1. health and fitness
2. disease

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MCC 534
Fluid therapy in septic shock
Emanuel P. Riversa,b, Anja Kathrin Jaehnea, Laura Eichhorn-Wharryb,
Samantha Browna and David Amponsaha
a
Department of Emergency Medicine and
Department of Surgery, Henry Ford Hospital, Wayne
State University, Detroit, Michigan, USA
b
Correspondence to Emanuel P. Rivers, MD, MPH, IOM,
Vice Chairman and Research Director, Department of
Emergency Medicine, Attending Staff, Emergency
Medicine and Surgical Critical Care, Henry Ford
Hospital, Clinical Professor, Wayne State University,
Detroit, MI, USA
Tel: +1 313 916 1801; e-mail: erivers1@hfhs.org
Current Opinion in Critical Care 2010,
16:000–000
Purpose of review
To examine the role of fluid therapy in the pathogenesis of severe sepsis and septic
shock. The type, composition, titration, management strategies and complications of
fluid administration will be examined in respect to outcomes.
Recent findings
Fluids have a critical role in the pathogenesis and treatment of early resuscitation of
severe sepsis and septic shock.
Summary
Although this pathogenesis is evolving, early titrated fluid administration modulates
inflammation, improves microvascular perfusion, impacts organ function and outcome.
Fluid administration has limited impact on tissue perfusion during the later stages of
sepsis and excess fluid is deleterious to outcome. The type of fluid solution does not
seem to influence these observations.
Keywords
colloid therapy, crystalloid therapy, fluid therapy, sepsis, septic shock, severe sepsis
Curr Opin Crit Care 16:000–000
ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
1070-5295
Introduction: The ebb and flow phase of fluid
management
In 1942, Cuthbertson [1] described the metabolic
response to inflammation, injury and shock in the ‘ebb
and flow’ phase. ‘During the ebb phase or resuscitation
phase, there is low cardiac output (CO), poor tissue
perfusion and a cold and clammy patient. During the
flow phase which is a staccato affair, the patient struggles
to break from the grip of the ebb phase which lasts
about 3 days. Upon entering the flow phase, the swollen
patient has an increased CO, normal tissue perfusion
when diuresis occurs and body weight falls steady’. This
eloquent description serves as the framework for the
clinical principles of fluid management in sepsis. This
review will examine the role of fluid therapy in the
pathogenesis of sepsis. The timing, type, composition,
titration, management strategies and complications of
fluid administration will be examined in respect to
outcome.
The pathogenesis of hypovolemia in sepsis
Sepsis-induced hypovolemia can be a result of vomiting,
diarrhea, sweating, edema, peritonitis or other exogenous
losses. Further contributions to hypovolemia may result
from a maldistributive defect with vasodilatation,
peripheral blood pooling, and extravasation of fluid into
the interstitial space and increased capillary endothelial
1070-5295 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
permeability. All of these mechanisms result in a decrease
in intravascular volume which gives rise to a critical
reduction in ventricular preload, ventricular diastolic pressure, stroke volume, CO, and systemic oxygen delivery.
Compensatory responses as a reaction to decreased circulating blood volume are mediated by the activation of
the sympathetic nervous system and include:
(1) A redistribution of blood flow away from skeletal
muscle beds and the splanchnic viscera to support
vital organ blood flow to the heart and brain [2,3]. The
movement of fluid into or out of the intravascular
compartment is determined by the hydrostatic and
oncotic pressure gradients between the microvascular
and the interstitial spaces. Precapillary vasoconstriction decreases microvascular blood pressure promoting the net movement of fluid from the interstitial
compartment into the vascular compartment [4].
Because of these factors, the type of fluid administered (crystalloid versus colloid) becomes an important and controversial component of the initial
resuscitation.
(2) An augmentation of myocardial contractility
increases stroke volume [2]. Pre-existing cardiac disease may alter this response and the clinical picture.
(3) There is a constriction of arterial and venous capacitance vessels, particularly in the splanchnic bed,
augmenting venous return [2,3]. The use of antihyDOI:10.1097/MCC.0b013e32833be8b3
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MCC 534
2 Intravenous fluids
pertensive medications and diuretics may alter
this response.
(4) A sustained release of adrenocortico-medullary hormones including cortisol, aldosterone and catecholamines such as epinephrine occurs [5]. Congestive
heart failure, renal failure, liver disease and adrenal
dysfunction may modify this salt and water homeostasis which will alter both requirements and elimination of fluid.
(5) The activation of the renin-angiotensin axis releases
aldosterone from the adrenal cortex. Changes in
serum osmolarity lead to arginine-vasopressin
(AVP) release from the posterior pituitary. Both
enhances fluid retention [3,6–8].
(6) Microcirculatory changes such as acidosis, pyrexia,
and increased red blood cell 2,3-diphosphoglycerate
occur, creating a local tissue environment to enhance
the unloading of oxygen to tissues. Multiple factors
may contribute to microvascular alterations, including driving pressure, alterations in red blood cell
rheology and viscosity (local hematocrit) and leukocyte adhesion to endothelial cells, endothelial dysfunction and interstitial edema.
The magnitude of compensatory mechanisms is dependent on the timing, severity of insults and the baseline
organ function status of the patient. Compensatory mechanisms are effective at restoring tissue perfusion for a
period during shock; however, if the initiating process is
not reversed the non-compensatory pathogenesis continues and leads to downstream complications. These
pathogenic mechanisms include endothelial disruption,
the generation of proinflammation and anti-inflammation, microcirculatory compromise, global tissue
hypoxia, organ dysfunction and death (Fig. 1).
