- Email: [email protected]
Periprocedural medication management
Perioperative Care and Operating Room Management 9 (2017) 12–15
Contents lists available at ScienceDirect
Perioperative Care and Operating Room Management journal homepage: www.elsevier.com/locate/pcorm
Periprocedural medication management☆
T
Paul J. Grant MD Perioperative and Consultative Medicine, Division of Hospital Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA
A B S T R A C T Periprocedural medication management is one of the most common tasks performed by the perioperative provider. But as surgery has become more frequently offered to patients with several medical comorbidities and taking multiple medications, this task can be difficult. This is further made challenging due to the limited published data on many, if not most, of the available medications. This article is based on a presentation given at the 12th Annual Perioperative Medicine Summit on March 9, 2017 in Fort Lauderdale, Florida. The medications discussed in this presentation were selected by the following criteria: availability of published data (i.e. statins), commonly prescribed agents (i.e. psychiatric and neurologic medications, oral diabetes agents), controversial perioperative medications (i.e. angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), and high-risk medications (i.e. immunomodulators). To avoid redundancy, medications discussed at other meeting sessions (i.e. anticoagulants, antiplatelet agents, beta-blockers, opioids, and insulin) were not included.
As surgical procedures and anesthetic care has become safer, surgery is more commonly offered to patients with multiple comorbidities. Such patients are typically prescribed several medications, many of which require careful management in the perioperative period. Some of the most specific preoperative information providers give to the surgical patient includes clear directions on how to take their medications before surgery. For example, some medications are advised to be taken on the morning of surgery, while others are to be held for a specific length of time. Additionally, it is routine for the perioperative clinician to advise on when medications can be safely restarted after surgery. Despite how frequently perioperative medication instructions are given, there is limited published information for many, if not most, drug classes. Alternatively, other drug classes (i.e. beta-blockers) have an abundance of published articles, but recommendations remain challenging due to the conflicting and controversial nature of the data. While the list of drug classes and their recommended perioperative management is exhaustive, this article includes the primary content of the “Periprocedural Medication Management” presentation from the 2017 Perioperative Medicine Summit. It should be noted that many important drug classes were not discussed during this presentation (i.e. anticoagulants, antiplatelet agents, beta-blockers, opioids, and insulin) as they were addressed in other meeting sessions. 1. General principles It should first be noted that most medications are well tolerated perioperatively and do not interfere with anesthesia. Furthermore, ☆
medications with known perioperative benefit should be continued without missing doses. Perhaps most importantly, agents with potential for rebound or withdrawal effects should always be continued perioperatively. Examples include opioids, benzodiazepines, corticosteroids, beta-blockers, and alpha-agonists (i.e. clonidine). Patients should also be encouraged to consume as much water as needed when swallowing their medications. It seems many patients are under the impression they need to limit their water intake to the smallest volume possible. This misconception has led to cases of patients choking on their morning medications prior to surgery. 2. Cardiovascular medications 2.1. HMG-CoA reductase inhibitors (statins) Statins appear to have perioperative cardiovascular risk reduction qualities via pleiotropic effects which include optimizing endothelial function, prevention of plaque rupture, and anti-inflammatory effects.1 Unlike the lipid-lowering effects of statins which takes weeks to months, these pleiotropic effects occur within hours to days. The published literature on perioperative statin therapy has been consistently positive with respect to cardiovascular risk reduction. Chopra et al.2 conducted a meta-analysis of statins on various perioperative outcomes. This analysis consisted of 15 randomized controlled trials with 2292 statin-naïve patients undergoing cardiac and noncardiac surgery. Statin exposure showed significant reductions in myocardial infarction (number needed to treat [NNT] 23) and hospital
Based on a presentation given at the 12th Annual Perioperative Medicine Summit (March 9th, 2017), Fort Lauderdale, FL, USA. E-mail address: [email protected].
https://doi.org/10.1016/j.pcorm.2017.11.004 Received 9 October 2017; Accepted 2 November 2017 Available online 04 November 2017 2405-6030/ © 2017 Elsevier Inc. All rights reserved.
Perioperative Care and Operating Room Management 9 (2017) 12–15
P.J. Grant
3. Oral diabetes medications
length of stay. More recently, an international prospective cohort study3 and a very large observational cohort analysis of patients in the Veterans Affairs Health System4 demonstrated significant improvements in many perioperative outcomes including a reduction in overall mortality. The 2014 American College of Cardiology/American Heart Association (ACC/AHA) perioperative guidelines5 recommend continuing statins for patients currently taking them. The guidelines also state statin initiation is reasonable for patients undergoing vascular surgery. Given more compelling data has emerged since the publication of these guidelines, it would also seem reasonable to start a statin for higher-risk patients undergoing major surgery, particularly if they have a traditional indication for such therapy (i.e. diabetes mellitus, coronary artery disease, congestive heart failure, prior stroke or transient ischemic attack, or peripheral vascular disease). When starting a statin, moderate or higher doses should be used as soon as possible, but even starting these agents a few days before surgery may provide benefit. Lastly, statins should be continued indefinitely if the patient has an appropriate indication.
