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Open Access 01-12-2022 | Diseases of the neuromuscular synapses and muscles | Study protocol

Paediatric Acute Respiratory Distress Syndrome Neuromuscular Blockade study (PAN-study): a phase IV randomised controlled trial of early neuromuscular blockade in moderate-to-severe paediatric acute respiratory distress syndrome

Authors: Michelle W. Rudolph, Sjoerdtje Slager, Johannes G. M. Burgerhof, Job B.M. van Woensel, Jan-Willem C. Alffenaar, Roelie M. Wösten - van Asperen, Matthijs de Hoog, Marloes M. IJland, Martin C. J. Kneyber, For the SKIC research consortium

Published in: Trials | Issue 1/2022

Abstract

Background

Paediatric acute respiratory distress syndrome (PARDS) is a manifestation of severe, life-threatening lung injury necessitating mechanical ventilation with mortality rates ranging up to 40–50%. Neuromuscular blockade agents (NMBAs) may be considered to prevent patient self-inflicted lung injury in PARDS patients, but two trials in adults with severe ARDS yielded conflicting results. To date, randomised controlled trials (RCT) examining the effectiveness and efficacy of NMBAs for PARDS are lacking. We hypothesise that using NMBAs for 48 h in paediatric patients younger than 5 years of age with early moderate-to-severe PARDS will lead to at least a 20% reduction in cumulative respiratory morbidity score 12 months after discharge from the paediatric intensive care unit (PICU).

Methods

This is a phase IV, multicentre, randomised, double-blind, placebo-controlled trial performed in level-3 PICUs in the Netherlands. Eligible for inclusion are children younger than 5 years of age requiring invasive mechanical ventilation with positive end-expiratory pressure (PEEP) ≥ 5 cm H₂O for moderate-to-severe PARDS occurring within the first 96 h of PICU admission. Patients are randomised to continuous infusion of rocuronium bromide or placebo for 48 h. The primary endpoint is the cumulative respiratory morbidity score 12 months after PICU discharge, adjusted for confounding by age, gestational age, family history of asthma and/or allergy, season in which questionnaire was filled out, day-care and parental smoking. Secondary outcomes include respiratory mechanics, oxygenation and ventilation metrics, pulmonary and systemic inflammation markers, prevalence of critical illness polyneuropathy and myopathy and metrics for patient outcome including ventilator free days at day 28, length of PICU and hospital stay, and mortality

Discussion

This is the first paediatric trial evaluating the effects of muscular paralysis in moderate-to-severe PARDS. The proposed study addresses a huge research gap identified by the Paediatric Acute Lung Injury Consensus Collaborative by evaluating practical needs regarding the treatment of PARDS. Paediatric critical care practitioners are inclined to use interventions such as NMBAs in the most critically ill. This liberal use must be weighed against potential side effects. The proposed study will provide much needed scientific support in the decision-making to start NMBAs in moderate-to-severe PARDS.

Trial registration

ClinicalTrials.govNCT02902055. Registered on September 15, 2016.

Schouten LR, Veltkamp F, Bos AP, van Woensel JB, Serpa Neto A, Schultz MJ, et al. Incidence and mortality of acute respiratory distress syndrome in children: a systematic review and meta-analysis. Crit Care Med. 2016;44(4):819–29. https://doi.org/10.1097/CCM.0000000000001388.CrossRefPubMed

Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1334–49. https://doi.org/10.1056/NEJM200005043421806.CrossRefPubMed

Tremblay LN, Slutsky AS. Ventilator-induced lung injury: from the bench to the bedside. Intensive Care Med. 2006;32(1):24–33. https://doi.org/10.1007/s00134-005-2817-8.CrossRefPubMed

Pinhu L, Whitehead T, Evans T, Griffiths M. Ventilator-associated lung injury. Lancet. 2003;361(9354):332–40. https://doi.org/10.1016/S0140-6736(03)12329-X.CrossRefPubMed

Terragni PP, Rosboch G, Tealdi A, Corno E, Menaldo E, Davini O, et al. Tidal hyperinflation during low tidal volume ventilation in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2007;175(2):160–6. https://doi.org/10.1164/rccm.200607-915OC.CrossRefPubMed

Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. The New England Journal of Medicine. 2010;363(12):1107–16. https://doi.org/10.1056/NEJMoa1005372.CrossRefPubMed

Alhazzani W, Alshahrani M, Jaeschke R, Forel JM, Papazian L, Sevransky J, et al. Neuromuscular blocking agents in acute respiratory distress syndrome: a systematic review and meta-analysis of randomized controlled trials. Crit Care. 2013;17(2):R43. https://doi.org/10.1186/cc12557.CrossRefPubMedPubMedCentral

