Current Practices of Intraventricular Antibiotic Therapy in the Treatment of Meningitis and Ventriculitis: Results from a Multicenter Retrospective Cohort Study.

BACKGROUND: Central nervous system (CNS) infections are particularly prevalent in the adult neurocritical care patient population and are associated with significant morbidity and mortality. Factors relevant to the nature of CNS infections pose significant challenges to clinicians treating afflicted patients. Intraventricular (IVT) administration of antibiotics may offer several benefits over systemic therapy; however, the outcomes and current practices of such treatments are poorly described in the literature. OBJECTIVE: To describe current practices and outcomes of patients receiving intraventricular antibiotic treatment for CNS infections in neurological intensive care units of academic medical centers nationwide. METHODS: A retrospective cohort study was conducted on patients admitted to intensive care units who received IVT antibiotic treatment at participating centers in the USA between January 01, 2003, and December 31, 2013. Clinical and laboratory parameters, microbiology, surgical and antimicrobial management, and treatment outcomes were collected and described. RESULTS: Of the 105 patients included, all received systemic antimicrobial therapy along with at least one dose of IVT antimicrobial agents. Intraventricular vancomycin was used in 52.4% of patients. The average dose was 12.2 mg/day for a median duration of 5 days. Intraventricular aminoglycosides were used in 47.5% of the patients, either alone or in combination with IVT vancomycin. The average dose of gentamicin/tobramycin was 6.7 mg/day with a median duration of 6 days. Overall mortality was 18.1%. Cerebrospinal fluid (CSF) culture sterilization occurred in 88.4% of the patients with a rate of recurrence or persistence of positive cultures of 9.5%. CONCLUSION: Intraventricular antimicrobial agents resulted in a high CSF sterilization rate. Contemporary use of this route typically results in a treatment duration of less than a week. Prospective studies are needed to establish the optimal patient population, as well as the efficacy and safety of this route of administration.

Antiepileptic drugs in critically ill patients.

BACKGROUND: The incidence of seizures in intensive care units ranges from 3.3% to 34%. It is therefore often necessary to initiate or continue anticonvulsant drugs in this setting. When a new anticonvulsant is initiated, drug factors, such as onset of action and side effects, and patient factors, such as age, renal, and hepatic function, should be taken into account. It is important to note that the altered physiology of critically ill patients as well as pharmacological and nonpharmacological interventions such as renal replacement therapy, extracorporeal membrane oxygenation, and target temperature management may lead to therapeutic failure or toxicity. This may be even more challenging with the availability of newer antiepileptics where the evidence for their use in critically ill patients is limited. MAIN BODY: This article reviews the pharmacokinetics and pharmacodynamics of antiepileptics as well as application of these principles when dosing antiepileptics and monitoring serum levels in critically ill patients. The selection of the most appropriate anticonvulsant to treat seizure and status epileptics as well as the prophylactic use of these agents in this setting are also discussed. Drug-drug interactions and the effect of nonpharmacological interventions such as renal replacement therapy, plasma exchange, and extracorporeal membrane oxygenation on anticonvulsant removal are also included. CONCLUSION: Optimal management of antiepileptic drugs in the intensive care unit is challenging given altered physiology, polypharmacy, and nonpharmacological interventions, and requires a multidisciplinary approach where appropriate and timely assessment, diagnosis, treatment, and monitoring plans are in place.

Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage: A Statement for Healthcare Professionals from the Neurocritical Care Society and Society of Critical Care Medicine.

BACKGROUND: The use of antithrombotic agents, including anticoagulants, antiplatelet agents, and thrombolytics has increased over the last decade and is expected to continue to rise. Although antithrombotic-associated intracranial hemorrhage can be devastating, rapid reversal of coagulopathy may help limit hematoma expansion and improve outcomes. METHODS: The Neurocritical Care Society, in conjunction with the Society of Critical Care Medicine, organized an international, multi-institutional committee with expertise in neurocritical care, neurology, neurosurgery, stroke, hematology, hemato-pathology, emergency medicine, pharmacy, nursing, and guideline development to evaluate the literature and develop an evidence-based practice guideline. Formalized literature searches were conducted, and studies meeting the criteria established by the committee were evaluated. RESULTS: Utilizing the GRADE methodology, the committee developed recommendations for reversal of vitamin K antagonists, direct factor Xa antagonists, direct thrombin inhibitors, unfractionated heparin, low-molecular weight heparin, heparinoids, pentasaccharides, thrombolytics, and antiplatelet agents in the setting of intracranial hemorrhage. CONCLUSIONS: This guideline provides timely, evidence-based reversal strategies to assist practitioners in the care of patients with antithrombotic-associated intracranial hemorrhage.

