University of Kentucky HealthCare

BACKGROUND: Acute treatment of cerebral edema and elevated intracranial pressure is a common issue in patients with neurological injury. Practical recommendations regarding selection and monitoring of therapies for initial management of cerebral edema for optimal efficacy and safety are generally lacking. This guideline evaluates the role of hyperosmolar agents (mannitol, HTS), corticosteroids, and selected non-pharmacologic therapies in the acute treatment of cerebral edema. Clinicians must be able to select appropriate therapies for initial cerebral edema management based on available evidence while balancing efficacy and safety. METHODS: The Neurocritical Care Society recruited experts in neurocritical care, nursing, and pharmacy to create a panel in 2017. The group generated 16 clinical questions related to initial management of cerebral edema in various neurological insults using the PICO format. A research librarian executed a comprehensive literature search through July 2018. The panel screened the identified articles for inclusion related to each specific PICO question and abstracted necessary information for pertinent publications. The panel used GRADE methodology to categorize the quality of evidence as high, moderate, low, or very low based on their confidence that the findings of each publication approximate the true effect of the therapy. RESULTS: The panel generated recommendations regarding initial management of cerebral edema in neurocritical care patients with subarachnoid hemorrhage, traumatic brain injury, acute ischemic stroke, intracerebral hemorrhage, bacterial meningitis, and hepatic encephalopathy. CONCLUSION: The available evidence suggests hyperosmolar therapy may be helpful in reducing ICP elevations or cerebral edema in patients with SAH, TBI, AIS, ICH, and HE, although neurological outcomes do not appear to be affected. Corticosteroids appear to be helpful in reducing cerebral edema in patients with bacterial meningitis, but not ICH. Differences in therapeutic response and safety may exist between HTS and mannitol. The use of these agents in these critical clinical situations merits close monitoring for adverse effects. There is a dire need for high-quality research to better inform clinicians of the best options for individualized care of patients with cerebral edema.

Aging-related neurodegenerative diseases (NDs) are the culmination of many different genetic and environmental influences. Prior studies have shown that RNAs are pathologically altered during the inexorable course of some NDs. Recent evidence suggests that microRNAs (miRNAs) may be a contributing factor in neurodegeneration. miRNAs are brain-enriched, small ( approximately 22 nucleotides) non-coding RNAs that participate in mRNA translational regulation. Although discovered in the framework of worm development, miRNAs are now appreciated to play a dynamic role in many mammalian brain-related biochemical pathways, including neuroplasticity and stress responses. Research about miRNAs in the context of neurodegeneration is accumulating rapidly, and the goal of this review is to provide perspective for these new data that may be helpful to specialists in either field. An overview is provided about the normal functions for miRNAs, including some of the newer concepts related to the human brain. Recently published studies pertaining to the roles of miRNAs in NDs--including Alzheimer's disease, Parkinson's disease and triplet repeat disorders-are described. Finally, a discussion is included with theoretical syntheses and possible future directions in exploring the nexus between miRNA and ND research.

There is uncertainty regarding the association of cognitive decline in Alzheimer disease (AD) with classic histopathologic features- neurofibrillary tangles (NFTs) and "neuritic" amyloid plaques (NPs). This uncertainty fuels doubts about the diagnostic importance of NFTs and NPs and leads to confusion regarding hypotheses of AD pathogenesis. Three hundred ninety subjects who underwent longitudinal premortem clinical workup and postmortem quantitative neuropathologic assessment served as the group to address this issue. Subjects with concomitant brain disease(s) were analyzed independently to more accurately assess the contribution of distinct pathologies to cognitive decline. More than 60% of patients of all age groups had important non-AD brain pathologies. However, subjects without superimposed brain diseases showed strong correlations between AD-type pathology counts (NFTs > NPs) and premortem Mini-Mental State Examination scores. The observed correlation was stronger in isocortex than in allocortex and was maintained across age groups including patients older than 90 years. A theoretical model is proposed in which our results are interpreted to support the "amyloid cascade hypothesis" of AD pathogenesis. Our data show that there are many important contributory causes to cognitive decline in older persons. However, NFTs and NPs should not be dismissed as irrelevant in AD based on clinicopathologic correlation.

