Clinical Response to Third-Line Angiotensin-II vs Epinephrine in Septic Shock: A Propensity-Matched Cohort Study.

BACKGROUND: The appropriate third-line vasopressor in septic shock patients receiving norepinephrine and vasopressin is unknown. Angiotensin-II (AT-II) offers a unique mechanism of action to traditionally used vasopressors in septic shock. OBJECTIVE: The objective of this study was to compare the clinical efficacy and safety of third-line AT-II to epinephrine in patients with septic shock. METHODS: A single-center, retrospective cohort study of critically ill patients was performed between April 1, 2019 and July 31, 2022. Propensity-matched (2:1) analysis compared adults with septic shock who received third-line AT-II to controls who received epinephrine following norepinephrine and vasopressin. The primary outcome was clinical response 24 hours after third-line vasopressor initiation. Additional efficacy and safety outcomes were investigated. RESULTS: Twenty-three AT-II patients were compared with 46 epinephrine patients. 47.8% of AT-II patients observed a clinical response at hour 24 compared with 28.3% of epinephrine patients (P = 0.12). In-hospital mortality (65.2% vs 73.9%, P = 0.45), cardiac arrhythmias (26.1% vs 26.1%, P = 0.21), and thromboembolism (4.3% vs 2.2%, P = 0.61) were not observed to be statistically different between groups. CONCLUSIONS AND RELEVANCE: Administration of AT-II as a third-line vasopressor agent in septic shock patients was not associated with significantly improved clinical response at hour 24 compared with epinephrine. Although underpowered to detect meaningful differences, the clinical observations of this study warrant consideration and further investigation of AT-II as a third-line vasopressor in septic shock.

Effect of Early Administration of Vasopressin on New-Onset Arrhythmia Development in Patients With Septic Shock: A Retrospective, Observational Cohort Study.

Background: Adjunctive vasopressin use in septic shock reduces catecholamine requirements and is associated with a lower incidence of new-onset arrhythmias (NOAs). The association of vasopressin timing on NOA development is ill-described. Objective: To determine whether early administration of vasopressin was associated with a lower incidence of NOA in septic shock patients. Methods: A retrospective analysis of intensive care unit (ICU) patients at a large, academic medical center. Septic shock patients who required vasopressin and norepinephrine were eligible for inclusion. Patients were excluded for receipt of other vasoactive agents, history of cardiac arrhythmias, or outside hospital admission. Early vasopressin was defined as receipt within 6 hours of septic shock onset. The primary outcome was incidence of NOA. Results: In total, 436 patients, 220 (50.4%) in the early and 216 (49.6%) in the late vasopressin group, were included. Early vasopressin was not associated with a lower incidence of NOA compared with late vasopressin (9% vs 7%, median absolute difference [95% confidence interval, CI]: -2.1 [-7.2, 3.0], P = 0.41). Early vasopressin patients were observed to have shorter shock duration (2 vs 4 days, median absolute difference [95% CI]: 2 [1, 2], P < 0.001), and ICU length of stay (6 vs 7 days, median absolute difference [95% CI]: 1 [0, 2], P = 0.02). Conclusions and Relevance: Early vasopressin use was not associated with a lower incidence of NOA. Additional studies are needed to elucidate the effect of vasopressin timing on NOA and other clinical outcomes.

Multicenter study evaluating target attainment of anti-Factor Xa levels using various enoxaparin prophylactic dosing practices in adult trauma patients.

