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Clinical Science  |   October 1995
Cardiorespiratory Effects of Positive End-expiratory Pressure during Progressive Tidal Volume Reduction (Permissive Hypercapnia) in Patients with Acute Respiratory Distress Syndrome
Author Notes
  • (Ranieri) Assistant Professor of Medicine.
  • (Mascia) Resident in Anesthesia and Intensive Care Medicine.
  • (Giuliani) Associate Professor of Anesthesia and Intensive Care Medicine.
  • (Fiore, Bruno, Brienza) Professor of Anesthesia and Intensive Care Medicine.
  • Received from the Istituto di Anestesiologia e Rianimazione, Ospedale Policlinico, Universita di Bari, Bari, Italy. Submitted for publication December 20, 1994. Accepted for publication June 12, 1995. Supported in part by Ministero dell' Universita e della Ricerca Scientifica e Tecnologica.
  • Address reprint requests to Dr. Ranieri: Istituto di Anestesiologia e Rianimazione, Universita di Bari, Ospedale Policlinico, Piazza Giulio Cesare, 70100 Bari, Italy.
Article Information
Clinical Science
Clinical Science   |   October 1995
Cardiorespiratory Effects of Positive End-expiratory Pressure during Progressive Tidal Volume Reduction (Permissive Hypercapnia) in Patients with Acute Respiratory Distress Syndrome
Anesthesiology 10 1995, Vol.83, 710-720.. doi:
Anesthesiology 10 1995, Vol.83, 710-720.. doi:
Methods: Nine sedated and paralyzed patients were studied. VTwas decreased gradually (50 ml every 20-30 min). Static volume-pressure (V-P) curves, hemodynamics, and gas exchange were measured.
Results: During mechanical ventilation with conventional VT, V-P curves on PEEP 0 (ZEEP) exhibited an upward convexity in six patients reflecting a progressive reduction in compliance with inflating volume, whereas PEEP resulted in a volume displacement along the flat part of this curve. After VTreduction, V-P curves in the same patients showed an upward concavity, reflecting progressive alveolar recruitment with inflating volume, and application of PEEP resulted in alveolar recruitment. The other three patients showed a V-P curve with an upward concavity; VTreduction increased this concavity, and application of PEEP induced greater alveolar recruitment than during conventional VT. With PEEP, cardiac index decreased by, respectively, 31% during conventional VTand 11% during low VT(P < 0.01); PaO2increased by 32% and 71% (P < 0.01), respectively, whereas right-to-left venous admixture (Qs/Qt) decreased by 11% and 40%, respectively (P < 0.01). The greatest values of PaO2, static compliance, and oxygen delivery and the lowest values of Qs/Qt (best PEEP) were obtained during application of PEEP with low VT(P < 0.01).
Conclusions: Although PEEP induced alveolar hyperinflation in most patients during mechanical ventilation with conventional VT, at low VT, there appeared to be a significant alveolar collapse, and PEEP was able to expand these units, improving gas exchange and hemodynamics.
Key words: Acute respiratory distress syndrome. Alveolar recruitment. Gas exchange. Hemodynamics. Permissive hypercapnia. Positive end-expiratory pressure.
IN patients with acute respiratory distress syndrome (ARDS), a ventilatory strategy based on large tidal volumes (VT) and PEEP has been proposed. [1-4] Tidal volumes (VT) of 10-15 ml/kg are used to prevent the microatelectasis that accompanies shallow breathing, adjusting respiratory rate to normalize pH and/or arterial carbon dioxide tension (PaCO2). Sufficient levels of positive end-expiratory pressure (PEEP) to recruit previously collapsed alveoli and ensure arterial oxygenation at an inspiratory oxygen fraction (FIO2) that does not cause oxygen toxicity [1-4] also has been suggested.
In experimental animals, [5-9] mechanical ventilation with high peak airway pressure and large VTresults in pulmonary edema, severe alterations in permeability, and diffuse alveolar damage very similar to the pathologic findings observed in patients with ARDS. Bearing in mind these experimental findings [5-9] and a retrospective review of clinical data, [10] the recent Consensus Conference on Mechanical Ventilation [11] recommended that, end-inspiratory static airway pressure ideally should be maintained at less than 35 cmH2O during ventilatory treatment of ARDS patients. To accomplish this goal, the Consensus Conference suggested reducing VTto as low as 5 ml/kg, allowing PaCO2to increase (permissive hypercapnia) provided there was no presence or risk of increased intracranial pressure. At the same time, PEEP should be applied (values of approximately 10-12 cmH2O) to avoid end-expiratory collapse of alveolar units. [11] 
In isolated lavaged rat lungs, Muscedere et al. [12] found that ventilation at low airway pressure caused a significant decrease in lung compliance and progressive lung injury. Recent studies also have shown that, in patients with ARDS, the application of PEEP may result in a volume displacement along the flat part of the static volume-pressure (V-P) relationship obtained on PEEP 0 (ZEEP) with no alveolar recruitment and overdistention of the functional lung units. [13,14] 
Despite recent editorials that suggest limiting airway pressure by decreasing VT, [15-19] there are no controlled studies assessing either clinical use or the consequences on respiratory mechanics, hemodynamics, and gas exchange of such a ventilatory strategy in patients with ARDS. We investigated the hypothesis that, although PEEP may induce hyperdistention of alveolar units already recruited by large V sub T, it may reverse the alveolar derecruitment consequent to VTreduction.
