Heparin and Hypotension

Healthy appearing patient with afib s/p ablation and returning for repeat ablation for recurrent afib. Anesthesia induced normally and patient VSS. 3 minutes after a request of a heparin bolus, patient dropped their SBP into the upper 40s, lower 50s. Patient recovered well after small bolus of epinephrine. ICE used to rule out pericardial effusion as well as confirm normal LVEF and RVEF.

From IndiaMart.com

The hemodynamic effects of heparin and their relation to ionized calcium levels. J THoRAc CARDIOVASC SURG 91:303-306, 1986.

Histamine blockade and cardiovascular changes following heparin administration during cardiac surgery. J Cardiothorac Anesth. 1990 Dec;4(6):711-4.

Heparin-Mediated Hypotension Associated with Cardiac Surgery. Anesthesia & Analgesia: September 2000 – Volume 91 – Issue 3 – p 766-767.

Preoperative Heparin Therapy Causes Immune-Mediated Hypotension Upon Heparin Administration for Cardiac Surgery. Journal of Cardiothoracic and Vascular Anesthesia. Volume 24, Issue 1, February 2010, Pages 69-72.

Prediction of heparin induced hypotension during cardiothoracic surgery: A retrospective observational study. Anaesth pain & intensiv care 2019;23(2):145-150.

Angiotensin Receptor Blocker (ARB) Reversal

From Angiotensin Axis Blocking Drugs In the Perioperative Period. Anesthesiology News, Feb 2016

What does an angiotensin receptor blocker (ARB) do?

Angiotensin II receptor blockers (ARBs) represent a newer class of effective and well tolerated antihypertensive agents 1. Several clinical studies have indicated the beneficial effects of ARBs in hypertensive patients such as reduction of left ventricular hypertrophy, decrease in ventricular arrhythmias, and improved diastolic function 1. Inhibitors of the renin-angiotensin system (RAS), either angiotensin converting enzyme (ACE) inhibitors or ARBs, mediate vasodilation and consequently decrease blood-pressure by different mechanisms 1. ARBs specifically inhibit angiotensin II from binding to its receptor, the Angiotensin-1 (AT 1) receptor on vascular smooth muscle cells. This blockade results in increased angiotensin II and normal bradykinin plasma levels. ARBs were developed to overcome several deficiencies of ACE inhibitors, which, by comparison, lead to decreased angiotensin II, but increased bradykinin levels. Hence, the key advantage of ARBs over ACE inhibitors is their lack of adverse effects related to bradykinin potentiation. ARBs have been shown to reduce morbidity and mortality associated with hypertension, and therefore, it is not surprising that an increasing number of patients scheduled for surgery are chronically treated with ARBs 2. However, RAS blockade increases the risk of severe hypotension during and after anesthetic induction. ACE-inhibitors are well known for inducing severe circulatory side effects during anesthesia, which led to the general recommendation to withhold the drug on the day of surgery 3.

Refractory hypotension during general anesthesia despite preoperative discontinuation of an angiotensin receptor blocker. F1000Research 2013, 2:12.

Comparison of Angiotensin‐Converting Enzyme Inhibitor and Angiotensin Receptor Blocker Management Strategies Before Cardiac Surgery: A Pilot Randomized Controlled Registry Trial. Journal of the American Heart Association. 2018;7:e009917.

Consequences of continuing renin angiotensin aldosterone system antagonists in the preoperative period: a systematic review and meta-analysis. BMC Anesthesiol. 2018 Feb 26;18(1):26.

From Angiotensin Axis Blocking Drugs In the Perioperative Period. Anesthesiology News, Feb 2016

How do I reverse an ARB in an emergency?

Chronic AT 1 blockade also reduces the vasoconstrictor response to α 1 receptors activated by norepinephrine, which explains why ARB-induced hypotension can be so resistant to phenylephrine, ephedrine and norepinephrine 2, 8 Clinical studies have shown significant vasoconstrictor effects of vasopressin and increased cardiac filling during echocardiographic measurements 2.

Vasopressin or its synthetic analogues can restore the sympathetic response and may be useful pressors in cases of refractory hypotension during anaphylaxis 9 and septic shock 10 as well as in patients on RAS inhibitors, although norepinephrine has been reported to have a more favorable effect on splanchnic perfusion and oxygen delivery 11.

Refractory hypotension during general anesthesia despite preoperative discontinuation of an angiotensin receptor blocker. F1000Research 2013, 2:12.

