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Ubaidur RahamanSenior Resident, Critical CareMedicineS.G.P.G.I.M.S.
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John H. Boyd, Jason forbes, Taka Aki Nakada, Keith R Walley, James A. Russell.
Fluid resuscitation in septic shock: A positive fluid balance and elevated
central venous pressures are associated with increased mortality.Crit Care Med 2011; 39(2)
Objective
To determine whether central venous pressure and fluid balance after resuscitation
for shock are associated with mortality
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Intravenous fluids are important component of resuscitation in septic shock
EGDT and Survival Sepsis Guidelines have set a target for fluid administration
Background
How much?
When should I stop
Positive fluid balance
Prolong mechanical ventilation
Increased hospital stay
Increased mortality
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Study design and methodology
Retrospective review of VAsopressin in Septic Shock Trial (VASST) study data,
Review of use of IV fluid during first 4 days
Outcome measures and endpointsFluid balance in the first 12 hours of resuscitation and during the next 4 days
Daily central venous pressure monitoring
VASST study was chosen for analysis
no mandatory fluid administration protocol,providing opportunity for studying prevalent practice of fluid administration
28 day mortality.
Two investigators of this study
James A. Russell and Keith R. Walley were also investigators in VASST study
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Prospective, randomized, interventional, double blind trail
Conducted
between July 2001- April 2006
in 27 centers in Canada, Australia and United States
778 patients, > 16 years ageHaving septic shock and receiving minimum of 5 gm of NE/minute
Vasopressin in Septic Shock Trail (VASST)N Eng J Med 2008; 358:9:877-887
Vasopressin versus Norepinephrine Infusion in Patients with Septic ShockJames A. Russell, Keith R. Walley, Joel Singer, Anthony C. Gordon, Paul C. Hebert, James Cooper, Cheryl L. Holmes, Sangeeta Mehta, John T.
Granton, Michelle M. Storms, Deborah J. Cook, Jeffery J. Pressneill, Dieter Ayers, for the VASST investigators
Patients were divided into 2 groups
blinded Vasopressin
0.01-0.03U/min In addition to open label vasopressorsblinded NE
5-15g/min
Both groups were comparable in demographic and baseline characteristics including
Comorbidity, severity of illness, and sepsis treatment and ventilation supports
continued
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Vasopressin in Septic Shock Trail (VASST)N Eng J Med 358:9:877-887
Vasopressin versus Norepinephrine Infusion in Patients with Septic ShockJames A. Russell, Keith R. Walley, Joel Singer, Anthony C. Gordon, Paul C. Hebert, James Cooper, Cheryl L. Holmes, Sangeeta Mehta, John T.
Granton, Michelle M. Storms, Deborah J. Cook, Jeffery J. Pressneill, Dieter Ayers, for the VASST investigators
End poing
Mortalilty rate 28 days after start of infusions
Conclusions
Low dose vasopressin did not reduce mortality rate as compared to NEamong patients with septic shock who were on NE
Subgroup analysisPatients with less severe septic shock ( receiving NE 5-14g/min),
mortality rate was lower in Vasopressin group than in NE group at 28 days.
( 26.5% vs. 35.7%, P=0.05)
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Statistical analysis
After correction of age and severity of illness, patients were divided into:
a) 4 fluid balance quartiles.
b) 3 CVP groups- 12
Survival analysis performed using Cox Stratified survival analysis
and regression analysis with Breslow method of Ties.
Hazard ratio for death were calculated relative to
(a) quartile 4 fluid balance; (b) central venous pressure >12 mmHg group,
using Cox proportional hazards.
Difference in fluid between survivors and non survivors was
analyzed using Mann- Whitney rank sum test.
