PaCO₂ and alveolar dead space are more relevant than PaO₂/FiO₂ ratio in monitoring the respiratory response to prone position in ARDS patients: a physiological study

Since its first description in 1967 [1], it has been accepted that acute respiratory distress syndrome (ARDS) includes a number of lung injuries of various origins whose consequences are decreased lung capacity available for ventilation, leading to the concept of "baby lung" [2]. Considerable progress has been made over the past decade in the ventilatory management of patients with ARDS. In particular, a strict limitation of tidal volume (V_T) and plateau pressure (Pplat) below 30 cmH₂O reduces mortality [3]. The application of positive end-expiratory pressure (PEEP) is recognized to recruit the lung and to restore functional residual capacity [4], but its optimum level is still widely debated [5].

The prone position (PP) may also be part of the ventilatory strategy. This method was proposed more than 30 years ago, initially in pathophysiological studies [6, 7]. Recently, Sud et al. [8] suggested, on the basis of pooled data from randomized, controlled trials, that PP may improve survival in the subgroup of patients with the most severe ARDS, that is, those with a ratio of partial pressure of arterial O₂ to fraction of inspired O₂ (PaO₂/FiO₂) < 100 mmHg. Many questions remain unresolved. In particular, response to PP is usually defined according to changes in PaO₂, with responders being those in whom the PaO₂/FiO₂ ratio increases > 20 mmHg after one to six hours in the PP [9‐11]. However, we have previously reported that PP allows recruitment of a slow compartment previously excluded from ventilation [12]. This was associated with a decrease in partial pressure of arterial CO₂ (PaCO₂), an indirect reflection of the reduction of the alveolar dead space (VD_alv) [12]. Gattinoni et al. [10] also reported that the prognosis is improved in patients in whom PaCO₂ declines after an initial PP session. Finally, VD_alv appears to be an independent risk factor for mortality in patients with ARDS [13]. In a recent study, Siddiki et al. [14] proposed evaluating the physiological dead space fraction (VD_physiol/V_T) by using a rearranged alveolar gas equation for PaCO₂ without any expired CO₂ measurement.

In this context, we conducted a prospective physiological study to evaluate the impact of PP on ventilatory mechanics, gas exchange and VD_alv. Our main objective was to validate our hypothesis that changes in PaCO₂ and VD_alv might be more relevant than changes in PaO₂ in defining the respiratory response to PP. Our second objective was to validate the method of evaluation of the VD_physiol/V_T proposed by Siddiki et al. [14].

In our unit, patients with a PaO₂/FiO₂ ratio < 100 mmHg after 24 to 48 hours of mechanical ventilation are systematically turned to PP when hemodynamically stable [15]. Our study was approved by the Ethics Committee of the "Société de Réanimation de Langue Française" (SRLF-CE 07-213). After obtaining informed consent from the patients' relatives, 15 patients were included in the study between January 2008 and March 2010. Inclusion criteria were (1) the presence of ARDS according to the definition of the Acute Respiratory Distress Syndrome Network [3]; (2) persistence of severe hypoxemia after 48 hours of mechanical ventilation, defined as a PaO₂/FiO₂ ratio < 100 mmHg; and (3) hemodynamic stability, defined as systolic blood pressure > 90 mmHg with norepinephrine infusion at a rate < 0.5 μg/kg/minute. Patients with chronic obstructive pulmonary disease were excluded.

All patients were ventilated in volume-controlled mode (Servo-i; Maquet SA, Ardon, France), sedated and paralyzed by infusion of atracurium. The heat and moisture exchanger was routinely removed and replaced by a heated humidifier to reduce instrumental dead space as previously reported [16]. The ventilator settings included a "moderately restricted" V_T of 6 to 8 mL/kg measured body weight, a respiratory rate allowing us to limit hypercapnia without generating intrinsic PEEP and an inspiration/expiration ratio of 1:2 with an end inspiratory pause of 0.5 seconds. Pplat was strictly limited < 30 cmH₂O, and the PEEP selected was that which corrected the intrinsic PEEP, if any [17]. Ventilator settings were kept constant throughout the study. A recruitment maneuver was never used, and suction was not systematically performed. All patients were continuously monitored in terms of blood pressure with an arterial catheter, heart rate and O₂ saturation by pulse oximetry.

The study was conducted during the first session of PP. Our sessions routinely last 15 to 18 hours per day. Blood gas analysis, Pplat, total PEEP, end-tidal CO₂ (P_etCO2) and mixed expired CO₂ (P_ECO2) were recorded with the patient in the supine position, just before turning the patient to the PP, and every 3 hours in the PP until 15 hours had elapsed. Expired CO₂ was measured by a sensor positioned between the proximal end of the endotracheal tube and the Y piece of the ventilator circuit (COSMO; Novametrix, Wallingford, CT, USA). The ratio of VD/V_T was calculated using the simplified Bohr equation [18] as follows: (1) VD_alv/V_T = 1 - P_etCO2/PaCO₂ and (2) VD_physiol/V_T = 1 - P_ECO2/PaCO₂.

