Arun Jose, MD

Study Overview

Objective. To determine the effect of mepolizumab on the annual rate of chronic obstructive pulmonary disease (COPD) exacerbations in high-risk patients.

Design. Two randomized double-blind placebo-controlled parallel trials (METREO and METREX).

Setting and participants. Participants were recruited from over 15 countries in over 100 investigative sites. Inclusion criteria were adults (40 years or older) with a diagnosis of COPD for at least 1 year with: airflow limitation (FEV1/FVC < 0.7); some bronchodilator reversibility (post-bronchodilator FEV1 > 20% and ≤ 80% of predicted values); current COPD therapy for at least 3 months prior to enrollment (a high-dose inhaled corticosteroid, ICS, with at least 2 other classes of medications, to obtain “triple therapy”); and a high risk of exacerbations (at least 1 severe [requiring hospitalization] or 2 moderate [treatment with systemic corticosteroids and/or antibiotics] exacerbations in past year).

Notable exclusion criteria were patients with diagnoses of asthma in never-smokers, alpha-1 antitrypsin deficiency, recent exacerbations (in past month), lung volume reduction surgery (in past year), eosinophilic or parasitic diseases, or those with recent monoclonal antibody treatment. Patients with the asthma-COPD overlap syndrome were included only if they had a history of smoking and met the COPD inclusion criteria listed above.

Intervention. The treatment period lasted for a total of 52 weeks, with an additional 8 weeks of follow-up. Patients were randomized 1:1 to placebo or low-dose medication (100 mg) using permuted-block randomization in the METREX study regardless of eosinophil count (but they were stratified for a modified intention-to-treat analysis at screening into either low eosinophilic count [< 150 cells/uL] or high [≥ 150 cells/uL]). In the METREO study, patients were randomized 1:1:1 to placebo, low-dose (100 mg), or high-dose (300 mg) medication only if blood eosinophilia was present (≥ 150 cells/uL at screening or ≥ 300 cells/uL in past 12 months). Investigators and patients were blinded to presence of drug or placebo. Sample size calculations indicated that in order to provide a 90% power to detect a 30% decrease in the rate of exacerbations in METREX and 35% decrease in METREO, a total of 800 patients and 660 patients would need to be enrolled in METREX and METREO respectively. Both studies met their enrollment quota.

Main outcome measures. The primary outcome was the annual rate of exacerbations that were either moderate (requiring systemic corticosteroids and/or antibiotics) or severe (requiring hospitalization). Secondary outcomes included the time to first moderate/severe exacerbation, change from baseline in the COPD Assessment Test (CAT) and St. George’s Respiratory Questionnaire (SGRQ), and change from baseline in blood eosinophil count, FEV1, and FVC. Safety and adverse events endpoints were also assessed.

A modified intention-to-treat analysis was performed overall and in the METREX study stratified on eosinophilic count at screening; all patients who underwent randomization and received at least one dose of medication or placebo were included in that respective group. Multiple comparisons were accounted for using the Benjamini-Hochberg Test, exacerbations were assumed to follow a negative binomial distribution, and Cox proportional-hazards was used to model the relationship between covariates of interest and the primary outcome.

Main results. In the METREX study, 1161 patients were enrolled and 836 underwent randomization and received at least 1 dose of medication or placebo. In METREO, 1071 patients were enrolled and 674 underwent randomization and received at least one dose of medication or placebo. In both studies the patients in the medication and placebo groups were well balanced at baseline across demographics (age, gender, smoking history, duration of COPD) and pulmonary function (FEV1, FVC, FEV1/FVC, CAT, SGRQ). In METREX, a total of 462 (55%) patients had an eosinophilic phenotype and 374 (45%) did not.

There was no difference between groups in the primary endpoint of annual exacerbation rate in METREO (1.49/yr in placebo vs. 1.19/yr in low-dose and 1.27/yr in high-dose mepolizumab, rate ratio of high-dose to placebo 0.86, 95% confidence interval [CI] 0.7–1.05, P = 0.14). There was no difference in the primary outcome in the overall intention-to-treat analysis in the METREX study (1.49/yr in mepolizumab vs. 1.52/yr in placebo, P > 0.99). Only when analyzing the high eosinophilic phenotype in the stratified intention-to-treat METREX group was there a significant difference in the primary outcome (1.41/yr in mepolizumab vs. 1.71/yr in placebo, P = 0.04, rate ratio 0.82, 95% CI 0.68–0.98).

There were no significant differences in any secondary endpoint in the METREO study. In the METREX study, mepolizumab treatment resulted in a significantly longer time to first exacerbation (192 days vs. 141 days, hazard ratio 0.75, 95% CI 0.60–0.94, P = 0.04) but no difference in the change in SGRQ (–2.8 vs. –3.0, P > 0.99) or CAT score (–0.8 vs. 0, P > 0.99). There was no significant difference in any measures of pulmonary function between the treatment and placebo groups (FEV1, FVC, FEV1/FVC). As expected, there was a significant decrease in peripheral blood eosinophil count in both studies in the medication arm. The incidence of adverse events and safety endpoints were similar between the trial groups in METREX and METREO.

Conclusions. In this pair of placebo-controlled double-blind randomized parallel studies, there was a significant decline in annual exacerbation rate in patients with an eosinophilic phenotype treated with mepolizumab in a stratified intention-to-treat analysis of one of two parallel studies (METREX). However, there was no significant difference in the primary outcome of the other parallel study (METREO), which included only those patients with an eosinophilic phenotype. Additionally, there was no significant difference in any secondary endpoints in either study. The medication was generally safe and well tolerated.

Commentary

Mepolizumab is a humanized monoclonal antibody that targets and blocks interleukin-5, a key mediator of eosinophilic activity. Due to its ability to decrease eosinophil number and function, it is currently approved as a therapy for severe asthma with an eosinophilic phenotype [1]. While asthma and COPD have historically been thought of as separate entities with distinct pathophysiologic mechanisms, recent evidence has suggested that a subset of COPD patients experience significant eosinophilic inflammation. This group may behave more like asthmatic patients, and may have a different response to medications such as inhaled corticosteroids, but the role of eosinophils to guide prognostication and treatment in this group is still unclear [2,3].

In this study, Pavord and colleagues investigated the use of the anti-IL5 drug mepolizumab in COPD patients at risk of exacerbations who demonstrated an eosinophilic phenotype. The physiologic rationale for the study was that eosinophilic inflammation is thought to be a driver of exacerbations in COPD patients with an eosinophilic phenotype, and therefore a decrease in eosinophilic number and function should result in a decrease in exacerbations. The authors conducted a well-designed placebo-controlled double-blind study with a clearly defined endpoint, met their enrollment goals as determined by their power calculations, and used COPD patients at high risk of exacerbations to enrich their study.

There was no difference in the primary outcome in the METREO arm of the study, which included patients with baseline eosinophilia (> 150 cells/uL) or in the overall intention-to-treat analysis in METREX (which did not screen patients on baseline eosinophil count). Only when stratified on baseline eosinophil count in the METREX study was a significant treatment effect found, where patients with high eosinophil count at baseline (> 150 cells/uL) had a decreased risk of exacerbations when treated with mepolizumab. Notably there was no difference in any secondary outcome in METREO or in METREX aside from a longer time to first exacerbation in METREX in the mepolizumab group. The authors use this data to conclude that mepolizumab treatment results in a lower rate of exacerbations and a longer time to the first exacerbation in COPD patients with an eosinophilic phenotype, and the extent of the treatment effect is related to blood eosinophil counts.

The authors conducted a well-designed and rigorous study, and used robust and appropriate statistical analysis; however, significant questions remain regarding their conclusions. The primary concern is the role of mepolizumab in the treatment of COPD patients to decrease exacerbations may be overstated. When including only those with baseline eosinophilia in the METREO arm, there was no significant difference between placebo and low or high dose of mepolizumab; however, there was an appropriate and expected decrease in blood eosinophils, indicating the medication worked as intended. In the overall intention-to-treat analysis in the METREX arm, there was no difference between mepolizumab and placebo, and only in the analysis of METREX stratified to eosinophil count was there a significant difference (with an upper confidence interval rate ratio [0.98] approaching unity).