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Daily fluid intake, urine output and
fluid balance at 12 hours and days1-4
Cumulative daily fluid intake, urine output
and fluid balance at 12 hours and days1-4
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Fluid intake, urine output, and net fluid balance (ml)
at 12 hours and day 4
Quartile 1 Quartile 2 Quartile 3 Quartile 4
At 12
hours
Intake 2900(2050-3900)
4520
(3700-5450)
6110
(5330-7360)10,100
(8430-12,100)
Output 2200(1100-3920)
1590
(960-2560)
1180
(600-2070)1260
(600-2400)
Balance 2880 4900
3
1/2
(-132-1480) (2510-3300) (4290-5530) (7110-10,100)
At
Day 4
Intake 16,100(12,800-19,700)
18,500
(15,700-22,500)
22,800
(19,700-26,700)30,600
(26,200-36,000)
Output 14,600(11,500-20,100)
11,000(8210-14,500)
9960(6940-12,900) 8350(5100-12,300)
Balance 1560(-723-3210)
8120
(6210-9090)
13,000
(11,800-14,700)20,500
(17,700-24,500)
11
2
1/2
13
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Cox survival curves forFluid balance quartiles
adjusted for age, APACHE II score and dose of NE
At 12 hours At day 4
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Hazard ratio fordeath according to fluid balance quartiles
Fluid balance Group Adjusted Hazard ratio vs quartile 4
12 hours
Quartile 1 0.569 (0.405-0.799)
Quartile 2 0.581 ( 0.414-0.816)
uar e . (0.562-1.033)
Day 4
Quartile 1 0.466 (0.299-0.724)
Quartile 2 0.512 (0.339-0.775)
Quartile 3 0.739 (0.503-1.087)
Hazard ratio are shown with 95% CI
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Positive fluid balance
Predicts mortality at 12 hours as well as at day 4
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Linear regression analysis for
correlation of fluid balance with CVP and dose of NE
CVP NE
at 12 hours
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Linear regression analysis for
correlation of fluid balance with CVP and dose of NE
CVP NE
at Day 4
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Positive fluid balance
Correlates modestly with CVP and dose of NE at 12 hours
but not at day 4.
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Cox survival curves for CVPadjusted for age, APACHE II score and dose of NE
At 12 hours At Day 4
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Hazard ratio fordeath according to CVP group
CVP Group Adjusted Hazard ratio vs
CVP > 12 mmHg
12 Hours
CVP < 8 mmHg 0.606 ( 0.363-0.913)
CVP 8-12 mmHg 0.762 ( 0.562-0.943)
Day 4
CVP < 8 mmHg 0.903 ( 0.484-1.686)
CVP 8-12 mmHg 0.764 ( 0.542-1.078)
Hazard ratio are shown with 95% CI
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A CVP
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12 hours fluid balance:
Survivors vs non survivors within CVP groups
CVP Group
Net fluid balance ( ml)
pSurvivors Non survivors
All patients 3444 (1861-5984) 4429 (2537-6560) 12 mmHg 3975 (2387-6614) 5237 (3140-7773) < 0.001
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Though at 12 hours less positive fluid balance was associated with lower mortality
overall
But in CVP < 8mmHg: reverse was true
(survivors tended towards a more positive fluid balance).
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AUTHORS
DISCUSSIONAnd
CONCLUSIONS
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A more positive fluid balance early in resuscitation and cumulatively over 4 days
is associated with an increased mortality.
.
CVP becomes unreliable marker of fluid responsiveness as well as
fluid balance after 12 hours.
Optimal survival occurred with a positive fluid balance ofapproximately 3 L at 12 hours.
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CVP achieved at 12 hours
12 mmHg- 62% of patients
SSG appeared in 2004 ( VASST study started enrollment in 2001)
Previous guidelines defined limit of fluid resuscitation as pulmonary edema.
Belief that patient might be having reduced ventricular compliance,
needing higher CVP (>12).
Why EGDT target CVP was overshot
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CVP not indicator of volume status
On oin Chan es in ventricular com liance
Ongoing changes in lung and thoracic compliance and resultant changes
in mechanical ventilatory support
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Mechanism of positive fluid balance leading to increased mortality
Increased EVLW- ALI and increased WOB- prolonged mechanical ventilation.
Delayed renal recovery and renal associated mortality.
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Positive fluid balance and mortality- when compared to EGDT study
VASST study EGDT study
12/6h
Intake 2900-10,100 5000 vs 3500EGDT vs standard arm
Day 4 Intake 16,100- 30,600 13,443 vs 13,358EGDT vs standard arm
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My
DISCUSSION
CONCLUSIONS
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Study strength number of patients- 778
Statistical analysis
Study limitations, weakness, potentials for bias
Retrospective nature
Type of fluid, crystalloid or colloid not documented.
