Authors are listed in alphabetic order. *Denotes group facilitator.

Acute Dialysis Quality Initiative Fifth International Consensus Conference

Workgroup Group 3

Fluid and Volume monitoring

Pat Brophy, MD

Juan Padilla, MD

Emil Pagannini, MD

Neesh Pannu, MD

Michael R. Pinsky, MD*

A. What are the criteria for sufficient volume?

Sufficiency of volume is that volume/vasomotor tone/contractile performance that

sustains tissue perfusion relative to its metabolic needs.

1. Why is blood volume an issue in determining organ perfusion?

Although an adequate intravascular volume is essential for tissue perfusion and

oxygenation, excessive intravascular volume promotes pulmonary edema which itself

impairs gas exchange. Thus, one balances euvolemia between hypovolemic shock and

volume overload. Importantly, the total blood volume is not as important and the

effective circulating blood volume and its associated vasomotor tone and cardiac

contractility. Total body water is distributed into three main anatomical parts, the

intravascular space, interstitial space and cellular and matrix mass. Although volume

overload primarily affects only the intravascular and interstitial spaces, hypovolemia, if

prolonged, can promote a generalized loss of volume from the cellular space as well. In

healthy subjects with free assess to water, normal thirst mechanisms and dieresis

control maintain adequate hydration without volume overload. However, with decreased

mental status and critical illness, hypovolemia can occur and induce renal hypoperfusion

and, if sustained, renal failure. Hemorrhage, hyper-emesis, diarrhea, burns and sepsis

ADQI

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all promote intravascular volume loss. Severe injury states, such as major trauma and

sepsis, are also associated with a generalized systemic inflammatory response that

causes marked impairment of vasomotor tone through generalized vascular endothelial

injury, induction of inducible nitric oxide synthase, which produces massive amounts of

the potent vasodilator nitric oxide, and the release from both immune effector cells and

the inflamed vascular endothelium of numerous vasodilators (e.g. prostacyclin) and

vasoconstrictors (e.g. HETE). These processes induce an impaired vasoregulatory

response primarily characterized by loss of vasomotor tone with its resultant increase in

unstressed volume and impaired autoregulation of blood flow distribution. Thus, for the

same circulating blood volume effective circulating blood volume is reduced decreasing

venous return and thus cardiac output; and for the same cardiac output, increasing blood

flow to metabolically active tissues is impaired owing to loss of normal autoregulatory

feedback. Furthermore, in subjects with impaired renal reserve, hypervolemia may

rapidly occur if excessive fluid is ingested, infused or resorbed from the interstitial space.

These events occur with polydypsia, over aggressive resuscitation efforts and following

resolution of a generalized cardiovascular inflammatory stress (e.g. cardiopulmonary

bypass or sepsis), respectively. Finally, hemodialysis with ultrafiltration removes solutes

and water from the intravascular space, independent of renal excretion. Although this

type of artificial diuresis is an essential aspect of fluid and electrolyte management of

patients with renal insufficiency, overly aggressive ultrafiltration can and often does

induce functional hypovolemia with its attendant circulatory shock manifestations,

including exacerbation of renal injury. Thus, defining when a subject is developing

functional hypovolemia, independent of their overall body volume status is an essential

aspect of titration of diuresis therapies. Accordingly, fluid management reflects both

intravascular fluid resuscitation to restore effective circulating blood volume and forced

diuresis under conditions of overly expanded blood volume that carries with it the risk of

pulmonary edema.

2. Problems with fluid resuscitation

a. Identifying occult hypoperfusion

A fundamental quality of adaptive autonomic response is to maintain an adequate

central arterial pressure to sustain coronary and cerebral blood flow. Thus, although

3

hypotension is always pathological normotension does not mean cardiovascular stability.

So how does one identify occult tissue hypoperfusion? Clearly, related signs of

sympathetic hyper-reactivity, such as tachycardia, vasoconstriction, diaphoresis, and

anxiety, are easy to identify. Tachycardia is a sensitive but non-specific marker of

increased sympathetic tone, whereas hyperlactecemia is a sensitive but non-specific

marker of tissue hypoperfusion. Recently, increased interest in measuring venous O2

saturation as a guide to identifying tissue hypoperfusion and defining when to stop

resuscitation has become popular. Central venous O2 saturation (ScvO2) as a rough

estimate of mixed venous O2 saturation (SvO2), can identify tissue hypoperfusion if less

than 70%, and can drive a treatment protocol that improves outcome from septic shock

(1). Clearly, the underlying principal of any method that attempts to assess the

adequacy of blood flow uses surrogate makers regional performance and oxygen

extraction. Newer approaches such as non-invasive measures of tissue SO2, using near

infrared oximetry (2), and differences in sublingual PCO2 and arterial PCO2 can identify

tissue hypoperfusion (3).

b. Defining preload-responsiveness

Kumar et al. (4) demonstrated that neither central venous pressure (CVP) or pulmonary

artery occlusion pressure (Ppao) values nor their changes in response to fluid

challenges reflected their respective ventricular end-diastolic volumes or changes,

respectively in patients receiving a fluid challenge for hemodynamic insufficiency.

Presumably, non-linear ventricular diastolic compliance relations and an incomplete

knowledge of actual transmural ventricular filling pressures are the reasons for this

failure. However, Starling’s Law of the Heart was still operative in this study. If end-

diastolic volume increased in response to volume loading, then stroke volume increased

as well. Thus, one should not use either CVP or Ppao values to define the state of

ventricular filling or the potential to response to a fluid challenge. Furthermore, changes

in either CVP or Ppao did not correlate with each other or with changes in either stroke

volume or end-diastolic volume of their respective ventricles.

Perel et al. suggested that one access systolic pressure variation (SPV) during positive-

pressure breathing to identify those subjects who would be preload responsive (5). They

4

reasoned that the natural variation in venous return induced by positive-pressure

ventilation must induce a subsequent change in systolic arterial pressure. Michard et al.

(6,7) reasoned that arterial pulse pressure variation (PPV) reflects changes in LV stroke

volume during positive-pressure ventilation between than SPV because PPV is not

influenced by the intrathoracic pressure-induced changes in both systolic and diastolic

arterial pressure. They compared SPV with PPV as predictors of the subsequent

increase in cardiac output in response to fluid loading in septic ventilator-dependent

patients. Their data demonstrated that both PPV and SPV of ≥15% were far superior to

measures than either Pra or Ppao in predicting an increase in cardiac output response to

volume loading. Furthermore, the greater the PPV or SPV, the greater was the increase

in cardiac output. However, PPV claimed a slight, though significant, advantage over

SPV in terms of greater precision and less bias. Since PPV attempts to monitor LV

stroke volume changes, it was not surprising that Feissel et al. (8) demonstrated that

aortic flow variation, as measured by transesophageal 2-D echocardiography pulsed

Doppler of the aortic outflow tract, followed a similar response to PPV in response to

fluid loading. The flow variation data are very important because, flow it is the primary

variable from which SPV and PPV derive their validity. Though less invasive than

arterial pressure monitoring, echocardiographic analysis is far from ideal as a

hemodynamic monitoring tool. It requires the continuous presence of an experienced

operator. Echocardiography requires using expensive and often scare equipment. And

finally, measures of aortic root flow variation cannot be made on-line or continuously

over prolonged periods of time. Still, recent minimally invasive esophageal pulsed

Doppler techniques have been developed that measure continuously descending aortic

flow on a beat-to-beat basis. To the extent that descending aortic flow varies

proportionally with aortic outflow, then these measures of descending aortic flow

accurately access stroke volume variation (SVV).

One can use this test to identify when subjects become effectively hypovolemic as well.

Consider a patient receiving hemodialysis in which some degree of intravascular volume

depletion is necessary to drive fluid from the interstitium into the vascular space. If the

ultrafiltration becomes too vigorous then the patient may develop functional

hypovolemia.

5

Unfortunately, measures of SPV, PPV and SVV all require that the subject be supported

on mechanical ventilation and have a fixed R-R interval, such that stroke volume

changes reflect dynamic changes in preload during to ventilation. Thus, none of these

parameters accurately predict fluid responsiveness in spontaneously breathing subjects

and/or in those with frequent ventricular ectopic beats or atrial fibrillation. To address this

issue, Monnet et al. demonstrated that the change in mean aortic flow, estimated by

esophageal Doppler measures of descending aortic flow, predicted volume

responsiveness (119). Specifically, if mean aortic flow increased by at least 10%, these

subjects were preload responsive, even though they were breathing spontaneously or

have arrhythmias. Although they measured mean aortic flow with an esophageal

Doppler probe, similar results should if one estimates dynamic changes in mean flow

using estimates of stroke volume from arterial pulse pressure analysis.

