxygen (PaO₂/FiO₂), PaCO₂, airway clearance, the incidence of pneumonia, respiratory rate, and pulmonary atelectasis.

Due to the small number of studies and observed heterogeneities in the study methodology and patient population, all the outcomes were summarised narratively.

Results

The database search yielded a total of 306 studies. After removing 68 duplicates, the titles and abstracts were screened for 238 studies. After excluding 199 irrelevant studies, the remaining 39 full-text articles were assessed for their eligibility. The reviewers identified seven studies including 630 patients, which met the eligibility criteria for systematic review (Fig 1). The study characteristics are described in Table 3.

Table 3. Study summary.

Author (Year)	Study design, N	Population	Inclusion and exclusion criteria	Intervention(s)	Outcomes
Antonaglia et al. (2006) [13]	RCT	Admitted to ICU with an acute exacerbation of COPD	Inclusion	IPV group	Gas exchange
	N = 80		Admitted to ICU within 12 hrs of emergency department admission	Duration: 25 to 30 min (via mouthpiece) twice / day	After the 1^st IPV session:
	N = 80			IPV Setting: 225 cycles / min, P_AW < 40 cmH₂O	IPV: ↑ pH^, ↓ PaCO₂^, ↑ PaO₂/FiO₂^**
	IPV: 20	Age: 69.75±6.56 years	RR >25 breaths/min		At discharge:
		Gender: Not reported	PaCO₂ >50 mmHg	Control group	IPV: pH (NS), ↓ PaCO₂^, ↑ PaO₂/FiO₂^
			pH: 7.10–7.35	Standard medical care (NIV via facial mask)	Control: pH (NS), ↓ PaCO₂^, ↑ PaO₂/FiO₂^
	CPT: 20				Cardio-respiratory parameters
	CPT: 20			CPT group	After the 1^st session:
	Control: 40		Exclusion	Duration: 25 to 30 min CPT (chest clapping, mobilisation, and postural drainage, and expiration with the glottis open) twice / day	IPV: ↓ RR^*, ↓ HR^
			Need for emergency intubation		ICU-LOS (days)
			GCS < 8		IPV: 7 [6–8], Control:10 [9–11]^, CPT: 9 [7.7–9.5] ^
			Haemodynamic instability		IPV: 7 [6–8], Control:10 [9–11]^, CPT: 9 [7.7–9.5] ^
			Failure > two additional organs		Pneumonia
			Failure > two additional organs		IPV: 2, Control: 11(NS), CPT: 4(NS)
Vargas et al. (2005) [15]	RCT	Admitted to ICU with an acute exacerbation of COPD	Inclusion	IPV group	Gas exchange
	RCT		Inclusion	IPV group	IPV: ↑ PaO₂^, ↓ PaCO₂^
	N = 33		Admitted to ICU as an emergency with acute exacerbation of COPD	Duration: 30 min (via a face mask) twice / day	Control: Not reported
				IPV Setting: 80–650 cycles / min, P_AW: 5-35cmH₂O, I/E: 1/2.5.	Cardio-respiratory parameters
					IPV: ↓ RR^*, Control: Not reported
	IPV: 16	Age = 69.71±5.44 years	RR ≥ 25 breaths/min	IPV sessions were stopped when a RR of < 25/min and a pH > 7.38 was reached	ICU-LOS (days)
	IPV: 16	Age = 69.71±5.44 years	PaCO₂ > 45 mmHg		IPV: 6.8±1.0, Control: 7.9±1.3^*
	Control: 17	Gender: Not reported	pH: 7.35 to 7.38 on room air > 10 minutes	Same drug protocol as the control	Need for NIV
					IPV: (0) 0%, Control: (6) 35.3%^*

				Control group
			Exclusion	Standard medical care
			Need for emergency intubation	Supplemental oxygen to maintain SpO₂ of 88–92%
			GCS ≤ 8	HOB elevated at a 45-degree angle
			Haemodynamic instability	Drug protocol including nebulised bronchodilators and corticosteroids
			Failure > two additional organs
			Tracheostomy
			Pneumothorax
			Recent oral/oesophageal/gastric surgery

Dimassi et al. (2011) [26]	Randomised (crossover) to receive IPV or NIV	ICU patients at risk of post-extubation failure	Inclusion	IPV group	Gas exchange
		ICU patients at risk of post-extubation failure	Intubation > 48 hours, who tolerated SBT plus at least 2 of the following:	Duration: 20 min (via a face mask)	IPV: PaCO₂ (NS), PaO₂/FiO₂ (NS)
		Age: 73 [58–75] years		IPV Setting: 250 cycles / min, driving pressure: 1.2 bar, I/E: 1 / 2.5	Control: ↓PaCO₂^**, PaO₂/FiO₂ (NS)
					Cardio-respiratory parameters
					IPV: ↓RR^, Control: ↓RR^
			Age > 65 years	Control group	Diaphragmatic work (PTPdi/breath)
			Age > 65 years	Control group	IPV: ↓20%, Control: ↓35% (NS)
		Gender: M 14, F 3	Underlying heart or respiratory failure, and	NIV
	N = 17		APACHE II score > 12	NIV Settings: Delivered via ventilator in pressure-support mode with PEEP. Tidal volume target 6-8ml/kg, PEEP 4–5 cmH₂O
	N = 17		Exclusion
	IPV: 8		Tracheostomy
	NIV: 9		Facial or cranial trauma or surgery
			Recent gastric/oesophageal surgery
			Active UGI bleeding
			Lack of cooperation
			Limit of therapy in ICU
Clini et al. (2006) [12]	RCT	Tracheostomised patients randomised to two treatment groups	Inclusion	IPV group	Gas exchange
			Mechanically ventilated ≥ 14 days	IPV + CPT	IPV group vs. Control group during the treatment period: ↓ pH (NS), ↑ PaO₂ (NS), ↑ PaO₂/FiO₂^*,
			Passed the SBT for at least 72 hours	Duration: 10 min (via tracheostomy tube) twice / day
			Passed the SBT for at least 72 hours	Duration: 10 min (via tracheostomy tube) twice / day	↓ PaCO₂ (NS)
	N = 46		Stable, conscious and able to adhere to active physiotherapy treatment	IPV Setting: 200–300 cycles / min	Cardiorespiratory parameters
		Age: 68.96±9.06 years		P_AW: 40 cm H₂O, I/E: 1:1.2	IPV group vs. Control group during the treatment period: ↑ MEP^*
		Age: 68.96±9.06 years	Sputum > 40ml/day
	IPV: 24	Gender: M 28, F 18	Exclusion	Control group	Pneumonia
	CPT: 22			CPT for one hour, twice / day	Day 5: IPV: 3, CPT: 5^*
				CPT for one hour, twice / day	One month: IPV: 0, CPT:2^*
			Persistent alterations of the sensorium
			Haemodynamic/respiratory instability
			Reconnection to ventilator < 72 hours
			On continuous sedatives and vasopressors
Huynh et al. (2019) [21]	Multicentre prospective observational study	Post-thoracic, upper abdominal and aortic surgery patients admitted to ICU	Inclusion	IPV group	Gas exchange Not measured
			Age ≥ 18 years post thoracic, upper abdominal and aortic surgery in addition to ICU	Received IPV in addition to standard care	Cardiorespiratory parameters Not measured
				Duration: 10 min per session	ICU-LOS (days)
			ASA class ≥ 3 OR 1 and 2 with one or more of the following: current smoker, COPD, BMI ≥ 30, age > 75 years	IPV for intubated patients six times / day	IPV: 3.4±3.5, CPT 5.4±8.7 (NS)
				non-intubated patients 4 times / day	Time on mechanical ventilation (hours)
	N = 419	Age: 59.25±14.73 years		IPV setting: 170–230 cycles / min	IPV: 29.7±44.8 to 94.1±199.2^*
		Age: 59.25±14.73 years			Pneumonia: 3 (1.4%) in both groups
		Gender: M 246, F 173

	IPV: 209		Exclusion	Control group	Hospital LOS (days)
	CPT: 210			Control group	IPV: 6.78±4.5, Control: 8.4±7.9^*
				Standard care including incentive spirometer Additional respiratory treatment was provided based on clinical indication
			Contraindication to positive pressure therapy; untreated tension pneumothorax, organ transplant, spinal surgery, and positive pressure ventilation at baseline
Tsuruta et al. (2006) [14]	Prospective observational study	Mechanically ventilated patients with compression atelectasis	Inclusion	IPV group	Gas exchange
			Acute respiratory failure due to compression atelectasis unresolved by conventional mechanical ventilation	IPV delivered via in-line ventilator circuit	Pre IPV compared to 24h post IPV
				Duration and frequency: Not reported	PaO₂/FiO₂ 189±63 to 280±55^**
				Setting: 300 cycles / min	PaCO₂: 38 to 37 (NS)
	N = 10	Age: 52±19 years			Cardiorespiratory parameters
			BMI > 25		HR (NS)
					Improvement of atelectasis
					Seven improved on chest CT scans
	IPV: 10	Gender: M 8, F 2	Exclusion		Ten improved on chest radiographs
	IPV: 10	BMI: 31±6	Infiltrations induced by infection and drugs
	Control: not assigned

Vargas et al. (2009) [27]	Prospective observational study	COPD patients with expiratory flow limitation were screened following extubation	Inclusion	IPV group	Gas exchange
			Diagnosis of COPD deemed stable 1 hour after extubation with:	Duration: 30 min (via a full-face mask)	↑ pH^, ↑ PaO₂^, ↓ PaCO₂^, ↑ SpO₂^
					Cardio-respiratory parameters
					HR (NS), ↓ RR^*
				IPV Setting: 250 cycles / min	Expiratory flow limitation: ↓ 31%^*
			RR < 30/min	P_AW: 20 cmH₂O, I/E: 1/2.5	Airway occlusion pressure: ↓ 28%^*
			Lack of respiratory acidosis with a pH > 7.35	Supplemental oxygen was interfaced into the mask to maintain SpO₂ 88–92%

