nmshp unmh pgy1s presentation · title: microsoft powerpoint - nmshp unmh pgy1s presentation...

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Residents’ Clinical PearlsMegan Eckstein, PharmD

Kendall Tucker, PharmD

Gabriela Cabanilla, PharmD

Nathan Duran, PharmD

Avni Patel, PharmD

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Conflicts of Interest

• None of the presenters have received support or commercial funding for this presentation, or for any products mentioned herein.

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IV Valproate for Managing Acute Migraines in the

Emergency Setting

Megan Eckstein, PharmDUNMH PGY-1 Pharmacy Resident

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Learning Objectives

For pharmacists:• Determine when and how IV valproate may be used for the treatment of acute

migraines in the emergency setting

For pharmacy technicians:• Identify the appropriate formulation and dose of valproate that should be used

for the treatment of acute migraines in the emergency setting

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Background Information

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Background

• 1.2 million ED visits per year due to acute migraine• Migraine:

• Severe headache• May have nausea/vomiting, light/sound sensitivity• With or without aura

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Orr SL, et al. Headache. 2016;56(6):911-40.Cutrer MF, Bajwa ZH. UpToDate. Updated March 27, 2017.

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American Headache Society ED Migraine Recommendations, 2016

Should offer:• Metoclopramide (IV)• Prochlorperazine (IV)• Sumatriptan (SC)

May avoid: • Diphenhydramine (IV)• Hydromorphone (IV)• Lidocaine (IV)• Morphine (IV)• Octreotide (IV)

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May offer: Acetaminophen (IV) Chlorpromazine (Parenteral) Diclofenac (IV) Haloperidol (Parenteral) Ketorolac (IV) Valproate (IV)

Orr SL, et al. Headache. 2016;56(6):911-40.

Primary Literature

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Summary of Open-Label Clinical Trials

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Study Interventions Results

Bakhshayesh, et al. (2013)

1. 30 subjects: 400 mg IV valproate

2. 30 subjects:10mg IM metoclopramide and 6 mg SQ sumatriptan

Favored VPASevere/moderate pain to mild/no pain at 1 hr:- Group 1: 53.3%- Group 2: 23.3%

Ghaderibarmi, et al. (2015)

1. 19 subjects:15 mg/kg IV valproate

2. 18 subjects:6 mg SQ sumatriptan

Favored VPAMean pain scores at 1 hr:- Group 1: 8.3 to 2.2- Group 2: 8.3 to 4.7

Bakhshayesh B, et al. Am J Emerg Med. 2013;31(3):540-4.Ghaderibarmi, F, et al. Acta Med Iran. 2015;53(10):633-6

IV VPA vs. Metoclopramide vs. Ketorolac (2014)

• Design: Randomized, double-blinded trial

• Population: 330 subjects, 110 subjects in each group

• Interventions:• 1,000 mg sodium valproate IV drip over 15 minutes• 10 mg metoclopramide IV drip over 15 minutes• 30 mg ketorolac IV drip over 15 minutes

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Friedman BW, et al. Neurology. 2014;82(11):976-83

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IV VPA vs. Metoclopramide vs. Ketorolac (2014)• Efficacy Results: Mean difference in improvement in 0 to 10 pain score

between baseline and 1 hour

• IV Valproate patients had improvement in pain scale by mean of 2.8 (CI 2.3, 3.3)

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Pairwise comparison Mean difference in pain scaleimprovement (95% CI)

VPA vs. Metoclopramide Favors metoclopramide: -1.9 (-2.8, -1.1)

VPA vs. Ketorolac Favors ketorolac:-1.1 (-2.0, -0.2)

Metoclopramide vs. Ketorolac 0.8 (-0.1, 1.7)


Clinical Trial: IV VPA vs. Metoclopramide vs. Ketorolac (2014)

• Safety Results:

• Serious adverse events not reported in any group

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Adverse Events Valproate Metoclopramide Ketorolac

Dizziness 5% 7% 8%

Upper GI complaint 2% 1% 4%

“Very restless” 1% 6% 1%

“Too drowsy to function” 6% 2% 2%


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IV VPA vs. Prochlorperazine (2003)

• Design: Randomized, double-blinded trial• Population: 40 acute migraine patients at a military ED• Interventions:

• 10 mg prochlorperazine IV over 2 minutes• 500 mg valproate IV over 2 minutes

• Results:• Prochlorperazine group:

• Significantly lower pain and nausea scores at 1 hour• 10% needed treatment for akathisia

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Tanen DA, et al. Ann Emerg Med. 2003;41(6):847-53.