3. End-points of resuscitation

Resuscitation from circulatory and respiratory failure represents the mainstay of

emergency and critical care management. However, laboratory studies have

demonstrated that restoration of total blood flow, arterial oxygenation and even arterial

pressure to otherwise normal levels by the use of vasoactive agents is not universally

good for either organ function and host outcome (9). Exogenous vasopressor therapy

impairs normal autoregulation of blood flow among organs and may induce occult tissue

ischemia in vital but silent vascular beds, such as the gut mucosa and renal subcortex.

Furthermore, microcirculatory oxygen utilization is more a function of local metabolic

demands and capillary flow than global blood flow or arterial O2 content. Regrettably,

significant regional ischemia or rescue can occur without perceptible changes in global

O2 uptake (VO2). Although fluid and vasopressor therapies may normalize organ

perfusion pressure they may not induce normal organ perfusion nor prevent organ

dysfunction. Still, it is clear from numerous clinical studies that tissue hypoperfusion is

bad and that avoidance of ischemia improves outcome from stress states. Thus, the

rapid restoration of normal hemodynamics by conventional means, including fluid

resuscitation and surgical repair, results in a superior outcome than inadequate or

delayed resuscitative efforts. Since critically ill patients often have abnormal blood flow

regulation, increasing oxygen delivery (DO2) to what would otherwise be considered

supranormal levels theoretically may treat the lethal occult tissue hypoxia that is a

6

hallmark of many forms of circulatory shock. Accordingly, interest centered on “hyper-

resuscitation” such that DO2 is exogenously increased to supranormal levels, levels

often seen in subjects who spontaneously survive acute circulatory insults, the so-called

“survivor levels of DO2.” Most studies that have aimed at augmenting DO2 or VO2 to

“survivor levels” have documented that if DO2 can increase, subjects do better (10).

However, this improvement in survival appears to be independent of whether the subject

was part of the group with intentional augmented DO2 (11). Furthermore, aggressive

therapies aimed at augmenting DO2 may actually increase mortality in experimental

groups (12). Thus, a low DO2 in a critically subject is probably a marker of critical illness,

rather than a parameter of effective resuscitative therapy. Interestingly, the most

impressive beneficial outcomes from clinical trials have all included prevention of

hypoperfusion rather than resuscitation from shock. Finally one recent prospective

clinical trial has documented that early aggressive resuscitation base don a logical

physiological paradigm markedly improved survival in patients in septic shock (1). In

that study and others, the appropriate assessment of circulatory performance is to define

as adequate or inadequate based on end-organ measures of tissue perfusion such as

SvO2, lactate and changes in other metabolic markers. Thus, aggressive hemodynamic

therapies in patients in septic shock or at risk for development of multiple organ

dysfunction and death improve survival. Often these benefits are seen without

measurable differences in DO2 or VO2 during therapy. The cumulative data to date

suggests that a major benefit of aggressive resuscitation therapy would be realized if

efforts were directed at more rapid identification of subjects at risk from the general

hospital population and the more rapid emergency resuscitation, transport and definitive

therapy of subjects in the field. However, once circulatory shock and/or organ

dysfunction has occurred there appears to be little additional benefit and real risk of

harm from aggressive resuscitation therapies that increase DO2 or VO2 to levels above

which would otherwise be considered normal.

Importantly, Lopes et al. showed that resuscitation guided by PPV reductions to < 10%

markedly improved outcomes in high risk surgery patients (120). Thus, one can use

simple measures of complex physiological processes to guide effective fluid

resuscitation therapies.

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B. Monitoring Volume Status

Monitoring of volume status and the utilization of fluid therapy in patients at risk for

developing or with established acute kidney injury (AKI) including those that are critically

ill is an important clinical issue. Indeed, several studies including those performed on

pediatric patients have implicated that excess fluid may be related to adverse outcomes

in critically ill patients particularly those with AKI requiring CRRT (13,14,15,16). It is not

clear from the literature, however, whether fluid overload is a cause of increased

morbidity or mortality or a marker representing the severity of underlying illness. What is

clear is that volume status monitoring is imperative in order to prevent or manage

patients developing AKI, particularly those who have not required the initiation of renal

replacement therapy. To date management has been based on local standard of care.

The following provides a description of the tools available for appropriate fluid

monitoring.

1. What are the indicators of sufficient volume?

Indicators of “sufficient volume” as previously defined need to be tailored in regard to

patient acuity and clinical diagnosis. As patient acuity increases so does the invasive

component and hence accuracy of monitoring. While filling pressure measurements

(central venous pressure (CVP) and pulmonary artery occlusion pressure (Ppao) have

been popular surrogate markers of preload and continue to be utilized as measures of

preload responsiveness, in general static measurements are not sensitive indicators of

hypovolemia. Their measurement may however crudely parallel effective circulating

volume. While low values can be indicative of hypovolemia, high values do not

necessarily mean that the patient is volume replete, and neither high or low values are

useful in predicting preload responsiveness (17-25). Changes in the pericardial restraint,

thoracic compliance or alterations in ventricular compliance can effect the relation

between filling pressures and ventricular end-diastolic volume. Thus, neither absolute

measures of filling pressure nor their change provide the clinician adequate information

to determine sufficient volume status and may lead to incorrect therapeutic decisions in

the most critically ill patients. Indeed recently, pulmonary artery catheter guided therapy

has been demonstrated to be associated with more complications and did not positively

impact survival (26). That is why such static hemodynamic indicators have been largely

replaced by dynamic indicators such as: inspiratory decrease in right atrial pressure

8

(ΔRAP), expiratory decrease in arterial systolic pressure (Δdown), respiratory changes in

pulse pressure (i.e. PPV) and respiratory changes in aortic blood velocity (ΔVpeak). All

of these measures are noted to be elevated in patients that are volume responders.

(Table 1)(27). Although dynamic parameters should be preferentially utilized over static

indicators in order to better predict fluid responsiveness, they do possess some

limitations in that, distorted signals due to fluid-filled catheters and arrhythmias may

reduce the precision of the measurements (28).

Table 1 Dynamic change in measured hemodynamic variables during ventilation

to predict preload responsiveness

Parameter Best threshold Reference

ΔRAP 1 mm Hg Magder (16)

ΔDown 5 mm Hg Tavernier (17)

ΔRAP 1 mm Hg Magder (18)

PPV 13 % Michard (19)

ΔVpeak 12 % Feissel (20)

Sufficient volume must be assessed within the context of the following variables i)

Tissue wellness, ii) Vasomotor tone, iii) Contractility, and iv) Preload responsiveness.

Measurement and monitoring of plasma volume, along with other commonly used

variables to assess fluid status particularly with respect to AKI must also be considered.

In terms of approaches to volume deficit/overload both in the presence and absence of

RRT, the following will serve as a guide as to at what point these monitoring tools may

be implemented and analyzed. Several important points must also be considered in

monitoring sufficient volume status.

a. Monitoring is context specific

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The choice of indicators used to evaluate sufficient volume in AKI will depend on the

health status of the patient, including: the presence of pre-existing renal disease (AKI

superimposed upon chronic kidney disease); the place, a patient on the general

hospital ward will require different monitoring tools than one in the intensive care

unit; the etiology, a patient with AKI on admission will require a different fluid

monitoring approach than one developing AKI after admission; and finally the

physiology, monitoring may be continuous or intermittent, invasive or non-invasive.

b. Therapy should be goal-directed The indicators should allow us to prescribe therapy aimed at restoring tissue

perfusion and preventing tissue hypoperfusion.

Hemodynamic monitoring is a central aspect of cardiovascular diagnosis and titration of

care. Circulatory shock primarily results in inadequate tissue blood flow. Although most

forms of shock may show some increase in cardiac output initially in response to fluid

loading, fully one-half of all hemodynamically unstable intensive care unit patients are

not preload-responsive (27). Furthermore, volume overload often worsens cor

pulmonale and can induce pulmonary and peripheral edema in heart failure states. To

review the relevant new clinical data addressing this important clinical issue, PubMed®

was searched (www.ncbi.nlm.nih.gov/PubMed)) for all papers published in 2004 using

the key words, resuscitation and hemodynamic monitoring, preload, fluid

responsiveness, and circulatory shock. The search was then narrowed to include only

non-review papers published in English that reflected clinical studies of patients within

the intensive care unit or operating room. All of the resultant 88 manuscripts identified

were reviewed and only those of particular relevance to the topic of assessing preload

and preload-responsiveness were summarized below. One older review article and one

position paper were also cited but only to place the current studies into a proper

perspective. Fundamental to hemodynamic monitoring is the interpretation of the

measured and derived data within the context of expected and known physiological

constructs, such as Starling’s Law of the Heart and global O2 supply and demand

relationships. These assumptions were directly addressed in recent publications.

