key: cord-0698525-4xu177wz
authors: Wilke, Trevor J.; Fremming, Bradley A.; Brown, Brittany A.; Markin, Nicholas W.; Kassel, Cale A.
title: 2020 Clinical Update in Liver Transplantation
date: 2021-02-06
journal: J Cardiothorac Vasc Anesth
DOI: 10.1053/j.jvca.2021.02.005
sha: 3774fa36b60fce1eb55e8942e2f5b4ecca0f5d96
doc_id: 698525
cord_uid: 4xu177wz

The gold standard treatment of end-stage liver disease continues to be liver transplantation (LT). The challenges of LT require skilled anesthesiologists to anticipate physiologic changes associated with end-stage liver disease (ESLD) as well as surgical considerations that affect multiple organ systems. While on the waiting list, patients may be placed new anticoagulation medications that can confound already complex coagulopathy in LT patients. Pain management is often an afterthought for such a complex procedure but appropriate medications can help control pain while limiting opioid medications. Surgical stress and medications for immunosuppression can affect perioperative glucose management in ways that have implications for patient and graft survival. 2020 provided a new challenge for anesthesiologist, the COVID-19 pandemic. The uncertainty of the novel respiratory virus challenged providers in beyond just LT patients.

Liver transplantation (LT) continues to be the mainstay of treatment for end-stage liver disease (ESLD).

This review article aims to provide an update from the literature on relevant topics for anesthesiologists caring for LT patients. COVID-19 challenged all healthcare providers this past year and anesthesiologists managing LT patients were no exception. As the role of anesthesiologists expands into perioperative management, management of anticoagulation medications may require intervention. Pain management for LT patients has implications intraoperatively as well as postoperatively. Perioperative glucose management presents a unique challenge in LT patients and appropriate management can have effects following LT as well.

Near the end of December 2019, people began to develop clinical characteristics of a viral pneumonia in Wuhan, China, which was quickly determined to be a novel coronavirus. This novel coronavirus would become known as severe acute respiratory syndrome coronavirus (SARS-CoV-2) and the rampant disease it spread to be known as coronavirus disease 2019 (COVID-19). 1 In just over two months from the initial case report, on December 12, 2019, the World Health Organization (WHO) would release a situation report on February 29, 2020, indicating 79,394 confirmed cases of SARS-CoV-2 and 2838 deaths had occurred. 2 Of these cases, 6009 had been confirmed in 53 countries outside of China.Error! Bookmark not defined. It was clear at this time that COVID-19 posed a significant threat to global public health. 3 SARS-CoV-2 is a ß-coronavirus meaning it is a single, positive-stranded RNA virus. 4 On the surface of the virus is an S-glycoprotein which binds to the human cellular receptor angiotensin-converting enzyme 2 (ACE2) and internalizes the virus. 5 ACE2 is most commonly found in the lower respiratory tract and can also be found in biliary and liver epithelial cells making the liver a potential target for infection.Error! Bookmark not defined. ,6 Elevated serum biochemistries, mainly aspartate aminotransferase (AST) and alanine aminotransferase (ALT), can become elevated in severe cases of COVID-19.Error! Bookmark not defined. Due to these findings, patients with nonalcoholic fatty liver disease (NAFLD), cirrhosis, and posttransplant patients were considered to be at an increased risk for severe COVID-19.Error! Bookmark not defined. ,7 In order to avert severe consequences on the transplant community, organizations involved in liver transplantation released recommendations and guidance for liver transplant programs and clinicians moving forward during the COVID-19 pandemic. 8 As early as February 27 th , the Infectious Diseases and Liver Transplantation Special Interest Group (SIG) of the International Liver Transplant Society (ILTS) released a statement saying risk of virus transmission from a donor is low, but present, as SARS-CoV-2 RNA had been identified in the plasma of infected patients. 9 At that time, without rapid testing readily available, it was recommended to avoid deceased and living organs retrieved from a donor in a high prevalence area.Error! Bookmark not defined. As for candidates, it was recommended to avoid transplanting a patient with developing or active respiratory symptoms as well as waiting 14 days if candidate travelled through a high prevalence area.Error! Bookmark not defined. In late March, the American Society of Transplant Surgeons (ASTS) released initial guidance from their COVID-19 Strike Force. At the forefront was inclusion of social distancing, hand sanitization, and respiratory precautions to be incorporated in all transplant protocols. 10 Another drastically important piece of this guidance was each program needed to assess program specific riskbenefit analyses on a case-by-case basis.Error! Bookmark not defined. This was due to the significant variance of infection rates throughout the United States at that time. Recommendations were to continue lifesaving and life altering transplants and for living donations to be placed on hold assuming the recipient could wait.Error! Bookmark not defined. As for deceased donors, testing them for COVID-19 needed to be a high priority and "prudence suggests that organs from positive donors not be accepted."Error! Bookmark not defined. Once hospitalized, it was important to prevent person-toperson transmission, in particular in the operating room and intensive care unit (ICU). Anesthesiologists and intensivists are at a very high risk to exposure due to performing aerosol generating proceduresError! Bookmark not defined., therefore they recommended transplant staff need proper training of protective gear including N95 masks.Error! Bookmark not defined.

