Chenshan Zhou, Pharmd October 30, 2018 New Drugs on the Block: Novel Therapies in Critical Care

Chenshan Zhou, PharmD October 30, 2018 New Drugs on the Block: Novel Therapies in Critical Care

Chenshan Zhou, PharmD PGY2 Critical Care Pharmacy Resident University of Utah Health

2 Disclosure

•Relevant Financial Conflicts of Interest ◦ CE Presenter, Chenshan Zhou: none ◦ CE mentor, Erin Lingenfelter: none •Off‐Label Uses of Medications ◦ 4‐factor prothrombin complex concentrate for the reversal of Xa inhibitors

3 Pharmacist Learning Objectives At the conclusion of this activity, pharmacists should be able to successfully: 1. List FDA‐approved indications for angiotensin II, andexanet alfa, clevidipine, and sugammadex 2. Describe the mechanism of action for the medications 3. Analyze the current literature regarding the safety and efficacy of these medications 4. Apply knowledge of these medications into clinical scenarios for FDA‐approved indications

4 Technician Learning Objectives At the conclusion of this activity, technicians should be able to successfully: 1. Name the generic and brand name for the following products: angiotensin II, andexanet alfa, clevidipine, and sugammadex 2. Identify cost differences of these medications 3. Manage proper storage, handling, and preparation of angiotensin II, andexanet alfa, clevidipine, and sugammadex

5 Angiotensin II (Giapreza®)

Giapreza (angiotensin II) [prescribing information]. 2017. 6 Mechanism of Action

Angiotensinogen Renin Angiotensin I ACEI Angiotensin II AT1 Receptor Vasoconstriction

Giapreza (angiotensin II) [prescribing information]. 2017. 7 Angiotensin II Dosing

Dose Starting 20 ng/kg/min via continuous IV infusion Titration Every 5 minutes Increments of up to 15 ng/kg/min Max during first 3 hours 80 ng/kg/min Maintenance 40 ng/kg/min Renal or hepatic impairment No dose adjustment

Giapreza (angiotensin II) [prescribing information]. 2017. 8 Drug Interactions: ACEIs

Angiotensinogen Renin Angiotensin I ACEI Angiotensin II AT1 Receptor Vasoconstriction

Giapreza (angiotensin II) [prescribing information]. 2017. 9 Drug Interactions: ARBs

Angiotensinogen Renin Angiotensin I ACEI Angiotensin II AT1 Receptor Vasoconstriction

Giapreza (angiotensin II) [prescribing information]. 2017. 10 Angiotensin II

•Monitoring: blood pressure •Safety warning related to thrombosis: arterial and venous thromboembolic (VTE) events have been reported oUse concurrent VTE prophylaxis •Other adverse effects: tachycardia, fungal infection, delirium, acidosis, hyperglycemia, peripheral ischemia

Giapreza (angiotensin II) [prescribing information]. 2017. 11 Angiotensin II

•Storage: intact vials under refrigeration • Diluted solution have BUD of 24 hours at room temperature or in the refrigerator •Dilute vial in normal saline •Average cost per day for an 80 kg patient with a rate of 20 ng/kg/min is estimated to be $1500 Fluid Vial Strength Infusion Bag Size Final Concentration Restricted? (mL) (ng/mL) No 2.5 mg/mL 500 5,000 2.5 mg/mL 250 10,000 Yes 5 mg/2 mL 500 10,000

Giapreza (angiotensin II) [prescribing information]. 2017. 12 ATHOS-3 Trial

Study Design Prospective, multi‐center, double‐blind, randomized controlled Population 321 patients with septic or other distributive shock Receiving > 0.2 mcg/kg/min of norepinephrine

Intervention Angiotensin II + standard of care vasopressors (n = 163) Placebo + standard of care vasopressors (n = 158) Primary Endpoint MAP response at 3 hours (defined as MAP increase ≥ 10mmHg or resultant MAP > 75mmHg)

