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Fluid resuscitation, to restore intravascular volume and improve oxygen delivery, is a crucial step in early resuscitation efforts of patients with sepsis or septic shock. The 2016 Surviving Sepsis Campaign guidelines suggest the use of dynamic versus static measures of fluid responsiveness and fluid resuscitation with at least 30 mL/kg of intravenous crystalloid within the first 3 hours followed by fluid administration if hemodynamic factors continue to improve. Despite these recommendations, risks to this practice may exist as multiple studies have demonstrated an association between a positive fluid balance and/or administration of large fluid volume and increase in mortality. These studies are limited by variations in their methodologic design; therefore, cause and effect cannot yet be determined. Future multicenter, randomized, controlled studies that evaluate fluid balance and fluid volume need to be conducted to clarify the role of fluid administration to patients with sepsis to maximize benefits and minimize risk.

Ketamine is being prescribed with greater frequency due to an emphasis on multimodal analgesia. With increasing use, uncommon adverse effects associated with ketamine are likely to surface. Limited reports of transient central diabetes insipidus (DI) occurring early after initiation (ie, within 10 hours) of ketamine have been reported. We present 2 cases of delayed onset (32 hours or more after initiation), ketamine-induced, transient central DI in patients cannulated for venovenous extracorporeal membranous oxygenation. No other causes of central DI were determined based upon physical examination or laboratory data, and both patients responded to treatment with desmopressin/vasopressin. The Naranjo adverse drug reaction probability scale noted a probable causation for each case. These cases demonstrate the possibility of a rare but serious complication of ketamine. Improvement after discontinuation of ketamine and administration of desmopressin/vasopressin appear to support a drug–effect association.

Dual antiplatelet therapy (DAPT) is the key for secondary prevention of acute coronary syndromes and percutaneous coronary intervention with stent placement. Premature discontinuation of DAPT can result in an increase in cardiac ischemic events and death. If early interruption of DAPT for urgent procedures or surgery is necessary, then ischemic and bleed risks must be balanced with bridging therapy. To date, no medications have a Food and Drug Administration indication for antiplatelet bridge therapy. We present a case of a woman with a history of gastrointestinal bleeding on DAPT for a drug-eluting stent who received cangrelor as bridge therapy prior to gastroduodenal biopsy.

Objective: To report a case of high on-treatment platelet reactivity (HTPR) with prasugrel maintenance therapy despite adequate initial platelet response to a loading dose. Case Summary: A 51-year-old woman presented to the emergency department complaining of chest pain. She was diagnosed with acute-on-chronic systolic heart failure and non-ST-elevated myocardial infarction (MI). She had a previous MI with bare metal stent placement and was taking aspirin and prasugrel 10 mg daily. Once admitted, a P2Y12 assay revealed HTPR (331 PRU); therefore, prasugrel was reloaded (60 mg). The next day a P2Y12 assay showed adequate platelet reactivity inhibition (118 PRU), so prasugrel 10 mg daily was continued in the hospital and on discharge. Seventeen days after discharge she was readmitted for possible ischemia. On day 3 of admission, a P2Y12 assay revealed HTPR (278 PRU); subsequently, prasugrel was discontinued and ticagrelor started. After 3 doses of ticagrelor, a P2Y12 assay was 97 PRU, so ticagrelor was continued. Five months have passed since discharge. The patient continues to take ticagrelor and has had no further cardiac events. Discussion: HTPR indicates hypo- or nonresponsiveness for antiplatelet agents and may result in serious adverse events. HTPR has rarely been reported with prasugrel or ticagrelor. An objective causality assessment of our case revealed a probable association between HTPR and prasugrel. Conclusion: Patient education and recognition of signs and symptoms associated with prasugrel HTPR may prevent morbidity and mortality from treatment failure. Additional research may determine incidence, risk factors, and optimal management of HTPR with prasugrel.

To review published literature regarding the effectiveness of angiotensin-converting enzyme (ACE) inhibitors for managing intermittent claudication (IC) associated with peripheral arterial disease (PAD).A search of MEDLINE/PubMed (1966-July 2013) using the MeSH terms intermittent claudication and angiotensin-converting enzyme inhibitors was conducted. Limits included articles written in English with human participants. Additional data were identified through bibliographic reviews.All English-language articles identified from the data sources were evaluated. Clinical trials and meta-analyses were included if they evaluated the efficacy of ACE inhibitors for improving functional capacity of patients with PAD with IC. In all, 9 clinical trials and 1 meta-analysis were identified and included for review. ACE inhibitors evaluated in the studies were captopril, lisinopril, perindopril, quinapril, and ramipril.Current medications approved for treating the symptoms and improving function in PAD with IC have limited efficacy. It has been suggested that ACE inhibitors may be effective in PAD with IC. Though data evaluating ACE inhibitors as a class in this patient population are conflicting, results of the largest and longest trial reported that ramipril increases maximum walking time and pain-free walking time and improves quality of life in patients with PAD with IC.ACE inhibitors may provide some relief of IC symptoms when used in patients with PAD. The greatest functional benefit has been seen with ramipril; it is unknown whether other agents in the class would show similar results. Well-controlled and designed studies with sufficient power and using diverse patient populations are needed.

