icu pharmacotherapy in disclosures special ......5/14/2015 1 icu pharmacotherapy in special...
Post on 25-Jun-2020
4 Views
Preview:
TRANSCRIPT
5/14/2015
1
ICU PHARMACOTHERAPY IN SPECIAL POPULATIONS:Part 1- General principles and drug dosing in morbid obesity
Jeffrey F. Barletta, Pharm.D., FCCMAssociate Professor & Vice ChairDepartment of Pharmacy PracticeMidwestern University, College of PharmacyGlendale, Arizona
Disclosures• Hospira, Inc.- Consultant• Cubist Pharmaceuticals- Consultant
Objectives• Part 1:
• Craft a dosing regimen for medication therapy in ICU patients using principles of dose individualization
• Develop a plan for crafting a medication regimen for a morbidly obese ICU patient.
• Part 2:• Describe the factors that influence drug dosing in patients on:
• Extracorporeal membranous oxygenation (ECMO)
• Renal replacement therapies (RRT)
• Molecular adsorbent recirculation systems (MARS)
How are ICU Patients Different?
Hyperdynamic
Altered fluid balance
End organ dysfunction
Artificial Organ support
Increased co-morbidities More medications
Augmented renal clearance
Increased chance for
failure
5/14/2015
2
Pharmacokinetic Alterations in Critical Illness
DistributionProtein binding
Body compositionVolume status
Absorption
Gut wall edemaGut stasisGI blood flowDrugsEnteral Nutrition
EliminationOrgan function
Blood flowInteracting drugs
Administered Dose
Effect Site Concentration
Pharmacologic Effect
Vdc Vdp
Dose Individualization
Principles of Dose Individualization • Pharmacokinetic evaluation
• Pharmacodynamic evaluation• Organism MIC• Time dependent vs. concentration dependent
• Loading doses
• Use of prolonged or continuous infusions
• Therapeutic drug monitoring
Therapeutic Drug Monitoring:Beta-lactams
Goal = Trough concentration 4 – 5 x MIC but not > 10 x MIC
Antibiotic
Pip/Tazo
Meropenem
Cefazolin
Ceftriaxone
Dose Maintained
23%
16%
0%
67%
n
116
51
6
33
Dose Increased
49%
57%
100%
21%
Dose Decreased
28%
27%
0%
12%
Roberts, et al. Int J Antimicrob Agents 2010;36:332-9.
5/14/2015
3
Are Recommended Doses High Enough?
0% 20% 40% 60% 80% 100%
TOTAL
Meropenem
Piperacillin
Doripenem
Ceftriaxone
Cefepime
Cefazolin
100% T > MIC
50% T > MIC
Roberts, et al. Clin Infect Dis 2014;58:1072-83.
(3 gm/day)
(6 gm/day)
(2 gm/day)
(1.75 gm/day)
(12 gm/day)
(3 gm/day)
*doses shown represent median dose/day
Augmented Renal Clearance
0%
20%
40%
60%
80%
100%
1 2 3 4 5 6 7Study Day
***65% of patients manifested ARC on at least one occasion***
Udy, et al. Crit Care Med 2014;42:520-27.
Augmented Renal Clearance
CrC
l
Study Day
Trauma
Surgical Emerg
Elective
Emergency
Udy, et al. Crit Care Med 2014;42:520-27.
DRUG DOSING IN MORBID OBESITY
5/14/2015
4
Prevalence of Obesity in the U.S.2011 – 2012
0
10
20
30
40
50
60
70
BMI ≥ 25 BMI ≥ 30 BMI ≥ 35 BMI ≥ 40
69
35.1
14.56.4
Ogden, et al. JAMA 2014;311:806-14.
