Efficacy and Adverse Events of High-Frequency Oscillatory Ventilation in Adult Patients With Acute Respiratory Distress Syndrome

A Meta-analysis

Chun-Ta Huang; Hsien-Ho Lin; Sheng-Yuan Ruan; Meng-Sui Lee; Yi-Ju Tsai; Chong-Jen Yu

Crit Care. 2014;18(R102)

Abstract and Introduction

Abstract

Introduction: Theoretically, high-frequency oscillatory ventilation (HFOV) achieves all goals of a lung-protective ventilatory mode and seems ideal for the treatment of adult patients with acute respiratory distress syndrome (ARDS). However, its effects on mortality and adverse clinical outcomes remain uncertain given the paucity of high-quality studies in this area. This meta-analysis was performed to evaluate the efficacy and adverse events of HFOV in adults with ARDS.

Methods: We searched PubMed, EMBASE and Cochrane Central Register of Controlled Trials through February 2014 to retrieve randomized controlled trials of HFOV in adult ARDS patients. Two independent reviewers extracted data on study methods, clinical and physiological outcomes and adverse events. The primary outcome was 30-day or hospital mortality. Risk of bias was evaluated with the Cochrane Collaboration's tool. Mortality, oxygenation and adverse effects of HFOV were compared to those of conventional mechanical ventilation. A random-effects model was applied for meta-analysis.

Results: A total of five trials randomly assigning 1,580 patients met inclusion criteria. Pooled data showed that HFOV significantly improved oxygenation on day one of therapy (four studies; 24% higher; 95% confidence interval (CI) 11 to 40%; P <0.01). However, HFOV did not reduce mortality risk (five studies; risk ratio (RR) 1.04; 95% CI 0.83 to 1.31; P = 0.71) and two early terminated studies suggested a harmful effect of HFOV in ARDS (two studies; RR 1.33; 95% CI 1.09 to 1.62; P <0.01). Safety profiles showed that HFOV was associated with a trend toward increased risk of barotrauma (five studies; RR 1.19; 95% CI 0.83 to 1.72; P = 0.34) and unfavorable hemodynamics (five studies; RR 1.16; 95% CI 0.97 to 1.39; P = 0.12).

Conclusions: HFOV improved oxygenation in adult patients with ARDS; however, it did not confer a survival benefit and might cause harm in the era of lung-protective ventilation strategy. The evidence suggests that HFOV should not be a routine practice in ARDS and further studies specifically selecting patients for this ventilator mode should be pursued.

Introduction

Acute respiratory distress syndrome (ARDS) is a syndrome resulting from acute, diffuse, inflammatory lung injury and is associated with increased pulmonary vascular permeability, increased lung weight and loss of aerated tissue.^[1] It is associated with a variety of systemic and pulmonary insults, and clinically characterized by acute onset of respiratory failure associated with hypoxemia refractory to oxygen therapy and bilateral radiographical opacities. ARDS is the most severe form of lung injury and carries an appreciable mortality rate.^[1]

Conventional mechanical ventilation (CMV) remains the cornerstone of therapy for ARDS patients; however, mechanical ventilation per se may worsen a preexisting lung injury through overdistension of alveoli and cyclic atelectasis, and produce ventilator-induced lung injury.^[2] In 2000, a landmark trial demonstrated that mechanical ventilation with a lower tidal volume (6 ml/kg) than was traditionally used (12 ml/kg) results in decreased mortality in patients with ARDS,^[3] and the observed benefit is probably explained by reduction of ventilator-induced lung injury. From then on, a lung-protective ventilation strategy has been widely adopted for the management of ARDS. However, despite progress in critical care and our better understanding of the pathophysiological mechanisms responsible for ARDS, its mortality remains as high as 48%.^[4]

High-frequency oscillatory ventilation (HFOV), developed by Lunkenheimer et al. in 1972,^[5] delivers very small tidal volumes (1 to 4 ml/kg) at a frequency range of 3 to 15 Hz while maintaining a high mean airway pressure. The evidence from observational studies showed that HFOV could improve oxygenation when employed as a rescue therapy after failing CMV in patients with ARDS.^[6–11] HFOV is a theoretically ideal lung-protective ventilation mode to prevent development of ventilator-induced lung injury by limiting excess alveolar distension and achieving greater lung recruitment. However, previous clinical trials failed to provide convincing evidence to prove the efficacy of HFOV in adult patients with ARDS due to small sample size.^[12–14] In addition, uncertainty exists regarding overall evidence for adverse effects of HFOV, such as barotrauma and hemodynamic compromise.^[15,16] Two large randomized controlled trials of HFOV in ARDS had published their results in early 2013.^[17,18] It is anticipated that an updated meta-analysis may help clarify the role of HFOV in adult ARDS.

In this study, we conducted a systematic review and meta-analysis to evaluate the efficacy of HFOV in terms of oxygenation and mortality and the adverse events associated with the use of HFOV.

