Evaluation of Corticosteroid Therapy in Childhood Severe Sepsis - a Randomised Pilot Study
Information source: Southampton University Hospitals NHS Trust
Information obtained from ClinicalTrials.gov on November 03, 2008
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Paediatric Sepsis; Pediatric Sepsis
Intervention: hydrocortisone (Drug)
Phase: Phase 2
Sponsored by: Southampton University Hospitals NHS Trust
Official(s) and/or principal investigator(s):
Saul N Faust, MBBS PhD, Study Chair, Affiliation: University of Southampton
Simon Nadel, MB BS, Principal Investigator, Affiliation: Imperial College London
Robert S Heyderman, MBBS PhD, Study Director, Affiliation: University of Liverpool
Diana M Gibb, MBChB MD, Study Director, Affiliation: Medical Research Council
Michael Levin, MBBCH PhD, Study Director, Affiliation: Imperial College London
Andrew Wolf, MBBChir MD, Principal Investigator, Affiliation: Univeristy of Bristol
John V Pappachan, MB BChir, Study Director, Affiliation: Southampton University Hospitals NHS Trust
Sarah Walker, MA PhD, Study Director, Affiliation: Medical Research Council
Carrol Gamble, PhD, Study Director, Affiliation: University of Liverpool / MCRN Clinical Trials Unit
Saul N Faust, MBBS PhD, Phone: 44 23 8079 4989, Email: firstname.lastname@example.org
Severe bacterial infections affecting multiple body organs, called severe sepsis (including
meningococcal sepsis), remain an important cause of death and disability among children.
Although early recognition, powerful antibiotics, and good intensive care have improved
outcome, we need new ways to further reduce the number of deaths. Research in adults has
shown that steroid replacement therapy might be useful. However, children are known to
respond differently to adults and a definitive trial in children is needed because of the
potentially harmful as well as beneficial effects of steroids.
This pilot study will provide the necessary information to allow the rational design of a
large trial conducted at multiple hospitals investigating the role of corticosteroid
replacement therapy in childhood sepsis. The study will provide information on how to measure
the effects of steroids, information on length of therapy and a better understanding of how
steroids work in children. The results emerging from this study will ultimately allow
paediatric intensive care clinicians to know whether or not steroids are safe and/or useful.
The primary objective of this open−label study is therefore to gather clinical and laboratory
data with which to inform the design of a large phase 3 double blind randomised controlled
trial (RCT). The study will provide basic limited safety data, information on length of
therapy and an assessment of possible clinical and laboratory endpoints to be used in
addition to mortality.
Definition of sepsis:
Presence of a documented infection (eg clinical evidence of pneumonia, skin or soft tissue
infection, purpura fulminans, urinary tract infection, abdominal infection) or a diagnostic
positive blood culture (community or hospital acquired) within the last 72 hours and at least
two of the following, one of which must be abnormal temperature or leucocyte count core
temperature of >38. 5°C or <36°C; tachycardia (mean heart rate >2 SD above normal for age);
mean respiratory rate > 2 SD above normal for age; leucocyte count elevated or depressed for
Definition of severe sepsis:
Sepsis plus cardiovascular organ dysfunction (the need for at least 5mcg/kg/min dopamine or
dobutamine, or any amount of adrenaline or noradrenaline support), acute respiratory distress
syndrome (ARDS), or 2 or more other organ dysfunctions.
Official title: Evaluation of Corticosteroid Therapy in Childhood Severe Sepsis (Steroids in Paediatric Sepsis, StePS) - a Randomised Pilot Study
Study design: Treatment, Randomized, Open Label, Uncontrolled, Parallel Assignment
primary efficacy endpoint is all cause mortality
primary toxicity endpoint is Serious Adverse Events, excluding sepsis-related events specified as secondary outcomes
time until shock reversal, defined as cessation of inotropic support for 24 hours
time to resolution of multiorgan dysfunction
time to resolution of base deficit
time to resolution of lactate
time to decision to discharge from ICU
laboratory analysis of adrenal function
laboratory analysis of inflammatory parameters (defined in protocol)
laboratory analysis of coagulation parameters (defined in protocol)
1. PURPOSE: The Need for a Paediatric Trial of Steroids in Sepsis - potential benefits and
risks Numerous targets for new therapies in sepsis have been identified, none of which
have been shown to have been of benefit in children. The results of adult studies cannot
therefore be extrapolated directly to childhood disease. Corticosteroids alter the
inflammatory balance in both beneficial and harmful ways in severe sepsis. Recent adult
studies have demonstrated transient adrenal insufficiency is associated with adverse
outcome and that corticosteroids increase survival in specific patient groups, and
steroid replacement has become a standard of care. There is little uniformity in the
approach to steroid replacement therapy amongst leading paediatric centres in the UK.
