Journal Club

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Journal Club:

Journal Club Ubaidur Rahaman Senior Resident, Critical Care Medicine S.G.P.G.I.M.S. Lucknow, India

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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 or reduce? Positive fluid balance Prolong mechanical ventilation Increased hospital stay Increased mortality

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METHODS

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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 VASST study was chosen for analysis no mandatory fluid administration protocol , providing opportunity for studying prevalent practice of fluid administration Outcome measures and endpoints Fluid balance in the first 12 hours of resuscitation and during the next 4 days Daily central venous pressure monitoring 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 age Having septic shock and receiving minimum of 5  gm of NE/minute Patients were divided into 2 groups blinded Vasopressin 0.01-0.03 U/min In addition to open label vasopressors blinded NE 5-15 g/min Both groups were comparable in demographic and baseline characteristics including Comorbidity, severity of illness, and sepsis treatment and ventilation supports continued Vasopressin in Septic Shock Trail (VASST) N Eng J Med 2008; 358:9:877-887 Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock James 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

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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 Shock James 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 Conclusions Low dose vasopressin did not reduce mortality rate as compared to NE among patients with septic shock who were on NE End poing Mortalilty rate 28 days after start of infusions Subgroup analysis Patients with less severe septic shock ( receiving NE 5-14 g/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- <8, 8-12, >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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RESULT

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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

Fluid intake, urine output, and net fluid balance (ml) at 12 hours and day 4:

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 710 (-132-1480) 2880 (2510-3300) 4900 (4290-5530) 8150 (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) 3 1/2 11 2 1/2 13

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At 12 hours Cox survival curves for Fluid balance quartiles adjusted for age, APACHE II score and dose of NE At day 4

Hazard ratio for death according to fluid balance quartiles:

Hazard ratio for death 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) Quartile 3 0.762 (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

Linear regression analysis for correlation of fluid balance with CVP and dose of NE:

Linear regression analysis for correlation of fluid balance with CVP and dose of NE CVP NE at 12 hours

Linear regression analysis for correlation of fluid balance with CVP and dose of NE :

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.

Cox survival curves for CVP adjusted for age, APACHE II score and dose of NE :

Cox survival curves for CVP adjusted for age, APACHE II score and dose of NE At 12 hours At Day 4

Hazard ratio for death according to CVP group:

Hazard ratio for death 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 <8 mmHg at 12 hours is associated with improved survival, whereas it does not correlate on subsequent days.

12 hours fluid balance: Survivors vs non survivors within CVP groups:

12 hours fluid balance: Survivors vs non survivors within CVP groups CVP Group Net fluid balance ( ml) p Survivors Non survivors All patients 3444 (1861-5984) 4429 (2537-6560) <0.001 CVP < 8 mmHg 3015 (1296-4987) 2281 (802-5711) NS CVP 8-12 mmHg 2727 (1227-5491) 3112 (1559-4809) NS CVP >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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AUTHOR’S DISCUSSION And CONCLUSIONS

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A more positive fluid balance early in resuscitation and cumulatively over 4 days is associated with an increased mortality. But there is a point at which too little fluid is indeed harmful. CVP becomes unreliable marker of fluid responsiveness as well as fluid balance after 12 hours. Optimal survival occurred with a positive fluid balance of approximately 3 L at 12 hours.

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CVP achieved at 12 hours <8 mmHg-9% of patients 8-12 mmHg- 28% of patients >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 Ongoing Changes in ventricular compliance 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 12/6 hours Intake 2900-10,100 5000 vs 3500 EGDT vs standard arm Day 4 Intake 16,100- 30,600 13,443 vs 13,358 EGDT vs standard arm

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My DISCUSSION AND 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 whether positive fluid balance is marker of SOI or administration of excessive fluid causes mortality.

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REVIEW OF LITERATURE

CHEST 2000; 117:1749–1754 Negative Fluid Balance Predicts Survival in Patients With Septic Shock* A Retrospective Pilot Study Fadi Alsous, Mohammad Khamiees, Angela DeGirolamo, Yaw Amoateng-Adjepong, Constantine A. Manthous:

CHEST 2000; 117:1749–1754 Negative Fluid Balance Predicts Survival in Patients With Septic Shock* A Retrospective Pilot Study Fadi 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 of treatment survived 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

N Engl J Med 2006;354:2564-75 Comparison of Two Fluid- Management Strategies in Acute Lung Injury The National Heart, Lung and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network:

N Engl J Med 2006;354:2564-75 Comparison of Two Fluid- Management Strategies in Acute Lung Injury The 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: -137±491 ml Liberal strategy group: 6992±502 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 Without increasing incidence or prevalence of shock during the study or use of dialysis during first 60 days N Engl J Med 2006;354:2564-75 Comparison of Two Fluid- Management Strategies in Acute Lung Injury The National Heart, Lung and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network No significant difference in 60 day mortality

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.:

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 ; S epsis O ccurrence 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

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):

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 overloaded patients had significantly higher APACHE III score, SOFA score, Mechanical ventilation and vasopressor requirements Fluid overload- increase in body weight ≥ 10% of baseline Mortality at 30 days and hospital discharge was significantly higher in patients with fluid overload continue

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):

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 finally implement it Thank You