The reversal of anticoagulants can be a complex process with limited data describing the optimal overall approach beyond a specific reversal agent. Recent advances in anticoagulation stewardship have created opportunities to standardize and optimize the reversal of anticoagulants, especially in urgent life-threatening bleeding events. This article explores how pharmacists provided anticoagulation stewardship activities positively impact outcomes related to urgent anticoagulation reversal.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.

Background: American Association for Thoracic Surgery and The International Society for Heart and Lung Transplantation (AATS/ISHLT) guidelines recommend warfarin in patients with continuous-flow left ventricular assist devices (LVADs) to reduce the risk of device thrombosis and systemic embolization. Left ventricular assist device patients often undergo elective and emergent procedures that require interrupted anticoagulation. Data and experience vary on the optimal strategy to rapidly reverse warfarin in LVAD patients when an emergent procedure is planned. Objective: The purpose of this study was to describe the use of 4-factor prothrombin complex concentrate (PCC4) for warfarin reversal in patients with LVADs undergoing elective and emergent procedures. Methods: This retrospective, single-center, cohort review describes the use of PCC4 in patients with LVADs who require warfarin reversal for elective or emergent procedures. The primary outcome was a composite incidence of pump thrombosis, venous thromboembolism, and ischemic stroke within 30 days of PCC4 administration. Results: In total, 14 patients received 17 administrations of PCC4. One patient received 3 administrations, and 1 other patient received 2 administrations during separate encounters. The median dose was 500 units or 6.6 units/kg (range = 4.2-14.1 units/kg). Of the PCC4 administrations, 82% (14/17) were for low bleed risk procedures and 76% (13/17) were for elective procedures. There were no cases of pump thrombosis, venous thromboembolism, or stroke within 30 days of the procedure. Conclusions and Relevance: Low-dose PCC4 appears to be a safe and effective temporary reversal strategy for patients with LVADs undergoing low-bleed risk elective procedures.

Anticoagulant therapy is commonly associated with a high incidence of avoidable adverse events, especially in the acute care setting. This has led to several initiatives by key national health care stakeholders, including specific attention to The Joint Commission's National Patient Safety Goals, to improve anticoagulation management. The subject of special populations has long been identified as challenging by clinicians with the use of anticoagulants. This is driven in part by numerous variables that can contribute to hard outcomes such as bleeding, thrombosis, length of stay, hospital re-admission, morbidity, and mortality. Despite the notable effort to improve the use of anticoagulants with numerous clinical trials, guidelines, guidance statements, and other sources of published evidence, notable difficulties continue to challenge practitioners in managing this class of medications. This is especially the case with very diverse critically ill populations where countless variables exist, many of which were never explored in trials or have historically been frequently excluded. Trials evaluating anticoagulation therapy often can only account for small portions of variables that may affect thrombosis and hemostasis, and study methods often do not reflect the constantly changing dynamic conditions seen in unique critically ill patients. Clinicians providing care to the numerous critically ill populations are faced with conditions that lead to relatively small therapeutic windows, which makes designing safe optimal anticoagulation management plans difficult when dealing with complex patients and mechanical support devices. The approach to crafting a successful management plan for anticoagulant therapy must incorporate the numerous variables that are continuously assessed and revised during the patient's time in the intensive care unit. We explore considerations and approaches when developing, assessing, and implementing an individualized or precision-based management plan that involves the use of anticoagulants in the critically ill. The skills and thought process provided will assist clinicians in managing this unique, variable, and challenging population.

See the Reply by Semla and Steinman in this issue.

Antithrombotic and hemostatic medications are essential, yet high-risk therapies commonly used for the prevention and treatment of thrombosis and bleeding. Since first demonstrating the ability to improve the safety and quality of heparin and warfarin-related care many years ago, pharmacists now play an important expanded role in more comprehensive and complex thrombosis and hemostasis management programs. Such programs encompass the prevention and treatment of thrombosis and bleeding across care settings, medical indications, and professional services. These programs impact not only appropriate use of antithrombotic medications, but also of antidotes, blood products, medical devices, laboratory testing, and other important aspects of care. In addition to providing direct patient care, pharmacists are increasingly involved in the development and implementation of system-level processes and quality improvement activities that require technical knowledge, leadership skills, and effective multidisciplinary collaboration. Evolution in health care regulation and accreditation standards, along with national efforts to advance the concept of Anticoagulation Stewardship, will likely accelerate the growth and expansion of thrombosis and hemostasis management programs, increasing the demand for well-trained and experienced clinical pharmacists. However, none of the existing accredited specialty pharmacy residency programs encompasses the full range of skills and experiences necessary for new pharmacists to practice effectively in this complex and rapidly evolving field. This manuscript describes the evolution of the Hemostasis and Antithrombotic Stewardship program at Brigham and Women's Hospital and the development of a novel postgraduate year 2 (PGY2) pharmacy residency in this specialty area. It provides details of the new PGY2 residency program curriculum and puts forth a vision of success for such programs at the local and national levels.

