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Kuwait Medical Association Scientific Conference
Kuwait City
March 19, 2016
Kianoush B. Kashani, MD, FASN, FCCP
©2013 MFMER | 3401734-1
©2013 MFMER | 3401734-2
ARDS
Overview
Kuwait Medical Association
Scientific Conference
Kuwait City
March 19, 2016
Kianoush B. Kashani, MD, FASN, FCCP
©2013 MFMER | 3401734-3
Objectives
• Definition
• Pathophysiology
• Risk factors
• Prognosis
• Contemporary treatment
©2016 MFMER | 3498115-4
ARDS: “Lung Attack”
• Diffuse injury to the blood-gas barrier
• Alveolar flooding
• Inflammation
• Change in surfactant properties
• PaO2/FIO2 <300
• Bilateral infiltrates c/w edema
• Absence of left atrial hypertension
Goss et al: 2003; Ware et al: 2000; Bachofen et al: 1982; Rubenfeld, 2005
©2016 MFMER | 3498115-5
The Berlin Definition
Within 1 week of insult
New or worsening respiratory symptoms
Bilateral opacities
Chest imaging
Not explained by effusions, lobar/lung collapse, or
nodules
Respiratory failure not fully explained by
Cardiac failure
Origin of edema
Fluid overload
Objective assessment  echocardiography, etc.
Oxygenation
PEEP or CPAP 5 cm H2O
Mild
 200 mm Hg < Pao2/FIO2 300 mm Hg
Moderate
 100 mm Hg < Pao2/FIO2 200 mm Hg
Severe
 Pao2/FIO2 100 mm Hg
Timing
©2016 MFMER | 3498115-6
ARDS
• Incidence ~100/106/year
• ~200,000 patients annually
• 75,000 deaths
• 3.5 million hospital days
• High mortality (~40%)
• Morbidity
• ↓ Long-term quality of life
• ↑ Cost
©2016 MFMER | 3498115-7
Incidence of ARDS in Olmsted County,
Minnesota: Combined Effect?
Incidence of ALI per
100,000 person years
120
100
80
60
40
20
0
2001
2002
2003
2004
2005
2006
2007
2008
Year
Li et al: Am J Resp Crit Care, 2011
©2016 MFMER | 3498115-8
Systematic Changes
in Critical Care Delivery
Multiple
Transfusion,
N(%)2
Leukoreduction
CPOE1 Decision Support For
Restrictive Transfusion
Male Donor Predominant Plasma Transfusion
27(3)
Lung Protective
Ventilation
Initial tidal
volume3
27(3)
24(2)
Web based
teaching tool
10.6
34(3)
26(3)
Transfusion
12(1)
12(1)
12(1)
Respiratory therapy protocol
(limiting initial volume according to predicted body weight in all patients)
8.7
Sepsis Order Set
Electronic
surveillance
7.7
6.8
CPOE1 decision support
Paper order set
Sepsis Team
Standards of Care for
Inpatient Pneumonia
Mechanical Ventilation
MICU4 sepsis team
Appropriate empiric antibiotics within
4 hours of hospital admission
Doubled intensivist staffing in the MICU4
Sepsis Resuscitation
24-hour on-site intensivist
Inpatient Pneumonia Care
Intensivist Staffing
Rapid Response Team
Monitored
Laboratory and
Data
Imaging
2001
2002
Medication
Charting
2003
Nursing
Notes
2004
Only implementation selected units
Implemented in whole hospital
Physician
Notes
CPOE
Complete
Electronic Medical Records
2005
2006
2007
2008
Li et al: Am J Resp Crit Care, 2011
©2016 MFMER | 3498115-9
Pathophysiology
Acid aspiration
Chemical
Capillary stress failure
Direct – SARS, Influenza, RSV, PCP
Biological
Mechanical
Indirect – SIRS, reperfusion, IL2, TRALI
Membrane
Injury
+
Inflammation
Coagulation
Oxidative
stress
↑ Permeability 
Pulmonary Edema
$$_
QALY
©2016 MFMER | 3498115-10
ARDS Pathogenesis
“Multiple Hit” Hypothesis
Risk factors to  risk of ALI (2nd
hit):
Patient at risk (1st hit)
• Pneumonia
• Toxic inhalation
• Pancreatitis
• Aspiration
• Trauma
• Sepsis
• Shock
• Age
• SNPs
• Alcohol
• Tobacco
• Thoracic and vascular
surgery
• Preexisting lung disease
• Vasculitis
• Radiation
• Chemotherapy
HOSPITAL
ADMISSION
High tidal volume, transfusion,
delayed resuscitation, inappropriate
antibiotics, aspiration, high FiO2
ARDS
Oxidative stress
Inflammation
0h
Coagulation
3h
6h
Capillary permeability
24h
48h
Apoptosis
Alveolar clearance
No ARDS
Risk modifiers to  risk of ALI:
PEEP, modulators of oxidative
stress, inflammation and coagulation
ICU
ADMISSION
©2016 MFMER | 3498115-11
Risk factors
• Chronic alcohol use
• Absence of diabetes mellitus
• Smoking
• Hypoalbuminemia
• Acidosis
• Obesity
• Silent aspiration
• Multiple “hits”
• VILI
• FIO2
• RBC, Platelet & FFP transfusion
• Fluid overload
©2016 MFMER | 3498115-12
Prognosis
1.0
Surviving
0.8
0.6
0.4
Mortality
ICU
17%
Hospital
27%
6 months
39%
0.2
0.0
0
20
40
60
80
100
120
140
160
180
Days
M Yilmaz ,et al. Crit Care Med 2007
©2016 MFMER | 3498115-13
Impact of ARDS on high risk patients
1.0
0.8
Surviving
No ARDS
0.6
ARDS
0.4
0.2
0.0
0
1
2
3
4
5
Year
Biehl et al: SCCM, 2014
©2016 MFMER | 3498115-14
Follow-Up of ICU Survivors
Physical weakness is profound
Memory difficulties
PTSD a consequence of memory deficits
Withdrawn patient is the ICU
Depressed
Delirious
Under-recognized cognitive dysfunction
Relatives have problems too
Nurse and relative diary  as a post-ICU therapy
Current Opinion in Critical Care 13:508-513, 2007
©2016 MFMER | 3498115-15
©2016 MFMER | 3498115-16
Non-Invasive Ventilation
• NIV failure  ↑ mortality
• Only a brief (hours) trial with close supervision
• High flow nasal oxygen (Optiflow) maybe
preferable to NIV
• Predictors of NIV failure:
• Presence of shock
• Metabolic acidosis
• ↑ Severity of illness
• ↓ PaO2/FiO2
Delclaux C et al: JAMA; 284:2352, 2000; Rana et al: Crit Care, 10:R79, 2006
©2016 MFMER | 3498115-17
Principles of Lung Protective Ventilation
Low Vt
Low Ppl
Volume
Overdistension
Atelectasis
PEEP
Airway pressure
Avoid:
Over-distension injury
Expiratory collapse
Yilmaz M, Gajic O, Eur J Anesth, 2007
©2016 MFMER | 3498115-18
Preventing VILI
Lower tidal volumes
Traditional tidal volumes
0.6
450 mL
Mortality
0.5
350 mL
0.4
0.3
0.2