It was once thought that exposure to metformin in the perioperative period posed a significant risk of developing lactic acidosis. It is now understood that metformin-associated lactic acidosis is an exceedingly rare event.11 Therefore, holding metformin on the morning of surgery is adequate for most patients with consideration of withholding it an additional day for patients with renal impairment or when intravenous contrast administration is planned. As for the other oral diabetes agents (i.e. sulfonylureas, thiazolidinediones, and sodium glucose transporter [SGLT] 2 inhibitors), they should also be held on the morning of surgery as patients are typically nil per os (NPO) on the day of surgery increasing the risk for hypoglycemia. In addition to the holding these agents on the morning of surgery, it should be noted that oral diabetes medications are also typically held for the entire hospitalization. There are several reasons why holding these agents is advised: – Unpredictable food intake in the perioperative patient. – Lack of ability to titrate these agents to achieve optimal blood sugar control in a timely manner. – Perioperative patients are at high risk for acute kidney injury which may affect the ability to use these medications. – The unexpected need for intravenous contrast during the hospitalization.
2.2. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) Whether to continue or hold ACE inhibitors and ARBs on the morning of surgery has long been a debated question. While the benefits of continuation may include improved postoperative blood pressure control and improved renal function, it is well known that exposure to these agents shortly before anesthesia induction will frequently cause hypotension.6 Recent studies have helped to answer the question of “hold versus continue” with more confidence. A retrospective study of 1154 orthopedic surgery patients showed that those receiving ACE/ARB therapy were more likely to encounter significant post-induction hypotension and postoperative acute kidney injury (AKI).7 Furthermore, those who developed postoperative AKI also had a significantly longer hospital length of stay. A study from the VISION investigators (an international prospective cohort study of patients undergoing noncardiac surgery) evaluated 4802 patients on ACE/ ARB therapy.8 Withholding ACE/ARB therapy on the day of surgery reduced the relative risk of intraoperative hypotension by 20%. Moreover, withholding these medications was associated with a 18% relative risk reduction of 30-day all-cause death, stroke, or myocardial injury. Due to this more recent data, it seems the 2014 ACC/AHA perioperative guidelines5 are now outdated as they state continuing ACE/ ARB therapy perioperatively is reasonable. Despite the lack of large randomized trials, the available data convincingly favors holding these agents on the day of surgery. However, it is important to ensure resumption of ACE/ARB therapy occurs in a timely manner postoperatively. A large cohort study of over 294,000 surgical patients on ACE inhibitors showed that non-resumption within 14 days postoperatively was not only common, but was associated with an increased 30-day mortality compared to those who restarted the medication.9
For these reasons, inpatient glycemic control is best achieved by using insulin therapy for the postoperative patient. 4. Psychiatric and neurologic medications Antidepressants are some of the most commonly prescribed medications in the United States. The primary concern with these medications in the perioperative period is the risk of withdrawal syndromes if they are suddenly discontinued. The most common withdrawal symptoms include gastrointestinal (i.e. abdominal pain, nausea, vomiting), cardiovascular (i.e. tachycardia, palpitations), psychiatric (i.e. anxiety), and neurologic (i.e. dizziness, tremulousness).12 In addition to antidepressants, medications for dementia (i.e. donepezil and memantine), antipsychotics, and anti-epileptics for seizure disorders should also be continued throughout the perioperative period without missing doses. The most commonly prescribed class of antidepressant medications are the selective serotonin reuptake inhibitors (SSRIs). In recent years, there has been concern about an increased risk of perioperative bleeding associated with these drugs. A retrospective review of patients undergoing total hip arthroplasty demonstrated a slightly higher mean blood loss (95 ml) in patients on SSRIs compared to controls, but this was not associated with an increased incidence of blood transfusion.13 A more recent study assessed SSRI exposure and bleeding in patients undergoing cardiac, vascular, spinal, and intracranial surgery.14 SSRI exposure was associated with a two-fold increase in blood product transfusion through the second postoperative day; a result largely driven by those undergoing cardiac surgery. The authors cautioned that randomized trials are needed to determine if continuation or withdrawal of SSRIs would be beneficial perioperatively. For now, most perioperative experts are continuing SSRIs perioperatively as it is believed the risk of a withdrawal syndrome likely outweighs the potential increased risk of bleeding. Parkinson’s disease is a neurologic disorder for which the primary symptoms (i.e. bradykinesia) are routinely treated with levodopa as the first line agent. Abrupt discontinuation of levodopa can cause disease flare, or perhaps more importantly, neuroleptic malignant syndrome. Thus, it is crucial to continue levodopa perioperatively, including dose administration as close to the beginning of anesthesia as possible. Although an intravenous formulation of levodopa exists, it is largely reserved for research purposes. With only having an enteral option