10

2. Preload is not preload-responsiveness Kumar et al. (4) demonstrated that neither

CVP or Ppao values nor their changes in response to fluid challenges reflected their

respective ventricular end-diastolic volumes or changes, respectively in patients

receiving a fluid challenge for hemodynamic insufficiency. Presumably, non-linear

ventricular diastolic compliance relations and an incomplete knowledge of actual

transmural ventricular filling pressures are the reasons for this failure. However,

Starling’s Law of the Heart was still operative in this study. If end-diastolic volume

increased in response to volume loading, then stroke volume increased as well. Thus,

one should not use either CVP or Ppao values to define the state of ventricular filling or

the potential to response to a fluid challenge. Furthermore, changes in either CVP or

Ppao did not correlate with each other or with changes in either stroke volume or end-

diastolic volume of their respective ventricles. These finding of discordance between

pulmonary artery catheter-derived data and directly measured indices of ventricular

performance were duplicated, in a fashion, by Bouchard et al. (29) who compared right

and left ventricular stroke work index with echocardiographic-derived indexes of left

ventricular performance, i.e. fractional area change in 64 intra-operative cardiac surgery

patients before and after bypass and before and after volume loading. A total of 186

simultaneous measurements were analyzed and compared. Correlations between right

and left ventricular stroke work index changes were poor (R= -0.28 to 0.16, P values

from 0.31 to 0.94) as were the correlations between left ventricular stroke work index

changes and fractional area change changes (R= -0.62 to 0.22, P values from 0.07 to

0.95). Thus, not only is preload not preload-responsiveness, but there is also a

significant discrepancy and limited relationship between the hemodynamic and

echocardiographic evaluation of left ventricular performance. Still, in the position paper

entitled Surviving Sepsis, sponsored by the major critical care societies, the

recommendation to use invasive monitoring as part of the assessment of circulatory

shock and its response to therapy was still made (30). However, this blue-ribbon panel

also accentuated monitoring other related hemodynamic variables, such as cardiac

output and mixed venous O2 saturation (SvO2). Still, the values for left and right

ventricular filling pressures recommended by this panel are not predictive of preload

responsiveness (31). Thus, their recommendations about O2 delivery may need to be

interpreted with caution as well.

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3. Alternatives to right heart catheterization.

In an attempt to bypass the need for right heart catheterization, Combes et al. (32)

demonstrated in 333 mechanically ventilated patients that a single transpulmonary

thermal injection from a central venous site using the PiCCO® system gave estimates of

cardiac function index and global ejection fraction that were similar to measures of left

ventricular (LV) ejection fraction made by transesophageal echocardiography (R = 0.87

and 0.82, respectively). Potentially, estimates of LV systolic function can be made

without the need for a pulmonary artery catheter. Importantly, patients with right

ventricular (RV) dysfunction were excluded, because PiCCO-derived parameters include

RV function whereas echo-derived measures are specific for LV performance. Thus,

extrapolation of these data to mechanically ventilated patients, many of whom may have

RV dysfunction associated with acute respiratory failure, may not be warranted.

If one does not need a pulmonary artery catheter, does one even need a central venous

catheter? Desjardins et al. (33) compared an anticubital vein-transduced pressure with

CVP in 19 cardiac surgery patients with or without mechanical ventilation. They found

that CVP and peripheral venous pressure were similar (mean pressure differences 0.72

to 0 mm Hg). Thus, peripheral venous pressure is a readily available surrogate for CVP.

Since CVP values < 10 mm Hg are associated with a decrease in cardiac output if

positive-end expiratory pressure is subsequently increased, these data have clinical

utility. Staal et al. attempted to bypass invasive catheterization completely (34) using

cardiac impedance techniques. They compared angiographically measured LV

volumes, using Simpson’s rule, with transcardiac conductance measured from surface

skin electrodes in 10 subjects undergoing angiography. Reliably stable data were

available in 8 of 10 subjects and gave good agreement in the estimate of LV volumes

(R2 = 0.78). It remains to be seen, however, if this technique gives a general volume

measure or can detect clinically relevant changes in LV volume over time and in

response to therapy.

An interesting study came from Gabbanelli et al. who used the time activity curve of

glucose dilution following a bolus infusion to estimate circulating blood volume (35).

They compared glucose decay curves to PiCCO-derived measures of central blood

12

volume daily for 5 days in 20 critically ill patients. Surprisingly, they demonstrated a

good correlation between the two techniques (R2 = 0.79). To the extent that measures

of central blood volume, as a surrogate for preload, are clinically useful, then this safe

technique using a readily available intravascular marker may be worth considering.

4. Functional Hemodynamic Monitoring

If absolute measures of cardiovascular values can not be used effectively as parameters

describing cardiovascular status or responsiveness, then more provocative maneuvers

need to be employed to improve the utility of these measures. Such provocative

approaches comprise the broad field of monitoring techniques, referred to a functional

hemodynamic monitoring.

Central to assessment of sufficient volume are the principles of Functional

Hemodynamic Monitoring.

• Is blood flow adequate to meet metabolic demands (tissue wellness)? • Will decreasing intravascular volume increase cardiac output and blood

pressure? • How can volume removal be increased (or decreased) to optimize fluid and

solute removal?

The commonly used indicators for tissue wellness, preload responsiveness, vasomotor

tone and cardiac contractility are reviewed below and summarized in table 2.

a. Indicators of Tissue Wellness. The current trend in monitoring is toward less invasive

methods and goal directed therapy [36]. Mixed venous oxygen saturation (SvO2)

remains the most accurate method by which to assess tissue wellness, however the

declining use of pulmonary artery catheters has limited the practical application of this

assessment tool in acute kidney injury. Recent interest in using central venous O2

saturation (ScvO2) as a surrogate for SvO2 has raised the issue of co-variability of these

two measures and the use of a specific threshold ScvO2 to identify tissue ischemia

(usually identified by an SvO2 < 70%) Rivers et al (37). Reinhart et al. (39) compared

both SvO2 and ScvO2 in 29 patients instrumented with both catheters followed

continuously for over 1000 hours making both fiberoptic and in vitro measures.

13

Importantly, they found that the central venous O2 catheter more accurately estimated

ScvO2 than spot in vitro measures and was not affected by either simultaneous infusion

of fluids through the catheter, or by changes in hematocrit, temperature or blood pH.

More importantly, although ScvO2 tracked SvO2, it tended to be 7 ± 4% higher.

Furthermore, changes in ScvO2 paralleled SvO2 changes 90% of the time when SvO2

changed by ≥ 5%. Thus, ScvO2 values of 74% may be associated with SvO2 values of

68%.

However, these global perfusion indices as well as measures of regional perfusion

and/or organ function are non-specific markers of volume status since organ dysfunction

and derangement in cellular metabolism may occur in the absence of tissue flow

abnormalities, particularly in sepsis. The gut mucosa is one of the earliest tissues to be

compromised and is especially vulnerable to hypoperfusion because of the

countercurrent flow in the microcirculation. Gastric tonometry has been shown to be

more sensitive than global hemodynamic parameters in detecting occult hypovolemia

(39,40). The gastric mucosal-arterial pCO2 gap (Pg-aCO2) is the variable of choice

because, it is independent of systemic acid-base disturbances (41,42).

Less invasive measures of tissue wellness include commonly used blood tests such as

serum lactate levels and the development of metabolic acidosis. Newer noninvasive

tools that may also be useful include monitoring of reoxygenation of tissue oxygen

saturation (StO2) after peripheral arterial occlusion, as well as sublingual CO2

monitoring, however the application of these technologies may be limited outside of the

ICU setting. Finally, clincal measures of tissue wellness include assessment of capillary

refill, peripheral cyanosis, tachycardia and blood pressure, although abnormalities in

these parameters are often late indicators of tissue wellness.

b. Indicators of Preload Responsiveness. A positive response to fluid administration or

preload responsiveness can be predicted by the presence of (mechanical ventilation-

induced) respiratory variations of systolic pressure (43-47), pulse pressure (48-52),

stroke volume (53), or aortic flow velocity (54), which are currently considered the most

reliable parameters to diagnose volume deficit (52,55). In less critically ill patients

14

preload responsiveness can be determined by evaluating variations in pulse oximetry

density and measuring intrathoracic blood volume measured with the COLD or PiCCO

system (transpulmonary thermo-dye dilution or transpulmonary thermodilution). Volume-

related preload indices show a better correlation with stroke volume (19,20,23,24,25,55-

60). End-diastolic ventricular volume can be measured with transesophageal

echocardiography. This method requires training and experience and may be subject to

interobserver variability (61-63). Right ventricular end-diastolic volume can be measured

with a pulmonary artery catheter equipped with a fast-response thermistor (64,65).

