Temporal Hemodynamic Effects of Permissive Hypercapnia Associated with Ideal PEEP in ARDS CARLOS ROBERTO RIBEIRO CARVALHO, CARMEN SILVIA VALENTE BARBAS, DENISE MACHADO MEDEIROS, RICARDO BORGES MAGALDI, GERALDO LORENZI FILHO, RONALDO ADIB KAIRALLA, DANIEL DEHEINZELIN, CARLOS MUNHOZ, MAURO KAUFMANN, MARCO FERREIRA, TERESA YAE TAKAGAKI, and MARCELO BRITTO PASSOS AMATO Respiratory Intensive Care Unit of the Pulmonary Division of the Hospital das Clínicas, University of São Paulo; and General ICU of the Santa Casa de Misencórdia, Porto Alegre, Brazil

The associated use of permissive hypercapnia (PHY) and high PEEP levels (PEEPIDEAL) has been recently indicated as part of a lung-protective-approach (LPA) in acute respiratory distress syndrome (ARDS). However, the net hemodynamic effect produced by this association is not known. We analyzed the temporal hemodynamic effects of this combined strategy in 48 patients (mean age 34 6 13 yr) with ARDS, focusing on its immediate (after 1 h), early (first 36 h), and late (2nd–7th d) consequences. Twenty-five patients were submitted to LPA—with the combined use of permissive hypercapnia (PHY), VT , 6 ml/kg, distending pressures above PEEP , 20 cm H2O, and PEEP 2 cm H2O above the lower inflection point on the static inspiratory P-V curve (PFLEX)—and 23 control patients were submitted to conventional mechanical ventilation. LPA was initiated at once, resulting in an immedi. ate increase in heart rate (p 5 0.0002), cardiac output (p 5 0.0002), oxygen delivery (DO2I, p 5 0.0003), and mixed venous PO2 (p 5 0.0006), with a maintained systemic oxygen consumption (p 5 0.52). The mean pulmonary arterial pressure markedly increased (mean increment 8.8 mm Hg; p , 0.0001), but the pulmonary vascular resistance did not change (p 5 0.32). Cardiac filling pressures increased (p , 0.001) and the systemic vascular resistance fell (p 5 0.003). All these alterations were progressively attenuated in the course of the first 36 h, despite persisting hypercapnia. Plasma lactate suffered a progressive decrement along the early period in LPA but not in control patients (p , 0.0001). No hemodynamic consequences of LPA were noticed in the late period and renal function was preserved. A multivariate analysis suggested that these acute hyperdynamic effects were related to respiratory acidosis, with no depressant effects ascribed to high PEEP levels. In contrast, high plateau pressures were associated with cardiovascular depression. Thus, as long as sufficiently low distending pressures are concomitantly applied, the sudden installation of PHY plus PEEPIDEAL induces a transitory hyperdynamic state and pulmonary hypertension without harmful consequences to this young ARDS population. Carvalho CRR, Barbas CSV, Medeiros DM, Magaldi RB, Filho GL, Kairalla RA, Deheinzelin D, Munhoz C, Kaufmann M, Ferreira M, Takagaki TY, Amato MBP. Temporal hemodynamic effects of permissive hypercapnia associated with ideal PEEP in ARDS. AM J RESPIR CRIT CARE MED 1997;156:1458–1466.

The beneficial effects of ventilatory strategies directed at minimizing cyclic parenchymal stretch during mechanical ventilation have been suggested (1–4). Using low distending pressures and permissive hypercapnia (PHY), Hickling and coworkers

(Received in original form April 22, 1996 and in revised form June 25, 1997) This work was partially presented at the 1994 International Conference, May 21– 25, Boston, Massachusetts, American Lung Association–American Thoracic Society. Supported by the Laboratório de Investigação Médica–HC-FMUSP; and INTERMED Equipamento Médico-Hospitalar LTDA. Correspondence and requests for reprints should be addressed to Dr. Carlos Roberto Ribeiro Carvalho, M.D., CEDOT—Centro Especializado em Doenças do Tórax, Rua Oscar Freire 2537, CEP 05409-012, São Paulo, SP - Brazil. Am J Respir Crit Care Med Vol 156. pp 1458–1466, 1997

found evidences suggesting an improved survival in ARDS patients (2). In a recent prospective and randomized study on ARDS, the association of low distending pressures, PHY and ideal PEEP levels (a strategy from now on called lung protective approach [LPA] resulted in increased chances of early weaning and lung recovery (1) with a lower ultimate ICU mortality rate (5). The massive presence of alveolar collapse during the ARDS process—cyclic or persistent—has been associated with an exacerbation of ventilator-induced lung injury (3, 6, 7). Accordingly, the use of PEEPIDEAL as part of a lung protective strategy has a good rationale (1, 3). By keeping end-expiratory pressures above the lower inflection point (PEEPFLEX) of the inspiratory pressure-volume (P-V) curve, one can expect near-maximal alveolar recruitment (8), minimal alveolar reopening with better distribution of tidal ventilation (9), and a

Carvalho, Barbas, Medeiros, et al.: Hemodynamics during Permissive Hypercapnia

consequent reduction of shear forces with an attenuated lung injury (6). But if PEEP has been consistently associated to a lung protective effect a major concern remains regarding its global hemodynamic impact. The well-known depressant effects of PEEP on venous return and systemic circulation (10, 11) is still considered as a potential source of problems in critically ill patients, specially when considering the great proportion of ARDS patients with hemodynamic instability. On the other hand, PHY is also a strategy encompassing important hemodynamic consequences. Contrary to PEEP, however, its characteristic impact is a marked hyperdynamic response, usually the net result of a strong sympathetic stimulation overcoming the direct depressant effects of carbon dioxide on cardiac contractility (12–14). In animals and anesthetized human subjects submitted to acute hypercapnia, this response is very predictable, with an increase in cardiac output, heart rate and pulmonary arterial pressures, a maintained or slightly increased stroke volume, and an associated decrement in systemic vascular resistance (12–14). The same hyperdynamic response has also been observed in ARDS patients, as long as an acute and significant raise in arterial PaCO2 is allowed (15–18). Considering then these opposing tendencies, what should we expect from the complex association between PHY and PEEPIDEAL? Could the depressant effects of PEEP on systemic circulation be counterbalanced by the stimulatory effects of PHY? Should we expect a dangerous sum of effects of PHY and PEEPIDEAL upon the pulmonary hypertension frequently found during the ARDS process? The answers to these questions are not obvious and, as far as we know, no consistent data has addressed this point in the medical literature. In December 1990, we started a prospective randomized study on mechanical ventilation comparing a lung protective strategy with the conventional wisdom in ARDS management. Although the primary endpoint of this protocol was a survival analysis (5), the study was also designed to provide a parallel examination of the hemodynamic consequences of PHY associated with ideal PEEP levels (2 cm H2O above the lower-PFLEX). The present study concerns this prospective collection of hemodynamic data. As we had a previous expectation about the fleeting nature of PHY effects, the primary goal of this study will be a descriptive analysis of its major hemodynamic consequences along the time. By using a multivariate analysis, we also tried to separate the respective contributions of PHY and PEEPIDEAL to the observed hemodynamic effects.