Survey of transplant-related pharmacy services at large comprehensive transplant centers in the United States.

CONTEXT: United Network for Organ Sharing (UNOS) 2011 bylaws and Centers for Medicare and Medicaid Services (CMS) regulations require a transplant pharmacist to be an active participant in the care of transplant patients. Transplant centers must be members in good standing with UNOS in order to perform transplants and must be certified by CMS to participate with Medicare. OBJECTIVE: To identify characteristics of transplant-related pharmacy services at comprehensive transplant centers. DESIGN: Survey regarding number of full-time equivalent (FTE) transplant pharmacists relative to number of annual transplants, transplant pharmacy model, roles in inpatient and clinic environments, training and specialization, funding sources, and expansion plans.Participants-Surveys were received from 14 (74%) of 19 identified centers that performed 200 to 400 kidney, liver, pancreas, simultaneous kidney/pancreas, heart, and lung transplants in 2010, representing 55 transplant pharmacists. RESULTS: A mean of 325 transplants were performed in 2010 at the surveyed centers. The mean number of pharmacist FTEs was 4.25, which yielded a transplant-to-pharmacist ratio of 76.5. Nine centers (64%) practiced in a pharmacy specialist-only model, 12 (86%) practiced in a service-based fashion, and 10 (71%) saw patients in clinic. Fifty-four pharmacists (98%) had obtained a PharmD degree, 45 (82%) had completed 1 postgraduate year, and 28 (51%) had completed 2 postgraduate years of training. Nine centers (64%) funded FTEs solely through the pharmacy department. Ten centers (71%) plan to expand transplant pharmacist staff by a mean of 1.4 FTEs. CONCLUSIONS: Large comprehensive transplant centers use multiple transplant pharmacists to perform patient care in the inpatient and outpatient environments. Most centers plan to expand FTEs. Further characterization of transplant pharmacists appears warranted.

Validity and reliability of The Johns Hopkins Adapted Cognitive Exam for critically ill patients.

OBJECTIVE: To validate The Johns Hopkins Adapted Cognitive Exam designed to assess and quantify cognition in critically ill patients. DESIGN: Prospective cohort study. SETTING: Neurosciences, surgical, and medical intensive care units at The Johns Hopkins Hospital. PATIENTS: One hundred six adult critically ill patients. INTERVENTIONS: One expert neurologic assessment and four measurements of the Adapted Cognitive Exam (all patients). Four measurements of the Folstein Mini-Mental State Examination in nonintubated patients only. Adapted Cognitive Exam and Mini-Mental State Examination were performed by 76 different raters. MEASUREMENTS AND MAIN RESULTS: One hundred six patients were assessed, 46 intubated and 60 nonintubated, resulting in 424 Adapted Cognitive Exam and 240 Mini-Mental State Examination measurements. Criterion validity was assessed by comparing Adapted Cognitive Exam with a neurointensivist's assessment of cognitive status (ρ = 0.83, p < .001). Ordinal logistic regression established optimal predicted cut points for cognitive status classification (≤ 28 = severely impaired, 29-55 = moderately impaired, ≥ 56 = mildly impaired or normal). Using these cut points, the Adapted Cognitive Exam appropriately classified cognitive status 90% of the time. Construct validity was assessed by comparing Adapted Cognitive Exam with Mini-Mental State Examination in nonintubated patients (ρ = 0.81, p < .001). Face validity was assessed by surveying raters who used both the Adapted Cognitive Exam and Mini-Mental State Examination and indicated the Adapted Cognitive Exam was an accurate reflection of the patient's cognitive status, more sensitive a marker of cognition than the Mini-Mental State Examination, and easy to use. The Adapted Cognitive Exam demonstrated excellent interrater reliability (intraclass correlation coefficient = 0.997; 95% confidence interval 0.997-0.998) and interitem reliability of each of the five subscales of the Adapted Cognitive Exam and Mini-Mental State Examination (Cronbach's α: range for Adapted Cognitive Exam = 0.83-0.88; range for Mini-Mental State Examination = 0.72-0.81). CONCLUSION: The Adapted Cognitive Exam is the first valid and reliable examination for the assessment and quantification of cognition in critically ill patients. It provides a useful, objective tool that can be used by any member of the interdisciplinary critical care team to support clinical assessment and research efforts.