Methods
Nine patients (eight men) with severe ARDS of varying etiology admitted to the intensive care unit of the Policlinico Hospital (University of Bari, Bari, Italy) were studied. Patient selection for the study was based on the criteria of ARDS as recently proposed by the American-European Consensus Conference on ARDS: acute onset, presence of hypoxemia (arterial oxygen tension (PaO2)/FIO2less or equal to 200 mmHg regardless of PEEP level), bilateral and diffuse opacities seen on frontal chest x-ray film, and absence of left ventricular failure with a pulmonary arterial occluded pressure (PAOP) less or equal to 18 mmHg. [20] None of the patients had a history of previous lung disease. Sex, weight, individual values of FIO2, PaO2, right-to-left venous admixture (Qs/Qt), static compliance of the respiratory system (Cst,rs) obtained on zero end-expiratory pressure (ZEEP), days of mechanical ventilation, and causes of ARDS are shown in Table 1. Applied PEEP before the study and PAOP amounted to 11 plus/minus 1 cmH2O and 12 plus/minus 1 mmHg, respectively (mean plus/minus SEM).
Table 1. Clinical Data of Patients
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Table 1. Clinical Data of Patients
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Flow (V) was measured with a heated pneumotachograph (Fleisch no. 2, Lausanne, Switzerland), connected to a differential pressure transducer (Validyne MP 45 plus/minus 2 cmH2O; Validyne, Northridge, CA), which was inserted between the y-piece of the ventilator circuit and the endotracheal tube. The pneumotachograph was linear over the experimental range of flow. Equipment dead space (not including the endotracheal tube) was 70 ml. Airway opening pressure (Pao) was measured proximal to the endotracheal tube with a pressure transducer (Validyne MP 45 plus/minus 100 cmH2O). To reduce the effects of compliance and resistance of the system connecting the endotracheal tube to the ventilator circuit, a single length of standard low compliance tubing supplied with the ventilator was used (2 cm ID, 60 cm long). During the measurements, the humidifier was disconnected from the inspiratory tubing. All patients had an intraarterial (radial artery) and a pulmonary artery catheter (7 Fr; Abbott, North Chicago, IL). All the above variables were recorded on an eight-channel pen recorder (7718 A Hewlett-Packard) and on a personal computer via a 12-bit analog-to digital converter at a sample rate of 100 Hz for subsequent data analysis. Volume was determined by digital integration of the flow signal. Cardiac output was measured by thermodilution (3300 Cardiac Output Computer, Abbott). Blood samples (arterial and mixed venous) were analyzed with an ABL 330 analyzer (Radiometer, Copenhagen, Denmark). The patients were nasotracheally intubated (Portex(C) cuffed endotracheal tube) with the inner diameter varying from 8 to 9 mm and were mechanically ventilated with a Siemens Servo Ventilator 900C (Siemens Elema AB, Berlin, Germany).
The investigation was performed in supine patients after sedation (0.1-0.2 mg/kg diazepam and 2-3 micro gram/kg fentanyl) and paralysis (0.1-0.2 mg/kg pancuronium bromide). Two levels of tidal volumes were used: conventional VTof 10-15 ml/kg and low VTof 5-8 ml/kg. Conventional VTwas adjusted to maintain a PaCO2level of 35-45 mmHg. The baseline value used in the study was 10.39 plus/minus 0.55 ml/kg (Table 2). Low VTwas obtained by halving V sub T, reducing the inspiratory time and duty cycle but leaving respiratory rate and inspiratory flow unchanged; the baseline value amounted to 5.50 plus/minus 0.20 ml/kg (Table 2). For each VT, PEEP levels of 0 and 10 cmH2O were applied. We chose 10 cmH2O because this was the PEEP level used before the study.
Table 2. Baseline Breathing Pattern during the Two Experimental Conditions
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Table 2. Baseline Breathing Pattern during the Two Experimental Conditions
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The experimental design decreed that VTbe decreased from conventional to low VT, whereas PEEP levels be randomized. Changes in VTwere achieved by progressively decreasing the previous VTby 50 ml every 20-30 min. Measurements after reduction in VTwere obtained after 2-3 h, whereas effects of changes in PEEP level were evaluated after 30-40 min. The entire experimental procedure lasted 7-8 h. All measurements of respiratory mechanics, hemodynamics, and gas exchange were made during the last 5-10 min of each experimental condition. Application of the two VTlevels was not randomized for two reasons: first because in clinical practice permissive hypercapnia is always implemented from normocapnic conditions, and second, because random changes in VTwould have considerably increased the duration of the study. The protocol was approved by the ethics committees, and written informed consent was obtained from each patient or next of kin. A physician not involved in the experimental procedure was always present to provide patient care.
Experimental Procedure
Intrinsic PEEP. Whenever the time required to complete passive expiration is greater than the expiratory duration set by the ventilator, the end-expiratory lung volume (EELV) will exceed the relaxation volume (Vr) of the respiratory system during mechanical ventilation, and the respiratory system will exert positive static pressure at end-expiration. This pressure is termed intrinsic PEEP (PEEPi). [13,14] PEEPi was measured by pressing the end-expiratory hold knob on the ventilator during a baseline ventilatory cycle. If PEEPi is present, Pao increases after airway occlusion, until a plateau is reached, corresponding to PEEPi. [13] This plateau pressure usually was reached in 3-4 s.
