Ignite Creation Date:
2024-05-06 @ 7:10 AM
Last Modification Date:
2024-10-26 @ 11:45 AM
Study NCT ID:
NCT02486783
Status:
COMPLETED
Last Update Posted:
2016-10-21
First Post:
2015-06-27
Brief Title:
Infection Sepsis and Meningitis in Surinamese Neonates
Sponsor:
Academic Hospital Paramaribo
Organization:
Academic Hospital Paramaribo
Study Overview
Official Title:
Infection Sepsis and Meningitis in Surinamese Neonates
Status:
COMPLETED
Status Verified Date:
2016-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
InSepSur
Brief Summary:
Suriname is a small developing country in South America with a population of half a million people Early neonatal death in Suriname is high with 16 per 1000 live births Unpublished data from the Suriname Perinatal and Infant Mortality Survey estimate contribution of infection to early neonatal mortality at 25 4 per 1000 live births of all deaths In comparison incidence rates of neonatal sepsis alone are 35 per 1000 live births These numbers indicate an increased burden of neonatal infection in Suriname versus the US In any case about 40 newborns that die each year of infection are a huge loss also considering the small Surinamese community Despite this overall idea on the impact of infectious disease in Surinamese neonates exact information regarding incidence type of infection eg localized viral early-onset or late-onset sepsis risk factors eg insufficient antenatal care maternal Group B-Streptococcus status etiology microbial causes morbidity antibiotic treatment type and duration and epidemiological determinants eg gestational age sex ethnicity are lacking
From a clinical perspective there is still a challenge to identify neonates with infection Neonates are often admitted with ambivalent clinical symptoms and receive preventive antibiotics that are costly promote pathogen-resistance and have negative long-term effects ie on the development of the intestinal bacterial flora Currently assessment of blood leukocyte or trombocyte counts and levels of CRP are insufficiently sensitive to be used as biomarkers while confirmation of actual sepsis or meningitis by positive culture results is relatively rare 05-3 in the United States This complicates decisions on duration of antibiotic treatment and hospitalization significantly while no other biomarkers exist
The circulating isoforms of adhesion molecules cAMs which mediate interactions of leukocytes with the vascular endothelium have been proposed as biomarkers for infection and sepsis During infection they accumulate in the bloodstream as a result of shedding which represents their removal from cell surfaces of endothelial cells and leukocytes by enzymes called sheddases Recently we have reviewed mechanisms behind shedding of cAMs in neonatal pediatric and adult sepsis The shedding process reflects a critical and active process in orchestrating interaction between leukocytes and the endothelium for an effective host response while minimizing collateral tissue damage As a result both plasma levels of cAMs and their sheddases are subject to change during infection and sepsis Additionally compelling albeit limited data suggest changes of levels of cAMs in CSF in adult and pediatric meningitis
To date some evidence exists of changes in levels of cAMs during malaria in children from Malawi and sepsis although not sensitive enough to predict outcomes in the clinic Those levels have never been assessed simultaneously with levels of their sheddases in blood or CSF as a diagnostic tool We propose that this combined approach may provide more detailed information about the extent of inflammatory activation in neonatesWhile a balance in levels is maintained under resting conditions or mild local infection it may be perturbed during sepsis or meningitis Thus simultaneous measurement of these levels could promote early identification of infection and may even distinguish between mild infection systemic infection or meningitis Currently manufacturers are rapidly developing Luminex technology as an advanced fast high-throughput and clinically feasible bedside tool for such an approach
We hypothesize that incidence rates of neonates with infection in Suriname are high We further hypothesize that upon signs of infection the simultaneous measurement of cAMs and their SEs in serum and CSF discriminates between infected and non-infected neonates We aim to 1 identify and follow neonates at the Academic Hospital Paramaribo with signs of infection to establish incidence rates of infection and 2 investigate diagnostic potential of our proposed biomarker combination in these neonates for infection type of infection eg local mild sepsis or meningitis and outcomes
From a clinical perspective there is still a challenge to identify neonates with infection Neonates are often admitted with ambivalent clinical symptoms and receive preventive antibiotics that are costly promote pathogen-resistance and have negative long-term effects ie on the development of the intestinal bacterial flora Currently assessment of blood leukocyte or trombocyte counts and levels of CRP are insufficiently sensitive to be used as biomarkers while confirmation of actual sepsis or meningitis by positive culture results is relatively rare 05-3 in the United States This complicates decisions on duration of antibiotic treatment and hospitalization significantly while no other biomarkers exist