Unable to decide whether fluid balance and CVP are simply
markers of Severity of illness or independently affect outcome
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Applicability and impact on intensive care physicians
good applicability and impact
But
Each patient is unique in dysfunction of cardiovascular, lung and renal physiology
and even in same patient this derangement is dynamic with time
so confusion will prevail- to give or not to give, how much to give, when not to give
Additional thoughts or comments
Fluid is not always an answer to optimize hemodynamics and perfusion,
as PEEP is not to improve oxygenation
Students conclusions and recommendations
A prospective randomized trail of conservative vs liberal fluid strategy in
septic shock is required to prove that whetherpositive fluid balance is
marker of SOI or administration of excessive fluid causes mortality.
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CHEST 2000; 117:17491754
Negative Fluid Balance Predicts Survival in Patients With Septic Shock*
A Retrospective Pilot StudyFadi Alsous, Mohammad Khamiees, Angela DeGirolamo, Yaw Amoateng-Adjepong, Constantine A.
Manthous
Retrospective study
36 patients, age16-85 years with septic shock
Patient undergone dialysis prior to admission not included
All 11 patients who achieved a negative balance of > 500 mL on 1 of the first 3 days
5 of 25 patient who failed to achieve a negative fluid balance of > 500 mL by day 3
of treatment survived
that negative fluid balance achieved in any of the first 3 days of septic shock portends
a good prognosis
Non survivors had higher mean APACHE II score and higher first day SOFA scores
were more likely to require vasopressors and mechanical ventilation
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N Engl J Med 2006;354:2564-75
Comparison of Two Fluid- Management Strategies in Acute Lung InjuryThe National Heart, Lung and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network
Randomized controlled prospective trail
1000 patients with ALI
Explicit protocol for fluid management was applied for 7 days
Both groups were comparable in baseline characteristics including comorbidity,
severity of illness and hemodynamics
Mean cumulative fluid balance during first 7 days
Conservative group: -137491 ml
Liberal strategy group: 6992502 ml
continue
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conservative strategy group during first 28 days had
Improved oxygenation index and lung injury score
Higher ventilator free days
Lesser ICU stay
N Engl J Med 2006;354:2564-75
Comparison of Two Fluid- Management Strategies in Acute Lung InjuryThe National Heart, Lung and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network
Without increasing incidence or prevalence of
shock during the study
or
use of dialysis during first 60 days
No significant difference in 60 day mortality
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Crit Care Med. 2006 Feb;34(2):344-53.
Sepsis in European intensive care units: results of the SOAP study.Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, Moreno R, Carlet J, Le Gall JR, Payen D;
Sepsis Occurrence in Acutely Ill Patients Investigators.
Prospective multicenter observational study
All new adult admissions to a participating intensive care unit between May 1 and 15, 2002
3,147 adult patients, median age- 64 yrs
positive fluid balance was among the strongest prognostic factors for death
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Kidney Int 2009;76:422-427
Fluid accumulation, survival and recovery of kidney function in critically ill
patients with acute kidney injury.Bouchard J, soroko SB, Chertow GM, Jonathan H, T. Alp I, Ravindra L. Mehta,
Program to Improve Care in Acute Renal Disease ( PICARD study Group)
Prospective multicenter observational study
618 adult critically ill patients with AKI
Fluid overload- increase in body weight 10% of baseline
Fluid overloaded patients had
significantly higher APACHE III score, SOFA score,
Mechanical ventilation and vasopressor requirements
Mortality at 30 days and hospital discharge was significantly higher in patients with fluid overload
continue
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Kidney Int 2009;76:422-427
Fluid accumulation, survival and recovery of kidney function in critically ill
patients with acute kidney injury.Bouchard J, soroko SB, Chertow GM, Jonathan H, T. Alp I, Ravindra L. Mehta,Program to Improve Care in Acute Renal Disease ( PICARD study Group)
In survivors percentage fluid accumulation was lower
at AKI diagnosis ( statistically non significant)
at dialysis initiation and cessation in patients requiring RRT
Patients who did not require RRT
Incremental increase in mortality, with proportional increase in days with fluid overload, after AKI diagnosis
In dialyzed patients, mortality increased, in relation to proportion of dialysis days with fluid overload
Patients with fluid overload at dialysis initiation, who ended dialysis without fluid overload, had better survival
Patients with fluid overload at peak creatinine level, were less likely to recover kidney function
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So first interpret it, then assimilate it and finallyimplement it
7KDQN
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