Delta EELV. Delta EELV is the difference between EELV during mechanical ventilation (with or without PEEP) and Vr on ZEEP. [13,14] It was assessed by reducing respiratory rate to the lowest value during a baseline breath, while removing PEEP when present. [13,14] In this way, sufficient time elapsed to complete expiration to Vr. To check that Vr had been reached, the expiratory tubing of the ventilator was occluded by pressing the end-expiratory hold button at the end of the prolonged expiration: If, after 3-4 s of occlusion, there was no increase in Pao, Vr had been reached.
Static Inflation V-P Curve. Static inflation V-P curve was obtained, as previously described, [13,14] by performing single-breath occlusions at different VT. Different inflation volumes were achieved by changing the respiratory frequency of the ventilator, while maintaining inspiratory flow at baseline level. Each occlusion was maintained until an apparent plateau in Pao was observed. This plateau pressure, which usually was reached in about 3-4 s, represents the static end-inspiratory alveolar pressure (Pst,rs). [13,14] After each test breath, baseline ventilation was resumed until Pao returned to its pretest configuration (usually in fewer than four breaths). Inflation volume was varied in random order. The static inflation V-P curves were constructed by plotting the different inflation volumes against the corresponding values of Pst,rs. Because Delta EELV was known, the V-P curves were related to Vr. A second-order polynomial equation was fitted to the experimental points obtained above Delta V = 0 [13,14] Equation 1where a, b, and c are constants. The nonlinear coefficient in Equation 1was used to describe the shape of the inspiratory V-P curve. [13,14] Positive values indicate upward concavity and a progressive increase in slope (i.e., compliance) with increasing volume, whereas negative values indicate upward convexity and a progressive decrease in slope (i.e., compliance) with inflating volume. [13,14] 
Alveolar Recruitment. The recruitment of previously collapsed alveoli consequent to application of PEEP (recruited volume) was identified as the upward shift along the volume axis of the V-P curve on PEEP relative to the curve on ZEEP and was quantified as the increase in volume with PEEP at the same Pst,rs (20 cmH2O; Figure 1and Figure 2). [13,14,21] Tension changes and stress relaxation, besides alveolar recruitment, must be considered in explaining the volume shift of the V-P curve with PEEP, [13,14,21] so that our estimation of alveolar recruitment with PEEP should be taken as the maximum estimate of the actual recruited volume.
Figure 1. Static inflation volume-pressure relationships of the total respiratory system in nine patients with acute respiratory distress syndrom during mechanical ventilation with tidal volume (VT) of 10-15 ml/kg during zero end-expiratory pressure (ZEEP; open circles) and 10 cmH sub 2 O of positive end-expiratory pressure (PEEP; closed circles). Delta V = changes in lung volume relative to the elastic equilibrium point of the respiratory system (Vr); Pst,rs = static elastic recoil pressure. Total PEEP (intrinsic PEEP + externally applied PEEP) values and the corresponding increase in end-expiratory lung volume relative to Vr (EELV) are indicated on ZEEP (closed squares) and on 10 cmH2O of applied PEEP (open squares). Equation 1was fitted to the experimental points above Delta V = 0.
Figure 1. Static inflation volume-pressure relationships of the total respiratory system in nine patients with acute respiratory distress syndrom during mechanical ventilation with tidal volume (VT) of 10-15 ml/kg during zero end-expiratory pressure (ZEEP; open circles) and 10 cmH sub 2 O of positive end-expiratory pressure (PEEP; closed circles). Delta V = changes in lung volume relative to the elastic equilibrium point of the respiratory system (Vr); Pst,rs = static elastic recoil pressure. Total PEEP (intrinsic PEEP + externally applied PEEP) values and the corresponding increase in end-expiratory lung volume relative to Vr (EELV) are indicated on ZEEP (closed squares) and on 10 cmH2O of applied PEEP (open squares). Equation 1was fitted to the experimental points above Delta V = 0.
Figure 1. Static inflation volume-pressure relationships of the total respiratory system in nine patients with acute respiratory distress syndrom during mechanical ventilation with tidal volume (VT) of 10-15 ml/kg during zero end-expiratory pressure (ZEEP; open circles) and 10 cmH sub 2 O of positive end-expiratory pressure (PEEP; closed circles). Delta V = changes in lung volume relative to the elastic equilibrium point of the respiratory system (Vr); Pst,rs = static elastic recoil pressure. Total PEEP (intrinsic PEEP + externally applied PEEP) values and the corresponding increase in end-expiratory lung volume relative to Vr (EELV) are indicated on ZEEP (closed squares) and on 10 cmH2O of applied PEEP (open squares). Equation 1was fitted to the experimental points above Delta V = 0.
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Figure 2. Static inflation volume-pressure relationships of the total respiratory system in nine patients with ARDS during mechanical ventilation with tidal volume (VT) of 5-8 ml/kg during zero end-expiratory pressure (ZEEP; open circles) and 10 cmH2O of positive end-expiratory pressure (PEEP; closed circles). Details and abbreviations as in Figure 1.
Figure 2. Static inflation volume-pressure relationships of the total respiratory system in nine patients with ARDS during mechanical ventilation with tidal volume (VT) of 5-8 ml/kg during zero end-expiratory pressure (ZEEP; open circles) and 10 cmH2O of positive end-expiratory pressure (PEEP; closed circles). Details and abbreviations as in Figure 1.
