Control of positive end-expiratory pressure (PEEP) for small animal ventilators

The choice of the adequate positive end-expiratory pressure (PEEP) is one of the main concerns about ventilatory settings for mechanical ventilation. From normal lung subjects during anesthesia to patients with acute lung injuries (ALI), the use of a PEEP equal to zero is practically absent in the current evidence based ventilatory therapy [1, 2].

In commercial microcontrolled artificial ventilators for humans, the up-to-date technology for PEEP control is most commonly done by an expiratory valve with a membrane that imposes a counter pressure regulated by an electromechanical device. At the beginning of expiration, the pulmonary pressure being higher than the PEEP enables the valve to open and expiration remains until equalization of both pressures or until the expiration ceases because of the start of the next inspiration.

An alternative approach is to eliminate the membrane valve by using an on-off valve to set the target PEEP. In this case, the valve is kept open to the atmosphere when expiration begins and closes when the target PEEP is achieved. Some potential benefits may be identified with this technique. First, the driving pressure for expiration is magnified, and consequently the expiratory time may be diminished [3, 4]. Second, the elimination of a membrane circumvents common adversities found in practice, mainly the mechanical oscillation of the membrane and the airflow resistance imposed by it. Additionally, an on-off valve can be easily miniaturized for small animal setups, in which minimal compressive volume of the respiratory circuit is mandatory.

The objective of this work is the evaluation of two PEEP control systems based on switching an on-off valve installed on the expiratory circuit. The first is the PEEP of a commercial ventilator and the second is a prototype developed by the authors. Both systems are based on the same principle, i.e., to close the on-off valve at a certain point of expiration, in order to achieve the target PEEP for the rest of the expiratory time. The performance of both systems for controlling the PEEP was tested in vitro and in vivo in a rat model.

The commercial ventilator was an INSPIRA model 557059 (Harvard Apparatus, MA, USA). The information available on the website of the manufacturer is that the PEEP feature "allows a positive pressure to be maintained between inspirations instead of falling to zero or near zero at the end of the expiratory phase. When the PEEP pressure is reached, the expiration valve closes until the next inspiration cycle begins." The PEEP generated by this ventilator was denominated PEEP-old. A specimen of the INSPIRA ventilator ASVP, serial number B-45397 (Harvard Apparatus, MA, USA) regularly purchased has been used in all tests.

In this work, a prototype PEEP controller was designed, to operate in conjunction with the ventilator INSPIRA. The system includes a miniaturized on-off valve 003-0459-900 (Parker, OH, USA) connected to the exhaust port of the ventilator. To control such valve, two signals, available from the ventilator, were employed: the airways opening pressure (P_ao-Inspira) and a binary signal of synchronism (S_I-E), in which the logical one indicates the occurrence of the inspiratory cycle and the logical zero, the expiratory cycle. These two signals were acquired at a sampling rate of 1000 Hz by an analog-to-digital (A/D) converter PCM-3718HG (Advantech, CA, US) installed on a personal computer PCM-6898 (AAEON Electronics, NJ, US) running a Simulink model using the Real-Time Windows Target (Mathworks, US). The controller reads P_ao-Inspira and S_I-E, and computes the duration of the opening of the on-off valve during the expiration, τ_exp. From S_I-E, for the n-th respiratory cycle the controller calculates the total duration of the expiration as reported by the ventilator, T_exp(n). Then, from P_ao-Inspira and the target PEEP (PEEP_T), the controller updates τ_exp for the n-th respiratory cycle by the law:

where PEEP_I is the intrinsic PEEP [3], measured immediately before the beginning of the n-th inspiration while the on-off valve is still closed, and g(PEEP_T) has values that depend on PEEP_T, equal to 0.08 (0 ≤ PEEP_T ≤ 3 cmH2O), 0.03 (3 < PEEP_T ≤ 5 cmH2O), 0.01 (5 < PEEP_T ≤ 10 cmH2O) and 0.006 (PEEP_T > 10 cmH2O). The values of g were adjusted empirically by numerical simulation in order to reduce the settling time as well as the under/overshoot of the response. The values of τ_exp were limited by software from T_exp/12 to T_exp. The controller outputs the signal to a driver circuit, switched by a digital output of the A/D card. The PEEP generated by this system is hereafter called PEEP-new.