Dizier S, Forel JM, Ayzac L, Richard JC, Hraiech S, Lehingue S, et al. Early hepatic dysfunction is associated with a worse outcome in patients presenting with acute respiratory distress syndrome: a post-hoc analysis of the ACURASYS and PROSEVA studies. PLoS One. 2015;10(12):e0144278. https://doi.org/10.1371/journal.pone.0144278.CrossRefPubMedPubMedCentral

Gainnier M, Roch A, Forel JM, Thirion X, Arnal JM, Donati S, et al. Effect of neuromuscular blocking agents on gas exchange in patients presenting with acute respiratory distress syndrome. Crit Care Med. 2004;32(1):113–9. https://doi.org/10.1097/01.CCM.0000104114.72614.BC.CrossRefPubMed

10.

Forel JM, Roch A, Marin V, Michelet P, Demory D, Blache JL, et al. Neuromuscular blocking agents decrease inflammatory response in patients presenting with acute respiratory distress syndrome. Crit Care Med. 2006;34(11):2749–57. https://doi.org/10.1097/01.CCM.0000239435.87433.0D.CrossRefPubMed

11.

National Heart L, Blood Institute PCTN, Moss M, Huang DT, Brower RG, Ferguson ND, et al. Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome. N Engl J Med. 2019;380(21):1997–2008. https://doi.org/10.1056/NEJMoa1901686.CrossRef

12.

Wilsterman ME, de Jager P, Blokpoel R, Frerichs I, Dijkstra SK, Albers MJ, et al. Short-term effects of neuromuscular blockade on global and regional lung mechanics, oxygenation and ventilation in pediatric acute hypoxemic respiratory failure. Ann Intensive Care. 2016;6(1):103. https://doi.org/10.1186/s13613-016-0206-9.CrossRefPubMedPubMedCentral

13.

Rowan CM, Klein MJ, Hsing DD, Dahmer MK, Spinella PC, Emeriaud G, et al. Early use of adjunctive therapies for pediatric acute respiratory distress syndrome: a PARDIE study. Am J Respir Crit Care Med. 2020;201(11):1389–97. https://doi.org/10.1164/rccm.201909-1807OC.CrossRefPubMedPubMedCentral

14.

Santschi M, Jouvet P, Leclerc F, Gauvin F, Newth CJ, Carroll CL, et al. Acute lung injury in children: therapeutic practice and feasibility of international clinical trials. Pediatr Crit Care Med. 2010;11(6):681–9. https://doi.org/10.1097/PCC.0b013e3181d904c0.CrossRefPubMed

15.

Santschi M, Randolph AG, Rimensberger PC, Jouvet P, Pediatric Acute Lung Injury Mechanical Ventilation Investigators tPALI, Sepsis Investigators N, et al. Mechanical ventilation strategies in children with acute lung injury: a survey on stated practice pattern*. Pediatr Crit Care Med. 2013;14:e332–7.CrossRef

16.

Valentine SL, Nadkarni VM, Curley MA, Pediatric Acute Lung Injury Consensus Conference G. Nonpulmonary treatments for pediatric acute respiratory distress syndrome: proceedings from the Pediatric Acute Lung Injury Consensus Conference. Pediatr Crit Care Med. 2015;16(5 Suppl 1):S73–85. https://doi.org/10.1097/PCC.0000000000000435.CrossRefPubMed

17.

Kneyber MCJ, de Luca D, Calderini E, Jarreau PH, Javouhey E, Lopez-Herce J, et al. Recommendations for mechanical ventilation of critically ill children from the Paediatric Mechanical Ventilation Consensus Conference (PEMVECC). Intensive Care Med. 2017;43(12):1764–80. https://doi.org/10.1007/s00134-017-4920-z.CrossRefPubMedPubMedCentral

18.

Chandra S, Goel S, Dawra R. Early Neuromuscular Blockade in Children with Pediatric Acute Respiratory Distress Syndrome. J Pediatr Intensive Care. 2020;9(3):201–6. https://doi.org/10.1055/s-0040-1708557.CrossRefPubMedPubMedCentral

19.

Bolton CF. Neuromuscular manifestations of critical illness. Muscle & nerve. 2005;32(2):140–63. https://doi.org/10.1002/mus.20304.CrossRef

20.

Martin LD, Bratton SL, Quint P, Mayock DE. Prospective documentation of sedative, analgesic, and neuromuscular blocking agent use in infants and children in the intensive care unit: a multicenter perspective. Pediatr Crit Care Med. 2001;2(3):205–10. https://doi.org/10.1097/00130478-200107000-00003.CrossRefPubMed

21.

