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OPINION
Purpose of review
We discuss the goals of resuscitation, in both the early and the later phases, measures of organ perfusion,
fluid responsiveness and the consequences of tissue edema.
Recent findings
The cost of over-aggressive fluid resuscitation is increased organ failure and mortality. In anticipation of the
upcoming trials on early goal-directed therapy, we explore strategies to maximize effectiveness of
resuscitation. Furthermore, we review recent data on the choice of fluid therapy.
Summary
Rapid diagnosis and early fluid resuscitation are crucial to patients with septic shock, initially with the
primary goal to relieve the overt tissue hypoxia. Early fluid therapy is important with the caveat that
patients must show an increase in their cardiac output. Beyond 612 h further positive fluid balance may
not usefully improve tissue oxygenation and may be counterproductive.
Keywords
albumin, early goal-directed therapy, edemagenesis, perfusion, resuscitation
INTRODUCTION
Early goal-directed therapy (EGDT) has profound
effects on clinical outcomes in septic shock patients
[1,2,3]. Targeted fluid resuscitation relieves overt
tissue hypoxia; however, over-aggressive fluid
therapy has deleterious effects on patient outcomes.
We discuss goals of resuscitation, both in the early
(first 6 h) and in the later phases (672 h), measures
of organ perfusion, fluid responsiveness and the
consequences of tissue edema. Furthermore, we
explore new directions in early goal-directed
therapy and the choice of fluid therapy.
Fluid resuscitation has vexed intensivists for
many generations and until recently was guided
by expert opinion [4] and loosely based on the
1983 Packman and Rackow article [5] that explored
increases in pulmonary artery wedge pressure leading to an increase in stroke volume index and cardiac index. Ironically, the authors also found a very
poor correlation with wedge pressure and central
venous pressure (CVP); a debate that persists today.
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KEY POINTS
Early identification and fluid resuscitation of septic
shock patients improves inadequate oxygen delivery
and mortality.
Fluid resuscitation should be aimed at the least amount
of fluid and lowest CVP to achieve an improvement in
end organ perfusion (improved ScvO2, lactate or urine
output).
Dynamic measure of fluid responsiveness should be
used prior to any volume resuscitation.
Fluid restrictive strategies have shown improved
outcomes in acute lung injury, kidney injury and
survival in septic shock patients.
Albumin provides a higher CVP, MAP with a lower
overall fluid balance in patients with sepsis and
improved survival in those patients with septic shock.
correct the initial phase of intravascular hypovolemia and inadequate oxygen delivery; however, care
has to be taken not to aggravate the second phase of
tissue injury by excessive fluid administration.
ENDPOINTS OF RESUSCITATION
A common fallacy in septic patients is the notion that
fluid resuscitation has succeeded when a number
is reached. The Rivers et al. trial taught us that a timesensitive protocolized approach based on numerical
goals improves outcomes. Yet, this approach bypasses crucial questions that must be addressed
during fluid resuscitation. First, is end organ perfusion adequate (so that additional fluid may not
be necessary)? Second, is the patient fluid responsive?
Third, what is the cost of giving additional fluids?
Fluid resuscitation early in the management of
septic shock is aimed at improving cardiac output.
Although much maligned over its poor correlation
with fluid responsiveness, central venous access and
its transduced pressure still exist as part of the initial
resuscitation [7]. The EGDT trial used a CVP of
8 mmHg or less to trigger an additional volume bolus
during the initial 6 h. The Surviving Sepsis Campaign
(SSC) guidelines propose a goal CVP of 812 mmHg
and further suggest consideration of a CVP of
1215 mmHg in patients who are mechanically
ventilated, or have known preexisting decreased
ventricular compliance, increased abdominal pressure or pulmonary arterial hypertension [7]. But this
higher CVP comes at the cost of increased tissue
edemagenesis, as described by the Starling equation,
so confirmation that a higher CVP increases oxygen
delivery and improves organ perfusion and function
is required.
Organ perfusion
The initial profile of sepsis has components of all
varieties of shock, but is often dominated by a
picture of a hypodynamic state with low stroke
volume. Only after adequate volume resuscitation,
does a vasodilatory state with low vascular resistance
emerge. The change also may include macrovascular-to-microvascular shunting and can be associated
with a histotoxic hypoxia component, elements of
which are difficult to identify.