Sepsis is a major cause of morbidity and mortality in critically ill patients, and despite advances in management, mortality remains high. In survivors, sepsis increases the risk for the development of persistent acquired weakness syndromes affecting both the respiratory muscles and the limb muscles. This acquired weakness results in prolonged duration of mechanical ventilation, difficulty weaning, functional impairment, exercise limitation, and poor health-related quality of life. Abundant evidence indicates that sepsis induces a myopathy characterized by reductions in muscle force-generating capacity, atrophy (loss of muscle mass), and altered bioenergetics. Sepsis elicits derangements at multiple subcellular sites involved in excitation contraction coupling, such as decreasing membrane excitability, injuring sarcolemmal membranes, altering calcium homeostasis due to effects on the sarcoplasmic reticulum, and disrupting contractile protein interactions. Muscle wasting occurs later and results from increased proteolytic degradation as well as decreased protein synthesis. In addition, sepsis produces marked abnormalities in muscle mitochondrial functional capacity and when severe, these alterations correlate with increased death. The mechanisms leading to sepsis-induced changes in skeletal muscle are linked to excessive localized elaboration of proinflammatory cytokines, marked increases in free-radical generation, and activation of proteolytic pathways that are upstream of the proteasome including caspase and calpain. Emerging data suggest that targeted inhibition of these pathways may alter the evolution and progression of sepsis-induced myopathy and potentially reduce the occurrence of sepsis-mediated acquired weakness syndromes.

PURPOSE: Medication and nutrient administration considerations after bariatric surgery are discussed. SUMMARY: Bariatric surgery is categorized by surgical technique (i.e., restrictive procedure or a combination of restrictive and malabsorptive procedures). Roux-en-Y gastric bypass is the most frequently performed bariatric surgery in the United States. Patients who have undergone this surgery are at risk for nutrient deficiencies. Several factors, such as pH and absorption sites, should be considered when providing these patients with appropriate supplementation. Drug solubility and surface area for absorption are also affected by gastric bypass procedures. By bypassing major portions of the small intestine, Roux-en-Y procedures drastically reduce the surface area for absorption. These changes may warrant manipulation in drug route or dose to ensure adequate delivery. Drugs with long absorptive phases that remain in the intestine for extended periods are likely to exhibit decreased bioavailability in these patients. The reduced size of the stomach after surgery can place patients at risk for adverse events associated with some medications. Medications implicated in such adverse events include nonsteroidal antiinflammatory drugs, salicylates, and oral bisphosphonates. Drugs that are rapidly and primarily absorbed in the stomach or duodenum are likely to exhibit decreased absorption in patients who have had combination restrictive-malabsorptive procedures. Because reduced drug absorption may result in decreased efficacy rather than toxicity, increased patient monitoring for therapeutic effects can help detect potential absorption problems. CONCLUSION: Selection of appropriate nutrient salts can improve nutrient replacement in patients who have undergone bariatric surgery. Changes in dosage forms based on drug characteristics can improve bioavailability.

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into an emergent global pandemic. Coronavirus disease 2019 (COVID-19) can manifest on a spectrum of illness from mild disease to severe respiratory failure requiring intensive care unit admission. As the incidence continues to rise at a rapid pace, critical care teams are faced with challenging treatment decisions. There is currently no widely accepted standard of care in the pharmacologic management of patients with COVID-19. Urgent identification of potential treatment strategies is a priority. Therapies include novel agents available in clinical trials or through compassionate use, and other drugs, repurposed antiviral and immunomodulating therapies. Many have demonstrated in vitro or in vivo potential against other viruses that are similar to SARS-CoV-2. Critically ill patients with COVID-19 have additional considerations related to adjustments for organ impairment and renal replacement therapies, complex lists of concurrent medications, limitations with drug administration and compatibility, and unique toxicities that should be evaluated when utilizing these therapies. The purpose of this review is to summarize practical considerations for pharmacotherapy in patients with COVID-19, with the intent of serving as a resource for health care providers at the forefront of clinical care during this pandemic.

