Martin Stocker

Use of Procalcitonin-Guided Decision-Making to Shorten Antibiotic Therapy in Suspected Neonatal Early-Onset Sepsis: Prospective Randomized Intervention Trial

Background: Diagnosis of neonatal early-onset sepsis is difficult because clinical signs and laboratory tests are non-specific. Early antibiotic therapy is crucial for treatment success. Objective: To evaluate the effect of procalcitonin (PCT)-guided decision-making on duration of antibiotic therapy in suspected neonatal early-onset sepsis. Methods: This single-center, prospective, randomized intervention study was conducted in a tertiary neonatal and pediatric intensive care unit in the Children’s Hospital of Lucerne, Switzerland, between June 1, 2005 and December 31, 2006. All term and near-term infants (gestational age ≧34 weeks) with suspected early-onset sepsis were randomly assigned either to standard treatment based on conventional laboratory parameters (standard group) or to PCT-guided treatment (PCT group). Minimum duration of antibiotic therapy was 48–72 h in the standard group, whereas in the PCT group antibiotic therapy was discontinued when two consecutive PCT values were below predefined age-adjusted cut-off values. Results: 121 newborns were randomly assigned either to the standard group (n = 61) or the PCT group (n = 60). The two groups were similar for baseline demographics, risk factors for early-onset sepsis, likelihood of infection as assessed by the attending physician and early conventional laboratory findings. There was a significant difference in the proportion of newborns treated with antibiotics ≧72 h between the standard group (82%) and the PCT group (55%) (absolute risk reduction 27%; odds ratio 0.27 (95% CI 0.12–0.62), p = 0.002). On average, PCT-guided decision-making resulted in a shortening of 22.4 h of antibiotic therapy. Clinical outcome was similar and favorable in both groups but sample size was insufficient to exclude rare adverse events. Conclusion:Serial PCT determinations allow to shorten the duration of antibiotic therapy in term and near-term infants with suspected early-onset sepsis. Before this PCT-guided strategy can be recommended, its safety has to be confirmed in a larger cohort of neonates.

Neonatal Procalcitonin Intervention Study (NeoPInS): Effect of Procalcitonin-guided decision making on Duration of antibiotic Therapy in suspected neonatal early-onset Sepsis: A multi-centre randomized superiority and non-inferiority Intervention Study

BackgroundEarly diagnosis and treatment of the newborn infant with suspected sepsis are essential to prevent severe and life threatening complications. Diagnosis of neonatal sepsis is difficult because of the variable and nonspecific clinical presentation. Therefore, many newborns with nonspecific symptoms are started on antibiotic treatment before the presence of sepsis has been proven. With our recently published single-centre intervention study we were able to show that Procalcitonin determinations allowed to shorten the duration of antibiotic therapy in newborns with suspected early-onset sepsis.Methods/DesignThe study is designed as randomized controlled international multicenter intervention trial on the efficacy and safety of Procalcitonin guided treatment. Term and near-term infants (gestational age ≥ 34 0/7 weeks) with suspected sepsis in the first 3 days of life requiring empiric antibiotic therapy will be included. The duration of antibiotic therapy in the standard group is based on the attending physicians assessment of the likelihood of infection (infection unlikely, possible, probable or proven). In the Procalcitonin group, if infection is considered to be unlikely or possible, antibiotic therapy is discontinued when two consecutive Procalcitonin values are within the normal range. Co-primary outcome measures are the duration of antibiotic therapy (superiority aspect of the trial) and the proportion of infants with a recurrence of infection requiring additional courses of antibiotic therapy and/or death in the first month of life (safety of study intervention, non-inferiority aspect of the trial). The number of infants to be included equals 800 per arm. With these numbers the power of the study to demonstrate superiority for duration of antibiotic therapy as well as non-inferiority regarding safety, i.e. excluding a disadvantage difference larger than 2% for the experimental arm, will both be greater than 80%.DiscussionBenefit of the study is a possible limitation of unnecessary use of antibiotics. The results of our first study suggest that there is a low risk on discontinuing antibiotic treatment too early, resulting in the development of a neonatal infection with its morbidity and mortality.Trial registrationThis trial is registered in the U.S. National Institutes of Healths register, located at http://www.clinicaltrials.gov. (NCT00854932).

