Immuno-Modulatory Effects of Intervertebral Disc Cells.

Low back pain is a highly prevalent, chronic, and costly medical condition predominantly triggered by intervertebral disc degeneration (IDD). IDD is often caused by structural and biochemical changes in intervertebral discs (IVD) that prompt a pathologic shift from an anabolic to catabolic state, affecting extracellular matrix (ECM) production, enzyme generation, cytokine and chemokine production, neurotrophic and angiogenic factor production. The IVD is an immune-privileged organ. However, during degeneration immune cells and inflammatory factors can infiltrate through defects in the cartilage endplate and annulus fibrosus fissures, further accelerating the catabolic environment. Remarkably, though, catabolic ECM disruption also occurs in the absence of immune cell infiltration, largely due to native disc cell production of catabolic enzymes and cytokines. An unbalanced metabolism could be induced by many different factors, including a harsh microenvironment, biomechanical cues, genetics, and infection. The complex, multifactorial nature of IDD brings the challenge of identifying key factors which initiate the degenerative cascade, eventually leading to back pain. These factors are often investigated through methods including animal models, 3D cell culture, bioreactors, and computational models. However, the crosstalk between the IVD, immune system, and shifted metabolism is frequently misconstrued, often with the assumption that the presence of cytokines and chemokines is synonymous to inflammation or an immune response, which is not true for the intact disc. Therefore, this review will tackle immunomodulatory and IVD cell roles in IDD, clarifying the differences between cellular involvements and implications for therapeutic development and assessing models used to explore inflammatory or catabolic IVD environments.

Evaluation of intrapleural fibrinolytic therapy and dosing strategies used for complicated pleural effusions.

OBJECTIVES: Compare the use of Tissue Plasminogen Activator (t-PA) and t-PA + Dornase (DNase) for the management of complicated pleural effusions, and to determine if a dose-response relationship exists for t-PA. METHODS: Retrospective cohort study that examined all adult patients at a large academic medical center who received intrapleural t-PA or t-PA + DNase for the management of a complicated pleural effusions. Outcomes were success of therapy [defined as avoidance of secondary interventions (i.e. VATSD or thoracotomy)], chest tube output pre- and post-administration, radiographic findings, t-PA dose and frequency, and bleeding complications. RESULTS: Thirty-five patients were enrolled: 25 received t-PA and 10 received t-PA + DNase. Successful pharmacologic treatment occurred in 88% of patients receiving t-PA and 100% of patients receiving t-PA + DNase (p = 0.54). In the t-PA group, chest tube output increased from 75 ml/12 h to 538 ml/12 h after administration of t-PA (p = 0.001), and from 103 ml/12 h to 502 ml/12 h (p = 0.001) in the t-PA + DNase group. Radiographic improvement occurred in 84% of t-PA patients and 90% of t-PA + DNase patients (p = 0.99). In the t-PA group, a successful response occurred in 92% of patients receiving a cumulative dose of ≤10 mg (n = 13) and 83% of patients receiving a cumulative dose of >10 mg (n = 12), p = 0.43. Patients who received a single t-PA dose compared to those who received multiple doses also had similar success rates (p = 1). There was one instance of bleeding following drug administration. CONCLUSION: Both t-PA and t-PA + DNase were highly effective for reducing a patient's need for surgical intervention. Higher cumulative doses or more frequency administrations did not appear to provide additional benefit.

Controlling amphipathic peptide adsorption by smart switchable germanium interfaces.