STUDY OBJECTIVE: Enoxaparin is standard of care for venous thromboembolism (VTE) prophylaxis in adult trauma patients, but fixed-dose protocols are suboptimal. Dosing based on body mass index (BMI) or total body weight (TBW) improves target prophylactic anti-Xa level attainment and reduces VTE rates. A novel strategy using estimated blood volume (EBV) may be more effective based on results of a single-center study. This study compared BMI-, TBW-, EBV-based, and hybrid enoxaparin dosing strategies at achieving target prophylactic anti-Factor Xa (anti-Xa) levels in trauma patients. DESIGN: Multicenter, retrospective review. DATA SOURCE: Electronic health records from participating institutions. PATIENTS: Adult trauma patients who received enoxaparin twice daily for VTE prophylaxis and had at least one appropriately timed anti-Xa level (collected 3 to 6 hours after the previous dose after three consecutive doses) from January 2017 through December 2020. Patients were excluded if the hospital-specific dosing protocol was not followed or if they had thermal burns with > 20% body surface area involvement. INTERVENTION: Dosing strategy used to determine initial prophylactic dose of enoxaparin. MEASUREMENTS: The primary end point was percentage of patients with peak anti-Xa levels within the target prophylactic range (0.2-0.4 units/mL). MAIN RESULTS: Nine hospitals enrolled 742 unique patients. The most common dosing strategy was based on BMI (43.0%), followed by EBV (29.0%). Patients dosed using EBV had the highest percentage of target anti-Xa levels (72.1%). Multiple logistic regression demonstrated EBV-based dosing was significantly more likely to yield anti-Xa levels at or above target compared to BMI-based dosing (adjusted odds ratio (aOR) 3.59, 95% confidence interval (CI) 2.29-5.62, p < 0.001). EBV-based dosing was also more likely than hybrid dosing to yield an anti-Xa level at or above target (aOR 2.30, 95% CI 1.33-3.98, p = 0.003). Other pairwise comparisons between dosing strategy groups were nonsignificant. CONCLUSIONS: An EBV-based dosing strategy was associated with higher odds of achieving anti-Xa level within target range for enoxaparin VTE prophylaxis compared to BMI-based dosing and may be a preferred method for VTE prophylaxis in adult trauma patients.

Major Publications in the Critical Care Pharmacotherapy Literature: 2022.

OBJECTIVES: A number of trials related to critical care pharmacotherapy were published in 2022. We aimed to summarize the most influential publications related to the pharmacotherapeutic care of critically ill patients in 2022. DATA SOURCES: PubMed/Medical Literature Analysis and Retrieval System Online and the Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update. STUDY SELECTION: Randomized controlled trials, prospective studies, or systematic review/meta-analyses of adult critically ill patients assessing a pharmacotherapeutic intervention and reporting clinical endpoints published between January 1, 2022, and December 31, 2022, were included in this article. DATA EXTRACTION: Articles from a systematic search and the Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update were included and stratified into clinical domains based upon consistent themes. Consensus was obtained on the most influential publication within each clinical domain utilizing an a priori defined three-round modified Delphi process with the following considerations: 1) overall contribution to scientific knowledge and 2) novelty to the literature. DATA SYNTHESIS: The systematic search and Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update yielded a total of 704 articles, of which 660 were excluded. The remaining 44 articles were stratified into the following clinical domains: emergency/neurology, cardiovascular, gastroenterology/fluids/nutrition, hematology, infectious diseases/immunomodulation, and endocrine/metabolic. The final article selected from each clinical domain was summarized following a three-round modified Delphi process and included three randomized controlled trials and three systematic review/meta-analyses. Article topics summarized included dexmedetomidine versus other sedatives during mechanical ventilation, beta-blocker treatment in the critically ill, restriction of IV fluids in septic shock, venous thromboembolism prophylaxis in critically ill adults, duration of antibiotic therapy for Pseudomonas aeruginosa ventilator-associated pneumonia, and low-dose methylprednisolone treatment in severe community-acquired pneumonia. CONCLUSIONS: This concise review provides a perspective on articles published in 2022 that are relevant to the pharmacotherapeutic care of critically ill patients and their potential impact on clinical practice.

Non-Antibiotic Approaches to Infection that Preserve the Microbiome in Critically Ill Patients.

