Inhaled bronchodilator administration during mechanical ventilation: how to optimize it, and for which clinical benefit?

Bronchodilators are frequently used in ICU patients, and are the most common medications administered by inhalation during mechanical ventilation. The amount of bronchodilator that deposits at its site of action depends on the amount of drug, inhaled mass, deposited mass, and particle size distribution. Mechanical ventilation challenges both inhaled mass and lung deposition by specific features, such as a ventilatory circuit, an endotracheal tube, and ventilator settings. Comprehensive in vitro studies have shown that an endotracheal tube is not as significant a barrier for the drug to travel as anticipated. Key variables of drug deposition are attachments of the inhalation device in the inspiratory line 10 to 30 cm to the endotracheal tube, use of chamber with metered-dose inhaler, dry air, high tidal volume, low respiratory frequency, and low inspiratory flow, which can increase the drug deposition. In vivo studies showed that a reduction by roughly 15% of the respiratory resistance was achieved with inhaled bronchodilators during invasive mechanical ventilation. The role of ventilatory settings is not as clear in vivo, and primary factors for optimal delivery and physiologic effects were medication dose and device location. Nebulizers and pressurized metered-dose inhalers can equally achieve physiologic end points. The effects of bronchodilators should be carefully evaluated, which can easily be done with the interrupter technique. With the non-invasive ventilation, the data regarding drug delivery and physiologic effects are still limited. With the bilevel ventilators the inhalation device should be located between the leak port and face mask. Further studies should investigate the effects of inhaled bronchodilators on patient outcome and methods to optimize delivery of inhaled bronchodilators during non-invasive ventilation.

Viscoelastic properties of lungs and thoracic wall of anesthetized mechanically ventilated piglets.

OBJECTIVE: To investigate the viscoelastic properties of lungs and thoracic wall in piglets. STUDY DESIGN: Prospective experimental study. ANIMALS: Six piglets weighting 30 kg. METHODS: Animals were tracheotomized, anesthetized and mechanically ventilated under controlled conditions. After control measurements of the mechanical properties of the lung of the pigs had been taken, acute lung injury (ALI) was induced by saline lavage. Lung and thoracic wall tissue resistance (DeltaR), which reflects viscoelastic properties and/or time constant inequalities, were determined by using a rapid airway occlusion technique during constant flow inflation (V), at constant tidal volume. was varied from 0.1-0.2 to 1.2 L second(-1) on a single breath. Multiple data sets of DeltaR of lung (DeltaR(L)) and thoracic wall (DeltaR(w)) to inspiratory time (T(I) = V(T)/V) were fitted to a model whose prediction equation was DeltaR = R(2)[1 -exp(-T(I)/tau(2))], where R(2) and tau(2) are the 'viscoelastic' resistance and time constant, respectively. Subscripts (L) and (W) are used to represent lung and thoracic wall, respectively (R(2L), R(2W), tau(2L), tau(2W)). Two more sets of physiological measurements were then taken--the first under zero end-expiratory pressure (ZEEP) and the second under a positive end-expiratory pressure (PEEP) of 10 cmH(2)O. RESULTS: Data of DeltaR adequately fitted to the prediction equation in all instances. In control, R(2,L) was 15.3 (10.7-22.6) cmH(2)O L(-1) second(-1) (median, interquartile range), tau(2,L) 3.3 (1.9-5.5) seconds, R(2,w) 6.5 (2.2-10.3) cmH(2)O L(-1) second(-1) and tau(2,w) 2.9 (1.1-4.3) seconds. In ALI, R(2,L) significantly increased to 129.6 (105.9-171.3) cmH(2)O L(-1) second(-1) on ZEEP but not significantly decreased to 48.9 (17.8-109.6) cmH(2)O L(-1) second(-1) with PEEP. The corresponding values of tau(2,L) were 7.1 (5.1-11.6) and 4.4 (3.1-5.5) seconds. The values pertaining to thoracic wall did not change significantly among conditions. CONCLUSIONS AND CLINICAL RELEVANCE: Viscoelastic properties of the lung and thoracic wall in piglets can be described by a viscoelastic model. Values of parameters of this model were markedly increased in ALI and decreased with PEEP.

Does gas exchange response to prone position predict mortality in hypoxemic acute respiratory failure?