Jain A, Wermuth HR, Dua A, Singh K, Maani CV. Rocuronium. Treasure Island (FL): StatPearls; 2020.

22.

Johnson PN, Miller J, Gormley AK. Continuous-infusion neuromuscular blocking agents in critically ill neonates and children. Pharmacotherapy. 2011;31(6):609–20. https://doi.org/10.1592/phco.31.6.609.CrossRefPubMed

23.

Dewachter P, Mouton-Faivre C. Allergic risk during paediatric anaesthesia. Annales francaises d'anesthesie et de reanimation. 2010;29(3):215–26. https://doi.org/10.1016/j.annfar.2009.11.014.CrossRefPubMed

24.

Field-Ridley A, Dharmar M, Steinhorn D, McDonald C, Marcin JP. ICU-Acquired Weakness Is Associated With Differences in Clinical Outcomes in Critically Ill Children. Pediatr Crit Care Med. 2016;17(1):53–7. https://doi.org/10.1097/PCC.0000000000000538.CrossRefPubMedPubMedCentral

25.

Pediatric Acute Lung Injury Consensus Conference G. Pediatric acute respiratory distress syndrome: consensus recommendations from the pediatric acute lung injury consensus conference. Pediatr Crit Care Med. 2015;16(5):428–39. https://doi.org/10.1097/PCC.0000000000000350.CrossRef

26.

Boerlage AA, Ista E, Duivenvoorden HJ, de Wildt SN, Tibboel D, van Dijk M. The COMFORT behaviour scale detects clinically meaningful effects of analgesic and sedative treatment. Eur J Pain. 2015;19(4):473–9. https://doi.org/10.1002/ejp.569.CrossRefPubMed

27.

Leclerc F, Duhamel A, Deken V, Le Reun C, Lacroix J, Leteurtre S, et al. Nonrespiratory pediatric logistic organ dysfunction-2 score is a good predictor of mortality in children with acute respiratory failure. Pediatr Crit Care Med. 2014;15(7):590–3. https://doi.org/10.1097/PCC.0000000000000184.CrossRefPubMed

28.

Plotz FB, Bouma AB, van Wijk JA, Kneyber MC, Bokenkamp A. Pediatric acute kidney injury in the ICU: an independent evaluation of pRIFLE criteria. Intensive Care Med. 2008;34(9):1713–7. https://doi.org/10.1007/s00134-008-1176-7.CrossRefPubMed

29.

Brunekreef B, Groot B, Rijcken B, Hoek G, Steenbekkers A, de Boer A. Reproducibility of childhood respiratory symptom questions. Eur Respir J. 1992;5:930–5.PubMed

30.

Boggs E, Minich N, Hibbs AM. Performance of commonly used respiratory questionnaire items in a cohort of infants born preterm. Open J Pediatr. 2013;3(03):260–5. https://doi.org/10.4236/ojped.2013.33045.CrossRefPubMedPubMedCentral

31.

Bird SJ. Diagnosis and management of critical illness polyneuropathy and critical illness myopathy. Curr Treat Options Neurol. 2007;9(2):85–92. https://doi.org/10.1007/s11940-007-0034-1.CrossRefPubMed

32.

Beardsley AL, Nitu ME, Cox EG, Benneyworth BD. An Evaluation of Various Ventilator-Associated Infection Criteria in a PICU. Pediatr Crit Care Med. 2016;17(1):73–80. https://doi.org/10.1097/PCC.0000000000000569.CrossRefPubMed

33.

Robinson PD, Latzin P, Verbanck S, Hall GL, Horsley A, Gappa M, et al. Consensus statement for inert gas washout measurement using multiple- and single- breath tests. Eur Respir J. 2013;41(3):507–22. https://doi.org/10.1183/09031936.00069712.CrossRefPubMed

34.

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):828–36. https://doi.org/10.1164/rccm.201810-2050CP.CrossRefPubMedPubMedCentral

35.

Pollack MM, Holubkov R, Funai T, Clark A, Moler F, Shanley T, et al. Relationship between the functional status scale and the pediatric overall performance category and pediatric cerebral performance category scales. JAMA pediatrics. 2014;168(7):671–6. https://doi.org/10.1001/jamapediatrics.2013.5316.CrossRefPubMedPubMedCentral

36.

Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. Journal of biomedical informatics. 2009;42(2):377–81. https://doi.org/10.1016/j.jbi.2008.08.010.CrossRefPubMed

37.

