Post on 12-Jul-2020
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
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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
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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
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(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.
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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
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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.
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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
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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).
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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.
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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
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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