	N = 25	Age: 63±8 years	Exclusion
		Gender: M 15, F 10	Need for emergency intubation
		Gender: M 15, F 10	GCS ≤ 8
	IPV: 25	BMI: 26±3	Hemodynamic instability
	Control: not assigned		Failure > two additional organs
			Tracheostomy
			Pneumothorax
			Recent oral/oesophageal/gastric surgery or facial deformity

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RCT = randomised controlled trial, IPV = intrapulmonary percussive ventilation, COPD = chronic obstructive pulmonary disease, CPT = chest physiotherapy, SBT = spontaneous breathing trial, RR = respiratory rate, HR = heart rate, MAP = mean arterial pressure, P_AW = airway pressure, MEP = maximal expiratory pressure, HOB = head of bed, I:E = inspiratory to expiratory cycle ratio, APACHE II = acute physiology and chronic health evaluation II, PPC = postoperative pulmonary complication, UGI = upper gastrointestinal, NIV = non-invasive ventilation, PTPdi = diaphragmatic pressure-time product, V_T = tidal volume, MEP = maximal expiratory pressure, ASA = American society of Anaesthesiologists, BMI = body mass index, NS = not significant,

* = statistically significant p ≤ 0.05,

** = statistically significant p ≤ 0.01

Study characteristics

Among the included studies, four studies were RCTs, one was a quasi-RCT with a historical control group, and the remaining two were prospective observational studies. The observational studies did not assign a control group for comparison [14, 27]. Study sample sizes ranged from 10 patients to 419 patients [14, 21] (Table 3). All the studies were conducted in the critical care setting, which included patients who were mechanically ventilated (34%), post-extubation (6%), requiring NIV (18%), and the remaining (42%) were requiring high oxygen therapy (FiO₂ ≥ 40%) and continuous positive airway pressure support.

Patient characteristics

Patient’s ages ranged from 18 to 95 years (mean age 63.7 years), with 60% males. One study did not report the mean age [26]. Common clinical conditions were post thoracic, aortic, or abdominal surgeries [21], acute respiratory failure secondary to COPD [13, 15, 27], post-extubation respiratory failure [26], pulmonary atelectasis [14], and tracheostomised patients with impaired respiratory function [12] (Table 3).

Intervention

In the included studies, the most common indications to use IPV interventions were to improve gas exchange, promote airway clearance and prevent or reverse pulmonary atelectasis. The treatment application varied among the studies. In most studies, IPV was delivered via a facemask or mouthpiece, whereas for those who were mechanically ventilated, IPV was delivered via an in-line ventilator circuit [14, 21] (Percussionaire Corporation, Sandpoint, ID, USA), and Metaneb^® (Hill-ROM corporation, USA). All these devices work on the same mechanical principles and use phasitron to deliver similar breath frequency (200 to 300 cycles/minute) and airway pressures (Table 3). The treatment dosage, such as duration and frequency of sessions per day, varied across the studies. For instance, the duration of a single treatment session ranged from 10 to 30 minutes, and the number of sessions ranged from a single session a day to up to six sessions a day [21]. The frequency of delivered breaths remained between 200 to 300 cycles per minute in all the included studies, whereas the airway pressure varied from 5 to 35 cmH₂O (Table 3). Notably, most of the studies did not specify the patient’s position during the treatment. IPV intervention was compared to CPT [12, 13, 21] which was reported as being used to promote airway clearance, improve gas exchange, and increase or restore lung volume. CPT included chest clapping, postural drainage, expiration with open glottis, incentive spirometer and mobilisation (Table 3). Duration of CPT session ranged from 30 minutes to 60 minutes once or twice a day. In two studies [15, 26], the control group received standard medical treatment, which included oxygen therapy, non-invasive ventilation, sitting up in bed (45 degrees), nebulised bronchodilators, and corticosteroids (Table 3).

Outcome measures

The common outcomes reported were ICU-LOS, the incidence of pneumonia, changes in PaO₂, PaO₂/FiO₂, PaCO₂, and respiratory rate. Less commonly, studies also recorded the incidence of pulmonary atelectasis, changes in diaphragmatic work, duration of mechanical ventilation, need for NIV, hospital length of stay, and mortality. Some of these physiological outcomes (PaO₂, PaO₂/FiO₂, PaCO₂ and respiratory rate) were recorded daily before and after the intervention and also at the time of discharge, whereas one study recorded these outcomes at five-day intervals for up to 15 days [12].

ICU length of stay

Among the included studies, three studies reported on ICU-LOS [13, 15, 21]. Antonaglia and colleagues (2006) [13] randomly allocated 40 critically ill patients with an acute exacerbation of COPD to the IPV group (n = 20) or CPT group (n = 20), where patients in both the groups were treated with NIV. In addition to NIV, patients in the CPT group received standard chest physiotherapy for 25–30 minutes, and those in the intervention group received 25–30 minutes of IPV twice a day (Table 3). Antonaglia et al. (2006) also included a historical control group (n = 40) for comparison that received standard medical treatment. A significantly shorter ICU-LOS in the IPV group (median = 7 [6, 8] days) than the control group was reported (median = 10 [9, 11] days), median difference -2.0 days (95% CI: -2.19; -1.81 days, p < 0.01). Similarly, a multicentre study by Huynh et al. (2019) [21] evaluated the effect of IPV in 419 postoperative (upper abdominal, aortic, and thoracic surgery) patients admitted to ICU, where the intervention group (n = 209) received IPV for 10 minutes four to six times a day, and the historical control group (n = 210) received CPT mainly in the form of incentive spirometry. Out of 419 patients, the ICU-LOS was reported only for 161 patients (Intervention = 79, Control = 82) where the ICU-LOS was found to be shorter but not statistically significant in the IPV group (IPV: mean 3.3 [3.5] days vs. Control: mean 5.4 [8.7] days, NS). Another study by Vargas et al. (2005) investigated the effects of IPV intervention in 33 patients with COPD with acute respiratory failure where the intervention group (n = 17) received IPV for 30 minutes twice a day, and the control group (n = 16) received standard medical treatment (Table 3). The study reported a significant reduction in length of stay in the IPV group compared to the control group (IPV: mean 6.8 [1.0] days vs. Control: 7.9 [1.3] days, p < 0.05) [15].

Incidence of pneumonia

Among the included studies, the incidence of pneumonia was reported by three studies [12, 13, 21]. Antonaglia et al. (2006) reported a small difference in the incidence of pneumonia in 40 patients with acute exacerbation of COPD (IPV: 2 vs. CPT: 4, NS) [13]. Similarly, Huynh et al. (2019) did not find any difference in the incidence of pneumonia in 419 patients with upper abdominal and thoracic surgery patients (IPV: 3 vs. CPT: 3, NS) [21]. However, one study reported a significant reduction in the incidence of pneumonia in tracheostomised patients treated with IPV (IPV: 3 vs. CPT: 5, p < 0.05) [12].

Gas exchange

a) PaO₂ and PaO₂/ FiO₂ ratio. Six studies (n = 211) reported an increase in oxygenation in the IPV group [12–15, 26, 27]. The increase in oxygenation was recorded as a change from baseline to post-intervention, as PaO₂ and or the PaO₂/ FiO₂ ratio.

Antonaglia et al. (2006) reported a significant change in PaO₂/ FiO₂ ratio from admission to discharge (seven days) in patients with COPD admitted to ICU (IPV: 173 [27] to 274 [15], Control: 181 [29] to 237 [20], p < 0.01) [13]. Similarly, Clini et al. (2006) also reported an improvement in PaO₂/FiO₂ ratio in 46 patients with tracheostomy randomised to receive either CPT or IPV in addition to CPT, after 15 days of intervention (IPV: 238 [51] to 289 [52], Control: 240 [34] to 255 [38], p < 0.05), median difference 21.65 (95% CI: -11.75 to– 55.05, p < 0.038) [12]. Similarly, Vargas et al. (2005) found a significant increase in PaO₂ in patients with COPD who received IPV intervention (56.9 [3] to 61 [0.8] mmHg, p < 0.05) [15]. These findings of increased oxygenation (PaO₂/FiO₂ ratio and PaO₂) in the IPV group were consistent with the findings of two observational studies [14, 27]. In contrast, one small study of 17 post-extubation patients, who received IPV intervention and NIV in random order, reported no significant change in the PaO₂/FiO₂ ratio [26].

b) Change in PaCO₂. A total of six studies evaluated a change in the PaCO₂ levels [12–15, 26, 27]. Antonaglia et al. (2006) recorded a significant reduction in PaCO₂ levels in patients with COPD in IPV and CPT group (IPV: 79 [7] to 58 [5.4], Control: 80 [6.5] to 64 [5.2] mmHg, p < 0.01) [13]. Similar findings were reported by Vargas et al. (2005), where a significant reduction in the PaCO₂ levels was seen in the IPV group (IPV: 57.6 [4.5] to 53.5 [2.3] mmHg, p < 0.05) [15]. The study did not report any data for the control group for comparison. In another small study by Vargas and colleagues (2009) in 25 patients (with no control group) with acute exacerbation of COPD found a reduction in PaCO₂ (IPV: 55.1 [3.7] to 52.5 [2.2] mmHg, p < 0.05) [27]. A small (not significant) reduction in PaCO₂ levels was also reported by Clini et al. (2006) in the IPV group without any change in the control group [12].

