Intensive Care Med (2003) 29:130134 DOI 10.

1007/s00134-002-1568-z

B R I E F R E P O RT

Luigi Barberis Emmanuello Manno Claude Gurin

Effect of end-inspiratory pause duration on plateau pressure in mechanically ventilated patients

Received: 23 April 2002 Accepted: 15 October 2002 Published online: 6 December 2002 Springer-Verlag 2002 Luigi Barberis was a research fellow at and received grants from the Department of Anaesthesiology, Turin, Italy

L. Barberis E. Manno Department of Anaesthesiology and Intensive Care Unit, Ospedale Maria Vittoria, Turin, Italy C. Gurin () Service de Reanimation Medicale et dAssistance Respiratoire, Hpital de la Croix-Rousse, 103, Grande Rue de la Croix-Rousse, 69004 Lyon, France e-mail: claude.guerin@chu-lyon.fr Tel.: +33-4-72071762 Fax: +33-4-72071774

Abstract Objective: To compare the values of plateau pressure (Pplat) recorded at different times after endinspiratory occlusion and those of static elastance (Est,rs) and total resistance (Rrs) of the respiratory system. Design: Physiological study. Setting: Medical intensive care unit of a university hospital. Patients: Eleven patients with ARDS and ten patients with COPD requiring tracheal intubation and mechanical ventilation were investigated. COPD patients were investigated on zero end-expiratory pressure (ZEEP) and ARDS patients on both ZEEP and positive end-expiratory pressure (PEEP). Measurements and results: Respiratory mechanics were assessed using the rapid airway occlusion technique. Tracheal pressure (Ptr) was measured downstream the endotracheal tube. Ptr was recorded 0.5 s, 1 s, 2 s, 3 s, and 5 s after a 5-s end-inspiratory occlusion. Est,rs and Rrs were computed at the same times using standard formula. In ARDS patients on ZEEP, Pplat amounted to

205, 205, 195, 195, and 185 cmH2O at 0.5, 1, 2, 3 and 5 s, respectively (P <0.001). In COPD patients, these values were 184 cmH2O, 174 cmH2O, 174 cmH2O, 164 cmH2O, and 164 cmH2O (P <0.001). Except for one ARDS patient on PEEP, Pplat was always less than 35 cmH2O, regardless of the time of measurement. As compared to 5 s, measurements at 0.5 s resulted in overestimation of Est,rs by 14% and 29% and in underestimation of Rrs by 34% and 24%, in ARDS and COPD patients, respectively. Conclusions: Very early post-occlusion values of Pplat were statistically greater than at 3 s or 5 s. This probably has no major impact on the occurrence of volutrauma. Clinicians must be aware, however, that Est,rs and Rrs are greatly modified by the time of recording of Pplat. Keywords End-inspiratory pause duration Plateau pressure Mechanically ventilated patients

Introduction
Recognition of the so-called plateau pressure (Pplat) as the key variable regarding judiciously adjusting ventilatory settings in mechanically ventilated patients with Acute Respiratory Distress Syndrome (ARDS) was an important step forward to prevent ventilator-induced lung injury. Pplat is taken as an estimate of end-inspiratory lung distension, i.e., of end-inspiratory alveolar

pressure, and previous recommendations advocated maintaining its value lower than 35 cmH20 [1]. The relevance of this approach yielded a remarkable demonstration in the NIH trial showing that using low tidal volume (VT) improves the survival of ARDS patients as compared with high VT [2]. Assessment of Pplat requires an end-inspiratory pause that can be done either manually by the clinician or automatically from the ventilator. However, the time at which after the end-inspiratory