Use of IV Valproate for Acute Migraines

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Advantages of Valproate

• Lack of cardiovascular side effects• No interactions with triptans or ergot alkaloids• Lack of sedation• No dependence formation

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Robertson CE, et al. 2010;30(2):201-11.

Warnings and Contraindications• Valproate does not have an official labeled or off-labeled indication for abortion of

acute migraines

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Contraindications: Hypersensitivity Pregnancy Hepatic disease or significant

impairment Urea cycle disorders Mitochondrial disorders

US Boxed Warnings: Hepatotoxicity Patients with mitochondrial disease Fetal risk Pancreatitis

Robertson CE, et al. 2010;30(2):201-11.Lexicomp. Valproic Acid and Derivatives. Updated August 21, 2017.

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Appropriate DosingDosing:• 500 – 1,000 mg IV • PO route has not yet been studied for aborting acute migraines

Product selection:• Sodium valproate available in 5 mL vials, 100 mg/mL

Preparation for administration:• ≥ 10 years of age: dilute dose in 50 mL of D5W, NS, or LR

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Orr SL, et al. Headache. 2016;56(6):911-40.Lexicomp. Valproic Acid and Derivatives. Updated August 21, 2017.

Appropriate AdministrationIV administration:• Per Lexicomp: Over 60 minutes at a rate ≤ 20 mg/minute• Also acceptable to administer at faster rates• 1.5-6 mg/kg/minute generally well tolerated in clinical trials• Open-label, prospective trial: Safety of Rapid IV Loading

• 40 subjects > 19 years of age with epilepsy• Undiluted VPA 20 or 30 mg/kg at 6 or 10 mg/kg/min• 81% of patients had pain/burning/prickling sensation during administration• No irritation lasting more than 3 minutes• No significant changes in vitals or cardiac conduction• No phlebitis at injection site

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Limdi NA, et al. Epilepsia. 2007;48(3):478-83. Lexicomp. Valproic Acid and Derivatives. Updated August 21, 2017.

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Summary

• VPA is not a first line agent for abortion of acute migraine in the ED• May be an acceptable alternative • Shown to be safe when administered at rates faster than those

recommended by the manufacturer

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Tranexamic Acid in Epistaxis

M. Gabriela Cabanilla, PharmD

PGY-1 Pharmacy Resident

UNM Hospitals

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Learning Objectives

Pharmacists:1. Describe the role of tranexamic

acid in the management of epistaxis

Technicians:1. Recognize the formulation of

tranexamic acid to be used in the management of epistaxis

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Epistaxis Review

• Common complaint; most are self-limiting

• Categorized based on site of bleeding

Erosion in the mucosa

Vessels become exposed

Vessels break22

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Epistaxis Review

Causes:• Direct trauma• Nose picking• Irritation• Dryness• Drugs

Treatment:• Squeezing the nose• Vasoconstrictor agents• Silver nitrate• Electrical cauterization• Nasal packing• Topical tranexamic acid

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TXA Review

• Anti-fibrinolytic agent• Lysine analog that competitively binds to the binding site on plasminogen preventing

clot breakdown

• Indications:• Tooth extractions• Menorrhagia• Cesarean sections• Traumatic hemorrhage• Perioperative bleeding

• Dosage forms in the USA:• Oral (bioavailability 35-45%)• IV

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TXA in Epistaxis

• Direct application of TXA to the bleeding surface has the potential to reduce bleeding with minimal systemic effects

• In severe cases, reducing bleeding would also reduce the need for blood transfusion

• TXA provides a quick and effective alternative method of treating epistaxis in emergency situations

