Early Resuscitation in Paediatric Sepsis using Inotropes and Metabolic Support – A Randomized Controlled Pilot Study (RESPOND)

Sepsis and serious infections are one of the most common reasons for children to present to Emergency Departments and Intensive Care Units.  Septic shock is the result of an infection, triggering a complex response by the body resulting in decreased blood pressure.  Decreased blood pressure can contribute to a decreased blood supply to organs and subsequently failure of one or more organs can result.  We know that early recognition and rapid initiation of treatment can improve outcomes for children with sepsis and/or septic shock.

When patients are admitted to hospital with sepsis and/or septic shock there are a variety of therapies they may receive. These include a combination of antibiotics, intravenous fluids (given through a drip), drugs to increase the blood pressures (inotropes), steroids (Hydrocortisone) and vitamins.   However, there is limited evidence and consensus around the current recommended management for sepsis in children. This is the reason why we need to do this study.

We aim to investigate in a multicentre pilot randomised controlled trial the use of intravenous fluids, early inotropes, steroids (Hydrocortisone) and vitamins in children with sepsis and/or septic shock.

Information for parents and guardians of our patients

What is RESPOND

RESPOND stands for Early Resuscitation in Paediatric Sepsis using Inotropes and Metabolic Support- A Randomized Controlled Pilot Study.

Fluid sparing and early Inotropes

Administration of intravenous fluids remains the foundation management of children with sepsis and/or septic shock requiring sepsis resuscitation. However, the timing and amount of fluids given during sepsis resuscitation remains controversial.  There is current evidence to suggest that large or excessive administration of intravenous fluids may potentially cause further complications and increase length of hospital stay/admission. In view of the potential harm associated with high volume fluid administration, this study proposes use of less fluid (fluid sparing) in combination with early administration of inotropes (drugs which increase blood pressure and work by increasing heart contractility) will improve outcomes in children with sepsis and/or septic shock.

Metabolic support:

In children with sepsis and/or septic shock, steroids (hydrocortisone) are often administered to improve circulation and restore blood pressure. The use of steroids for treatment of severe infections has been studied for more than fifty years.  Currently there is no agreement amongst doctors around the world if administration of steroids improves the overall recovery and survival of children with sepsis and/or septic shock.

Over the last few years, evidence has suggested that administering Vitamin C and Thiamine (Vitamin B1), enhances the effects of steroids (Hydrocortisone) when used in the treatment of children with sepsis and/or septic shock. Vitamin C and Thiamine are widely, and safety used in critically ill patients. Vitamin C is a powerful and naturally occurring antioxidant and in children with sepsis and/or septic shock, low levels of circulating Vitamin C are reported. During sepsis and/or septic shock Vitamin C is known to have effects on multiple effects on capillaries which is thought to contribute to improving blood flow, preventing organ failure. Thiamine is a water-soluble vitamin which plays an essential role in cellular metabolism.  In patients with sepsis and/or septic shock the role of Thiamine is not clear, however Thiamine deficiency is common. The combination of hydrocortisone and vitamins (Vitamin C and Thiamine) is termed ‘metabolic support’.  It is thought the treatment of sepsis and/or septic shock with early metabolic resuscitation is thought to improve patient outcomes.

Why are we conducting the RESPOND trial?

Currently we do not know what is the best treatment for children with sepsis and/or septic shock.  The purpose of this study is to compare if treatment with a reduced amount of fluids in combination with early administration of inotropes, hydrocortisone, and vitamins (Vitamin C and Thiamine) is associated with less complications, faster recovery and improved outcomes of children with sepsis and/or septic shock in comparison to standard treatment.

Who can take part in the trial?

Inclusion criteria for the RESPOND ED (early inotropes versus standard fluid resuscitation)
Children age ≥28days and <18 years which are recognized as sepsis or septic shock, with the decision of the treating physician to launch the sepsis treatment bundle are eligible if patients have received at least 20ml/kg fluid bolus(es) in the past four hours and the clinician decides to continue treating signs of shock.

Inclusion criteria RESPOND PICU (metabolic resuscitation versus shock treatment)
Children age ≥28 days and <18 years which are admitted to the Paediatric Intensive Care Unit with a diagnosis of suspected septic shock requiring vasopressors/inotropes for >2 hours.

What does be part of RESPOND involve?

Children admitted to PICU/ED requiring medical treatment for septic shock, who meet the above inclusion criteria could be enrolled in this project. There is a 50/50 chance (coin toss) to either one of two (2) treatment groups and a portion of blood will be sampled.

