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issues of timing , choice , amount of fluids , and type of volume assessments to guide therapy continue to be investigated . while early volume resuscitation and goal - directed therapy have been shown to improve mortality and morbidity [ 2 , 3 ] and lessen the risk of acute kidney injury , management of patients with established acute lung injury reveals that a more conservative or 
studies of the assessment of fluid status have shown that simple central venous pressure ( cvp ) monitoring is as effective , and safer , than more invasive means such as pulmonary artery occlusion pressure .
it is clear , however , that cvp does not tell the entire story , as patients with high right sided pressures may have reduced , normal , or increased effective circulating volume .
bioimpedance vectorial analysis ( biva ) allows determination of extracellular fluid volume and total body water from measurements of resistivity of tissues to single or multifrequency emitted signals .
. however , the use of biva in critically ill patients has not been extensively studied , and the data used to determine volume status have been derived from hemodynamically stable patients [ 6 , 7 ] .
brain natriuretic peptide ( bnp ) is a biomarker used to identify patients with fluid overload and congestive heart failure . in critical care , it has been shown to correlate with mortality and morbidity , though it has not been used to guide therapy [ 9 , 10 ] .
we conducted a pilot study to examine the relationships between cvp , biva , and bnp in order to determine which measure , or combination of measures , relate to volume status in critically ill , ventilated patients .
this study was approved by the institutional review board of the san bortolo hospital , vicenza , italy , and conducted in the intensive care unit ( icu ) .
any adult patient requiring mechanical ventilation was eligible . because of the technical requirements for biva , patients with any upper or lower limb amputation , severe rhabdomyolysis , or erysipelas of both upper or lower limb were excluded .
as the study required serial measurements over time , any patient not expected to survive 7296 hours was excluded .
any patient with recent cardiac surgery was also excluded , as bnp and cvp may be grossly skewed .
as published , biva vectors were derived in caucasians , we excluded non - caucasians .
a sample size of 3040 patients was enrolled without formal sample - size calculations . within 4872 hours of initiating mechanical ventilation , baseline assessment was undertaken including cvp , biva , and blood sample for bnp , hematocrit , and creatinine .
bnp was determined using triage meterpro ( biosite inc . , san diego , ca ) .
cvp was obtained through a central venous catheter connected to a calibrated transducer using the level of the right atrium as a reference point .
biva was performed using a plethysmograph emitting 800-a and 50-khz alternating sinusoidal current ( efg electrofluidgraph , akern s.r.l .
clinical data were recorded , including primary illness , systolic blood pressure ( sbp ) , diastolic blood pressure ( dbp ) , mean arterial pressure ( map ) , heart rate ( hr ) , weight , urine output , pressor doses , po2 , fio2 , and mean airway pressure .
additional measurements were made at 24 and 48 hour intervals to minimize diurnal variation in bnp .
cvp was categorized as  low  ( < 4  cm h2o ) ,  high 
three patterns were considered according to published references for resistance / height ( r / h ) based on normals , adjusted for age , sex , and weight : long vectors outside the 75% tolerance ellipse ( upper pole of the target ) were categorized as  dehydrated  and short vectors outside the 75% tolerance ellipse ( lower pole of the target ) as  hyperhydrated  , while the remainder were  normohydrated  .  
oxygenation index ( o2i ) was calculated as the mean airway pressure divided by the ratio of po2/fio2 and multiplied by 100 , and the result was then divided into tertiles .  
using least - squares regression , measures of cvp over time were used to estimate slope , and cvp was categorized as  falling 
( < 2  cm/24h ) ,  rising  ( > 2  cm/24  h ) , or  stable  ( cvp from 2 to 2  cm/24  h ) .
biva change over time was estimated as the slope of r / h by time , and > 30  ohm / m / day was categorized as  falling ecf  ; < 30  ohm / m / day was  rising ecf  , and values within 30  ohm / m / day were considered  stable ecf  .
absolute values of bnp were used to estimate slope of bnp , and these slopes were divided into tertiles .
