Recombinant human activated protein C for severe sepsis in neonates

Kylat RI, Ohlsson A

Background - Methods - Results - References

Cover sheet

Title

Reviewers

Kylat RI, Ohlsson A

Dates

Date edited: 20/02/2006
Date of last substantive update: 09/02/2006
Date of last minor update: / /
Date next stage expected 01/02/2008
Protocol first published: Issue 3, 2005
Review first published: Issue 2, 2006

Contact reviewer

Dr Ranjit I Kylat
Neonatologist
Neonatology
Duke University, Division of Neonatology
Box 3179, DUMC
Durham
North Carolina USA
2770
Telephone 1: 1 919 954 3778
Facsimile: 1 919 341 4006
E-mail: rkylat@gmail.com

Contribution of reviewers

Ranjit Kylat was involved in all stages of the review including registering the title, developing and writing the protocol, conducting the literature search, selecting the studies for inclusion/exclusion, developing data abstraction forms, assessing study quality, reviewing results and writing the text of the review. He contacted authors for additional data on published and unpublished trials.
Arne Ohlsson contributed to all stages of the review including refining the title, developing and writing the protocol, developing data abstraction forms, searching for articles, assessing study methodology and writing, revising and editing the text of the full review.

Internal sources of support

Duke University, NC, USA
Mount Sinai Hospital, Toronto, Ontario, CANADA

External sources of support

None

What's new

Dates

Date review re-formatted: / /
Date new studies sought but none found: / /
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: / /
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /

Text of review

Synopsis

Recombinant human activated protein for severe sepsis in neonates

Sepsis (a generalized blood stream infection) is common in neonates. Severe sepsis carries a high mortality and morbidity even with current critical care management. Activated Protein C (APC) is a protein formed within the human body to prevent formation of blood clots and helps in breaking down clots. Recombinant human ACP (rhAPC) is a synthesized version of APC using recombinant technology. It has been shown to reduce mortality in severe sepsis in adults. The review authors investigated whether treatment of severe sepsis in newborn infants with rhAPC will help to reduce mortality and severe morbidity. The review authors found no controlled studies in this age group. There is a need for randomized controlled clinical trials before the use of rhAPC for the treatment of severe sepsis for newborn infants can be recommended in clinical practice.

Abstract

Background

Sepsis is a common problem in both preterm and term infants. Although the overall incidence of neonatal sepsis has declined over the past decade, mortality remains high. Recombinant human activated protein C (rhAPC) has been shown to possess a broad spectrum of activity modulating coagulation and has been shown in septic adults to reduce mortality. In septic children, an open label study has shown similar pharmacokinetics, adverse reaction profile and frequency as in adults with severe sepsis.

Objectives

To determine whether treatment with rhAPC will reduce mortality and/or morbidity in neonates with severe sepsis.

Search strategy

Searches were carried out in July 2005 by the review authors independently of MEDLINE (1966 to July 2005), EMBASE (1980 to July 2005), CINAHL (1982 to July 2005), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2005), abstracts of annual meetings of the Pediatric Academic Societies and Society for Pediatric Research which were published in Pediatric Research from 1980, and contacts were made with subject experts. Doctoral dissertations, theses and the Science Citation Index for articles on activated protein C were searched from 1980. No language restriction was applied.

Selection criteria

Studies were included if they were randomized or quasi-randomized trials, assessing the efficacy of rhAPC compared to placebo or no intervention as an adjunct to antibiotic therapy of suspected or confirmed severe sepsis in term and preterm infants less than 28 days old. Eligible trials were required to report treatment effects on at least one of the following outcomes: all cause mortality during initial hospital stay, neurological development and neurodevelopmental assessment at two years of age or later, length of hospital stay, duration of ventilation, chronic lung disease in survivors, periventricular leukomalacia, intraventricular hemorrhage, necrotizing enterocolitis, bleeding, and any other adverse events.

Data collection & analysis

Both review authors independently evaluated the papers for inclusion criteria and quality, and abstracted information for the outcomes of interest. Differences were resolved by mutual discussion. The statistical methods were to include relative risk, risk difference, number needed to treat to benefit or number needed to treat to harm for dichotomous and weighed mean difference for continuous outcomes reported with 95% confidence intervals. A fixed effects model was to be used for meta-analysis. Heterogeneity tests, including the I² statistic, were to be performed to assess the appropriateness of pooling the data.

Main results

No eligible trials were identified.

Reviewers' conclusions

Despite the scientific rationale for its use, there are insufficient data to support the use of rhAPC for the management of severe sepsis in newborn infants. There is a need for large well-designed trials to elucidate the effectiveness of rhAPC to reduce mortality and adverse outcomes in neonates with severe sepsis. The results of such trials would guide clinical practice. Currently, a cautious approach to the use of rhAPC is warranted due to the high incidence of bleeding with its use; especially as severe sepsis in preterm infants is commonly associated with bleeding problems and intraventricular hemorrhage. Its use is not recommended outside of randomized controlled trials.

Background

Sepsis is defined as a systemic inflammatory response syndrome (SIRS) in the presence of, or as a result of, suspected or proven infection (Bone 1992; Levy 2003; Goldstein 2005; Weigand 2004). Severe sepsis is defined as sepsis with one of the following features: cardiovascular organ dysfunction, acute respiratory distress syndrome (ARDS), or dysfunction of two or more organs (Goldstein 2005). The neonate is more susceptible to infections due to an immature immune system (Kapur 2002; Lewis 2001). Bacterial sepsis is the leading cause of neonatal mortality, affecting 32,000 live births annually in the USA (Stoll 1998). The definition of early and late onset sepsis varies with early sepsis defined as < 72 hours, < 4 days and < 7 days depending on the author (Stoll 2004; Klein 2001; Edwards 2002; Lukacs 2004). The increasing survival of very low birth weight (VLBW) infants has resulted in a cohort of infants at increased risk for recurrent infections. Even after reductions in mortality due to advances in supportive care and introduction of maternal intrapartum antibiotic prophylaxis, the mortality rate for both early and late onset neonatal sepsis is still high (Stoll 2002; Stoll 2003; Lukacs 2004). Infections among VLBW infants are associated with high mortality, poor growth and poor neurodevelopmental outcomes (Stoll 2004).