The in situ control of reversible protein adsorption to a surface is a critical step towards biofouling prevention and finds utilisation in bioanalytical applications. In this work, adsorption of peptides is controlled by employing the electrode potential induced, reversible change of germanium (100) surface termination between a hydrophobic, hydrogen terminated and a hydrophilic, hydroxyl terminated surface. This simple but effective 'smart' interface is used to direct adsorption of two peptides models, representing the naturally highly abundant structural motifs of amphipathic helices and coiled-coils. Their structural similarity coincides with their opposite overall charge and hence allows the examination of the influence of charge and hydrophobicity on adsorption. Polarized attenuated total reflection infrared (ATR-IR) spectroscopy at controlled electrode potential has been used to follow the adsorption process at physiological pH in deuterated buffer. The delicate balance of hydrophobic and electrostatic peptide/surface interactions leads to two different processes upon switching that are both observed in situ: reversible adsorption and reversible reorientation. Negatively charged peptide adsorption can be fully controlled by switching to the hydrophobic interface, while the same switch causes the positively charged, helical peptide to tilt down. This principle can be used for 'smart' adsorption control of a wider variety of proteins and peptides and hence find application, as e.g. a bioanalytical tool or functional biosensor.

Pre Versus Post Implementation of a Pharmacologic Antishivering Protocol During Targeted Temperature Management Following Cardiac Arrest.

BACKGROUND: Targeted temperature management (TTM) is endorsed by various guidelines to improve neurologic outcomes following cardiac arrest. Shivering, a consequence of hypothermia, can counteract the benefits of TTM. Despite its frequent occurrence, consensus guidelines provide minimal guidance on the management of shivering. The purpose of this study was to evaluate the impact of a pharmacologic antishivering protocol in patients undergoing TTM following cardiac arrest on the incidence of shivering. METHODS: A retrospective observational cohort study at a large academic medical center of adult patients who underwent TTM targeting 33 °C following out-of-hospital (OHCA) or in-hospital cardiac arrest (IHCA) was conducted between January 2013 and January 2019. Patients were included in the preprotocol group if they received TTM prior to the initiation of a pharmacologic antishivering protocol in 2015. The primary outcome was incidence of shivering between pre- and postprotocol patients. Secondary outcomes included time from arrest (IHCA) or admission to the hospital (OHCA) to goal body temperature, total time spent at goal body temperature, and percentage of patients alive at discharge. All pharmacologic agents listed as part of the antishivering protocol were recorded. RESULTS: Fifty-one patients were included in the preprotocol group, and 80 patients were included in the postprotocol group. There were no significant differences in baseline characteristics between the groups, including percentage of patients experiencing OHCA (75% vs. 63%, p = 0.15) and time from arrest to return of spontaneous circulation (17.5 vs. 17.9 min, p = 0.96). Incidence of patients with shivering was significantly reduced in the postprotocol group (57% vs. 39%, p = 0.03). Time from arrest (IHCA) or admission to the hospital (OHCA) to goal body temperature was similar in both groups (5.1 vs. 5.3 h, p = 0.57), in addition to total time spent at goal body temperature (17.7 vs. 18 h, p = 0.93). The percentage of patients alive at discharge was significantly improved in the postprotocol group (35% vs. 55%, p = 0.02). Patients in the postprotocol group received significantly more buspirone (4% vs. 73%, p < 0.01), meperidine (8% vs. 34%, p < 0.01), and acetaminophen (12% vs. 65%, p < 0.01) as part of the pharmacologic antishivering protocol. Use of neuromuscular blockade significantly decreased post protocol (19% vs. 6%, p = 0.02). CONCLUSIONS: In patients undergoing TTM following cardiac arrest, the implementation of a pharmacologic antishivering protocol reduced the incidence of shivering and the use neuromuscular blocking agents. Prospective data are needed to validate the results and further evaluate the safety and efficacy of an antishivering protocol on clinical outcomes.

Burnout Among Pharmacy Preceptors in Northern California.