The mean arterial pressure is the driving pressure for perfusion for most organs and, although
autoregulated in tissues such as brain and kidney,
when it declines below a lower limit, flow becomes
dependent on the MAP [8]. Small studies found no
benefit to higher MAP goals in terms of arterial
lactate, urinary output or splanchnic perfusion
[9]. The sepsis and mean arterial pressure trial
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Intravenous fluids
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FLUID RESPONSIVENESS
Now well documented is the inability of the CVP
to predict volume responsiveness. CVP is often
thought of as a surrogate for right ventricular enddiastolic volume which, in turn, is an indicator of
preload responsiveness. The flaw lies not only in the
curvilinear shape of the ventricular diastolic pressurevolume curve, but also in alterations in ventricular compliance that occur during critical illness
due to pressures transmitted from adjacent compartments. Mark and Cavallazzi [21] performed a metaanalysis of 43 studies from the ICU and operating
room and found a correlation coefficient between
baseline CVP and change in stroke volume index
and cardiac index of 0.18, indicating essentially
no relationship.
A common approach in the ICU is a fluid challenge. Osman et al. [22] evaluated 150 fluid
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FLUID CONSEQUENCES
Recent evidence is emerging, suggesting that overexuberant fluid resuscitation is detrimental. Boyd
et al. [14] demonstrated higher mortality with a
more positive fluid balance at 12 h and day 4. Lowest
mortality at 12 h was observed in those with a CVP
less than 8 mmHg, followed by 812 mmHg and
lastly greater than 12 mmHg had the highest
mortality. No correlation between CVP and fluid
balance was seen on days 14. The fluid expansion
as supportive therapy trial group explored fluid
bolus therapy versus no fluid bolus therapy in
African children admitted to hospitals with severe
febrile illness and impaired perfusion. The trial [32]
was stopped early after preliminary results showed
an increased 48-h and 4-week mortality in the fluid
bolus group. Post-trial exploration revealed that
despite a greater perfusion increase at 1 h in the
bolus arm, a higher proportion of terminal events
were caused by cardiovascular collapse at 48 h [33].
Retrospective review of the Acute Respiratory
Distress Syndrome Network ventilator-tidal volume
trial revealed that negative cumulative fluid balance
at 4 days was associated with more ventilator and
ICU free days and lower odds ratio of mortality [34].
Another prospective trial in patients with acute lung
injury found a conservative strategy of fluid management improved oxygenation and shortened
mechanical ventilation and ICU care [35]. A number
of studies looking at restrictive versus liberal strategies of fluid administration perioperatively have
shown lower rates of postoperative complications
and mortality in the former [36,37].
Sepsis-induced acute kidney injury (AKI) is not
only the result of hypoperfusion, but the interaction
between inflammation and oxidative stress, microvascular dysfunction and adaptive changes in tubular
epithelium [38]. A recent retrospective study looking
at kidney injury and hemodynamics found that a
higher CVP was associated with risk of developing
new or persistent AKI [39 ,40]. Analysis of the Sepsis
Occurrence in Acutely Ill Patients trial showed that in
patients with AKI, mean fluid balance remained
an independent risk factor for mortality [41]. In
&
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Intravenous fluids
the Randomized Evaluation of Normal vs. Augmented Level study in critically ill patients, a negative
mean daily fluid balance was associated with
increased renal replacement free days, ICU free days
and survival [42].
In summation, we are left with the need for
rapid diagnosis and early fluid resuscitation,
possibly primarily to relieve overt tissue hypoxia.
Beyond the initial fluid loading during the first
612 h, further positive fluid balance may be counterproductive. EGDT, now in its teenage years, is still
being questioned; however, there can be no doubt
that an imperative to diagnose and respond quickly
to septic patients is vital to their survival. Perhaps, it
is necessary to make a clear distinction between
fluid resuscitation during the first 6 h and the following 672 h in which the end-point goals are very
different and are based on clear evidence that further fluids will improve organ function.
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CHOICE OF FLUIDS
Although the need for early fluid resuscitation in
septic patients is accepted, the choice of fluid therapy
remains controversial. Crystalloids include various
salt concentrations of isotonic saline (0.45%, 0.9%,
3%) and the balanced salt solutions (Hartmans,
Ringers lactate, PlasmaLyte). Crystalloids are inexpensive, rapidly expand the intra and extravascular
fluid compartments, improve end organ perfusion
and have minimal risks of anaphylactoid reactions
[45]. The colloids are a heterogeneous group of fluids,
including albumin, gelatins, hydroxyethyl starch
(HES) and dextran containing fluids. Colloids rapidly
improve intravascular volume and oncotic pressure;
thereby resuscitation may require less time and volume. Colloid resuscitation can improve oxgygen
transport, myocardial contractility and cardiac
output [46]; however, until recently no data have
clearly demonstrated their superiority in critically ill
patients in terms of pulmonary edema, length of stay
or mortality [47].