In critically ill patients, the gut microbiota is subjected to various factors including antimicrobial exposure, modified gastrointestinal transit, nutrition support, as well as infection, which may lead to dysbiosis during the intensive care unit and hospital stay. Dysbiosis occupies an increasingly important role in driving morbidity and perhaps mortality in the critically ill or injured. Given that antibiotics lead to dysbiosis, it is relevant to understand the range of non-antibiotic approaches to infection-including those related to multi-drug-resistant organisms-that may leave the microbiome unimpacted. These strategies most prominently include the elimination of unabsorbed antibiotic agents from the digestive tract, pro-/pre-/synbiotics, fecal microbiota transplant, selective digestive and oropharyngeal decontamination, phage therapy, anti-sense oligonucleotides, structurally nanoengineered antimicrobial peptide polymers, and vitamin C-based lipid nanoparticles for adoptive macrophage transfer. Herein, we review the rationale for these therapies, current data regarding their use in critically ill patients, and the therapeutic potential for strategies that are not yet deployed in human medical care.

Prospective Observational Evaluation of Predatory Journals in Critical Care Pharmacy Practice: Defining Characteristics Associated With Receiving Unsolicited Invitations to Publish.

Open-access publishing promotes accessibility to scholarly research at no cost to the reader. The emergence of predatory publishers, which exploit the author-pay model by charging substantial publication fees for publication in journals with questionable publishing processes, is on the rise. Authors are solicited through aggressive marketing tactics, though who is targeted is not well described. The purpose of this study was to identify characteristics associated with critical care pharmacists that make them targets of unsolicited invitations to publish. A prospective, observational study of critical care pharmacists was performed. Participants archived emails received by their professional email that were unsolicited invitations to submit their original work for publication in a journal (unsolicited journals). Variables were evaluated to determine which were associated with unsolicited invitations; these were compared to legitimate journals, defined as all PubMed-indexed journals in which the participants were previously published. Twenty-three pharmacist participants were included, all of whom were residency and/or fellowship trained and practicing in an academic medical center. Participants had a median of 7 years of experience since their post-graduate training, 6 years since their last change in professional email address, and 2 years since their first PubMed-indexed publication. From these participants, 136 unsolicited and 59 legitimate journals were included. The average number of invitations increased 1.04 (95% CI, 1.02-1.05) times for every additional PubMed-indexed publication (P < .001). Most unsolicited journals were considered predatory. Legitimate and unsolicited journals differed significantly. The number of previous PubMed-indexed publications strongly correlates with the likelihood of critical care pharmacists receiving unsolicited publication invitations, often from predatory journal.

The safety and efficacy of push dose vasopressors in critically ill adults.

PURPOSE: To evaluate practice patterns, efficacy, and safety of push dose pressors (PDP) in critically ill patients outside of the operating room (OR) at a large academic medical center. MATERIALS AND METHODS: This was a single-center, retrospective cohort study (June 2018 to July 2020) conducted at a 1273-bed academic medical center. The primary outcome was efficacy, defined as a 25% increase in systolic blood pressure, and the cohort was analyzed according to PDP response (i.e. responders versus non-responders). A logistic regression model was used to assess predictors of response to PDPs. Safety outcomes included the incidence of hypertension, bradycardia, and tachycardia. RESULTS: 1727 patients were included in the final analysis. The median doses of phenylephrine and epinephrine administered were 400 µg (IQR 200-888 µg) and 50 µg (IQR 20-100 µg). The primary outcome was achieved in 102 (71.8%) patients in the epinephrine group and 1140 (55.9%) of patients in the phenylephrine group. Adverse effects after PDP receipt were minimal, with the most common being hypertension in 6.6% and 13.4% of the phenylephrine and epinephrine groups respectively. CONCLUSIONS: This study demonstrates that PDP phenylephrine and epinephrine are safe and efficacious in treating the acute hypotensive period.

Thromboembolic Complications After Receipt of Prothrombin Complex Concentrate.