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pause the value of Pplat is recorded varies between clinically-oriented and physiologically-oriented studies. For instance, in the NIH study [2], Pplat was recorded 0.5 s after the end-inspiratory pause set at the ventilator whereas in physiological studies an end-inspiratory pause of longer duration, i.e., 35 s, is applied [3, 4]. From a physiological point of view, long duration of the end-inspiratory pause is advocated to eliminate the dynamic pressure dissipation and to properly reach the endinspiratory static elastic equilibrium. It is well known that, after an end-inspiratory occlusion, airway pressure exhibits an immediate rapid drop, reflecting pressure dissipation within the conducting airways, followed by a slow decay to Pplat, reflecting the viscoelastic properties of lung or thoracic tissues and/or pendelluft phenomenon, in normal subjects [5] and in patients with ARDS [6] or Chronic Obstructive Pulmonary Disease (COPD) [7]. In addition, the value of Pplat is used to compute the total resistance (Rrs) and the static elastance (Est,rs) of the respiratory system [5, 6, 7]. Therefore, one should expect differences in Pplat, rs, and Est,rs by using values of Pplat recorded at different times after end-inspiratory occlusion. There is, however, no systematic study in previous literature investigating the amplitude and the potential clinical impact of the time-induced error in the estimation of respiratory system elastance and resistance, as measured by the end-inspiratory occlusion technique. We undertook the present systematic study to test this hypothesis and quantify these differences.

Table 1 Anthropometric characteristics and days to investigation of 11 ARDS patients and 10 COPD patients. (ARDS acute respiratory distress syndrome, COPD chronic obstructive pulmonary disease, Days number of days between onset of mechanical ventilation and investigation) ARDS 1 2 3 4 5 6 7 8 9 10 11 meanSD COPD 1 2 3 4 5 6 7 8 9 10 meanSD Gender F M F M F F M M M M M Age (years) 39 46 68 72 61 60 66 59 63 65 55 5910 67 61 46 64 76 73 72 58 61 61 649 Height (cm) 160 170 165 170 168 175 170 139 175 164 161 16510 170 171 168 168 175 170 160 155 168 170 1686 Weight (kg) 60 64 60 128 58 98 71 48 70 68 53 7023 87 60 75 80 77 66 52 111 56 70 7317 Days 1 2 2 4 11 4 1 2 2 4 3 33 3 1 1 2 3 1 1 2 10 3 33

M M M F M M M F M M

Patients and methods

Patients Eleven patients with ARDS and ten patients with COPD (Table 1) requiring tracheal intubation and mechanical ventilation were studied, some of them having previously been used for other purposes [4, 8]. For the 11 ARDS patients, at the time of investigation, the meanSD values of PaO2/FiO2 ratio were 13246, PaCO2 468 mmHg, and pH 7.360.07. The corresponding values in COPD patients amounted to 17243, 479 mmHg, and 7.410.06, respectively. Pulmonary function data obtained before acute respiratory failure were available in seven patients with COPD showing a vital capacity of 7029% of predicted and forced expired volume in 1 s of 3921% of that predicted. ARDS occurred in a medical context for nine patients and in a post-operative context for the remaining two. The medical conditions were pneumonia in seven patients and lymphoma in two. Post-operative context included septic shock due to Serratia marcescens after hepatectomy and septic shock due to Escherichia coli after esophageal surgery. The acute respiratory failure in the patients with COPD was triggered by exacerbation in seven patients and pneumonia in the remaining three. The investigation was approved by the Institutional Ethics Committee in Lyon, and informed consent was obtained from the next of kin for each patient. The patients were orotracheally intubated (Mallinckrodt cuffed endotracheal tube, 7.58.5 mm internal diameter; Mallinckrodt, Athlone, Ireland) and mechanically ventilated in volume-controlled mode with a square wave inspiratory flow (Siemens Elema 900 C Servo Ventilator, Solna, Sweden). During the study all patients were se-

