AU2012243429A1 - System and process for determining a positive end-expiratory pressure for a mechanical ventilation system - Google Patents

Abstract

A process for determining a positive end-expiratory pressure for a mechanical ventilation system, including: determining values for compliance of a patient's respiratory system during mechanical ventilation of the patient using respective positive end-expiratory pressure (PEEP) values; and processing the compliance values and the PEEP values to determine a PEEP value as substantially being a lowest PEEP value that provides a highest compliance value.

Description

WO 2012/139159 PCT/AU2012/000370 SYSTEM AND PROCESS FOR DETERMINING A POSITIVE END-EXPIRATORY PRESSURE FOR A MECHANICAL VENTILATION SYSTEM TECHNICAL FIELD 5 The present invention relates to a system and process for determining a positive end expiratory pressure for a mechanical ventilation system and use of the mechanical ventilation system in therapeutic protocols. BACKGROUND Many patients who are admitted to intensive care units require some form of ventilatory 10 (breathing) assistance via a mechanical ventilator, either to support and treat a diseased lung, or to assist ventilation whilst the patient recovers from another problem. Mechanical ventilators provide ventilatory support via positive pressure, which means that these machines move the lungs by blowing gas into the lungs under pressure. The amount of pressure applied to the lung is directly proportional to the resultant volume of gas in the 15 lung. The clinician needs to set the ventilator to deliver the correct pressure to inflate the lung during each 'breath' (positive inspiratory pressure, or PIP), and also to deliver the correct pressure between inflations to prevent the lung totally collapsing or being too distended (positive end-expiratory pressure, or PEEP). 20 When done properly, mechanical ventilation is life saving and safe. but when applied poorly the lung is at risk of injury from either inadequate or excessive applied pressure for both PIP and PEEP. Modern ventilators are now very complex devices with internal central processing units 25 able to perform and apply intricate mathematical algorithms. Nearly all modern ventilators have in built safety modes that try to avoid the inadvertent delivery of excessive PIP. Each manufacturer has a different proprietary name for these modes, but all are based on a volume-targeted algorithm whereby the clinician sets the amount of gas (volume) that is believed to be needed to adequately inflate the lung (referred to- as the tidal volume), and WO 2012/139159 PCT/AU2012/000370 -2 the ventilator applies an algorithm to determine what PIP will achieve this. Modern ventilators can do this as they are able to measure the volume of gas that goes into and out of the lung. The resultant tidal volume is dependent on the PIP and PEEP the ventilator applies to the lung and the compliance of the patient's respiratory system (Cs). 5 Compliance is a mechanical term that refers to the ability of the patient's lungs and chest wall to move when a pressure is applied. A very sick lung has a low C, and a normal lung a relatively high C,. explaining why patients with severe lung disease require higher pressures during mechanical ventilation. Volume targeted modalities are now commonly used during mechanical ventilation in an ICU, especially in the treatment of lung disease in 10 the preterm infant, whose lungs are especially vulnerable to injury from inappropriate pressures. Current volume targeted modalities simply focus on the PIP, and ignore the importance of optimising the PEEP during mechanical ventilation. yet there is now evidence in all age 15 groups that inappropriate PEEP results in greater lung injury and mortality. The problem has been how to determine the optimal PEEP. Although methods to determine the optimal PEEP exist, most of them use oxygenation as a measure of lung volume or other techniques that claim to measure end expiratory lung volume (for example, gas wash-out techniques). Thus., the clinician determines the PEEP that results in the best oxygen levels 20 for that patient at that time during a procedure that is referred to as a 'lung volume optimisation' manoeuvre or LVO manoeuvre. During an LVO manoeuvre, the clinician applies a series of step-wise increases in PEEP to determine the PEEP that recruits lung volume (increases lung volume) and/or overdistension of the lung (defined as a reduction in oxygenation). Then the PEEP is reduced in a step-wise manner until lung collapse 25 (inadequate pressure and volume) occur, again defined by a fall in oxygen. The optimal PEEP is then defined as the lowest PEEP that maintained the best oxygenation during the LVO manoeuvre. The inventors have identified a fundamental problem with an oxygen-based approach to 30 LVO, namely that oxygen levels in the blood are affected by many parameters and organs, including the heart and the pulmonary blood vessels. Thus, the response seen by the WO 2012/139159 PCT/AU2012/000370 -3 clinician may not accurately reflect lung volume at any given PEEP. Additionally, only one commercially available ventilator has an in-built system to monitor oxygen levels and, thus, is able to apply a closed loop feedback system to the ventilator. This means that LVO manoeuvres cannot be readily automated in most cases, vet an automated LVO technique 5 would be quicker and more attractive to clinicians. -It is desired to provide a process for determining a positive end-expiratory pressure for a mechanical ventilation system. a mechanical ventilation system. and a method of treating a subject with a pathological lung disease or who is at risk of developing same that alleviate 10 one or more difficulties of the prior art, or that at least provide a useful alternative. SUMMARY Some embodiments of the present invention provide a process for determining a positive end-expiratory pressure for a mechanical ventilation system, including: determining values for compliance of a patient's respiratory system during 15 mechanical ventilation of said patient using respective positive end-expiratory pressure (PEEP) values; and processing the compliance values and the PEEP values to determine a PEEP value as substantially being a lowest PEEP value that provides a highest compliance value. 20 In some embodiments, the quasi-optimal PEEP value is determined by selecting from the PEEP values the lowest PEEP value whose corresponding compliance value is substantially equal to the highest compliance value of the determined compliance values. In other embodiments, the PEEP value can be determined from the PEEP values and their 25 associated respective compliance values, but need not be equal to one of those PEEP values. In some embodiments, the step of determining includes: applying mechanical ventilation to lungs of said patient in a volume targeted mode 30 to inflate said lungs by delivering a predetermined tidal volume of gas to said lungs WO 2012/139159 PCT/AU2012/000370 -4 adequate for CO 2 removal, and to deflate said lungs to a positive end-expiratory pressure (PEEP) value; determining a value for compliance of the patient's respiratory system during said mechanical ventilation and corresponding to the PEEP value; 5 repeatedly increasing the PEEP value of the mechanical ventilation in a stepwise manner and determining a corresponding value for the compliance of the patient's respiratory system for each increased PEEP value until the compliance of the patient's respiratory system has not increased for at least two consecutive PEEP increment steps, thereby providing a maximum PEEP value and a corresponding maximum compliance 10 value; and repeatedly decreasing the PEEP value of the mechanical ventilation in a stepwise manner and determining a corresponding value for the compliance of the patient's respiratory system for each decreased PEEP value until the compliance of the patient's respiratory system has decreased over at least two consecutive PEEP decrement steps. 15 It will be apparent those skilled in the art that the conditions of the process that the compliance of the patient's respiratory system (i) has not increased and (ii) has decreased need to be understood as being subject to the accuracy of the determined compliance values. In general, these are determined in modern ventilators based on gas flow sensors 20 whose relative accuracy is typically about ±6%, and consequently any comparison of the determined compliance values need to be evaluated within these constraints. Accordingly, in respective embodiments, compliance values are taken to be equal if they differ by 0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12%, respectively, corresponding to the estimated relative accuracies of the determined compliance values in those embodiments. 25 In some embodiments, the step of processing includes selecting from the determined PEEP values a PEEP value whose value is the lowest of the determined PEEP values whose corresponding compliance value is substantially equal to. the maximum compliance value.