Additionally there was no significant difference between the 2 groups across a number of clinically important secondary endpoints, including pulmonary function measurements and symptomatic scores. Only the time to exacerbation was significantly longer in the mepolizumab group in METREX.

Taken together, this calls into question the conclusion that a decrease in eosinophil counts due to mepolizumab has resulted in a lower rate of exacerbations, particularly as a higher dose of mepolizumab did not result in a stronger effect. The lack of difference between groups in secondary endpoints is also concerning, as those would be expected to improve with a decrease in exacerbations [4,5]. As the authors point out, their evidence suggests that eosinophils may be an important biomarker in COPD and may aid in the therapeutic decision-making process. However, given the inconsistencies in the data as noted above, it would be difficult to rely on the evidence from this study alone to support their conclusion regarding the clinical utility of mepolizumab in COPD.

The authors discuss a number of limitations that may account for the lack of consistent effect seen in this study. Aside from the standard limitations applicable to any clinical trial, they note the potential confounding effect of previous oral glucocorticoid therapy in reducing eosinophil counts. This may have masked the eosinophilic phenotype in some study patients, leading to the attenuated effect of mepolizumab seen in this study.

The authors also note that information that might be potentially valuable for identifying treatment responders, such as a history of allergies and atopy, were not available. Inclusion of those patients may be helpful in enriching the trial with potential treatment-responders, and future studies may benefit from focusing on COPD patients with a more atopic phenotype who more closely resemble those with the asthma-COPD overlap syndrome.

A final limitation to discuss is the focus on blood eosinophilic counts. Due to the difficulty of measuring sputum eosinophils, and the reasonable degree of correlation between blood and sputum in asthmatic patients, blood eosinophils have largely supplanted sputum eosinophils as markers of TH2 CD4 T-cell activity in the pulmonary system [6]. This substitution is also used in the COPD population, however, due to the differences in pathophysiology it is unclear if eosinophils in asthmatic patients behave similarly to those in COPD patients [7]. Additionally, the cutoff of 150 cells/uL has been obtained primarily from sub-group analysis of previous studies on COPD patients, but it is unclear if this cutoff truly reflects elevated sputum eosinophilia. While there is likely some degree of correlation between blood and sputum eosinophilia in COPD patients, a lack of significant effect seen in this study may be due to an incorrect cutoff for elevated eosinophilia and a reliance on blood eosinophils over sputum counts. Further studies utilizing sputum eosinophils may be of value in addressing this limitation.

Applications for Clinical Practice

In this study, Pavord and colleagues found a potential benefit of mepolizumab treatment for reducing exacerbations in COPD patients with an eosinophilic phenotype. The conflicting results regarding the underlying physiology and the weak treatment effect suggest this medication may not be ready for use in clinical practice without additional supporting evidence. From a practical standpoint, the high cost of medication (~$2500 per month) and marginal benefit of treatment imply that treatment with mepolizumab in COPD patients may not be cost-effective, and even treatment in individual patients on a trial basis should be discouraged until additional supporting data becomes available. Of primary concern are the optimal selection of COPD patients that will achieve benefit with mepolizumab treatment, and the optimal dose of medication to achieve that benefit. The results presented here do not satisfactorily answer these questions, and additional studies are required.

—Arun Jose, MD, The George Washington University, Washington, DC

Study Overview

Objective. To determine the effect of mepolizumab on the annual rate of chronic obstructive pulmonary disease (COPD) exacerbations in high-risk patients.

Design. Two randomized double-blind placebo-controlled parallel trials (METREO and METREX).

Setting and participants. Participants were recruited from over 15 countries in over 100 investigative sites. Inclusion criteria were adults (40 years or older) with a diagnosis of COPD for at least 1 year with: airflow limitation (FEV1/FVC < 0.7); some bronchodilator reversibility (post-bronchodilator FEV1 > 20% and ≤ 80% of predicted values); current COPD therapy for at least 3 months prior to enrollment (a high-dose inhaled corticosteroid, ICS, with at least 2 other classes of medications, to obtain “triple therapy”); and a high risk of exacerbations (at least 1 severe [requiring hospitalization] or 2 moderate [treatment with systemic corticosteroids and/or antibiotics] exacerbations in past year).

Notable exclusion criteria were patients with diagnoses of asthma in never-smokers, alpha-1 antitrypsin deficiency, recent exacerbations (in past month), lung volume reduction surgery (in past year), eosinophilic or parasitic diseases, or those with recent monoclonal antibody treatment. Patients with the asthma-COPD overlap syndrome were included only if they had a history of smoking and met the COPD inclusion criteria listed above.

Intervention. The treatment period lasted for a total of 52 weeks, with an additional 8 weeks of follow-up. Patients were randomized 1:1 to placebo or low-dose medication (100 mg) using permuted-block randomization in the METREX study regardless of eosinophil count (but they were stratified for a modified intention-to-treat analysis at screening into either low eosinophilic count [< 150 cells/uL] or high [≥ 150 cells/uL]). In the METREO study, patients were randomized 1:1:1 to placebo, low-dose (100 mg), or high-dose (300 mg) medication only if blood eosinophilia was present (≥ 150 cells/uL at screening or ≥ 300 cells/uL in past 12 months). Investigators and patients were blinded to presence of drug or placebo. Sample size calculations indicated that in order to provide a 90% power to detect a 30% decrease in the rate of exacerbations in METREX and 35% decrease in METREO, a total of 800 patients and 660 patients would need to be enrolled in METREX and METREO respectively. Both studies met their enrollment quota.

Main outcome measures. The primary outcome was the annual rate of exacerbations that were either moderate (requiring systemic corticosteroids and/or antibiotics) or severe (requiring hospitalization). Secondary outcomes included the time to first moderate/severe exacerbation, change from baseline in the COPD Assessment Test (CAT) and St. George’s Respiratory Questionnaire (SGRQ), and change from baseline in blood eosinophil count, FEV1, and FVC. Safety and adverse events endpoints were also assessed.

A modified intention-to-treat analysis was performed overall and in the METREX study stratified on eosinophilic count at screening; all patients who underwent randomization and received at least one dose of medication or placebo were included in that respective group. Multiple comparisons were accounted for using the Benjamini-Hochberg Test, exacerbations were assumed to follow a negative binomial distribution, and Cox proportional-hazards was used to model the relationship between covariates of interest and the primary outcome.

Main results. In the METREX study, 1161 patients were enrolled and 836 underwent randomization and received at least 1 dose of medication or placebo. In METREO, 1071 patients were enrolled and 674 underwent randomization and received at least one dose of medication or placebo. In both studies the patients in the medication and placebo groups were well balanced at baseline across demographics (age, gender, smoking history, duration of COPD) and pulmonary function (FEV1, FVC, FEV1/FVC, CAT, SGRQ). In METREX, a total of 462 (55%) patients had an eosinophilic phenotype and 374 (45%) did not.

There was no difference between groups in the primary endpoint of annual exacerbation rate in METREO (1.49/yr in placebo vs. 1.19/yr in low-dose and 1.27/yr in high-dose mepolizumab, rate ratio of high-dose to placebo 0.86, 95% confidence interval [CI] 0.7–1.05, P = 0.14). There was no difference in the primary outcome in the overall intention-to-treat analysis in the METREX study (1.49/yr in mepolizumab vs. 1.52/yr in placebo, P > 0.99). Only when analyzing the high eosinophilic phenotype in the stratified intention-to-treat METREX group was there a significant difference in the primary outcome (1.41/yr in mepolizumab vs. 1.71/yr in placebo, P = 0.04, rate ratio 0.82, 95% CI 0.68–0.98).