0.1
0.0
0.15-0.40
0.41-0.50
0.51-0.62
0.63-1.5
Quartile of Static Compliance
(mL/cmH2O per kg of predicted body weight)
Brower et al: NEJM, 1999
©2016 MFMER | 3498115-19
Modality of choice
• Assist controlled
• VC
• TV 6-8 ml/kg IBW
• Plateau pressure < 30 cmH2O
©2016 MFMER | 3498115-20
Management: TV
Cumulative rate
1.0
0.8
0.6
All (n=2255)
ARDS severity
0.4
Mild (n=672)
Moderate (n=1050)
Severe (n=533)
0.2
0.0
0
2
4
6
8
10
12
14
16
Tidal volume (mL/kg of predicted body weight)
Bellani et al: JAMA 315(8):788, 2016
©2016 MFMER | 3498115-21
Management: Plateau Pressure
Cumulative rate
1.0
0.8
0.6
All (n=735)
0.4
ARDS severity
Mild (n=196)
Moderate (n=362)
Severe (n=195)
0.2
0.0
10
15
20
25
30
35
40
45
Plateau pressure (cm H2O)
Bellani et al: JAMA 315(8):788, 2016
©2016 MFMER | 3498115-22
Plateau pressure (cm H2O)
Management: TV and PP
40
Mild (n=5)
Moderate (n=21)
Severe (n=30)
35
Mild (n=2)
Moderate (n=8)
Severe (n=12)
30
25
20
15
Mild (n=155)
Moderate (n=288)
Severe (n=140)
10
1
2
3
4
Mild (n=81)
Moderate (n=128)
Severe (n=45)
5
6
7
8
9 10 11 12 13 14 15
Tidal volume (mL/kg of predicted body weight)
Bellani et al: JAMA 315(8):788, 2016
©2016 MFMER | 3498115-23
Respir Care; 49(7):742, 2004
©2016 MFMER | 3498115-24
Barriers to Implementation of Lung
Protective Mechanical Ventilation
Adjusted OR (95% CI)
P Value
1.18 (1.02-1.38)
.028
NS
NS
1.40 (1.05-1.88)
.023
BMI per SD (7.3 kg/m2)
NS
NS
Height per SD (10 cm)
0.55 (0.48-0.63)
.0001
Weight, per SD (22 kg)
NS
NS
0.78 (0.67-0.92)
.003
Direct lung injury
NS
NS
Dialysis
NS
NS
AIDS
NS
NS
Radiographic lung injury score per SD (0.57)
0.83 (0.70-0.95)
.009
Non-volume-control ventilator mode
3.07 (1.78, 5.27)
.0001
Serum bicarbonate per SD (5.5 mmol/L)
0.83 (0.71-0.97)
.017
Duration of ICU stay (2 d)
0.84 (0.73-0.98)
.02
Age, per SD (16 y)
Sex, female
Race, which vs nonwhite
SAPS II, per SD (14)
Walkey et al: J Crit Care Volume 27, Issue 3, June 2012
©2016 MFMER | 3498115-25
©2016 MFMER | 3498115-26
Standardized Approach to
Severe Hypoxemia
• Step 1: Cover basics
• ABC
• Neuromuscular blockade
• FIO2 to 100%
• Basic assessment and stabilization
• Airway assessment
• Ventilator circuit
• Breath sounds
• Pulse
• Minimize oxygen consumption
©2016 MFMER | 3498115-27
Standardized Approach to
Severe Hypoxemia
• Step 2: Assessment
• CXR, ECHO, VBG, RM
• Shock (low SvO2) vs. shunt vs. both?
• Recruitability
• RV dysfunction
• Pulmonary hypertension
• PE
• Lobar atelectasis
• LV dysfunction
• Intracardiac shunt
©2016 MFMER | 3498115-28
Standardized Approach to
Severe Hypoxemia
• Step 3: Customized management
• Shock treatment based on type of shock
• Recruitable lungs
• Without shock  Higher PEEP
• With shock  Prone position
• Bronchoscopy for lobar atelectasis
• Inhaled vasodilators for pulmonary HTN
• ECMO
• VV for refractory pulmonary dysfx
• AV for refractory cardiopulmonary dysfx
©2016 MFMER | 3498115-29
Short-Term Paralysis
Early Severe ARDS
Probability of survival
1.0
0.8
Cisatracurium
0.6
Placebo
0.4
0.2
0.0
0
10
20
30
40
50
60
70
80
90
Days after enrollment
Papazian L, Forel J-M, Gacouin A, et al: Neuromuscular Blockers in
Early Acute Respiratory Distress Syndrome; New England Journal of Medicine;363(12):1107-16
©2016 MFMER | 3498115-30
HFO
• ~50-300 breaths / min
• Very low tidal volume
• “Open lung”
• Potentially
minimize VILI
• No proven
mortality benefit
Probability of survival
• Gas exchange by
convection
1.0
0.8
Control
0.6
0.4
HFOV
0.2
P=0.004 by log-rank test
0.0
0
15
30
45
60
Days since randomization
Ferguson et al NEJM 2013
©2016 MFMER | 3498115-31
Inhaled NO
Risk ratio (95% CI)
• Improves V/Q mismatch
 ↑ oxygenation
• Adjunctive treatment of
pulmonary hypertension
• No mortality benefit
0.1
0.2
Favours
nitric oxide
0.5 1.0
2.0
5.0
10
Favours
control
Adhikari BMJ, 2007
©2016 MFMER | 3498115-32
ECMO
Patient Inclusion Criteria
• Adult patients (18-65 years)
• Severe, but potentially reversible,
respiratory failure
• Uncompensated hypercapnea
with a pH <7.20
Patient Exclusion Criteria
• ↑ pressure and/or FiO2 >7 days
• Intra-cranial bleeding
• Contraindication for heparin
• Moribund
Survival: 57 of 90 vs 47 of 87; P=0.07
©2016 MFMER | 3498115-33
Prone position
• Risk
• ET tube dislodgment
• Pressure ulcers
• Prolonged sessions
in severe cases
• > 16h/day
• Mortality benefit
Cumulative
probability of survival
• Improves V/Q mismatch
 ↑ oxygenation
1.0
Prone group
0.8
0.6
Supine group
0.4
0.2
P<0.001
0.0
0
10 20 30 40 50 60 70 80 90
Days
Guerine et al NEJM, 2013
©2016 MFMER | 3498115-34
©2016 MFMER | 3498115-35
Prevent Fluid Overload
Alive,
liberal
strategy
1.0
Proportion of patients
8,000.0
6,000.0
4,000.0
mL
2,000.0
0.0
-2,000.0
0.8
Alive,
conservative
strategy
Breathing
without
assistance,
conservative
strategy
0.6
Breathing
without
assistance,
liberal strategy
0.4
0.2
0.0
0 1 2 3 4 5 6 7 8
0
10
20
30
40
50
Days
©2016 MFMER | 3498115-36
Corticosteroids
Wt
Risk Ratio
Experimental
Control
Study of Subgroup Events Total Events Total (%) M-H, Random, 95% CI
1.1.2 High dose
Bernard 1987
30
50
31
49 22.3
0.95 (0.69, 1.29)
Laggner 1987
4
8
4
8
4.9
1.00 (0.38, 2.66)
Weigelt 1985
18
39
13
42 11.6
1.49 (0.85, 2.62)
Subtotal (95% CI)
97
99 38.7
1.05 (0.81, 1.37)
Total events
52
48
Heterogeneity: Tau2 = 0.00; Chi2 = 2.00, df = 2 (P=0.37); I2 = 0%
Test for overall effect: Z = 0.36 (P=0.72)
1.1.3 Low dose
Annane 2006
54
85
67
92 28.9
0.87 (0.71, 1.07)
Confalonieri 2005
0
23
7
23 0.7
0.07 (0.00, 1.10)
Marik 1993
1
14
3
16 1.1
0.38 (0.04, 3,26)
McHardy 1972
3
40
9
86 3.1
0.72 (0.20, 2.51)