Respiratory rate

Among the included studies, four studies evaluated the effects of IPV intervention on a patient’s respiratory rate (RR) [13, 15, 26, 27]. Vargas and colleagues (2005) found a significant reduction in RR in COPD patients in the IPV group (36 [2] to 31 [2] breaths per minute, p < 0.05) with no change in the control group [15]. In another study in 25 COPD patients, Vargas et al. (2009) reported a small reduction in RR (IPV: 22.6 [2.3] to 21.4 [1.7] breaths per minute, p < 0.05) [27]. Similarly, a small but significant reduction in respiratory rate was observed by Dimassi et al. (2011) in 17 post-extubation patients (23, [19–27] to 22, [17–24] breaths per minute, p < 0.01) [26]. In contrast, reports from Antonaglia et al. (2006) study did not demonstrate any significant change in RR [13]. Overall, three out of four studies reported a small but significant reduction in respiratory rate post IPV intervention. This small change in RR does not seem to be clinically relevant.

Airway clearance

Three studies in this review reported an observed increase in airway clearance with IPV intervention; however, none of them measured the expectorated sputum weight (wet or dry) [12, 13, 15] or other measures of mucous clearance.

Adverse events and tolerance

None of the studies reported any major adverse events related to IPV intervention [12–14, 21, 26]. Vargas et al. (2005) reported a single incidence of haemoptysis in one patient, unrelated to IPV intervention [15]. One study did not report on adverse events [27]. Four studies [12, 13, 15, 26], based on their observational findings, stated that the IPV intervention was well-tolerated; none of the studies asked specific questions pertaining to IPV tolerance. A recent multicentre study found one minor episode of IPV intolerance, which resolved quickly, and therapy was resumed 8 hours later [21].

Discussion

This systematic review synthesised the evidence of the effectiveness of IPV intervention in critical care patients. The findings of this review provide weak evidence to support the effectiveness of IPV intervention in reducing ICU-LOS, improving gas exchange, and reducing the respiratory rate in critically ill patients compared to chest physiotherapy techniques or standard medical management. Similar findings in patients with chronic lung disease have been reported in another systematic review, including 12 studies (278 patients) in patients with acute exacerbation of COPD, cystic fibrosis and bronchiectasis in a range of clinical settings [22]. This review by Reychler et al. (2018) found that the use of IPV intervention in patients hospitalised with an acute exacerbation of COPD (n = 178) improved gas exchange (PaO₂ and PaCO₂) compared to various respiratory physiotherapy techniques and might reduce hospital LOS. Our systematic review is the first one to summarise the effectiveness of IPV intervention in the critical care population. The findings of our systematic review should be viewed with caution since there were various methodological (study design, outcome measures), clinical (patient population and application of IPV), and statistical (small sample size and lack of control group) heterogeneities observed. In addition, the interventions received by the comparator groups among the included studies also varied from “usual chest physiotherapy” [12] or “standard respiratory physiotherapy” [13] to “standard treatment,” which only included medical management [15].

Studies that measured the effect of IPV on length of stay demonstrated some beneficial effects, where the median ICU-LOS appeared to be shortened by 1 to 2 days in the IPV group. However, significant heterogeneity was observed among the studies that reported on ICU-LOS. Two studies (Vargas et al. 2005 and Antonaglia et al. 2006) included patients with acute exacerbation of COPD whereas, Huynh et al. (2019) included upper abdominal and thoracic surgery patients. Huynh et al. (2019) did not find a significant reduction in ICU-LOS but reported a significant reduction in hospital LOS in the IPV group (IPV: 6.78 [4.98] vs. CPT: 8.40 [7.9] days p < 0.02). This outcome of hospital LOS, however, should be interpreted with caution as the non-randomised study design and the treatment frequency in the IPV group may introduce some bias. The duration and frequency of IPV intervention also varied among the included studies. A meta-analysis was performed, but due to the small number of studies and observed heterogeneity, it was not included in the main body of this review. Interestingly, the pooling of ICU-LOS data revealed that the magnitude and direction of the effect of IPV in reducing the ICU-LOS were similar in all three studies (S1 File).

Studies have reported that IPV improves gas exchange (PaO_2, PaO₂/FiO₂ ratio, and PaCO₂) in ventilated and non-ventilated patients [13, 14]. In this review, five out of six studies reported an improvement in gas exchange post IPV intervention [12–15, 27]. Notably, the time points of this outcome measurement varied among the studies; for example, Antonaglia et al. (2006) measured PaO₂ immediately prior to, and 30 minutes following the first IPV session and also at the time of discharge from ICU, whereas Tsuruta and colleagues (2006) recorded changes in PaO₂ at 3 hours interval for up to 24 hours [13, 14]. In contrast, Clini et al. (2006) measured the PaO₂ and PaO₂/FiO₂ ratio at five days intervals [12]. Despite lack of consistency across the studies, an improvement in oxygenation post IPV session(s) was found by the majority of the included studies. Short-term improvement in oxygenation could be attributed to the oxygen source which is used to drive the IPV device. Two studies reported the washout or stabilisation time prior to measuring oxygen levels [12, 13], whereas the time of measurement of oxygen levels in relation to IPV was not clear in other studies. Further, increases seen in oxygenation can be driven by the applied positive pressure, which may facilitate gas exchange by increasing overall functional residual capacity [28]. Also, positive pressure has been found to unload respiratory muscles, which subsequently reduces the oxygen cost of breathing, as demonstrated by Dimassi and colleagues (2011) [26], where the application of IPV led to a 20% reduction in diaphragm loading in post-extubation respiratory failure patients. In addition to these benefits, IPV can also augment oxygenation by promoting airway clearance. Some authors hypothesised that the improvement in oxygenation could, in part, be due to improved airway clearance post IPV intervention [20, 22]. In this review, three studies reported an observed increase in airway clearance with IPV intervention [12, 13, 15].

In addition to improved oxygenation, improved pulmonary ventilation has also been shown to reduce PaCO₂ levels in patients with COPD [29, 30] when treated with IPV. The applied positive pressure by IPV reduces the airway obstruction and thereby increases the expiratory flow in patients with airflow limitation secondary to COPD [29, 30]. A study in 25 patients with COPD demonstrated an increase in expiratory flow rate after IPV intervention (27). Studies also noted reduced PaCO₂ levels after application of IPV intervention in patients with COPD and patients with tracheostomy [12–15, 26]. Based on the available evidence, it appears that IPV may have a role in reducing PaCO₂ in hypercapnic respiratory failure patients.

The incidence of pneumonia in critically ill patients is well documented [3, 10, 31]. While there is some evidence that IPV may be effective as an airway clearance modality [18], its role in reducing or preventing the incidence of pneumonia in critically ill patients remains poorly studied. In this review, out of three studies [12, 13, 21], only one reported a significant reduction in the incidence of pneumonia in the IPV group compared to the CPT group [12]. Surprisingly, the number of cases of pneumonia in all the included studies was very small in both the IPV and control groups. Although statistically significant, this small reduction in the incidence of pneumonia does not appear to be clinically meaningful. Evidence does not currently support the use of IPV to prevent or treat pneumonia in critically ill patients (S1 File). Further research is needed to evaluate the role of IPV in reducing the incidence of pneumonia. Similarly, despite airway clearance being one of the main indications of IPV intervention, only three studies reported an observed increase in secretion clearance. Surprisingly, none of these studies measured sputum yield [12, 13, 15]. Difficulties with accurate measurement of sputum yield have been well documented [32]. Due to the lack of data regarding airway clearance in the included studies, the role of IPV in airway clearance remains unclear.

Clinicians have been using IPV to improve lung volumes by recruiting partially or fully collapsed lung units [29, 30]. Despite this, the effect of IPV intervention in preventing or treating pulmonary atelectasis in acutely ill patients remains poorly researched. One reason may be that measuring the changes in pulmonary atelectasis can be challenging and expensive in a clinical setting. Deakins and Chatburn (2002) [33] used series of chest x-rays in paediatric patients, whereas Tsuruta and colleagues (2006) used chest x-rays and computed tomography scans [14]. Huynh et al. (2019) reported a significant reduction in several postoperative pulmonary complications, including atelectasis; however, it is unclear how this was assessed. In our review, only one study reported a resolution in compression atelectasis in mechanically ventilated patients [14]. Due to the small sample size of this observational study, the current level of evidence remains inconclusive regarding the role of IPV in treating pulmonary atelectasis in critically ill patients.

The clinical benefit of an intervention can be influenced by several factors such as adverse effects, poor treatment tolerance and patient compliance. The studies included in this review found IPV intervention to be safe. None of the studies reported any serious adverse events related to IPV intervention. A recent report of 35 critical care patients found that the application of IPV was safe in a critical care setting [34]. Furthermore, most of the studies in this review also reported that the IPV intervention was well tolerated by patients. However, the studies did not incorporate a subjective measure of tolerance of IPV intervention; instead, this was inferred from observation and treatment completion rates. Only one study, in 17 patients at risk of extubation failure, performed a subjective evaluation of IPV tolerance using a five-point scale (“severe discomfort” = 1 to “very good level of comfort” = 5). An average score of 3 (“acceptable level of comfort”) was provided by 16 patients, whereas one patient found IPV to be very noisy [26]. Further studies are required that incorporate a subjective evaluation of the patient’s experience with IPV intervention in critical care.

Limitation

This systematic review has some limitations. The number of studies retrieved was small. While there is a chance that we were unable to find all the relevant studies, we minimised this by searching five databases and six trial registries for the last 40 years of publications. Heterogeneities resulting from differences in study design, patient population, dosage, and frequency of IPV intervention were frequently observed in the included studies. Further, small sample sizes and poor methodological quality introduces some bias and weakens the strength of conclusions of this review.

