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First published online on June 15, 2007
Chest, doi:10.1378/chest.07-0409
doi:10.1378/chest.07-0409
(Chest. 2007; 132:836-842)
© 2007 American College of Chest Physicians
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Pulmonary Dead Space Fraction and Pulmonary Artery Systolic Pressure as Early Predictors of Clinical Outcome in Acute Lung Injury*

Magda Cepkova, MD; Vineet Kapur, MD; Xiushui Ren, MD; Thomas Quinn, MD; Hanjing Zhuo, MD, MPH; Elyse Foster, MD; Kathleen D. Liu, MD, PhD and Michael A. Matthay, MD

* From the Cardiovascular Research Institute (Drs. Zhuo and Matthay), and the Departments of Medicine (Drs. Ren, Foster, and Liu) and Anesthesia, (Drs. Cepkova, Kapur, and Quinn), University of California, San Francisco, San Francisco, CA.

Correspondence to: Michael A. Matthay, MD, Critical Care Medicine, 505 Parnassus Ave, Room M-917, San Francisco, CA 94143-0624; e-mail: Michael.matthay{at}ucsf.edu

Abstract

Study objective: The primary objective of this study was to test whether an elevated systolic pulmonary artery (PA) pressure or an elevated pulmonary dead space fraction (VD/VT) in early acute lung injury (ALI) is associated with poor clinical outcomes in the era of lung-protective ventilation.

Design: Prospective observational cohort study.

Setting: ICUs of a university hospital.

Patients: Forty-two patients with ALI receiving mechanical ventilation.

Measurements: PA pressure was measured noninvasively using transthoracic echocardiography. VD/VT was measured by volumetric capnography (NICO Cardiopulmonary Management System; Novametrix; Wallingford, CT).

Main results: There was no difference in the mean systolic PA pressure in patients who died compared to those who survived (43 ± 9 mm Hg vs 41 ± 9 mm Hg, p = 0.54) [mean ± SD]. In contrast to the PA systolic pressure, VD/VT was significantly higher in patients who died compared to those who survived (0.61 ± 0.09 vs 0.53 ± 0.10, p = 0.02). Similarly, VD/VT was higher in patients with < 7 ventilator-free days during the first 28 days after enrollment compared to those with > 7 ventilator-free days (0.61 ± 0.08 vs 0.52 ± 0.11, p = 0.008).

Conclusion: In the era of lung-protective ventilation, systolic PA pressure early in the course of ALI is elevated but not predictive of outcome. However, elevated VD/VT in early ALI is associated with increased mortality and with fewer ventilator-free days.

Key Words: acute lung injury • ARDS • pulmonary dead space fraction • systolic pulmonary artery pressure • transthoracic echocardiography

Acute lung injury (ALI) is a major cause of acute respiratory failure, with significant morbidity and mortality. The incidence of ALI is approximately 200,000 patients per year in the United States12 with a mortality rate of 30 to 40%. There is convincing evidence from radiologic studies34 and pathology5 that abnormalities of pulmonary blood flow and injury to the lung microcirculation are prominent features of ALI. Increased pulmonary artery (PA) pressure in patients with ALI has been well documented in earlier studies678 using right-heart catheterization. In several studies,91011 pulmonary hypertension in patients with ALI has been associated with poor prognosis. However, all of these studies were done prior to the introduction of a lung-protective, low-tidal-volume ventilation strategy for patients with ALI. A prospective, observational study12 in patients with ARDS reported that increased pulmonary dead space fraction (VD/VT) is a feature of early ARDS, and that an elevated VD/VT is independently associated with an increased risk of death. Elevated VD/VT in the early phase of ALI may be explained in part by lung vascular injury and obstruction with an elevation in PA pressures as well as an increase in ventilation of poorly perfused alveoli secondary to ventilation/perfusion mismatch or overinflation of normally compliant lung units.

We performed a prospective, observational study to test whether early noninvasive measurement of systolic PA pressures or VD/VT would identify patients with poorer clinical outcomes. In contrast to prior studies, this study was done in patients with ALI who received a lung-protective, low-tidal-volume ventilation strategy.

