Fluent Essays

PLEASE READ FULL INSTRUCTIONS. NO PLAGIARISM! NO QUOTES, MUST PARAPHRASE. I WILL CHECK FOR RECYCLED WORK AND PLAGIARISM. THIS ASSIGNMENT IS DUE 08/16/21 AT 9PM PST. IF YOU CANT MEET THIS DEADLINE, DONT AGREE TO DO MY ASSIGNMENT. PRICE ISNT NEGOTIABLE. PLEASE READ GRADING RUBRIC. TEACHERS USE THE GRADING RUBRIC TO DETERMINE GRADE. IF DIRECTIONS ARENT BEING FOLLOWED, I WILL DISPUTE RIGHT AWAY. LETS AVOID THAT.   YOU MUST USE TEMPLATE PROVIDED AND PLEASE READ THE ARTICLE ATTACHED.    Prior to beginning work on this assignment, review the multimedia file How to Read a Scholarly Article (Links to an external site.). Using the Research Study Evaluation Template  download, you will critically evaluate the assigned research article.  The Research Study Evaluation   Must include a separate title page with the following: Title of paper Student’s name Course name and number Instructor’s name Date submitted Must use the template provided. Must address the article with critical thought by examining, reflecting, and evaluating the article from an objective viewpoint, using facts to support your argument in the conclusion section of the template. Must properly cite the source article in APA style, as outlined in the Writing Center (Links to an external site.). Peak Oxygen Uptake and Mortality in Cystic Fibrosis: Systematic Review and Meta-Analysis Fernanda Maria Vendrusculo, João Paulo Heinzmann-Filho, Juliana Severo da Silva, Margarita Perez Ruiz, and Márcio Vinícius Fagundes Donadio BACKGROUND: Aerobic fitness, as measured by peak oxygen uptake (V̇O2 peak), correlates with survival in children and adults with cystic fibrosis (CF). We sought to evaluate the effects of V̇O2 peak on mortality rates in subjects with CF. METHODS: An online search in PubMed, Embase, LILACS, and SciELO databases was conducted, and cohort studies that assessed mortality rates after oxygen absorption measurements during a maximal exercise test were included. Data were extracted independently by 2 reviewers. The quality analysis of the selected articles was performed using the Newcastle-Ottawa scale. The main outcome evaluated was the mortality of subjects with CF. Whenever possible, and if appropriate, a random effect meta-analysis was performed. RESULTS: Six cohort studies were included in this systematic review including 551 subjects. Five studies were classified with high methodological quality. Two analyses were carried out to evaluate the influence of V̇O2 peak on mortality. Total difference standardized mean between V̇O2 peak averages in the survival or non-survival groups was �0.606 (95\% CI � �0.993 to �0.219, P � .002). In addition, subjects with a lower V̇O2 peak had a significantly higher mortality risk (relative risk 4.896, 95\% CI � 1.086 to 22.072, P � .039) in an 8-y follow-up period. CONCLUSION: Low levels of peak oxygen uptake are associated with an increase of 4.9 in the risk of mortality in subjects with CF. This indicates that V̇O2 could be an important follow-up variable to measure, in addition to FEV1. Key words: cystic fibrosis; oxygen consumption; exercise capacity; exercise test; mortality; survival. [Respir Care 2019;64(1):91–98. © 2019 Daedalus Enterprises] Introduction Cystic fibrosis (CF) is a multisystemic genetic disease characterized by progressive loss of lung function and con- sequent limitation of aerobic fitness.1 Although morbidity and mortality are still a major concern in the disease man- agement, life expectancy is increasing each year with ad- vancement in the diagnosis and treatment; according to data from the Cystic Fibrosis Foundation, the expected median survival in the year 2015 was 41.7 y.2 Thus, as lung function is better maintained and aging of patients increases, other comorbidities rise and there is a growing importance of factors such as the preservation of aerobic fitness status.3 In general, many factors have been associated with a worse prognosis in individuals with CF, among them sex,4 decline in lung function,4-7 number of exacerbations,6,7 nutritional status,7-9 chronic colonization of the airways,10,11 and peak oxygen consumption (V̇O2 peak). 