2.3. Loop diuretics Although data regarding perioperative loop diuretic management is limited, a randomized clinical trial was undertaken to assess whether these agents affect intraoperative blood pressure during elective noncardiac surgery.10 A total of 212 patients on chronic loop diuretic therapy at 3 tertiary care preoperative clinics in Canada and the United States were randomized to taking versus holding this medication on the morning of surgery. The authors found no significance difference in any of the outcomes assessed including intraoperative hypotension, intraoperative vasopressor or intravenous fluid use, postoperative cardiovascular events, renal function, and electrolytes. Given these results, it doesn’t appear to matter whether loop diuretics are held or continued on the day of surgery. 13
Perioperative Care and Operating Room Management 9 (2017) 12–15
P.J. Grant
reached general consensus regarding the management of TNF-α blockers in the perioperative period.23,24 Although these recommendations are specific for patients with RA, it is reasonable to extrapolate this information to other patient populations taking these agents. In summary:
available for levodopa, continuation of this medication in the perioperative period while important, can be challenging. 5. Immunomodulators Immunomodulator medications are used for several common medical conditions including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriasis, and inflammatory bowel disease. The clinical dilemma with respect to the perioperative management of these medications relates to the risk of continuing them (increased infection risk, compromised wound healing) versus the risk of discontinuing them (increased risk of disease flare compromising postoperative recovery and rehabilitation).15 The following are the major immunomodulator medications and recommendations for their perioperative management.
– The potential benefit of preventing postoperative infections by stopping TNF-α blockers should be balanced against the risk of perioperative disease flare. – TNF-α inhibitors are typically held for 1 dosing cycle (approximately 2–3 half-lives) prior to surgery. For example: Etanercept (Enbrel): 1 week. Infliximab (Remicade): 6–8 weeks. Adalimumab (Humira): 2 weeks.
5.1. Methotrexate
– Postoperatively, these medications should be held for 1–2 weeks and not restarted until adequate wound healing is observed with no evidence of infection.
• • •
Of all of the immunomodulator medications, methotrexate has the largest body of published data with respect to perioperative management. The majority of these trials studied orthopedic surgery patients with the largest including 388 patients with RA who were randomized to continuing or holding methotrexate for two weeks before and after surgery.16 The incidence of postoperative infection or surgical complications were followed for one year. Patients who continued methotrexate had a significantly lower rate of RA flare, yet no difference in infection, when compared to those holding for two weeks before and after surgery. Subsequent to this earlier work, multiple other studies have shown similar findings. In summary, not only does the evidence indicate that methotrexate is safe before and after elective surgery, underlying disease activity is better controlled. Thus, the currently available data do not suggest a need to discontinue methotrexate for the purpose of surgery.17 An exception may be for patients with significant renal or hepatic impairment, or for patients undergoing surgery to treat a serious infection. In these cases, it may be reasonable to hold methotrexate for 1–2 weeks perioperatively.
5.3. Other immunomodulators Rituximab (Rituxan) is a monoclonal antibody (targeting CD20 Bcell antigen) with increasing clinical use for many disease states including lymphomas, RA, vasculitides, and others. Rituximab has a halflife of 76 h but its effects will last for greater than 6 months. Compared to the TNF-α antagonists, rituximab appears to have a lower risk of bacterial infections and has shown to be safe in patients with prior recurrent bacterial infections.25 Although it is common practice to delay surgery until the end of a dosing cycle of rituximab (with the assumption that the drug effect has diminished), infection risk does not appear to be associated with the timing of prior infusion.26 Hydroxychloroquine (Plaquenil) is a commonly prescribed medication for SLE and RA. Continuation of this medication does not appear to increase the risk of infection perioperatively.21,27 Azathioprine, sulfasalazine, and cyclosporine are other disease-modifying anti-rheumatic drugs (DMARDs) that are thought to be safe to continue perioperatively. There are limited studies evaluating leflunomide (Arava) in the perioperative period. While one study demonstrated an increased risk of surgical wound complications,28 another study did not.29 Given these findings, it seems appropriate to hold leflunomide for 1–2 weeks before surgery, particularly in higher-risk patients and/or those anticipated to have large surgical wounds. Tofacitinib (Xeljanz), a janus-associated kinase (JAK) inhibitor, has gained recent popularity for the treatment of RA. Tofacitinib is a potent immunomodulator but without any published data regarding its perioperative management. Given its short half-life, discontinuing this medication up to 1 week prior to surgery is reasonable.