The circulating isoforms of adhesion molecules cAMs which mediate interactions of leukocytes with the vascular endothelium have been proposed as biomarkers for infection and sepsis During infection they accumulate in the bloodstream as a result of shedding which represents their removal from cell surfaces of endothelial cells and leukocytes by enzymes called sheddases Recently we have reviewed mechanisms behind shedding of cAMs in neonatal pediatric and adult sepsis The shedding process reflects a critical and active process in orchestrating interaction between leukocytes and the endothelium for an effective host response while minimizing collateral tissue damage As a result both plasma levels of cAMs and their sheddases are subject to change during infection and sepsis Additionally compelling albeit limited data suggest changes of levels of cAMs in CSF in adult and pediatric meningitis
To date some evidence exists of changes in levels of cAMs during malaria in children from Malawi and sepsis although not sensitive enough to predict outcomes in the clinic Those levels have never been assessed simultaneously with levels of their sheddases in blood or CSF as a diagnostic tool We propose that this combined approach may provide more detailed information about the extent of inflammatory activation in neonatesWhile a balance in levels is maintained under resting conditions or mild local infection it may be perturbed during sepsis or meningitis Thus simultaneous measurement of these levels could promote early identification of infection and may even distinguish between mild infection systemic infection or meningitis Currently manufacturers are rapidly developing Luminex technology as an advanced fast high-throughput and clinically feasible bedside tool for such an approach
We hypothesize that incidence rates of neonates with infection in Suriname are high We further hypothesize that upon signs of infection the simultaneous measurement of cAMs and their SEs in serum and CSF discriminates between infected and non-infected neonates We aim to 1 identify and follow neonates at the Academic Hospital Paramaribo with signs of infection to establish incidence rates of infection and 2 investigate diagnostic potential of our proposed biomarker combination in these neonates for infection type of infection eg local mild sepsis or meningitis and outcomes
Detailed Description:
Study Design
The Academic Hospital Paramaribo AZP has the largest perinatal care facility in Suriname Recently the AZP opened the countrys only neonatal intensive care unit NICU This study aims to include all neonates presenting here and at the high and medium care facilities with clinical signs of infection sepsis or meningitis age 0-1 month that require infection work up Along with the inclusion of these neonates follows a detailed epidemiological description of newborns with infectious disease Inclusion will take place by one of 10 residents with approval from one of the 5 attending pediatricians Along with standard blood draws for infection parameters at t0 and t48 hours blood culture at t0 hours and CSF culture at t0 hours serum and CSF will be separated for our biomarker study For all neonates normal local protocol for the management of infection sepsis or meningitis will be followed This includes antibiotic treatment for 7 days when 1 clinical suspicion of infection at admission was high 2 infection parameters are aberrant at 48 hours 3 blood culture is positive Otherwise antibiotic treatment is stopped after 48 hours Further protocol includes necessary changes in respiratory support circulatory fluid support and feeding Medical treatments can be cardiotonics and treatments for hyperglycemia and seizures Neonates are divided over 5 groups based on course of antibiotic treatment and culture results 1 Baseline controls no signs of infection neonates admitted for serial blood draws at t0 and 48 hours for uncomplicated hyperbilirubinemia with jaundice but without other signs of infection 2 Signs of infection further divided in 2a No infection antibiotics stopped after 48 hours negative cultures 2b Clinical infection 7 day antibiotics negative cultures 2c Sepsis positive bacterial blood culture 2d Meningitis positive bacterial CSF culture
Sample size and power