Nunnally, Mark E. MD, FCCM; Dager, William E. PharmD, BCPS, MCCM, FASHP, FACCP, FCSHP; Patel, Hariyali MHA; Al-Hazzani, Waleed MD; Nadkarni, Vinay M. MD, FCCM; Kane-Gill, Sandra L. PharmD, MSc, FCCM, FCCP Author Information

Developing optimal management plans can be straightforward, or at other times more challenging when multiple unique situations exist requiring a more individualized approach.1, 2 Many pharmacologic regimens are developed based on clinical trials assessing their use in general populations with fewer or more limited insights that include or explore the critically ill. Use of medications off-label or in populations not previously studied in randomized control trials is very common in the critically ill. Such groups may be referred to as special populations. Because the critically ill are a diverse, complex, and constantly changing population, clinicians frequently need to adapt to meet the needs and presentations of these more complex patients with multiple acute and constantly changing clinical conditions. Frequent assessment of the patient's pharmacological management needs and implementation of a safe and optimal plan may be necessary. Identification of unique factors present where precision-based pharmacological management requires more management, discussion of goals, and plan development are key to optimal pharmacotherapeutic management decisions. This commentary, as part of the themed issues on precision-based pharmacotherapy, emphasizes some universal considerations and a logical approach to developing and implementing a precision-based pharmacotherapy regimen. The key considerations are especially applicable to intensive care settings. Precision-based pharmacological management plans may include weighing the presence of factors that have opposing effects, multiple drug or disease-related interactions, comorbid conditions, or socioeconomic backgrounds. Building management plans typically starts with a multidisciplinary team approach with the available evidence and an awareness of unique influencing situations that may not have been included in clinical trials or the numbers involved being too small to draw conclusions on optimal outcomes. In addition, defined outcomes in clinical trials may have focused on surrogate indicators such as laboratory measures compared to hard outcomes of mortality, morbidity, or length of stay. Another challenge is determining the impact of multiple factors, both pharmacology-related and non-pharmacologic interventions, that may influence either the pharmacotherapy or the clinical problems being addressed. Most data on primary outcomes related to the usage of pharmacological agents may have explored only single factors or a narrow group of combined outcomes. When multiple factors driving outcomes are present, clinicians may need to weigh each factor present and make any necessary modifications to the management plan.1 Provided are some considerations when developing a management plan that is personalized or individualized to the patient's clinical presentation and is executed in a precision-based or unique management approach to optimize outcomes. Selected skill sets to accomplish this are described in Table 1. This contrasts with a narrow, agent or situation focused approach that looks only at a specific problem. When providing a focused or silo approach, consider how each modifying factor will fit with others and then assess how it all fits together. When multiple problems exist, consider a rule of systems approach to assess the overall situation. This requires an assessment that explores any influencing factors that may impact your portion of the management plan. The plan can be sub-optimal if it is not correctly executed and within a desirable time period. Each should be regarding the overall impact or influence on the entire patient's situation. Example: Management of a potential adverse drug effect. Any past agents given (for example, thrombocytopenia can take 2 weeks to occur), influences incurred by the presence of a genetic or disease state; presence of, or availability of agents that may currently blunt or available to reverse the effects of an agent or consideration of other drivers to the event and whether it is concentration or immune related. The brevity of the situation should be the starting point of an assessment and any subsequent plan consideration. Effective communication between clinicians of all disciplines involved is critical. Different practice specialties may see the situation or resolution differently. Having their input may avoid to potential for missing important components of any pharmacotherapy management plan. Engaging with other disciplines. Understand what is currently happening at the bedside. Melding of the pharmacotherapy plan with other management measures and observations to fit all the moving pieces together can optimize the care provided. Be cautious with single one-way messaging (e.g., text message on a recommendation or suggestion to change the plan without any interactive discussion). Influencing factors being considered may be missed in the absence of information exchange and discussion of the overall plan. Communicate thoughts, clarify any questions, (including assumptions and considerations) before engaging clinicians prior to the end or after their shift has been completed. Complex pharmacotherapy orders for less frequently used or difficult medication regimens create additional challenges. Discuss earlier and be prepared if you choose to order it when staff levels and resources are more nor limited. Decisions are only as good as the information provided. Inaccurate, incomplete, or dated information may not accurately reflect the current situation. Missing any critical influencing factor may compromise the plan. Not all of the necessary information may be documented or present in the electronic record. Current and timely information that comprehensively reflects the current situation should be assessed. Bedside observations can be weighed to what is currently documented in the electronic medical record. Considerations for management decisions being developed should be open to input for all clinicians involved as they unfold. The plan should also be one that can be flexible and implementable. You can always change your mind and redirect the plan. Apart from selected situations in less complex situations, a multidisciplinary approach should be followed when developing a precision-based management plans that improve outcomes.6, 7 Develop professional relationships on a continuous basis with all the disciplines involved. Understand each clinician's approach or style to patient care. Do not just be a name from phone calls, face to face can be important to building trust and respect for your thoughts. Understand how your insights and recommendations impact other parts of management plan. Avoid a siloed approach that only focuses on your discipline. Frequently, each practitioner involved in management has areas of strength, as well as weakness, in either knowledge or application when developing and implementing a management plan. Effectively working together includes listening to other thoughts, asking the right questions, providing any necessary input that is open for discussion and adjusting accordingly. Start with the available evidence. Modify based on the full assessment of the situation. Increase, decrease the dose or interval as needed. Sometimes a loading dose may be necessary to achieve adequate serum concentrations. The maintenance dose may be the part modified. Smaller doses and titration to effect may be an approach when the therapeutic window is narrower. When sorting out such regimens, a follow-up plan should be developed to assist in determining when to make modifications as new information is available. The more unclear or tenuous the situation, the more frequent