Objective. The objectives of this study were to investigate the incidence of burnout syndrome among pharmacy preceptors and to identify predictors for the development of burnout in this population.Methods. This cross-sectional survey study examined burnout syndrome among pharmacy preceptors in Northern California. Preceptors were included if they self-identified as a preceptor to advanced pharmacy practice experience (APPE) students or to postgraduate pharmacy residents in their first year of residency. Burnout was assessed using the Maslach Burnout Inventory Human Services Survey, and preceptors were classified as having burnout syndrome if they scored high on emotional exhaustion and also either scored high on depersonalization or scored low on personal accomplishment. Additionally, respondents' demographics, workplace environment, workload, and day-to-day workflow were queried to help determine predictors of burnout syndrome among this population.Result. The study included 113 pharmacy preceptors. Of the preceptors, 22% reported scores consistent with burnout, with 57% of preceptors scoring positive for burnout in one of the three burnout criteria. On multivariate regression analysis, two independent risk factors for burnout syndrome were identified: preceptors who precepted many difficult or unmotivated learners per year and preceptors who did not feel their contributions as preceptors were appreciated by their institution.Conclusion. The rate of burnout among pharmacy preceptors is high, with preceptors exhibiting high emotional exhaustion and low levels of personal accomplishment. Predictors of burnout syndrome for this population appear to be precepting many difficult or unmotivated learners and not feeling that one's contributions as a preceptor are appreciated.

Performance on advanced pharmacy practice experiences after implementation of mock acute care patient simulations.

INTRODUCTION: We sought to compare student performance on acute care advanced pharmacy practice experiences (APPEs) pre- and post-incorporation of mock acute care patient simulations into the curriculum. METHODS: A series of mock acute care APPE simulations (MACAS) were developed and incorporated into Touro University California College of Pharmacy curriculum for first- and second-year pharmacy students. Results for student performance on Acute Care I and Acute Care II APPEs were collected for students who received none, one year, or two years of the MACAS. Student admission characteristics and didactic academic performance (grade point average [GPA]) were also gathered. Student characteristics and APPE performance were compared across cohorts of students who received none, one year, and two years of MACAS. Multivariate models were created to measure the impact of the MACAS while controlling for student characteristics. RESULTS: The final cohort included 394 students. In unadjusted analyses, students with one or two years of MACAS received significantly higher preceptor acute care APPE evaluations for communication, professionalism, and patient scores vs. students who received no MACAS. In multivariate models controlling for age, gender, and undergraduate GPA, one year of MACAS increased student acute care APPE communication, professionalism, and patient care scores, relative to no MACAS. Similar increases in acute care APPE scores were seen for students who received two years of MACAS. CONCLUSIONS: MACAs significantly improved acute care APPE scores relative to students with no MACAS. This improvement in acute care APPEs occurred after students received a single year of MACAS.

Multiscale Regulation of the Intervertebral Disc: Achievements in Experimental, In Silico, and Regenerative Research.

Intervertebral disc (IVD) degeneration is a major risk factor of low back pain. It is defined by a progressive loss of the IVD structure and functionality, leading to severe impairments with restricted treatment options due to the highly demanding mechanical exposure of the IVD. Degenerative changes in the IVD usually increase with age but at an accelerated rate in some individuals. To understand the initiation and progression of this disease, it is crucial to identify key top-down and bottom-up regulations' processes, across the cell, tissue, and organ levels, in health and disease. Owing to unremitting investigation of experimental research, the comprehension of detailed cell signaling pathways and their effect on matrix turnover significantly rose. Likewise, in silico research substantially contributed to a holistic understanding of spatiotemporal effects and complex, multifactorial interactions within the IVD. Together with important achievements in the research of biomaterials, manifold promising approaches for regenerative treatment options were presented over the last years. This review provides an integrative analysis of the current knowledge about (1) the multiscale function and regulation of the IVD in health and disease, (2) the possible regenerative strategies, and (3) the in silico models that shall eventually support the development of advanced therapies.

Effects of a Clonidine Taper on Dexmedetomidine Use and Withdrawal in Adult Critically Ill Patients-A Pilot Study.