Expert opinion has emphasised that guidance is interim while awaiting appropriate
paediatric studies. Steroids are perceived as "safe" and "cheap" but should not be
introduced into paediatric practice without further research. Sepsis in childhood
differs in terms of mortality (around 10% overall in children vs in excess of 40% in
adults), background immunity, co−morbidity, and causative organisms. Given the lower
overall mortality in childhood sepsis, steroids have the potential to disrupt the
inflammatory balance in children causing greater harm than benefit. It is not known
which patients should be targeted for therapeutic intervention; what are the most
appropriate endpoints; whether the length of steroid therapy can be shorter in children;
or whether immunological rebound will occur.
2. DESIGN and METHODOLOGY:
This is an open randomised prospective pilot exploratory study of corticosteroid replacement
therapy in three centres. Adrenal function measurements will be assessed on entry to the
study. To investigate the inflammatory profile and the impact of corticosteroid replacement,
blood will be taken for cytokine and coagulation protein analysis. This study will provide
the pilot data necessary for the design of a definitive trial of corticosteroid replacement
therapy with the identification of variables likely to improve our ability to stratify
patients for intervention and the mechanistic characterisation of the modulatory effects of
steroids on inflammation in children with severe sepsis. Enrolment will be undertaken in two
stages (see flowsheet diagrams in protocol). Forty five eligible children will be randomly
allocated to steroid replacement therapy for 2 days (n=30) or intensive investigation without
intervention (n=15) in a 2: 1 randomisation (stage 1); 45 subjects (stage 2) will then be
randomly allocated to steroid replacement therapy for 5 days (n=30) or intensive
investigation without intervention (n=15). Randomisation will the undertaken in accordance
with a computer−generated list and will be stratified by age (<1 years; 1 year or more).
Progression from stage 1 to stage 2 will follow an interim analysis by a Trial Monitoring
Group to ensure safety. This escalating approach will provide safety data, information on
length of therapy and an assessment of possible clinical and laboratory endpoints in addition
to mortality, reducing the potential for adverse events in the pilot phase while providing
data relevant to this population. A large excess of serious adverse events in stage 1 will
result in study termination. After careful consideration by the investigators and during the
peer review process, placebo will not be used in this study, which will inform a future large
phase 3 randomised controlled trial.
RESEARCH PARTICIPANTS WILL RECEIVE THE FOLLOWING INTERVENTIONS THAT ARE NOT PART OF ROUTINE
CLINICAL CARE (Please also refer to figures 1−4 in the protocol that we are unable to
reproduce here): Children will be screened on admission to PICU. Entry into the study
following consent involves a clinical test of endocrine function involving 2 blood tests. The
list of procedures conducted in the study is as follows:
1. confirm eligibility requirements, assess pre−existing conditions and medical history,
record weight, height, vital signs, data to inform clinical severity scores, complete
infection assessment, clinically relevant laboratory investigations
2. corticotrophin stimulation test
3. multiple study samples (endocrine, cytokine and coagulation tests)
4. corticosteroid treatment if randomised to treatment group
5. follow−up in routine clinic
Minimum age: 3 Months.
Maximum age: 14 Years.
- Severe sepsis where enrolment can occur within 20 hours of first contact with
paediatric intensive care, or within 20 hours of the diagnosis of severe sepsis when
this diagnosis is made on PICU. Randomisation should occur within 24 hours of first
contact with paediatric intensive care, or within 24 hours of the diagnosis of severe
sepsis when this diagnosis is made on PICU.