5.2. Tumor necrosis factor-alpha (TNF-α) antagonists The TNF-α antagonists (i.e. etanercept, infliximab, adalimumab) have become an important class of medications for the treatment of many autoimmune disorders. Despite their efficacy, a major side effect of these agents is infection. Known infection types include bacterial, opportunistic, and tuberculosis reactivation. A meta-analysis of randomized, placebo-controlled trials that included 3493 patients demonstrated a “serious infection” risk odds ratio of 2.0 (95% CI, 1.3–3.1) with a number needed to harm of only 59 patients.18 While these drugs have also been investigated in the perioperative setting, the data are limited to smaller trials with results sometimes conflicting when assessing outcomes such as surgical site infection and wound dehiscence.19–21 Practical considerations regarding TNF-α antagonists include understanding that the risk of infection is highest at the start of treatment. Furthermore, patients with established disease are more likely to flare upon stopping these agents when compared to those with early disease.22 When making decisions about the perioperative management of these medications, factors that should be taken into consideration include: the patients underlying disease severity, history of disease flare while on or off the drug, type of surgery (i.e. surgical site, duration), other patient risk factors for infection (i.e. patient age, corticosteroid exposure, presence of diabetes), and patient preference. Communication with the patient’s rheumatologist (or other prescribing physician) is strongly advised and can significantly help with perioperative decision making surrounding these medications. National rheumatologic societies and perioperative experts have
References 1. Farmer JA. Pleiotropic effect of statins. Curr Atheroscler Rep. 2000;2:208–217. 2. Chopra V, Wesorick DH, Sussman JB, et al. Effect of perioperative statins on death, myocardial infarction, atrial fibrillation, and length of stay. Arch Surg. 2012;147:181–189. 3. Berwanger O, Le Manach Y, Suzumura EA, et al. Association between pre-operative statin use and major cardiovascular complications among patients undergoing noncardiac surgery: the VISION study. Eur Heart J. 2016;37:177–185. 4. London MJ, Schwartz GG, Hur K, Henderson WG. Association of perioperative statin use with mortality and morbidity after major noncardiac surgery. JAMA Intern Med. 2017;177:231–242. 5. Fleisher LA, Fleischmann KE, Auerbach AD, et al. ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;2014(64):e77–e137. 6. Rosenman DJ, McDonald FS, Ebbert JO, et al. Clinical consequences of withholding versus administering renin-angiotensin-aldosterone system antagonists in the preoperative period. J Hosp Med. 2008;3:319–325. 7. Nielson E, Hennrikus E, Lehman E, Mets B. Angiotensin axis blockade, hypotension,
14
Perioperative Care and Operating Room Management 9 (2017) 12–15
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8.
9.
10. 11.
12. 13. 14. 15. 16.
17. 18.
19.
and acute kidney injury in elective major orthopedic surgery. J Hosp Med. 2014;9:283–288. Roshanov PS, Rochwerg B, Patel A, et al. Withholding versus continuing angiotensinconverting enzyme inhibitors or angiotensin II receptor blockers before noncardiac surgery. Anesthesiology. 2017;126:16–27. Mudumbai SC, Takemoto S, Cason BA, et al. Thirty-day mortality risk associated with the postoperative nonresumption of angiotensin-converting enzyme inhibitors: a retrospective study of the Veterans Affairs Healthcare System. J Hosp Med. 2014;9:289–296. Khan NA, CampbellNR, Frost SD, et al. Risk of intraoperative hypotension with loop diuretics: a randomized controlled trial. Am J Med. 2010;123(1059):e1–e8. Salpeter S, Greyber E, Pasternak G, Salpeter E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus (Review). Cochrane Database Syst Rev. 2010:4 [CD002967]. Wolfe RM. Antidepressant withdrawal reactions. Am Fam Physician. 1997;56:455–462. Van Haelst IM, Egberts TC, Doodeman HJ, et al. Use of serotonergic antidepressants and bleeding risk in orthopedic patients. Anesthesiology. 2010;122:631–636. Sajan F, Conte JV, Tamargo RJ, et al. Association of selective serotonin reuptake inhibitors with transfusion in surgical patients. Anesth Analg. 2016;123:21–28. Mushtaq S, Goodman SM, Scanzello CR. Perioperative management of biologic agents used in treatment of rheumatoid arthritis. Am J Ther. 2011;18:426–434. Grennan DM, Gray J, Loudon J, Fear S. Methotrexate and early postoperative complications in patients with rheumatoid arthritis undergoing elective orthopedic surgery. Ann Rheum Dis. 2001;60:214–217. Heldmann F, Braun J. Perioperative use of methotrexate. Clin Exp Rheumatol. 2010;28(5 Suppl 61):S110–S113. Bongartz T, Sutton AJ, Sweeting MJ, et al. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. J Am Med Assoc. 2006;295:2275–2285. Ruyssen-Witrand A, Gossec L, Salliot C, et al. Complication rates of 127 surgical
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23.
