5/5/2015
Obesity Epidemic
Impact of Body Mass Index on
Norepinephrine Requirements and
Hemodynamics in Septic Shock
Kara Zacholski, PharmD
PGY2 Critical Care
Detroit Medical Center, Detroit Receiving Hospital
• In 2012, 34% of all adults in the United States
had a body mass index (BMI) greater than 30
• Obesity has been identified as a risk factor for
developing multiple comorbidities including
infections
• Overall, the incidence of sepsis in the United
States has been increasing
The speaker has no actual or potential conflicts of interest in relation to this presentation.
Defining BMI/Obesity
Classification
Underweight
Normal
Overweight
Obesity
Class 1
Class 2
Class 3
Ogden CL et al. NCHS Data Brief. 2013;131:1-7
Martin GS et al. N Engl J Med. 2003;348(16):1546-1554
Obesity and Sepsis
BMI (kg/m2)
< 18.5
18.5 – 24.9
25 – 29.9
30 – 34.9
35 – 39.9
≥ 40
• In rodents, obesity exacerbates:
• Sepsis-induced inflammation
• Microvascular dysfunction
• Surgical ICU patients (n=406) with an ICU stay ≥ 4
days demonstrated increased mortality in patients
with BMI > 40
• Matched cohort of medical-surgical ICU patients
(n=1,927) found BMI > 30 to be an independent risk
factor for mortality in the ICU
Singer G et al. Shock. 2009;31(3):275-279
Nasraway SA Jr et al. Crit Care Med. 2006;34:964-970
Bercault N et al. Crit Care Med. 2004;32:998-1003
https://www.nhlbi.nih.gov/health/educational/lose_wt/BMI/bmi_dis.htm
Obesity and Sepsis Outcomes
Obesity and Sepsis Outcomes
Gaulton TG et al.
• One year analysis of Medicare patients admitted with severe
sepsis (n=1,404)
• Retrospective analysis of patients admitted with sepsis (n=1,770)
found no difference in 28 day mortality in BMI ≥ 30 group
Kuperman EF et al.
• Retrospective analysis of patients with primary billing code of
sepsis (n=792) compared outcomes of five BMI categories
• Lower BMI was associated with increased mortality
Wacharasint P et al.
• Retrospective analysis of septic shock patients from the VASST
trial compared BMI < 25, BMI 25 – 30, and BMI > 30 and found the
adjusted hazard ratio was 2% lower for every 1 unit increase in
BMI
Gaulton TG et al. Intern Emerg Med. 2014;9:213-221
Kuperman EF et al. BMC Infect Dis. 2013;377(13):1-8
Wacharasint P et al. Crit Care Med. 2013;17:R122
Mortality
Normal
weight
Overweight
Obese
Severely
Obese
62%
53.1%
46%
44.7%
p<0.001
******************************
• Retrospective analysis of septic shock patients (n=2,882)
– Lower mortality in obese and morbidly obese WHO classes
• OR 0.80 (95% CI 0.66 – 0.97)
• OR 0.61 (95% CI 0.44 – 0.85)
– Adjusted for sepsis interventions
• OR 0.80 (95% CI 0.62 – 1.02)
• OR 0.69 (95% CI 0.45 – 1.04) Prescott HC et al. Crit Care Med. 2014;42(8):1766-74
Arabi et al. Crit Care. 2013;17(2):R72
1
5/5/2015
Sepsis Management
Norepinephrine Dosing in Obesity
• Fluid resuscitation 30 mL/kg IV crystalloids
• Norepinephrine (NE) is recommended as the
first-line vasopressor in septic shock
– Dosing recommendations do not address obesity
– Weight-based (mcg/kg/min) vs. non-weight-based
(mcg/min)
– Minimal primary literature to support a specific dose
range
• Society of Critical Care Medicine report dose
ranges of 0.01 – 3.3 mcg/kg/min
• No dosing recommendations exist in
obesity
• Onset: 1-2 minutes
• Short half life (2 minutes)
• NE has a low volume of distribution
• NE should be dosed on lean body weight
• Vd approximates blood volume
Dellinger RP et al. Crit Care Med. 2013;41(2):580-637
Hollenberg SM et al. Crit Care Med. 2004;32(9):1928-1948
Beloeil H et al. Br J Anaesth. 2005;95:782-8
Norepinephrine Bitartrate [package insert]. Lake Forest, IL: Hospira, Inc.; 2007
At Detroit Medical Center
• Prior to 2008:
– Standard dose: 2 – 20 mcg/min. Max 20 mcg/min
• Changed to weight-based dosing in 2008:
– Physician orders drip with starting rate
– Nurse initiates infusion and titrates to effect up to 1
mcg/kg/min, Max weight is 100 kg.