The pathophysiology of sepsis involves activation of immunologic defence systems including complement, pro-inflammatory, anti-inflammatory, procoagulation, anticoagulation, fibrinolytic and immunological cascades in the presence of endotoxins or microbiological products. Although the host pro-inflammatory response is an essential response in the defence against invading organisms, if it is inadequate or excessive or if anti-inflammatory response is predominant, it can lead to apoptosis, organ failure and death. Formation of microvascular thrombi and resultant anticoagulation mechanisms have a role in organ dysfunction and disseminated intravascular coagulation. When thrombin is coupled with an endothelial cell glycoprotein called thrombomodulin, it converts protein C to its activated form. Activated Protein C (APC) promotes fibrinolysis by inhibiting plasminogen activator inhibitor-1 (PAI-1) and thrombin activatable fibrinolysis inhibitor. APC inhibits thrombosis by inhibiting factors Va and VIII a. It has anti-inflammatory actions through the inhibition of pro-inflammatory cytokine release by blocking tumor necrosis factor (TNF) production and adhesion to selectins. However, APC has a short half-life, and the pool of circulating protein C is rapidly depleted in severe sepsis, as conversion to the activated form is impaired. This shifts the homeostatic balance towards greater systemic inflammation, intravascular coagulation and multiorgan failure. There is increased mortality with greater reduction of APC. Administration of APC, but not protein C, can theoretically limit microvascular injury and thrombosis (Healy 2002; Aird 2004; Jagneaux 2004; Hotchkiss 2003; Balk 2004; Rice 2005; Yan 2001).

The outcome of sepsis is influenced by the timeliness of administration of appropriate therapy. Greater understanding of the pathophysiology has identified multiple potential therapeutic targets for interventions to improve outcome in patients with sepsis. Modifiers of the pro-inflammatory and anti-inflammatory strategies like anti-TNF monoclonal antibody, anti endotoxin antibodies and interleukin-1 receptor antagonist have not been effective (Balk 2004; Marshall 2004; O'Brien 2003). The coagulation and fibrinolytic abnormalities seen in sepsis have also been targeted. However, trials of anti-thrombin III, recombinant tissue plasminogen activator (rTPA), tissue factor pathway inhibitor (TFPI) and PAI-1 have been disappointing (Healy 2002; Hotchkiss 2003; Balk 2004; Rice 2004; Rice 2005; Gluck 2004; Zuppa 2004). Pentoxifylline, an anti TNF agent, has been shown to be beneficial in preterm infants (Lauterbach 1999). Intravenous immunoglobulin for prevention of neonatal sepsis does not decrease mortality, whereas its use for treatment of suspected or proven infection may decrease mortality (Ohlsson 2004a; Ohlsson 2004 b).

Recombinant human Activated Protein C (rhAPC) [Drotrecogin Alfa (activated) or Xigris] was studied in adults with severe sepsis [Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial] (Bernard 2001).There was a 6.1% absolute risk reduction in 28-day all-cause mortality, but an increase in serious bleeding complications (3.5% absolute incidence) were noted in the treatment group compared with the placebo group (2.0%). The number needed to treat to prevent one death, extrapolated from the PROWESS trial, was 16. The major adverse effect found in this and in the "Extended Evaluation of recombinant human Activated Protein C United States Trial" (ENHANCE US), a single arm, phase 3B, multicenter study of Drotrecogin alfa (activated) in severe sepsis, was bleeding. The number needed to harm (for serious bleeding) was 66 (Bernard 2004).

Although a variety of scales have been used to assess severity and predict risk [some incorporating organ dysfunction, such as Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential (sepsis-related) Organ Failure Assessment (SOFA) in adults, Pediatric Index of Mortality (PIM) and Pediatric Risk of Mortality III (PRISM III) in children and Clinical Risk Index for Babies (CRIB) and Score for Neonatal Acute Physiology II (SNAP II) in neonates], there are no easy to use, standardised scales (Goldstein 2005; Knaus 1985; Network 1993; Pollack 1996; Richardson 2001; Shann 1997; Vincent 1996). RhAPC has been approved for use in the USA and EU and is currently indicated for the reduction of mortality in adults with severe sepsis who are at high risk for death with multiple dysfunctional organs or high APACHE II scores (Bernard 2004; Manns 2002; Knaus 1985; FDA 2002; EMEA 2002). The Surviving Sepsis Committee has recommended use of rhAPC for the management of severe sepsis in adults. (Dellinger 2004; Carcillo 2002; Carcillo 2003; Parker 2004; Parker 2005). Neonates have a higher mortality for sepsis than older children or adults, and hence is likely to show more benefit to an advantageous therapy. There are several case reports and trials of rhAPC use in severe sepsis in children and neonates with apparent clinical benefit (Barton 2004; Parker 2005; Rawicz 2002; Sajan 2004; Strohler 2004). However, newborn infants with sepsis are at increased risk for major bleeding, and hence appropriate checks are warranted to prevent indiscriminate use.

Prevention of sepsis remains the key in reducing the mortality and as stressed in the Cochrane review of "Intravenous immunoglobulin for preventing infection in preterm and/or low-birth-weight infants" neonatal critical care units with high nosocomial infection rates may want to compare and adjust their infection control policies to those settings with low rates using bench marking techniques (Ohlsson 2004a; Horbar 2001). Attention to simple techniques such as hand hygiene and central line care should be the first line of defence and may prevent most but not all infections. The use of adjunctive treatments such as rhAPC may be justified in early onset sepsis and the cases of nosocomial sepsis occurring in spite of preventive measures.

Despite advances in critical care and introduction of newer treatments, the mortality related to sepsis among neonates remains high. In our search for newer adjunctive treatments to further reduce mortality of severe sepsis in neonates, rhAPC may be a useful addition to the armamentarium, as this is the only new treatment shown to be efficacious in adults.

Objectives

Primary Objective:

To determine the effect of intravenous rhAPC as an adjunct to antimicrobial therapy and conventional critical care management on mortality (to 28 days of age) in neonates with suspected or confirmed severe sepsis

Secondary objectives:

To determine the effects of rhAPC for treatment of neonates with suspected or confirmed severe sepsis on:
i) adverse neurological outcome at 18 months of age or later
ii) the length of hospital stay to discharge in survivors
iii) the duration of ventilation, development of chronic lung disease, intraventricular hemorrhage, periventricular leukomalacia and necrotizing enterocolitis and
iv) safety of rhAPC; adverse effects attributable to its use (e.g.; bleeding)

Subgroup analysis:
i) differences in outcome based on gestational age, birth weight, time of onset of sepsis, on severity of sepsis and also based on the type of infecting microorganism.

Criteria for considering studies for this review

Types of studies

Randomized or quasi-randomized controlled trials.