There were no significant differences in any secondary endpoint in the METREO study. In the METREX study, mepolizumab treatment resulted in a significantly longer time to first exacerbation (192 days vs. 141 days, hazard ratio 0.75, 95% CI 0.60–0.94, P = 0.04) but no difference in the change in SGRQ (–2.8 vs. –3.0, P > 0.99) or CAT score (–0.8 vs. 0, P > 0.99). There was no significant difference in any measures of pulmonary function between the treatment and placebo groups (FEV1, FVC, FEV1/FVC). As expected, there was a significant decrease in peripheral blood eosinophil count in both studies in the medication arm. The incidence of adverse events and safety endpoints were similar between the trial groups in METREX and METREO.

Conclusions. In this pair of placebo-controlled double-blind randomized parallel studies, there was a significant decline in annual exacerbation rate in patients with an eosinophilic phenotype treated with mepolizumab in a stratified intention-to-treat analysis of one of two parallel studies (METREX). However, there was no significant difference in the primary outcome of the other parallel study (METREO), which included only those patients with an eosinophilic phenotype. Additionally, there was no significant difference in any secondary endpoints in either study. The medication was generally safe and well tolerated.

Commentary

Mepolizumab is a humanized monoclonal antibody that targets and blocks interleukin-5, a key mediator of eosinophilic activity. Due to its ability to decrease eosinophil number and function, it is currently approved as a therapy for severe asthma with an eosinophilic phenotype [1]. While asthma and COPD have historically been thought of as separate entities with distinct pathophysiologic mechanisms, recent evidence has suggested that a subset of COPD patients experience significant eosinophilic inflammation. This group may behave more like asthmatic patients, and may have a different response to medications such as inhaled corticosteroids, but the role of eosinophils to guide prognostication and treatment in this group is still unclear [2,3].

In this study, Pavord and colleagues investigated the use of the anti-IL5 drug mepolizumab in COPD patients at risk of exacerbations who demonstrated an eosinophilic phenotype. The physiologic rationale for the study was that eosinophilic inflammation is thought to be a driver of exacerbations in COPD patients with an eosinophilic phenotype, and therefore a decrease in eosinophilic number and function should result in a decrease in exacerbations. The authors conducted a well-designed placebo-controlled double-blind study with a clearly defined endpoint, met their enrollment goals as determined by their power calculations, and used COPD patients at high risk of exacerbations to enrich their study.

There was no difference in the primary outcome in the METREO arm of the study, which included patients with baseline eosinophilia (> 150 cells/uL) or in the overall intention-to-treat analysis in METREX (which did not screen patients on baseline eosinophil count). Only when stratified on baseline eosinophil count in the METREX study was a significant treatment effect found, where patients with high eosinophil count at baseline (> 150 cells/uL) had a decreased risk of exacerbations when treated with mepolizumab. Notably there was no difference in any secondary outcome in METREO or in METREX aside from a longer time to first exacerbation in METREX in the mepolizumab group. The authors use this data to conclude that mepolizumab treatment results in a lower rate of exacerbations and a longer time to the first exacerbation in COPD patients with an eosinophilic phenotype, and the extent of the treatment effect is related to blood eosinophil counts.

The authors conducted a well-designed and rigorous study, and used robust and appropriate statistical analysis; however, significant questions remain regarding their conclusions. The primary concern is the role of mepolizumab in the treatment of COPD patients to decrease exacerbations may be overstated. When including only those with baseline eosinophilia in the METREO arm, there was no significant difference between placebo and low or high dose of mepolizumab; however, there was an appropriate and expected decrease in blood eosinophils, indicating the medication worked as intended. In the overall intention-to-treat analysis in the METREX arm, there was no difference between mepolizumab and placebo, and only in the analysis of METREX stratified to eosinophil count was there a significant difference (with an upper confidence interval rate ratio [0.98] approaching unity).

Additionally there was no significant difference between the 2 groups across a number of clinically important secondary endpoints, including pulmonary function measurements and symptomatic scores. Only the time to exacerbation was significantly longer in the mepolizumab group in METREX.

Taken together, this calls into question the conclusion that a decrease in eosinophil counts due to mepolizumab has resulted in a lower rate of exacerbations, particularly as a higher dose of mepolizumab did not result in a stronger effect. The lack of difference between groups in secondary endpoints is also concerning, as those would be expected to improve with a decrease in exacerbations [4,5]. As the authors point out, their evidence suggests that eosinophils may be an important biomarker in COPD and may aid in the therapeutic decision-making process. However, given the inconsistencies in the data as noted above, it would be difficult to rely on the evidence from this study alone to support their conclusion regarding the clinical utility of mepolizumab in COPD.

The authors discuss a number of limitations that may account for the lack of consistent effect seen in this study. Aside from the standard limitations applicable to any clinical trial, they note the potential confounding effect of previous oral glucocorticoid therapy in reducing eosinophil counts. This may have masked the eosinophilic phenotype in some study patients, leading to the attenuated effect of mepolizumab seen in this study.

The authors also note that information that might be potentially valuable for identifying treatment responders, such as a history of allergies and atopy, were not available. Inclusion of those patients may be helpful in enriching the trial with potential treatment-responders, and future studies may benefit from focusing on COPD patients with a more atopic phenotype who more closely resemble those with the asthma-COPD overlap syndrome.

A final limitation to discuss is the focus on blood eosinophilic counts. Due to the difficulty of measuring sputum eosinophils, and the reasonable degree of correlation between blood and sputum in asthmatic patients, blood eosinophils have largely supplanted sputum eosinophils as markers of TH2 CD4 T-cell activity in the pulmonary system [6]. This substitution is also used in the COPD population, however, due to the differences in pathophysiology it is unclear if eosinophils in asthmatic patients behave similarly to those in COPD patients [7]. Additionally, the cutoff of 150 cells/uL has been obtained primarily from sub-group analysis of previous studies on COPD patients, but it is unclear if this cutoff truly reflects elevated sputum eosinophilia. While there is likely some degree of correlation between blood and sputum eosinophilia in COPD patients, a lack of significant effect seen in this study may be due to an incorrect cutoff for elevated eosinophilia and a reliance on blood eosinophils over sputum counts. Further studies utilizing sputum eosinophils may be of value in addressing this limitation.

Applications for Clinical Practice

In this study, Pavord and colleagues found a potential benefit of mepolizumab treatment for reducing exacerbations in COPD patients with an eosinophilic phenotype. The conflicting results regarding the underlying physiology and the weak treatment effect suggest this medication may not be ready for use in clinical practice without additional supporting evidence. From a practical standpoint, the high cost of medication (~$2500 per month) and marginal benefit of treatment imply that treatment with mepolizumab in COPD patients may not be cost-effective, and even treatment in individual patients on a trial basis should be discouraged until additional supporting data becomes available. Of primary concern are the optimal selection of COPD patients that will achieve benefit with mepolizumab treatment, and the optimal dose of medication to achieve that benefit. The results presented here do not satisfactorily answer these questions, and additional studies are required.

—Arun Jose, MD, The George Washington University, Washington, DC

Study Overview

Objective. To determine the effect of mepolizumab on the annual rate of chronic obstructive pulmonary disease (COPD) exacerbations in high-risk patients.

Design. Two randomized double-blind placebo-controlled parallel trials (METREO and METREX).

Setting and participants. Participants were recruited from over 15 countries in over 100 investigative sites. Inclusion criteria were adults (40 years or older) with a diagnosis of COPD for at least 1 year with: airflow limitation (FEV1/FVC < 0.7); some bronchodilator reversibility (post-bronchodilator FEV1 > 20% and ≤ 80% of predicted values); current COPD therapy for at least 3 months prior to enrollment (a high-dose inhaled corticosteroid, ICS, with at least 2 other classes of medications, to obtain “triple therapy”); and a high risk of exacerbations (at least 1 severe [requiring hospitalization] or 2 moderate [treatment with systemic corticosteroids and/or antibiotics] exacerbations in past year).