5,11,12 It is known that the reduction of V̇O2 peak is of multifactorial origin, given that the mechanisms that can limit aerobic fitness include respiratory, cardiovascular, and of peripheral mus- cles.13 Therefore, performance on the cardiopulmonary ex- ercise test (CPET) depends on more than lung function and thus reflects the effects of the disease on other organ systems earlier on,14 although FEV1 has still been cited as Drs Heinzmann-Filho, Donadio, Vendrusculo, and Ms da Silva, are af- filiated with the Laboratory of Pediatric Physical Activity, Centro Infant, Institute of Biomedical Research, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil. Dr Perez Ruiz is affiliated with the School of Doctoral Studies and Research, Universidad Europea de Madrid, Madrid, Spain. The authors have disclosed no conflicts of interest. Correspondence: Márcio Donadio, Laboratory of Pediatric Physical Ac- tivity, Centro Infant, Institute of Biomedical Research, Av. Ipiranga, 6690, 2° andar, Porto Alegre, Rio Grande do Sul, CEP 90610-000, Bra- zil. E-mail: [email protected] DOI: 10.4187/respcare.06185 RESPIRATORY CARE • JANUARY 2019 VOL 64 NO 1 91 the best predictor of mortality in children and adults with CF.4,11,12 Thus, considering only lung function as a disease progression marker may not identify other factors that lead to morbidity and mortality in these subjects. Therefore, aerobic fitness evaluation through CPET seems to be a more comprehensive method.15 CPET is considered the gold standard for evaluating aerobic fitness and has been used not only to follow the evolution of the disease,16 because it evaluates the perfor- mance and interaction of the cardiovascular, respiratory, and metabolic systems,17 but also for the prescription of physical exercise.18 In addition, studies have shown high reproducibility of CPET for young19 and adult20 subjects with CF, demonstrating a coefficient of variation of 9.3\% and 6.9\%, respectively. Moreover, the recent statement on exercise testing in CF recommends performing CPET in individuals aged � 10 y as an important part of the annual review process.15 Exercise intolerance due to hyperinflation and increased respiratory work caused by airway obstruction may be present as the disease advances,21 although it is increas- ingly common to find some pediatric patients who do not present dynamic hyperinflation during exercise. Aerobic fitness correlates with survival in children12 and adults5,11 with CF. Nixon et al11 was the first to demonstrate that V̇O2 peak (� 45 mL/kg/min) could be a predictor of survival in young individuals. A few years later, this finding was replicated by the study of Pianosi et al,12 which showed that subjects with V̇O2 peak � 82\% of predicted had a better rate of survival. Thus, we hypothesized that a low V̇O2 peak was an independent predictor of mortality in individuals with CF. Therefore, we performed a systematic review and quanti- tative meta-analysis of all available studies that reported the effects of peak oxygen consumption on mortality rates in individuals with CF. Methods This systematic review was performed following the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines,22 and data were described according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.23 The protocol of this re- view was registered in the international prospective regis- ter of systematic reviews and was accepted under the num- ber CRD42016045759. Search Strategy Studies were identified from the following databases: PubMed, Embase, LILACS, and SciELO. The terms used were (“exercise test” or “exercise testing” or “cardiopul- monary exercise test” or “cardiopulmonary exercise test- ing” or “peak oxygen uptake” or “maximal oxygen con- sumption” or “exercise tolerance” or “exercise capacity”) and (“mortality” or “survival”) and (“cystic fibrosis”). No filters were used. A manual search was performed on the bibliographic references of the selected articles to search for additional publications that were pertinent to the study purpose. The searches were conducted in March 2017. Study Selection Two authors (FMV and JSdS) independently