Conflict of Interest

I hereby certify that, to the best of my Medications and the knowledge, no aspect of my current personal or professional situation might Orthopaedic Nurse reasonably be expected to affect significantly my views on the subject on which I am presenting. MaryAnne Cronin, BS, MS, PharmD, BCPS

Learner Outcome Objectives 1. Discuss the concept of “rapid recovery” following As a result of this learning activity, the orthopedic surgery participant will apply knowledge and 2. Discuss the pharmacology of preventing surgical infection skills to implement best practices 3. Discuss the pharmacology of multimodal pain related to medications in the care of management orthopaedic patients 4. Discuss the prevention and treatment of opioid‐ induced constipation 5. Discuss the pharmacology of blood management (minimizing postoperative anemia)

1 Objectives Excellence with Fiscal Responsibility

6. Discuss the pharmacology of preventing and April 2016: total joint replacement procedures will be treating postoperative nausea and vomiting reimbursed as a “Bundled Payment” by Medicare 7. Discuss the pharmacology of preventing – One predetermined dollar amount to ALL postoperative venous thromboembolism, providers of patient care for the procedure and the following 90 days including risk stratification – Reimbursed dollars will be reduced for 8. Discuss the interruption of chronic postoperative complications and low patient anticoagulation for surgery satisfaction scores 9. Describe drug‐induced QT prolongation

Fast Track Surgery – Keys to Success The orthopedic nurse is pivotal 1. Optimize inpatient management to achieving successful patient outcomes! a. Pain b. Postoperative N&V c. Hydration d. Minimize postoperative anemia e. Ambulation 2. Safe transitions of care a. Continue multimodal pain management after DC b. First appointment to surgeon 7‐14 days postop

2 What are the postoperative Audience Workplace: complications that impede Where do you practice? rapid recovery? 1. Hospital 2. Outpatient clinic 3. Ambulatory surgery center 4. Rehabilitation facility 5. Other

Surgical Site Infection

Bratzler DW et al. Surgical Infections. 2013;14(1):73‐156. Northwell Health policy: Adult Antibiotic Prophylaxis in Surgery . 2016 revision.

3 Antimicrobial Perioperative Dosing Cefazolin  2 Gram IVPB if < 120 kg  3 Gram IVPB if ≥ 120 kg  Administer within 1 hour of incision and q8h x 2 doses postop  Intraoperative redose after 4 hours at ½ preop dose; begin postop doses 8 hrs after Managing Postoperative Pain INTRAOP dose

Clindamycin  900 mg IVPB  Administer within 1 hour of incision and q8h x 2 doses postop  Intraoperative redose after 6 hours at same dose as preop dose; begin postop doses 8 hrs after INTRAOP dose

Vancomycin  15 mg/kg up to MAXIMUM DOSE: 3000 mg  Administer within 2 hrs of incision and postop x1 dose 12 hrs later (creatinine clearance < 30 mL/min: no postop dose necessary)  No intraoperative redose (long half‐life)

Bratzler DW et al. Surgical Infection. 2013;14(1): 73‐153. Northwell Health Guideline: Adult Antibiotic Prophylaxis in Surgery. 2016 revision.

Multimodal Pain Management Acute Pain vs Chronic Pain

• Acute pain may be mild and short‐lived, or it might be severe and last for weeks or months (clonidine) (amitriptyline) • In most cases, acute pain does not last longer (lidocaine) than six months, and it disappears when the underlying cause of pain has been treated or (ketamine) has healed (gabapentin) • Unrelieved acute pain, however, might lead to chronic pain

(NSAIDs, COX‐2 inhibitors)

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4 Mechanism of Action of COX‐1 and COX‐2 inhibitors Nonsteroidal Anti‐inflammatory Drugs (NSAIDs) and COX‐2 inhibitors (constitutive) (inducible)

Can NSAIDs and COX‐2 inhibitors (as a class of drugs) be safely administered to patients with a history of cardiovascular disease? 1. Yes 2. No

When aspirin and ibuprofen are administered together, all cause mortality was shown to nearly double and CV mortality increased by about 75%. Always administer low dose aspirin (enteric coated) at least 2 hours PRIOR to ibuprofen (immediate release aspirin, at least 30 min).

MacDonald and Wei. Lancet. 2003;361:573‐574. Catella‐Lawson F et al. NEJM. 2001; 345 (25):1809‐17.