- Requiring mechanical ventilation (The subjects must be mechanically ventilated for
entry into the study but this is not time limited. It is routine practice at study
centres to pre-emptively ventilate children with evolving sepsis)
- Concomitant steroid therapy, vasopressor treatment >24 hrs or use of etomidate (not
recommended for use in children less than 10 years and selectively inhibits 11
- Patients who have a recognised indication for steroids
- Other immunosuppressive/immunomodulatory therapy (not including intravenous
immunoglobulin which is considered standard therapy in toxic shock syndrome and may be
given for this indication)
- Significant immunocompromise (eg HIV infection)
- Advanced malignancy
- Cardiopulmonary resuscitation
- Children not likely to survive the time period of the maximum study intervention (5
- Patients who have undergone organ transplantation (including bone marrow
- Patients undergoing plasma exchange or whole blood exchange transfusion
- Treatment with an investigational drug or device within the last 30 days prior to
- Patients who have experienced a prior episode of infection or sepsis during the
- Patients who are pregnant (a pregnancy test will be carried out for females of 11
years and above as is standard practice for clinical trials).
- Immediate families of investigators or site personnel directly affiliated with the
study. Immediate family is defined as child or sibling, whether biological or legally
Locations and Contacts
Saul N Faust, MBBS PhD, Phone: 44 23 8079 4989, Email: email@example.com
Southampton University Hospitals NHS Trust, Southampton, UK SO16 6YD, United Kingdom; Recruiting
Saul N Faust, MBBS PhD, Phone: 44 23 8079 4989, Email: firstname.lastname@example.org
Helen Cracknell, Phone: 44 7917 560685, Email: email@example.com
Saul N Faust, Principal Investigator
John V Pappachan, Sub-Investigator
Michael Marsh, Sub-Investigator
Iain Macintosh, Sub-Investigator
Peter Wilson, Sub-Investigator
Kim Sykes, Sub-Investigator
Gareth Jones, Sub-Investigator
Serena Cotterell, Sub-Investigator
Imperial College Healthcare NHS Trust, London, UK W2 1NY, United Kingdom; Not yet recruiting
Simon Nadel, Phone: 44 20 7886 2494, Email: firstname.lastname@example.org
Annabelle Smale, Email: Annabelle.Smale@imperial.nhs.uk
Simon Nadel, Principal Investigator
Michael Levin, Sub-Investigator
Parviz Habibi, Sub-Investigator
David Inwald, Sub-Investigator
Mehrengise Cooper, Sub-Investigator
Bristol Royal Hospital for Children, Bristol, UK BS2 8BJ, United Kingdom; Not yet recruiting
Andrew Wolf, Phone: 44 7919 974721, Email: email@example.com
Natalie Fineman, Phone: 44 117 342 0211, Email: firstname.lastname@example.org
Andrew Wolf, Principal Investigator
James Fraser, Sub-Investigator
Stephen Marriage, Sub-Investigator
Peter Davis, Sub-Investigator
Margrid Schindler, Sub-Investigator
David Grant, Sub-Investigator
Ian Jenkins, Sub-Investigator
Patricia Weir, Sub-Investigator
Peter Murphy, Sub-Investigator
UK NIHR Medicines For Children Research Network
Aneja R, Carcillo JA. What is the rationale for hydrocortisone treatment in children with infection-related adrenal insufficiency and septic shock? Arch Dis Child. 2007 Feb;92(2):165-9. Epub 2006 Sep 26. Review.
Booy R, Habibi P, Nadel S, de Munter C, Britto J, Morrison A, Levin M; Meningococcal Research Group. Reduction in case fatality rate from meningococcal disease associated with improved healthcare delivery. Arch Dis Child. 2001 Nov;85(5):386-90.
Despond O, Proulx F, Carcillo JA, Lacroix J. Pediatric sepsis and multiple organ dysfunction syndrome. Curr Opin Pediatr. 2001 Jun;13(3):247-53. Review.
Stoll BJ, Holman RC, Schuchat A. Decline in sepsis-associated neonatal and infant deaths in the United States, 1979 through 1994. Pediatrics. 1998 Aug;102(2):e18.
Thorburn K, Baines P, Thomson A, Hart CA. Mortality in severe meningococcal disease. Arch Dis Child. 2001 Nov;85(5):382-5.
Watson RS, Carcillo JA, Linde-Zwirble WT, Clermont G, Lidicker J, Angus DC. The epidemiology of severe sepsis in children in the United States. Am J Respir Crit Care Med. 2003 Mar 1;167(5):695-701. Epub 2002 Nov 14.
Cohen J. The immunopathogenesis of sepsis. Nature. 2002 Dec 19-26;420(6917):885-91. Review.