Materials and Methods

Study Design and Patient Selection
This was a prospective observational cohort study conducted in the ICU of a tertiary care university hospital. The protocol was approved by the Institutional Committee on Human Research, and informed consent was obtained from the patients or their surrogates. All patients with ALI admitted to the adult ICU of Moffitt-Long Hospital at the University of California San Francisco between December 2004 and May 2006 were eligible for the study. Inclusion criteria were age ≥ 18 years, positive pressure ventilation via an endotracheal tube or tracheostomy, and diagnosis of ALI. The definition of ALI was according to the American-European Consensus Conference13 criteria: PaO2/fraction of inspired oxygen (FIO2) ratio ≤ 300 for ALI and ≤ 200 for ARDS, acute-onset bilateral infiltrates on chest radiography, and pulmonary artery wedge pressure < 18 mm Hg or no clinical evidence of left atrial hypertension. Patients were excluded if they met diagnostic criteria for ALI for > 48 h, severe COPD (defined as FEV1 < 50% predicted, a history of intubation for COPD exacerbation, and receiving home oxygen therapy or long-term systemic steroids for COPD), preexisting primary or secondary pulmonary hypertension, or a history of congestive heart failure with left ventricular (LV) ejection fraction < 40%. Patients not expected to survive > 6 months due to an underlying medical condition were also excluded. We screened all patients requiring mechanical ventilation in our ICUs. Of 188 patients meeting ALI criteria, 42 patients who had no exclusion criteria and an available surrogate were enrolled.

Clinical Data Collection
The demographic and clinical data were collected using standardized data collection forms. The primary etiology of ALI was assessed based on a detailed review of the clinical history. Sepsis was defined as suspected infection and presence of at least two of the systemic inflammatory response syndrome criteria. Pneumonia was defined as new infiltrates on chest radiographs and the presence of at least two of the following three criteria: fever (temperature > 38.3°C), leukocytosis (WBC count > 12,000/µL), or purulent secretions. Aspiration had to be either witnessed or there needed to be documented evidence of aspiration of gastric contents from the endotracheal tube. Baseline characteristics, demographic data, and relevant physiologic data were recorded on day 1 of the study. APACHE (acute physiology and chronic health evaluation) II scores at the time of the enrollment into the study were calculated.

Pulmonary Dead Space Measurements
We measured VD/VT using volumetric capnography (NICO Cardiopulmonary Management System; Novametrix; Wallingford, CT)14 to calculate the partial pressure of mixed-expired CO2, which is then used in the Enghoff modification of the Bohr equation as follows15:

Formula
where PeCO2 is mixed-expired CO2. An arterial blood gas sample is obtained when the mean expired CO2 variability on the NICO monitor is ≤ 1 mm Hg within 5 min; these values are then used to calculate VD/VT. The NICO monitor has been validated as an accurate measurement of pulmonary dead space in patients with ALI.16

Echocardiographic Measurement
Transthoracic echocardiographic studies were completed using commercially available ultrasound systems (Sequoia; Siemens Ultrasound; Mountain View, CA; or Phillips Ultrasound 5500; Phillips; Andover, MA). The recordings were subsequently analyzed by an investigator (X.R.) who was blinded to the subjects’ clinical history.

PA systolic pressure was calculated by estimating the systolic pressure gradient across the tricuspid valve from the peak flow velocity of the tricuspid regurgitant jet1718 and adding this value to the right atrial (RA) pressure. Agitated saline solution was used to enhance the quality of the tricuspid regurgitant jet in the event that a full and complete Doppler flow envelope was not seen.19 RA pressure was directly measured using pressure tracings from a central venous catheter at the time of the echocardiogram.

Right ventricular (RV) size and systolic function were qualitatively assessed as normal, mildly, moderately, or severely reduced according to our echocardiography laboratory protocol. LV end-diastolic and end-systolic volumes were calculated using the biplane method of discs.20 These volumes were used to calculate LV ejection fraction. Cardiac output was calculated using the standard volume-flow formula, with measurements of LV outflow diameter as used by Kitabatake et al21 and Mowat et al22 and stroke distance as used by Goldman et al.23

Statistical Analysis
Data analysis was conducted using statistical software (STATA 9.0; StataCorp; College Station, TX). The study had two primary outcomes: death prior to hospital discharge, and ventilator-free days. Ventilator-free days were defined as the number of days from day 1 of the study to day 28 that a patient breathed without assistance, if the period of unassisted breathing lasted at least 48 consecutive h. For the analysis of continuous variables, ventilator-free days were dichotomized as ≤ 7 days and > 7 days, as we have done in prior studies.2425 Results were expressed as mean ± SD. We used Student t test and Fisher exact test for the between-group comparisons. Pearson product-moment correlation was used to examine the relationship between the VD/VT and other variables. All tests of significance were two tailed, with a p value < 0.05 considered statistically significant.