24. 25.
26.
27. 28.
29.
15
procedures performed in rheumatic patients receiving tumor necrosis factor alpha blockers. Clin Exp Rheumatol. 2007;25:430–436. Den Broeder AA, Creemers MC, Fransen J, et al. Risk factors for surgical site infections and other complications in elective surgery patients with rheumatoid arthritis with special attention for anti-tumor necrosis factor: a large retrospective study. J Rheumatol. 2007;34:689–695. Bibbo C, Goldberg JW. Infectious and healing complications after elective orthopaedic foot and ankle surgery during tumor necrosis factor-alpha inhibition therapy. Foot Ankle Int. 2004;25:331–335. Goh L, Jewell T, Laversuch C, Samanta A. Should anti-TNF therapy be discontinued in rheumatoid arthritis patients undergoing elective orthopedic surgery? A systematic review of the evidence. Rheumatol Int. 2012;32:5–13. Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008;59:762–784. Ding T, Ledingham J, Luqmani R, et al. BSR and BHPR rheumatoid arthritis guidelines on safety of anti-TNF therapies. Rheumatology. 2010;49:2217–2219. Toussirot E, Pertuiset E, Sordet C, et al. Safety of rituximab in rheumatoid arthritis patients with a history of severe or recurrent bacterial infection: observational study of 30 cases in everyday practice. Jt Bone Spine. 2010;77:142–145. Godot S, Gottenberg JE, Paternotte S, et al. Safety of surgery after rituximab therapy in 133 patients with rheumatoid arthritis: data from the autoimmunity and rituximab registry. Arthritis Care Res. 2013;65:1874–1879. Escalante A, Beardmore TD. Risk factors for early wound complications after orthopedic surgery for rheumatoid arthritis. 1995;22:1844–1851. Fuerst M, Mohl H, Baumgartel K, Ruther W. Leflunomide increases the risk of early healing complications in patients with rheumatoid arthritis undergoing elective orthopedic surgery. Rheumatol Int. 2006;26:1138–1142. Tanaka N, Sakahashi H, Sato E, et al. Examination of the risk of continuous leflunomide treatment on the incidence of infectious complications after joint arthroplasty in patients with rheumatoid arthritis. J Clin Rheumatol. 2003;9:115–118.
Contents lists available at ScienceDirect
Perioperative Care and Operating Room Management journal homepage: www.elsevier.com/locate/pcorm
Periprocedural medication management☆
T
Paul J. Grant MD Perioperative and Consultative Medicine, Division of Hospital Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA
A B S T R A C T Periprocedural medication management is one of the most common tasks performed by the perioperative provider. But as surgery has become more frequently offered to patients with several medical comorbidities and taking multiple medications, this task can be difficult. This is further made challenging due to the limited published data on many, if not most, of the available medications. This article is based on a presentation given at the 12th Annual Perioperative Medicine Summit on March 9, 2017 in Fort Lauderdale, Florida. The medications discussed in this presentation were selected by the following criteria: availability of published data (i.e. statins), commonly prescribed agents (i.e. psychiatric and neurologic medications, oral diabetes agents), controversial perioperative medications (i.e. angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), and high-risk medications (i.e. immunomodulators). To avoid redundancy, medications discussed at other meeting sessions (i.e. anticoagulants, antiplatelet agents, beta-blockers, opioids, and insulin) were not included.