During tests, the signals of interest were also continuously monitored and digitized at a sampling rate of 1000 Hz by an A/D converter 6008 (National Instruments, TX, US) and stored in a personal computer running a program written in LabVIEW (National Instruments, TX, US).

In vitro tests

Figure 1-a shows the experimental set-up. A physical model of the respiratory system (RS) of a rat has been used for tests. It consisted of a bottle of 500 ml, whose compliance, around 0.5 ml/cmH₂O, is within the range of the compliance of a healthy RS of a rat [5]. A Y piece for rats 73-2846 (Harvard Apparatus, Ma, US) was inserted into the compliance model. An additional resistor, representing the airways resistance (R_aw), was not included in the model since the cannula of the Y piece presented a resistance in the order of magnitude of the airways resistance of a rat with healthy lungs [6]. The P_ao (P_ao-monitor) was monitored with a pressure transducer 163PC01D48 (Honeywell, NJ, US) connected to a T piece placed in the expiratory limb, close to the Y piece. In the instances when the PEEP-old was evaluated, tubes and connections were employed as suggested by the manufacturer. When the PEEP-new was tested, the set-up was the same with the inclusion of the on-off valve. The total expiratory circuit resistance from the cannula to the atmosphere including all connecting tubes, the ventilator's on-off valve and the additional on-off valve for PEEP-new control system was of 390 cmH2O.l^-1.s^-1. The additional on-off valve represented about 50% of the total expiratory circuit resistance.

Both PEEP generators were tested with the same respiratory settings. The ventilator was set in volume control mode with a tidal volume (V_T) of 3 ml, a respiratory frequency (RF) of 60 breaths per minute, an inspiratory to expiratory time ratio (I:E) of 1:1, and ventilated with ambient air.

The PEEP-old was tested for the targets of 3, 5 and 10 cmH₂O, in increasing as well as decreasing steps. The trials were triplicate. Since the results with PEEP-old showed large deviations from the target PEEP (more than 5 cmH₂O), the following test was performed only for the PEEP-new method. Initially, the PEEP was set to zero cmH₂O, and sequentially it was changed to 3, 5, 10, 15, 10, 5, 3 and again zero cmH₂O. The duration of each PEEP step was of 1 min, controlled by the computer. Again, the trials were repeated three times.

The PEEP-old controller did not pass the tests since the PEEP obtained largely deviated from the target PEEP in both in vitro and in vivo tests. Most apparently, its controller responds instantaneously to the pressure, closing the valve when the P_ao reaches the target PEEP during expiration, and thus the dynamic evaluation tests were not performed. In almost all circumstances, after a PEEP condition was set, the ventilator reported a "high PEEP alarm" indicating that the actual end-expiratory pressure exceeded 11 cmH₂O or the target PEEP plus 5 cmH₂O, whichever was less. Since the ventilator did not include a safety valve, the high PEEP condition continued to be present until the operator changed the settings. The P_ao waveform during the PEEP-old control showed that the valve was switched at the moment when the P_ao was equal to the target PEEP. Considering that at the switching of the valve P_ao was equal to the elastic pressure minus the resistive pressure of the respiratory system, and the resistive pressure was zeroed by interrupting the flow, the P_ao suddenly rose by the same amount (see Figure 2). The in vitro PEEP deviation was higher than in vivo, most probably because the cannula employed in vitro was more resistive than the total resistance in the in vivo experiments, which included a Y-piece plus a flexible catheter and the animal's airways.

The PEEP-new controller presented an adequate performance. The in vitro tests resulted in a maximal PEEP deviation from the target of 0.2 cmH₂O, maximal overshoot of 1.3 cmH₂O and maximal settling time of 10.2 s for all trials and all PEEP values (Table 1). The evaluation in vivo showed a similar performance, with the exception of animal #3, in which during the descending phase of the PEEP step change test at PEEP of 2 cmH₂O, the presence of liquids in the airways resulted in increase of the airways resistance. In consequence, the controller opened the expiratory valve to the atmosphere for a period very close to the expiratory period and for some target PEEP, high overshoot/undershoot occurred during a PEEP step change. Nevertheless, also in these circumstances the controller could adjust the PEEP to the target.