Notable exclusion criteria were patients with diagnoses of asthma in never-smokers, alpha-1 antitrypsin deficiency, recent exacerbations (in past month), lung volume reduction surgery (in past year), eosinophilic or parasitic diseases, or those with recent monoclonal antibody treatment. Patients with the asthma-COPD overlap syndrome were included only if they had a history of smoking and met the COPD inclusion criteria listed above.

Intervention. The treatment period lasted for a total of 52 weeks, with an additional 8 weeks of follow-up. Patients were randomized 1:1 to placebo or low-dose medication (100 mg) using permuted-block randomization in the METREX study regardless of eosinophil count (but they were stratified for a modified intention-to-treat analysis at screening into either low eosinophilic count [< 150 cells/uL] or high [≥ 150 cells/uL]). In the METREO study, patients were randomized 1:1:1 to placebo, low-dose (100 mg), or high-dose (300 mg) medication only if blood eosinophilia was present (≥ 150 cells/uL at screening or ≥ 300 cells/uL in past 12 months). Investigators and patients were blinded to presence of drug or placebo. Sample size calculations indicated that in order to provide a 90% power to detect a 30% decrease in the rate of exacerbations in METREX and 35% decrease in METREO, a total of 800 patients and 660 patients would need to be enrolled in METREX and METREO respectively. Both studies met their enrollment quota.

Main outcome measures. The primary outcome was the annual rate of exacerbations that were either moderate (requiring systemic corticosteroids and/or antibiotics) or severe (requiring hospitalization). Secondary outcomes included the time to first moderate/severe exacerbation, change from baseline in the COPD Assessment Test (CAT) and St. George’s Respiratory Questionnaire (SGRQ), and change from baseline in blood eosinophil count, FEV1, and FVC. Safety and adverse events endpoints were also assessed.

A modified intention-to-treat analysis was performed overall and in the METREX study stratified on eosinophilic count at screening; all patients who underwent randomization and received at least one dose of medication or placebo were included in that respective group. Multiple comparisons were accounted for using the Benjamini-Hochberg Test, exacerbations were assumed to follow a negative binomial distribution, and Cox proportional-hazards was used to model the relationship between covariates of interest and the primary outcome.

Main results. In the METREX study, 1161 patients were enrolled and 836 underwent randomization and received at least 1 dose of medication or placebo. In METREO, 1071 patients were enrolled and 674 underwent randomization and received at least one dose of medication or placebo. In both studies the patients in the medication and placebo groups were well balanced at baseline across demographics (age, gender, smoking history, duration of COPD) and pulmonary function (FEV1, FVC, FEV1/FVC, CAT, SGRQ). In METREX, a total of 462 (55%) patients had an eosinophilic phenotype and 374 (45%) did not.

There was no difference between groups in the primary endpoint of annual exacerbation rate in METREO (1.49/yr in placebo vs. 1.19/yr in low-dose and 1.27/yr in high-dose mepolizumab, rate ratio of high-dose to placebo 0.86, 95% confidence interval [CI] 0.7–1.05, P = 0.14). There was no difference in the primary outcome in the overall intention-to-treat analysis in the METREX study (1.49/yr in mepolizumab vs. 1.52/yr in placebo, P > 0.99). Only when analyzing the high eosinophilic phenotype in the stratified intention-to-treat METREX group was there a significant difference in the primary outcome (1.41/yr in mepolizumab vs. 1.71/yr in placebo, P = 0.04, rate ratio 0.82, 95% CI 0.68–0.98).

There were no significant differences in any secondary endpoint in the METREO study. In the METREX study, mepolizumab treatment resulted in a significantly longer time to first exacerbation (192 days vs. 141 days, hazard ratio 0.75, 95% CI 0.60–0.94, P = 0.04) but no difference in the change in SGRQ (–2.8 vs. –3.0, P > 0.99) or CAT score (–0.8 vs. 0, P > 0.99). There was no significant difference in any measures of pulmonary function between the treatment and placebo groups (FEV1, FVC, FEV1/FVC). As expected, there was a significant decrease in peripheral blood eosinophil count in both studies in the medication arm. The incidence of adverse events and safety endpoints were similar between the trial groups in METREX and METREO.

Conclusions. In this pair of placebo-controlled double-blind randomized parallel studies, there was a significant decline in annual exacerbation rate in patients with an eosinophilic phenotype treated with mepolizumab in a stratified intention-to-treat analysis of one of two parallel studies (METREX). However, there was no significant difference in the primary outcome of the other parallel study (METREO), which included only those patients with an eosinophilic phenotype. Additionally, there was no significant difference in any secondary endpoints in either study. The medication was generally safe and well tolerated.

Commentary

Mepolizumab is a humanized monoclonal antibody that targets and blocks interleukin-5, a key mediator of eosinophilic activity. Due to its ability to decrease eosinophil number and function, it is currently approved as a therapy for severe asthma with an eosinophilic phenotype [1]. While asthma and COPD have historically been thought of as separate entities with distinct pathophysiologic mechanisms, recent evidence has suggested that a subset of COPD patients experience significant eosinophilic inflammation. This group may behave more like asthmatic patients, and may have a different response to medications such as inhaled corticosteroids, but the role of eosinophils to guide prognostication and treatment in this group is still unclear [2,3].

In this study, Pavord and colleagues investigated the use of the anti-IL5 drug mepolizumab in COPD patients at risk of exacerbations who demonstrated an eosinophilic phenotype. The physiologic rationale for the study was that eosinophilic inflammation is thought to be a driver of exacerbations in COPD patients with an eosinophilic phenotype, and therefore a decrease in eosinophilic number and function should result in a decrease in exacerbations. The authors conducted a well-designed placebo-controlled double-blind study with a clearly defined endpoint, met their enrollment goals as determined by their power calculations, and used COPD patients at high risk of exacerbations to enrich their study.

There was no difference in the primary outcome in the METREO arm of the study, which included patients with baseline eosinophilia (> 150 cells/uL) or in the overall intention-to-treat analysis in METREX (which did not screen patients on baseline eosinophil count). Only when stratified on baseline eosinophil count in the METREX study was a significant treatment effect found, where patients with high eosinophil count at baseline (> 150 cells/uL) had a decreased risk of exacerbations when treated with mepolizumab. Notably there was no difference in any secondary outcome in METREO or in METREX aside from a longer time to first exacerbation in METREX in the mepolizumab group. The authors use this data to conclude that mepolizumab treatment results in a lower rate of exacerbations and a longer time to the first exacerbation in COPD patients with an eosinophilic phenotype, and the extent of the treatment effect is related to blood eosinophil counts.

The authors conducted a well-designed and rigorous study, and used robust and appropriate statistical analysis; however, significant questions remain regarding their conclusions. The primary concern is the role of mepolizumab in the treatment of COPD patients to decrease exacerbations may be overstated. When including only those with baseline eosinophilia in the METREO arm, there was no significant difference between placebo and low or high dose of mepolizumab; however, there was an appropriate and expected decrease in blood eosinophils, indicating the medication worked as intended. In the overall intention-to-treat analysis in the METREX arm, there was no difference between mepolizumab and placebo, and only in the analysis of METREX stratified to eosinophil count was there a significant difference (with an upper confidence interval rate ratio [0.98] approaching unity).

Additionally there was no significant difference between the 2 groups across a number of clinically important secondary endpoints, including pulmonary function measurements and symptomatic scores. Only the time to exacerbation was significantly longer in the mepolizumab group in METREX.