WO 2012/139159 PCT/AU2012/000370 -5 In some embodiments, the process includes: increasing the PEEP value of the mechanical ventilation to a PEEP value substantially equal to the maximum PEEP value; decreasing the PEEP value of the mechanical ventilation to the selected PEEP 5 value; and applying mechanical ventilation to said lungs of said patient in said volume targeted mode using the selected PEEP value. Some embodiments of the present invention provide a process for determining a positive 10 end-expiratory pressure for a mechanical ventilation system, including: applying mechanical ventilation to lungs of a patient in a volume targeted mode to inflate said lungs by delivering a predetermined tidal volume of gas to said lungs adequate for CO 2 removal, and to deflate said lungs to a positive end-expiratory pressure (PEEP) value; 15 determining a value for compliance of the patient's respiratory system during said mechanical ventilation and corresponding to the PEEP value; repeatedly increasing the PEEP value of the mechanical ventilation in a stepwise manner and determining a corresponding value for the compliance of the patient's respiratory system for each increased PEEP value until the compliance of the patient's 20 respiratory system has not increased for at least two consecutive PEEP increment steps, thereby providing a maximum PEEP value and a corresponding maximum compliance value; repeatedly decreasing the PEEP value of the mechanical ventilation in a stepwise manner and determining a corresponding value for the compliance of the patient's 25 respiratory system for each decreased PEEP value until the compliance of the patient's respiratory system has decreased over at least two consecutive PEEP decrement steps; increasing the PEEP value of the mechanical ventilation to a PEEP value. substantially equal to the maximum PEEP value; selecting from the determined PEEP values a PEEP value whose value is the lowest 30 of the determined PEEP values whose corresponding compliance value is substantially equal to the maximum compliance value; WO 2012/139159 PCT/AU2012/000370 -6 decreasing the PEEP value of the mechanical ventilation to the selected PEEP value; and applying mechanical ventilation to said lungs of said patient in said volume targeted mode using the selected PEEP value. 5 In some embodiments, the mechanical ventilation for each PEEP value is maintained for a predetermined number of inflation and deflation cycles. however, this is not typically the case. In most cases, the mechanical ventilation for each PEEP value is maintained for a period of time sufficient for the patient's respiratory system to have substantially stabilised, 10 as set by the clinician based on the patient's lung pathology and the quasi-static or static time constant of the patient's lung. The times required for stabilisation typically range from about 10 seconds to about 20 minutes for infants, and from about 2 minutes to about 20 minutes for adults. 15 In some embodiments, said repeatedly increasing is performed until the compliance of the patient's respiratory system has not increased for two consecutive PEEP increment steps. In some embodiments, said repeatedly decreasing is performed until the compliance of the patient's respiratory system has decreased for two consecutive PEEP decrement steps. 20 Some embodiments of the present invention provide a process to determine a positive end expiratory pressure for mechanical ventilation of a newborn infant, including: determining values for compliance of the newborn infant's respiratory system during mechanical ventilation of said newborn infant using respective positive end 25 expiratory pressure (PEEP) values; processing the, compliance values and the PEEP values to determine a PEEP value as substantially being a lowest PEEP value that provides a highest compliance value. 30 The process may include applying mechanical ventilation to said lungs of said newborn infant using the determined PEEP value.

WO 2012/139159 PCT/AU2012/000370 -7 Some embodiments of the present invention provide a process to determine.a positive end expiratory pressure for mechanical ventilation of a patient having a pathological lung disease, including: 5 determining values for compliance of the patient's respiratory system during mechanical ventilation of said patient using respective positive end-expiratory pressure (PEEP) values; processing the compliance values and the PEEP values to determine a PEEP value as substantially being a lowest PEEP value that provides a highest compliance 10 value. The present invention also provides a mechanical ventilation system configured to execute any one of the above processes. 15 The present invention also provides a mechanical ventilation system including one or more data processing components programmed to execute any one of the above processes. The present invention also provides a computer-readable storage medium having stored thereon processor-executable instructions that, when executed by a processor 'of a 20 processor-controlled mechanical ventilation system, cause the mechanical ventilation system to execute any one of the above processes. The computer-readable storage medium may be in the form of an integrated circuit or memory chip, a CD-ROM, DVD-ROM, hard disk or solid state drive, or other form of 25 non-volatile storage.

WO 2012/139159 PCT/AU2012/000370 -8 Some embodiments of the present invention provide a mechanical ventilation system, including: at least one gas inlet to receive at least one gas to be supplied to lungs of a patient; 5 a gas outlet to be coupled to lungs of said patient; user interface components configured to display ventilation data to a user of the system and to receive ventilation control inputs from said user; one or more data processing components configured to receive data representing the supply of gas to the patient and to receive control data representing 10 said ventilation control inputs, and to control the supply of said gas to said patient in accordance with said ventilation control inputs; mechanical ventilation components configured to supply said gas to said patient under control of said data processing components; wherein the data processing components are configured to determine values for 15 compliance of the patient's respiratory system for respective values for positive end expiratory pressure (PEEP) for ventilating said patient, and to determine a quasi-optimal PEEP value as being a lowest PEEP value that provides a highest compliance value. Some embodiments of the present invention provide a mechanical ventilation system, 20 including: at least one gas inlet to receive at least one gas to be supplied to lungs of a patient; a gas outlet to be coupled to lungs of said patient; user interface components configured to display ventilation data to a user of 25 the system and to receive ventilation control inputs from said user; one or more data processing components configured to receive data representing the supply of gas to the patient and to receive control data representing said ventilation control inputs, and to control the supply of said gas to said patient in accordance with said ventilation control inputs; 30 mechanical ventilation components configured to supply said gas to said patient under control of said data processing components; WO 2012/139159 PCT/AU2012/000370 -9 wherein the data processing components are configured to cause the mechanical ventilation system to: apply mechanical ventilation to lungs of a patient in a volume targeted mode to inflate said lungs by delivering a predetermined tidal volume of gas to said lungs 5 adequate for CO 2 removal, and to deflate said lungs to a positive end-expiratory pressure (PEEP) value; determine a value for compliance of the patient's respiratory system during said mechanical ventilation and corresponding to the PEEP value; repeatedly increase the PEEP value of the mechanical ventilation in a stepwise 10 manner and determine a corresponding value Ior the compliance of the patient's respiratory system for each increased PEEP value until the compliance of the patient's respiratory system has not increased for at least two consecutive PEEP increment steps, thereby providing a maximum PEIEP value and a corresponding maximum compliance value; 15 repeatedly decrease the PEEP value of the mechanical ventilation in a stepwise manner and determine a corresponding value for the compliance of the patient's respiratory system for each decreased PEEP value until the compliance of the patient's respiratory system has decreased over at least two consecutive PEEP decrement steps; 20 increase the PEEP value of the mechanical ventilation to a PEEP value substantially equal to the maximum PEEP value; select from the determined PEEP values a PEEP value whose value is the lowest of the determined PEEP values whose corresponding compliance value is substantially equal to the maximum compliance value; 25 decrease the PEEP value of the mechanical ventilation to the selected PEEP value; and apply mechanical ventilation to said lungs of said patient in said volume targeted mode using the selected PEEP value.

