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Fluid is a
Drug!Sean M Bagshaw, MD, MSc
Division of Critical Care Medicine
Faculty of Medicine and Dentistry
University of Alberta
Critical Care Canada ForumSunday, November 10, 2013
Disclosures
• Salary support from Canada/Alberta government
• Grant support from Canada/Alberta government
• Speaking honoraria/travel from academic
institutions/medical centers
• Speaking/consulting/travel from:
– Gambro Inc., Alere Inc., Spectral Diagnostics Inc.
Learning Objectives
• What I will try to convince you:
– There are phases to Fluid Therapy in critical
illness
– Fluid Therapy should be goal directed
– Fluid has cumulative and toxic adverse
effects
– Treating fluid as a DRUG will guide optimal
dosing and reduce toxicity
Fluid
Balance
Time
Maintenance/
Homeostasis Removal/
Recovery
R
E
S
U
C
I
T
A
T
I
O
N
Phases of Fluid Therapy
I II III
Goldstein et al J Int Care Med 2013
Stabilization De-escalation
Rivers et al NEJM 2001
Preload
Perfusion
Tissue hypoxia• Identification/diagnosis
• Therapeutic Monitoring
– Individualized
• Early/Aggressive Initial
Resuscitation
– Hemodynamic stabilization
– Shock reversal
– Then ~ REASSESS!!
Phase I of Fluid
Therapy Paradigm
Jansen et al AJRCCM 2010
n=348
Jansen et al AJRCCM 2010
n=348
Jansen et al AJRCCM 2010
Hospital mortality adj-HR 0.61 (95% CI, 0.43-0.87, p=0.006)
Boyd et al CCM 2011
n=778
Phase II of Fluid Paradigm
• Maintenance of fluid balance homeostasis and/or prevention of worsening (+/-unnecessary) fluid overload
– Assess need for all fluids (i.e., nutrition, medications, blood products)
– Assess ability to maintain fluid balance (i.e., AKI)
– Assess patient’s current fluid accumulation status
• Retrospective cohort study (n=212) adult patients with ALI
+ septic shock
• Exposure:
– Adequate Initial Fluid Resuscitation (AIFR)
• >20 ml/kg bolus before vasopressors
• CVP >8 mmHg after vasopressors within 6 hours
– Conservative Late Fluid Management (CLFM)
• Even to (-) fluid balance for at least 2 consecutive days in the first 7 days after sepsis onset
• Primary Outcome: hospital survival
Murphy et al CHEST 2009
Survivors Non-Survivors p
Fluid within 6 hr (mL/kg) 45.5 42.9 0.13
CVP measured (%) 92.0 70.1 <0.001
AIFR (%) 79.2 54.0 <0.001
FB (7-day) (mL) 8,062 13,694 <0.001
CLFM (%) 72.8 34.5 <0.001
FB (ICU) (%) 8,037 19,335 <0.001
FB (Hospital) (%) 6,603 22,231 <0.001
Murphy et al CHEST 2009
Daily Fluid Balance Cumulative Fluid Balance
Murphy et al CHEST 2009
18.3
41.9
56.6
77.1
0
10
20
30
40
50
60
70
80
90
AIFR/CLFM AIFR/No CLFM No AIFR/CLFM No AIFR/No CLFM
Ho
spit
al
Mo
rtali
ty (
%)
Murphy et al CHEST 2009
AIFR not achieved ~ OR 4.94
CLFM not achieved ~ OR 6.13
Wiedemann et al NEJM 2006
Variable CON LIB p
Death (d 60) (%) 25.5 28.4 0.30
Ventilator-free
days (d 1-28)14.6 12.1 0.001
ICU-free days
(d 1-28)13.4 11.2 0.001
RRT (day 60) (%) 10 14 0.06
Percent Fluid Overload (%FO)
%FO = Σ [FLUID IN – FLUID OUT]
[Admission Weight (kg)]x 100
Goldstein et al Pediatrics 2001
Payen et al Crit Care 2008
Any ARF 36% (n=1120)
Early ARF 75% (n=842)
Late ARF 25% (n=278)
CRRT 25% (n=278)
Early AKI
Late AKI
No AKI
Mean fluid balance (L/24hr)
HR 1.21, 95%CI, 1.13-1.28, p<0.001
Grams et al CJASN 2011
Fluid balance (per L/day) on 60-day mortality
OR 1.61 (95% CI, 1.32-19.6, p<0.001)
CONSERVATIVE GROUP
•Less fluid!