evaluated article titles and abstracts, thereby selecting the studies to be included in the review. Cohort studies of subjects with CF that assessed mortality rates after oxygen uptake mea- surements during a maximal exercise test were included. Articles that did not use variables of the maximal exercise test to predict mortality, articles that assessed the mortality of individuals already on the lung transplant list (because the inclusion of severely ill individuals would potentially bias the analysis), review studies, case studies, experimen- tal models, abstracts, response letters, editorials, and du- plicate publications, as well as those that did not meet inclusion criteria, were excluded after the analysis of the abstract or full text. Disagreements over the inclusion cri- teria of a particular study were discussed and resolved through consensus. A third author (MVFD) evaluated and resolved the discrepancies whenever disagreement or doubts between the 2 authors remained. Data Extraction The following data were extracted from each of the selected studies: title, first author’s name, year of publi- cation, country of origin, language of publication, type of study, age of subjects, sample size, type of equipment used, type of protocol used, duration of follow-up, V̇O2 peak, breathing reserve, ventilatory equivalent for peak oxygen consumption (V̇E/V̇O2), and ventilatory equivalent for carbon dioxide production (V̇E/V̇CO2). In addition, data from the variables of the cardiopulmonary exercise test and other variables that could predict the mortality of CF patients were collected. Any discrepancies were resolved by consensus among the researchers. Moreover, whenever appropriate, an attempt to contact authors of the included studies was performed in order to request additional in- formation. Quality Analysis The quality analysis of the selected articles was per- formed individually by 2 authors (FMV and JPH-F) using the Newcastle-Ottawa Scale, which assigns a maximum of 9 points to the highest quality studies according to the 3 evaluated parameters: selection (4 points), comparability PEAK OXYGEN UPTAKE AND MORTALITY IN CF 92 RESPIRATORY CARE • JANUARY 2019 VOL 64 NO 1 (2 points), and outcome (3 points).24 The overall quality of the study was defined as poor (score 0 –3), reasonable (score 4 – 6), or high (score 7–9). The findings were dis- cussed together with a third author (MVFD), and the dis- crepancies or doubts were resolved by consensus. Synthesis of Data and Statistical Analysis When possible and appropriate, a randomized meta- analysis of the studies was conducted. The standard dif- ference of the V̇O2 peak averages between the survival and non-survival groups was performed by extracting the av- erage data, sample size, and P value from each study in- cluded in that analysis. The association of high or low V̇O2 peak with mortality was calculated between the survival and non-survival groups by extracting the relative risk and the 95\% CI and/or the number of events (death) and the total of participants in each group, using the DerSimonian- Laird randomized model. Forest plots with the point size reflecting study weight were used to graphically represent the results of meta- analysis. The I2 and Q tests were used to quantify the degree of heterogeneity between the studies. It was not possible to evaluate the bias of publication with the Egg- er’s test due to the small number of studies included in each analysis. All analysis were performed in the compre- hensive meta-analysis software (Biostat, Englewood, New Jersey). Results A total of 8,698 articles were found (3,886 in PubMed, 4,787 in EMBASE, and 25 in LILACS). Of these, 2,786 studies were excluded because they were repeated in the database searches, and 5,904 studies were excluded because they did not meet the eligibility criteria of our study. Eight studies were assessed for eligibility, and after analysis of the full text, 2 studies were excluded for in- cluding individuals already on a transplant list.25,26 There- fore, 6 studies were included in this review, and 4 studies were included in the meta-analysis. Figure 1 