Results

Baseline Characteristics
A total of 42 patients with ALI were enrolled in the study (23 women and 19 men; mean age, 62 ± 17 years). Of the 42 patients enrolled, 15 patients (36%) died and 27 patients (64%) survived. The demographics, etiology of ALI, and comorbidities are summarized in Table 1 . Baseline physiologic variables are summarized in Table 2 . Systolic PA pressure measurements were successfully obtained in 39 of the 42 patients. Three patients had an incomplete tricuspid regurgitation jet despite agitated saline solution injection. Mean systolic PA pressure was elevated (42 ± 9 mm Hg). VD/VT was measured in 39 patients and was also increased (0.56 ± 0.10). VD/VT was not measured in three subjects who received pressure support ventilation at the time of enrollment. The tidal volume per kilogram of predicted body weight at the time of the VD/VT measurement was 7.0 ± 1.3 mL/kg.


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  		Table 1.. Baseline Demographics and Clinical Characteristics of the 42 Study Subjects*

 

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  		Table 2.. Baseline Physiologic Variables of the 42 Study Subjects*

 
Systolic PA Pressure as Predictor of Outcome in Early ALI
There was no difference in mean systolic PA pressures in patients who died compared to those who survived (43 ± 9 mm Hg vs 41 ± 9 mm Hg, p = 0.54; Fig 1 ). Likewise, mean systolic PA pressures were not different in patients with < 7 days of unassisted breathing during the first 28 days after enrollment than in those with > 7 days of unassisted breathing (41 ± 9 mm Hg vs 44 ± 9 mm Hg, p = 0.25). There was also no difference in systolic PA pressures between patients with ARDS and ALI (43 ± 8 mm Hg vs 40 ± 11 mm Hg, p = 0.39) and between patients with direct vs indirect lung injury (42.3 ± 9 mm Hg vs 41.4 ± 10 mm Hg, p = 0.8).


Figure 1
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  		Figure 1.. Box plot summary of systolic PA pressures in survivors and nonsurvivors. Horizontal lines represent the median, boxes encompass the 25th to 75th percentiles and error bars encompass the 10th to 90th percentile. The graph shows no significant difference between the two groups.

 
Low-tidal-volume ventilation has long been associated with hypoxemia,26 which may increase PA pressure. Moreover, acute permissive hypercapnia during lung-protective strategy has been shown to cause an acute increase in PA pressure.27 Therefore we examined the potential correlation between systolic PA pressure and baseline pH, PaCO2, and PaO2/FIO2 ratio. There was no correlation between systolic PA pressure and any of the three parameters: pH, r = – 0.03, p = 0.8; PaCO2, r = 0.17, p = 0.03; and PaO2/FIO2 ratio, r = – 0.23, p = 0.15.

Pulmonary Dead Space Fraction as Predictor of Outcome in Early ALI
In contrast to systolic PA pressure, VD/VT was significantly higher in patients who died than in those who survived (0.61 ± 0.09 vs 0.53 ± 0.10, p = 0.02; Fig 2 ). Similarly, VD/VT was increased in patients with < 7 ventilator-free days during the first 28 days after enrollment compared to patients with > 7 ventilator-free days (0.61 ± 0.08 vs 0.52 ± 0.11, p = 0.008). There was also a significant difference in VD/VT in patients with ARDS vs patients with ALI (0.58 ± 0.10 vs 0.50 ± 0.11, p = 0.017). In contrast, there was no statistically significant difference in VD/VT in patients with direct vs indirect lung injury (0.57 ± 0.10 vs 0.51 ± 0.14, p = 0.15). Indices of oxygenation were not statistically significant predictors of mortality. PaO2/FIO2 ratio in those who died compared to those who survived was 150 vs 193 (p = 0.098). The oxygenation index was 13.8 in those who died, compared to 9.2 in those who survived (p = 0.06).


Figure 2
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  		Figure 2.. Box plot summary of VD/VT in survivors and nonsurvivors. Horizontal lines represent the median, boxes encompass the 25th to 75th percentiles, and error bars encompass the 10th to 90th percentile. VD/VT was significantly higher in patients who died (p = 0.02).

 
Pulmonary Dead Space Fraction: Relationship With Other Physiologic Variables
There was a moderate inverse correlation between PaO2/FIO2 ratio and VD/VT (r = – 0.5, p = 0.001). Similarly, there was a moderate correlation between the VD/VT and the level of positive end-expiratory pressure (r = 0.41, p = 0.008). VD/VT was only weakly associated with systolic PA pressures (r = 0.28, p = 0.08; Fig 3 ), and there was no correlation between VD/VT and cardiac output (r = – 0.16, p = 0.37) or cardiac index (r = – 0.07, p = 0.68).