•0.9L vs. 2.2L per day,
p<0.001
•6.0L vs. 10.2L 6-day
cumulative, p<0.001
n=306
• Fluid Removal ~ passive/active
• Should not be an emergency!
• Should facilitate weaning of mechanical support
• Should not predispose to iatrogenic hemodynamic
instability or organ injury
– Body has not evolved natural mechanisms to
remove excess ↑ Na+ and water
• “De-resuscitation” in MODS/AKI
Phase III of Fluid Paradigm
Fluid is a Drug!
Steps for Prescribing a Drug Prescribing Fluid Therapy
Define the clinical problem Hypovolemia
Fluid is a Drug!
Steps for Prescribing a Drug Prescribing Fluid Therapy
Define the clinical problem Hypovolemia
Specify the therapeutic objective Restore fluid deficit
Fluid is a Drug!
Steps for Prescribing a Drug Prescribing Fluid Therapy
Define the clinical problem Hypovolemia
Specify the therapeutic objective Restore fluid deficit
Verify the suitability of the drug Crystalloid or colloid
Fluid is a Drug!
Steps for Prescribing a Drug Prescribing Fluid Therapy
Define the clinical problem Hypovolemia
Specify the therapeutic objective Restore fluid deficit
Verify the suitability of the drug Crystalloid or colloid
Write a prescription to start the
drug
MD writes order, verified and
administered by RN
Fluid is a Drug!
Steps for Prescribing a Drug Prescribing Fluid Therapy
Define the clinical problem Hypovolemia
Specify the therapeutic objective Restore fluid deficit
Verify the suitability of the drug Crystalloid or colloid
Write a prescription to start the
drug
MD writes order, verified and
administered by RN
Monitor therapeutic response of
the drug
Hemodynamic/tissue perfusion
response, dose-response toxicity
Fluid is a Drug!
Steps for Prescribing a Drug Prescribing Fluid Therapy
Define the clinical problem Hypovolemia
Specify the therapeutic objective Restore fluid deficit
Verify the suitability of the drug Crystalloid or colloid
Write a prescription to start the
drug
MD writes order, verified and
administered by RN
Monitor therapeutic response of
the drug
Hemodynamic/tissue perfusion
response, dose-response toxicity
Write an order to discontinue the
drug
MD writes order, administered by
RN
Fluid is a Drug!
• How should we prescribe fluid therapy?
– Context specific/phase of critical illness
– Contingent on responsiveness/objective
– Existing evidence of overdose
• Prescription should be individualized
– Type/composition
– Dose/volume
• Prescription should be constantly reassessed
Not ALL hypotension needs fluid*
Maitland et al NEJM 2011
32 bags ≈ 9000 mg NaCl ≈
n=30 (15 mL/kg) 0.9% NS PL-148
Δ [Cl-] +6.9* +0.6
Δ [HCO3-] -4.0* -0.7
Δ BE -5.0* -1.2
Metabolic Acidosis is Iatrogenic!
