Knee Arthroplasty Intra-Articular Injection cocktail

Intraoperative cocktail injection in knee arthroplasty for reduction of postoperative pain.

1. Cocktail An Antidote for Pain Anurag Mittal

2. Why Pain Management is Important

3. Why Pain Management is Important Pain Delays recovery Decreases patient satisfaction Delays rehabilitation Delirium Depression

4. Evolution of Perioperative Pain Management for TKA (Total Knee Arthroplasty) 1980s 1990s 2000s 2010s IV or IM Narcotics IV Narcotics via patient controlled analgesia (PCA) Multi-modal, pre-emptive analgesia with peripheral nerve blocks Multi-modal pre-emptive analgesia with Peri-articular Injections

5. Why Use Periarticular Multimodal Cocktail Injection? Significantly reduce consumption of analgesics infection pain after surgery intra-articular bleeding duration of time required to perform straight-leg raise overall narcotic consumption the hospital stay

6. Why Use Periarticular Multimodal Cocktail Injection? (Cont’d) Improve range of motion (ROM) patient satisfaction rate following surgery the time the agents would act locally

7. The Modalities of Decreasing Pain

8. Periarticular Cocktail Injection

9. My Peri-Articular Cocktail Injection Constituent Epinephrine Ketorolac Ropivacaine Morphine Cefuroxime Normal Saline Volume 0.3 ml (1 mg/1 ml) 1 ml (30 mg/1 ml) 40 ml (0.75%) 10 ml (5 mg/5 ml) 750 mg 50 ml 0.9% In two 50 ml syringes

10. When is it given? 1st: After bony cuts 1st 2nd 2nd: After implantation of femoral and tibial implants

11. Where is it given? (1st) Upper left Figure 1. Lateral capsule + Lateral collateral ligament Upper right Figure 2. Medial collateral ligament Lower left Figure 3. Far medial capsule Upper right Figure 4. IC Region **No injection in Posterolateral capsule 15 ml 15 ml 10 ml 10 ml

12. Where is it given? (2nd) Upper left figure 1. Superior capsule Upper middle figure 2. Medial capsule Upper right figure 3. Anterior capsule Lower left figure 4. Superior vastus medialis oblique Lower right figure 5. Inferior vastus medialis oblique 10 ml 10 ml 10 ml 10 ml 10 ml

13. Pharmacological Aspects of Cocktail Injection Constituents

14. Epinephrine Group Catecholamine ( Sympathomimetic monoamine) MOA Nonselective agonist of all adrenergic receptors Increase peripheral resistance via α1 receptor-dependent vasoconstriction Half-life Less than 5 minutes (IV) Use in TKA Vasoconstrictor Reduce the toxicity of the local anesthetic by reducing the rate the drug is released into the circulation . Reduce intraoperative bleeding and postoperative hemoglobin loss Minimize the need for blood transfusion Side Effect Increased risk of vasoconstriction and sloughing of tissue ( Concurrent use with local anesthetics for injection of areas such as fingers, toes, ears)

15. Ketorolac Group Potent Nonsteroidal antiinflammatory drug ( NSAID ) MOA Blocks prostaglandin complex formation and production through its S-enantiomeric form. Half-life S-enantiomer: approximately 2.5 hours (SD±0.4) R-enantiomer: 5 hours (SD±1.7) Racemate: 5 to 6 hours Use in TKA Analgesia that does not possess any sedative or anxiolytic activities Side Effect Gastrointestinal bleeding, kidney failure (may result in hospitalization and even fatal outcome)

16. Ropivacaine Group Amino amide local anesthetic MOA Increases the threshold for electrical excitation in the nerve Half-life IV terminal half-life of 1.8 h Use in TKA Local anesthetic Side Effect May be chondrotoxic (continuous intra-articular postoperative use)

17. Morphine Group phenanthrene opioid receptor agonist MOA Agonists of the μ (main), 🇰, δ Half-life The plasma half-life is 2-3 hours. Use in TKA Perioperative analgesia Side Effect (Acute dose-related effects) Respiratory depression ; anorexia, nausea, vomiting and constipation ; euphoria, dizziness, drowsiness and confusion; dry mouth and spasm of the urinary and biliary tract; hypotension, bradycardia and palpitations. Prolonged administration may result in physical dependence .

