Acute respiratory distress syndrome (ARDS) is associated with increased capillary-alveolar permeability, alveolar collapse, reduced compliance, increased intrapulmonary shunt and hypoxemia. Most patients require mechanical ventilation to open the lung, reduce the work of respiratory muscles and ensure adequate gas exchange. But mechanical ventilation can cause and exacerbate lung injury if alveolar overdistension or repetitive collapse and reopening of unstable alveolar units occur with each tidal breath.1-3 To minimize the damage, lung protective ventilatory strategies have been proposed, including low tidal volume (VT) to avoid lung overdistension and a higher-than-traditional positive end-expiratory pressure (PEEP) level (greater than 12 to 15 cmH2O) to generate alveolar recruitment and prevent cycling end-expiratory collapse during mechanical ventilation.4,5
Recent randomized controlled trials have demonstrated a decrease in the mortality among patients with ARDS receiving low VT.6-8 However, association with higher PEEP did not further improve the outcome.9 For effectiveness of higher PEEP, it should recruit alveolar and increase the end-expiratory lung volume (EELV) and avoid lung overdistension. In patients with a limited amount of recruitable lung, the higher PEEP may cause lung overdistension of already inflated units, which is more harmful than beneficial.
It is still controversial as to the implementation of higher PEEP in patients with ARDS.10 We hypothesized that the effectiveness of the higher PEEP in lung recruitment and protection could be unpredictable. The higher PEEP levels are not suitable for all patients with ARDS and the optimal PEEP levels should be individualized. The objectives of this study were: (1) to compare the lower and higher PEEP in patients with ARDS ventilated with low VT; (2) to investigate the relationship between the recruited lung volume by higher PEEP and relevant independent variables; (3) to provide a bedside estimate of the percentage of potentially recruitable lung by higher PEEP.
A total of 24 patients with ARDS were studied during the period from April 2006 to May 2007. ARDS was diagnosed according to the criteria proposed by the American-European Consensus Conference on ARDS.11 All of them were studied in the early phase that mined ARDS was diagnosed for less than 7 days and all were mechanically ventilated. Patients’ demographic and clinical characteristics are listed in Table 1.
The exclusion criteria included age younger than 16 years, pregnancy, bone marrow transplant recipient, patients with chronic obstructive pulmonary disease, severe neuromuscular disease, increased intracranial pressure and chronic liver disease.
No subjects were excluded because of a refusal or other problems. The clinical research on PEEP patients received approval from the Ethical Committee of Nanjing University.
The clinical characteristics of the patients were recorded before the study. At baseline, patients were ventilated in volume control mode (VCV) with a constant inspiratory flow, VT 8 ml/kg predicted body weight, respiratory rate 15 breaths/min, inspiratory-to-expiratory ratio 1:2, fraction of inspiratory oxygen (FiO2) 1.0 and PEEP 0. A quasi-static pressure-volume curve of the respiratory system and the lower inflation pressure (LIP) of the inflation volume-pressure curve were measured.12 After a 30-minute ventilation period, a lung recruiting maneuver (RM) was performed in which the patients underwent ventilation for two minutes in the pressure-controlled mode at an inspiratory plateau pressure of 45 cmH2O, PEEP 16 cmH2O, respiratory rate 10 breaths per minute, inspiratory-to-expiratory ratio 1:2, and FiO2 1.0. At the end of RM, EELV was obtained after PEEP removal until no airflow was observed. RM was performed again in the pressure-controlled mode at an inspiratory plateau pressure 55 cmH2O if EELV increase induced by RM was lower than 150 ml, PEEP, respiratory rate, inspiratory-to-expiratory ratio, and FiO2 were the same as above. At the end of the second RM, EELV was obtained again after PEEP removal. Because PEEP removal can induce significant lung derecruitment, RM was performed again, each patient was ventilated with a PEEP of 8 cmH2O for 4 hours and subsequently after RM was performed, with PEEP of 16 cmH2O for 4 hours in VCV, VT 6 ml/kg predicted body weight, respiratory rate 15 breaths/min, inspiratory-to-expiratory ratio 1:2 and FiO2 1.0. At the baseline and end of each PEEP level period, gas exchange, hemodynamic data, lung mechanics, and stress index “b” of the dynamic pressure-time curve were recorded.13 At the end of each PEEP level period, intrinsic PEEP (PEEPi)14 and recruited volume by PEEP were measured (Figure 1).