Meduri 1998a
2
16
5
8 2.5
0.20 (0.05, 0.81)
Meduri 2007
15
63
12
28 10.3
0.56 (0.30, 1.03)
Mikami 2007
1
15
0
16 0.5
3.19 (0.14, 72.69)
Steinberg 2006
18
66
24
66 13.4
0.75 (0.45, 1.25)
Wagner 1956
1
52
1
61 0.72
1.17 (0.08, 18.30)
Subtotal (95% CI)
374
396 61.3
0.68 (0.49, 0.96)
Total events
95
128
Heterogeneity: Tau2 = 0.06; Chi2 = 11.39, df = 8 (P=0.18); I2 = 30%
Test for overall effect: Z = 2.20 (P=0.03)
Subtotal (95% CI)
471
495 100.0
0.84 (0.66, 1.06)
Total events
147
176
Heterogeneity: Tau2 = 0.04; Chi2 = 15.56, df = 11 (P=0.16); I2 = 29%
Test for overall effect: Z = 1.50 (P=0.13)
0.1 0.2
0.5
Favors Steroid
1.0 2
5
10
Favors Control
J Crit Care Sep;25(3):420, 2010
©2016 MFMER | 3498115-37
Patients alive (%)
Wake Up and Breath
100
SAT plus SBT
Usual care plus SBT
80
60
40
Patients Events
167
74
168
97
20
0
0
60
120
180
240
300
360
Days after randomization
Patients at risk
SAT plus SBT
Usual care plus SBT
167
167
110
85
96
73
92
67
91
66
86
65
76
59
Girard et al: Lancet, 2008
©2016 MFMER | 3498115-38
Physical Therapy
Proportion of patients (%)
80
Intervention (n=49)
Control (n=55)
60
Home*
Acute
rehabilitation
Subacute
rehabilitation
Long-term
rehabilitation
Nursing
home
Hospice
Death
40
20
0
Subsequent Location of
Patients after
Hospital Discharge
Intervention Control
(n=49)
(n=55)
21 (43%) 13 (24%)
13 (27%) 17 (31%)
0 (0%)
6 (11%)
5 (10%)
3 (5%)
1 (2%)
1 (2%)
0 (0%)
1 (2%)
9 (18%) 14 (25%)
*P=0.06 for comparison of home discharge
to all other possible locations for the
comparison of both groups
Trans- Using
ferring
the
from bed toilet
to chair
Activity of daily living
Schweickert et al: Lancet, 2009
©2016 MFMER | 3498115-39
©2016 MFMER | 3498115-40
Checklist for Lung Injury Prevention (CLIP)
Clip Elements
Lung protective
mechanical ventilation
Aspiration precautions
Definition
•
•
•
•
•
•
•
•
Tidal volume between 6-8 mL/kg predicted body weight
Plateau pressure <30 cm H2O
PEEP ≥5 cm H2O
Minimize FIO2 (target O2sat 88-92% after early shock)
Intubation supervised by experienced providers
Elevated head of the bed
Oral care with chlorhexidine
Gastric acid neutralization
Adequate empiric
antimicrobial treatment According to suspected site of infection, health care exposure,
and immune suppression
and source control
Limiting fluid overload
ARDSnet FACCT protocol after early shock
Restrictive transfusion
Hemoglobin target >7 g/dL
Assess readiness
for extubation
As soon as feasible
©2016 MFMER | 3498115-41
Sepsis
Overview
Kuwait Medical Association
Scientific Conference
Kuwait City
March 19, 2016
Kianoush B. Kashani, MD, FASN, FCCP
©2013 MFMER | 3401734-42
Objectives
• Be familiar with definitions
• Recognize the importance of sepsis
• Discuss essential elements of sepsis
management
©2016 MFMER | 3498115-43
Incidence
Incidence/
10,000 discharges
• Annual incidence of severe sepsis:
• 300 to 1,031/100,000 Crit Care Med 2013;41:1167
800
+7.4% (6.8, 7.9%)
600
400
+4.7% (3.8, 5.5%)
+7.2% (4.4, 10.0%)
+10.6% (8.1, 13.1%)
+59.3% (39.9, 78.8%)
200
0
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
Year
Angus
Martin
Septicemia
Dombrovskiy
Explicit severe sepsis/septic shock
Clin Infec Dis; 60:88, 2015
©2016 MFMER | 3498115-44
Incidence
Rate per 10,000 population
50
37.7
40
Hospitalizations with septicemia or sepsis
30
24.0
22.1
Hospitalizations for septicemia or sepsis
20
11.6
10
0
2000
2001
2002
2003
2004
2005
2006
2007
2008
Year
Note: Significant linear trend from 2000 through 2008 for both categories
SOURCE: CDC/NCHS, National Hospital Discharge Survey, 2000-2008
NCHS Data Brief; 62, 2011
©2016 MFMER | 3498115-45
Incidence Comparison
Acute MI Hospitalization
• In 2008, range from 222-397 /100,000
PLoS ONE; 8(5):e64457, 2013
• In 2007, 222 /100,000
Acute myocardial infarction rates: population-based rates per 100,000 persons
Year
Absolute
Description
2001
2002
2003
2004
2005
2006
2007
P
change
ALL
314
285
268
248
245
229
222 <0.0001
92
Relative
change
29.2
Age Categories
<45
30
27
27
22
24
23
45 to <55
219
191
191
164
165
55 to <65
465
416
392
337
65 to <75
812
734
662
1,598
1,461
1,337
75
23
<0.0001
7
24.6
166
160 <0.0001
59
26.7
337
319
307 <0.0001
158
34.0
623
578
539
530 <0.0001
282
34.8
1,298
1,269
1,140
1,080 <0.0001
518
32.4
Am J Cardiol; 109:1589, 2012
©2016 MFMER | 3498115-46
Incidence Comparison
Stroke
• CDC estimates 795,000 strokes per year
(CDC.gov/stroke/facts.htm)
• 2.5 /100,000
Age 65y
IRR (95% CI) for
incident stroke
3.00
P value for linear trend <0.001
2.00
1.50
1.00
0.75
0.50
1990
1993
1996
1999
2002
2005
2008
2011
Calendar year
JAMA; 312:259, 2014
©2016 MFMER | 3498115-47
Sepsis Mortality
• Early recognition and intervention
•  ↓ sepsis mortality
Trial Start Year
1991-1995
n=1,040
1996-2000
n=5,363
2001-2005
n=4,745
2006-2009
n=2,288
P
Observed mortality, %
46.9
35.9
26.6
29.2
0.009
Predicted mortality, %
49.8
53.9
43.0
54.6
0.77
0.94
(0.86-1.03)
0.67
(0.64-0.70)
0.62
(0.58-0.65)
0.53
(0.50-0.57)
0.02
28-day Mortality Measure
Standardized mortality ratio
(95% CI)
Crit Care Med; 42:625, 2014
©2016 MFMER | 3498115-48
Mortality in Australia and New Zealand, 2000-2012
Mean Annual Mortality in Patients With Severe Sepsis
Mortality (%)
40
30
20
10
0
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
No. of patients
2,708 3,783
4,668 5,221
6,375
6,987 7,627
8,529
8,797 10,277 11,367 12,213 12,512
JAMA April 2, 2014 Volume 311, Number 13
©2016 MFMER | 3498115-49
Operationalization of Clinical Criteria Identifying
Patients With Sepsis and Septic Shock
Patient with suspected infection
No
qSOFA ≥2?