shows the flow chart of the articles found and the reasons for the exclusion of studies. The selected articles included a total of 551 subjects, and the sample size of each study varied between 28 and 149 subjects, with ages ranging from 10 to 30.2 y and follow-up time between 2.8 and 8 y (Table 1). Only 2 stud- ies presented CFTR genotype classification, although no separate analyses were performed.9,10 All studies used the cycle ergometer to perform CPET. However, when eval- uating the type of protocol, 3 studies used the Godfrey protocol,9-11 2 performed a ramp protocol,5,27 and 1 study12 used a step increment. The V̇O2 peak, breathing reserve, V̇E/V̇O2, and V̇E/V̇CO2 data from each article are presented in Table 2. Regarding the overall methodological quality, 5 of the included studies5,9,11,12,27 were classified as high quality, and two5,11 of these received the maximum score (9 points). On the other hand, only 1 article10 was classified as rea- sonable quality and was assigned 6 points. Table 3 pres- ents the parameters evaluated in the Newcastle-Ottawa Scale. Table 4 shows the data of significant variables to predict mortality in CF subjects. V̇O2 peak was significant in 5 stud- ies,5,9-12 and breathing reserve was significant in 1 study.9 In the study by Nguyen et al,27 only the arterial-alveolar oxygen gradient was significant. With regard to other vari- ables, FEV1 was significant in 5 studies,5,9,11,12,27 body mass index (BMI) was significant in 2 studies,9,27 and Records identified through database searching Duplicates removed 2,786 Records excluded 5,904 Studies included individuals awaiting lung transplantation: 2 Studies presented only data of total sample: 2 Full-text articles assessed for eligibility 8 Records screened 5,912 Studies included in systematic review 6 Studies included in meta-analysis 4 Studies included in meta-analysis of standard mean difference 2 Studies included in meta-analysis of relative risk 2 PubMed: 3,886 Embase: 4,787 LILACS: 25 SciELO: 0 No CPET performed: 2,450 No CF individuals: 1,807 Review papers: 1,163 No access to abstract: 241 Experimental models: 206 No outcomes of interest: 37 8,698 Fig. 1. Flow chart. CPET � cardiopulmonary exercise testing; CF � cystic fibrosis. PEAK OXYGEN UPTAKE AND MORTALITY IN CF RESPIRATORY CARE • JANUARY 2019 VOL 64 NO 1 93 Pseudomonas cepacia colonization was significant in 1 study.11 To determine the influence of CPET variables on the mortality of subjects with CF, 3 studies9,11,12 used Cox proportional hazards, whereas the other 3 studies used log rank tests,10 multivariate logistic regression,27 and chi- square tests.5 Meta-analysis Two different analyses were carried out to evaluate the influence of V̇O2 peak on mortality in subjects with CF, and 2 studies were included in each analysis. Figure 2A shows data from articles reporting differences between averages of V̇O2 peak in the survival and non-survival groups. The I2 analysis did not show heterogeneity be- tween studies (I2 � 0\%, P � .84). The total difference standardized mean was �0.606 (CI 95\% � �0.993 to �0.219, P � .002), indicating that subjects in the non- survival group had a lower V̇O2 peak compared to survi- vors. Subjects with a lower V̇O2 peak (� 45 mL/kg/min or � 82\% of predicted) were associated with a signifi- cantly higher risk for mortality (relative risk 4.896, 95\% CI � 1.086 to 22.072, P � .039). There was a small but not significant heterogeneity in the studies (I2 � 31.56\%, P � .23) included in this analysis (Fig. 2B). It was not possible to generate funnel charts in the analysis because of the small number of studies included. Discussion Low aerobic fitness has been reported in individuals with CF and is associated with several factors, including impairment of lung function,28 poor nutritional status,29 low muscle power,28 cardiac dysfunction,30 high level of inflammation,10 and physical deconditioning.28 V̇O2 peak, defined as the peak amount of oxygen that can be trans- ferred and utilized during exercise, is the main parameter in the evaluation of aerobic capacity.18 Our systematic review and meta-analyses demonstrate