that a patient was extubated , the last available mean airway pressure was carried forward , and the most recent arterial blood gas values were used to estimate the o2i for the purpose of calculating the slope .  
the agreement between slopes of cvp , biva , and bnp against o2i were estimated using kappa statistics .
univariate correlations were assessed at baseline for o2i , cvp , biva , and bnp .
slopes of change were also assessed between these variables and hemodynamic parameters , fluid balance , and other clinical parameters such as hematocrit and creatinine .
thirty - four patients were enrolled in the study , 22 ( 64.7% ) were male , and the most common admitting diagnosis was trauma , in 12 ( 35.3% ) .
the majority of patients were not on pressors or inotropes at baseline , and the mean noradrenaline dose was  0.007  0.004 
cg / kg / min ; dopamine was  1.6  0.5  cg / kg / min . in cross - sectional analysis at baseline
, there was no relationship between tertiles of cvp , biva or bnp with o2i ; however , a weak correlation could be demonstrated between the continuous variables of cvp and o2i ( r = 0.39 ; p = .021 ) ( see figure 1 ) and a weak negative correlation between cvp and biva ( r = 0.38 ; p = .025 ) .  
twenty - six subjects had data available beyond the first study day to allow estimation of slopes of change of cvp , biva , bnp , and o2i . for these subjects ,
mean slope of change of cvp was 0.03  mmhg / day , slope of biva was 6.1  ohm / m / day , slope of bnp was 60.3  pg / ml / day and slope of o2i was 0.12 per day .  
comparing tertiles of cvp , biva , and bnp slopes with the slope of o2i revealed modest agreement between bnp and o2i ( kappa = 0.25 ; p = .067 ) and no agreement between the other variables .
similarly , using spearman correlation , the slope of bnp was weakly correlated with o2i ( r = 0.40 ;  p = .044 ) as shown in figure 3 . in a regression model
examining all of the baseline variables and slopes of cvp , biva , and bnp as potential variables , only bnp was significantly associated with o2i , and this was strengthened by including cvp in the model . for each tertile increase in the slope of bnp ,
this is the first study attempting to find the most appropriate combination of minimally invasive bedside tools for volume assessment in critically ill patients requiring mechanical ventilation . while none of the markers at baseline , individually or in combination , were helpful in predicting those subjects whose oxygenation would improve or worsen , we identified that changes in bnp over time were correlated with important changes in o2i .
furthermore , there was some indication that combining cvp and bnp in multivariable modeling further strengthened the latter variable 's association with change in o2i .  
it is intuitive to think that measures of volume , be they measures of intravascular or extravascular ( interstitial ) volume , would be related to lung function and oxygenation .
for instance , animal studies have shown that fluid balance can influence both the onset and resolution of severe  high - permeability  pulmonary edema [ 12 , 13 ] .
excess extravascular lung water is a feature of all types of pulmonary edema , and lower extravascular lung water correlates with fluid balance , decreased ventilator days , and icu length of stay .
we chose cvp since local practice was such that most mechanically ventilated patients had central venous access appropriate for measurement of cvp .
furthermore , studies indicate a high level of agreement between clinical measures such as the external jugular pressure and the cvp ; hence , a ready estimate of cvp would be available in all subjects .
we chose biva for its ease of use and noninvasive nature and its ability to provide an estimate of extravascular water .
bnp was chosen for its ability to respond to myocardial stretch   and its utility in previous studies as a predictor of outcome [ 9 , 10 ] .
we did not find the addition of measures of biva to help in the fluid assessment of our cohort of patients .
previously , piccoli and colleagues   demonstrated a modest degree of inverse correlation between cvp and impedance vector components , though this was stronger in the group that had significantly elevated cvp and weaker in the group with lower cvp .
these authors suggested that the combination of cvp and biva might be useful in the volume assessment and management of critically ill patients .
we were unable to demonstrate any correlation between biva and cvp , nor was the combination predictive of oxygenation .