Purpose: Patients presenting with life-threatening bleeding associated with oral anticoagulants (OACs) are challenging with few available treatments. Prothrombin complex concentrate (PCC) is an option for OAC reversal in the setting of life-threatening bleeding with a relatively benign safety profile. Little is known about the risk of developing thromboembolic complications (TEC) in patients receiving PCC who were previously anticoagulated. The aim of this study is to characterize the rate of TEC after receipt of PCC. Methods: All adult patients who received 4-Factor PCC for life-threatening bleeding were retrospectively evaluated over a 2-year time period. Data collected included anticoagulant and indication, bleeding source, PCC dose, INR, and TEC within 14 days of PCC dose, including venous thromboembolism (VTE), acute myocardial infarction, and ischemic stroke. Results: Three hundred thirty-three patients received 383 PCC doses. Of these, 55 (16.5%) patients developed TEC, including VTE, ischemic stroke, and acute myocardial infarction. There was increased rivaroxaban use in patients who developed TEC (25.4% vs 12.2%; P = .011). Additionally, there were more patients who had anticoagulation for a previous TEC in those who developed a new TEC (38.2% vs 23.4%; P = .022). Lastly, there was a higher rate of TEC in those who received >1 dose of PCC (21.8% vs 7.9%; P = .002). Conclusion: PCC administration in the setting of life-threatening bleeding is not benign. Risk of TEC increases in patients who have rivaroxaban reversal, receive a repeat dose of PCC, and have a TEC indication for their anticoagulation and these factors should be further investigated.

Evaluation of Amiodarone Use for New-Onset Atrial Fibrillation in Critically Ill Patients With Septic Shock.

Objective: To describe the use of amiodarone in critically ill, septic shock patients experiencing new-onset atrial fibrillation (NOAF) during the acute resuscitative phase of septic shock. Methods: Single-center, retrospective review of adult medical or surgical intensive care unit (ICU) patients with septic shock and NOAF. All patients received amiodarone for NOAF during the acute resuscitative phase of septic shock. The cohort was analyzed via descriptive statistics. Associations between amiodarone exposure and clinical outcomes were analyzed via a Cox proportional-hazards model. An a priori defined sensitivity analysis of hospital survivors was also employed. Main Results: A total of 239 patients were included in the analysis. Patients had a median baseline Charlson Comorbidity Index of 4 (interquartile range [IQR]: 2-6) and were acutely ill with a median Acute Physiology and Chronic Health Evaluation II (APACHE II) score of 18 (IQR: 13-22) and an incidence of mechanical ventilation of 85%. In-hospital mortality was 56% with median ICU and hospital length of stay (LOS) of 9 and 15 days, respectively. Included patients received a median of 2760 (IQR: 1110-6415) mg of intravenous (IV) amiodarone during their ICU stay. Receipt of more than or equal to 2700 mg of amiodarone was identified as an independent factor associated with longer ICU LOS (hazard ratio [HR]: 1.30; 95% confidence interval [CI], 1.10-2.28). In a sensitivity analysis of hospital survivors (n = 105), receipt of more than or equal to 2700 mg of amiodarone remained independently associated with longer ICU LOS (HR: 1.64; 95% CI, 1.05-2.58). Conclusions: Exposure to more than or equal to 2700 mg of amiodarone in the setting of NOAF and septic shock is positively correlated with longer ICU LOS. Identifying opportunities to limit amiodarone exposure and address/resolve potential precipitating causes of NOAF in this clinical scenario may reduce the morbidity associated with septic shock.

Effect of Vasopressin Dose on Hemodynamic Response in Obese Patients With Septic Shock: A Retrospective Observational Study.