WO 2012/139159 PCT/AU2012/000370 - 10 The mechanical ventilation system of the present invention is useful in therapeutic protocols including for treating a subject with pathological lung disease. The present invention contemplates a method of treating a subject with a pathological lung 5 disease or who is at risk of developing same, said method comprising administering to said subject open lung ventilation (OLV) with a mechanical ventilator wherein a positive end expiratory pressure (PEEP) for the mechanical ventilator is determined by: determining values for compliance of the subject's respiratory system during the mechanical ventilation of said subject using respective PEEP values; and 10 processing the compliance values and the PEEP values to determine a PEEP value as substantially being a lowest PEEP value that provides a highest compliance value. BRIEF DESCRIPTION OF THE DRAWINGS 15 Some embodiments of the present invention are hereinafter described, by way of example only, with reference to the accompanying drawings, wherein: Figure I is a flow diagram of an embodiment of a process for determining a positive end-expiratory pressure for a mechanical ventilation system; Figure 2 is a block diagram of an embodiment of a system for determining a 20 positive end-expiratory pressure for a mechanical ventilation system; Figures 3 to 6 are graphs of end-expiratory lung volume (EELV), the pressure differential AP=PIP-PEEP, the alveolar-arterial oxygen partial pressure difference (AaDO 2 ), and respiratory system compliance (Crs), respectively, as a function of time after initiation of a recruitment manoeuvre in accordance with an embodiment of the present 25 invention.

WO 2012/139159 PCT/AU2012/000370 DETAILED DESCRIPTION Abbreviations AaDO 2 Alveolar-arterial oxygen partial pressure difference CPAP Continuous positive applied pressure 5 Cs Respiratory System Compliance EELV End-expiratory Lung Volume

F

1 o 2 Fraction of inspired oxygen Paco2 Partial arterial pressure of CO 2 PEEP Positive End-expiratory Pressure 10 PEEP 0 Opening PEEP (maximum PEEP obtained during the OLV strategy) PEEPp Optimum PEEP as determine by the specific OLV strategy PPV Positive Pressure Ventilation SI Sustained Inflation SIPPV Synchonised Intermittent Positive Pressure Ventilation 15 Spo2 Peripheral oxygen saturation TTV Targeted Tidal Volume VT Tidal Volume Over 7000 newborn infants develop respiratory failure in Australasia annually. The 20 majority are born prematurely with surfactant-deficient lungs. Those infants born at 29 weeks or earlier are at the greatest risk of severe short and long-term complications and constitute a major health-care burden. Due to their respiratory and neurological immaturity, many need prolonged respiratory support (mechanical ventilation) to survive, at a cost of more than A$2000 per infant per day. However, ventilation of these immature 25 lungs can lead to damage and the development of chronic lung disease, which is associated with prolonged hospital stay and long-term morbidity. Evidence of this ventilator-induced lung injury can be found even after the first few supported inflations in the delivery room. Thus, the inventors have identified that more refined strategies of ventilation, applicable from these very first inflations, are required to minimise the damage caused to the preterm 30 lung, and believe that the mechanical ventilation strategies used at birth can be improved to WO 2012/139159 PCT/AU2012/000370 - 12 optimise regional aeration, lung mechanics and pulmonary blood flow and, thus, minimise lung injury in a preterm lung model. To this end, the inventors have determined that there is a relationship between the 5 compliance of a patient's respiratory system Crs and lung volume during mechanical ventilation that is similar to that of oxygenation. Hence, when the lung is overdistended or collapsed, Crs deteriorates, irrespective of the degree of lung disease. Similarly, the inventors have determined that the optimal PEEP provides the best (maximum) Crs during an LVO manoeuvre in a preterm lamb model and a small series of ventilated infants at the 10 Royal Children's Hospital. Based on these insights, the inventors have developed processes for determining an optimal or at least quasi-optimal PEEP value based on using the compliance values Crs measured and displayed by modern ventilators. 15 In some embodiments of the present invention, a process for determining a positive end expiratory pressure for a mechanical ventilation system includes determining values for compliance of a patient's respiratory system during mechanical ventilation of said patient using respective positive end-expiratory 20 pressure (PEEP) values; and processing the compliance values and the PEEP values to determine a PEEP value as substantially being a lowest PEEP value that provides a highest compliance value. 25 In some embodiments, the quasi-optimal PEEP value is determined by selecting from the PEEP values the lowest PEEP value whose corresponding compliance value is substantially equal to the highest compliance value of the determined compliance values. In other embodiments, the PEEP value can be determined from the PEEP values and their associated respective compliance values, but need not be equal to one of those PEEP 30 values.

WO 2012/139159 PCT/AU2012/000370 - 13 In some embodiments, the step of determining includes: applying mechanical ventilation to lungs of said patient in a volume targeted mode to inflate said lungs by delivering a predetermined tidal volume of gas to said lungs adequate for CO 2 removal, and to deflate said lungs to a positive end-expiratory 5 pressure (PEEP) value; determining a value for compliance of the patient's respiratory system during said mechanical ventilation and corresponding to the PEEP value; repeatedly increasing the PEEP value of the mechanical ventilation in a stepwise manner and determining a corresponding value for the compliance of the patient's 10 respiratory system for each increased PEEP value until the compliance of the patient's respiratory system has not increased for at least two consecutive PEEP increment steps, thereby providing a maximum PEEP value and a corresponding maximum compliance value; and repeatedly decreasing the PEEP value of the mechanical ventilation in a stepwise 15 manner and determining a corresponding value for the compliance of the patient's respiratory system for each decreased PEEP value until the compliance of the patient's respiratory system has decreased over at least two consecutive PEEP decrement steps. It will be apparent those skilled in the art that the conditions of the process that the 20 compliance of the patient's respiratory system (i) has not increased and (ii) has decreased need to be understood as being subject to the accuracy of the determined compliance values. In general, these are determined in modem ventilators based on gas flow sensors whose relative accuracy is typically about ±6%, and consequently any comparison of the determined compliance values need to be evaluated within these constraints. Accordingly, 25 in respective embodiments, compliance values are taken to be equal if they differ by 0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12%, respectively, corresponding to the estimated relative accuracies of the determined compliance values in those embodiments. In some embodiments, the step of processing includes selecting from the determined PEEP 30 values a PEEP value whose value is the lowest of the determined PEEP values whose corresponding compliance value is substantially equal to the maximum compliance value.

WO 2012/139159 PCT/AU2012/000370 -14 In some embodiments, the process includes: increasing the PEEP value of the mechanical ventilation to a PEEP value substantially equal to the maximum PEEP value; 5 decreasing the PEEP value of the mechanical ventilation to the selected PEEP value; and applying mechanical ventilation to said lungs of said patient in said volume targeted mode using the selected PEEP value. 10 In some embodiments of the present invention, a process for determining a positive end expiratory pressure for a mechanical ventilation system includes: applying mechanical ventilation to lungs of a patient in a volume targeted mode to inflate said lungs by delivering a predetermined tidal volume of gas to said lungs adequate for CO 2 removal, and to deflate said lungs to a positive end-expiratory 15 pressure (PEEP) value; determining a value for compliance of the patient's respiratory system during said mechanical ventilation and corresponding to the PEEP value; repeatedly increasing the PEEP value of the mechanical ventilation in a stepwise manner and determining a corresponding value for the compliance of the patient's 20 -respiratory system for each increased PEEP value until the compliance of the patient's respiratory system has not increased for at least two consecutive PEEP increment steps, thereby providing a maximum PEEP value and a corresponding maximum compliance value; repeatedly decreasing the PEEP value of the mechanical ventilation in a stepwise 25 manner and determining a corresponding value for the compliance of the patient's respiratory system for each decreased PEEP value until the compliance of the patient's respiratory system has decreased over at least two consecutive PEEP decrement steps; increasing the PEEP value of the mechanical ventilation to a PEEP value substantially equal to the maximum PEEP value; WO 2012/139159 PCT/AU2012/000370 - 15 selecting from the determined PEEP values a PEEP value whose value is the lowest of the determined PEEP values whose corresponding compliance value is substantially equal to the maximum compliance value; decreasing the PEEP value of the mechanical ventilation to the selected PEEP 5 value; and applying mechanical ventilation to said lungs of said patient in said volume targeted mode using the selected PEEP value. In some embodiments, the mechanical ventilation for each PEEP value is maintained for a 10 predetermined number of inflation and deflation cycles. However, this is not typically the case. In most cases, the mechanical ventilation for each PEEP value is maintained for a period of time sufficient for the patient's respiratory system to have substantially stabilised, as dictated by the patient's lung pathology and the quasi-static or static time constant of the patient's lung. The times required for stabilisation typically range from about 10 seconds 15 to about 20 minutes for infants, and from about 2 minutes to about 20 minutes for adults. In some embodiments, said repeatedly increasing is performed until the compliance of the patient's respiratory system has not increased for two consecutive PEEP increment steps. 20 In some embodiments, said repeatedly decreasing is performed until the compliance of the patient's respiratory system has decreased for two consecutive PEEP decrement steps. In some embodiments of the present invention, a process to determine a positive end expiratory pressure for mechanical ventilation of a newborn infant includes: 25 determining values for compliance of the newborn infant's respiratory system during mechanical ventilation of said newborn infant using respective positive end expiratory pressure (PEEP) values; processing the compliance values and the PEEP values to determine a PEEP value as substantially being a lowest PEEP value that provides a highest compliance 30 value.

