about 50% of patients admitted to the intensive care unit ( icu ) have systemic inflammatory response syndrome ( sirs ) . of these , 30% have or eventually develop sepsis .
mortality rates in critically ill patients with sirs are high , ranging from 10% to 20% .
. this will assist clinicians in reevaluation and intensification of therapy , which could prevent progression of organ failure and the associated increased in mortality .
neutrophil gelatinase - associated lipocalin ( ngal ) is a small molecule of 25 kda , which is covalently bound to gelatinase from neutrophils and expressed at low concentrations in several human tissues , including kidneys , lungs , stomach , and colon .
ngal binds to iron through its siderophores ; it can deplete bacterial iron and plays an important role in immunity to bacterial infection .
ngal expression is markedly induced by inflammation , such as in acute bacterial infections , severe sepsis and septic shock , asthma or chronic obstructive airway disease , or emphysematous lung .
the limitation of that study was that we only analyzed on admission plasma ngal concentration .
of interest is how the dynamic of ngal changes as a tool of mortality prediction as has been shown previously that single measurements of biomarkers were not predictive ; however , their dynamic concentrations were predictive .
a further analysis looking at the dynamic of ngal over several days for prediction of mortality may be of interest .
this was a secondary analysis of a single - center , prospective , observational study of hospital tengku ampuan afzan , kuantan , pahang , malaysia .
the study was an extension of the boss - icu study , registered under the national medical research register ( nmr-11 - 1102 - 9248 ) .
only patients with available ngal data measured serially for the first 3 days were included in this analysis .
all consented patients aged above 18 years with established sirs based on the criteria defined by the american college of chest physician / society of critical care medicine ( accp / sccm ) were recruited in the study .
sirs is defined by the presence of at least two of the following four indicators : ( 1 ) a body temperature above 38.0c or below 36.0c ; ( 2 ) a heart rate above 90 beats / min ; ( 3 ) a respiratory rate above 20 breaths / min ; ( 4 ) a white blood cell count higher than 12,000 or lower than 4000 cells/l or more than 10% immature ( band ) form .
consent from legally accepted representative was taken as the patients were mostly unconscious or undergoing resuscitation .
patients with age < 18 years , no written consent , or who had received antibiotics for more than 24 h before screening were excluded from the study .
blood samples were collected within 24 h of icu admission and daily for 3 consecutive days .
the samples were centrifuged at 3600 rpm for 15 min and the plasma were stored at 80c .
plasma ngal was analyzed using the triage ngal test ( biosite , san diego , usa ) .
plasma electrolytes were analyzed using the olympus au2700 chemistry - immunoanalyzer ( olympus , philadelphia , usa ) .
ngal at 24 and 48 h ( ngal-24 and ngal-48 ) was defined as 24 and 48 h ngal minus day 1 ngal .
ngal clearance ( ngalc ) at 24 and 48 h ( ngalc-24 and ngalc-48 ) was defined as the percentage of ngal-24 and ngal-48 to day 1 ngal .
statistical analysis was performed using pasw version 18.0 ( ibm , somers , new york , usa ) , and prism 5.0 ( graph pad , la jolla , california , usa ) .
results are presented as mean  standard deviation for normally distributed variables or median ( interquartile range ) for nonnormally distributed variables .
comparison of variables between the two groups was analyzed using independent t - test for normally distributed variables or mann  whitney test for nonnormally distributed variables .
differences between three groups were analyzed using one - way analysis of variance , with post hoc least significant difference analysis .
the diagnostic and predictive performance of ngal were assessed by area under the curve ( auc ) of receiver operating characteristic ( roc ) curve of the sensitivity versus 1-specificity .
the optimal cutoff point was defined as the measured quantity , which maximized sensitivity and specificity .
survival analysis was performed using kaplan  meier and cox regression survival analyses for calculation of hazard ratios ( hrs ) .
all auc , hr , and integrated discrimination improvement were presented with 95% confidence intervals .
statistical analysis was performed using pasw version 18.0 ( ibm , somers , new york , usa ) , and prism 5.0 ( graph pad , la jolla , california , usa ) .
results are presented as mean  standard deviation for normally distributed variables or median ( interquartile range ) for nonnormally distributed variables .
comparison of variables between the two groups was analyzed using independent t - test for normally distributed variables or mann  whitney test for nonnormally distributed variables .
differences between three groups were analyzed using one - way analysis of variance , with post hoc least significant difference analysis .
the diagnostic and predictive performance of ngal were assessed by area under the curve ( auc ) of receiver operating characteristic ( roc ) curve of the sensitivity versus 1-specificity .