assessments and adjustments considered. If the plan has risks involved, assess more frequently and be ready to adapt. Include any available pharmacokinetic (Table 2) or pharmacogenomic influences.5, 8, 9 Skill: Once a concept is proposed, assess the plan and patient's situation, and identify and track any gaps. When dealing with emergent situations, avoid any necessary delays in additional dosing if the regimen has not achieved desired results. Once the situation has stabilized, back off to sustain the necessary effects as feasible. Utilizing the management plan developed, assess as necessary depending on the acuity of the issue the need for adjustments. Include any new drivers identified or management decisions that may influence the situation. Be current on the patient's clinical course and any changes in their prognosis. If organ failure is present, is it declining, stable or improving. Skill set example for existing critical challenges to adapt into practice: When driving an automobile in traffic and bad weather, you constantly assess and adjust to avoid a mishap. You're looking at multiple factors and proactively compensating as situations occur to reach your goal or destination safely. One skill in making an adjustment different than the implemented management plan is to state that despite a previous recommendation, a change may be necessary based on new information that is now available. Descriptions of this for fluid/vasoactive agents, pain/sedation/delirium, thrombosis/hemostasis, anticonvulsants or transplantation are provided in other publications in this precision-based edition.3, 5, 8-11 Be aware of assumptions. Confirm that any assumptions are correct when the plan or assessments are not in line with expectations. Was the medication given as expected? Is the patient taking their medication from home as directed? Short acting agents given multiple time daily may be missed if the patient is off the intensive care unit for a test or procedure. If the patient is on hemodialysis, it can be difficult to time medications when the dialysis approach or time changes without communication. Routine orders to give an agent post dialysis regimen could lead to undesirable low serum concentrations of a medication if dialysis increased or held. Avoid ordering medications or lab draws during the nursing shift change. During assessment of a continuous vancomycin infusion, was it stopped for several hours to transfuse blood and restarted shortly prior to a serum level being drawn. Was it assumed that any medication documented as given actually occurred? Patients may refuse the drug, spit it up, vomit up the contents, or be removed with residuals. Is the weight accurate, and what portion may be excessive fluid compared to adipose tissue? Other examples include the assumption that information in the medical record is current and accurate, and that laboratory information in precise and all values are believable. Initial assessments, especially in urgent situations, may be incomplete. As time permits, identify and fill in any gaps. New situations may arise that can impact on the management plan. Decisions to implement a long-term regimen may be evidence based, but will the patient be able to follow it? Changes in organ function or adding an interacting drug should be identified and addressed. If the route of elimination needed is lost, how should the regimen be modified? Patients in the ICU will have various levels of comprehension. Some will be unconscious, sedated, various types of delirium, and others not.5, 11 Nevertheless, there is frequent confusion and uncertainty. When possible, discussing a patients' medication regimen at the bedside can frequently provide additional insights on how to personalize their medication therapy to be optimally successful, which may not be how it is normally prescribed. If a patient is having seizures, are there any medications that may encourage or lower the seizure threshold.10 This is especially important if a selected serum level has to be sustained to achieve desired effects. Will they be able to take the medications at home three times, or even twice daily? Are they using over-the-counter agents that are not listed in their medical history, which may influence their medication regimen. When initiating a long-term regimen, working with the patient, can it be accomplished? What approach provides the best options (partial success can be better than optimal evidence-based regimens that will not succeed). A patient is now nothing by mouth (NPO) but requires antiplatelet therapy for cardiac stent. Assessment may consider how much time has passed and if antiplatelet therapy is needed. If it was recent, should a parenteral antiplatelet regimen be considered. One of the first steps in a precision-based approach is a comprehensive overview of the situation, the goals of therapy, and recognition of all potential influencing factors. Influencing factors such as disease states including organ failure or concurrent drug–drug interactions, for example, can be stable and consistent while at other times being transient and changing (Table 2). Changes may be in the direction of increasing impact on the situation (e.g., going into acute organ injury, progression of the patient's clinical presentation, or initiation of influencing therapy), at a stable phase for a period, or in a recovery stage where the influencing factor is resolving. Watching the big picture is one part, but it should not be considered snapshot, but more of a series of assessments. Identification of trends and adjusting in advance or in a prospective manner may reduce the risk of overdosing or underdosing medications. Think about the big picture. If the interaction can potentially be at higher risk for seizures, consider removing any drugs that could lower the seizure threshold. In some cases, additional medication may be considered for prophylaxis against a potential complication. Having a forward-thinking plan in place should the interaction or adverse event rapidly unfold should be part of the management plan. Identify if any medication should be discontinued. Be considerate of the rebound effects when stopping a medication or stopping a critical drug therapy (e.g., immunotherapy, anticonvulsant, antiplatelet or cardiovascular agents). The first skill in dealing with this is to note all factors potentially altering a drug's effects and know the ranges in the degree of interaction and direction (higher or lower effect) and the onset of the interaction. Assess what overall direction may occur as the combined result of the interaction. The first step is to assess the ability to remove and replace, if necessary, any interacting drugs to ones that may not have an effect on other drugs in the regimen. Next is to identify what critical consequences may occur from the interaction, and determine how this will be assessed, and the need for any additional adjustments, or if something may need to be added if necessary. The potential for missed doses while a patient is off the floor or the route of administration is lost should be identified and necessary changes in the management plan implemented. Single doses or the continued effects of recently discontinued medications (e.g., long acting opiates, anticonvulsants, cardiovascular agents) that may blunt the effects of another agent. Identify any drugs or process that may reduce elimination of a drug, and to what extent. If the dose was not modified, is a potentially elevated drug serum level present acceptable. The route of elimination and any factors such as drug–drug or drug–disease interaction should be identified, and plan adjusted accordingly. Changes in the above factors including onset and off set should be incorporated into management plan. Agents may be combined to augment each other or have synergistic effects. If a single agent is not