5 PRECISION trial PRECISION trial, continued

• FDA mandated trial for celecoxib CV safety following the removal of rofecoxib (Vioxx) in 2004 • Over 10 years, 69% of patients stopped taking drug, • Approximately 24,000 patients randomized to 3 groups: 27% discontinued followup and 15% withdrew celecoxib 100mg BID, ibuprofen 600mg TID, and naproxen consent/withdrew continued participation in the study 375mg BID • Designed as an intent‐to‐treat (if you’re randomized, • Only 10% of patients received a higher dose for each drug, your analyzed) and on‐treatment analyses for if they were diagnosed with RA (celecoxib 200mg BID, noninferiority ibuprofen 800mg TID, naproxen 500mg BID) • Moderate doses of celecoxib were found to be • Concurrent low dose ASA (≤325mg) was permitted • Designed to show noninferiority. Treatment duration was noninferior to ibuprofen or naproxen with regard to 2‐3 years and followup was maintained for 3‐4 years total. CV safety

Nissan SE et al. PRECISION trial. NEJM. 2016. DOI: 10.1056/NEJMoa1611593. Nissan SE et al. PRECISION trial. NEJM. 2016. DOI: 10.1056/NEJMoa1611593.

NSAID Use and Selection: High‐dose Celecoxib study outcomes Important Considerations • Age • 2035 patients • Concomitant use of aspirin followed for 3 years • Risk for NSAID renal toxicity – 100% of patients – Avoid in CKI, stages 4 and 5 followed for 2.8 yrs – Use with caution in patient with – 77% of patient • CKI stage 3 followed for 3 yrs • Risk for intravascular volume depletion with reduced renal perfusion (eg, CHF, cirrhosis) • Risk for NSAID GI toxicity • Risk for NSAID CV complication

Hochberg MC et al. Arthritis Care Res. 2012;64:465‐474. Solomon SD et al. NEJM.2005;352(11): 1071‐1080. Antman EM et al. Circulation. 2007;115:1634‐1642.

6 Treatment of Neuropathic Pain: Mechanism of Action of Opiates Gabapentin (Neurontin) Pregabalin (Lyrica) • Bind to  (mu),  (delta) and  (kappa) receptors • Gamma‐aminobutyric acid (GABA) analogs that inhibits present on sensory‐afferent neurons excitatory neurotransmitter release in CNS tissues. The • Hyperpolarize nociceptors of damaged tissue, exact mechanism of action is not fully understood. preventing signal transduction • Useful in neuropathic pain • Mimic action of endogenous opioids on neurons by • AEs: peripheral edema, dizziness, somnolence preventing release of neurotransmitters • Emerging literature has shown significant AEs without • Inhibit GABAergic transmission at the midbrain a reduction in opiate use for postsurgical pain1,2

1Hamilton TW et al. JBJS. 2016;98:1340‐50. 2YaDeau JT et al. BJA. 2015;115(2):285‐93.

Metabolism of Opiates • Influenced by individual genetic variability (pharmacogenomics) • Opioids metabolized by hepatic enzymes • Patients can be extensive metabolizers, intermediate metabolizers, or poor metabolizers • Poor metabolizers =  adverse events

7 Transdermal patches: NARCOTIC CROSS ALLERGENICITY Avoid heat exposure CHART • GROUP 1 GROUP 2 GROUP 3 GROUP 4 Heating pads, tanning beds, electric blankets, Morphine Meperidine Methadone These synthetic hot tubs, saunas, and heated water beds can Hydromorphone Diphenoxylate Propoxyphene compounds are Heroin Loperamide unrelated – not increase release of drug from transdermal Codeine Fentanyl cross allergenic patch, putting the patient at increased risk for Oxycodone with any other Hydrocodone compounds. toxicity Levorphanol Butorphanol Buprenorphine Nalbuphene • Hot baths and sunbathing should also be Oxymorphone discouraged Tramadol • Fentanyl absorption  by 30% with a rise in body temp to 104F.