– Physician must be contacted for further dose
escalation
– Max of 3.3 mcg/kg/min, or 330 mcg/min
Impact of Body Mass Index on
Norepinephrine Requirements and
Hemodynamics in Septic Shock
Kara Zacholski, PharmD1
Linda A. Park, PharmD, BCPS1
Krista Wahby, PharmD2
1Department
of Pharmacy Services, Detroit Receiving Hospital, Detroit, Michigan
of Pharmacy, Harper University Hospital, Detroit, Michigan
2Department
Objective
Study Description
• To determine if patients with a higher BMI
achieve their target MAP quicker than patients
with a lower BMI due to receiving higher doses
of NE
• Assess whether using a maximum dosing weight
of 100 kg affects the time to achieve goal MAP
• Retrospective analysis of patients admitted to
an intensive care unit within Detroit Medical
Center with septic shock from 2012 – 2015
– Stratified patients into 3 distinct BMI groups
• BMI < 30, BMI 30 – 40, and BMI > 40
• Received NE as initial vasopressor
• Assessed whether using a maximum dosing
weight of 100 kg affects the time to achieve
goal MAP
2
5/5/2015
Methods
Methods
• Primary Outcomes
– Time to achieve mean arterial pressure (MAP) greater than 65
mmHg for 3 consecutive hours
– To compare the time to MAP goal in patients where a
maximum dosing weight of 100 kg versus those where total
body weight was used
• Secondary Outcomes
–
–
–
–
–
–
Duration of NE
Dosing of NE
Adverse effects
ICU and hospital length of stay (LOS)
Ventilator days
Mortality
Exclusion
• Age 18 – 89 years old
• Admitted to DMC
intensive care unit
with septic shock
• Received NE as firstline vasopressor
• Transferred from an
outside hospital
• History of amputation
• Pregnant
Definitions
Results
Excluded
(n=127)
Identified by
NE report
(n=1842)
Inclusion
Reviewed
(n=267)
Other VPs (n=35)
Cardiac Surgery
(n=21)
Neurology (n=14)
Cardiogenic shock
(n=14)
Hemorrhagic shock
(n=13)
Other (n=28)
• Adverse Effects
– Acute kidney injury: increase in SCr ≥ 0.5
from baseline
– Ischemic tissues: documented skin changes
or necrosis on physical exam
– Elevated liver enzymes: ≥ 2x baseline
BMI < 30
(n=50)
BMI 30 – 40
(n=50)
BMI > 40
(n=40)
Statistical Analysis
• Analyzed using Prism 5
• Chi squared test was used for categorical data
• ANOVA was used for 3-group comparison of
continuous data
• Student t-test was used for 2-group comparison
of continuous data
• P-value ˂ 0.05 considered statistically significant
Baseline Demographics
Characteristics
BMI < 30 BMI 30 – 40 BMI > 40
(n=50)
(n=50)
(n=40)
p-value
Male Gender+
37 (74)
27 (54)
12 (30)
<0.001
Age (years)**
54 ± 15
64 ± 14
58 ± 13
0.192
Weight (kg)**
74 ± 14
99 ± 15
137 ± 37
0.001
BMI**
25 ± 3
34 ± 3
50 ± 11
<0.001
Admitted from ED+
36 (72)
34 (68)
34 (85)
0.1674
SOFA score**
12 ± 5
12 ± 4
14 ± 3
0.0964
44 (88)
33 (85)
0.2653
3.0 ± 1.9
2.6 ± 1.7
0.1001
30.3
19.0
0.153
Mechanical Ventilation+
38 (76)
Crystalloid boluses prior to
3.5 ± 1.8
NE (L)**
Crystalloid boluses (mL/kg)**
47.3
+n
(%)
** Mean + SD
3
5/5/2015
Baseline Demographics
Line+
19 (38)
18 (36)
16 (40)
0.9268
28 (56)
25 (50)
25 (30)
0.4941
44 (90)
33 (87)
0.2004
BMI
80
p<0.001
70
60
37 (77)
BMI
Treatment with steroids+
Treatment with additional
VPs+
Presence of Arterial
Stratification of BMIs
BMI < 30 BMI 30 – 40 BMI > 40
p-value
(n=50)
(n=50)
(n=40)
Characteristics
50
Anti-hypertensive PTA+