working, should additional agents be added to augment therapy. After adding an agent, set goals to know targets are achieved. If not accomplished, what may be the next step. As the condition improves, a plan on how to taper off the agents should be developed and management plan incorporate parameters to assess the patients progress. Examples can include antimicrobial agents, anti-convulsant, antiarrhythmics, presser support, pain, agitation, and sedation. Bleeding may be enhanced with combination of anticoagulant plus antiplatelet agents. Sedation by long acting or tissue buildup of combined sedative with opiates and benzodiazepines. Is something occurring or present that may diminish the effects of an agent? If an antidote is considered to intentionally reverse the agent's effects, how much is necessary and how long the effects will last. Is full or partial reversal desired. Is there a need to initiate an alternative agent in place of the agent reversed? Adverse drug-related effects could be related to the serum concentration, or sensitivity to an agent. Be aware of any related adverse events in the patient's history including allergies. Another skill may involve the use of antidotes. For some drugs a set dose is suggested based on the assessed factors present. Be aware of the threshold for which an excessive drug level can occur, identify any situations depressing elimination and symptoms of an excessive pharmacologic effect. If an agent with a narrow therapeutic window and potential for a drug-related adverse effects, include in the plan what to look for and should it occur, how to manage it (decreased the dose, use a reversal agent or how to treat the reaction).12 Keep in mind that multiple drivers and agents may be creating the adverse event noted. If using an antidote, will its effects last as long as the agent being reversed, or will additional doses be needed unit the adverse effect driven by the drug resolves. Complete reversal may not be necessary, and if so, is there a need to use an alternative agent to sustain the necessary support. In the case of an excessive digoxin level causing a severe heart block, it may require seven vials of the antidote to reverse the level. You only have two available. Consider giving a partial dose (along with noting the potassium level and need to correct) instead of waiting for the full dose to be administered if this leads to delaying management. Also assess any additional medication or situations leading up to the high digoxin level as well as any further factors driving a heart block such as a beta-adrenergic blocker that may be interacting to create the heart block. The presence of a high potassium level may also require a separate management plan. Acute heart failure and related pre-renal failure along with poor compliance or removal of the diuretic therapy and addition of amiodarone may be influencing triggers, and the management plan may need to be addressed. If the heart block was third degree, the amiodarone may need to be stopped if it potentially reduces ventricular escape beats. Can other management approaches such as dialysis remove the agent? Reversal or neutralizing of an existing drug can lead to recurrence of the clinical problem pharmacologically depressed. Alternative therapies may need to be initiated. Identify if any disease process (for example, diabetes and dextrose containing products, bariatric surgery and enteral tube placement, lipid emulsions, and high triglycerides) or organ failure (reduction in elimination or protein binding) will impact the response to a medication regimen. Changes in organ function could represent improvement or decline in function and you may need to consider the trend and adapt the management plan in advance to be prospective instead of reactionary. Are additional support processes influencing the level of organ function and impacting the medication regimen (For example, mechanical support devices and hemodialysis). Organ failure or concurrent disease processes can range from insignificant, mild and stable to critical and constantly changing. One example is relative to acute renal failure. Use the most current serum creatinine (Scr) compared (trended) to previous values, urine output (UO) and trend to make a snapshot assessment of renal function and if is changing devise an adjusted medication regimen. The UO can determine acute changes in renal function and if it is recovering or declining. This may provide information earlier, allow an assessment regarding a renally adjusted medication regimen where the therapeutic window is narrower. Was a reduction in SCr occurring post hydration in a dehydrated patient or post hemodialysis? Did we assume no hemodialysis when it occurred during the middle of the night and not yet charted into the medical record in a place one would easily see it? In the setting of dialysis, was there a change in the dialysis prescription where a higher or lower amount of drug could be removed in the last session, especially if the dialyzable drug was administered shortly prior to initiating dialysis. Did dialysis only go for 15–30 min then stopped secondary to blood pressure or circuit thrombosis issues. Consider a fluid overloaded patient with acute heart failure and low blood pressure during sepsis. We would want to consider all three situations but understand where rate-limiting steps are. Which of the three diseases is most tenuous? We need to assess all sources of fluids, the level of heart failure including both ejection fraction and left ventricular end diastolic volume, all available hemodynamic measures, and if the infection is being optimally treated. If the infection continues to advance and the patient becomes neutropenic, should we consider a more aggressive antibiotic regimen? Most data on adjusting antibiotic regimens comes from stable chronic renal insufficiency and not reflective of elimination in acute kidney injury, which can be substantially higher, thus leading to potential underdosing in the first place.13 When looking at the literature or guidelines supporting management approaches when multiple severe disease states are present, such populations were frequently excluded in trials creating limitations in any related guideline recommendations leading to a need for precision-based management. Several situations can impact drug therapy in the overweight or underweight populations, and it is important to use the correct weight to a given agent.14 What is the cause of the increased or decreased body weight and is it acute (Fluids) or chronic (Excessive adipose tissue, long history of being bedridden and limited muscle mass or post amputations)? How may it impact the volume of distribution (Vd) and if the drug distributes to these areas? In morbid obesity, have set doses of drugs (especially lipophilic and high Vd (L/Kg) able to reach desired serum levels? Anasarca related fluid overload may be the result of poor cardiac function, which may additionally have poor elimination not only of fluids, but drugs as well. Acute weight gain in the hospital may be the result of fluid resuscitation. If rapid serum levels are needed, a bolus dose may be considered.3 Assess the drugs Vd. If it is close to the blood volume (e.g., 5 L) and the drug is a large molecule, dosing on ideal body weight may be a consideration (e.g., Intravenous Immune Globulin or IVIG). If the Vd is large, consider where it is distributed. Digoxin has a large Vd, but to skeletal tissue, not the adipose space, so dosing is not on total body weight. Other agents may distribute to deeper adipose tissue compartments and be dosed on total body weight. Body weight is also used in renal assessment equations, and typically related to muscle tissue producing creatinine, so ideal body weight may be considered. However, a lot of the data used to create breakoffs, used total body weight in the