Optimisation of simulated team training through the application of learning theories: a debate for a conceptual framework

BackgroundAs a conceptual review, this paper will debate relevant learning theories to inform the development, design and delivery of an effective educational programme for simulated team training relevant to health professionals.DiscussionKolb’s experiential learning theory is used as the main conceptual framework to define the sequence of activities. Dewey’s theory of reflective thought and action, Jarvis modification of Kolb’s learning cycle and Schön’s reflection-on-action serve as a model to design scenarios for optimal concrete experience and debriefing for challenging participants’ beliefs and habits. Bandura’s theory of self-efficacy and newer socio-cultural learning models outline that for efficient team training, it is mandatory to introduce the social-cultural context of a team.SummaryThe ideal simulated team training programme needs a scenario for concrete experience, followed by a debriefing with a critical reflexive observation and abstract conceptualisation phase, and ending with a second scenario for active experimentation. Let them re-experiment to optimise the effect of a simulated training session. Challenge them to the edge: The scenario needs to challenge participants to generate failures and feelings of inadequacy to drive and motivate team members to critical reflect and learn. Not experience itself but the inadequacy and contradictions of habitual experience serve as basis for reflection. Facilitate critical reflection: Facilitators and group members must guide and motivate individual participants through the debriefing session, inciting and empowering learners to challenge their own beliefs and habits. To do this, learners need to feel psychological safe. Let the group talk and critical explore. Motivate with reality and context: Training with multidisciplinary team members, with different levels of expertise, acting in their usual environment (in-situ simulation) on physiological variables is mandatory to introduce cultural context and social conditions to the learning experience. Embedding in situ team training sessions into a teaching programme to enable repeated training and to assess regularly team performance is mandatory for a cultural change of sustained improvement of team performance and patient safety.

Prospective Population-based Study of RSV-related Intermediate Care and Intensive Care Unit Admissions in Switzerland over a 4-Year Period (2001–2005)

Objectives:Respiratory syncytial virus (RSV) infections are a leading cause of hospital admissions in small children. A substantial proportion of these patients require medical and nursing care, which can only be provided in intermediate (IMC) or intensive care units (ICU). This article reports on all children aged < 3 years who required admission to IMC and/or ICU between October 1, 2001 and September 30, 2005 in Switzerland.Patients and Methods:We prospectively collected data on all children aged < 3 years who were admitted to an IMC or ICU for an RSV-related illness. Using a detailed questionnaire, we collected information on risk factors, therapy requirements, length of stay in the IMC/ICU and hospital, and outcome.Results:Of the 577 cases reported during the study period, 90 were excluded because the patients did not fulfill the inclusion criteria; data were incomplete in another 25 cases (5%). Therefore, a total of 462 verified cases were eligible for analysis. At the time of hospital admission, only 31 patients (11%) were older than 12 months. Since RSV infection was not the main reason for IMC/ICU admission in 52% of these patients, we chose to exclude this subgroup from further analyses. Among the 431 infants aged < 12 months, the majority (77%) were former near term or full term (NT/FT) infants with a gestational age ≥ 35 weeks without additional risk factors who were hospitalized at a median age of 1.5 months. Gestational age (GA) < 32 weeks, moderate to severe bronchopulmonary dysplasia (BPD), and congenital heart disease (CHD) were all associated with a significant risk increase for IMC/ICU admission (relative risk 14, 56, and 10, for GA ≤ 32 weeks, BPD, and CHD, respectively). Compared with NT/FT infants, high-risk infants were hospitalized at an older age (except for infants with CHD), required more invasive and longer respiratory support, and had longer stays in the IMC/ICU and hospital.Conclusions:In Switzerland, RSV infections lead to the IMC/ICU admission of approximately 1%–2% of each annual birth cohort. Although prematurity, BPD, and CHD are significant risk factors, non-pharmacological preventive strategies should not be restricted to these high-risk patients but also target young NT/FT infants since they constitute 77% of infants requiring IMC/ICU admission.

Cooling for Newborns with Hypoxic Ischemic Encephalopathy

adverse effects of cooling and ‘early’ indicators of neurodevelopmental outcome. Data Collection and Analysis: Four review authors independently selected, assessed the quality of and extracted data from the included studies. Study authors were contacted for further information. Meta-analyses were performed using risk ratios (RR) and risk differences (RD) for dichotomous data, and weighted mean difference for continuous data with 95% confidence intervals (CI). Main Results: We included 11 randomized controlled trials in this updated review, comprising 1,505 term and late preterm infants with moderate/severe encephalopathy and evidence of intrapartum asphyxia. Therapeutic hypothermia resulted in a statistically significant and clinically important reduction in the combined outcome of mortality or major neurodevelopmental disability to 18 months of age (typical RR 0.75 (95% CI 0.68–0.83); typical RD –0.15, 95% CI –0.20 to –0.10); number needed to treat for an additional beneficial outcome (NNTB) 7 (95% CI 5–10) (8 studies, 1,344 infants). Cooling also resulted in statistically significant reductions in mortality (typical RR 0.75 (95% CI 0.64–0.88), typical RD –0.09 (95% CI –0.13 to –0.04); NNTB 11 (95% CI 8–25) (11 studies, 1,468 infants) and in neurodevelopmental disability in survivors (typical RR 0.77 (95% CI 0.63–0.94), typical RD –0.13 (95% CI –0.19 to –0.07); NNTB 8 (95% CI 5–14) (8 studies, 917 infants). Some adverse effects of hypothermia included an increase sinus bradycardia and a significant increase in thrombocytopenia. Cochrane Abstract