that subjects with Table 1. Main Methodological Characteristics of the Studies Study Country of Origin Type of Cohort Sample Size Age, y* Follow-up, y Hulzebos et al9 Netherlands Prospective 127 12.7 (11–14) 7.5 Van de Weert-van Leeuwen et al10 Netherlands Prospective 149 13.2 (12–13) 2.8 Nguyen et al27 France Retrospective 51 30.2 (16–67) 3 Pianosi et al12 Canada Prospective 28 10 (7–16) 8† Moorcroft et al5 United Kingdom Retrospective 87 19.8 (15–40) 5 Nixon et al11 United States Prospective 109 17 (7–35) 8 * Mean (range). † Approximate value. Table 2. Main Results of Cardiopulmonary Exercise Test Variables of the Studies Included in the Systematic Review Study Baseline V̇O2 Peak Breathing Reserve at Maximum Exercise V̇E/V̇O2 V̇E/V̇CO2 Hulzebos et al9 41.5 � 8.8 mL/kg/min 0.25 � 0.1* 37.4 � 6.8 32.3 � 5.4 93.3 � 17.9\% predicted Van de Weert-van Leeuwen et al10 41.4 � 8.8 mL/kg/min NR NR NR 96.2 � 18.2\% predicted Nguyen et al27 Died: 51.8 � 15.6\% predicted 100.1 � 20.5† NR NR Survived: 66.1 � 20.7\% predicted 74.5 � 21.3† Pianosi et al12 41.2 mL/kg/min 0.92‡ NR NR Moorcroft et al5 Died: 53.7\% predicted NR Died: 38.7 NR Survived: 66.6\% predicted Survived: 32.4 Nixon et al11 35 mL/kg/min NR NR NR 70\% predicted * 1 � (Peak minute ventilation � maximum voluntary ventilation). † Peak minute ventilation (\%) of maximum voluntary ventilation. ‡ Peak minute ventilation/maximum voluntary ventilation. V̇O2 � oxygen uptake NR � not reported V̇E/V̇O2 � ventilatory equivalent for oxygen V̇E/V̇CO2 � ventilatory equivalent for carbon dioxide PEAK OXYGEN UPTAKE AND MORTALITY IN CF 94 RESPIRATORY CARE • JANUARY 2019 VOL 64 NO 1 lower V̇O2 peak rates (ie, values � 82\% of predicted or 45 mL/kg/min) demonstrated a 4.9-fold increased risk for a fatal outcome, indicating that measurement of aerobic fitness could be a tool for prognosis in patients with CF. Furthermore, the difference between means indicated that subjects in the non-survival group had a lower V̇O2 peak compared to the survivors. This association of oxygen consumption with mortality has also been described for individuals with COPD31,32 and chronic heart failure.33,34 To our knowledge, this is the first meta-analysis to eval- uate the association of V̇O2 peak with mortality in subjects with CF. Nguyen et al27 was the only study included that found no relationship between V̇O2 peak and mortality. They dem- onstrated only that alveolar-arterial gradient for oxygen at peak exercise was significantly associated with mortality. On the other hand, the remaining articles demonstrated an association between V̇O2 peak and mortality. However, other variables, including FEV1 and BMI, were also sig- nificant in predicting mortality. A higher BMI has been associated with an increased likelihood of survival in sub- jects with CF,7-9,35 corroborating the results from Nguyen et al27 and Hulzebos et al.9 Furthermore, FEV1 has been considered the best predictor of mortality in subjects with CF,4,11,12 including those on lung transplant lists.36 Ac- cording to Kerem et al4 individuals with FEV1 � 30\% of predicted should be referred for lung transplantation. Moor- croft et al5 showed that, despite the correlation of V̇O2 peak with survival, FEV1 is still the best indicator of prognosis. On the other hand, Rosenthal37 described that lung func- tion between 8 y and 12 y was a poor indicator of the risk of dying or being transplanted. Moreover, Pianosi et al12 demonstrated that the change in V̇O2 peak over time is more useful as a prognostic marker than the commonly used longitudinal decline in FEV1. In addition, abnormal- ities in aerobic fitness in early disease in stable subjects may reflect changes that are not detected with spirometry, given that Dodd et al38 have demonstrated that the corre- lation between thoracic computed tomography abnormal- ities and exercise limitation is stronger than the correlation between spirometry and BMI with exercise limitation. Thus, it is possible that V̇O2 peak is a better prognostic marker early in life than FEV1, considering that CPET is depen- dent on more than lung function and thus reflects the ef- fects of