Background: Chronic neuropathic pain has been recognized as contributing to a significant proportion of chronic pain globally. Among these, spinal pain is of significance with failed back surgery syndrome (FBSS), generating considerable expense for the health care systems with increasing prevalence and health impact. Objective: To assess the role and effectiveness of spinal cord stimulation (SCS) in chronic spinal pain. Study Design: A systematic review of randomized controlled trials (RCTs) of SCS in chronic spinal pain. Methods: The available literature on SCS was reviewed. The quality assessment criteria utilized were Cochrane review criteria to assess sources of risk of bias and Interventional Pain Management Techniques – Quality Appraisal of Reliability and Risk of Bias Assessment (IPM – QRB) criteria for randomized trials. The level of evidence was based on a best evidence synthesis with modified grading of qualitative evidence from Level I to Level V. Data sources included relevant literature published from 1966 through March 2015 that were identified through searches of PubMed and EMBASE, manual searches of the bibliographies of known primary and review articles, and all other sources. Outcome Measures: RCTs of efficacy with a minimum 12-month follow-up were considered for inclusion. For trials of adaptive stimulation, high frequency stimulation, and burst stimulation, shorter follow-up periods were considered. Results: Results showed 6 RCTs with 3 efficacy trials and 3 stimulation trials. There were also 2 cost effectiveness studies available. Based on a best evidence synthesis with 3 high quality RCTs, the evidence of efficacy for SCS in lumbar FBSS is Level I to II. The evidence for high frequency stimulation based on one high quality RCT is Level II to III. Based on a lack of high quality studies demonstrating the efficacy of adaptive stimulation or burst stimulation, evidence is limited for these 2 modalities. Limitations: The limitations of this systematic review continue to require future studies illustrating effectiveness and also the superiority of high frequency stimulation and potentially burst stimulation. Conclusion: There is significant (Level I to II) evidence of the efficacy of spinal cord stimulation in lumbar FBSS; whereas, there is moderate (Level II to III) evidence for high frequency stimulation; there is limited evidence for adaptive stimulation and burst stimulation. Key words: Neuropathic pain, chronic spinal pain, failed back surgery syndrome, spinal cord stimulation, high frequency stimulation, burst stimulation, adaptive stimulation

OBJECTIVE: This single-center study tested the hypothesis that preoperative risk factors and surgical complexity predict more variation in hospital costs than complications. BACKGROUND: Complications after surgical operations have been shown to significantly increase hospital cost. The impact on complication-related costs of preoperative risk factors is less well known. METHODS: The National Surgical Quality Improvement Program (NSQIP) preoperative risk factors, surgical complexity, and outcomes, along with hospital costs, were analyzed for a random sample of 5875 patients on 6 surgical services. Operation complexity was assessed by work RVUs (Centers for Medicare and Medicaid Services Resource Based Relative Value Scale). The difference in mean hospital costs associated with all variables was analyzed. Multiple linear regression was used to determine the cost variation associated with all variables separately and combined. RESULTS: Fifty-one of 60 preoperative risk factors, work RVUs, and 22 of 29 postoperative complications were associated with higher variable direct costs (P < 0.05). Linear regressions showed that risk factors predicted 33% (P < 0.001) of cost variation, work RVUs predicted 23% (P < 0.001), and complications predicted 20% (P < 0.001). Risk factors and work RVUs together predicted 49% of cost variation (P < 0.001) or 16% more than risk factors alone. Adding complications to this combined model modestly increased prediction of costs by 4% for a total of 53% (P < 0.001). CONCLUSION: Preoperative risk factors and surgical complexity are more effective predictors of hospital costs than complications. Preoperative intervention to reduce risk could lead to significant cost savings. Payers and regulatory agencies should risk-adjust hospital cost assessments using clinical information that integrates costs, preoperative risk, complexity of operation, and outcomes.

An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer's disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.

BACKGROUND: Patients surviving critical illness develop muscle weakness and impairments in physical function; however, the relationship between early skeletal muscle alterations and physical function at hospital discharge remains unclear. The primary purpose of this study was to determine whether changes in muscle size, strength and power assessed in the intensive care unit (ICU) predict physical function at hospital discharge. METHODS: Study design is a single-center, prospective, observational study in patients admitted to the medicine or cardiothoracic ICU with diagnosis of sepsis or acute respiratory failure. Rectus femoris (RF) and tibialis anterior (TA) muscle ultrasound images were obtained day one of ICU admission, repeated serially and assessed for muscle cross-sectional area (CSA), layer thickness (mT) and echointensity (EI). Muscle strength, as measured by Medical Research Council-sum score, and muscle power (lower-extremity leg press) were assessed prior to ICU discharge. Physical function was assessed with performance on 5-times sit-to-stand (5STS) at hospital discharge. RESULTS: Forty-one patients with median age of 61 years (IQR 55-68), 56% male and sequential organ failure assessment score of 8.1 ± 4.8 were enrolled. RF muscle CSA decreased significantly a median percent change of 18.5% from day 1 to 7 (F = 26.6, p = 0.0253). RF EI increased at a mean percent change of 10.5 ± 21% in the first 7 days (F = 3.28, p = 0.081). At hospital discharge 25.7% of patients (9/35) met criteria for ICU-acquired weakness. Change in RF EI in first 7 days of ICU admission and muscle power measured prior to ICU were strong predictors of ICU-AW at hospital discharge (AUC = 0.912). Muscle power at ICU discharge, age and ICU length of stay were predictive of performance on 5STS at hospital discharge. CONCLUSION: ICU-assessed muscle alterations, specifically RF EI and muscle power, are predictors of diagnosis of ICU-AW and physical function assessed by 5x-STS at hospital discharge in patients surviving critical illness.

