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Optimization of Positive End-Expiratory Pressure Targeting the Best Arterial Oxygen Transport in the Acute Respiratory Distress Syndrome: The OPTIPEP Study

Chimot, Loïc*; Fedun, Yannick; Gacouin, Arnaud; Campillo, Boris; Marqué, Sophie; Gros, Antoine; Delour, Pierre§; Bedon-Carte, Sandrine§; Le Tulzo, Yves

doi: 10.1097/MAT.0000000000000496
Clinical Critical Care
Free
SDC

The optimal setting for positive end-expiratory pressure (PEEP) in mechanical ventilation remains controversial in the treatment of acute respiratory distress syndrome (ARDS). The aim of this study was to determine the optimum PEEP level in ARDS, which we defined as the level that allowed the best arterial oxygen delivery (DO2). We conducted a physiologic multicenter prospective study on patients who suffering from ARDS according to standard definition and persistent after 6 hours of ventilation. The PEEP was set to 6 cm H2O at the beginning of the test and then was increased by 2 cm H2O after at least 15 minutes of being stabilized until the plateau pressure achieved 30 cm H2O. At each step, the cardiac output was measured by transesophageal echocardiography and gas blood was sampled. We were able to determine the optimal PEEP for 12 patients. The ratio of PaO2/FiO2 at inclusion was 131 ± 40 with a mean FiO2 of 71 ± 3%. The optimal PEEP level was lower than the higher PEEP despite a constant increase in SaO2. The optimal PEEP levels varied between 8 and 18 cm H2O. Our results show that in patients with ARDS the optimal PEEP differs between each patient and require being determined with monitoring.

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From the *Department of Anesthesiology and Critical Care Medicine, Hôtel Dieu, CHU de Nantes, France; Medical Intensive Care, Hôpital Pontchaillou, Université de Rennes 1, Rennes, France; INSERM U936, University of Rennes 1, Rennes, France; and §Intensive Care Unit, Centre Hospitalier de Périgueux, Périgueux, France.

L.C. helped literature search, data collection, study design, analysis of data, manuscript preparation, and review of manuscript; Y.F. helped literature search, data collection, study design, analysis of data, manuscript preparation, and review of manuscript; A.G. helped literature search, data collection, study design, analysis of data, manuscript preparation, and review of manuscript; B.C. helped analysis of data, review of manuscript; S.M. helped data collection, study design, review of manuscript; A.G. helped data collection, study design, and review of manuscript; P.D. helped data collection, review of manuscript; S.B.C. helped data collection, review of manuscript; Y.L.T. helped literature search, data collection, study design, analysis of data, manuscript preparation, and review of manuscript.

Disclosure: The authors have no conflicts of interest to report.

The current study has been presented orally in 40th SRLF Meeting 2012.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML and PDF versions of this article on the journal’s Web site (www.asaiojournal.com).

Correspondence: Loïc Chimot, Service d’anesthésie Réanimation, Hôpital Hotel Dieu – CHU Nantes, 1 place Alexis-Ricordeau, 44093 Nantes cedex, France. Email: loic.chimot@gmail.com.

Acute respiratory distress syndrome (ARDS) treatments were improved notably with the improvement of the setting of positive mechanical ventilation.1–5 However, positive end-expiratory pressure (PEEP) setting protocols have not yet reduced mortality rates.6,7 Increased PEEP appears benefit to lungs (blood oxygenation, alveolar recruitment) and worse for circulation (vena cava compression, enhanced pulmonary arterial pressure) resulting in a decreasing of pulmonary blood flow and cardiac output (CO).8–17

The correction of cellular hypoxia requires blood oxygenation and sufficient flow to guarantee oxygen transport.18 Positive end-expiratory pressure has antagonistic effects on oxygen delivery (DO2). In 1975, Suter et al.19 conducted a trial to find the best PEEP, which was defined as the level that achieved the best DO2. This level in 15 patients was around 8 ± 4 cm H2O. Strategies for mechanical ventilation is really different today, including in the setting of low tidal volume.5 These upgrades are due to greater knowledge about ARDS and hemodynamic care.12,20–22 Improvements in DO2 could also improve the prognosis for patients suffering from ARDS.23

The aim of the current physiologic pilot study was to reach the best DO2 by varying the PEEP level for patients suffering from ARDS with current ventilation and circulatory management strategies.

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Methods

Patients

All patients hospitalized in the intensive care unit at University Hospital of Rennes and at Hospital of Périgueux from December 2010 to December 2012 with the eligibility criteria (acute respiratory failure, bilateral radiologic infiltrate, no increased loading pressure in the left ventricle [LV], and PaO2/FiO2 < 200 with a PEEP level above 5 cm H2O) and required mechanical ventilation for more than 6 hours were included. Eligibility was dependent on hemoglobin higher than 8 g/dl. Exclusion criteria were severe systolic cardiac failure (LV-ejection fraction or an LV-fractional area contraction (LVFAC) less than 40%), inotropic requirement, nitric oxide inhalation, circulatory assistance, prone position, supraventricular arrhythmia, acute cor pulmonale (ACP), presence of a chest tube, pregnancy, and younger than 18 years.