Figure 2. Static inflation volume-pressure relationships of the total respiratory system in nine patients with ARDS during mechanical ventilation with tidal volume (VT) of 5-8 ml/kg during zero end-expiratory pressure (ZEEP; open circles) and 10 cmH2O of positive end-expiratory pressure (PEEP; closed circles). Details and abbreviations as in Figure 1.
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Alveolar Hyperinflation. Hyperinflation of already ventilated alveoli consequent to application of PEEP was identified when the V-P curve on PEEP was displaced along the flat part of the curve on ZEEP. [13,14] 
Static Compliance of the Respiratory System. Static compliance of the respiratory system (Cst,rs) was computed dividing the baseline inflation volume by the corresponding value of end-inspiratory Pst,rs--(PEEP + PEEPi). [13] 
Hemodynamics and Gas Exchange. Intravascular pressure measurements were obtained over several respiratory cycles. End-expiratory pressure measurements were recorded. These values were referred to atmospheric pressure. Cardiac output was measured and blood samples (arterial and mixed venous) were collected at each level of PEEP, immediately before measurements of respiratory mechanics. Cardiac output was determined by the thermodilution technique using injection of 5 ml cold (< 8 degrees) 5% dextrose solution. Five serial determinations were taken regardless of the respiratory cycle. Variance of individual thermodilution cardiac output at each level of PEEP was always < 10%. Heart rate was monitored. Cardiac index was computed by dividing cardiac output by the body surface area. Arterial (CaO2) and mixed venous (Cv with barO2) oxygen contents were calculated, respectively, from PaO2, Pv with barO2, and measured arterial (SaO2) and venous (Sv with barO2) oxygen saturation using the formula: oxygen content (ml/dl) = (fractional saturation *symbol* hemoglobin concentration *symbol* 1.39) + (0.003 *symbol* PO2). Oxygen delivery (D with dotO2) was computed as the product of CaO2and cardiac index (CI). Oxygen consumption (V wit dotO2) was calculated as: V with dot O2= CI *symbol* (CaO2- Cv with barO2). Qs/Qt was calculated using the equation: Q with dot s/Q with dot t = (CcO2- CaO2)/(CcO2- Cv with barO2), where Cc sub O2(oxygen content of alveolar capillary blood) was calculated assuming capillary oxygen tension to be equal to the alveolar oxygen tension calculated using the alveolar gas equation.
Values were expressed as mean plus/minus SEM. Regression analysis was performed with the least-square method. Values obtained at different tidal volumes and levels of PEEP were compared using the repeated measures two-way analysis of variance (ANOVA), the factors being tidal volume and PEEP. If significant (P less or equal to 0.05), the values obtained at different tidal volumes and PEEP levels were compared with those obtained during mechanical ventilation with VTat 10-15 ml/kg and ZEEP using the paired t test as modified by Dunnett. [22] 
Results
During mechanical ventilation with conventional VT(Figure 1), in patients 1-4, 6, and 8, static inflation V-P curves on ZEEP exhibited a convex shape and a progressive decrease in slope with increasing inflation volume, as reflected by the negative values of nonlinear coefficients in Equation 1(Table 3). In these patients, application of PEEP resulted in a volume displacement along the static V-P curves obtained on ZEEP, with a progressive straightening of the V-P curves. In the remaining patients (5, 7, and 9), static inflation V-P curves exhibited a concave shape on ZEEP with a progressive increase in slope and positive values for the nonlinear coefficient in Equation 1(Table 3). An upward shift along the volume axis of the static inflation V-P curves was observed with PEEP in these patients.
Table 3. Nonlinear Coefficients in Equation 1, Delta EELV and Recruited Volume on 10 cmH2O of PEEP during Mechanical Ventilation with Standard and Low VT
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Table 3. Nonlinear Coefficients in Equation 1, Delta EELV and Recruited Volume on 10 cmH2O of PEEP during Mechanical Ventilation with Standard and Low VT
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In patients 1-4, 6, and 8, the static V-P curves on ZEEP during mechanical ventilation with low VT(Figure 2) became curvilinear toward the horizontal axis (Figure 2) as indicated by the positive values of the nonlinear coefficients in Equation 1(Table 3). V-P curves on PEEP appeared raised along the volume axis with respect to the V-P curves on ZEEP (Figure 2). In patients 5, 7, and 9, the inspiratory V-P curve on ZEEP appeared more arched than during conventional VT, as indicated by the more positive values of the nonlinear coefficients in Equation 1(Table 3). Application of PEEP resulted in a larger upward displacement along the volume axis than during mechanical ventilation with conventional VT(Table 3).
The upward displacement of the V-P curves with PEEP indicates recruitment of previously closed lung units. It was quantified in terms of the increase in volume at Pst,rs of 20 cmH2O. [13,14] The recruited volume with PEEP and the corresponding changes in Delta EELV at both VTlevels are shown in Table 3During mechanical ventilation with conventional VT, recruited volume amounted to 0.17 plus/minus 0.07 l versus 0.75 plus/minus 0.09 l with low VT(P < 0.0001). The average percentage volume recruited to Delta EELV was 19 plus/minus 5% during mechanical ventilation with conventional VTand increased to 60 plus/minus 5% during mechanical ventilation with low VT(P < 0.0001).