Boldrick JC, Alizadeh AA, Diehn M, Dudoit S, Liu CL, Belcher CE, Botstein D, Staudt LM, Brown PO, Relman DA. Stereotyped and specific gene expression programs in human innate immune responses to bacteria. Proc Natl Acad Sci U S A. 2002 Jan 22;99(2):972-7.
Nau GJ, Richmond JF, Schlesinger A, Jennings EG, Lander ES, Young RA. Human macrophage activation programs induced by bacterial pathogens. Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1503-8. Epub 2002 Jan 22.
Faust SN, Heyderman RS, Levin M. Disseminated intravascular coagulation and purpura fulminans secondary to infection. Baillieres Best Pract Res Clin Haematol. 2000 Jun;13(2):179-97. Review.
Bone RC, Grodzin CJ, Balk RA. Sepsis: a new hypothesis for pathogenesis of the disease process. Chest. 1997 Jul;112(1):235-43. Review. No abstract available.
van Dissel JT, van Langevelde P, Westendorp RG, Kwappenberg K, Frölich M. Anti-inflammatory cytokine profile and mortality in febrile patients. Lancet. 1998 Mar 28;351(9107):950-3.
Hotchkiss RS, Swanson PE, Freeman BD, Tinsley KW, Cobb JP, Matuschak GM, Buchman TG, Karl IE. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med. 1999 Jul;27(7):1230-51.
Hibberd ML, Sumiya M, Summerfield JA, Booy R, Levin M. Association of variants of the gene for mannose-binding lectin with susceptibility to meningococcal disease. Meningococcal Research Group. Lancet. 1999 Mar 27;353(9158):1049-53.
Nadel S, Newport MJ, Booy R, Levin M. Variation in the tumor necrosis factor-alpha gene promoter region may be associated with death from meningococcal disease. J Infect Dis. 1996 Oct;174(4):878-80.
Arnalich F, López-Maderuelo D, Codoceo R, Lopez J, Solis-Garrido LM, Capiscol C, Fernandez-Capitán C, Madero R, Montiel C. Interleukin-1 receptor antagonist gene polymorphism and mortality in patients with severe sepsis. Clin Exp Immunol. 2002 Feb;127(2):331-6.
Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001 Nov 8;345(19):1368-77.
van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive insulin therapy in the critically ill patients. N Engl J Med. 2001 Nov 8;345(19):1359-67.
Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr; Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001 Mar 8;344(10):699-709.
Marik PE, Zaloga GP. Adrenal insufficiency in the critically ill: a new look at an old problem. Chest. 2002 Nov;122(5):1784-96. Review.
Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med. 1987 Sep 10;317(11):653-8.
Sprung CL, Caralis PV, Marcial EH, Pierce M, Gelbard MA, Long WM, Duncan RC, Tendler MD, Karpf M. The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled study. N Engl J Med. 1984 Nov 1;311(18):1137-43.
Cronin L, Cook DJ, Carlet J, Heyland DK, King D, Lansang MA, Fisher CJ Jr. Corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature. Crit Care Med. 1995 Aug;23(8):1430-9.
Bollaert PE, Fieux F, Charpentier C, Lévy B. Baseline cortisol levels, cortisol response to corticotropin, and prognosis in late septic shock. Shock. 2003 Jan;19(1):13-5.
Hatherill M, Tibby SM, Hilliard T, Turner C, Murdoch IA. Adrenal insufficiency in septic shock. Arch Dis Child. 1999 Jan;80(1):51-5.
van Woensel JB, Biezeveld MH, Alders AM, Eerenberg AJ, Endert E, Hack EC, von Rosenstiel IA, Kuijpers TW. Adrenocorticotropic hormone and cortisol levels in relation to inflammatory response and disease severity in children with meningococcal disease. J Infect Dis. 2001 Dec 15;184(12):1532-7. Epub 2001 Dec 3.
Marik PE, Zaloga GP. Adrenal insufficiency during septic shock. Crit Care Med. 2003 Jan;31(1):141-5.
Annane D, Sebille V, Troche G, Raphael JC, Gajdos P, Bellissant E. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA. 2000 Feb 23;283(8):1038-45.
Pizarro CF, Troster EJ, Damiani D, Carcillo JA. Absolute and relative adrenal insufficiency in children with septic shock. Crit Care Med. 2005 Apr;33(4):855-9.