Types of participants

Newborn infants and neonates (< 28 days old, at any gestational age or birth weight) with confirmed or suspected severe sepsis and treated with antimicrobials
- Confirmed sepsis is defined as clinical signs and symptoms consistent with infection and microbiologically proven, with a positive blood culture, CSF culture, urine culture (obtained by a suprapubic tap) or culture from a normally sterile site (e.g. pleural fluid, peritoneal fluid or autopsy specimens) for bacteria, virus or fungi
- Suspected sepsis is defined as clinical signs and symptoms consistent with sepsis without isolation of a causative organism
- Severe sepsis as evidenced by organ dysfunction (need for mechanical ventilation, hypotension or perfusion abnormalities, or need for inotrope or vasopressors or two or more organ dysfunction - liver, renal, coagulation, neurological or hematological abnormalities)

Types of interventions

Intravenous rhAPC in any dosage and any duration used as an adjunct to treat suspected or confirmed severe neonatal sepsis (treatment group) compared with placebo, or no intervention or any control non-experimental treatment other than rhAPC in the control group. Studies will be eligible whether or not other known treatments for sepsis (e.g. antibiotics, antifungal or antiviral medications) or respiratory support (with positive pressure ventilation or high frequency ventilation) or hemodynamic support were provided during the period of rhAPC treatment.

Types of outcome measures

Primary outcome:

The primary outcome is effect on 28 day all-cause mortality.

Secondary outcomes:

i) All-cause mortality during hospital stay.
ii) Severe disability, defined as any of blindness, deafness, cerebral palsy or cognitive delay (score more than 2 standard deviations below the mean for a recognized psychometric test for neurodevelopmental outcome assessed by a validated test, e.g. Bayley Scales), or adverse neurological outcome, at 18 months of age or later. These outcomes will be reported both as a composite outcome and individually (see xi-xv)
iii) Length of hospital stay in survivors to discharge
iv) Duration of assisted ventilation through an endotracheal tube in days (in all patients and in survivors)
v) Chronic lung disease (CLD) defined as requiring supplemental oxygen at 28 days of age and at 36 weeks corrected gestational age
vi) Intraventricular hemorrhage; any grade and grade III & IV
vii) Periventricular leukomalacia (cystic changes in the periventricular areas)
viii) Necrotizing enterocolitis (NEC): all Bell stages; stage 3 - 4 or need for surgery
ix) Retinopathy of prematurity (ROP): all stages; stage 3 - 5 or need for surgery
x) Nosocomial infections
xi) Blindness
xii) Deafness
xiii) Cerebral Palsy
xiv) Cognitive deficit
xv) Adverse effects attributable to rhAPC [e.g.; hemorrhage (intraventricular hemorrhage, bleeding from venepuncture or arterial puncture sites, hematuria, gastro-intestinal bleeding, pulmonary hemorrhage)]
xvi) Post hoc analyses will be considered for adverse effects reported by the authors but not identified a priori in this protocol

Search strategy for identification of studies

This review used the search strategy of the Cochrane Neonatal Review Group (CNRG). Relevant trials (RCTs and quasi-RCTs) were searched in the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2005), MEDLINE (January 1966 to July 2005), PRE MEDLINE (current), EMBASE (January 1980 to July 2005), LILACS (1982 to July 2005) and CINAHL (January 1982 to July 2005), the Oxford Database of Perinatal Trials and the CNRG's Neonatal Trials Register. Computerized searches were carried out by both the authors independently. MeSH search terms (all headings): activated protein C OR Xigris OR Drotrecogin Alpha OR rhAPC AND (sepsis OR septicemia OR septicaemia OR septic shock OR infection OR sepsis syndrome); limits: age groups, newborns; publication type, clinical trials. Also searches were made through Gateway (http://gateway.nlm.nih.gov/gw/Cmd). We also searched in a variety of ways to make sure that we did not miss any studies.
# 1 explode 'sepsis' [all subheadings in MIME, MJME]
# 2 sepsis or septicemia or septicaemia or sep* or septic or infection
# 3 # 1 or # 2
# 4 severe
# 5 # 3 and #4
# 6 explode 'infant - newborn' [all subheadings in MIME, MJME]
# 7 Newborn*or Neonat*
# 8 # 6 or # 7
# 9 # 5 and # 8
# 10 "activated protein C'[all subheadings on MIME, MJME]
# 11 protein C
# 12 Xigris
# 13 "Drotrecognin alpha activated"
# 14 Drotrecognin*
# 15 # 10 or # 11 or # 12 or # 13 or # 14
# 16 # 9 and # 15
No language restriction was applied.
Additionally we searched abstracts of proceedings of Pediatric Academic Societies (American Pediatric Society, Society for Pediatric Research) and European Society for Paediatric Research (1990-2005), the database of dissertation abstracts, relevant doctoral theses and dissertations, conference and symposia proceedings, the bibliography of selected articles and journal hand searching in the English Language. Forward searches were made using SciSearch with key articles. Contacts were made with manufacturers of rhAPC, Eli Lilly Pharmaceuticals Inc. (www.lilly.com, www.lillytrials.com, www.xigris.com), authors of previously published works and subject experts for any unpublished material or to provide additional data and for ongoing trials. Also the Pharmaceutical and clinical pharmacology databases, e-PIC core, Ceuted and new products of Royal Pharmaceutical Society, International Pharmaceutical abstracts (IPA) of the American Society of Health System Pharmacists. We searched the web sites of the following organizations and other websites: American Academy of Pediatrics (www.aap.org); Australian clinical trials registry (www.actr.org.au); Medical Research council trials register (www.mrc.ac.uk); UK national research registry ( www.update-software.com/national); Food and Drug administration (www.fda.gov); Health Technology Assessment (www.ncchta.org); International Sepsis Forum (www.sepsisforum.org); Society of Critical Care Medicine (www.sccm.org); American Thoracic Society (www.thoracic.org); Infectious Diseases Society of America (www.idsociety.org); European Society of Clinical Microbiology and Infectious Diseases (www.escmid.org ); European Society of Intensive Care Medicine (www.esicm.org); European Society of Emergency Medicine (www.diesis.com/eusem); www.centerwatch.com; www.trialscentral.org; www.controlled-trials.com and www.clinicaltrials.gov. We attempted to identify all relevant studies regardless of language or publication status (published, unpublished, in press, and in progress).

Methods of the review

STUDY SELECTION

The standardized review methods for conducting a systematic review, as described in the Cochrane Collaboration Handbook and CNRG Guidelines for Reviewers and Editors were used for assessing the methodological quality of the studies. The titles and the abstracts of studies identified by the search strategy were assessed by the two authors independently for eligibility for inclusion in this review using pre-determined criteria based on the inclusion criteria. If this could not be done reliably by title and abstract, then the full text version was obtained for assessment. The results were compared and any disagreements resolved by discussion and consensus. We requested additional information from corresponding study authors. Full text versions of all included studies were obtained for quality assessment.