Improving door-to-antibiotic time in severely septic emergency department patients.

BACKGROUND: The Surviving Sepsis Campaign (SSC) guidelines recommend that broad-spectrum antibiotics be administered to severely septic patients within 3 h of emergency department (ED) admission. Despite the well-established evidence regarding the benefit of timely antibiotics, adoption of the SSC recommendation into daily clinical practice has been slow and sporadic. STUDY OBJECTIVE: To study the impact of storing broad-spectrum antibiotics in an ED automated dispensing cabinet (ADC) on the timeliness of antibiotic administration in severely septic patients presenting to the ED. METHODS: Retrospective observational study of timeliness of antibiotic administration in severely septic patients presenting to a community ED before and after adding broad-spectrum antibiotics to the ED ADC. Data on 56 patients before and 54 patients after the intervention were analyzed. The primary outcome measure was mean order-to-antibiotic time. Secondary outcome measures included mean door-to-antibiotic time and percentage of patients receiving antibiotics within 3 h. RESULTS: The final analysis was on 110 patients. Order-to-antibiotic administration time was reduced by 29 min post-intervention (55 min vs. 26 min, 95% confidence interval [CI] 12.5-45.19). Mean door-to-antibiotic time was also reduced by 70 min (167 min vs. 97 min, 95% CI 37.53-102.29). The percentage of severely septic patients receiving antibiotics within 3h of arrival to the ED increased from 65% pre-intervention to 93% post-intervention (95% CI 0.12-0.42). CONCLUSION: Storing key antibiotics in an institution's severe sepsis antibiogram in the ED ADC can significantly reduce order-to-antibiotic times and increase the percentage of patients receiving antibiotics within the recommended 3 h of ED arrival.

The use of lacosamide in refractory status epilepticus.

BACKGROUND: Case reports suggest lacosamide may have a role in status epilepticus (SE). The purpose of this case series is to describe the use of lacosamide in refractory SE (RSE) at our institution. METHODS: Observational study of all patients admitted to the neurosciences intensive care unit with RSE who received at least one dose of lacosamide from October 2009 to September 2010. RESULTS: Nine patients received lacosamide after failure of at least two other agents. Lacosamide was started a median of 2 days (range: 0-14 days) after the onset of SE. The most frequently used dosing regimen was an initial intravenous dose of 200 mg followed by 200 mg every 12 h. Most patients had received 3 (range: 2-5) AEDs prior to lacosamide. Levetiracetam was used prior to lacosamide in all cases. No patients evaluated responded to lacosamide according to our predefined criteria. One patient developed angioedema after receiving two doses; another patient developed angioedema where timing in relation to the lacosamide was unclear. Care was withdrawn in three of the nine patients for reasons unrelated to lacosamide. Lacosamide was continued at discharge on all surviving patients except in one case of angioedema. CONCLUSIONS: This is the largest case series to date describing the use of lacosamide in patients with RSE. Despite the novel mechanism of action, we observed no evidence that lacosamide is effective in RSE; however, our sample size was small. Further study is needed to determine the role of lacosamide in SE, especially early in the treatment course.

Validity and reliability of an intuitive conscious sedation scoring tool: the nursing instrument for the communication of sedation.

