Study On Management Of Nosocomial Infection And Early-detection System For Infection In Neonatal Intensive Care Unit

IntroductionNosocomial infection (NI) is a significant complication for critical ill patients treated in the neonatal intensive care unit (NICU) and results in considerable morbidity and mortality. With advance in perinatal medicine and neonatal intensive care, the survival rate of preterm infants is rising obviously. However, the morbidity of preterm infants has not been decreased with the increased survival rate. The infection rate among survivors is still high, especially for very low birth weight (VLBW) and extremely low birth weight infants (ELBW). Neonates hospitalized in NICU have greater likelihood of a critical illness, and invasive monitoring and procedures make them more vulnerable to acquisition of health care-associated infections. The device-associated infection (DAI), especially ventilator associated pneumonia (VAP) and Central-line associated bloodstream infection (CLABSI), are raising more and more attention both from international and domestic neonatal healthcare workers because of worsening neonatal outcomes and associated neurodevelopmental impairment among survivors. Reducing DAI may short length of NICU stay, cut health care costs, decrease the morbidity and mortality among neonates and improve their short- term and long-term prognosis.Ventilator-associated pneumonia (VAP), defined as pneumonia that develops at least 48 hours after introduction of mechanical ventilation (MV) is one of the most common health care-associated infections in neonates. Given the immaturity of neonate’s immune system, MV and other invasive treatment measures are very likely to increase the risk of oropharyngeal or tracheobronchial colonization with pathogenic bacteria, which adhere to the epithelial cells of the respiratory tract. VAP occurs when bacterial, fungal, or viral pathogens enter the normally sterile lower respiratory tract and lung parenchyma. With the rapid development in China, increasing number of neonatal intensive care units (NICUs) are being established across the country. Consequently, increasing numbers of very premature babies are surviving. Because many of them require MV, VAP has become a major challenge. VAP has a large influence on neonatal survival, morbidity, hospital costs, and duration of NICU stay.Central line-associated bloodstream infections (CLABSI), defined as sepsis that develops after 48 hours of central venous catheterization, are a significant source of sepsis in NICU. Central venous catheters or central lines (CL) have been routinely used in NICUs in developed countries to provide long-term venous access for delivering parenteral nutrition (TPN) and medication for over three decades. By contrast, indwelling CL has been only introduced as routine practice in Chinese NICUs during the past decade. CLABSI is one of the most serious complications of CL insertion, which result in considerable morbidity and mortality, increase duration of hospital stay and health cost. Therefore, reduction and prevention of CLABSI are critical to increase the survival rate and improve outcome of neonates treated in NICU.NI can progress to sever sepsis, Multiple organ dysfunction syndrome (MODS) and even death very quickly even with advance antibiotics. The clinical symptoms of NI are often subtle and nonspecific. Infants may often appear asymptomatic until the infection is well established. Therefore, early and accurate diagnosis is challenging. Unfortunately, no single biomarker has proven successful in accurately detecting LONS, and most biomarker tests require serial sampling for to allow a trend to be established to be useful for diagnosis. The need to take multiple blood samples also increases the risk of introducing secondary infection in neonates.In the era of sophisticated electronic information and computerized techniques, bedside medical devices are used in NICU to monitor the clinical condition of neonates. The monitors graphically display complex physiological data for physiological data streams Subtle changes in physiological data may be predictive for a future event. However, large physiological data stream are discarded automatically without further analysis. There are few infrastructure, tools and techniques to utilize this data to its fullest potential to support clinical management and retrospectively analysis.Studies have reported that physiological parameters such as heart rate and respiratory rate would fluctuate and change because of proinflammatory cytokines released in the early stage of infection. Continuously monitor, collect and further analyse these physiological streams, by which to detect its abnormal changes early may provide new ways for non-invasive and early warning system for sepsis and other serious infections in NICU.Currently, quality improvement based on evidence-based practice is prevalent in developed countries, the standard and unified infection surveillance method recommended by CDC is used during infection monitoring process in developed countries. Researchers have created "Care bundles" which is a group of interventions that, when executed together, result in better outcomes than when implemented individually. Meanwhile, healthcare workers in developed countries are trying to combine information technology, health informatic, and clinical expertise to explore the "big data" exist in physiological parameters to early detect neonatal nosocomial infection, which could translate the potential information in neonates’ physiological data into high-quality evidence-based clinical decision