ASSESSMENT OF METHODOLOGICAL QUALITY

If studies were located that met our inclusion criteria, we planned to independently rate each of the elements of methodological quality using the standard criteria developed by the CNRG and information were to be collected regarding details of the method of randomization (generation of allocation sequence), stratification of allocation, allocation concealment (masking of randomization), masking of the drug intervention, masking of the outcome assessment, completeness of follow-up, whether intention to treat analyses were possible from the available data and if the number of patients lost to follow up or subsequently excluded from the study were recorded, causes for drop outs and exclusions from the trial and whether the trial was single or multi-centered. Allocation concealment was to be graded A, B or C (A- Adequate allocation concealment, B- Uncertainty about whether the allocation was adequately concealed and C- Inadequate allocation concealment). Forms were designed for trial inclusion /exclusion, data extraction and for requesting additional information from authors of the original reports.

DATA EXTRACTION

Ranjit Kylat (RK) drew up a standard data extraction form, and Arne Ohlsson (AO) validated it. If studies were located that met our inclusion criteria, we were to independently extract data using the data acquisition forms and were to contact the authors of trials to provide missing data where possible and necessary. RK was to enter the data into the computer and AO was to check the data and compare for any differences, which was then to be resolved by discussion. We were to use data extraction of sample characteristics to cross check the validity of the randomization process.

DATA ANALYSIS

If studies were located that met our inclusion criteria, statistical analyses were to be performed according to the recommendations of the CNRG. Analyses were to be done for all infants, and for the sub-groups defined under 'Criteria for considering studies for this review '. All infants randomized were to be analyzed on 'an intention to treat basis' irrespective of whether or not they survived to receive their allocated treatment completely. Study investigators were to be contacted to obtain unpublished data for all patients randomized but not analyzed on an intention to treat basis. Treatment effects in the individual trials were to be analyzed. Heterogeneity of treatment effects between trials were to be assessed to check the appropriateness of pooling data and performing meta-analyses. The statistical package (RevMan 4.2.8) provided by the Cochrane Collaboration was to be used. For dichotomous categorical outcomes, a pooled estimate of treatment effect for each outcome across studies was to be calculated as typical relative risk (RR) and typical risk difference (RD). For continuous outcomes, weighted mean difference (WMD) for change from baseline or post-treatment values was also to be calculated. Ninety five per-cent confidence intervals were to be used for each measure of treatment effect. If there was a statistically significant reduction in RD then the number needed to treat (NTT) was to be calculated. Results of the I² statistic were to be reported. We planned to perform a sensitivity analysis based on the methodological quality of the studies, including and excluding quasi-randomized studies.
Additional subgroup analyses were planned a priori for separate estimation of effect size including only the trials which were double masked. The following sub-group analyses were planned for the intravenous Activated Protein C versus no treatment or Activated protein C versus placebo:

1. Gestational age: i) Preterm neonates (< 37 completed weeks gestation) ii) Term infants (= />37 completed weeks of gestation)
2. Gestational age: i) < 30 weeks ii) =/> 30 weeks
3. Birth weight: i) < less than 1500 g ii) 1500 - 2500 g iii) =/> 2500 g
4. Time of onset of sepsis: i) Early onset sepsis (sepsis <72 hrs) ii) Late onset sepsis (sepsis =/>72 hrs)
Another definition of early versus late infection will also be included with cutoff < 7 days and =/>7 days.
5. Suspected or confirmed sepsis.
6. Severity of sepsis i) dysfunction of two organs ii) dysfunction of more than 4 organ systems; or i) medications needed for hemodynamic support ii) no medication for hemodynamic support needed
7. Type of organism identified: i) bacterial ii) fungal iii) viral

A sensitivity analysis was planned, including only trials which were truly randomized. We planned to explore the funnel plots to look for evidence of publication bias.

Description of studies

No randomized controlled trials (RCT) or quasi RCTs studies were found meeting the inclusion criteria for this review.
However, we did identify a number of studies using rhAPC in children, that are discussed below and may be important as a background to the development and design of possible future trials in neonates. We chose to report on these 'excluded studies' under this heading of 'Description of studies' even if they apply to populations that are older than 28 days or include study designs other than RCTs. These studies were identified through the same search strategy of the literature as for neonates but without an age restriction.

Case reports, retrospective case series and nonrandomized trials of use of rhAPC in the pediatric population

Rawicz described the use of rhAPC in a full term neonate weighing 2750 g with early onset enterococcal sepsis, multiorgan dysfunction and disseminated intravascular coagulopathy. Six hours after the start of therapy, coagulation parameters returned to normal. Apart from pyloric stenosis surgery at five weeks, the infant had a normal recovery (Rawicz 2002). There are case reports of a four day old 35 week gestational age neonate with severe Group B streptococcal sepsis and multiorgan dysfunction, who was treated with rhAPC and had an uneventful recovery (Strohler 2004) and its use in a teenage girl with sepsis (Manco-Johnson 2004). Sajan et al describes use of rhAPC in a four month old infant weighing 3500 g with Gram negative septic shock with Serratia Marcescens. This patient had no apparent adverse effects during rhAPC infusion and recovered, but had transient systemic hypertension and incidental detection of bilateral small occipital hemorrhages 22 days after infusion (Sajan 2004). Wyss reports retrospective data of six open label reports of rhAPC use in children (newborn to 18 years). Details of the number of subjects less than 28 days and their outcomes are awaited (Wyss 2004). There was a case series of the use of rhAPC in three children outside the neonatal age group with meningococcal purpura fulminans, two of whom survived without any adverse effects (Martinon-Torres 2004). A 12 day old neonate with group B Streptococcal septic shock was treated with 24 micrograms / kg of rhAPC for 96 hours and the infant recovered without any adverse effects (Frommhold 2005). There was also a report of 14 patients with purpura fulminans who were treated with rhAPC on compassionate grounds (EVAS) (FDA b; FDA c; Eli Lilly 2005a)

Prospective nonrandomized studies of use of rhAPC in the pediatric population

The Global ENHANCE trial was conducted in 400 sites in 25 countries. These 71 sites enrolled 195 pediatric patients in a single arm study (with no controls) (Eli Lilly 2005a; Vincent 2003). All cause mortality was 26.4 %. Separate pediatric data were not published, but of the 195 enrolled children, 188 received rhAPC and data from 187 were analyzed (one was lost to follow up and not included in efficacy analysis). There were 43 (23%) children less than one year ( the number less than 28 days is unknown); 28 day mortality was 14% in this group. 58/188 (30.9%) experienced serious bleeding during the 28 day study period. 6/188 (3.2%) experienced a serious adverse event that was considered to be study drug related, and one resulted in death. All serious adverse events were due to bleeding (Eli Lilly 2005a). We are still awaiting the details of infants less than 28 days from the study sponsor.
An open label multicenter nonrandomized, sequential pediatric trial (EVAO) of rhAPC included 83 children (term newborns to 18 years of age) (Barton 2004). In this two part study, pediatric patients with severe sepsis (by PIM score) received sequential escalating dose of rhAPC. Outcome measures were plasma pharmacokinetics, concentration and clearance, D-dimer, protein C, antithrombin levels and safety information. The second part of the study used age specific infusion rates based on data from the first part of the study. No clinical endpoints, including mortality, were considered. All patients had coagulopathy with raised D-dimers and eighty one percent had acquired protein C deficiency. The number of patients less than one month is not known, and none of the outcomes of interest were evaluated. Overall serious bleeding events (4.8%) and mortality at 14 days (9.6%) were not statistically different from the 10.8% mortality predicted by the PIM score.