18. Cefuroxime Group Broad-spectrum cephalosporin antibiotic resistant to beta-lactamase ( 2nd generation ) MOA Binds to specific penicillin-binding proteins (PBPs) located inside the bacterial cell wall, it i nhibits bacterial cell wall synthesis Gram positive coverage: Less active compared to 1st generation cephalosporin (e.g. cephalexin, cefazolin) Gram negative coverage: Haemophilus influenza, Enterobacter aerogenes, Neisseria, Proteus mirabilis, Escheria coli, Klebsiella pneumonia No anaerobic coverage Half-life Approximately 80 minutes (IM or IV) Use in TKA Treatment of many different types of bacterial infections Side Effect Swelling, redness, or pain at the injection site

19. Other Cocktail Injections

20. Other Cocktail Injections - Ranawat Chitranjan S. Ranawat, M.D.

21. Comparison with Ranawat Injection Ranawat Cocktail TK Cocktail Epinephrine 1:1000 (0.3 cc) Epinephrine 0.3 ml (1 mg/1 ml) Methylprednisolone acetate 40 mg (1 cc) Ketorolac 1 ml (30 mg) Bupivacaine 0.5% (24 cc) Ropivacaine 40 ml Morphine sulphate 8 mg (0.8 cc) Morphine 10 ml Cefuroxime 750 mg (10 cc) Cefuroxime 750 mg Sodium chloride 0.9% (22 cc) Normal Saline 50 ml 98.1 cc

22. Ketorolac vs. Methylprednisolone Ketorolac (TK) Methylprednisolone (Ranawat) Group Potent NSAID for short term use Corticosteroid Use Anti-inflammatory and analgesic Cautions (rabbit) Dose-dependent inhibitory effect on bone repair Increase the incidence of articular infection Mechanical side effects Cartilage breakdown Loss of elasticity of the articular cartilage

23. Ropivacaine vs. Bupivacaine Ropivacaine (TK) Bupivacaine (Ranawat) Lipophilicity less more sensory nerve block selectivity more selective selective CNS toxicity less more Duration of motor block similar Analgesic efficacy stronger weaker Onset of action more rapid delayed Post-op analgesia time shorter longer Chondrotoxicity less more

24. Other Modifications of Ranawat Cocktail (1) 0.5% bupivacaine 20 ml clonidine 150 mcg morphine 4.5 mg adrenaline 1000 mcg Cefuroxime-sodium 1.5 gm ketorolac 1.5 gm Prem Kakar, Vinod Gagrani, [...], and Gurpreet Popli, Post-operative analgesia regime following joint replacement, Indian J Anaesth. 2011 May-Jun; 55(3): 305–306

25. Clonidine Group imidazole derivative MOA α2 receptor agonist pre-synaptic: inhibit release of neuropeptides that stimulate nociceptors post-synaptic: hyperpolarize and decrease the activity of nociceptive neurons by releasing inhibitory neurotransmitter Use in TKA Analgesics Limitation Intra-articular administration has limited analgesic effect (mild and short lasting) Side effect hypotension, bradycardia

26. Other Modifications of Ranawat Cocktail (2) Morphine sulphate 5 mg Ketorolac 30 mg Ropivacaine 0.5% 50-74 kg 200 mg 75-99 kg 300 mg 100-125 kg 400 mg Epinephrine 50-74 kg 100 mcg 75-99 kg 200 mcg 100-125 kg 300 mcg Normal Saline to bring quantity to 120 ml weight-based doses Mayo clinic Henry Clarke, M.D. and Mark Spangehl, M.D., orthopedic surgeons at Mayo Clinic in Arizona

27. A nomogram for calculating the maximum dose of local anaesthetic, D. J. Williams, J. D. Walker, Anaesthesia 2014, 69, p.847–853 David Cone, Jane H. Brice, Theodore R. Delbridge, J. Brent Myers, Emergency Medical Services: Clinical Practice and Systems Oversight, John Wiley & Sons, 2014. 12. 30, p.409