Figure 3
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  		Figure 3.. Scatter plot of systolic PA pressure and VD/VT in studied patients with ALI. There was only weak correlation between systolic PA pressure and VD/VT (r = 0.28), and this association was not statistically significant (p = 0.08).

 
RV Dilation and Systolic Function and Systolic PA Pressures
RV volume and systolic function was normal in 31 patients (72%), and RV dilation was present in 11 patients (26%). Three patients with moderate ventricular dilation also exhibited RV systolic dysfunction (Table 3 ). There was no overall mortality difference between the patients with RV dilation and without RV dilation (4 of 11 patients [36%] vs 11 of 31 patients [36%], p = 0.96), and there was no difference in ventilator-free days (12.6 days vs 11.2 days, respectively; p = 0.72). Also, there was no difference in VD/VT in patients with RV dilation and without RV dilation (0.58 vs 0.56, p = 0.57). Interestingly, there was no difference in systolic PA pressures in patients with RV dilation and without RV dilation (43 ± 10 mm Hg vs 42 ± 9 mm Hg, p = 0.71).


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  		Table 3.. Hemodynamic and Echocardiographic Variables of the 42 Study Subjects*

 
Discussion

Abnormalities of pulmonary blood flow and progressive and irreversible obstruction of the microvasculature35 resulting in pulmonary hypertension678 are one of the hallmarks of ALI, first described by Zapol and Snider28 in 1977. Several subsequent studies91011 using right-heart catheterization in patients with ARDS have confirmed that PA hypertension is common and can be associated with poor prognosis. However, these early studies examined PA pressure at varying points after the onset of ARDS, thus not differentiating between the early phase, subacute phase, or even the chronic phase of ARDS. For example, Zapol and Snider28 enrolled patients within 2 weeks of the onset of ARDS. In our prospective study, we found that the systolic PA pressure was elevated in patients with early ALI who received a lung-protective ventilation strategy. However, systolic PA pressure was not different in survivors and nonsurvivors.

The first study to show that PA pressure was elevated in the early phase of ARDS was a large multicenter, observational study by Squara et al11 of 586 patients with severe ARDS (PaO2/FIO2 ratio < 150). There were 424 patients with a PA catheter in place at the time of enrollment. Elevated systolic PA pressure at baseline was an independent predictor of mortality (odds ratio, 1.11 to 1.32; p = 0.02). However, even though the median time of enrollment was 24 h after the onset of ARDS, 8% of the patients were enrolled after > 72h, which could have altered the outcome. The most recent study evaluating PA pressures as a predictor of outcome was a study by Suchyta et al,29 who enrolled 215 patients with ARDS, 162 with a PA catheter in place. Significant pulmonary hypertension developed in both survivors and nonsurvivors, but in contrast to previous studies29 there were no statistical differences in the initial mean PA pressure (26 ± 8 mm Hg vs 27 ± 11 mm Hg) or even highest mean PA pressure (37 ± 9 mm Hg vs 39 ± 12 mm Hg).

One of the key differences between our study and much of the previous literature was that we measured PA pressure noninvasively using cardiac echocardiography. It has become clear that right-heart catheterization is usually not beneficial in the management of patients with ALI, most recently in the ARDS Network randomized clinical trial30 of fluid management guided by PA catheter vs central venous catheter. Therefore, right-heart catheterization is used infrequently in this patient population in our ICU; given its invasive nature, its use in an observational study could not have been justified. Cardiac echocardiography, which is noninvasive and readily available, is increasingly used in the critical care setting for diagnostic and monitoring purposes. These two methods allow for slightly different hemodynamic measurements. While PA catheters allow for more accurate measurement of PA pressures, including diastolic and systolic pressures, cardiac echocardiography provides essential information about RV and LV geometry and function, which enabled us to assess the incidence of RV dilation and failure in our study population. However, because it is not possible to consistently estimate the PA diastolic pressure using echocardiography, we assessed systolic rather than the mean PA pressure. Our findings are consistent with the study by Suchyta et al29 because we found that systolic PA pressures do not differ in survivors and nonsurvivors of ALI/ARDS.

In this study, we also tested the relationship of systolic PA pressure and VD/VT. Interestingly, we found only a weak correlation between systolic PA pressure and VD/VT. However, we did find an important correlation of VD/VT with mortality, as well as with ventilator-free days. Even though elevated VD/VT has classically been considered a feature of late ARDS, studies1231 have shown that it is also a prominent feature of early ARDS. Furthermore, the study by Nuckton et al12 demonstrated that an elevated VD/VT was associated with mortality in ARDS patients.

