1. Cost Considerations When Optimizing Sedation in the ICU
John W. Devlin, PharmD, FCCP, FCCM
Associate Professor
Northeastern University School of Pharmacy
Adjunct Associate Professor
Tufts University School of Medicine
Boston, Massachusetts
1) Optimizing patient comfort is a major goal when caring for patients in the ICU
2) Today, I would like to present a case of a 75 y/o lady I helped care for in the medical ICU at NEMC and who illustrates many of the dilemma that critical care pharmacists are faced with when trying to optimize patient comfort in the ICU
3) This case also provides a nice context for me to present some of the research I have completed in the first year of my fellowship 1

2. Faculty Disclosure
It is the policy of The France Foundation to ensure balance, independence, objectivity, and scientific rigor in all its sponsored educational activities. All faculty, activity planners, content reviewers, and staff participating in this activity will disclose to the participants any significant financial interest or other relationship with manufacturer(s) of any commercial product(s)/device(s) and/or provider(s) of commercial services included in this educational activity. The intent of this disclosure is not to prevent a person with a relevant financial or other relationship from participating in the activity, but rather to provide participants with information on which they can base their own judgments. The France Foundation have identified and resolved any and all conflicts of interest prior to the release of this activity.
Dr. Devlin has received grant/research support from Hospira. He has served as a consultant for AstraZeneca and Hospira.

3. Curriculum Learning Objectives
Manage adult patients who need sedation and analgesia while receiving ventilator support according to current standards and guidelines
Use validated scales for sedation, pain, agitation and delirium in the management of these critically ill patients
Assess recent clinical findings in sedation and analgesia management and incorporate them into the management of patients in the acute care and procedural sedation settings

4. Activity Learning Objectives
Understand the sedation-related factors that may influence patient care costs in the ICU
Discuss the influence of sedation protocolization and interruption on care costs
Compare the cost-efficiency of available sedation regimens in the ICU
Develop a cost-effective regimen for sedation in the ICU

5. ICU Sedation: The Balancing Act and Ventilatory Optimization
Patient Comfort
and Ventilatory Optimization
Oversedation
Prolonged mechanical ventilation
Increase length of stay
Increased risk of complications
- Ventilator-associated pneumonia
Increased diagnostic testing
Inability to evaluate for delirium G O A L
Undersedation
Patient recall
Device removal
Ineffectual mechanical ventilation
Initiation of neuromuscular blockade
Myocardial or cerebral ischemia
Decreased family satisfaction w/care
Jacobi J, et al. Crit Care Med. 2002;30: 5 5

6. Influence of Sedation Practices on Health Care Costs Outcomes and Costs of Undersedation
Tachycardia ⇨ myocardial ischemia
Use of neuromuscular blockers
Prolonged neuromuscular weakness common
Median $66,713 in additional costs (1995 costs)
Short and long-term psychological effects
Cost of device removal
10 patients removed 42 devices (GI/vascular)
74% were “significantly agitated” within 2 hr
Total $7606 or $181/event (1997 costs)
Annual cost at 42-bed ICU > $250,000
Dasta JF, et al. Crit Care Clin. 2009;25:
Rudis MI, et al. Crit Care Med. 1996; 24:
Fraser GL, et al. Pharmacotherapy. 2001;21:1-6. 6

7. Oversedation in the ICU Is Common
Payen J, et al. Anesthesiology. 2007;106:
Incidence of Inadequate Sedation
A recent abstract by Kaplan and Bailey reported observational data when blinded BIS values were collected during standard practice care on patients who were receiving continuous infusions of sedatives and neuromuscular blocking agents.
The results suggested that more than 54% of patients were receiving more sedation than was necessary, more than 15% were receiving less sedation than was necessary, and only about 31% were appropriately sedated.
References
1. Kress et al. N Engl J Med. 2000;342:
2. Dasta JF, et al. Crit Care Med. 2005;33:
N = 274 MICU patients
32% unarousable
21% no spontaneous motor activity
Little variation over 24 hours in LOC, motor activity, or drug dose given
RNs thought only 2.6% of patients were “oversedated” .
Weinert CR, et al. Crit Care Med. 2007;35:

8. Costs of Oversedation in the ICU
More days on mechanical ventilation = more of the costly negative
sequelae associated with mechanical ventilation:
– Ventilator-associated pneumonia:
Occurs in 10%-20% of patients receiving mechanical ventilation for > 48 hrs
Mean ICU LOS of 6.1 additional days (95% CI, )
Additional cost of evaluating and treating a patient with VAP = $10,019
– Venous thrombosis:
Incremental cost per event = $3,000 (in 2000 $)
Costs associated with increased use of head CT scan/neurology consult
Costs associated with increased frequency of sedation-related adverse
events and drug withdrawal effects
Propofol-related infusion syndrome
Lorazepam-related propylene glycol toxicity
Costs associated with increased neurocognitive sequelae
PTSD
Delirium
Safdar N, et al. Crit Care Med. 2005; 33:
Dasta JF, et al. Crit Care Clin. 2009; 25:
Devlin JW, et al. Crit Care Med (in press).
Gunther ML, et al. Crit Care Clin. 2007; 23:

9. Influence of Sedation Practices on Health Care Costs
ICU costs account for more than 1/3 of total inpatient costs
Incremental cost of mechanical ventilation = $1522 per day
Factors Affecting ICU Cost.
Health care consumes 14% of the United States’ gross domestic product; inpatient care is responsible for ~1/3 of these health care costs.
One of the largest cost drivers in the hospital setting is the intensive care unit (ICU), which despite accounting for 10% of the beds in U.S. hospitals, accounts for nearly 1/3 of total inpatient costs. Daily ICU care costs 3 to 5 times more than care provided on a general medical/surgical floor.
Much of this increased cost may be due to interventions such as mechanical ventilation (MV). Patients who require MV represent approximately 33% of all patients admitted to the ICU and incur a disproportionately high share of the total cost of ICU treatment.
Studies demonstrate that ICU patients who require >3 weeks of MV account for 50% of ICU cost. In addition to the economic consequences, it is well established that prolonged ICU stays and MV predispose patients to a greater risk of nosocomial infection and death.1
Incorporation of a daily sedation interruption policy into a medical ICU guideline can significantly reduce ICU stays and days of MV. Also, opioid administration and ICU complications are reduced in patients receiving daily sedation interruption2
References
1. Dasta JF, et al. Crit Care Med. 2005;33:
2. Wittbrodt ET. Pharmacotherapy. 2005;25(5 Pt 2):3S-7S.
Dasta JF, et al. Crit Care Med. 2005;33:

10. Influence of Sedation Practices on
Health Care Costs
Use of a spontaneous awakening–spontaneous breathing trial protocol reduces duration of mechanical ventilation and length of ICU stay
Outcome
SBT
SAT+SBT
P-value
Ventilator-free days 12 15
0.02
Time-to-event, days
Successful extubation 7 5
0.05
ICU discharge 13 9
0.01
Hospital discharge 19
0.04
Factors Affecting ICU Cost.
Health care consumes 14% of the United States’ gross domestic product; inpatient care is responsible for ~1/3 of these health care costs.
One of the largest cost drivers in the hospital setting is the intensive care unit (ICU), which despite accounting for 10% of the beds in U.S. hospitals, accounts for nearly 1/3 of total inpatient costs. Daily ICU care costs 3 to 5 times more than care provided on a general medical/surgical floor.
Much of this increased cost may be due to interventions such as mechanical ventilation (MV). Patients who require MV represent approximately 33% of all patients admitted to the ICU and incur a disproportionately high share of the total cost of ICU treatment.
Studies demonstrate that ICU patients who require >3 weeks of MV account for 50% of ICU cost. In addition to the economic consequences, it is well established that prolonged ICU stays and MV predispose patients to a greater risk of nosocomial infection and death.1
Incorporation of a daily sedation interruption policy into a medical ICU guideline can significantly reduce ICU stays and days of MV. Also, opioid administration and ICU complications are reduced in patients receiving daily sedation interruption2
References
1. Dasta JF, et al. Crit Care Med. 2005;33:
2. Wittbrodt ET. Pharmacotherapy. 2005;25(5 Pt 2):3S-7S.
Girard TD, et al. Lancet. 2008;371:

11. Pharmacist-Enforced Sedation Protocol
156 MICU patients prescribed continuous sedation
Protocol encouraged 25% down-titration when patients more sedated than goal
Before/after design evaluating impact of pharmacist promoting protocol on at least a daily basis.
P <
Median Days of Mechanical Ventilation
6.9
5.2
Marshall, J, et al. Crit Care Med. 2008;36 (2):

12. Influence of Sedation Practices on Health Care Costs: Delirium
Choice of sedative influences incidence of delirium
Delirium is associated with increased health care costs
$ 14,730
$50,000
$41,836
$40,000
All P ≤ 0.002
$ 9,014
$30,000
$27,106
Median Cost
$22,346
$20,000
$13,332
$10,000
Never Delirium (n = 41)
Ever Delirium (n = 183) $0
ICU Cost
Hospital Cost
Milbrandt EB, et al. Crit Care Med. 2004;32:

13. Characteristics of the Ideal ICU Pharmacoeconomic Study
Decision tree that is consistent with standard ICU care
Developed by multidisciplinary panel of experts
Includes all possible alternative therapies (eg, choice of sedative) as well as the most important positive and negative clinical outcomes
Use of rigorous RCT(s) to define efficacy
Cost estimates (ie, drug costs, patient charges etc) should be collected prospectively
Costs related to drug dispensing, administration, monitoring and adverse events should be included
Comprehensive sensitivity analysis
Hay JW, et al. Value Health Oct 28. [epub ahead of print]
Dasta JF, Kane-Gill SL. Crit Care Clin. 2009;25: 13

14. Cost-Effectiveness Analysis
Compares cost and outcomes of two different interventions
All costs are related to a single, common outcome
Duration of mechanical ventilation, mortality
Helps answer the question: Is a new therapy with a higher acquisition cost worth it?
A useful tool to help improve health care resource utilization at both the bedside and the institutional (eg, guidelines) level
Hay JW, et al. Value Health Oct 28. [epub ahead of print] 14

15. Cost-Effectiveness Analysis Outcomes
Intermediate effectiveness outcomes/surrogate endpoints
mm Hg blood pressure reduction
% serum cholesterol reduction
Duration at the targeted level of sedation
Final effectiveness outcomes
Mortality, years of life gained, presence of disease
Length of mechanical ventilation or ICU stay
Preferred but not easily measured
What is a reasonable common effect of measurement when comparing treatments for anxiolysis?
Frequency of side effects
Duration at target sedation score**
Nurse satisfaction with titrability
Duration of treatment with anxiolytic 15

16. Cost Minimization Analysis
Compares two or more treatments demonstrated to have equal efficacy
Cost is measured in dollars
A measure of efficacy (eg, duration of mechanical ventilation) is not measured since it is assumed to be equivalent between 2 groups
Helps the clinician(s) choose the least costly treatment
Hay JW, et al. Value Health Oct 28. [epub ahead of print] 16

17. Drug Acquisition Cost (70 kg patient, per day)
Lorazepam 3 mg/hr: $35
Midazolam 5 mg/hr $42
Propofol 30 mcg/kg/min: $150
Dexmedetomidine 0.5 mcg/kg/hr: $274
Tufts Medical Center 2010 Pricing 17

18. Propofol vs Continuous Midazolam
Randomized, unblinded pharmacoeconomic study
Considered sedation drug costs and costs associated with ICU care (eg, MD consult, RN care, testing, etc) but did not measure actual ICU LOS or charges associated with it
Propofol resulted in faster extubation time
LOS in the ICU and total cost per patient did not differ
Analysis of Covariance*
Extubation Time
Sedative Drug Cost
Coefficient
P-value
Constant
0.58
0.02
4.61
0.001
Treatment effect (TE)
Propofol vs midazolam
-1.43
1.27
Sedation time (ST)
0.003
0.04
0.007
Interaction TE x ST
-0.005
*Both extubation time and sedative drug cost were log-transformed 2
Anis A, et al. Anesthesiology. 2002;96:

19. Midazolam vs Lorazepam vs Propofol
Hypothetical cohort study
Compared the expected costs of short, intermediate and long-term sedation with propofol, lorazepam and midazolam
Preparation, administration, adverse drug reactions (ADRs), therapeutic failures
Relied on estimates from already published studies
MacLaren R, et al. Pharmacotherapy. 2005;