The Cochrane review [48] from 1998 compared
albumin to crystalloids in 30 randomized controlled
trials in critically ill patients with hypovolemia,
burns or hypoalbuminemia and found that the
pooled relative risk of death was significantly higher
with albumin. The crystalloid versus hydroxyethyl
starch trial compared crystalloid versus HES and
found no difference in 90-day mortality, but despite
an overall lower rate of AKI there was more need for
renal replacement therapy in the HES group [49].
The 6S trial group compared hydroxyethyl starch to
Ringers acetate in patients with severe sepsis for
ICU fluid resuscitation [50]. The group that received
HES had an increased risk of death at 90 days and
were more likely to require renal replacement
therapy.
The saline versus albumin fluid evaluation trial
compared albumin to saline for initial fluid resuscitation in ICU patients and showed no difference in
the rates of organ failure, ICU time, renal replacement or mortality [47]. However, when the investigators performed a subgroup analysis of patients
with severe sepsis the adjusted odds ratio for death
was 0.71 (95% CI: 0.520.97; P 0.03) for albumin
[51]. The CRISTAL trial compared a number of
colloids to crystalloids as part of a multicountry
collaboration to assess primarily death at 28 days
and a number of secondary outcomes [52]. Overall,
there was no difference at 28 days; however, 90-day
mortality was lower among patients receiving
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&&
CONCLUSION
Despite decades of research into mechanisms and
many failed trials of therapeutics, mortality from
septic shock still remains shockingly high. EDGT
was one of the first modalities to provide some
benefit, yet questions remain whether they are
the right goals. There can be no question that early
identification and adequate fluid resuscitation is
crucial and that over-aggressive fluid resuscitation
leads to complications; however, where that breaking point is remains unclear.
Acknowledgements
Support: Canadian Institutes of Health Research.
Conflicts of interest
Both authors state no conflict of interest.
1. Rivers E, Nguyen B, Havstad S, et al., Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis
and septic shock. N Engl J Med 2001; 345:13681377.
2. Jones AE, Brown MD, Trzeciak S, et al., Emergency Medicine Shock Research
Network Investigators. The effect of a quantitative resuscitation strategy on
mortality in patients with sepsis: a meta-analysis. Crit Care Med 2008;
36:27342739.
3. Russell JA, Walley KR, Singer J, et al., VASST Investigators. Vasopressin
versus norepinephrine infusion in patients with septic shock. N Engl J Med
2008; 358:877887.
4. Guidelines for the management of severe sepsis and septic shock. The
International Sepsis Forum. Intensive Care Med 2001; 27 Suppl 1:S8092.
5. Packman MI, Rackow EC. Optimum left heart filling pressure during fluid
resuscitation of patients with hypovolemic and septic shock. Crit Care Med
1983; 11:165169.
6. Early Goal-Directed Therapy Collaborative Group of Zhejiang Province. [The
effect of early goal-directed therapy on treatment of critical patients with
severe sepsis/septic shock: a multicenter, prospective, randomized, controlled study]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2010; 22:331334.
7. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012.
Intensive Care Med 2013; 39:165228.
8. Lamia B, Chemla D, Richard C, Teboul JL. Clinical review: interpretation of
arterial pressure wave in shock states. Crit Care 2005; 9:601606.
9. LeDoux D, Astiz ME, Carpati CM, Rackow EC. Effects of perfusion pressure
on tissue perfusion in septic shock. Crit Care Med 2000; 28:27292732.
10. Asfar P, Meziani F, Hamel JF, et al., SEPSISPAM Investigators. High versus
&&
low blood-pressure target in patients with septic shock. Engl J Med 2014;
370:15831593.
Important recent paper showing MAP goals of 6570 mmHg compared to 80
85 mmHg with same outcome in septic shock patients.
11. Jhanji S, Stirling S, Patel N, et al. The effect of increasing doses of norepinephrine on tissue oxygenation and microvascular flow in patients with septic
shock. Crit Care Med 2009; 37:19611966.
12. Pope JV, Jones AE, Gaieski DF, et al., Emergency Medicine Shock Research
Network (EMShockNet) Investigators. Multicenter study of central venous
oxygen saturation (ScvO(2)) as a predictor of mortality in patients with sepsis.
Ann Emerg Med 2010; 55:4046.