OBJECTIVE: To determine whether gas exchange response to a first prone position session can predict patient outcome in hypoxemic acute respiratory failure. METHODS: Data from a previous multicenter randomized controlled trial were retrospectively analyzed for relationship between PaO(2)/FIO(2) ratio and PaCO(2) changes during the first 8-h prone position session to day 28 mortality rate; 370 prone position sessions were analyzed. Arterial blood gas was measured in supine position before proning and in prone position at the end of the session. Gas exchange improvement was defined as increase in the PaO(2)/FIO(2) ratio of more than 20% (PaO(2)R) or decrease in PaCO(2) of more than 1 mmHg (PaCO(2)R). MAIN RESULTS: The 28-day mortality rate was 26.5% in PaO(2)R-PaCO(2)R, 31.7% in PaO(2)R-PaCO(2)NR, 38.9% in PaO(2)NR-PaCO(2)R, and 43% in PaO(2)NR-PaCO(2)NR (log-rank 14.02, p = 0.003). In a Cox proportional hazards model the gas exchange response was a significant predictor to patient outcome with a 82.5% increase in risk of death in the case of PaO(2)NR-PaCO(2)R or PaO(2)NR-PaCO(2)NR, relative to the gas exchange improvement response (odds ratio 1.825). However, after adjusting for the difference in oxygenation between day 2 and day 1 the gas exchange response does no longer reach significance. CONCLUSION: In patients with hypoxemic acute respiratory failure initial improvement in gas exchange in the first PP session was associated with a better outcome, but this association disappeared when the change in oxygenation from day 1 to day 2 was taken into account, suggesting that underlying illness was the most important predictor of mortality in this patient population.

Assessment of airway closure from deflation lung volume-pressure curve: sigmoidal equation revisited.

OBJECTIVE: To assess a sigmoidal equation for describing airway closure. DESIGN: Experimental study. SETTING: University laboratory. PARTICIPANTS: Eight piglets mechanically ventilated on zero end-expiratory pressure (ZEEP). INTERVENTIONS: Control and lung saline lavage. MEASUREMENTS AND RESULTS: Lungs were inflated up to transpulmonary pressure of 30 cmH(2)O at constant flow (0.12l s(-1)) then deflated at the same flow rate up to the point at which oesophageal pressure was constant, which was assumed to represent complete airway closure. The deflation volume-transpulmonary pressure curve was fitted to: (1) a sigmoidal equation focusing on inflexion point and pressure at maximal compliance increase and (2) an exponential equation above an inflexion point determined by eyeballing. Data deviate from the exponential equation at the point of airway closure onset. The zero-volume intercept was determined. Complete airway closure was reached at -8.3+/-3.5cmH(2)O in control conditions and at -1.3+/-3.7 cmH(2)O after lavage (p < 0.05). Between control and lavage, onset of airway closure was 3.0+/-1.9 vs. 6.0+/-2.8 cmH(2)O (p <0.05), inflexion point 3.2+/-1.8 vs. 7.7+/-2.6 cmH(2)O (p <0.001), pressure at maximal compliance increase -1.9+/-0.7 vs. -0.03+/-2.1cmH(2)O (p <0.05) and zero-volume intercept -1.5+/-1.4 vs. 0.3+/-2.3cmH(2)O (p <0.05). CONCLUSIONS: During mechanical ventilation airways stay open and close around ZEEP in control but are closed above ZEEP after lavage. Inflexion point might reflect onset of airways closure in control. Pressure at maximal compliance increase was not a marker of complete airways closure. In control and lavage, pressure at maximal compliance increase and zero-volume intercept were reasonably equivalent.

Effects of inhaled fenoterol and positive end-expiratory pressure on the respiratory mechanics of patients with chronic obstructive pulmonary disease.

BACKGROUND: During acute ventilatory failure in patients with chronic obstructive pulmonary disease (COPD), applying external positive end-expiratory pressure (PEEPe) will reopen small airways and, thus, may enhance peripheral deposition as well as the physiological effects of inhaled beta-2 agonists. OBJECTIVE: To investigate the efficacy of inhaled fenoterol applied by zero end-expiratory pressure (ZEEPe) or PEEPe. METHODS: Ten patients with COPD who were intubated and mechanically ventilated received fenoterol (10 mg/4 mL) via the ventilator using a jet nebulizer for 30 min on ZEEPe and PEEPe set at 80% of the total PEEP in a random order. The total resistance of the respiratory system (rapid airway occlusion technique), change in end-expiratory lung volume and expiratory flow limitation were assessed before and 5 min, 15 min, 30 min, 60 min and 240 min after fenoterol inhalation. RESULTS: Before inhalation and 60 min after inhalation, the total PEEP, the change in end-expiratory lung volume and the total resistance of the respiratory system were 8+/-3 cmH2O and 6+/-3 cmH2O, 0.61+/-0.34 L and 0.43+/-0.32 L, and 26+/-7 cmH2O/L/s and 23+/-6 cmH2O/L/s, respectively, with ZEEPe, and 9+/-3 cmH2O and 8+/-3 cmH2O (P<0.05 versus ZEEPe), 0.62+/-0.34 L and 0.62+/-0.37 L (P<0.05 versus ZEEPe), and 26+/-9 H2O/L/s and 25+/-9 H2O/L/s, respectively, with PEEPe. Three patients became not flow-limited under the combination of PEEPe and fenoterol. CONCLUSIONS: In patients with COPD, fenoterol combined with PEEPe has opposing effects on respiratory mechanics. First, it does not significantly reduce lung hyperinflation or inspiratory resistances. Second, it allows expiratory flow limitation reversal in some patients. These findings result from the net effect on end-expiratory lung volume of each intervention. This implies that if fenoterol is used in combination with PEEPe, the level of PEEPe should be reassessed during the time course of the drug to prevent any further lung hyperinflation.