• Topical TXA has been used in various surgical procedures• Effectively reduces bleeding• Improves surgical field

Dell’Amore A, et al. Heart Lung Circ. 2012;21:706-710 25

Supporting Evidence

• TXA gel vs Placebo• Design: RCT double blind study• Sample size: 68 subjects• Intervention:

• TXA nasal cavity filled with 15 mL of 10% TXA gel for 30 min• Placebo gel for 30 min

• Complications: no difference, “bad taste” in both groups• Re-bleeding: trend to reduce re-bleed after TXA but not significant or better

than placebo

Tibbelin A, et al. ORL J Otorhinolaryngol Relat Spec. 1995;57(4):207-209. 26

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Supporting EvidenceEFFICACY ENDPOINT TXA (%) PLACEBO (%) P-VALUE

Bleeding stop time ≤ 30 min

60 76 n.s.

Re-bleed within 8 days 11 31 n.s.

Re-bleed within 30 days 44 66 n.s.

PREDISPOSING FACTORS TXA (%) PLACEBO (%)

Aspirin use within 2 weeks

49 53

Severity of re-bleeding• Slight• Moderate• Severe

137313

39583

Tibbelin A, et al. ORL J Otorhinolaryngol Relat Spec. 1995;57(4):207-209. 27n.s. = not significant

Supporting Evidence

• Epinephrine + Lidocaine vs TXA• Design: RCT single blind study• Sample size: 216 subjects• Intervention:

• TXA cotton pledget soaked in IV TXA (500 mg in 5 mL) for 10 mins• EPI + LIDO cotton pledget soaked in epi 1:100000 + lido 2% for 10 mins

• Complications: no difference, nausea/vomiting in both groups• Re-bleeding: significantly lower with TXA

Zahed R, et al. Am J Emerg Med 2013;31(9):1389-92. 28

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Supporting Evidence

EFFICACY ENDPOINT EPI + LIDO(%)

TXA(%)

OR (95% CI) P-VALUE

Bleeding stop time ≤ 10 min

31.2 71 2.28 (1.68-3.09) < 0.001

Discharge time ≤ 2 hours

6.4 95.3 14.8 (7.2-30.4) < 0.001

Complications in the ED

11 4.7 0.42 (0.16-1.16) 0.128

Re- bleeding in the first 24 hrs

12.8 4.7 0.36 (0.14-0.98) 0.034

Re-bleeding in 1 week 11 2.8 0.26 (0.07-0.88) 0.018

Zahed R, et al. Am J Emerg Med 2013;31(9):1389-92. 29

How it is used at UNMH

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Key Points

• Different approaches to treat epistaxis• TXA is one of them

• Topical TXA has little systemic absorption• Limited data comparing topical TXA to

current treatment modalities• Dose: 500 mg (5 mL) soaked in a cotton

pledget

Peri-Operative Management of Direct Oral Anticoagulants

(DOACs)Avni Patel, PharmD

UNMH PGY-1 Pharmacy Practice Resident

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Learning Objectives

For pharmacists: Differentiate between the peri-operative management of DOACs

compared to warfarin

For pharmacy technicians: Identify DOACs currently used for anticoagulation

Peri-Operative Warfarin Management

• CHEST 2012 Guidelines• Stop warfarin 5 days before surgery• Resume 12 to 24 hours after surgery and when there is adequate hemostasis• Bridging is suggested for patients at high risk for thromboembolism with

mechanical heart valve, atrial fibrillation, or venous thromboembolism (VTE)

• Bridging is based on expert opinion

• Recent evidence suggests bridge therapy for patients who have the highest risk for thromboembolism

• Over 90% of warfarin patients should not receive bridge therapy

CHEST 2012; 141(2)(Suppl):e326S–e350S.Rose AJ, et al. Circ Cardiovasc Qual Outcomes. 2016;9:00-00.

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Background: DOACs

• Widely used alternatives to warfarin for stroke prevention in non-valvular atrial fibrillation and management of venous thromboembolism (VTE)

• Safety and efficacy of DOACs• Significantly lower bleeding risk compared to warfarin• Efficacy comparable to warfarin

Burnett AE, et al. Jour Thromb. Thrombolysis 2016; 41: 206-32Raval AN, et al. Circulation. 2017;135:e604-e633.

