1. Critical Care Pharmacology
Monika Makowiecki, PharmD
PGY2 Critical Care Pharmacy Resident
July 8, 2019

2. Objectives
Review guideline recommendations for the management of ICU sedation and delirium
Apply primary literature to the management of vasopressors in the ICU

3. Patient Case
JS is a 75 year old female with HTN, DM, and dyslipidemia admitted for septic shock secondary to community-acquired pneumonia. She required emergent intubation due to acute respiratory failure. How will the “sedation” of this patient be managed?

4. Definitions Pain Sedation Agitation Delirium
Unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage
Pain
State of quiet or calmness induced by sedation medication
Sedation
Psychomotor disturbance with marked increase in motor and psychological activity
Agitation
Acute onset cerebral dysfunction with change or fluctuation in baseline mental status, inattention and either disorganized thinking or an altered level of consciousness
Delirium
Crit Care Med 2002;30: Crit Care Med 2007;11(3): Crit Care Med 2013; 41: Crit Care Med 2018; 46(9) e

5. ABCDEF Bundle For optimizing ICU patient recovery and outcomes
Evidence-based
Bundle elements individually and collectively can help reduce delirium, improve pain management and reduce long-term consequences for adult intensive care unit (ICU) patients
Crit Care Clin 2017;33(2):

6. Pain

7. Pain in the ICU
Incidence of pain is > 50% in both medical and surgical ICU patients
82% of patients remembered pain of ETT
77% of patients remembered experiencing moderate to severe pain during ICU stay
Causes of pain
Trauma/burns
Surgery/procedures/wound care/suctioning
Lines, tubes, drains
Turning
“What’s routine to us is hardly
routine to the patient”
- G Fraser
Crit Care Med 2013; 41: Crit Care Med 2018; 46(9) e

8. 2018 PADIS Guidelines Treatment of Pain Assessment of Pain
Patients able to reliably communicate:
Self-report of pain via NRS is the reference standard (ungraded)
Patients unable to reliably communicate:
BPS and CPOT demonstrate greatest validity and reliability (ungraded)
Guidelines recommend AGAINST
Use of vital signs alone as indicators for pain (ungraded)
Vital signs should be used as a cue (ungraded)
Analgesia first:
Optimize analgesia before adding sedative agent*
Utilize lowest effective dose of opioid (conditional, moderate)
Adjunctive agents for pain management (conditional, VL):
Acetaminophen and NSAIDs
Low-dose ketamine
Neuropathic pain medication (gabapentin, carbamazepine, pregabalin)
Carbamazepine is a CYP 3A4 inducer
PADIS – pain, agitation, delirium, immobility, sleep
NRS – numeric rating scale
BPS – behavioral pain scale
CPOT – critical care pain observation tool
*May not be appropriate for pts with alcohol or drug withdrawal, pts necessitating neuromuscular blockade, pts with elevated ICP, and status epilepticus
Crit Care Med 2018; 46(9) e

9. Analgesia Opioids Usual dose range Elimination Fentanyl
mcg/hr or mcg IVP
Hepatic (CYP3A4)
Hydromorphone
mg/hr or mg IVP
Hepatic (active metabolite is renally cleared)
Morphine
mg/hr or 1-4 mg IVP
Hepatic (active metabolite is renally cleared)
Remifentanil
mcg/kg/min
Plasma esterase
Non-Opioids
Usual dose range
Elimination
Acetaminophen
mg q 6 hrs (IV-not available, PO, PR)
Hepatic
Ibuprofen
mg q 6 hrs (IV, PO)
Renal
Ketorolac
10-30 mg q 6 hrs (IV, PO)
Ketamine
0.5 – 1 mg/kg (IV) or 10 mg (Intranasal)
Carbamazepine
50 – 100 mg BID (PO)
Gabapentin
1200 – 3600 mg divided TID (PO)
J Pharm Pract 2011;24: Chest. 2008;133: Crit Care Med 2013;41:

10. Agitation/Sedation

11. Agitated Coma Agitation in the ICU
Combative: procedures held, pulling at lines/tubes/drains
Increased ICU and hospital LOS,
fewer MV-free days, delirium, mortality
Crit Care Med 2018; 46(9) e
Crit Care Med 2013;41:

12. 2018 PADIS Guidelines and 2013 PAD Guidelines:
Pain, Agitation, Delirium
Recommend RASS and SAS as the most valid and reliable tools for evaluating sedation in ICU patients (B)
Suggest light sedation vs deep sedation (conditional, low)
Suggest propofol or dexmedetomidine over benzodiazepines for sedation (conditional, low)
Suggest propofol over benzodiazepines for sedation in adults after cardiac surgery (conditional, low)
Recommend daily interruption (unless contraindicated) or light target level of sedation (+1B)
Recommend promoting sleep by optimizing patients’ environments (+1c)
RASS – Richmond Agitation Sedation Scale
SAS – Sedation Agitation Scale
Crit Care Med 2018; 46(9) e
Crit Care Med 2013;41:

13. RASS Scale
Crit Care Med 2013;41:

14. Sedatives Sedative Dose range Clearance Propofol 5 - 100 mcg/kg/min
Hepatic (conjugation)
Dexmedetomidine
mcg/kg/hr
Hepatic
Midazolam
mg/hr, mg IVP
Hepatic (CYP3A4, active metabolite renally cleared)
Lorazepam
mg/hr,
2 - 6 mg IV/PO q4 - 6 hrs
Loyola max ranges
Dex: (bolus of mcg/kg rarely given due to risk of hypotension/bradycardia)
J Pharm Pract 2011;24:27-34 Chest 2008;133:

15. Daily Interruption and Light Sedation
Study
Patients
Intervention
Outcome
Strom et al.
ICU patients requiring MV (n=140)
No sedation vs. sedation
Propofol for 1st 48 hrs, then midazolam
Both groups received boluses of morphine
Higher MV-free days (13.8 vs. 9.6 days, p=0.0191)
Shorter ICU LOS (13.1 vs 22.8 days, p=0.0316)
Shorter hospital LOS
Higher agitation rates
Girard et al.
ICU patients requiring MV (n=336)
Daily spontaneous awakening trial + SBT vs. sedation/usual care + SBT
Higher MV-free days (14.7 vs 11.6 days, p=0.02)
Shorter ICU/hospital LOS
More self-extubations but reintubation rates similar
LOS: length of stay
MV: mechanical ventilation,
SBT: spontaneous breathing trial
Caution in substance abuse, seizures
If light sedation goal (e.g., RASS 0 to -1), daily interruption may not be necessary
In NO sedation group, there was higher MV-free days, shorter ICU LOS, shorter hospital LOS but higher rates of agitation
Lancet 2010;375: Lancet 2008;371:

16. MIDEX/PRODEX Trials
Patients requiring mechanical ventilation > 24 h
Two phase 3 multicenter, randomized, double-blind trials
MIDEX: midzolam + dexmedetomidine
PRODEX: propofol + dexmedetomidine
Endpoints:
Primary: Proportion of time in target range (RASS 0 to -3), duration of mechanical ventilation (MV)
Secondary: ICU LOS, patient cooperation
Results:
No difference in time in target sedation or duration of MV between MIDEX/PRODEX
No difference in ICU LOS
Significant difference in patient cooperation/interaction in both MIDEX/PRODEX
JAMA. 2012;307(11):

17. MIDEX/PRODEX Trials ADEs Limitations
More bradycardia/AV-block with dexmedetomidine
1/10 patients won’t respond to dexmedetomidine
Limitations
Patients in MIDEX trial received significantly less dexmedetomidine
~ ½ the dose compared to patients in PRODEX trial
Patients in MIDEX trial received significantly higher total dose of rescue medications
Patients with light to moderate sedation  no patients received deep sedation
Selection bias  very slow enrollment rate
Limitations: now what doses of Dex they gave
JAMA. 2012;307(11):

18. Delirium

19. Delirium in the ICU Affects ~ 80% of mechanically ventilated adults
Cardinal signs/symptoms
Disturbed level of consciousness  reduced clarity/awareness
Reduced ability to focus, sustain, shift attention
Change in cognition  memory deficit, disorientation, language disturbance
Types of Delirium
Hyperactive: hallucinations and delusions
Hypoactive: confusion and sedation (often misdiagnosed)
Mixed: combination of hyperactive and hypoactive
Crit Care Med 2013;41:

20. 2018 PADIS and 2013 PAD Guidelines
Recommend routine monitoring for delirium using a validated tool (+1B)
Recommend CAM-ICU and ICDSC as the most reliable and valid tools for assessment of delirium in ICU patients (B)
Monitoring
CAM-ICU – confusion assessment method for the ICU
ICDSC – intensive care delirium screening checklist
PADIS – pain, agitation, delirium, immobility, sleep
PAD – pain, agitation, delirium
CAM-ICU – confusion assessment method for the ICU
ICDSC – intensive care delirium screening checklist
Crit Care Med 2018; 46(9) e
Crit Care Med 2013;41:

21. 2018 PADIS and 2013 PAD Guidelines
Suggest against haloperidol, atypical antipsychotics, dexmedetomidine, HMG-CoA reductase inhibitors, or ketamine for delirium prevention (conditional, VL)
Suggest not routinely using haloperidol, an atypical antipsychotic, or an HMG-CoA reductase inhibitor to treat delirium (conditional, low)
Suggest using dexmedetomidine for delirium in mechanically ventilated adults where agitation is precluding weaning/extubation (conditional, low)
Suggest utilizing nonpharmacologic interventions to reduce modifiable risk factors for delirium such as improving cognition, optimizing sleep, mobility, hearing, and vision (conditional, low)
Management:
PADIS – pain, agitation, delirium, immobility, sleep
PAD – pain, agitation, delirium
Crit Care Med 2018; 46(9) e
Crit Care Med 2013;41:

23. Atypical Antipsychotics for Delirium
Medication
(route)
Dosing
Sedation
EPS
QTc Prolongation
Comments
Quetiapine
(PO, NG)
mg BID ++ +
+++
Consider for hyperactive delirium or agitated mixed delirium
Larger PM vs. AM doses may help with sleep cycle
Risperidone
0.5 mg BID
Consider for hypoactive delirium
Less sedating and less likely to cause hypotension due to no histamine receptor activity
Asenapine
(SL, NG)
5-10 mg BID
Lowest risk of QTc prolongation
Sublingual tablet
Olanzapine
(IM, PO, NG, SL)
PO: 5-20 mg daily IM: 5-10 mg PRN
(max 30 mg/day)
Consider in patients with hyperactive delirium and no enteral access
Ziprasidone
(IM, PO, NG)
PO: mg BID
IM: 10 mg q2 hours or
20 mg q4 hours (max 40 mg/day)
High risk of QTc prolongation

24. Early mobilization
Physical inactivity contributes to muscle atrophy, atelectasis, insulin resistance, reduced quality of life
Early PT/OT associated with lower sedative use, delirium rates and higher rates of independent functional status at discharge
Lancet 2009;373: Arch Phys Med Rehabil 2010;91:

25. Case Revisited
JS is a 75 year old female with HTN, DM, and dyslipidemia admitted for septic shock secondary to community-acquired pneumonia. Overnight she required emergent intubation for acute respiratory failure
The ABCDEF order-set was used to order fentanyl and propofol for analgesia and sedation
She is now requiring fentanyl at 75 mcg/hr and propofol at 40 mcg/kg/min
Subsequently, she is hypotensive despite adequate fluid resuscitation. How will you manage her vasopressor therapy?

26. Vasopressors

27. Sympathetic Receptors
Alpha 1 receptors (α1)
Located in heart and blood vessels
↑ Contractility
↑ Vasoconstriction
Dopaminergic
Located in vascular smooth muscle
Renal, coronary, cerebral, splanchnic
↑ Vasodilation
Beta 1 receptors (β1)
Located in heart
↑ Heart rate
↑ Contractility
↑ Rate of conduction
Beta 2 receptors (β2)
Located in bronchial and GI smooth muscle and blood vessels
↑ Vasodilation
Bronchodilation
Relaxation of GI smooth muscle

28. Vasopressors Isoproteronol β Dobutamine Dopamine Epinephrine
Norepinephrine
Phenylephrine α

29. Norepinephrine (Levophed®)
FIRST LINE agent for most types of shock
Potent α and β agent
Good agent to  SVR in high output shock
Actions
0.01 to 3 mcg/kg/min
Central line administration strongly preferred!
May be used peripherally (only the 8 mg/250 mL concentration) in emergent situations and requires central access within 4 hours
Dosing
8 mg/250 mL
16 mg/250 mL (central line only)
Concentrations
Both premixed

30. Vasopressin (Vasostrict®)
V1 receptors on vascular smooth muscles
Typically used as 2nd line pressor to decrease norepinephrine requirements
Useful in septic shock, when added to norepinephrine in fluid resuscitated patients
Actions
Fixed-dosage: 0.04 units/min
Should NOT be titrated when used for septic shock
Higher doses cause constriction of coronary arteries
Dosing
20 units/100 mL (central line only)
100 units/100mL (central line only)
Concentration
Less clear role in other shock states
20 – premixed
100 - compounded