Adults ≥ 20 years old
Size Descriptors• Total body weight• Ideal body weight
• Surrogate for LBW• Devine method [50 (if ♂) or 45.5 (if ♀) + 2.3 kg/inch > 5 ft]
• Lean body weight• ♂: (9270 x TBW) / (6680 + 216 x BMI)• ♀: (9270 x TBW) / (8780 + 244 x BMI)
• Adjusted body weight• Originated from aminoglycoside dosing• Correction factor usually 0.4 but much variability exists
• Body mass index• Descriptor used to characterize obesity
• Body surface area• Limited evidence to support it’s use• Oncology medications Devine. Drug Intell Clin Pharm 1974;8:650-5.
Janmahasatian, et al. Clin Pharmacokinet 2005; 44:1051-65.Bauer, et al. Eur J Clin Pharmacol 1983;24:643-7.
Limitations of Size DescriptorsAll weights are not created equal
Generalized Treatment Approach• Published dosing recommendations are usually appropriate for
patients with mild to moderate forms of obesity (BMI < 35 kg/m2).
• The 2 independent PK parameters used to describe drug distribution are volume of distribution (Vd) & clearance (Cl).
• Drugs with a small Vd do not widely distribute into adipose tissue.
• Large Vd does not necessarily mean high lipophilicity.
• Clearance tends to increase with increasing size but to what extent is variable.
• Don’t forget about ADE’s.
5/14/2015
5
Estimating Clearance
Method
Measured CrCl
Cockcroft-Gault (TBW)
Cockcroft-Gault (IBW)
Cockcroft-Gault (AdjBW 0.3)
Cockcroft-Gault (AdjBW 0.4)
Cockcroft-Gault (LBW)
Salazar-Corcoran
Mean ± SD
110 ± 44
217 ± 113
85 ± 29
129 ± 55
142 ± 63
102 ± 43
155 ± 65
Bias
-
-107 (-133, -82)
+24 (15, 34)
-20 (-32, -8)
-32 (-46, -19)
+8 (-2.6, 19)
-46 (-60, -32)
Interpretation
Reference
Overestimate
Underestimate
Overestimate
Overestimate
Underestimate
Overestimate
Demirovic, et al. Am J Health-Syst Pharm 2009;66:642-8.
Treatment Algorithm
Evaluate clinical trials
Evaluate pharmacokinetic trials
Assess for dose proportionality
Search for studies with similar agents
Consider an alternative agent
Drug Dosing in Morbid Obesity:ANTICOAGULANTS
Patient Case• 64 year old female who is admitted to the ICU following
surgery to repair her hip which she fractured secondary to a ground-level fall. Her weight is 160 kg (BMI = 47 kg/m2) and her SCr = 0.9 mg/dL.
• What therapy should we give for VTE prophylaxis?
A. Enoxaparin 40 mg sub-q daily
B. Enoxaparin 40 mg sub-q twice daily
C. Enoxaparin 80 mg sub-q daily
D. Enoxaparin 80 mg sub-q twice daily
E. Heparin 5,000 units sub-q thrice daily
5/14/2015
6
BMI-Adjusted Enoxaparin Dosing Strategy: Anti Xa-Levels
Borkgren-Okonek, et al. Surg Obes Relat Dis 2008;4:625-31.
0
10
20
30
40
50
60
70
80
BMI ≤ 50 BMI > 5040 mg Q 12 hr 60 mg Q 12 hr
N=124Wt = 126 kg; BMI = 45
N=99Wt = 161 kg; BMI = 57
Anti-Xa levels:
Subtherapeutic(< 0.18)
Therapeutic (0.18 – 0.44)
Supratherapeutic(> 0.44)
Enoxaparin in Surgical ICU Patients: Anti-Xa Levels
Enoxaparin 0.5 mg/kg Q 12 hoursWeight = 137 kg (range, 97 – 267)BMI = 46.4 kg/m2 (range, 36 – 77)
91% Mean = 0.34 IU/ml
DVT = 1/23Major bleeding = 0Minor bleeding = 1/23
Ludwig, et al. Ann Pharmacother 2011;45:1356-62.
Enoxaparin Dose in Bariatric Surgery: Incidence of VTE
0%
2%
4%
6%
8%
10%
30 mg BID 40 mg BID
Post-op VTE
5.4%(5/92) 0.5%
(2/389)
(BMI = 51.7) (BMI = 50.4)
* p<0.01
Scholten, et al. Obes Surg 2002;12:19-24.