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Table 1. Characteristics of the five adult studies included in the review
	Derdak et al. 2002 [12]	Shah et al. 2004 [13]	Bollen et al. 2005 [14]	Ferguson et al. 2013 [18]	Young et al. 2013 [17]
Patients, number	148	28	61	548	795
Mean age, year	49.5	49.2	52.5	54.5	55.4
Male sex, number (%)	86 (58%)	18 (64%)	42 (69%)	320 (58%)	495 (62%)
APACHE II, mean^a	22	19.0	20.7	29	21.8
Enrollment period	1997–2000	Not reported	1997–2001	2007–2012	2007–2012
Enrollment criteria	PaO₂/F_IO₂ ≦200 with PEEP ≧10 cmH₂O	ARDS^b	PaO₂/F_IO₂ < 200	PaO₂/F_IO₂ ≦200 with F_IO₂ ≧0.5	PaO₂/F_IO₂ ≦200 with PEEP ≧5 cmH₂O
Mean PaO₂/F_IO₂ at enrollment	112.5	110.6	22.4^c	117.5	113
Ventilator days prior to study	3.5 (mean)	<5	1.9 (mean)	2.2 (mean)	2.2 (mean)

^aScored at randomization, except the study by Ferguson et al., in which scored at admission to the intensive care unit; ^bbased on the American-European Consensus Conference definition of the acute respiratory distress syndrome; ^coxygenation index. APACHE II, Acute Physiology and Chronic Health Evaluation II; PaO₂, partial pressure of oxygen in arterial blood; F^IO₂, fraction of inspired oxygen; PEEP, positive end-expiratory pressure; ARDS, acute respiratory distress syndrome.

Table 2. Ventilator settings in included studies
	Derdak et al. 2002 [12]	Shah et al. 2004 [13]	Bollen et al. 2005 [14]	Ferguson et al. 2013 [18]	Young et al. 2013 [17]
HFOV
Mean airway pressure	5 cmH₂O above mean airway pressure on CMV	5 cmH₂O above mean airway pressure on CMV	5 cmH₂O above mean airway pressure on CMV	30 cmH₂O	5 cmH₂O above plateau pressure on CMV
Frequency, Hz	5	5	5	3–12	10
Amplitude	To achieve chest wall vibration to the level of the midthigh	To achieve chest wall to midthigh vibration	According to PaCO₂ and to achieve chest wall vibration	90 cmH₂O	A cycle volume of 100 ml
CMV
Mode	Pressure control ventilation	Pressure control ventilation	Pressure control ventilation	Pressure control ventilation	Pressure control ventilation
Tidal volume	6–10 ml/kg (actual body weight)	A mean of 7–8 ml/kg (ideal body weight)	A mean of 8–9 ml/kg (ideal body weight)	6 ml/kg (predicted body weight)	6–8 ml/kg (ideal body weight)
Adjustment of PEEP	Study protocol	ARDS Network protocol	Not reported	Lung Open Ventilation Study	ARDS Network protocol

HFOV, high-frequency oscillatory ventilation; CMV, conventional mechanical ventilation; PaCO₂, partial pressure of carbon dioxide in arterial blood; PEEP, positive end-expiratory pressure; ARDS, acute respiratory distress syndrome.

Table 3. Risk of bias assessment
	Derdak et al. 2002 [12]	Shah et al. 2004 [13]	Bollen et al. 2005 [14]	Ferguson et al. 2013 [18]	Young et al. 2013 [17]
Random sequence generation	Low	Low	Low	Low	Low
Allocation concealment	Low	Low	Low	Low	Low
Incomplete outcome data	Low	Low	Unclear	Low	Low
Selective reporting	Low	Low	Low	Low	Low
Other sources of bias
Unplanned crossovers <5%	Low	Low	Low	Low	Low
Premature termination of trial	Low	Low	Unclear	Unclear	Low
Overall risk of bias	Low	Low	Unclear	Unclear	Low

Table 4. Effects of high-frequency oscillatory ventilation on physiological outcomes in patients with acute respiratory distress syndrome
Outcome	Number of studies (patients)	Ratio of means (95% CI); P value	P value for heterogeneity; I²
PaO₂/F_IO₂
Day 1	4 (1032)	1.24 (1.11–1.40); <0.001	0.119; 49%
Day 2	4 (1032)	1.13 (0.94–1.37); 0.2	0.002; 79%
Day 3	4 (1032)	1.16 (0.99–1.35); 0.072	0.012; 73%
Mean airway pressure, cmH₂O
Day 1	4 (785)	1.31 (1.25–1.36); <0.001	0.001; 81%
Day 2	3 (237)	1.28 (1.18–1.38); <0.001	0.002; 84%
Day 3	4 (785)	1.25 (1.15–1.36); <0.001	<0.001; 90%
PaCO₂, mmH₂O
Day 1	5 (1580)	0.97 (0.87–1.07); 0.494	<0.001; 94%
Day 2	4 (1032)	0.96 (0.83–1.11); 0.554	<0.001; 97%
Day 3	5 (1580)	1.11 (0.99–1.23); 0.068	<0.001; 96%

CI, confidence interval; PaO₂, partial pressure of oxygen in arterial blood; F_IO₂, fraction of inspired oxygen; PaCO₂, partial pressure of carbon dioxide in arterial blood.

Table 5. Adverse effects of included studies
Derdak et al. 2002 [12]	Barotrauma. Air leak developed or worsened: HFOV 7/75, CMV 9/73.
	Hypotension. Intractable hypotension: HFOV 0/75, CMV 2/73.
	Endotracheal tube obstruction: HFOV 4/75, CMV 3/73.
Shah et al. 2004 [13]	Barotrauma: HFOV 0/15, CMV 1/13.
Shah et al. 2004 [13]	Hypotension: HFOV 1/15, CMV 0/13.
Bollen et al. 2005 [14]	Barotrauma. Air leak (therapy failure): HFOV 1/37, CMV 1/24.
Bollen et al. 2005 [14]	Hypotension (therapy failure): HFOV 4/37, CMV 1/24.
Ferguson et al. 2013 [18]	Barotrauma. New-onset barotrauma: HFOV 46/256, CMV 34/259^a.
Ferguson et al. 2013 [18]	Hypotension. Vasopressor on study day 1: HFOV 202/260, CMV 157/256.
Young et al. 2013 [17]	Barotrauma. Reported as serious adverse events: HFOV 1/398, CMV 0/397.
	Hypotension. Vasoactive or inotropic agent on study day 1: HFOV 173/370, CMV 177/392.