Comparison of Ventilator-Free Days at 14 and 28 days as a Clinical Trial Outcome in Low- and Middle-Income Countries
Praveen Kumar-M, Pramod K Gupta
Children, Clinical trials, Composite outcome measures, Intensive care, Low- and middle-income countries, Ventilator-free days
Citation Information :
Kumar-M P, Gupta PK. Comparison of Ventilator-Free Days at 14 and 28 days as a Clinical Trial Outcome in Low- and Middle-Income Countries. Indian J Crit Care Med 2020; 24 (10):960-966.
Objectives: Reporting ventilator-free days (VFDs) with time frame of 28 days is a popular composite outcome measure (COM) in trials. However, early deaths and shorter pediatric intensive care unit (PICU) stay predominate in low- and middle-income countries (LMICs). A shorter time frame may reduce sample size required. We planned to compute sample size requirements for different effect sizes from datasets of previously conducted prospective studies for 28-day and 14-day time frames (VFD28 vs VFD14) to examine the hypothesis. Materials and methods: The VFD28 and VFD14 were defined. Datasets of five prospective studies from PICU of our hospital were analyzed to estimate sample sizes for target reductions of 1–9 days in VFDs and other COMs for the two time frames. Reconfirmation of results was done with datasets of two other studies from PICUs of two geographical extremes of the country. Results: Time-to-event occurred within 14 days in majority of patients. Sample size required for VFD14 is about one-fifth to one-sixth of what is required for VFD28 for target reductions of 1–9 days for all the enrolled studies. The same was true for other COMs as well. The hypothesis was supported by datasets of two other studies used for reconfirmation. Conclusion: Choice of time frame for assessing VFDs and other COMs in clinical trials should be guided by the clinical context. A shorter time frame may be rewarding in terms of smaller sample size in the prevalent clinical setting of LMICs. Further confirmation with more datasets and prospective studies is desirable.
Schoenfeld DA, Bernard GR. ARDS network. Statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome. Crit Care Med 2002;30(8):1772–1777. DOI: 10.1097/00003246-200208000-00016.
Weiss SL, Fitzgerald JC, Pappachan J, Wheeler D, Jaramillo-Bustamante JC, Salloo A, et al. Sepsis prevalence, outcomes, and therapies (SPROUT) study investigators and pediatric acute lung injury and sepsis investigators (PALISI) network. global epidemiology of pediatric severe sepsis: the sepsis prevalence, outcomes, and therapies study. Am J Respir Crit Care Med 2015;191(10):1147–1157. DOI: 10.1164/rccm.201412-2323OC.
Montori VM, Permanyer-Miralda G, Ferreira-González I, Busse JW, Pacheco-Huergo V, Bryant D, et al. Validity of composite end points in clinical trials. BMJ 2005;330(7491):594–596. DOI: 10.1136/bmj.330.7491.594.
Bodet-Contentin L, Frasca D, Tavernier E, Feuillet F, Foucher Y, Giraudeau B. Ventilator-free day outcomes can be misleading. Crit Care Med 2018;46(3):425–429. DOI: 10.1097/CCM.0000000000002890.
Contentin L, Ehrmann S, Giraudeau B. Heterogeneity in the definition of mechanical ventilation duration and ventilator-free days. Am J Respir Crit Care Med 2014;189(8):998–1002. DOI: 10.1164/rccm.201308-1499LE.
Hernández G, Ospina-Tascón GA, Damiani LP, Estenssoro E, Dubin A, Hurtado J, et al. For the ANDROMEDA-SHOCK investigators and the latin America intensive care network (LIVEN). Effect of a resuscitation strategy targeting peripheral perfusion status vs Serum lactate levels on 28-day mortality among patients with septic shock: the ANDROMEDA-SHOCK randomized clinical trial. JAMA 2019;321(7):654–664. DOI: 10.1001/jama.2019.0071.
Weiss SL, Fitzgerald JC, Balamuth F, Alpern ER, Lavelle J, Chilutti M, et al. Delayed antimicrobial therapy increases mortality and organ dysfunction duration in pediatric sepsis. Crit Care Med 2014;42(11):2409–2417. DOI: 10.1097/CCM.0000000000000509.
Moisey LL, Mourtzakis M, Cotton BA, Premji T, Heyland DK, Wade CE, et al. Skeletal muscle predicts ventilator-free days, ICU-free days, and mortality in elderly ICU patients. Crit Care 2013;17(5):R206. DOI: 10.1186/cc12901.
Fu Y, Chong SL, Lee JH, Liu C, Fu S, Loh TF, et al. The impact of early hyperglycaemia on children with traumatic brain injury. Brain Inj 2017;31(3):396–400. DOI: 10.1080/02699052.2016.1264629.
Agus MS, Wypij D, Hirshberg EL, Srinivasan V, Faustino EV, Luckett PM, et al. HALF-PINT study investigators and the PALISI network. Tight glycemic control in critically ill children. N Engl J Med 2017;376(8):729–741. DOI: 10.1056/NEJMoa1612348.