What can we conclude…
• Most data are with enoxaparin
• Doses higher than 40 mg daily are required
• Exactly how much higher is not clear
• Bariatric surgery versus critically ill patients
5/14/2015
7
Patient Case- Clinical Course• It is POD#3 and the patient complains of pain and swelling in her left leg. Ultrasound confirms a DVT.• Hgb & Hct = 9 g/dL & 27%• SCr = 1.0 mg/dL• Weight = 160 kg
• How should we treat the DVT?
A. Unfractionated heparin
B. Low molecular weight heparin
C. IVC filter
Heparin
• Volume of distribution is similar to blood volume.
• Published nomograms are based on TBW.• 80 unit/kg bolus• 18 units/kg/hr infusion
• Few studies have included large numbers with morbid obesity.
Heparin Response & Obesity
P=.005
Barletta JF, et al. Surg Obes Relat Dis 2008;4:748-53
Morbidly Obese Non-Morbidly Obese(BMI = 53; Wt = 151 kg) (BMI = 31; Wt = 97 kg)
Supra-therapeutic aPTT Values & BMI
BMI Group
Pat
ient
s w
ith S
upra
-the
rape
utic
aP
TT
P=.018
5/14/2015
8
Unfractionated Heparin in a 388 kg Patient
Myzienski, et al. Pharmacotherapy 2010;30:105e-12e.
Final infusion rate = 3650 units/hour 9.4 units/kg/hr (TBW)
18.7 units/kg/hr (AdjBW)
aPTT Heparin dose
Patient Case- Clinical Course
The hospital is experiencing a critical shortage of unfractionated heparin. What is your strategy for dosing LWMH in this patient?
A. Actual body weight with a dose capping strategy
B. Actual body weight but no dose capping strategy
C. Adjusted body weight
D. Ideal body weight
Clinical Studies in Obese Patients
PharmacodynamicYee, 2000Wilson, 2001Barrett, 2001Sanderink, 2002Hainer, 2002Smith, 2003Bazinet, 2005
Clinical Outcomes/VTEMerli, 2001Al-Yaseen, 2005RIETE, 2005
Clinical Outcomes/ACSFRISC, 1996Klein, 1997Spinler, 2003
10378124352181
283193294
356NA921
NObese Pts
DalteparinDalteparinEnoxaparinEnoxaparinTinzaparinDalteparinEnoxaparin
EnoxaparinDalteparin
NA
DalteparinDalteparinEnoxaparin
Drug
10690
100130118
-
81114112
--
94
Avg. Wt (kg)
-56-190
78-144101-16594-176
-
44-15591-182101-160
47-12542-12560-159
Wt. Range (kg)
Nutescu, et al. Ann Pharmacother 2009;43:1064-83.
Clinical Outcomes: Enoxaparin & Obesity
Spinler, et al. Am Heart J 2003;146:33-41.
Age (yrs)
Weight (kg)
BMI (kg/m2)
Any Hemorrhage
Major Hemorrhage
61 ± 11
94 ± 14
33.8 ± 4
8.5%
0.8%
65 ± 12
73 ± 11
25.4 ± 2.8
6.8%*
1.3%
Obese(n=921)
Non-Obese(n=2595)
Subgroup Analysis from the ESSENCE and TIMI 11B Studies
*p=.004
5/14/2015
9
Clinical Outcomes: Enoxaparin & Obesity
0
2
4
6
8
10
12
≤ 100 101-120 121-150 > 150
6.6
4.6
5.6
11.4
Maj
or B
leed
ing
Rat
e (%
)
The CRUSADE Initiative
Spinler, et al. Pharmacotherapy 2009;29:631-38.