Dynamic tests such as fluid challenges or lifting the legs with observation of trends in

filling pressure and stroke volume responses have broader application (64,65). Finally in

specific circumstances urine and blood tests such the BUN/SCr ratio, the urine fractional

excretion of urea (FeUrea) and the urine fractional excretion of sodium (FeNa) may also

indicate insufficient renal perfusion.

c. Indicators of Vasomotor Function and Contractility. Measures of vasomotor tone and

cardiac contractility can be directly assessed in the intensive care unit using a variety of

both invasive and noninvasive methods, but must generally be inferred outside of the

ICU setting.

d. Classical Monitoring Tools. The renal system has the primary role of maintaining fluid

homeostasis on a continual basis. Perterbations in intravascular volume lead to a series

of physiological changes aimed at preserving tissue perfusion. A reduction in

intravascular volume results in a rapid water and sodium resorption by the kidneys. A

variety of clinical parameters are available to assess such states. These include; Blood

pressure, tachycardia, altered of mental state, poor capillary refill, core peripheral

temperature gradient, and oliguria/anuria. Unfortuneately, these tend to be rather late

indicators of sufficient volume status and detect more severe states of hypovolemia (66-

69). The application of such signs in terms of percent dehydration, including changes in

body weight, has long been utilized in the pediatric population (70).

15

The use of biochemical parameters and urinary chemistries have also been employed in

assessing sufficient volume status and potential AKI development in both adult and

pediatric patients. History and clinical suspicion remain important. Simple tests using

either urine and serum or a combination of both may help in defining sufficient volume

state. Many entities leading to AKI demonstrate specific patterns of biochemical and

urinary findings that are useful in assessing sufficient volume status.

5. Renal Function Tests

Renal function tests may be categorized mainly by those that measure renal blood flow,

glomerular function, and/or tubular function. The latter tests measure urinary

concentrating ability and sodium and urea handling. These may provide some useful

indices in order to distinguish between prerenal and intrinsic AKI. Additionally these tests

may be helpful in deciding whether the AKI is potentially volume responsive (71).

Examples of tubular function tests:

• Urinary concentrating ability • Urine to plasma osmolar rartio • Free water clearance • Urine to plasma creatinine ratio • Urine sodium • Fractional excretion of sodium (FeNa) • Fractional excretion of urea • Indices of tubular injury

o β2 microglobulin o Urinary N-acetyl beta D-glucosaminidase o Neutrophil gelatinase associated lipocalin o IL-18 (72)

Even though some thresholds have been established for these tests in order to

differentiate prerenal and intrarenal AKI, there is not a single test with complete efficacy.

Urinary indices may be misinterpreted and unable to distinguish between volume

responsive AKI and intrarenal injury (73,74).

a. Urine and blood tests. AKI may characterized by increases in blood urea nitrogen

(BUN) and serum creatinine (Cr) levels. Evaluation of the pediatric patient takes on a

16

different dimension compared to adult patients with ARF. The normal creatinine values

in pediatrics are varied and depend on age and body mass (75). Indeed, AKI in pediatric

patients may go undiagnosed if the clinician doesn’t take into account the size and age

of the patient as many laboratories do not specify age appropriate creatinine ranges.

Creatinine clearance in children and adolescents may be approximated by using the

Schwartz equation (76).

b. Serum Urea/Creatinine ratio. Urea is passively reabsorbed in the proximal tubule due

to increased sodium and water reabsorption seen in hypovolemia. Thus, a high serum

urea/creatinine ratio is suggestive of prerenal AKI. Where serum urea and creatinine are

reported in mg/dl, a ratio exceeding 20:1 suggests prerenal causes and a ratio of 10-

15:1 suggests ATN. Where serum creatinine is reported in µmol/L and urea reported in

mmol/L a urea-to-creatinine ratio>0.10 and urea>10 mmol/L (60 mg/dl) is suggestive of

prerenal ARF (77,78).

This ratio is of limited value in the setting of high patient catabolic rate, gastrointestinal

bleeding or corticosteroid administration. Under these circumstances urea will be

elevated and therefore the ratio will be elevated in the absence of hypovolemia. A high

ratio may also be noted in patients with decreased muscle mass. A normal ratio cannot

exclude prerenal causes of AKI in the presence of decreased protein intake or liver

disease.

c. Fractional excretion of sodium (FENa). Urine sodium can be used to estimate the

patient’s sufficient volume status. In situations of hypovolemia, urine sodium is usually

less than 20 Meq/L (79). However, low urine sodium may be found in normovolemia

associated with acute glomerulonephritis (80). The contrary can also be seen, where

high urine sodium is noted in the face of hypovolemia in cases of diuretic use, Bartter’s

syndrome, adrenal insufficiency and chronic renal disease among others (81-83). Water

reabsorption also influences urine sodium. For example, in polyuric patients with

diabetes insipidus, a daily normal excretion of sodium can be associated with low urine

sodium due to dilution and thus labeled as hypovolemia. To avoid this situation, the renal

handling of water can be assessed by using FENa.

17

FENa is easily calculated from a random urine sample. It is often used in cases of AKI. In

cases of hypovolemia, most sodium should be reabsorbed in the proximal tubule and

thus the FENa should be less than 1 percent. If the tubules are damaged as seen in acute

tubular necrosis, the FENa is often in the range of 2-3% (79,84). The FENa can be

calculated as follows (80).

( ) 100% ×=+

+

filteredNaofQuantityexcretedNaofQuantity

FeNa 100××

×=

UcrPPcrU

Na

Na

Where, the amount of Na excreted is equal to the product of urine concentration of Na

(UNa) and urine volume (V); the amount of Na filtered is equal to the product of the

plasma concentration of Na (PNa) and the glomerular filtration rate( Ucr X V/Pcr).

FENa can be less than 1% in conditions other than hypovolemia such as congestive heart

failure, nephrotic syndrome or hepatic cirrhosis (79). It can also be less than 1% in

contrast nephropathy or heme pigmentation nephropathy (79). Urine sodium and FENa

are unreliable if diuretics are given. If measured, urine should be collected based on the

half-life of the diuretics administered. Caution should also be exercised in the neonatal

population when using this ratio. FENa is appropriately elevated in newborns making the

transition from intra to extra uterine life. This ratio is even less reliable in those infants

born pre-term.

d. Fractional excretion of urea (FEUN): Due to the limited value of the FENa in

circumstances where diuretics have been administered the measurement of fractional

excretion of urea (FEUN) has been proposed as an alternative. In states of clinical

dehydration, the urinary excretion of urea should also decrease (85). The FEUN should

be less than 35% in hypovolemic states of prerenal AKI while in the case of ATN it

should be above 50%. A hospital based prospective study conducted comparative

analysis of FENa and FEUN in their respective abilities to differentiate between prerenal

AKI and acute tubular necrosis in the presence of diuretics (86). In this study, FEUN

(<35%) had a better sensitivity and specificity (85% and 92%, respectively) in

differentiating AKI due to pre-renal causes vs. ATN particularly where diuretics were

employed. More importantly, a high positive predictive value of 98% was noted for the

FEUN. Studies evaluating FEUN in children with ARF are limited.

18

e. Other laboratories: While changes in hemotocrit have been thought to reveal changes

in volume status, intuitively, one can recognize the limited value of this measure. The

hematocrit may be elevated in patients with decreased volume status due to dehydration

or quite low in those with acute hemmorhage, both states however can lead to a

reduction in sufficient volume to maintain appropriate renal perfusion pressure.

f. Urinalysis and Urine sediment as a determination of sufficient volume. The urinary

sediment is an essential part of the work-up of AKI as it may provide clues as to the

underlying pathophysiology involved. Indeed every nephrologist should be able to

prepare and review spun urines in order to identify histological clues for diagnosis.