METHODS Since December 1990, 48 patients with ARDS were enrolled in this study. The present report includes the first 28 patients already described in a previous publication focusing the pulmonary effects associated with the New Approach (1). Criteria for entry were an underlying disease process known to be associated with ARDS along with a Lung Injury Score (LIS) > 2.5 (19) and a pulmonary arterial wedge pressure (PWEDGE) , 16 mm Hg. Exclusion criteria were previously defined (1). The study protocol was approved by the Hospital’s Medical Ethics Committee and informed consent was obtained from the patient or next of kin.

Initial Homogenizing Procedures After verifying a provisory LIS . 2.5, a Swan-Ganz no. 7F catheter (Baxter) was inserted in a central vein. Besides radiological control, the validation of zone-3 condition of the occluded pulmonary arterial catheter tip was assessed by two mechanical maneuvers (1, 20).

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After confirming a PWEDGE , 16 mm Hg, all selected patients were pre-expanded until observing a PWEDGE . 8 mm Hg and a hemoglobin . 10 g/dl, receiving then similar infusions of dobutamine (target doses of 5 mg/kg/min) and nonadrenaline (minimal doses to maintain average systemic blood pressure . 60 mm Hg). They were subsequently sedated and paralyzed, and submitted to a fixed ventilatory support with : volume controlled ventilation, tidal volume (VT) 10 ml/ kg, respiratory rate 15 cycles/min, FIO2 100%, and PEEP 5 cmH2O or the minimum needed to maintain the arterial oxygen saturation . 85%. Thirty minutes after the stabilization of these conditions—with stable and equivalent doses of vasoactive drugs—a full set of respiratory, hemodynamic, and laboratory measurements was obtained. This period was called control-period and the baseline measures obtained at this time were used to calculate the predictor scores shown in Table 1. This initial but provisory infusion rate of catecholamines was strictly kept constant from this time until the next measurements corresponding to Time 1, a time period when both ventilatory strategies were implemented. The hemodynamic optimization (see below) was started only after collecting this second set of data (after Time 1). Criteria for defining sepsis at entry and organ-failure were the same from the previous publication (1). Pneumonia at entry was objectively assessed by a preestablished algorithm for infectious care used in our unit. A bedside P-V static curve was obtained for all patients, soon after the control period. Although PFLEX determinations were useful only for the LPA group, the procedure was performed in all patients for homogenizing purposes. The overall procedure was done without disconnecting the patient from the ventilator, following all the steps described in a previous publication (1). A well-defined lower inflection point (PFLEX) could be obtained in 44 patients.

Randomization After obtaining the P-V curve, the patient was randomly assigned (sealed envelopes) to one of the two arms of the protocol: the conventional arm (C) and the lung-protective-approach arm (LPA), consisting of two different ventilatory strategies along with identical hemodynamic and general support. All the nutritional and dialyzing procedures, as well as the infectious care were kept the same for both groups, being described elsewhere (1).

General Ventilatory Support The two different ventilatory approaches were immediately initiated and rigorously maintained until extubation or death. The P-V curve was performed only once, before the randomization. All patients were ventilated with an Inter-7 ventilator (INTERMED Equipamento Médico-Hospitalar LTDA, São Paulo, Brazil) or a Servo Siemens 900C (Siemens-Elema Sweden) connected to a closed system for aspirating tracheal secretions. In both groups, the target PaO2 was 80 mm Hg and the PEEP level was never set below 5 cm H2O. The weaning protocol was the same for both arms (1).

The Conventional Approach (Control Group) Arterial PaCO2 levels were kept between 25 and 38 mm Hg (target 5 35 mm Hg), independently of airway pressures. Priority was given to the maintenance of an FIO2 , 60%, with adequate oxygen transport . indexes ( DO2I). To reach these goals, the initial ventilatory parameters were: VT 5 12 ml/kg; volume assisted/controlled mode; flow-rates adjusted to avoid auto-PEEP and to keep inspiratory/expiratory ratio , 1:1; inspiratory pause 5 0.4 s; respiratory rates between 10 and 24 cycles/min (depending on PaCO2); and minimum PEEP levels > 5 cm H2O, which were increased according to a stepwise algorithm (1) looking for a compromise between a safe FIO2 and a safe hemodynamic profile.

The Lung-Protective-Approach (LPA) Priority was given to the maintenance of an open lung, independent of hemodynamic concerns or considerations about the required FIO2. Parenchymal overdistention was also aimed, disregarding PaCO2 levels. The following general strategies were adopted: (1) VT was kept , 6 ml/ kg and the respiratory (RR) , 30 cycles/min even during pressure support cycles; permissive hypercapnia and continuous infusions of

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fentanyl and diazepam were used as needed to avoid discomfort and tachypnea. Initial PaCO2 levels of up to 80 mm Hg were tolerated and slow sodium bicarbonate infusions were permitted if pHa , 7.2; (2) Inspiratory pressures above PEEP (termed driving pressures) were kept below 20 cm H2O and peak airway pressures were kept below 40 cm H2O; (3) The initial PEEP/CPAP level was preset at 2 cm H2O above PFLEX; independent of hemodynamic considerations or FIO2 levels (this level was called PEEPIDEAL). When auto-PEEP was present, the total PEEP (external PEEP plus auto-PEEP) was considered and adjusted in order to match this PEEPIDEAL. Whenever a sharp PFLEX could not be determined on the P-V static curve, a total PEEP level of 16 cm H2O was initiated, corresponding to the mean value of PEEPIDEAL found in a previous unpublished study on ARDS at our institution; (4) PC-IRV was the ventilatory mode of choice during critical periods of severe lung injury (signalized by FIO2 requirements above 50%). Once the patient presented signals of lung recovery (FIO2 , 50%) he was stepwise placed under VAPSV (21) or PSV. A complete description of all the stepwise maneuvers employed in each arm was presented elsewhere (1).