support.Comparing with developed countries, healthcare-associated infection, especially DAI control awareness among healthcare workers in NICU is relatively weak, the affect of VAP and CLABSI on health care costs is especially significant in the developing world whereas most relative studies have been conducted in developed countries. Reports on the success of VAP and CLABSI intervention strategies are scarce. Most Physicians in Chinese NICU still practice infection control casually and based on experience. Meanwhile, how to take advantage of interdisciplinary in the information era, explore the "big data" exist in physiological parameters to earlier detection of neonatal infection in NICU is also a frontier topic in front of us.In the first two parts of this study, the "Healthcare bundles" were developed to control VAP and CLABSI in our NICU, VAP and CLABSI incidence density were monitored continuously using the standard calculate method recommend by CDC; in the third part of this study we build a real-time physiological data collection and permanent store platform to do preliminary data mining for earlier detection of neonatal infection which was the first in China. There are two primary aims of the first two parts of this study, one aim is to provide reliable epidemiologic data and characterization of VAP and CLABSI among neonatal patients in our hospital, another aim is to evaluate the efficacy of a multi-faceted infection control program ("bundles") in reducing VAP and CLABSI in our NICU. These two investigations can provide important information for future comparative studies and to encourage and promote the use of surveillance and CLABSI preventive strategies in other Chinese hospitals. By the third part of this study, we aimed to investigate whether there have subtle changes exist in physiological data behaviors present prior to the clinical suspicion of neonatal infection, which should provide an exciting opportunity to advance our knowledge of healthcare informatics application and to offer some important insights into healthcare "big data".The Ethics Committee of children’s hospital at Fudan University approved the study protocol.Part Ⅰ:Efficacy of an infection control program in reducing ventilator-associated pneumonia in a Chinese neonatal intensive care unitBackground:With the rapid development of China, increasing numbers of very premature babies are surviving. Ventilator-associated pneumonia (VAP) has become a major challenge. VAP has a large influence on neonatal survival, morbidity, hospital costs, and duration of NICU stay. The affect of VAP is especially significant in the developing world whereas most relative studies have been conducted in developed countries. Measures employed in preventing VAP in developing countries are rarely reported.Objectives:1. To investigate the incidence, the distribution of pathogens and antibiotic sensitivity of VAP in our NICU2. To evaluate the efficacy of a multi-faucet infection control program (bundles) to reduce VAP in a neonatal intensive care unit (NICU) in China.Methods:This is a prospective before-after study. The hospital relocated to a new site from June 2008 and the intervention was initiated in NICU from phase 2. The first phase was from Feb 1,2006 to Jan 1,2007(pre-intervention phase), the second phase was from Aug 1,2008 to July 31,2009 (partial intervention phase) and the third phase was from Jan 1,2010 to Dec 31,2010(systemic intervention phase). Related data were collected for comparing VAP incidence and pathogen distribution during these three phases after a bundle of infection preventive measures were gradually implemented step by step. STATA 10.0 was applied for statistic analysis in this study.Results:1. A total of 491 neonates were enrolled during the study period. MV patients accounted for 5.0%,6.8%,7.8% among general hospitalized neonates in these three phases. The primary reason for use of MV were premature respiratory distress syndrome (47.9%)2. Of 491 ventilated patients,92 (18.7%) developed VAP corresponding to 27.3 per 1,000 ventilator-days. The rate decreased from 48.8 per 1,000 ventilator-days in phase 1 to 25.7 per 1,000 ventilator-days in phase 2 and further diminished to 18.5 per 1,000 ventilator-days in phase 3 (P<0.001). Overall mortality rate of admitted neonates significantly decreased from 14.0% in Phase 1 to 2.9% in Phase 2 and 2.7% in phase 3 (P=0.000).3.66 strains of pathogens were isolated among 92 patients with VAP, Gram-negative bacilli (63 strains,95.5%) were the primary VAP microorganisms in all phases, and the most common organisms isolated for VAP during these three period were Acinetobacter baumannii(43 strians,65.2%)and Klebsiella pneumoniae(10 strains, 15.2%).4. In phase 1, antimicrobial susceptibility testing showed that all Acinetobacter baumannii were resistant to cephalosporin, and antimicrobial susceptibility of carbapenems were 57.9%, and eight multi-drug resistant bacterial strains were isolated. After implemented the infection-control practices during the second phase, 75% Acinetobacter baumannii were sensitive to cephalosporins, the difference is significant compares to phase 1(P=0.000), and there were no multi-drug resistant or carbapenem-resistant strains isolated in phase 2. However, in phase 3, the antimicrobial susceptibility to the third-generation cephalosporin and carbapenems declined to 5%(P=0.001) and 20%(P=0.01) respectively.10 multi-drug-resistant strains were isolated.Conclusions:1. Implementing a multi-faceted infection control program resulted in significant reduction in VAP rate with long-term effects.2. The VAP incidence