Taken together, this calls into question the conclusion that a decrease in eosinophil counts due to mepolizumab has resulted in a lower rate of exacerbations, particularly as a higher dose of mepolizumab did not result in a stronger effect. The lack of difference between groups in secondary endpoints is also concerning, as those would be expected to improve with a decrease in exacerbations [4,5]. As the authors point out, their evidence suggests that eosinophils may be an important biomarker in COPD and may aid in the therapeutic decision-making process. However, given the inconsistencies in the data as noted above, it would be difficult to rely on the evidence from this study alone to support their conclusion regarding the clinical utility of mepolizumab in COPD.

The authors discuss a number of limitations that may account for the lack of consistent effect seen in this study. Aside from the standard limitations applicable to any clinical trial, they note the potential confounding effect of previous oral glucocorticoid therapy in reducing eosinophil counts. This may have masked the eosinophilic phenotype in some study patients, leading to the attenuated effect of mepolizumab seen in this study.

The authors also note that information that might be potentially valuable for identifying treatment responders, such as a history of allergies and atopy, were not available. Inclusion of those patients may be helpful in enriching the trial with potential treatment-responders, and future studies may benefit from focusing on COPD patients with a more atopic phenotype who more closely resemble those with the asthma-COPD overlap syndrome.

A final limitation to discuss is the focus on blood eosinophilic counts. Due to the difficulty of measuring sputum eosinophils, and the reasonable degree of correlation between blood and sputum in asthmatic patients, blood eosinophils have largely supplanted sputum eosinophils as markers of TH2 CD4 T-cell activity in the pulmonary system [6]. This substitution is also used in the COPD population, however, due to the differences in pathophysiology it is unclear if eosinophils in asthmatic patients behave similarly to those in COPD patients [7]. Additionally, the cutoff of 150 cells/uL has been obtained primarily from sub-group analysis of previous studies on COPD patients, but it is unclear if this cutoff truly reflects elevated sputum eosinophilia. While there is likely some degree of correlation between blood and sputum eosinophilia in COPD patients, a lack of significant effect seen in this study may be due to an incorrect cutoff for elevated eosinophilia and a reliance on blood eosinophils over sputum counts. Further studies utilizing sputum eosinophils may be of value in addressing this limitation.

Applications for Clinical Practice

In this study, Pavord and colleagues found a potential benefit of mepolizumab treatment for reducing exacerbations in COPD patients with an eosinophilic phenotype. The conflicting results regarding the underlying physiology and the weak treatment effect suggest this medication may not be ready for use in clinical practice without additional supporting evidence. From a practical standpoint, the high cost of medication (~$2500 per month) and marginal benefit of treatment imply that treatment with mepolizumab in COPD patients may not be cost-effective, and even treatment in individual patients on a trial basis should be discouraged until additional supporting data becomes available. Of primary concern are the optimal selection of COPD patients that will achieve benefit with mepolizumab treatment, and the optimal dose of medication to achieve that benefit. The results presented here do not satisfactorily answer these questions, and additional studies are required.

—Arun Jose, MD, The George Washington University, Washington, DC

Study Overview

Objective. To determine if there is an association between low tidal volume (VT) ventilation and neurocognitive outcomes in patients after out-of-hospital cardiac arrest (OHCA).

Design. Retrospective cohort study.

Setting and participants. Data was obtained from retrospective review of all adults admitted between 2008 and 2014 to one of 2 centers (A or B) with nontraumatic OHCA requiring mechanical ventilation for greater than 48 hours. The study physicians screened records primarily using chart review with secondary confirmation of the diagnosis of OHCA and eligibility criteria. Patients with an outside hospital stay greater than 24 hours, intracranial hemorrhage, use of extracorporeal membranous oxygenation (ECMO), use of airway pressure release mode of ventilation, chronic dependence on mechanical ventilation, or missing data were excluded. Of the 579 patients with OHCA, 256 (44.2%) met the inclusion criteria and were included in the main analysis. A total of 97 patients were identified as having high VT (defined as > 8 mL/kg of predicted body weight [PBW]) and were matched to 97 of the 159 patients identified as having a low VT as part of the propensity-matched subgroup analysis using 1:1 optimal caliper matching.

Main outcome measure. The primary outcome was a favorable neurocognitive outcome at hospital discharge (Cerebral Performance Category score [CPC] of 1 or 2). A CPC of 1 or 2 corresponds to normal life or life that is disabled but independent, respectively. A CPC of 3 is disabled and dependent, and a CPC of 5 is alive but brain dead. Two physicians blinded to VT and other measures of illness severity calculated the CPC via chart review. Discordant scores were resolved by consensus, and a Kappa statistic was calculated to quantify agreement between investigators. Secondary outcomes included ventilator-free days, hospital-free days, ICU-free days, shock-free days, and extrapulmonary organ failure–free days. Logistic regression with backward elimination was used to identify predictors of receiving VT ≤ 8 mL/kg PBW to be used in the propensity-matched analysis, along with relevant predictors identified from the literature. The odds ratio for the primary outcome was calculated using both logistic regression analysis and propensity-matched analysis. Other methods of sensitivity analysis (propensity quintile adjustment, inverse-probability-of-treatment weighting) were used to confirm the robustness of the initial analysis to different statistical methods. A P value of < 0.05 was considered significant.

Main results. Of the study patients, approximately half (49% in high VT, 52% in low VT) had an initial rhythm of ventricular tachycardia or ventricular fibrillation. Patients with low VT were significantly younger (mean age 59 yr vs. 66 yr), taller (mean height 177 cm vs. 165 cm), and heavier (mean weight 88 kg vs. 81 kg). There were also significantly fewer females in the low VT group (19% vs. 46%). There were no significant differences between baseline comorbidities, arrest characteristics, or illness severity between the 2 groups with the exception of significantly more patients in the low VT underwent therapeutic hypothermia (87% vs. 76%) and were admitted to hospital A (69% vs. 55%). There were no significant differences between the groups across ventilator parameters aside from tidal volume. The average VT in mL/kg PBW was 9.3 in the high VT group and 7.1 in the low VT group over the first 48 hours.

In the multivariate regression analysis, significant independent predictors of receiving high VT included height, weight, and hospital of admission. The final propensity model to predict VT included age, height, weight, sex, illness severity measures (APACHE-II score and presence of circulatory shock in the first 24 hours of admission), arrest characteristics, and respiratory characteristics (initial pH, initial PaCO2, PaO2:FiO2 ratio, and initial peak inspiratory pressure) as covariates. The use of low VT was significantly associated with a favorable neurocognitive outcome in the multivariate regression analysis (odds ratio [OR] 1.65, 95% confidence interval [CI] 1.18–2.29). This association held in both the propensity matched analysis (OR 1.68, 95% CI 1.11–2.55) as well as conditional logistic regression analysis using propensity score as a covariate (OR 1.61, 95% CI 1.13–2.28).

In the propensity-adjusted conditional logistic regression analysis, a lower VT (1 mL/kg of PBW decrease) was significantly associated with ventilator-free days (OR 1.78, 95% CI 0.39–3.16), shock-free days (OR 1.31, 95% CI 0.10–2.51), ICU-free days (OR 1.38, 95% CI 0.13–2.63), and hospital-free days (OR 1.07, 95% CI 0.04–2.09). There was a nonsignificant trend towards improved survival to hospital discharge (OR 1.23, 95% CI 0.95–1.60, P = 0.115). After propensity score adjustment, lower VT was not associated with therapeutic hypothermia (OR 0.14, 95% CI −0.19 to 0.47), and in the multivariate regression analysis there was no association between favorable neurocognitive outcome and therapeutic hypothermia (P = 0.516). While there was a significant association between lower VT and site of admission (Hospital A: OR 1.50, 95% CI 1.04–2.17 per 1 mL/kg of PBW decrease), there was no association between favorable neurocognitive outcome and hospital site of admission in the final adjusted regression analysis (P = 0.588).

Conclusion. In this retrospective cohort study, lower VT in the first 48 hours of admission following OHCA was independently associated with favorable neurocognitive outcomes as measured by the CPC score, as well as more ventilator-free, shock-free, ICU-free, and hospital-free days.