Control of ventricular rate is recommended for patients with paroxysmal, persistent, or permanent atrial fibrillation (AF). Existing rate-control options, including beta-blockers, nondihydropyridine calcium channel blockers, and digoxin, are limited by adverse hemodynamic effects and their ability to attain target heart rate (HR). Ivabradine, a novel HR-controlling agent, decreases HR through deceleration of conduction through If (‘funny’) channels, and is approved for HR reduction in heart failure patients with ejection fraction less than 35% and elevated HR, despite optimal pharmacological treatment. Because If channels were thought to be expressed solely in sinoatrial (SA) nodal tissue, ivabradine was not investigated in heart failure patients with concomitant AF. Subsequent identification of hyperpolarization-activated cyclic nucleotide-gated cation channel 4 (HCN4), the primary gene responsible for If current expression throughout the myocardium, stimulated interest in the potential role of ivabradine for ventricular rate control in AF. Preclinical studies of ivabradine in animal models with induced AF demonstrated a reduction in HR, with no significant worsening of QT interval or mean arterial pressure. Preliminary human data suggest that ivabradine provides HR reduction without associated hemodynamic complications in patients with AF. Questions remain regarding efficacy, safety, optimal dosing, and length of therapy in these patients. Prospective, randomized studies are needed to determine if ivabradine has a role as a rate-control treatment in patients with AF.

Dual antiplatelet therapy (DAPT) is the key for secondary prevention of acute coronary syndromes and percutaneous coronary intervention with stent placement. Premature discontinuation of DAPT can result in an increase in cardiac ischemic events and death. If early interruption of DAPT for urgent procedures or surgery is necessary, then ischemic and bleed risks must be balanced with bridging therapy. To date, no medications have a Food and Drug Administration indication for antiplatelet bridge therapy. We present a case of a woman with a history of gastrointestinal bleeding on DAPT for a drug-eluting stent who received cangrelor as bridge therapy prior to gastroduodenal biopsy.

Objective To provide a comprehensive review of the pharmacotherapy associated with the provision of mechanical circulatory support (MCS) to patients with end-stage heart failure and guidance regarding the selection, assessment, and optimization of drug therapy for this population. Data Sources: The MEDLINE/PubMed, EMBASE, and Cochrane databases were searched from 1960 to July 2010 for articles published in English using the search terms mechanical circulatory support, ventricular assist system, ventricular assist device, left ventricular assist device, right ventricular assist device, biventricular assist device, total artificial heart, pulsatile, positive displacement, axial, centrifugal, hemostasis, bleeding, hemodynamic, blood pressure, thrombosis, antithrombotic therapy, anticoagulant, antiplatelet, right ventricular failure, ventricular arrhythmia, anemia, arteriovenous malformation, stroke, infection, and clinical pharmacist. Study Selection And Data Extraction: All relevant original studies, metaanalyses, systematic reviews, guidelines, and reviews were assessed for inclusion. References from pertinent articles were examined for content not found during the initial search. Data Synthesis: MCS has advanced significantly since the first left ventricular assist device was implanted in 1966. Further advancements in MCS technology that occurred in the tatter decade are changing the overall management of end-stage heart failure care and cardiac transplantation. These pumps allow for improved bridge-to-transplant rates, enhanced survival, and quality of life. Pharmacotherapy associated with MCS devices may optimize the performance of the pumps and improve patient outcomes, as well as minimize morbidity related to their adverse effects. This review highlights the knowledge needed to provide appropriate clinical pharmacy services for patients supported by MCS devices. Conclusions: The HeartMate II clinical investigators called for the involvement of pharmacists in MCS patient assessment and optimization. Pharmacotherapeutic management of patients supported with MCS devices requires individualized care, with pharmacists as part of the team, based on the characteristics of each pump and recipient.

