Sedation Variability Increases Incidence of Delirium in Adult Medical Intensive Care Unit Patients at a Tertiary Academic Medical Center.

BACKGROUND: Variability in sedation may increase the incidence of delirium and mortality, as well as increased intensive care unit (ICU) and hospital lengths of stay (LOS), despite mean Richmond Agitation Sedation Scale (RASS) scores at goal. Coefficient of variation (CV) can be used to represent variability with a higher ratio indicating increased variability. STUDY QUESTION: Do patients with an increased variability in sedation, as evaluated by CV in RASS, have an increased incidence of delirium? METHODS: We conducted a retrospective chart review of adult medical ICU patients requiring mechanical ventilation (MV) for ≥24 hours between January and April 2013. Patients were excluded if intubated at an outside hospital, neuromuscularly blocked, suffering from anoxic brain injury, or had a goal RASS of -4 or -5. Outcomes assessed included the presence of delirium, as evaluated by the Confusion Assessment Method, RASS, CV in RASS, duration of MV, ICU, and hospital LOS, and survival. RESULTS: Of 45 included patients, 32 experienced delirium during their ICU admission and 13 did not. The groups were similar at baseline. There was no difference in mean RASS when comparing the delirium and nondelirium groups (-1.6 ± 1.3 vs. -1.8 ± 0.8, respectively; P = 0.61). Patients with delirium had a greater CV in RASS (0.3 ± 0.135 vs. 0.2 ± 0.105; P = 0.02), a longer MV duration [4 (2-8) vs. 3 (2-3) days; P = 0.045], and a trend toward increased ICU LOS [8 (5-12.25) vs. 4 (3-8) days; P = 0.096], but no difference in hospital LOS [13 (10-25) vs. 18 (9-39) days; P = 0.83] and survival (71.9% vs. 69.2%; P = 1.0). CONCLUSION: Medical ICU patients with delirium had a higher CV in RASS compared with patients without delirium, suggesting that greater variability in sedation may increase the incidence of delirium. Patients with delirium also had a greater duration of MV and a trend toward longer ICU LOS.

Implementation of a Prolonged Infusion Guideline for Time-Dependent Antimicrobial Agents at a Tertiary Academic Medical Center.

Administration of time-dependent beta-lactam antibiotic as a prolonged infusion may maximize the pharmacodynamic target of time above the minimum inhibitory concentration. We describe the implementation of a prolonged infusion at a tertiary academic medical center, and a 1-year compliance analysis with the guideline. After performing a thorough literature search, a guideline was developed by members of the Department of Infectious Diseases and Department of Pharmacy. Approval and endorsement of the guideline was obtained by the Antimicrobial Subcommittee and Pharmacy and Therapeutics Committee. Physical champions were instrumental in the implementation of the guideline institution-wide. We then performed a 1-year retrospective analysis of guideline compliance from January 1, 2011 to December 31, 2011. Noncompliant administrations were obtained from smart infusion pumps. The total number of doses administered was taken from pharmacy information resources. In total, nearly 85,000 time-dependent doses were administered. Compliance with the prolonged infusion guideline was 89%. Rates of compliance did not significantly differ between medications (P = 0.555). Obtaining support from key stakeholders in collateral services and institutional leadership was vital for the success of this guideline. Compliance with the guideline 1 year after implementation was high. Implementation of a prolonged infusion guideline is feasible with institutional support and motivation.

Treatment of heparin-induced thrombocytopenia before and after the implementation of a hemostatic and antithrombotic stewardship program.