0.9%NS
(n=26)
RL
(n=25)p
sCr (72 hr post-op) (µmol/L) 203 185 0.7
pH (end of surgery) 7.28 7.37 <0.001
[Cl-] (end of surgery) 111 106 <0.001
Metabolic acidosis (n, %) 8 (31) 0 (0) 0.004
[K+] > 6 mmol/L (n, %) 5 (19) 0 (0) 0.05
O’Malley et al Anesth Analg 2005
• Population: US surgical patients undergoing major GI
surgery
• Design: Retrospective observational cohort
– Prospectively defined patient population; study exposure and
endpoints; and analysis plan including risk adjustment using
multivariate regression modeling and propensity scoring
• Data Source:
– Premier Perspective Database (Jan 2005 – Dec 2009)
• Exposure: 0.9% saline vs. buffered solution (plasma-lyte)
• Outcome: All-cause mortality and morbidity events
Shaw et al Ann Surg 2012
Shaw et al Ann Surg 2012
Risk-Adjusted (Pre-Specified) Outcomes – All Patients
Shaw et al Ann Surg 2012
Investigations/interventions relative to metabolic acidosis
• 8 fold difference
in afferent
arteriolar diameter
within physiologic
chloride range
Hansen et al Hypertension 1998
Chowdhury et al 2012 Ann Surg
Serum Chloride Strong Ion Difference
Chowdhury et al 2012 Ann Surg
Renal Blood Flow ∆ Renal Cortex Perfusion
Yunos et al CCM 2011
VariableControl
(n=828)
Intervention
(n=816)P
Saline (L) 2411 52 <0.001
Gelatin (saline) (L) 538 0 <0.001
Hartmann’s (L) 469 3205 <0.001
Plasmalyte (L) 65 160 <0.001
Albumin 4% (saline) (L) 269 80 <0.001
Cl- /pt (mmol) 648 485 <0.001
↓ Cl- administered by 140,290 mmol
Yunos et al CCM 2011
VariableControl
(n=21,694)
Intervention
(n=19,807)P
[Na] > 156 mmol/L (%) 0.9 0.2 <0.001
BE <-5 mEq/L (%) 9.1 6.0 <0.001
pH <7.3 (%) 6.0 4.9 <0.001
BE >5 mEq/L (%) 25.4 32.8 0.01
pH >7.5 (%) 10.5 14.7 <0.001
Total Cost (USD) 15,077 3,915 <0.001
Yunos et al JAMA 2012
Incidence AKIControl
(n=760)
Intervention
(n=773)P
Stage 1 (n, %) 71 (9.0) 57 (7.4) 0.16
Stage 2 (n, %) 48 (6.3) 23 (3.0) 0.002
Stage 3 (n, %) 57 (7.5) 42 (5.4) 0.10
Stage 2/3 (n, %) 105 (14.0) 65 (8.4) <0.001
Adjusted OR (age, sex, APACHE II, diagnosis)
AKI 0.52 (95% CI, 0.37-0.75, p<0.001)
RRT 0.52 (95% CI, 0.33-0.81, p=0.004)
Outcomes 10% HES
(n=262)
RL
(n=275)
p
AKI (%) 91 (34.9) 62 (22.8) 0.002
RRT (%) 81 (31.0) 51 (18.8) 0.001
Transfusion (%) 199 (76.0) 189 (68.7) 0.06
VISEP Brunkhorst et al NEJM 2009
VISEP Brunkhorst et al NEJM 2009
Scandinavian Starch for Severe Sepsis
Septic Shock TrialScandinavian Critical Care Trials Group
6STRIAL
0
5
10
15
20
25
30
HES Ringer's
22
16
Mo
rtali
ty (
%)
RR 1.35; 95% CI, 1.01-1.80, p=0.044
0
10
20
30
40
50
60
HES Ringer's
51
43
Renal Replacement Therapy Death or RRT at 90-Days
RR 1.17; 95% CI, 1.01-1.36, p=0.039Perner et al NEJM 2012
Scandinavian Starch for Severe Sepsis
Septic Shock TrialScandinavian Critical Care Trials Group
6STRIAL
Kaplan Meier curves of survival censored at 90 days
Days
0 20 40 60 80
Su
rviv
al D
istr
ibu
tio
n F
un
ctio
n
0.0
0.2
0.4
0.6
0.8
1.0
Perner et al NEJM 2012
Myburgh et al NEJM 2012
n=7000
Myburgh et al NEJM 2012
6% HES 0.9% Saline p
RRT Utilization (%) 7.0 5.8 0.04
Adverse events (%) 5.3 2.8 <0.001
n=7000
Summary
• Fluid is a Drug ~ considering its toxic cumulative effects to guide optimal dosing may improve outcome
• Volume and Timing of Fluid are critical
• (Excessive) Fluid accumulation is bad – predictor of less favorable outcome
• Fluid type/composition can alter serum biochemical profile and contribute to qualitative toxic effects
• Need to better understand ideal strategies to either i)
use less or ii) (safely) mitigate and/or remove excess
extravascular fluid
Thank You For Your Attention!
Questions?
Acknowledgements
Stuart Goldstein
Anders Perner