WO 2012/139159 PCT/AU2012/000370 -16 The process may include applying mechanical ventilation to said lungs of said newborn infant using the determined PEEP value, In some embodiments of the present invention, a process to determine a positive end 5 expiratory pressure for mechanical ventilation of a patient having a pathological lung disease includes: determining values for compliance of the patient's respiratory system during mechanical ventilation of said patient using respective positive end-expiratory pressure (PEEP) values; 10 processing the compliance values and the PEEP values to determine a PEEP value as substantially being a lowest PEEP value that provides a highest compliance value. The processes first determine values for the compliance of a patient's respiratory system 15 during mechanical ventilation using respective PEEP values. The compliance and PEEP values are then used to determine an optimal or at least quasi-optimal PEEP value as the lowest of the PEEP values that provides the highest compliance value. Typically, the optimal PEEP value is determined by selecting the lowest PEEP value whose corresponding compliance value is substantially equal to the highest of the determined 20 compliance values, although it will be apparent to those skilled in the art that this need not be the case if, for example, interpolation or other estimation methods are used to determine a PEEP value that might be between two of the PEEP values that were used to determine the compliance values. 25 The processes can be performed manually by an operator of a standard mechanical ventilator using the compliance values determined and displayed by the ventilator, or can be performed in an automated manner by a modified mechanical ventilator. Given that modem mechanical ventilators are controlled by one or microprocessors and associated software and use feedback processes to control the ventilation of a patient, and moreover 30 that such ventilators already determine compliance values during ventilation, it will be WO 2012/139159 PCT/AU2012/000370 - 17 apparent that the processes described herein can be implemented in existing mechanical ventilation systems by modifying only the software of such ventilation systems. In some embodiments, the process consists of the following: 5 1. Applying mechanical ventilation in a .volume targeted mode to deliver a tidal volume adequate for CO 2 removal. If the patient is spontaneously breathing, a synchronised mode is also set. 2. Setting the maximum PIP to the highest value the clinician believes is acceptable. 3. repeatedly increasing the PEEP in 2 cm H 2 0 increments until no further 10 improvement in the Crs (as displayed on the ventilator) is observed over two consecutive PEEP increment steps. The lung is then said to have been recruited. The fact that no further improvement in Crs is demonstrated indicates that over distension is likely to occur with further increases in PEEP. In some embodiments, the PEEP is increased every 10-15 inflations, but it will be understood by those 15 skilled in the art that other values can be used. Indeed, the time needed at each PEEP value depends on the patient's size and lung disease. A preterm infant will likely only need 10-15 inflations, but an adult will require longer. 4. Repeatedly decreasing the PEEP in 2 cm H 2 0 decrements until Crs has fallen over two consecutive PEEP decrements, thus indicating that the previously recruited 20 lung is now collapsing or under-inflated. 5. The PEEP is then increased to the highest PEEP achieved, and maintained at that value for the same number of inflations used during every PEEP step previously. 6. Finally, the PEEP is then reduced to the lowest PEEP value that nevertheless resulted in the best Cr, during' the procedure. 25 WO 2012/139159 PCT/AU2012/000370 - 18 The advantages of this process include: 1. It is individualised to each patient. 2. It is based solely on a parameter that is only influenced by the lung. 3. It is independent of oxygenation. 5 4. The use of a volume targeted modality minimises the risk of inadvertently high PIP being applied during the procedure, as the ventilator will automatically adjust PIP with PEEP changes. Also, when performed manually, the clinician only has to adjust one knob/dial (i.e., the PEEP setting). 5. It uses a parameter already measured by modern ventilators and used in other 10 ventilator modes (volume targeted modes). The advantages of this include a. It is relatively easy to integrate into current ventilator software processes based on closed-loop feedback of measured Crs. b. A ventilator could have a 'LVO' button which the clinician could press and the ventilator will automatically find the correct PEEP, in a similar fashion 15 to how they currently determine the correct PIP. c. Similarly, the ventilator could be programmed to automatically repeat the LVO if it determines a significant deviation in the C,, after an LVO optimisation. In volume targeted modalities, the only reason why a C, would change at a constant PEEP would be a change in the patient's lung 20 disease, in which case the optimal PEEP for that patient at that point in time may he different. Another potential advantage of the ventilator processes described herein are that they are patient adaptive, and thus may result-in less time on a ventilator and less lung injury. 25 The processes described herein are suitable for use .on neonatal, paediatric, and adult patients, including patients with various lung pathologies, including lung (alveolar) collapse (atelectasis) and atelectatic lung disease such as adult respiratory distress syndrome (ARDS), for example, and newborn respiratory distress syndrome (RDS) or 30 hyaline membrane disease (HMD), for which the processes described herein would be preferred methods of treatment. The processes can be used with non-invasive ventilation WO 2012/139159 PCT/AU2012/000370 - 19 systems such as in-home use ventilators with leak-proof face masks. The processes can be used with human or animal patients. Hence, enabled herein is a method of treating a subject with a pathological lung disease or 5 who is at risk of developing same, said method comprising administering to said subject open lung ventilation (OLV) with a mechanical ventilator wherein a positive end expiratory pressure (PEEP) for the mechanical ventilator is determined by: determining values for compliance of the subject's respiratory system during the mechanical ventilation of said subject using respective PEEP values; and 10 processing the compliance values and the PEEP values to determine a PEEP value as substantially being a lowest PEEP value that provides a highest compliance value. The ventilator inflations are synchronised to the subject's positive inflationary pressure (PIP) and wherein the delivered inflation pressure is adjusted to maintain a constant tidal 15 volume (Vr). In use, the method includes: applying mechanical ventilation to lungs of the subject in a volume targeted mode to inflate said lungs by delivering a predetermined VT of gas to said lungs adequate 20 for CO 2 removal, and to deflate said lungs to a positive end-expiratory pressure (PEEP) value; determining a value for compliance of the subject's respiratory system during said mechanical ventilation and corresponding to the PEEP value; repeatedly increasing the PEEP value of the mechanical ventilation in a 25 stepwise manner and determining a corresponding value for the compliance of the subject's respiratory system for each increased PEEP-value until the compliance of the subject's respiratory system has not increased for at least two consecutive PEEP increment steps, thereby providing a maximum PEEP value and a corresponding maximum compliance value; 30 repeatedly decreasing the PEEP value of the mechanical ventilation in a stepwise manner and determining a corresponding value for the compliance of the WO 2012/139159 PCT/AU2012/000370 - 20 subject's respiratory system for each decreased PEEP value until the compliance of the subject's respiratory system has decreased over at least two consecutive PEEP decrement steps; increasing the PEEP value of the mechanical ventilation to a PEEP value 5 substantially equal to the maximum PEEP value; selecting from the determined PEEP values a PEEP value whose value is the lowest of the determined .PEEP values whose corresponding compliance value is substantially equal to the maximum compliance value; decreasing the PEEP value of the mechanical ventilation to the selected PEEP 10 value; and applying mechanical ventilation to said lungs of said subject in said volume targeted mode using the selected PEEP value. Some embodiments of the present invention provide a mechanical ventilation system 15 configured to execute any one of the above processes. Some embodiments of the present invention provide a mechanical ventilation system including one or more data processing components programmed to execute any one of the above processes. 20 Some embodiments of the present invention provide a computer-readable storage medium having stored thereon processor-executable instructions that, when executed by a processor of a processor-controlled mechanical ventilation system, cause the mechanical ventilation system to execute any one of the above processes. 25 The computer-readable storage medium may be in the form of an integrated circuit or memory chip, a CD-ROM, DVD-ROM, hard disk or solid state drive, or other form of non-volatile storage WO 2012/139159 PCT/AU2012/000370 -.21 Some embodiments of the present invention provide a mechanical ventilation system, including: at least one gas inlet to receive at least one gas to be supplied to lungs of a patient; 5 a gas outlet to be coupled to lungs of said patient; user interface components configured to display ventilation data to a user of the system and to receive ventilation control inputs from said user; one or more data processing components configured to receive data representing the supply of gas to the patient and to receive control data representing 10 said ventilation control inputs, and to control the supply of said gas to said patient in accordance with said ventilation control inputs; mechanical ventilation components configured to supply said gas to. said patient under control of said data processing components; wherein the data processing components are configured to determine values for 15 compliance of the patient's respiratory system for respective values for positive end expiratory pressure (PEEP) for ventilating said patient, and to determine a quasi-optimal PEEP value as being a lowest PEEP value that provides a highest compliance value. Figure 2 is a block diagram of an embodiment of a processor-controlled mechanical 20 ventilation system or ventilator 200. The ventilator 200 includes at least one gas inlet 202 for receiving at least one gas, and a gas outlet 204 to be coupled to lungs of a patient. Mechanical ventilation components 206 pressurise the gas to supply the gas through the outlet 204 at a positive pressure to ventilate the patient. The mechanical ventilation components 206 are controlled by a data processing subsystem 208 based on ventilation 25 data representing the supply of gas to the patient received from one or more sensors 210 and also ventilation control inputs entered by an operator of the ventilator using user input controls 212. Thus the ventilation of the patient is performed in accordance with the ventilation control inputs and using feedback from the sensors 210, WO 2012/139159 PCT/AU2012/000370 - 22 The data processing subsystem 208 includes standard computer components, and the processes described herein as implemented as programming instructions of one or more software modules 214 stored on at least one non-volatile storage medium 216 (e.g., hard disk, solid-state drive, PROM, EPROM, and the like). However, it will be apparent that at 5 least parts of the processes could alternatively be implemented as one or more dedicated hardware components, such as application-specific integrated circuits (ASICs) and/or field programmable gate arrays (FPGAs), for example. The data processing subsystem 208 also includes random access memory (RAM) 218, at 10 least one processor 220, and external interfaces 222, 224, 226, 228, all interconnected by a bus 230. One of the external interfaces 222 is connected to user input controls 212, which may be in the form of a standard keyboard, buttons, or touchscreen, for example. A display adapter 228 is connected to a display device such as an LCD panel display 232 to display input and output parameters to the operator. 15 In use, the data processing subsystem 208 controls the mechanical ventilation components 206 to ventilate the patient in a volume targeted mode using an initial (PEEP) value, and then repeatedly increases the PEEP value in a stepwise manner as described above to determine compliance values corresponding to the PEEP values, all of which are stored in 20 the RAM 218. The data processing subsystem 208 then controls the mechanical ventilation components 206 to decrease the PEEP values as described above and determine corresponding compliance values, all of which are also stored in RAM 218. The data processing subsystem 208 then processes the stored PEEP values and associated 25 compliance values as described above to determine a PEEP value that is or approximates the lowest PEEP value that provides a compliance value equal to or substantially equal to the maximum compliance value determined for all of the PEEP values used to ventilate the patient. The data processing subsystem 208 then controls the mechanical ventilation components 206 to ventilate the patient in a volume targeted mode using the determined 30 (PEEP) value.