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passed: (1) target hemoglobin concentrations > 12 g/dl; (2) a minimal dobutamine infusion-rate of 5 mg/kg/min for all; (3) maintenance of PWEDGE , 16 mm Hg; and (4) dopamine infusions at doses , 3 mg/kg/ min whenever oliguria was present. Rigid guidelines for packed red blood cells and colloid infusions, daily negative fluid balances, avoidance of signs of systemic oxygen debt; and progressive doses of dobutamine (as needed, up to 30 mg/kg/min) or norepinephrine were applied (1).

Sedation Only fentanyl (up to 8 mg/d) and diazepam (up to 250 mg/d) were used in this study, sometimes associated with pancuronium administered intermittently. The protocol for sedation was the same for both arms, but patients in LPA certainly received higher doses since generous infusions of sedatives were employed at any signal of increased respiratory drive caused by hypercapnia. Fentanyl (continuous infusion) was used for all patients, even during weaning. During daily measurements of compliance in both arms, all patients received transient infusions of succinylcholine (1 mg/kg).

Hemodynamic Measurements and Support Mean pulmonary artery pressure (PAPM) and other intravascular pressures including PWEDGE were measured at end-expiration, maintaining the patient connected to the ventilator. Cardiac output was measured by the thermodilution technique, using 5–6 injections of 10 ml cold saline (, 48 C) started at random relative to respiratory cycles. All measurements were registered in an HP-78339A monitor (Hewlett-Packard, USA), used to calculate vascular resistance indexes,. left and right ventricle stroke work indexes, the oxygen deliv· ery ( DO2I), the oxygen consumption (VO2I), and the extraction ratio, according to standard formulas. Systemic and pulmonary arterial blood samples were collected soon after cardiac-output determinations. A full set of measurements, including plasma lactate, blood-gases and hemoglobin determinations was performed one hour after the initiation of the randomized strategy (Time 1), and again after precisely 8, 16, and 24 h. Subsequently, at least one set of measurements was performed each day until extubation or death. When frequent measures were required during the day (for hemodynamic optimization), the average value was used as the representative value for that day. Soon after collecting data regarding Time 1, patients in both arms of the protocol were submitted to a stepwise algorithm of hemodynamic optimization (1) strictly followed till extubation, which encom-

Statistics Whenever possible, statistical tests used were shown in figures and tables. All reported p values are two-tailed and calculated with the BMDP statistical software. The comparative analysis of respiratory and hemodynamics parameters along the time (Tables 3 and 4 and Figures 1–5) was performed by considering the incremental areas under the individual curves (AUC) which represented the average tendency of a variable along some specific time-interval. The area was calculated for each patient after considering the measurements during the control-period as the relative origin. Thus, negative areas indicated a progressive decrement in the respective variable from the control period up to the considered time-interval. Three time-intervals were considered: the immediate-changes interval (the area under the short line linking the control measure to the measure at Time 1), the early-changes interval (the area under the line joining the five measurements performed from Time 1 up to the first 36 h) and the late-changes interval (the area under the line joining the six measurements collected from the second up to the seventh day). To avoid bias that might occur in the analysis if a patient did not complete a whole interval (producing an artifactual decrement in the calculated area or trend), these areas were divided

TABLE 1 PATIENT CHARACTERISTICS AT ENTRY (OBSERVED DURING THE CONTROL PERIOD)*

Age, yr Days on mechanical ventilation before entry Extra-pulmonary organ failures APACHE II Score (standard) Risk of death, % APACHE II Score† (adjusted) Risk of death, %† Critical Care Score System (37) Murray’s Score (19) Ventilator Score (38) Pneumonia at entry Sepsis at entry PO2/FIO2 at entry Lower PFLEX Static compliance at entry, ml/cm H2O

Protective Approach (n 5 25)

Conventional (n 5 23)

Significance

32 6 12 2.0 6 1.9 2.7 6 1.3 29 6 7 68 6 18 25 6 7 58 6 22 20 6 6 3.4 6 0.4 87 6 13 52% 88% 114 6 55 14.9 6 4.0 27.7 6 8.3

36 6 14 2.3 6 2.6 2.7 6 1.6 27 6 6 59 6 19 24 6 6 51 6 20 17 6 7 3.2 6 0.4 83 6 14 61% 78% 138 6 66 13.7 6 4.1 30.3 6 6.5

(p 5 0.29) (p 5 0.74) (p 5 0.90) (p 5 0.32) (p 5 0.11) (p 5 0.53) (p 5 0.26) (p 5 0.17) (p 5 0.10) (p 5 0.25) (p 5 0.57) (p 5 0.45) (p 5 0.19) (p 5 0.37) (p 5 0.21)

* Values in the table are representing the mean 6 SD. The categorical variables were compared through the Fisher exact test. The continuous variables were compared through two-tail t tests, with appropriate log or square-root transformations. † APACHE II (39) was always extracted from the worst values during the first 24 h following the randomization. However, in order to avoid the overestimating effects of permissive hypercapnia, it was calculated in two ways: a) standard score, considering the worst physiological parameters collected from the control-period up to the first 24 h of the protocol (disregarding the effects of sedation), and b) adjusted score, considering the blood-gas and the heart rate values collected exclusively during the control-period as representative of the first 24 h (with the remainder physiologic parameters collected as the standard score).

Carvalho, Barbas, Medeiros, et al.: Hemodynamics during Permissive Hypercapnia TABLE 2 PRIMARY DIAGNOSIS AT ENTRY (PREDISPOSING CAUSE OF ARDS) Protective Approach (n 5 25)

Conventional (n 5 23)

Leptospirosis (4) Aspirative pneumonia (4) Pneumocystis pneumonia (4) Atypical pneumonia (2) Puerperal sepsis 1 DIC (4) S.L.E. 1 pneumonia (2) Acute pancreatitis (1) Disseminated tuberculosis (1) Near drowning (1) Intracranial hemorrhage (1) Pulmonary contusion (1)

Leptospirosis (4) Bacterial pneumonia (3) Pneumocystis pneumonia (1) Atypical pneumonia (4) Puerperal sepsis 1 DIC (2) S.L.E. 1 sepsis (2) Acute pancreatitis (1) Soft tissue infection with sepsis (2) Abdominal sepsis (2) Immune alveolar hemorrhage (1) Polytransfusion (1)

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along the time. The normality assumption was always checked for the dependent variables. As there was a high degree of multicollinearity among the variables studied, the reported p values were not adjusted for multiple comparisons, except for those corrections intrinsically performed during the multivariate analysis.