OBJECTIVES: Prolonged use of dexmedetomidine has become increasingly common due to its favorable sedative and anxiolytic properties. Hypersympathetic withdrawal symptoms have been reported with abrupt discontinuation of prolonged dexmedetomidine infusions. Clonidine has been used to transition patients off dexmedetomidine infusions for ICU sedation. The objective of this study was to compare the occurrence of dexmedetomidine withdrawal symptoms in ICU patients transitioning to a clonidine taper versus those weaned off dexmedetomidine alone after prolonged dexmedetomidine infusion. DESIGN: This was a single-center, prospective, double cohort observational study conducted from November 2017 to December 2018. SETTING: Medical-surgical, cardiothoracic, and neurosurgical ICUs in a tertiary care hospital. PATIENTS: We included adult ICU patients being weaned off dexmedetomidine after receiving continuous infusions for at least 3 days. INTERVENTIONS: Patients were either weaned off dexmedetomidine alone or with a clonidine taper at the discretion of the providers. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the incidence of at least two dexmedetomidine withdrawal symptoms during a single assessment within 24 hours of dexmedetomidine discontinuation. Time on dexmedetomidine after wean initiation and difference in medication cost were also evaluated. Forty-two patients were included in this study: 15 received clonidine (Group C) and 27 weaned off dexmedetomidine alone (Group D). There was no significant difference in the incidence of two or more withdrawal symptoms between groups (73% in Group C vs 59% in Group D; p = 0.51). Patients in Group C spent less time on dexmedetomidine after wean initiation compared with patients in Group D (19 vs 42 hr; p = 0.02). An average cost savings of $1,553.47 per patient who received clonidine was observed. No adverse effects were noted. CONCLUSIONS: Our study demonstrated that patients receiving clonidine were able to wean off dexmedetomidine more rapidly, with a considerable cost savings and no difference in dexmedetomidine withdrawal symptoms, compared with patients weaned off dexmedetomidine alone. Clonidine may be a safe, effective, and practical option to transition patients off prolonged dexmedetomidine infusions.

Reduced Versus Conventional Dose Insulin for Hyperkalemia Treatment.

BACKGROUND: Using a reduced dose of 5 units of regular insulin has been proposed as a strategy to mitigate the risk of hypoglycemia when treating hyperkalemia. The comparative efficacy and safety of this strategy to conventional 10 units is not well established. OBJECTIVE: To compare the effectiveness of reduced and conventional dosed insulin for hyperkalemia treatment. METHODS: Electronic medication administration reports of conventional or reduced doses of insulin given for hyperkalemia treatment were reviewed from July 2013 to September 2015. The primary outcome was reduction in serum potassium. RESULTS: Ninety-two administrations of reduced dose insulin and 309 administrations of conventional dose insulin were included. No significant difference was found in potassium reduction between the groups (-0.096 mmol/L, P value = .2210). Post hoc subgroup analysis of patients with serum potassium > 6 mmol/L revealed a lower reduction in potassium in the reduced dose group compared to the conventional dose group (difference: -0.238 mmol/L, P value = .018). CONCLUSIONS: Conventional dose insulin may be more effective than reduced dose regular insulin at baseline serum potassium levels >6 mmol/L in the treatment of hyperkalemia. Frequent monitoring of serum potassium and glucose after administration of insulin is necessary to confirm adequate response and avoidance of hypoglycemia.

Implementation of Mock Acute Care Advance Pharmacy Practice Experience Simulations and an Assessment Rubric.

Objective. To implement a mock acute care advanced pharmacy practice experience series into the didactic training of second-year pharmacy students and validate an accompanying assessment rubric. Methods. Three 90-minute acute care patient simulation laboratory sessions were developed with input from clinical specialists, preceptors, students, and faculty members. An accompanying student evaluation rubric was also developed. The assessment rubric was validated using pairs of preceptor raters to determine inter-rater reliability, along with predictive validity on advanced pharmacy practice experience (APPE) acute care scores. A student survey was also conducted. Results. The mock acute care APPEs were successfully implemented into the didactic curriculum. The assessment rubric had good inter-rater reliability and good predictive validity with acute care APPEs. Survey results indicated that students found the mock acute care APPE simulation laboratories useful. Conclusion. Other schools seeking to enhance their students' preparedness for and performance in acute care APPEs should consider implementing acute care APPE simulations in the didactic curriculum.