Fluid therapy modulates early inflammation. In the human
model of endotoxemia isotonic prehydration significantly
attenuates the concentrations of proinflammatory cytokines (TNF-a, IL-8 and IL-1b), whereas the concentration
of the anti-inflammatory cytokine IL-10 demonstrates a
trend towards higher concentrations. Prehydration results
in a shift towards an anti-inflammatory cytokine pattern.
This effect is associated with a reduction of endotoxininduced symptoms and fever, whereas the endotoxininduced changes in hemodynamic parameters remain
unchanged. More importantly, the peak activity of the
inflammatory response is between 1 and 6 h after introduction of the insult, which gives rise to the concept of early and
late resuscitation as distinct therapeutic entities [10].
Fluids may increase microvascular perfusion by increasing
thedriving pressure or by decreasing blood viscosity (hemodilution) and modulating interactions between the endothelium and circulating cells. Angiotensin II is believed to
play a role in the induction of inflammation. Mild hypovolemia activates the sympathetic nervous system leading to
increased concentrations of circulating catecholamines
which activates cytokine-producing cells containing a
and b-adrenoreceptors. During adrenaline infusion, endotoxin induces less TNF-a and more IL-10, indicating that
b-adrenergic stimulation exerts anti-inflammatory effects.
In-vitro studies demonstrated that noradrenaline exhibits
proinflammatory properties. By stimulating the a-adrenoreceptors of macrophages and lung mononuclear cells,
noradrenaline augments TNF-a secretion in various
inflammation-inducing models. Because fluid infusion
decreases the stimulus for activation of vasoactive agents,
it influences inflammation [11].
Clinical manifestations of hypovolemia
Fluid therapy effects on the pathogenesis of
severe sepsis and septic shock
In animal models, fluid therapy has been shown to
improve outcome. Natanson et al. [9] compared the
efficacy of antibiotics, cardiovascular support (fluids
and dopamine titrated by intravascular monitoring to
hemodynamic endpoints) and a combination of these
two therapies in dogs with septic shock. Survival rates
were 0, 13, 13, and 43% in groups receiving no therapy
(controls), antibiotics alone, cardiovascular support
alone, or combined therapy [9]. The improved survival
observed in the group receiving combined therapy considerably exceeded that in the groups receiving either
therapy alone. Although survivors and nonsurvivors in the
combined therapy group required similar quantities of
fluid therapy, nonsurvivors gained significantly more
weight, suggesting abnormal vascular permeability with
extravascular retention of fluids in the nonsurvivors indicating a more pronounced ebb phase.
When a clinician is confronted with a profoundly hypotensive patient and a source of infection, the diagnosis of
septic shock is straightforward. Although hypovolemia is
present in virtually all patients ranging from sepsis to
septic shock, quantitating volume status is one of the
most difficult management steps. The clinical assessment
of hypovolemia is historically nonsensitive and nonspecific. In a post-hoc analysis of Fluids and Catheters
Treatment Trial in acute lung injury (FACTT) this
hypothesis was examined. When physical examination
findings of an ineffective circulation (capillary refill time
>2 s, skin mottling, and cool extremities) were compared
to parameters obtained from a pulmonary artery catherter, it was found that they are not useful predictors of a
low cardiac index (CI) or low SvO2 [12,13].
Titrating fluid therapy
Optimizing fluid therapy not only modulates inflammation, it also decreases the need for vasopressor therapy,
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MCC 534
Fluid therapy in septic shock Rivers et al. 3
Figure 1 Compensatory and non-compensatory responses to shock
Compensatory
Infection and volume loss
(decrease in DO2)
Renin-angiotensin,
vasopressin and ADH
Splanchnic viscera, skin,
kidneys and skeletal muscle
Non-compensatory
Endothelial cells
Complement
kinins
endorphins
ICAM-1
ELAM-1
oxidants
CNS stimulation
Cortisol
and catecholamines
Redistribution of blood volume to
heart and brain (hypovolemia)
Arterio-venous
constriction
Peripheral vasodilation and
vasoconstriction (tissue hypoxia)
Gut hypoperfusion and
mucosal breakdown
Activation of inflammation and
panendothelial dysruption
Endotoxin release
Leukocytes
Platelets
Monocytes/macrophages
Adherence
proteases
oxidants
Arachidonic acid
metabolites
platelet activating
factor
Coagulation
cascade
Pro and
anti-inflammatory
mediators and
apoptotic proteins
Cellular and organ dysfunction
necrosis and/or apoptosis
(myocardial suppression)
Impaired uptake and utilization:
microcirculatory alterations
increased diffusion distance
Local and global tissue hypoxia
Oxygen debt
Reversible or irreversible
organ dysfunction
steroid use and more invasive monitoring with pulmonary
artery and arterial line catheterization [10,14]. Decreasing
vasopressor use which causes a false elevation in cardiac
filling pressures eliminates pressure volume misinterpretations. It is these mulifactorial reasons which associate
vasopressors use to increased mortality [15,16]. The goal
of fluid resuscitation in severe sepsis and septic shock is
not merely achieving a predetermined value, but rather
optimizing systemic oxygen delivery (cardiac preload,
afterload, arterial oxygen content, contractility or stroke
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MCC 534
4 Intravenous fluids
Figure 2 The hemodynamic, oxygen transport and utilization components of tissue perfusion
Systemic oxygen extraction
Systemic oxygen delivery
×
=
(OER-%) = (1-SvO2)
(DO2)
Hemoglobin
Cardiac output
heart rate × stroke volume
Arterial oxygen
content (CaO2)
Pulmonary
gas
exchange
(PaO2, SaO2)
Systemic oxygen
consumption (VO2)
Systemic oxygen demands:
stress
pain
hyperthermia
shivering
work of breathing
Stroke volume (SV)
cardiac output/heart rate
Heart rate
Microcirculation
Contractility
Preload
(CVP, PAOP,
SVV, PPV, FTc)
Systemic vascular
resistance (SVR)
MAP-CVP or PAOP × 80
CO
volume), and ultimately balancing tissue oxygen
demands (Fig. 2) [17]. The goal is to infuse adequate
volume to restore perfusion before the onset of irreversible tissue damage without raising cardiac filling pressure
to a level that produces hydrostatic pulmonary edema.