WO 2012/139159 PCT/AU2012/000370 - 23 EXAMPLE 1 127d GA lambs (n=8/group, mean weight 2.97kg) were ventilated for 70 min and randomly divided into three groups with respective ventilation strategies from delivery, as follows: 5 1. Sustained Inflation (SI): the lambs in this group were mechanically ventilated by initially applying sustained ventilation for a period of 20 sec at a PIP pressure of 35cm H20, followed by cyclic deflation and inflation and introduction of a surfactant into the lungs at 10 min; the gas for tidal inflation was nominally 21% 02 (FiO 2 =0.21) using a Targeted Tidal Volume (TTV) of 7mL/kg, and a PEEP value 10 of 6cm H 2 0, but during the ventilation both FiO 2 and TTV were adjusted to maintain SpO2 (peripheral oxygen saturation) at 88-92% and PaCO 2 (partial pressure of arterial C0 2 ) at 45-55mmHg; 2. SurfSI: in this strategy, the surfactant was administered prior to delivery, but otherwise the strategy was as described above for SI; and 15 3. Stepwise PEEP recruitment (SPR): in this group, PEEP was increased by 2cm H 2 0 every 10 inflations from 4 to 20cm H 2 0 using PPV+TTV, and was then decreased in decrements of 2 cm H 2 0 every 10 inflations until the corresponding Crs values decreased over two consecutive PEEP decrement steps. In this process, the lung is transiently exposed to a lowdr PEEP than that resulting in the best C, to 20 identify an optimal or quasi-optimal PEEP value that does provide the highest Cr. The PEEP was then transiently increased to 20 cm H 2 0 for ten intlations to re recruit the lung, and then returned to the PEEP value (Mean (SD) PEEP 7.9(l.6)cmH 2 0) resulting in the best value of Cs. The surfactant was administered at 10 min. 25 For each group, regular arterial gas analysis was performed from 8 to 70 min. SP 0 2, pressure, Crs, total and regional tidal volume (VT) and end-expiratory lung volume (EELV). Respiratory inductive plethysmography and electrical impedance tomography were recorded for the first 15 min, and with arterial gases. The results from the lambs in each group were subjected to statistical analysis using 2-way ANOVA to provide a single result 30 for each group.

WO 2012/139159 PCT/AU2012/000370 - 24 Figures 3 to 6 are graphs of end-expiratory lung volume (EELV), the pressure differential AP=PIP-PEEP, the alveolar-arterial oxygen partial pressure difference (AaDO 2 ), and respiratory system compliance (Crs), respectively, as a function of time after initiation of the recruitment manoeuvre. 5 From Figures 3 to 6, it is apparent that the SPR and SurfSl strategies resulted in better EELV, Cr, and AaDO 2 compared to SI, with EELV being 18(SD 9)mL/kg after SPR vs 4(6)mL/kg after SI (p<0.0001).. Crs was 0.22 (0.1)mL/cmH 2 0 greater than SI for both SurfSI and SPR (p<0.05). Surfactant administration generally negated these differences, but by 70 min SPR again resulted in better AaDO 2 , Crs and EELV compared to SI. The SI 10 group required a higher TTV (p=0.0017; ANOVA) to maintain the desired PaCO 2 range. SI resulted in the least uniform distribution of ventilation. The results demonstrate that a stepwise PEEP strategy applied at birth emphasizing time and pressure-based recruitment, and titratable to patients' lung mechanics, is practical and demonstrates short-term results similar to a surfactant-replete lung. The strategy applied at 15 birth results in better short-term respiratory outcomes than a sustained inflation in a preterm lamb model.