31. Vasopressin Primary Literature
Trial
Patient Population
Study Arms
Primary Endpoint
Conclusion
VASST
Patients with septic shock resistant to fluids and low-dose norepinephrine
(> 5 µg/min)
Norepinephrine (n = 396):
Titrated from 5 µg/min to 15 µg/min
Vasopressin (n = 382):
Titrated from 0.01 to 0.03 units/min
28-day mortality
No significant difference in mortality
Trend toward reduced 28 and 90-day mortality with vasopressin in patients with less-severe shock
VANISH
Patients with septic shock requiring vasopressors within 6 hours after shock onset
Vasopressin + Hydrocortisone (n = 101):
Vasopressin + Placebo (n = 104):
Vasopressin titrated to 0.06 units/min
Norepinephrine + Hydrocortisone (n = 101):
Norepinephrine + Placebo (n = 103):
Norepinephrine titrated to 12 mcg/min
IV Hydrocortisone taper:
50 Q6h x 5 days -> Q12h x 3 days -> daily x 3 days
Kidney failure-free days during 28-day period post randomization
Early vasopressin use did not improve number of kidney failure-free days compared to norepinephrine
VASST – I = more NE, vs vaso plus NE
VANISH – vaso did decrease norepi requirements --
Noradrenaline reduces renal perfusion by preferentially binding α-receptors on renal afferent arterioles. In contrast, the binding of vasopressin to V1a receptors on glomerular efferent arterioles results in vasoconstriction and increases glomerular filtration.
Trials have suggested a lower AKI incidence and a reduced need for renal replacement therapy (RRT) in patients with shock treated with vasopressin compared with other vasopressors, but definitive evidence is lacking
NEJM 2008;358: NEJM 2010;362:

32. Epinephrine (Adrenalin®)
Second line for sepsis
β and α agent
More mesenteric ischemia than norepinephrine
May have more right heart effects
Actions
mcg/kg/min
Dosing
5 mg in 250 mL
10 mg in 250 mL (central line only)
Concentration
May cause increased lactate levels
Epinephrine transiently increases lactate levels through an increase in glycolysis in skeletal muscle --
beta-agonists such as epinephrine are known to raise serum lactate levels secondary to hepatic stimulation of glycogenolysis/glycolysis [i.e. increased B-type lactate]; ostensibly, this effect is counterbalanced by epinephrine’s ability to augment cardiac output and, therefore, tissue oxygen delivery

33. 400 mg/250 mL concentration available in crash carts in premixed bag
Dopamine (Intropin®)
Positive chronotrope and inotrope at higher doses
Last line therapy in most situations
Actions
Dopaminergic (2-4 mcg/kg/min)
β (5-10 mcg/kg/min)
α (10-20 mcg/kg/min)
Dosing
400 mg/250 mL
800 mg/250 mL (central line only)
Concentrations
400 mg/250 mL concentration available in
crash carts in premixed bag
Both premix

34. Dopamine and Mortality
Trial
Patient Population
Study Arms
Primary Endpoint
Conclusion
SOAP II
Patients with various shock states
Norepinephrine (n = 821):
Titration: 0.02 mcg/kg/min; max 0.19 mcg/kg/min
Dopamine (n = 858):
Titrated by 2 mcg/kg/min; max 20 mcg/kg/min
28-day mortality
No significant difference in mortality
Dopamine associated with arrhythmias
Dopamine versus norepinephrine in the treatment of septic shock: a meta-analysis
Patients with septic shock (North America, Australia, NZ, India)
5 observational trials and 6 RCTs
Norepinephrine (n=1474):
Doses: mcg/kg/min
Dopamine (n = 1294):
Doses: 1-20 mcg/kg/min
DA vs NE
Observational: RR 1.23; 95% CI ; (p < 0.01)
RCTs: RR 1.12; CI 1.01–1.20; (p = 0.035)
Dopamine versus norepinephrine in the treatment of cardiogenic shock: Meta-Analysis
Patients with cardiogenic shock (Asia and Africa)
9 RCTs
Norepinephrine (n=241)
Dopamine (n = 269):
RR: 1.611, 95% CI 1.219–2.129; (p <.001)
RCT = randomized controlled trial; DA= Dopamine; NE=Norepinephrine
Crit Care Med 2012 Vol. 40, No Rui Q et al. Medicine (Baltimore). 2017;96(43):e8402.