Hemodynamic monitoring used to accomplish these goals
is noted in Table 1 [18]. Thus, it is important to have a
command of physiologic variables that are responsible for
tissue perfusion. These variables further serve as diagnostic tools and therapeutic roadmaps for characterization and
management of the patient presenting with shock.
Commonly used methods to assess the adequacy of
volume status or cardiac preload include blood pressure,
heart rate, urine output, central venous pressure (CVP) or
pulmonary artery occlusion pressure (PAOP). Multicenter outcome studies have shown that the central venous
catheter measurements are equal to the volume assessments via pulmonary artery catheter in fluid management. However, neither CVP nor PAOP correlates well
with the true parameter of interest, left-ventricular enddiastolic volume (LVEDV) [19]. Thus, measuring a ‘normal’ CVP or PAOP may not rule out inadequate preload.
Extremely high or low CVP or PAOP values are informative; however, intermediate readings are not clinically
useful. Furthermore, changes in CVP or PAOP fail to
correlate well with changes in stroke volume [20]. In
Metabolic endpoints
SvO2 > 65%
ScvO2 > 70%
lactate < 2 mM/l
base deficit < 5 mEq/l
pH > 7.3
(a-v)CO2 < 5mmHg
pHi > 7.31
urine output > 0.5 cc/kg/h
order to assess fluid responsiveness, the fluid challenge
has been the traditional method for decades. In the
volume-responsive phase, a change in CVP of 2 mmHg
will produce an easily measurable change in CO, whereas
in the plateau phase there is no change in CO with a
change in CVP [21].
Echocardiography can be used to estimate LVEDV, but
this approach is very dependent on the skill and training
of the individual using it [22]. Isolated measurements of
LVEDV fail to predict the hemodynamic response to
alterations in preload [23]. Pulse pressure variation (PPV)
during a positive pressure breath can be used to predict
the responsiveness of CO to changes in preload [24]. PPV
is defined as the difference between the maximal pulse
pressure and the minimum pulse pressure divided by the
average of these two pressures [24]. PPV has been compared to CVP, PAOP, and systolic pressure variation as
predictors of preload responsiveness. Patients were classified as preload responsive if their CI increased by at least
10–15% after rapid infusion of standard volume of intravenous fluid [25]. Receiver operator curve characteristics
(ROC) demonstrated that PPV was the best predictor of
preload responsiveness. Atrial arrhythmias and spontaneous breathing can interfere with the usefulness of
this technique [23]. PPV in mechanically ventilated
patients remains a useful approach for assessing preload
responsiveness [23].
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MCC 534
Fluid therapy in septic shock Rivers et al. 5
Table 1 Tools for assessing volume status
Static measures of fluid responsiveness
Dynamic measures of fluid responsiveness
Noninvasive cardiac output
Systemic arterial-venous CO2 difference
Ultrasound and echocardiography
Circulating blood volume measurement
CVP or right atrial pressure, PAOP or PAWP, right-ventricular end-diastolic volume index,
left-ventricular end-diastolic area, global end-diastolic volume and intrathoracic blood
volume index [26]. May not reliably reflect the left-ventricular filling pressure in clinical states
that produce pulmonary hypertension or compliance changes in the right or left heart.
Common iliac venous pressure can approximate CVP [17,27,28]. If cardiac output increases
after a fluid challenge and stroke volume variation decreases, this can be a sign of resolving
hypovolemia.
Fall in systolic pressure compared with end-expiratory baseline or inspiratory decrement in
PPV, peak aortic blood flow velocity variation, respiratory variation in vena cava diameter,
passive leg raising and plethysmographic pulse wave variation [29]. In ventilated patients,
measures of SVV using arterial pulse contour analysis estimates CO and can demonstrate
fluid responsiveness. A pulse pressure variation of 13% is highly sensitive and specific
for detecting preload responsiveness [26].
CO can be measured by PPV, pulse contour analysis, transesophageal Doppler, thoracic
cutaneous bioimpedance, lithium dilution or transpulmonary thermodilution [30].
Increased arterial-mixed venous carbon dioxide gradients or (a-v)CO2 are seen in acute
circulatory failure, and inversely correlate with the CI. Central venous and pulmonary
artery CO2 values can be interchanged to determine CI [31]. Measuring PCO2 has been
advocated as a way to monitor perfusion of the gastrointestinal tract. Small increases
(5–15 mm Hg) in the difference between arterial and gastric mucosal PCO2 become
apparent before other signs of hemodynamic instability [32,33].
Intracardiac, vena caval diameters, left-ventricular end-diastolic area after a fluid challenge
or passive leg raising may be used to asses volume status. Controlled compression
sonography is a valuable tool for measuring venous pressure in peripheral veins and allows
reliable indirect assessment of CVP. Ultrasound can also be used to assist in-line placement
and cardiac output measurement [34]. It can also be a diagnostic tool to detect
myocardial dysfunction, pericardial disease, aortic disease, intraperitoneal blood and
pneumothoraces [35].
There is a statistically significant, but weak, correlation between blood volume results and PAOP,
but no correlation with CVP, CI, and stroke volume index. Circulating blood volume
measurements may be useful in critically ill patients when clinical appraisal of intravascular
volume is uncertain. This remains to be validated in a larger, prospective randomized trial [36].