  1. Fluid Sparing and Early Inotropes: small fluid bolus and commencement of inotrope infusion.
  2. Current Standard Care Fluid Management: large fluid bolus, prior to consideration of inotropes.

If there is no improvement in your child’s condition after the above treatment and they are admitted to the intensive care unit, they will then be eligible for the next intervention of the study. For the next part of the study your child will be randomly assigned again to either one of two (2) treatment groups

  1. Early Metabolic Treatment: receive Hydrocortisone, Vitamin C and Thiamine.
  2. Current Standard Care Treatment : ‘Standard Treatment’ does not include Hydrocortisone, Vitamin C or Thiamine. However, the standard treatment group can receive Hydrocortisone, Vitamin C or Thiamine if clinically indicated at the discretion of the Intensive Care medical team

When children may have suspected or known sepsis and/or septic shock, blood is sampled, and routine testing is conducted.  When routine sampling of bloods is occurring an additional small portion of blood will be collected and stored for future diagnostic discovery and validation of novel markers of sepsis and sepsis severity.

We will follow up the child at hospital discharge, one month and six months after their enrolment on the study to see how they are going. We will try and do this via a phone call, or mail unless the child is still in hospital. The one month follow up will include a brief five-minute questionnaire on how the child is going. The six month follow up will include surveys and questionnaires for parents to complete to help us understand how their child and family are going and the support needed for families that have a child who experienced sepsis. We will be asking you questions around your child’s development and quality of life. These questions will take approximately two hours to complete and parents will have the option to do so online, on paper or on the phone.

This study may not have any direct benefits for child enrolled, however it will help us find out if the management of sepsis and/or septic shock in children using the proposed treatment of fluid-sparing and metabolic support reduces complications, hospital length of stay and improves outcomes for children.

Consent

Where possible, we will talk to parents/guardians before starting the treatment and get the consent to include their child in the trial. However, due to the emergency nature of sepsis and septic shock, it is anticipated that in certain situations timely informed consent may not be feasible in which case consent to continue (delayed consent) will be used.  Our Children’s Health Queensland Hospital and Health Service Human Research Ethics Committee has given this study special approval, whereby children can be included in the study before you have given consent. This is because the RESPOND Study does not put child at risk of any harm. Informed consent will be sought from the parent/guardian as soon as possible once the child has been stabilized and the parent/guardian has had time to adjust to the emergency environment.

The Children’s Health Queensland Hospital and Health Service Human Research Ethics Committee (HREC) has approved this study. If you have any concerns and/or complaints about the project, the way it is being conducted or your child’s rights as a research participant, and would like to speak to someone independent of the project, please contact the HREC Coordinator.
t: 3069 7002
e: CHQETHICS@health.qld.gov.au

Participating sites

  • Queensland Children’s Hospital, Brisbane, Queensland, Australia
  • Gold Coast University Hospital, Gold Coast, Queensland, Australia
  • Sunshine Coast University Hospital, Birtinya, Queensland, Australia
  • Westmead Children’s Hospital, Sydney, New South Wales, Australia
  • Randwick Children’s Hospital, Sydney, New South Wales, Australia
  • Princess Margaret Children`s Hospital, Perth, Western Australia
  • Starship Children’s Hospital, Auckland, New Zealand