(see A )
Sepsis still
suspected?
Yes
No
Monitor clinical condition;
reevaluate for possible
sepsis if clinically indicated
Yes
Assess for evidence
of organ dysfunction
SOFA ≥2?
(see B )
No
A
qSOFA Variables
Respiratory rate ≥ 22/m
Altered mental status
Systolic blood pressure ≤ 100 mmHg
B
SOFA Variables
PaO2/FiO2 ratio
Glasgow Coma Scale score
Mean arterial pressure
Administration of vasopressors with
type and dose rate of infusion
Serum creatinine or urine output
Bilirubin
Platelet count
Monitor clinical condition;
reevaluate for possible
sepsis if clinically indicated
Yes
Sepsis
Despite adequate fluid resuscitation:
1. Vasopressors required to maintain
MAP ≥65 mm Hg
AND
2. Serum lactate level >2 mol/L
Yes
No
Septic shock
Singer et al: JAMA 315(8):801, 2016
©2016 MFMER | 3498115-50
Sequential (Sepsis-Related) Organ Failure
SOFA Assessment Score
Score
System
Respiration
Pao2/F102
(mm Hg) (kPa)
Coagulation
Platelets
(x103/L)
Liver
Bilirubin (mg/dL)
(mol/L)
Cardiovascular
0
1
2
3
4
400 (53.3)
<400 (53.3)
<300 (40)
<200 (26.7) with
respiratory support
<100 (13.3) with
respiratory support
150
<150
<100
<50
<20
<1.2 (20)
1.2-1.9 (20-32)
2.0-5.9 (33-101)
6.0-11.9 (102-204)
>12.0 (204)
MAP 70 mm Hg MAP <70 mm Hg
Dopamine <5 or
dobutamine
(any dose)b
Dopamine 5.1-15
Dopamine >15 or
or epinephrine 0.1
epinephrine >0.1
or norepinephrine 0.1b or norepinephrine >0.1
CNS
GCS
Renal
Creatinine
(mg/mL)
Urine output
(mL/d)
15
<1.2 (110)
13-14
10-12
1.2-1.9 (110-170) 2.0-3.4 (171-299)
6-9
<6
3.5-4.9 (300-440)
>5.0 (440)
<500
<200
Singer et al: JAMA 315(8):801, 2016
©2016 MFMER | 3498115-51
Sepsis Mortality
Variable
In-hospital mortality†
All patients
Patients with severe sepsis
Patients with septic shock
Patients with sepsis syndrome
28-day mortality†
60-day mortality†
Standard Therapy
(n=133), no. (%)
59 (46.5)
19 (30.0)
40 (56.8)
44 (45.5)
61 (49.2)
70 (56.9)
NEJM; 345:1368, 2001
©2016 MFMER | 3498115-52
Early Goal Directed Therapy
Supplemental oxygen ±
endotracheal intubation and
mechanical ventilation
Central venous and
arterial catheterization
Sedation, paralysis
(if intubated), or both
CVP
<8 mm Hg
Crystalloid
Colloid
8-12 mm Hg
MAP
<65 mm Hg
>90 mm Hg
Vasoactive agents
65 and 90 mm Hg
ScvO2
70%
No
<70%
Transfusion of red cells
until hematocrit 30%
70%
<70%
Inotropic agents
Goals
archived
NEJM; 345:1368, 2001
©2016 MFMER | 3498115-53
Sepsis Mortality
Kaplan-Meier Estimates of Mortality and Causes of In-Hospital Death*
Standard
Early GoalTherapy
Directed Therapy Relative Risk (95%
(n=133)
(n=130)
Variable
CI)
No. (%)
In-hospital mortality†
All patients
59 (46.5)
38 (30.5)
0.58 (0.38-0.87)
Patients with severe sepsis
19 (30.0)
9 (14.9)
0.46 (0.21-1.03)
Patients with septic shock
40 (56.8)
29 (42.3)
0.60 (0.36-0.98)
Patients with sepsis syndrome
44 (45.4)
35 (35.1)
0.66 (0.42-1.04)
†
28-day mortality
61 (49.2)
40 (33.3)
0.58 (0.39-0.87)
60-day mortality†
70 (56.9)
50 (44.3)
0.67 (0.46-0.96)
‡
Causes of in-hospital death
SCD
–
25/119 (21.0)
12/117 (10.3)
–
Multi-ogran failure
26/119 (21.8)
19/117 (16.2)
P
0.009
0.06
0.04
0.07
0.01
0.03
0.02
0.27
NEJM; 345:1368, 2001
©2016 MFMER | 3498115-54
Surviving Sepsis Campaign Care Bundles
To be completed within 3 hours
1. Measure lactate level
2. Obtain blood cultures prior to administration of antibiotics
3. Administer broad spectrum antibiotics
4. Administer 30 mL/kg crystalloid for hypotension or lactate 4 mmol/L
To be completed within 6 hours
5. Apply vasopressors (for hypotension that does not respond to
initial fluid resuscitation) to maintain a mean arterial pressure
(MAP) 65 mm Hg
6. In the event of persistent arterial hypotension despite volume
resuscitation (septic shock) or initial lactate 4 mmol/L (36 mg/dL):
• Measure central venous pressure (CVP)*
• Measure central venous oxygen saturation (Scvo2)*
7. Remeasure lactate if initial lactate was elevated*
* Targets for quantitative resusciation included in the guidelines are CVP
of 8 mm Hg, Scvo2 of 70%, and normalization of lactate
http://www.survivingsepsis.org/Bundles/Documents/SSC_Bundle.pdf