RESULTS

by the time span of recordings for each patient (obtaining so an average trend parameter). Differences in these trend parameters between both groups (LPA versus C) were analyzed by independent-sample t tests with appropriate transformations. The absolute values of AUC so obtained estimating the changes or “D” in each parameter were also submitted to a stepwise multiple linear regression aimed at scrutinizing the relationship between the changes in respiratory parameters (the AUCs obtained for PEEP, PaCO2, airway pressures, compliance measurements, etc.) and the changes in hemodynamic parameters (the AUCs calculated for the PAPM recordings, PWEDGE, cardiac index, etc.) during the same time interval. We decided to focus the analysis on the immediate changes only (from control to Time 1 period), avoiding complex interactions

The patient’s characteristics and the primary diagnosis at entry are summarized on Tables 1 and 2. No statistically significant differences could be detected between both arms. As established by the protocol, the installation of permissive hypercapnia was abrupt. Starting with a PaCO2 close to 35 mm Hg at the control period, the patients in LPA experienced an instantaneous increment of 23 6 11 mm Hg (mean 6 SD) in the PaCO2 levels at Time 1. The maximal PaCO2 observed was 114 mm Hg. The average maximal value reached during the first week was 70 6 18 mm Hg. The minimal pHa observed was 6.88 and the average minimal pHa during the first week was 7.13 6 0.14. Three patients in LPA never exhibited a pHa below 7.30. As shown on Figure 1, the average PaCO2 in LPA remained significantly elevated (> 20 mm Hg above the values found in C) along the whole week (p , 0.00001). In contrast, the arterial pH exhibited a progressive recovery to baseline conditions soon after the first 36 h. Eleven patients received slow bicarbonate infusions (, 50 mEq/h with a mean total dose of 380 6 260 mEq) and, among them, seven were submitted to dialysis. The evolution of hemodynamic variables were analyzed all along the first week of mechanical ventilation (Figures 2–5).

Figure 1. Evolution of pH and Pa CO2 along the first week of mechanical ventilation. Bars represent 1 SEM. Early changes (shaded) are artificially split from late changes. The corresponding significance level (analyzing AUC) expresses the different evolution between both groups during the interval. *p , 0.00001 for the immediate differences from control-period up to Time 1. NS 5 not significant; AUC 5 incremental area under the curve.

Figure 2. Evolution of cardiac index and heart rate along the first week of mechanical ventilation. Bars represent 1 SEM. Early changes (shaded) are artificially split from late changes. The corresponding significance level (analyzing AUC) expresses the different evolution between both groups during the interval. *p , 0.0002 for the immediate differences from control-period up to Time 1. NS 5 not significant; AUC 5 incremental area under the curve.

Parentheses represent the number of patients with the same corresponding diagnosis.

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Figure 3. Evolution of vascular resistances along the first week of mechanical ventilation. Bars represent 1 SEM. Early changes (shaded) are artificially split from late changes. The corresponding significance level (analyzing AUC) expresses the different evolution between both groups during the interval. *p 5 0.00005 for the immediate differences from control-period up to Time 1. NS 5 not significant; AUC 5 incremental area under the curve.

In spite of the equivalent infusions of fluids and vasoactive drugs accomplished in both arms (Table 3), the hemodynamic profiles significantly differed between both groups and according to the interval studied: Baseline Measurement

As expected, both groups presented a very similar hemodynamic condition at the control-period, receiving a rather similar hemodynamic support (METHODS). At this time, both arms presented a global hemodynamic profile compatible with a hyperdynamic state and high plasma lactate levels (Figures 2 to 5, see control measures) Early Changes

The major hemodynamic effects associated with LPA were transitory, lasting for only 36–48 h. Most effects were maximal at time 1 (a time-period during which the catecholamine infusions were kept as during the control-period), decreasing progressively after that. Some few effects (for instance, lactate changes and the increments in PWEDGE, Figures 4, 5) achieved their maximal expressions some hours later. Figures 2–5 and Table 3 demonstrate that there were three major blocks of early hemodynamic effects associated with LPA: (1) the hyperdynamic changes in the systemic circulation (increase in cardiac output and heart-rate, associated with a fall in systemic vascular resistance); (2) a large increment in pulmonary vascular pressures (increase in PAPM, right atrial pressure and PWEDGE, resulting in an increment of the right ventricular work of more than 40%); and (3) the alterations in

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Figure 4. Evolution of pulmonary arterial pressure (mean) and PWEDGE along the first week of mechanical ventilation. Bars represent 1 SEM. Early changes (shaded) are artificially split from late changes. The corresponding significance level (analyzing AUC) expresses the different evolution between both groups during the interval. *p , 0.0005 for the immediate differences from controlperiod up to Time 1. NS 5 not significant; AUC 5 incremental area under the curve.

· the systemic oxygenation status (increase in DO2I and PvO2, associated with a latter fall in plasma lactate levels). Late Changes

As shown on Figures 2–5 and Table 3, the major hemodynamic effects associated with the LPA are no longer observed after the first 36 h. This return to baseline conditions coincided with the progressive recovery of arterial pH observed afterwards (Figure 1). In order to point out this transient aspect, Figures 1–5 were split into the early-changes-interval (up to first 36 h) and the late-changes-interval, with separate statistical analysis. In contrast, Table 4 demonstrates the persistence of some beneficial respiratory effects in LPA. The static compliance improved progressively (p , 0.00001) and the PaO2/FIO2 ratio remained well above that of C along the whole week (p , 0.00001), despite progressively lower mean airway pressures. At the end of the first week of mechanical ventilation, the patient in the LPA group had received a mean of 200 6 114 ml/day of packed red blood cells, whereas the patient in C received 314 6 290 ml/day (p 5 0.09). The mean cumulative fluid balance was: 5.2 6 3.7 l for LPA: and 6.0 6 3.8 l for C group; (p 5 0.70) Multivariate Analysis

Considering the major hemodynamic alterations observed in LPA at Time 1 (immediate changes), we performed a stepwise multiple regression analysis focusing the following questions: 1. Were the changes in cardiac output related to changes in airway pressures or to PHY? (dependent variable 5 D cardiac output; independent variables examined: DPaCO2, DPaO2, DpH,

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Figure 5. Evolution of oxygen delivery and plasma lactate along the first week of mechanical ventilation. Bars represent 1 SEM. Early changes (shaded) are artificially split from late changes. The corresponding significance level (analyzing AUC) expresses the different evolution between both groups during the interval. *p , 0.0005 for the immediate differences from control-period up to Time 1. NS 5 not significant; AUC 5 incremental area under the curve.