As the pandemic progressed, the American Association for the Study of Liver Disease (AASLD) released their expert panel consensus statement. Of special interest was the section regarding patients with decompensated cirrhosis and patients on the liver transplant waiting list. They encouraged transplant centers to continually analyze the burden of COVID-19 locally and how this would affect patients waiting for a liver transplant.Error! Bookmark not defined. At that time, it was expected to see a reduction in organ recovery based on institutional resource limitation, making risk stratification even more important than normal.Error! Bookmark not defined. Many hospitals were instituting the Center for Medicare and Medicaid Services (CMS) recommendations on limiting nonessential surgeries in order to conserve resources. Transplant surgery was excluded from this and categorized as Tier 3b which means "do not postpone."Error! Bookmark not defined. Finally, the experts discussed specifically SARS-CoV-2 in donors and recipients. Stating donors who test positive are medically ineligible for donation and recommend not performing transplants in positive recipients.Error! Bookmark not defined. All of this information was shown in a flow chart for a quick reference guide to decision making which is seen in Figure 1 . The potential decline in transplantation warranted clinicians in the community to consider using organs from COVID-19 positive donors in order to maximize all possible deceased donor organs. 14 The argument being patients with a significantly high MELD score, 40 or more, may have a better clinical outcome if they received an organ from a SARS-CoV-2 positive donor due to a high likelihood of death without transplantation.Error! Bookmark not defined. Utilization of livers from SARS-CoV-2 positive donors was felt to be dangerous by most others due to hepatocellular injury of patients with COVID-19, possible direct viral infection of the liver, and first-pass absorption through the gut. 15 A literature review showed no known SARS-CoV-2 donors were used for liver transplantation in the United States. There have been multiple case reports of SARS-CoV-2 positive recipients receiving liver transplants after resolution of symptoms or negative tests with good outcomes. 16, 17, 18, 19 A more comprehensive analysis was performed later in the pandemic to better understand the impact of COVID-19 on liver transplantation in the United States. 20 This study used the Scientific Registry of Transplant Recipients to compare waitlist registrations, waitlist mortality, and DDLTs from March to August of 2020 on expected values based on trends from January of 2016 to January of 2020. They also investigated local COVID-19 incidence at the state-level and center-level to provide further insight on COVID-19's impact. In states with the highest COVID-19 incidence from March 15 th to April 30 th , there were 33% fewer new listings, 59% more waitlist deaths, and 34% fewer DDLTs than expected. Error! Bookmark not defined. However, states with lowest COVID-19 incidence during this time frame had no change in new listings or DDLTs. Error! Bookmark not defined. Using the guidelines and recommendations by multiple national societies, August waitlist outcomes were occurring at the rates seen in previous years, and DDLTs were actually occurring 13% more frequently across all states. Error! Bookmark not defined. In a matter of months, the transplant community had adjusted focus on the pandemic, institute changes to improve patient care, and nearly normalized liver transplantation practice throughout the US.

hospitalization altered the ability to safely care for critical ill COVID-19 patients in addition to post-LT patients. Yet some centers, including our institution, saw an increase in transplants this past year for reasons that are not clear to the authors. Recognition should be given to the various organizations and societies as their recommendations aided in the continuation of transplants during this time and inevitably saved numerous lives via liver transplantation. As the pandemic continues to progress, so does our knowledge of the disease and the best way to handle it. Research related to the full impact of COVID-19 on liver transplantation will be of interest in the years to come.