Do we bridge patients on DOACs?

• DOACs and low molecular weight heparin (LMWH) are pharmacokinetically similar

• DOACs have a rapid onset and offset which precludes the need for bridging with heparin or LMWH

• Overlapping these agents will lead to overanticoagulation and increase bleeding risk

DO NOT BRIDGE PATIENTS ON

DOACS

Burnett AE, et al. Jour Thromb. Thrombolysis 2016; 41: 206-32

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When to stop and re-start DOACs?Elective Procedures• Timing of cessation and

resumption of DOACs is individualized

• Patient’s renal function• Half-life of DOAC• Bleeding risk for elective

procedure


Pharmacokinetics of Oral Anticoagulants

Warfarin(Coumadin)

Dabigatran(Pradaxa)

Rivaroxaban(Xarelto)

Apixaban(Eliquis)

Edoxaban(Savaysa)

Target(s) IIa, VIIa, IXa, Xa IIa Xa Xa Xa

Peak effect 4-5 days 1-2 h 2-4 h 3-4 h 1-2 hHalf-life* 40 h 12-28 h 5-13 h ~12 h (8-15 h) 10-14 hRenalelimination^ None 80% 36% 27% ~ 50%

Antidote Vitamin K Idarucizumab None None None

Raval AN, et al. Circulation. 2017;135:e604-e633.Lexicomp. 2017 Wolters Kluwer Clinical Drug Information.

*Half-life for DOACs is variable based on patient’s renal function^Renal elimination of active/unchanged metabolites

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Renal function and DOAC half-life

• Reduced renal function increases DOAC half-life

• May require holding for a longer period of time prior to procedure

Direct Oral AnticoagulantCrCl Half-life

Dabigatran (Pradaxa)CrCl > 80 mL/min t1/2 ~ 14 h

CrCl 50 – 80 mL/min t1/2 ~ 17 hCrCl 30 – 49 mL/min t1/2 ~ 19 hCrCl 15 – 29 mL/min t1/2 ~ 28 h

CrCl < 15 mL/min t1/2 ~ unknown

Rivaroxaban (Xarelto)CrCl ≥ 30 mL/min t1/2 ~ 8 – 9 h

CrCl 15 – 29 mL/min t1/2 ~ 10 hCrCl < 15 mL/min t1/2 ~ unknown

Apixaban (Eliquis)CrCl > 50 mL/min t1/2 ~ 7 – 8 h

CrCl 15 – 49 mL/min t1/2 ~ 17 – 18 hCrCl < 15 mL/ming t1/2 ~ unknown

Edoxaban (Savaysa)CrCl > 30 mL/min t1/2 ~ 8 – 10 h

CrCl 15 – 29 mL/min t1/2 ~ 17 hCrCl < 15 mL/min t1/2 ~ unknown


Procedural Bleed RiskDOAC Cessation and Resumption

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Procedural Bleed Risk DOAC Cessation Timing

DOAC Resumption Timing

Minimal bleed riskEndoscopy without surgery

Ophthalmology (ex. cataract)

Does not require interruption --

Low bleed riskDental procedures (ex. 3+ teeth extraction)

Shoulder/foot/hand surgery

Interrupt for 2 – 3 half-lives

~ 24 hours post-operatively

High bleed riskCardiac procedures

(ex. coronary artery bypass)Urologic procedures (ex. kidney biopsy)

Interrupt for 4 – 5 half-lives

48 – 72 hours post-operatively



DOAC Cessation/Re-initiation Guidance Direct Oral Anticoagulant Number of doses to hold prior to procedure Re-initiation time post-op

CrCl Half-life Low Bleeding Risk High Bleeding Risk Low Bleeding Risk High Bleeding RiskDabigatran (Pradaxa) – Twice daily dosing

1 day afterprocedure

(~ 24 h postop)

2-3 days afterprocedure

(~ 48–72 h postop)