35. Phenylephrine (Neosynephrine®)
Strong, pure α agent
Vasoconstriction with minimal  in heart rate or contractility
Often causes reflex bradycardia
Does not spare the heart or brain
BP at the expense of perfusion
Actions
0.5 to 9 mcg/kg/min
Dosing
25 mg/250 mL
50mg/250 mL
Concentration
both compounded
Can be administered peripherally for up to 4 hours

36. New Vasopressor: Angiotensin II

37. Angiotensin II (Giapreza®)
ATHOS-3: investigated effectiveness of angiotensin II for treatment of vasodilatory shock unresponsive to high-dose vasopressors
Interventions
Angiotensin II (n = 163): 20 ng/kg/minute (max = 200 ng/kg/min)
Placebo (n = 158)
Inclusion
Vasodilatory shock despite fluid resuscitation (25 mL/kg) over previous 24 hours
High dose vasopressors (> 0.2 mcg/kg/min norepinephrine or equivalent for > 6 h)
Endpoints
MAP at 3 hours (response defined as MAP > 75 mmHg)
MOA: Acts in the SNC to increase vasopressin production
How would this make a difference
What if patient on ACEi or ARB?
NEJM 2017;377:419-30

38. Results MAP at 3 hours Secondary Endpoints Angiotensin II: 69.9%
Placebo: 23.4%
P < 0.001
Secondary Endpoints
Mean change in cardiovascular SOFA score at 48 hrs
-1.75 (angiotensin II) vs (p = 0.01)
Mean change in total SOFA score at 48 hrs
1.05 (angiotensin II) vs (p = 0.49)
Mortality
All cause mortality at day 7  29% (angiotensin II) vs. 35% ; p = 0.22
All-cause mortality at 28 days  46% (angiotensin II) vs. 54% ; p = 0.12
MAP ↑ rapidly in angiotensin II group  ng/kg/min dose ↓ in 67% patients within 30 minutes
Limitations
MAP goal > 75 mmHg
Primary endpoint is non-mortality related
Small sample size
Safety
Potential for venous and arterial thrombotic and thromboembolic events
Not discussed in trial
NEJM 2017;377:419-30

39. Inotropes

40. Dobutamine (Dobutrex®)
β1 agonist – increased myocardial contractility and increased HR
β2 agonist – systemic vasodilation
Actions
mcg/kg/min
Dosing
Half-life: ~2 minutes
Pharmacokinetics
Increased HR and BP (tachyphylaxis after 72 hours)
Myocardial ischemia and arrhythmias at doses > 15 mcg/kg/min
Malignant ventricular arrhythmias at any dose
Adverse effects
500 mg/250 mL and 1000 mg/250 mL (central line only)
Concentrations
Dobutamine stimulates b1 and b2 receptors in a 3:1 ratio
Both premixed

41. Milrinone (Primacor®)
Phosphodiesterase-III (PDE-3) inhibitor
Decreases hydrolysis of cAMP leading to increase in intracellular Ca2+ influx
Positive inotropy (increased cardiac output) and vascular smooth muscle relaxation (vasodilation)
Actions
mcg/kg/min
Dosing
Half-life: ~2 hours
Pharmacokinetics
Hypotension, ventricular arrhythmias/angina, bronchospasm
May accumulate in renal dysfunction
Adverse effects
20 mg/100 mL
Concentrations
premixed

42. Isoproterenol (Isuprel®)
American Heart Association Guideline:
Consider in cardiogenic shock secondary to bradycardia
Indication
Potent β1 and β2 agonist
Relaxes bronchial, GI, and skeletal smooth muscle
Mechanism
mcg/min (titrate by 0.5 mcg/min every 10 minutes)
Dosing
Tachycardia, arrhythmias, myocardial necrosis
Adverse effects
Low affinity for alpha-adrenergic receptors
It acts upon beta-1 adrenergic receptors and, unlike dobutamine, has a prominent chronotropic effect. The drug's high affinity for the beta-2 adrenergic receptor causes vasodilation and a decrease in MAP. Therefore, its utility in hypotensive patients is limited to situations in which hypotension results from bradycardia.
MOA: lowers peripheral vascular resistance, primarily in skeletal muscle but also in renal and mesenteric vascular beds
Cost: recent price increase ~$ /vial

43. General Vasopressor/Inotrope “Rules”
Obtain CENTRAL LINE
Peripheral Infusion ~ 4 hours
Low concentrations of: dopamine, norepinephrine, and phenylephrine +/- arterial line
Always monitor for ischemia/extravasation
Dobutamine/milrinone are MD titrate only!

44. Useful Order Sets ABCDEF Neuromuscular blockade
Endotool (insulin infusion)
Desensitization
Toxicology/antidote
Sepsis Sepsis Sepsis!!

45. Acknowledgement Tim Cober, PharmD, BCPS, BCCCP
MICU Clinical Pharmacist

46. Questions?