CI, cardiac index; CO, cardiac output; CVP, central venous pressure; PAOP, pulmonary artery occlusion pressure; PPV, pulse pressure variation.
dextrans, and gelatins). Colloids include the starches,
hetastarch and pentastarch, human serum albumin, gelatin, and dextran. Colloids are dissolved in either normal
saline or a balanced salt solution. Recent reviews suggest
that there are no clinically significant differences among
the various colloid solutions when used for shock resuscitation [38]. When compared to saline-based solutions,
hetastarch dissolved in a calcium-containing low-chloride
balanced salt solution may be associated with less acidosis
and use of blood products [39] (Table 3).
Crystalloid therapy
The two most commonly used crystalloid solutions are
0.9% sodium chloride solution (normal saline or NaCl)
and Ringer’s lactate solution. The composition of these
two fluids is shown in Table 2. Although normal saline
and Ringer’s lactate solution have been regarded by many
clinicians as being essentially interchangeable, accumulating data support the view that the use of large volumes
of normal saline, but not Ringer’s lactate solution, promotes the development of hyperchloremic metabolic
acidosis [37].
Due to their higher molecular weight, colloids stay in the
intravascular space significantly longer than crystalloids
with an intravascular half-life for albumin of 16 h versus
30–60 min for normal saline and lactated Ringer’s
solution [41,42]. When titrated to the same PAOP,
Colloids are higher-molecular-weight solutions that
increase plasma oncotic pressure. Colloids can be classified as either natural (albumin) or artificial (starches,
Table 2 Composition and osmolarity of crystalloid solutions [11]
Solution
NaCl 0.9%
NaCl and glucose
Ringer’s lactatea
Plasmalyte B
Normasolb
a
b
Osmolarity
(mOsm/l)
Naþ
(mmol/l)
Cl
(mmol/l)
Kþ
(mmol/l)
Ca2þ
(mmol/l)
308
264
275
298.5
280
154
31
130
140
140
154
31
110
98
98
4
5
5
3
Glucose
(mg/l)
HCO3(mmol/l)
Lactate
(mmol/l)
40
Energy
(kcal/l)
320
28
50
Hartmann’s solution or lactated Ringer’s solution.
Normasol contains acetate 27 mmol/l and gluconate 23 mmol/l.
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6 Intravenous fluids
Table 3 Physiological characteristics and clinical effects of commonly used intravenous solutions [11,40] (table obtained from publication)
Available formulations
Albumin solutions
Dextrans
3%, 6%, 10%
Hetastarch
10% Pentastarch 10% Dextran-40
Gelatins
Crystalloids
3% Dextran-60,
6% Dextran-70
Succinylated and cross-linked;
2.5%, 3%, 4% urea-linked: 3.5%
Normal
saline
Ringer’s
lactate
40
70
30–35
0
0
326
23–50
100–200
280-324
20–60
100–200
280–324
20–60
80–140
300–350
25–42
70–80
285–308
0
20–25
250–273
0
20–25
8–36
12–24
1–2
8–24
4–6
1–4
1–4
16–24
þ
50
þþ
2–12
þþ
4–6
þþþ
12
þþþ
2–9
þ
0.5
þ
0.5
þ
Allergic
reactions
Renal
dysfunction
Renal
dysfunction
Anaphylactoid
reactions
Anaphylactoid
reactions
Transmitted Transmitted Coagulopathy
infection
infection
Pruritus
Coagulopathy
Allergic
reactions
Interference
with blood
cross-matching
Allergic
reactions
Interference with
blood cross-matching
High calcium
content (urealinked forms)
Anaphylactoid
reactions
Anaphylactoid
reactions
Anaphylactaid
reactions
4%, 5%
20%, 25%
69
69
4 50
280
290
20–30
70–100
310
70–100
300–500
300–310
23–50
100–200
12–24
12–24
16–24
þ
Allergic
reactions
Pruritus
COP, colloid osmotic pressure.
a
Expressed as percentage of administered volume.
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Hyperchloremic Hyperkalemia
metabolic acidosis
MCC 534
Molecular weight,
average (kD)
Osmolality, mOim/l
COP, mmHg
Maximum volume
expansion,a %
Duration of volume
expansion, h
Plasmatic half-life, h
Potential to adverse
reactions
Possible side effects
Starches
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Fluid therapy in septic shock Rivers et al. 7
Table 4 Descriptions of fluid therapy
Normal saline
Lactated Ringer’s
Hypertonic saline
Albumin [47]
Hydroxyethyl starch
Dextrans
Gelatins
Normal saline is a slightly hyperosmolar solution containing 154 mEq/l of both sodium and chloride.
Due to the relatively high chloride concentration, normal saline carries a risk of inducing hyperchloremic
metabolic acidiosis when given in large amounts [42].
LR results in a buffering of the acidemia which is advantageous over normal saline. Due to the fact that
LR contains potassium, albeit a very small amount, there is a small risk of inducing hyperkalemia in patients
with renal insufficiency or renal failure. There is a theoretic issue of using LR because of the significant immune
activation and induction of cellular injury caused by the D-isomer of lactated Ringer’s.
Hypertonic saline exerts immunomodulatory effects through suppression of neutrophil activation and modulation
of and proinflammatory and anti-inflammatory cytokines. In-vitro experiments demonstrate that hypertonic
saline reduces endotoxin-induced TNF-a production, whereas IL-10 production is augmented and, therefore,
helps to restore the proinflammatory/anti-inflammatory balance. Hypertonic saline has led to rapid plasma
volume expansion, improvement in myocardial contractility and performance, reduction in endothelial and
myocardial edema, and enhancement of immune function in experimental models of sepsis. Human data
are lacking [46].