CrCl > 80 mL/min t1/2 ~ 14 h 2 doses 5 – 6 dosesCrCl 50 – 80 mL/min t1/2 ~ 17 h 3 – 4 doses 6 – 7 dosesCrCl 30 – 49 mL/min t1/2 ~ 19 h 4 – 5 doses 7 – 8 dosesCrCl 15 – 29 mL/min t1/2 ~ 28 h 5 – 7 doses 9 – 12 doses

CrCl < 15 mL/min t1/2 ~ unknown Hold until resolved or consider transition to warfarin or UFH

Rivaroxaban (Xarelto) – Once daily dosingCrCl ≥ 30 mL/min t1/2 ~ 8 – 9 h 1 dose 2 doses

CrCl 15 – 29 mL/min t1/2 ~ 10 h 1 – 2 doses 2 – 3 doses


Apixaban (Eliquis) – Twice daily dosingCrCl > 50 mL/min t1/2 ~ 7 – 8 h 2 doses 4 doses

CrCl 15 – 49 mL/min t1/2 ~ 17 – 18 h 3 – 4 doses 6 – 7 doses


Edoxaban (Savaysa) – Once daily dosingCrCl > 30 mL/min t1/2 ~ 8 – 10 h 1 dose 2 doses

CrCl 15 – 29 mL/min t1/2 ~ 17 h 2 doses 3 – 4 doses


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DOAC Cessation/Re-initiation Guidance Direct Oral Anticoagulant Number of doses to hold prior to procedure Re-initiation time post-op

CrCl Half-life Low Bleeding Risk High Bleeding Risk Low Bleeding Risk High Bleeding RiskApixaban (Eliquis) – Twice daily dosing

1 day afterprocedure

(~ 24 h postop)

2-3 days afterprocedure

(~ 48–72 h postop)CrCl > 50 mL/min t1/2 ~ 7 – 8 h 2 doses 4 doses

CrCl 15 – 49 mL/min t1/2 ~ 17 – 18 h 3 – 4 doses 6 – 7 doses

CrCl < 15 mL/ming t1/2 ~ unknown Hold until resolved or consider transition to warfarin or UFH


Summary

• Do not bridge patients on DOACs

• DOACs are managed very differently compared to warfarin peri-operatively

• Timing of cessation and resumption of a DOAC is based on: • Patient’s renal function• Half-life of the DOAC• Bleeding risk for elective procedure

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Use of Methylene Blue in Refractory Shock

By: Nathan Duran PGY-1 Pharmacy Resident

University of New Mexico Hospital

Objectives

• Pharmacist: Identify a potential scenario in which methylene blue may be utilized for shock.

• Technician: Identify the common uses of methylene blue.

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Background

• Standard of Care: Fluids and vasopressors

• Other options• Hydrocortisone + Thiamine + Vitamin C• Methylene Blue (MB)

• Shock States for methylene blue• Distributive shock (Vasodilatory or Vasoplegic)• Dysregulation of vasodilation

• Ex: Septic shock, vasoplegia syndrome

1. Hosseinian L, et al. Anesthesia & Analgesia 2016;122(1):194-201

Proposed Mechanism of Action:

• Inhibits the synthesis of nitric oxide +

• Inhibits nitric oxide from activating guanylate cyclase by binding to iron in heme complexpreventing the production of cyclic guanylate monophosphate (cGMP)

=• Reduces vasodilation (increases SVR and MAP)

1. Methylene Blue. Lexi-Drugs. Lexicomp®. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed September 10th, 2017. 2. Jang DH, et al. Journal of Medical Toxicology. 2013;9(3):242-249. doi:10.1007/s13181-013-0298-7.