the disease on other organ systems earlier on; however, further studies are needed to directly address this question. Information obtained through CPET plays an important role in the care and follow-up of patients with CF because of its contribution to prognosis and functional informa- tion.18 Thus, an annual follow-up of V̇O2 peak is relevant to identify individuals at risk for a worsening prognosis,15 as well as those who may benefit from more intense ther- apy,39 considering that aerobic fitness correlates with sur-Ta bl e 3. N ew ca st le -O tt aw a S ca le : M et ho do lo gi ca l Q ua li ty of C oh or t S tu di es In cl ud ed in th e S ys te m at ic R ev ie w S tu dy R ep re se nt at iv en es s of th e E xp os ed C oh or t S el ec ti on of th e U ne xp os ed C oh or t† A sc er ta in m en t of E xp os ur e‡ O ut co m e of In te re st N ot P re se nt at S ta rt of S tu dy C on tr ol fo r Im po rt an t F ac to r or A dd it io na l F ac to r§ A ss es sm en t of O ut co m e F ol lo w -u p L on g E no ug h fo r O ut co m e to O cc ur � F ol lo w -u p of C oh or t A de qu at e T ot al Q ua li ty S co re H ul ze bo s et al 9 * * * * * * * * 8 V an de W ee rt -v an L ee uw en et al 1 0 * * * * * * 6 N gu ye n et al 2 7 * * * * * * * 7 P ia no si et al 1 2 * * * * * * * * 8 M oo rc ro ft et al 5 * * * * ** * * * 9 N ix on et al 1 1 * * * * ** * * * 9 A st ud y co ul d be aw ar de d a m ax im um of 1 st ar (* ) fo r ea ch it em ex ce pt fo r th e it em C on tr ol fo r Im po rt an t F ac to r or A dd it io na l F ac to r. T he de fi ni ti on /e xp la na ti on of ea ch co lu m n of th e N ew ca st le -O tt aw a S ca le is av ai la bl e on li ne .2 4 † T he ca te go ry do es no t ap pl y to th e ex po su re in ve st ig at ed in th e sy st em at ic re vi ew . T hu s, al l st ud ie s w er e eq ua ll y gr ad ed . ‡ D es cr ip ti on of th e er go m et er an d th e pr ot oc ol us ed . § A m ax im um of 2 st ar s co ul d be aw ar de d in th is it em . S tu di es re ce iv in g 1 st ar : T es te d F E V 1 on a m ul ti va ri at e, un iv ar ia te or m ix ed m od el an al ys is ; 2 st ar s: te st ed 3 of th e 4 va ri ab le s (a ge , bo dy m as s in de x, se x, an d ch ro ni c co lo ni za ti on by P se u d o m o n a s a er u g in o sa or B u rk h o ld er ia ce p a ci a ) in th e m od el s de sc ri be d pr ev io us ly . � C oh or t st ud ie s w it h a m ea n/ m ed ia n fo ll ow -u p ti m e � 5 y (6 0 m on th s) re ce iv ed 1 st ar ; if th e m ea n fo ll ow -u p ti m e w as no t cl ea rl y in di ca te d, th en th e st ud y re ce iv ed no st ar . PEAK OXYGEN UPTAKE AND MORTALITY IN CF RESPIRATORY CARE • JANUARY 2019 VOL 64 NO 1 95 vival in children12 and adults5,11 with CF. In addition, it is well-established that exercise increases V̇O2 peak, indicat- ing its importance as a therapeutic tool that could influ- ence prognosis.40 The studies included in this systematic review and meta- analysis showed variation in follow-up time, ranging from 2.8 y to 8 y. Considering that these are studies to evaluate mortality, a short follow-up time may be considered as a limitation because it could influence this outcome. In ad- dition, it is already known that the evolution of CF is characterized by a decline in lung function and exercise limitation,1 highlighting the role of long-term follow-up periods in the evaluation of mortality rates. As for the reported variables of CPET, the included studies showed a large variability, which prevented us from including some articles in certain analyses and to evaluate the influence of other variables such as ventila- tory reserve data, V̇E/V̇O2, and V̇E/V̇CO2. A high breathing reserve index at the lactate threshold represents a reduc- tion of pulmonary mechanical reserve and was already reported as a predictor of mortality in individuals with CF waiting for lung transplantation.25 In addition, V̇E/V̇O2 mea- Table 4. Variables Used as Mortality Predictors in Patients with Cystic Fibrosis Study Exercise Capacity Variables Other Variables Hulzebos et al9 V̇O2/kg (\% predicted): 2.96 (1.06–8.23)* FEV1\%: 17.84 (4.02–79.08)* Breathing reserve: 3.35 (1.19–9.48)* BMI: 8.1 (2.93–22.51)* Van de Weert-van Leeuwen et al10 Maximum V̇O2/kg (\% predicted) � 80: 96.3\% mortality† NA Maximum V̇O2/kg (\% predicted) � 80: 80.0\% mortality Nguyen et al27 Peak P(A-a)O2: 0.794 (0.668–0.943, P � .009)‡ FEV1\%: 1.015 (0.904–1.139, P � .80)‡ Body mass index: 1.8 (1.1–2.9, P � .03)‡ Pianosi et al12 Peak V̇O2 intercept: 0.910 (0.816–1.014, P � .09)* FEV1 intercept: 0.915 (0.868–0.964, P � .001)* Peak V̇O2 slope: 0.048 (0.005–0.430, P � .007)* FEV1 slope: 0.008 (0.0003–0.210, P � .004)* Moorcroft et al5 Peak V̇O2 (cut-off 56\%): 64\% sensitivity and 72\% specificity FEV1 (cut-off 55\%): 91\% sensitivity and 74\% specificity Nixon et al11 Peak V̇O2 \% (� 58 vs � 82): 3.2 (1.2–8.6, P � .02)§ FEV1\% (� 50 vs � 65): 1.1 (0.4–2.7, P � .83)§ Pseudomonas cepacia (present vs absent): 5.0 (2.6–9.5, P � .001)§ * Hazard ratio (95\% CI). † P � .02. ‡ Odds ratio (95\% CI). § Relative risk (95\% CI). V̇O2 � oxygen uptake P(A-a)O2 � alveolar-arterial oxygen difference BMI � body mass index Study or Subgroup Nguyen et al27 Moorcroft et al5 Total (95\% CI) Heterogeneity: Tau2 = 0; Chi2 = 0.039, df = 1 (P = .84); I2 = 0\% Test for overall effect: Z = −3.071 (P = .002) 51.8 53.7 66.1 66.6 14 22 36 37 65 102 .041 .02 .002 37.93 62.07 100 −0.656 (−1.284 to −0.028) −0.575 (−1.066 to −0.085) −0.606 (−0.993 to −0.219) 0 6 6 7 41 48 16 36 52 12 71 83 .035 .02 .039 23.46 76.54 100 19.615 (1,229 to 313,077) 3.20 (1.195 to 8.567) 4.896 (1.086 to 22.072) Study or Subgroup Pianosi et al12 Nixon et al11 Total (95\% CI) Total events Heterogeneity: Tau2 = 0.519; Chi2 = 1.461, df = 1 (P = .23); I2 = 31.56\% Test for overall effect: Z = 2.068 (P = .039) Non survivorA B Non survivor Means Total Means P Weight, \%Total Survivor Survivor IV, Random, 95\% CI Std. Mean Difference High peak VO2 . . Events EventsTotal P Weight, \%Total Low–moderate peak VO2 High peak VO2 . . Low–moderate peak VO2 M-H, Random, 95\% CI Risk Relative M-H, Random, 95\% CI Risk Relative IV, Random, 95\% CI Std. Mean Difference −1.00 −0.50 0.50 0.01 0.1 1 10 100 0 1.00 Fig. 2. Meta-analysis of studies that reported mean difference in V̇O2 peak between survival or non-survival groups (A) and the association (relative risk, 95\% CI) of V̇O2 peak (high vs. low–moderate) with mortality (B). Low V̇O2 peak was considered when � 45 mL/kg/min or 82\% of predicted. PEAK OXYGEN UPTAKE AND MORTALITY IN CF 96 RESPIRATORY CARE • JANUARY 2019 VOL 64 NO 1 surement has also been shown to be important in predict- ing mortality.5,9 Despite the relevance of the analyzed vari- ables, it is important to recognize that CPET is not widely available in CF centers and requires specific equipment and expert personnel to perform and interpret the test. On the other hand, increasing life expectancy and new thera- peutic options are changing the clinical presentation of CF, and markers such as lung function are better maintained over time, highlighting the importance of other factors such as aerobic fitness. Thus, studies designed to evaluate the prognostic value of CPET as compared to nutritional status, lung function, and other exercise tests are needed to further understand the role of aerobic fitness as a disease progression marker in CF. Regarding the methodological quality of the studies in- cluded, in general, a high quality was found because only 1 study10 presented a reasonable classification according to the Newcastle-Ottawa Scale, which strengthens our sys- tematic review and meta-analysis. In addition, the I2 test in the analysis of the difference between means did not show heterogeneity, and the relative risk analysis showed a low heterogeneity among the included studies, which may con- firm the power of the analysis presented, despite the small number of articles. One of the main limitations of this study is the small number of articles included in each analysis and the vari- ability of the parameters evaluated. Due to the different presentations of data, only 2 articles were included in each of the analyses. Therefore, it was not possible to perform a funnel chart to evaluate publication bias of the studies. A short follow-up period, especially for a …