In October 2013, we implemented a hemostatic and antithrombotic (HAT) stewardship program with the primary focus of ensuring appropriate use of intravenous direct thrombin inhibitors (DTI) in patients with heparin-induced thrombocytopenia (HIT). We sought to compare the duration and cost of DTI therapy for the management of HIT before and after implementation of the HAT stewardship program. Following institutional review board approval, we conducted a single center, retrospective chart review of all patients with a suspected diagnosis of HIT as assessed by an anti-heparin-PF4 enzyme-linked immunosorbent assay 6 months pre-HAT and post-HAT implementation. Patients were excluded if they were initiated on a DTI at an outside hospital, had a prior episode of HIT, or received mechanical circulatory support. Clinical characteristics, including demographics, comorbidities, medications, laboratory values, clinical and safety outcomes, length of stay, and mortality, were collected. A total of 592 patients were included; 333 patients were evaluated pre-HAT, while 259 patients were evaluated post-HAT. The mean duration of DTI treatment was significantly decreased in the post-HAT cohort (6.64 vs 5.17 days, p = 0.01), primarily driven by decreased duration of use for patients with suspected HIT (4.07 vs 2.86 days, p = 0.01). The HAT Stewardship program demonstrated a total decrease in annual costs associated with the diagnosis and management of HIT of $248,500. Our results indicate that the implementation of the HAT stewardship program had a significant impact on reducing the duration and costs of DTI therapy and the costs of laboratory evaluations in the management of HIT at our institution.

Evaluation of Warfarin Reversal with 4-Factor Prothrombin Complex Concentrate Compared to 3-Factor Prothrombin Complex Concentrate at a Tertiary Academic Medical Center.

BACKGROUND: The U.S. Food and Drug Administration recently approved a four-factor prothrombin complex concentrate (4-PCC) for warfarin reversal. The literature supporting its use over three-factor prothrombin complex concentrate (3-PCC) is limited. OBJECTIVE: Our objective was to retrospectively compare the efficacy of 3-PCC to 4-PCC in reversing warfarin in patients who were actively bleeding. METHODS: We conducted a single-center, retrospective cohort analysis of adult patients who received 3-PCC or 4-PCC for international normalized ratio (INR) reversal. Our study excluded patients not actively bleeding and not on warfarin. The main outcome was the percentage of patients who achieved warfarin reversal defined as INR ≤ 1.3 at first INR check post factor administration. We recorded baseline data including PCC dose, location of bleed, pre- and posttreatment INR, and time to INR reversal. RESULTS: We included a total of 53 patients. Intracranial hemorrhage was the most common site of bleeding (26 [74.3%] in 3-PCC vs. 12 [66.7%] in 4-PCC). The mean dose of 3-PCC was 25.5 units/kg, compared to 27.9 units/kg of 4-PCC. The mean baseline INR was 2.3 in the 3-PCC group and 3 in the 4-PCC group (p = 0.03), and the first posttreatment INRs were 1.4 and 1.2, respectively (p < 0.01). Warfarin reversal was achieved in 15 (42.9%) patients who received 3-PCC and 15 (83.3%) patients who received 4-PCC (p < 0.01). Faster time to INR reversal was noted in the 4-PCC group vs. the 3-PCC group (3.7 vs. 5 h, p = 0.48). CONCLUSION: A higher percentage of patients achieved warfarin reversal with 4-PCC compared to 3-PCC treatment. A prospective randomized control trial is necessary to confirm our results.

Direct Thrombin Inhibitor Resistance and Possible Mechanisms.

Objective: To report 3 cases in which doses of bivalirudin higher than commonly used in clinical practice were required in order to achieve therapeutic anticoagulation as monitored by the activated partial thromboplastin time (aPTT). Case Summary: The medical records of 3 patients who required large doses of bivalirudin to remain therapeutic were thoroughly reviewed. In all 3 patients, bivalirudin was initiated at a rate appropriate for the patients' renal function and titrated using a nurse-driven protocol with recommended dose adjustments based on aPTT. Indications for bivalirudin were anticoagulation in intra-aortic balloon pump, treatment of deep vein thrombosis, and heparin-induced thrombocytopenia with thrombosis. Target aPTT was achieved between 25.5 and 134 hours after initiation despite appropriate titration intervals per protocol. Discussion: Bivalirudin is a direct thrombin inhibitor frequently used off-label for the medical management of heparin-induced thrombocytopenia. It typically exhibits predictable, dose-dependent anticoagulation. Heparin-induced thrombocytopenia was suspected in 2 of the 3 cases and confirmed in 1. In all 3 patients, target aPTT was initially achieved with doses between 0.456 and 1.0 mg/kg/h after a median of 30.7 hours; up to 1.8 mg/kg/h was required to maintain therapeutic aPTT. In 2 of the cases, the international normalized ratio also increased unexpectedly upon achievement of therapeutic aPTT values. Conclusion: Direct thrombin inhibitors may be subject to resistance mechanisms similar to those previously described in patients receiving heparin. The anticoagulation status of these patients remains unknown.