the optimal cutoff point was defined as the measured quantity , which maximized sensitivity and specificity .
survival analysis was performed using kaplan  meier and cox regression survival analyses for calculation of hazard ratios ( hrs ) .
all auc , hr , and integrated discrimination improvement were presented with 95% confidence intervals .
a total of 151 patients were included in the study . of these , 53 ( 35.1% ) died in the hospital .
mortality increases with increasing number of sirs criteria ( chi - square test , p = 0.05 ; table 1 ) . comparing between each stage , the differences in mortality were significant only between 2 and 4 sirs criteria ( p = 0.04 ) .
table 2 compares the baseline demographic , clinical characteristics , and outcome between patients survivors and nonsurvivors .
nonsurvivors were older and had higher sequential organ failure assessment ( sofa ) and simplified acute physiology score ii ( saps ii ) scores as compared to survivors .
mortality with number of systemic inflammatory response syndrome criteria demographics and clinical characteristics between survivors and nonsurvivors the temporal profile of ngal between survivors and nonsurvivors is shown in figure 1 .
ngal concentrations were consistently higher in nonsurvivors compared to survivors from day 1 to day 3 ( mann  whitney test , p < 0.04 ) .
ngal and ngalc at 48 h ( ngal-48 and ngalc-48 ) were higher in nonsurvivors compared to survivors . in contrast , there were no differences in ngal kinetics at 24 h [ table 3 ] .
temporal profiles of plasma neutrophil gelatinase - associated lipocalin concentration between survivors and nonsurvivors within the first 3 days of intensive care unit admission . mann 
whitney test , p = 0.04 ( day 1 ) , p = 0.02 ( day 2 ) , and p = 0.007 ( day 3 ) .
repeated measures analysis of variance showed the difference between subjects , p < 0.0001 , and within subjects , p = 0.28 .
neutrophil gelatinase - associated lipocalin concentrations and  neutrophil gelatinase associated lipocalin between survivors and nonsurvivors the auc of the roc curve for prediction of mortality is shown in figure 2 and table 4 .
ngal kinetics at 48 h ( ngal-48 and ngalc-48 ) but not 24 h was predictive of mortality .
the differences of the auc between static and dynamic ngal are presented in table 5 . of these ,
the differences between day 1 and day 3 ngal were significant ( 0.05 [ 0.10.001 ] , p = 0.04 ) .
for dynamic ngal , the differences were significant for ngal kinetics at 24 versus 48 h , with p = 0.03 for both . when comparing static versus dynamic ngal , differences were only shown for day 3 ngal versus ngal-24 ( p = 0.04 ) .
the area under the curve of the sensitivity over 1-specificity curve for static and dynamic neutrophil gelatinase - associated lipocalin concentration .
area under receiver operating characteristics curve for prediction of mortality the differences in the area under curve between static and kinetic of neutrophil gelatinase - associated lipocalin the utility of ngal and its kinetics for prediction of mortality were further evaluated after adjusting for other covariates . after adjusting for age , presence of acute kidney injury ( aki ) , and severity of illness ( saps ii ) ,
only day 3 ngal , ngal-48 , and ngalc-48 were independently predictive of mortality [ table 6 ] .
multivariate analysis for prediction of mortality survival analysis of ngalc-48 at a cutoff point of 24% was analyzed [ figure 3 ] .
there was lower survival in patients with ngalc at 48 h of more than 24% compared to those with lower cutoff point ( log mantel  cox , p = 0.03 ) .
after adjusted for age and severity of illness , patients with ngalc-48 more than 24% were twice more likely to die at 30 days compared to those less than the cutoff point ( cox regression analysis , odds ratio 2.10 [ 1.054.18 ] , p = 0.03 ) .
survival analysis of neutrophil gelatinase - associated lipocalin clearance at 48 at a cutoff point of 24% .
patients with neutrophil gelatinase - associated lipocalin clearance at 48 h of more than 24% were more likely to die within 30 days compared to those with lower cutoff point ( log mantel  cox , p = 0.03 ) .
ngal concentrations were consistently higher in nonsurvivors compared to survivors from day 1 to day 3 ( mann  whitney test , p < 0.04 ) .
ngal and ngalc at 48 h ( ngal-48 and ngalc-48 ) were higher in nonsurvivors compared to survivors . in contrast , there were no differences in ngal kinetics at 24 h [ table 3 ] .
temporal profiles of plasma neutrophil gelatinase - associated lipocalin concentration between survivors and nonsurvivors within the first 3 days of intensive care unit admission . mann  whitney test , p = 0.04 ( day 1 ) , p = 0.02 ( day 2 ) , and p = 0.007 ( day 3 ) .