Chawla L, et al. Crit Care Resusc. 2017;19(1):43‐49. 13 ATHOS-3 Trial: Baseline Characteristics

Median age 64 years (22‐89 years) Type of shock 91% Septic 9% Distributive ≥2 vasopressors prior to study 83% drug administration Norepinephrine 97% Vasopressin 67%

Chawla L, et al. Crit Care Resusc. 2017;19(1):43‐49. 14 ATHOS-3 Trial: Baseline Vasopressor Dose

Dose (mcg/kg/min) Patient (%) <0.35 51.7 ≥0.35‐ 0.49 19 ≥0.50 29.3

Chawla L, et al. Crit Care Resusc. 2017;19(1):43‐49. 15 ATHOS-3 Trial: Results

Angiotensin II Placebo P‐value (n = 163) (n = 158) Achievement of target MAP at hour 3 114 (69.9%) 37 (23.4%) <0.001 Mean change in cardiovascular SOFA score −1.75±1.77 −1.28±1.65 0.01 at hour 48 Mean change in total SOFA score at hour 48 1.05±5.50 1.04±5.34 0.49 Mean change in norepinephrine‐equivalent −0.03±0.10 0.03±0.23 <0.001 dose from baseline to hour 3 All‐cause mortality at day 7 47 (29%) 55 (35%) 0.22 All‐cause mortality at day 28 75 (46%) 85 (54%) 0.12

Chawla L, et al. Crit Care Resusc. 2017;19(1):43‐49. 16 ATHOS-3 Trial: Results

Chawla L, et al. Crit Care Resusc. 2017;19(1):43‐49. 17 ATHOS-3 Trial: Adverse Events

Adverse Event Angiotensin II (n = 163) Placebo (n = 158) Thromboembolic events 21 (12.9%) 8 (5.1%) Deep vein thrombosis 7 (4.3%) 0 (0%) Thrombocytopenia 16 (9.8%) 11 (7%) Tachycardia 14 (8.6%) 9 (5.7%) Fungal infection 10 (6.1%) 2 (1.3%) Delirium 9 (5.5%) 1 (0.6%) Acidosis 9 (5.5%) 1 (0.6%) Hyperglycemia 7 (4.3%) 4 (2.5%) Peripheral ischemia 7 (4.3%) 4 (2.5%)

Chawla L, et al. Crit Care Resusc. 2017;19(1):43‐49. 18 ATHOS-3 Trial

Conclusion Angiotensin II effectively increased blood pressure in patients with vasodilatory shock that did not respond to high doses of conventional vasopressors Limitations • Primary endpoint of increase in MAP of ≥ 10mmHg or a MAP >75mmHg within 3 hours showed little difference over time • Angiotensin II only reduced norepinephrine use minimally • No morbidity or mortality benefits • Long term safety?

Celi A, et al. Expert Rev Cardiovasc Ther. 2010;8(12):1723‐9. Ekholm M, et al. Thromb Res. 2009;124(1):110‐5. Chawla L, et al. Crit Care Resusc. 2017;19(1):43‐49. Russell J, et al. N Engl J Med. 2008;358(9):877‐87. 19 Pharmacist Question 1

A 75 YOM is admitted to the medical ICU with septic shock on max dose of norepinephrine and vasopressin. Despite these interventions, the patient’s MAP is 50. The provider ask you to dose angiotensin II for this patient. Based on current literature, what starting dose would you recommend? a) 10 ng/kg/min via continuous IV infusion b) 20 ng/kg/min via continuous IV infusion c) 40 ng/kg/min via continuous IV infusion d) 80 ng/kg/min via continuous IV infusion

20 Technician Question 1

•What is the AWP cost per day of angiotensin II for an 80 kg patient with a rate of 20 ng/kg/min and how should this medication be delivered? a) $1000, technician sends the medication via pneumatic tube b) $1500, technician sends the medication via pneumatic tube c) $1500, technician hand‐delivers medication to the nurse ASAP d) $2000, technician to deliver the medication to the automatic dispensing cabinet on the next run