Hemostasis in patients with liver disease is a delicate balance as these patients exhibit both hyper-and hypo-coagulable properties. 21, 22 Previously cirrhotic patients were thought to be 'auto-anticoagulated' due to their decreased production of clotting factors, elevated INR, thrombocytopenia, and platelet dysfunction. 23 Clinically significant bleeding continues to be the prevailing concern though excessive clot formation has also been recognized as an important issue in these patients. 24 Atrial fibrillation (AF) the most common cardiac arrhythmia and increases with age. Additionally, the risk of venous thromboembolism (VTE) and portal vein thrombosis (PVT) contribute to morbidity in older patients. As older patients are listed for LT, these comorbidities are seen more commonly. 25, 26 A meta-analysis by Ambrosino et al suggests that cirrhotic patients demonstrate a 1.7-fold increased risk for VTE and noted a higher prevalence in males. They suggested cirrhosis was an independent risk factor for VTE. 27 Additionally, Lee et al denoted a 1.5-fold increase in AF in the cirrhotic patient population. 28 Currently, there are no specific consensus guidelines for the treatment and prevention of VTE in patients with advanced liver disease. 29 Traditionally, patients with advanced liver disease were treated with vitamin-K antagonists (VKA) or low molecular weight heparin (LMWH) due to low costs, physician experience with these medications and reversibility. 30, 31, 32 Nonetheless, VKAs and LMWH have not become a mainstay of prevention due to altered pharmacokinetics and pharmacodynamics, decreased plasma levels of Proteins C and S further augmenting pharmacologic efficacy, dietary restrictions with warfarin, as well as the implicit difficulty in monitoring VKA effectiveness in patients with an abnormal INR. 33 Direct Oral Anti-Coagulants (DOACs) are recommended over Vitamin K Antagonists (VKAs) when appropriate as the current treatment modality for both VTE and AF in the general population. 34, 35 These medications have not been extensively studied in patients with advanced liver disease, as Child-Turcotte-Pugh C (CTP-C) patients were initially excluded from Phase III trials. Error! Bookmark not defined., 36 Advantages of DOACs include oral administration (as compared to LMWH), similar efficacy, predictable mechanism of action independent of antithrombin levels, standard dosing schedules, and no required monitoring. 37 A meta-analysis of 152,116 patients from phase III RCTs for DOACs demonstrated that DOACs were not associated with increased risk of drug-induced liver injury in the general population. 38 Another study in 2017 assessed over 113,717 patients with nonvalvular AF and found that DOACs were associated with lower rates of hepatic injury hospitalization as compared to VKAs (warfarin). Dabigatran demonstrated the lowest risk for hepatic injury among this population. Error! Bookmark not defined., 39 Neither of these metaanalyses included patients with advanced liver disease, although based upon more recent retrospective findings pharmacologic effects may potentially be extrapolated to the cirrhotic population. A 2013 randomized double-blinded, double-dummy trial comparing the DOAC edoxaban with warfarin in AF patients with the primary efficacy end point of stroke or systemic thrombus and a primary safety endpoint of major bleeding. 40 Within this study, 1083 of 21,105 patients enrolled (5.1%) had a history of mild liver disease. Patients with liver disease had a known increased risk of bleeding however there was no difference in the efficacy or safety of edoxaban when compared to warfarin in patients in this subgroup. Additionally, there were no significant differences in liver related adverse events. 41 Patients with advanced liver disease were primarily excluded from RCTs due to potential risk of bleeding, but emerging retrospective research has demonstrated that DOACs have comparable or lower rates of bleeding in cirrhotic patients when directly compared to standard therapies. Error! Bookmark not defined.

A number of systematic reviews and meta-analyses have proposed similar safety and efficacy profiles. A retrospective cohort study demonstrated that DOACs were safer and more effective than warfarin in AF patients with liver disease. 45 DOACs were associated with lower risk of ischemic stroke, intracranial hemorrhage, gastrointestinal bleeding, major bleeding events and all cause deaths. These results were consistent across the sub-group of participants that were noted to have significant active liver disease. Error! Bookmark not defined. Several meta-analyses of retrospective studies have demonstrated comparable safety and efficacy profiles between DOACs and VKAs but there is difficulty applying this data to patients with severe or end-stage liver disease. Error! Bookmark not defined. Though the retrospective data is promising, there remains a lack of prospective studies. 46, 47 PVT is recognized problem for patients awaiting or receiving liver transplantation, occurring in up to 20% of patients with cirrhosis. Error! Bookmark not defined. Both meta-analysis and retrospective studies have demonstrated safety and efficacy of LMWH and VKA treatment for PVT. 48 groups treated with LMWH, VKA or DOACs. Uniquely, this study used meta-regression analysis to assess effect based upon the patient's CTP classification and found the severity of disease did not appear to influence outcomes. 50 The role of DOACs in patients with liver disease has not been discretely defined but recent literature supports their use as an effective and safe treatment in this patient population.