BACKGROUND: No clear association between standard vasopressin doses and body mass index exists, despite potential pharmacokinetic and pharmacodynamic variability among patients with septic shock. It is unknown if higher doses may alter hemodynamic response. OBJECTIVE: The purpose of this study was to evaluate the effect of vasopressin dose on hemodynamic response in obese patients with septic shock. METHODS: A single-center, retrospective cohort study was conducted in adult, obese patients with septic shock receiving catecholamine vasopressors and vasopressin. Patients were analyzed according to vasopressin dose received: standard dose (≤0.04 U/min) and high dose (>0.04 U/min). The primary outcome was percentage change in norepinephrine equivalent (NEQ) dose. RESULTS: A total of 182 patients were included in the analysis, with 136 in the standard-dose vasopressin group and 46 in the high-dose vasopressin group. There was no difference in percentage change in NEQ dose at 6 hours after standard- or high-dose vasopressin attainment (-28.6% vs -19.1%; P = 0.166). A greater increase in mean arterial pressure (MAP) at 6 hours was observed with receipt of high-dose vasopressin (23.3% vs 15.3%; P = 0.023). Duration of shock and length of stay were significantly longer in patients who received high-dose vasopressin, with no difference in in-hospital mortality. CONCLUSION AND RELEVANCE: This represents the first analysis comparing standard and higher doses of vasopressin in obese patients with septic shock. Receipt of high-dose vasopressin was not associated with a difference in catecholamine requirement or improved outcomes. Further studies are warranted to provide guidance on the use of high-dose vasopressin in septic shock.

A high-fat high-sugar diet in adolescent rats impairs social memory and alters chemical markers characteristic of atypical neuroplasticity and parvalbumin interneuron depletion in the medial prefrontal cortex.

Brain plasticity is a multifaceted process that is dependent on both neurons and extracellular matrix (ECM) structures, including perineuronal nets (PNNs). In the medial prefrontal cortex (mPFC) PNNs primarily surround fast-spiking parvalbumin (PV)-containing GABAergic interneurons and are central to regulation of neuroplasticity. In addition to the development of obesity, high-fat and high-sugar (HFHS) diets are also associated with alterations in brain plasticity and emotional behaviours in humans. To examine the underlying involvement of PNNs and cortical plasticity in the mPFC in diet-evoked social behaviour deficits (in this case social recognition), we exposed adolescent (postnatal days P28-P56) rats to a HFHS-supplemented diet. At P56 HFHS-fed animals and age-matched controls fed standard chow were euthanized and co-localization of PNNs with PV neurons in the prelimbic (PrL) and infralimbic (IL) and anterior cingulate (ACC) sub regions of the PFC were examined by dual fluorescence immunohistochemistry. ΔFosB expression was also assessed as a measure of chronic activity and behavioural addiction marker. Consumption of the HFHS diet reduced the number of PV+ neurons and PNNs in the infralimbic (IL) region of the mPFC by -21.9% and -16.5%, respectively. While PV+ neurons and PNNs were not significantly decreased in the ACC or PrL, the percentage of PV+ and PNN co-expressing neurons was increased in all assessed regions of the mPFC in HFHS-fed rats (+33.7% to +41.3%). This shows that the population of PV neurons remaining are those surrounded by PNNs, which may afford some protection against HFHS diet-induced mPFC-dysregulation. ΔFosB expression showed a 5-10-fold increase (p < 0.001) in each mPFC region, supporting the hypothesis that a HFHS diet induces mPFC dysfunction and subsequent behavioural deficits. The data presented shows a potential neurophysiological mechanism and response to specific diet-evoked social recognition deficits as a result of hypercaloric intake in adolescence.

The nucleus accumbens shell in reinstatement and extinction of drug seeking.

The contexts where drugs are self-administered have important control over relapse and extinction of drug-seeking behavior. The nucleus accumbens shell (AcbSh) is essential to this contextual control over drug-seeking behavior. It has been consistently implicated in both the expression of context-induced reinstatement and the expression of extinction, across a variety of drug classes and other rewards. Here, we review the evidence linking AcbSh to the extinction and reinstatement of drug seeking. We consider whether this dual role can be linked to known heterogeneities in AcbSh cell types, their major afferents, and their major efferents. We show that although these heterogeneities are each important and can determine extinction vs. reinstatement, they do not seem adequate to explain the body of findings from the behavioral literature. Rather, we suggest that this functional specialization of AcbSh may be more profitably viewed in terms of the segregation and compartmentalization of AcbSh channels.

Distinct Accumbens Shell Output Pathways Promote versus Prevent Relapse to Alcohol Seeking.