In the present implementation of the PEEP-new method, some features available in the commercial ventilator were used, such as the S_I-E signal and the P_ao-Inspira. Nevertheless, the PEEP-new may be developed for a general ventilator, simply employing the set-up for in vivo experiments (Figure 1, right panel) where the P_ao as well as the flow rate were monitored independently. In such a case, the inspiratory or expiratory phases may be identified by the sign of the flow rate. Additionally, the present controller design did not use any information regarding the mechanics of the RS to control the on-off valve switching moment. Alternatively, Pino and Giannella-Neto [4] showed by numerical simulations a PEEP control technique with the real-time estimation of the RS expiratory time constant, including the breathing circuit and the endotracheal tube, and the control was adequate also for RS including viscoelastic properties.

Setting the PEEP at PEEP_I was employed by East et al. [3] in pressure-controlled inverse ratio ventilation (PCIRV), to provide high mean airway pressure (Paw) at the lowest peak inspiratory pressure, while maintaining a desired level of PEEP_I, tidal volume, and arterial pH. In order to maximize the Paw, the lowest expiratory time was chosen without any expiratory pause. In the present work a simple protocol was designed to control the PEEP during volume control mode. We did not control I:E which was fixed in 1. Have the I:E control been also considered, we could, as proposed by East et al. [3], seek to maximize the mean Paw, or conversely, as previously described [4], to minimize the mean Paw by extending the expiratory pause for a chosen PEEP. Clinically, some consequences may be foreseen. East et al. [3] reported hemodynamic effects with a decrease of the cardiac output and an increase in both pulmonary artery and right atrium pressures. It may be hypothesized that the hemodynamic effects of the minimization of the mean Paw would be the opposite. A lower mean alveolar pressure is potentially favorable to minimize the effects of PEEP on the pulmonary vascular resistance by preventing dynamic hyperinflation [8]. However, a ventilatory effect in the lungs could be considered as well, since the decrease of the mean Paw could reduce recruitment of alveolar units, with the impairment of gas exchange and increase of venous admixture. These speculations deserve a clinical evaluation. Technically, despite the algorithm of East et al. [3] being more complex since it considers more controls than ours, in what concerns specifically the PEEP controller both methods are based on a similar integral controller in which the updating of the effective expiratory period depends on the difference [PEEP_I - PEEP_T].

Some limitations of this study must be reported. The present controller, as it is, cannot be used with spontaneously breathing subjects. Furthermore, the present controller was tuned for the mechanical ventilation of rats. In consequence, the reported performance indices cannot be generalized to other species. The controller law parameters may have to be retuned for use with different respiratory mechanics. The hardware presented a respiratory circuit resistance which was appropriate for ventilating rats and mice; however for larger animals, the on-off valve must be less resistive.

The use of small animals for studies related to the mechanical ventilation settings and its effects on ventilator-induced lung injuries and inflammatory responses is very frequent. Some commercial ventilators for humans may be suitable to typical respiratory rates and tidal volumes for rats [9], albeit the breathing circuit must be adapted in order to minimize the compressed volume. For mouse models, however, a small animal ventilator is mandatory since the V_T may be smaller than 200 μl. The PEEP-new may represent an alternative for an accurate PEEP implementation capable of being computer controlled, as in the time-programmed PEEP step change test shown in Figure 3. The availability of the flow rate and P_ao allows estimating the parameters of respiratory mechanics and, furthermore, the entire system can be programmed to automatically control the PEEP as performed by Jandre and coworkers [10].

The PEEP-old controller resulted in PEEP values always higher than the target, in both in vitro and in vivo tests. The PEEP-new controller presented acceptable performance, considering accuracy and temporal response. This novel PEEP generator may be implemented at reasonable costs and may prove useful in many applications for small animal ventilators.