Abnormalities in urinary sediment are strong indicators of Intrinsic AKI (87,88). A

relatively bland acellular +/- clear hyaline casts ( typically composed of Tamm-Horsfall

protein secreted by epithelial cells from the loop of Henle ) urine in the face of a history

of low effective circulating blood volume would reaffirm the potential diagnosis of

prerenal AKI (88,89). Benign sediment may be seen in patients with postrenal AKI,

however hematuria and pyuria can occur, as many will have intraluminal obstruction due

to stones or blood clots. Table 3 (90) provides a guide to commonly associated

microscopic urinary sediment and urinalysis findings associated with prerenal, renal and

postrenal AKI.

g. Novel markers of AKI: Serum creatinine is an easily measured marker of AKI.

However, it is generally appreciated that serum creatinine is a relatively inaccurate

marker of AKI since a rise in creatinine signifies that damage has already occurred. With

improved molecular biology techniques, understanding the molecular underpinnings of

AKI have been greatly enhanced in the last few years. This increased knowledge has led

to the discovery of early markers of AKI and hence sufficient volume status. The

principal utility of these markers is to detect early signs of injury that could lead the

clinician to alter fluid management in order to prevent further damage to the kidneys.

Early markers may also serve to predict severity of injury and help in monitoring the

effect of intervention.

19

Two excellent reviews on biomarkers in AKI have been recently published (91,92).

Biomarkers should ideally be non invasive, reproducible, accurate, reliable and have a

high predictive ability (specific and sensitive). They should also be easy to perform and

the results should be rapidly available. To date few markers have been used in

prospective clinical studies and the most promising ones will be discussed.

i. Cystatin C: Cystatin C is a cysteine protease inhibitor protein that, unlike

serum creatinine is freely filtered, completely reabsorbed and catabolyzed by the tubular

epithelial cells, and not secreted. It is stable and not influenced by body mass, gender or

age. More interestingly, its measurement is simple, automated and easily available (93).

One prospective study in an adult population at risk for AKI showed that an increase of

50% in serum cystatin C level predicted AKI one to two days prior to a rise in serum

creatinine (94). Another study demonstrated that cystatin C had a better correlation with

GFR than serum creatinine in critically ill adults (95). Cystatin C levels were also able to

predict the need for renal replacement therapy but could not differentiate among various

causes of AKI. Cystatin C measurement has also been useful in kidney transplantation

(96). In children, cystatin C has also been demonstrated to correlate with AKI in children

suffering from malaria (97). So far, no prospective study on the value of cystatin C in

predicting AKI in children has been published.

ii. Kidney injury molecule (KIM-1): KIM-1 is a transmembrane receptor that is

cleaved and found in urine following ischemic injury (98). Based on a small study, KIM-1

measurement was able to differentiate ischemic renal injury from prerenal causes and

chronic kidney disease (98). To date, no large study has validated the predictive value

of KIM-1 in AKI in adults. KIM-1 is also undergoing analysis and evaluation for its

usefulness as a predictive tool for AKI in children.

iii. Neutrophil gelatinase-associated lipocalin (NGAL): NGAL is a protein

bound to gelatinase first described in neutrophils (99). Circulating NGAL is normally

reabsorbed at the level of the proximal tubule and following ischemia, NGAL is secreted

in the thick ascending limb and is found in the urine. A study in 71 children undergoing

cardiopulmonary bypass surgery measured urinary NGAL 2 hours post surgery (100).

20

Twenty children had an increase in urinary NGAL and this increase preceded a rise in

serum creatinine by 2 to 4 days. The specificity and sensitivity were excellent i.e.: 98 %

and 100%, respectively. NGAL has been recently proven to be useful predictor of AKI in

patients with HUS (101). NGAL may be increased in patients with infections. Thus its

value in diagnosing early AKI in complicated, septic patients may be limited. Urinary

NGAL measurement has recently become commercially available.

iv. Interleukin-18 (IL-18): IL-18 is a pro-inflammatory cytokine cleaved to the

mature form by caspase-1 and found in the urine following ischemia (102). Many

studies have observed an increase in urinary IL-18 that predicts an increase in serum

creatinine in diverse patient populations (103-105). It has also been used to differentiate

among the diverse causes of ARF (103). When combined with NGAL, it predicted the

duration of AKI in children following cardiac surgery (100). It’s easy to perform and a

commercial assay is available.

v. Other markers: Many other markers such sodium/hydrogen exchanger

isoform 3(NHE3), N-acetyl-β-glucosaminidase (NAG), matrix metalloproteinase 9 (MMP-

9) may be useful in early detection of AKI but presently the assays are not easily

performed nor is there enough preliminary data to support their use at this time (98,106).

h. Utility of these novel renal injury markers

The value of these markers in predicting AKI is under intense study (92,107). While

urinary IL-18 and NGAL are good predictors of AKI, in situations of complex critically ill

patients their value may be diminished. Serum cystatin C measurement is promising but

large prospective studies in patient populations with complex diseases need to be

performed before its utility can be fully established. Before these markers make a

significant impact on clinical management in patients developing AKI, there is a need for

simple, accurate, inexpensive and rapid methods of measuring them. Prospective

studies in diverse pediatric patient groups developing AKI are in process and the results

are highly anticipated.

21

While these predominantly classical tools for monitoring sufficient volume status and the

development of AKI have been the mainstay of therapeutic fluid guidance in the past,

they fail to recognize many cases of occult hypovolemia and indeed have limited value in

states of established AKI where fluid overload becomes the main concern. Since

cardiac function and the size of the intravascular space are variables in determining

effective circulating volume, the use of blood or plasma volume monitoring techniques

provide limited information of sufficient fluid status unto themselves. However, these

techniques used in conjunction with the techniques outlined above and below may

provide a relatively reasonable assessment of sufficient volume status during RRT and

provide guidance for intervention.

What should be the end-point of fluid resuscitation?

Fluid resuscitation should be targeted to a specific preload, stroke volume and/or cardiac

output rather than to a specific MAP. Careful assessment of the hemodynamic response

to fluid challenge not only allows the diagnosis of hypovolemia but also allows titration of

fluid. Parameters of preload responsiveness are probably the best variables to define

the adequacy of fluid resuscitation (52,27). It is unclear whether increasing

hemodynamic variables to supranormal values has a beneficial effect on outcome.

Trauma and perioperative patients seem to benefit whereas septic patients do not (108).

It is also not clear whether the endpoints of fluid resuscitation should be different in

patients with AKI because of the limited capacity to eliminate fluid excess. Whether the

use of more invasive monitoring improves outcome remains to proven. Data on the use

of the PAC even suggest the opposite (67,109). A small randomized trial showed that

resuscitation based on the measurement of EVLW results in a less positive fluid balance

and a shorter duration of mechanical ventilation and ICU stay (110). In patients on renal

replacement therapy, blood volume (111-113) and cardiac output (114,115) can be

monitored with specific techniques applied to the extracorporeal circuit.

Table 3. Characteristic Urinalysis by Renal Failure Etiology

ARF

Diagnosis

URINALYSIS

22

Prerenal Causes

Normal

Renal (intrinsic) Causes

Acute Tubular Necrosis Granular casts, epithelial

cells

Glomerulonephritis RBCs, RBC casts, marked

proteinuria

Interstitial Nephritis RBCs, WBCs, ±

eosinophils, granular casts

Vascular Disorders Normal or RBCs,

proteinuria

Postrenal Causes Normal or RBCs, casts,

pyuria

C. What should be monitored during fluid removal with RRT or with diuresis?

The approach to volume management will need have clear and established goals which

may change as the patients’ situation changes. Thus the principles of “goal directed”

therapy need to be established with clear endpoints and schedules. It should be

understood that the total loss or the rate of loss may or may not mirror the total intake or

rate of intake. The ultimate goal of therapy for total loss is to (a) normalize organ

perfusion; (b) normalize organ turgor; (c) normalize fluid compartmentalization; (d)

normalize fluid composition.

The ultimate goal of therapy rate of removal is to maximize therapy effect while avoiding

complications. These include (a) intravascular disturbances based on altered refilling

rates, disease state vascular permeability variations, overly (or underly) aggressive

unaltered removal, therapy choice and finally choice of dialysate/hemofiltrate

replacement composition; (b) volume composition, acid/base and nutritional changes

based in large part by therapy choice and replacement/dialysate composition and (c)

medication ineffectiveness judged by loss across therapy variations and approaches.

23

Before we can judge the appropriate indicators for monitoring the therapy chosen, one

needs to ask some basic questions related to the specific goal desired. These basic

questions to be answered are:

What are the physiologic principles that govern fluid distribution?

What is (are) the target organ (s) considered with volume removal?

What is the total amount projected to be removed?

What method would be the most appropriate?