Objectives To describe the appropriateness and safety of induction immunosuppression for patients at risk for fatal rejection, and to describe the safety and effectiveness profiles of the induction regimens available in the United States. Data Sources MEDLINE/PubMed database, EMBASE database, Google Scholar; references from pertinent articles were also reviewed to identify additional data. Study Selection A systematic literature review from January 1, 1980, through June 30, 2008, was performed. Included articles ranged from case series to prospective randomized controlled double-blind placebo-controlled trials that detailed the following topics with respect to induction immunosuppression: risk of fatal rejection, renal sparing, malignancy, OKT3, rabbit or equine antithymocyte globulin, daclizumab, basiliximab, and alemtuzumab. Results Patients at highest risk for fatal rejection experienced a survival benefit from induction immunosuppression, whereas all other patients experienced no benefit or harm. Most of the early data detail positive experiences with polyclonal antibody regimens. Several newer trials compare the use of polyclonal strategies with the use of anti-CD25 targeted monoclonal antibodies. Few researchers have assessed the usefulness of an anti-CD52 approach. Overall, induction therapy remains a poorly studied and widely variable practice among the major US heart transplant centers. Conclusion At present, the unrestricted use of induction for all patients does not seem prudent. Induction should be individualized for each patient on the basis of a well-designed protocol, careful analysis of the transplant center's demographics, and the effectiveness and safety profiles of the regimens used.

The temporary total artificial heart (TAH-t) has emerged as an effective bridge to transplantation for individuals with biventricular failure. Implantation of a TAH-t creates a hypercoagulable state requiring a multidrug approach that includes low-dose unfractionated heparin (UFH) in order to minimize thromboembolism. A concern with UFH is the development of heparin-dependent antibodies, which develop in up to 50% of patients receiving the drug as part of cardiopulmonary bypass. If UFH therapy continues postoperatively, the risk of heparin-induced thrombocytopenia approaches 3%. Small investigations have demonstrated that bivalirudin, given as a bolus of 0.75-1 mg/kg followed by an infusion at 1.75-2.5 mg/kg/hour, is an effective alternative to UFH for therapeutic anticoagulation during coronary artery bypass surgery, valve replacement, or both. We describe a series of five adults (age range 24-58 yrs) who received bivalirudin as an alternative to low-dose UFH after TAH-t implantation. None of the patients had documented heparin-induced thrombocytopenia. Treatment was started at the discretion of the treating physician, and adjustments were based principally on the results of thromboelastography. Additional general monitoring included activated partial thromboplastin time, prothrombin time, international normalized ratio, fibrinogen, D-dimer, platelet count, hemoglobin, hematocrit, and platelet aggregation studies. Bivalirudin therapy was continued until successful warfarin implementation. All five patients received bivalirudin in addition to standard antithrombotic therapy. Bivalirudin treatment started at a dosage of 0.005 or 0.01 mg/kg/hour with titration to maintain normocoagulability, which occurred (without concomitant warfarin therapy) within the dosage range of 0.01-0.02 mg/kg/hour. Duration of TAH-t implantation was a mean of 38.8 days (range 25-60 days), and bivalirudin was continued for a mean of 15.2 days (range 7-24 days). No major hemorrhagic events occurred during treatment, and all patients successfully transitioned to warfarin therapy. Low-dose bivalirudin, as an alternative to UFH, maintained normocoagulability after TAH-t implantation. Further investigation is warranted to define the role and dosing of bivalirudin in this situation.

Background The purpose of this study was to examine: (a) the extent to which patients report having used conventional and nonconventional treatments for osteoarthritis in family medicine settings and (b) how patient characteristics are related to the use of these treatments. Methods A survey was sent to 2,178 patients with arthritis. The current analysis focuses on the 557 patients with osteoarthritis. Multivariable logistic regression was used to analyze the data. Results Sixty-three percent of patients reported the use of conventional and unconventional therapies. White patients and patients experiencing greater pain were more likely to report the use of conventional therapies. Female, married, and more educated patients, and persons reporting more pain and greater difficulty sleeping were significantly more likely to report the use of nonconventional therapies. Conclusion Providers should make sure to ask patients about all treatments they are using for their osteoarthritis.

Left ventricular support devices (LVADs) are associated with a propensity toward gastrointestinal bleeding. A postulated mechanism is related to gastrointestinal arteriovenous malformations secondary to nonpulsatile flow. We describe a case of LVAD-related, gastrointestinal bleeding successfully treated with a combination of subcutaneous and intramuscular depot formulations of octreotide.