Kelmenson DA, Held N, Allen RR, Quan D, Burnham EL, Clark BJ, et al. Outcomes of ICU patients with a discharge diagnosis of critical illness polyneuromyopathy: a propensity-matched analysis. Crit Care Med 2017;45(12):2055–2060. DOI: 10.1097/CCM.0000000000002763.
Yoshikawa H, Iwata M, Matsuzaki H, Ono R, Murakami Y, Taba N, et al. Impact of omalizumab on medical cost of childhood asthma in Japan. Pediatr Int 2016;58(5):425–428. DOI: 10.1111/ped.12936.
Watson RS, Carcillo JA. Scope and epidemiology of pediatric sepsis. Pediatr Crit Care Med 2005;6(3 Suppl):S3–S5. DOI: 10.1097/01.PCC.0000161289.22464.C3.
Carcillo JA, Sward K, Halstead ES, Telford R, Jimenez-Bacardi A, Shakoory B, et al. Eunice kennedy shriver national institute of child health and human development collaborative pediatric critical care research network Investigators. A systemic inflammation mortality risk assessment contingency table for severe sepsis. Pediatr Crit Care Med 2017;18(2):143–150. DOI: 10.1097/PCC.0000000000001029.
Carcillo JA, Halstead ES, Hall MW, Nguyen TC, Reeder R, Aneja R, et al. Eunice kennedy shriver national institute of child health and human development collaborative pediatric critical care research network investigators. Three hypothetical inflammation pathobiology phenotypes and pediatric sepsis-induced multiple organ failure outcome. Pediatr Crit Care Med 2017;18(6):513–523. DOI: 10.1097/PCC.0000000000001122.
Spicer AC, Calfee CS, Zinter MS, Khemani RG, Lo VP, Alkhouli MF, et al. A simple and robust bedside model for mortality risk in pediatric patients with acute respiratory distress syndrome. Pediatr Crit Care Med 2016;17(10):907–916. DOI: 10.1097/PCC.0000000000000865.
Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, et al. ACURASYS study investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 2010;363(12):1107–1116. DOI: 10.1056/NEJMoa1005372.
Baranwal AK, Murthy AS, Singhi SC. High-dose oral ambroxol for early treatment of pulmonary acute respiratory distress syndrome: an exploratory, randomized, controlled pilot trial. J Trop Pediatr 2015;61(5):339–350. DOI: 10.1093/tropej/fmv033.
Ghosh S, Baranwal AK, Bhatia P, Nallasamy K. Suspecting hyperferritinemic sepsis in iron-deficient population: do we need a lower plasma ferritin threshold? Pediatr Crit Care Med 2018;19(7):e367–e373. DOI: 10.1097/PCC.0000000000001584.
Tan B, Wong JJ, Sultana R, Koh JCJW, Jit M, Mok YH, et al. Global case-fatality rates in pediatric severe sepsis and septic shock: a systematic review and meta-analysis. JAMA Pediatr 2019;173(4):352–362. DOI: 10.1001/jamapediatrics.2018.4839.
Haque A, Siddiqui NR, Munir O, Saleem S, Mian A. Association between vasoactive-inotropic score and mortality in pediatric septic shock. Indian Pediatr 2015;52(4):311–313. DOI: 10.1007/s13312-015-0630-1.
Khan MR, Maheshwari PK, Masood K, Qamar FN, Haque AU. Epidemiology and outcome of sepsis in a tertiary care PICU of Pakistan. Indian J Pediatr 2012;79(11):1454–1458. DOI: 10.1007/s12098-012-0706-z.
Kaur G, Vinayak N, Mittal K, Kaushik JS, Aamir M. Clinical outcome and predictors of mortality in children with sepsis, severe sepsis, and septic shock from Rohtak, Haryana: a prospective observational study. Indian J Crit Care Med 2014;18(7):437–441. DOI: 10.4103/0972-5229.136072.
Barreira ER, Munoz GO, Cavalheiro PO, Suzuki AS, Degaspare NV, Shieh HH, et al. Epidemiology and outcomes of acute respiratory distress syndrome in children according to the Berlin definition: a multicenter prospective study. Crit Care Med 2015;43(5):947–953. DOI: 10.1097/CCM.0000000000000866.
Gupta S, Sankar J, Lodha R, Kabra SK. Comparison of prevalence and outcomes of pediatric acute respiratory distress syndrome using pediatric acute lung injury consensus conference criteria and Berlin definition. Front Pediatr 2018;6:93. DOI: 10.3389/fped. 2018.00093.
Lalgudi Ganesan S, Jayashree M, Chandra Singhi S, Bansal A. Airway pressure release ventilation in pediatric acute respiratory distress syndrome. A randomized controlled trial. Am J Respir Crit Care Med 2018;198(9):1199–1207. DOI: 10.1164/rccm.201705-0989OC.