dated with midazolam (0.2 mg.kg-1) and paralyzed with atracurium (0.30.6 mg.kg-1). The baseline ventilatory settings, which were kept constant throughout the experiment, are listed in Table 2. Airflow (V) was measured with a heated pneumotachograph (Fleisch No. 2, Lausanne, Switzerland) inserted between the endotracheal tube and the Y-piece of the ventilator. The pressure drop across the two ports of the pneumotachograph was measured with a differential piezoelectric pressure transducer (163PC01D36 12.7 cmH2O; Micro switch, Freeport, Ill., USA). Airway pressure was measured proximal to the endotracheal tube (Pao) from a port inserted between endotracheal tube and pneumotachograph and connected to a piezoelectric pressure transducer (143PC03D, 176 cmH2O; Micro switch, Freeport, Ill., USA). Tracheal pressure (Ptr) was measured via a polyethylene catheter (1.5 mm ID) with multiple side holes and an occluded end hole, placed 2 cm past the carinal end of the endotracheal tube and connected to a piezoelectric pressure transducer (143PC03D, 176 cmH2O; Micro switch, Freeport, Ill., USA). The equipment dead space (not including the endotracheal tube) was 150 ml. All variables were recorded on a IBM compatible computer by a 12-bit analogue-digital board (DT2801-A) interfaced with data acquisition software (Labdat RHT-Infodat, Montreal, Canada) at a sample frequency of 100 Hz. Subsequent data analysis was made with Anadat (RHTInfodat). In this analysis, VT was obtained by digital integration of the V signal. Special care was taken to avoid gas leaks in the equipment and around the tracheal cuff. To reduce the effects of the compliance of the system connecting the subjects to the ventilator on the mechanics measurements, a single length of standard low-compliance adult tubing was used (2 cm ID, 110-cm long) and the humidifier was omitted from the inspiratory line. During the study, a physician not involved in the experiment was always present to provide patient care.

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Table 2 Baseline ventilatory settings. Values are meanSD. (VT inflation volume, V inflation flow, f respiratory frequency, Ti inspiratory time, Te expiratory time, Ttot total duration of the breathing cycle) VT (ml.kg-1) ARDS (n=11) COPD (n=10) 10.12.9 10.32.5 V (l.s-1) 0.60.2 0.60.1 f (min-1) 15.02.0 14.02.0 Ti (s) 1.20.2 1.20.2 Te (s) 3.40.7 3.00.5 Ti/Ttot 0.30.1 0.30.1

Procedure and data analysis Patients were investigated supine on ZEEP. Patients with ARDS were also assessed at PEEP set by the clinician. Respiratory mechanics were determined by the constant-V rapid airway occlusion method previously described in detail [5, 6, 7]. The total positive end-expiratory pressure (PEEPt) was obtained from a 3-s end-expiratory occlusion. The maximal inspiratory pressure (Pmax) and the plateau pressure at 0.5 s, 1 s, 2 s, 3 s, and 5 s after endinspiratory occlusion were recorded. Since after end-expiratory or end-inspiratory occlusion there was no airflow at the site of pressure measurement, the values of Pao and Ptr were very close. Therefore, the values pertaining to Ptr only were used for the following computations. Separate computations of Rrs were obtained by dividing the differences between Pmax and Ptr at 0.5 s, 1 s, 2 s, 3 s, and 5 s by the V immediately preceding the end-inspiratory occlusion [5]. In calculation of Rrs the errors introduced by the closing time of the ventilator valve were corrected [9]. Separate computations of Est,rs were obtained by dividing the differences between the values of Ptr at 0.5 s, 1 s, 2 s, 3 s, and 5 s and PEEPt by VT [5]. Values were expressed as meanSD. The values obtained at different times after end-inspiratory occlusion, were compared using ANOVA for repeated measures. In case of difference, the values were compared to those at 5 s, taken as the control, using the Dunnets paired t-test. A p-value <0.05 was accepted as statistically significant. For statistical analysis, we used SigmaStat software (version 2.03, 19921997, SPSS).

