A Statistical Analysis Proposal: Validity of ROX index for ...



A Statistical Analysis Proposal: Validity of ROX index for Nasal High Flow Therapy in Critical Care Patients, including those with hypercapnic respiratory failure Raquel D’ Espiney1*, Alex Robbins2*, Joe Vincent1, Vladimir Macavei1, J F Martin - Lazaro1 and Yize Wan2.Intensive Care Unit, Newham University Hospital. London, UK.Adult Critical Care Unit, Royal London Hospital, London, UK.*Co-authors contributed equally to this study IntroductionNasal high flow therapy (NHFT) has been shown to be an effective respiratory support in patients with hypoxaemic respiratory failureADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1164/rccm.201803-0589OC","ISSN":"15354970","abstract":"Rationale: One important concern during high-flow nasal cannula (HFNC) therapy in patients with acute hypoxemic respiratory failure is to not delay intubation. Objectives: To validate the diagnostic accuracy of an index (termed ROX and defined as the ratio of oxygen saturation as measured by pulse oximetry/FIO2 to respiratory rate) for determining HFNC outcome (need or not for intubation). Methods: This was a 2-year multicenter prospective observational cohort study including patients with pneumonia treated with HFNC. Identification was through Cox proportional hazards modeling of ROXassociation withHFNCoutcome. The most specific cutoff of the ROX index to predict HFNC failure and success was assessed. Measurements and Main Results: Among the 191 patients treated with HFNC in the validation cohort, 68 (35.6%) required intubation. The prediction accuracy of the ROX index increased over time (area under the receiver operating characteristic curve: 2 h, 0.679; 6 h, 0.703; 12 h, 0.759). ROX greater than or equal to 4.88 measured at 2 (hazard ratio, 0.434; 95% confidence interval, 0.264-0.715; P = 0.001), 6 (hazard ratio, 0.304; 95% confidence interval, 0.182-0.509; P,0.001), or 12 hours (hazard ratio, 0.291; 95% confidence interval, 0.161-0.524; P,0.001) after HFNC initiation was consistently associated with a lower risk for intubation. A ROX less than 2.85, less than 3.47, and less than 3.85 at 2, 6, and 12 hours of HFNC initiation, respectively, were predictors of HFNC failure. Patients who failed presented a lower increase in the values of the ROX index over the 12 hours. Among components of the index, oxygen saturation as measured by pulse oximetry/FIO2 had a greater weight than respiratory rate. Conclusions: In patients with pneumonia with acute respiratory failure treated with HFNC, ROX is an index that can help identify those patients with low and those with high risk for intubation.","author":[{"dropping-particle":"","family":"Roca","given":"Oriol","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Caralt","given":"Berta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Messika","given":"Jonathan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Samper","given":"Manuel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sztrymf","given":"Benjamin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hernández","given":"Gonzalo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"García-De-Acilu","given":"Marina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Frat","given":"Jean Pierre","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Masclans","given":"Joan R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ricard","given":"Jean Damien","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Respiratory and Critical Care Medicine","id":"ITEM-1","issue":"11","issued":{"date-parts":[["2019","6"]]},"page":"1368-1376","publisher":"American Thoracic Society","title":"An index combining respiratory rate and oxygenation to predict outcome of nasal high-flow therapy","type":"article-journal","volume":"199"},"uris":[""]}],"mendeley":{"formattedCitation":"¹","plainTextFormattedCitation":"1","previouslyFormattedCitation":"¹"},"properties":{"noteIndex":0},"schema":""}1. A ROX index (ROXI=[SpO2/FiO2]/RR), defined as the ratio of SpO2/FIO2 to respiratory rate, can predict the risk of failure. Patients who had a ROX index ≥4.88 after 2, 6 and 12 hours of HFNC therapy were less likely to be intubated, even after adjusting for potential covariates. However, studies of NHFT and the predictive ability of the ROX index have thus far frequently excluded those with hypercapnic respiratory failure, patients who represent a significant proportion of ICU admissions for ventilatory support.Clinical outcomes for patients treated with NHFT for hypercapnic respiratory failure are less well understood as research to date has frequently excluded hypercapnic patients. However, there is growing evidence that suggests NHFT could be beneficial in patients with Type II respiratory failure. ObjectivesThis retrospective observational cohort study aimed to validate the diagnostic accuracy of the ROX index for determining HFNC outcomes in those with Type 1 and Type 2 respiratory failure. Our objectives were:To demonstrate that a ROX index >4.88 is a predictive of HFNT success in those with type 1 respiratory failure and type 2 respiratory failureTo examine the ROX index values for those in Type 1 and 2 respiratory failure and investigate if the optimum predictive cut off values are significantly different between the 2 groups To use the ROX index to define a population