High-fidelity simulation increases pharmacy resident perceived competence during medical emergencies.

INTRODUCTION: Our objective was to assess postgraduate year one (PGY1) pharmacy resident perceived competence during medical emergencies before and after implementation of a longitudinal simulation training curriculum. METHODS: At the University of California San Francisco (UCSF) Medical Center, PGY1 pharmacy residents serve as primary code team responders for code blue, code sepsis, and code stroke, among other medical emergencies. In 2015, the UCSF Residency Training Program implemented a longitudinal simulation curriculum for PGY1 pharmacy residents. Throughout the residency year, residents participated in four simulation lab sessions that addressed various medical emergencies. To assess the impact that the simulation curriculum had on resident perceived competence during medical emergencies, a 19-question survey (13 clinical questions and six control questions) was distributed to the residents at the end of the residency year. Resident responses from the 2015 to 2016 and 2016 to 2017 surveys were compared to a control residency class from 2014 to 2015 who did not undergo the simulation curriculum. RESULTS: Simulation-trained PGY1 pharmacy residents reported significantly greater perceived competence in five of the twelve medical emergency scenarios (acute coronary syndromes, symptomatic bradycardia, supraventricular tachycardia, ventricular tachycardia, and cardiac arrest) as compared to non-simulation-trained controls. In addition, the PGY1 pharmacy residents felt that their performance as a clinical pharmacist would significantly improve as a result of the simulation curriculum. CONCLUSIONS: Incorporation of a longitudinal simulation curriculum into PGY1 pharmacy resident training can positively impact resident self-reported competence when performing essential pharmacist functions during medical emergencies.

Impact of Quetiapine Therapy on QTc Prolongation in Critically Ill Patients.

BACKGROUND: Quetiapine is an atypical antipsychotic commonly utilized for the management of delirium in critically ill patients. The impact of quetiapine on QTc in the critically ill population is largely unknown. OBJECTIVE: The purpose of this study was to evaluate QTc prolongation following administration of quetiapine for the management of delirium in critically ill patients. METHODS: This was a single-center prospective, observational cohort study. QTc measurements of patients who received at least one dose of quetiapine were compared with a control group receiving melatonin. The primary outcome was mean change in QTc from baseline to maximum serum drug concentration after the first dose of quetiapine. RESULTS: No significant change in QTc was observed from baseline to post-quetiapine administration, with a mean change in QTc of 2.7 ms (438.4 ± 43.2 ms vs 441.1 ± 36.4 ms; P = 0.50). When comparing mean change in QTc between the quetiapine group and melatonin group, the difference was not significant (2.7 ± 37.8 ms vs -0.18 ± 32.0 ms, P = 0.73). Conclusion and Relevance: This study represents one of the first prospective studies evaluating the impact of quetiapine on QTc. The results of this study demonstrate a nonsignificant statistical and clinical change in the QTc following quetiapine administration in critically ill patients utilizing telemetry measurements. Routine QTc monitoring with formal electrocardiogram(s) following quetiapine administration may not be warranted.

Effectiveness of Melatonin for the Prevention of Intensive Care Unit Delirium.