Contexts exert bi-directional control over relapse to drug seeking. Contexts associated with drug self-administration promote relapse, whereas contexts associated with the absence of self-administration protect against relapse. The nucleus accumbens shell (AcbSh) is a key brain region determining these roles of context. However, the specific cell types, and projections, by which AcbSh serves these dual roles are unknown. Here, we show that contextual control over relapse and abstinence is embedded within distinct output circuits of dopamine 1 receptor (Drd1) expressing AcbSh neurons. We report anatomical and functional segregation of Drd1 AcbSh output pathways during context-induced reinstatement and extinction of alcohol seeking. The AcbSh→ventral tegmental area (VTA) pathway promotes relapse via projections to VTA Gad1 neurons. The AcbSh→lateral hypothalamus (LH) pathway promotes extinction via projections to LH Gad1 neurons. Targeting these opposing AcbSh circuit contributions may reduce propensity to relapse to, and promote abstinence from, drug use.

Pharmacokinetics and Pharmacodynamics of Antimicrobials in Critically Ill Patients.

Critically ill patients with severe infections often have altered pharmacokinetic and pharmacodynamic variables that lead to challenging treatment decisions. These altered variables can often lead to inadequate dosing and poor treatment outcomes. The pharmacokinetic parameters include absorption, distribution, metabolism, and excretion. Pharmacodynamics is the relationship between drug serum concentrations and pharmacologic and toxicologic properties of the medication. In addition to these altered parameters, these critically ill patients frequently are receiving organ support in the forms of continuous renal replacement therapy or extra-corporeal membrane oxygenation. Altered pharmacodynamics can lead to decreased end-organ perfusion, which can ultimately lead to treatment failure or exposure-related toxicity. The most common antimicrobials utilized in the intensive care unit are classified by the pharmacodynamic principles of time-dependent, concentration-dependent, and concentration dependent with time-dependence. Thus, the aim of this review is to outline pharmacokinetic and pharmacodynamic changes of critically ill patients with severe infections and provide strategies for optimal antibiotic agent dosing in these patients.

Clinical Experience With Pharmacological Venous Thromboembolism Prophylaxis in the Underweight and Critically Ill.

BACKGROUND: The optimal regimen for pharmacological prophylaxis of venous thromboembolism (VTE) in underweight, critically ill patients is unknown. OBJECTIVE: To describe prescribing patterns for VTE prophylaxis in underweight (≤50 kg or body mass index ≤18.5 kg/m(2)), critically ill patients and identify the prevalence of VTE and bleeding. METHODS: This was a retrospective cohort study that included patients who received standard- or reduced-dose VTE prophylaxis for ≥48 hours. RESULTS: A total of 295 individuals were included in the study. The majority of underweight patients in this study (79.7%) received unfractionated heparin, 5000 units 3 times daily. No statistically significant difference in the prevalence of clinically relevant VTEs between the reduced- and standard-dose groups was observed (4.4% vs 5.6%, P = 1.00), but a higher proportion of bleeding events was identified within the standard-dose group (6.7% vs 11.2%, P = 0.4). CONCLUSIONS: Empirical dose reductions of VTE prophylaxis are infrequently used in underweight, critically ill patients. Further studies need to be conducted that assess the safety and efficacy of reduced-dose VTE prophylactic regimens in this population to determine if acceptable efficacy can be achieved, with lower risks of bleeding.

Evaluation of an updated insulin infusion protocol at a large academic medical center.

PURPOSE: The performance of an updated insulin infusion protocol was evaluated at a large, academic medical center. METHODS: A retrospective medical record review was performed after a one-month run-in period for all patients at a large, academic, tertiary care medical center in whom the insulin infusion per protocol was administered from January 1 through February 28, 2014. Data were evaluated to determine the median blood glucose (BG) level, time to achieve BG in the target range, number of BG checks per patient per day, time elapsed between each BG check, and the frequency of hypoglycemia (BG concentration of ≤70 mg/dL). RESULTS: A total of 170 patients were included. The median preinfusion BG was 244 mg/dL (interquartile range [IQR], 204-304 mg/dL), which decreased to a median of 168 mg/dL (IQR, 147.5-199.5 mg/dL) when the protocol was utilized. However, 70 patients (41%) had a median BG concentration of ≥180 mg/dL, and 25 patients' (15%) BG value remained above 180 mg/dL. The median time to achieve the goal BG value was 4.2 hours (95% confidence interval, 3.2-5.1 hours). BG checks were performed a median of every 2.1 hours (IQR, 1.4-2.3 hours). Hypoglycemia was rare, occurring in only 2 (1.2%) patients. CONCLUSION: The median BG with an updated insulin infusion protocol approached the upper limit of the target BG range, and 41% of patients had a median BG above the goal range. Protocol specifications for the frequency of BG monitoring were not commonly followed, but the frequency of hypoglycemia was extremely low.