As surgical procedures and anesthetic care has become safer, surgery is more commonly offered to patients with multiple comorbidities. Such patients are typically prescribed several medications, many of which require careful management in the perioperative period. Some of the most specific preoperative information providers give to the surgical patient includes clear directions on how to take their medications before surgery. For example, some medications are advised to be taken on the morning of surgery, while others are to be held for a specific length of time. Additionally, it is routine for the perioperative clinician to advise on when medications can be safely restarted after surgery. Despite how frequently perioperative medication instructions are given, there is limited published information for many, if not most, drug classes. Alternatively, other drug classes (i.e. beta-blockers) have an abundance of published articles, but recommendations remain challenging due to the conflicting and controversial nature of the data. While the list of drug classes and their recommended perioperative management is exhaustive, this article includes the primary content of the “Periprocedural Medication Management” presentation from the 2017 Perioperative Medicine Summit. It should be noted that many important drug classes were not discussed during this presentation (i.e. anticoagulants, antiplatelet agents, beta-blockers, opioids, and insulin) as they were addressed in other meeting sessions. 1. General principles It should first be noted that most medications are well tolerated perioperatively and do not interfere with anesthesia. Furthermore, ☆
medications with known perioperative benefit should be continued without missing doses. Perhaps most importantly, agents with potential for rebound or withdrawal effects should always be continued perioperatively. Examples include opioids, benzodiazepines, corticosteroids, beta-blockers, and alpha-agonists (i.e. clonidine). Patients should also be encouraged to consume as much water as needed when swallowing their medications. It seems many patients are under the impression they need to limit their water intake to the smallest volume possible. This misconception has led to cases of patients choking on their morning medications prior to surgery. 2. Cardiovascular medications 2.1. HMG-CoA reductase inhibitors (statins) Statins appear to have perioperative cardiovascular risk reduction qualities via pleiotropic effects which include optimizing endothelial function, prevention of plaque rupture, and anti-inflammatory effects.1 Unlike the lipid-lowering effects of statins which takes weeks to months, these pleiotropic effects occur within hours to days. The published literature on perioperative statin therapy has been consistently positive with respect to cardiovascular risk reduction. Chopra et al.2 conducted a meta-analysis of statins on various perioperative outcomes. This analysis consisted of 15 randomized controlled trials with 2292 statin-naïve patients undergoing cardiac and noncardiac surgery. Statin exposure showed significant reductions in myocardial infarction (number needed to treat [NNT] 23) and hospital
Based on a presentation given at the 12th Annual Perioperative Medicine Summit (March 9th, 2017), Fort Lauderdale, FL, USA. E-mail address: [email protected].
https://doi.org/10.1016/j.pcorm.2017.11.004 Received 9 October 2017; Accepted 2 November 2017 Available online 04 November 2017 2405-6030/ © 2017 Elsevier Inc. All rights reserved.
Perioperative Care and Operating Room Management 9 (2017) 12–15
P.J. Grant
3. Oral diabetes medications
length of stay. More recently, an international prospective cohort study3 and a very large observational cohort analysis of patients in the Veterans Affairs Health System4 demonstrated significant improvements in many perioperative outcomes including a reduction in overall mortality. The 2014 American College of Cardiology/American Heart Association (ACC/AHA) perioperative guidelines5 recommend continuing statins for patients currently taking them. The guidelines also state statin initiation is reasonable for patients undergoing vascular surgery. Given more compelling data has emerged since the publication of these guidelines, it would also seem reasonable to start a statin for higher-risk patients undergoing major surgery, particularly if they have a traditional indication for such therapy (i.e. diabetes mellitus, coronary artery disease, congestive heart failure, prior stroke or transient ischemic attack, or peripheral vascular disease). When starting a statin, moderate or higher doses should be used as soon as possible, but even starting these agents a few days before surgery may provide benefit. Lastly, statins should be continued indefinitely if the patient has an appropriate indication.
It was once thought that exposure to metformin in the perioperative period posed a significant risk of developing lactic acidosis. It is now understood that metformin-associated lactic acidosis is an exceedingly rare event.11 Therefore, holding metformin on the morning of surgery is adequate for most patients with consideration of withholding it an additional day for patients with renal impairment or when intravenous contrast administration is planned. As for the other oral diabetes agents (i.e. sulfonylureas, thiazolidinediones, and sodium glucose transporter [SGLT] 2 inhibitors), they should also be held on the morning of surgery as patients are typically nil per os (NPO) on the day of surgery increasing the risk for hypoglycemia. In addition to the holding these agents on the morning of surgery, it should be noted that oral diabetes medications are also typically held for the entire hospitalization. There are several reasons why holding these agents is advised: – Unpredictable food intake in the perioperative patient. – Lack of ability to titrate these agents to achieve optimal blood sugar control in a timely manner. – Perioperative patients are at high risk for acute kidney injury which may affect the ability to use these medications. – The unexpected need for intravenous contrast during the hospitalization.