STUDY OBJECTIVE: Intensive care unit (ICU) delirium is an acute brain dysfunction that has been associated with increased mortality, prolonged ICU and hospital lengths of stay, and development of post-ICU cognitive impairment. Melatonin may help to restore sleep and reduce the occurrence of ICU delirium. The purpose of this study was to evaluate the effectiveness of melatonin for the prevention of ICU delirium in critically ill adults. DESIGN: Retrospective, observational cohort study. SETTING: Large academic medical center. PATIENTS: A total of 232 adults were included who were admitted to the medical-surgical or cardiac ICUs between 2013 and 2017 who had a negative Confusion Assessment Method for the ICU (CAM-ICU). Of those, patients who received melatonin for at least 48 hours were included in the melatonin group (n=117). Patients were included in the control group if they were admitted to the ICU for at least 4 days (average time of melatonin initiation) and did not receive melatonin or antipsychotics within the first 4 days of their ICU stay (n=115). MEASUREMENTS AND MAIN RESULTS: The primary outcome was development of delirium, which was assessed by using the CAM-ICU twice daily by nursing staff. The development of delirium was significantly lower in the melatonin group: 9 (7.7%) versus 28 (24.3%) patients (p = 0.001). This finding remained significant in multivariate logistic models controlling for age, sex, history of hypertension, need for emergent surgery, Acute Physiology and Chronic Health Evaluation II score, mechanical ventilation, ICU length of stay, dexmedetomidine use, and benzodiazepine use. For those patients who developed delirium, patients in the control group had, on average, 20.9 delirium-free days without coma in 28 days compared with 19.9 days in the melatonin group (p = 0.72). In the melatonin group, melatonin was used for a mean ± SD of 6.3 ± 7.9 days, with a median dose of 3.5 mg/night (range: 1-10 mg). CONCLUSION: The development of ICU delirium was significantly lower in the melatonin group compared with that in the control group. To our knowledge, this is one of the only studies that has examined the use of melatonin for the prevention of ICU delirium. Melatonin may be a promising agent for the prevention of ICU delirium; however, a randomized study is needed to further validate its efficacy.

Incidence of Dexmedetomidine Withdrawal in Adult Critically Ill Patients: A Pilot Study.

To determine the incidence of dexmedetomidine withdrawal in adult critically ill patients. DESIGN: This was a prospective, observational study of patients from November 2017 to December 2018. SETTING: Medical-surgical, cardiothoracic, and neurosurgical ICUs in a tertiary care hospital. PATIENTS: Adult critically ill patients on dexmedetomidine infusions for at least 3 days. INTERVENTIONS: Indicators of withdrawal were assessed at baseline and at least daily during the dexmedetomidine wean period. Delirium was assessed using the Confusion Assessment Method for the ICU. Sedation was assessed using the Richmond Agitation-Sedation Scale. The Withdrawal Assessment Tool-1 was performed and vital signs were recorded during each assessment. Patients were considered positive for dexmedetomidine withdrawal if they had two or more of the following symptoms: positive Confusion Assessment Method for the ICU, Richmond Agitation-Sedation Scale greater than +1, positive Withdrawal Assessment Tool-1 assessment, tachycardia (heart rate > 90 beats/min), and hypertension (systolic blood pressure > 140 mm Hg or mean arterial pressure > 90). MEASUREMENTS AND MAIN RESULTS: Forty-two patients were included in the study, with 64% of patients experiencing signs of dexmedetomidine withdrawal. The median time on dexmedetomidine for all patients was 9.6 days (5.8-12.7 d), and the median dose of dexmedetomidine received was 0.8 µg/kg/hr (0.5-1 µg/kg/hr). Of the patients who were positive for withdrawal, the most prevalent withdrawal symptoms observed included delirium, hypertension, and agitation (93%, 48%, and 33%, respectively). We found no correlation between chronic opioid tolerance and incidence of withdrawal symptoms. Peak dexmedetomidine doses greater than 0.8 µg/kg/hr and cumulative daily doses of dexmedetomidine greater than 12.9 µg/kg/d were associated with a higher incidence of withdrawal. CONCLUSIONS: The majority of patients in our study demonstrated signs that may be indicative of dexmedetomidine withdrawal. Peak and cumulative daily dexmedetomidine dose, rather than duration of therapy, may be associated with a higher incidence of withdrawal signs. Regular screening of patients on prolonged dexmedetomidine infusions is recommended to ensure safe and effective use in critically ill patients.

CE: Original Research: The Efficacy and Safety of an RN-Driven Ketamine Protocol for Adjunctive Analgesia During Burn Wound Care.