Angiotensin Axis Blocking Drugs In the Perioperative Period. Anesthesiology News, Feb 2016.

  • When conventional therapies such as: decreasing the anesthetic agent, volume expansion, phenylephrine, ephedrine, norepinephrine, and epinephrine are not effective, exogenous vasopressin may improve hypotension. To date, at least 5 clinical trials have demonstrated that patients on chronic ACEI/ARB undergoing general anesthesia, respond to exogenous vasopressin derivatives with an increase in blood pressure and fewer hypotensive episodes.6,7 Typically, a 0.5-1 unit bolus of AVP is administered to achieve a rise in mean arterial pressure.4 The subsequent recommended infusion dose is 0.03U/min for AVP and 1-2 mcg/kg/h for terlipressin. Caution should be used as V1 agonists have been associated with the following deleterious effects: reduction in cardiac output and systemic oxygen delivery, decreased platelet count, increased serum aminotransferases and bilirubin, hyponatremia, increased pulmonary vascular resistance, decrease in renal blood flow, increase in renal oxygen consumption, and splanchnic vasoconstriction.
  • Studies involving cardiac surgical patients suggest that MB treatment for patients with VS may reduce morbidity and mortality.5 It has also been suggested that the early use (preoperative use in patients at risk for VS) of MB in patients undergoing coronary artery bypass grafting may reduce the incidence of VS.5,9A bolus dose of 1-2mg/kg over 10-20 minutes followed by an infusion of 0.25mg/kg/hr for 48-72 hours is typically utilized in clinical practice and trials (with a maximum dose of 7 mg/kg).10 Side effects include cardiac arrhythmias (transient), coronary vasoconstriction, increased pulmonary vascular resistance, decreased cardiac output, and decreased renal and mesenteric blood flow.1 Both pulse and cerebral oximeter readings may not be reliable during MB administration due to wavelength interference.11,12 The use of MB is absolutely contraindicated in patients with severe renal impairment because it is primarily eliminated by the kidney.13 It may also cause methemoglobinemia and hemolysis.13 At high doses, neurotoxicity may occur secondary to the generation of oxygen free radicals. Neurologic dysfunction may be more severe in patients receiving serotoninergic agents such as: tramadol, ethanol, antidepressants, dopamine agonists and linezolid. Recommended doses for VS ranging from 1-3 mg/kg do not typically cause neurologic dysfunction.14 However, recent reports suggest that MB in doses even ≤ 1mg/kg in patients taking serotonin reuptake inhibitors (SSRIs) may lead to serotonin toxicity due to its monoamine oxidase (MAO) inhibitor property.15

Vasoplegic Syndrome and Renin-Angiotensin System Antagonists. APSF Newsletter, Circulation 94,429 • Volume 27, No. 1 • Summer-Spring 2012.

Vasopressin for persistent hypotension due to amlodipine and olmesartan overdose: A case report. Ann Med Surg (Lond). 2021 May; 65: 102292.

Vasoplegic syndrome following cardiothoracic surgery—review of pathophysiology and update of treatment options. Crit Care. 2020; 24: 36.

Refractory hypotension during general anesthesia despite preoperative discontinuation of an angiotensin receptor blocker. F1000Research 2013, 2:12.

Terlipressin for refractory hypotension following angiotensin-II receptor antagonist overdose. Anaesthesia, 2006,61, pages 402–414.

Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017 Aug 3;377(5):419-430.

Vasopressin: physiology and clinical use in patients with vasodilatory shock: a review. Neth J Med. 2005 Jan;63(1):4-13.

Treatment of intraoperative refractory hypotension with terlipressin in patients chronically treated with an antagonist of the renin-angiotensin system. Anesth Analg. 1999 May;88(5):980-4.

Role of vasopressinergic V1 receptor agonists in the treatment of perioperative catecholamine-refractory arterial hypotension. Best Pract Res Clin Anaesthesiol. 2008 Jun;22(2):369-81.

Predicting response to methylene blue for refractory vasoplegia following cardiac surgery. Pharmacotherapy Conference: 2013 American College of Clinical Pharmacy Annual Meeting. October 2013.

Anesthesia for Latissimus Dorsi Flap for Breast Reconstruction

What is a latissimus dorsi flap?

From MDAnderson.org

Latissimus Dorsi Flap in Breast Reconstruction. Cancer Control. 2018 Jan-Dec; 25(1): 1073274817744638.