21 Andexanet Alfa (Andexxa®)

22 Andexanet Alfa Mechanism of Action

Factor Xa Inhibitor Factor Xa Inhibitor

Mutated Thrombin protease generating cannot S –S protease generate GLA S –S thrombin

Factor Xa receptor complex Factor Xa decoy‐ andexanet alfa

Lexicomp. Andexanet Alfa. 2018. 23 Andexanet Alfa Dose

Timing of FXa Inhibitor Last Dose Before Last Dose of FXa Andexanet Alfa Initiation Inhibitor <8 Hours or Unknown ≥8 Hours ≤5 mg Low dose Apixaban >5 mg/unknown High dose Low dose ≤10 mg Low dose Rivaroxaban >10 mg/unknown High dose

Lexicomp. Andexanet Alfa. 2018. 24 Andexanet Alfa

Bolus IV Infusion Low dose 400 mg IV 4 mg/minute High dose 800 mg IV 8 mg/minute

Andexanet Alfa. Accessed online 9/10/18 via: https://www.portola.com/ Lexicomp. Andexanet Alfa. 2018. 25 Andexanet Alfa

•Black box warning: thromboembolic risks, ischemic risks, cardiac arrest, sudden deaths •Monitoring: VTE complications •Estimated cost is $25,000 for low dose

Black Box. Accessed online 9/10/18 via: https://www.pexels.com/photo/black‐gift‐box‐190930/ Lexicomp. Andexanet Alfa. 2018. 26 Andexanet Alfa

Refrigerator Room Temperature Intact vials Yes N/A Reconstituted vials ≤24 hours ≤8 hours Reconstituted solution ≤16 hours ≤8 hours

•Reconstitution: do not shake •Use polyolefin or polyvinyl chloride IV bag

Connolly S, et al. N Engl J Med. 2016;375(12):1131‐41. 27 ANNEXA-4 Trial

Study Design Multicenter, prospective, open‐label, single‐group study Population N = 67 Acute major bleeding within 18 hours after the administration of a factor Xa inhibitor Intervention Andexanet bolus + 2‐hour infusion Primary Changes in anti‐factor Xa activity Endpoints Clinical hemostatic efficacy during a 12‐hour period

Connolly S, et al. N Engl J Med. 2016;375(12):1131‐41. 28 ANNEXA-4 Trial: Results

Rivaroxaban Apixaban (n = 32) (n = 31) Median decrease in anti‐factor Xa 89% 93% activity after bolus Median decrease from baseline in 39% 30% anti‐factor Xa activity 4hours after end of infusion

Connolly S, et al. N Engl J Med. 2016;375(12):1131‐41. 29 ANNEXA-4 Trial

Conclusion Initial bolus followed by 2‐hour infusion of andexanet substantially reduced anti‐factor Xa activity in patients with acute major bleeding associated with factor Xa inhibitors, with effective hemostasis occurring in 79%. Limitations • Single group cohort, no comparison group • Only included patients with severe bleeding • Patients were included in the efficacy analysis only if the baseline value for anti–factor Xa activity was ≥ 75 ng/mL

Connolly S, et al. N Engl J Med. 2016;375(12):1131‐41. 30 Pharmacist Question 2

A 75 YOM is admitted to the neurosurgical ICU with an intracranial bleed after a fall at home. The patient takes edoxaban for atrial fibrillation. The resident on call ask you if we can reverse his anticoagulation with andexanet alfa. Is this true? a) Yes, andexanet alfa reverses all Xa inhibitors b) No, andexanet alfa is only approved for the reversal of apixaban and rivaroxaban

31 Technician Question 2

Which of the following is the proper storage for andexanet alfa? a) Intact vials can be stored at room temperature b) Intact vials can be stored in the freezer c) Reconstituted solution is good for 8hours or less at room temperature or 16 hours or less in the refrigerator d) Reconstituted solution is good for 36 hours at room temperature or in the refrigerator