Wong JJ, Loh TF, Testoni D, Yeo JG, Mok YH, Lee JH. Epidemiology of pediatric acute respiratory distress syndrome in Singapore: risk factors and predictive respiratory indices for mortality. Front Pediatr 2014;2:78. DOI: 10.3389/fped.2014.00078.
Kumar R, Singhi S, Singhi P, Jayashree M, Bansal A, Bhatti A. Randomized controlled trial comparing cerebral perfusion pressure-targeted therapy versus intracranial pressure-targeted therapy for raised intracranial pressure due to acute CNS infections in children. Crit Care Med 2014;42(8):1775–1787. DOI: 10.1097/CCM.0000000000000298.
Panico FF, Troster EJ, Oliveira CS, Faria A, Lucena M, João PRD, et al. Risk factors for mortality and outcomes in pediatric acute lung injury/acute respiratory distress syndrome. Pediatr Crit Care Med 2015;16(7):e194–e200. DOI: 10.1097/PCC.0000000000000490.
Rudd KE, Kissoon N, Limmathurotsakul D, Bory S, Mutahunga B, Seymour CW, et al. The global burden of sepsis: barriers and potential solutions. Crit Care 2018;22(1):232. DOI: 10.1186/s13054-018- 2157-z.
Yehya N, Harhay MO, Curley MAQ, Schoenfeld DA, Reeder RW. Reappraisal of ventilator-free days in critical care research. Am J Respir Crit Care Med 2019;200(7):828–836. DOI: 10.1164/rccm.201810-2050CP.
Aparna S, Efficacy of high dose oral ambroxol therapy in children ventilated for Acute Lung Injury: a randomized placebo-controlled double-blind pilot study. MD (Pediatrics) dissertation submitted to Postgraduate Institute of Medical Education & Research, Chandigarh, India. December, 2008.
Choudhary A, A pilot randomized controlled trial comparing lower versus higher hemoglobin threshold for transfusion in children with acute respiratory distress syndrome. DM (Pediatric Critical Care) dissertation submitted to Postgraduate Institute of Medical Education & Research, Chandigarh, India. December, 2016.
Gupta S, A randomized controlled trial of normal saline versus plasmalyte as resuscitation fluid in children with septic shock. DM (Pediatric Critical Care) dissertation submitted to Postgraduate Institute of Medical Education & Research, Chandigarh, India. December, 2016.
Yadav B, Bansal A, Jayashree M. Clinical profile and predictors of outcome of pediatric acute respiratory distress syndrome in a PICU: a prospective observational study. Pediatr Crit Care Med 2019;20(6):e263–e273. DOI: 10.1097/PCC.0000000000001924.
Jain P, Comparative study on the outcome of early goal-directed therapy (EGDT) versus standard care in pediatric septic shock patients: A prospective open labelled randomized controlled trial. DM (Pediatric Critical Care) dissertation submitted to Jawaharlal Institute of Postgraduate Medical Education & Research, Puducherry, India. December, 2017.
Core Team R, R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. (2018). Available at: https://www.R-project.org/ Accessed Jan 1, 2019.
Champely S, pwr: Basic Functions for Power Analysis. 2018; Available at: https://CRAN.R-project.org/package=pwr Accessed Jan 1, 2019.
Wickham H, ggplot2: Elegant Graphics for Data Analysis. 2016; Available at: http://ggplot2.org. Accessed Jan 1, 2019.
Robin X, Turck N, Hainard A, Tiberti N, Lisacek F, Sanchez JC, et al. pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinformatics 2011;12(1):77. DOI: 10.1186/1471-2105-12-77.
Moss M, Huang DT, Brower RG, Ferguson ND, Ginde AA, Gong MN, et al. Early neuromuscular blockade in the acute respiratory distress syndrome. N Engl J Med 2019;380(21):1997–2008. DOI: 10.1056/NEJMoa1901686.
Hirshberg EL, Lanspa MJ, Peterson J, Carpenter L, Wilson EL, Brown SM, et al. Randomized feasibility trial of a low tidal volume-airway pressure release ventilation protocol compared with traditional airway pressure release ventilation and volume control ventilation protocols. Crit Care Med 2018;46(12):1943–1952. DOI: 10.1097/CCM.0000000000003437.
Villar J, Ferrando C, Martínez D, Ambrós A, Muñoz T, Soler JA, et al. For dexamethasone in ARDS network. dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med 2020;8(3):267–276. DOI: 10.1016/S2213-2600(19)30417-5.
Novack V, Beitler JR, Yitshak-Sade M, Thompson BT, Schoenfeld DA, Rubenfeld G, et al. Alive and ventilator free: A hierarchical, composite outcome for clinical trials in the acute respiratory distress syndrome. Crit Care Med 2020;48(2):158–166. DOI: 10.1097/CCM.0000000000004104.