©2016 MFMER | 3498115-55
80
30
70
Mortality (%)
25
20
60
19.9
60.0
15
40
12.2
10
5
0
n=
50
20
Control
7.0
30
10
2004
2005
2006
2007
2008
2009
2010
151
158
118
150
290
305
254
0
Total bundle compliance (%)
Multicenter Implementation of a Severe
Sepsis and Septic Shock Treatment Bundle
Miller et al: Am J Respir Crit Care Med 1;188(1):77, 2013
©2016 MFMER | 3498115-56
0.35
0.40
0.25
0.30
Mortality
Compliance
Surviving Sepsis Campaign: Association Between
Performance Metrics and Outcomes in a 7.5-Year Study
0.15
0.20
Slope = 0.7% drop in mortality/quarter
P<0.001
0.05
0.10
0
2
4
6
8 10 12 14 16
Management bundle
0
2
4
6
8 10 12 14 16
Site quarter of SSC participation
Levy et al: Crit Care Med 43(1):3, 2015
©2016 MFMER | 3498115-57
Septic Shock patients presenting to ED (N = 1,341)
Randomized to 1 of 3 resuscitation care
pathways
1.Protocol-Based EGDT
• Team-based prompted “Rivers algorithm”
2.Protocol-Based Standard therapy
• Team-based prompted “modified algorithm”
• Did not require ScvO2 and lower PRBC threshold
3.Usual Care
• Bed-side provider directed care without
prompts/team
New Engl J Med; 370:1683, 2014
©2016 MFMER | 3498115-58
ProCESS Trial
Cumulative In-Hospital Mortality to 60 Days
50
Protocol-based EGDT
Protocol-based standard therapy
Usual care
40
Mortality
(%)
30
20
10
P=0.52 by log-rank test
0
0
No. at risk
Protocol-based EGDT
Protocol-based standard
therapy
Usual care
10
20
30
40
50
60
Days
439
446
373
389
356
376
348
368
347
366
347
366
347
365
456
396
376
371
371
371
370
New Engl J Med; 370:1683, 2014
©2016 MFMER | 3498115-59
Characteristics of the Patients at Baseline*
Characteristic
Mechanical ventilation – no. (%)
Invasive
Noninvasive
Vasopressor infusion – no. (%)
Total intravenous fluids
Volume – mL
Volume per weight – mL/kg
Median interval after presentation to
emergency department (IQR) – hr
Until final inclusion criterion
was met
Until randomization
EGDT
(n=793)
Usual Care
(n=798)
71 (9.0)
60 (7.6)
173 (21.8)
64 (8.0)
48 (6.0)
173 (21.7)
2515±1244
34.6±19.4
2591±1331
34.7±20.1
1.4 (0.6-2.5)
1.3 (0.5-2.4)
2.8 (2.1-3.9)
2.7 (2.0-3.9)
Adapted from New Engl J Med; 371:1496, 2014
©2016 MFMER | 3498115-60
ARISE Trial
Probability of survival
1.0
EGDT
0.8
Usual care
0.6
0.4
0.2
0.0
0
No. at risk
792
796
30
60
90
Days since randomization
677
670
660
357
646
646
NEJM 371:1496, 2014
©2016 MFMER | 3498115-61
Early, Goal-Directed Resuscitation
ProMISe Trial
Characteristic
Age (yr)
Male sex, no. (%)
Refractory hypotension, no. (%)
SBP (mm Hg)
MAP (mm Hg)
Hyperlactatemia, no. (%)
Blood lactate level (mmol/liter)
Intravenous fluids administered
Before hospitalization until
randomization, no./total no. (%)
Median total before hospitalization
until randomization (IQR) (mL)
Supplemental oxygen, no./total no. (%)
Median time from presentation in emergency
department to randomization (IQR) (hr)
EGDT
n=625
66.4±14.6
356 (57.0)
338 (54.1)
77.7±11.0
58.8±15.8
409 (65.4)
7.0±3.5
Usual care
n=626
64.3±15.5
367 (58.6)
348 (55.6)
78.4±10.2
59.0±10.7
399 (63.7)
6.8±3.2
612/625 (97.9)
606±3.2
1950
(1000-2500)
397/539 (73.7)
2.5 (1.8-3.5)
2000 (1000-2500)
407/542 (75.1)
2.5 (1.8-3.5)
New Engl J Med 372:1301, 2015
©2016 MFMER | 3498115-62
ProMISe Trial
Probability of survival
1.0
Usual care
0.8
EGDT
0.6
0.4
0.2
Adjusted hazard ratio 0.94 (0.79-1.11); P=0.46
P=0.63 by log-rank test
0.0
0
No. at risk
625
626
15
30
45
60
75
90
445
445
440
439
Days since randomization
492
487
470
469
461
464
449
448
New Engl J Med 372:1301, 2015
©2016 MFMER | 3498115-63
What is Important and What Can We Agree
On?
• Early recognition
• Early antibiotics
• Adequate fluids
©2016 MFMER | 3498115-64
Critical Importance of Timing
Unadjusted mortality (%)
230
40
180
30
130
20
10
80
0
30
Control
1
2
3
Study year
4
O/E
1.2
1.0
0.8
0.4
Actual/predicted mortality
Minutes
Median time to interventions
50
Unadjusted mortality
Mortality observed/expected mortality APACHE III
Median time to 3 most rapid interventions P<0.001
5
Crit Care Med 35:11, 2007
©2016 MFMER | 3498115-65
What is Important and What Can We Agree
On?