Enoxaparin Dosing & Bleeding rates
TBW (kg)
≤ 100
101 – 120
121 – 150
> 150
9.6%
7.3%
6.1%
6.5%
6.6%
4.6%
5.6%
11.4%
0.78 (0.69 – 0.89)
0.68 (0.48 – 0.95)
0.99 (0.57 – 1.7)
2.42 (0.7 – 8.37)
ReducedDose
RecommendedDose
Adjusted OR(95% CI)
Bleeding Rates
Reduced dose: < 0.95 mg/kgRecommended dose: 0.95 – 1.05 mg/kg
Spinler, et al. Pharmacotherapy 2009;29:631-38.
Drug Dosing in Morbid Obesity:ANTIMICROBIALS
Ph’kinetic / Ph’dynamic Principles
Cmax
MICT>MIC PAE
Time
Con
cent
ratio
n
Cmax:MIC
AUIC
Cmin
5/14/2015
10
Ph’kinetic / Ph’dynamic Alterations with Obesity
Cmax
MICShorterT>MIC
PAE
Time
Con
cent
ratio
n
Decreased Cmax:MIC
Decreased AUIC
Cmin
Pharmacokinetic / Pharmacodynamic Considerations
Clinical success
Drug Dose
Drug Concentration at Effect Site
PD goalsAchieved
T > MICAUIC
Cmax:MIC
Pharmacologic Effect
?
Drug Dose
Drug Concentration at Effect Site
PharmacokineticVariability
PD Goals
???
Surgical Prophylaxis: Cefazolin
0 2 4 6 8
BMI>50 : Cefazolin 3 gm
BMI>50 : Cefazolin 2 gm
BMI>40 : Cefazolin 2 gm
Hours
T>MIC
Protective duration
(*MIC = 8)
(*T>MIC = 70%)
Ho, et al. Surgical Infect 2012;13:33-7.
(Mean BMI = 44 ± 3)
(Mean BMI = 56 ± 9)
(Mean BMI = 55 ± 3)
Tissue Concentrations: Cefazolin 2 gm x1
Non-obese, after 180 minObese, after 120 min
Non-obese, after 240 min
Obese, after 180 min
Obese, after 240 min
Non-obese, after 120 min
Pro
babi
lity
of ta
rget
atta
inm
ent
Brill, et al. J Antimicrob Chemother 2014;69:715-23.
5/14/2015
11
Piperacillin/tazobactam in a Trauma/Surgical ICU
Sturm, et al. Pharmacotherapy 2014;34:28-35
Dose
3.375 g every 8 hours
3.375 g every 6 hours
3.375 g every 6 hours
4.5 g every 8 hours
4.5 g every 6 hours
4.5 g every 6 hours
Infusion
4
0.5
4
4
0.5
4
MIC
1632
1632
1632
1632
1632
1632
PD Goal Achieved
100%29%
100%78%
100%62%
100%93%
100%100%
100%100%
9 ICU patients
TBW = 164 kg
BMI = 57
Cefepime in Bariatric Surgery
0
20
40
60
80
100
120
0.0625 0.125 0.25 0.5 1 2 4 8 16
10 patients; wt = 139 kg; BMI = 48
Rich, et al. Obes Surg 2012;22:465-71.
% T
ime
> M
IC
MIC (mg/L)
2 gm Q8 hrs2 gm Q12 hrs
Meropenem in ICU Patients
Cheatham, et al. J Clin Pharmacol 2013;54:324-30.
9 ICU patients
Weight = 152 kg
BMI = 55
Levofloxacin Pharmacodynamics
MIC
Time
Con
cent
ratio
n AUIC
PD Goals:Gram +: AUIC > 35Gram - : AUIC > 125
Levofloxacin 750 mg Q24; AUC ≈ 108
MIC ≈ 0.86
Ortho-McNeil. Levofloxacin (Levaquin) package insert. 2008.
5/14/2015
12
Levofloxacin- PK / PD in Obesity
Vd = 83 L; T½ = 7 hrsAUC = 90
MIC threshold = 0.72
Vd = 80 L; T½ = 7.9 hrsAUC = 108
MIC threshold = 0.86
Cook, et al. Antimicrob Agents Chemother 2011;55:3240-3.Ortho-McNeil. Levofloxacin (Levaquin) package insert. 2008.