Fig. 1 MeanSD values of pressure at the airway opening (PaO) and tracheal pressure (Ptr) in patients with acute respiratory distress syndrome (ARDS) and with chronic obstructive pulmonary disease (COPD) at 0.5 s, 1 s, 2 s, 3 s, and 5 s after end-inspiratory occlusion. * P 0.05 versus 5 s

Results
In COPD and in ARDS patients, the mean values of PEEPt from Ptr on ZEEP were 73 cmH2O and 44 cmH2O, respectively. The values of Pplat were not significantly different between Pao and Ptr at any time after end-inspiratory occlusion (Fig.1). These values significantly decreased from 0.5 s to 5 s after end-inspiratory occlusion in both ARDS and COPD patients on ZEEP (Fig. 1). As compared to 5 s, the values significantly differed at 0.5 s, 1 s, and 2 s (Fig. 1). The variations of Pplat (Ptr) at 0.5 s, 1 s, 2 s, and 3 s relative to 5 s were 11%3%, 7%2%, 4%2%, and 2%2% (P <0.001) in ARDS and 17%9%, 12%6%, 6%5% and 4%2% (P <0.001) in COPD patients, respectively. There was a significant decrease in Est,rs and a significant increase in Rrs from 0.5 to 5 s in both groups of patients (Table 3). As for Pplat, the significant differences of Est,rs and Rrs were obtained at 0.5, 1 and 2 s as compared to 5 s. The variations of Est,rs at 0.5 s, 1 s, 2 s, and 3 s relative to 5 s were 14%4%, 9%3%, 5%3%, and 3%2% (P <0.001) in ARDS patients. In COPD patients the cor-

Fig. 2 Individual values of tracheal plateau pressures recorded on PEEP in 11 ARDS patients at 0.5 s, 1 s, 2 s, 3 s, and 5 s after endinspiratory occlusion

responding values amounted to 29%14%, 21%11%, 11%9%, and 6%3% (P <0.001). The variations of Rrs were 34%10%, -21%7%, -11%6%, and 5%6% (P <0.001) in ARDS patients. In COPD patients the corresponding values were 24%9%, -17%6%, -7%4%, and 5%3% (P <0.001). In ARDS patients on PEEP (average 103 cmH2O), the values of Pplat were also greater at 0.5 s, 1 s, and 2 s as compared to 5 s (Fig.2); similar results than on ZEEP were obtained on PEEP for Est,rs and Rrs (not shown).

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Table 3 Static elastance and total resistance of the respiratory system of 11 ARDS and 10 COPD patients at zero end-expiratory pressure. Values are meanSD (Time time from end-inspiratory occlusion, Est,rs static elastance of respiratory system, Rrs total resistance of respiratory system) ARDS COPD

Time (s) Est,rs Rrs Est,rs Rrs (cmH2Ol1) (cmH2Ol1s) (cmH2Ol1) (cm H2Ol1s) 0.5 1 2 3 5 258 * 248 * 237 * 237 227 86 * 96 * 107 * 117 117 164 * 154 * 144 * 134 133 1816 * 1916 * 2017 * 2118 2219

* P <0.05 s versus 5 s

Fig. 3 Record of tracheal pressure over time in the bench study. The straight and stable plateau pressure during end-inspiratory occlusion (arrow) indicates the absence of any apparent leak in the set-up

Discussion
Before discussing our results some methodological considerations have to be pointed out. First, we measured airway pressure proximal and distal to the endotracheal tube and found that both values were similar. This was predictable given that during airway occlusion any true airflow resistance no longer participates in the pressure drop, therefore eliminating the resistive component of the endotracheal tube. We used Ptr to compute Rrs as the total resistance of the respiratory system, in order to exclude any participation by the airflow resistance in the endotracheal tube. To be consistent throughout the study, all the results have been expressed using the values of Ptr. The nearly perfect agreement between Pao and Ptr has important clinical implications because the pressure monitored in practice is usually Pao and not Ptr. However, the pressure provided routinely is actually measured inside the ventilator and some difference between the latter and Pao can be expected depending on the compliance of the circuit. Second, measuring Ptr requires insertion of a catheter and hence connections which could induce some leaks. To make sure that no leak was present during the measurement, a bench study was performed with our entire set-up showing that a 5-s end-inspiratory occlusion did not result in any leak (Fig. 3) Finally, it should be stressed again that the strength of the present study is that it is, to our knowledge, the first attempt to systematically investigate the amplitude and the potential clinical impact of the time-induced error in the estimation of respiratory system elastance and resistance, as measured by the popular rapid airway end-inspiratory occlusion technique. As expected, we found that measuring Pplat very early after end-inspiratory occlusion overestimated the true static end-inspiratory elastic pressure by 11% in ARDS patients and by 17% in COPD patients on ZEEP. The slow decay in pressure, which follows the rapid initial