Alveolar recruited volume measurement
Volume-pressure curves during each PEEP level period were plotted on the same pressure/volume axis by referring them to the elastic equilibrium volume of the respiratory system. The recruited volume was measured as the difference in lung volume for 20 cmH2O static airway opening pressure read on the volume-pressure curve.15 When 16 cmH2O PEEP induced a recruited volume of more than 150 ml, patients were defined as recruiters. Otherwise, patients were considered non-recruiters.16
Stress index b measurement
A dynamic inflation pressure-time curve during baseline and the study period in VCV with a constant inspiratory flow was achieved along with mechanical ventilation, and was quantitatively analyzed by fitting it to the equation: Airway opening pressure = a inflated time b + c; coefficient b was defined as stress index, b <1 corresponds to the curve with an upward concavity, indicating progressive increase in compliance of respiratory system with inflation and b >1 corresponds to the curve with an upward convexity, indicating progressive decrease in compliance of respiratory system and alveolar overdistension with inflation.13
Hemodynamic data, gas exchange, and lung mechanics measurement
Mean arterial and central venous pressure were monitored by using pressure transducers. Arterial blood samples were assessed by blood gas analyzer. Flow and airway opening pressure were recorded at the same time, airway opening pressure at an end-expiratory of a regular breath (PEEPexternal) and 5 seconds after the onset of an end-expiratory occlusion (PEEPtotal) were measured. Intrinsic PEEP was acquired as the difference between PEEPtotal and PEEPexternal.14 Static lung compliance (Cst) was calculated with the following equation: Cst = VT / (Pplat - PEEPtotal).
The expression of mean ± standard deviation (SD) was used for all parameters except PEEPi and fluid balance, which were not under normal distribution and were expressed with median (interval of quartile). All statistical analyses were performed with SPSS 11.0 software for windows. Analysis of PEEPi and fluid balance at baseline and during study period were carried out using Wilcoxon test. For multiple groups, analysis of variance (ANOVA) was performed followed by q test. Logistic regression analysis was used to investigate the possible association between alveolar recruitment and potentially relevant physiologic and clinical variables. A P <0.05 was considered statistically significant.
A total of 24 patients were enrolled in the study. According to the alveolar recruited volume, 14 patients were defined as recruiters and 10 patients were non-recruiters. The baseline characteristics of the two study groups are shown in Table 1, no differences were observed between the two groups.
In the recruiter's group, RM induced a significant increase in EELV from (436±225) ml to (752±291) ml. Among the 14 recruiters, EELV increase induced by the first RM was higher than 150 ml in 13 recruiters. One patient's EELV increase was higher than 150 ml induced only by the second RM and the alveolar recruited volume was higher than 150 ml induced by 16 cmH2O PEEP who was defined as a recruiter. In the non-recruiter's group, the effects of the first and second RM on EELV were not significant.
Alveolar recruited volumes induced by PEEP 16 cmH2O were (425±65) ml in recruiters and (125±37) ml in non-recruiters respectively. Compared with non-recruiters, alveolar recruitment volume induced by PEEP 8 cmH2O showed no difference in recruiters. Changing PEEP from 8 cmH2O to 16 cmH2O induced a dramatic increase in alveolar recruitment volume only in recruiters (Figure 2).
Ventilatory variables, gas exchange and lung mechanics at baseline and at each 4-hour study period are shown in Table 2.
At baseline, there was no significant difference between the two groups. Compared with the baseline, the PaO2/FiO2 ratio significantly increased in both groups after the application of the PEEP 8 cmH2O at 2 and 4 hours. Compared with the PEEP 8 cmH2O period, after the application of the PEEP 16 cmH2O at 2 and 4 hours, the ratio remained unchanged in non-recruiters, whereas it increased significantly in recruiters. Compared with the baseline, PaCO2 increased significantly in non-recruiters during PEEP 16 cmH2O at 2 and 4 hours. However, no statistical significance was reached in recruiters.