calculations. May need to adapt any tube related administration to make sure the drug can be administered enterally, and any potential change in bioavailability. Three major renal failure situations can occur in the critically ill. Acute kidney injury (AKI), chronic kidney disease (CKD) or both together. Drug elimination may be influenced by the severity of the kidney's ability to remove renally eliminated drugs. Elimination in AKI can be notably faster (e.g., 35%) compared to CKD.13 Many dosing charts are based on first dose analysis in stable ambulatory CKD patients, and not the critically ill. AKI can present itself in three phases, acute progressing failure (Scr rising and urine output (UO) declining), stable phase (little change in UO or Scr), and recovery (UO increasing and Scr declining. Serum Creatinine values will reflect yesterday's renal function and common equations depend on the Scr being at steady state. Scr assay sensitivity has changed and is typically 0.2 mg/dL lower than assessments done before 2000. UO is more time sensitive to direction of kidney function; however, changes in cardiac output, fluid administrations and use of diuretics may influence UO. Initial dosing in renal failure, especially with sepsis and antibiotics, AKI and increased volumes of distribution may need to consider a loading dose to achieve adequate levels.15 Initial dosing for most antibiotics (except vancomycin and aminoglycosides) in sepsis or severe infections should not be adjusted downwards for at least 24–48 h.16 First dose PK analysis with most drug elimination studies in renal failure may overestimate elimination as tissue distribution for the plasma may over estimated clearance from the body out of the plasma. Hemodialysis can impact drug elimination, and may depend on the approach, intensity, and duration. Be aware of the dialysis plans and adjust accordingly each day.15 Timing of dialysis, approach or if it is done can occur. Make sure this is assessed daily. Consider an order to contact pharmacy if the planned approach to dialysis is changed. Liver failure can have multiple effects on drug elimination depending on what pathways are impacted, which is variable. Reduction in proteins produced in the liver (e.g., albumin) may impact drug binding and oncotic pressures. Is the impairment related to injury of hepatocytes, or functional pathways? Dosing considerations may need to explore each agent individually to selected form of liver impairment.17 Severe renal impairment may also impact selected cytochrome P450 pathways including 3A4.18 Thus, agents that are primarily eliminated in the liver may have reduced elimination in severe renal impairment. As noted above in renal failure, phases of liver injury can occur, and should be watched and drug doing assessed accordingly. The use of albumin replacement to support oncotic pressures is controversial and depends on the situation. As a routine approach based solely on low albumin levels, it is currently discouraged. Reduction in clotting factors (increased international normalized ratio) may increase risks for bleeding when using antithrombotic agents, however, in liver failure natural anticoagulants (protein C and s) are also reduced. The resulting coagulopathy may not create a sufficient level of auto anticoagulation as reflected by INR values.19 Assessing heart failure is multifactorial and depends on several factors such as the estimated ejection fraction (EF) in addition to the left ventricular end diastolic volume. Heart failure can lead to reduction in both renal and hepatic drug elimination by reduction in cardiac output. Post cardiac or respiratory arrest and resuscitation or major hemorrhagic events, what should be done in the post resuscitative period? The degree of heart failure should continuously be assessed daily and any impact on drug elimination or volume of distribution (especially drugs that distribute to intravascular spaces). The level of pitting edema and location in addition to fluid input and output (noting loss from the skin and expiration). Echocardiography can be considered to assess function and approaches to management. Cardiac support may depend on if the cause of failure is cardiogenic or not and if the patient is wet or dry. What is the current central venous pressure, afterload demand or systemic vascular resistance on the heart? The presence of permanent or temporary cardiac support devices improving cardiac output, including the level of support provided, should be assessed daily, and changes taken into consideration with management plans. Keep in mind the balance between fluids, arterial and venous pressures and heart rate when assessing the situation. Respiratory failure can impact the elimination of some drugs, (however, in most cases other pathways may compensate). Mechanical ventilation parameters can assist in assessing the degree of respiratory failure and guide pharmacotherapy decisions, both systemically as well as inhalation delivered. Combination of mechanical support and pharmacologic agents are frequently used and assessed and adapted each day. It is important to combine both in assessments. In situations where the central venous pressures are low, and positive end-expiratory pressures (PEEP) high (over 10 mmHg), cardiac out may be impaired leading to a reduce in drug elimination.20 If there will be a desire to advance or deescalate neurologic acting agents, have a plan that include how dosing will be changed including what and when to assess. Additional CNS-related situations including psychological, emotional or sleep deprivation occurrences can occur and should be incorporated into the plan. Consider adapting the pharmacotherapy plan to work with the patient's situation and needs. Consider timing doses and phlebotomy to allow sleep. Be aware of the need for or not regarding antibiotic prophylaxis. Keep aware of any potential infection and initiate the correct spectrum antibiotics without any delay once the situation allows (the infection declared itself and cultures sent). Adapt and focus antimicrobial therapy based on cultures and location of the infection. Adapt any antibiotic dosing to potential pharmacokinetic or pharmacodynamic factors present.21 In situations where the immune system is compromised, more aggressive initial dosing should be considered if warranted. Consider any antibiotic and antiviral agents that may impact the elimination of other drugs. Planned or emergent invasive procedures should be noted and discussed with all engaged providers involved in either the procedure, or the pharmacotherapy management plan. Medication administered as part of the procedure process should be noted and include assessments of medication already in use. Use of anticoagulants, and if still active during the procedure should be noted. Any medications with pharmacokinetic or pharmacologic effects beyond the operative room should be identified. Have a transition plan prior to and after the procedure? Communication between all clinicians involved in managing the overall pharmacotherapy plan (including any pre-operative plans) should be included. Pre-procedure antibiotics are commonly given to prevent procedure-related infection and may be part of an established order set. Avoid stacking antibiotics if the patient is already receiving them to avoid excessive levels (for example vancomycin) and given close to the incision time. For long procedures and critical scheduled medications, a plan for administration during the procedure should be considered. Pain and agitation plans should be developed and assessed prior to, during and post the procedure. Insertion or removal of any epidural catheters should be coordinated with any antithrombotic therapies. In the case of emergent bedside procedures, consider adding any necessary pharmacologic support including short term prophylactic antibiotics if