Augmented renal clearance (ARC) is a phenomenon in critically ill patients characterized by increased creatinine clearance and elimination of renally eliminated medications. Patients with severe neurologic injury, sepsis, trauma, and burns have been consistently identified as at risk of ARC, with mean creatinine clearances ranging from 170 ml/minute to more than 300 ml/minute. Several potential mechanisms may contribute to the occurrence of ARC including endogenous responses to increased metabolism and solute production, alterations in neurohormonal balance, and therapeutic maneuvers such as fluid resuscitation. Augmented renal clearance is associated with suboptimal exposure to critical medications, including β-lactams and vancomycin, increasing the risk of treatment failure. Although definitive screening tools are not yet known, critical care pharmacists must be vigilant in recognizing when ARC may be a contributing factor affecting expected treatment outcomes in individual patients. Optimizing dosing strategies in critically ill patients with ARC remains a goal of continued research. The current review discusses the clinical characteristics and methods of identifying patients at risk of ARC, potential mechanisms for ARC, and describes pharmacotherapy dosing considerations in patients with ARC.

Intracerebroventricular drug administration is a method that bypasses the blood-brain barrier and other mechanisms that limit drug distribution into the brain, allowing high drug concentrations to enter the central compartment. Instillation of drugs directly into the ventricles of the brain must be done carefully and with full consideration of factors affecting the efficacy and safety of this route of administration. These factors include the osmolarity, pH, volume, and presence of preservatives and diluents of the drug solution being administered. Very few studies have formally investigated intraventricular therapies, and dosing recommendations may vary widely depending on the agent and the patient. Many antimicrobials have been given intraventricularly, although very few prospective studies have evaluated this strategy. There are wide variations among the reports regarding dosage regimens and the pharmacokinetics of the antimicrobials used. Guidance on appropriate formulations and their use is lacking. Clinicians should be aware of their patients' ongoing disease processes and neurologic status, as well as pertinent physiochemical properties of drugs when formulating them for intracerebroventricular administration; a high index of suspicion should be maintained when monitoring patients for adverse drug events after instillation.

Mosquito-borne diseases are a major threat to human health and are responsible for millions of deaths globally each year. Vector control is one of the most important approaches used in reducing the incidence of these diseases. However, increasing mosquito resistance to chemical insecticides presents challenges to this approach. Therefore, new strategies are necessary to develop the next generation vector control methods. Because of the target specificity of dsRNA, RNAi-based control measures are an attractive alternative to current insecticides used to control disease vectors. In this study, Chitosan (CS) was cross-linked to sodium tripolyphosphate (TPP) to produce nano-sized polyelectrolyte complexes with dsRNA. CS-TPP-dsRNA nanoparticles were prepared by ionic gelation method. The encapsulation efficiency, protection of dsRNA from nucleases, cellular uptake, in vivo biodistribution, larval mortality and gene knockdown efficiency of CS-TPP-dsRNA nanoparticles were determined. The results showed that at a 5:1 weight ratio of CS-TPP to dsRNA, nanoparticles of less than 200 nm mean diameter and a positive surface charge were formed. Confocal microscopy revealed the distribution of the fed CS-TPP-dsRNA nanoparticles in midgut, fat body and epidermis of yellow fever mosquito, Aedes aegypti larvae. Bioassays showed significant mortality of larvae fed on CS-TPP-dsRNA nanoparticles. These assays also showed knockdown of a target gene in CS-TPP-dsRNA nanoparticle fed larvae. These data suggest that CS-TPP nanoparticles may be used for delivery of dsRNA to mosquito larvae.