OBJECTIVE: To develop a symmetrical 7-level scale (+3, "dangerously agitated" to -3, "deeply sedated") that is both intuitive and easy to use, the Nursing Instrument for the Communication of Sedation (NICS). DESIGN: Prospective cohort study. SETTING: University medical center. PATIENTS: Mixed surgical, medical intensive care unit (ICU) population. INTERVENTIONS: Patient assessment. MEASUREMENTS AND MAIN RESULTS: Criterion, construct, face validity, and interrater reliability of NICS over time and comparison of ease of use and nursing preference between NICS and four common intensive care unit sedation scales. A total of 395 observations were performed in 104 patients (20 intubated [INT], 84 non intubated) by 59 intensive care unit providers. Criterion validity was tested comparing NICS WITH the 8-point level of arousal scale, demonstrating excellent correlation (rs = .96 overall, .95 non intubated, 0.85 intubated, all p < .001). Construct validity was confirmed by comparing NICS with the Richmond Agitation-Sedation Scale, demonstrating excellent correlation (rs = .98, p < .001). Face validity was determined in a blinded survey of 53 intensive care unit nurses evaluating NICS and four other sedation scales. NICS was highly rated as easy to score, intuitive, and a clinically relevant measure of sedation, and agitation and was preferred overall (74% NICS, 17% Richmond Agitation-Sedation Scale, 11% Other, p < .001 NICS vs. Richmond Agitation-Sedation Scale). Interrater reliability was assessed, using the five scales at three timed intervals, during which 37% of patients received sedative medication. The mean NICS score consistently correlated with each of the other scales over time with an rs of >.9. Using the intraclass correlation coefficient as a measure of Interrater reliability, NICS scored as high, or higher than Richmond Agitation-Sedation Scale, Riker Sedation-Agitation Scale, Motor Activity Assessment Scale, or Ramsay over the three time periods. CONCLUSION: NICS is a valid and reliable sedation scale for use in a mixed population of intensive care unit patients. NICS ranked highest in nursing preference and ease of communication and may thus permit more effective and interactive management of sedation.

Defects in Processes of Care for Pharmacologic Prophylaxis Are Common Among Neurosurgery Patients Who Develop In-Hospital Postoperative Venous Thromboembolism.

BACKGROUND: Venous thromboembolism (VTE) is a cause of considerable morbidity and mortality in hospitalized patients. An evidence-based algorithm was developed and implemented at our institution to guide perioperative VTE prophylaxis management. OBJECTIVE: We evaluated compliance with prescription of risk-appropriate VTE prophylaxis and administration of prescribed VTE prophylaxis in neurosurgery patients. METHODS: This was a retrospective analysis of postoperative neurosurgery patients at a single institution with subsequent diagnosis of acute VTE during their inpatient stay. Descriptive statistics were used to characterize pharmacologic VTE prophylaxis and prescribing patterns. RESULTS: The incidence of VTE in our neurosurgery population was 248/13,913 (1.8%). Of the 123 patients, the median time to VTE diagnosis was 96 hours after surgery (interquartile range [IQR], 58-188 hours). A total of 108 patients (87.8%) were prescribed risk-appropriate VTE prophylaxis, among whom 61 (56.5%) received all doses as prescribed. Fifty-three patients (43.1%) missed ≥1 dose of prescribed prophylaxis and the median missed doses was 3 (IQR, 0-3). The median time to first dose of pharmacologic VTE prophylaxis was 42 hours (IQR, 28-51). More than half (n = 63, 51.2%) of the VTE risk assessments contained ≥1 error, of which 15 (23.8%) would have resulted in a change in recommendation. CONCLUSIONS: Our evidence-based VTE prophylaxis algorithm was not accurately completed in more than half of patients. Many patients who developed VTE had a defect in their VTE prophylaxis management during their inpatient stay. Research to improve optimal VTE prevention practice in neurosurgery patients is needed.

Improving the role of intraventricular antimicrobial agents in the management of meningitis.

PURPOSE OF REVIEW: The aim is to review the role of intraventricular administration of antimicrobial agents in the treatment of patients with bacterial and fungal meningitis. RECENT FINDINGS: This article discusses indications for intraventricular antimicrobial agents, choice of antibiotics, strategies to monitor pharmacokinetics of central nervous system compartments and unanswered issues for this management approach. SUMMARY: Intraventricular administration of antimicrobials may be necessary in certain difficult- to- eradicate central nervous system infections. There is a significant need for clinical trials and management guidelines in this area.

Update in the diagnosis and management of central nervous system infections.