15 Obese Patients(Wt = 162 kg; BMI = 55) Non-Obese Patients
Aminoglycosides• Antibiotic class with the most data in obesity.
• Both Vd and Cl are increased but much variability.
• Adjusted body weight is recommended.
• Comfort level with large doses may hinder ability to reach goal concentrations in a timely fashion.
Vancomycin• PK alterations with obesity:
• Increased Vd (13% - 49%) • Increased Cl (131-156%)
• PK parameters better correlated with TBW.
• “For obese patients, initial dosing can be based on TBW and then adjusted based on serum concentrations” (Grade A, LOE = II)
Blouin R, et al. Antimicrob Agents Chemother 1982;21:575-80.Pai MP, Bearden DT. Pharmacotherapy 2007;27:1081-91.Rybak, et al. Am J Health-Syst Pharm 2009;66:82-98.
Bauer, et al. Eur J Clin Pharmacol 1998;54:621-5.
Vancomycin: Pharmacokinetic Alterations
0 50 100 150 200 250 300TBW
Cle
aran
ce
350
300
250
200
150
100
50
0
0 50 100 150 200 250 300TBW
100
80
60
40
20
0Vol
ume
of D
istr
ibut
ion
Volume of Distribution Clearance
R=0.490, p<.05 R=0.948, p<.001
5/14/2015
13
5,000 simulated patients
Is Trough the Right Parameter?Distribution of Vancomycin Trough Values with AUC ≥ 400
Median: 13.3 (1.9 – 72.6)
Neely, et al. Antimicrob Agents Chemother 2014;58:309-16.
Vancomycin & Outcome: Trough vs. AUC?
MIC ≥ 1.5
Vanco trough 15 – 20 mg/L
AUC : MIC < 430 (Etest)
AUC : MIC < 399 (BMD)
Success
30%
18%
25%
23%
Failure
45%
30%
50%
45%
P-value
.236
.338
.039
.065
Multivariate Analysis:
AUC : MIC < 430 (Etest):OR (95% CI) = 4.39 (1.26 – 15.35), p=.02
AUC : MIC < 399 (BMD):OR (95% CI) = 3.73 (1.1 – 12.61), p=.034
Jung, et al. Int J Antimicrob Agents 2014;43:179-83.
Linezolid
Wt
BMI
AUC
Cmax
Vd (L)
Cl (L/hr)
Moderate Obesity
99 ± 14
36.2 ± 1.7
130 ± 60
20.9 ± 5
44.1 ± 10
7.83 ± 1.77
Morbid Obesity
120 ± 16
45.3 ± 3.2
109 ± 26
18.8 ± 2.6
62 ± 40
7.39 ± 2
P-value
-
-
.320
.237
.089
.619
Bhalodi, et al. Antimicrob Agents Chemother 2013;57:1144-49.
20 Adult Volunteers; Dose = 600 mg Q 12hrs
Linezolid
Wt
BMI
AUC
Cmax
Vd (L)
Cl (L/hr)
Moderate Obesity
99 ± 14
36.2 ± 1.7
130 ± 60
20.9 ± 5
44.1 ± 10
7.83 ± 1.77
Morbid Obesity
120 ± 16
45.3 ± 3.2
109 ± 26
18.8 ± 2.6
62 ± 40
7.39 ± 2
P-value
-
-
.320
.237
.089
.619
Bhalodi, et al. Antimicrob Agents Chemother 2013;57:1144-49.Muzevich, et al. Ann Pharmaocther 2013;47:e25
20 Adult Volunteers; Dose = 600 mg Q 12hrs
Case Report
265 kg
82 kg/m2
-
4.13
FAILURE
5/14/2015
14
Conclusion• Drug dosing in ICU patients should be individualized.
• High quality evidence in the critically ill obese patient is lacking.
• Assess for principles of dose proportionality.
• Consider ADE’s.
• Attainment of pharmacodynamic goals must be considered.
top related