: Objective: Traditional analgesic regimens often fail to control the severe pain patients experience during burn wound care, and the drugs are frequently administered at doses that can cause oversedation and respiratory depression. Ketamine may be an ideal agent for adjunctive analgesia in such patients because of its unique mechanism of action and lack of association with respiratory depression. This study evaluated the efficacy and safety of a critical care RN-driven protocol for IV ketamine administration during burn wound care. METHODS: This retrospective cohort study examined all adult burn patients who received ketamine as part of a critical care RN-driven ketamine protocol for burn wound care from September 2011 through September 2013. Efficacy outcomes were opioid and benzodiazepine requirements (expressed as fentanyl and midazolam equivalents, respectively) four hours after ketamine administration compared with four hours before such administration. Safety parameters assessed were neurologic, hemodynamic, and respiratory effects. RESULTS: Twenty-seven patients received 56 ketamine doses as part of this protocol; the mean (SD) dose was 0.75 (0.35) mg/kg. Twenty patients (74%) were male and seven (26%) were female; mean age was 39 years. The average percentage of total body surface area burned was 23.4%. With the protocol, opioid and benzodiazepine requirements were reduced by 29% and 20%, respectively. One patient experienced an episode of oversedation after concomitant administration of ketamine and fentanyl. No patients experienced neurologic or hemodynamic complications following ketamine administration. CONCLUSIONS: The administration of ketamine during burn wound care using a critical care RN-driven protocol was associated with reduced opioid and benzodiazepine requirements and few adverse effects. Prospective studies are needed to investigate additional patient outcomes and the independent administration of ketamine by critical care RNs.

Divergent humoral responses to 23-valent pneumococcal polysaccharide vaccine in critically-ill burn and neurosurgical patients.

INTRODUCTION: Critically ill hospitalized patients are at increased risk of infection so we assessed the immunogenicity of 23-valent pneumococcal polysaccharide vaccine (PPSV23) administered within six days of injury. METHODS: This prospective observational study compared the immunogenicity of PPSV23 among critically ill burn and neurosurgical patients at a tertiary, academic medical center. Patients received PPSV23 vaccination within six days of ICU admission per standard of care. Consent was obtained to measure concentrations of vaccine-specific IgG to 14 of 23 serotype capsule-specific IgG in serum prior to and 14-35 days following PPSV23. A successful immunologic response was defined as both a ≥2-fold rise in capsule-specific IgG from baseline and concentrations of >1 mcg/mL to 10 of 14 measured vaccine serotypes. Immunologic response was compared between burn and neurosurgical patients. Multiple variable regression methods were used to explore associations of clinical and laboratory parameters to immunologic responses. RESULTS: Among the 16 burn and 27 neurosurgical patients enrolled, 87.5% and 40.7% generated a successful response to the vaccine, respectively (p = 0.004). Both median post-PPSV23 IgG concentrations (7.79 [4.56-18.1] versus 2.93 [1.49-8.01] mcg/mL; p = 0.006) and fold rises (10.66 [7.44-14.56] versus 3.48 [1.13-6.59]; p<0.001) were significantly greater in burn compared with neurosurgical patients. Presence of burn injury was directly and days from injury to immunization were inversely correlated with successful immunologic response (both p<0.03). Burn injury was associated with both increased median antibody levels post-PPSV23 and fold rise to 14 vaccine serotypes (p<0.03), whereas absolute lymphocyte count was inversely correlated with median antibody concentrations (p = 0.034). CONCLUSION: Critically ill burn patients can generate successful responses to PPSV23 during acute injury whereas responses among neurosurgical patients is comparatively blunted. Further study is needed to elucidate the mechanisms of differential antigen responsiveness in these populations, including the role of acute stress responses, as well as the durability of these antibody responses.

Major publications in the critical care pharmacotherapy literature: January-December 2017.