Sample size and power analysis is complicated because The Suriname Perinatal and Infant Mortality Survey only provides data on mortality as a result of infection amongst other causes without data on the incidence of neonatal infection We estimate an incidence of admission for clinical signs for infection of 50 per 1000 live births 5 at the NICU of the AZP An annual birth rate at the AZP of about 3000 live births per year gives us n150 neonates with signs of infection divided over four groups Based on these estimations the recommended sample size of the whole population would be n1538 margin of error 1 and CI 99 Since the incidence of newborns for which exclusion criteria apply and incidence of the subgroups are currently unknown and to compensate for loss to follow up we decided to include over a one-year period n3000 The biomarker study is exploratory in nature and we aim for a baseline control group of n40 larger n may be difficult to establish due to practical constraint In our analysis we will adjust for gestational age and ethnicity Absence of prior data on levels of biomarkers in relation to neonatal infection prevents us from estimating power With analysis of sera and CSF from our 150 inclusions we aim to perform that for future follow-up biomarker studies
Methodology
Epidemiology The following data will be recorded upon t0 hours and during t48 hours admission date and time maternal age gender maternal Group-B-streptococcus culture result maternal fever premature prolonged rupture of membranes PPROM gestational age if unknown according to Ballard delivery location and mode Apgar scores birth weight gender ethnicity leukocyte count and differentiation trombocyte count CRP antibiotic treatment type duration sepsis earlylate onset line survivalexpiration The Score for Neonatal Acute Physiology II will be scored at t0 and 48 hours
Serum separation Whole blood will be collected by vena puncture in one serum microtainer 500 μL Serum samples will be separated by centrifugation at 2500 xg for 15 minutes and kept on ice until storage All serum and CSF samples will be stored at -80C in the central laboratory of the AZP Batched serum and CSF samples will be packaged on dry-ice max 24 hours according to the International Air Transport Association guidelines and transported to the Endothelial Biomedicine and Vascular Drug Targeting Laboratory in Groningen
Luminex Technology Our laboratory in Groningen has extensive experience with the use of Luminex arrays for the measurement of multiple adhesion molecules at once in clinical patient samples ie multiplexing Currently the technique is applied successfully in basic and translational research and is gradually making its way into the clinic allowing for the compilation of a diagnostic multi-array of molecules for complex diseases such as sepsis or cancer See Table 1 for specific adhesion molecules and their associated shedding enzymes that we include in our array Measurement of soluble L- E- and P-selectin Intercellular adhesion molecule ICAM-1 vascular cell adhesion molecule VCAM-1 neutrophil elastase NE Matrix-metalloproteinase-9 MMP-9 tissue-inhibitor of metalloproteinase TIMP-1 and ADAM metallopeptidase domain 17 ADAM-17 will be performed with Luminex NE and ADAM-17 will be analyzed by ELISA as long as Luminex is not yet available for these molecules We will also use Luminex to measure circulating Angiopoetin-1 and -2 and soluble Tie-2 receptor as markers of endothelial cell activation For Luminex assays Life Technologies appropriate diluted volumes of samples will be aliquoted in 96 well plates Simultaneous analysis will take place with the Luminex 100 Analyzer Life Technologies ELISA will be performed according to the manufacturers protocol RD systems
Statistical Analysis
Incidence rates end epidemiological determinants will be calculated at the end of the inclusion period Categorical variables will be presented as numbers and percentages and continuous variables as mean - SD or if not normally distributed as median - 10th percentile Categorical data will be compared with chi-square and continuous variables with the independent t-test or two-way ANOVA To assess the independent effect of biomarker combinations cAMSE ratios on the occurrence of infections multivariate logistic regression will be performed with infection as dependent and cAMSE ratios gestational age and ethnicity as independent variables We will calculate Spearman rank correlation to assess bivariable association between biomarkers Diagnostic accuracy of cAMSE ratios will be assessed by using the Receiver Operating Characteristic ROC-based area under the curve Other test characteristics such as predictive value and likelihood ratios will be calculated P-values 005 will be considered statistically significant Statistical analysis will be performed using Stata StataCorp
Difficulties and Limitations
First separation of serum from neonates could lead to low volumes yet Luminex technology is designed for the assessment of high numbers of molecules in low volumes According to local protocol CSF collection is not performed in baseline controls and not in neonates that are not suspect for meningitis Measurement of two time-points may be insufficient to detect changes in time We will not be able to identify viral causes of infection since proper diagnostics are currently not available in Suriname
Ethical concerns for the Surinamese situation