Bollaert PE, Charpentier C, Levy B, Debouverie M, Audibert G, Larcan A. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med. 1998 Apr;26(4):645-50.
Briegel J, Forst H, Haller M, Schelling G, Kilger E, Kuprat G, Hemmer B, Hummel T, Lenhart A, Heyduck M, Stoll C, Peter K. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study. Crit Care Med. 1999 Apr;27(4):723-32.
Briegel J, Kellermann W, Forst H, Haller M, Bittl M, Hoffmann GE, Büchler M, Uhl W, Peter K. Low-dose hydrocortisone infusion attenuates the systemic inflammatory response syndrome. The Phospholipase A2 Study Group. Clin Investig. 1994 Oct;72(10):782-7.
Keh D, Boehnke T, Weber-Cartens S, Schulz C, Ahlers O, Bercker S, Volk HD, Doecke WD, Falke KJ, Gerlach H. Immunologic and hemodynamic effects of "low-dose" hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover study. Am J Respir Crit Care Med. 2003 Feb 15;167(4):512-20. Epub 2002 Nov 8.
Leone M, Boutière-Albanèse B, Valette S, Camoin-Jau L, Barrau K, Albanèse J, Martin C, Dignat-George F. Cell adhesion molecules as a marker reflecting the reduction of endothelial activation induced by glucocorticoids. Shock. 2004 Apr;21(4):311-4.
Maxime V, Fitting C, Annane D, Cavaillon JM. Corticoids normalize leukocyte production of macrophage migration inhibitory factor in septic shock. J Infect Dis. 2005 Jan 1;191(1):138-44. Epub 2004 Nov 30.
Mussack T, Briegel J, Schelling G, Biberthaler P, Jochum M. Effect of stress doses of hydrocortisone on S-100B vs. interleukin-8 and polymorphonuclear elastase levels in human septic shock. Clin Chem Lab Med. 2005;43(3):259-68.
Oppert M, Schindler R, Husung C, Offermann K, Gräf KJ, Boenisch O, Barckow D, Frei U, Eckardt KU. Low-dose hydrocortisone improves shock reversal and reduces cytokine levels in early hyperdynamic septic shock. Crit Care Med. 2005 Nov;33(11):2457-64.
Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troche G, Chaumet-Riffaut P, Bellissant E. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002 Aug 21;288(7):862-71.
Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y. Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis. BMJ. 2004 Aug 28;329(7464):480. Epub 2004 Aug 2. Review.
Minneci PC, Deans KJ, Banks SM, Eichacker PQ, Natanson C. Meta-analysis: the effect of steroids on survival and shock during sepsis depends on the dose. Ann Intern Med. 2004 Jul 6;141(1):47-56. Review.
Prigent H, Maxime V, Annane D. Clinical review: corticotherapy in sepsis. Crit Care. 2004 Apr;8(2):122-9. Epub 2003 Sep 29. Review.
Keh D, Sprung CL. Use of corticosteroid therapy in patients with sepsis and septic shock: an evidence-based review. Crit Care Med. 2004 Nov;32(11 Suppl):S527-33. Review.
Sessler CN. Steroids for septic shock: back from the dead? (Con). Chest. 2003 May;123(5 Suppl):482S-9S. Review.
Fessler MB, O'Brien JM, Douglas IS. Laboratory predictors of relative adrenal insufficiency in septic shock. Crit Care Med. 2003 Aug;31(8):2251-2; author reply 2252-3. No abstract available.
Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, Weiss YG, Benbenishty J, Kalenka A, Forst H, Laterre PF, Reinhart K, Cuthbertson BH, Payen D, Briegel J; CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008 Jan 10;358(2):111-24.
Nadel S, Goldstein B, Williams MD, Dalton H, Peters M, Macias WL, Abd-Allah SA, Levy H, Angle R, Wang D, Sundin DP, Giroir B; REsearching severe Sepsis and Organ dysfunction in children: a gLobal perspective (RESOLVE) study group. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet. 2007 Mar 10;369(9564):836-43.
Hildebrandt T, Mansour M, Al Samsam R. The use of steroids in children with septicemia: review of the literature and assessment of current practice in PICUs in the UK. Paediatr Anaesth. 2005 May;15(5):358-65. Review. No abstract available.