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Proposed Mechanism of Action:

• Inhibits the synthesis of nitric oxide +

• Inhibits nitric oxide from activating guanylate cyclase by binding to iron in heme complexpreventing the production of cyclic guanylate monophosphate (cGMP)

=• Reduces vasodilation (increases SVR and MAP)

1. Methylene Blue. Lexi-Drugs. Lexicomp®. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed September 10th, 2017. 2. Jang DH, et al. Journal of Medical Toxicology. 2013;9(3):242-249. doi:10.1007/s13181-013-0298-7.

xx

1. Jang DH, et al. Journal of Medical Toxicology. 2013;9(3):242-249. doi:10.1007/s13181-013-0298-7.

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Kirov, et al. (2001) • Study Design: Prospective, single-center, randomized, open-label, placebo-controlled

study• Population: 20 patients with septic shock treated with a least one vasopressor• Interventions: Control group (Isotonic Saline, n=10) vs. Methylene Blue (n=10)

Results MB vs. Control

Survival MB (5, 50%) vs control (3, 30%)

Vasopressor Support

Norepinephrine: 87% reduction w/MB

Epinephrine: 81% reduction w/MB

Dopamine: 40% reduction w/MB

Hemodynamics MAP at 24 hours: 86.6 vs 69.9, P<0.05

1. Kirov MY, et al. Crit Care Med 2001;29:1860–7.

• Conclusion: Improved survival, decreased cardiac depression, and reduced need for vasopressor support

Leyh, et al. (2001)• Study Design: Retrospective, observational study• Objective: Effects of MB on hemodynamics, norepinephrine dosage,

and clinical outcomes. • Population: 54 patients with refractory vasoplegia syndrome after CPB

treated with MB.

Results Time PointsVariable Before MB 1 hr after MB 6 hr after MB 12 hr after MB

Mean arterial Pressure (mmHg) 68 ± 9 72 ± 12 P=0.02 71 ± 9, P=0.02 73 ± 10, P=0.02

SVR (dyne*S/cm5) 547 ± 108 766 ± 194, P<0.001 796 ± 153, P<0.001 876 ± 184, P<0.001

Cardiac Output (L/min) 7.6 ± 3.1 6.5 ± 2.8, P<0.001 6.1 ± 2.4 P<0.001 5.8 ± 1.9, P<0.001

1. Leyh R, et al. The Journal of Thoracic and Cardiovascular Surgery 2003;125(6):1426-1431.

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Leyh, et al. (2001)

• Conclusion: A single dose of MB significantly improved patients hemodynamic profile and reduced NE doses.

1. Leyh R, et al. The Journal of Thoracic and Cardiovascular Surgery 2003;125(6):1426-1431.

Levin, et al. (2004)

• Study Design: Randomized, controlled trial• Population: Elective cardiac surgery patients with vasoplegic

syndrome. • Intervention: MB (1.5mg/kg IV over 1 hour) vs Placebo

(standard vasopressors)• Results: 638 operations, 56 patients developed VS

• MB (N=28) vs Placebo (N=28) • Mortality: 0 vs 6 deaths (0% vs 21.4%), p=0.01

1. Levin R, et al. The Annals of Thoracic Surgery 2004;77(2):496-499.

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Weiner, et al. (2013)• Study Design: Single center, retrospective analysis• Population: Patients with vasoplegia syndrome given MB after

cardiopulmonary bypass from 2007-2008• MB Dose: Bolus dose of 2 mg/kg, followed by an infusion of 0.5 mg/kg/hr for 6

hours

• Results:• In-hospital mortality: OR 4.26 (95% CI 1.49-12.12, p=0.007)• Morbidity Composite: OR: 4.80 (95% CI 1.85-12.43, p=0.001)• Hyperbilirubinemia: OR: 6.58 (95% CI 2.91-14.89, p<0.001)

• Conclusion: MB was associated with worse outcomes

1. Weiner MM, et al. J Cardiothorac Vasc Anesth. 2013 Dec;27(6):1233-8

• Resolution of symptoms: MB group vs Placebo: 2 hours vs 48 hours

• Conclusion: MB reduced the risk of mortality while also reducing the time until symptom resolution.