20. Midazolam vs Lorazepam vs Propofol
Total Cost ($)
Probability of Being Least Costly (%)
Short
Lorazepam
497
(13.5 hrs)
Midazolam
294 14
Propofol
272 86
Intermediate
932
(14.3 hrs)
587
97.5
674
2.5
Long
1604 84
(119.8 hrs)
1737 16
2003
MacLaren R, et al. Pharmacotherapy. 2005;

21. Carson SS, et al. Crit Care Med. 2006;34:1326-32.
Scheduled Intermittent Lorazepam vs Propofol with Daily Interruption in MICU Patients
Lorazepam (N = 64)
Propofol (N = 68)
P-value
Ventilator days (median)
8.4 (4.6 to 14.7)
5.8 (3.5 to 10.3)
0.04
ICU LOS
10.4 (6.7 to 16.8)
8.3 (5.2 to 15.2)
0.20
APACHE II
22.9 ± 7.7
20.7 ± 7.3
0.05
Daily sedation dose
11.5 (3.8 to 22.7) mg
24.4 ± 16.3 mcg/kg/min -
Morphine dose (mg/day)
10.7 (5.4 to 25.8)
31.6 (16.2 to 71.6)
0.001
Use of haloperidol
12% 9%
0.80
Carson SS, et al. Crit Care Med. 2006;34: 21

22. Intermittent Lorazepam vs Propofol
(DIS in both arms)
Comprehensive
MacLaren and colleagues also consider administration and prep time, ADEs such as VAP, post sedation agitation, neurologic changes…. NO one considered delirium AND delirium has gained substantial attention recently. In fact, BNZ use is an independent risk factor for delirium.
DIS= Daily Interruption of Sedation
Cox CE, et al. Crit Care Med. 2008;36: 22

23. Propofol Is More Cost-Effective Than Intermittent Lorazepam
Use of propofol associated with lower total costs ($45,631 vs $52,009)
Three more ventilator-free days with propofol
Propofol was less costly or more effective in 94% of the 1000 simulations
Cox C, et al. Crit Care Med. 2008;36:

24. Propofol is More Cost-Effective Than Intermittent Lorazepam
Propofol less expensive 2 `
0.5
Ratio of propofol to lorazepam MV days
Average duration of MV
Cost of ICU day
Hospital mortality
Cost of hospital ward day
Probability of propofol intolerance
Probability of lorazepam intolerance
Crossover group from propofol
Physician costs
Cost of propofol
Daily propofol dose, mg
Cost of lorazepam
Daily lorazepam dose, mg
Low
High
Lorazepam more
effective
$1,825
$9,488
75% 5%
$1,892
$631
20%
0%c
20% 0%
Lorazepam
Midazolam
High
Low
$11.37
$60.77
4,347
949
$0.81
$7.82 23 4
-$35
-$30
-$25
-$20
-$15
-$10
-$5 $0 $5
$10
$15
$20
$25
$30
$35
Cost Difference Between Lorazepam and Propofol ($ Thousands)
Cox CE, et al. Crit Care Med. 2008;36:

25. Addition of Dexmedetomidine to Midazolam and/or Propofol in Cardiac Surgery Patients Reduced Mean Total Treatment Charges
P < 0.05
12-month retrospective administrative claims database analysis
Comparison of patients receiving either midazolam plus propofol (M+P) or dexmedetomidine plus M+P (D+M+P)
The D+M+P cohort showed significant reductions in per patient total charges
Pharmacoeconomic Analysis: Reduced Mean Total Treatment Charges.
The primary outcomes for the D+M+P cohort showed significant reductions in per patient total charges (approximately $18,000, P<.05), total LOS (0.6 days, P<.0001), ICU/CCU days (3.87, P<.0001), and mortality (2%, P=.0142). While pharmacy charges were higher (approximately $4000 per patient), lower ICU/CCU, operating room, room/board, and respiratory charges were observed in the D+M+P cohort. Mechanical ventilation was also shorter by approximately 0.5 days in D+M+P (P<.0001).
Conclusions: These initial findings of a real-world assessment of dexmedetomidine use with other agents suggest favorable hospital clinical and economic outcomes. Further research to better understand the patient-mix, medication dosing, and causality is warranted through randomized clinical trials.
Reference
Dasta JF, et al. Pharmacotherapy. 2006;26:
M+P, n = 9996
D+M+P, n = 356
Dasta JF, et al. Pharmacotherapy. 2006;26:

26. Addition of Dexmedetomidine to Midazolam and/or Propofol in Cardiac Vessel Surgery Patients
Mean Total Charges
Mean Length of Stay
Mortality Rate
P < 0.05
P < 0.01
P =
Pharmacoeconomic Analysis: Reduced Charges, Hospitalization, and Mortality in Patients With Cardiac Vessel.
Procedures.
Similar to the general findings, cardiac surgery D+M+P patients appeared to have better outcomes than their M+P peers, averaging a half day shorter total length of stay, fewer days in the ICU/CCU, and a significantly lower mortality rate.
Reference
Dasta JF, et al. Pharmacotherapy. 2006;26:
M+P, n = 7577
D+M+P, n = 293
Dasta JF, et al. Pharmacotherapy. 2006;26:

27. MENDS: Dexmedetomidine Versus Lorazepam
Dexmedetomidine resulted in more days alive without delirium or coma (P = 0.01) and a lower prevalence of coma (P < 0.001) than lorazepam
Dexmedetomidine resulted in more time spent within sedation goals than lorazepam (P = 0.04)
Differences in 28-day mortality and delirium-free days were not significant 12 10 8
Days 6 4
MENDS: Dexmedetomidine Versus Lorazepam Effect on Acute Brain Dysfunction1
Investigators compared dexmedetomidine with lorazepam in 106 adult mechanically ventilated medical and surgical ICU patients to determine whether dexmedetomidine reduces the duration of delirium and coma in mechanically ventilated ICU patients while providing adequate sedation compared with lorazepam.
The main outcome measures were days alive without delirium or coma and percentage of days spent within 1 Richmond Agitation-Sedation Scale (RASS) point of the sedation goal.
Sedation with dexmedetomidine resulted in more days alive without delirium or coma (median days, 7.0 versus 3.0; P=.01) and a lower prevalence of coma (63% versus 92%; P <.001)
Patients sedated with dexmedetomidine spent more time within 1 RASS point of their sedation goal compared those sedated with lorazepam (median percentage of days, 80% versus 67%; P=-.04). The 28-day mortality in the dexmedetomidine group was 17% versus 27% in the lorazepam group (P =.18), and the cost was similar between both groups.
The investigators concluded that use of dexmedetomidine resulted in more days alive without delirium or coma and more time at the targeted level of sedation than with a lorazepam infusion.
Reference
1. Pandharipande PP, et al. JAMA. 2007;298: 2
Dexmedetomidine n = 52
Lorazepam n = 51
Delirium/Coma-Free
Days
Delirium-Free
Days
Coma-Free
Days
Pandharipande PP, et al. JAMA. 2007;298:

28. MENDS Trial: Cost of Care
Outcome
Lorazepam
Dexmedetomidine
P-value
Pharmacy
20.6 (10,42)
27.4 (16,46)
0.15
Respiratory
2.9 (2,6)
3.5 (2,7)
0.35
ICU cost
59.5 (36,83)
61.4 (37,108)
0.32
$ – Costs represented in thousands, US dollars (Median, IQR)
MENDS Trial: Cost of Care
Maximizing Efficacy of Targeted Sedation and Reducing Neurological Dysfunction (MENDS) Trial
This study was designed to determine whether dexmedetomidine reduced the duration of delirium and coma in mechanically ventilated ICU patients while providing adequate sedation, compared with lorazepam.
The median calculated cost for drug was $4675 in the dexmedetomidine group, and was $2335 in the lorazepam group. Across all charges, the median total hospital cost was $ higher in the dexmedetomidine group, but this difference was not statistically significant.
Reference
Pandharipande PP, et al. JAMA. 2007;298:
Pandharipande PP, et al. JAMA. 2007;298:

29. SEDCOM Trial: Efficacy Outcomes
Midazolam (n = 122)
Dexmedetomidine (n = 244)
P-value
Time in target sedation range, %
75.1
77.3
0.18
Patients completing daily arousal test
103 (84.3%)
225 (92%)
0.09
Patients requiring sedation interruption
112 (91.8%)
222 (91%)
0.85
Duration of sedation, days
4.1
3.5
0.01
Time to extubation, days
5.6
3.7
ICU length of stay, days
7.6
5.9
0.24
Delirium prevalence
93 (76.6%)
132 (54%)
0.001
Delirium-free days
1.7
2.5
0.002
Patients receiving open-label midazolam
60 (49%)
153 (63%)
0.02
Midazolam dose, mg/kg
0.11
0.65
Patients receiving fentanyl
97 (79.5%)
180 (73.8%)
0.25
Fentanyl dose, µg/kg
9.6
6.4
0.27
SEDCOM Trial: Efficacy Outcomes
There was no significant difference between groups in the primary end point of the percentage of time during which patients were within the targeted sedation range of -2 to +1 on the RASS.
Analyses of several secondary end points revealed various significant differences between the midazolam and dexmedetomidine treatment groups. Patients receiving dexmedetomidine had a shorter sedation duration and a shorter time to extubation. Additionally, patients receiving dexmedetomidine were less likely to experience delirium and had more delirium-free days than midazolam-treated patients.
In addition to the differences listed on the slide, patients treated with dexmedetomidine exhibited better communication, cooperation, and tolerance score than did patients receiving midazolam. These measures were associated with greater tolerance of the ICU and mechanical ventilation.
Reference
Riker RR, et al. JAMA. 2009;301:
Riker RR, et al. JAMA. 2009;301:

30. SEDCOM Trial Time to Extubation ICU Length of Stay P = 0.01 P = 0.24
Riker, RR, et al. JAMA. 2009;301:

31. SEDCOM Trial: Prevalence of Delirium
Midazolam
Dexmedetomidine
dexmedetomidine versus midazolam, P < 0.001
Long-Term Sedation: Dexmedetomidine Versus Midazolam
Delirium was assessed with the CAM-ICU scale. At baseline, 60.3% of patients receiving dexmedetomidine and 59.3% of patients receiving midazolam were CAM-ICU positive.
Analysis of delirium through a generalized estimating equation revealed a significant difference between groups; patients receiving dexmedetomidine exhibited a 24.9% decrease in delirium.
Reference
Riker RR, et al. JAMA. 2009;301:
Treatment Day
Sample Size
57 92
42 60
44 34
Riker RR, et al. JAMA. 2009;301:

32. A Cost Minimization Analysis of a Clinical Trial Dexmedetomidine vs Midazolam
Assumed equal sedation efficacy
Cost minimization analysis
Compared costs of care between groups and selected the therapy generating the lowest cost
Economic analysis performed post-hoc and from the institutional perspective
Costs were estimated from multiple databases and published literature
Dasta JF, et al. Crit Care Med. 2010;38:
Riker RR, et al. JAMA. 2009;301:
Dasta JF, et al. Crit Care Med. 2005;33:

33. A Cost Minimization Analysis of a Clinical Trial Dexmedetomidine vs
A Cost Minimization Analysis of a Clinical Trial Dexmedetomidine vs. Midazolam
Components of total ICU costs
Cost of ICU stay
Cost of mechanical ventilation
Cost of adverse drug reactions probably or possibly related to study drug
Acquisition cost of study drugs
Median regression approach was used to compare two treatment regimens
Dasta JF, et al. Crit Care Med. 2010;38:

34. SEDCOM Cost of Care Median drug costs Dex $1166 Midazolam $60
Total ICU patient savings with Dex: $9679
Reduced ICU stay
Reduced MV
Dasta JF, et al. Crit Care Med. 2010;38:

35. A Cost Minimization Analysis of a Clinical Trial Dexmedetomidine vs Midazolam
Dasta JF, et al. Crit Care Med. 2010;38:

36. Summary
Choice of sedation practices have a substantial influence on the cost of care in the ICU
Maintaining patients at the sedation goal through sedation protocolization (that may include daily sedation interruption) will avoid the costly sequelae of both under- and oversedation
Both propofol and dexmedetomidine are more cost- beneficial than benzodiazepines
Future studies need to evaluate the cost-effectiveness of propofol vs dexmedetomidine in non-cardiac surgery ICU patients