Reference

  1. Schlapbach LJ, Straney L, Alexander J, et al. Mortality related to invasive infections, sepsis, and septic shock in critically ill children in Australia and New Zealand, 2002-13: a multicentre retrospective cohort study. Lancet Infect Dis 2015;15:46-54.
  2. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med 2013;39:165-228.
  3. Reinhart K, Daniels R, Kissoon N, Machado FR, Schachter RD, Finfer S. Recognizing Sepsis as a Global Health Priority – A WHO Resolution. N Engl J Med 2017;377:414-7.
  4. Fleischmann C, Scherag A, Adhikari NK, et al. Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and Limitations. Am J Respir Crit Care Med 2016;193:259-72.
  5. Kissoon N, Uyeki TM. Sepsis and the Global Burden of Disease in Children. JAMA Pediatr 2016;170:107-8.
  6. Liu L, Oza S, Hogan D, et al. Global, regional, and national causes of child mortality in 2000-13, with projections to inform post-2015 priorities: an updated systematic analysis. Lancet 2015;385:430-40.
  7. Ladhani S, Pebody RG, Ramsay ME, Lamagni TL, Johnson AP, Sharland M. Continuing impact of infectious diseases on childhood deaths in England and Wales, 2003-2005. Pediatr Infect Dis J 2010;29:310-3.
  8. Lantto M, Renko M, Uhari M. Changes in infectious disease mortality in children during the past three decades. Pediatr Infect Dis J 2013;32:e355-9.
  9. Weiss SL, Fitzgerald JC, Pappachan J, et al. Global epidemiology of pediatric severe sepsis: the sepsis prevalence, outcomes, and therapies study. Am J Respir Crit Care Med 2015;191:1147-57.
  10. Hartman ME, Linde-Zwirble WT, Angus DC, Watson RS. Trends in the epidemiology of pediatric severe sepsis*. Pediatr Crit Care Med 2013;14:686-93.
  11. Schlapbach LJ, Aebischer M, Adams M, et al. Impact of sepsis on neurodevelopmental outcome in a Swiss National Cohort of extremely premature infants. Pediatrics 2011;128:e348-57.
  12. Venkatesh B, Finfer S, Cohen J, et al. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med 2018;378:797-808.
  13. Ostrowski JA, MacLaren G, Alexander J, et al. The burden of invasive infections in critically ill Indigenous children in Australia. Med J Aust 2017;206:78-84.
  14. Agyeman P, Schlapbach LJ, Giannoni E, et al. Epidemiology of Blood Culture-proven Bacterial Sepsis in Children in Switzerland – a Prospective Population-based Cohort Study. The Lancet Child and Adolescent Health 2017.
  15. Cvetkovic M, Lutman D, Ramnarayan P, Pathan N, Inwald DP, Peters MJ. Timing of death in children referred for intensive care with severe sepsis: implications for interventional studies. Pediatr Crit Care Med 2015;16:410-7.
  16. Schlapbach LJ, MacLaren G, Festa M, et al. Prediction of pediatric sepsis mortality within 1 h of intensive care admission. Intensive Care Med 2017;43:1085-96.
  17. Weiss SL, Balamuth F, Hensley J, et al. The Epidemiology of Hospital Death Following Pediatric Severe Sepsis: When, Why, and How Children With Sepsis Die. Pediatr Crit Care Med 2017;18:823-30.
  18. Weiss SL, Fitzgerald JC, Balamuth F, et al. Delayed antimicrobial therapy increases mortality and organ dysfunction duration in pediatric sepsis. Crit Care Med 2014;42:2409-17.
  19. Rhodes A, Phillips G, Beale R, et al. The Surviving Sepsis Campaign bundles and outcome: results from the International Multicentre Prevalence Study on Sepsis (the IMPreSS study). Intensive Care Med 2015;41:1620-8.
  20. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008;36:296-327.
  21. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med 2017;43:304-77.
  22. Institute TG. Stopping Sepsis: National Action Plan. 2018.
  23. Davis AL, Carcillo JA, Aneja RK, et al. American College of Critical Care Medicine Clinical Practice Parameters for Hemodynamic Support of Pediatric and Neonatal Septic Shock. Crit Care Med 2017;45:1061-93.
  24. Carcillo JA, Fields AI, American College of Critical Care Medicine Task Force Committee M. Clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock. Crit Care Med 2002;30:1365-78.
  25. Sinitsky L, Walls D, Nadel S, Inwald DP. Fluid overload at 48 hours is associated with respiratory morbidity but not mortality in a general PICU: retrospective cohort study. Pediatr Crit Care Med 2015;16:205-9.
  26. Angus DC, Barnato AE, Bell D, et al. A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators. Intensive Care Med 2015;41:1549-60.