What time course is most appropriate at specific timeframes?

Once these issues have been established, the choice of indicators used to monitor

volume removal will need to be chosen. This choice will be based upon invasive or non-

invasive methods as well as target goals for specific organ function. Perhaps the most

limiting factor is the compartment with which one is connected. Most extracorporeal

therapy relay on the plasma space as entry to bodily fluids. It is therefore important to

utilize indicators which will judge this “relative” space as a gage to entry into areas of

interest. Indeed the relative changes in volume in this space may help in judging the rate

dependency of the effort as well as the arrival point of therapy.

The most frequently utilized indicator is pressure. Although CVP elevations (> 10 mm

Hg) reflects volume overload, if present, values < 10 mm Hg have no prognostic

implications. As described above, only functional measures, like PPV and SVV during

positive pressure breathings of the change in mean flow during passive leg raising of 30

24

reflect well preload responsiveness. Hopefully, pulse oximetry density change can be

used as a surrogate for PPV, making this parameter more useful.

Another popular indicator of rate adjustment has been the relative blood volume as

judged by hematocrit change in a constant RBC environment or albumin concentration

variation over a timed constant ultrafiltration. Both the nature of volume removed as well

as the ability of volume replenishment across compartmental barriers into this space can

be projected by these relative concentration changes (see physiology). While this is

extremely important in the performance of the extracorporeal therapy per se, it may be

less clear whether these changes have physiological effects in avoidance of

hemodynamic complications. There is also no advantage to the “absolute” blood volume

determination in the dynamic state, but may have a role in end-point judgement. Overall

tissue perfusion can be a relatively simple yet quite important monitor to volume

management.

25

References:

1. Rivers E, Nguyen B, Havstad S et al. Early goal-directed therapy in the treatment of

severe sepsis and septic shock. N Engl J Med 2001; 345:1368-77.

2. Crookes BA, Cohn SM, Burton E et al. Noninvasive muscle oxygenation to guide fluid resuscitation after traumatic shock. Surgery 2004;135:662-670.

3. Nakagawa Y, Weil MH, Tang W et al. Sublingual capnometry for diagnosis and

quantitation of circulatory shock. Am J Respir Crit Care Med 1998; 157:1838-

1843.

4. Kumar A, Anel R, Bunnell E et al. Pulmonary artery occlusion pressure and central

venous pressure fail to predict ventricular filling volume, cardiac performance, or

the response to volume infusion in normal subjects. Crit Care Med 2004; 32:691-

9.

5. Perel A, Pizov R, Cotev S. Systolic blood pressure variation is a sensitive indicator of

hypovolemia in ventilated dogs subjected to graded hemorrhage. Anesthesiology

1987; 67:498-502.

6. Michard F, Boussat S, Chemla D et al. Relation between respiratory changes in

arterial pulse pressure and fluid responsiveness in septic patients with acute

circulatory failure. Am J Respir Crit Care 2000; 162:134-8.

7. Michard F, Alaya S, Zarka V et al. Global end-diastolic volume as a predictor of

cardiac preload in patients with septic shock. Chest 2003; 124:1900-8.

8. Feissel M, Michard F, Mangin I, Ruyer O, Faller JP, Teboul JL. Respiratory changes

in aortic blood velocity as an indicator of fluid responsiveness in ventilated patients

with septic shock. Chest 2001; 119: 867-73.

26

9. Cilley et al. Low oxygen delivery produced by anemia, hypoxia, and low cardiac output. J Surg Res, 1991; 51:425-33.

10. Velmahos GC, Demetriades D, Shoemaker WC, et al. Endpoints of resuscitation of

critically injured patients: normal or supranormal? A prospective randomized trial.

Ann Surg 2000; 232:409-18.

11. Gutierrez G, Palizas F, Doglio G, et al. Gastric intramucosal pH as a therapeutic

index of tissue oxygenation in critically ill patients. Lancet 339:195-9; 1992.

12. Hayes MA, Timmins AC, Yau EH, et al. Evaluation of systemic oxygen delivery in the

treatment of the critically ill. N Engl J Med 1994; 330:1717-22

13. Gillespie RS, Seidel K, Symons JM. Effect of fluid overload and dose of replacement

fluid on survival in hemofiltration. Pediatr Nephrol. 2004; 19:1394-9.

14. Goldstein SL, Somers MJ, Baum MA et al. Pediatric patients with multi-organ

dysfunction syndrome receiving continuous renal replacement therapy. Kidney Int.

2005; 67:653-8.

15. Goldstein SL, Currier H, Graf Cd et al. Outcome in children receiving continuous

venovenous hemofiltration. Pediatrics. 2001; 107:1309-12.

16. Foland JA, Fortenberry JD, Warshaw BL, Pettignano R, Merritt RK, Heard ML,

Rogers K, Reid C, Tanner AJ, Easley KA. Fluid overload before continuous

hemofiltration and survival in critically ill children: a retrospective analysis. Crit

Care Med. 2004; 32:1771-6.

27

17. Shippy CR, Appel PL, Shoemaker WC. Reliability of clinical monitoring to assess

blood volume in critically ill patients. Crit Care Med 1984; 12:107-112.

18. Baek SM, Makabali GG, Bryan-Brown CW, Kusek JM, Shoemaker WC. Plasma

expansion in surgical patients with high central venous pressure (CVP); the

relationship of blood volume to hematocrit, CVP, pulmonary wedge pressure, and

cardiorespiratory changes. Surgery 1975; 78:304-315.

19. Lichtwarck-Aschoff M, Beale R, Pfeiffer UJ. Central venous pressure, pulmonary

artery occlusion pressure, intrathoracic blood volume, and right ventricular end-

diastolic volume as indicators of cardiac preload. J Crit Care 1996; 11:180-188.

20. Godje O, Peyerl M, Seebauer T, Lamm P, Mair H, Reichart B: Central venous

pressure, pulmonary capillary wedge pressure and intrathoracic blood volumes as

preload indicators in cardiac surgery patients. Eur J Cardiothorac Surg 1998;

13:533-9.

21. Buhre W, Weyland A, Schorn B, Scholz M, Kazmaier S, Hoeft A, Sonntag H.

Changes in central venous pressure and pulmonary capillary wedge pressure do

not indicate changes in right and left heart volume in patients undergoing coronary

artery bypass surgery. Eur J Anaesthesiol 1999; 16:11-7.

22. Marik PE. Pulmonary artery catheterization and esophageal doppler monitoring in

the ICU. Chest 1999; 116:1085-91.

23. Sakka SG, Bredle DL, Reinhart K, Meier-Hellmann A. Comparison between

intrathoracic blood volume and cardiac filling pressures in the early phase of

hemodynamic instability of patients with sepsis or septic shock. J Crit Care 1999;

14:78-83.

28

24. Bindels AJ, van der Hoeven JG, Graafland AD, de Koning J, Meinders AE.

Relationships between volume and pressure measurements and stroke volume in

critically ill patients. Crit Care 2000; 4:193-9.

25. Wiesenack C, Prasser C, Keyl C, Rodijg G. Assessment of intrathoracic blood

volume as an indicator of cardiac preload: single transpulmonary thermodilution

technique versus assessment of pressure preload parameters derived from a

pulmonary artery catheter. J Cardiothorac Vasc Anesth 2001; 15:584-8.

26. The National Heart , Lung and Blood Institute Acute Respiratory Distress Syndrome

(ARDS) Clinical Trials Network. Pulmonary-Artery versus Central Venous Catheter

to Guide Treatment of Acute Lung Injury. N Engl J Med 2006; 354: 2213-24.

27. Michard F, Teboul J L. Predicting Fluid Responsiveness in ICU Patients. A Critical

analysis of The Evidence. Chest 2002; 121:2000-8.

28. Michard F. Volume Management using Dynamic Parameters. The Good, the Bad

and The Ugly. Chest 2005; 128:1902-4.

29. Bouchard MJ, Denault A, Couture P, et al. Poor correlation between hemodynamic

and echocardiographic indexes of left ventricular performance in the operating

room and intensive care unit. Crit Care Med 2004; 32:644-8.

30. Dellinger RP, Carlet JM, Masur H, et al. for the Surviving Sepsis Campaign

Management Guidelines Committee. Surviving Sepsis Campaign Guidelines for

management of severe sepsis and septic shock. Crit Care Med 2004; 32:858-73.

31. Osman D, Ridel C, Ray P, Monnet X, Anguel N, Richard C, Teboul JL. Cardiac filling

pressures are not appropriate to predict hemodynamic response to volume

challenge. Crit Care Med 2007; 35:64-8.

