1. 0 2 4 6 8 10 12 Time (s) Volume (L) Flow (L/s) 0.4 0.0 -0.4 -0.8 0.6 0.4 0.2 0.0 inspiration expiration To advance the delivery of an EVW for routine clinical ventilation. While delivering the EVW in sheep we will create transient airway constriction or a model of ARDS. In both cases, we will assess the EVW’s ability to: maintain blood gases track the frequency dependence of dynamic R and E assess correlation between degradation of in blood gases and mechanical constriction conditions Enhanced Ventilator Waveform (EVW) for Tracking Frequency Dependence of Dynamic Resistance (R) and Elastance (E) C. Bellardine 1, E.P. Ingenito 2, A. Hoffman 3, F. Lopez 4, W. Sanborn 4, and K.R. Lutchen 1 1 Biomedical Engineering, Boston University, Boston, MA, 2 Pulmonary Division, Brigham and Women's Hospital, Boston, MA, 3 Tufts Veterinary School of Medicine, N. Grafton, MA, 4 Puritan Bennett/Tyco Healthcare, Pleasanton, CA INTRODUCTION Mechanical ventilation is required when a patient cannot generate sufficient pressures to maintain ventilation. The lungs’ ability to generate these pressures is governed primarily by two physical properties: 1) the elastic recoil and 2) the resistance of the respiratory system (R and E). With lung disease, R and E become elevated and increasingly more frequency dependent. The R and E from 0.1 to 8 Hz reflect the level and pattern of lung disease [1]. Modern clinical ventilators only apply simple flow waveforms containing energy primarily at one frequency. Therefore, the frequency dependence of R and E cannot be tracked. We have recently invented new broadband ventilation patterns known as Enhanced Ventilator Waveforms (EVWs) which contain discrete frequencies (from 0.1 to 8 Hz) blended to provide a tidal breath followed by a passive exhalation [2] (Fig 1). In principle, these waveforms allow for estimation of R and E from 0.1 to 8 Hz during ventilation. GOALS DATA ANALYSIS METHODS 1.Lutchen, K.R. and B. Suki. “Understanding pulmonary mechancis using the forced oscillation technique.” Bioengineering Approaches to Pulmonary Physiology and Medicine. 1996. 2.Kaczka, D.W., E. Ingenito, and K.R. Lutchen. “A technique to determine inspiratory impedance during mechanical ventilation: Implications for flow limited patients.” Annals of Biomedical Engineering. 27: 340-355, 1999. RESULTS I (Figure 3) Figure 2. The EVW was implemented in a prototype of the NPB840 (Puritan Bennett/Tyco Healthcare) ventilator shown above. Figure 3. (A) a mild responder, (B) a moderate responder, and (C) a severe responder. The top panels display the arterial blood gas measurements which were taken periodically. The middle and bottom panels display the dynamic R and E estimates calculated from the EVW. The EVW was applied in 5 sheep before and after a bronchial challenge. Measured arterial O 2 and CO 2. EVW processed to obtain dynamic inspiratory R and E vs. frequency. PROTOCOL:  Stabalize sheep on conventional ventilation for 15 minutes  Collect baseline dynamic R and E measurements  Switch to the EVW for 30 minutes. Obtain O 2, CO 2, and R and E measurements every at 0, 15, and 30 minutes.  Deliver nebulized carbochol (16mg/ml for 2 minutes). Monitor response through blood gas and R and E measurements at 5, 15, and 30 minutes.  Deliver albuterol MDI. Obtain final R and E estimates. The EVW was then applied in the same 5 sheep before and during an oleic acid lung injury model of ARDS and blood gases were once again tracked.. Figure 1. EVW flow and volume are plotted vs. time. Note the enhanced frequency content in the inspiratory flow waveform and also the passive expiratory sections. In all sheep the EVW provided clinically effective ventilation during and after bronchoconstriction. Data revealed a range of constriction conditions from mild and homogeneous to severe and heterogeneous with airway closures. The latter were correlated with significant drops in O2, which suggests overdistension of a small alveolar surface leading to V/Q mismatch. Often there was lack of complete improvement in R and E with albuterol or recruitment maneuvers. This was consistent with a pattern of airway closures that would not reopen. In the ARDS lung injury model, the EVW revealed the progression of the disease state and also provided effective ventilation. We conclude that the EVW is a viable new ventilation method that can simultaneously provide clinically unique information regarding the mean level and heterogeneity of lung constriction. The degree of heterogeneity directly reflects the mechanical requirements of breathing and potential ventilation- perfusion mismatches. This unique information could be the basis to of more knowledgeable and effective clinician intervention with regards to treatment and ventilator weaning strategies. SUMMARY A feedback algorithm was designed to compensate for the patient tubing and ensure that the desired EVW (Fig 1) was delivered at the airway opening. The flow and pressure at the airway opening was measured (Q ao and P ao, respectively). The inspiratory segments of the pressure and flow data were then isolated and fit to a trigonometric Fourier Series using the technique previously described by Kaczka [2]. The corresponding low frequency components of R and E were recalculated to adjust for transient artifacts. The Q ao and P ao were low pass filtered to isolate the low frequency components and fit to the following equation using a standard linear regression. Low frequency R and E were then re-estimated. After 30 minutes of ventilation with the EVW and prior to the bronchial challenge, blood gases are maintained and there are no significant changes in R and/or E from baseline. The EVW is successful at ventilation. With increased response, the R and E are elevated at all frequencies. The elevated E at low frequencies is indicative of airway closures. There is also more frequency dependence in both R and E. The severe responder shows significant evidence of airway closure (elevated E at 0.2 Hz) and heterogeneous constriction (more frequency dependence). This should impact ventilation distribution. In fact, oxygen levels are extremely depressed and carbon dioxide levels are elevated. Administration of Albuterol (a brochodialator) did not result in a complete improvement in R and E. This is consistent with a pattern of airway closures that would not reopen. This is highly apparent in the moderate and severe case. Figure 4. Correlation between decrease in arterial PaO2 levels and increases in airway resistance (A), heterogeneity (B), and airway closure (C). The decrease in oxygen is weakly correlated with increases in airway resistance, however, strongly correlated with increases in heterogeneity and airway closures (I.e. loss of surface area). Both increased heterogeneity and airway closures are consistent with a substantial degradation of ventilation distrubution APPLICATIONS TO ARDS (Figure 5) RESULTS II (Figure 4) (B) (C)(A) (B)(C) MILDMODERATESEVERE Figure 5. Arterial blood gas measurements take at baseline and at 10m after the initial and final oleic acid doses (A) and the corresponding dynamic R (B) and E estimates (C) calculated from the EVW. (A) (B)(C) The EVW was additionally applied in the same 5 sheep before and during an oleic acid injury model of ARDS. Doses of oleic acid were administered every 10 minutes until a significant drop in arterial oxygen was obtained (<200mmHg) signifying severe pulmonary edema. Blood gas and EVW measurements were collected throughout the experiment. With increased severity of ARDS, there were increased airway closures, increased heterogeneity or frequency dependence of both R and E, and elevated R and E values at all frequencies.