28. References Albert Schweitzer quote https://www.azquotes.com/quote/548046 Peri-Operative Pain Management for Total Knee Replacements - Mayo Clinic https://www.youtube.com/watch?v=R0Q4adIYF-Q TK Orthopedic Institution Patient Care Protocols Tulane Doctors ~ Orthopaedics ~ Total Knee Arthroplasty (TKA)/Knee Arthritis https://medicine.tulane.edu/tulane-doctors/orthopaedics/problems-conditions/total-knee-arthroplasty-tkaknee-arthritis Malone KJ, Matuszak S, Mayo D, Greene P. The effect of intra-articular epinephrine lavage on blood loss following total knee arthroplasty.Source: Malone, K J. Orthopedics Volume: 32 Issue: 2 (2009-02-01) p. 100. ISSN: 0147-7447 Drugs.com Ketorolac Injection https://www.drugs.com/pro/ketorolac-injection.html Pacifici GM: Metabolism and pharmacokinetics of morphine in neonates: A review. Clinics (Sao Paulo). 2016 Aug;71(8):474-80. doi: 10.6061/clinics/2016(08)11. [PubMed:27626479] World Health Organization, Essential Medicines and Health Products Information Portal https://apps.who.int/medicinedocs/en/d/Jh2929e/7.html Drugbank, Cefuroxime, https://www.drugbank.ca/drugs/DB01112 Maheshwari, Aditya & Blum, Yossef & Shekhar, Laghvendu & Ranawat, Amar & Ranawat, Chitranjan. (2009). Multimodal Pain Management after Total Hip and Knee Arthroplasty at the Ranawat Orthopaedic Center. Clinical orthopaedics and related research. 467. 1418-23. 10.1007/s11999-009-0728-7. Ranawat Orthopaedics http://www.ranawatorthopaedics.com/ Ho, Mei-Ling*; Chang, Je-Ken*; Wang, Gwo-Jaw* Antiinflammatory Drug Effects on Bone Repair and Remodeling in Rabbits, Clinical Orthopaedics and Related Research: April 1995 - Volume 313 - Issue - p 270–278 Cheng KY, Feng B, Peng HM, et al. The analgesic efficacy and safety of peri-articular injection versus intra-articular injection in one-stage bilateral total knee arthroplasty: a randomized controlled trial. BMC Anesthesiol. 2020;20(1):2. Published 2020 Jan 4.

29. References Parfitt K. Corticosteroids The complete drug reference (2nd ed.), Pharmaceutical Press, London (1999), p. 1010 Gaurav Kuthiala and Geeta Chaudhary, Ropivacaine: A review of its pharmacology and clinical use, Indian J Anaesth. 2011 Mar-Apr; 55(2): 104–110. Campo, M.M., Kerkhoffs, G.M.M.J., Sierevelt, I.N. et al. A randomised controlled trial for the effectiveness of intra-articular Ropivacaine and Bupivacaine on pain after knee arthroscopy: the DUPRA (DUtch Pain Relief after Arthroscopy)-trial. Knee Surg Sports Traumatol Arthrosc 20, 239–244 (2012) doi:10.1007/s00167-011-1562-5 Jayaram P1, Kennedy DJ2, Yeh P3, Dragoo J4, Chondrotoxic Effects of Local Anesthetics on Human Knee Articular Cartilage: A Systematic Review. PM R. 2019 Apr;11(4):379-400. doi: 10.1002/pmrj.12007. Epub 2019 Mar 15. Prem Kakar, Vinod Gagrani, [...], and Gurpreet Popli, Post-operative analgesia regime following joint replacement, Indian J Anaesth. 2011 May-Jun; 55(3): 305–306 Henry Clarke, M.D. and Mark Spangehl, M.D., orthopedic surgeons at Mayo Clinic in Arizona, https://www.youtube.com/watch?v=R0Q4adIYF-Q Shah VI, Upadhyay S, Shah K,. Sheth AN, Kshatriya A, Saini D. Multimodal cocktail injection relieves Postoperative Pain and improves Early Rehabilitation following Total Knee Replacement: A Prospective, Blinded and Randomized Study. J Recent Adv Pain 2017;3(1):14-24 Catterall W.A., Mackie K.Local anesthetics L.L. Burnton, J.S. Lazo, K.L. Parker (Eds.), The pharmacological basis of therapeutics (11th ed.), McGraw-Hill, New-York (2006), p. 369 Arun Mullaji FRCS Ed, MCh Orth, MS Orth, Raj Kanna MS Orth, Gautam M. Shetty MS Orth, Vipul Chavda BPT, MPT, D.P. Singh PhD, Efficacy of Periarticular Injection of Bupivacaine, Fentanyl, and Methylprednisolone in Total Knee Arthroplasty: A Prospective, Randomized Trial, The Journal of Arthroplasty Volume 25, Issue 6, September 2010, Pages 851-857 Li JW, Ma YS, Xiao LK. Postoperative Pain Management in Total Knee Arthroplasty. Orthop Surg. 2019;11(5):755–761.