We have received approval from the Surinamese Ethical Board on March 9th 2015 Upon eligibility of a newborn at least one parent or guardian will be asked for participation of their child into the study and will be given written information in Dutch If the patient is illegible or does not understand Dutch oral explanation will be given in a language that is understood either English or Sranan Tongo Written informed consent with either signature or fingerprint is obtained from a parent or guardian for the collection of all clinical data blood and CSF Blood draws for serum separation and spinal tap for CSF collection will only take place along with interventions according to local protocol ie no additional blood draws or spinal taps will take place All samples will be treated anonymously and receive a sample ID
Withdrawal of individual subjects
Parents or guardians of subjects can initiate leave of the study at any time for any reason if they wish to do so without any consequences The investigator can decide to withdraw a subject for medical reasons or when subjects are non-cooperative ie resist blood draws
Premature termination of the study
There are no situations expected that would lead to premature termination of the study
Safety reporting
Adverse and serious adverse events population base We do not expect any serious adverse events related to drawing blood
Administrative aspects and publication
Handling and storage of data and documents Paper data will be stored by the coordinating investigator in a unique folder which will be accessible by the coordinating investigator and the investigators involved in the study The data will also be stored electronically in an Excel database The principal investigator will enter the data The file will be only accessible by the investigators and data exchange through email will be encrypted with a password Each participant will receive a unique participation number after signing informed consent which corresponds to the sample ID of the blood sample
Amendments
Amendments are changes made to the research after a favorable opinion by the accredited ethical board has been given All amendments will be notified that gave a favorable opinion A substantial amendment is defined as an amendment to the terms of the ethical board application or to the protocol or any other supporting documentation that is likely to affect to a significant degree
The safety or physical or mental integrity of the subjects of the trial
The scientific value of the trial
The conduct or management of the trial or
The quality or safety of any intervention used in the trial
All substantial amendments will be notified to the ethical board and to the competent authority Non-substantial amendments will not be notified to the accredited ethical board and the competent authority but will be recorded and filed by the sponsor
Annual progress report
The sponsorinvestigator will submit a summary of the progress of the study to the accredited ethical board once a year Information will be provided on the date of inclusion of the first subject numbers of subjects included and numbers of subjects that have completed the trial serious adverse events serious adverse reactions other problems and amendments
End of study report
The investigator will notify the accredited ethical board of the end of the study within a period of 8 weeks The end of the study is defined as the last patients last visit In case the study is ended prematurely the investigator will notify the accredited ethical board including the reasons for the premature termination Within one year after the end of the study the investigatorsponsor will submit a final study report with the results of the study including any publications or abstracts of the study to the accredited ethical board
Public disclosure and publication policy
The final publication of the study results will be written by the study coordinators on the basis of the statistical analysis performed A draft manuscript will be submitted to all co-authors for review After revisions the manuscript will be sent to a peer reviewed scientific journal The study coordinators must approve any publication abstract or presentation based on patients included in the study
The Academic Hospital Paramaribo AZP has the largest perinatal care facility in Suriname Recently the AZP opened the countrys only neonatal intensive care unit NICU This study aims to include all neonates presenting here and at the high and medium care facilities with clinical signs of infection sepsis or meningitis age 0-1 month that require infection work up Along with the inclusion of these neonates follows a detailed epidemiological description of newborns with infectious disease Inclusion will take place by one of 10 residents with approval from one of the 5 attending pediatricians Along with standard blood draws for infection parameters at t0 and t48 hours blood culture at t0 hours and CSF culture at t0 hours serum and CSF will be separated for our biomarker study For all neonates normal local protocol for the management of infection sepsis or meningitis will be followed This includes antibiotic treatment for 7 days when 1 clinical suspicion of infection at admission was high 2 infection parameters are aberrant at 48 hours 3 blood culture is positive Otherwise antibiotic treatment is stopped after 48 hours Further protocol includes necessary changes in respiratory support circulatory fluid support and feeding Medical treatments can be cardiotonics and treatments for hyperglycemia and seizures Neonates are divided over 5 groups based on course of antibiotic treatment and culture results 1 Baseline controls no signs of infection neonates admitted for serial blood draws at t0 and 48 hours for uncomplicated hyperbilirubinemia with jaundice but without other signs of infection 2 Signs of infection further divided in 2a No infection antibiotics stopped after 48 hours negative cultures 2b Clinical infection 7 day antibiotics negative cultures 2c Sepsis positive bacterial blood culture 2d Meningitis positive bacterial CSF culture