Commentary

Neurocognitive impairment following nontraumatic OHCA is common, estimated to occur in roughly half of all survivors [1]. Similar to the acute respiratory distress syndrome (ARDS), the post–cardiac arrest syndrome (PCAS) is recognized as a systemic process with multi-organ effects thought to be mediated in part by inflammatory cytokines [2]. While the beneficial role of low VT in patients with ARDS is well established, currently there are no recommendations for specific VT targets in post–cardiac arrest care, and the effect of VT on outcomes following cardiac arrest is unknown [3].

In this study, Beitler and colleagues suggest a possible association between VT and neurocognitive outcomes following OHCA. Using retrospective data drawn from 2 centers, and employing both regression analysis and propensity matching, the authors identified a significant beneficial effect of lower VT on neurocognitive outcomes in their cohort. This benefit held regardless of the statistical analytic method employed and was present even when correcting for the difference between groups in hospital admission site and use of therapeutic hypothermia in the original cohort. The authors also demonstrated a lower VT was associated with a number of secondary outcomes including fewer hospital, ICU, and ventilator days. While the statistical methods employed by the authors are robust and attempt to account for the limitations inherent to observational studies, a number of questions remain.

First, as the authors appropriately note, causality cannot be proven from a retrospective study. While the analytic methods employed by the authors serve to limit the effect of residual confounding, they do not eliminate it. Although unlikely, it is possible low VT may be a marker for an unmeasured variable that leads to more favorable neurocognitive outcomes. Further research into a possible casual association between VT and neurocognitive outcomes is needed.

The authors also suggest a number of inflammatory-related mechanisms for the association between lower VT and improved neurocognitive outcomes, which they collectively name “brain-lung communication.” While this is a physiologically attractive hypothesis in light of what is known regarding PCAS, the retrospective nature of the study prevents measurement of any inflammatory markers or cytokine levels that might strengthen this hypothesis. As it stands, further exploration of the mechanisms that might link lower VT to improved neurocognitive outcomes will be required before a more definitive statement regarding brain-lung communication can be accepted.

Although the authors identified an association between lower VT and a number of secondary outcomes, their results show there were no significant associations between lower VT and fewer days of extrapulmonary organ failure or improved survival. Given the contradictory nature of some of these secondary outcomes (such as an association with fewer shock-free days but no association with less extrapulmonary organ failure, a known consequence of hemodynamic shock), the true impact of low VT on these outcomes is unclear. While it is logical that the association between lower VT and some secondary outcomes (such as fewer ICU days and fewer ventilator-dependent days) is a result of improved neurocognitive outcomes, further work is required to elucidate the true clinical significance of these secondary outcomes.

Finally, while there was no significant difference between groups in terms of initial pH or PCO2, and these variables were included in the propensity matching analysis, both groups had mean initial PCO2 levels that were elevated (47 mm Hg and 49 mm Hg in the high and low VT groups, respectively). These values are above the physiological range (35–45 mm Hg) recommended by the 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care [3]. The authors suggest that the recommended eucapnic targets can be met in a low VT strategy by increasing the respiratory rate. However, current literature suggests that patients with ARDS exposed to higher respiratory rates may have more frequent exposure to ventilator-induced lung injury (VILI) stresses and an increased rate of lung injury [4]. While there are no clinical trials proving the benefit of a low vs. high respiratory rate strategy, current recommendations for reducing the risk of VILI include limiting the respiratory rate. It is unclear at this time if an increase in the respiratory rate would increase the incidence of VILI and negate any potential benefit provided by low VT in these patients, but this would be an important cost to account for when employing a low VT strategy.

Applications for Clinical Practice

In this study, Beitler and colleagues found that using a low VT ventilation strategy in OHCA patients was associated with improved neurocognitive outcomes. This study is primarily useful as a hypothesis generator. Further research into the effects of ventilator parameters such as VT on the inflammatory cascade, neurocognitive outcomes in other groups of patients (such as those with ARDS), and the existence of a “brain-lung communication” pathway is warranted. From a practical standpoint, evidence continues to mount that lower VT is associated with a number of beneficial effects that are not limited to patients with ARDS [5]. This study would support the current practice of many intensivists to utilize a low VT strategy unless a compelling contraindication exists, as the potential benefits are substantial and the risks minimal. However, this practice will have to be balanced with the need to avoid hypercapnia, and the elevated respiratory rates used to achieve eucapnia may have unforeseen consequences.

—Arun Jose, MD, The George Washington University, Washington, DC

Study Overview

Objective. To determine if there is an association between low tidal volume (VT) ventilation and neurocognitive outcomes in patients after out-of-hospital cardiac arrest (OHCA).

Design. Retrospective cohort study.

Setting and participants. Data was obtained from retrospective review of all adults admitted between 2008 and 2014 to one of 2 centers (A or B) with nontraumatic OHCA requiring mechanical ventilation for greater than 48 hours. The study physicians screened records primarily using chart review with secondary confirmation of the diagnosis of OHCA and eligibility criteria. Patients with an outside hospital stay greater than 24 hours, intracranial hemorrhage, use of extracorporeal membranous oxygenation (ECMO), use of airway pressure release mode of ventilation, chronic dependence on mechanical ventilation, or missing data were excluded. Of the 579 patients with OHCA, 256 (44.2%) met the inclusion criteria and were included in the main analysis. A total of 97 patients were identified as having high VT (defined as > 8 mL/kg of predicted body weight [PBW]) and were matched to 97 of the 159 patients identified as having a low VT as part of the propensity-matched subgroup analysis using 1:1 optimal caliper matching.

Main outcome measure. The primary outcome was a favorable neurocognitive outcome at hospital discharge (Cerebral Performance Category score [CPC] of 1 or 2). A CPC of 1 or 2 corresponds to normal life or life that is disabled but independent, respectively. A CPC of 3 is disabled and dependent, and a CPC of 5 is alive but brain dead. Two physicians blinded to VT and other measures of illness severity calculated the CPC via chart review. Discordant scores were resolved by consensus, and a Kappa statistic was calculated to quantify agreement between investigators. Secondary outcomes included ventilator-free days, hospital-free days, ICU-free days, shock-free days, and extrapulmonary organ failure–free days. Logistic regression with backward elimination was used to identify predictors of receiving VT ≤ 8 mL/kg PBW to be used in the propensity-matched analysis, along with relevant predictors identified from the literature. The odds ratio for the primary outcome was calculated using both logistic regression analysis and propensity-matched analysis. Other methods of sensitivity analysis (propensity quintile adjustment, inverse-probability-of-treatment weighting) were used to confirm the robustness of the initial analysis to different statistical methods. A P value of < 0.05 was considered significant.

Main results. Of the study patients, approximately half (49% in high VT, 52% in low VT) had an initial rhythm of ventricular tachycardia or ventricular fibrillation. Patients with low VT were significantly younger (mean age 59 yr vs. 66 yr), taller (mean height 177 cm vs. 165 cm), and heavier (mean weight 88 kg vs. 81 kg). There were also significantly fewer females in the low VT group (19% vs. 46%). There were no significant differences between baseline comorbidities, arrest characteristics, or illness severity between the 2 groups with the exception of significantly more patients in the low VT underwent therapeutic hypothermia (87% vs. 76%) and were admitted to hospital A (69% vs. 55%). There were no significant differences between the groups across ventilator parameters aside from tidal volume. The average VT in mL/kg PBW was 9.3 in the high VT group and 7.1 in the low VT group over the first 48 hours.