Branco RG, Russell RR. Should steroids be used in children with meningococcal shock? Arch Dis Child. 2005 Nov;90(11):1195-6. Review. No abstract available.
Carcillo JA, Fields AI; American College of Critical Care Medicine Task Force Committee Members. Clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock. Crit Care Med. 2002 Jun;30(6):1365-78. Review.
Kleinman ME. Clinical practice parameters for pediatric and neonatal septic shock: to have or to have not? Crit Care Med. 2002 Jun;30(6):1400-1. No abstract available.
Parker MM, Hazelzet JA, Carcillo JA. Pediatric considerations. Crit Care Med. 2004 Nov;32(11 Suppl):S591-4. Review.
Feezor RJ, Cheng A, Paddock HN, Baker HV, Moldawer LL. Functional genomics and gene expression profiling in sepsis: beyond class prediction. Clin Infect Dis. 2005 Nov 15;41 Suppl 7:S427-35. Review.
Proulx F, Fayon M, Farrell CA, Lacroix J, Gauthier M. Epidemiology of sepsis and multiple organ dysfunction syndrome in children. Chest. 1996 Apr;109(4):1033-7.
Barsness KA, Bensard DD, Partrick DA, Calkins CM, Hendrickson RJ, McIntyre RC Jr. Endotoxin induces an exaggerated interleukin-10 response in peritoneal macrophages of children compared with adults. J Pediatr Surg. 2004 Jun;39(6):912-5; discussion 912-5.
Johnston JA, Yi MS, Britto MT, Mrus JM. Importance of organ dysfunction in determining hospital outcomes in children. J Pediatr. 2004 May;144(5):595-601.
Slater A, Shann F, Pearson G; Paediatric Index of Mortality (PIM) Study Group. PIM2: a revised version of the Paediatric Index of Mortality. Intensive Care Med. 2003 Feb;29(2):278-85. Epub 2003 Jan 23.
Leteurtre S, Duhamel A, Grandbastien B, Lacroix J, Leclerc F. Paediatric logistic organ dysfunction (PELOD) score. Lancet. 2006 Mar 18;367(9514):897; author reply 900-2. No abstract available.
Leteurtre S, Martinot A, Duhamel A, Proulx F, Grandbastien B, Cotting J, Gottesman R, Joffe A, Pfenninger J, Hubert P, Lacroix J, Leclerc F. Validation of the paediatric logistic organ dysfunction (PELOD) score: prospective, observational, multicentre study. Lancet. 2003 Jul 19;362(9379):192-7. Erratum in: Lancet. 2006 Mar 18;367(9514):897; author reply 900-2. Lancet. 2006 Mar 18;367(9514):902.
Vogeser M, Groetzner J, Küpper C, Briegel J. Free serum cortisol during the postoperative acute phase response determined by equilibrium dialysis liquid chromatography-tandem mass spectrometry. Clin Chem Lab Med. 2003 Feb;41(2):146-51.
Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free cortisol in critically ill patients. N Engl J Med. 2004 Apr 15;350(16):1629-38.
Arlt W, Hammer F, Sanning P, Butcher SK, Lord JM, Allolio B, Annane D, Stewart PM. Dissociation of serum dehydroepiandrosterone and dehydroepiandrosterone sulfate in septic shock. J Clin Endocrinol Metab. 2006 Jul;91(7):2548-54. Epub 2006 Apr 11.
Yu SL, Chen HW, Yang PC, Peck K, Tsai MH, Chen JJ, Lin FY. Differential gene expression in gram-negative and gram-positive sepsis. Am J Respir Crit Care Med. 2004 May 15;169(10):1135-43. Epub 2004 Mar 4.
Dorn LD, Lucke JF, Loucks TL, Berga SL. Salivary cortisol reflects serum cortisol: analysis of circadian profiles. Ann Clin Biochem. 2007 May;44(Pt 3):281-4.
Kirschbaum C, Hellhammer DH. Salivary cortisol in psychoneuroendocrine research: recent developments and applications. Psychoneuroendocrinology. 1994;19(4):313-33. Review.
Wetherell MA, Crown AL, Lightman SL, Miles JN, Kaye J, Vedhara K. The four-dimensional stress test: psychological, sympathetic-adrenal-medullary, parasympathetic and hypothalamic-pituitary-adrenal responses following inhalation of 35% CO2. Psychoneuroendocrinology. 2006 Jul;31(6):736-47. Epub 2006 Apr 18.