warranted. Depending on the acuity of the situation, the status of the patient, and evolving influencing factors (Table 2), clinicians should utilize all resources available to provide an accurate assessment of the situation and discuss approaches to managing each situation and related treatment goals. In many cases, the electronic medical record can be incomplete and not current. It may require clinicians to reach out to the bedside or seek at the moment information to get a real-time assessment of the situation and what may be necessary to include and adapt the management plan. Management plans need to have a starting point followed by an assessment and modification process based on identified influencing factors (Table 2). One approach is to consider the typical standard therapy regimen that incorporates some of the identified factors, such as a dose that is modified for the patient's renal dysfunction, as a starting point. The next step will involve any necessary modifications to other factors present to either intensify or decrease the dosing regimen. For example, assessing if an immunocompromised patient is presenting with renal failure, hemodynamic instability, and life-threatening sepsis with a poor prognosis. The initial regimen may include a more aggressive initial dose regimen, which in 1–2 days can be backed down to avoid any related toxicity if the therapeutic range is narrower. The plan should consider what information may be sought and then be subsequently ordered to support any needed clarifications or revisions. This sets practitioners up for success with the necessary information on a timely and coordinated basis to optimize their ability to make decisions. Clinicians should always keep in mind to adapt as the situation changes. Do not consider a developed plan to be solid and unable to be changed. In the critically ill, a patient's course can be unpredictable, and new challenges or information arise that may require a plan alteration. This can happen shortly after any recommendation or decision. Constantly, while managing a patient, we assume that a component of the care process would have occurred and does not need further consideration. As you follow your patients, keep in mind your assumptions, especially when components included in any assessments do not add up or conflict with each other. Was something ordered done at the correct time? Where medications are actually given, as it is common that medications are held for a given scenario (antihypertensives for hypotension, insulin for hypoglycemia, orals when nothing per mouth (NPO), a continuous infusion if the line is needed for blood transfusions, or turned off during a procedure). When unexpected events occur, consider your assumptions and explore if the plan needs to be revised. Some diseases have a constant presentation with minimal variables or changes for patients during their stay in the intensive care unit. Examples may include hyperlipidemia, endocrine-related diseases, obesity, etc. Management decisions should consider the impact of any present disease state and make sure that no new related acute issues driven by the disease state need to be addressed. Assumptions may consider that this is not the critical problem to focus management on and continue the previous management plan unless intentionally revised. Other challenges with a given acute disease process include the severity and urgency of the situation and how it is changing. Disease state interactions that may influence what we are seeing in our assessments. Keep track of any clinical problems present and how they may influence other disease states, medication regimens, or laboratory and disease state assessments. Step-by-step adjustment can be determined with any necessary revisions while considering the progression of the disease state as well as the potential emergence of new ones. Additional challenges may include the influence of any mechanical support devices or unique patient presentations such as excessive fluid overload or bowel obstructions, for example, that can also influence medication pharmacokinetic properties and require modifications.3 The presence of the device and any modifications in its use, including implementation and removal, should be considered. Typically, most reported drug interactions are validated as a single driver, or at least thought to be the only driver on another drug. Drug interactions are also associated with prolonged ICU stays.4 When multiple interacting agents in addition to a disease-related interaction are present, it is hard to predict their impact. Confidence in the combined influence of the interactions declines. Some patients may be more prone to experience an adverse drug-related event than others for multiple reasons. If a trend for a potential adverse event, such as laboratory values trending in the direction of a potential adverse event (for example, neutropenia with an antibiotic or thrombocytopenia with heparin), is noted but not yet to the point to modify. Request more information to identify the trend earlier or any confirmatory pieces of information to see the magnitude or how fast it is developing or stabilizing instead of waiting for the scheduled daily values or assessment to occur. Then make revisions earlier to minimize the event. Optimal precision-based care approaches should start with looking back for any factors that may contribute to the current situation and future management decisions. Decisions and assessments that could influence post-critical care issues should always be part of the assessment process. We may assume that a patient was taking their medication as directed; however, that may not have been the case and influence admission to the ICU. The patient may have come in with excessive drug effects secondary to a drug or disease state interaction, and subsequent home discharge on the previous regimen may place them right back at risk. Certain interventions may require follow-up and assessment prior to discharge instead of assuming the post-ICU or primary care physician will address them. For example, a patient's home medication may have been discontinued or replaced with a separate agent. A chronic therapy agent may have been started that is not available to them as an outpatient, or in the case of opioid stewardship, a plan to pull them off should have started the day they were initially prescribed.5 Optimal management of the critically ill is a complex process in a very diverse population of patients with multiple influencing factors present. Pharmacotherapy-related management will be in part evidence based; however, many will require a more individualized or precision-based approach. Examples of key considerations on how to approach precision-based management concepts are described in the attached tables to guide clinicians in implementing optimal drug-related management plans. The author declares no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

Thromboembolism is a common and deadly consequence of COVID-19 infection for hospitalized patients. Based on clinical evidence pre-dating the COVID-19 pandemic and early observational reports, expert consensus and guidance documents have strongly encouraged the use of prophylactic anticoagulation for patients hospitalized for COVID-19 infection. More recently, multiple clinical trials and larger observational studies have provided evidence for tailoring the approach to thromboprophylaxis for patients with COVID-19. This document provides updated guidance for the use of anticoagulant therapies in patients with COVID-19 from the Anticoagulation Forum, the leading North American organization of anticoagulation providers. We discuss ambulatory, in-hospital, and post-hospital thromboprophylaxis strategies as well as provide guidance for patients with thrombotic conditions who are considering COVID-19 vaccination.