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Respiratory Setting

Respiratory settings (Evita XL and Evita Infinity, Dräger, Lübeck, Germany) were: tidal volume of 6 ml/kg of ideal weight with a maximum plateau pressure (Pplat) of 30 cm H2O, a respiratory rate set to obtain a pH between 7.30 and 7.45 without limiting expiratory flow. Before each test, the physician freely selected the PEEP level. No maneuvers that influenced lung volume (endotracheal suction, patient mobilization) were performed during the hour before. Patients were sedated by midazolam and morphine or sufentanil with a Ramsay score goal of 6, and then paralyzed by cisatracurium. All patients were positioned in strict supine position.

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Hemodynamic Monitoring

All patients had arterial catheters and central venous catheter introduced in the superior cava territory. Hemodynamic survey was conducted by transesophageal echocardiography (TEE).

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Protocol

A steady-state point was made before the test phase to ensure absence of exclusion criteria. Positive end-expiratory pressure was set at 6 cm H2O (low PEEP), then FiO2 adapted to obtain SpO2 > 84%. If it was not possible, the PEEP was increased in steps of 2 cm H2O every 5 minutes until the desired SpO2. During the test, every setting was unchanged except PEEP level. After stabilizing the SpO2, the first measurements were obtained (Pplat measured after a 4-second end-inspiratory pause, total PEEP [PEEPtot] measured after an end-expiratory pause). Static compliance was calculated by: tidal volume/(Pplat − PEEPtot). These measurements were repeated at each step. Subsequently, the PEEP level was increased by a step of 2 cm H2O after at least 15 minutes following the preceding level. At each step, TEE measurements of tolerance were obtained at the beginning (5 minutes after changing the PEEP level). After 15 minutes, the other TEE measurements and arterial and venous gas blood samples were obtained. Tolerance checking consisted of 1) Superior vena cava (SVC) collapse was absent. If so, a fluid challenge (500 ml crystalloid for 20 minutes) was performed and eventually repeated. 2) Mean arterial pressure (MAP) was maintained between 65 and 75 mmHg with norepinephrine adaptation. 2) Hemoglobin was maintained above 8 g/dl after the last fluid challenge, and blood was transfused if needed. Each of these three precedent items were corrected before restarting the procedure. 4) Acute cor pulmonale was absent. If present, the protocol was stopped. Echocardiography was performed to determine CO, and DO2 was calculated as: CO × CaO2 (arterial oxygen content = PaO2 × 0.003 + 1.34 × hemoglobin × SaO2). A similar formula was applied for mixed venous oxygen content (CvO2) to calculate the peripheral oxygen extraction ratio:

= (CaO2 − CvO2)/CaO2. The absolute quantity of consumption of oxygen (VO2) was calculated with: (CaO2 − CvO2) × (CO/body surface).24 The end of the test phase (high PEEP) was achieved when Pplat reached 30 cm H2O (or a maximum PEEP of 20 cm H2O).

The optimal PEEP was defined by the level that allowed the best DO2.

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Echocardiographic Measurements

Measurements were made by TEE (Sonos 5500, Philips, Andover, MA; Acuson CV70, Siemens). For the study, three of the unit seniors were recording the echocardiography data. Hypovolemia was diagnosed by the presence of a collapse of SVC (ΔSVC) > 36%.16 Left ventricle systolic function was evaluated with measurement of LVFAC. Right ventricle (RV) function was evaluated with the ratio RV/LV. Acute cor pulmonale was defined by a ratio >1. Cardiac output was determined by multiplying the multiplate LV outflow tract area with the velocity time integral, at end-expiratory time (mean of three measures), and heart rate (HR). In addition, the permeable foramen ovale (PFO) was examined with a contrast test, as previously described, twice (low PEEP, high PEEP).25

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Statistics

Means associated with standard deviations (mean ± SD) and absolute and relative frequencies [n (%)] were used to describe characteristics of the study population. Comparisons were performed with either the Wilcoxon signed-rank test or the Friedman test for repeated and dependent measures. Statistical dependence between continuous variables was assessed by the Spearman’s rank correlation coefficient and was presented as scatter plots with linear regression lines. Two-tailed p values were reported, and p < 0.05 was considered statistically significant.