Effects of systematic prone positioning in hypoxemic acute respiratory failure: a randomized controlled trial.

CONTEXT: A recent trial showed that placing patients with acute lung injury in the prone position did not increase survival; however, whether those results hold true for patients with hypoxemic acute respiratory failure (ARF) is unclear. OBJECTIVE: To determine whether prone positioning improves mortality in ARF patients. DESIGN, SETTING, AND PATIENTS: Prospective, unblinded, multicenter controlled trial of 791 ARF patients in 21 general intensive care units in France using concealed randomization conducted from December 14, 1998, through December 31, 2002. To be included, patients had to be at least 18 years, hemodynamically stable, receiving mechanical ventilation, and intubated and had to have a partial pressure of arterial oxygen (PaO2) to fraction of inspired oxygen (FIO2) ratio of 300 or less and no contraindications to lying prone. INTERVENTIONS: Patients were randomly assigned to prone position placement (n = 413), applied as early as possible for at least 8 hours per day on standard beds, or to supine position placement (n = 378). MAIN OUTCOME MEASURES: The primary end point was 28-day mortality; secondary end points were 90-day mortality, duration of mechanical ventilation, incidence of ventilator-associated pneumonia (VAP), and oxygenation. RESULTS: The 2 groups were comparable at randomization. The 28-day mortality rate was 32.4% for the prone group and 31.5% for the supine group (relative risk [RR], 0.97; 95% confidence interval [CI], 0.79-1.19; P = .77). Ninety-day mortality for the prone group was 43.3% vs 42.2% for the supine group (RR, 0.98; 95% CI, 0.84-1.13; P = .74). The mean (SD) duration of mechanical ventilation was 13.7 (7.8) days for the prone group vs 14.1 (8.6) days for the supine group (P = .93) and the VAP incidence was 1.66 vs 2.14 episodes per 100-patients days of intubation, respectively (P = .045). The PaO2/FIO2 ratio was significantly higher in the prone group during the 28-day follow-up. However, pressure sores, selective intubation, and endotracheal tube obstruction incidences were higher in the prone group. CONCLUSIONS: This trial demonstrated no beneficial outcomes and some safety concerns associated with prone positioning. For patients with hypoxemic ARF, prone position placement may lower the incidence of VAP.

Physiological effects of constant versus decelerating inflation flow in patients with chronic obstructive pulmonary disease under controlled mechanical ventilation.

OBJECTIVE: To study the cardiorespiratory effects of inspiratory flow rate and waveform in COPD patients. DESIGN: Prospective physiological investigation with randomized allocations of experimental conditions. SETTING: A 14-bed medical ICU in a 1000-bed university hospital. PATIENTS AND PARTICIPANTS: Ten COPD intubated, sedated and paralyzed patients with chronic obstructive pulmonary disease (COPD), mechanically ventilated for acute respiratory failure. INTERVENTIONS: In volume-controlled mode, three inflation flow rates of 0.40, 0.70, and 1.10 l/s for 20 min with a constant (CF) or a decelerating (DF) inflation flow profile. Each patient received all six experimental conditions in a random order. Tidal volume and respiratory frequency were similar during the experimental conditions. MEASUREMENTS AND RESULTS: Arterial blood gases, hemodynamics ( n=8), and respiratory mechanics were measured with zero end expiratory pressure. Between flow rates the median (25th-75th percentiles) values of PaO(2)/FIO(2) were 232 (132-289), 253 (161-338), 231 (163-352) for CF and 253 (143-331), 249 (164-360), 231 mmHg (187-351), for DF, respectively; the maximal airway pressures were 25.6, 28.3, 34.6 cmH(2)O for CF and 21.7, 29.6, 34.8 cmH(2)O for DF, respectively, the mean airway pressures were 8.9, 6.1, 5.4 cmH(2)O for CF and 9.1, 7, 6.5 cmH(2)O for DF, respectively. CONCLUSIONS: Changing the ventilator in volume-controlled mode with a DF or CF profile has no significant cardiorespiratory effect in intubated COPD patients mechanically ventilated for acute respiratory failure.