Beta-blocker within 48 hours
prior to NE+
Anti-hypertensive within 48
hours prior to NE+
Appropriate antibiotics+
27 (54)
38 (76)
33 (83)
0.0070
13 (26)
9 (18)
14 (36)
0.1606
13 (26)
16 (32)
20 (50)
0.0515
10
49 (98)
50 (100)
50 (100)
0.4039
0
Negative cultures+
4 (8)
14 (28)
4 (10)
0.0115
40
30
20
< 30
30 - 40
> 40
BMI Groups
VP: Vasopressors
PTA: Prior to admission
+n (%)
Results – Primary Outcome
Results – Primary Outcome
• No difference in time to achieve adequate MAP > 65
mmHg among the 3 groups
• No difference in time to achieve adequate MAP > 65
comparing maximum dosing weight of 100 kg to total body
weight (< 100 kg)
Time (Hours)
Time to MAP > 65 mmHg for 3 Hours
p=ns
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
129 ±33 kg‡
< 30
30 - 40
BMI Groups
77 ± 14 kg‡
> 40
ns: not significant
Results - Dose at MAP Goal
‡Average
weight; TBW: total body weight
Results – Median NE Dosing
Dose at goal MAP-TBW
Dose (mcg/kg/min)
3.5
p=ns
3.0
*
2.5
*p=0.0229
2.0
1.5
1.0
0.5
0.0
< 30
30 - 40
> 40
BMI Groups
4
5/5/2015
Results – Patients on NE
Results – Reached 1 mcg/kg/min
p=ns
Results – Secondary Outcomes
Results – Reached > 3 mcg/kg/min
• Duration of NE was longer in the BMI > 40
group compared to the BMI < 30
p=ns
*p=0.01
*
*
Results – ICU and Hospital LOS
ICU Length of Stay
Hospital Length of Stay
p=ns
Ventilator Days
p=ns
< 30
< 30
0
5
10
Days
15
20
30 - 40
*
< 30
0
5
10 15
Days
20
> 40
BMI Groups
30 - 40
p=ns
*
> 40
BMI Groups
30 - 40
Mortality
*p=0.01
> 40
BMI Groups
> 40
BMI Groups
Results – Ventilator Days and Mortality
0
10
Days
30 - 40
< 30
20
0
50
Percent
100
NS: not significant
5
5/5/2015
Results – Adverse Effects
100
Acute Kidney Injury
Adverse Effects
*p=0.008
90
p=ns
30 - 40
70
Percent
p=ns
< 30
80
> 40
60
50
p=0.207
40
p=0.362
p=0.622
30
p=0.855
20
p=0.678
10
0
AKI
New CRRT Elevation of
Starts
AST/ALT
Tissue
Ischemia
Arrhythmias
NSTEMIs
HD: hemodialysis
Study Limitations
Conclusion
•
•
•
•
• No difference in time to achieve a MAP > 65
mmHg among the 3 groups
• Using a maximum dosing weight of 100 kg does
not prolong the time to goal MAP
• BMI > 40 had the longest duration of NE and
received the lowest volume of fluid resuscitation
• Ventilator days and incidence of AKI were the
highest in the BMI > 40 group
Retrospective analysis
Small sample of septic shock patients
No power calculation
Nurse driven titration of NE (not
standardized)
Learning Question #1
Learning Question #2
Which of the following describes how volume of
distribution is affected in obese patients?
Which of the following is the recommended
volume of fluid resuscitation for patients
with severe sepsis?
A.
B.
C.
D.
No changes are seen in volume of distribution
Decreased distribution of hydrophilic medications
Decreased distribution of lipophilic medications
Increased distribution of lipophilic medications
A.
B.
C.
D.
10 mL/kg bolus
20 mL/kg bolus
30 mL/kg bolus
40 mL/kg bolus
6
5/5/2015
Acknowledgements
• Krista Wahby, PharmD
• Linda A. Park, PharmD, BCPS
Impact of Body Mass Index on
Norepinephrine Requirements and
Hemodynamics in Septic Shock
Kara Zacholski, PharmD
PGY2 Critical Care
Detroit Medical Center, Detroit Receiving Hospital
[email protected]
The speaker has no actual or potential conflicts of interest in relation to this presentation.
7