The current study extends these earlier findings in two important ways. First, our study included patients who met the European-American consensus criteria for ALI, and not just patients with ARDS. Second, in contrast to the previous studies, all of our patients received a low-tidal-volume ventilation strategy, which has had a clear impact on patient mortality, and which may have an impact on measured pulmonary dead space. As in the study of Nuckton et al,12 we found a significant correlation of an early elevation in pulmonary dead space with mortality and with ventilator-free days. Since VD/VT is a relatively straightforward, noninvasive measurement, a significantly elevated VD/VT early in the course of ALI/ARDS may have useful prognostic implications, recognizing that dead space on its own is not sufficient to accurately predict prognosis. Also, as we did in this study, pulmonary dead space can be noninvasively, accurately, and rapidly measured in patients receiving mechanical ventilation.16 Clinicians should consider incorporating this measurement along with indexes of oxygenation and airway pressures in their assessment of the physiologic abnormalities in patients with ALI.

Elevated VD/VT in the early phase of ALI probably reflects alterations in the distribution of pulmonary blood flow and may be explained by several mechanisms. Pulmonary vascular injury leading to vasoconstriction and vascular obstruction452832 due to microthrombi and endothelial swelling, as well as maldistribution of pulmonary blood flow (which occurs in hyperdynamic cardiovascular states such as sepsis and end-stage liver disease),3334 are plausible explanations for an elevated VD/VT. High positive end-expiratory pressure could increase VD/VT by regional overdistention of well-ventilated alveoli (and therefore increase in zone I conditions in the lung)35 or by reduction in cardiac output.3637 An increase in VD/VT can also be associated with high levels of intrapulmonary shunting.33 In this study, we found a moderate correlation between PaO2/FIO2 ratio and VD/VT. This relationship has previously been reported by Kallet et al31 (r = 0.57, p < 0.0001).

RV dilation and dysfunction have been previously shown to be present in some patients with ALI and associated with a poor outcome. Jardin et al38 published an echocardiographic study in 1985 that showed that acute cor pulmonale (ACP) was highly prevalent in patients with ARDS (61%) and significantly associated with higher mortality (57% in patients with acute cor pulmonale vs 33% in patients without ACP). However, the same authors reported in another study39 16 years later that in patients with ALI managed with a lung-protective ventilation strategy, the incidence of ACP (25%) was much lower and there was no association with mortality (32% in patients with and without ACP). Our findings are consistent with the results of this second study39 conducted with the lung-protective ventilation strategy: we found that 26% of subjects had RV dilation, but there was no association with mortality. These results contrast with those of Her,40 who found in 20 subjects with ARDS that those with a high VD/VT had a significantly lower RV stroke work index. They did not demonstrate a difference in PA pressure, RA pressure, or cardiac index between those with high and low VD/VT. Her40 concluded that patients with a high VD/VT had more RV dysfunction than those with a low VD/VT.

A potential limitation of our study is its relatively small size. However, our study is comparable in size to other studies that have carefully characterized multiple hemodynamic and respiratory parameters, such as the study of Her40 and the studies of Jardin and colleagues38 and Viellard-Baron et al.39 Furthermore, all of our patients were enrolled within 48 h of meeting criteria for ALI, ensuring a relatively homogeneous patient population.

In conclusion, in the era of lung-protective ventilation strategy, we found that systolic PA pressure early in the course of ALI is elevated but not predictive of outcome. However, elevated VD/VT in early ALI is associated with increased mortality and with fewer ventilator-free days. The measurement of VD/VT can provide additional physiologic information regarding the initial degree of impairment in patients with ALI. Thus, we believe that the VD/VT provides a noninvasive measure that can be used along with indexes of oxygenation and airway pressures to assess the severity of lung injury early in the course of this major cause of morbidity and mortality in critically ill patients.2

Footnotes

Abbreviations: ACP = acute cor pulmonale; ALI = acute lung injury; FIO2 = fraction of inspired oxygen; LV = left ventricle/ventricular; PA = pulmonary artery; RA = right atrium; RV = right ventricle/ventricular; VD/VT = pulmonary dead space fraction

This research was supported in part by National Heart, Lung, and Blood Institute grants HL74005 and HL58156, and also KL2RR024130 from the National Center for Research Studies.

The authors have no conflicts of interest to disclose.

Received for publication February 13, 2007. Accepted for publication May 15, 2007.

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