  27. Maitland K, Kiguli S, Opoka RO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med 2011;364:2483-95.
  28. Inwald DP, Canter R, Woolfall K, et al. Restricted fluid bolus volume in early septic shock: results of the Fluids in Shock pilot trial. Arch Dis Child 2019;104:426-31.
  29. Macdonald SPJ, Keijzers G, Taylor DM, et al. Restricted fluid resuscitation in suspected sepsis associated hypotension (REFRESH): a pilot randomised controlled trial. Intensive Care Med 2018;44:2070-8.
  30. Macdonald SPJ, Taylor DM, Keijzers G, et al. REstricted Fluid REsuscitation in Sepsis-associated Hypotension (REFRESH): study protocol for a pilot randomised controlled trial. Trials 2017;18:399.
  31. Finfer S, Myburgh J, Bellomo R. Intravenous fluid therapy in critically ill adults. Nature reviews Nephrology 2018;14:541-57.
  32. Long E, Babl F, Dalziel S, et al. Fluid resuscitation for paediatric sepsis: A survey of senior emergency physicians in Australia and New Zealand. Emergency medicine Australasia : EMA 2015;27:245-50.
  33. Gelbart B, Schlapbach L, Festa M, al. e. Fluid bolus therapy in critically ill children: a survey of practice among paediatric intensive care doctors in Australia and New Zealand. Critical care and resuscitation : journal of the Australasian Academy of Critical Care Medicine 2018;in press.
  34. Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med 2018;378:809-18.
  35. Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862-71.
  36. Annane D, Pastores SM, Arlt W, et al. Critical illness-related corticosteroid insufficiency (CIRCI): a narrative review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM). Intensive Care Med 2017;43:1781-92.
  37. Annane D, Pastores SM, Rochwerg B, et al. Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Intensive Care Med 2017;43:1751-63.
  38. Wong HR, Atkinson SJ, Cvijanovich NZ, et al. Combining Prognostic and Predictive Enrichment Strategies to Identify Children With Septic Shock Responsive to Corticosteroids. Crit Care Med 2016;44:e1000-3.
  39. Wong HR, Cvijanovich NZ, Anas N, et al. Developing a clinically feasible personalized medicine approach to pediatric septic shock. Am J Respir Crit Care Med 2015;191:309-15.
  40. Menon K, McNally D, O’Hearn K, et al. A Randomized Controlled Trial of Corticosteroids in Pediatric Septic Shock: A Pilot Feasibility Study. Pediatr Crit Care Med 2017;18:505-12.
  41. Barabutis N, Khangoora V, Marik PE, Catravas JD. Hydrocortisone and Ascorbic Acid Synergistically Prevent and Repair Lipopolysaccharide-Induced Pulmonary Endothelial Barrier Dysfunction. Chest 2017;152:954-62.
  42. Sweeney TE, Perumal TM, Henao R, et al. A community approach to mortality prediction in sepsis via gene expression analysis. Nat Commun 2018;9:694.
  43. Donnino MW, Andersen LW, Chase M, et al. Randomized, Double-Blind, Placebo-Controlled Trial of Thiamine as a Metabolic Resuscitator in Septic Shock: A Pilot Study. Crit Care Med 2016;44:360-7.
  44. Moskowitz A, Andersen LW, Huang DT, et al. Ascorbic acid, corticosteroids, and thiamine in sepsis: a review of the biologic rationale and the present state of clinical evaluation. Crit Care 2018;22:283.
  45. Marik PE. “Vitamin S” (Steroids) and Vitamin C for the Treatment of Severe Sepsis and Septic Shock! Crit Care Med 2016;44:1228-9.
  46. Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest 2017;151:1229-38.
  47. Kuhn SO, Meissner K, Mayes LM, Bartels K. Vitamin C in sepsis. Curr Opin Anaesthesiol 2018;31:55-60.
  48. Talisa VB, Yende S, Seymour CW, Angus DC. Arguing for Adaptive Clinical Trials in Sepsis. Front Immunol 2018;9:1502.
  49. van Werkhoven CH, Harbarth S, Bonten MJM. Adaptive designs in clinical trials in critically ill patients: principles, advantages and pitfalls. Intensive Care Med 2019;45:678-82.
  50. Woodcock J, LaVange LM. Master Protocols to Study Multiple Therapies, Multiple Diseases, or Both. N Engl J Med 2017;377:62-70.
  51. Brown AR, Gajewski BJ, Aaronson LS, et al. A Bayesian comparative effectiveness trial in action: developing a platform for multisite study adaptive randomization. Trials 2016;17:428.
  52. Berry SM, Connor JT, Lewis RJ. The platform trial: an efficient strategy for evaluating multiple treatments. JAMA 2015;313:1619-20.
  53. Bhatt DL, Mehta C. Adaptive Designs for Clinical Trials. N Engl J Med 2016;375:65-74.