Successful treatment of bilateral renal fungal balls with liposomal amphotericin B and fluconazole in an extremely low birth weight infant

Abstract At the age of 8 weeks, an extremely low birth weight infant (gestational age 26 0/7 weeks, birth weight 740 g) had non-obstructing bilateral renal fungal balls. Urine cultures had repeatedly grown Candida albicans. Combination therapy with liposomal amphotericin B intravenously and fluconazole orally was administered for 6 weeks. Monotherapy with fluconazole was then continued until complete resolution of the renal fungal balls. Conclusion Combination therapy with liposomal amphotericin B and fluconazole was successful in eliminating non-obstructing bilateral renal fungal balls and obviated the need for surgical intervention.

The Journey Towards Lung Protective Respiratory Support in Preterm Neonates

The aim of this conceptual review is to provide the reader with a broad perspective on progress made in respiratory support of preterm infants over the past five decades. Landmark discoveries are described in their historical context and underlying theories of lung protection are discussed. The review finishes by integrating different approaches and perspectives into a state-of-the-art concept for lung-protective ventilation in this fragile patient population. Improvements in neonatal respiratory support in the 1970s and 1980s have contributed to dramatic improvements of mortality and morbidity rates among neonates with respiratory failure. Continuous positive airway pressure, antenatal corticosteroids and surfactant replacement therapy revolutionized the care of preterm infants. With the recognition that atelectrauma, volutrauma and oxygen toxicity are the main factors contributing to ventilator-induced lung injury, lung-protective strategies, including noninvasive respiratory support, tidal volume targeting during conventional mechanical ventilation and high frequency ventilation were developed in the 1990s. Given the fact that progress made in the last decade has only resulted in minor improvements in mortality and morbidity rates of neonates with respiratory failure, it seems unlikely that further refinements of current technologies will produce giant leaps forward in high-resource countries. It appears that entirely new approaches would be required. In contrast, knowledge and technology transfer of basic respiratory support strategies (e.g. use of oxygen, simple systems to provide continuous positive airway pressure), could have an enormous impact on the prognosis of neonates with respiratory failure in low-resource countries.

Procalcitonin-guided decision making for duration of antibiotic therapy in neonates with suspected early-onset sepsis: a multicentre, randomised controlled trial (NeoPIns)

BACKGROUND Up to 7% of term and late-preterm neonates in high-income countries receive antibiotics during the first 3 days of life because of suspected early-onset sepsis. The prevalence of culture-proven early-onset sepsis is 0·1% or less in high-income countries, suggesting substantial overtreatment. We assess whether procalcitonin-guided decision making for suspected early-onset sepsis can safely reduce the duration of antibiotic treatment. METHODS We did this randomised controlled intervention trial in Dutch (n=11), Swiss (n=4), Canadian (n=2), and Czech (n=1) hospitals. Neonates of gestational age 34 weeks or older, with suspected early-onset sepsis requiring antibiotic treatment were stratified into four risk categories by their treating physicians and randomly assigned [1:1] using a computer-generated list stratified per centre to procalcitonin-guided decision making or standard care-based antibiotic treatment. Neonates who underwent surgery within the first week of life or had major congenital malformations that would have required hospital admission were excluded. Only principal investigators were masked for group assignment. Co-primary outcomes were non-inferiority for re-infection or death in the first month of life (margin 2·0%) and superiority for duration of antibiotic therapy. Intention-to-treat and per-protocol analyses were done. This trial was registered with ClinicalTrials.gov, number NCT00854932. FINDINGS Between May 21, 2009, and Feb 14, 2015, we screened 2440 neonates with suspected early-onset sepsis. 622 infants were excluded due to lack of parental consent, 93 were ineligible for reasons unknown (68), congenital malformation (22), or surgery in the first week of life (3). 14 neonates were excluded as 100% data monitoring or retrieval was not feasible, and one neonate was excluded because their procalcitonin measurements could not be taken. 1710 neonates were enrolled and randomly assigned to either procalcitonin-guided therapy (n=866) or standard therapy (n=844). 1408 neonates underwent per-protocol analysis (745 in the procalcitonin group and 663 standard group). For the procalcitonin group, the duration of antibiotic therapy was reduced (intention to treat: 55·1 vs 65·0 h, p<0·0001; per protocol: 51·8 vs 64·0 h; p<0·0001). No sepsis-related deaths occurred, and 9 (<1%) of 1710 neonates had possible re-infection. The risk difference for non-inferiority was 0·1% (95% CI -4·6 to 4·8) in the intention-to-treat analysis (5 [0·6%] of 866 neonates in the procalcitonin group vs 4 [0·5%] of 844 neonates in the standard group) and 0·1% (-5·2 to 5·3) in the per-protocol analysis (5 [0·7%] of 745 neonates in the procalcitonin group vs 4 [0·6%] of 663 neonates in the standard group). INTERPRETATION Procalcitonin-guided decision making was superior to standard care in reducing antibiotic therapy in neonates with suspected early-onset sepsis. Non-inferiority for re-infection or death could not be shown due to the low occurrence of re-infections and absence of study-related death. FUNDING The Thrasher Foundation, the NutsOhra Foundation, the Sophia Foundation for Scientific research.