During baseline mechanical ventilation with conventional VT, end-inspiratory Pst,rs on ZEEP amounted to 23.4 plus/minus 1.0 cmH2O. Application of PEEP increased Pst,rs up to 39.2 plus/minus 1.0 cmH sub 2 O (P < 0.001). During baseline mechanical ventilation with low VT, end-inspiratory Pst,rs amounted to 11.4 plus/minus 1.7 and 21.0 plus/minus 1.7 cmH2O (P < 0.001) on ZEEP and on 10 cmH2O of applied PEEP, respectively. On ZEEP, Pst,rs during conventional VTwas significantly higher than during low VT(P < 0.001). Cst,rs during baseline mechanical ventilation with conventional VTamounted on ZEEP to 0.041 plus/minus 0.004 l/cmH2O and decreased (P < 0.0001) to 0.031 plus/minus 0.003 l/cmH2O with 10 cmH2O of applied PEEP. During baseline mechanical ventilation with low VTand ZEEP, Cst,rs was significantly lower (P < 0.01) than during conventional VT, amounting to 0.033 plus/minus 0.003 l/cmH2O. Application of PEEP significantly (P < 0.0001) increased Cst,rs up to 0.066 plus/minus 0.008 l/cmH2O.
The effects of PEEP on hemodynamics during mechanical ventilation with conventional and low VTare shown in Table 4Cardiac index and SVI-decreased (P < 0.001), whereas MPAP increased (P < 0.05) with PEEP during conventional VT; during mechanical ventilation, low VT, and PEEP, they remained unchanged. Cardiac index and SVI were significantly (P < 0.05) higher during low VTthan during conventional VTventilation at both PEEP levels. VTreduction did not affect MPAP either on ZEEP or on PEEP. PAOP and RAP significantly (P < 0.01) increased with PEEP during both conventional and low VTand were higher (P < 0.01) during conventional than during low VTat both PEEP levels. Tidal volume reduction and application of PEEP did not modify heart rate or MBP. These effects of PEEP on hemodynamics, when expressed as a percentage of the values on ZEEP, were systematically greater during mechanical ventilation with conventional than with low VT.
Table 4. Effects of PEEP on Hemodynamics during Mechanical Ventilation with the Two Different VT
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Table 4. Effects of PEEP on Hemodynamics during Mechanical Ventilation with the Two Different VT
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(Table 5) shows the effects of PEEP on gas exchange during mechanical ventilation with conventional and low VT. PEEP significantly increased PaO2and SaO2, whereas (Q with dot s/Q with dot t decreased with both VT(P < 0.001). With PEEP, during conventional VT, Pv with barO2and Sv with barO2remained unchanged, whereas they increased (P < 0.01) during low VT. D with dotO2and V with dotO2decreased (P < 0.001) with PEEP during conventional VT, whereas during low VT, D with dotO2increased (P < 0.001) and V with dotO2remained unchanged with 10 cmH2O of PEEP. PaCO2and arterial pH on ZEEP amounted to 41 plus/minus 1 mmHg and 7.42 plus/minus 0.04, respectively, during mechanical ventilation with conventional VTand remained unchanged with 10 cmH2O of applied PEEP. During low VT, PaCO2and arterial pH on ZEEP amounted to 64 plus/minus 5 mmHg and 7.24 plus/minus 0.02 (P < 0.0001), respectively. Application of PEEP significantly (P < 0.01) decreased PaCO2and increased arterial pH. On ZEEP, VTreduction significantly (P < 0.05) increased Q with dot s/Q with dot t Pv with barO2, Sv with barO2, and D with dotO2and decreased PaO2, SaO2, and V with dotO2. The effects of PEEP on gas exchange relative to ZEEP values are shown in Table 5. As can be seen, PEEP can significantly improve gas exchange during low VTventilation.
Table 5. Effects of PEEP on Gas Exchange during Mechanical Ventilation with the Two Different VT
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Table 5. Effects of PEEP on Gas Exchange during Mechanical Ventilation with the Two Different VT
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Discussion
Since the original description of ARDS, [1] the use of large tidal volume and the application of PEEP to restore functional residual capacity and improve arterial oxygenation by the recruitment of collapsed alveoli has become the conventional ventilatory treatment. [2,4] The presence of massive extraalveolar air [4,23] and the cardiovascular depression [24] due to positive pressure breathing were the only clinical side effects pointed out during such ventilatory therapy. However, in normal animals, mechanical ventilation with high peak airway pressure and large VTresulted in pulmonary edema and alveolar damage. [5-8] Furthermore, mechanical ventilation aggravated previous injury to animal lungs due to increased shear stress in the bronchioles and alveoli caused by repeated opening and closing of alveolar units and by regional overdistention produced by uneven distribution of the time constants. [25-27] 
Several clinical investigations have questioned the ability of a ventilatory procedure based on large VTand PEEP to improve respiratory mechanics and gas exchange [13,14,28,29] and pointed out the potential for harm. [30] Studies comparing conventional VTwith low VTfor the same PEEP level have shown a systematic increase in cardiac index and D with dotO2. [28,29] On the other hand, PEEP resulted in alveolar recruitment only in those patients who had a Pst,rs value on ZEEP lower than 25 cmH2O. [14] In addition, Rouby et al. [30] reported that parenchymal air cysts and emphysema-like lesions were found in 86% of the post mortem lungs of ARDS patients previously ventilated with a VTamounting to 12 plus/minus 3 ml/kg. These lesions were found to be more evident in the healthy, normally aerated lung regions. [30] Lee et al. [31] reported the results of a study in which 103 patients were randomized to receive mechanical ventilation with PEEP using a conventional VT(12 ml/kg) and a low V sub T (6 ml/kg). A lower rate of pulmonary infections as well as a shorter duration of intubation and intensive care unit stay was found in patients ventilated with low VT. In a retrospective study, Hickling et al. [10] indicated that limiting peak inspiratory pressure by reducing VTand disregarding hypercapnia decreased predicted hospital mortality in 50 patients with ARDS. In view of these experimental [5-8,25-27] and clinical studies, [10,13,14,28-31] several published editorials and review articles have strongly favored a ventilatory strategy that attempts to control alveolar pressure rather than arterial PCO2. [15-19] However, only in one clinical study, [32] the effects on respiratory mechanics, hemodynamics, and gas exchange of a new ventilatory therapy based on reduction of Pst,rs and permissive hypercapnia have been investigated in patients with ARDS. Our data show that tidal volume reduction promoted alveolar collapse and decreased oxygenation than reduced by PEEP. In fact, PEEP had little effect on the V-P relationship in most patients ventilated with conventional tidal volumes because these alveoli were recruited by the large inflating pressure. On the other hand, at low tidal volume values, there was significant alveolar collapse, and PEEP was able to recruit the alveoli.