DPEEP, Dplateau pressures, Dpeak pressures, Dmean airway pressures, DVT, DRR, Dminute ventilation, Dcompliance, DPvO2). The immediate increments in cardiac index (CI) were not related to PEEP changes (p 5 0.48) or to the changes in mean airway pressure (p 5 0.45), either in a univariate or in a multivariate model. In contrast, a strong and positive relationship was found between DCI and PaCO2 changes (r 5 0.47; p 5 0.002, best multivariate model), and a negative association between DCI and changes in plateau pressures (p , 0.0001; r 5 20.57; best multivariate model encompassing DPaCO2 also as an independent variable). 2. Were the immediate changes in pulmonary vascular pressures related to changes in airway pressures or to PHY? (dependent variable 5 DPAPM; independent variables 5 the same scrutinized in the analysis above). The correlation between pulmonary hypertension (DPAPM) and PaCO2 changes was very strong in a univariate model (r 5 0.68; p , 0.00001) and this positive association was maintained even after forcing the inclusion of DPEEP, DPPLAT or D mean-airway-pressures in a multivariate model (r 5 0.49; p 5 0.001). In the same way, the variations in filling pressures (dependent variables 5 D-right-atrial-pressure or DPWEDGE) exhibited significant and positive relationships with the increments in PaCO2 (r 5 0.55; p 5 0.0002, considering DPWEDGE versus DPaCO2; and r 5 0.61; p 5 0.0001, considering DRAP versus DPaCO2) which were maintained even after the forced inclusion of DPEEP in a multivariate model (p , 0.01, for both). The high degree of collinearity between DPEEP and DPaCO2 preclude us from discarding some PEEP effect upon the raised vascular pressures. However, the analysis above suggested that a great part of the increment in vascular pressures was associated to PaCO2effects independently of PEEP influences.

TABLE 3 HEMODYNAMIC PARAMETERS DURING THE FIRST WEEK OF MV* Mean Value During the Period Variable Hemoglobin, g/dl †

Fluid balance , ml/d Dobutamine†, infusion rate mg/kg/min Noradrenaline†, infusion rate mg/min Systemic arterial pressure, mm Hg Right atrial pressure, mm Hg Diuresis†, ml/h Creatinine clearance†, ml/min Mixed venous PO2, mm Hg O2 consumption, ml/min/m2 Living patients considered in the analysis:

LPA C LPA C LPA C LPA C LPA C LPA C LPA C LPA C LPA C LPA C

Control

Time 1

First 36 hours

2nd–7th Day

10.9 (0.4) 10.9 (0.5) — — 6.0 (0.9) 5.2 (0.9) 2.2 (1.2) 2.7 (1.3) 85 (3) 87 (3) 9 (1) 10 (1) — — — — 45 (2) 42 (2) 178 (14) 188 (11)

10.6 (0.4) 10.6 (0.5) — — 6.1 (1.0) 5.4 (0.9) 2.4 (1.4) 3.1 (2.2) 87 (3) 86 (3) 13 (1)§ 10 (1) — — — — 60 (3)§ 42 (2) 166 (11) 171 (13)

10.5 (0.2) 10.6 (0.2) 1,219 (549) 1,547 (360) 7.0 (0.4) 7.4 (0.6) 3.3 (0.7) 5.4 (1.3) 87 (2) 86 (2) 12 (1)§ 10 (1) 111 (10) 89 (9) 47 (6) 57 (5) 52 (2)‡ 39 (1) 174 (13) 171 (13)

11.8 (0.1) 12.1 (0.3) 602 (143) 812 (155) 7.5 (0.5) 8.6 (0.7) 1.0 (0.2) 3.1 (0.6) 93 (1) 89 (2) 12 (1) 12 (1) 89 (5) 114 (6) 64 (5) 56 (4) 47 (2) 42 (2) 178 (15) 173 (15)

LPA: n 5 25 C: n 5 23

LPA: n 5 25 C: n 5 23

LPA: n 5 25 C: n 5 19

LPA: n 5 23 C: n 5 14

* Values in the table correspond to the mean of the average value representing all measurements performed during the corresponding time-interval, for each patient (at least five measurements for the first 36 h, and at least six measurements from the second till the seventh day). Parentheses represent standard error of mean (SEM). † The comparison between LPA and C was made by calculating the total area under the curve (taking the absolute zero as the origin of the graphic, rather than the baseline measurement) when analyzing these variables. No significant differences were found. As the measurements of diuresis and IV infusions are very imprecise during short periods, they were not reported at the control period and Time 1. ‡ p , 0.01. § p , 0.001 (comparing LPA versus C during the same time-period, considering the differences in incremental AUC).

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TABLE 4 RESPIRATORY PARAMETERS DURING THE FIRST WEEK OF MV* Mean Value During the Period Variable PaO2/FIO2, mm Hg Static compliance, ml/cm H2O PEEP, cm H2O Mean airway pressure, cm H2O Plateau Pressure, cm H2O

LPA C LPA C LPA C LPA C LPA C

Control

Time 1

First 36 hours

2nd–7th Day

114 (11) 138 (14) 27.7 (1.7) 30.3 (1.4) 6.2 (0.8) 5.8 (0.4) 14.4 (0.8) 12.9 (0.7) 32.5 (1.7) 28.8 (1.4)

210 (17)‡ 140 (12) 28.5 (2.2) 30.9 (1.3) 16.3 (0.8)‡ 6.3 (0.6) 25.0 (1.3)‡ 14.9 (0.8) 32.6 (1.6) 33.5 (1.7)

216 (8)‡ 137 (6) 32.0 (1.3)† 30.4 (0.7) 16.5 (0.4)‡ 7.7 (0.4) 24.5 (0.7)‡ 16.5 (0.5) 30.5 (0.7)‡ 35.6 (0.8)

238 (6)‡ 147 (7) 40.6 (1.4)‡ 29.1 (1.0) 13.4 (0.5)† 9.3 (0.6) 17.1 (0.6) 18.7 (0.8) 24.0 (0.8)‡ 37.8 (1.1)

* Values in the table correspond to the mean of the average value representing all measurements performed during the corresponding time-interval, for each patient (at least five measurements for the first 36 h, and at least six measurements from the second till the seventh day). Parentheses represent standard error of mean (SEM). † p , 0.01. ‡ p , 0.001 (comparing LPA versus C during the same time-period, considering the differences in incremental AUC).