A Retrospective Study of Latissimus Dorsi Flap in Immediate Breast Reconstruction. Front. Oncol., 04 November 2021. https://doi.org/10.3389/fonc.2021.598604

Anesthetic Techniques

Regional Anesthesia For Breast Reconstruction. [Updated 2022 Feb 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.

Anaesthesia for breast surgery. BJA Education, 18(11): 342e348 (2018).

Anaesthesia for free flap breast reconstruction. BJA Education, Volume 16, Issue 5, May 2016, Pages 162–166.

Paravertebral Analgesia with Levobupivacaine Increases Postoperative Flap Tissue Oxygen Tension after Immediate Latissimus Dorsi Breast Reconstruction Compared with Intravenous Opioid Analgesia. Anesthesiology February 2004, Vol. 100, 375–380.

Treatment of Post-Latissimus Dorsi Flap Breast Reconstruction Pain With Continuous Paravertebral Nerve Blocks: A Retrospective Review. Anesth Pain Med. 2016 Oct; 6(5): e39476.

Paravertebral blocks and enhanced recovery after surgery protocols in breast reconstructive surgery: patient selection and perspectives. J Pain Res. 2018;11:1567-1581.

Comparison of local and regional anesthesia modalities in breast surgery: A systematic review and network meta-analysis. J Clin Anesth. 2021 Sep;72:110274.

Efficacy of regional anesthesia techniques for postoperative analgesia in patients undergoing major oncologic breast surgeries: a systematic review and network meta-analysis of randomized controlled trials. Can J Anaesth. 2022 Apr;69(4):527-549.

Efficacy of erector spinae plane block for analgesia in breast surgery: a systematic review and meta-analysis. Anaesthesia. 2021 Mar;76(3):404-413.

Erector Spinae Plane Block Similar to Paravertebral Block for Perioperative Pain Control in Breast Surgery: A Meta-Analysis Study. Pain Physician. 2021 May;24(3):203-213.

Erector Spinae Plane Block for Mastectomy and Breast Flap Reconstructive Surgery: A Three Case Series. Open Journal of Anesthesiology
Vol.10 No.01(2020), Article ID:97889,8 pages.

Tranexamic Acid vs. Amicar

** Updated June 2022**

Over the years, our hospital has been using Amicar… until there was a drug shortage.  With that drug shortage came a different drug called tranexamic acid.  We’ve been using it for awhile and I can’t seem to tell a difference in coagulation between the two drugs.  Let’s break down each one and also discuss cost-effectiveness.

Amicar

What is it?


From MedPage Today

Tranexamic Acid

What is it?

Tranexamic acid acts by reversibly blocking the lysine binding sites of plasminogen, thus preventing plasmin activation and, as a result, the lysis of polymerised fibrin.12 Tranexamic acid is frequently utilised to enhance haemostasis, particularly when fibrinolysis contributes to bleeding. In clinical practice, tranexamic acid has been used to treat menorrhagia, trauma-associated bleeding and to prevent perioperative bleeding associated with orthopaedic and cardiac surgery.13–16 Importantly, the use of tranexamic acid is not without adverse effects. Tranexamic acid has been associated with seizures,17 18 as well as concerns of possible increased thromboembolic events, including stroke which to date have not been demonstrated in randomised controlled trials.

Fibrinolysis is the mechanism of clot breakdown and involves a cascade of interactions between zymogens and enzymes that act in concert with clot formation to maintain blood flow.25 During extracorporeal circulation, such as cardiopulmonary bypass used in cardiac surgery, multiplex changes in haemostasis arise that include accelerated thrombin generation, platelet dysfunction and enhanced fibrinolysis.26 Tranexamic acid inhibits fibrinolysis, a putative mechanism of bleeding after cardiopulmonary bypass, by forming a reversible complex with plasminogen.