the principle difference between our study and that of piccoli is that the minority of patients in the latter study were receiving mechanical ventilation , while this was a requirement for eligibility in our study .
this may have played a role since mechanical ventilation with positive end - expiratory pressure ( peep ) likely and systematically elevated the cvp and possibly weakened any potential relationship between cvp and biva . moreover , all the patients in our study had relatively high values of peep ( 810  cmh2o ) .
we were able to demonstrate that change in bnp was associated with change in o2i , and this relationship was strengthened modestly in multivariable regression by including slope of change of cvp .
the choice of o2i as an outcome may be justly criticized as a surrogate , but the study population was not large enough for us to predict more clinically important outcomes such as lung injury scores , length of icu stay , or days of mechanical ventilation , for example .
however , o2i has been shown to be strongly associated with these more important outcomes in the acute respiratory distress syndrome ( ards ) clinical trials network study .
another limitation of the study is that the methods used to assess volume were not compared against other methods such as echocardiography , ultrasound of the inferior vena cava , pulse pressure variation , or strove volume variation .  
this is a fair criticism ; however , the study presented is the first in a series of pilot endeavours , the intent of which is to examine varying combinations of volume assessment .  
, saint - prex switzerland ) to measure stroke volume variation in critically ill patients in our institution are underway
. a larger study would have allowed us to explore more extreme values with greater confidence .
for instance , inspection of the figures reveals greater variability at the extremes , and a larger sample size would have allowed a more sophisticated analysis of the relationships to see if nonlinear modeling would have provided a tighter fit with the data .
an additional limitation is the patient population , in whom the predominant admitting diagnosis was trauma ( approximately one third ) . while the remainder had a variety of conditions including respiratory failure , decreased level of consciousness , sepsis , and intracranial hemorrhage or stroke ; generalizability to the critical care population as a whole is difficult .
another potential limitation relates to our choice of waiting for 4872 hours to enroll patients , during which time they could have stabilized to a point that may have dampened the strength of the relationships we observed .
our results are consistent with the recent work of levitt and colleagues , who carried out a similar prospective cohort study of critically ill patients and compared various measures of volume status . as in their study
however , our study differs in that we examined the combination of these parameters in multivariable modeling and found them to provide complementary information in predicting improvements in oxygenation . in summary ,
bedside measures of volume status , cvp and biva , were unhelpful alone in predicting favorable changes in o2i , while changes in bnp over time did correlate with changes in o2i .
there was some indication that combining cvp and bnp improved the ability to predict change in o2i . whether or not interventions to optimize both cvp and bnp
will result in improved outcomes in ventilated , critically ill patients will require further prospective study .
purpose . strategies for volume assessment of critically ill patients are limited , yet early goal - directed therapy improves outcomes . 
 central venous pressure ( cvp ) , bioimpedance vectorial analysis ( biva ) , and brain natriuretic peptide ( bnp ) are potentially useful tools . 
 we studied the utility of these measures , alone and in combination , to predict changing oxygenation . 
 methods . 
 thirty - four mechanically ventilated patients , 26 of whom had data beyond the first study day , were studied . 
 relationships were assessed between cvp , biva , bnp , and oxygenation index ( o2i ) in a cross - sectional ( baseline ) and longitudinal fashion using both univariate and multivariable modeling . 
 results . at baseline , 
 cvp and o2i were positively correlated ( r = 0.39 ; p = .021 ) , while cvp and biva were weakly correlated ( r = 0.38 ; p = .025 ) . 
 the association between slopes of variables over time was negligible , with the exception of bnp , whose slope was correlated with o2i ( r = 0.40 ; p = .044 ) . 
 comparing tertiles of cvp , biva , and bnp slopes with the slope of o2i revealed only modest agreement between bnp and o2i ( kappa = 0.25 ; p = .067 ) . in a regression model , only bnp 
 was significantly associated with o2i ; however , this was strengthened by including cvp in the model . conclusions . 
 bnp seems to be a valuable noninvasive measure of volume status in critical care and should be assessed in a prospective manner .