DISCUSSION This study showed that permissive hypercapnia associated with ideal PEEP levels can be acutely induced without any obvious deleterious influence on hemodynamics. Even in the context of a great proportion of patients with sepsis and hemodynamic instability (Table 1) with many patients needing nonadrenaline infusions to keep arterial blood pressures > 60 mm Hg this combined strategy was well tolerated, producing a consistent hyperdynamic response. Although this study was not blinded to the investigators, the equivalent hemodynamic support strictly accomplished in both groups (Table 3), allowed us to interpret the different hemodynamic profiles as an almost exclusive consequence of the different ventilatory strategies. The immediate hyperdynamic response observed in LPA, characterized by an enhanced cardiac output due to an increased heart rate, a maintained stroke volume and a decreased systemic vascular resistance, is consistent with the reported effects of acute hypercapnia in intact animals and anesthetized humans (12–14). This similarity suggests that the observed response in LPA was predominantly a PHY response. Despite the marked increment of PEEP and mean airway pressure, we did not find any indication of cardiovascular depression in these patients. Accordingly, either because these patients had a very low lung compliance with a damped transmission of end-expiratory pressures to the cardiovascular system or because PHY could obscure any possible depressant effect of high PEEP levels, the combined use of PEEPIDEAL was extremely well tolerated in our patients. The net result was almost a pure PHY effect. Of note, there was a spontaneous attenuation of this hyperdynamic response along the first 36 h, despite persisting hypercapnia. This fading effect coincided with the progressive return of arterial pH to baseline levels. The absence of depressant PEEP effects in our work must be considered into the particular context of this study design: although using PEEP levels as high as 24 cm H2O in the LPA group, the distending pressures above PEEP never exceeded 20 cm H2O (and the absolute PPLAT never exceeded 40 cm H2O). Had the strict control of PPLAT in this group been less rigid, the results might be rather different. Some recent studies have observed a marked depression of the cardiovascular system associated with the use of high VT and consequently of high PPLAT (22, 23). This observation allow us to speculate that part of the depressant effects classi-

cally attributed to PEEP was, in fact, the result of associated high inspiratory pressures and not a direct PEEP-effect per se. The result of our multivariate analysis, indicating a strong and negative correlation between changes in cardiac output and changes in PPLAT is in consonance with this reasoning. Of note, we did not find any correlation between changes in PEEP and changes in cardiac output (p 5 0.48). Our findings differ from the results of McIntyre (16) and Simon (17) who did not find significant changes in hemodynamic variables during PHY. In our opinion, the gradual and modest increment in PaCO2 obtained in both studies can easily explain these differences. Actually, despite the combined use of PEEPIDEAL, our data are in close agreement with the short term hyperdynamic response observed by Puybasset (15) and Thorens (18). The most striking effect associated with LPA was the immediate pulmonary hypertension. The mean increment of PAPM was about 9 mm Hg and, as suggested by the multivariate analysis, this increment was closely related to the raise in PaCO2 (each 10 mm Hg increment in PaCO2 was associated to a 3 mm Hg increment in PAPM: 95% confidence interval: 1.6– 4.4 mm Hg). In association with pulmonary hypertension, two other hemodynamic perturbations were also observed: an overflow condition in the pulmonary vascular bed created by an increased cardiac output and an increased effective downstream pressure observed as acute elevations of PWEDGE in this group. Interestingly, we did not observe any increment in pulmonary vascular resistance associated to PHY (p . 0.20). Considering all these findings together, the logical conclusion is that PHY was related to pulmonary hypertension through indirect mechanisms: by its stimulating effects on cardiac output (as discussed previously) and by increasing the cardiac filling pressures (elevating all the pressures in the pulmonary vascular system—discussed later). Apparently, the pulmonary vascular tone was not directly affected by LPA and this result differs from previous studies on PHY effects, where the authors showed a consistent vasoconstrictor response of the pulmonary bed to hypercapnia (12, 15, 24, 25). The data above must be carefully analyzed, since some controversy stands on the exact meaning of the raw calculations of pulmonary vascular resistance extracted from singlepoint measures (26, 27). As already demonstrated, in face of an acutely increased cardiac output and/or an associated raised

Carvalho, Barbas, Medeiros, et al.: Hemodynamics during Permissive Hypercapnia

PWEDGE, both conditions occurring in LPA, the assumption that PWEDGE represents the effective vascular outflow pressure might lead to a fake reduction in the calculated value of pulmonary vascular resistance, despite a well-preserved vascular tone (26, 27). Another word of caution should be dedicated to the fact that this lack of vasoconstrictor response was obtained during a marked and concomitant change in airway pressures. Considering the J-shaped function of pulmonary vascular resistance according to progressive PEEP levels (28), one could speculate that our patients were below to a reasonable lung volume during the control period and that the use of PEEPIDEAL brought these patients closer to their optimal lung volume where the vascular bed is maximally recruited and the vascular resistance reaches its minimal. Therefore, both mechanisms above could have obscured some underlying increment in pulmonary vascular tone associated to PHY. Interestingly, some recent reports showed a controversial and direct vasodilator effect of CO2 on pulmonary vessels (12, 29) and, in a recent study in adult patients with ARDS, Thorens et al also observed a preserved “single-point” pulmonary vascular resistance during PHY (18). A marked and immediate increment in filling pressures, RAP and PWEDGE, was observed in the LPA group. We speculate that this phenomenon was the combined result of two conditions: the use of PHY and the use of high PEEP levels. According to some experimental data, a marked loading effect may be produced by PHY (12, 15, 30). Acute raises in PaCO2 seem to elicit constriction of the vascular capacitance system (sympathetically mediated), increasing the mean circulatory filling pressure and, consequently, the atrial filling pressures. Although this effect has not been consistently described in humans, it is interesting to notice that some trend in this direction could be observed in two recent clinical studies (15, 18). Despite all the limitations of the post-hoc multiple regression analysis performed in our study, the results also indicated some active role of the acute raise in PaCO2 on systemic filling pressures independently of any PEEP-mediated effect. On the other hand, PEEP increments usually result in increased intra-atrial pressures (10, 11), although through a different and complex mechanism. According to recent experimental data, whenever PEEP increases the mean circulatory filling pressure (by increasing the effective systemic volemia), it also externally constrains the cardiac chambers and, accordingly, the transmural atrial pressures are maintained or even diminished (31). The net result is usually a maintained or decreased pre-load and venous return. One could say that whereas PHY has the potential for increasing the true filling pressure with an increased venous return (30), the use of high PEEP would have the potential for increasing intra-atrial pressures but not the true pre-load. As we did not measure juxtacardiac or esophageal pressures, it is difficult to make some definite statement about the effective pre-load in our patients. However, as the patients in LPA did not present any change in the systolic volume along the time, marked changes in the effective pre-load were very unlikely. At this point we must consider some potential adverse effects of our LPA: Intracranial pressure. Besides the wellknown vasodilator effects of PHY on the brain (12), the marked increment in atrial pressures observed in LPA might adversely affect patients with documented intracranial hypertension. In our personal experience, however, we have submitted head-trauma patients to LPA (after installing intracranial pressure monitoring) and found that the strategy can be well tolerated in many cases. Right ventricle. Despite marked pulmonary hypertension,