repeated measures analysis of variance showed the difference between subjects , p < 0.0001 , and within subjects , p = 0.28 .
neutrophil gelatinase - associated lipocalin concentrations and  neutrophil gelatinase associated lipocalin between survivors and nonsurvivors
the auc of the roc curve for prediction of mortality is shown in figure 2 and table 4 .
ngal kinetics at 48 h ( ngal-48 and ngalc-48 ) but not 24 h was predictive of mortality .
the differences of the auc between static and dynamic ngal are presented in table 5 . of these , the differences between day 1 and day 3 ngal were significant ( 0.05 [ 0.10.001 ] , p = 0.04 ) . for dynamic ngal ,
the differences were significant for ngal kinetics at 24 versus 48 h , with p = 0.03 for both . when comparing static versus dynamic ngal , differences were only shown for day 3 ngal versus ngal-24 ( p = 0.04 ) .
the area under the curve of the sensitivity over 1-specificity curve for static and dynamic neutrophil gelatinase - associated lipocalin concentration .
area under receiver operating characteristics curve for prediction of mortality the differences in the area under curve between static and kinetic of neutrophil gelatinase - associated lipocalin
the utility of ngal and its kinetics for prediction of mortality were further evaluated after adjusting for other covariates . after adjusting for age , presence of acute kidney injury ( aki ) , and severity of illness ( saps ii ) ,
only day 3 ngal , ngal-48 , and ngalc-48 were independently predictive of mortality [ table 6 ] .
survival analysis of ngalc-48 at a cutoff point of 24% was analyzed [ figure 3 ] .
there was lower survival in patients with ngalc at 48 h of more than 24% compared to those with lower cutoff point ( log mantel  cox , p = 0.03 ) .
after adjusted for age and severity of illness , patients with ngalc-48 more than 24% were twice more likely to die at 30 days compared to those less than the cutoff point ( cox regression analysis , odds ratio 2.10 [ 1.054.18 ] , p = 0.03 ) .
survival analysis of neutrophil gelatinase - associated lipocalin clearance at 48 at a cutoff point of 24% .
patients with neutrophil gelatinase - associated lipocalin clearance at 48 h of more than 24% were more likely to die within 30 days compared to those with lower cutoff point ( log mantel  cox , p = 0.03 ) .
in this prospective study , we showed that day 3 ngal and ngal kinetics at 48 h were independently predictive of mortality in critically ill patients with sirs .
in contrast , plasma ngal measured on icu admission was not independently predictive of mortality .
patients with ngalc at 48 h at a cutoff point of 24% were twice more likely to die compared to those at a lower cutoff point .
it is common in intensive care settings , occurring in more than 50% of patients admitted to the icu , higher in surgical icu .
about one - third of sirs patients have or eventually develop sepsis , and about 10%20% died . in our study ,
similarly , we showed that mortality occurred in 58% of patients with 4 sirs criteria compared to 42% in those with 3 sirs criteria and 28% with 2 sirs criteria .
the differences in mortality were significant between 2 and 4 sirs criteria ( p = 0.04 ) .
this could alert an intensivist for reevaluation or intensification of therapy , for example , early dialysis , modification of antimicrobial therapy , or the need for additional diagnosis measures , which could prevent progression of organ failure and the associated increased in mortality .
it has been investigated as a biomarker of sepsis and aki and prediction of mortality .
this may be of limited value due to variability of biomarker secretion at different phases of critical illness and unknown time lapsed between insult and icu admission .
we showed that plasma ngal measured on icu admission was not predictive of mortality after adjusting for age , presence of aki , and severity of illness .
in contrast , plasma ngal measured after 48 h was independently predictive with an odds ratio of 2.58 ( 1.265.29 ) .
we showed that day 3 ngal and ngal kinetics at 48 h were moderately predictive of mortality with auc of > 0.60 .
the auc is a measure of discrimination that is how well a given test ( e.g. , a new biomarker ) separates those with and without disease as determined by the gold standard .
hence , auc of day 3 ngal and ngal kinetics at 48 h of 0.64 is not assumed to be predictive of mortality .
in addition , differences between the auc of static versus dynamic ngal was only significant between day 3 and ngal-24 . however , the main limitation of the auc is that its calculation is based on rank , merely considering the comparative rank between those with and without the disease
. it does not take into account the extent of change of the biomarker or its distribution .
any change of rank in those at low distribution will have the same impact in those at high distribution .