32 Clevidpine (Cleviprex®)

Cleviprex (clevidipine)[prescribing information]. 2011. 33 Clevidipine

•Dihydropyridine calcium channel blocker (CCB) •Contraindications: allergy to soy or eggs, defective lipid metabolism, severe aortic stenosis •Adverse effects: atrial fibrillation, hypertriglyceridemia, hypotension •Monitoring: blood pressure, heart rate, triglycerides

Cleviprex (clevidipine)[prescribing information]. 2011. Blood Pressure. Accessed online 9/10/18 via: https://www.flickr.com/photos/163595523@N02/26643341777/in/photolist‐GAo6gF‐m2fsbt‐vqvXCP‐vHnh56‐vGq41w‐vGZHuT‐dnrRcW‐m2g3Qg‐dgQXB5‐7gULV5‐ 235H3mw‐8jdnJg‐53LXw5‐hfLDF4‐m2gy7U‐arjhua‐m2f6AF‐5e1pfA‐59rJnK‐8Kbfg9‐b7n112‐259qr4a‐ptSaav‐m2eCwF‐e3uh9L‐6uGryK‐m2g6hS‐m2fFXr‐m2ff78‐m2h7xf‐nsfKsn‐NnaEpS‐6qEThm‐mR6HqK‐m2gdug‐ 34 2972yee‐bFjW7D‐7RnSmp‐icj3Ef‐dYuZc2‐8kG6mG‐9A4Qni‐m2h4AJ‐gzfxEb‐aLQ9KT‐m2gcKk‐m2fyFx‐au57bQ‐jSDtS‐mKq4kr Clevidipine

Dose Initial 1 to 2 mg/hour Titration Can double dose every 90 seconds Maintenance 4 to 6 mg/hour Max 21 mg/hour Renal or hepatic adjustment No dose adjustment

Cleviprex (clevidipine)[prescribing information]. 2011. 35 Clevidipine

•Administration: Do not dilute. Invert vial gently to ensure uniformity of emulsion •Storage: refrigerator. Protect from light. •25 mg/50 mL (per mL): $1.67 •50 mg/100 mL (per mL): $1.67

Cleviprex (clevidipine)[prescribing information]. 2011. 36 Clevidipine vs Nicardipine in NSICU

Study Design Retrospective review Population N = 57 Clevidipine (n = 19) Nicardipine (n = 38) Primary Time to target SBP Endpoints Percentage of time within target BP range

Finger J, et al. Neurocrit Care. 2017;26(2):167‐173. 37 Clevidipine vs Nicardipine in NSICU Results

Clevidipine Nicardipine P‐value (n = 19) (n = 38) Median time to target SBP 30 min 46 min 0.13 Time spent within target BP 79% 78% 0.64 Total volume 530 mL 1254 mL 0.02

Finger J, et al. Neurocrit Care. 2017;26(2):167‐173. 38 Clevidipine vs Nicardipine in NSICU

Conclusion • No statistically significant differences in acute BP management between the two agents • Trend toward shorter time to target and significantly less volume administered in the clevidipine group • Either agent are viable options in a NSICU population Limitations • Retrospective • Small sample size

Finger J, et al. Neurocrit Care. 2017;26(2):167‐173. 39 Pharmacist Question 3

You are working in the central pharmacy at night when a physician call down asking you how to switch a patient from nicardipine drip to a clevidipine drip. What would you recommend? a) Stop nicardipine drip and start clevidipine drip at 1 mg/hour b) Stop nicardipine drip and start clevidipine drip at 4mg/hour c) Start clevidipine drip at 1 mg/hour, titrate clevidipine up by doubling the dose every 90 seconds while titrating down nicardipine d) Start clevidipine drip at 4 mg/hour, titrate clevidipine up by doubling the dose every 90 seconds while titrating down nicardipine

40 Technician Question 3

What is the brand name of clevidipine? a) Clopidogrel b) Cleviprex c) Capoten d) Cardizem