WO 2012/139159 PCT/AU2012/000370 -25 Example 2 This study investigates the safety and feasibility of two strategies of recruiting end expiratory lung volume, and determines the optimal positive end-expiratory pressure (PEEP) setting, in premature infants with acute respiratory failure, requiring conventional 5 mechanical ventilation at the time of exogenous surfactant therapy. It is proposed that in a subject such as a preterm infant requiring conventional mechanical ventilation for acute respiratory failure: 1. The use of a ventilation strategy that identifies an optimal PEEP results in better 10 gas exchange in the short term. 2. There is a relationship between the timing of such a ventilation strategy and the administration of exogenous surfactant therapy This study compares an OLV strategy using synchronised (SIPPV) and volume targeted 15 (TTV) conventional mode of PPV with the current PEEP strategy in preterm infants at the time of surfactant administration. Furthermore, this study investigates the influence of using oxygenation or CRS or both to determine the optimal PEEP during an OLV strategy. An OLV strategy is developed that uses a mode of PPV called SIPPV+TTV to provide feedback to the clinician regarding PEEP and lung volume. This mode synchronises the 20 ventilators inflations to the patients' spontaneous effort (SIPPV) and automatically adjusts the delivered inflation pressure (PIP) to maintain a constant, clinician-set tidal volume (TTV), thus minimising inadvertent over-distension. The PIP is controlled by the patients own lung compliance (CRS); CRS is known to be influenced by lung volume and thus PEEP, and is displayed on all modem ventilators. Practically, this strategy uses the TTV mode to 25 avoid exposure to high inflating pressures during a positive end-expiratory pressure (PEEP) recruitment phase. The clinician also gets two forms of feedback, oxygenation and CRS, to define overdistension and collapse. In addition, as the ventilator adjusts most of the settings automatically, the clinician only needs to adjust PEEP and oxygen. In lamb models, this approach results in better lung volume, oxygenation and lung mechanics than 30 SIPPV+TTV with the standard PEEP of 6 cm H 2 0.

WO 2012/139159 PCT/AU2012/000370 -26 Methods Study population Preterm infants between 24-29 weeks' completed gestation are selected if they: 1. Are requiring intubation and conventional mechanical ventilation with 5 SIPPV+TTV from no later than 24 hours of age. 2. Meet the criteria for exogenous surfactant administration (clinical evidence of increased work of breathing and need for more than 30% inspired oxygen). 3. TTV is set at ;4 mL/kg to maintain a Paco2 of at least 45 mmHg on an arterial or capillary blood gas (if available). 10 Infants are not selected if they are: 1. Likely to be extubated to CPAP within 2 hours 2. Requiring <30% inspired oxygen at time of randomisation 3. Had previous surfactant therapy 15 4. Known to have a significant congenital, chromosomal and/or cardiac anomalies 5. Have profound bradycardia. Enrolled infants who meet the study criteria are randomised to one of three treatment arms prior to surfactant therapy. Randomisation is via a block randomisation code managed by 20 CEBU designed to maximise the chance of matching known confounding factors, such as gender and maternal antenatal corticosteroid therapy. Once randomised the infant receives one of three ventilation strategies at the time of surfactant administration. Infants enrolled prior to birth are randomised on admission to the NICU, so as not to delay surfactant administration. 25 This strategy compares an OLV PEEP strategy using SIPPV+TTV immediately prior to or immediately after exogenous surfactant administration with a control ventilation group of preterm infants <24 hours old. The definition of opening PEEPo (maximum PEEP) and optimal PEEP (PEEPopt) is defined by oxygenation. 30 WO 2012/139159 PCT/AU2012/000370 - 27 Ventilation Strategy Groups A) Control Group: This group receives standard care, consisting of SIPPV at a PEEP 6 cm H 2 0 and TTV at 4-6 mL/kg (PIP maximum set at 25 cm H 2 0). Infants then receive 5 exogenous surfactant therapy (2.5mL/kgCurosurfrm) via a pre-measured feeding catheter through the ETT using a closed-circuit system. Post-surfactant therapy ventilation management is provided as required. B) Pre-surfactant OLV: Infants randomised to this group receive an OLV manoeuvre 10 using SIPPV+TTV immediately prior to surfactant therapy. This consists of the following: a. Starting at a PEEP of 6 cm H 2 0, TTV set at that required at the time of implementation (4-6 mL/kg) and PIP maximum set at 25 cm H 2 0, the PEEP. is increased by 1 cm H 2 0. Spo2 and FiO 2 is continually observed. b. The PEEP is further increased by 1 cm H 2 0 if there is an improvement in 15 oxygenation or no change in oxygenation. An improvement in oxygenation is defined as an improvement in Spo2 such that FiO 2 needs to be reduced to maintain target Spo 2 range. PEEP is held at each step for a minimum of 2 mins and a maximum of 5 mins, unless acute desaturation (defined as Spo 2 <85% and an increase in FiO 2 of at least 0.1). -20 c. At each PEEP step, FiO 2 is adjusted to maintain a Spo2 between 88 - 94% (preferably pre-ductal). PEEP is increased to a maximum of 10 cm H 2 0 or the PEEP in which the following occur: i. There is no further benefit in either oxygenation after two increases in PEEP or 25 ii. FiO 2 needs to increased by at least 0.1 to maintain Spo2 range This resultant PEEP will be defined the opening pressure (PEEPO). d. PEEP is then be decreased by 1 cm H 2 0 every 2-5 mins until either: i. PEEP of 5 cm H 2 0 or ii. PEEP in which the there is an increase in FiO 2 by 0.1 to maintain Spo2 30 range. This PEEP represents the closing pressure of the lung.

WO 2012/139159 PCT/AU2012/000370 -28 e. If the lowest PEEP is associated with deoxygenation, then the PEEP is increased to the highest that was obtained during the incremental phase for 2 mins before being decreased to either 5 cm H 2 0 or 1 cm H 2 0 above that which resulted in deterioration during the decremental phase. This is defined as the optimal pressure 5 (PEEPpt) f. Surfactant is then administered as per .the control group. C) Post-surfactant OLV: Infants in this group receive exogenous surfactant as per the Control group. Immediately after surfactant therapy, an OLV strategy is performed using 10 steps a) - d) of the pre-surfactant OLV group. Animal data strongly suggest that an OLV manoeuvre immediately before surfactant is better than after but some practitioners consider that a post-surfactant OLV manoeuvre is safer in human infants. Ventilation strategy post surfactant administration: 15 All groups have the following standardised approach to ventilation after surfactant: 1) FiO 2 set to maintain an oxygen saturation of 88-94% (ideally pre-ductal). 2) TTV range of 4.0-6.0 mL/kg to maintain an arterial or capillary blood Paco2 of 45 55 mmHg and/or pH >7.25. 3) Second dose of surfactant permitted if the infant requires a FiO 2 >0.3 and has 20 increased work of breathing. 4) PEEP to remain at that set during the surfactant period unless: a. FiO 2 has increased by >0.2 and a second dose of surfactant has already been administered b. The infant is in air and weaning towards extubation likely in the next 6 25 hours. 5) Infants should be considered for extubation to CPAP if: a. They are able to maintain adequate CO 2 removal and work of breathing in a TTV 3.5 - 4.0 mL/kg b. Are in air if < 72 hours old or the best FiO 2 obtainable for at least 24 hours, 30 at the discretion of the treating clinician.