The influence of pharmacotherapy regimens on surgical patient outcomes is increasingly appreciated in the era of enhanced recovery protocols and institutional focus on reducing postoperative complications. Specifics related to medication selection, dosing, frequency of administration, and duration of therapy are evolving to optimize pharmacotherapeutic regimens for many enhanced recovery protocolized elements. This review provides a summary of recent pharmacotherapeutic strategies, including those configured within electronic health record (EHR) applications and functionalities, that are associated with the minimization of the frequency and severity of postoperative complications (POCs), shortened hospital length of stay (LOS), reduced readmission rates, and cost or revenue impacts. Further, it will highlight preventive pharmacotherapy regimens that are correlated with improved patient preparation, especially those related to surgical site infection (SSI), venous thromboembolism (VTE), nausea and vomiting (PONV), postoperative ileus (POI), and emergence delirium (PoD) as well as less commonly encountered POCs such as acute kidney injury (AKI) and atrial fibrillation (AF). The importance of interprofessional collaboration in all periprocedural phases, focusing on medication management through shared responsibilities for drug therapy outcomes, will be emphasized. Finally, examples of collaborative care through shared mental models of drug stewardship and non-medical practice agreements to improve operative throughput, reduce operative stress, and increase patient satisfaction are illustrated.

BACKGROUND:The American College of Chest Physicians Clinical Practice Guideline on the Perioperative Management of Antithrombotic Therapy addresses 43 Patients-Interventions-Comparators-Outcomes (PICO) questions related to the perioperative management of patients who are receiving long-term oral anticoagulant or antiplatelet therapy and require an elective surgery/procedure. This guideline is separated into four broad categories, encompassing the management of patients who are receiving: (1) a vitamin K antagonist (VKA), mainly warfarin; (2) if receiving a VKA, the use of perioperative heparin bridging, typically with a low-molecular-weight heparin; (3) a direct oral anticoagulant (DOAC); and (4) an antiplatelet drug.METHODS:Strong or conditional practice recommendations are generated based on high, moderate, low, and very low certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology for clinical practice guidelines.RESULTS:A multidisciplinary panel generated 44 guideline recommendations for the perioperative management of VKAs, heparin bridging, DOACs, and antiplatelet drugs, of which two are strong recommendations: (1) against the use of heparin bridging in patients with atrial fibrillation; and (2) continuation of VKA therapy in patients having a pacemaker or internal cardiac defibrillator implantation. There are separate recommendations on the perioperative management of patients who are undergoing minor procedures, comprising dental, dermatologic, ophthalmologic, pacemaker/internal cardiac defibrillator implantation, and GI (endoscopic) procedures.CONCLUSIONS:Substantial new evidence has emerged since the 2012 iteration of these guidelines, especially to inform best practices for the perioperative management of patients who are receiving a VKA and may require heparin bridging, for the perioperative management of patients who are receiving a DOAC, and for patients who are receiving one or more antiplatelet drugs. Despite this new knowledge, uncertainty remains as to best practices for the majority of perioperative management questions.

Background There are inadequate data on the optimal strategy for transitioning factor Xa inhibitors (FXai; apixaban, rivaroxaban) to unfractionated heparin (UFH) infusions. Objective In patients transitioning from an FXai to an UFH infusion, this study compared the safety and efficacy of monitoring UFH infusions using an activated partial thromboplastin time (aPTT) titration scale versus utilizing an UFH-calibrated anti-Xa titration scale aided by a novel institutional guideline. Methods A retrospective cohort analysis was conducted on adult patients transitioning from an FXai to an UFH infusion at 2 medical centers from June 1, 2018, to November 1, 2020. One institution utilized aPTT while the other institution primarily used UFH-calibrated anti-Xa. The primary endpoint was a composite of death, major bleeding, or new thrombosis during the hospitalization with a planned noninferiority analysis. Secondary outcomes were also collected including the amount and duration of UFH administered between cohorts. Results The incidence rate of the primary composite endpoint was 6.3% in the anti-Xa group and 11% in the aPTT group (P < 0.001 for noninferiority, P = 0.138 for superiority) meeting noninferiority criteria. No statistical differences were seen in new thrombosis, major bleeding, or any bleeding. Conclusion and Relevance This represents the first report of a comparison between aPTT versus anti-Xa monitoring in relation to clinical outcomes for patients transitioning from an FXai to an UFH infusion. A transition guideline primarily utilizing an UFH-calibrated anti-Xa assay appears to be a safe alternative to aPTT monitoring and can aid facilities in the management of patients during these complex transitions.