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we did not observe any clinical signal of right ventricle dysfunction or arrhythmia in our study. The systolic volume was preserved during LPA (data not shown) indicating that those patients made use of their cardiac reserve, keeping the right stroke volume despite an increased afterload. These findings are in accordance with recent evidences suggesting that right ventricular failure is relatively rare in ARDS (32). The best conduct in the presence of a documented cardiac or coronary disease, however, is an open question. The increased heart rate and right ventricular overload elicited by LPA might have harmful consequences to an ischemic myocardium. Pulmonary edema. It is reasonable to suppose that, not only the increments in pulmonary arterial pressure and PWEDGE, but also the pulmonary overflow elicited by LPA might alter the longitudinal distribution of pulmonary resistance, increasing the effective pressures at the filtration site in the lung (33) and worsening lung edema. Although we have already demonstrated improved lung function associated with LPA (1), the situation could be even better if the intravascular pressures were minimized (34). In this context, the associated use of nitric oxide (15, 34) or alkalinizing agents (25) to attenuate pulmonary hypertension might be good theoretical alternatives. Finally, notwithstanding the major hemodynamic alterations observed in the LPA patients, no organ dysfunction appeared during the 7-d period that could be related to this strategy. Moreover, we observed a significant decrease in the levels of lactate in the first 36 h of the protocol (Figure 5). As long as differences in global oxygen debt cannot account for · these findings ( VO2I was the same in both groups), there are three possible explanations for this decrease: one is the blockade of the glycolytic pathway caused by respiratory acidosis (35), the other is the local increase of oxygen availability in small territories provided by higher PvO2 (18) and/or splanchnic vasodilatation associated to high CO2 tensions, and finally, a fairly attractive hypothesis is the reduction of systemic effects or cytokine release triggered by persisting lung injury imposed by our conventional ventilatory support (36). Whether the observed reduction is due to one or the other of the above is beyond the scope of the present study. In conclusion, the data above are demonstrating that the cardiovascular tolerance to the immediate installation of PHY—from a PaCO2 close to 35 mm Hg up to 60–80 mm Hg— plus high PEEP levels (PEEPIDEAL) was very adequate in our population (mean age 5 34 yr). So, except for situations of previous heart and/or neurological disease, we believe that the installation of PHY in a progressive and gradual manner is not justifiable and may consist in a risky waste of time. Acknowledgment : The authors thank Drs. Eduardo C. Meyer, Mauro R. Tucci, Pedro Caruso, Guilherme Schettino, Ivany A. L. Schettino, Cristiane Hoelz, Elnara Negri, Chin An Lin, Eloisa A. Silva, Vasco Moskovici, Laerte Pastore, Fabio Gomes, Sergio Demarzo, Cristiane Morais, Eduardo de Oliveira Fernandes, Roselaine Oliveira, Marcia Xavier Barreto, Michelle Grunauer, and all residents working in our units during the last 5 yr for their dedication and special collaboration to the patient care during the protocol. They also wish to thank Dr. Rosangela Santoro de Souza Amato for her assistance in the manuscript and to INTERMED Equipamento Médico-Hospitalar Ltda, and Siemens-Elema AB for technical support.

References 1. Amato, M. B. P., C. S. V. Barbas, D. Medeiros, G. P. P. Schettino, G. Lorenzi Filho, R. A. Kairalla, D. Deheinzelin, C. Morais, E. Fernandes, T. Y. Takagaki, and C. R. R. Carvalho. 1995. Beneficial effects of the “open lung approach” with low distending pressures in ARDS: a prospective randomized study on mechanical ventilation. Am. J. Respir. Crit. Care Med. 152:1835–1846. 2. Hickling, K. G., J. Walsh, S. Henderson, and R. Jackson. 1994. Low mortality rate in adult respiratory distress syndrome using low-volume, pressure-limited ventilation with permissive hypercapnia: a prospec-

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tive study. Crit. Care Med. 22:1568–1578. 3. Snyder, J. V., and A. Froese. 1987. Respirator lung. In J. V. Snyder and M. R. Pinsky, editors. Oxigen Transport in the Critically Ill. Year Book Medical Publishers, Inc., Chicago. 358–373 4. Gattinoni, L., A. Pesenti, D. Mascheroni, R. Marcolin, R. Fumagalli, F. Rossi, G. Iapichino, C. Romagnoli, L. Uziel, A. Agostoni, T. Kolobow, and G. Damia. 1986. Low-frequency positive-pressure ventilation with extracorporeal CO2 removal in severe acute respiratory failure. J.A.M.A. 256:881–886. 5. Amato, M. B. P., C. S. V. Barbas, D. Medeiros, G. Lorenzi Filho, R. A. Kairalla, D. Deheinzelin, R. B. Magaldi, and C. R. R. Carvalho. 1996. Improved survival in ARDS: beneficial effects of a lung protective strategy (abstract). Am. J. Respir. Crit. Care Med. 153:A531. 6. Muscedere, J. G., J. B. M. Mullen, and A. S. Slutsky. 1994. Tidal ventilation at low airway pressures can augment lung injury. Am. J. Respir. Crit. Care Med. 149:1327–1334. 7. Taskar, V., J. John, E. Evander, B. Robertson, and B. Jonson. 1997. Surfactant dysfunction makes lung vulnerable to repetitive collapse and reexpansion. Am. J. Respir. Crit. Care Med. 155:313–320. 8. Gattinoni, L., A. Pesenti, L. Avalli, F. Rossi, and M. Bombino. 1987. Pressure-volume curve of total respiratory system in acute respiratory failure: computed tomographic scan study. Am. Rev. Respir. Dis. 136: 730–736. 9. Gattinoni, L., P. Pelosi, S. Crotti, and F. Valenza. 1995. Effects of positive end-expiratory pressure on regional distribution of tidal volume and recruitment in adult respiratory distress syndrome. Am. J. Respir. Crit. Care Med. 151:1807–1814. 10. Nanas, S., and S. Magder. 1992. Adaptations of the peripheral circulation to PEEP. Am. Rev. Respir. Dis. 146:688–693. 11. Fessler, H. E., R. G. Brower, R. A. Wise, and S. Permutt. 1991. Effects of positive endexpiratory pressure on the gradient for venous return. Am. Rev. Respir. Dis. 143:19–24. 12. Feihl, F., and C. Perret. 1994. Permissive hypercapnia. How permissive should we be? Am. J. Respir. Crit. Care Med. 150:1722–1737. 13. Walley, K. R., T. H. Lewis, and L. D. H. Wood. 1990. Acute respiratory acidosis decreases left ventricular contractility but increases cardiac output in dogs. Circ. Res. 67:628–635. 14. Sechzer, P. H., L. D. Egbert, H. W. Linde, D. Y. Cooper, R. D. Dripps, and H. L. Price. 1960. Effect of CO2 inhalation on arterial pressure, ECG and plasma catecholamines and 17-OH corticosteroids in normal man. J. Appl. Physiol. 15:454–458. 15. Puybasset, L., T. Stewart, J. J. Rouby, P. Cluzel, E. Mourgeon, M. F. Belin, M. Arthaud, C. Landault, and P. Viars. 1994. Inhaled nitric oxide reverses the increase in pulmonary vascular resistance induced by permissive hypercapnia in patients with acute respiratory distress syndrome. Anesthesiology 80:1254–1267. 16. McIntyre, R. C., J. V. Haenel, F. A. Moore, R. R. Read, J. M. Burch, and E. E. Moore. 1994. Cardiopulmonary effects of permissive hypercapnia in the management of adult respiratory distress syndrome. J. Trauma 37:433–438. 17. Simon, R. J., S. Mawilmada, and R. R. Ivatury. 1994. Hypercapnia: is there a cause for concern? J. Trauma 37:74–81. 18. Thorens, J. B., P. Jolliet, M. Ritz, and J. C. Chevrolet. 1996. Effects of rapid permissive hypercapnia on hemodynamics, gas exchange, and oxygen transport and consumption during mechanical ventilation for the acute respiratory distress syndrome. Intensive Care Med. 22:182– 191. 19. Murray, J. F., M. A. Matthay, J. M. Luce, and M. R. Flick. 1988. An expanded definition of the adult respiratory distress syndrome. Am. Rev. Respir. Dis. 138:720–723. 20. Teboul, J. L., M. Besbes, P. Andrivet, O. Axler, D. Douguet, M. Zelter,