PEEPi was not significantly different in non-recruiters and recruiters at baseline, so was Cst. Compared with the baseline, PEEP 8 cmH2O induced a significant increase of Cst at 2 and 4 hours in recruiters and non-recruiters, compared with the PEEP 8 cmH2O period, after the application of the PEEP 16 cmH2O at 2 and 4 hours, Cst remained unchanged in non-recruiters, whereas it increased significantly in recruiters. Pplat was not significantly different in non-recruiters and recruiters at baseline, while compared with non-recruiters, Pplat was notably lower in recruiters after the application of PEEP 8 cmH2O and PEEP 16 cmH2O (Table 2).
At baseline, stress index b was lower than 1 in both recruiters and the non-recruiters and there was no significant difference between the two study groups. Compared with baseline, after the application of PEEP 8 cmH2O, b showed a substantial increase both in recruiters and non-recruiters, but it already reached 0.96 in non-recruiters. Improving PEEP to 16 cmH2O, b was still lower than 1 in recruiters; however, it was higher than 1 in non-recruiters (Table 2).
The hemodynamic variables remained unchanged in recruiters and non-recruiters at baseline and during the different PEEP levels. Fluid balance during the study period was not statistically different in recruiters and non-recruiters (Table 3).
We analyzed the relationship between the alveolar recruitment induced by PEEP and PEEP induced changes in PaO2/FiO2 and Cst. As shown in Figures 3 and 4, changes in PaO2/FiO2 and Cst after PEEP increasing were independently associated with the alveolar recruitment. From the analysis of the relationship between RM-induced change in EELV and the alveolar recruitment induced by PEEP, we found a significant correlation (Figure 5).
PEEP is critical for patients with ARDS, unfortunately almost 40 years later, the question of how much PEEP is enough remains relevant. In a post hoc analysis, Barbas et al17 showed that PEEP higher than 16 cmH2O was significantly correlated with an improved survival rate. Takeuchi et al18 demonstrated that a higher PEEP level was more effective in maintaining gas exchange and minimizing lung injury than a lower PEEP level in the sheep ARDS model.
However, when the ARDS Clinical Trails Network investigators conducted a rigorous, prospective, randomized, controlled trial, the results suggested that in patients with ARDS who received mechanical ventilation with a low tidal volume, clinical outcomes were similar whether higher or lower PEEP levels were used.9 Controversy regarding the optimal level of PEEP has persisted despite years of investigation into this question.10 The theory behind the beneficial effects of PEEP is that it may prevent the cycling opening and closing of the pulmonary units, and keep the lung open throughout the respiratory cycle. Accordingly, higher PEEP may be beneficial only if a given ARDS lung has a sufficient potential for recruitment.19
In this study, alveolar recruitment induced by lower and higher PEEP was detected first. The lower PEEP induced alveolar recruitment in all patients; however alveolar further recruitment by higher PEEP was obtained only in 14 of 24 patients who were defined as recruiters. The result is consistent with the study conducted by Gattinoni et al20 whose study provided direct visual evidence that the percentage of potentially recruitable lung was extremely variable and was strongly associated with the response to PEEP. In addition, alveolar recruitment may have effects on gas exchange and lung mechanics. The PaO2/FiO2 and Cst were both improved significantly in recruiters during higher PEEP ventilation periods, consistent with the alveolar recruitment. For the same minute ventilation, the PaCO2 decreased in the recruiters, showing the recruitment of perfused lung regions. On the contrary, the PaCO2 improved in the non-recruiters, indicating that PEEP induced alveolar overdistention and the higher PEEP would be harmful in these patients. From these findings, we concluded that higher PEEP was not suitable for all the patients with ARDS.
Experimental data suggested that the shape of the airway pressure-time curve during constant flow inflation corresponds to alveolar recruitment and respiratory elastance in patients with ARDS.13 The curve was fitted to a power equation: airway pressure = a timeb + c, where coefficient b (stress index) values and alveolar recruitment and hyperinflation were significantly correlated. In our study, b was raised gradually following the PEEP improvement in recruiters, consistent with the lung recruitment volume, indicating that the lower PEEP was not able to completely meet the requirement for alveolar recruitment. However, b was larger than 1 when PEEP improved to 16 cmH2O in non-recruiters, predicting alveolar hyperinflation and no further alveolar recruitment.