13. Wacharasint P, Nakada TA, Boyd JH, et al. Normal-range blood lactate
concentration in septic shock is prognostic and predictive. Shock 2012;
38:410.
14. Boyd JH, Forbes J, Nakada TA, et al. Fluid resuscitation in septic shock: a
positive fluid balance and elevated central venous pressure are associated
with increased mortality. Crit Care Med 2011; 39:259265.
15. Levy MM, Dellinger RP, Townsend SR, et al., Surviving Sepsis Campaign. The
Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Crit Care Med
2010; 38:367374.
16. Nguyen HB, Kuan WS, Batech M, et al. Outcome effectiveness of the severe
sepsis resuscitation bundle with addition of lactate clearance as a bundle
item: a multinational evaluation. Crit Care 2011; 15:R229.
17. Lee SW, Hong YS, Park DW, et al. Lactic acidosis not hyperlactatemia as a
predictor of in hospital mortality in septic emergency patients. Emerg Med J
2008; 25:659665.
18. Jones AE, Shapiro NI, Trzeciak S, et al., Emergency Medicine Shock Research
Network (EMShockNet) Investigators. Lactate clearance vs central venous
oxygen saturation as goals of early sepsis therapy: a randomized clinical trial.
JAMA 2010; 303:739746.
19. Vernon C, Letourneau JL. Lactic acidosis: recognition, kinetics, and associated prognosis. Crit Care Clin 2010; 26:255283.
20. Puskarich MA, Trzeciak S, Shapiro NI, et al., Emergency Medicine Shock
Research Network (EMSHOCKNET). Prognostic value and agreement of
achieving lactate clearance or central venous oxygen saturation goals during
early sepsis resuscitation. Acad Emerg Med 2012; 19:252258.
21. Marik PE, Cavallazzi R. Does the central venous pressure predict fluid
responsiveness? An updated meta-analysis and a plea for some common
sense. Crit Care Med 2013; 41:17741781.
22. 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;
35:6468.
23. Marik PE, Monnet X, Teboul JL. Hemodynamic parameters to guide fluid
therapy. Ann Intensive Care 2011; 1:1.
24. Marik PE, Cavallazzi R, Vasu T, Hirani A. Dynamic changes in arterial waveform
derived variables and fluid responsiveness in mechanically ventilated patients:
a systematic review of the literature. Crit Care Med 2009; 37:2642
2647.
www.co-criticalcare.com
383
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Intravenous fluids
25. Blasco V, Leone M, Textoris J, et al. [Venous oximetry: physiology and
therapeutic implications]. Ann Fr Anesth Reanim 2008; 27:7482.
26. Feissel M, Michard F, Mangin I, et al. Respiratory changes in aortic blood
velocity as an indicator of fluid responsiveness in ventilated patients with
septic shock. Chest 2001; 119:867873.
27. Monnet X, Rienzo M, Osman D, et al. Esophageal Doppler monitoring predicts
fluid responsiveness in critically ill ventilated patients. Intensive Care Med
2005; 31:11951201.
28. Barbier C, Loubie`res Y, Schmit C, et al. Respiratory changes in inferior vena
cava diameter are helpful in predicting fluid responsiveness in ventilated
septic patients. Intensive Care Med 2004; 30:17401746.
29. Feissel M, Michard F, Faller JP, Teboul JL. The respiratory variation in inferior
vena cava diameter as a guide to fluid therapy. Intensive Care Med 2004;
30:18341837.
30. Monnet X, Osman D, Ridel C, et al. Predicting volume responsiveness by
using the end-expiratory occlusion in mechanically ventilated intensive care
unit patients. Crit Care Med 2009; 37:951956.
31. Keren H, Burkhoff D, Squara P. Evaluation of a noninvasive continuous
cardiac output monitoring system based on thoracic bioreactance. Am J
Physiol Heart Circ Physiol 2007; 293:H583H589.
32. Maitland K, Kiguli S, Opoka RO, et al., FEAST Trial Group. Mortality after fluid
bolus in African children with severe infection. N Engl J Med 2011;
364:24832495.
33. Maitland K, George EC, Evans JA, et al., FEAST Trial Groups. Exploring
mechanisms of excess mortality with early fluid resuscitation: insights from the
FEAST trial. BMC Med 2013; 11:68.
34. Rosenberg AL, Dechert RE, Park PK, Bartlett RH; NIH NHLBI ARDS
Network. Review of a large clinical series: association of cumulative
fluid balance on outcome in acute lung injury: a retrospective review of
the ARDSnet tidal volume study cohort. J Intensive Care Med 2009; 24:35
46.