Implementation of a Hemostatic and Antithrombotic Stewardship program.

Hemostatic and antithrombotic (HAT) agents are high risk, high cost products. They require close monitoring and dose titration to adequately treat or prevent thrombosis while avoiding bleeding events. Incorporating the principles of inpatient anticoagulation management service into a stewardship program not only improves outcomes and decreases cost, but also improves transitions of care, exposes gaps in therapy management, and leads to the development of institution specific protocols and guidelines. We implemented a HAT Stewardship to provide real time clinical surveillance and management of these agents in an effort to optimize appropriate use, decrease serious adverse events, and minimize costs. The stewardship is staffed daily by an interdisciplinary team comprised of a pharmacist, hematology attending, and medical director. The stewardship focuses on (1) management of heparin-induced thrombocytopenia (HIT), (2) management of patients with Hemophilia A/B with inhibitors and acquired Factor VIII deficiency due to inhibitors, (3) oversight of anticoagulation in patients on extracorporeal membrane oxygenation and (4) assistance with anticoagulation management for patients with mechanical cardiac assist devices. Through implementation of this service, we have been able to demonstrate improved patient care and a positive economic impact exceeding the cost of this program by almost sixfold. Other centers should consider instituting a HAT Stewardship to maximize patient outcomes and minimize adverse events.

Impact of Low-Dose Fluconazole on Tacrolimus Dosing in Renal Transplant.

BACKGROUND: The interaction between azole antifungal therapy and immunosuppressant tacrolimus (TAC) is a barrier to use. OBJECTIVE: This study quantified the drug interaction between low-dose fluconazole (LDF) and TAC to determine the appropriate TAC dose adjustment when used concurrently in renal transplant recipients. METHODS: We conducted a single-center retrospective chart review of renal transplant patients >18 years who received LDF or nystatin (NYS), and TAC. The primary outcome was the difference in tacrolimus total daily dose (TAC TDD) for LDF versus NYS groups. Secondary outcomes included days with supratherapeutic, therapeutic and subtherapeutic tacrolimus levels, time to therapeutic level, incidence of adverse drug reactions and graft rejection. RESULTS: We evaluated 94 patients and included 81. Low-dose fluconazole received a greater TAC TDD prior to post-operative day (POD) 10 (10.5 ± 4.7 mg vs. 7.1 ± 4.5 mg, p < 0.001), but a decreased TAC TDD POD 10 - 30 (8.6 ± 2.2 mg vs. 9.8 ± 0.8 mg, p < 0.001) and following LDF discontinuation (6.9 ± 0.1 mg vs. 9.0 ± 0.4 mg, p < 0.001). Low-dose fluconazole had more patient-days with supratherapeutic (17.9 ± 7.0 vs. 13.9 ± 8.5; p = 0.02) but fewer with subtherapeutic (6.7 ± 5.7 vs. 12.9 ± 7.2; p < 0.01) TAC levels. There was no difference in patient-days with therapeutic TAC levels (15.9 ± 5.8 vs. 14.4 ± 6.6, p = 0.28), meanwhile LDF required less patient-days to therapeutic TAC level (7.1 ± 2.7 vs. 11.5 ± 7.7; p < 0.01). There was no difference in adverse drug reactions between groups and no incidence of graft rejection. CONCLUSION: A 20% reduction in TAC TDD is warranted in renal transplant patients when used concomitantly with LDF to achieve therapeutic levels.