pressure drop after end-inspiratory occlusion, reflects pendelluft and/or viscoelastic properties of lung and chest wall tissues [5]. It has previously been suggested that time-constant inequalities contribute little to the slow decay in patients with ARDS [6] and with COPD as well [7]. In contrast, these studies emphasized the prevalent role of the viscoelastic properties in this pressure dissipation. Since the viscoelastic behavior involves timedependence in the respiratory mechanics, the difference between ARDS and COPD patients in the changes of Pplat, Ers and Rrs over time post-occlusion might be explained by some differences in ventilatory settings and particularly in inspiratory time. This was not the case (Table 2). Therefore, greater values of the viscoelastic constants in COPD than in ARDS patients may explain the greater Pplat difference between measurements at 0.5 s and 5 s in the patients currently investigated. Due to the design of this study, our experiment cannot answer this question. It must be pointed out that on both ZEEP and PEEP, in all patients but one (Fig. 1), the values of Pplat were below the safety threshold of 35 cmH2O regardless of the post-occlusion time of measurement. These findings only showed, however, that a Pplat of 35 cmH2O measured at 0.5 s after the onset of the occlusion guarantees a real end-inspiratory alveolar pressure below this recommended Pplat. Our results also suggest that setting VT to achieve Pplat at 0.5 s <35 cmH2O is a strict criterion in the attempt to prevent volutrauma and/or that volutrauma prevention was achieved by inducing excessive levels of hypoventilation and hypercapnia. Using the following equation VT = (Pplat at 0.5 s-Pplat at 5 s)/Est,rs at 5 s, where Est,rs at 5 s is the true Est,rs, the theoretical increase in VT warranted by differences between Pplat at 0.5 s and Pplat at 5 s was computed from the present data. The corresponding values of the underestimated VT setting amounted to 9233 ml in patients with ARDS and to 208106 ml in patients with COPD. The overestimation of Est,rs by 14% and 29% and the underestimation of Rrs by 34% and 24%, in patients

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with ARDS and COPD, respectively, are clinically relevant. These variables can easily be monitored from the ventilator [10] and may be used to adjust the ventilatory settings and to assess the effect of therapy as bronchodilating agents. The resulting imprecise diagnosis may lead to underestimation of bronchoconstriction and, hence, delayed or underprescription of bronchodilating drugs. Finally, in order to properly address within- or between-patient comparisons in both clinical and research applications standardization of the measurements is required. From our results, it was also observed that Pplat at 3 s is not different from that at 5 s and that, therefore, an 3-s end-inspiratory pause may be sufficient. Therefore, Pplat, Ers, and Rrs obtained from measurements done after a 3-s end-inspiratory pause are as accurate as those obtained after a 5-s end-inspiratory occlusion regarding physiological events. Our data show that measurement of

Pplat at 0.5 s after the onset of the end-inspiratory occlusion leads to an erroneous partitioning of Ptr between its resistive and elastic components. Therefore, our study provides evidence that measuring Pplat at 3 s after endinspiratory occlusion should be advised and that this value should be used to compute resistance and elastance of the respiratory system. Measurements of Pplat taken within 2 s from inspiratory occlusion must be discouraged. If they seem to have no major impact on the occurrence of volutrauma, they can lead to other clinical errors. In conclusion, there is a statistically significant difference in the values of plateau pressure recorded very early after an end-inspiratory pause as compared to those recorded at 3 s or 5 s. This probably has no major impact on the occurrence of volutrauma. Clinicians must be aware, however, that the values of Est,rs and Rrs are greatly modified by the time of recording of Pplat.

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