WO 2012/139159 PCT/AU2012/000370 - 29 6) Use of other therapies, including high-frequency ventilation and intotropes, is at the discretion of the treating clinical team. Measurements 5 For the 20-mins before surfactant, and any OLV manoeuvre, and for 60-mins after Spo 2 , HR, BP, FiO 2 and CRS at minutely intervals. Ventilator settings are recorded at each PEEP step or every 5-minutes. Thereafter, required inspired oxygen concentration (and modified Oxygenation Index), 10 ventilation settings, CO 2 and heart rate are measured hourly for the first 72 hours (primary outcomes). The need for a second dose of exogenous surfactant, complications, age at extubation and duration of all respiratory support (secondary outcomes) are also recorded. 15 Adverse events, including pneumothorax, other airleak syndromes, intra-caranial haemorrhages and inadvertent or failed extubation, are assessed after recruitment of the first five, and then ten infants in the OLV gro ups and protocol refinements made as needed. 20 Outcome The purpose of this study is to determine the benefit and safety of the OLV strategies. Hence, a method for treating a subject is contemplated herein with a pathological lung 25 disease or who is at risk of developing same, said method comprising administering to said subject open lung ventilation (OLV) with a mechanical ventilator wherein a positive end expiratory pressure (PEEP) for the mechanical ventilator is determined by: determining values for compliance of the subject's respiratory system during the mechanical ventilation of said subject using respective PEEP values; and WO 2012/139159 PCT/AU2012/000370 - 30 processing the compliance values and the PEEP values to determine a PEEP value as substantially being a lowest PEEP value that provides a highest compliance value. 5 The ventilator inflations are synchronised to the subject's positive inflationary pressure (PIP) and wherein the delivered inflation pressure is adjusted to maintain a constant tidal volume (VT). Many modifications will be apparent to those skilled in the art without departing from the 10 scope of the present invention.

Claims (29)

1. A process for 'determining a positive end-expiratory pressure for a mechanical ventilation system, including: determining values for compliance of a patient's respiratory system during 5 mechanical ventilation of said patient using respective positive end-expiratory pressure (PEEP) values; and processing the compliance values and the PEEP values to determine a PEEP value as substantially being a lowest PEEP value that provides a highest compliance value. 10

2. The process of claim 1, wherein the processing includes determining the PEEP value by selecting from the PEEP values the lowest PEEP value whose corresponding compliance value is substantially equal to the highest compliance value of the determined compliance values. 15

3. The process of claim 1, wherein the processing includes determining 'the PEEP value from the PEEP values and their associated respective compliance values, but wherein the determined PEEP value is not equal to one of those PEEP values. 20

4. The process of any one of claims 1 to 3, wherein the determining includes: applying mechanical ventilation to lungs of said patient in a volume targeted mode to inflate said lungs by delivering a predetermined tidal volume of gas to said lungs adequate for CO 2 removal, and to deflate said lungs to a positive end expiratory pressure (PEEP) value; 25 determining a value for compliance of the patient's respiratory system during said mechanical ventilation and corresponding to the PEEP value; repeatedly increasing the PEEP value of the mechanical ventilation in a stepwise manner and determining a corresponding value for the compliance of the patient's respiratory system for each increased PEEP value until the compliance of 30 the patient's respiratory system has not increased for at least two consecutive PEEP WO 2012/139159 PCT/AU2012/000370 -32 increment steps, thereby providing a maximum PEEP value and a corresponding maximum compliance value; and repeatedly decreasing the PEEP value of the mechanical ventilation in a stepwise manner and determining a corresponding value for the compliance of the 5 patient's respiratory system for each decreased PEEP value until the compliance of the patient's respiratory system has decreased over at least two consecutive PEEP decrement steps.

5. The process of any one of claims I to 4, wherein the processing includes selecting 10 from the determined PEEP values a PEEP value whose value is the lowest of the determined PEEP values whose corresponding compliance value is substantially equal to the maximum compliance value.

6. The process of claim 5, further including: 15 increasing the PEEP value of the mechanical ventilation to a PEEP value substantially equal to the maximum PEEP value; decreasing the PEEP value of the mechanical ventilation to the selected PEEP value; and applying mechanical ventilation to said lungs of said patient in said volume 20 targeted mode using the selected PEEP value.

7. The process of any one of claims 1 to 6, wherein the mechanical ventilation for each PEEP value is maintained for a period of time sufficient for the patient's respiratory system to have substantially stabilised, as dictated by the patient's lung 25 pathology.

8.. The process of any one of claims 1 to 7, including applying mechanical ventilation to said lungs of said patient using the determined PEEP value. 30 WO 2012/139159 PCT/AU2012/000370 - 33

9. A process for determining a positive end-expiratory pressure for a mechanical ventilation system, including: applying mechanical ventilation to lungs of a patient in a volume targeted mode to inflate said lungs by delivering a predetermined tidal volume of gas to said lungs 5 adequate for CO 2 removal, and to deflate said lungs to a positive end-expiratory pressure (PEEP) value; determining a value for compliance of the patient's respiratory system during said mechanical ventilation and corresponding to the PEEP value; repeatedly increasing the PEEP value of the mechanical ventilation in a 10 stepwise manner and determining a corresponding value for the compliance of the patient's respiratory system for each increased PEEP value until the compliance of the patient's respiratory system has not increased for at least two consecutive PEEP increment steps, thereby providing a maximum PEEP value and a corresponding maximum compliance value; 15 repeatedly decreasing the PEEP value of the mechanical ventilation in a stepwise manner and determining a corresponding value for the compliance of the patient's respiratory system for each decreased PEEP value until the compliance of the patient's respiratory system has decreased over at least two consecutive PEEP decrement steps; 20 increasing the PEEP value of the mechanical ventilation to a PEEP value substantially equal to the maximum PEEP value; selecting from the determined PEEP values a PEEP value whose value is the lowest of the determined PEEP values whose corresponding compliance value is substantially equal to the maximum compliance value; 25 decreasing the PEEP value of the mechanical ventilation to the selected PEEP value; and applying mechanical ventilation to said lungs of said patient in said volume targeted mode using the selected PEEP value 30

10. The process of any one of claims I to 9, wherein the patient is a newborn infant. WO 2012/139159 PCT/AU2012/000370 -34

11. The process of any one of claims I to 9, wherein the patient is an adult having a pathological lung disease. 5

12. A mechanical ventilation system configured to execute any one of the above processes.

13. A mechanical ventilation system including one or more data processing components programmed to execute any one of the above processes. 10

14. A computer-readable storage medium having stored thereon processor-executable instructions that, when executed by a processor of a processor-controlled mechanical ventilation system, cause the mechanical ventilation system to execute the process of any one of claims I to 11. 15

15. A mechanical ventilation system, including: at least one gas inlet to receive at least one gas to be supplied to lungs of a patient; a gas outlet to be coupled to lungs of said patient; 20 user interface components configured to display ventilation data to a user of the system and to receive ventilation control inputs from said user; one or more data processing components configured to receive data representing the supply of gas to the patient and to receive control data representing said ventilation control inputs, and to control the supply of said gas to said patient 25 in accordance with said ventilation control inputs; mechanical ventilation components configured to supply said gas to said patient under control of said data processing components; wherein the data processing components are configured to determine values for compliance of the patient's respiratory system for respective values for positive 30 end-expiratory pressure (PEEP) for ventilating said patient, and to determine a WO 2012/139159 PCT/AU2012/000370 -35 quasi-optimal PEEP value as being a lowest PEEP value that provides a highest compliance value.