Post-liver transplant complications from thromboembolic events can negatively affect patient and organ outcomes. 51 Thrombotic events occur in 2-11% of patients following liver transplantation. 52 A small retrospective study associated DOACs with less bleeding risk when postoperative transplant patients were matched to warfarin treated controls. 53 While anticoagulation selection should continue to depend on specific patient factors including renal function, drug-drug interactions and insurance coverage, DOACs appear to be safe for use in cirrhotic patients before and after transplantation.

A national survey of organ transplant programs in 2019 suggests DOACs are being prescribed with the perception that they pose a similar bleeding risk to traditional VTE anticoagulation. Apixiban was the anticoagulation most commonly prescribed for patients on the transplant waitlist. DOAC reversal agent use prior to transplant was noted to be uncommon, primarily occurring before thoracic organ transplant. 54 As illustrated by Vuilleumier, management of DOAC-related bleeding during liver transplant may be burdensome, but reversal agents for DOACs as noted in Table 1 may prove to be truly valuable tools. 55 Guidelines published in the American Journal of Hematology (2019), recommend that Prothrombin Complex Concentrates (PCC) be used for treatment of life-threatening bleeding when reversal agents are unavailable. 56 Pain Management in LT Pain can be a divisive issue in liver transplant patients. One can argue that LT is among the most extensive abdominal operations in terms of duration and stress for the patient with the large abdominal incision and the use of multiple retractors, which contribute to postoperative pain. 57 Despite these factors, postoperative pain following liver transplantation has been shown to be not as severe as compared to open cholecystectomy or hepatic resection. 58, 59 While the administration of opioids intraoperatively and postoperatively has long been considered a viable option, the opioid epidemic has forced clinicians to revisit their approach to perioperative pain management. The new approach to a comprehensive analgesic plan should seek to improve respiratory function, aid in early mobilization and accelerate postoperative recovery with limited opioid consumption.

In the context of this epidemic, combined with the prevalence of substance use disorders among liver transplant recipients, more thought should be given to the implementation of multimodal pain management regimens in an effort to reduce perioperative opioid use after liver transplantation. 60 In fact, multimodal analgesic approaches have resulted in reduced opioid utilization in liver transplant recipient populations. Error! Bookmark not defined. What non-opioid agents can a provider use in LT patients can be a challenge. A recent review of multimodal analgesics for LT patients provides an evidence-based approach to pain management. The authors recommendations are listed in Table 2 . While most therapies are familiar to anesthesiologists, the evidence remains limited on their utility in LT patients. 61 Even with limited data, Kutzler et al. sought to investigate the development of a comprehensive multidisciplinary opioid avoidance pathway (OAP) for LT recipients at their institution. 62 The OAP was developed by a multidisciplinary team of health care specialists and offered to all liver transplant recipients regardless of substance use history. Table 3 illustrates the general pathway for patients from pre-transplant to their post-transplant care. Ultimately, they found this pathway reduced morphine milligram equivalents by 92% per post-operative day with no difference in length of stay compared to historical cohorts. Error! Bookmark not defined. This difference was most pronounced in the first five days postoperatively. Of note, two patients in the OAP group use zero opioids during their admission. Their approach was able to provide an analgesic regimen that effectively reduced inpatient and outpatient opioid utilization.

Opioid-sparing techniques are used in many surgeries and can play a critical role in pain management for LT patients as opioids may have negative consequences in ELSD due to alterations of liver function and drug pharmacokinetics. The majority of opioid metabolism is liver dependent and the extent of liver disease can have a significant impact on this metabolism. Furthermore, hypoalbuminemia, common in LT patients, causes free drug concentration to increase, resulting in enhanced distribution and higher concentration of drug at the site of action. 63 End-stage liver disease patients may also exhibit an increased density and affinity of central mu-opioid receptors in the brain contributing to the increased sensitivity to opiate agonists in such populations. 64 In addition, opioids may precipitate or aggravate hepatic encephalopathy. Error! Bookmark not defined.