Created by M.Cronin, PharmD

Tramadol (Ultram) Hydromorphone (Dilaudid) • Centrally‐acting synthetic opioid analgesic that exerts its effect by binding mu‐opioid receptors and through the weak inhibition of norepinephrine and serotonin reuptake • Drug interactions with SSRIs or SNRIs  serotonin syndrome • Often better tolerated by patients sensitive to opiates

8 Does a validated risk Minimize Postoperative stratification tool exist for Nausea and Vomiting prevention of PONV? (PONV) 1. Yes 2. No

Risk Stratification for PONV Prevention of PONV

Simplified Risk Assessment Score 80% RISK FACTORS POINTS 80% Female gender 1 70% 60% Non‐smoker 1 60% PONV 50% 40% of

History of PONV 1 40%

Postoperative opioids 1 Risk 30% 20% 20% 10% 10% 0% 01234 # risk factors

Apfel et al. Anesthesiology 1999;91:693–700

9 Pharmacologic Protocols: Treatment of PONV Total Joint Arthroplasty

Total Joint Arthroplasty program protocol, Northwell Health, Syosset Hospital

Postoperative Pain Management INTRAOPERATIVE Medications

Total Joint Arthroplasty program protocol, Northwell Health, Syosset Hospital Total Joint Arthroplasty program protocol, Northwell Health, Syosset Hospital

10 • Effective Pain Management is a Shared Responsibility communication with the between Patient and Nurse patient is key to appropriate pain med administration • Remember: older patients and nonverbal patients will sometimes exhibit NEGATIVE symptoms of pain (eg, withdrawal, altered mental status, no appetite, combative, noncommunicative).

Preventing Constipation

Opioid‐induced Constipation . Drink at least 6(8‐ounce) glasses of non‐caffeinated (Acute) beverages every day . Eat 5 to 9 servings of fresh fruits and vegetables per day . Use a stool softener such as docusate sodium (Colace®) 100 mg TID

11 Treating Acute‐onset Opioid‐induced Constipation . Constipation should be treated with a laxative Minimize Stimulant : senna (Senokot®) or bisacodyl (Dulcolax®) Postoperative Anemia Osmotic: Polyethylene Glycol PEG 3350 (Miralax®) . Patients should be advised to AVOID using bulk‐forming laxatives when constipated due to a narcotic . Common bulk‐forming laxatives include psyllium (Metamucil®), polycarbophil (FiberCon®), Benefiber®, and methylcellulose (Citrucel®) . Bulk fiber laxatives can cause an intestinal blockage

Tranexamic acid • FDA‐approved to prevent excessive blood loss in pts with hemophilia undergoing tooth extraction, and to treat menorrhagia • Found to have utility in minimizing morbidity and mortality in trauma patients • Finally moved into the surgical arena, where it has been shown to significantly reduce postoperative blood loss and transfusion requirements

12 Preventing Postoperative Venous Thromboembolism (VTE)

Total Joint Arthroplasty program protocol, Northwell Health, Syosset Hospital

Prophylaxis for Venous Thromboembolism (VTE) Which of the following drugs are FDA‐ approved for the prevention of VTE following hip fracture surgery?

1. Rivaroxaban (Xarelto) 2. Dabigatran (Pradaxa) 3. Enoxaparin (Lovenox) 4. Aspirin

13 Aspirin – where does it fit into the FDA‐approved VTE Prophylaxis picture? following Orthopedic Surgery • Before 2012, ACCP guidelines for VTE prophylaxis recommended AGAINST using ASA • In the 2012 9th edition, acknowledged ASA as an option for the first time • CMS did not recognize ASA as an acceptable option until 2013‐2014

• The literature is “gray” with respect to ASA Different doses, different surgical techniques over the years Conclusions drawn: ASA can be effective, but in low risk patients

Warfarin Monotherapy When warfarin is administered Prothrombotic State postoperatively as monotherapy to During first 4 days prevent VTE, does it initially put the Warfarin inhibits of warfarin FII, VII, IX, X and therapy, patient is patient at increased risk for thrombosis? procoagulant prothrombotic and proteins C and S. not effectively Depletion of FVII anticoagulated will  INR, until FII and FX 1. Yes sometimes >2.0. levels reduced by 2. No >50%. Half‐life: Must bridge FVII: 6 hrs Protein C: 6 hrs with LMWH to FX: 40 hrs protect patient FII: 60‐70 hrs for at least 4 days and until INR >2.0. 56

14 Risk Stratification and Guidelines for Perioperative Interruption of Anticoagulation Risk Stratification and Guidelines for Perioperative Interruption of Anticoagulation: Abbreviations and References

AF = atrial fibrillation; TIA = transient ischemic attack; HTN = hypertension; DM = diabetes mellitus; CHF = congestive heart failure; NOAC = novel oral anticoagulants; AVR = aortic valve replacement