was still high compared with the developed countries, further studies are required to investigate the infection control strategies.3. Gram-negative bacilli were the primary VAP microorganisms in our NICU and Acinetobacter baumannii (65.2%) was the most frequently isolated microorganism.4. The pathogens spectrum changes in different periods. Regular analysis and monitoring pathogen’s species and the variance of drug resistance in local patients with VAP are important to guide the clinical use of antimicrobial agents and to effectively control the incidence of VAP.Part II:Study on the Effects of "Care Bundles" in Reducing Central Line-associated Bloodstream Infections in a Chinese Neonatal Intensive Care UnitBackground:Over the past decade, central line (CL) has been introduced to the NICU in China and practiced rapidly as a routine in NICU. Most critically ill neonates, including extremely low birth weight (ELBW) and very low birth weight (VLBW) infants, are frequently managed with CL, which placed this immune-compromised population at high risk of CLABSI. "Care bundles" and scientific quality improvement methodology have been used to reduce central-line associated bloodstream infections (CLABSIs) in developed countries. These efforts have significantly reduced CLABSIs and the CLABSI incidence even fallen to zero in some NICUs in developed countries. Few data are available on CLABSIs in Chinese NICUs. CLABSI prevention in Chinese NICU is still based on experience. Measures employed in preventing CLABSI in developing countries are rarely reported.Objectives:1. To investigate the incidence and the distribution of pathogens of CLABSI in our NICU2. To evaluate the impact of a multi-faceted evidence-based practices (bundles) on the occurrence of CLABSI in our NICU, by which to provide effective strategies for clinical practice.Methods:We conducted a prospective before-after intervention study with a 1-year follow-up among patients with central lines at the NICU of the Children’s Hospital of Fudan University, between January 2008 and December 2010. Patients with CL indwelling for>48 hours and who had been hospitalized in NICU for≥5 days were recruited. The study was conducted in three phases which is before (phase 1,1 January 2008 to 31 December 2008), during(phase 2,1 January 2009 to 31 December 2009), and after (phase 3,1 January 2010 to 31 December 2010) intervention. Multi-faceted evidence-based practices were introduced in phase 2 and continued in phase 3 with successive surveillance. CLABSI were prospectively monitored and compared. STATA 10.0 was applied for statistic analysis in this study.Results:1. A total of 171 patients with CL were observed with the bed-days of 10399. There were 29,51, and 91 enrolled newborns in phase 1, phase2, and phase 3, respectively. There were no significant differences in terms of clinical characteristics between these 3 groups.2. Of 171 patients,29 of them developed CLABSI with the CLABSI rate of 17.0%, and the overall CLABSI incidence density decreased significantly from 16.7 per 1,000 CL-days in phase 1 to 7.6 per 1,000 CL-days in phase 2 and to 5.2 per 1,000 CL-days in phase 3 (P<0.001).3.22 strains of pathogens were identified during the study period, one episode with 2 pathogens was identified. Gram-negative bacterium (54.5%) was the predominant pathogen in CLABSI generally, and the most common Gram-negative bacilli isolated for CLABSI during these three Phases were Acinetobacter baumannii (6 strians. 27.3%) and Klebsiella pneumonia (4strains,18.1%). Coagulase-negative staphylococci (7strains,31.8%) was the most frequently isolated microorganism. Gram-positive bacterium caused CLABSI has an increasing trend during 3 phases.Conclusions1. A multi-faceted infection control program is effective in sustaining reduction of CLABSI rate among neonates.2. The CLABSI incidence was still high compared with the developed countries. Further studies are required to investigate the infection control strategies.3. Gram-negative bacterium was the predominant pathogen of CLABSI. Coagulase-negative staphylococci were the most frequently isolated microorganism.4. The pathogens spectrum of CLABSI changes in different periods. Gram-positive bacterium has an increasing trend during 3 phases. Regular analysis and monitoring pathogen’s species of CLABSI and the variance of drug resistance in local NICU are important to guide the clinical rational use of antimicrobial agents and to effectively control the incidence of CLABSI. Coagulase-negative staphylococci were the most frequently isolated microorganism.4. The pathogens spectrum of CLABSI changes in different periods. Gram-positive bacterium has an increasing trend during 3 phases. Regular analysis and monitoring pathogen’s species of CLABSI and the variance of drug resistance in local NICU are important to guide the clinical rational use of antimicrobial agents and to effectively control the incidence of CLABSI.Part Ⅲ:Earlier Detection of Infection using Temporal Analysis of Continuous Physiological Data Streams in a Chinese Neonatal Intensive Care UnitBackground:Infection is an important cause of morbidity and mortality in neonates. Proinflammatory cytokine released in the early stage of serious infection would result in changes of heart rate, respiratory rate, blood pressure and other physiological parameter via automatic immune- automatic nervous system-heart interactions on the cell level. There is a growing body of evidence to prove the potential to utilize physiological data to assist with the prediction of the onset of clinical events. If the high volume of physiological parameter