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32. 33.

34.

35.

36.

37.

38. 39.

VOL 156

1997

F. Lemaire, and C. Brun-Buisson. 1992. A bedside index assessing the reliability of pulmonary artery occlusion pressure measurements during mechanical ventilation with positive end-expiratory pressure. J. Crit. Care 7:22–29. Amato, M. B. P., C. S. V. Barbas, J. Bonassa, P. H. N. Saldiva, W. A. Zin, and C. R. R. Carvalho. 1992. Volume-assured pressure support ventilation (VAPSV). A new approach for reducing muscle workload during acute respiratory failure. Chest 102:1225–1234. Leatherman, J. W., R. L. Lari, C. Iber, and A. L. Ney. 1991. Tidal volume reduction in ARDS. Effect on cardiac output and arterial oxygenation. Chest 99:1227–1231. Kiiski, R., J. Takala, A. Kari, and J. Milic-Emili. 1992. Effect of tidal volume on gas exchange and oxygen transport in the adult respiratory distress syndrome. Am. Rev. Respir. Dis. 146:1131–1135. Vittanen, A., M. Salmenperä, J. Heinonen, and M. Hynynen. 1989. Pulmonary vascular resistance before and after cardiopulmonary bypass. The effect of PaCO2. Chest 95:773–778. Chang, A. C., H. A. Zucker, P. R. Hickey, and D. L. Wessel. 1995. Pulmonary vascular resistance in infants after cardiac surgery: role of carbon dioxide and hidrogen ion. Crit. Care Med. 23:568–574. Ducas, J., M. Stitz, S. Gu, U. Schick, and R. M. Prewitt. 1992. Pulmonary vascular pressure-flow characteristics. Effects of dopamine before and after pulmonary embolism. Am. Rev. Respir. Dis. 146:307–312. Hasinoff, L., J. Ducas, U. Schick, and R. M. Prewitt. 1990. Pulmonary vascular pressure-flow characteristics in canine pulmonary embolism. J. Appl. Physiol. 68:462–467. Canada, E., J. L. Benumof, and F. R. Tousdale. 1982. Pulmonary vascular resistance correlates in intact normal and abnormal canine lungs. Crit. Care Med. 10:719–723. Baudouin, S. V., and T. W. Evans. 1993. Action of carbon dioxide on hypoxic pulmonary vasoconstriction in the rat lung: evidence against specific endothelium-derived relaxing factor-mediated vasodilation. Crit. Care Med. 21:740–746. Rothe, C. F., P. M. Stein, C. L. MacAnespie, and M. L. Gaddis. 1985. Vascular capacitance responses to severe systemic hypercapnia and hypoxia in dogs. Am. J. Physiol. 249:H1061–H1069. Takata, M., and J. L. Robotham. 1991. Ventricular external constraint by the lung and pericardium during positive end-expiratory pressure. Am. Rev. Respir. Dis. 143:872–875. Vincent, J. L. 1995. Is ARDS usually associated with right ventricular dysfunction or failure? Intensive Care Med. 21:195–196. Younes, M., Z. Bshouty, and J. Ali. 1987. Longitudinal distribution of pulmonary vascular resistance with very high pulmonary blood flow. J. Appl. Physiol. 62:344–358. Benzing, A., P. Bräutigam, K. Geiger, T. Loop, U. Beyer, and E. Moser. 1995. Inhaled nitric oxide reduces pulmonary transvascular albumin flux in patients with acute lung injury. Anesthesiology 83:1153–1161. Huckabee, W. E. 1958. Relationships of pyruvate and lactate during anaerobic metabolism. I. Effects of infusion of pyruvate or glucose and of hyperventilation. J. Clin. Invest. 37:244–254. Tremblay, L., F. Valenza, S. P. Ribeiro, J. Li, and A. S. Slutsky. 1997. Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model. J. Clin. Invest. 99:944–952. Yeung, H. C., M. W. Lu, E. G. Martinez, and V. K. Puri. 1990. Critical Care Scoring System: new concept based on hemodynamics data. Crit. Care Med. 18:1347–1352. Smith, P. E. M., and I. J. Gordon. 1986. An index to predict outcome in adult respiratory distress syndrome. Intensive Care Med. 12:86–89. Knaus, W. A., E. A. Draper, D. P. Wagner, and J. E. Zimmerman. 1985. APACHE II: a severity of disease classification system. Crit. Care Med. 13:818–829.