  54. Gasparini M, Chevret S. Intensive care medicine in 2050: clinical trials designs. Intensive Care Med 2019;45:668-70.
  55. Matics TJ, Sanchez-Pinto LN. Adaptation and Validation of a Pediatric Sequential Organ Failure Assessment Score and Evaluation of the Sepsis-3 Definitions in Critically Ill Children. JAMA Pediatr 2017;171:e172352.
  56. Schlapbach LJ, Straney L, Bellomo R, MacLaren G, Pilcher D. Prognostic accuracy of age-adapted SOFA, SIRS, PELOD-2, and qSOFA for in-hospital mortality among children with suspected infection admitted to the intensive care unit. Intensive Care Med 2017.
  57. Agyeman PKA, Schlapbach LJ, Giannoni E, et al. Epidemiology of blood culture-proven bacterial sepsis in children in Switzerland: a population-based cohort study. The Lancet Child & Adolescent Health 2017;1:124-33.
  58. Lin JC, Spinella PC, Fitzgerald JC, et al. New or Progressive Multiple Organ Dysfunction Syndrome in Pediatric Severe Sepsis: A Sepsis Phenotype With Higher Morbidity and Mortality. Pediatr Crit Care Med 2017;18:8-16.
  59. Woolfall K, Frith L, Gamble C, et al. How parents and practitioners experience research without prior consent (deferred consent) for emergency research involving children with life threatening conditions: a mixed method study. BMJ open 2015;5:e008522.
  60. Harron K, Woolfall K, Dwan K, et al. Deferred Consent for Randomized Controlled Trials in Emergency Care Settings. Pediatrics 2015;136:e1316-22.
  61. Brierley J, Larcher V. Emergency research in children: options for ethical recruitment. J Med Ethics 2011;37:429-32.
  62. Scott HF, Brou L, Deakyne SJ, Kempe A, Fairclough DL, Bajaj L. Association Between Early Lactate Levels and 30-Day Mortality in Clinically Suspected Sepsis in Children. JAMA Pediatr 2017;171:249-55.
  63. Schlapbach LJ, MacLaren G, Straney L. Venous vs Arterial Lactate and 30-Day Mortality in Pediatric Sepsis. JAMA Pediatr 2017;171:813.
  64. Shankar-Hari M, Phillips GS, Levy ML, et al. Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016;315:775-87.
  65. Morin L, Ray S, Wilson C, et al. Refractory septic shock in children: a European Society of Paediatric and Neonatal Intensive Care definition. Intensive Care Med 2016;42:1948-57.
  66. Scott HF, Brou L, Deakyne SJ, Fairclough DL, Kempe A, Bajaj L. Lactate Clearance and Normalization and Prolonged Organ Dysfunction in Pediatric Sepsis. J Pediatr 2016;170:149-55 e1-4.
  67. Heinrich S, Birkholz T, Ihmsen H, Irouschek A, Ackermann A, Schmidt J. Incidence and predictors of difficult laryngoscopy in 11,219 pediatric anesthesia procedures. Paediatr Anaesth 2012;22:729-36.
  68. Pollack MM, Holubkov R, Funai T, et al. Relationship between the functional status scale and the pediatric overall performance category and pediatric cerebral performance category scales. JAMA Pediatr 2014;168:671-6.
  69. Desai AD, Zhou C, Stanford S, Haaland W, Varni JW, Mangione-Smith RM. Validity and responsiveness of the pediatric quality of life inventory (PedsQL) 4.0 generic core scales in the pediatric inpatient setting. JAMA Pediatr 2014;168:1114-21.
  70. Farris RW, Weiss NS, Zimmerman JJ. Functional outcomes in pediatric severe sepsis: further analysis of the researching severe sepsis and organ dysfunction in children: a global perspective trial. Pediatr Crit Care Med 2013;14:835-42.
  71. Shoemaker WC, Belzberg H, Wo CC, et al. Multicenter study of noninvasive monitoring systems as alternatives to invasive monitoring of acutely ill emergency patients. Chest 1998;114:1643-52.
  72. Schlapbach LJ, Straney L, Gelbart B, et al. Burden of disease and change in practice in critically ill infants with bronchiolitis. Eur Respir J 2017;49.
  73. Richard J-C, Bayle F, Bourdin G, et al. Preload dependence indices to titrate volume expansion during septic shock: a randomized controlled trial. Critical Care 2015;19.

Location

Centre for Children’s Health Research
Queensland Children’s Hospital Precinct
Paediatric Critical Care Research Group
Level 6, 62 Graham Street
South Brisbane, Qld, 4101
Australia

Central team (CCHR – Brisbane)

For study queries contact

Study Coordinators

Zoe Sever
e: z.sever@uq.edu.au
Natalie Sharp
e: natalie.sharp2@health.qld.gov.au

e: respond@uq.edu.au

Principal Investigator

Dr Sai Raman
e: sainath.raman@uq.edu.au