Objective To review available evidence about the safety and efficacy of alemtuzumab for induction of immunosuppression in heart transplant recipients. Data sources Searches of MEDLINE, EMBASE, and Cochrane databases were conducted. Key search terms included alemtuzumab, Campath-1H, CD52, lymphocyte, cytolytic, induction, immunosuppression, rejection, and cardiac transplantation. Additional pertinent data were identified through a search of abstracts from major transplant meetings. Study Selection and Data Extraction All English-language articles and abstracts identified from the data sources were evaluated. All primary data were eligible for inclusion if they evaluated the safety or efficacy of alemtuzumab for induction of immunosuppression in heart transplant patients. One retrospective cohort, 1 case series, 1 case-control series, and 1 open-label trial were identified and included for review. Data Synthesis Acute cellular rejection occurs in 40% to 70% of heart transplant recipients within the first 6 months after transplant and is associated with significant morbidity and mortality. Depleting and nondepleting antibodies have displayed positive outcomes in inducing immunosuppression; however, the ideal induction strategy that balances efficacy and toxicity remains elusive. Alemtuzumab, a cytolytic anti-CD52 antibody, has been used to induce immunosuppression in kidney, pancreas, liver, intestine, and lung transplant recipients, and its use in heart transplant has been investigated. Studies of use of alemtuzumab to induce immunosuppression in heart transplant patients have shown low rates of rejection; however, it has not been directly compared with other immunosuppression-inducing agents and safety data are limited. Conclusions Although alemtuzumab may be a practical option for inducing immunosuppression, data are insufficient to recommend its routine use in deference to more established agents. Large, randomized clinical trials with extended durations of follow-up must be conducted to characterize its efficacy and safety further.

Objective: To review published literature regarding the safety and effectiveness of intrapericardial triamcinolone for the treatment of autoreactive pericarditis. Data Sources: Searches of MEDLINE (1966–June 2010) and Cochrane Database (1993–June 2010) were conducted. Limits included articles published in English reporting on human subjects. Additional data were identified through bibliographic reviews. Study Selection and Data Extraction: All English-language articles identified from the data sources were evaluated. Trials, studies, and case reports were eligible for inclusion if they evaluated the safety and/or efficacy of intrapericardial triamcinolone for the management of autoreactive pericarditis. Data Synthesis: Systemic corticosteroids offer an effective treatment option for autoreactive pericarditis; however, their use is limited by adverse effects and they are an independent risk factor for pericarditis recurrence. One case series and 3 open-label trials evaluating intrapericardial triamcinolone for the management of autoreactive pericarditis are reviewed. Included studies were limited by small sample sizes (N = 2–84), lack of control groups, short durations of follow-up (24 h to 12 mo), use of adjuvant agents, omission of patient demographic data, subjective report of symptom relief, and lack of consistent dose of intrapericardial triamcinolone. Despite these limitations, the data suggest symptom resolution and reduced pericarditis recurrence with administration of intrapericardial triamcinolone to patients with autoreactive pericarditis. Conclusions: There is growing evidence that intrapericardial triamcinolone is safe and effective for the management of autoreactive pericarditis. The appropriate regimen (dose and duration of treatment), adverse effect profile, and specific therapeutic role require further investigation.

The CardioWest temporary total artificial heart serves as a viable bridge to orthotopic heart transplantation in patients who are experiencing end-stage refractory biventricular heart failure. This device is associated with a low, albeit still substantial, risk of thrombosis. Platelet interactions with artificial surfaces are complex and result in continuous activation of contact proteins despite therapeutic anticoagulation. We searched the medical literature (publication dates, January 1962-October 2009) in order to evaluate means of mitigating adverse events that have occurred after implantation of the CardioWest temporary total artificial heart.We conclude that the use of a multitargeted antithrombotic approach, involving anticoagulation (bivalirudin and warfarin) and antiplatelet therapy (dipyridamole and aspirin), can mitigate the procoagulative effects of mechanical circulatory assist devices, particularly those that are associated with the CardioWest temporary total artificial heart. Careful monitoring with use of a variant multisystem approach, involving efficacy tests (thrombelastography and light transmittance aggregometry), safety tests (laboratory analyses), and warfarin genomics, may maximize the therapeutic actions and minimize the bleeding risks that are associated with the multitargeted antithrombotic approach. The development and monitoring of individualized antithrombotic regimens require that informed health professionals appreciate the complexities and grasp the hazards that are associated with these therapies.