Conclusions

This systematic review is the first to summarise the evidence of the IPV intervention in patients admitted to critical care. The findings of this review provide weak evidence to support the use of IPV intervention in reducing ICU and hospital LOS, reducing respiratory rate, and improving gas exchange in critically ill patients. The therapeutic value of IPV in airway clearance and treating pulmonary atelectasis remains inconclusive, requiring further investigations. This review is based on a small number of available studies, mostly with small sample sizes. Hence, there is a need for more adequately powered randomised control trials to investigate the effectiveness of IPV intervention in improving outcomes such as ICU LOS, gas exchange, airway clearance, prevention or treatment of pneumonia and pulmonary atelectasis compared to routinely applied airway clearance and lung recruitment physiotherapy interventions in critical care population. In addition, there is also an indication for studies to evaluate patients’ experiences with IPV intervention and their preference compared to routinely practiced respiratory physiotherapy interventions in critical care settings.

Supporting information

S1 Checklist

(DOCX)

Click here for additional data file.^{(31.8KB, docx)}

S1 Table. Search strategy.

(DOCX)

Click here for additional data file.^{(15.5KB, docx)}

S1 File. Meta analysis.

(DOCX)

Click here for additional data file.^{(48.4MB, docx)}

S2 File. Search results titles and abstracts.

(XLSM)

Click here for additional data file.^{(183.3KB, xlsm)}

S3 File. Data extraction.

(XLSX)

Click here for additional data file.^{(57.5KB, xlsx)}

Acknowledgments

We would like to thank Ms. Kanchana Ekanayake, Academic Liaison Librarian, The University of Sydney, for her assistance with the database search.

Abbreviations

COPD: chronic obstructive pulmonary disease
CPT: chest physiotherapy
FiO₂: fraction of inspired oxygen
IPV: intrapulmonary percussive ventilation
ICU-LOS: intensive care unit length of stay
NIV: non-invasive ventilation
PaCO₂: partial pressure of arterial carbon dioxide
PaO₂: partial pressure of arterial oxygen
SpO₂: saturation of peripheral oxygen

Data Availability

The search results and results of data extraction for this systematic review are included in the Supporting Information files.

Funding Statement

The authors received no specific funding for this work.

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PLoS One. doi: 10.1371/journal.pone.0255005.r001

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Shane Patman

13 May 2021

PONE-D-21-11360

Effect of intrapulmonary percussive ventilation on intensive care unit length of stay, incidence of pneumonia and gas exchange in critically ill patients: a systematic review

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Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This manuscript reports a narrative review of reports on the effects of intrapulmonary percussive ventilation (IPV) applied to patients managed in intensive care units (ICU). Only 4 of the 7 included reports were randomised controlled trials; and only 2 studies achieved a PEDro score greater than 5; the overall risk of bias in these studies was moderate. The authors concluded “IPV may have a role in reducing ICU and hospital length of stay (LOS), reducing respiratory rate and improving gas exchange in critically ill adult patients.” (lines 539-541).

The methodology adopted for this systematic review is appropriate. However, it is my view that the clinical or therapeutic value of IPV was not sufficiently introduced and explained. The 7 studies included in this review compared IPV with ‘routine traditional chest physiotherapy’ or ‘standard medical care’, however I have two concerns with such comparisons and consider that the following points deserve discussion in the manuscript.

1- Routine traditional chest physiotherapy

Chest physiotherapy (CPT) is an old term which refers to a combination of secretion removal ‘techniques’. Furthermore, contemporary respiratory physiotherapy is no longer ‘routinely’ applied to patients. While the term CPT was the term used in the studies included in this review, the presentation of this current manuscript should reflect a clear understanding of the contemporary role of respiratory physiotherapy. Hence an analytical critique of the validity of using ‘CPT’ as a mechanical modality comparator should be included in the discussion.

2- Indications for and outcome measures of clinical intervention.

The effect of any intervention can only be appropriately reflected if the intervention employed follows relevant indications and is evaluated with appropriate outcome measures. The scientific value of a review will be improved if it includes discussion of the clinical implications of the reported ‘outcome measure(s)’. For example, is ‘reducing respiratory rate’ an expected positive outcome of IPV? If so, in what type of patients? The ‘Intervention’ subsection (lines 295-296) mentions that the “Most common indication to use IPV was to improve gas exchange, promote airway clearance and prevent or reverse pulmonary atelectasis”, but the only focused outcome measure reported in the studies reviewed was gas exchange. It should be noted that IPV is in fact a high frequency percussive ventilation mode and the ventilator is driven by an oxygen source, so it is not surprising that this intervention could result in a short duration of increased oxygenation. How then should a marginal improvement in oxygenation for a short duration after an intervention be interpreted? What are the clinical implications and clinical value of gas exchange improvement for a brief period after application of this mode of ventilation? I believe readers of this manuscript would expect a more thorough discussion of the clinical indications for ‘therapeutic’ IPV and how these indications could be met.

I would like to suggest:

1. The ‘Introduction’ section be strengthened by including a more detailed explanation of the proposed ‘therapeutic’ mechanism of IPV, and what IPV is supposed to achieve. For example, how might the ‘Birdian flow’ generated by IPV, facilitate lung expansion and secretion removal. Lines 139-144 state that “IPV is used in a range of patients…”. Please include the reasons and who recommended such use, and what were the reported ‘outcomes’ in patients with COPD, burns and thoracic surgery.

2. Include the discussion of the 2 concerns raised above.

3. The conclusion be reworded to: ‘the evidence to support IPV’s role in reducing ICU and hospital LOS, and improvement in gas exchange is weak. The therapeutic value of IPV in secretion removal and lung recruitment requires further investigation’.

Reviewer #2: Overall this is a well done systematic review.

There are few minor points to query

At 461 the reason for the improvement in oxygenation and PaCO2 is discussed. The reasons suggested are also facilitated by standard mechanical ventilation eg increase in FRC, unloading of diaphragm and also modalities such as NIV. Why would the modality of either IPV added to MV or used instead of NIV in a non ventilated patient have benefits?. There have been more specific or physiological reasons suggested which I think should be discussed in more depth.

486-487 – Grammar could be improved in this sentence

Reviewer #3: The authors have conducted a systematic review process on an interesting topic of IPV use in the critical care environment. While most of the methodology appears sound, there are some areas for clarification / improvement. Analysis of reported results appears to have mistakes or be incorrectly interpreted. Overall, this has led to the authors painting a positive slant on the findings, whereas the results appear more disparate and combined with the high risk of bias…..probably doesn’t reflect being able to report that it may reduce LOS, improve gas exchange and reduce RR.

Line 86: Out of 306 studies. Consider deleting or clarifying that 306 was number resultant from the search e.g. Out of 306 identified abstracts,

Line 81, 169. If an update of the search has been done to include up to 2021, this should be reflected here (rather than 2019)

Line 141. Consider deleting “few”.

Line 148, 151, 174-175. Consider better and consistent terms. :non-critically ill stable patients”. Maybe most studies were stable patients on ward rather than critical care settings. Avoid interchanging between critically ill and acutely ill.

Line 181. Therapeutic purposes. Continuous mechanical ventilation would be a therapeutic purpose. Consider another term to define the applications you were after e.g. its intermittent application for goals of airway clearance or lung recruitment.

Line 184-188. Some of these, but probably not all would have been of primary interest i.e. set primary & secondary outcomes; but some arisen from what was reported in the papers. Please clarify. You would have had a primary outcome measure/aim to determine, and also have the methods indicate you recorded outcome measures from across all studies. In your results then you will report that you found that not enough papers reported this to be able to do a metaanalysis and you report the other outcome measures found (as per section 312-318). Should align to statements in 260-265 e.g. where pneumonia is mentioned, but not atelectasis which the earlier section reported as an inclusion. Please clarify / revise.

Line 214, 215. Cochrane and PEDro scales presented, then statement of moderate risk of bias. “Moderate” is not a listed category in either of the scales as presented.

Line 281-282, 288. Are these needed? It was essentially the inclusion criteria. Reporting the % of patients on each device might be more of interest.

Line 295-296. Were these indications stated in the papers or is this the authors’ description of the indications to use the equipment? Please clarify / confirm.

Greater use of referencing and or referrals to Tables is needed throughout the results section so it is clear where results came from e.g. lines 308-309

Line 341, 347. Revise sentences

Line 348. Data presented show an higher incidence of pneumonia in the IPV group, but the discussion is indicating the IPV group was lower. Please check / revise.

The results and conclusions seem biased towards indicating some potential benefit. Data has not been able to be pooled though. The associations of possible affect seem over-emphasised.

LOS – Largest study result NSD, but reported as shorter.

Pneumonia – only 1 of 3 studies showed a significant change

PaO2. Lines 363-364; 380-381. These do not appear to be between group comparisons reporting significance. Both groups improved oxygenation across the period.

Discussion. The low quality of the studies included should be emphasised at the onset. Start with lines 425-431. Discussion will need significant review once results of study reviewed. Avoid repeating results in the discussion.

Reviewer #4: This systematic review investigates the Effect of intrapulmonary percussive ventilation on intensive care unit length of stay, incidence of pneumonia and gas exchange in critically ill patients. My only criticism relates to the broad inclusion criteria " Studies that reported the effects of IPV, high-frequency ventilation, and high-frequency oscillation where these interventions were primarily used for therapeutic purposes were included,...". IPV is not the same as high frequency ventilation or high frequency oscillation. HFV and HFO may often be applied via oscillatory vests which are not the same as IPV delivered via a face mask/mouthpiece or artificial airway.

Reviewer #5: Effect of intrapulmonary percussive ventilation on intensive care unit length of stay,

incidence of pneumonia and gas exchange in critically ill patients: a systematic review.

Thank you for the opportunity to review this manuscript. The topic is interesting and relevant for clinical practice. I have some comments that the authors may wish to consider when making revisions. These link to the abstract and main paper.

Introduction

The title implies an interest in outcomes relating to presence or absence of pneumonia and components of gas exchange as well as LOS.

Aims and research question have more consistent outcomes outlined; and lines 152-154 more detail.

Could the explicit aims of IPV be provided so that these could considered with this review of literature and resulting aims; this would also then link to the discussion again later (somewhat addressed in lines 131-136)

Information about IPV use in the literature is presented. The study by Reychler 2018 evaluated airway clearance and gas exchange; was the current review not interested in airway clearance too (albeit in critical care settings)?