of patients with Type 2 respiratory failure who benefit from HFNT and are unlikely to fail this treatment For those that fail HFNT in either group we will report the time to failure and test for significant difference OutcomesThe primary outcome is the failure of HFNT as demonstrated by escalation to non invasive ventilation, mechanical ventilation or death.Secondary outcomes are the time to failure of HFNT and survival to discharge from ICU.MethodsThis was a retrospective cohort study which included all patients admitted to Newham Intensive Care Unit and treated with Nasal high flow therapy for either hypoxaemic (Type 1 respiratory failure) or hypercapnic (Type 2 respiratory failure) during a one year period during 2019. Type 1 failure?is defined by a PaO2?of <8 kPa with a normal or low PaCO2.?Type 2 failure?is defined by a PaO2?of <8 kPa and a PaCO2?of >6 kPaADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1136/thorax.57.3.192","ISSN":"00406376","PMID":"11867822","abstract":"### Nomenclature\n\nNon-invasive ventilation (NIV) refers to the provision of ventilatory support through the patient's upper airway using a mask or similar device. This technique is distinguished from those which bypass the upper airway with a tracheal tube, laryngeal mask, or tracheostomy and are therefore considered invasive. In this document NIV refers to non-invasive positive pressure ventilation, and other less commonly used techniques such as external negative pressure or rocking beds will not be discussed. (NIPPV is an alternative abbreviation but it is more cumbersome and involves ambiguity as to whether “N” is for “non-invasive” or “nasal”.)\n\nContinuous positive airway pressure (CPAP) in this document refers to the non-invasive application of positive airway pressure, again using a face or nasal mask rather than in conjunction with invasive techniques. Although it might be open to debate as to whether the use of non-invasive CPAP in acute respiratory failure constitutes ventilatory support, it is included in this document because of the confusion which commonly arises between NIV and CPAP in clinical practice.\n\n### Background\n\nOne of the first descriptions of the use of NIV using nasal masks was for the treatment of hypoventilation at night in patients with neuromuscular disease.1,2 This has proved to be so successful that it has become widely accepted as the standard method of non-invasive ventilation used in patients with chronic hypercapnic respiratory failure caused by chest wall deformity, neuromuscular disease, or impaired central respiratory drive. It has largely replaced other modalities such as external negative pressure ventilation and rocking beds.\n\nWithin a few years of its introduction, NIV was starting to be used in acute hypercapnic respiratory failure and in patients with abnormal lungs rather than an impaired respiratory pump. Initial anecdotal reports were followed by larger series and then by randomised trials. Analysis of these trials has shown …","author":[{"dropping-particle":"","family":"Baudouin","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turner","given":"L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blumenthal","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cooper","given":"B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Davidson","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Davison","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Elliott","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kinnear","given":"William","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Paton","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sawicka","given":"E.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Thorax","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2002","3","1"]]},"page":"192-211","publisher":"BMJ Publishing Group Ltd","title":"Non-invasive ventilation in acute respiratory failure: British thoracic society standards of care committee","type":"article","volume":"57"},"uris":[""]}],"mendeley":{"formattedCitation":"²","plainTextFormattedCitation":"2"},"properties":{"noteIndex":0},"schema":""}2.Baseline demographic data including age, sex, comorbidities, reason for admission to intensive care, pre admission observations, pre initiation arterial blood gas results will be recorded. Respiratory observations will be recorded at 2, 6, 12 hours. Outcomes will be defined as failure of HFNT, demonstrated by either escalation to Non invasive ventilation, mechanical ventilation or death.For type 1 respiratory failure patients with subsequent arterial blood gases that demonstrate they have developed type 2 respiratory failure we will analyse them as members of the type 1 group throughout as this was the indication the HFNT was initially commenced for and developing type 2 failure is likely to represent failure of HFNT as a therapy for this patient. Data will be held in Excel (Microsoft Excel) and analysed in R (R Core Team). We will compare baseline variables between those admitted and treated with HFNT in Type 1 Respiratory failure and those admitted and treated for Type 2 respiratory failure. We will also compare baseline respiratory variables at 2, 6 and 12 hours.ROX Index validity will be assessed before the therapy (ROX0), at 2h (ROX2), at 6h (ROX6) and 12h (ROX12) two groups will be analysed those with type 1 and