Commonly used opioids in LT, fentanyl and sufentanil, are extensively metabolized by the liver. 65 Fentanyl, a synthetic opioid analgesic, has a high hepatic extraction ratio and is highly protein bound; largely to albumin. 66 Clearance of fentanyl is determined by hepatic blood flow and high hepatic extraction of fentanyl and anesthesiologists should be cognizant that an abrupt increase in plasma fentanyl concentration is observed during the anhepatic phase. Furthermore, an opposite abrupt decrease in the plasma fentanyl concentration is observed during the neohepatic phase. Error! Bookmark not defined. Redistribution is largely responsible for the duration of action of fentanyl after single bolus doses while hepatic elimination is more responsible for the duration of action with continuous infusions of fentanyl. Continuous infusions should be used with great caution so as not to result in over sedation or prolonged postoperative mechanical ventilation. Because fentanyl is largely devoid of histaminereleasing properties, it may be preferred in the setting of hemodynamic instability. Error! Bookmark not defined.

Sufentanil has high hepatic extraction as well as relevant extrahepatic elimination. 67 A minimal increase in sufentanil drug concentration during the anhepatic phase is suspected. Despite sufentanil relying on partial extrahepatic metabolism, its use in end stage liver disease patients still requires close attention as its analgesic potency is higher than fentanyl with more immediate respiratory depression and bradycardia. It has been reported that sufentanil produces shorter lasting respiratory depression and longer lasting analgesia when compared to fentanyl. 68 Hypotension is a well described effect seen with sufentanil and appears to be dose dependent and impacted by the degree of volume depletion; the latter being a critical consideration in the setting of liver transplantation.

In addition to the considerations of acute pain in liver transplant patients, the impact of chronic pain among liver transplant patients is not well studied. Madan, et al. highlighted the common occurrence of chronic pain among liver transplant candidates and its relative undertreatment. 69 Opioid prescribing has increased significantly and excessive opioid prescribing is prevalent, particularly after surgical care. 70 Liver transplant patients represent a population vulnerable to opioid exposure given the prevalence of substance use disorders and the associated risk of opioid misuse. 71 Indeed, a recent review of opioid use while on the transplant waiting list and following transplant revealed concerning trends. Higher opioid use while on the waiting list was associated with higher mortality and graft failure rates than did nonopioid users. 72 Interestingly, the use of opioids had no effect within the first year following LT. Recently the use of opioids while on the waiting list was shown to increase the risk for development of chronic post-surgical pain. 73 In the study of LT patients found 18.9% were on opioids prior to LT and those patients had higher opioid consumption at 24 hours and 7 days. Furthermore, the development of chronic post-surgical pain was more common in the opioid group.

Pain management for LT patients requires thoughtful preparation and planning and anesthesiologists are well-suited to help in this process. Early identification of patients on opioids at listing allows for consideration to opioid-weaning prior to transplantation. 74 Use of multi-modal analgesia medications dosed to account for end-organ dysfunction associated with ESLD is essential. Utilization of regional anesthesia should also be considered in LT patients as an opioid-sparing option. Anesthesiologists should continue to lead future research into which therapies are most beneficial for LT patients.

Hyperglycemia in the perioperative period commonly occurs as a result of critical illness, surgical stress, and medications administered. There remain deleterious effects of hyperglycemia in surgical patients that include but are not limited to: increased mortality, increased wound infection rates, and risk factors for postoperative pneumonia and acute kidney injury. 75, 76, 77 Management of blood glucose in LT can be challenging given the significant surgical stress and delivery of large doses of steroids. What effects hyperglycemia has on long-term outcomes remains unclear with new evidence published recently.

Additionally, the development of diabetes mellitus (DM) following transplant is uncommon and anesthesiologists should be aware of the effect this has on cardiovascular function and overall survival.

Early research into glycemic control in LT has been ongoing for years albeit retrospectively. Building on intensive care data on blood glucose (BG) control 78 , Ammori, et al reviewed 184 patients who underwent LT to compare outcomes compared to mean BG levels. 79 They found a lower rate of infections in the first 30 days for the tighter BG group (mean BG < 150 mg/dL) and improved survival at 1

year and 2 years. In 2010, Wallia, et al retrospectively reviewed 113 LT and 31 liver-kidney patients to examine the role of BG control on LT outcomes. 80 They found rejection to be more common if patient's mean BG during the hospitalization was > 200 mg/dL than if their mean BG was < 200 mg/dL. Interestingly enough, the incidence of prolonged ventilation was higher in the lower BG arm for reasons that were not clear to the authors.