With the exception of patients 5, 7, and 9, during mechanical ventilation with a VTof 10-15 ml/kg, the static inflation V-P curves on ZEEP showed a concavity toward the horizontal axis indicating a progressive decrease in compliance with inflating volume (Figure 1). In these patients, the increase in functional residual capacity due to PEEP resulted in displacement of the V-P curve along the upper flat part of the V-P curves on ZEEP (Figure 1). [13,14,21] In patients 5, 7, and 9, the V-P curve during mechanical ventilation with conventional VTand ZEEP showed a convexity toward the volume axis, indicating that compliance increased with inflation volume. In these patients, PEEP caused a shift along the V-P curve, suggesting that alveolar recruitment or other changes in lung properties had occurred (Figure 1). [13,14,21] On the other hand, when our patients were mechanically ventilated with a VTof 5-8 ml/kg, the static V-P curve showed concavity toward the volume axis; in all patients, the application of PEEP resulted in alveolar recruitment of previously collapsed alveoli (Figure 2). [13,14] 
To explain the clinical and physiologic implications of these results, the complex relationship between airway pressure and lung volume must be discussed. The interpretation of our experimental findings is based on the assumption that a static V-P curve with downward concavity represents lungs with all available alveoli recruited and becoming overdistended, whereas V-P curves with upward concavity indicate that alveoli are being progressively recruited. [13,14] During baseline mechanical ventilation with conventional VT, patients who had V-P curves with a downward concavity on ZEEP (patients 1-4, 6, and 9) had an end-inspiratory Pst,rs value amounting to 21.9 plus/minus 0.1 cmH2O. They were therefore close to their maximal volume, i.e., in the flat part of the static V-P curve. Conventional VTwas thus able to recruit and even hyperinflate the recruitable lung zones through the concomitant increase in end-inspiratory Pst,rs. In this case, the application of PEEP caused further hyperinflation of the alveoli already recruited by large tidal volumes. After reduction of VTto 5-8 ml/kg, the V-P curves of patients 1-4, 6, and 8 showed upward concavity and end-inspiratory Pst,rs amounted to 11.4 plus/minus 1.7 cmH2O during baseline ventilation. Under these circumstances, an alveolar derecruitment related to the lower inflating pressure can be attributed to VTreduction. In this case, the application of PEEP elicited a larger increase in recruited volume compared with higher baseline inflation volume and was able to counteract the alveolar derecruitment induced by low-VTventilation. During baseline conventional VTand ZEEP, patients 5, 7, and 9 had lower Pst,rs values (17.5 plus/minus 0.1 vs 21.9 plus/minus 0.1 cmH2O) than the other patients. In these, conventional VTdid not inflate the lung along the flat part of the V-P curve (Figure 1), and hence application of PEEP resulted in alveolar recruitment. Tidal volume reduction enhanced this behavior in the sense that tidal inflation on ZEEP occurred along the initial part of the static inflation V-P curve, characterized by a more rapid progressive increase in compliance. Moreover, application of PEEP induced a larger amount of alveolar recruitment (Table 3).
More than 15 yr ago, Suter et al. [24] noted that "optimum" compliance in ARDS was jointly determined by PEEP and tidal volume. Pelosi et al. [33] extended that observation with elegant computed tomography studies demonstrating differences in gas/tissue ratios at the extremes of the conventional tidal cycle that are eliminated by 10-15 cmH2O of PEEP. A direct correlation between Cst,rs measurements and the amount of aerated lung regions quantified with the computed tomography scan technique was demonstrated by Pelosi et al. and Gattinoni et at. [33,34] Our data show that the greater number of aerated alveoli, i.e., the highest values of Cst,rs were observed during mechanical ventilation with conventional VTon ZEEP and during mechanical ventilation with low V sub T and PEEP. The application of PEEP during conventional VTand the VTreduction on ZEEP decreased Cst,rs, indicating that, during such conditions, normal and recruited alveoli were hyperinflated or minimized, respectively.