41 Sugammadex (Bridion®)

Bridion (sugammadex) [prescribing information]. 2015. 42 Sugammadex

rocuronium or Sugammadex Complex vecuronium

Bridion (sugammadex) [prescribing information]. 2015. 43 Sugammadex Dosing

Level of Dose Indication Blockade Moderate 2 mg/kg 2nd twitch response to TOF stimulation Deep 4 mg/kg 1‐2 post‐tetanic counts, no twitch response to TOF stimulation Profound 16 mg/kg Emergency use in Rocuronium reversal only cannot intubate, cannot ventilate

Bridion (sugammadex) [prescribing information]. 2015. 44 Sugammadex

•Adverse effects: hypotension, prolong QT, bradycardia, headache, nausea, vomiting •Monitoring: train‐of‐four, EKG, respiratory function, anaphylaxis, coagulation •Drug interactions: oral contraceptives, tamoxifene

Train. Accessed online 9/10/18 via: Bridion (sugammadex) [prescribing information]. 2015. https://www.flickr.com/photos/andy_hoare/5149552586/in/photolist‐8R3Nzq‐dYvkHG‐ Dirkmann D, et al. Anesthesiology. 2016;124(6):1277‐1285. iqX8zU‐fDuMoz‐pbJJd9‐rabg27‐raVZhJ‐q59K8t‐p7xivy‐8yUg7H‐KisPLZ‐REas7G‐pQi2mc‐ Karalapillai D, et al. Critical Care and Resuscitation. 2013;15(1), 57‐62. cAkSRw‐ekccHd‐napPZf‐VhBcwc‐pycBPV‐p9TRGt‐S9aSFM‐rA1zxt‐8ZLp7V‐Gok6Re‐hA1UV3‐ Paech M, et al. Anaesthesia. 2017;73(3):340‐347. 27qSbWd‐cZ1nHL‐2ar6nx4‐c6SZ1f‐iASrPG‐22wiemN‐rRSKHq‐Rq6HCs‐qCHLwZ‐pwpzco‐ Soto R, et al. Am J Ther. 2016;23(6):e1654‐e1662. nzeD6R‐orddEZ‐fGyERZ‐qV2sGF‐npExpm‐ork8JZ‐WeDXy5‐qHHs4k‐c4ALKN‐bsejgh‐na7uZL‐ Srivastava A, et al. British Journal of Anaesthesia. 2009;103(4), 622. nQZDaN‐piraDh‐DNAEWg‐7WcFSH‐nCu5Jz 45 Sugammadex

Readministration of Rocuronium or Vecuronium after Reversal (up to 4 mg/kg) Minimum Waiting Time NMBA and Dose to be Administered 5 minutes 1.2 mg/kg rocuronium 4 hours 0.6 mg/kg rocuronium or 0.1 mg/kg vecuronium

Bridion (sugammadex) [prescribing information]. 2015. 46 Sugammadex

•Administer as rapid IV push over 10 seconds •Store at room temperature. Protect from light. •200 mg/2 mL (per mL): $57.00 •500 mg/5 mL (per mL): $41.76

Bridion (sugammadex) [prescribing information]. 2015. Chambers D, et al. Health Technol Assess. 2010;14(39):1‐211. Carron M, et al. Clinicoecon Outcomes Res. 2016;8:43‐52. Hristovska A, et al. Cochrane Database of Systematic Reviews. 2017. Carron M, et al. Clin Interv Aging. 2017; 13:13‐24. Jones R, et al. Anesthesiology 2008;109(5):816‐824. 47 SIGNAL Trial

Study Design Phase III, multicenter, randomized, safety‐assessor blinded Population Patients aged ≥18 years, American Society of Anesthesiologists class 1‐4, scheduled to undergo surgery under general anesthesia Intervention Sugammadex 4 mg/kg Neostigmine 70 mcg/kg with glycopyrrolate 14 mcg/kg at 1‐2 post‐tetanic counts Primary Endpoint Time from start of study drug administration to recovery of the train‐of‐four ratio to 0.9