Dosing:

  • Ortho/Spine
  • OB
  • Trauma

Currently at our hospital (June 2022):

TXA DOSING AND ADMINISTRATION OVERVIEW

How supplied from PharmacyTXA 1000mg/10mL vials Will not provide premade bags like with Amicar; Amicar is a more complex mixture than TXA Will take feedback on this after go-live and reassess
Where it will be supplied from PharmacyPOR-SUR1 Omnicell (in HeartCore Room)   Perfusion Tray (will replace aminocaproic acid vials 6/7)  
Recommended Dosing (see below for evidence)~20 mg/kg total dose Can give as: 20 mg/kg x 1, OR 10 mg/kg x 1, followed by 1-2 mg/kg/h*   Perfusion may also prime bypass solution with 2 mg/kg x 1*
Preparation & AdministrationIV push straight drug (1000mg/10mL) from vial   AND/OR   Mix vial of 1000mg/10mL TXA with 250mL NS for continuous infusion*

TXA & Amicar ADRs

  • Seizure risk may be increased also by duration of prolonged open-chamber surgery based on findings from Zuffery, et al. Anesthesiology 2021.
  • Per OR pharmacist at Scripps Mercy, they have not seen an increased incidence of seizures in their patient-population (anecdotally)

DOSING EVIDENCE

There are a number of dosing strategies in the literature. What I recommend for maximal safety and efficacy is taken from Zuffery, et al. Anesthesiology 2021 meta-analysis and is practiced at Scripps Mercy.

  • ~ 20 mg/kg total dose recommended in this meta-analysis.
  • Two dosing strategies they report that were as effective as high-dose but with lower seizure risk than high dose:

Abdominal Compartment Syndrome

A Clinician’s Guide to Management of Intra-abdominal Hypertension and Abdominal Compartment Syndrome in Critically Ill Patients. Crit Care 24, 97 (2020). https://doi.org/10.1186/s13054-020-2782-1

From Crit Care 24, 97 (2020).

Abdominal compartment syndrome among surgical patients. World J Gastrointest Surg. 2021 Apr 27; 13(4): 330–339.

Patients with ACS will usually be critically ill and unable to provide history and symptoms. On physical exam, patients present with a distended abdomen. However, palpation and abdominal circumference are not reliable for the diagnosis of ACS[25].

A prospective study in postoperative ICU patients showed physicians have less than a 50% chance to identify IAH by clinical examination[25]. The clinical abdominal exam as IAP assessment has an estimated sensitivity of 56%-60% and specificity of 80%-87%[25,26].

Signs of ACS will present as the end-organ effect from the physiologic changes (Table ​(Table2).2). The most notorious signs are usually abdominal distention, oliguria, high ventilatory pressures, diminished cardiac output, and metabolic acidosis[26].

Abdominal Compartment Syndrome. StatPearls, Nov 2021.

The more commonly used method is an indirect measurement such as intravesicular catheter pressures (e.g., Foley catheter), which has become the gold standard due to its widespread availability and limited invasiveness. The trans-bladder technique involves using aseptic clamping the drainage tubing of the Foley then connecting the Foley to a three-way stop tap adjusted to the level of the mid-axillary line at the iliac crest to zero transducers follow by injecting 25 cc of sterile saline into the bladder.  Measurements should be taken at end-expiration and complete supine position and expressed in mmHg.  Bladder pressures below 5 mm Hg are expected in healthy patients. Pressures between 10 to 15 mm Hg can be expected following abdominal surgery and in obese patients. Bladder pressures over 25 mm Hg are highly suspicious of abdominal compartment syndrome and should be correlated clinically. It is recommended that pressure measurements be trended to show and recognize the worsening of intra-abdominal hypertension.

Contraindications to using bladder pressures include bladder trauma, neurogenic bladder, BPH, and pelvic hematoma. Bladder pressures may be inaccurate if the patient is not sedated or lying flat.[9][10]

How to Measure Intrabdominal Pressure

From London Health Science Centre

The primary treatment for ACS is surgical decompression. However, the early use of non-surgical interventions may prevent the progression of IAH to ACS. Early recognition involves supportive care to include keeping patients comfortable with pain well-controlled.  Decompressive procedures such as NG tube placement for gastric decompression, rectal tube placement for colonic decompression, and percutaneous drainage of abscesses, ascites, or fluid from the abdominal compartment. The neuromuscular blockade has been described to be used as a brief trial in an attempt to relax the abdominal musculature, leading to a significant decrease in abdominal compartment pressures in the ventilated ICU patient. If conservative and medical management does not resolve the IAH and further organ damage is noted, surgical decompression using emergent laparotomy may be considered. [11][2]

After surgical laparotomy for compartment syndrome, the abdominal fascia may be closed using temporary closure devices such as (vacs, meshes, and zippers). The fascia can be appropriately closed after 5 to 7 days after the compartment pressures and swelling have decreased.