Evaluation of sedatives, analgesics, and neuromuscular blocking agents in adults receiving extracorporeal membrane oxygenation.

PURPOSE: The objective of this study was to evaluate the use of sedative, analgesic, and neuromuscular blocking agents (NMBAs) in patients undergoing extracorporeal membrane oxygenation (ECMO) support. MATERIALS AND METHODS: This was a 2-year, prospective, observational study of adult intensive care unit patients on ECMO support for more than 48hours. RESULTS: We analyzed 32 patients, including 15 receiving VA (venoarterial) ECMO and 17 VV (venovenous) ECMO. The median daily dose of benzodiazepines (midazolam equivalents) was 24mg, and the median daily dose of opioids (fentanyl equivalents) was 3875 µg. There was a moderate negative correlation between the day of ECMO and the median daily benzodiazepine dose (r=-0.5515) and a very weak negative correlation for the median daily opioid dose (r=-0.0053). On average, patients were sedated to Richmond Agitation Sedation Scale scores between 0 and -1. Continuous infusions of opioids, benzodiazepines, propofol, dexmedetomidine, and NMBAs were administered on 404 (85.1%), 199 (41.9%), 95 (20%), 32 (6.7%), and 60 (12.6%) ECMO days, respectively. Patients in the VA arm received a continuous infusion opioid (96.4% vs 81.6% days; P<.001) and benzodiazepine (58.2% vs 37.0% days; P<.001) more frequently. CONCLUSIONS: Patients received relatively low doses of sedatives and analgesics while at a light level of sedation on average. Patients rarely required neuromuscular blockade.

Levothyroxine Tablet Malabsorption Associated with Gastroparesis Corrected with Gelatin Capsule Formulation.

Treatment of hypothyroidism with levothyroxine sodium often requires multiple dose adjustments and can be complicated by patients with gastric and intestinal dysfunction that limits absorption. In these cases, doses are often titrated higher than commonly used in clinical practice. Multiple formulations of levothyroxine are currently available and some may be preferred in cases of malabsorption. We report a case of a 42-year-old female who presented with a living unrelated kidney transplant evaluation with myxedema while being treated with levothyroxine sodium tablets. She was noted to have gastroparesis secondary to Type I diabetes mellitus which may have contributed to levothyroxine malabsorption. Changing to a gelatin capsule formulation quickly corrected her thyroid function assays. This case suggests that gastroparesis may affect absorption of levothyroxine tablets and the gelatin capsules may be an effective alternative therapy.

Aminocaproic acid for the management of bleeding in patients on extracorporeal membrane oxygenation: Four adult case reports and a review of the literature.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is associated with a significant risk of bleeding and thrombosis. Despite high rates of bleeding and bleeding-related mortality in patients on ECMO, there is little evidence available to guide clinicians in the management of ECMO-associated bleeding. METHODS: We report the use of aminocaproic acid in four patients with bleeding on ECMO and a review of the literature. RESULTS: High D-dimer levels and low fibrinogen levels suggested that an antifibrinolytic agent may be effective as an adjunct to control bleeding. After aminocaproic acid administration, bleeding was controlled in each patient as evidenced by clinical and laboratory parameters. One patient suffered a cardiac arrest and care was withdrawn. CONCLUSIONS: In patients on ECMO with evidence of fibrinolysis, aminocaproic acid may be an effective option to control bleeding and to stabilize clot formation.

Pathophysiology, assessment, and management of pain in critically ill adults.