150/151 Care- the role of IPV in preventing or reversing atelectasis is possibly only one only unanswered question.

Line 134: The term conventional chest physiotherapy (ref 12) is used; is there an explanation of this please.

Line 263- is atelectasis one of the outcomes of interest? it seems so

Lines 264, 265 – this seems in conflict to results presented in the supplementary files

Methods

Patients > or =16years – is this a consistent international cut off for adult critical care units? I am curious that there is potential for studies (included or excluded) conducted in a mixed peadiatric:adult population dependent on the age cut off.

The mixed study design does detract somewhat from the review and it may be useful to group the presentation of results from the RCTs/quasi randomised and discuss the weight of evidence relating to these.

Additionally, is it possible to appraise and accurately score the quality of an abstract or a non RCT using the PEDro scale which is designed for the quality appraisal of a fully reported RCT(Lines 213 a-215). There are other tools available for appraisal of non RCTs.

Same with Cochrane ROB tool – how can an observational study score under the item “random sequence generation”.

Results

It may be worth considering the weight/magnitude of the results relating to outcomes from the RCTs; and then presenting the results from the observational studies separately. Otherwise, there is a nice overview of outcome measures included overall (Lines 311-318 onwards), followed by relevant results sections.

294 presents an overview of the intervention (dose, interface etc). there should be a summary of the control group/comparator groups used.

295/296 – interesting that use of IPV relating to airway clearance is included here, but limited reference to this earlier.

Lines 361-361- unsure of the term “most significant” here

Table 1 & 2 – as per methods please consider the suitability of the Cochrane ROB and the PEDro scale for non RCTs.

Discussion

Were there any papers which overlapped with the Reychler 2018 study?

Line 425 what does routine chest physiotherapy refer to here; please consider the term routine, or use quotations if this is directly from the publication.

430/431 refer to previous comment in terms of judging ROB and quality.

456-459 This is confusing as the review indicated that meta analysis not possible due to heterogeneity. In the supplementary material the I squared statistic does indeed support this high heterogeneity; this implies uncertainty about this specific result and its interpretation (i.e. from the supplementary material).

481-407 Could this discussion be more concise. a/a further pooled data yet this is not reported in the results as according to the methods meta analysis was not feasible.

Line 486 Check the word “don’t”!

The discussion is quite long.

Perhaps consider a paragraph summarising the clinical implications in terms of patient selection, intervention (timing and dose) etc or add this to the conclusion. The review sates “more clinical trials with larger sample sizes are warranted to further add to the findings of this review”; this is a very broad statement. Could the authors consider a more focused suggestion to guide the next steps for future research e.g. using the PICO to frame this; It would be interesting to debate what study design should be considered

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Reviewer #1: Yes: Alice YM Jones

Reviewer #2: No

Reviewer #3: No

Reviewer #4: Yes: George Ntoumenopoulos

Reviewer #5: No

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PLoS One. 2021 Jul 28;16(7):e0255005. doi: 10.1371/journal.pone.0255005.r002

Author response to Decision Letter 0

26 Jun 2021

Response to the editor

Dear Editor,

Thank you for the opportunity to revise our manuscript. Our responses to the editors’ and reviewers’ comments are outlined below under each comment. Since there were numerous comments, for clarity, we have left the comments in black font (as received), and used blue font for our responses. In addition, we have used green font in italics with quotation marks to show the sections that has been amended in the manuscript. All the responses have page number, the heading and subheading and the line numbers, so that it can be easily located in the revised manuscript. The line numbers indicated in our responses match with the line numbers in the unmarked version (“Manuscript”) and not the tracked version. So please refer to the clean version when going through the following responses. Tracked version is also provided as per your request. Thank you.

Our responses are as follows;

When submitting your revision, we need you to address these additional requirements.

1) Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

Response: The manuscript (Title page and main body) is prepared according to PLOS ONE style.

Response: All the tables (Table 1, Table 2 and Table 3) are included/embedded in the main body of the manuscript.

3) Please include a copy of Table 3 which you refer to in your text. (We note you currently have two tables which are both titled 'Table 2'.)

Response: Table 3 is included now in the body of manuscript as per your request.

Response: Captions have been provided at the end of the manuscript as per the journal guidelines.

Response: During the first submission, we stated that information will be provided upon request (we meant journal’s request). Apologies if this caused any confusion. Since this is a systematic review, we do not have patient related data. There are no restrictions with providing any information related to this systematic review. The search strategy (S1 Table) has been uploaded already which will allow replicating the search. In addition, please let us know if you require any additional information.

Response to reviewer’s comments

Review Comments to the Author

1- Routine traditional chest physiotherapy

Response: Thank you for the helpful suggestion regarding clarifying terminology used. In the included studies, terms such as “chest physiotherapy” (CPT) and “standard respiratory physiotherapy” have been used by the authors. For consistency throughout the manuscript, we have used the term “chest physiotherapy” has been used in this systematic review. However, there was one instance where the term “conventional chest physiotherapy” was used which has now been replaced by “chest physiotherapy”. Also, based on reviewer’s suggestion, further explanation and clarification of “chest physiotherapy” has been added in the introduction and result section.

Please see page 5, Introduction: Lines128-132 “Chest physiotherapy interventions (CPT) such as chest percussion & vibrations, postural drainage, positioning, thoracic expansion exercises, manual hyperinflation, ventilator hyperinflation and airway suctioning aim to promote airway secretion clearance, increase alveolar recruitment…”

Please see page 18, Results/Intervention: Lines 296-298 “CPT included chest clapping, postural drainage, expiration with open glottis, incentive spirometer and mobilisation (Table 3). Duration of CPT session ranged from 30 minutes to 60 minutes once or twice a day”

2- Indications for and outcome measures of clinical intervention.

Response: Thank you for reviewer’s valuable input and suggestions. There are multiple questions in the above comment, so we have responded to them in separate sections.

Respiratory rate can be high in critical care patients with excessive secretions or underlying pulmonary atelectasis. IPV is mainly used to remove bronchial secretions and recruit lung units thereby improving gas exchange with the potential corollary of a reduction in respiratory rate. Although IPV is primarily not used for treating tachypnoea, reduction in respiratory rate is a surrogate measure of improved respiratory status hence it is important to measure this. The changes in respiratory rate in the included studies are very small and we agree that they are not clinically meaningful. This has been acknowledged in the manuscript.

Please see page 22, Results/Respiratory rate: Lines 386-388“Overall, three out of four studies reported a small but significant reduction in respiratory rate post IPV intervention. This small change does not seem to be clinically relevant.”

Further, we agree with the reviewer’s observation that although IPV may have a role in secretion clearance, gas exchange and pulmonary atelectasis, the commonly reported and measured outcome in the included studies was “gas exchange”. Three studies reported an observed improvement in secretion clearance, but this was not measured. We have acknowledged this.

Please see page 22, Results/Airway clearance: Lines 391-393 “Three studies in this review reported an observed increase in airway clearance with IPV intervention; however, none of them measured the expectorated sputum weight (wet or dry)(12,13,15) or other measures of mucociliary clearance”.

In addition, included studies have also reported on atelectasis, respiratory rate, and pneumonia as outcomes which are reported in results and in the Discussion section. We have also reported and discussed airway clearance in the results and discussion section.

Please see page 22, Results/Airway clearance: lines 391-393 as above “Three studies in this review reported an observed increase in airway clearance with IPV intervention; however, none of them measured the expectorated sputum weight (wet or dry)(12,13,15) or other measures of mucous clearance”.

Page 24, Discussion: lines 458-460 “Some authors hypothesised that the improvement in oxygenation could, in part, be due to improved airway clearance post IPV intervention(20,22). In this review, three studies reported an observed increase in airway clearance with IPV intervention”

It is true that oxygen is the driving gas for IPV device, which may cause a transient increase in the oxygen levels. A washout or stabilisation period of 15-30 minutes is recommended before measurement of oxygen. In the included studies, some studies (Antonaglia et al. 2006 and Clini et al. 2006) have reported a stabilisation period whereas this was not clear in other studies which may introduce some bias. This has now been mentioned and discussed in the ‘discussion” section.

Pease see page 24, Discussion: Lines 448-451 “Short term improvement in oxygenation could be attributed to the oxygen source which is used to drive the IPV device. Two studies reported the washout or stabilisation time prior to measuring oxygen levels(12,13) whereas the time of measurement of oxygen levels in relation to IPV was not clear in other studies”

I would like to suggest:

Response: The reviewer’s suggestion has been taken into consideration and further details have been added in the “Introduction” section.

Please see page 5, Introduction: Lines 136-143 “IPV is a non-continuous form of high-frequency ventilation delivered by a pneumatic device that provides small bursts of sub-physiological tidal breaths at a frequency of 60 - 600 cycles/minute superimposed on a patient's breathing cycle(16–18). The high frequency breaths create shear forces causing dislodgement of the airway secretions. Furthermore, the IPV breath cycle has an asymmetrical flow pattern characterised by larger expiratory flow rates, which may propel the airway secretions towards the central airway(18). In addition, the applied positive pressure recruits the lung units, resulting in a more homogeneous distribution of ventilation and improved gas exchange”

Lines 139-144 state that “IPV is used in a range of patients…”. Please include the reasons and who recommended such use, and what were the reported ‘outcomes’ in patients with COPD, burns and thoracic surgery.

Response: We have now added the requested details about the types of clinical conditions and indications (with citations).

Please see page 5, Introduction: Lines 143-148 “In acute care and critical care settings, IPV intervention is used in a range of patients, from spontaneously breathing patients to those receiving invasive mechanical ventilation where IPV breaths can be superimposed on a patient’s breathing cycle or superimposed on breaths delivered by a mechanical ventilator. The most common indications for IPV use are reported as removal of excessive bronchial secretions, improving gas exchange, and recruitment of atelectatic lung segments(12–14,18).”