Faust SN, Levin M, Harrison OB, Goldin RD, Lockhart MS, Kondaveeti S, Laszik Z, Esmon CT, Heyderman RS. Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N Engl J Med. 2001 Aug 9;345(6):408-16.
Pathan N, Hemingway CA, Alizadeh AA, Stephens AC, Boldrick JC, Oragui EE, McCabe C, Welch SB, Whitney A, O'Gara P, Nadel S, Relman DA, Harding SE, Levin M. Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock. Lancet. 2004 Jan 17;363(9404):203-9.
Heyderman RS, Ison CA, Peakman M, Levin M, Klein NJ. Neutrophil response to Neisseria meningitidis: inhibition of adhesion molecule expression and phagocytosis by recombinant bactericidal/permeability-increasing protein (rBPI21). J Infect Dis. 1999 May;179(5):1288-92.
Klein NJ, Ison CA, Peakman M, Levin M, Hammerschmidt S, Frosch M, Heyderman RS. The influence of capsulation and lipooligosaccharide structure on neutrophil adhesion molecule expression and endothelial injury by Neisseria meningitidis. J Infect Dis. 1996 Jan;173(1):172-9.
Ison CA, Heyderman RS, Klein NJ, Peakman M, Levin M. Whole blood model of meningococcal bacteraemia--a method for exploring host-bacterial interactions. Microb Pathog. 1995 Feb;18(2):97-107.
Goldstein B, Giroir B, Randolph A; International Consensus Conference on Pediatric Sepsis. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med. 2005 Jan;6(1):2-8. Review.
Luscombe M, Owens B. Weight estimation in resuscitation: is the current formula still valid? Arch Dis Child. 2007 May;92(5):412-5. Epub 2007 Jan 9. Erratum in: Arch Dis Child. 2007 Jul;92(7):657.
Bellomo R, McGrath B, Boyce N. Effect of continuous venovenous hemofiltration with dialysis on hormone and catecholamine clearance in critically ill patients with acute renal failure. Crit Care Med. 1994 May;22(5):833-7.
Derkx B, Wittes J, McCloskey R. Randomized, placebo-controlled trial of HA-1A, a human monoclonal antibody to endotoxin, in children with meningococcal septic shock. European Pediatric Meningococcal Septic Shock Trial Study Group. Clin Infect Dis. 1999 Apr;28(4):770-7.
Levin M, Quint PA, Goldstein B, Barton P, Bradley JS, Shemie SD, Yeh T, Kim SS, Cafaro DP, Scannon PJ, Giroir BP. Recombinant bactericidal/permeability-increasing protein (rBPI21) as adjunctive treatment for children with severe meningococcal sepsis: a randomised trial. rBPI21 Meningococcal Sepsis Study Group. Lancet. 2000 Sep 16;356(9234):961-7.
Barton P, Kalil AC, Nadel S, Goldstein B, Okhuysen-Cawley R, Brilli RJ, Takano JS, Martin LD, Quint P, Yeh TS, Dalton HJ, Gessouron MR, Brown KE, Betts H, Levin M, Macias WL, Small DS, Wyss VL, Bates BM, Utterback BG, Giroir BP. Safety, pharmacokinetics, and pharmacodynamics of drotrecogin alfa (activated) in children with severe sepsis. Pediatrics. 2004 Jan;113(1 Pt 1):7-17.
Humphreys N, Bays SM, Parry AJ, Pawade A, Heyderman RS, Wolf AR. Spinal anesthesia with an indwelling catheter reduces the stress response in pediatric open heart surgery. Anesthesiology. 2005 Dec;103(6):1113-20.
Weale NK, Rogers CA, Cooper R, Nolan J, Wolf AR. Effect of remifentanil infusion rate on stress response to the pre-bypass phase of paediatric cardiac surgery. Br J Anaesth. 2004 Feb;92(2):187-94.
Duncan HP, Cloote A, Weir PM, Jenkins I, Murphy PJ, Pawade AK, Rogers CA, Wolf AR. Reducing stress responses in the pre-bypass phase of open heart surgery in infants and young children: a comparison of different fentanyl doses. Br J Anaesth. 2000 May;84(5):556-64.
Starting date: April 2008
Ending date: January 2010
Last updated: September 5, 2008