Objective To review the literature regarding the efficacy of genetic testing for determining the appropriate initial dose of warfarin and the effect that this testing has on the safety and efficacy of therapy. Data Sources: Searches of MEDLINE (1966–May 2008) and Cochrane Database (1993–May 2008) were conducted using the search terms warfarin, anticoagulation, pharmacogenomics, pharmacogenetics, CYP2C9, VKORC1, and interindividual variability. Limits included articles written in English with human subjects. Additional data were identified through bibliographic reviews. Study Selection And Data Extraction: All English-language articles identified from the data sources were evaluated. Studies were eligible for inclusion if they evaluated the efficacy of pharmacogenomic testing to improve outcomes with initiation of warfarin therapy. Data Synthesis: The use of warfarin presents numerous challenges in clinical practice. Four studies (N = 38, 48, 200, 297) evaluating the efficacy of genetic testing for determining the initial dose of warfarin therapy have been published. Results show that time to therapeutic international normalized ratio (INR) and time to stable warfarin dose are similar regardless of genotype. When conventional warfarin dosing was compared with pharmacogenomic-based dosing, no significant difference was seen between groups in terms of time spent within the target INR range (41.5% vs 41.7%; no p value reported). Similar results were found in a subsequent study in which patients receiving conventional dosing were outside their target INR range 33.1% of the time compared with 30.7% of the lime for patients whose dose was guided by pharmacogenomics (p = 0.47). Conclusions: There is growing evidence that variant alleles for CYP2C9 and VKORC1 genotypes account for a proportion of the variability seen in warfarin dosing. The currently available literature related to the use of pharmacogenomic testing in the initiation of warfarin therapy does not show improved outcomes in either safety or efficacy with warfarin therapy and therefore does not support the routine use of pharmacogenomic testing when initiating warfarin therapy.

Objective: To review the published literature regarding the effectiveness or preprocedural statin therapy for the prevention of cardiac events after percutaneous coronary intervention (PCI). Data Sources: Searches of MEDLINE (1966–May 2007) and Cochrane Database (1993–May 2007) were conducted using the search terms statins, HMG-CoA reductase inhibitors, percutaneous coronary intervention, and myocardial necrosis. Limits included articles written in English with human subjects. Additional data were identified through bibliographic reviews. Study Selection and Data Extraction: All English-language articles identified from the data sources were evaluated. Trials and studies were eligible for Inclusion if they evaluated the effectiveness of preprocedural statin therapy for the prevention of cardiac events after PCI. Data Synthesis: Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) provide benefits relative to morbidity and mortality as primary and secondary prevention of cardiovascular events. In addition to lowering concentrations of low-density lipoprotein cholesterol, statins have documented pleiotropic effects including plaque stabilization as well as reductions in inflammation, platelet activation/adhesion, thrombosis, and oxidative stress. One retrospective analysis, 4 prospective observational studies, and 3 randomized controlled trials evaluating preprocedural statin therapy for the prevention of cardiac events after PCI were reviewed. Included studies were limited by small sample sizes (N = 153–5052), short durations of follow-up (24 h-21 mo), use of surrogate markers of myocardial necrosis, various degrees of coronary disease and procedure-specific factors, and lack of consistent choice of agent, dose, and duration of statin therapy. Despite these limitations, the data suggest reduced post-PCI myocardial necrosis with preprocedural statin therapy when given before elective PCI in stable patients, as well as when given before PCI in patients with recent acute coronary syndrome. Conclusions: There is growing evidence that preprocedural statin therapy reduces the incidence of post-PCI myocardial necrosis. The appropriate regimen (drug, dose, duration of treatment before the procedure), as well as the predictive role of concomitant disease states (eg, hyperiipidemia), requires further Investigation.

Objective: To review published literature evaluating the effectiveness of mycophenolate mofetil for the treatment of myasthenia gravis (MG). Data Sources: Searches of MEDLINE (1966–August 2005) and Cochrane Database (1993–August 2005) were conducted. Studies conducted in humans and published in English were retrieved. Additional data were identified through subsequent bibliographic reviews. Data Synthesis: Interruption of T- and B-lymphocyte proliferation in various autoimmune diseases has been investigated. Mycophenolate is known to inhibit lymphocyte proliferation and has shown improved clinical responses in several autoimmune diseases including lupus erythematosus, rheumatoid arthritis, and systemic vasculitis. Data suggesting similar benefits in MG treatment have been reported in case reports, retrospective analyses, an open-label trial, and a randomized, double-blind trial. Conclusions: Limited evidence from retrospective analyses and clinical trials suggests that mycophenolate is a possible treatment option for patients with MG. Improvement in clinical symptoms and a steroid-sparing effect have been reported when mycophenolate is used in this patient population. Larger, randomized, controlled, and comparative trials are needed to establish optimal dose, time to effect, specific therapeutic role, and long-term safety for mycophenolate when used for treating MG.