2. Include the discussion of the 2 concerns raised above.

Response: Concerns addressed.

Please see page 23, Discussion: Lines 419-422 “In addition the interventions received by the control groups among the included studies also varied from “usual chest physiotherapy”(12) or “standard respiratory physiotherapy”(13) to “standard treatment” which included medical management(15)”.

Page 24, Discussion: Lines 458-459 “Some authors hypothesised that the improvement in oxygenation could, in part, be due to improved airway clearance post IPV intervention(20,22).”

Page 24, Discussion: Lines 448-451 “Short term improvement in oxygenation could be attributed to the oxygen source which is used to drive the IPV device. Two studies have reported the washout or stabilisation time prior to measuring oxygen levels(12,13) whereas it was not clear in other studies.”

Response: The “Conclusions” section has been revised and reworded as per reviewer’s suggestions.

Please see page 27, Conclusions: lines 524-528 “The findings of this review provide weak evidence to support the use of IPV intervention in reducing ICU and hospital LOS, reducing respiratory rate, and improving gas exchange in critically ill patients. The therapeutic value of IPV in airway clearance and treating pulmonary atelectasis remains inconclusive, requiring further investigations.”

Reviewer #2: Overall this is a well done systematic review.

There are few minor points to query

Response: Participants in the cited studies who receive invasive and non-invasive mechanical ventilation will have similar physiological benefits such as increase in FRC and partial unloading of the diaphragm, However, IPV has airway clearance properties (explained in the Introduction section) which may have an added advantage over mechanical ventilation. This is now discussed in the Introduction and Discussion section as below;

Please see page 5, Introduction: Lines 136-141 “IPV is a non-continuous form of high-frequency ventilation delivered by a pneumatic device that provides small bursts of sub-physiological tidal breaths at a frequency of 60 - 600 cycles/minute superimposed on a patient's breathing cycle(16–18). The high frequency breaths create shear forces causing dislodgement of the airway secretions. Furthermore, the IPV breath cycle has an asymmetrical flow pattern characterised by larger expiratory flow rates, which may propel the airway secretions towards the central airway”

Please see page 24, Discussion: Lines 453-459 “Also, positive pressure has been found to unload respiratory muscles which subsequently reduces the oxygen cost of breathing, as demonstrated by Dimassi and colleagues (2011)(26) where the application of IPV led to a 20% reduction in diaphragm loading in post-extubation respiratory failure patients. In addition to these benefits, IPV can also augment oxygenation by promoting airway clearance. Some authors hypothesised that the improvement in oxygenation could, in part, be due to improved airway clearance post IPV intervention.”

486-487 – Grammar could be improved in this sentence

Response: We have checked the grammar and also the word “don’t” is now replaced by “does not”.

Please see page 25, Discussion: Line 475-476. “Although statistically significant, this small reduction in pneumonia does not appear to be clinically meaningful”.

Response: Thank you for the reviewer’s detailed interpretation and valuable suggestions on this manuscript. We have reviewed all the analyses and made some amendments in the interpretation of the findings of this review that are now mentioned in both the Discussion and Conclusions section. Please see our responses below to specific points made by this reviewer;

Please see page 22, Discussion: Lines 406-409 “The findings of this review provide weak evidence to support the effectiveness of IPV intervention in reducing ICU-LOS, improving gas exchange and reducing respiratory rate in critically ill patients compared to chest physiotherapy techniques or standard medical management”.

Please see page 27, Conclusions: Lines 523-528 “This systematic review is the first to summarise the evidence of the IPV intervention in patients admitted to critical care. The findings of this review provide weak evidence to support the use of IPV intervention in reducing ICU and hospital LOS, reducing respiratory rate, and improving gas exchange in critically ill patients. The therapeutic value of IPV in airway clearance and treating pulmonary atelectasis remains inconclusive, requiring further investigations.”

Line 86: Out of 306 studies. Consider deleting or clarifying that 306 was number resultant from the search e.g. Out of 306 identified abstracts,

Response: This has been amended as per reviewer’s suggestion.

Please see page 3, Abstract/Results: Line 85 “Out of 306 identified abstracts, seven studies (630 patients) met the eligibility criteria”.

Line 81, 169. If an update of the search has been done to include up to 2021, this should be reflected here (rather than 2019)

Response: This has now been updated to “2021” in both the Abstract and in Methods/Search Strategy section.

Please see page 3, Abstract/Methods: Lines 77- 78 “A systematic search of intrapulmonary percussive ventilation in intensive care unit (ICU) was performed on five databases from 1979 to 2021”

Page 7, Methods/search strategy: Lines 171-173 “The first stage included database searches on MEDLINE, EMBASE, CINAHL, Web of Science, and PEDro, from 1979 (when IPV was first introduced) to February 2021”

Line 141. Consider deleting “few”.

Response: Deleted “few” as per the reviewer’s suggestion. It read “In the last two decade, few studies have reported….”, now after amendment, it reads “In the last two decades, studies have reported IPV in the critical….” Please see page 6, Introduction: line 149

Response: In response to the reviewer’s comment, the terms “non-critically ill” and “non-acutely ill” has been replaced with “stable patients” and “critically ill patients” throughout the manuscript.

Please see page 6, Introduction, Lines 157-158 “Most of the studies reviewed by Reychler and colleagues (2018) included stable patients”

Page 6 Introduction: Lines 155-157. “The question regarding the role of IPV in preventing or reversing atelectasis and reducing the incidence of pneumonia in critically ill patients remains unanswered”

Page 7, Methods/Inclusion and exclusion criteria: Lines 183-184 “Studies that included stable patients in the inpatient, outpatient, or community-based settings were excluded.”

Response: This has been amended as per reviewer’s suggestion,

Please see page 7, Methods/Inclusion criteria: Lines 187-192 “Studies that reported the effects of IPV, high-frequency ventilation, and high-frequency oscillation where these interventions were primarily used intermittently for short duration to promote airway clearance, reverse or treat pulmonary atelectasis, or to improve gas exchange were included, whereas the studies that used these interventions to provide continuous mechanical ventilation were excluded.”

Response: As per reviewer #3 suggestion, we have clarified our primary and secondary outcomes of interest, “atelectasis” is now added.

Please see page 12, Methods/outcome measures: Lines 243- 246 “The primary outcome of interest was ICU-LOS. Secondary outcomes included PaO2, the ratio of the partial pressure of arterial oxygen and fraction of inspired oxygen (PaO2/FiO2), PaCO2, airway clearance, the incidence of pneumonia, respiratory rate, and pulmonary atelectasis.”

Line 214, 215. Cochrane and PEDro scales presented, then statement of moderate risk of bias. “Moderate” is not a listed category in either of the scales as presented.

Response: In response to the reviewer’s comment, we have amended our description of the risk of bias.

Please see page 9, Methods: Lines 224-227 “Overall, based on the Cochrane assessment tool, three out of four studies appear to have a low risk of bias whereas in one study the risk of bias was high. On the PEDro scale, the quality of the studies ranged from “poor” to “good.”

Line 281-282, 288. Are these needed? It was essentially the inclusion criteria. Reporting the % of patients on each device might be more of interest.

Response: As per reviewer’s suggestion we have deleted the following sentence

“All the studies were conducted in the critical care setting where patients were receiving invasive mechanical ventilation, non-invasive ventilation, or were breathing spontaneously with supplemental oxygen.”

And have added “Study sample sizes ranged from 10 patients to 419 patients(14,21) (Table 3). All the studies were conducted in the critical care setting which included patients who were mechanically ventilated (34%), post extubation (6%), requiring NIV (18%) and the remaining (42%) were requiring high oxygen therapy (FiO2 ≥ 40%) and continuous positive airway pressure support.” (See page 17, Results/Study characteristics: Lines 266-270)

Line 295-296. Were these indications stated in the papers or is this the authors’ description of the indications to use the equipment? Please clarify / confirm.

Response: These indications were used by the authors of the included studies. This has now been made clearer.

Please see page 17, Results/Intervention: line 280-282 “In the included studies, most common indications to use IPV intervention were to improve gas exchange, promote airway clearance and prevent or reverse pulmonary atelectasis.”

Greater use of referencing and or referrals to Tables is needed throughout the results section so it is clear where results came from e.g. lines 308-309

Response: Point noted with thanks. Tables have now been referenced more frequently throughout the Results section as per the reviewer’s suggestion. Please see page 18, Methods/Intervention: Lines 286-299.

Line 341, 347. Revise sentences

Response: The sentences have been revised as requested.

(i) Please see page 19, Results/Length of stay: Lines 329-332 “Another study by Vargas et al. (2005) investigated the effects of IPV intervention in 33 patients with COPD with acute respiratory failure where the intervention group (n = 17) received IPV for 30 minutes twice a day, and the control group (n =16) received standard medical treatment.”

(ii) Please see page 20, Results/Incidence of pneumonia: Lines 338-340 “Antonaglia et al. (2006) reported a small (not significant) difference in the incidence of pneumonia in 40 patients with acute exacerbation of COPD (IPV: 2 vs. CPT: 4, NS).”

Line 348. Data presented show an higher incidence of pneumonia in the IPV group, but the discussion is indicating the IPV group was lower. Please check / revise.

Response: Noted with thanks. This was a typographical error which has been corrected.

Please see page 20, Results/Incidence of pneumonia: Lines 338-340 “Antonaglia et al. (2006) reported a small (not significant) difference in the incidence of pneumonia in 40 patients with acute exacerbation of COPD (IPV: 2 vs. CPT: 4, NS).”

The results and conclusions seem biased towards indicating some potential benefit. Data has not been able to be pooled though. The associations of possible affect seem over-emphasised.

LOS – Largest study result NSD, but reported as shorter.