OBJECTIVES: Mounting evidence has shown that critically ill patients are commonly thiamine deficient. We sought to test the hypothesis that critically ill patients with septic shock exposed to thiamine would demonstrate improved lactate clearance and more favorable clinical outcomes compared with those not receiving thiamine. DESIGN: Retrospective, single-center, matched cohort study. SETTING: Tertiary care academic medical center. PATIENTS: Adult patients admitted with an International Classification of Diseases, 9th Edition, or International Classification of Diseases, 10th Edition, diagnosis code of septic shock to either the medicine or surgery ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients who received IV thiamine supplementation within 24 hours of hospital admission were identified and compared with a matched cohort of patients not receiving thiamine. The primary objective was to determine if thiamine administration was associated with a reduced time to lactate clearance in septic shock. Secondary outcomes included 28-day mortality, acute kidney injury, and need for renal replacement therapy, and vasopressor and mechanical ventilation-free days. Two-thousand two-hundred seventy-two patients were screened, of whom 1,049 were eligible. The study consisted of 123 thiamine-treated patients matched with 246 patients who did not receive thiamine. Based on the Fine-Gray survival model, treatment with thiamine was associated with an improved likelihood of lactate clearance (subdistribution hazard ratio, 1.307; 95% CI, 1.002-1.704). Thiamine administration was also associated with a reduction in 28-day mortality (hazard ratio, 0.666; 95% CI, 0.490-0.905). There were no differences in any secondary outcomes. CONCLUSIONS: Thiamine administration within 24 hours of admission in patients presenting with septic shock was associated with improved lactate clearance and a reduction in 28-day mortality compared with matched controls.

The provision of adequate nutrition support for patients with traumatic brain injury (TBI) has been a clinical challenge for decades. The primary and secondary injuries create unique metabolic derangements along with accompanying issues such as optimal timing and route of nutrition, appropriate fluid and electrolytes, drug administration, rehabilitation, and dysphagia. Enteral nutrition is clearly established as the preferential route of nutrition support for this population vs parenteral nutrition. There appears to be a consensus on early initiation of enteral nutrition, but less definitive are recommendations on advancement timing and formula components. Nutrition therapies should include exact fluid resuscitation goals specific for TBI and strict electrolyte monitoring to avoid extreme fluid, electrolyte, or glucose shifts that could be detrimental to the patient. While the critical care patient often tolerates small bowel feeding, the long-term rehabilitation patient should transition to and tolerate gastric feeding. Drug-nutrient and adverse drug reactions such as diarrhea should be routinely evaluated in patients receiving enteral nutrition. Monitoring for dysphagia is critical to avoid the costly negative aspects associated with aspiration and to capitalize on quality of life and appropriate oral nutrition. Emphasizing the priority of early nutrition support within a multi-disciplinary team may be the critical key for successful provision and tolerance of nutrition support in the TBI population.

BACKGROUND: Peripheral nerve damage resulting in pain, loss of sensation, or motor function may necessitate a reconstruction with a bridging material. The RANGER® Registry was designed to evaluate outcomes following nerve repair with processed nerve allograft (Avance® Nerve Graft; Axogen; Alachua, FL). Here we report on the results from the largest peripheral nerve registry to-date. METHODS: This multicenter IRB-approved registry study collected data from patients repaired with processed nerve allograft (PNA). Sites followed their own standard of care for patient treatment and follow-up. Data were assessed for meaningful recovery, defined as ≥S3/M3 to remain consistent with previously published results, and comparisons were made to reference literature. RESULTS: The study included 385 subjects and 624 nerve repairs. Overall, 82% meaningful recovery (MR) was achieved across sensory, mixed, and motor nerve repairs up to gaps of 70 mm. No related adverse events were reported. There were no significant differences in MR across the nerve type, age, time-to-repair, and smoking status subgroups in the upper extremity (p > .05). Significant differences were noted by the mechanism of injury subgroups between complex injures (74%) as compared to lacerations (85%) or neuroma resections (94%) (p = .03) and by gap length between the <15 mm and 50-70 mm gap subgroups, 91 and 69% MR, respectively (p = .01). Results were comparable to historical literature for nerve autograft and exceed that of conduit. CONCLUSIONS: These findings provide clinical evidence to support the continued use of PNA up to 70 mm in sensory, mixed and motor nerve repair throughout the body and across a broad patient population.

Neuroendovascular techniques for treating cerebral aneurysms and other cerebrovascular pathology are increasingly becoming the standard of care. Intraluminal stents, aneurysm coils, and other flow diversion devices typically require concomitant antiplatelet therapy to reduce thromboembolic complications. The variability inherent with the pharmacodynamic response to common antiplatelet agents such as aspirin and clopidogrel complicates optimal selection of antiplatelet agents by clinicians. This review serves to discuss the literature related to antiplatelet use in neuroendovascular procedures and provides recommendations for clinicians on how to approach patients with variable response to antiplatelet agents, particularly clopidogrel.