PURPOSE: The pathophysiology of pain in critically ill patients, the role of pain assessment in optimal pain management, and pharmacologic and nonpharmacologic strategies for pain prevention and treatment are reviewed. SUMMARY: There are many short- and long-term consequences of inadequately treated pain, including hyperglycemia, insulin resistance, an increased risk of infection, decreased patient comfort and satisfaction, and the development of chronic pain. Clinicians should have an understanding of the basic physiology of pain and the patient populations that are affected. Pain should be assessed using validated pain scales that are appropriate for the patient's communication status. Opioids are the cornerstone of pain treatment. The use of opioids, administered via bolus dosing or continuous infusion, should be guided by patient-specific goals of care in order to avoid adverse events. A multimodal approach to pain management, including the use of regional analgesia, may improve patient outcomes and decrease opioid-related adverse events, though there are limited relevant data in adult critically ill patient populations. Nonpharmacologic strategies have been shown to be effective adjuncts to pharmacologic regimens that can improve patient-reported pain intensity and reduce analgesic requirements. Analgesic regimens need to take into account patient-specific factors and be closely monitored for safety and efficacy. CONCLUSION: Acute pain management in the critically ill is a largely underassessed and undertreated area of critical care. Opioids are the cornerstone of treatment, though a multimodal approach may improve patient outcomes and decrease opioid-related adverse events.

Early vasopressin reduces incidence of new onset arrhythmias.

PURPOSE: The objective of this study was to determine the effect of early vs late vasopressin therapy on catecholamine dose and duration. MATERIALS AND METHODS: We conducted a single-center, retrospective chart review of adult patients admitted to the medical intensive care unit between January 2010 and December 2011 with septic shock requiring catecholamine and vasopressin therapy. Patients were included in the early group if vasopressin was initiated within 6 hours and the late group if vasopressin was initiated between 6 and 48 hours of catecholamine(s). RESULTS: Duration of catecholamine and vasopressin therapy was similar between the 35 patients in the early group and the 36 in the late group. Vasopressin therapy was associated with a decrease in catecholamine requirements in both groups. Early vasopressin was associated with fewer new onset arrhythmias (37.1% vs 62.9%, P<.001). There was no difference in mortality, hospital, or intensive care unit length of stay between the early and late group vasopressin groups (88.6% vs 88.9%, P=1; 14 vs 10 days, P=.48; 9 vs 7 days, P=.71, respectively). CONCLUSIONS: Early initiation of vasopressin therapy in adult critically ill patients with septic shock was associated with no difference in total catecholamine requirements but decreased incidence of new onset arrhythmias.

Role of dexmedetomidine in adults in the intensive care unit: an update.

PURPOSE: The role of dexmedetomidine for the management of pain, agitation, and delirium in adult patients in the intensive care unit (ICU) is reviewed and updated. SUMMARY: Searches of MEDLINE (July 2006-March 2012) and an extensive manual review of journals were performed. Relevant literature with a focus on data published since our last review in 2007 was evaluated for topic relevance and clinical applicability. Optimal management of pain, agitation, and delirium in ICUs requires a systematic and multimodal approach aimed at providing comfort while maximizing outcomes. Dexmedetomidine is among multiple agents, including opioids, propofol, benzodiazepines, and antipsychotics, used to facilitate and increase patients' tolerability of mechanical ventilation. This article reviews the newest evidence available for dexmedetomidine use for sedation and analgesia in medical-surgical ICUs. Adverse effects associated with dexmedetomidine were similar among the studies examined herein. The most common adverse effects with dexmedetomidine were bradycardia and hypotension, in some cases severe enough to warrant the use of vasoactive support. Due to the adverse events associated with rapid dosage adjustment and bolus therapy, dexmedetomidine may not be the best agent for treating acute agitation. CONCLUSION: In medical-surgical ICUs, dexmedetomidine may be a viable non-benzodiazepine option for patients with a need for light sedation. In cardiac surgery patients, dexmedetomidine appears to offer no advantage over propofol as the initial sedative. The role of dexmedetomidine in unique patient populations such as neurosurgical, trauma, and obstetrics is yet to be established.