the additional value of a new biomarker to an available clinical diagnostic or predictor assessment ( the reference model ) may be better assessed by the multivariate logistic regression analysis .
ngal kinetics has an added value in reference to the saps ii for prediction of mortality .
this is shown in the multivariate logistic regression analysis which showed that ngal kinetics at 48 h predicted mortality even after adjusted for saps ii .
we did not include both sofa and saps ii as both contain almost similar parameters and are strongly correlated ( r = 0.718 , p < 0.0001 ) .
dynamic changes of biomarker had been shown to better predict outcome such as mortality compared to a single time point collection .
the added value of calculating the dynamic changes of biomarker is that it integrates change over time , which captures function of both severity and duration of injury .
dynamic changes of creatinine , procalcitonin , and urinary cystatin c had been shown to be predictive of outcome .
the extent of changes in ngal may be influenced by its baseline concentration as has been shown previously that ngal was higher in patients with sepsis compared to sirs . to adjust for this
, we calculated the relative changes of ngal in relation to day 1 plasma ngal .
we showed that both the actual and relative dynamic changes of ngal after 48 h were independently predictive of mortality .
the cutoff point of ngalc or its dynamic changes is of interest as this could assist clinicians in identifying at - risk patient .
we showed that patients with 48 h ngalc of more than 24% were twice more likely to die compared to those with clearance of less than the cutoff point . from this , we suggest that ngal could be measured on admission and repeated 48 h later to assist in identifying at - risk patients who may benefit from reevaluation and intensification of therapy .
second , the strict inclusion criteria of patients with sirs in this study limit generalizability of the finding to other patient groups in the icu . finally , ngal was measured within 24 h of icu admission .
measurement within 24 h may capture earlier changes that occur with the kidney cellular injury .
however , a study had shown that there was no difference in ngal performance when measured earlier at the emergency department or later in the icu .
second , the strict inclusion criteria of patients with sirs in this study limit generalizability of the finding to other patient groups in the icu . finally , ngal was measured within 24 h of icu admission .
measurement within 24 h may capture earlier changes that occur with the kidney cellular injury .
however , a study had shown that there was no difference in ngal performance when measured earlier at the emergency department or later in the icu .
ngal kinetics and its dynamics over 48 h were independently predicted mortality in critically ill patients with sirs .
patients with ngalc at 48 h at a cutoff point of more than 24% were twice more likely to die compared to those at a lower cutoff point
. this could assist clinicians in risk stratification of this group of high - risk patients .
this study was funded by the ministry of higher education fundamental research grant scheme ( frgs/1/2015/skk02/uiam/02/3 ) .
this study was funded by the ministry of higher education fundamental research grant scheme ( frgs/1/2015/skk02/uiam/02/3 ) .
 background and aims : about 50% of patients admitted to the intensive care unit have systemic inflammatory response syndrome ( sirs ) , and about 10%20% of them died . 
 early risk stratification is important to reduce mortality . 
 plasma neutrophil gelatinase - associated lipocalin ( ngal ) is increased by inflammation and infection . 
 its ability to predict mortality in sirs patients is of interest . 
 we evaluated the ability of serial measurement of ngal for the prediction of mortality in critically ill patients with sirs.materials and methods : this is a secondary analysis of a single - center , prospective , observational study . 
 patients who fulfill the sirs criteria were recruited in the study . 
 delta ngal at 24 and 48 h ( ngal-24 and ngal-48 ) was defined as 24 and 48 h ngal minus day 1 ngal ; ngal clearance ( ngalc ) was defined as percentage of ngal over day 1 ngal . 
 the primary outcome of the study is in - hospital mortality.results:a total of 151 patients were analyzed , of which 53 ( 35% ) died . 
 nonsurvivors were older ( 51 vs. 45 , p = 0.03 ) and had higher sequential organ failure assessment ( 9  7 vs. 7  4 , p = 0.02 ) and simplified acute physiology score ii ( 47  15 vs. 40  15 , p = 0.01 ) scores as compared to survivors . 
 ngal concentrations over 3 days were higher in nonsurvivors compared to survivors ( repeated measures analysis of variance , p = 0.02 ) . 
 day 1 ngal , ngal-24 , and ngalc-24 were not independently predictive of mortality . however , day 3 ngal , ngal-48 , and ngalc-48 were predictive after adjusted for age and severity of illness ( odds ratio 9.1 [ 1.9741.7]).conclusions : ngal dynamics over 48 h independently predicted mortality in critically ill patients with sirs 
 . this could assist clinicians in risk stratification of this group of high - risk patients . 