Response: Thanks for reviewer’s valuable feedback, it has been mentioned in the manuscript that the reduction in the LOS in Huynh et al (2019) study is shorter but statistically not significant. (Please see page19, Results/Length of stay, Lines 325:327).

We also acknowledge reviewer’s point about data pooling. For the LOS data, we performed a meta-analysis (supplied as supplementary, see “S1 File”) where the average median difference of all the three studies showed a shorter LOS with a p-value <0.01(Antonaglia et al. 2006, Vargas et al. 2006 and Huynh et al. 2019). However due to small number of studies the meta-analysis is not included in the main body of the manuscript. This may have influenced our conclusions; however, we agree that the risk of bias remains high in most studies which adds another perspective to the outcomes. Based on the reviewer’s feedback we have made some amendments to the study conclusions.

Please see page 27, Conclusions: Lines 523-528. “This systematic review is the first to summarise the evidence of the IPV intervention in patients admitted to critical care. The findings of this review provide weak evidence to support the use of IPV intervention in reducing ICU and hospital LOS, reducing respiratory rate, and improving gas exchange in critically ill patients. The therapeutic value of IPV in airway clearance and treating pulmonary atelectasis remains inconclusive, requiring further investigations.”

Pneumonia – only 1 of 3 studies showed a significant change.

Response: As the reviewer correctly notes, only 1 in 3 studies showed difference in the incidence of pneumonia with the use of IPV. This is reflected in our conclusion that IPV does not seem to be effective in preventing or reducing the incidence of pneumonia.

Please see page 25, Discussion: Lines 472-478“In this review, out of three studies(12,13,21), only one reported a significant reduction in the incidence of pneumonia in the IPV group compared to the CPT group(12). Although statistically significant, this small reduction in pneumonia does not appear to be clinically meaningful. Surprisingly, the number of cases of pneumonia in all the included studies was very small in both the IPV and control groups. Evidence does not currently support the use of IPV to prevent or treat pneumonia in critically ill patients”

PaO2. Lines 363-364; 380-381. These do not appear to be between group comparisons reporting significance. Both groups improved oxygenation across the period.

Response: Thank you for pointing this out and we apologise for causing confusion here by inserting the p-value twice (typographical error) which doesn’t reflect the actual study findings by Antonaglia et al 2006. The comparison is in fact `between group` comparisons (Please see Antonaglia et al 2006, Table 4, page 2942). This error has been rectified by removing one of the p-values from PaO2/ FiO2 and PaCO2 results.

Please see page 20, Results/ PaO2 and PaO2/FiO2 ratio: Lines 350-352 “Antonaglia et al. (2006) reported a significant change in PaO2/ FiO2 ratio from admission to discharge (seven days) in patients with COPD admitted to ICU (IPV: 173 �27] to 274 �15], Control: 181 �29] to 237 �20], p < 0.01)”.

Page 21, Results/Change in PaCO2: Lines 366-368 “Antonaglia et al. (2006) recorded a significant reduction in PaCO2 levels in patients with COPD in IPV and CPT group (IPV: 79 �7] to 58 �5.4], Control: 80��6.5] to 64 �5.2] mmHg, p < 0.01)”

Response: As per reviewer’s suggestion, we have now highlighted the quality of papers and risk of bias in the methods, results and discussion section.

(1) Please see page 12, Methods/Outcome measures: Lines 247-248 “Due to the small number of studies and observed heterogeneities in the study methodology and patient population, all the outcomes were summarised narratively”

(2) Please see page 23, Discussion: Lines 416-419 “The findings of our systematic review should be viewed with caution since there were various methodological (study design, outcome measures), clinical (patient population and application of IPV) and statistical (small sample size and lack of control group) heterogeneities observed.”

(3) Please see page 27, Limitations: Lines 517-520 “Heterogeneities resulting from differences in study design, patient population, dosage, and frequency of IPV intervention were frequently observed in the included studies. Further, small sample sizes and poor methodological quality introduces some bias and weakens the strength of conclusions of this review.”

Response: As reviewer 4 notes, our broad inclusion criteria may have initially identified irrelevant studies.

IPV has been used clinically for more than four decades and yet it remains poorly defined. Clinical classification (based on the breath frequency) of different high frequency ventilators (including IPV) is unclear (Kallet et al 2013: Resp Care, Vargas et al 2005: Crit Care, Salim et al 2005: Crit Care Med). In most of the studies, IPV remains the most used terminology, however as reviewer 4 notes, infrequently, terminologies such as HFV (High frequency ventilation) and HFO (High frequency oscillation) and CHFO (Chest high frequency oscillation) have also been used interchangeably. Hence, to ensure we retrieved all the relevant studies in our review, we included these terminologies in our search (please see the supplementary table: Table 1S: Search strategy). These retrieved studies were then screened carefully according to our selection criteria.

As correctly noted by the reviewer that HFV can be applied via a vest (worn by patients) also commonly known as High Frequency Chest Wall Oscillation (HFCWO). HFCWO is applied externally via a vest whereas IPV is applied internally via airways achieving different physiological effects via completely different mechanisms. Hence, HFCWO was not used in our search strategy. All studies identified by the search strategy were then screened according to our selection criteria to ensure only studies of IPV were included in our systematic review.

Reviewer #5: Effect of intrapulmonary percussive ventilation on intensive care unit length of stay, incidence of pneumonia and gas exchange in critically ill patients: a systematic review.

Introduction

The title implies an interest in outcomes relating to presence or absence of pneumonia and components of gas exchange as well as LOS.

Aims and research question have more consistent outcomes outlined; and lines 152-154 more detail.

Response: Airway clearance is one of the clinical indications for IPV. We did include various search terms to retrieve all the relevant studies that measured “airway clearance” (Please see the supplementary table attached, Table 1S: Search strategy). Despite that, we could not evaluate airway clearance because only three included studies reported that an increased sputum clearance was observed but not measured (quantified) making it vague observation only and therefore difficult to include in our outcome measures; this has been acknowledged and discussed in the Results and Discussion section.

Please see page 25 & 26, Discussion: Lines 479-484 “Similarly, despite airway clearance being one of the main indications of IPV intervention, only three studies reported an observed increase in secretion clearance. Surprisingly, none of these studies measured sputum yield(12,13,15). Difficulties with accurate measurement of sputum yield have been well documented(32). Due to lack of data regarding the airway clearance in the included studies, the role of IPV in airway clearance remains unclear”

150/151 Care- the role of IPV in preventing or reversing atelectasis is possibly only one only unanswered question.

Response: Reviewer 5’s comments suggest that our sentence (line 150-151) was not clear enough to explain the intention of this review properly. We have therefore rephrased this sentence.

Please see page 6, Introduction: Lines 155-157 “The question regarding the role of IPV in preventing or reversing atelectasis and reducing the incidence of pneumonia in critically ill patients remains unanswered.”

Line 134: The term conventional chest physiotherapy (ref 12) is used; is there an explanation of this please.

Response: Please see our response to a similar comment by reviewer #1. In response to the reviewer’s question, the term “conventional” has been removed and “chest physiotherapy” is used for consistency throughout the manuscript.

Please see amendment on page 5, Introduction: Lines 133-135“In addition to these chest physiotherapy (CPT) interventions, intrapulmonary percussive ventilation (IPV) is used in patients with underlying pulmonary…..”

Line 263- is atelectasis one of the outcomes of interest? it seems so

Response: Atelectasis is an outcome of interest. This has been amended and made clearer in the outcome measures section.

Please see page 12, Methods/Outcome measures: Lines 243-246 “The primary outcome of interest was ICU-LOS. Secondary outcomes included PaO2, the ratio of the partial pressure of arterial oxygen and fraction of inspired oxygen (PaO2/FiO2), PaCO2, airway clearance, the incidence of pneumonia, respiratory rate, and pulmonary atelectasis.”

Lines 264, 265 – this seems in conflict to results presented in the supplementary files

Response: The meta-analysis is performed for LOS and pneumonia outcomes but due to the small number of studies it was not included in the main body of the manuscript, instead all the outcomes are summarised narratively. The meta-analysis, however, still presents some interesting findings which might interest some readers and hence has been included as supplementary material.

In response to reviewer 5’s comment, we have now changed the description and now meta-analysis is only mentioned in the discussion section for interested readers.

Please see page 23 & 24, Discussion: Lines 434-437 “A meta-analysis was performed, but due to the small number of studies and observed heterogeneity, it was not included in the main body of this review. Interestingly, pooling of ICU-LOS data revealed that the magnitude and direction of the effect of IPV in reducing the ICU-LOS was similar in all three studies (S1).”

Methods

Response: In most Australian hospitals the age group 16 to 17 can be managed in either paediatric or adult unit. To include only 18+ age would potentially exclude a portion of the population that may be managed in adult ICU’s in Australia.

Same with Cochrane ROB tool – how can an observational study score under the item “random sequence generation”.

Response: The Cochrane ROB tool is most suited to RCTs, as it assumes that the study being assessed is an RCT. As a result, we considered reviewer’s suggestion and removed three studies from the ROB analysis that did not used randomisation. The new Cochrane ROB table now has 4 studies that are RCTs. Please see Table1 on page 10.

PEDro, however does allow assessment of studies that did not use random allocation; hence we have not made any changes to PEDro assessment table. Due to the scoring system of PEDro tool, it is easy to do head-to-head comparison of all the studies which is much easier for the readers to compare the study quality. Additionally, to our knowledge there is no single assessment tool that would be suitable for the remaining three studies that did not use randomisation as the study design of these three studies that did not use randomisation and their study design differs. This means we may need to use two additional assessment tools which may be confusing and may not help readers with interpretation.

Results

Response: Thank you for recognising that we have summarised the study findings nicely.

We have performed meta-analyses (supplementary material “S1 File”) where the direction and magnitude of outcomes are presented for ICU length of stay and pneumonia outcomes.