16. The mechanical ventilation system of claim 15, wherein the data processing 5 components are configured to determine the quasi-optimal PEEP value by selecting from the PEEP values the lowest PEEP value whose corresponding compliance value is substantially equal to the highest compliance value of the determined compliance values. 10

17. The mechanical ventilation system of claim 15, wherein the data processing components are configured to determine the quasi-optimal PEEP value from the PEEP values and their associated respective compliance values, but wherein the determined PEEP value is not equal to one of those PEEP values. 15

18. The mechanical ventilation system of any one of claims claim 15 to 17, wherein the data processing components are configured to determine the quasi-optimal PEEP value by: applying mechanical ventilation to lungs of said patient in a volume targeted mode to inflate said lungs by delivering a predetermined tidal volume of gas to said 20 lungs adequate for CO 2 removal, and to deflate said lungs to a positive end expiratory pressure (PEEP) value; determining a value for compliance of the patient's respiratory system during said mechanical ventilation and corresponding to the PEEP value; repeatedly increasing the PEEP value of the mechanical ventilation in a 25 stepwise manner and determining a corresponding value for the compliance of the patient's respiratory system for each increased PEEP value until the compliance of the patient's respiratory system has not increased for at least two consecutive PEEP increment steps, thereby providing a maximum PEEP value and a corresponding maximum compliance value; and WO 2012/139159 PCT/AU2012/000370 - 36 repeatedly decreasing the PEEP value of the mechanical ventilation in a stepwise manner and determining a corresponding value for the compliance of the patient's respiratory system for each decreased PEEP value until the compliance of the patient's respiratory system has decreased over at least two consecutive PEEP 5 decrement steps.

19. The mechanical ventilation system of any one of claims claim 15 to 18, wherein the data processing components are configured to determine the quasi-optimal PEEP value by selecting from the determined PEEP values a PEEP value whose value is 10 the lowest of the determined PEEP values whose corresponding compliance value is substantially equal to the maximum compliance value.

20. The mechanical ventilation system of claim 19, wherein the data processing components are further configured to: 15 increase the PEEP value of the mechanical ventilation to a PEEP value substantially equal to the maximum PEEP value; decrease the PEEP value of the mechanical ventilation to the selected PEEP value; and apply mechanical ventilation to said lungs of said patient in said volume 20 targeted mode using the selected PEEP value.

21. The mechanical ventilation system of any one of claims claim 15 to 20, wherein the data processing components are further configured to maintain the mechanical ventilation for each PEEP value for a period of time sufficient for the patient's 25 respiratory system to have substantially stabilised, as dictated by the patient's lung pathology.

22. The mechanical ventilation system of any one of claims claim 15 to 21, wherein the data processing components are further configured to apply mechanical ventilation 30 to said lungs of said patient using the determined PEEP value. WO 2012/139159 PCT/AU2012/000370 - 37

23. A mechanical ventilation system, including: at least one gas inlet to receive at least one gas to be supplied to lungs of a patient; 5 a gas outlet to be coupled to lungs of said patient; user interface components configured to display ventilation data to a user of the system and to receive ventilation control inputs from said user; one or more data processing components configured to receive data representing the supply of gas to the patient and to receive control data representing 10 said ventilation control inputs, and to control the supply of said gas to said patient in accordance with said ventilation control inputs; mechanical ventilation components configured to supply said gas to said patient under control of said data processing components; wherein the data processing components are configured to cause the 15 mechanical ventilation system to: apply mechanical ventilation to lungs of a patient in a volume targeted mode to inflate said lungs by delivering a predetermined tidal volume of gas to said lungs adequate for CO 2 removal, and to deflate said lungs to a positive end-expiratory pressure (PEEP) value; 20 determine a value for compliance of the patient's respiratory system during said mechanical ventilation and corresponding to the PEEP value; repeatedly increase the PEEP value of the mechanical ventilation in a stepwise manner and determine a corresponding value for the compliance of the patient's respiratory system for each increased PEEP value until the compliance of the 25 patient's respiratory system has not increased for at least two consecutive PEEP increment steps, thereby providing a maximum PEEP value and a corresponding maximum compliance value; repeatedly decrease the PEEP value of the mechanical ventilation in a stepwise manner and determine a corresponding value for the compliance of the patient's 30 respiratory system for each decreased PEEP value until the compliance of the WO 2012/139159 PCT/AU2012/000370 -38 patient's respiratory system has- decreased over at least two consecutive PEEP decrement steps; increase the PEEP value of the -mechanical ventilation to a PEEP value substantially equal to the maximum PEEP value; 5 select from the determined PEEP values a PEEP value whose value is the lowest of the determined PEEP values whose corresponding compliance value is substantially equal to the maximum compliance value; decrease the PEEP value of the mechanical ventilation to the selected PEEP value; and 10 apply mechanical ventilation to said lungs of said patient in said volume targeted mode using the selected PEEP value.

24. A method of treating a subject with a pathological lung disease or who is at risk of developing same, said method comprising administering to said subject open lung 15 ventilation (OLV) with a mechanical ventilator wherein a positive end-expiratory pressure (PEEP) for the mechanical ventilator is determined by: determining values for compliance of the subject's respiratory system during the mechanical ventilation of said subject using respective PEEP values; and processing the compliance values and the PEEP values to determine a PEEP 20 value as substantially being a lowest PEEP value that provides a highest compliance value.

25. The method of claim 24 wherein the ventilator inflations are synchronised to the subject's positive inflationary pressure (PIP) and wherein the delivered inflation 25 pressure is adjusted to maintain a constant tidal volume (V-).

26. The method of claim 24 or 25, including: applying mechanical ventilation to lungs of the subject in a volume targeted mode to inflate said lungs by delivering a predetermined Vr of gas to said lungs WO 2012/139159 PCT/AU2012/000370 -39 adequate for CO 2 removal, and to deflate said lungs to a positive end-expiratory pressure (PEEP) value; determining a value for compliance of the subject's respiratory system during said mechanical ventilation and corresponding to the PEEP value; 5 repeatedly increasing the PEEP value of the mechanical ventilation in a stepwise manner and determining a corresponding value for the compliance of the subject's respiratory system for each increased PEEP value until the compliance of the subject's respiratory system has not increased for at least two consecutive PEEP increment steps, thereby providing a maximum PEEP value and a corresponding 10 maximum compliance value; repeatedly decreasing the PEEP value of the mechanical ventilation in a stepwise manner and determining a corresponding value for the compliance of the subject's respiratory system for each decreased PEEP value until the compliance of the subject's respiratory system has decreased over at. least two consecutive PEEP 15 decrement steps; increasing the PEEP value of the mechanical ventilation to a PEEP value substantially equal to the maximum PEEP value; selecting from the determined PEEP values a PEEP value whose value is the lowest of the determined PEEP values whose corresponding compliance value is 20 substantially equal to the maximum compliance value; decreasing the PEEP value of the mechanical ventilation to the selected PEEP value; and applying mechanical ventilation to 'said lungs of said subject in said volume targeted mode using the selected PEEP value. 25

27. The method of any one of claims 24 to 26, wherein the subject is a human newborn infant. WO 2012/139159 PCT/AU2012/000370 - 40

28. The method of any one of claims 24 to 27, wherein the pathological lung disease is selected from lung collapse, atelactic lung disease, and respiratory distress syndrome. 5

29. The method of any one of claims 24 to 27 wherein the pathological lung disease is acute respiratory failure.