Brains that have many neurofibrillary tangles (NFTs) in medial temporal lobe structures (Braak stage III or IV) but no cortical neuritic plaques (NPs) may be a diagnostic dilemma; they also raise questions about the amyloid cascade hypothesis of Alzheimer disease (AD) in which NFT development is thought to occur downstream of the development of amyloid plaques. To determine the clinical, demographic, and biological factors related to NFT+/NP- cases, we analyzed 26 NFT+/NP- patient brains identified from the University of Kentucky AD Center autopsy cohort (n=502); most of these patients were at least 85 years old and lacked profound antemortem cognitive impairment. A subset of the cases had NFTs in the medulla oblongata. Aberrant trans-activator regulatory DNA-binding protein 43 immunohistochemical staining was seen in 5 of the 26 cases with the clinical diagnoses of AD or mild cognitive impairment. We also queried cases in the National Alzheimer's Coordinating Center Registry (n=5,108) and found 219 NFT+/NP- cases. Those patients had a relatively high likelihood of belonging to a birth cohort with the highest incidence of influenza infection during the 1918 to 1919 pandemic. This observation may link the pathogenesis in NFT+/NP- cases to encephalitis during childhood. We conclude that NFT+/NP- cases comprise approximately 5% of aged individuals in multiple data sets; these cases are not necessarily within the spectrum of AD.

Recent reports have demonstrated that vancomycin (VAN) may lead to an increase in the incidence of acute kidney injury (AKI) when it is combined with antipseudomonal beta-lactams. This study compared the incidence of AKI associated with VAN plus piperacillin-tazobactam (TZP) or cefepime (FEP). This was a retrospective, matched cohort study that was conducted at an academic medical center between September 2010 and September 2014 and that included adult patients without severe chronic or structural kidney disease, dialysis, pregnancy, cystic fibrosis, or a hospital transfer receiving TZP-VAN or FEP-VAN for at least 48 h. The primary outcome was the difference in the AKI incidence between the TZP-VAN and FEP-VAN groups, evaluated using the risk, injury, failure, loss of kidney function, and end-stage kidney disease (RIFLE) criteria. Patients in the two groups were matched on the basis of age, sex, severity of illness, baseline creatinine clearance, hypotension, number of nephrotoxicity risk factors, and intravenous contrast exposure. In total, 4,193 patients met all inclusion criteria (3,605 received TZP-VAN and 588 received FEP-VAN). The unadjusted AKI incidence was 21.4% in patients receiving TZP-VAN, whereas it was 12.6% in patients receiving FEP-VAN (P < 0.001). After the patients were matched, 1,633 patients receiving TZP-VAN and 578 patients receiving FEP-VAN were evaluated. The AKI incidence remained higher in patients receiving TZP-VAN than in those receiving FEP-VAN (21.4% versus 12.5%, P < 0.0001). This trend remained true for all classifications of the RIFLE criteria. After controlling for remaining confounders, TZP-VAN therapy was associated with 2.18 times the odds of AKI than FEP-VAN therapy (95% confidence interval, 1.64 to 2.94 times) in logistic regression. AKI was significantly more common in patients receiving vancomycin in combination with piperacillin-tazobactam than in those receiving vancomycin in combination with cefepime. This finding reinforces the need for the judicious use of combination empirical antimicrobial therapy.

OBJECTIVE: To conduct a systematic literature review of spinal cord stimulation (SCS) for pain. DESIGN: Grade the evidence for SCS. METHODS: An international, interdisciplinary work group conducted literature searches, reviewed abstracts, and selected studies for grading. Inclusion/exclusion criteria included randomized controlled trials (RCTs) of patients with intractable pain of greater than one year's duration. Full studies were graded by two independent reviewers. Excluded studies were retrospective, had small numbers of subjects, or existed only as abstracts. Studies were graded using the modified Interventional Pain Management Techniques-Quality Appraisal of Reliability and Risk of Bias Assessment, the Cochrane Collaborations Risk of Bias assessment, and the US Preventative Services Task Force level-of-evidence criteria. RESULTS: SCS has Level 1 evidence (strong) for axial back/lumbar radiculopathy or neuralgia (five high-quality RCTs) and complex regional pain syndrome (one high-quality RCT). CONCLUSIONS: High-level evidence supports SCS for treating chronic pain and complex regional pain syndrome. For patients with failed back surgery syndrome, SCS was more effective than reoperation or medical management. New stimulation waveforms and frequencies may provide a greater likelihood of pain relief compared with conventional SCS for patients with axial back pain, with or without radicular pain.