In our patients, the reduction in VTinduced a decrease in the hemodynamic consequences of PEEP. Cardiac index and SVI fell with PEEP by 30 plus/minus 2 and 34 plus/minus 1%, respectively, during conventional VTand 9 plus/minus 1% and 4 plus/minus 1%, respectively, during low VT. These results can be explained by the lower values of end-inspiratory Pst,rs obtained when PEEP was applied during mechanical ventilation with low VT. These lower Pst,rs values thus could have minimized the amount of alveolar pressure transmitted to intrathoracic vasculature (preload effect) and/or the increase in alveolar pressure relative to pericardial pressure (after-load effect). [35,36] Whereas, during conventional VT, PEEP decreased the pressure gradient for venous return by increasing RAP by 65 plus/minus 3% of its value on ZEEP, an increase of 16 plus/minus 1% in RAP value on ZEEP was observed when PEEP was applied during mechanical ventilation with low VT. MPAP, routinely used as an index of right ventricular afterload, increased with PEEP by 21 plus/minus 2% of its values on ZEEP during mechanical ventilation with conventional VT, whereas it increased by only 11 plus/minus 1% during mechanical ventilation with low VT. However, the right ventricle is exposed to the same intrathoracic pressure as the pulmonary artery so that accepting a single downstream pressure value regardless of flow as a legitimate index of "afterload" is a gross oversimplification. Only more accurate measurements can assess the hemodynamic consequences of low-VTventilation.
Because DO2is the product of cardiac index and CalciumO2, the effects of PEEP during the different VTused in this study represent the balance of the effects of the two different ventilatory strategies on these factors. During mechanical ventilation with conventional VT, CaO2increased from 10.33 plus/minus 0.21 to 13.61 plus/minus 0.70 ml/dl (P < 0.0001; 32 plus/minus 2%). However, this increase was unable to compensate for the 30 plus/minus 3% reduction in cardiac index due to PEEP, and hence, DO2significantly fell when PEEP was applied. Instead, the reduction in cardiac index with PEEP with low VTamounted only to 9 plus/minus 1%, whereas CaO2increased by 23 plus/minus 2% of the values on ZEEP (from 10.37 plus/minus 0.31 to 12.76 plus/minus 0.63 ml/dl on ZEEP and on 10 cmH2O of applied PEEP, respectively, P < 0.001). This increase in CaO2was able to counterbalance the reduction in cardiac index, so that PEEP increased DO2during mechanical ventilation with low VT.
The effects of acute hypercapnia on pulmonary and systemic circulation have been evaluated extensively in experimental models. [37,38] In intact animals, acute hypercapnia causes pulmonary vasoconstriction and an increase in heart rate, cardiac index, and pulmonary and systemic arterial hypertension. It is likely that most of these effects are mediated by the release of endogenous catecholamines. Puybasset et al. [32] studied the effects of permissive hypercapnia in 11 consecutive ARDS patients in whom the increase in PaCO2was rapidly induced by halving the minute ventilation from the baseline level. In their study, measurements were obtained 60-90 min after VT. reduction. A significant increase in PaCO2from 38 plus/minus 2 to 65 plus/minus 5 mmHg and a significant decrease in arterial pH from 7.41 plus/minus 0.01 to 7.22 plus/minus 0.02 were observed as a consequence of the reduction in VTfrom 655 plus/minus 40 to 330 plus/minus 28 ml. Acute hypercapnia induced a significant increase in systemic and pulmonary artery pressures, heart rate, and plasma concentrations of norepinephrine. In our study, low VTconditions were obtained by decreasing inflating volume stepwise by 50 ml every 20-30 min, so that the procedure lasted 205 plus/minus 15 min. When the targeted VTwas obtained, measurements of the physiologic variables were obtained after 170 plus/minus 25 min. In our study, VTreduction induced increases in PaCO2and decreases in arterial pH (Table 5) similar to those reported in Puybasset et al.'s study. [32] However, we observed no changes in heart rate or pulmonary and systemic arterial pressures (Table 4). The differences between the effects of permissive hypercapnia in Puybasset et al.'s, [32] and our study can be explained by the longer time used to reduce VTin our study. Many concerns regarding hypercapnia are related to the prolonged extracellular acidosis with which it is associated. However, the majority of effects of acute hypercapnia are mediated by intracellular pH. [19] It is now apparent that the changes in intracellular pH have a markedly different time course to those of extracellular pH after acute hypercapnia. Carbon dioxide spreads freely through both extracellular and intracellular spaces, and acute hypercapnia results in similar PCO2and pH changes in both spaces. [39] However, intracellular pH returns to 90% of normal within 3 h, whereas extracellular renal pH correction occurs slowly and is still incomplete after 3 days. [39] It may be assumed that, in our patients, the compensation for the fall in intracellular pH occurred during the slow step-by-step reduction in VTand the following 2-3 h, so that the adrenergic mediated effects of acute hypercapnia were minimized. Only direct measurements of plasma catecholamine concentrations, not performed in our study, could confirm this assumption.