Fascia Iliaca blocks for TAVR under conscious sedation

Editorial: The use of Fascia iliaca Block with Minimal Conscious Sedation in Transcatheter Aortic Valve Replacement: Advances in TAVR Anesthesia. Cardiovasc Revasc Med. 2020 May;21(5):602-603. doi: 10.1016/j.carrev.2020.03.017.

Local Anesthesia-Conscious Sedation: The Contemporary Gold Standard for Transcatheter Aortic Valve Replacement. JACC Cardiovasc Interv. 2018 Mar 26;11(6):579-580. doi: 10.1016/j.jcin.2018.01.238.

Transfemoral Transcatheter Aortic Valve Replacement Using Fascia Iliaca Block as an Alternative Approach to Conscious Sedation as Compared to General Anesthesia. Cardiovasc Revasc Med. 2020 May;21(5):594-601. doi: 10.1016/j.carrev.2019.08.080. Epub 2019 Sep 7.

**NYSORA U/S guided Fascia Iliaca nerve block**

From EMbeds.co.uk – FOAMed @ CHT-ED

TCT-808 Transfemoral Transcatheter Aortic Valve Replacement Using Fascia Iliaca Block as an Alternative Approach to Conscious Sedation as Compare to General Anesthesia: Findings From a Single Center. J Am Coll Cardiol. 2019 Oct, 74 (13_Supplement) B792

Tricuspid Clip

Updated: August 2021

Echocardiographic Imaging for Transcatheter Tricuspid Edge‐to‐Edge Repair. Journal of the American Heart Association. 2020;9:e015682.

State of the Art Review of Echocardiographic Imaging in the Evaluation and Treatment of Functional Tricuspid Regurgitation. Circ Cardiovasc Imaging.2016;9:e005332.

Screening TEE for Transcatheter Tricuspid Valve Repair. Cardiac Interventions Today. May/June 2020.

Echocardiography for Tricuspid Valve Intervention. Cardiac Interventions Today. July/August 2018.

Tricuspid Clip in Tricuspid Regurgitation. Amer Coll of Card, Feb 2020.

Percutaneous management of tricuspid regurgitation. Image-guided step-by-step MitraClip procedure. REC Interv Cardiol. 2020;2:118-128.

Intraprocedural Imaging of Transcatheter Tricuspid Valve Interventions. JACC: Cardiovascular Imaging,Volume 12, Issue 3, March 2019, Pages 532-553.

Transcatheter Tricuspid Valve Intervention: Coaptation Devices. Front. Cardiovasc. Med., 13 August 2020.

 


 
From US Cardiology Review

Dexmedetomidine

From DrugStoreNews

What is dexmedetomidine?

Current role of dexmedetomidine in clinical anesthesia and intensive care. Anesth Essays Res. 2011 Jul-Dec; 5(2): 128–133.

Dexmedetomidine: a novel sedative-analgesic agent. Proc (Bayl Univ Med Cent). 2001 Jan; 14(1): 13–21.

Resources:

Perioperative Dexmedetomidine Improves Outcomes of Cardiac Surgery. Circulation. 2013;127:1576–1584.

Dexmedetomidine sedation reduces atrial fibrillation after cardiac surgery compared to propofol: a randomized controlled trial. Critical Care volume 20, Article number: 298 (2016).

The effect of dexmedetomidine on outcomes of cardiac surgery in elderly patients. J Cardiothorac Vasc Anesth. 2016 Dec; 30(6): 1502–1508.

Prevalence of Delirium with Dexmedetomidine Compared with Morphine Based Therapy after Cardiac Surgery: A Randomized Controlled Trial (DEXmedetomidine COmpared to Morphine-DEXCOM Study). Anesthesiology 11 2009, Vol.111, 1075-1084.

Effects of Perioperative Dexmedetomidine on Postoperative Mortality and Morbidity: A Systematic Review and Meta-analysis. Clinical Therapeutics/Volume 41, Number 1, 2019.

Effect of Intravenous Acetaminophen vs Placebo Combined With Propofol or Dexmedetomidine on Postoperative Delirium Among Older Patients Following Cardiac SurgeryThe DEXACET Randomized Clinical Trial. JAMA. 2019;321(7):686-696.

Dexmedetomidine for reduction of atrial fibrillation and delirium after cardiac surgery (DECADE): a randomised placebo-controlled trial. The Lancet. VOLUME 396, ISSUE 10245, P177-185, JULY 18, 2020.

Role of dexmedetomidine infusion after coronary artery bypass grafting. The Cardiothoracic Surgeon volume 28, Article number: 4 (2020).

