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Critical Care Pharmacology

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Presentation on theme: "Critical Care Pharmacology"— Presentation transcript:

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:

22

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?


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