• Early recognition
• Early antibiotics
• Adequate fluids
©2016 MFMER | 3498115-66
Early Appropriate Antibiotics
Odds ratio of death
(95% confidence interval)
100
10
1
Time from hypotension onset (hr)
Crit Care Med 2006;34:1589, 2006
©2016 MFMER | 3498115-67
Early Antibiotics
0.40
0.36
• n=17,990
• 165 ICUs
• Any antibiotics
0.32
0.28
0.24
0.20
0-1
1-2
OR 1.14
P=0.021
OR 1.19
P=0.009
2-3
3-4
OR 1.24
P=0.006
OR 1.47
P<0.001
OR 1.52
P<0.001
4-5
5-6
>6
Time to first antibiotic (hours)
Crit Care Med 42:1749, 2014
©2016 MFMER | 3498115-68
What is Important and
What Can We Agree On
• Early recognition
• Early antibiotics
• Adequate fluids
• Next topic
©2016 MFMER | 3498115-69
Vasopressors: Surviving Sepsis Guideline
1. Vasopressor therapy initially to target a mean arterial pressure (MAP) of 65 mm Hg
(grade 1C)
2. Norepinephrine as the first choice vasopressor (grade 1B)
3. Epinephrine (added to and potentially substituted for norepinephrine) when an additional
agent is needed to maintain adequate blood pressure (grade 2B)
4. Vasopressin 0.03 units/minute can be added to norepinephrine (NE) with intent of either
raising MAP or decreasing NE dosage (UG)
5. Low does vasopressin is not recommended as the single initial vasopressor for treatment
of sepsis-induced hypotension and vasopressin doses higher than 0.03-0.04 units/minute
should be reserved for salvage therapy (failure to achieve adequate MAP with other
vasopressor agents) (UG)
6. Dopamine as an alternative vasopressor agent to norepinephrine only in highly selected
patients (eg, patients with low risk of tachyarrhythmias and absolute or relative
bradycardia) (grade 2C)
7. Phenylephrine is not recommended in the treatment of septic shock except in
circumstances where (a) norepinephrine is associated with serious arrhythmias, (b)
cardiac output is known to be high and blood pressure persistently low or (c) as salvage
therapy when combined inotrope/vasopressor drugs and low dose vasopressin have
failed to achieve MAP target
(grade 1C)
8. Low-dose dopamine should not be used for renal protection (grade 1A)
9. All patients requiring vasopressors have an arterial catheter placed as soon as practical if
resources are available (UG)
Crit Care Med 34:589, 2006
©2016 MFMER | 3498115-70
Cumulative survival
Vasopressors: Does it Matter?
1.0
1.0
0.8
0.8
0.6
0.6
0.4
0.4
Log rank=4.61
P=0.032
0.2
0.0
Cumulative survival
0
5
10
Dopamine
No dopamine
15
20
25
0.0
30
0
1.0
1.0
0.8
0.8
0.6
0.6
0.4
0.4
Log rank=14.36
P<0.001
0.2
Epinephrine
No epinephrine
0.0
Dobutamine
No dobutamine
Log rank=1.27
P=0.261
0.2
5
10
15
20
30
Norepinephrine
No norepinephrine
Log rank=0.05
P=0.824
0.2
25
0.0
0
5
10
15
Days
20
25
30
0
5
10
15
20
25
30
Days
Crit Care Med 34:589, 2006
©2016 MFMER | 3498115-71
Vasopressor
Probability of survival
1.0
P=0.27
at day 28
0.9
P=0.10
at day 90
0.8
0.7
Vasopressin
0.6
0.5
Norepinephrine
0.4
0
No. at risk
367
382
10
20
30
40
50
60
70
80
90
Days since initiation of the study drug
301
289
272
247
249
230
240
212
234
205
232
200
230
194
226
193
220
191
NEJM 358:877, 2008
©2016 MFMER | 3498115-72
Sepsis
Immediate Considerations
Cultures
Test
Cultures should be taken ASAP
Before antimicrobial therapy
Measure Lactate
Antibiotics
Antibiotics should be initiated ASAP
According to likely pathogen, site of infection,
immune status, and allergy
Source
Remove dead tissue, pus, or infected device for source
control
control
Fluid
Start fluid bolus (~30 mL/kg)
challenge
Repeat as needed
Achieve adequate tissue perfusion
Vasopressors Add vasopressors for shock despite fluid resuscitation
Steroids
Add steroids for shock despite vasopressors
Limit oxygen Consider mechanical ventilation, use analgesics,
consumption sedatives, and neuromuscular blockers
©2016 MFMER | 3498115-73
Take home points
• Focus on
• Early recognition
• Early antibiotics
• Sufficient fluids
• Norepinephrine is preferred initial vasopressor
• Steroids if pressor resistant hypotension
• Lactate improvement improves survival
©2016 MFMER | 3498115-74
Fluid management for critically ill patients
Fluid Responsiveness & Optimum Type of Fluids
Kuwait Medical Association
Scientific Conference
Kuwait City
March 19, 2016
Kianoush B. Kashani, MD, FASN, FCCP
©2013 MFMER | 3322132-75
Outlines
Objectives
IV fluid management
• Fluid overload
• Fluid responsiveness
• Fluid types
• Colloid vs. crystalloid
• Chloride-rich vs. balanced
©2013 MFMER | 3322132-76
Excessive fluid resuscitation
Marik Annals of Intensive Care 2014, 4:21
©2013 MFMER | 3322132-77
Effects of Volume Overload on Mortality
1.0
0.8
Survival
1st quartile
0.6
2nd quartile
0.4
3rd quartile
0.2
4th quartile
0.0
0
5
10
15
20
25
Days
Boyd et al: Crit Care Med 39(2), 2011
©2013 MFMER | 3322132-78
Effects of Volume Overload on Mortality
90-day mortality (%)
Percentage of Patients With Fluid Accumulation
Prior to RRT Initiation
80
Fluid overload: >10%
admission weight
60
40
20
0
<0 (46)
0-5 (94)
5-10 (67) 10-15 (44) ≥15 (32)
Fluid accumulation, % (no. of patients)
Vaara et al: FINNAKI trial. Critical Care 16:R197, 2012
©2013 MFMER | 3322132-79
Goal Directed Fluid Management
Complications
Optimal CO
Fluid volume
©2013 MFMER | 3322132-80
Hospital mortality (%)
Too Much of a Good Thing
15
10
5
0
<7.5
15
22.5
30
37.5
45
52.5
60
67.5
Total fluid received prior to 8-hour repeat lactate
test, by 7.5 mL/kg increments
Ann Am Thorac Soc 10:466, 2013
©2013 MFMER | 3322132-81
Relationship between the
different stages of fluid
resuscitation. Reproduced
with permission from ADQI
Patients’ volume status at
different stages of resuscitation.
Reproduced with permission
from ADQI
Volume
status
Rescue
Optimization
Stabilization
Deescalation
Optimization
Deescalation
Rescue
Stabilization
British Journal of Anaesthesia 113 (5): 740, 2014
©2013 MFMER | 3322132-82
©2013 MFMER | 3322132-83
Fluid Responsiveness
“Increase in SV or CO of at least
10-15% after 500-mL bolus
crystalloid volume expansion over
10-15 minutes”
http://emcrit.org/podcasts/fluid-responsiveness-with-dr-paul-marik/
Lakhal et al: Critical Care, 2011
©2013 MFMER | 3322132-84
©2013 MFMER | 3322132-85
Fluid bolus
• If they are hypotensive, have elevated lactate,
have reduced urine output
• Recall tachycardia may also be due to fever
• Bolus is not:
• 250 mL
• 100 cc/hr
• Bolus is given within 15 minutes
• 500 to 1000 mL at a time
©2013 MFMER | 3322132-86
Fluid Challenge
• Rate of infusion
• 500-1000 mL crystalloids
• 300-500 mL colloids
• Over 30 min
• Goal: Reversal of perfusion failure
• Hypotension, tachycardia, oliguria, etc
• Safety limits
• CVP of 15 mm Hg measured every 10 min
Vincent et al: Crit Care Med 34:1333, 2006
©2013 MFMER | 3322132-87
Fluid Challenge
• It is a treatment used as a test
• Not negligible amount of fluids
• Potentially harmful
• Does not predict fluid responsiveness
• Successful in only 50% cases
Vincent et al: Crit Care Med 34:1333, 2006
©2013 MFMER | 3322132-88
Fluid Challenge Response Rate
Pt
(no.)