Recently a prospective, randomized control trial examined glucose control for LT patients at a single institution comparing strict BG control versus conventional BG control. 81 Strict BG control was defined as 80-120 mg/dL as opposed to conventional control defined as BG of 180-200 mg/dL. The primary outcomes measured were patient and graft survival at one year. At one-year, overall survival was not statistically different (88% vs. 88%, p = 0.999) and in fact, there was no difference at 3 years (86% vs. 84%, p = 0.999) or 5 years (82% vs. 78%, p = 0.617). Rates of complications (bile leak, bile stricture, CVA, major cardiac event, re-operation, and wound dehiscence) were similar between both groups. Clinically, the strict control group required more insulin (24.4 units on average) compared to the conventical group (10.0 units). Hypoglycemic events (defined as BG < 70 g/dL) were more common in the strict group but not statistically significant.

Post-operative acute kidney injury (AKI) is common in LT patients, affecting 17% to 95% of patients. 82 The effect of BG on AKI is not well understood for LT patients though. Yoo et al. utilized time-weighted average glucose levels to evaluate if poor glucose control was associated with AKI. Their retrospective study grouped patients into four categories based on glucose levels as well as different quartiles based on the variability of BG levels through 48 hours. Post-operative AKI occurred in 43.1% of patients overall. Error! Bookmark not defined. Patients in the third and fourth quartiles for BG control were at higher risk for AKI. The authors suggest that glucose variability rather than hyperglycemia alone may be a risk factor for post-operative AKI though further prospective studies may be helpful.

Development of post-transplant diabetes mellitus (PTDM) occurs in 12-45% of patients who undergo LT. 83 With an increasing number of patients are receiving LT for non-alcoholic fatty liver disease (NAFLD) the effects of PTDM in patients in these patients are not well understood. A review of 415 patients focused on graft steatosis, rejection, and patient survival as it relates to PTDM. Rates of PTDM were 34.7%, 46.9%, and 56.2% at 1, 3, and 5 years respectively. 84 Notably, half the cases of PTDM developed by 6 months with 75% by 12 months indicating a rapid onset following transplant. Rejection was higher in the PTDM group (31.9%) than in the non-PTDM group (21.8%).Error! Bookmark not defined.

Indeed, these findings are consistent with early findings that PTDM following LT showed worse patient and graft survival. 85 In addition to the development of DM following LT, presenting for LT with pre-existing DM carries risk.

Long-term follow of LT patients with a median of 14 years found that pre-transplant DM independently predicted atherosclerotic vascular events (AVE). 87 Defining AVE as specific conditions with evidence of atherosclerotic disease were as follows: myocardial infarction, angina, transient ischemic attack, stroke, and intermittent claudication. The authors also noted that pre-transplant DM doubled their risk for AVE.

As discussed in this paper, identifying patients with DM may help further risk stratify them before transplantation.

Even patients without DM are at risk for hyperglycemia following LT given the surgical stress and administration of medications such as methylprednisolone and calcineurin inhibitors. With the risks of hyperglycemia on outcomes and the risk of development of DM post-transplant, intervention may prevent long-term complications. In this single center trial, patients were assigned to different glucose control regimens (< 140 mg/dL vs. < 180 mg/dL). Post-operative glucose readings were followed and noted when > 200 mg/dL. Based on their findings, four factors were noted that predicted early hyperglycemia following LT. They were shorter length of stay, use of glucose-lowering medications at discharge, donor female gender, and donor white race. 88 While limited by a single center's data, this study may prove useful in identifying patients at risk for post-operative hyperglycemia and DM.

Previous retrospective data on peri-operative hyperglycemia indicated risks to patient and graft survival.

However, more recent data suggests that tight glucose control may not be as essential as previously thought. That said, we know the development of PTDM and metabolic syndrome following LT is common and may predispose patients to cardiovascular events. 89 With NAFLD continuing to increase as an indication for LT, more may need to be done to identify how best to manage perioperative glucose levels. Further studies are needed to evaluate the effects perioperative glucose management on outcomes and what, if any, interventions can improve both short and long-term outcomes.