Randomized trials of rhAPC use in the pediatric population

The RESOLVE/EVBP trial (Resolution of organ failure in pediatric patients with severe sepsis) in children with severe sepsis was a large multicenter trial, initiated in November 2002 with a planned enrolment of six hundred children (Dalton 2003; Eli Lilly 2005b). This pediatric study was terminated in March 2005 after enrolling over four hundred children, as rhAPC was unlikely to show significant result for the primary endpoint "Composite time to complete organ failure resolution". The results were not published (Eli Lilly 2005b). There was no difference in 28 day all-cause mortality [16.9% (34/201) in the rhAPC group and 18.2% (36/198) in the placebo group] of the first 400 subjects enrolled. It is of note that four subjects had major intracranial hemorrhages during the infusion period in the rhAPC group (three of them being less than 60 days of age), while there was only one intracranial hemorrhage during the infusion period in the placebo group (Eli Lilly 2005b).

Methodological quality of included studies

Not applicable, as no eligible studies were found meeting the inclusion criteria for this review.

Results

No results are reported as no studies were found meeting the inclusion criteria for this review. No eligible trials were identified that tested the efficacy of rhAPC in the treatment of severe sepsis in neonates. However, we did identify a number of studies using rhAPC in children which are described in detail in the "Description of studies" section above.

Discussion

The mortality and morbidity from neonatal sepsis remains high. Antimicrobials are obviously the mainstay of therapy, but there is a concerning increase in the incidence of multidrug resistant organisms (Stoll 2002; Stoll 2004). Improved understanding of pathophysiological processes in sepsis gives compelling and logical reasons that, as an adjunct to antimicrobials and traditional critical care, modulating the pro-inflammatory, anti-inflammatory, coagulant, fibrinolytic and immune mechanism may help in reducing the mortality and morbidity in severe sepsis, especially in the preterm and low birth weight infant. To date, there is no single agent, apart from antibiotics, antiviral and antifungal treatment, that has convincingly shown in reproducible RCTs to be an effective adjunctive therapy in neonatal sepsis.

In a systematic review, Carr reported that there was insufficient evidence to support use of G-CSF or GM-CSF either as treatment of neonatal sepsis, or as prophylaxis to prevent systemic infection in high risk neonates (Carr 2005). Similarly, Ohlsson et al concluded that there was insufficient evidence to support the routine administration of IVIG for neonatal sepsis (Ohlsson 2004 b). Pentoxifylline had shown promise as an adjunctive agent in the treatment of neonatal sepsis. Treatment with pentoxifylline led to a statistically significant reduction in mortality in preterm neonates with confirmed late onset sepsis (Lauterbach 1999). However, caution must be exercised in interpreting the results because there were methodological weaknesses and the results have not been reproduced outside the single center where it was studied (Haque 2005).

The search strategy used for this review identified retrospective case reports and prospective open label data, but no randomized clinical trials with any relevant clinical outcomes. Two case reports on use of rhAPC in severe neonatal sepsis reported no major adverse effects (Frommhold 2005; Rawicz 2002). There was a single prospective nonrandomized study in children that was open label and designed for the evaluation of safety, pharmacokinetics and pharmacodynamics of rhAPC in children (Barton 2004). The only randomized clinical trial (RESOLVE /EVBP) in children with severe sepsis has been terminated and results are not published (Eli Lilly 2005b). Of note, a trial to examine the effects of rhAPC in 11,000 low risk adult patients (Early stage severe sepsis or ADDRESS trial) was terminated due to lack of efficacy (Deans 2004). The results of this study, show no beneficial treatment effect, but there was an increased incidence of serious bleeding complications, indicating that rhAPC should not be used in adults with severe sepsis who are at low risk for death, such as those with single-organ failure or an APACHE II score less than 25 (Abraham 2005).

In adult patients with severe sepsis, economic evaluation and systematic effectiveness reviews of the use of rhAPC has shown to rhAPC to be beneficial, but significant concerns still exist (Manns 2002; Fowler 2003; Angus 2003; Catalan 2004; Green 2005; Warren 2002; Eichacker 2003; Girbes 2003; NICE 2004). The drug is currently licensed only for the FDA approved indication- severe sepsis in the adult patient with high mortality risk. There is only one case report of its use in a pregnant 19 year old woman at 18 weeks of gestation, who had septic shock with no adverse effects on mother or fetus (Medve 2005). The mortality rates of severe sepsis in children are much lower than in adults with severe sepsis (ranging from 7 - 12%) (Kutko 2003). The case fatality rate of severe sepsis in neonates (reported range: 9.6% - 13.5%) is comparable to other age groups in childhood (10.3%), but the mortality rates can be variable and depends on whether the predominant population is ELBW and preterm infants or previously healthy full term infants (Watson 2003). There are very few large epidemiologic studies addressing the severity of neonatal sepsis, but the incidence of multiorgan dysfunction is thought to be high in neonatal sepsis. Overall sepsis related mortality in newborn infants is much less than in adults, and the benefit of rhAPC when used as an adjunct may not be significant unless large numbers are enrolled. The incidence of thrombocytopenia, coagulation dysfunction and disseminated intravascular coagulation is extremely high in neonates with severe sepsis and rhAPC may be contraindicated in such situations.

Given that we found no randomized controlled trials which use rhAPC in severe sepsis in neonates this systematic review does not establish if the administration of rhAPC to neonates with severe sepsis is beneficial or detrimental. The nonrandomized trials done in children had very few neonates enrolled without any separate outcome data. Thus the efficacy of rhAPC treatment for severe neonatal sepsis has not been adequately evaluated to date.

The use of rhAPC should be investigated in properly controlled research trials in neonates before any recommendations can be made. Thoughtful assessment of potential benefits and risks, especially intracranial hemorrhage, in individual patients have to be weighed. Although not recommended, any center tempted to use rhAPC outside of clinical trials should do so with strict adherence to protocol and with the understanding that there is a risk of serious bleeding especially intracranial hemorrhage, as currently there is no evidence that it is beneficial in newborn infants. In the interim, focus should be on the prevention of sepsis with simple, cost effective and easy to practice established strategies like hand hygiene, strict adherence to sterile, aseptic techniques during procedures, early introduction of enteral feeding and optimal parenteral nutrition. Within the context of randomized controlled trials, the use of adjunctive treatments such as rhAPC is justified in severe early onset sepsis and cases of nosocomial sepsis occurring in spite of preventive measures.