35. Wiedemann HP, Wheeler AP, Bernard GR, et al., National Heart, Lung, and
Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials
Network. Comparison of two fluid-management strategies in acute lung injury.
N Engl J Med 2006; 354:25642575.
36. Bundgaard-Nielsen M, Secher NH, Kehlet H. Liberal vs. restrictive perioperative fluid therapya critical assessment of the evidence. Acta Anaesthesiol Scand 2009; 53:843851.
37. Lobo SM, Ronchi LS, Oliveira NE, et al. Restrictive strategy of intraoperative
fluid maintenance during optimization of oxygen delivery decreases major
complications after high-risk surgery. Crit Care 2011; 15:R226.
38. Gomez H, Ince C, De Backer D, et al. A unified theory of sepsis-induced acute
kidney injury: inflammation, microcirculatory dysfunction, bioenergetics, and
the tubular cell adaptation to injury. Shock 2014; 41:311.
39. Legrand M, Dupuis C, Simon C, et al. Association between systemic hemo&
dynamics and septic acute kidney injury in critically ill patients: a retrospective
observational study. Crit Care 2013; 17:R278.
New data emerging on role of fluid overload and kidney injury.
384
www.co-criticalcare.com
40. Teixeira C, Garzotto F, Piccinni P, et al., For the NEFROlogia e Cura INTensiva
(NEFROINT). Fluid balance and urine volume are independent predictors of
mortality in acute kidney injury. Crit Care 2013; 17:R14.
41. Payen D, de Pont AC, Sakr Y, et al., Sepsis Occurrence in Acutely Ill Patients
(SOAP) Investigators. A positive fluid balance is associated with a worse
outcome in patients with acute renal failure. Crit Care 2008; 12:R74.
42. Bellomo R, Cass A, Cole L; RENAL Replacement Therapy Study Investigators. An observational study fluid balance and patient outcomes in the
Randomized Evaluation of Normal vs. Augmented Level of Replacement
Therapy trial. Crit Care Med 2012; 40:17531760.
43. Ranieri VM, Thompson BT, Barie PS, et al. Drotrecogin alfa (activated) in
adults with septic shock. N Engl J Med 2012; 366:20552064.
44. Yealy DM, Kellum JA, Huang DT; ProCESS Investigators. A randomized trial of
protocol-based care for early septic shock. N Engl J Med 2014; 370:1683
1693.
45. Choi PT, Yip G, Quinonez LG, Cook DJ. Crystalloids vs. colloids in fluid
resuscitation: a systematic review. Crit Care Med 1999; 27:200210.
46. Hankeln K, Radel C, Beez M, et al. Comparison of hydroxyethyl starch and
lactated Ringers solution on hemodynamics and oxygen transport of critically
ill patients in prospective crossover studies. Crit Care Med 1989; 17:133
135.
47. Finfer S, Bellomo R, Boyce N, et al., SAFE Study Investigators. A comparison
of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J
Med 2004; 350:22472256.
48. Cochrane Injuries Group Albumin Reviewers. Human albumin administration
in critically ill patients: systematic review of randomised controlled trials. BMJ
1998; 317:235240.
49. Phillips DP, Kaynar AM, Kellum JA, Gomez H. Crystalloids vs. colloids: KO at
the twelfth round? Crit Care 2013; 17:319.
50. Perner A, Haase N, Guttormsen AB, et al., Scandinavian Critical Care Trials
Group. Hydroxyethyl starch 130/0.42 versus Ringers acetate in severe
sepsis. N Engl J Med 2012; 367:124134.
51. Finfer S, McEvoy S, Bellomo R, et al., SAFE Study Investigators. Impact of
albumin compared to saline on organ function and mortality of patients with
severe sepsis. Intensive Care Med 2011; 37:8696.
52. Annane D, Siami S, Jaber S, et al., CRISTAL Investigators. Effects of fluid
resuscitation with colloids vs crystalloids on mortality in critically ill patients
presenting with hypovolemic shock: the CRISTAL randomized trial. JAMA
2013; 310:18091817.
53. Caironi P, Tognoni G, Masson S, et al., ALBIOS Study Investigators. Albumin
&&
replacement in patients with severe sepsis or septic shock. N Engl J Med
2014; 370:14121421.
Albumin to achieve an increase in serum albumin levels improves mortality in septic
shock patients, but not those with lesser severity.
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; 340:409417.
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