In the multivariate regression analysis, significant independent predictors of receiving high VT included height, weight, and hospital of admission. The final propensity model to predict VT included age, height, weight, sex, illness severity measures (APACHE-II score and presence of circulatory shock in the first 24 hours of admission), arrest characteristics, and respiratory characteristics (initial pH, initial PaCO2, PaO2:FiO2 ratio, and initial peak inspiratory pressure) as covariates. The use of low VT was significantly associated with a favorable neurocognitive outcome in the multivariate regression analysis (odds ratio [OR] 1.65, 95% confidence interval [CI] 1.18–2.29). This association held in both the propensity matched analysis (OR 1.68, 95% CI 1.11–2.55) as well as conditional logistic regression analysis using propensity score as a covariate (OR 1.61, 95% CI 1.13–2.28).

In the propensity-adjusted conditional logistic regression analysis, a lower VT (1 mL/kg of PBW decrease) was significantly associated with ventilator-free days (OR 1.78, 95% CI 0.39–3.16), shock-free days (OR 1.31, 95% CI 0.10–2.51), ICU-free days (OR 1.38, 95% CI 0.13–2.63), and hospital-free days (OR 1.07, 95% CI 0.04–2.09). There was a nonsignificant trend towards improved survival to hospital discharge (OR 1.23, 95% CI 0.95–1.60, P = 0.115). After propensity score adjustment, lower VT was not associated with therapeutic hypothermia (OR 0.14, 95% CI −0.19 to 0.47), and in the multivariate regression analysis there was no association between favorable neurocognitive outcome and therapeutic hypothermia (P = 0.516). While there was a significant association between lower VT and site of admission (Hospital A: OR 1.50, 95% CI 1.04–2.17 per 1 mL/kg of PBW decrease), there was no association between favorable neurocognitive outcome and hospital site of admission in the final adjusted regression analysis (P = 0.588).

Conclusion. In this retrospective cohort study, lower VT in the first 48 hours of admission following OHCA was independently associated with favorable neurocognitive outcomes as measured by the CPC score, as well as more ventilator-free, shock-free, ICU-free, and hospital-free days.

Commentary

Neurocognitive impairment following nontraumatic OHCA is common, estimated to occur in roughly half of all survivors [1]. Similar to the acute respiratory distress syndrome (ARDS), the post–cardiac arrest syndrome (PCAS) is recognized as a systemic process with multi-organ effects thought to be mediated in part by inflammatory cytokines [2]. While the beneficial role of low VT in patients with ARDS is well established, currently there are no recommendations for specific VT targets in post–cardiac arrest care, and the effect of VT on outcomes following cardiac arrest is unknown [3].

In this study, Beitler and colleagues suggest a possible association between VT and neurocognitive outcomes following OHCA. Using retrospective data drawn from 2 centers, and employing both regression analysis and propensity matching, the authors identified a significant beneficial effect of lower VT on neurocognitive outcomes in their cohort. This benefit held regardless of the statistical analytic method employed and was present even when correcting for the difference between groups in hospital admission site and use of therapeutic hypothermia in the original cohort. The authors also demonstrated a lower VT was associated with a number of secondary outcomes including fewer hospital, ICU, and ventilator days. While the statistical methods employed by the authors are robust and attempt to account for the limitations inherent to observational studies, a number of questions remain.

First, as the authors appropriately note, causality cannot be proven from a retrospective study. While the analytic methods employed by the authors serve to limit the effect of residual confounding, they do not eliminate it. Although unlikely, it is possible low VT may be a marker for an unmeasured variable that leads to more favorable neurocognitive outcomes. Further research into a possible casual association between VT and neurocognitive outcomes is needed.

The authors also suggest a number of inflammatory-related mechanisms for the association between lower VT and improved neurocognitive outcomes, which they collectively name “brain-lung communication.” While this is a physiologically attractive hypothesis in light of what is known regarding PCAS, the retrospective nature of the study prevents measurement of any inflammatory markers or cytokine levels that might strengthen this hypothesis. As it stands, further exploration of the mechanisms that might link lower VT to improved neurocognitive outcomes will be required before a more definitive statement regarding brain-lung communication can be accepted.

Although the authors identified an association between lower VT and a number of secondary outcomes, their results show there were no significant associations between lower VT and fewer days of extrapulmonary organ failure or improved survival. Given the contradictory nature of some of these secondary outcomes (such as an association with fewer shock-free days but no association with less extrapulmonary organ failure, a known consequence of hemodynamic shock), the true impact of low VT on these outcomes is unclear. While it is logical that the association between lower VT and some secondary outcomes (such as fewer ICU days and fewer ventilator-dependent days) is a result of improved neurocognitive outcomes, further work is required to elucidate the true clinical significance of these secondary outcomes.

Finally, while there was no significant difference between groups in terms of initial pH or PCO2, and these variables were included in the propensity matching analysis, both groups had mean initial PCO2 levels that were elevated (47 mm Hg and 49 mm Hg in the high and low VT groups, respectively). These values are above the physiological range (35–45 mm Hg) recommended by the 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care [3]. The authors suggest that the recommended eucapnic targets can be met in a low VT strategy by increasing the respiratory rate. However, current literature suggests that patients with ARDS exposed to higher respiratory rates may have more frequent exposure to ventilator-induced lung injury (VILI) stresses and an increased rate of lung injury [4]. While there are no clinical trials proving the benefit of a low vs. high respiratory rate strategy, current recommendations for reducing the risk of VILI include limiting the respiratory rate. It is unclear at this time if an increase in the respiratory rate would increase the incidence of VILI and negate any potential benefit provided by low VT in these patients, but this would be an important cost to account for when employing a low VT strategy.

Applications for Clinical Practice

In this study, Beitler and colleagues found that using a low VT ventilation strategy in OHCA patients was associated with improved neurocognitive outcomes. This study is primarily useful as a hypothesis generator. Further research into the effects of ventilator parameters such as VT on the inflammatory cascade, neurocognitive outcomes in other groups of patients (such as those with ARDS), and the existence of a “brain-lung communication” pathway is warranted. From a practical standpoint, evidence continues to mount that lower VT is associated with a number of beneficial effects that are not limited to patients with ARDS [5]. This study would support the current practice of many intensivists to utilize a low VT strategy unless a compelling contraindication exists, as the potential benefits are substantial and the risks minimal. However, this practice will have to be balanced with the need to avoid hypercapnia, and the elevated respiratory rates used to achieve eucapnia may have unforeseen consequences.

—Arun Jose, MD, The George Washington University, Washington, DC

Study Overview

Objective. To determine if there is an association between low tidal volume (VT) ventilation and neurocognitive outcomes in patients after out-of-hospital cardiac arrest (OHCA).

Design. Retrospective cohort study.

Setting and participants. Data was obtained from retrospective review of all adults admitted between 2008 and 2014 to one of 2 centers (A or B) with nontraumatic OHCA requiring mechanical ventilation for greater than 48 hours. The study physicians screened records primarily using chart review with secondary confirmation of the diagnosis of OHCA and eligibility criteria. Patients with an outside hospital stay greater than 24 hours, intracranial hemorrhage, use of extracorporeal membranous oxygenation (ECMO), use of airway pressure release mode of ventilation, chronic dependence on mechanical ventilation, or missing data were excluded. Of the 579 patients with OHCA, 256 (44.2%) met the inclusion criteria and were included in the main analysis. A total of 97 patients were identified as having high VT (defined as > 8 mL/kg of predicted body weight [PBW]) and were matched to 97 of the 159 patients identified as having a low VT as part of the propensity-matched subgroup analysis using 1:1 optimal caliper matching.

Main outcome measure. The primary outcome was a favorable neurocognitive outcome at hospital discharge (Cerebral Performance Category score [CPC] of 1 or 2). A CPC of 1 or 2 corresponds to normal life or life that is disabled but independent, respectively. A CPC of 3 is disabled and dependent, and a CPC of 5 is alive but brain dead. Two physicians blinded to VT and other measures of illness severity calculated the CPC via chart review. Discordant scores were resolved by consensus, and a Kappa statistic was calculated to quantify agreement between investigators. Secondary outcomes included ventilator-free days, hospital-free days, ICU-free days, shock-free days, and extrapulmonary organ failure–free days. Logistic regression with backward elimination was used to identify predictors of receiving VT ≤ 8 mL/kg PBW to be used in the propensity-matched analysis, along with relevant predictors identified from the literature. The odds ratio for the primary outcome was calculated using both logistic regression analysis and propensity-matched analysis. Other methods of sensitivity analysis (propensity quintile adjustment, inverse-probability-of-treatment weighting) were used to confirm the robustness of the initial analysis to different statistical methods. A P value of < 0.05 was considered significant.