Lemmens et al. BMC Anesthesiology. 2010, 10:15. 48 SIGNAL Trial Results

Sugammadex Neostigmine Median time to recovery of 2.7 min 49.0 min the Train of Four ratio to 0.9 Adverse events 97.3% 97.4% Serious adverse events 2 3

Lemmens et al. BMC Anesthesiology. 2010, 10:15. 49 SIGNAL Trial

Conclusion Recovery from profound vecuronium‐induced block is significantly faster with sugammadex, compared with neostigmine. Neostigmine did not rapidly reverse profound neuromuscular block Limitations Underpowered for safety endpoints

Lemmens et al. BMC Anesthesiology. 2010, 10:15. 50 Sugammadex vs Neostigmine

Sugammadex Neostigmine MOA Direct Indirect Onset of Action <3 mins (often faster) 10‐30 mins Duration ‐‐ 2.5‐4 hours Half‐Life 2 hours 24‐113 mins (extended in renal impairment) Metabolism Not metabolized Hepatic Excretion Urine (95% unchanged drug) Urine (50% unchanged drug) Bridion (sugammadex) [prescribing information]. 2015. Carron M, et al. Clinicoecon Outcomes Res. 2016;8:43‐52. Carron M, et al. Clin Interv Aging. 2017; 13:13‐24. 51 Sugammadex vs Neostigmine

Study Type Results Putz, et al RCT Sugammadex shorter more predictable; 2016 PACU time difference not significant Yagan, et al RCT Sugammadex group significantly lower use of 2017 ondansetron during 24 hour period.

Hristovska, et al Meta‐ Sugammadex faster reversal times despite level of NMB. 2017 Analysis Significantly fewer adverse effects than neostigmine.

52 Upcoming Medications

•Selepressin

◦ V1A‐selective vasopressin analogue •Adrecizumab ◦ Antibody against adrenomedullin

Clock. Accessed online 9/10/18 via: https://www.flickr.com/photos/robghijsen/6662852681/in/photolist‐b9LRYn‐27b7rrN‐Sx81Y9‐SUuy91‐KdeNJN‐CMqsJU‐e2s4wG‐HyZzz‐ 6VXZcY‐21h1sSm‐UNH53M‐87J8Kx‐FUMhsJ‐cgBDM‐8vgoc‐ULPTmd‐7cEpDb‐ccBDt7‐dVSjoZ‐fnm8go‐7sg8Pt‐FWPZpZ‐212rrvW‐oo39wz‐LNn4CD‐549pZq‐6nEpjJ‐QMijZQ‐ eJa3a2‐apimDX‐99zxf7‐26aCcUT‐9c9xPc‐21PKotb‐erJ16j‐yxptF‐9ESxhY‐diVAu‐GNxN8H‐apikh8‐e8aYs1‐bimHuR‐73ZW4S‐ayaXVF‐Jkkzrv‐99zyKC‐MaTQj‐CS4d4‐7hw2rn‐6bhLog 53 Pharmacist Question 4

A 65 YOM had surgery 30 minutes ago where the resident used sugammadex to reverse his neuromuscular blockade. Now the patient is fighting the vent and the attending wants to use neuromuscular blocker for ventilator compliance. Based on sugammadex’s mechanism of action, what alternative neuromuscular blocker would you recommend to the physician? a) Pancuronium b) Rocuronium c) Vecuronium d) Cisatucurium

54 References for Angiotensin II

•Celi A, Cianchetti S, Dell'Omo G, et al. Angiotensin II, tissue factor and the thrombotic paradox of hypertension. Expert Rev Cardiovasc Ther. 2010;8(12):1723‐9. •Chawla L, Russell J, Bagshaw S, et al. Angiotensin II for the Treatment of High‐Output Shock 3 (ATHOS‐3): protocol for a phase III, double‐blind, randomised controlled trial. Crit Care Resusc. 2017;19(1):43‐49. •Ekholm M, Jekell A, Wallen N, et al. Angiotensin II infusion in man is proinflammatory but has no short‐term effects on thrombin generation in vivo. Thromb Res. 2009;124(1):110‐5. •Giapreza (angiotensin II) [prescribing information]. San Diego, CA; La Jolla Pharmaceutical Company: 2017. •Russell J, Walley K, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358(9):877‐87.

