Adaptive Support Ventilation (ASV) Is a Closed-Loop Ventilation Mode Conceived to Provide

Adaptive Support Ventilation versus conventional ventilation for total ventilatory support in acute respiratory failure

Giorgio A. Iotti, Andrea Polito, Mirko Belliato, Daniela Pasero, Gaetan Beduneau, Marc Wysocki, Josef X. Brunner, Antonio Braschi, Laurent Brochard, Jordi Mancebo, V. Marco Ranieri, Jean-Christophe M. Richard, Arthur S. Slutsky

Electronic Supplementary Material

Extended Methods Patients The study was conducted between October 2004 and November 2005 in three general and three medical intensive care units of university hospitals or university-affiliated hospitals in three European countries (Réanimation Médicale - Hôpital Henri Mondor of Créteil, and Réanimation Médicale - Hôpital Charles Nicolle of Rouen, in France; Rianimazione - Ospedale Ss. Antonio e Biagio of Alessandria, Rianimazione 1 - Fondazione IRCCS Policlinico S. Matteo of Pavia, and Rianimazione 1 - Ospedale S. Giovanni Battista – Molinette of Torino, in Italy; Servei Medicina Intensiva - Hospital Sant Pau of Barcelona, in Spain). The study was conducted in accordance with the standards of the Declaration of Helsinki and approved by the Ethics Committee of each participating institution. Written informed consent was obtained prior to inclusion from each patient’s representative. We included adult patients who were intubated, sedated and passively ventilated on volume-control ventilation (VCV) or pressure-control ventilation (PCV) for ≥24 hours, who were stable from a respiratory and hemodynamic point of view, and in whom continued sedation and passive ventilation was expected for at least 6 hours. Exclusion criteria were pregnancy, moribund state, brain injury requiring strict control of PaCO2, hemodynamic instability and/or respiratory instability. Besides the common clinical criteria, hemodynamic instability was defined as a need to change the cardio-vasoactive drugs infusion or need for blood volume expanders over the prior 3 hours, while respiratory instability was defined as need for major changes in the ventilator settings over the prior 3 hours. Patients with inverse ratio ventilation or airleaks on conventional ventilation were also excluded, because by design adaptive support ventilation (ASV) does not provide an I:E ratio higher than 1:1, and its typical performance can be affected by airleaks.

1 At inclusion, each patient was assigned to one of three categories: patients with restrictive lung disease, patients with obstructive lung disease or patients with healthy lungs. Patients with restrictive lung disease included those with acute lung injury (ALI) / acute respiratory distress syndrome (ARDS) [1] or restrictive pulmonary disease of other origin. Patients with obstructive lung disease included those with exacerbated chronic obstructive pulmonary disease (COPD) [2] or acute severe asthma [3]. Patients with healthy lungs were patients who needed mechanical ventilation because of ventilatory pump failure, with normal chest X-ray and no obvious underlying respiratory disease.

Materials During the study, patients were ventilated with Galileo Gold ventilators (Hamilton Medical AG, Bonaduz, CH). Data on respiratory pattern and mechanics were collected with the proximal sensors and monitoring utilities of the ventilator, and recorded by the DataLogger software (Hamilton Medical, Bonaduz, CH) on a laptop connected to the ventilator data board. We obtained a continuous breath-by-breath recording of ventilator settings and monitoring data during the entire study, and real-time recordings of airway opening pressure, airflow and volume for at least 30 s at the end of each study step, for off-line calculation of the mechanical work of inspiration. The latter, i.e. the work performed by the ventilator to generate a breath, was calculated by integrating the product of airflow and airway opening pressure above external PEEP over the inspiratory time [4]. Plateau pressure and intrinsic PEEP (PEEPi) were measured by applying 4-s occlusion manoeuvres, at end-inspiration and end-expiration respectively. Arterial blood samples for gas analysis were obtained from arterial catheters. Basic hemodynamic data were read and recorded from the vital signs monitor of each patient.

Design of the study For each patient, the study was designed to obtain data representative of three conditions: conventional ventilation, ASV set at the same minute ventilation as observed during conventional ventilation (isoMV-ASV), and ASV set to obtain the same PaCO2 as observed during conventional ventilation (isoCO2-ASV). The first step of the study entailed measurements while the patient was on conventional ventilation. Each patient was studied on the ventilation mode (VCV or PCV) and the ventilation settings determined by the patient’s attending physician, according to the current practice of each centre. The only necessary change was the replacement of the ventilator in patients who were not already ventilated by a Galileo Gold. Also the humidification system (active humidifier or heat and moisture exchanger) was not varied. In