Levin, et al. (2004)

1. Levin R, et al. The Annals of Thoracic Surgery 2004;77(2):496-499.

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Clinical Study-SummaryStudy Population Methylene Blue

Dose Outcomes

Kirov 2001 Septic Shock

Bolus: 2 mg/kg over 15 minsInfusion: Titration from0.5 mg/kg/hr x 1 hour-> 2.0 mg/kg/hr x hour then stop

MB may have benefit survival, hemodynamics, and reduce dose of

vasopressors

Leyh 2001 Vasoplegia 2mg/kg over 20 minutes MB Improved hemodynamics

Levin 2004 Vasoplegia 1.5mg/kg IV over 1 hour MB improved mortality

Weiner 2013 Vasoplegia

Bolus: 2 mg/kgInfusion: 0.5 mg/kg/hrfor 6 hours

MB associated with worse outcomes

Potential Dosing Strategies

Septic Shock: • Bolus: 2mg/kg IV bolus in 50mL D5W over 15 minutes followed by infusion• IV infusion: 2 hours after completion of bolus; admixed in 250mL D5W

• 0.25 mg/kg/hr for 1 hour • 0.5 mg/kg/hr for 1 hour• 1.0 mg/kg/hr for 1 hour• 2.0 mg/kg/hr for 1 hour, then stop

Vasoplegia Sydrome• Lexicomp: One time dose of 1.5– 2 mg/kg IV over 20-60 min• UNM Hospital protocol: 1.5 mg/kg infused over 1 hour (100mL D5W)

1. Leyh R, et al. The Journal of Thoracic and Cardiovascular Surgery 2003;125(6):1426-1431.2. Kirov MY, et al. Crit Care Med 2001;29:1860–7.

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Contraindications/Precautions

• Serotonin Syndrome• Avoid use with SSRIs, SNRIs, monoamine oxidase inhibitors, TCAs linezolid, cocaine, MDMA

agonists, and Amphetamines• Potentially fatal

• Contraindicated in Patients with G-6-PD Deficiency• Hemolysis and Methemoglobinemia

• Avoid in severe pulmonary arterial hypertension • Caution: Patients with acute lung injury, ARDS, or PaO2:FiO2 ratio (< 300 mm Hg)

• Contraindicated in patients with severe renal failure

1. Shear T, Greenberg S. Anesthesia Patient Safety Foundation Newsletter 2012;27(1):18-19.2. Leyh R, et al. The Journal of Thoracic and Cardiovascular Surgery 2003;125(6):1426-1431.3. Methylene Blue. Lexi-Drugs. Lexicomp®. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed September 10th, 2017.

Other Adverse Effects

• Cardiac arrhythmias• Coronary vasoconstriction• Decrease in cardiac output• Decrease renal blood flow• Decrease in mesenteric blood flow• Increase in pulmonary vascular resistance(Typically seen in doses >2mg/kg)

1. Shear T, Greenberg S. Anesthesia Patient Safety Foundation Newsletter 2012;27(1):18-19.2. Methylene Blue. Lexi-Drugs. Lexicomp®. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed September 10th, 2017.3. Leyh R, et al. The Journal of Thoracic and Cardiovascular Surgery 2003;125(6):1426-1431.

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Monitoring

• Vasopressor adjustments

• Blue-green coloring of the urine, mucous membranes, sclera, and skin

• Interference with pulse oximetry

• Methemoglobin levels after• 1-hour after initiation• End of infusion• 6-hours post infusion

1. Kirov MY, Evgenov OV, Evgenov NV, et al. Crit Care Med 2001;29:1860–7.2. Leyh R, et al. The Journal of Thoracic and Cardiovascular Surgery 2003;125(6):1426-1431.

Summary

• Controversial

• Evaluated on a case-by-case scenario as a last line approach to refractory shock forms

• Need for higher quality of evidence to establish ideal indication, dosage, and duration

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Fishing for Fats:SMOFlipid criteria for use

Kendall Tucker, PharmD

UNMH PGY-1 Pharmacy Resident

Objectives

• For Pharmacists: Discuss SMOFlipid emulsion and criteria for use in patients requiring parenteral nutrition.

• For Pharmacy Technicians: Recognize differences between SMOFlipid emulsion and other parenteral lipid emulsions.