Due to small number of studies with each study reporting different outcomes it was difficult to perform this for RCTs and observational studies separately. However as per the suggestion above, we have separated the RCTs from the observational studies in Table 1. Please see table 1 on page 10.

294 presents an overview of the intervention (dose, interface etc). there should be a summary of the control group/comparator groups used.

Response: A description of control group has been added as per the reviewer’s suggestion.

Please see page 18, Results/Intervention: Lines 296-301 “CPT included chest clapping, postural drainage, expiration with open glottis, incentive spirometer and mobilisation. Duration of CPT session ranged from 30 minutes to 60 minutes once or twice a day. In some studies(15,26), the control group received standard medical treatment which included oxygen therapy, non-invasive ventilation, sitting up in bed, nebulised bronchodilators and corticosteroids (Table 3).”

295/296 – interesting that use of IPV relating to airway clearance is included here, but limited reference to this earlier.

Response: This has been rectified based on similar comments from another reviewer.

Please see page 7, Methods/Inclusion and exclusion criteria: Lines 187-190 “Studies that reported the effects of IPV, high-frequency ventilation, and high-frequency oscillation where these interventions were primarily used intermittently for short duration to promote airway clearance, reverse or treat pulmonary atelectasis”

Lines 361-361- unsure of the term “most significant” here

Response: The term “most significant” has been omitted now. Previously it read “The most significant change in PaO2/FiO2 ratio was reported by Antonaglia….” After amendment it reads “Antonaglia et al. (2006) reported a significant change in PaO2/ FiO2 ratio from admission to discharge….” (Page 20, Results/ PaO2 and PaO2/ FiO2 ratio: Lines 350-352.

Table 1 & 2 – as per methods please consider the suitability of the Cochrane ROB and the PEDro scale for non RCTs.

Response: Thank you for the feedback. We carefully looked into this and found that Cochrane ROB tool is more suited to RCTs as it assumes that the study being assessed is an RCT. As a result, we took the reviewer’s suggestion on board and removed three studies that did not use randomisation. The new Cochrane ROB table now has 4 studies that used random allocation. Please see table 1 on page 10.

PEDro scale, however does allow assessment of studies that did not use random allocation; hence we have not made any changes to PEDro assessment table (Table 2). One advantage of using PEDro tool is that it allows readers to make head-to-head comparisons of all the study qualities directly. Further, to the best of our knowledge there are no assessment tools that would be suitable for the remaining three studies that did not use randomisation as the study design of these three studies do differ. This means we may need to use two additional assessment tools which may detract the readers even more. Please see Table 2.

Discussion

Were there any papers which overlapped with the Reychler 2018 study?

Response: Yes, there were three papers that overlapped with Reychler study.

Line 425 what does routine chest physiotherapy refer to here; please consider the term routine, or use quotations if this is directly from the publication.

Response: The term “Routine chest physiotherapy” has now been clearly explained with terms used by the included studies. “Chest physiotherapy” (CPT) is the used terminology throughout this manuscript for consistency.

Please see Page 22, Discussion: Lines 406-409. “The findings of this review provide weak evidence to support the effectiveness of IPV intervention in reducing ICU-LOS, improving gas exchange and reducing respiratory rate in critically ill patients compared to chest physiotherapy techniques or standard medical management.”

430/431 refer to previous comment in terms of judging ROB and quality.

Response: The ROB and quality has been discussed now in the manuscript.

(1) Please see page 9, Methods/Assessment of quality and risk of bias: Lines 224-227 “Overall, based on the Cochrane assessment tool, three out of four studies appear to have a low risk of bias whereas in one study(26) the risk of bias was high. On the PEDro scale, the quality of the studies ranged from “poor” to “good”).

(2) Please see Page 27, Limitation: lines 519-520 “Further, small sample sizes and poor methodological quality introduces some bias and weakens the strength of conclusions of this review.”

Also, the assessment table (Table1) has been modified where the observational studies have been removed as per reviewer’s suggestions. Please see Table 1 and Table 2 on page 10 and 11.

Response: Meta analyses were not included in the main body of manuscript due to small number of studies and heterogeneities among them, but supplied as supplementary for further reading. The I2 shows heterogeneity but a further statistical analysis such as “p-curve analysis” and “leave one out method” further explains the small effect of heterogeneity on the outcomes.

We agree with the reviewer that our sentence (“Due to the heterogeneity, meta-analysis could not be included in this review, however, interestingly, pooling of ICU-LOS data revealed that the magnitude …….”) caused some confusion.

This has been amended, and now it reads “A meta-analysis was performed, but due to the small number of studies and observed heterogeneity, it was not included in the main body of this review. However, interestingly, pooling of ICU-LOS data revealed that the magnitude and direction of the effect of IPV in reducing the ICU-LOS was similar in all three studies (S1).” Please see page 23 & 24, Discussion: Lines 434 and 437.

481-407 Could this discussion be more concise. a/a further pooled data yet this is not reported in the results as according to the methods meta analysis was not feasible.

Line 486 Check the word “don’t”!

Response: We have made the discussion more concise (Please see numerous changes to Discussion section in the tracked version of manuscript supplied).

Further, the reason for not including meta-analysis has been clarified now as above (in the methods and Discussion section).

Please see page 23 & 24, Discussion: Lines 434 and 437. “A meta-analysis was performed, but due to the small number of studies and observed heterogeneity, it was not included in the main body of this review. However, interestingly, pooling of ICU-LOS data revealed that the magnitude and direction of the effect of IPV in reducing the ICU-LOS was similar in all three studies (S1).”

Please see page 12, Methods/Outcome measures: Lines 247-248“Due to the small number of studies and observed heterogeneities in the study methodology and patient population, all the outcomes were summarised narratively.”

The word “don’t” has been replaced with word “does not”

Please see page 25, Discussion: Lines 475-476 “Although statistically significant, this small reduction in pneumonia does not appear to be clinically meaningful”

The discussion is quite long. Perhaps consider a paragraph summarising the clinical implications in terms of patient selection, intervention (timing and dose) etc or add this to the conclusion.

The review sates “more clinical trials with larger sample sizes are warranted to further add to the findings of this review”; this is a very broad statement. Could the authors consider a more focused suggestion to guide the next steps for future research e.g. using the PICO to frame this; It would be interesting to debate what study design should be considered

Response: We have made the discussion more concise (Please see numerous changes to Discussion section in the tracked version of manuscript supplied).

Additionally, as per reviewer’s comments, the authors have created a more focussed recommendation for future research using the PICO framework.

Please see page 27 and 28, Conclusions: Lines 528-536“This review is based on a small number of available studies mostly with small sample sizes, hence, there is a need for more adequately powered randomised control trials to investigate the effectiveness of IPV intervention in improving outcomes such as ICU LOS, gas exchange, airway clearance, prevention or treatment of pneumonia and pulmonary atelectasis compared to routinely applied airway clearance and lung recruitment physiotherapy interventions in critical care population. In addition, there is also an indication for studies to evaluate patients’ experiences with IPV intervention and their preference compared to routinely practiced respiratory physiotherapy interventions in critical care settings.”

Since this review is based on a small number of studies providing weak evidence, we don’t feel that a recommendation regarding the dosage and duration can be made for clinical implications. However, for readers we have summarised the most common treatment application method and dosage of IPV intervention that was found among the included studies.

Please see page 18, Results/Intervention: Lines 290-294.“….the duration of a single treatment session ranged from 10 to 30 minutes, and the number of sessions ranged from a single session a day to up to six sessions a day(21). The frequency of delivered breaths remained between 200 to 300 cycles per minute in all the included studies, whereas the airway pressure varied from 5 to 35 cmH2O (Table 3). Notably, most of the studies did not specify the patient's position during the treatment.”

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PLoS One. doi: 10.1371/journal.pone.0255005.r003

Decision Letter 1

Shane Patman

8 Jul 2021

Effect of intrapulmonary percussive ventilation on intensive care unit length of stay, the incidence of pneumonia and gas exchange in critically ill patients: a systematic review

PONE-D-21-11360R1

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PLoS One. doi: 10.1371/journal.pone.0255005.r004

Acceptance letter

Shane Patman

15 Jul 2021

PONE-D-21-11360R1

Effect of intrapulmonary percussive ventilation on intensive care unit length of stay, the incidence of pneumonia and gas exchange in critically ill patients: a systematic review

Dear Dr. Hassan:

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Checklist

(DOCX)

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S1 Table. Search strategy.

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S1 File. Meta analysis.

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S2 File. Search results titles and abstracts.

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S3 File. Data extraction.

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Data Availability Statement

The search results and results of data extraction for this systematic review are included in the Supporting Information files.

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PERMALINK

Effect of intrapulmonary percussive ventilation on intensive care unit length of stay, the incidence of pneumonia and gas exchange in critically ill patients: A systematic review

Anwar Hassan

William Lai

Jennifer Alison

Stephen Huang

Maree Milross

Roles

Abstract

Background

Research question

Methods

Results

Interpretation

Introduction

Methods

Search strategy

Inclusion and exclusion criteria

Study review and data extraction

Fig 1. PRISMA flow chart.

Assessment of quality and risk of bias

Table 1. Cochrane assessment of the risk of bias.

Table 2. Quality assessment using PEDro scale [25].

Outcome measures

Results

Table 3. Study summary.

Study characteristics

Patient characteristics

Intervention

Outcome measures

ICU length of stay

Incidence of pneumonia

Gas exchange

Respiratory rate

Airway clearance

Adverse events and tolerance

Discussion

Limitation

Conclusions

Supporting information

Acknowledgments

Abbreviations

Data Availability

Funding Statement

References

Decision Letter 0

Shane Patman

Roles

Author response to Decision Letter 0

Decision Letter 1

Shane Patman

Roles

Acceptance letter

Shane Patman

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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