Reviewers' conclusions

Implications for practice

Despite the scientific rationale, no conclusions could be made, as there are insufficient data available to support the use of rhAPC in severe neonatal sepsis. More research is needed before the use of rhAPC can be recommended in clinical practice. For now its use should be restricted to the setting of randomized control trials. A cautious approach is warranted due to the high incidence of bleeding with its use; especially as severe sepsis in preterm infants is commonly associated with bleeding problems and intraventricular hemorrhage. There should also be adequate emphasis on prevention of sepsis through simple, cost effective and proven measures like hand hygiene.

Implications for research

There is a need for adequately powered trials to determine the safety and efficacy of rhAPC therapy for severe neonatal sepsis. Researchers should be encouraged to initially undertake RCT's of rhAPC in the treatment of confirmed or suspected severe neonatal sepsis in full term infants. If there is a minimal adverse effect profile and there are clinically significant outcomes, it would be justified to study less severe forms of sepsis in full term infants and subsequently preterm and LBW infants, who have the highest risk of serious bleeding and intracranial hemorrhage. Researchers should be encouraged to report on clinically important co-morbidities of sepsis (e.g. chronic lung disease, periventricular leukomalacia, duration of assisted ventilation, necrotizing enterocolitis amongst others) and long term neurological outcome. Researchers might also compare rhAPC with other adjuncts to antimicrobials, such as early goal directed fluid resuscitation, tight glycemic control, modulators of inflammation (e.g. Pentoxifylline, low dose corticosteroids), immunomodulators (e.g. intravenous immunoglobulins), hematopoetic colony stimulating factors, anticoagulants or fibrinolytics (e.g. low dose heparin) among others in reducing mortality and morbidity due to severe neonatal sepsis.

Acknowledgements

None

Potential conflict of interest

None

Characteristics of excluded studies

Study	Reason for exclusion
Barton 2004	Not RCT, prospective no controls, no hard clinical endpoints, age: term newborn to < 18 years
Eli Lilly 2005a	Not RCT, No controls, prospective, pediatric data not published, Global ENHANCE, Term newborn to < 18 years
Eli Lilly 2005b	RCT, RESOLVE trial terminated and not published, > 38 weeks GA to < 18 years
Frommhold 2005	Not RCT, case report of 12 day neonate with Gr B Strep sepsis
Manco-Johnson 2004	Not RCT, case report of use in 1 adolescent
Martinon-Torres 2004	Not RCT, case series of 3 children 1 -16 years
Rawicz 2002	Not RCT, case report of a newborn infant with early onset enterococcal sepsis
Sajan 2004	Not RCT, case report of a 4 month old infant with Serratia sepstic shock
Strohler 2004	Not RCT, case report of 35 week Gestational age 4 day infant with Gr B Strep sepsis
Wyss 2004	Not RCT, case series of 6 studies, newborn to < 18 years

References to studies

References to excluded studies

Barton 2004 {published data only}

Barton P, Kalil AC, Nadel S, Goldstein B, Okhuysen-Cawley R, Brilli RJ et al. Safety, pharmacokinetics, and pharmacodynamics of drotrecogin alfa (activated) in children with severe sepsis. Pediatrics 2004;113:7-17.

Eli Lilly 2005a {unpublished data only}

Eli Lilly. Xigris®- results in pediatric patients in the global ENHANCE trial: An overview. Lilly Research Labratories. Medical Information on Xigris® for physicians 2005.

Eli Lilly 2005b {unpublished data only}

Eli Lilly. Xigris (drotrecogin alfa [activated]: The RESOLVE Trial. Eli Lilly: Xigris: Medical information for physicians.

Frommhold 2005 {published data only}

Frommhold D, Birle A, Linderkamp O, Zilow E, Poschl J. Drotrecogin alpha (activated) in neonatal septic shock. Scandinavian Journal of Infectious Disease 2005;37:306-8.

Manco-Johnson 2004 {published data only}

Manco-Johnson MJ, Knapp-Clevenger R. Activated protein C concentrate reverses purpura fulminans in severe genetic protein C deficiency. Journal of Pediatric and Hematological Oncology 2004;26:25-7.

Martinon-Torres 2004 {published data only}

Martinon-Torres F, Iglesias Meleiro JM, Fernandez Sanmartin M, Rodriquez Nunez A, Martinon Sanchez JM. Proteìna C activada humana recombinante en el tratmiento de ninos con purpura fulminante meningococica [Recombinant human activated protein C in the treatment of children with meningococcal purpura fulminans]. Anales de Pediatria (Barcelona, Spain) 2004;61:261-5.

Rawicz 2002 {published data only}

Rawicz M, Sitkowska B, Rudzinska I, Kornacka MK, Bochenski P. Recombinant human activated protein C for severe sepsis in a neonate. Medical Science Monitor 2002;8:CS90-4.

Sajan 2004 {published data only}

Sajan I, Da-Silva SS, Dellinger RP. Drotrecogin alfa (activated) in an infant with gram-negative septic shock. Journal of Intensive Care Medicine 2004;19:51-5.

Strohler 2004 {published data only}

Strohler B, Patel N, Grzeszczak M, Churchwell K. Use of activated protein C in a preterm neonate with Group B Streptococcal sepsis. Pediatric Critical Care Medicine 2004;5:512.

Wyss 2004 {published data only}

Wyss VL, Cunneen J, Short MA, Turlo MA. Assessment of severe sepsis in children: Experiences from pediatric patients receiving Drotrecogin Alfa (activated). Journal of Emergency Nursing 2004;30:409.

* indicates the primary reference for the study

Other references

Additional references

Abraham 2005

Abraham E, Laterre PF, Garg R, Levy H, Talwar D, Trzaskoma BL et al; Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) Study Group. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. New England Journal of Medicine 2005;353:1332-41.

Aird 2004

Aird WC. Natural anticoagulant inhibitors: activated protein C. Best Practice and Research in Clinical Haematology 2004;17:161-82.

Angus 2003

Angus DC, Linde-Zwirble WT, Clermont G, Ball DE, Basson BR, Ely EW, Laterre PF et al. Cost-effectiveness of drotrecogin alfa (activated) in the treatment of severe sepsis. Critical Care Medicine 2003;31:1-11.

Balk 2004

Balk RA. Optimum treatment of severe sepsis and septic shock: evidence in support of the recommendations. Disease-A-Month 2004;50:168-213.

Bernard 2001

Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriquez A et al. Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. New England Journal of Medicine 2001;344:699-709.