Liver transplant anesthesiologists manage complex patients before, during, and after a complex procedure. The unique challenges of ESLD patients extend to multiple organ systems and require vigilance to manage. The COVID-19 pandemic presented new challenges to providers this year not only to protect their patients but to protect themselves. While managing limited resources early in the pandemic the concern of limiting life-saving transplants was a real concern. However, useful guidance from national transplant organizations proved invaluable in navigating the new normal of COVID-19.

The use of DOAC's may provide patients with a better side effect profile for patients at risk for forming new clots or treating existing colt burden. Understanding how to manage these medications and recognizing the role of reversal agents play as well as the risk of bleeding is critical for transplant anesthesiologists. Opioids have long been the mainstay of pain management for surgery, including LT patients. Their use is not without challenges as long-term use may lead to worse clinical outcomes.

Multi-modal analgesia seeks to limit opioid use by employing many non-opioid medications but they may have limitations in ESLD. Finally, the consequences of hyperglycemia during LT may trivial, especially compared to the long-term of effects of diabetes mellitus following transplant.

Review of the 2019 novel coronavirus (SARS-CoV-2) based on current evidence

Coronavirus disease 2019 (COVID-19) Situation Report -40

Hospital capacity and operations in the Coronavirus Disease 2019 (COVID-19) pandemic-planning for the Nth patient

Coronavirus and SARS-CoV-2: A brief overview

Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor

Clinical best practice advice for hepatology and liver transplant providers during the COVID-19 pandemic: AASLD Expert Panel consensus statement

Non-alcoholic fatty liver diseases in patients with COVID-19: A retrospective study

Coronavirus Disease 2019: Implications of emerging infections for transplantation

COVID-19 statement from the Infectious Disease and Transplantation SIG

ASTS COVID 19 strike force guidance to members on the evolving pandemic

Changes in liver transplant center practice in response to Coronavirus Disease 2019: Unmasking dramatic center-level variability

Organ donation during the COVID-19 pandemic

Early impact of COVID-19 on transplant center practices and policies in the United States

Emerging evidence to support not always "just saying no" to SARS-CoV-2 positive donors

Utilization of deceased donors during a pandemic: Argument against using SARS-CoV-2-positive donors

Changes in liver transplant center practice in response to Coronavirus 2019: Unmasking dramatic center-level variability

Urgent liver transplantation soon after recovery from COVID-19 in a patient with decompensated liver cirrhosis

Liver transplant in a recently COVID-19 positive child with hepatoblastoma

Successful orthotopic liver transplantation in a patient with a positive SARS-CoV2 test and acute liver failure secondary to acetaminophen overdose

Liver transplantation in the United States during the COVID-19 pandemic: National and center-level responses

Cirrhosis as a risk factor for venous thrombosis

Perioperative thromboprophylaxis in liver transplant patients

Retrospective review on the safety and efficacy of direct oral anticoagulants compared with warfarin in patients with cirrhosis

Changing concepts of cirrhotic coagulopathy

Direct oral anticoagulants in patients with liver disease in the era of non-alcoholic fatty liver disease global epidemic: A narrative review

Direct-acting oral anticoagulants (DOACs) in cirrhosis and cirrhosisassociated portal vein thrombosis

The risk of venous thromboembolism in patients with cirrhosis. A systematic review and meta-analysis

Direct oral anticoagulants in patients with atrial fibrillation and liver disease

Safety of direct oral anticoagulants in patients with cirrhosis: A systematic review and meta-analysis

Newer oral anticoagulants in the treatment of acute portal vein thrombosis in patients with and without cirrhosis

Effects of anticoagulants in patients with cirrhosis and portal vein thrombosis: A systematic review and meta-analysis

Direct oral anticoagulants and warfarin in patients with cirrhosis: A comparison of outcomes

The coagulopathy of chronic liver disease

Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report

Antithrombotic therapy for atrial fibrillation: CHEST guideline and expert panel report

Rates of bleeding and discontinuation of direct oral anticoagulants in patients with decompensated cirrhosis

Direct oral anticoagulants in cirrhotic patients: Current evidence and clinical observations

Risk of drug-induces liver injury with the new oral anticoagulants: Systematic review and meta-analysis

Prospective study of oral anticoagulants and risk of liver injury in patients with atrial fibrillation