FC
(no.)
Fluid infused
Volume
infused
(mL)
Calvin et al
28
28
5% Alb
250
20-30
SV >10%
71
Schneider et al
18
18
FFP
500
30
SV >10%
72
Reuse et al
41
41
4.5% Alb
300
30
CO >10%
63
Magder et al
33
33
9% NaCl
100-950
CO >250 mL/min
52
Diebel et al
15
22
R lactate
Colloids
300-500
500
CO >10%
59
Diebel et al
32
65
R lactate
300-500
CO >20%
40
Wagner and
Leatherman
25
36
9% NaCl
938±480
7-120
SV >10%
56
Tavemier et al
15
35
HES
500
30
SV >15%
60
Magder and
Lagonidis
29
29
25% Alb
9% NaCl
100
150-400
15
CO >250 mL/min
45
Tousignant et al
40
40
HES
500
15
SV >20%
40
Michard et al
40
40
HES
500
30
CO >15%
40
Feissel et al
19
19
HES
8 mL/kg
30
CO >15%
53
334
406
Source
Total
Speed
of FC
(min)
Definition of
response
Rate of
response
(%)
52
Michard et al: CHEST 121:2000, 2002
©2013 MFMER | 3322132-89
©2013 MFMER | 3322132-90
Fluid infusion  LV stroke volume only if
both ventricles preload responsive
Stroke volume
Preload unresponsiveness
Preload responsiveness
Ventricular preload
©2013 MFMER | 3322132-91
Static measures of preload cannot reliably
predict fluid responsiveness
Stroke volume
Normal heart
Preload responsiveness
Failing heart
Preload unresponsiveness
Ventricular preload
©2013 MFMER | 3322132-92
Baseline PAOP or CVP
Do Not Predict Volume Responsiveness
25
20
15
15
CVP
PAOP
20
10
10
5
5
0
0
Responder
Nonresponder
Responder
Nonresponder
Osman et al: Crit Care Med 35:64, 2007
©2013 MFMER | 3322132-93
Fluid Types
Colloids Vs. Crystalloids
©2013 MFMER | 3322132-94
The Volume Properties of 1-L Fluid Infusion
Fluid
Volume (mL)
Intracellular
Extra-cellular
interstitial
Intravascular
D5W
660
255
85
NS or LR
-100
825
275
3% NaCI
-2950
2690
990
5% albumin
0
500
500
Whole blood
0
0
1000
Courtesy: Dr. Afessa
©2013 MFMER | 3322132-95
Probability of survival
1.0
Saline
0.9
Albumin
0.8
0.7
0.6
0.5
Outcomes
RR
Albumin
Saline
P
Death (28 days)
0.99
20.9
21.1
NS
Trauma (n=1,186)
1.36
13.6
10
0.06
TBI (n=460)
1.62
24.5
15.1
0.009
Severe sepsis (n=1,218)
0.87
30.7
35.3
0.09
ARDS (n=127)
0.93
39.3
42.4
0.72
0.4
0
4
8
12
16
20
24
28
Days
©2013 MFMER | 3322132-96
Study ID
Rackow et al
Metildi et al
Rackow et al
Boldt et al
Boldt et al
Boldt et al
Boldt et al
Boldt et al
Boldt et al
The SAFE study investigators
Veneman et al
Maitland et al
Maitland et al
Akech et al
Friedman et al
van der Heijden et al
Dolecek et al
OR (95% CI)
2.08 (0.28-15.77)
0.45 (0.04-5.81)
1.00 (0.17-5.77)
1.00 (0.22-4.56)
0.73 (0.15-3.49)
1.33 (0.30-5.91)
0.72 (0.15-3.54)
1.88 (0.39-9.01)
1.29 (0.64-2.58)
0.81 (0.64-1.03)
1.31 (0.26-6.72)
1.19 (0.23-6.11)
0.17 (0.04-0.80)
0.12 (0.01-1.05)
0.85 (0.23-3.21)
0.79 (0.11-5.49)
0.51 (0.13-2.07)
0.82 (0.67-1.00)
Overall (I2=0.0%, P=0.728)
0.1
1
Events,
Albumin
5/7
10/12
5/10
5/15
4/15
7/14
4/14
6/14
25/75
185/603
5/8
4/23
2/56
1/44
5/15
2/6
4/30
279/961
Events,
control
6/11
11/12
5/10
5/15
5/15
6/14
5/14
4/14
21/75
217/615
14/25
3/20
11/61
7/44
10/27
7/18
6/26
343/1,016
Weight
(%)
0.61
0.84
1.14
1.52
1.67
1.37
1.63
1.04
6.38
67.91
1.16
1.21
4.63
3.12
2.17
1.06
2.54
100.00
10
↓ mortality  OR 0.82 (95% CI, 0.67-1, P=0.047)
©2013 MFMER | 3322132-97
Albumin Supplementation: ALBIOS
Probability of survival
1.0
0.9
0.8
0.7
Albumin
0.6
Crystalloids
0.5
0.4
P=0.39
0.3
0
No. at risk
903
907
10
20
30
40
50
60
70
80
90
529
511
523
504
Days since randomization
733
729
647
652
597
598
567
676
556
551
545
538
535
521
NEJM 370:2247, 2014
©2013 MFMER | 3322132-98
Cumulative incidence
of death
0.3
Crystalloids
0.2
Colloids
0.1
0.0
0
5
10
15
20
25
30
Days since randomization
Colloids
n=1,414
Crystalloids
n=1,443
Death
Within 28 days
No.
359
%
25.4
No.
390
%
27.0
RR (95% CI)
0.96 (0.88-1.04)
P
0.26
Within 90 days
434
30.7
493
34.2
0.92 (0.86-0.99)
0.03
In ICU
355
25.1
405
28.1
0.92 (0.85-1.00)
0.06
In hospital
426
30.1
471
32.6
0.94 (0.87-1.02
0.07
Annane et al: CRISTAL study. JAMA, 2013
©2013 MFMER | 3322132-99
Hydroxyethyl Starch (HES)
Probability of survival
1.0
0.8
Ringer’s acetate
0.6
HES 130/0.42
0.4
0.2
0.0
0
10
20
30
40
50
60
70
80
90
Days since randomization
NEJM 367:124, 2012
©2013 MFMER | 3322132-100
Fluid Types
Chloride rich Vs.