29

32. Combes A, Berneau JB, Luyt CE, et al. Estimation of left ventricular systolic function

by single transpulmonary thermodilution. Intensive Care Med 2004; 30:1377-83.

33. Desjardins R, Denault AY, Belisle S, et al. Can peripheral venous pressure be

interchangeable with central venous pressure in patients undergoing cardiac

surgery? Intensive Care Med 2004; 30:627-32.

34. Staal EM, Baan J, Jukema JW, et al. Transcardiac conductance for continuous

measurement of left ventricular volume: validation vs. angiography in patients.

Intensive Care Med 2004; 30:1370-6.

35. Gabbanelli V, Pantanetti S, Donati A, et al. Initial distribution volume of glucose as

noninvasive indicator of cardiac preload. Comparison with intrathoracic blood

volume. Intensive Care Med 2004; 30:2067-73.

36. Polanco P. Pinsky MR. Practical Issues of Hemodynamic Monitoring at the Bedside.

Surg Clin of N A 2006: 86:1431-56

37. Rivers E, Nguyen B, Havstad S, et al. Early goal directed therapy in the treatment of

severe sepsis and septic shock. N Engl J Med 2001; 345: 19: 1368-1377

39. Reinhart K, Kuhn HJ, Hartog C, et al. Continuous central venous and pulmonary

artery oxygen saturation monitoring in the critically ill. Intensive Care Med 2004;

30:1572-8.

39. Hamilton-Davies C, Mythen MG, Salmon JB, Jacobson D, Shukla A, Webb AR.

Comparison of commonly used clinical indicators of hypovolaemia with

gastrointestinal tonometry. Intensive Care Med 1997; 23:276-81.

30

40. Guzman JA, Lacoma FJ, Kruse JA. Relationship between systemic oxygen supply

dependency and gastric intramucosal PCO2 during progressive hemorrhage. J

Trauma 1998; 44:696-700.

41. Hamilton MA, Mythen MG. Gastric tonometry: where do we stand? Curr Opin Crit

Care 2001; 7:122-7.

42. Chapman MV, Mythen MG, Webb AR, Vincent JL. Report from the meeting:

Gastrointestinal Tonometry: State of the Art. 22nd-23rd May 1998, London, UK.

Intensive Care Med 2000; 26:613-22.

43. Szold A, Pizov R, Segal E, Perel A. The effect of tidal volume and intravascular

volume state on systolic pressure variation in ventilated dogs. Intensive Care Med

1989; 15:368-71.

44. Marik PE. The systolic blood pressure variation as an indicator of pulmonary

capillary wedge pressure in ventilated patients. Anaesth Intensive Care 1993;

21:405-8.

45. Rooke GA, Schwid HA, Shapira Y. The effect of graded hemorrhage and

intravascular volume replacement on systolic pressure variation in humans during

mechanical and spontaneous ventilation. Anesth Analg 1995; 80:925-32.

46. Preisman S, Pfeiffer U, Lieberman N, Perel A. New monitors of intravascular volume:

a comparison of arterial pressure waveform analysis and the intrathoracic blood

volume. Intensive Care Med 1997: 23:651-7.

31

47. Perel A. Assessing fluid responsiveness by the systolic pressure variation in

mechanically ventilated patients. Systolic pressure variation as a guide to fluid

therapy in patients with sepsis-induced hypotension. Anesthesiology 1998;

89:1309-10.

448. Michard F, Teboul JL. Using heart-lung interactions to assess fluid responsiveness

during mechanical ventilation. Crit Care 2000; 4:282-9.

49. Denault AY, Gorcsan J, 3rd, Pinsky MR. Dynamic effects of positive-pressure

ventilation on canine left ventricular pressure-volume relations. J Appl Physiol

2001; 91:298-308.

50. Gunn SR, Pinsky MR. Implications of arterial pressure variation in patients in the

intensive care unit. Curr Opin Crit Care 2001; 7:212-7.

51. Michard F, Boussat S, Chemla D, Anguel N, Mercat A, Lecarpentier Y, Richard C,

Pinsky MR, Teboul JL. Relation between respiratory changes in arterial pulse

pressure and fluid responsiveness in septic patients with acute circulatory failure.

Am J Respir Crit Care Med 2000, 162:134-138.

52. Pinsky MR. Functional hemodynamic monitoring. Intensive Care Med 2002; 28:386-

8.

53. Reuter D, Felbinger, TW, Schmidt, C, Kilger, E, Goedje, O, Lamm, P, Goetz, AE.

Respiratory changes in aortic blood velocity as an indicator of fluid responsiveness

in ventilated patients with septic shock. Intensive Care Med 2002; 119:867-73.

54. Feissel M, Michard F, Mangin I, Ruyer O, Faller JP, Teboul JL. Respiratory changes

in aortic blood velocity as an indicator of fluid responsiveness in ventilated patients

with septic shock. Chest 2001; 119:867-873.

32

55. Diebel LN, Wilson RF, Tagett MG, Kline RA. End-diastolic volume. A better indicator

of preload in the critically ill. Arch Surg 1992; 127:817-821.

56. Lichtwarck-Aschoff M, Zeravik J, Pfeiffer UJ. Intrathoracic blood volume accurately

reflects circulatory volume status in critically ill patients with mechanical

ventilation. Intensive Care Med 1992; 18:142-7.

57. Durham R, Neunaber K, Vogler G, Shapiro M, Mazuski J. Right ventricular end-

diastolic volume as a measure of preload. J Trauma 1995; 39:218-23.

58. Chang MC, Blinman TA, Rutherford EJ, Nelson LD, Morris JA, Jr.. Preload

assessment in trauma patients during large-volume shock resuscitation. Arch Surg

1996; 131:728-31.

59. Cheatham ML, Nelson LD, Chang MC, Safcsak K. Right ventricular end-diastolic

volume index as a predictor of preload status in patients on positive end-expiratory

pressure. Crit Care Med 1998; 26:1801-6.

60. Neumann P. Extravascular lung water and intrathoracic blood volume: double versus

single indicator dilution technique. Intensive Care Med 1999; 25:216-9.

61. Brown JM. Use of echocardiography for hemodynamic monitoring. Crit Care Med

2002; 30:1361-4.

62. Roewer N, Greim CA. Echocardiography in intensive care medicine. Acta

Anaesthesiol Scand Suppl 1997; 111:87-9.

33

63. Tousignant CP, Walsh F, Mazer CD. The use of transesophageal echocardiography

for preload assessment in critically ill patients. Anesth Analg 2000; 90:351-5.

64. Stephan F, Flahault A, Dieudonne N, Hollande J, Paillard F, Bonnet F: Clinical

evaluation of circulating blood volume in critically ill patients-contribution of a

clinical scoring system. Br J Anaesth 2001; 86:754-62.

65. Webb A. The fluid challenge. In Oxford textbook of Critical Care. Edited by Webb

AS, M; Singer, M, Suter, P: Oxford University Press; 1999:32-4.

66. Palazzo M. Circulating volume and clinical assessment of the circulation. Br J

Anaesth 2001; 86:743-6.

67. Marik PE. Assessment of intravascular volume: a comedy of errors. Crit Care Med

2001; 29:1635-6.

68. McGee S, Abernethy WB, 3rd, Simel DL. The rational clinical examination. Is this

patient hypovolemic? JAMA 1999; 281:1022-9.

69. Porter JI, RR. In search of the optimal end point of resuscitation in trauma patients. J

Trauma 1998; 44:908-14.

70. Stone B. Fluids and Electrolytes. In: The Harriet Lane Handbook 17th Ed.. Robertson

J. and Shilkofski N. (Eds.) Elsevier Mosby, New York pp.283-308.

71. Moitra V. Diaz G. Salden R. Monitoring Hepatic and Renal Fucntion Anesthesiolgy

Clin 2006; 24: 857-80.

34

72. Parih C, Abraham E. Ancukiewicz M Edelstein C. Urine IL-18 Is an Early Diagnostic

Marker for Acute Kidney Injury and Predicts Mortality in the Intensive Care Unit. J

Am Soc Nephrol 2005; 16:3046-52.

73. Schrier R. Urinary Indices and Microscopy in Sepsis Related Acute Renal Failure.

Am J Kidney Dis 2006; 48:838-41.

74. Bagshaw SM. Langenberg C. Bellomo R. Urinary Indices and Microscopy in Sepsis

Related acute Renal Failure: A Systematic Review. Am J Kidney Dis 2006;

46:695-705.