Efficacy and safety of edoxaban in elderly patients with atrial fibrillation in the ENGAGE AF-TIMI 48 trial

Edoxaban versus warfarin in patients with atrial fibrillation and history of liver disease

Direct oral anticoagulants in cirrhosis

Direct oral anticoagulants in cirrhosis patients pose similar risks of bleeding when compared to traditional anticoagulation

The efficacy and safety of direct oral anticoagulants vs traditional anticoagulants in cirrhosis

Cirrhosis is a risk factor for atrial fibrillation: A nationwide, population-based study

Direct oral anticoagulants in patients with liver cirrhosis: A systematic review

Direct oral anticoagulants and cirrhosis: More evidence still needed for efficacy and safety in portal vein thrombosis

Utility of oral anticoagulants as prophylaxis of recurrent portal thrombosis after liver transplantation

Rivaroxaban and apixaban for initial treatment of acute venous thromboembolism of atypical location

Treatment response and bleeding events associated with anticoagulant therapy of portal vein thrombosis in cirrhotic patients: Systematic review and meta-analysis

Perioperative thromboelastometry for adult living donor liver transplant recipients with a tendency to hypercoagulability: A prospective observational cohort study

Perioperative thrombotic complications in liver transplantation

Safety of direct-acting oral anticoagulants relative to warfarin in a matched cohort of liver transplant recipients

Utilization of direct-acting oral anticoagulation in solid organ transplant patients: A national survey of institutional practices

Orthotopic liver transplant in a patient anticoagulated with rivaroxaban: A case report

Reversal of direct oral anticoagulants: guidance from the anticoagulation forum

Pain control after liver transplantation surgery

Comparison of analgesic requirements after liver transplantation and cholecystectomy

Orthotopic liver transplant patients require less postoperative morphine than do patients undergoing hepatic resection

Implementation of a multimodal pain management order set reduces perioperative opioid use after liver transplantation

Nonopioid modalities for acute postoperative pain in abdominal transplant recipients

Opioid avoidance in liver transplant recipients: Reduction in postoperative opioid use through a multidisciplinary multimodal approach

Analgesic considerations for liver transplantation patients

Up-regulation of central mu-opioid receptors in a model of hepatic encephalopathy: A potential mechanism for increased sensitivity to morphine in liver failure

Hepatic disposition of alfentanil and sufentanil in patients undergoing orthotopic liver transplantation

The population pharmacokinetics of fentanyl in patients undergoing living-donor liver transplantation

Hepatic disposition of sufentanil in patients undergoing coronary bypass surgery

Differences in magnitude and duration of opioid-induced respiratory depression and analgesia with fentanyl and sufentanil

Chronic pain among liver transplant candidates

Classifying preoperative opioid use for surgical care

Alcohol substance use in liver transplant patients

Survival implications of opioid use before and after liver transplantation

Perioperative opioid use and chronic post-surgical pain after liver transplantation: A single center observational study

Preoperative narcotic weaning in the perioperative patient: Now is the time

Importance of perioperative glycemic control in general surgery

Perioperative hyperglycemia and risk of adverse events among patients with and without diabetes

The Emory University perioperative algorithm in the management of hyperglycemia and diabetes in non-cardiac surgery patients

Intensive insulin therapy in critically ill patients

Effect of intraoperative hyperglycemia during liver transplantation

Post-transplant hyperglycemia is associated with increased risk of liver allograft rejection

Intraoperative glycemic control in patients undergoing orthotopic liver transplant: A single center prospective randomized study

Association between perioperative hyperglycemia or glucose variability and postoperative acute kidney injury after liver transplantation: A retrospective observational study

Hyperglycemia and diabetes mellitus following organ transplantation

The impact of post-transplant diabetes mellitus on liver transplant outcomes

Negative impact of new-onset diabetes mellitus on patient and graft survival after liver transplantation: Long-term follow up

Sustained posttransplantation diabetes is associated with long-term major cardiovascular events following liver transplantation

Pre-transplant diabetes predicts atherosclerotic vascular events and cardiovascular mortality in liver transplant recipients: A long-term follow-up study

Development of a predictive model for hyperglycemia in nondiabetic recipients after liver transplantation

Management of metabolic syndrome and cardiovascular risk after liver transplantation

Table 1 -Direct Oral Anticoagulants with Reversal Agents 56