Sample size and power
Sample size and power analysis is complicated because The Suriname Perinatal and Infant Mortality Survey only provides data on mortality as a result of infection amongst other causes without data on the incidence of neonatal infection We estimate an incidence of admission for clinical signs for infection of 50 per 1000 live births 5 at the NICU of the AZP An annual birth rate at the AZP of about 3000 live births per year gives us n150 neonates with signs of infection divided over four groups Based on these estimations the recommended sample size of the whole population would be n1538 margin of error 1 and CI 99 Since the incidence of newborns for which exclusion criteria apply and incidence of the subgroups are currently unknown and to compensate for loss to follow up we decided to include over a one-year period n3000 The biomarker study is exploratory in nature and we aim for a baseline control group of n40 larger n may be difficult to establish due to practical constraint In our analysis we will adjust for gestational age and ethnicity Absence of prior data on levels of biomarkers in relation to neonatal infection prevents us from estimating power With analysis of sera and CSF from our 150 inclusions we aim to perform that for future follow-up biomarker studies
Methodology
Epidemiology The following data will be recorded upon t0 hours and during t48 hours admission date and time maternal age gender maternal Group-B-streptococcus culture result maternal fever premature prolonged rupture of membranes PPROM gestational age if unknown according to Ballard delivery location and mode Apgar scores birth weight gender ethnicity leukocyte count and differentiation trombocyte count CRP antibiotic treatment type duration sepsis earlylate onset line survivalexpiration The Score for Neonatal Acute Physiology II will be scored at t0 and 48 hours
Serum separation Whole blood will be collected by vena puncture in one serum microtainer 500 μL Serum samples will be separated by centrifugation at 2500 xg for 15 minutes and kept on ice until storage All serum and CSF samples will be stored at -80C in the central laboratory of the AZP Batched serum and CSF samples will be packaged on dry-ice max 24 hours according to the International Air Transport Association guidelines and transported to the Endothelial Biomedicine and Vascular Drug Targeting Laboratory in Groningen
Luminex Technology Our laboratory in Groningen has extensive experience with the use of Luminex arrays for the measurement of multiple adhesion molecules at once in clinical patient samples ie multiplexing Currently the technique is applied successfully in basic and translational research and is gradually making its way into the clinic allowing for the compilation of a diagnostic multi-array of molecules for complex diseases such as sepsis or cancer See Table 1 for specific adhesion molecules and their associated shedding enzymes that we include in our array Measurement of soluble L- E- and P-selectin Intercellular adhesion molecule ICAM-1 vascular cell adhesion molecule VCAM-1 neutrophil elastase NE Matrix-metalloproteinase-9 MMP-9 tissue-inhibitor of metalloproteinase TIMP-1 and ADAM metallopeptidase domain 17 ADAM-17 will be performed with Luminex NE and ADAM-17 will be analyzed by ELISA as long as Luminex is not yet available for these molecules We will also use Luminex to measure circulating Angiopoetin-1 and -2 and soluble Tie-2 receptor as markers of endothelial cell activation For Luminex assays Life Technologies appropriate diluted volumes of samples will be aliquoted in 96 well plates Simultaneous analysis will take place with the Luminex 100 Analyzer Life Technologies ELISA will be performed according to the manufacturers protocol RD systems
Statistical Analysis
Incidence rates end epidemiological determinants will be calculated at the end of the inclusion period Categorical variables will be presented as numbers and percentages and continuous variables as mean - SD or if not normally distributed as median - 10th percentile Categorical data will be compared with chi-square and continuous variables with the independent t-test or two-way ANOVA To assess the independent effect of biomarker combinations cAMSE ratios on the occurrence of infections multivariate logistic regression will be performed with infection as dependent and cAMSE ratios gestational age and ethnicity as independent variables We will calculate Spearman rank correlation to assess bivariable association between biomarkers Diagnostic accuracy of cAMSE ratios will be assessed by using the Receiver Operating Characteristic ROC-based area under the curve Other test characteristics such as predictive value and likelihood ratios will be calculated P-values 005 will be considered statistically significant Statistical analysis will be performed using Stata StataCorp