Central nervous system (CNS) infections presenting to the emergency room include meningitis, encephalitis, brain and spinal epidural abscess, subdural empyema, and ventriculitis. These conditions often require admission to an intensive care unit (ICU) and are complications of ICU patients with neurologic injury, contributing significantly to morbidity and mortality. Reducing morbidity and mortality is critically dependent on rapid diagnosis and, perhaps more importantly, on the timely initiation of appropriate antimicrobial therapy. New insights into the role of inflammation and the immune response in CNS infections have contributed to development of new diagnostic strategies using markers of inflammation, and to the study of agents with focused immunomodulatory activity, which may lead to further adjunctive therapy in human disease.

Impact of intraoperative cefazolin on postoperative seizures after elective repair of unruptured cerebral aneurysm.

PURPOSE: The impact of intraoperative cefazolin on postoperative seizures after elective repair of an unruptured cerebral aneurysm was evaluated. METHODS: Chart review of a prospectively accrued database was performed for patients admitted from January 1, 2003, through December 31, 2013. Patients were included in the study if they underwent elective repair of an unruptured aneurysm with surgical clipping or wrapping. The primary objective was to determine if the use of cefazolin increased patients' odds of having a seizure within six hours of surgical intervention. Univariate comparisons were conducted on all variables for patients who received cefazolin and patients who were treated with other antibiotics. Multivariable logistic regression was performed to assess the impact of cefazolin administered intraoperatively on postoperative seizures, while accounting for other covariates. RESULTS: Of the 520 patients included, 53 (10.2%) patients developed seizures within six hours after surgery. A total of 439 (84.4%) patients received cefazolin intraoperatively. There were no differences in baseline characteristics between the patients who received cefazolin compared with those who did not. The frequency of seizures did not significantly differ between patients treated with cefazolin versus other antibiotics (11.2% versus 4.9%, respectively; p = 0.08). Multivariable regression revealed that the use of cefazolin did not increase the odds of having a seizure postoperatively compared with patients treated with other antibiotics (odds ratio, 2.4; 95% confidence interval, 0.82-7.15). CONCLUSION: No relationship was found between the intraoperative use of cefazolin and the development of seizures during the six hours after the repair of unruptured cerebral aneurysms.

Advances in the management of central nervous system infections in the ICU.

This chapter focuses on early aggressive management of common infections of the central nervous system that require monitoring in an ICU setting. These include meningitis, encephalitis, brain and epidural abscess, subdural empyema and ventriculitis. It emphasizes priorities in evaluation and management due to increasing morbidity and mortality as a result of failure to appreciate non-specific symptoms or administer timely therapy. The emergence of organisms resistant to penicillin and cephalosporins has also further complicated the early management of bacterial meningitis. Current antimicrobial guidelines are provided along with discussion of new diagnostic and therapeutic strategies and controversial aspects of management.

Pharmacy on demand: New technologies to enable miniaturized and mobile drug manufacturing.

PURPOSE: Developmental pharmaceutical manufacturing systems and techniques designed to overcome the shortcomings of traditional batch processing methods are described. SUMMARY: Conventional pharmaceutical manufacturing processes do not adequately address the needs of military and civilian patient populations and healthcare providers. Recent advances within the Defense Advanced Research Projects Agency (DARPA) Battlefield Medicine program suggest that miniaturized, flexible platforms for end-to-end manufacturing of pharmaceuticals are possible. Advances in continuous-flow synthesis, chemistry, biological engineering, and downstream processing, coupled with online analytics, automation, and enhanced process control measures, pave the way for disruptive innovation to improve the pharmaceutical supply chain and drug manufacturing base. These new technologies, along with current and ongoing advances in regulatory science, have the future potential to (1) permit "on demand" drug manufacturing on the battlefield and in other austere environments, (2) enhance the level of preparedness for chemical, biological, radiological, and nuclear threats, (3) enhance health authorities' ability to respond to natural disasters and other catastrophic events, (4) minimize shortages of drugs, (5) address gaps in the orphan drug market, (6) support and enable the continued drive toward precision medicine, and (7) enhance access to needed medications in underserved areas across the globe. CONCLUSION: Modular platforms under development by DARPA's Battlefield Medicine program may one day improve the safety, efficiency, and timeliness of drug manufacturing.

Elevating pharmacists' scope of practice through a health-system clinical privileging process.