In our patients, the pulmonary vascular resistance index (PVRI) during conventional VTventilation and ZEEP was 121 plus/minus 11 dyne *symbol* s *symbol* cm sup -5 and increased significantly (P < 0.01) to 138 plus/minus 10 dyne *symbol* s *symbol* cm sup -5 with progressive VTreduction. These values are close to those found in normal subjects [35,36] and are substantially lower than those reported in Puybasset et al.'s study. [32] Therefore, considering the normally flat PAP-flow relationship, [35,36] it is not surprising that the increase in cardiac index consequent to VTreduction did not result in a marked increase in PAP. Instead, in Puybasett et al.'s study, the hypercapnia-induced increase in cardiac index resulted in a significant and marked increase in PAP because of the more pronounced slope of the PAP-flow relationship. [32,35,36] 
In conclusion, our data show that application of PEEP during mechanical ventilation with a VTof 10-15 ml/kg induced hyperinflation of alveoli already recruited by tidal inflation, whereas PEEP applied during mechanical ventilation with a VTof 5-8 ml/kg induced alveolar recruitment counteracting the alveolar collapse induced by the low VT. Although these results confirm the clinical applicability of permissive hypercapnia, randomized controlled studies are required to prove its capacity to improve outcome in patients with ARDS.
The authors thank the physicians and nursing staff of Policlinico Hospital for their cooperation. They also thank M. Pinsky, M.D., and J. J. Rouby, M.D., for their suggestions and criticisms, and Mary V. C. Pragnell, B.A., for help in revising the manuscript.
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Figure 1. Static inflation volume-pressure relationships of the total respiratory system in nine patients with acute respiratory distress syndrom during mechanical ventilation with tidal volume (VT) of 10-15 ml/kg during zero end-expiratory pressure (ZEEP; open circles) and 10 cmH sub 2 O of positive end-expiratory pressure (PEEP; closed circles). Delta V = changes in lung volume relative to the elastic equilibrium point of the respiratory system (Vr); Pst,rs = static elastic recoil pressure. Total PEEP (intrinsic PEEP + externally applied PEEP) values and the corresponding increase in end-expiratory lung volume relative to Vr (EELV) are indicated on ZEEP (closed squares) and on 10 cmH2O of applied PEEP (open squares). Equation 1was fitted to the experimental points above Delta V = 0.
Figure 1. Static inflation volume-pressure relationships of the total respiratory system in nine patients with acute respiratory distress syndrom during mechanical ventilation with tidal volume (VT) of 10-15 ml/kg during zero end-expiratory pressure (ZEEP; open circles) and 10 cmH sub 2 O of positive end-expiratory pressure (PEEP; closed circles). Delta V = changes in lung volume relative to the elastic equilibrium point of the respiratory system (Vr); Pst,rs = static elastic recoil pressure. Total PEEP (intrinsic PEEP + externally applied PEEP) values and the corresponding increase in end-expiratory lung volume relative to Vr (EELV) are indicated on ZEEP (closed squares) and on 10 cmH2O of applied PEEP (open squares). Equation 1was fitted to the experimental points above Delta V = 0.
Figure 1. Static inflation volume-pressure relationships of the total respiratory system in nine patients with acute respiratory distress syndrom during mechanical ventilation with tidal volume (VT) of 10-15 ml/kg during zero end-expiratory pressure (ZEEP; open circles) and 10 cmH sub 2 O of positive end-expiratory pressure (PEEP; closed circles). Delta V = changes in lung volume relative to the elastic equilibrium point of the respiratory system (Vr); Pst,rs = static elastic recoil pressure. Total PEEP (intrinsic PEEP + externally applied PEEP) values and the corresponding increase in end-expiratory lung volume relative to Vr (EELV) are indicated on ZEEP (closed squares) and on 10 cmH2O of applied PEEP (open squares). Equation 1was fitted to the experimental points above Delta V = 0.
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Figure 2. Static inflation volume-pressure relationships of the total respiratory system in nine patients with ARDS during mechanical ventilation with tidal volume (VT) of 5-8 ml/kg during zero end-expiratory pressure (ZEEP; open circles) and 10 cmH2O of positive end-expiratory pressure (PEEP; closed circles). Details and abbreviations as in Figure 1.
Figure 2. Static inflation volume-pressure relationships of the total respiratory system in nine patients with ARDS during mechanical ventilation with tidal volume (VT) of 5-8 ml/kg during zero end-expiratory pressure (ZEEP; open circles) and 10 cmH2O of positive end-expiratory pressure (PEEP; closed circles). Details and abbreviations as in Figure 1.
Figure 2. Static inflation volume-pressure relationships of the total respiratory system in nine patients with ARDS during mechanical ventilation with tidal volume (VT) of 5-8 ml/kg during zero end-expiratory pressure (ZEEP; open circles) and 10 cmH2O of positive end-expiratory pressure (PEEP; closed circles). Details and abbreviations as in Figure 1.
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Table 1. Clinical Data of Patients
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Table 1. Clinical Data of Patients
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Table 2. Baseline Breathing Pattern during the Two Experimental Conditions
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Table 2. Baseline Breathing Pattern during the Two Experimental Conditions
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Table 3. Nonlinear Coefficients in Equation 1, Delta EELV and Recruited Volume on 10 cmH2O of PEEP during Mechanical Ventilation with Standard and Low VT
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Table 3. Nonlinear Coefficients in Equation 1, Delta EELV and Recruited Volume on 10 cmH2O of PEEP during Mechanical Ventilation with Standard and Low VT
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Table 4. Effects of PEEP on Hemodynamics during Mechanical Ventilation with the Two Different VT
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Table 4. Effects of PEEP on Hemodynamics during Mechanical Ventilation with the Two Different VT
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Table 5. Effects of PEEP on Gas Exchange during Mechanical Ventilation with the Two Different VT
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Table 5. Effects of PEEP on Gas Exchange during Mechanical Ventilation with the Two Different VT
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