2.2. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) Whether to continue or hold ACE inhibitors and ARBs on the morning of surgery has long been a debated question. While the benefits of continuation may include improved postoperative blood pressure control and improved renal function, it is well known that exposure to these agents shortly before anesthesia induction will frequently cause hypotension.6 Recent studies have helped to answer the question of “hold versus continue” with more confidence. A retrospective study of 1154 orthopedic surgery patients showed that those receiving ACE/ARB therapy were more likely to encounter significant post-induction hypotension and postoperative acute kidney injury (AKI).7 Furthermore, those who developed postoperative AKI also had a significantly longer hospital length of stay. A study from the VISION investigators (an international prospective cohort study of patients undergoing noncardiac surgery) evaluated 4802 patients on ACE/ ARB therapy.8 Withholding ACE/ARB therapy on the day of surgery reduced the relative risk of intraoperative hypotension by 20%. Moreover, withholding these medications was associated with a 18% relative risk reduction of 30-day all-cause death, stroke, or myocardial injury. Due to this more recent data, it seems the 2014 ACC/AHA perioperative guidelines5 are now outdated as they state continuing ACE/ ARB therapy perioperatively is reasonable. Despite the lack of large randomized trials, the available data convincingly favors holding these agents on the day of surgery. However, it is important to ensure resumption of ACE/ARB therapy occurs in a timely manner postoperatively. A large cohort study of over 294,000 surgical patients on ACE inhibitors showed that non-resumption within 14 days postoperatively was not only common, but was associated with an increased 30-day mortality compared to those who restarted the medication.9
For these reasons, inpatient glycemic control is best achieved by using insulin therapy for the postoperative patient. 4. Psychiatric and neurologic medications Antidepressants are some of the most commonly prescribed medications in the United States. The primary concern with these medications in the perioperative period is the risk of withdrawal syndromes if they are suddenly discontinued. The most common withdrawal symptoms include gastrointestinal (i.e. abdominal pain, nausea, vomiting), cardiovascular (i.e. tachycardia, palpitations), psychiatric (i.e. anxiety), and neurologic (i.e. dizziness, tremulousness).12 In addition to antidepressants, medications for dementia (i.e. donepezil and memantine), antipsychotics, and anti-epileptics for seizure disorders should also be continued throughout the perioperative period without missing doses. The most commonly prescribed class of antidepressant medications are the selective serotonin reuptake inhibitors (SSRIs). In recent years, there has been concern about an increased risk of perioperative bleeding associated with these drugs. A retrospective review of patients undergoing total hip arthroplasty demonstrated a slightly higher mean blood loss (95 ml) in patients on SSRIs compared to controls, but this was not associated with an increased incidence of blood transfusion.13 A more recent study assessed SSRI exposure and bleeding in patients undergoing cardiac, vascular, spinal, and intracranial surgery.14 SSRI exposure was associated with a two-fold increase in blood product transfusion through the second postoperative day; a result largely driven by those undergoing cardiac surgery. The authors cautioned that randomized trials are needed to determine if continuation or withdrawal of SSRIs would be beneficial perioperatively. For now, most perioperative experts are continuing SSRIs perioperatively as it is believed the risk of a withdrawal syndrome likely outweighs the potential increased risk of bleeding. Parkinson’s disease is a neurologic disorder for which the primary symptoms (i.e. bradykinesia) are routinely treated with levodopa as the first line agent. Abrupt discontinuation of levodopa can cause disease flare, or perhaps more importantly, neuroleptic malignant syndrome. Thus, it is crucial to continue levodopa perioperatively, including dose administration as close to the beginning of anesthesia as possible. Although an intravenous formulation of levodopa exists, it is largely reserved for research purposes. With only having an enteral option
2.3. Loop diuretics Although data regarding perioperative loop diuretic management is limited, a randomized clinical trial was undertaken to assess whether these agents affect intraoperative blood pressure during elective noncardiac surgery.10 A total of 212 patients on chronic loop diuretic therapy at 3 tertiary care preoperative clinics in Canada and the United States were randomized to taking versus holding this medication on the morning of surgery. The authors found no significance difference in any of the outcomes assessed including intraoperative hypotension, intraoperative vasopressor or intravenous fluid use, postoperative cardiovascular events, renal function, and electrolytes. Given these results, it doesn’t appear to matter whether loop diuretics are held or continued on the day of surgery. 13
Perioperative Care and Operating Room Management 9 (2017) 12–15
P.J. Grant
reached general consensus regarding the management of TNF-α blockers in the perioperative period.23,24 Although these recommendations are specific for patients with RA, it is reasonable to extrapolate this information to other patient populations taking these agents. In summary:
available for levodopa, continuation of this medication in the perioperative period while important, can be challenging. 5. Immunomodulators Immunomodulator medications are used for several common medical conditions including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriasis, and inflammatory bowel disease. The clinical dilemma with respect to the perioperative management of these medications relates to the risk of continuing them (increased infection risk, compromised wound healing) versus the risk of discontinuing them (increased risk of disease flare compromising postoperative recovery and rehabilitation).15 The following are the major immunomodulator medications and recommendations for their perioperative management.