PURPOSE: The privileging of pharmacists for clinical activities and the impact that privileging has on enhancing the scope of pharmacy practice in health systems are reviewed. SUMMARY: Health-system pharmacists or pharmacy leaders must gain a thorough understanding of the credentialing and privileging process as they broaden their scope of practice. Clinical privileging affords an expanded scope of practice that is recognized at the institutional level and formally elevates the pharmacist to that of a nonphysician provider. The installation of privileging processes is expected to take many months to complete for individual institutions and should begin now in anticipation of provider status. Model institutions, including Truman Medical Centers, Johns Hopkins Hospital, and The Ohio State University Wexner Medical Center, are highlighted in this article and provide their individual approach to clinical privileging that can be applied to other institutions. The development and evaluation of these programs have given valuable insight into how this individual approach translates to health systems across the country and how the pharmacy profession can continue to unite to convey the value of pharmacists in improving patient care. CONCLUSION: In preparation for the potential approval of pharmacist provider status across the United States, it is essential that pharmacists are privileged by the medical staff at their respective institution. Clinical privileges must be strategically developed with a focus on cost and quality aims and meeting the needs of patients. Implementation and maintenance of high-performing pharmacy privileging programs require both successful leadership and management skills and an understanding of the interprofessional nature of healthcare.

The Creation of a Biocontainment Unit at a Tertiary Care Hospital. The Johns Hopkins Medicine Experience.

In response to the 2014-2015 Ebola virus disease outbreak in West Africa, Johns Hopkins Medicine created a biocontainment unit to care for patients infected with Ebola virus and other high-consequence pathogens. The unit team examined published literature and guidelines, visited two existing U.S. biocontainment units, and contacted national and international experts to inform the design of the physical structure and patient care activities of the unit. The resulting four-bed unit allows for unidirectional flow of providers and materials and has ample space for donning and doffing personal protective equipment. The air-handling system allows treatment of diseases spread by contact, droplet, or airborne routes of transmission. An onsite laboratory and an autoclave waste management system minimize the transport of infectious materials out of the unit. The unit is staffed by self-selected nurses, providers, and support staff with pediatric and adult capabilities. A telecommunications system allows other providers and family members to interact with patients and staff remotely. A full-time nurse educator is responsible for staff training, including quarterly exercises and competency assessment in the donning and doffing of personal protective equipment. The creation of the Johns Hopkins Biocontainment Unit required the highest level of multidisciplinary collaboration. When not used for clinical care and training, the unit will be a site for research and innovation in highly infectious diseases. The lessons learned from the design process can inform a new research agenda focused on the care of patients in a biocontainment environment.

Comparison of free fraction serum valproic acid concentrations between inpatients and outpatients.

PURPOSE: The differences in free fraction serum valproic acid concentrations between inpatients and outpatients were compared, and factors associated with therapeutic discordance were evaluated. METHODS: This retrospective, single-center, cross-sectional study included patients with both a free and a total valproic acid concentration drawn within 30 minutes of each other between January 7, 2003, and June 1, 2011. Serum valproic acid concentrations were stratified by admission status (inpatient versus outpatient). In the primary analysis, for patients who had multiple paired concentrations drawn, one free valproic acid level and one total valproic acid level (i.e., one pair) were chosen at random for each inpatient. Information regarding patient demographics, laboratory data, and concomitant medication therapy was collected. Single and multivariable logistic regressions were performed to determine the odds of therapeutic discordance. RESULTS: During the study period, inpatient concentrations were measured in 220 patients, and outpatient concentrations were measured in 41 patients. The median total valproic acid concentration in the inpatient group was significantly lower than that in the outpatient group (54 µg/mL versus 83 µg/mL, p < 0.001). The median free fraction of inpatient levels was nearly twice as high as that of outpatient levels (28.8% versus 15.5%, p < 0.001). Levels drawn in inpatients were therapeutically discordant 63% of the time compared to only 19% in outpatients (p < 0.001). Multivariable logistic regression identified low albumin as an independent risk factor for therapeutic discordance. CONCLUSION: The median free fraction of valproic acid was significantly higher in inpatients than in outpatients. Low albumin concentration was a predictor of discordance between free and total valproic acid concentrations.