Harris PA, Taylor R, Minor BL, Elliott V, Fernandez M, O'Neal L, et al. The REDCap consortium: Building an international community of software platform partners. J Biomed Informat. 2019;95:103208.CrossRef

38.

Burmester M, Mok Q. How safe is non-bronchoscopic bronchoalveolar lavage in critically ill mechanically ventilated children? Intensive Care Med. 2001;27(4):716–21. https://doi.org/10.1007/s001340100904.CrossRefPubMedPubMedCentral

39.

Valentine SL, Nadkarni VM, Curley MA, Pediatric Acute Lung Injury Consensus Conference G. Nonpulmonary Treatments for Pediatric Acute Respiratory Distress Syndrome: Proceedings From the Pediatric Acute Lung Injury Consensus Conference. Pediatr Crit Care Med. 2015;16(5 Suppl 1):S73–85. https://doi.org/10.1097/PCC.0000000000000435.CrossRefPubMed

40.

Pollack MM, Holubkov R, Glass P, Dean JM, Meert KL, Zimmerman J, et al. Functional Status Scale: new pediatric outcome measure. Pediatrics. 2009;124(1):e18–28. https://doi.org/10.1542/peds.2008-1987.CrossRefPubMed

41.

Yehya N, Thomas NJ. Relevant Outcomes in Pediatric Acute Respiratory Distress Syndrome Studies. Frontiers in pediatrics. 2016;4:51. https://doi.org/10.3389/fped.2016.00051.CrossRefPubMedPubMedCentral

42.

Stick S. Pediatric origins of adult lung disease. 1. The contribution of airway development to paediatric and adult lung disease. Thorax. 2000;55(7):587–94. https://doi.org/10.1136/thorax.55.7.587.CrossRefPubMedPubMedCentral

43.

Tennant PW, Gibson GJ, Parker L, Pearce MS. Childhood respiratory illness and lung function at ages 14 and 50 years: childhood respiratory illness and lung function. Chest. 2010;137(1):146–55. https://doi.org/10.1378/chest.09-0352.CrossRefPubMed

44.

Svanes C, Sunyer J, Plana E, Dharmage S, Heinrich J, Jarvis D, et al. Early life origins of chronic obstructive pulmonary disease. Thorax. 2010;65(1):14–20. https://doi.org/10.1136/thx.2008.112136.CrossRefPubMed

45.

Stern DA, Morgan WJ, Wright AL, Guerra S, Martinez FD. Poor airway function in early infancy and lung function by age 22 years: a non-selective longitudinal cohort study. Lancet. 2007;370(9589):758–64. https://doi.org/10.1016/S0140-6736(07)61379-8.CrossRefPubMedPubMedCentral

46.

Vasquez-Hoyos P, Diaz-Rubio F, Monteverde-Fernandez N, Jaramillo-Bustamante JC, Carvajal C, Serra A, et al. Reduced PICU respiratory admissions during COVID-19. Arch Dis Child. 2020;106(8):808–11. https://doi.org/10.1136/archdischild-2020-320469.CrossRef

47.

Sperotto F, Wolfler A, Biban P, Montagnini L, Ocagli H, Comoretto R, et al. Unplanned and medical admissions to pediatric intensive care units significantly decreased during COVID-19 outbreak in Northern Italy. Eur J Pediatr. 2021;180(2):643–8. https://doi.org/10.1007/s00431-020-03832-z.CrossRefPubMed

Title: Paediatric Acute Respiratory Distress Syndrome Neuromuscular Blockade study (PAN-study): a phase IV randomised controlled trial of early neuromuscular blockade in moderate-to-severe paediatric acute respiratory distress syndrome
Authors: Michelle W. Rudolph
Sjoerdtje Slager
Johannes G. M. Burgerhof
Job B.M. van Woensel
Jan-Willem C. Alffenaar
Roelie M. Wösten - van Asperen
Matthijs de Hoog
Marloes M. IJland
Martin C. J. Kneyber
For the SKIC research consortium
Publication date: 01-12-2022
Publisher: BioMed Central
Keywords: Diseases of the neuromuscular synapses and muscles
Acute Respiratory Distress-Syndrome
Pediatric Intensive Care
Critical Illness Polyneuropathy
Myopathy
Rocuronium
Published in: Trials / Issue 1/2022
Electronic ISSN: 1745-6215
DOI: https://doi.org/10.1186/s13063-021-05927-w

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Paediatric Acute Respiratory Distress Syndrome Neuromuscular Blockade study (PAN-study): a phase IV randomised controlled trial of early neuromuscular blockade in moderate-to-severe paediatric acute respiratory distress syndrome

Abstract

Background

Methods

Discussion

Trial registration

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Discussion

Trial registration

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