Albumin is a protein derived from human plasma. It is available in varying strengths from 4 to 25%. The Saline
versus Albumin Fluid Evaluation (SAFE) study compared fluid resuscitation with albumin or saline on mortality
and found similar 28-day mortalities and secondary outcomes in each arm [48]. However, a subset analysis of
patients with sepsis and acute lung injury resuscitated with albumin showed a decrease in mortality, although
statistically it was insignificant. There was a significant increase in mortality in trauma patients particularly
with head injury [42].
Hydroxyethyl starch (HES) is a synthetic colloid derived from hydrolyzed amylopectin, which has been found
to be harmful, causing renal impairment at recommended doses and impairing long-term survival at high
doses [49]. HES can also cause coagulopathy and bleeding complications from reduced factor VIII and von
Willebrand factor levels, as well as impaired platelet function. HES increases the risk of acute renal failure
among patients with sepsis and reduces the probability of survival. HES should be avoided in sepsis [49–51].
Dextrans are not frequently used for rapid plasma expansion, but rather to lower blood viscosity. This class can
cause renal dysfunction, as well as anaphylactoid reactions.
Gelatins are produced from bovine collagen. Because they have a much smaller molecular weight, they are not
as effective expanding plasma volume; however, they cost less [52]. They too have been reported to cause
renal impairment, as well as allergic reactions ranging from pruritus to anaphylaxis. Gelatins are not currently
available in North America. Because of the significant calcium content of Hemaccel, blood should not be
infused through tubing previously used for this product.
colloids and crystalloids restore tissue perfusion to the
same magnitude, although two to four times more volume
of crystalloids is required to achieve the same endpoint
[43]. This obviously depends on the stage of shock and
capillary permeability.
improve in the late phase even in patients with the worst
microvascular perfusion at baseline [53].
The optimal hemoglobin (macrovascular and
microvascular hematocrit)
The outcome advantages between crystalloid and
colloids continue to remain unresolved in septic shock
[40]. Table 4 compares the most commonly used fluid
therapies. Meta-analyses of the results from trials comparing crystalloids versus colloids suggest that outcome is
not affected by the choice of fluid [44,45].
Appropriate hemoglobin levels in shock remain controversial because there is a paucity of literature for patients
in septic shock. The controversy is largely based on a
study by Hebert et al. [54] which found tolerance to lower
hemoglobin levels in stable ICU patients. Hemoglobin
concentrations may vary in the central, peripheral and
microvascular circulations.
Fluid therapy and the microcirculation
The combination of anemia and global tissue hypoxia
provides the physiologic rationale for transfusion of red
blood cells (RBCs) during this delivery-dependent
(increased lactate and low ScvO2) phase. Anemia may
also result from hemodilution. It is this particular phase
that has gone unstudied in previous trials of hemoglobin
maintenance strategies. Whereas transfusion therapy has
received increasing scrutiny in critical illness, recent data
are conflicting [55]. Furthermore, there are findings that
suggest that the sublingual microcirculation is globally
unaltered by RBC transfusion in septic patients and can
improve in patients with altered capillary perfusion at
baseline [56]. The risks and benefits of RBC transfusion
Microvascular alterations are frequent in patients with
septic shock, even when global oxygen delivery seems
adequate. Common findings include a decrease in functional capillary density and heterogeneity of blood flow
with perfused capillaries in close vicinity to nonperfused
capillaries. These alterations are more severe in nonsurvivors than in survivors, and their persistence is associated with organ failure and death [53]. Fluids improve
the microcirculation in early but not in late sepsis. These
effects are independent of the systemic effects of fluids
and are observed with crystalloid as well as with albumin
solutions. In addition, microvascular perfusion failed to
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MCC 534
8 Intravenous fluids
should be assessed in every patient before transfusion.
Although maintaining stable patients arbitrarily at hemoglobin of 10 is not supported, for hemodynamically compromised patients, especially those with coronary artery
disease, transfusion may be warranted.
overall fluid volume in the first 72 h was essentially equal
in both groups. In a subset analysis, patients who were on
hemodialysis at enrollment had a more pronounced
mortality reduction and decrease in mechanical ventilation despite similar volume administration [62].
Negative consequences of fluid therapy
The FACTT isolated the manipulation of volume
therapy as a controlled intervention which began an
average of 43 h after ICU admission and 24 h after the
establishment of acute lung injury (ALI) [63]. Although
there was no difference in 60-day mortality, patients in
the conservative strategy group had significantly
improved lung and central nervous system function
and a decreased need for sedation, mechanical ventilation, and ICU care. However, there was a statistically
significant 0.3-day increase in cardiovascular failure free
days in the liberal compared to the conservative fluid
group, suggesting that caution should be used in applying
a conservative fluid strategy during the resuscitation
phase. When liberal fluid management strategies are
utilized early, there were no differences in pulmonary
function and the use of mechanical ventilation. In fact,
this early liberal strategy decreases the incidence of
mechanical ventilation over the first 72 h of hospitalization. This may be due to the modulating effects on IL-8,
which has been identified as a culprit within the first 72 h
of presentation [64,65].
Fluid overload and positive fluid balance has been associated with worse outcomes in critically ill patients [57–59].
In the setting of sepsis, edema is attributed to a combination of increased capillary permeability to proteins and
increased net transcapillary hydrostatic pressure through
reduced precapillary vasoconstriction. The use of positive
end-expiratory pressure (PEEP) in these patients can also
exacerbate fluid and salt retention and decrease lymphatic
drainage. In addition, several studies have shown that
mechanical ventilation and PEEP reduce urine output;
however, their effects on glomerular filtration rate and
renal blood flow are inconsistent and may reflect differences in hydration status and lung injury. Fluid accumulation can contribute to impair organ function by different
mechanisms. Tissue edema can impair gut absorption,
kidney excretion, increased abdominal pressure leading
to abdominal compartment syndrome [60]. High-risk
patients are the elderly, renal failure, malnutrition and
mechanical ventilation [18]. We should not only focus on
daily fluid balances but also on the cumulative fluid
balance, as duration of fluid accumulation might influence
outcomes.