The distribution of the optimal PEEP in the general population was estimated with the Gaussian distribution assumption. Parameters of the optimal PEEP distribution (µ, σ) were approximated by estimating the mean and standard deviation of the optimal PEEP in the study sample (mean, SD). The standard deviation defines the width of the normal distribution and reflects how much variation of a measurement occurs in the general population. In the current study, the width of the interval containing 95% of the optimal PEEP distribution (W95%) was used as a measure of the optimal PEEP variation in the general population. W95% was defined as W95% = m + Z (α = 5%) × σ (mZ (α = 5%) × σ) = 2 × 1.96 × σ, where σ represented either the lower or the upper limit of the 95% confidence interval of σ.

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Ethical Considerations

The current study has received the approval by the French ethics and scientific committee (CPP Ouest V). It was recorded at French authorities (AFSSAPS n°2010-A00942-37) and in clinical trial (NCT01256333).

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Results

Studied Population

Twelve patients were included in the study. The baseline characteristics are summarized in Table 1 and hemodynamic and ventilation in Table 3 in the initial section. None of the patients exhibited spontaneous respiratory motion. Table 2 presents the level of PEEP at different phases of the test. The mean pretest PEEP setting was 9 ± 3 cm H2O. It was not possible to maintain the pH > 7.30 for five patients because of the apparition of an expiratory flow limitation. The pretest hemoglobin was 10.4 ± 1.6 g/dl. Three patients benefited from staying in a prone position during the following hospitalization, after the test period. Nitric oxide inhalation and circulation assistance were not required. None of the patients required fluid loading. Seven patients needed norepinephrine. Arrhythmias were not observed. Two patients had a moderate PFO at low PEEP.

Table 1

Table 1

Table 2

Table 2

Table 3

Table 3

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Ventilation Evolution

All patients except one achieved a Pplat of 30 cm H2O. Static compliance was low before the test period (34.9 ± 11.9 ml/cm H2O) and, as PEEP increased, there was a significant decline (from 35.6 ± 14.6 to 29.8 ± 10.0 ml/cm H2O, p < 0.05).

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Optimal Positive End-Expiratory Pressure

Two patients required a low PEEP higher than 6 cm H2O (8 and 12 cm H2O). The optimal PEEP ranged from 8 to 18 cm H2O (Table 2). The FiO2 was set for the test with a mean of 71 ± 3 mm Hg. Oxygen delivery at the optimal PEEP level was significantly higher than at the other PEEP levels. Arterial oxygen content and PaO2/FiO2 increased after the optimal PEEP until the higher PEEP level, but this result remained insignificant (Table 3).

The mean of the optimal PEEP level in the study sample was 12 ± 3 cm H2O. The mean of the optimal PEEP level in the general population could be estimated to be between 10 and 14.5 cm H2O with a standard deviation between 2.4 and 5.3 cm H2O. A 95% confidence interval was used to estimate the mean and standard deviation. The range for the optimal PEEP in the general population (W95%) was estimated to be 9.3 and 20.9 cm H2O using the inferior and superior limit of the 95% confidence interval of the standard deviation, respectively (see Figure, Supplemental Digital Content, http://links.lww.com/ASAIO/A128).

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Parameters Associated with DO2

Cardiac output followed the variation of DO2 (Figure 1). The relationship between DO2 and CO shows a strong positive correlation (p < 0.0001, ρ = 0.838).

Figure 1

Figure 1

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Oxygen Consumption of Peripheral Tissues

A weak negative correlation existed between DO2 and

(p = 0.0001, ρ = −0.536), and a positive correlation was found between DO2 and VO2 (p = 0.0006, ρ = 0.446). The percent of

decreased as long as DO2 increased, showing increased peripheral shunt. However, global oxygen consumption of peripheral tissues increased with DO2.

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PEEP Tolerance

The test was stopped for one patient due to development of ACP. However, there were no changes in the RV/LV ratios in any other patients (Table 3). The ΔSVC increased significantly as the PEEP level increased, but this increase was not significant. Left ventricle function and hemodynamic parameters were not changed. Norepinephrine dose (0.07 ± 0.21 vs. 0.22 ± 0.18 µg/kg/min, p = 0.31), MAP, and HR were unchanged. No severe adverse events were observed. The PFO became worse in one patient (none to moderate). The two patients who had PFO at the beginning had PaO2/FiO2 ratios < 100 at inclusion. In comparison with other patients, the PaO2/FiO2 ratios did not increase below 100. Lactate (1.95 ± 1.02 vs. 2.14 ± 1.47 mmol/L, p = 0.76) and base excess (−3.3 ± 4.27 vs. 2.14 ± 5.14, p = 0.43) did not change.

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Discussion

Our study was designed to determinate the optimum DO2 level with variation of the PEEP level. As we expected, there was a great heterogeneity of optimal PEEP levels ranging from 8 to 18 cm H2O in the study sample. However, an optimal PEEP level can be determined for each patient with improved DO2.