75. Wong AF, Bolinger AM, Gambertoglio JG. Pharmacokinetics and drug dosing in

children with decreased renal function. In: Holliday MA, Barratt TM, Avner ED,

Eds. Pediatric Nephrology. 3rd Ed. Baltimore, MD: Williams and Wilkins, 1994: p

1306.

76. Schwartz GM, Brion LP, Spitzer A. The use of plasma creatinine concentration for

estimating glomerular filtration rate in infants, children, and adolescents. Pediatric

Clinics of North America 1987; 34:571-90.

77. Morgan DB, Carver ME, Payne RB. Plasma creatinine and urea: creatinine ratio in

patients with raised plasma urea. Br Med J. 1977; 2(6092):929-32.

78. Acute renal failure: urea:creatinine ratio was not very helpful in diagnosing prerenal

failure. Evidence-Based On-Call databaseURL:

http://www.eboncall.org/CATs/1844.htm.

79. Rose, B.D, Meaning and application of urine chemistries. Clinical Physiology of acid-

base and electrolyte disorders, 2001. 5th edition: pp. 405-414.

35

80. Miller TR, et al., Urinary diagnostic indices in acute renal failure: a prospective study.

Ann Intern Med, 1978; 89:47-50.

81. Jeck N, et al., The diuretic- and Bartter-like salt-losing tubulopathies. Nephrol Dial

Transplant, 2000; 15( Suppl 6):19-20.

82. Rodriguez-Soriano J., et al., Hyperkalemic distal renal tubular acidosis in salt-losing

congenital adrenal hyperplasia. Acta Paediatr Scand, 1986; 75:425-32.

83. Danovitch GM, Jacobson E, Licht A, Absence of renal sodium adaptation in chronic

renal failure. Am J Nephrol, 1981; 1:173-6.

84. Zarich S, Fang LS, Diamond JR, Fractional excretion of sodium. Exceptions to its

diagnostic value. Arch Intern Med, 1985; 145:108-12.

85. Goldstein MH, Lenz PR, Levitt MF, Effect of urine flow rate on urea reabsorption in

man: urea as a “tubular marker”. J Appl Physiol, 1969; 26:594-9.

86. Carvounis CP, Nisar S, Guro-Razuman S, Significance of the fractional excretion of

urea in the differential diagnosis of acute renal failure. Kidney Int, 2002; 62:2223-

9.

87. Tsai JJ,Yeun JY, Kumar VA, Don BR. Comparison and interpretation of urinalysis

performed by a nephrologist versus a hospital-based clinical laboratory. Am J

Kidney Dis. 2005; 46:820-9.

88. Patel HP. The abnormal urinalysis. Pediatr Clin North Am, 2006; 53:325-37.

36

89. Simerville JA, Maxted WC, pahira JJ. Urinalysis: A Comprehensive Review

American Family Physician 2005; 71:1153-62.

90. Brady HR, Clarkson MR, Lieberthal W. Acute renal failure: In Brenner BM (ed):

Brenner & Rector’s The Kidney, 7th Edition. Philadelphia, Saunders, 2004: pp.

1215-70.

91. Zhou H, et al., Acute Kidney Injury Biomarkers-Need, Present Status, and Future

Promise. J Am Soc Nephrol (NephSAP). 2006; 5:63-71.

92. Trof RJ, Di Maggio F, Leemreis J, Groeneveld AB. Biomarkers of acute renal injury

and renal failure Shock. 2006; 26:245-53.

93. Herget-Rosenthal S, et al., Prognostic value of tubular proteinuria and enzymuria in

nonoliguric acute tubular necrosis. Clin Chem, 2004; 50:552-8.

94. Herget-Rosenthal S, et al., Early detection of acute renal failure by serum cystatin C.

Kidney Int, 2004; 66:1115-22.

95. Villa P, et al., Serum cystatin C concentration as a marker of acute renal dysfunction

in critically ill patients. Crit Care, 2005; 9:R139-43.

96. White C, et al., Estimating glomerular filtration rate in kidney transplantation: a

comparison between serum creatinine and cystatin C-based methods. J Am Soc

Nephrol, 2005; 16:3763-70.

97. Burchard GD, et al., Renal dysfunction in children with uncomplicated, Plasmodium

falciparum malaria in Tamale, Ghana. Ann Trop Med Parasitol, 2003; 97:345-50.

37

98. Han WK, et al., Kidney Injury Molecule-1 (KIM-1): a novel biomarker for human renal

proximal tubule injury. Kidney Int, 2002; 62:237-44.

99. Kjeldsen L, Cowland JB, Borregaard N, Human neutrophil gelatinase-associated

lipocalin and homologous proteins in rat and mouse. Biochim Biophys Acta, 2000;

1482: 272-83.

100. Mishra J, et al., Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker

for acute renal injury after cardiac surgery. Lancet, 2005; 365(9466):1231-8.

101. Trachtman H, et al., Urinary neutrophil gelatinase-associated lipocalcin in D+HUS:

a novel marker of renal injury. Pediatr Nephrol, 2006.

102. Melnikov VY, et al., Impaired IL-18 processing protects caspase-1-deficient mice

from ischemic acute renal failure. J Clin Invest, 2001; 107:1145-52.

103. Parikh, C.R., et al., Urinary interleukin-18 is a marker of human acute tubular

necrosis. Am J Kidney Dis, 2004; 43 405-14.

104. Parikh CR, et al., Urine IL-18 is an early diagnostic marker for acute kidney injury

and predicts mortality in the intensive care unit. J Am Soc Nephrol, 2005; 16:3046-

52.

105. Parikh CR, et al., Urinary IL-18 is an early predictive biomarker of acute kidney

injury after cardiac surgery. Kidney Int, 2006; 70:199-203.

38

106. du Cheyron D, et al., Urinary measurement of Na+/H+ exchanger isoform 3 (NHE3)

protein as new marker of tubule injury in critically ill patients with ARF. Am J

Kidney Dis, 2003; 42:497-506.

107. Goldstein SL. Pediatric acute kidney injury: it’s time for real progress. Pediatr

Nephrol. 2006; 21:891-5.

108. Poeze M, Greve JW, Ramsay G. Goal-oriented haemodynamic therapy: a plea for

a closer look at using peri-operative oxygen transport optimisation. Intensive Care

Med 2000; 26:635-7.

109. Connors AF Jr, Speroff T, Dawson NV, Thomas C, Harrell FE Jr, Wagner D,

Desbiens N, Goldman L, Wu AW, Califf RM, et al.: The effectiveness of right heart

catheterization in the initial care of critically ill patients. SUPPORT Investigators.

JAMA 1996; 276:889-97.

110. Mitchell JP, Schuller D, Calandrino FS, Schuster DP. Improved outcome based on

fluid management in critically ill patients requiring pulmonary artery

catheterization. Am Rev Respir Dis 1992; 145:990-8.

111. Basile C. Should relative blood volume changes be routinely measured during the

dialysis session? Nephrol Dial Transplant 2001; 16:10-12.

112. Leypoldt JK, Cheung AK. Evaluating volume status in hemodialysis patients. Adv

Ren Replace Ther 1998; 5:64-74.

113. Leypoldt JK, Lindsay RM. Hemodynamic monitoring during hemodialysis. Adv Ren

Replace Ther 1999, 6:233-42.

39

114. Krivitski NM, Depner TA. Cardiac output and central blood volume during

hemodialysis: methodology. Adv Ren Replace Ther 1999; 6:225-32.

118.Pandeya S, Lindsay RM. The relationship between cardiac output and access flow

during hemodialysis. ASAIO J 1999; 45:135-8.

119. Monnet X, Rienzo M, Osman D, Anguel N, Richard C, Pinsky MR, Teboul JL.

Response to leg raising predicts fluid responsiveness in critically ill. Crit Care Med

2006, 34:1402-7.

120. Lopes M, Oliveira MA, Pereira VOS, Lemos IPB, Auler Jr JOC, Michard F. Goal-

directed fluid management based on pulse pressure variation monitoring during

high-risk surgery: a pilot randomized controlled trial. Crit Care 2007; 11: R100-9.

Authors:

In alphabetic order:

Patrick Brophy, MD University of Michigan Email: pbrophy@med.umich.edu Juan Padilla, MD Universidad de Iberoamerica Email: apadilla@racso.co.cr

Emil Pagannini, MD Email: PAGANIE@ccf.org

Nees Pannu, MD Division of Nephrology and Immunology CSB 11-107h E:Mail: neesh.pannu@ualberta.ca Michael R. Pinsky, MD University of Pittsburgh Medical Center E-mail : pinskymr@upmc.edu