Influence of Colistin Dose on Global Cure in Patients with Bacteremia Due to Carbapenem-Resistant Gram-Negative Bacilli.

The increasing prevalence of multidrug-resistant (MDR) nosocomial infections accounts for increased morbidity and mortality of such infections. Infections with MDR Gram-negative isolates are frequently treated with colistin. Based on recent pharmacokinetic studies, current colistin dosing regimens may result in a prolonged time to therapeutic concentrations, leading to suboptimal and delayed effective treatment. In addition, studies have demonstrated an association between an increased colistin dose and improved clinical outcomes. However, the specific dose at which these outcomes are observed is unknown and warrants further investigation. This retrospective study utilized classification and regression tree (CART) analysis to determine the dose of colistin most predictive of global cure at day 7 of therapy. Patients were assigned to high- and low-dose cohorts based on the CART-established breakpoint. The secondary outcomes included microbiologic outcomes, clinical cure, global cure, lengths of intensive care unit (ICU) and hospital stays, and 7- and 28-day mortalities. Additionally, safety outcomes focused on the incidence of nephrotoxicity associated with high-dose colistin therapy. The CART-established breakpoint for high-dose colistin was determined to be >4.4 mg/kg of body weight/day, based on ideal body weight. This study evaluated 127 patients; 45 (35%) received high-dose colistin, and 82 (65%) received low-dose colistin. High-dose colistin was associated with day 7 global cure (40% versus 19.5%; P = 0.013) in bivariate and multivariate analyses (odds ratio [OR] = 3.40; 95% confidence interval [CI], 1.37 to 8.45; P = 0.008). High-dose colistin therapy was also associated with day 7 clinical cure, microbiologic success, and mortality but not with the development of acute kidney injury. We concluded that high-dose colistin (>4.4 mg/kg/day) is independently associated with day 7 global cure.

Role of the striatopallidal pathway in renewal and reacquisition of alcohol seeking.

The ventral pallidum (VP) is a key component of the neural circuitry mediating relapse to drug seeking, but the critical afferent pathways to VP recruited during relapse remain poorly understood. We studied the role of the nucleus accumbens core (AcbC) → VP pathway in ABA renewal and reacquisition of alcohol seeking. Rats received application of adenoviral vectors encoding eYFP, ChR2(H134R), or eNpHr3.0 to AcbC and implantation of fiber optic cannulas into VP to permit photostimulation of AcbC terminals there. Rats were then trained to self-administer alcoholic beer in 1 context (A), extinguished in a second context (B), tested in the extinction (ABB) and training (ABA) contexts, and were then tested for reacquisition of alcoholic beer seeking. There was ABA renewal of alcohol seeking, but neither optogenetic excitation nor inhibition of the AcbC → VP pathway affected this renewal. In contrast, optogenetic inhibition of the AcbC → VP striatopallidal pathway reduced reacquisition of alcohol seeking-measured either by the number of active nosepokes emitted or by the number of alcohol rewards earned and consumed. Moreover, optogenetic excitation of the AcbC → VP striatopallidal pathway increased magazine entries during reacquisition test. This finding shows the importance of the AcbC → VP pathway in controlling relapse when the drug reinforcer is present on test and is consistent with a role for the AcbC → VP pathway in regulating the hedonic or incentive motivational properties of drug reinforcers.