2 all cases, we had a 60-min stabilization period on conventional ventilation before starting data collection. During this period we performed a short study of total respiratory system mechanics by the constant inspiratory flow, end-inspiratory and end-expiratory occlusion method (4-s occlusion duration), to obtain reference measurements for maximum inspiratory resistance, quasi-static compliance and PEEPi [5,6]. The second step of the study was to study the patient while on ASV set so as to aim for the same minute ventilation that the patient had received while on conventional ventilation. This step was called isoMV-ASV. For this purpose the Galileo Gold ventilator was switched to ASV, with the minute volume control set at the same value as the expired minute ventilation observed during the previous step of conventional ventilation, and with unchanged PEEP and FiO2. The other relevant controls of ASV, i.e. PBW and inspiratory pressure limit were set as follows. PBW was calculated from height and sex, for males as equal to 50 + 0.91(centimetres of height - 152.4); for females as equal to 45.5 + 0.91(centimetres of height - 152.4) [7]. In patients humidified with a heat and moisture exchanger, the PBW setting was increased by 10%, according to the indications of the ASV user’s manual (Hamilton Medical, Bonaduz, CH). The inspiratory pressure limit was generally set at 35 cmH2O. Only in the obstructive disease group a higher pressure limit was allowed, because obstructed patients may require substantial overpressure to be ventilated. In these patients the pressure limit was set, between a minimum of 35 and a maximum of 50 cmH2O, at 10 cmH2O above the peak pressure observed during the first study step on conventional ventilation. Data collection for isoMV-ASV was performed 30 minutes after the start. The conduct of the rest of the study depended on the PaCO2 level measured during the isoMV condition. When the PaCO2 difference between isoMV-ASV and conventional ventilation was lower than ±3 mmHg, the isoMV and isoCO2 conditions were considered coincident, and hence the study was concluded. When the PaCO2 difference was equal or higher than ±3 mmHg, the study continued with further steps in which the only change was a readjustment of the minute volume setting intended to achieve the isoCO2 condition. Readjustments were made prospectively and based on a principle of constancy of the product between minute ventilation and PaCO2. Data collection for each attempt to achieve the isoCO2-ASV condition were performed after a stabilization period of 30 minutes. In each patient, after the first study step, the ventilator settings to be applied in a given study step depended on data obtained during the previous steps. In order to facilitate the correct application of this process, investigators entered data into a PC-based tool expressly

3 designed for data recording and simultaneous calculation of ventilator settings to be applied according to the study protocol.

Additional Results and Discussion An additional comparison for plateau pressure between conventional ventilation and ASV is shown in E-Figure 1, plotting the individual changes in plateau pressure between conventional ventilation and isoCO2-ASV. During ASV plateau pressure exceeded 30 cmH2O only in few cases, with a maximum value of 33 cmH2O. It can be noted that in all cases of high plateau pressure during ASV, the same parameter was high during conventional ventilation as well, thus highlighting the difficulty to obtain a protective ventilation in these patients. Probably a further limitation of plateau pressure could have been obtained only by permitting more hypoventilation and higher levels of PaCO2.

E-Figure 1. Individual changes in plateau pressure (Pplat) between conventional ventilation and ASV at unchanged arterial PCO2 (isoCO2-ASV). Different symbols represent the three different pathophysiological groups: restrictive disease (triangles), obstructive disease (diamonds) or healthy lungs patients (circles). Dotted line: identity line. Dashed lines correspond to a pressure of 30 cmH2O (a theoretical safety limit).

The value of expiratory time constant as a synthetic descriptor of the passive mechanical status of the respiratory system is analyzed in E-Figure 2. In patients with restrictive lung disease, the time constant accurately reflected the degree of impairment of total respiratory system compliance, the latter ranging between extremely low values and

4 virtually normal values. In patients with restrictive disease, compliance was the main determinant of time constant (r2 = .649), while the correlation between respiratory system resistance and time constant was poor (r2 = .019). Differently, in patients with obstructive lung disease the time constant reflected the severity of the exhalation disorder due to airway obstruction (high resistance) and/or reduced elastic recoil (high compliance). E-Figure 2 shows the correlation of time constant with resistance (r2 = .291) and compliance (r2= .486) in obstructed patients.

E-Figure 2. Relationships between expiratory time constant (RCe) and total respiratory system resistance (Rtot) and compliance (Ctot) measured by least squares fit in restrictive disease patients and obstructed patients (left and right panel respectively) during ASV. The plots include all the individual data obtained during ASV set to achieve the same arterial PCO2 as during conventional ventilation (isoCO2-ASV). Empty and full symbols represent Ctot and Rtot, respectively. Regression lines are shown, except for Rtot in patients with restrictive disease (not significant).