– The potential benefit of preventing postoperative infections by stopping TNF-α blockers should be balanced against the risk of perioperative disease flare. – TNF-α inhibitors are typically held for 1 dosing cycle (approximately 2–3 half-lives) prior to surgery. For example: Etanercept (Enbrel): 1 week. Infliximab (Remicade): 6–8 weeks. Adalimumab (Humira): 2 weeks.
5.1. Methotrexate
– Postoperatively, these medications should be held for 1–2 weeks and not restarted until adequate wound healing is observed with no evidence of infection.
• • •
Of all of the immunomodulator medications, methotrexate has the largest body of published data with respect to perioperative management. The majority of these trials studied orthopedic surgery patients with the largest including 388 patients with RA who were randomized to continuing or holding methotrexate for two weeks before and after surgery.16 The incidence of postoperative infection or surgical complications were followed for one year. Patients who continued methotrexate had a significantly lower rate of RA flare, yet no difference in infection, when compared to those holding for two weeks before and after surgery. Subsequent to this earlier work, multiple other studies have shown similar findings. In summary, not only does the evidence indicate that methotrexate is safe before and after elective surgery, underlying disease activity is better controlled. Thus, the currently available data do not suggest a need to discontinue methotrexate for the purpose of surgery.17 An exception may be for patients with significant renal or hepatic impairment, or for patients undergoing surgery to treat a serious infection. In these cases, it may be reasonable to hold methotrexate for 1–2 weeks perioperatively.
5.3. Other immunomodulators Rituximab (Rituxan) is a monoclonal antibody (targeting CD20 Bcell antigen) with increasing clinical use for many disease states including lymphomas, RA, vasculitides, and others. Rituximab has a halflife of 76 h but its effects will last for greater than 6 months. Compared to the TNF-α antagonists, rituximab appears to have a lower risk of bacterial infections and has shown to be safe in patients with prior recurrent bacterial infections.25 Although it is common practice to delay surgery until the end of a dosing cycle of rituximab (with the assumption that the drug effect has diminished), infection risk does not appear to be associated with the timing of prior infusion.26 Hydroxychloroquine (Plaquenil) is a commonly prescribed medication for SLE and RA. Continuation of this medication does not appear to increase the risk of infection perioperatively.21,27 Azathioprine, sulfasalazine, and cyclosporine are other disease-modifying anti-rheumatic drugs (DMARDs) that are thought to be safe to continue perioperatively. There are limited studies evaluating leflunomide (Arava) in the perioperative period. While one study demonstrated an increased risk of surgical wound complications,28 another study did not.29 Given these findings, it seems appropriate to hold leflunomide for 1–2 weeks before surgery, particularly in higher-risk patients and/or those anticipated to have large surgical wounds. Tofacitinib (Xeljanz), a janus-associated kinase (JAK) inhibitor, has gained recent popularity for the treatment of RA. Tofacitinib is a potent immunomodulator but without any published data regarding its perioperative management. Given its short half-life, discontinuing this medication up to 1 week prior to surgery is reasonable.
5.2. Tumor necrosis factor-alpha (TNF-α) antagonists The TNF-α antagonists (i.e. etanercept, infliximab, adalimumab) have become an important class of medications for the treatment of many autoimmune disorders. Despite their efficacy, a major side effect of these agents is infection. Known infection types include bacterial, opportunistic, and tuberculosis reactivation. A meta-analysis of randomized, placebo-controlled trials that included 3493 patients demonstrated a “serious infection” risk odds ratio of 2.0 (95% CI, 1.3–3.1) with a number needed to harm of only 59 patients.18 While these drugs have also been investigated in the perioperative setting, the data are limited to smaller trials with results sometimes conflicting when assessing outcomes such as surgical site infection and wound dehiscence.19–21 Practical considerations regarding TNF-α antagonists include understanding that the risk of infection is highest at the start of treatment. Furthermore, patients with established disease are more likely to flare upon stopping these agents when compared to those with early disease.22 When making decisions about the perioperative management of these medications, factors that should be taken into consideration include: the patients underlying disease severity, history of disease flare while on or off the drug, type of surgery (i.e. surgical site, duration), other patient risk factors for infection (i.e. patient age, corticosteroid exposure, presence of diabetes), and patient preference. Communication with the patient’s rheumatologist (or other prescribing physician) is strongly advised and can significantly help with perioperative decision making surrounding these medications. National rheumatologic societies and perioperative experts have
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