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What is SMOF?Alternative 20% Intravenous Lipid emulsion (IVLE)

Indication: Source of calories (2kcal/mL) and essential fatty acids for parenteral nutrition in adults when oral or enteral nutrition is not possible, insufficient or contraindicated.

Although not approved, has also seen some use in pediatric patients

Only alternative lipid emulsion available for use in the USA

Fresenius Kabi. Smoflipid® 20%. 2016.

Alternative IVLEs vs Soy-based IVLEs

Alternative IVFEs such as MCT, Olive Oil and Fish oil are metabolized through different pathways compared to Soybean oil and may lead to less proinflammatory effects and less immune suppression. It has been theorized that using alternative based lipid emulsions might potentially lead to better clinical outcomes

Vanek vw, et al. Nutri Clin Pract. 2012;27(2):150-92

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SMOF vs Soy-based IVLEsTable 1. SMOF vs Other IVLEs Intralipid Nutrilipid SMOFlipid

Product composition Soybean Oil100%

Soybean Oil 100% Soybean Oil 30%MCT 30%Olive Oil 25%Fish Oil 15%

Fat Composition (%, mean values)

Linolenic (ω-3) 7.5 7.5 2.5

Eicosapentaenic (EPA ω-3) 0 0 2.3

Docosahexaenoic (DHA ω-3) 0 0 2.3

Linoleic (ω-6) 53 53 19.5

Oleic (ω-9) 24.5 23.5 29

α-tocopherol (mg/L) N/A N/A ~200

Ratio of ω-6: ω-3 Fatty Acids 7:1 7:1 2.5:1Fresenius Kabi. Smoflipid® 20%. 2016.

Clinical Guidelines

American Society for Parenteral and Enteral Nutrition (ASPEN)• “Alternative IVFEs may provide outcome benefit over soy-based

IVFEs…”

• “…Based on expert opinion, we suggest that their use be considered in the critically ill patient who is an appropriate candidate for PN”

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McClave SA, et al. JPEN. 2016;40(2):159-211.

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Advantages of SMOF

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Study Study Design Comparators Results

Tian et al. Nutr Rev. 2013;71(12):815-21

6 study meta-analysisevaluating 306 patients

SMOF vs Soybeanemulsion vs OliveOilemulsion

SMOF associated withlower levels of hepatic enzymes (AST/ALT/AlKPhos) and trigylcerides

Klek et al. Clin Nutr. 2013; 32(2):224-31

Randomized, double-blind, multi-center controlled trial evaluating 76 patients

SMOF vs Soybean emulsion

Mean concentrations of ALT, AST and total bilirubin were significantly lower in SMOF emulsion compared to Soybean emulsion

Mateu et al. JPEN. 2014; 40(5):705-712

Retrospective, observational study including 38 patients

Evaluated patients switched to multiple oil IVLE from Olive-oil based IVLE following hypertriglyceridemia

Approximately 25% average reduction in triglycerides.

What does it mean?

• SMOFlipid has been shown to decrease LFTs and decrease triglycerides

• None of these studies demonstrated differences in clinical outcomes

• Manzanares et al 2015• 10 RCT meta-analysis including 733 patients that examined fish oil containing IVLEs

vs non-fish oil containing IVLEs• No difference in overall mortality, mechanical ventilation days or length of stay.• Infections were lower in the fish-oil containing IVLE group, however SMOFlipid was

only used in two of the studies

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Cost Considerations

• 20% SMOFlipid(250mL): $27.60 (AWP)

• 20% Intralipid/Nutrilipid (250mL): $44.75 (AWP)

• Cost varies per institution

• Some institutions report increased cost for SMOFlipid products which may be cost prohibitive towards using SMOFlipid in every patient

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SMOFlipid vs other IVLEs

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Summary

• SMOFlipid is a multi-oil alternative intravenous lipid emulsion approved for use in adults

• SMOFlipid and other lipid emulsions may look similar – important to pay close attention to labeling

• SMOFlipid has not demonstrated improved clinical outcomes over plant-based IVLEs

• Alternative IVLEs such as SMOFlipid may provide some advantage over plant-based IVLEs in elevated LFTs and elevated triglycerides.

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