type 2 respiratory failure, this will then be subdivided into those successfully managed with HNFT and those who fail therapy, defined as escalation to Non invasive ventilation, mechanical ventilation or death. Quantitative variables will be expressed as median (interquartile range) and categorical variables will be expressed as frequency (percentage). Continuous variables will be compared using the Student t test or U-Mann Whitney test. Differences in categorical variables will be assessed with Chi square or Fisher exact test. Multiple imputation will be used to estimate data for missing fields and this will be used for the main analysisADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1136/bmj.b2393","ISSN":"17561833","PMID":"19564179","abstract":"We are enthusiastic about the potential for multiple imputation and other methods 14 to improve the validity of medical research results and to reduce the waste of resources caused by missing data. The cost of multiple imputation analyses is small compared with the cost of collecting the data. It would be a pity if the avoidable pitfalls of multiple imputation slowed progress towards the wider use of these methods. It is no longer excusable for missing values and the reason they arose to be swept under the carpet, nor for potentially misleading and inefficient analyses of complete cases to be considered adequate. We hope that the pitfalls and guidelines discussed here will contribute to the appropriate use and reporting of methods to deal with missing data.","author":[{"dropping-particle":"","family":"Sterne","given":"Jonathan A.C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"White","given":"Ian R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carlin","given":"John B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Spratt","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Royston","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kenward","given":"Michael G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wood","given":"Angela M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpenter","given":"James R.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"BMJ (Online)","id":"ITEM-1","issue":"7713","issued":{"date-parts":[["2009","7","18"]]},"page":"157-160","publisher":"British Medical Journal Publishing Group","title":"Multiple imputation for missing data in epidemiological and clinical research: Potential and pitfalls","type":"article","volume":"339"},"uris":[""]}],"mendeley":{"formattedCitation":"³","plainTextFormattedCitation":"3","previouslyFormattedCitation":"³"},"properties":{"noteIndex":0},"schema":""}3. However, as we are seeking to demonstrate that there is no difference in the outcomes for HFNT applied to Type 1 and 2 respiratory failure an overly conservative model with excessive imputed data may miss significant differences. Given this we will additionally handle data missingness with a pairwise deletion strategy which will be valid if missing data is missing at random. We will compare the ability of a ROX score to predict the success or failure of HFNT in those with T1RF and T2RF by calculating AUROC values, we will use the previously validated cut off of 4.88.We will undertake a uni- and multivariate Cox regression to describe the HR of having an ROX >4.88 to treatment failure as defined above. We will separate analysis by type of respiratory failure and in multivariate analysis include baseline demographics such as age, sex, comorbidities. We will also perform parametric testing on those that fail HFNT and demonstrate if there is a significant difference in the time to treatment failure between those with type 1 and type 2 respiratory failure.We will then calculate the optimum cut off from our data set by AUROCs for ROX at different interval and then use these to repeat comparisons.Given the expected low number of type 2 respiratory failure patients and to account for some patients who may develop both type 1 and type 2 respiratory failure during the same admission episode or progress from type 1 to type 2 respiratory failure we will add a sensitivity analysis to the Cox multivariate regression to give context to our results. Table 1. Baseline characteristicsT1RF T2RFAgeGenderComorbiditiesApache scoreTable 2. Respiratory Variables a 2,6,12 hours post initiationT1RF T2RFRR 2 HourssO2FiO2ROXRR 6 HourssO2FiO2ROX28575005441950011430054419500Figure 1. Receiver Operated Curves for ROX index and outcome in HFNT of T1RF and T2RFBibliographyADDIN Mendeley Bibliography CSL_BIBLIOGRAPHY 1. Roca O, Caralt B, Messika J, et al. An index combining respiratory rate and oxygenation to predict outcome of nasal high-flow therapy. Am J Respir Crit Care Med [Internet] American Thoracic Society; 2019 [cited 2020 Jul 2]; 199: 1368–76 Available from: . Baudouin S, Turner L, Blumenthal S, et al. Non-invasive ventilation in acute respiratory failure: British thoracic society standards of care committee [Internet]. Thorax. BMJ Publishing Group Ltd; 2002 [cited 2020 Jun 27]. p. 192–211 Available from: . Sterne JAC, White IR, Carlin JB, et al. Multiple imputation for missing data in epidemiological and clinical research: Potential and pitfalls [Internet]. BMJ. British Medical Journal Publishing Group; 2009 [cited 2020 Jun 27]. p. 157–60 Available from: ................
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