Balanced
©2013 MFMER | 3322132-101
Fact
• 1 liter NS = 9 grams od sodium
• WHO recommended sodium intake = 2 g/d
• Average sodium intake in the US = 3.3 g/d
©2013 MFMER | 3322132-102
Fact
One bag of potato chips = 250 mg Na
One NS bag = 36 bags of potato chips
©2013 MFMER | 3322132-103
Na
Cl
IV fluid composition
135-145 mmol/L
98-107 mmol/L
Solution
Na
Cl
Ca
K
Mg
Lactate
Acetate
Gluconate
pH
Normal saline
154
154
0
0
0
0
0
0
5
Ringer's
lactate
130
109
1.5
4
0
28
0
0
6.5
Hartmann
131
111
2
5
0
29
0
0
6.5
Plasma-Lyte
148
140
98
0
5
1.5
0
27
23
7.4
©2013 MFMER | 3322132-104
Luminal diameter (µm)
16
14
12
10
8
6
4
2
0
0
20
40
60
80
100
120
Chloride concentration (mmol/L)
©2013 MFMER | 3322132-105
0.9% NS
n=26
LR
n=25
Scr (72-hr postop)
2.3
2.1
0.7
pH (end of surgery)
7.28
7.37
<0.001
[Cl-] (end of surgery)
111
106
<0.001
Metabolic acidosis, no. (%)
8 (31)
0 (0)
0.004
[K+] >6 mmol/L, no. (%)
5 (19)
0 (0)
0.05
P
©2013 MFMER | 3322132-106
P<0.0001
102
0
20
0
-20
-40
-60
60 90 120 180 240
Time (min)
P=0.008
0
Weight
2.0
1.5
1.0
0.5
P=0.022
0.0
0
60 90 120 180 240
Time (min)
7
14 21 28 35
 mean renal artery
flow velocity (cm/s)
104
Cortical Perfusion
40
RBF
4
2
0
-2
-4
P=0.045
-6
0
Time (min)
 extravascular
fluid volume (mL)
106
 renal cortical tissue
perfusion (mL/100 g/min)
108
 weight (kg)
Serum chloride
(mmol/L)
Serum CI
110
14
28
42
90
Time (min)
EV Volume
1,600
1,200
800
400
P=0.029
0
0
60 90 120 180 240
Time (min)
©2013 MFMER | 3322132-107
Association Between a Chloride-Liberal vs ChlorideRestrictive Intravenous Fluid Administration Strategy and
Kidney Injury in Critically Ill Adults
Control period
n=760
RIFLE class
Intervention period
n=773
No.
%
95% CI
No.
%
95% CI
P
Risk
71
9.0
7.2-11.0
57
7.4
5.5-9.0
0.16
Injury
48
6.3
4.5-8.1
23
3.0
1.8-4.2
0.002
Failure
57
7.5
5.6-9.0
42
5.4
3.8-7.1
0.10
105
14.0
11-16
65
8.4
6.4-10.0
<0.001
Injury and failure
JAMA 308(15):1566, 2012
©2013 MFMER | 3322132-108
Meeting inclusion criteria (n=654,844)
Analytic sample
(n=53,448)
Received
balanced fluids
(n=3,396)
1:1 propensity
score matching
Received
balanced fluids
(n=3,365)
<20% balanced
fluids (n=1,107)
>40% balanced
fluids (n=1,203)
20-40% balanced
fluids (n=1,055)
Received nonbalanced fluids
(n=50,052)
Excluded (n=601,396)
• Surgical pt (n=100,685)
• Not in ICU by day 2 (n=356,483)
• Not on vasopressors by day 2
(n=94,302)
• Died or discharged by day 2
(n=20,104)
• <3 consecutive days of antibiotics
(n=4,216)
• Missing/invalid fluid values
(n=25,596)
Received nonbalanced fluids
(n=3,365)
Pt were also matched within
strata based on proportions of
balanced fluids received
Raghunathan et al. Crit Care Med 2014; 42:1585–1591
©2013 MFMER | 3322132-109
Results
Association Between Resuscitation With Balanced Fluids and
Primary and Secondary Outcomes in Propensity-Matched Cohorts
Balance
fluid-matched
cohort
No-balanced
fluid-matched
cohort
Absolute in-hosp mortality
19.6%
(69/3,365)
22.8%
(768/3,365)
RR 0.86
0.8, 0.9
P=0.001
AKI with dialysis
4.52%
(142/3,144)
4.74%
(149/3,144)
RR 0.95
0.8, 1.2
AKI without dialysis
7.12%
(159/2,655)
7.50%
(199/2,655)
RR 0.95
0.8, 1.2
11.26
11.37
Absolute
diff -0.11
-0.6, 0.3
5.39
5.50
Absolute
diff -0.11
-0.4, 0.2
Outcome
Hospital LOS survivors (d)
ICU LOS survivors (d)
Effect
estimate
95% CI
Raghunathan et al. Crit Care Med 2014; 42:1585–1591
©2013 MFMER | 3322132-110
Absolute in-hosp mortality (%)
24
20
16
12
8
95% CI
Adjusted mortality (marginal fixed effects)
4
0
0
20
40
60
80
100
Total balanced fluid by day 2 (%)
Raghunathan et al. Crit Care Med 2014; 42:1585–1591
©2013 MFMER | 3322132-111
• 0.9% Saline vs Plasma-Lyte for ICU fluid Therapy
(SPLIT) trial
• Australia-New Zealand
• Prospective, multicenter, blinded
• Cluster-randomized, double-crossover
• 4 tertiary ICUs in New Zealand
• 2200 patients
©2013 MFMER | 3322132-112
Primary and Secondary Outcomes
Outcomes for Patients in Intensive Care Unit Receiving
Buffered Crystalloid vs Saline Fluid Therapy
Buffered crystalloid
n=1,067
Variable
Saline
n=1,025
No.
%
No.
%
102
9.6
94
9.2
Absolute
difference
(95% CI)
Relative risk
(95% CI)
P
Primary
outcome
Acute kidney
injury or failure
0.4
1.04
0.77
(-2.1 to 2.9) (0.80 to 1.36)
No difference between NS and balanced solutions for AKI
or failure
Young, et al. JAMA: October 2015
©2013 MFMER | 3322132-113
Take home points
• Avoid fluid overload
• Use fluids based on each individual patient’s
needs
• Treat IV fluid like all other medications
• No difference between colloids and
crystalloids
• Avoid NS for massive IVF resuscitation
©2013 MFMER | 3322132-114
‫شكرا‬
“The best interest of the patient is the only interest to be considered”
©2013 MFMER | 3322132-115
Questions & Discussion
©2016 MFMER | 3498115-116