Background Literature suggests that 2 mg of vitamin K intravenously (IV) provides a similar effect as 10 mg to reverse warfarin. Doses <5 mg haven’t been studied in depth. Objective The objective was to determine the international normalized ratio (INR) reduction effect of ultra low-dose (ULD) IV vitamin K. Methods This retrospective, observational cohort study compared IV vitamin K doses of 0.25-0.5 mg (ULD) versus 1-2 mg (standard low dose [SLD]). The primary outcome assessed ΔINR at 36 hours; secondary outcomes assessed ΔINR at 12 hours and 30-day venous thromboembolism (VTE) and mortality rates. Results Of 88 patients identified (median baseline INR [IQR], 5.1 [3.1, 7.3] vs 4.5 [2.8, 8.2], ULD vs SLD, respectively), 59 had an INR at 12 hours. The ULD had fewer 12-hour INR values <2, with no statistical difference in the ΔINR at 12 hours between the ULD and SLD cohorts (median ΔINR, 2.2 [1.1, 3.4] vs 2.2 [1.1, 6.3]; P = 0.54; median INR, 2.3 vs 1.8). A total of 41 patients had both a 12- and 36-hour INR. No significant difference in the ΔINR between the 12- and 36-hour values occurred (median ΔINR, 0.52 [0.2, 0.91] vs ΔINR, 0.46 [0.18, 0.55]; P = 0.61), suggesting no rebound or excessive reversal and no difference in 30-day rates of VTE ( P > 0.99) or death ( P = 0.38). Conclusion and Relevance ULD IV vitamin K reversed INR similarly to doses of 1-2 mg without rebound. A ULD strategy may be considered in patients requiring more cautious reversal.

Purpose To determine a patient’s clinical course based on the use of an activated partial thromboplastin time (aPTT) or heparin anti-Xa assay when transitioning from rivaroxaban or apixaban to an unfractionated heparin infusion. Methods A retrospective chart review was conducted to investigate how unfractionated heparin infusions were managed at a tertiary care hospital in the setting of recent apixaban or rivaroxaban administration. Patients were separated into 2 cohorts based on the chosen heparin infusion monitoring assay: heparin anti-Xa or aPTT. The primary composite outcome was total number of bleeding and thrombotic events; the secondary composite outcome was average incidence of heparin infusion holds and rate changes per patient. Results Data were collected from 76 patients (heparin anti-Xa = 69, aPTT = 7). Due to the limited number of patients within the aPTT cohort, this data was excluded from the analysis, and heparin anti-Xa descriptive statistics were reported without statistical comparisons. In the heparin anti-Xa group, a total of 10 bleeds and 1 thrombus were discovered. Additionally, the average number of infusion holds and rate changes was 0.841 and 2.65 times per patient, respectively, for those patients monitored via heparin anti-Xa assay. Conclusion In the presence of a recently administered oral anti-Xa anticoagulant, more down-titrations occurred in the initial 6 hours of the heparin infusion when measuring anti-Xa activity, and most up-titrations occurred after 36 hours. Baseline heparin anti-Xa activity may be a useful tool to identify patients with residual plasma concentrations of apixaban and rivaroxaban to help better individualize heparin therapy.

The preferred assay for measuring and adjusting unfractionated heparin (UFH) infusion to achieve optimal outcomes during extracorporeal membrane oxygenation (ECMO) is not well established. This retrospective cohort study explored safety and efficacy outcome differences between anti-factor Xa (anti-Xa) and activated partial thromboplastin time (aPTT) for UFH in adult venoarterial ECMO. Forty-one patients were included and analyzed. The UFH rate at first goal and time to goal were both higher in the aPTT versus anti-Xa cohort but did not achieve statistical significance (12.14 vs. 9.58 unit/kg/hour (p = 0.29), 20.22 vs. 12.05 hours (p = 0.11)). The aPTT cohort was in target goals 35.0% of the time versus 47.7% in the anti-Xa cohort (p = 0.13), above goal 41.0% vs. 17.3% (p = 0.02), and below-goal 24.0% versus 35.0% of the time (p = 0.34). Minimum heparin rates in the aPTT cohort were 6.28 vs. 3.33 unit/kg/hour in the anti-Xa cohort (p = 0.07), and the maximum UFH rate was 18.77 unit/kg/hour vs. 15.48 unit/kg/hour (p = 0.10). Our findings suggest that aPTT monitoring may result in a delay to target attainment, higher UFH rates, and overall exposure.

Purpose. To determine a patient's clinical course based on the use of an activated partial thromboplastin time (aPTT) or heparin anti-Xa assay when transitioning from rivaroxaban or apixaban to an unfractionated heparin infusion. Methods. A retrospective chart review was conducted to investigate how unfractionated heparin infusions were managed at a tertiary care hospital in the setting of recent apixaban or rivaroxaban administration. Patients were separated into 2 cohorts based on the chosen heparin infusion monitoring assay: heparin anti-Xa or aPTT. The primary composite outcome was total number of bleeding and thrombotic events; the secondary composite outcome was average incidence of heparin infusion holds and rate changes per patient. Results. Data were collected from 76 patients (heparin anti-Xa = 69, aPTT = 7). Due to the limited number of patients within the aPTT cohort, this data was excluded from the analysis, and heparin anti-Xa descriptive statistics were reported without statistical comparisons. In the heparin anti-Xa group, a total of 10 bleeds and 1 thrombus were discovered. Additionally, the average number of infusion holds and rate changes was 0.841 and 2.65 times per patient, respectively, for those patients monitored via heparin anti-Xa assay. Conclusion. In the presence of a recently administered oral anti-Xa anticoagulant, more down-titrations occurred in the initial 6 hours of the heparin infusion when measuring anti-Xa activity, and most up-titrations occurred after 36 hours. Baseline heparin anti-Xa activity may be a useful tool to identify patients with residual plasma concentrations of apixaban and rivaroxaban to help better individualize heparin therapy.