Date Published: February 3, 2016
Publisher: Public Library of Science
Author(s): Helmut D. Hummler, Katharina Banke, Marla R. Wolfson, Giuseppe Buonocore, Michael Ebsen, Wolfgang Bernhard, Dimitrios Tsikas, Hans Fuchs, Edgardo Szyld.
Permissive hypercapnia has been shown to reduce lung injury in subjects with surfactant deficiency. Experimental studies suggest that hypercapnic acidosis by itself rather than decreased tidal volume may be a key protective factor.
To study the differential effects of a lung protective ventilatory strategy or hypercapnic acidosis on gas exchange, hemodynamics and lung injury in an animal model of surfactant deficiency.
30 anesthetized, surfactant-depleted rabbits were mechanically ventilated (FiO2 = 0.8, PEEP = 7cmH2O) and randomized into three groups: Normoventilation-Normocapnia (NN)-group: tidal volume (Vt) = 7.5 ml/kg, target PaCO2 = 40 mmHg; Normoventilation-Hypercapnia (NH)-group: Vt = 7.5 ml/kg, target PaCO2 = 80 mmHg by increasing FiCO2; and a Hypoventilation-Hypercapnia (HH)-group: Vt = 4.5 ml/kg, target PaCO2 = 80 mmHg. Plasma lactate and interleukin (IL)-8 were measured every 2 h. Animals were sacrificed after 6 h to perform bronchoalveolar lavage (BAL), to measure lung wet-to-dry weight, lung tissue IL-8, and to obtain lung histology.
PaO2 was significantly higher in the HH-group compared to the NN-group (p<0.05), with values of the NH-group between the HH- and NN-groups. Other markers of lung injury (wet-dry-weight, BAL-Protein, histology-score, plasma-IL-8 and lung tissue IL-8) resulted in significantly lower values for the HH-group compared to the NN-group and trends for the NH-group towards lower values compared to the NN-group. Lactate was significantly lower in both hypercapnia groups compared to the NN-group. Whereas hypercapnic acidosis may have some beneficial effects, a significant effect on lung injury and systemic inflammatory response is dependent upon a lower tidal volume rather than resultant arterial CO2 tensions and pH alone.
Neonates with respiratory distress syndrome (RDS), and children and adults with acute respiratory distress syndrome (ARDS) often require supplemental oxygen and mechanical ventilation because of decreased arterial PO2, which by itself may induce further ventilator induced lung injury (VILI) and result in significant mortality and morbidity [1–3]. Current approaches to reduce VILI take into account the concept of “volutrauma” emphasizing the mechanical stress by shear forces as a key factor inducing further injury when an often heterogeneously injured lung with protein-rich fluid filled alveoli is exposed to mechanical in- and deflation with gas [1,3,4]. Reducing tidal volume may attenuate mechanical disruption of the alveolar-capillary barrier, but may result in hypercapnic acidosis, which often is referred to as “permissive hypercapnia”. Hypercapnia has been shown to improve ventilation-perfusion matching resulting in improved PaO2, which may allow reduction of ventilator settings and thus contribute to lung protection. Clinical data clearly suggests that a low tidal volume ventilatory strategy is lung-protective and may improve outcome [1,6,7]. Utilization of this “permissive hypercapnia” strategy in patients was associated with improved outcome in several clinical studies in adults with ARDS [6–8], but not in studies in preterm infants with RDS, both terminated early [9,10]. The traditional concept of reducing mechanical stress induced by shear forces via low tidal volume ventilation as the key factor of “permissive hypercapnia” to reduce VILI has recently been challenged. Experimental data on lung-protective effects of hypercapnic acidosis without reduction in tidal volume in models of ischemia-reperfusion injury , ventilator induced lung injury [12,13] and surfactant deficiency  have challenged the concept that the decrease in tidal volume is the main factor for lung protection. Furthermore, reducing tidal volume may be associated with impaired oxygenation secondary to increased intrapulmonary shunt . These studies have demonstrated that hypercapnic acidosis, induced by adding CO2 into the inspiratory gas, attenuates lung injury compared to normocapnic control animals, although tidal volume was identical. However, there are no studies assessing the degree of lung injury in subjects with surfactant deficiency exposed to hypercapnia with a “normal” tidal volume proven to be lung protective in clinical studies , as compared to a strategy with a similar degree of hypercapnia using very small tidal volumes. Therefore, we compared the effects of a lung protective ventilator strategy using a very small tidal volume resulting in permissive hypercapnia to that of a normal tidal volume with hypercapnia induced by increasing FiCO2 and a ventilator strategy of a normal tidal volume and normocapnia on gas exchange, lung injury, and hemodynamics in an animal model of surfactant deficiency (ARDS). We hypothesized that hypercapnia improves PaO2 by attenuating the degree of lung injury during a hypoventilation strategy with very small tidal volumes only.
Of the 30 animals, 27 survived to the end of the experimental period. Two animals of the NN-, and one animal of the NH-group died prematurely due to cardiovascular failure. Fig 1 shows gas exchange, pH and lactate levels over time. PaO2 was significantly higher in the HH- vs. the NN-group. PaCO2 was maintained close to the respective targets in all 3 groups. Arterial pH and lactate were lower in both hypercapneic groups as compared to the NN-group (p<0.05). The aim of this study was to evaluate the effects of hypercapnic acidosis on the degree of lung injury in this animal model of surfactant deficiency. The design chosen for this study allows separating the protective effects by elevated PCO2 levels from the lung protective effects of a small tidal volume. Although there seems to be some effect of hypercapnic acidosis on PaO2, the hypothesis that hypercapnic acidosis improves PaO2 was proven for the combined effect of a small tidal volume and hypercapnia only. Furthermore, PaO2 was increased in the HH-group despite a lower peak and mean airway pressure as compared to both other groups. Lung injury was decreased in these animals as judged by wet-to-dry weight, BAL-Protein, histology. However, we could not prove similar protective effects in the animals of the NH-group. Furthermore, systemic IL-8 levels were significantly lower in the HH-group only, suggesting that systemic inflammation is reduced during low tidal volume use only. This finding suggests more loss of alveolar and systemic compartmentalization in NN- and NH-groups which has been described in animals exposed to injurious mechanical ventilation . We conclude that in this model of surfactant deficiency hypercapnic acidosis combined with a low tidal volume improves arterial oxygenation and protects against inflammation and lung injury. However, these effects were not significant for hypercapnic acidosis with a normal tidal volume, showing that either low tidal volume alone or the combination of low tidal volume with permissive hypercapnia is essential for lung protection. More research is needed to study the interaction between tidal volume and CO2 and their effects on hemodynamics and other systemic effects. Furthermore, clinical trials using different target ranges of tidal volume and PaCO2 looking at side effects and including long-term follow-up of these patients need to be performed to assess whether this approach of protective ventilation with permissive hypercapnia can be recommended for routine clinical use. Source: http://doi.org/10.1371/journal.pone.0147807