The estimated VD_physiol/V_T ratio was calculated as 1 - [(0.86 × VCO_2est)/(VE × PaCO₂)], where VCO_2est is the estimated CO₂ production calculated using the Harris-Benedict equation [19] and VE is the expired minute ventilation.

Intrinsic PEEP was measured during a four-second end-expiratory occlusion period. Pplat was measured during a 0.5-second end-inspiratory pause. Respiratory system compliance (Crs) was calculated as Crs = V_T/(Pplat - PEEP_total). Responders to PP were defined in two different ways: (1) an increase in PaO₂/FiO₂ ratio > 20 mmHg after 15 hours of PP or (2) a decrease in PaCO₂ > 2 mmHg after 15 hours of PP.

Two patients were excluded from the study because of a history of severe chronic obstructive pulmonary disease, which left a study population of 13 patients. The patients' median age was 53 years (1st to 3rd interquartile range, 48 to 59 years), their median Simplified Acute Physiology Score II score was 62 (1st to 3rd interquartile range, 35 to 71) and their median Sequential Organ Failure Assessment score was 11 (1st to 3rd interquartile range, 8-13). All patients except one had ARDS of pulmonary origin. Eight patients had pneumonia, with six cases related to streptococcus pneumonia and two due to influenza (H1N1 virus). Two patients had aspiration, one had toxic shock syndrome and two had ARDS due to miscellaneous causes. No patient had abdominal hypertension or traumatic lung injury. Eleven patients required norepinephrine infusion. Respiratory parameters and blood gas analysis at the time of inclusion are reported in Table 1.

A significant increase in PaO₂/FiO₂ ratio occurred after 15 hours of PP, from 70 mmHg (51 to 77) in the supine position to 99 mmHg in the prone (83 to 139) (P < 0.0001) (Table 2). A significant decrease in PaCO₂ was also observed, from 58 mmHg (52 to 60) to 52 mmHg (47 to 56) (P = 0.04) (Table 2), with the lowest value occurring after nine hours of PP. As noted in Table 2, Pplat was significantly reduced (P = 0.0004) and Crs improved (from 16 mL/cmH₂O (13 to 30) to 18 mL/cmH₂O (15 to 30); P = 0.02). Finally, the VD_alv/V_T ratio was significantly reduced from 0.42 (0.35 to 0.47) to 0.40 (0.26 to 0.45), with the lowest value occurring after three hours in PP (hour 3) (0.31) (Table 2).

Seven patients were classified as "PaO₂ responders" and six were classified as "PaO₂ nonresponders" according to PaO₂/FiO₂ ratio changes. No differences in VD_alv/V_T ratios or PaCO₂ or Pplat alterations during PP were observed between groups (Table 3 and Figure 1), whereas Crs increased more in the responders (Table 3). Seven patients were also classified as "PaCO₂ responders" and six as "PaCO₂ nonresponders" according to the PaCO₂ changes. However, when compared with the PaO₂/FiO₂ classification, four patients were classified differently. As shown in Table 4 and Figure 2, VD_alv/V_T, PaO₂/FiO₂, PaCO₂, Pplat and Crs were significantly more altered in responders than in nonresponders. As shown in Figure 3, we found no correlation between changes in VD_alv/V_T and changes in PaO₂/FiO₂ (P = 0.95), whereas we found a negative correlation between changes in VD_alv/V_T and changes in Crs (r = 0.29, P = 0.03).

As shown in Figure 4, estimated VD_physiol/V_T systematically underestimated measured VD_physiol/V_T, with a poor concordance correlation coefficient of 0.19 (95% confidence interval (95% CI) 0.091 to 0.28), a bias of 0.16 and an agreement between -0.05 and 0.37. Concerning changes in VD_physiol/V_T during PP, estimated VD_physiol/V_T had a concordance correlation coefficient of 0.51 (95% CI 0.32 to 0.66) (Figure 4).

One of the objectives of our study was to describe alterations in VD_alv induced by PP. ARDS is characterized by a heterogeneous lung with the existence of a slow compartment [18, 20], defined as areas available for, but partially or totally excluded from, ventilation due in part to a bronchiolar collapse [12, 21]. In a previous study, we reported that PP may induce recruitment of this slow compartment, as suggested by its ability to counteract intrinsic PEEP and to decrease the expiratory time constant [12]. In the same study, we also reported that PP leads to a decrease in PaCO₂, suggesting diminution of VD_alv (alveolar dead space) [12]. Our present study demonstrates that PP may induce a decrease in VD_alv. It occurred from the third hour and was maintained throughout the PP session. VD_alv may be the consequence of nonperfused or poorly perfused lung areas in ventilated anterior areas, but also of a slow compartment partially excluded from ventilation. Our results suggest that PP induces functional lung recruitment, especially since decreases in VD_alv related to PP were associated with a decrease in Pplat and strongly correlated with improvement in compliance. Interestingly, in a previous study of 16 ARDS patients, Pelosi et al. [22] did not find a decrease in VD_physiol after 120 minutes in PP. One of the explanations for this discrepancy could be the different levels of PEEP in the two studies: 12.3 cmH₂O in Pelosi et al.'s study and only 6 cmH₂O in our study. However, Protti et al. [23], in a study of patients ventilated with a PEEP of 13 cmH₂O, demonstrated a strong relation between lung recruitability and decreased PaCO₂ related to PP. Pelosi et al. also did not report a decrease in Pplat in PP, as we found, but after returning patients to the supine position [22]. This could be explained by the fact that they used roll under the upper part of the chest wall, leading to a significant impairment in chest wall compliance [22], whereas we did not.