Difficulties and Limitations
First separation of serum from neonates could lead to low volumes yet Luminex technology is designed for the assessment of high numbers of molecules in low volumes According to local protocol CSF collection is not performed in baseline controls and not in neonates that are not suspect for meningitis Measurement of two time-points may be insufficient to detect changes in time We will not be able to identify viral causes of infection since proper diagnostics are currently not available in Suriname
Ethical concerns for the Surinamese situation
We have received approval from the Surinamese Ethical Board on March 9th 2015 Upon eligibility of a newborn at least one parent or guardian will be asked for participation of their child into the study and will be given written information in Dutch If the patient is illegible or does not understand Dutch oral explanation will be given in a language that is understood either English or Sranan Tongo Written informed consent with either signature or fingerprint is obtained from a parent or guardian for the collection of all clinical data blood and CSF Blood draws for serum separation and spinal tap for CSF collection will only take place along with interventions according to local protocol ie no additional blood draws or spinal taps will take place All samples will be treated anonymously and receive a sample ID
Withdrawal of individual subjects
Parents or guardians of subjects can initiate leave of the study at any time for any reason if they wish to do so without any consequences The investigator can decide to withdraw a subject for medical reasons or when subjects are non-cooperative ie resist blood draws
Premature termination of the study
There are no situations expected that would lead to premature termination of the study
Safety reporting
Adverse and serious adverse events population base We do not expect any serious adverse events related to drawing blood
Administrative aspects and publication
Handling and storage of data and documents Paper data will be stored by the coordinating investigator in a unique folder which will be accessible by the coordinating investigator and the investigators involved in the study The data will also be stored electronically in an Excel database The principal investigator will enter the data The file will be only accessible by the investigators and data exchange through email will be encrypted with a password Each participant will receive a unique participation number after signing informed consent which corresponds to the sample ID of the blood sample
Amendments
Amendments are changes made to the research after a favorable opinion by the accredited ethical board has been given All amendments will be notified that gave a favorable opinion A substantial amendment is defined as an amendment to the terms of the ethical board application or to the protocol or any other supporting documentation that is likely to affect to a significant degree
The safety or physical or mental integrity of the subjects of the trial
The scientific value of the trial
The conduct or management of the trial or
The quality or safety of any intervention used in the trial
All substantial amendments will be notified to the ethical board and to the competent authority Non-substantial amendments will not be notified to the accredited ethical board and the competent authority but will be recorded and filed by the sponsor
Annual progress report
The sponsorinvestigator will submit a summary of the progress of the study to the accredited ethical board once a year Information will be provided on the date of inclusion of the first subject numbers of subjects included and numbers of subjects that have completed the trial serious adverse events serious adverse reactions other problems and amendments
End of study report
The investigator will notify the accredited ethical board of the end of the study within a period of 8 weeks The end of the study is defined as the last patients last visit In case the study is ended prematurely the investigator will notify the accredited ethical board including the reasons for the premature termination Within one year after the end of the study the investigatorsponsor will submit a final study report with the results of the study including any publications or abstracts of the study to the accredited ethical board
Public disclosure and publication policy
The final publication of the study results will be written by the study coordinators on the basis of the statistical analysis performed A draft manuscript will be submitted to all co-authors for review After revisions the manuscript will be sent to a peer reviewed scientific journal The study coordinators must approve any publication abstract or presentation based on patients included in the study
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None