Additional results concerning the times of the respiratory cycle are shown in E-Figures 3 and 4. During conventional ventilation the respiratory duty cycle (inspiratory time:total cycle time ratio -Ti/Ttot-) was widely variable between patients (range between 10% and 45%), but it was not correlated with the expiratory time constant (E-Figure 3). Apparently, when setting conventional ventilation, the clinicians’ choice for Ti/Ttot was independent from observations about patient’s respiratory disease and mechanics. Conversely, during ASV there was a clear negative relationship between Ti/Ttot and expiratory time constant, especially in the range of time constants between the lowest values and 1 second. In case of short time constant, i.e. of low susceptibility to dynamic pulmonary hyperinflation, the ASV algorithm tended to an I:E ratio of 1:1. On the contrary, when the expiratory time constant was longer,

5 ASV lowered the I:E ratio, with the aim of prolonging the expiratory time. In case of very long time constants, however, ASV tended to minimize dynamic pulmonary hyperinflation mainly by lowering the respiratory frequency. E-Figure 4 shows that the inspiratory time has a minimum limit, equal to one time constant, and conceived to preserve an inspiratory time possibly sufficient to meet a severe increase of inspiratory resistance. E-Figure 4 also plots expiratory time against expiratory time constant, showing that in a large number of cases the expiratory time corresponded to 3.5 times the time constant, while it was never lower than 2 times the time constant.

E-Figure 3. Relationships between respiratory duty cycle (inspiratory time:total cycle time ratio -Ti/Ttot-) and expiratory time constant (RCe), during conventional ventilation (upper panel) and during ASV (lower panel) set to achieve the same arterial PCO2 (isoCO2-ASV). Different symbols represent the three different pathophysiological groups: restrictive disease (triangles), obstructive disease (diamonds) or healthy lungs patients (circles). The fitted curves were calculated on data points of the three groups altogether by the LOWESS procedure (tension 66%). Dashed line of upper panel: maximum Ti/Ttot value in conventional ventilation admitted by study protocol for patient inclusion. Dashed lines of lower panel: maximum and minimum Ti/Ttot values admitted by ASV algorithm.

6 E-Figure 4. Relationships between times of the respiratory cycle and expiratory time constant (RCe) during ASV: inspiratory time (Ti) in upper panel and expiratory time (Te) in lower panel. Plots include all the individual data obtained during ASV set to achieve the same arterial PCO2 as during conventional ventilation (isoCO2-ASV). Different symbols represent the three different pathophysiological groups: restrictive disease (triangles), obstructive disease (diamonds) or healthy lungs patients (circles). Lines correspond to the main rules of the ASV algorithm for setting the respiratory times. The Ti of ASV should be of at least one RCe (corresponding to the dashed line of the upper panel), with minimum and maximum values of 0.5 and 2 s respectively (corresponding to the dotted lines of the upper panel). The primary Te-target of ASV is of 3.5 times the RCe (corresponding to the dotted line of the lower panel), and the minimum Te is of at least twice the RCe (corresponding to the dashed line of the lower panel).

In comparison with the results of Belliato [8], in the present study ASV provided a lower Ti/Ttot in the restricted patients and in the patients with healthy lungs (Fig. 3 and E- Figure 3). This difference is explained by a slight change in the definition of the target for the expiratory time in the ASV algorithm, that is of 3.5 times the time constant in Galileo Gold, while it was of 3 times the time constant in previous software versions.

7 References

1. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, LeGall JR, Morris A, Spragg R, The Consensus Committee (1994) Report of the American-European consensus conference on ARDS: definitions, mechanisms, relevant outcomes and clinical trial coordination. Intensive Care Med 20:225-232 2. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS (2001) Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO global initiative for chronic obstructive lung disease (GOLD) workshop summary. Am J Respir Crit Care Med 163:1256-1276 3. McFadden ER Jr (2003) Acute severe asthma. Am J Respir Crit Care Med 168:740-759 4. Banner MJ, Kirby RR, Gabrielli A, Blanch PB, AJ Layon AJ (1994) Partially and totally unloading respiratory muscles based on real-time measurements of work of breathing. A clinical approach. Chest 106;1835-1842 5. D’Angelo E, Calderini E, Torri G, Robatto FM, Bono D, Milic-Emili J (1989) Respiratory mechanics in anesthetized paralyzed humans: effects of flow, volume, and time. J Appl Physiol 67:2556-2564 6. Maltais F, Reissmann H, Navalesi P, Hernandez P, Gursahaney A, Ranieri VM, Sovilj M, Gottfried SB (1994) Comparison of static and dynamic measurements of intrinsic PEEP in mechanically ventilated patients. Am J Respir Crit Care Med 150:1318-1324 7. Devine BJ (1974) Gentamicin pharmacokinetics. Drug Intell Clin Pharm 8:650-655 8. Belliato M, Palo A, Pasero D, Iotti GA, Mojoli F, Braschi A (2004) Evaluation of adaptive support ventilation in paralysed patients and in a physical lung model. Int J Artif Organs 27:709-716