Alveolar recruitment is an inspiratory phenomenon and sufficient plateau pressure must be provided to open the lung.21 In the study, RM was defined as the potential for recruitment with the use of a inspiratory pressure of 45 cmH2O, while PEEP was both 16 cmH2O in lower PEEP and higher PEEP periods in order to maintain the effects of alveolar recruitment equally. It is known that in some patients with ARDS, higher inspiratory pressure levels are required to open some lung units. We chose to apply the second RM with 55 cmH2O inspiratory pressure if the 45 cmH2O RM could not improve the EELV, consistent with the effects of higher PEEP, RM improved EELV significantly in the recruiters. Because of the potential for lung injury and hemodynamic compromise, we chose to only apply the RM with 55 cmH2O inspiratory pressure. In animal and human research some investigators have used sustained inflation; applying airway pressure of higher than 55 cmH2O with an associated reduction in alveolar atelectasis in patients with ARDS.22 This study may underestimate the full potential for alveolar recruitment.
The use of alveolar recruited volume is not a pragmatic solution for the calibration of higher PEEP. In most clinical settings, it is imperative to develop simpler clinical or physiological variables to predict or estimate alveolar recruitment. In our recruiters, oxygenation and Cst changes were both related with alveolar recruitment volume change after the higher PEEP ventilation, the use of these respiratory physiological variables that can be measured at the bedside may be effective to ascertain the percentage of potentially recruitable lung by higher PEEP. In addition, EELV changes made by RM would also be helpful for indicating alveolar recruitment by higher PEEP.
As demonstrated in table 2, there was no significant difference in any hemodynamic variables and fluid balance between recruiters and non-recruiters during the lower PEEP and higher PEEP study periods. Cardiac output was not detected in this study, so we could not show if PEEP induced ventricular dysfunction. We speculate that low compliance in ARDS has resisted the PEEP induced hemodynamic impairment.
PEEPi would improve the PEEPtotal level in mechanical ventilation. Patients with ARDS could generate PEEPi when subjected to high respiratory rate or short expiratory time. In our study period, the respiratory rate was 20 breaths/min and the expiratory time was enough for lung emptying. PEEPi was low and not different in recruiters and non-recruiters.
There are possible explanations why we set PEEP levels artificially. First, lung protective ventilatory strategies have proposed higher PEEP levels, greater than 12 to 15 cmH2O, while a traditional PEEP level was 4 to 8 cmH2O.17 Second, the ARDS Network proposed an arbitrary FiO2/PEEP scale to reach the same oxygenation protocol to set PEEP level. However, the oxygenation changes are not necessarily related to lung recruitment. Furthermore, the FiO2/PEEP scales are not parallel but seem to converge at high FiO2 levels. Third, a sharp LIP could not be identified on the inflation volume-pressure curve of the respiratory system in four patients. So we used a PEEP of 8 cmH2O and a PEEP 16 cmH2O for comparing the effects of lower and higher PEEP.9
The ARDS patients in our study were ventilated with lower and higher PEEP for 4 hours for the following reasons. First, it was not certain whether higher or lower PEEP was suitable for the ARDS patients. Second, trail showed that 20 minutes would be needed for obtaining a blood gas sample in ARDS patients after application of PEEP. Last, we wanted to prevent disturbing factors through limiting the trail time. Further studies are required to evaluate the long-term effect of a suitable PEEP.
The results of this study indicated that the potential for alveolar recruitment may vary among the ARDS population. The higher PEEP levels should be limited to recruiters. The use of simpler clinical or physiological variables to predict or estimate alveolar recruitment has been suggested. Improving in PaO2/FiO2 and Cst after increasing PEEP, the EELV change made by RM and the shape of the pressure-time curve could be applied to PEEP. Further studies are required to determine optimal PEEP in ARDS patients.
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