Liberal or conservative fluid management strategies or
is it timing?
The concept of early goal-directed therapy (EGDT),
based on a study by Rivers and colleagues [61], not only
changed the landscape of sepsis management but also reinvigorated the debates regarding resuscitation and fluid
management in sepsis. High-risk sepsis patients were
randomized to conventional therapy or goal-directed
resuscitation to ‘normal’ physiologic endpoints during
the first 6 h after presentation. EGDT is a stepwise
physiologic approach that includes optimization of preload, afterload, arterial oxygen content, contractility and
the minimization of oxygen demands. Rather than targeting specific values for CO, systemic DO2 or systemic VO2,
EGDT targets the achievement of an ScvO2 greater than
70% as an additional endpoint rather than only an
optimized CVP.
Using this carefully planned algorithm for resuscitation
(Fig. 3), EGDT improved 30-day mortality from 46.5 to
30.5%. The outcome findings of this study and its socioeconomic impact have been confirmed extensively since
this seminal publication. However, because the treatment arm received an average of 2 l more fluid than
the control arm in the first 6 h, the fluid therapy has
received the most attention. It should be noted that the
The findings of the FACTT trial are not at odds with
EGDT. This study has brought attention to the negative
consequences of overzealous fluid administration. The
protocol used in FACTT is not identical to standard
practice. In order to generalize these results and avoid
mitigating the salutary findings, multiple variables must
be considered when applying a conservative fluid management approach [11]. The exclusion of patients on
hemodialysis, overt renal insufficiency, heart failure
and the relatively young age of the patients studied
(about 50 years of age) make FACTT a departure from
the reality that many clinicians will face in the treatment
of ALI or sepsis.
As Cuthbertson decribed in 1942, the clinician must
also make an accurate clinical assessment of the flow
phase while paying particular attention to the untoward
complications upon instituting conservative fluid strategies and active diuresis. Although pathogenically well
described, the clinical landmark that separates the ebb
from flow phase is frequently indistinct and complex.
In ALI the ebb phase is characterized by an increase in
lung water due to direct permeability changes on lung
capillaries and systemic influences on water balance
[8,9]. In the absence of manipulating fluid balance in
this phase of ALI, pulmonary edema, myocardial complications, respiratory insufficiency and the continued
need for ventilator support result. Thus, conservative
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MCC 534
Fluid therapy in septic shock Rivers et al. 9
Figure 3 Protocol for early goal-directed therapy in septic shock
Suspected infection and
document source
within 2 hours
The high risk patient:
blood pressure < 90 mmHg after
20−40 cc/kg volume challenge or
lactic acid > 4 mmole/liter
Antibiotics within
hour and source
control
< 8 mmHg
Crystalloid
CVP
> 8−12 mmHg
Decrease
oxygen
consumption
< 65 or > 90 mmHg
Vasoactive agent (s)
MAP
> 65−90 mmHg
> 70%
< 70%
ScvO2
Packed red blood
cells to Hct > 30%
< 70%
> 70%
Ionotrope (s)
No
Goals
achieved
Reproduced from [61].
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MCC 534
10 Intravenous fluids
Figure 4 Fluid management strategies in sepsis
Fluid mobilization and
liberate from mechanical
ventilation
Severe sepsis and
septic shock
The Ebb phase:
Sodium and water conservation,
hypovolemia, vasodilation, myocardial
suppression, increase metabolic demands and
impaired tissue oxygen utilization
Compensated sepsis:
The flow phase:
Shock reversal and volume replete
avidity for water and sodium, low
plasma oncotic pressure, increased
lung water, generalized edema
Conservation of fluids and/or
diuresis,
closely monitor electrolytes
and volume status
Co-morbidities and considerations:
Incomplete source control, ongoing inflamation
complicated by:
renal failure
myocardial dysfunction
liver disease
endocrinopathies
-hypothyroidism
-adrenal dysfunction
Prolonged mechanical ventilation (increased anti-diuretic hormone)
Pre-existing hypertension (increased sodium and water retention)
Identify and treat:
Underlying disorder
Persistant Ebb phase:
Impaired fluid mobilization
Reproduced from [63].
fluid strategies, perhaps even with a ‘diuretic provocation’, with appropriate cautions to preserve organ perfusion and avoid metabolic derangements are therapeutically sound (Fig. 4).
and withdrawal of fluid during appropriate phases of
inflammation.
Conclusion
The FACTT trial and subsequent studies differentiate
adequate initial fluid resuscitation from conservative late
fluid management. Whereas appropriate fluid resuscitation based on the resuscitation or ebb phase leads to
improved outcomes, liberal and late fluid resuscitation is
a negative contributor to outcome [66]. Thus, there are
significant benefits to both a goal-directed administration
Fluids are critical in the pathogenesis and treatment of
early resuscitation of severe sepsis and septic shock.
Although this pathogenesis is evolving, early titrated fluid
administration modulates inflammation, improves microvascular perfusion, impacts organ function and outcome.
Fluid administration has limited impact on tissue perfusion during the later stages of sepsis and excess fluid is
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MCC 534
Fluid therapy in septic shock Rivers et al. 11
deleterious to outcome. The type of fluid solution does
not seem to influence these observations. Fluid therapy
remains a clinical decision based on the understanding of
the pathogenic landscape of the disease.
Acknowledgements
Conflicts of interests: None related to this publication. Dr Rivers
receives research funding from the NIH. In the last 5 years he has been
a consultant to Esai Pharmaceuticals, Agennix, Astra Zeneca and
Idaho Technologies.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
of special interest
of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 000–000).
20 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; 18:142–147.