Bernard 2004

Bernard GR, Margolis BD, Shanies HM, Ely EW, Wheeler AP, Levy H, Wong K et al. Extended evaluation of recombinant human activated protein C United States Trial (ENHANCE US): a single-arm, phase 3B, multicenter study of drotrecogin alfa (activated) in severe sepsis. Chest 2004;125:2206-16.

Bone 1992

Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992;101:1644-55.

Carcillo 2002

Carcillo JA, Fields AI; American College of Critical Care Medicine Task Force Committe Members. Clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock. Critical Care Medicine 2002;30:1365-78.

Carcillo 2003

Carcillo JA. Pediatric septic shock and multiple organ failure. Critical Care Clinics 2003;19:413-40.

Carr 2005

Carr R, Modi N, Dore C. G-CSF and GM-CSF for treating or preventing neonatal infections. In: The Cochrane Database Systematic Reviews, Issue 3, 2005.

Catalan 2004

Catalan Agency for Health Technology Assessment and Research (CAHTA). Assessment of the scientific evidence on the use of recombinant activated C protein - (activated) alpha-drotrecogin - in severe sepsis. Catalan agency for health technology assessment and research 2004;34.

Dalton 2003

Dalton HJ. Recombinant activated protein C in pediatric sepsis. Pediatric Infectious Disease Journal 2003;22:743-5.

Deans 2004

Deans KJ, Minneci PC, Banks SM, Natanson C, Eichacker PQ. Substantiating the concerns about recombinant human activated protein C use in sepsis. Critical Care Medicine 2004;32:2542-43.

Dellinger 2004

Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J et al for Surviving Sepsis Campaign Management Guidelines Committee. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Critical Care Medicne 2004;32:858-73.

Edwards 2002

Edwards MS. Postnatal bacterial infections. In: Fanaroff AA, Martin RJ, editor(s). Neonatal-Perinatal Medicine: Diseases of the fetus and infant. Seventh edition. St Louis: Mosby, 2002:706-45.

Eichacker 2003

Eichacker PQ, Natanson C. Recombinant human activated protein C in sepsis: inconsistent trial results, an unclear mechanism of action and safety concerns resulted in labeling restrictions and the need for phase IV trials. Critical Care Medicine 2003;31:S94-6.

EMEA 2002

European Agency for the evaluation of medicinal products: committee for proprietary medicinal products. European public assessment report (EPAR) - Xigris. www.emea.eu.int/pdfs/human/opinion/13844705en.pdf , www.emea.eu.int/pdfs/human/press/pr/12130705en.pdf 2002.

FDA 2002

Food and Drug Administration: Anti-Infective Advisory Committee. FDA Clinical Review: Drotrecogin Alfa (activated) [recombinant human activated protein C (rhAPC)] Xigris, BLA # 125029/0. www.fda.gov/cder/biologics/review/droteli112101r1.pdf ,www.fda.gov/medwatch/safety/2005/Xigris_dearhcp_4-21-05.pdf , www.fda.gov/medwatch/safety/2005/safety05.htm, www.fda.gov/ohrms/dockets/ac/01/minutes/3797m1.doc 2002:1-161.

FDA b

US Food and Drug Administration. Anti-infective drug advisory committee. Breifing document for Xigris for the treatment of severe sepsis. http://www.fda.gov/ohrms/dockets/ac/01/briefing/3797b1_01_FDAbriefing.doc.

FDA c

US Food and Drug Administration. FDA clinical review Drotrecogen alfa (activated) (Recombinant Activated Protein C ( rhAPC) Xigris BLA#125029/0. www.fda.gov/cder/biologics/review/droteli112101r2.pdf, www.fda.gov/cder/biologics/review/droteli112101r3.pdf, www.fda.gov/cder/biologics/review/droteli112101r4.pdf, www.fda.gov/cder/biologics/review/droteli112101r5.pdf, www.fda.gov/cder/biologics/review/droteli112101r7.pdf.

Fowler 2003

Fowler R A, Hill-Popper M, Stasinos J, Petrou C, Sanders G D, Garber A M. Cost-effectiveness of recombinant human activated protein C and the influence of severity of illness in the treatment of patients with severe sepsis. Journal of Critical Care 2003;18:181-91.

Girbes 2003

Girbes AR, Polderman KH. A definite role for treatment with activated protein C in sepsis? Standard use is premature. Journal of Thrombosis and Haemostasis 2003;1:2469-71.

Gluck 2004

Gluck T, Opal SM. Advances in sepsis therapy. Drugs 2004;64:837-59.

Goldstein 2005

Goldstein B, Giroir B, Randolph A; International Consesnus Conference on Pediatric Sepsis. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatric Critical Care Medicine 2005;6:2-8.

Green 2005

Green C, Dinnes J, Takeda A, Shepherd J, Hartwell D, Cave C, Payne E et al. Clinical effectiveness and cost-effectiveness of drotrecogin alfa (activated) (Xigris) for the treatment of severe sepsis in adults: a systematic review and economic evaluation. Health Technology Assessment 2005;9:1-126, iii-xiii.

Haque 2005

Haque K, Mohan P. Pentoxifylline for neonatal sepsis. In: The Cochrane Database of Systematic Reviews, Issue 3, 2005.

Healy 2002

Healy DP. New and emerging therapies for sepsis. Annals of Pharmacotherapeutics 2002;36:648-54.

Horbar 2001

Horbar JD, Rogowski J, Plsek PE, Delmore P, Edwards WH, Hocker J et al. Collaborative quality improvement for neonatal intensive care. NIC/Q Project Investigators of the Vermont Oxford Network. Pediatrics 2001;107:14-22.

Hotchkiss 2003

Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. New England Journal of Medicine 2003;348:138-50.

Jagneaux 2004

Jagneaux T, Taylor DE, Kantrow SP. Coagulation in sepsis. American Journal of Medical Science 2004;328:196-204.

Kapur 2002

Kapur R, Yoder MC, Polin RA. Developmental Immunology. In: Fanaroff AA, Martin RJ, editor(s). Neonatal-Perinatal Medicine: Diseases of the Fetus and Infant. Seventh edition. Vol. 2. St Louis: Mosby, 2002:676-706.

Klein 2001

Klein JO. Bacterial Sepsis and Meningitis. In: Remington JS, Klein JO, editor(s). Infectious Diseases of the Fetus and Newborn Infant. Fifth edition. Philadelphia: Saunders WB, 2001:943-98.

Knaus 1985

Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Critical Care Medicine 1985;13:818-29.

Kutko 2003

Kutko MC, Calarco MP, Flaherty MB, Helmrich RF, Ushay HM, Pon S et al. Mortality rates in pediatric septic shock with and without multiple organ system failure. Pediatric Critical Care Medicine 2003;4:333-7.

Lauterbach 1999

Lauterbach R, Pawlik D, Kowalczyk D, Ksyinski W, Helwich E, Zembala M. Effect of immunomodulating agent, pentoxifylline, in the treatment of sepsis in prematurely delivered infants: a placebo controlled, double-blind trial. Critical Care Medicine 1999;27:807-14.