During the increase in PEEP level, the DO2 curve showed a Gaussian form with an apogee so determination of an optimal PEEP level requires continuous monitoring of DO2. This result differed from the study by Suter et al.19 The authors proposed to keep the mean value of “best PEEP” (8 ± 4 cm H2O). Total compliance varied jointly to DO2 in that study, prompting the authors to use this parameter to select the PEEP level. However, ventilator settings differed from contemporary methods: tidal volume was set to 15 ml/kg. In our study, the PEEP interval defined by mean ± SD would contain the optimal PEEP of 85% to 49% of the general population according respectively to the optimistic or pessimistic estimations, proving the necessity to follow the DO2 variation until the best level. Because it is difficult to continuously monitor DO2 at the bedside, CO varied jointly and should be a good parameter. Finally, compliance was not a pertinent parameter with a drop during increasing PEEP as previously described.26

The optimal PEEP was systematically different from the high PEEP level advocated in several studies.6 However, these previous studies have several limitations. First, none of those demonstrated advantages for reduced mortality and morbidity. Improvements were for PaO2/FiO2, SaO2, and CaO2, in accordance with our results. Second, there were no data recorded for hemodynamic evolution. The current study was a pilot and physiologic trial and could not provide evidence that improving DO2 was better. Determination of this required more studies with a higher population and a control group.

Cardiac output evolution was biphasic during the increase in PEEP and reached a maximum. The increase in PEEP contributes to the reduction in CO, as observed previously.19 Because MAP and CVP did not change, we speculate this was due to variations in pulmonary vascular resistance which depend on lung volume by the way of the stretch on alveolar capillaries and extra-alveolar vessels (evolution like U way).17 Thus, the increased lung volume induced was most likely to limit the compression of the alveolar capillaries. Other physiopathology mechanisms also influenced this condition: hypoxemic pulmonary vasoconstriction and decreased lung compliance.

There was no evidence of poor tolerance in cardiac parameters during the study. The ΔSVC increased significantly but was inferior to the fluid-loading indication (10 ± 6%).16 A large increase in PEEP level slightly influenced the transmural pressure. It was explained by the probably limited increase in pleural pressure due to the reduced lung-pleural transmission of pressure occurred with low compliance of lung, as suggested by the absence of increased CVP.27 The RV/LV ratio was unchanged, suggesting that it is safe for the RV to increase the PEEP level until the high PEEP. However, one patient developed an ACP before the high PEEP was reached. However, the RV/LV ratio was high (0.92) at the beginning of the test, and a slight increase was enough to reach the critical value. It was amazing to note that the DO2 and CO increased in this patient until the study was terminated. This observation raises questions regarding ACP and mechanical ventilation.28 Although the negative effects of RV after load on pulmonary pressure are accepted, the RV/LV ratio of 1.0 should be modulated with CO evolution.29 We observed only one PFO opening, which was not consistent with previous publications. The most hypoxemic patients had a moderate PFO at the inclusion and showed less improvement. An increase in intracardiac shunting in association with the increased intrapulmonary pressure may explain this difference. In the study of Mekontso Dessap,25 the same change in PaO2/FiO2 ratio was observed.

Except one subgroup meta-analysis, no other studies have showed that a PEEP level setting to decrease mortality.30 Fatalities usually occur because of the multiple organ failure. Long-term evolution of survivors was marked by moderate alteration in respiratory function, but particularly by extrapulmonary alterations (neuromuscular, cognitive).31 Direct effects of tissue hypoxia from the acute phase may be one of the reasons. In the current study, the objective was to improve DO2. To our knowledge, there is no evidence that this improvement in ARDS decreases mortality or long-term complications. This question supports evidence to conduct studies to challenge it. Moreover, this is consistent with the results of extracorporeal membrane of oxygenation, which facilitates a large improvement in DO2.32

Our study had several limitations. First, there were a small number of patients. This study does not indicate whether this improvement in DO2 will bring real clinical benefit. The aim of the study was to evaluate the direct effect of the PEEP and we restricted our inclusion criteria to obtain a homogeneous population. In this way, we excluded number of patients that could be observed in other particular clinical situations.33,34 Test period was realized at the beginning of the ARDS, and the most severe patients had benefited from prone position sessions in the following of their stay in intensive care unit. A clearer understanding of the effects of agents modifying the DO2 variations and used in usual therapeutic is required to expand the applicability. Finally, the test phase was applied only once for each patient and continuous application must be challenged.

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Conclusion

This physiologic pilot study showed that PEEP can be increased to an optimal level, corresponding to the best DO2. This requires a continuous monitoring because each patient is different. This level differed from the currently recommended PEEP setting. Further studies are required to determine whether this setting can improve the prognosis of patients suffering from ARDS.

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Acknowledgment

Guarantor: Dr. Loïc Chimot.

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References

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Keywords:

ARDS; artificial respiration; positive end expiratory pressure; heart lung interaction; oxygen transport

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