The most beneficial reported effect of PP is oxygenation improvement [24, 25]. However, this better oxygenation can be due to (1) lung recruitment related to restoration of functional residual capacity [7] and improvement of the diaphragmatic movement in the posterior part [26‐28] or (2) simply to an improvement in the ventilation/perfusion ratio due to a decreased hydrostatic gradient between the anterior and posterior parts of the lung [26, 29]. Whereas the first mechanism is crucial, one can say that the second mechanism is less important. This is why the second objective of our study was to test whether the response to PP in terms of PaCO₂ was physiologically more relevant than in terms of PaO₂/FiO₂ ratio. Gattinoni et al. [10] reported that an increase in PaO₂/FiO₂ ratio > 20 mmHg after six hours of PP is not predictive of the patient's prognosis, whereas a decline in PaCO₂ ≥1 mmHg is. In our present study, 7 of 13 patients were PaO₂ responders (increased PaO₂/FiO₂ ratio > 20 mmHg after 15 hours of PP). However, changes in Pplat, PaCO₂ and VD_alv did not differ between PaO₂ responders and PaO₂ nonresponders. On the other hand, 7 of 13 patients were PaCO₂ responders (decreased PaCO₂ > 2 mmHg after 15 hours of PP). PaCO₂ responders had a significant decrease in Pplat and VD_alv, as well as a significant increase in oxygenation and compliance, compared with nonresponders. Our results are in accordance with a recent study of 32 ARDS patients [23], in which the investigators reported that PaCO₂ variation induced by PP, and not PaO₂/FiO₂ variation, is associated with lung recruitability. Interestingly, in our study, changes in VD_alv were not correlated with changes in oxygenation but were strongly correlated with changes in compliance of the respiratory system.

An unexpected result of our work concerns the change over time of respiratory mechanics, blood gas analysis and VD_alv. For many years, our PP protocol has been to turn patients to PP for up to 15 to 18 hours per day for 3 days [15]. In the study by Mancebo et al. [30], which concluded that PP may reduce mortality in patients with severe ARDS, PP sessions lasted 20 hours/day. In a recent study, we demonstrated that PP sessions that lasted 18 hours/day were independently associated with survival [31]. In the present study, the maximum effect of PP for VD_alv, PaCO₂ and Pplat occurred six to nine hours after turning patients to PP. Later the effect seemed to be a decline. How this affects the effect of PP on patient prognosis remains to be elucidated.

The second objective of our study was to validate a recently proposed method to evaluate the VD_physiol/V_T ratio [14]. The method is based on CO₂ production calculated from the Harris-Benedict equation [19] and on the expired minute ventilation. Siddiki et al. [14] reported that it was associated with mortality in acute lung injury patients in a dose-response manner and proposed its routine use to estimate VD_physiol/V_T. However, they did not report any comparison with measured VD_physiol/V_T. In the present study, we have demonstrated that this method significantly underestimates VD_physiol/V_T, rendering it not accurate enough to assess the degree of lung injury. Interestingly, changes in estimated VD_physiol/V_T during PP appeared better correlated with changes in measured VD_physiol/V_T and could be proposed in the future in this field. Siddiki et al. [14] proposed the method in the context of a much larger series than ours and in patients with less severe ARDS, rendering it difficult to draw any definitive conclusions.

Our work is limited by the small number of patients included. This is a consequence of our routine protocol, which strictly restricts PP to patients with the most severe ARDS, that is, those with a PaO₂/FiO₂ ratio < 100 mmHg after 48 hours of ventilation. This also explains why it is not possible to link our results to outcomes. However, despite this limitation, we consider our results relevant from a physiological point of view.

In conclusion, our study demonstrates that PP induces a decrease in PaCO₂ and VD_alv. This is related to an improvement in respiratory mechanics, with a decrease in Pplat and an increase in compliance. Testing the response to PP appeared to be physiologically more relevant using PaCO₂ changes than PaO₂/FiO₂ changes. How this may affect management at the bedside remains to be studied. Estimated VD_physiol/V_T ratios systematically underestimated measured VD_physiol/V_T ratios.