Epidemiology of blood culture-proven bacterial sepsis in children in Switzerland: a population-based cohort study

BACKGROUND Sepsis is a leading cause of childhood mortality worldwide. We assessed population-based incidence and outcomes of blood culture-proven bacterial sepsis in children in Switzerland. METHODS We did a multicentre, prospective, cohort study at ten paediatric hospitals in Switzerland. We included neonates and children younger than 17 years with blood culture-proven bacterial sepsis. Children were eligible if they met criteria for systemic inflammatory response syndrome-according to 2005 paediatric consensus definition- at the time of blood culture sampling. Incidence was calculated by dividing the number of annual sepsis episodes in the study for the years 2012-15 by the end-of-year resident paediatric population in Switzerland. The primary outcome was in-hospital mortality in the first 30 days after sepsis onset. FINDINGS Between Sept 1, 2011, and Dec 31, 2015, we enrolled 1096 children to our study. Of 1181 episodes of blood culture-proven bacterial sepsis, 382 (32%) occurred in 379 previously healthy children, 402 (34%) in 391 neonates, and 397 (34%) in 341 children with comorbidities. Incidence was 25·1 cases per 100 000 (95% CI 23·8-26·4) in children and 146·0 cases per 100 000 (133·2-159·6) in neonates. Central line-associated bloodstream infections and primary bloodstream infections accounted for 569 (48%) of 1181 episodes, and organ dysfunction was present in 455 (39%) of 1181 episodes. Escherichia coli (242 of 1181 [20%]), Staphylococcus aureus (177 of 1181 [15%]), coagulase-negative staphylococci (135 of 1181 [11%]), and Streptococcus pneumoniae (118 of 1181 [10%]) were the most prevalent pathogens in our study, accounting for 57% of episodes. The overall case-fatality ratio was 7% (82 of 1181 episodes; 95% CI 5·6-8·6), and it was higher in neonates (11%, 45 of 402 episodes; 8·4-14·8; adjusted odds ratio [OR] 4·41, 95% CI 1·75-11·1) and children with comorbidities (7%, 27 of 397 episodes; 4·6-9·9; OR 4·97, 1·84-13·4) compared with previously healthy children (3%, ten of 382 episodes; 1·3-4·9). The case-fatality ratio was 1% (five of 726 episodes [95% CI 0·3-1·7]) for children without organ dysfunction, which increased to 17% (77 of 455 episodes [13·7-20·8]) when organ dysfunction was present (adjusted OR 4·84, 95% CI 1·40-16·7). INTERPRETATION The burden of blood culture-proven bacterial sepsis on child health remains considerable. We recorded key differences in predominant organisms, severity, and outcome between neonates, previously healthy children, and children with comorbidities. Although for most episodes of blood culture-proven bacterial sepsis, no organ dysfunction was seen, presence of organ dysfunction was strongly associated with mortality. FUNDING Swiss National Science Foundation, Swiss Society of Intensive Care, Bangerter Foundation, Vinetum and Borer Foundation, and Foundation for the Health of Children and Adolescents.

Incidence and Outcome of Group B Streptococcal Sepsis in Infants in Switzerland

The incidence and outcome of group B streptococcal (GBS) sepsis were assessed prospectively between September 2011 and February 2015 in all tertiary care pediatric hospitals of Switzerland. We describe a low incidence of GBS early-onset sepsis (0.12/1000 livebirths) and a predominance of GBS late-onset sepsis (0.36/1000 livebirths), a pattern that has not been reported in other countries.