55 References for Andexanet Alfa

•Connolly S, Milling T, Eikelboom J, et al. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2016;375(12):1131‐41. •Lexicomp. Andexanet Alfa. Hudson, Ohio: Lexi‐Comp, Inc. 2018.

56 References for Clevidipine

•Cleviprex (clevidipine)[prescribing information]. Parsippany, NJ; Fresenius KabiAustria GmbH, Graz, Austria: 2011. •Finger J, Kurczewski L, Brophy G. Clevidipine Versus Nicardipine for Acute Blood Pressure Reduction in a Neuroscience Intensive Care Population. Neurocrit Care. 2017;26(2):167‐173.

57 References for Sugammadex

•Bridion (sugammadex) [prescribing information]. Whitehouse Station, NJ; Merck & Co., Inc: 2015. •Carron M, Baratto F, Zarantonello F, et al. Sugammadex for reversal of neuromuscular blockade: a retrospective analysis of the clinical outcomes and cost‐effectiveness in a single center. Clinicoecon Outcomes Res. 2016 18;8:43‐52. •Carron M, Bertoncello F, Ieppariello G. Profile of sugammadex for reversal of neuromuscular blockade in the elderly: current perspectives. Clin Interv Aging. 2017; 13:13‐24. •Chambers D, Paulden M, Paton F, et al. Sugammadex for the reversal of muscle relaxation in general anaesthesia: a systematic review and economic assessment. Health Technol Assess. 2010;14(39):1‐211. •Dirkmann D, Britten MW, Pauling H, et al. Anticoagulant Effect of Sugammadex: Just an In Vitro Artifact. Anesthesiology. 2016;124(6):1277‐1285. •Hristovska A, Duch P, Allingstrup M, et al. Efficacy and safety of sugammadex versus neostigmine in reversing neuromuscular blockade in adults. Cochrane Database of Systematic Reviews. 2017. •Jones R, Caldwell JE, Brull S, et al. Reversal of Profound Rocuronium‐induced Blockade with Sugammadex: A Randomized Comparison with Neostigmine. Anesthesiology 2008;109(5):816‐824..

58 References for Sugammadex

•Karalapillai D, Kaufman M, Weinburg L. Sugammadex. Critical Care and Resuscitation. 2013;15(1), 57‐62. •Lemmens H, El‐Orbany M, Berry J, et al. Reversal of profound vecuronium‐induced neuromuscular block under sevoflurane anesthesia: sugammadex versus neostigmine. BMC Anesthesiology. 2010;10:15. •Paech M, Kaye R, Baber C, et al. Recovery characteristics of patients receiving either sugammadex or neostigmine and glycopyrrolate for reversal of neuromuscular block: a randomized controlled trial. Anaesthesia. 2017;73(3):340‐347. •Putz L, Dransart C, Jamart J, Marotta ML, Delnooz G, Dubois PE. Operating room discharge after deep neuromuscular block reversed with sugammadex compared with shallow block reversed with neostigmine: a randomized controlled trial. J Clin Anesth. 2016; 35: 107‐113. •Soto R, Jahr J, Pavlin J et al. Safety and Efficacy of Rocuronium With Sugammadex Reversal Versus Succinylcholine in Outpatient Surgery—A Multicenter, Randomized, Safety Assessor–Blinded Trial. Am J Ther. 2016;23(6):e1654‐e1662. •Srivastava A, Hunter J. Reversal of neuromuscular block. British Journal of Anaesthesia. 2009;103(4), 622. •Yağan Ö, Taş N, Mutlu T, et al. Comparison of the effects of sugammadex and neostigmine on postoperative nausea and vomiting. Brazilian Journal of Anesthesiology (English Edition). 2017;67(2):147‐152.