data from bedside monitor devices could be stored and analysis, it might help physician to find the subtle changes exist in physiological data, which is predictive for neonatal infection. As such the infected neonates can be treated earlier and therefore have better prognosis. There are few infrastructure, tools and techniques to utilize this data streams to its fullest potential to support clinical management and retrospectively analysis. Big volumes of physiological data and information was wasted and not be fully used. The rapid and accurate integration of data from numerous medical systems is essential for quality, evidence-based decision making within the NICU and to help physicians to detect interested clinical events earlier.Objectives:1. To establish an environment which can collect and store the multi-dimensional and high-fidelity physiological data form bedside monitors, by which to realize the long term storage and retrospective analysis of the physiological data.2. To test whether heart rate variability (HRV) and respiratory rate variability (RRV) behaviors present prior to the clinical suspicion of infection especially the neonatal sepsis, by which to explore the application value of HRV and RRV in the infection early detection system.Methods:Cooperate with the research team in The Hospital for Sick Children in Toronto and University of Ontario Institute of Technology, Canada, to set up an Artemis system for our local real-time physiological data collection and storage. We collected physiological data with this local Artemis platform prospectively from April 1st 2013 to September 30th 2013. Using the STDMnO frame provided by the cooperator, Carolyn McGregor, and SAS software together, to do the time series analysis for the HRV and RRV for the enrolled patients. Match the Clinical event with the data analysis result, comparing HRV and RRV between sepsis and non-sepsis patients, and between before and after sepsis treatment for sepsis patients to investigate the changes of HRV and RRV before and after neonatal infection.Results:1. Establishment of local Artemis platform at Children’s Hospital of Fudan University successfully. Given the environment of our NICU, the platform may collect physiological data (SPO2, respiratory rate, heart rate and blood pressure) from 21 bedside monitors synchronously. The data are processed by IBM streams and transfer into the DB2. This platform realizes the physiological data’s locally storage and retrospective analysis.2. We enrolled 80 patients during the research period. Thirty eight episodes of infection occurred in 37 patients, including 29 episodes of late onset neonatal sepsis (8 episodes of lab-confirmed sepsis and 21 episodes of clinical sepsis),8 episodes of urine tract infection and 1 episodes of meningitis. The initial analysis result shows the patients with severe infection have decreased HRV and normal RRV.3. Forty eight patients’physiological data is relatively intact which can be used in the time-series analysis and met the standard of data mining. Six patients with sepsis (3 with lab confirmed sepsis and 3 with clinical sepsis) and 37 patients without sepsis were included. Average minutes of normal HRV per hour was compared between sepsis and non-sepsis patients. Relative alignment for sepsis patients considering average of 48 hours of data prior to diagnosis (30.42±6.06min/hour VS 33.6±6.02min/hour, P=0.18), average of 96 hours of data prior to diagnosis (30.2±6.02min/hour VS 33.6±6.02min/hour, P=0.17), average of all data prior to diagnosis (29.5±4.72min/hour VS 33.6±6.02min/hour, P=0.08) was compared with all other patients include all data. The average minutes of normal HRV per hour was lower with in patients with sepsis, but the difference have no statistic significance.4. Examine sepsis patients only with matched pairs analysis for sepsis patients (before and after sepsis treatment):1) when the发’Before’ period is average HRV (29.24 min) from all data leading up to point of sepsis diagnosis, ’After’ period is average HRV(33.62 min) from all data from 48 hours after day of sepsis diagnosis, there is a statistically significant increase in normal HRV after sepsis diagnosis as compared to before sepsis diagnosis (p=0.003), the mean difference is 4.38 additional minutes of normal HRV per hour after sepsis treatment(95%CI [2.1,6.7]).2) when the ’Before’ period is average HRV from 72 hours leading up to point of sepsis diagnosis, ’After’ period is average HRV from 72 hours after sepsis diagnosis, there is a statistically significant increase in normal HRV after sepsis diagnosis as compared to before sepsis diagnosis (p=0.04), the mean difference is 3.83 additional minutes of normal HRV(95%CI [1.4,5.9]).3) when ’Before’ period is average HRV from 72 hours leading up to point of sepsis diagnosis, ’After’ period is average HRV from 1 week after sepsis diagnosis, there is a statistically significant increase in normal HRV after sepsis diagnosis as compared to before sepsis diagnosis (p=0.006), the mean difference is 3.52 additional minutes of normal HRV(95%CI [1.3,5.8]).Conclusion1. The physiological data collection and storage platform (Artemis platform) was established in Chinese NICU base on the available bedside monitor and NICU environment.2. The stability and performance of the Artemis platform established in the NICU still need to be optimized and improved.3. HRV decreased in the sepsis patients according to our pilot study result.4. There may have a special time window to detect the decrease of HRV in the early stage of sepsis. Large cohort study is needed to further confirm the hypothesis.