21 Magder S. Central venous pressure monitoring. Curr Opin Crit Care 2006;
12:219–227.
22 Smith MD, MacPhail B, Harrison MR, et al. Value and limitations of transesophageal echocardiography in determination of left ventricular volumes and
ejection fraction. J Am Coll Cardiol 1992; 19:1213–1222.
23 Gunn SR, Pinsky MR. Implications of arterial pressure variation in patients in
the intensive care unit. Curr Opin Crit Care 2001; 7:212–217.
24 Michard F, Chemla D, Richard C, et al. Clinical use of respiratory changes in
arterial pulse pressure to monitor the hemodynamic effects of PEEP. Am J
Respir Crit Care Med 1999; 159:935–939.
25 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 Med 2000; 162:134–138.
26 Michard F, Lopes M, Auler J-O. Pulse pressure variation: beyond the fluid
management of patients with shock. Crit Care 2007; 11:131.
27 Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two fluidmanagement strategies in acute lung injury. N Engl J Med 2006; 354:2564–
2575.
1
Cuthbertson DP. Post-shock metabolic response. Lancet 1942; 239:433–
436.
28 Osman D, Ridel C, Ray P, et al. Cardiac filling pressures are not appropriate to
predict hemodynamic response to volume challenge. Crit Care Med 2007;
35:64–68.
2
Chien S. Role of the sympathetic nervous system in hemorrhage. Physiol Rev
1967; 47:214–288.
29 Hadian M, Pinsky MR. Functional hemodynamic monitoring. Curr Opin Crit
Care 2007; 13:318–323.
3
Reilly PM, Wilkins KB, Fuh KC, et al. The mesenteric hemodynamic response
to circulatory shock: an overview. Shock 2001; 15:329–343.
30 Prentice D, Sona C. Esophageal Doppler monitoring for hemodynamic
assessment. Crit Care Nurs Clin North Am 2006; 18:189–193; x.
4
Gann DS, Carlson DE, Byrnes GJ, et al. Role of solute in the early restitution of
blood volume after hemorrhage. Surgery 1983; 94:439–446.
5
Marik PE, Zaloga GP. The central nervous system hypothalamic-pituitaryadrenal axis in sepsis. Crit Care Med 2002; 30:490–491.
31 Cuschieri J, Rivers EP, Donnino MW, et al. Central venous-arterial carbon
dioxide difference as an indicator of cardiac index. Intensive Care Med 2005;
31:818–822.
6
Givertz MM. Manipulation of the renin-angiotensin system. Circulation 2001;
104:E14–E18.
7
Cumming AD, Driedger AA, McDonald JW, et al. Vasoactive hormones in the
renal response to systemic sepsis [erratum appears in Am J Kidney Dis 1988
Apr;11(4):363]. Am J Kidney Dis 1988; 11:23–32.
8
Danser AH. Local renin-angiotensin systems: the unanswered questions. Int J
Biochem Cell Biol 2003; 35:759–768.
9
Natanson C, Danner RL, Reilly JM, et al. Antibiotics versus cardiovascular
support in a canine model of human septic shock. Am J Physiol 1990;
259:H1440–H1447.
10 Dorresteijn MJ, van Eijk LT, Netea MG, et al. Iso-osmolar prehydration shifts
the cytokine response towards a more anti-inflammatory balance in human
endotoxemia. J Endotoxin Res 2005; 11:287–293.
11 Grocott MP, Mythen MG, Gan TJ. Perioperative fluid management and clinical
outcomes in adults. Anesth Analg 2005; 100:1093–1106.
12 Strehlow MC. Early identification of shock in critically ill patients. Emerg Med
Clin North Am 2010; 28:57–66; vii.
An excellent overview from the acute care setting.
13 Grissom CK, Morris AH, Lanken PN, et al. Association of physical examination
with pulmonary artery catheter parameters in acute lung injury. Crit Care Med
2009; 37:2720–2726.
A secondary analysis from a multicenter study that shows that the physical
examination is poor in assessing hemodynamic status.
14 Packman MI, Rackow EC. Optimum left heart filling pressure during fluid
resuscitation of patients with hypovolemic and septic shock. Crit Care Med
1983; 11:165–169.
15 Nouira S, Elatrous S, Dimassi S, et al. Effects of norepinephrine on static and
dynamic preload indicators in experimental hemorrhagic shock. Crit Care Med
2005; 33:2339–2343.
16 Levy MM, Macias WL, Vincent JL, et al. Early changes in organ function
predict eventual survival in severe sepsis. Crit Care Med 2005; 33:2194–
2201.
17 Dellinger RP, Levy MM, Carlet JM, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2008.
Crit Care Med 2008; 36:296–327.
18 Durairaj L, Schmidt GA. Fluid therapy in resuscitated sepsis: less is more.
Chest 2008; 133:252–263.
19 Godje O, Peyerl M, Seebauer T, et al. Central venous pressure, pulmonary
capillary wedge pressure and intrathoracic blood volumes as preload indicators
in cardiac surgery patients. Eur J Cardiothorac Surg 1998; 13:533–539.
32 Hamilton-Davies C, Mythen MG, Salmon JB, et al. Comparison of commonly
used clinical indicators of hypovolaemia with gastrointestinal tonometry.
Intensive Care Med 1997; 23:276–281.
33 Yee JB, McJames SW. Use of gastric intramucosal pH as a monitor during
hemorrhagic shock. Circ Shock 1994; 43:44–48.
34 Beaulieu Y. Bedside echocardiography in the assessment of the critically ill.
Crit Care Med 2007; 35:S235–S249.
35 Rozycki GS. Surgeon-performed ultrasound: its use in clinical practice. Ann
Surg 1998; 228:16–28.
36 Takanishi DM Jr, Biuk-Aghai EN, Yu M, et al. The availability of circulating
blood volume values alters fluid management in critically ill surgical patients.