Main results. Of the study patients, approximately half (49% in high VT, 52% in low VT) had an initial rhythm of ventricular tachycardia or ventricular fibrillation. Patients with low VT were significantly younger (mean age 59 yr vs. 66 yr), taller (mean height 177 cm vs. 165 cm), and heavier (mean weight 88 kg vs. 81 kg). There were also significantly fewer females in the low VT group (19% vs. 46%). There were no significant differences between baseline comorbidities, arrest characteristics, or illness severity between the 2 groups with the exception of significantly more patients in the low VT underwent therapeutic hypothermia (87% vs. 76%) and were admitted to hospital A (69% vs. 55%). There were no significant differences between the groups across ventilator parameters aside from tidal volume. The average VT in mL/kg PBW was 9.3 in the high VT group and 7.1 in the low VT group over the first 48 hours.

In the multivariate regression analysis, significant independent predictors of receiving high VT included height, weight, and hospital of admission. The final propensity model to predict VT included age, height, weight, sex, illness severity measures (APACHE-II score and presence of circulatory shock in the first 24 hours of admission), arrest characteristics, and respiratory characteristics (initial pH, initial PaCO2, PaO2:FiO2 ratio, and initial peak inspiratory pressure) as covariates. The use of low VT was significantly associated with a favorable neurocognitive outcome in the multivariate regression analysis (odds ratio [OR] 1.65, 95% confidence interval [CI] 1.18–2.29). This association held in both the propensity matched analysis (OR 1.68, 95% CI 1.11–2.55) as well as conditional logistic regression analysis using propensity score as a covariate (OR 1.61, 95% CI 1.13–2.28).

In the propensity-adjusted conditional logistic regression analysis, a lower VT (1 mL/kg of PBW decrease) was significantly associated with ventilator-free days (OR 1.78, 95% CI 0.39–3.16), shock-free days (OR 1.31, 95% CI 0.10–2.51), ICU-free days (OR 1.38, 95% CI 0.13–2.63), and hospital-free days (OR 1.07, 95% CI 0.04–2.09). There was a nonsignificant trend towards improved survival to hospital discharge (OR 1.23, 95% CI 0.95–1.60, P = 0.115). After propensity score adjustment, lower VT was not associated with therapeutic hypothermia (OR 0.14, 95% CI −0.19 to 0.47), and in the multivariate regression analysis there was no association between favorable neurocognitive outcome and therapeutic hypothermia (P = 0.516). While there was a significant association between lower VT and site of admission (Hospital A: OR 1.50, 95% CI 1.04–2.17 per 1 mL/kg of PBW decrease), there was no association between favorable neurocognitive outcome and hospital site of admission in the final adjusted regression analysis (P = 0.588).

Conclusion. In this retrospective cohort study, lower VT in the first 48 hours of admission following OHCA was independently associated with favorable neurocognitive outcomes as measured by the CPC score, as well as more ventilator-free, shock-free, ICU-free, and hospital-free days.

Commentary

Neurocognitive impairment following nontraumatic OHCA is common, estimated to occur in roughly half of all survivors [1]. Similar to the acute respiratory distress syndrome (ARDS), the post–cardiac arrest syndrome (PCAS) is recognized as a systemic process with multi-organ effects thought to be mediated in part by inflammatory cytokines [2]. While the beneficial role of low VT in patients with ARDS is well established, currently there are no recommendations for specific VT targets in post–cardiac arrest care, and the effect of VT on outcomes following cardiac arrest is unknown [3].

In this study, Beitler and colleagues suggest a possible association between VT and neurocognitive outcomes following OHCA. Using retrospective data drawn from 2 centers, and employing both regression analysis and propensity matching, the authors identified a significant beneficial effect of lower VT on neurocognitive outcomes in their cohort. This benefit held regardless of the statistical analytic method employed and was present even when correcting for the difference between groups in hospital admission site and use of therapeutic hypothermia in the original cohort. The authors also demonstrated a lower VT was associated with a number of secondary outcomes including fewer hospital, ICU, and ventilator days. While the statistical methods employed by the authors are robust and attempt to account for the limitations inherent to observational studies, a number of questions remain.

First, as the authors appropriately note, causality cannot be proven from a retrospective study. While the analytic methods employed by the authors serve to limit the effect of residual confounding, they do not eliminate it. Although unlikely, it is possible low VT may be a marker for an unmeasured variable that leads to more favorable neurocognitive outcomes. Further research into a possible casual association between VT and neurocognitive outcomes is needed.

The authors also suggest a number of inflammatory-related mechanisms for the association between lower VT and improved neurocognitive outcomes, which they collectively name “brain-lung communication.” While this is a physiologically attractive hypothesis in light of what is known regarding PCAS, the retrospective nature of the study prevents measurement of any inflammatory markers or cytokine levels that might strengthen this hypothesis. As it stands, further exploration of the mechanisms that might link lower VT to improved neurocognitive outcomes will be required before a more definitive statement regarding brain-lung communication can be accepted.

Although the authors identified an association between lower VT and a number of secondary outcomes, their results show there were no significant associations between lower VT and fewer days of extrapulmonary organ failure or improved survival. Given the contradictory nature of some of these secondary outcomes (such as an association with fewer shock-free days but no association with less extrapulmonary organ failure, a known consequence of hemodynamic shock), the true impact of low VT on these outcomes is unclear. While it is logical that the association between lower VT and some secondary outcomes (such as fewer ICU days and fewer ventilator-dependent days) is a result of improved neurocognitive outcomes, further work is required to elucidate the true clinical significance of these secondary outcomes.

Finally, while there was no significant difference between groups in terms of initial pH or PCO2, and these variables were included in the propensity matching analysis, both groups had mean initial PCO2 levels that were elevated (47 mm Hg and 49 mm Hg in the high and low VT groups, respectively). These values are above the physiological range (35–45 mm Hg) recommended by the 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care [3]. The authors suggest that the recommended eucapnic targets can be met in a low VT strategy by increasing the respiratory rate. However, current literature suggests that patients with ARDS exposed to higher respiratory rates may have more frequent exposure to ventilator-induced lung injury (VILI) stresses and an increased rate of lung injury [4]. While there are no clinical trials proving the benefit of a low vs. high respiratory rate strategy, current recommendations for reducing the risk of VILI include limiting the respiratory rate. It is unclear at this time if an increase in the respiratory rate would increase the incidence of VILI and negate any potential benefit provided by low VT in these patients, but this would be an important cost to account for when employing a low VT strategy.

Applications for Clinical Practice

In this study, Beitler and colleagues found that using a low VT ventilation strategy in OHCA patients was associated with improved neurocognitive outcomes. This study is primarily useful as a hypothesis generator. Further research into the effects of ventilator parameters such as VT on the inflammatory cascade, neurocognitive outcomes in other groups of patients (such as those with ARDS), and the existence of a “brain-lung communication” pathway is warranted. From a practical standpoint, evidence continues to mount that lower VT is associated with a number of beneficial effects that are not limited to patients with ARDS [5]. This study would support the current practice of many intensivists to utilize a low VT strategy unless a compelling contraindication exists, as the potential benefits are substantial and the risks minimal. However, this practice will have to be balanced with the need to avoid hypercapnia, and the elevated respiratory rates used to achieve eucapnia may have unforeseen consequences.

—Arun Jose, MD, The George Washington University, Washington, DC