Levy 2003

Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Critical Care Medicine 2003;31:1250-6.

Lewis 2001

Lewis DB, Wilson CB. Developmental immunology and role of host defenses in fetal and neonatal susceptibility to infection. In: Remington JS, Klein JO, editor(s). Infectious Diseases of the Fetus and Newborn Infant. Fifth edition. Philadelphia: Saunders WB, 2001:25-139.

Lukacs 2004

Lukacs LL, Schoendorf KC, Schuchat A. Trends in sepsis-related neonatal mortality in the United States, 1985-1998. Pediatric Infectious Diseases Journal 2004;23:599-603.

Manns 2002

Manns BJ, Lee H, Doig CJ, Johnson D, Donaldson C. An economic evaluation of activated protein C treatment for severe sepsis. New England Journal Medicine 2002;347:993-1000.

Marshall 2004

Marshall JC. Sepsis: current status, future prospects. Current opinion in Critical Care 2004;10:250-64.

Medve 2005

Medve L, Csitari IK, Molnar Z, Laszl A. Recombinant human activated protein C treatment of septic shock syndrome in a patient at 18th week of gestation: a case report. American Journal of Obstetrics and Gynecology 2005;193:864-5.

Network 1993

The International Neonatal Network. The CRIB (clinical risk index for babies) score: a tool for assessing initial neonatal risk and comparing performance of neonatal intensive care units. The International Neonatal Network. Lancet 1993;342(885):193-8.

NICE 2004

National Institute for clinical excellence. Drotrecogin alfa (activated) for severe sepsis. Technology Appraisal Guidance (www.nice.org.uk/TA084guidance) 2004;84:1-31.

O'Brien 2003

O'Brien JM Jr, Abraham E. New approaches to the treatment of sepsis. Clinics in Chest Medicine 2003;24:521-48.

Ohlsson 2004 b

Ohlsson A, Lacy JB. Intravenous immunoglobulin for suspected or subsequently proven infection in neonates. In: The Cochrane Database of Systematic Reviews, Issue 1, 2004.

Ohlsson 2004a

Ohlsson A, Lacy JB. Intravenous immunoglobulin for preventing infection in preterm and/or low-birth-weight infants. In: The Cochrane Database of Systematic Reviews, Issue 1, 2004.

Parker 2004

Parker MM, Hazelzet JA, Carcillo JA. Pediatric considerations. Critical Care Medicine 2004;32:S591-4.

Parker 2005

Parker MM. Pediatric definitions for sepsis: it's about time! Pediatric Critical Care Medicine 2005;6:83-4.

Pettenazzo 2004

Pettenazzo A, Malusa T. Use of protein C concentrate in critical conditions: clinical experience in pediatric patients with sepsis. Minerva Anestesiologica 2004;70:357-63.

Pollack 1996

Pollack MM, Patel KM, Ruttimann UE. PRISM III: an updated Pediatric Risk of Mortality score. Critical Care Medicine 1996;24:743-52.

Rice 2004

Rice TW, Bernard GR. Drotrecogin alfa (activated) for the treatment of severe sepsis and septic shock. American Journal of Medical Science 2004;328:205-14.

Rice 2005

Rice TW, Bernard GR. Therapeutic intervention and targets for sepsis. Annual Review of Medicine 2005;56:225-48.

Richardson 2001

Richardson DK, Corcoran JD, Escobar GJ, Lee SK. SNAP-II and SNAPPE-II: Simplified newborn illness severity and mortality risk scores. Journal of Pediatrics 2001;138:92-100.

Shann 1997

Shann F, Pearson G, Slater A, Wilkinson K. Pediatric index of mortality (PIM): a mortality prediction model for children in intensive care unit. Intensive Care Medicine 1997;23:201-7.

Stoll 1998

Stoll BJ, Holman RC, Schuchat A. Decline in sepsis-associated neonatal and infant deaths in the United States, 1979 through 1994. Pediatrics 1998;102:e18.

Stoll 2002

Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA, Ehrenkranz RA et al. Changes in pathogens causing early-onset sepsis in very-low-birth-weight infants. New England Journal of Medicine 2002;347:240-7.

Stoll 2003

Stoll BJ, Hansen N. Infections in VLBW infants: studies from the NICHD Neonatal Research Network. Seminars in Perinatology 2003;27:293-301.

Stoll 2004

Stoll BJ, Hansen NI, Adams-Chapman I, Fanaroff AA, Hintz SR, Vohr B, Higgins RD; National Institute of Child Health and Human Development Neonatal Research Network. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. Journal of American Medical Association 2004;292:2357-65.

Vincent 1996

Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Medicine 1996;22:707-10.

Vincent 2003

Vincent J-L, Light B, Wright TJ. Global ENHANCE results indicate organ function improvement with drotrecogin alfa (activated) in severe sepsis patients. Chest 2003;124:103S.

Warren 2002

Warren HS, Suffredini AF, Eichacker PQ, Munford RS. Risks and benefits of activated protein C treatment for severe sepsis. New England Journal of Medicine 2002;347:1027-30.

Watson 2003

Watson RS, Carcillo JA, Linde-Zwirble WT, Clermont G, Lidicker J, Angus DC. The epidemiology of severe sepsis in children in the United States. American Journal of Respiratory and Critical Care Medicine 2003;167:695-701.

Weigand 2004

Weigand MA, Hörner C, Bardenheuer HJ, Bouchon A. The systemic inflammatory response syndrome. Best Practice and Research Clinical Anaesthesiology 2004;18:455-75.

Yan 2001

Yan SB, Helterbrand JD, Hartman DL, Wright TJ, Bernard GR. Low levels of protein C are associated with poor outcome in severe sepsis. Chest 2001;120:915-22.

Zuppa 2004

Zuppa AF, Nadkarni VM. Recent developments in the pharmacological approach to pediatric critical care. Current Opinion in Anaesthesiology 2004;17:223-8.

Notes

Published notes

Contact details for co-reviewers

Dr Arne Ohlsson
Director Evidence Based Neonatal Care and Outcomes Research
Department of Paediatrics
Mount Sinai Hospital
600 University Avenue
Toronto
Ontario CANADA
M5G 1X5
Telephone 1: +1 416 586 8379
Telephone 2: +1 416 341 0444
Facsimile: +1 416 586 8745
E-mail: aohlsson@mtsinai.on.ca

The review is published as a Cochrane review in The Cochrane Library, Issue 2, 2006 (see http://www.thecochranelibrary.com for information). Cochrane reviews are regularly updated as new evidence emerges and in response to comments and criticisms, and The Cochrane Library should be consulted for the most recent version of the Review.