Am J Surg 2009; 197:232–237.
This study adds to the physiologic understanding of what is the true assessment of
volume status.
37 Kellum JA. Fluid resuscitation and hyperchloremic acidosis in experimental
sepsis: improved short-term survival and acid-base balance with Hextend
compared with saline. Crit Care Med 2002; 30:300–305.
38 Alderson P, Schierhout G, Roberts I, Bunn F. Colloids versus crystalloids for
fluid resuscitation in critically ill patients. Cochrane Database Syst Rev
2000:CD000567.
39 Gan TJ, Bennett-Guerrero E, Phillips-Bute B, et al. Hextend, a physiologically
balanced plasma expander for large volume use in major surgery: a randomized phase III clinical trial. Hextend Study Group. Anesth Analg 1999;
88:992–998.
40 Evidence-based colloid use in the critically ill: American Thoracic Society
Consensus Statement. Am J Respir Crit Care Med 2004; 170:1247–59.
41 Shoemaker WC. Relation of oxygen transport patterns to the pathophysiology
and therapy of shock states. Intensive Care Med 1987; 13:230–243.
42 Vincent JL, Gerlach H. Fluid resuscitation in severe sepsis and septic shock:
an evidence-based review. Crit Care Med 2004; 32:S451–S454.
43 Rackow EC, Falk JL, Fein IA, et al. Fluid resuscitation in circulatory shock: a
comparison of the cardiorespiratory effects of albumin, hetastarch, and saline
solutions in patients with hypovolemic and septic shock. Crit Care Med 1983;
11:839–850.
44 Choi PT, Yip G, Quinonez LG, Cook DJ. Crystalloids vs. colloids in fluid
resuscitation: a systematic review. Crit Care Med 1999; 27:200–210.
45 Schierhout G, Roberts I. Fluid resuscitation with colloid or crystalloid solutions
in critically ill patients: a systematic review of randomised trials. Br Med J
1998; 316:961–964.
46 Singh A, Carlin BW, Shade D, Kaplan PD. The use of hypertonic saline for fluid
resuscitation in sepsis: a review. Crit Care Nurs Q 2009; 32:10–13.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
CE: Namrta; MCC/534; Total nos of Pages: 12;
MCC 534
12 Intravenous fluids
47 All you need to read in the other general journals. BMJ 2008; 336:744–
745.
48 Finfer S, Bellomo R, Boyce N, et al. A comparison of albumin and saline for
fluid resuscitation in the intensive care unit. N Engl J Med 2004; 350:2247–
2256.
57 Bouchard J, Soroko SB, Chertow GM, et al. Fluid accumulation, survival and
recovery of kidney function in critically ill patients with acute kidney injury.
Kidney Int 2009; 76:422–427.
58 Payen D, de Pont AC, Sakr Y, et al. A positive fluid balance is associated with
a worse outcome in patients with acute renal failure. Crit Care 2008; 12:R74.
49 Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin therapy and
pentastarch resuscitation in severe sepsis. N Engl J Med 2008; 358:
125–139.
59 Schuller D, Mitchell JP, Calandrino FS, Schuster DP. Fluid balance during
pulmonary edema. Is fluid gain a marker or a cause of poor outcome? Chest
1991; 100:1068–1075.
50 Wiedermann CJ. Systematic review of randomized clinical trials on the use of
hydroxyethyl starch for fluid management in sepsis. BMC Emerg Med 2008;
8:1.
60 Kula R, Szturz P, Sklienka P, et al. A role for negative fluid balance in septic
patients with abdominal compartment syndrome? Intensive Care Med 2004;
30:2138–2139.
51 Sriskandan S, Altmann DM. The immunology of sepsis. J Pathol 2008;
214:211–223.
61 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–
1377.
52 Vincent JL, Weil MH. Fluid challenge revisited. Crit Care Med 2006;
34:1333–1337.
53 Ospina-Tascon G, Neves AP, Occhipinti G, et al. Effects of fluids on micro
vascular perfusion in patients with severe sepsis. Intensive Care Med 2010;
36:949–955.
A study which examines the time sensitive response of the microcirculation to fluid
therapy.
54 Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized,
controlled clinical trial of transfusion requirements in critical care. Transfusion
Requirements in Critical Care Investigators, Canadian Critical Care Trials
Group. N Engl J Med 1999; 340:409–417.
55 Vincent JL, Sakr Y, Sprung C, et al. Are blood transfusions associated with
greater mortality rates? Results of the sepsis occurrence in acutely ill patients
study. Anesthesiology 2008; 108:31–39.
56 Sakr Y, Chierego M, Piagnerelli M, et al. Microvascular response to red blood
cell transfusion in patients with severe sepsis. Crit Care Med 2007;
35:1639–1644.
62 Donnino M, Shirazi E, Wira C, et al. Early goal-directed therapy in patients with
end-stage renal disease. Critical Care 2004; 8:163.
63 Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two fluidmanagement strategies in acute lung injury. N Engl J Med 2006; 354:2564–
2575.
64 Rivers EP, Kruse JA, Jacobsen G, et al. The influence of early hemodynamic
optimization on biomarker patterns of severe sepsis and septic shock. Crit
Care Med 2007; 35:2016–2024.
65 Miller EJ, Cohen AB, Matthay MA. Increased interleukin-8 concentrations in
the pulmonary edema fluid of patients with acute respiratory distress syndrome from sepsis. Crit Care Med 1996; 24:1448–1454.
66 Murphy CV, Schramm GE, Doherty JA, et al. The importance of fluid manage ment in acute lung injury secondary to septic shock. Chest 2009; 136:102–
109.
Very important article which examines not only the timing but liberal and conservative approach to fluid management and outcome.
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