CHADS2 = CHF‐HTN‐Age ≥75‐DM‐prior stroke or TIA (each get 1 point except stroke/TIA = 2 points) 1Therapeutic enoxaparin: 1.5 mg/kg SC once daily or 1 mg/kg SC twice daily 2Prophylactic dose is usually effective unless clinician assesses a need for more aggressive anticoagulation 3NOACs are only indicated for nonvalvular AF 4Prescribing information, Dabigatran (Pradaxa®) and Edoxaban (Savaysa®)

Douketis JD et al.. Chest 2012. 141(2 Suppl);e326s‐350s. Nishimura RA et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease. JACC

Interruption of Warfarin for Patients Interruption of Warfarin for Patients with AF: with Atrial Fibrillation: the BRIDGE trial the BRIDGE trial, cont’d Findings: • Approximately 1800 patients with paroxysmal or • No‐bridging was non‐inferior to bridging with treatment permanent AF taking warfarin. Average CHADS2 score: 2.3 doses LMWH with respect to arterial thrombosis • Warfarin interrupted 5 days prior to surgery. Patients • Major bleeding was statistically significantly lower in the randomized to receive treatment doses of LMWH or no‐bridging group than in the bridging group (1.3% vs placebo starting 3 days prior to procedure until 24 hrs 3.2%, RR 0.41, 95% CI, P=0.005 before, then for 5‐10 days after procedure • Studied risk of postop thromboembolism (arterial or Approx 10% of pts underwent orthopedic surgery. Since risk venous) versus risk of postop major bleeding if treatment of postop venous thromboembolism is high in this pt doses of LMWH were used to bridge warfarin until INR population, we continue to bridge patients with >2.0. PROPHYLACTIC doses of LMWH while titrating warfarin

Douketis JD et al. NEJM. 2015. DOI:10.1056/NEJMoa1501035 Douketis JD et al. NEJM. 2015. DOI:10.1056/NEJMoa1501035

15 Non‐vitamin K Oral Anticoagulants (NOACs) NOAC Drug Interactions DABIGATRAN RIVAROXABAN APIXABAN (Pradaxa) (Xarelto) (Eliquis) Direct factor IIa (thrombin) Direct factor Xa Direct factor Xa Drug class inhibitor inhibitor inhibitor 5‐9 hours Half –life (hrs) 14‐17 hours 9‐14 hours (11‐13 elderly)

Renal excretion 80% of absorbed drug 66% 27% (unchanged drug)

Capsules cannot be crushed, May be crushed May be crushed Formulation issues broken, or chewed ( drug and mixed with and mixed with bioavailability by 75%) applesauce water May be taken with or 10mg dose: with With or without Food effects without food or without food food

NOAC Procedure Interruption Specific Drug Interactions with NOACs Recommendations

16 Of the 3 NOACs approved for Reversal Agents prevention of VTE following total joint GUIDANCE FOR REVERSAL OF NEW ORAL ANTICOAGULANTS replacement which one currently has Apixaban Dabigatran Rivaroxaban (Eliquis) (Pradaxa) (Xarelto) Activated charcoal 25‐50 G PO if an approved reversal agent? Yes Yes Yes last dose ingested <3 hrs prior Coagulation test (nonspecific) PT aPTT PT 27% renal 80% renal 33% renal Fluid resuscitation/renal excretion 1. Apixaban (Eliquis) excretion excretion excretion Yes (dialysis will 2. Dabigatran (Pradaxa) remove Dialyzable? No No 60% of drug in 2‐3 3. Rivaroxaban (Xarelto) h) PCC4 (Kcentra®) 25‐50 units/kg Use Praxbind 25‐50 units/kg 4. None of these agents has a reversal agent Andexanet‐ Andexanet‐ Idarucizumab Antidote (expedited, phase (expedited, phase (Praxbind) III study) III study)

Total Joint Arthroplasty program protocol, Northwell Health, Syosset Hospital Total Joint Arthroplasty program protocol, Northwell Health, Syosset Hospital

17 QT Interval Drug‐induced QT Interval Prolongation

Drugs that Prolong QT Interval Minimizing Postoperative Confusion/Delirium

18 Drug‐induced Postoperative Confusion • American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults Thank – Minimize unnecessary medications you! postoperatively, eg, H2RAs (eg, famotidine), sedatives, hypnotics • Multimodal pain management to minimize opioid administration

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