PURPOSE: To summarize selected meta-analyses and trials related to critical care pharmacotherapy published in 2017. The Critical Care Pharmacotherapy Literature Update (CCPLU) Group screened 32 journals monthly for impactful articles and reviewed 115 during 2017. Two meta-analyses and eight original research trials were reviewed here from those included in the monthly CCPLU. Meta-analyses on early, goal-directed therapy for septic shock and statin therapy for acute respiratory distress syndrome were summarized. Original research trials that were included evaluate thrombolytic therapy in severe stroke, hyperoxia and hypertonic saline in septic shock, intraoperative ketamine for prevention of post-operative delirium, intravenous ketorolac dosing regimens for acute pain, angiotensin II for vasodilatory shock, dabigatran reversal with idarucizumab, bivalirudin versus heparin monotherapy for myocardial infarction, and balanced crystalloids versus saline fluid resuscitation. CONCLUSION: This clinical review provides perspectives on impactful critical care pharmacotherapy publications in 2017.

Hypersensitivity Reaction Following Administration of Low-Dose Oral Vancomycin for the Treatment of Clostridium difficile in a Patient With Normal Renal Function.

Systemic absorption of oral vancomycin for the treatment of Clostridium difficile is thought to be trivial in patients without risk factors for increased systemic absorption and is often overlooked in clinical practice. A 51-year-old male elicits a suspected immunoglobulin E-mediated hypersensitivity following administration of low-dose oral vancomycin for the treatment of severe C difficile. The patient had normal renal function and was administered low doses of the medication, however, had a medical history significant for diverticulitis. Applying the Naranjo adverse drug reaction probability scale, a score of 5 was obtained, indicating a probable association between the administration of oral vancomycin and the hypersensitivity reaction. This case demonstrates that hypersensitivity reactions following low-dose oral vancomycin administration in patients with severe C difficile are possible, despite having normal renal function. Other risk factors for systemic absorption of oral vancomycin need to be evaluated in the literature, including severity of disease and underlying gastrointestinal processes.

Thiocyanate Accumulation in Critically Ill Patients Receiving Nitroprusside Infusions.

PURPOSE: This study evaluated thiocyanate concentrations and factors associated with thiocyanate accumulation in intensive care unit patients receiving nitroprusside with and without sodium thiosulfate coadministration. MATERIALS AND METHODS: This retrospective study evaluated critically ill adults who received nitroprusside infusions and had at least one thiocyanate concentration. Patients with thiocyanate accumulation (concentrations ≥30 µg/mL) were compared to patients without accumulation. Factors associated with accumulation were determined by Spearman correlation and multivariate regression. RESULTS: Thiocyanate concentrations (n = 192) were obtained from 87 patients. Fourteen of the 87 (16%) patients experienced thiocyanate accumulation with a mean (SD) thiocyanate concentration of 44 ± 11 µg/mL. Patients with accumulation had received greater cumulative nitroprusside doses (28 vs 8.2 mg/kg, P < .01), greater cumulative sodium thiosulfate doses (16.8 vs 10.1 mg/kg, P < .01), and longer infusion durations (10.9 vs 6.0 days, P < .01), compared to patients without accumulation. Sodium thiosulfate coadministration resulted in greater thiocyanate concentrations (22.8 ± 16.7 vs 16.8 ± 14.9 µg/mL, P = .01), despite utilization of lower cumulative nitroprusside doses (10.2 vs 14.6 mg/kg, P = .03). Cumulative nitroprusside dose ( r2 .44, P < .001) and cumulative sodium thiosulfate dose ( r2 .32, P < .001) demonstrated a significant correlation with measured thiocyanate concentrations. Thiocyanate accumulation was independently associated with cumulative nitroprusside dose in mg/kg (regression coefficient 0.75, 95% CI 0.63-0.89; P < .01). No clinically significant adverse effects of cyanide or thiocyanate toxicity were observed. CONCLUSIONS: Cumulative nitroprusside dose was independently associated with thiocyanate accumulation. Despite elevated thiocyanate levels in 16% of patients, there was no clinical evidence of cyanide or thiocyanate toxicity. Routine monitoring of thiocyanate concentrations appears most warranted in patients receiving higher cumulative doses of nitroprusside.