Dexmedetomidine as an Option for Opioid Refractory Pain in the Hospice Setting. J Palliat Med. 2019 Nov;22(11):1478-1481.


Dexmedetomidine as an adjunct in regional anesthesia

The comparison of the effects of dexmedetomidine, fentanyl and esmolol on prevention of hemodynamic response to intubation

Surgical Antibiotic Prophylaxis

2018 MDAnderson

ASHP

StatPearls: Preoperative Antibiotic Prophylaxis. Feb 2021

Univ of Michigan

New Guidelines for Antimicrobial Prophylaxis in Surgery. Infectious Diseases in Clinical Practice: May 2013 – Volume 21 – Issue 3 – p 185-186.

TABLE 2
Recommendations for Antimicrobial Agents for Selected Surgical Procedures.
New Guidelines for Antimicrobial Prophylaxis in Surgery
Infectious Diseases in Clinical Practice21(3):185-186, May 2013.
TABLE 1
Recommended Doses and Redosing Interval for Surgical Prophylaxis.
New Guidelines for Antimicrobial Prophylaxis in Surgery
Infectious Diseases in Clinical Practice21(3):185-186, May 2013.

Ketamine and Methadone: Is more of a good thing better?

I’ve done a good deal of research on the benefits of an ERAS and Cardiac ERAS protocol to help with decreased length of hospital stay as well as early extubations and perioperative adjuvant pain control with ketamine, methadone, regional anesthesia, adjuvants to regional, etc.

What about ketamine and methadone in combination to aid decreased postoperative narcotic use?

  • Perioperative Methadone and Ketamine for Postoperative Pain Control in Spinal Surgical Patients: A Randomized, Double-blind, Placebo-controlled Trial. Anesthesiology Newly Published on March 2021. doi: https://doi.org/10.1097/ALN.0000000000003743.
    • 0.2 mg/kg of methadone (based on ideal body weight, up to a maximal dose of 20 mg)250 mg of ketamine was added to the dextrose 5% in water bag (total volume 500 ml). 500 ml bags were connected to a pump that was programed to deliver an infusion of ketamine dosed at ideal body weight (or an equal volume of dextrose 5% in water) at a rate of 0.3 mg · kg−1 · h−1 from induction of anesthesia until surgical closure, at which time the infusion was decreased to 0.1 mg · kg−1 · h−1. The infusion was maintained at a rate of 0.1 mg · kg−1 · h−1 in the postanesthesia care unit (PACU) and for the next 48 postoperative hours. Dosing of ketamine was based on recommendations in the literature17,18  and from clinical experience at our institution.
  • From Perioperative Methadone and Ketamine for Postoperative Pain Control in Spinal Surgical Patients: A Randomized, Double-blind, Placebo-controlled Trial. Anesthesiology Newly Published on March 2021. doi: https://doi.org/10.1097/ALN.0000000000003743.

    Management of Neuropathic Chronic Pain with Methadone Combined with Ketamine: A Randomized, Double Blind, Active-Controlled Clinical Trial. Pain Physician. 2017 Mar;20(3):207-215.

    Role of Ketamine and Methadone as Adjunctive Therapy in Complex Pain Management: A Case Report and Literature Review. Indian J Palliat Care. 2017 Jan-Mar; 23(1): 100–103.

    Ketamine: an introduction for the pain and palliative medicine physician. Pain Physician. 2007 May;10(3):493-500.

    Prescription of Controlled Substances: Benefits and Risks. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan.2020 Jun 27.

    The perioperative combination of methadone and ketamine reduces post-operative opioid usage compared with methadone alone. Acta Anaesthesiol Scand. 2012 Nov;56(10):1250-6.

    The similarities and differences in impulsivity and cognitive ability among ketamine, methadone, and non-drug users. Psychiatry Res. 2016 Sep 30;243:109-14.

    Comparison of ketamine-dexmedetomidine-methadone and tiletamine-zolazepam-methadone combinations for short-term anaesthesia in domestic pigs. Vet J. 2015 Sep;205(3):364-8.

    A Systematic Review of NMDA Receptor Antagonists for Treatment of Neuropathic Pain in Clinical Practice. Clin J Pain. 2018 May;34(5):450-467.

    [Drugs for postoperative analgesia: routine and new aspects: Part 2: opioids, ketamine and gabapentinoids]. Anaesthesist. 2008 May;57(5):491-8.