Enhanced recovery after surgery (ERAS® ) Society abdominal and thoracic surgery recommendations: A systematic review and comparison of guidelines for perioperative and pharmacotherapy core items.

INTRODUCTION: Worldwide, ERAS® Society guidelines have ushered in a new era of perioperative care. The purpose of this systematic review is to compare published core elements and pharmacotherapy recommendations embedded within ERAS® Society abdominal and thoracic surgery (ATS) guidelines. Determining whether a consensus exists for pharmacological core items would make future guideline preparation for similar surgeries more standardized and could improve patient care by reducing unnecessary protocol variations. METHODS: From the ERAS® Society website as of May 2023, 16 current ERAS® published ATS guidelines were included in the analysis to determine consensus and differing statements regarding each ERAS® perioperative and pharmacotherapy-related item. The aims were to (a) determine whether a consensus for each item could be derived, (b) identify gaps in ERAS® protocol development, and (c) propose potential research directions for addressing the identified gaps in the literature. RESULTS: Core items with consensus included: preoperative smoking and alcohol cessation; avoiding bowel reparation and fasting; multimodal preanesthetic, perioperative analgesia, and postoperative nausea and vomiting regimens; low molecular weight heparins for in-hospital and at-home venous thromboembolism prophylaxis; antibiotic prophylaxis; skin preparation; goal-directed perioperative fluid management with balanced crystalloids; perioperative nutrition care; ileus prevention with peripherally-acting mu receptor antagonists; and glucose control. CONCLUSION: While consensus was found for aspects of 21 current ERAS® guideline core items related to pharmacotherapy choice, details related to doses, regimen, timing of administration as well as unique aspects pertaining to specific surgeries remain to be researched and harmonized to promote guideline consistency and further optimize patient outcomes.

Effect of Pharmacoprophylaxis on Postoperative Outcomes in Adult Elective Colorectal Surgery: A Multi-Center Retrospective Cohort Study within an Enhanced Recovery after Surgery Framework.

BACKGROUND: The application of enhanced recovery after surgery principles decreases postoperative complications (POCs), length of stay (LOS), and readmissions. Pharmacoprophylaxis decreases morbidity, but the effect of specific regimens on clinical outcomes is unclear. METHODS AND MATERIALS: Records of 476 randomly selected adult patients who underwent elective colorectal surgeries (ECRS) at 10 US hospitals were abstracted. Primary outcomes were surgical site infection (SSI), venous thromboembolism (VTE), postoperative nausea and vomiting (PONV), pain, and ileus rates. Secondary outcomes included LOS and 7- and 30-day readmission rates. RESULTS: POC rates were SSI (3.4%), VTE (1.5%), PONV (47.9%), pain (58.1%), and ileus (16.1%). Cefazolin 2 g/metronidazole 500 mg and ertapenem 1 g were associated with the shortest LOS; cefotetan 2 g and cefoxitin 2 g with the longest LOS. No SSI occurred with ertapenem and cefotetan. More Caucasians than Blacks received oral antibiotics before intravenous antibiotics without impact. Enoxaparin 40 mg subcutaneously daily was the most common inpatient and discharge VTE prophylaxis. All in-hospital VTEs occurred with unfractionated heparin. Most received rescue rather than around-the-clock antiemetics. Scopolamine patches, spinal opioids, and IV lidocaine continuous infusion were associated with lower PONV. Transversus abdominis plane block with long-acting local anesthetics, celecoxib, non-anesthetic ketamine bolus, ketorolac IV, lidocaine IV, and pregabalin were associated with lower in-hospital pain severity rates. Gabapentinoids and alvimopan were associated with lower ileus rates. Acetaminophen, alvimopan, famotidine, and lidocaine patches were associated with shorter LOS. CONCLUSIONS: Significant differences in pharmacotherapy regimens that may improve primary and secondary outcomes in ECRS were identified. In adult ECRS, cefotetan or ertapenem may be better regimens for preventing in-hospital SSI, while ertapenem or C/M may lead to shorter LOS. The value of OA to prevent SSI was not demonstrated. Inpatient enoxaparin, compared to UFH, may reduce VTE rates with a similar LOS. A minority of patients had a documented PONV risk assessment, and a majority used as-needed rather than around-the-clock strategies. Preoperative scopolamine patches continued postoperatively may lower PONV and PDNV severity and shorter LOS. Alvimopan may reduce ileus and shorten LOS. Anesthesia that includes TAP block, ketorolac IV, and pregabalin use may lead to reduced pain rates. Acetaminophen, alvimopan, famotidine, and lidocaine patches may shorten LOS. Given the challenges of pain management and the incidence of PONV/PDNV found in this study, additional studies should be conducted to determine optimal opioid-free anesthesia and the benefit of newer antiemetics on patient outcomes. Moreover, future research should identify latent pharmacotherapy variables that impact patient outcomes, correlate pertinent laboratory results, and examine the impact of order or care sets used for ECRS at study hospitals.

Ketamine in Critically Ill Patients: Use, Perceptions, and Potential Barriers.

Objective: To evaluate practitioner use of ketamine and identify potential barriers to use in acutely and critically ill patients. To compare characteristics, beliefs, and practices of ketamine frequent users and non-users. Methods: An online survey developed by members of the Society of Critical Care Medicine (SCCM) Clinical Pharmacy and Pharmacology Section was distributed to physician, pharmacist, nurse practitioner, physician assistant and nurse members of SCCM. The online survey queried SCCM members on self-reported practices regarding ketamine use and potential barriers in acute and critically ill patients. Results: Respondents, 341 analyzed, were mostly adult physicians, practicing in the United States at academic medical centers. Clinicians were comfortable or very comfortable using ketamine to facilitate intubation (80.0%), for analgesia (77.9%), procedural sedation (79.4%), continuous ICU sedation (65.8%), dressing changes (62.4%), or for asthma exacerbation and status epilepticus (58.8% and 40.4%). Clinicians were least comfortable with ketamine use for alcohol withdrawal and opioid detoxification (24.7% and 23.2%). Most respondents reported "never" or "infrequently" using ketamine preferentially for continuous IV analgesia (55.6%) or sedation (61%). Responses were mixed across dosing ranges and duration. The most common barriers to ketamine use were adverse effects (42.6%), other practitioners not routinely using the medication (41.5%), lack of evidence (33.5%), lack of familiarity (33.1%), and hospital/institutional policy guiding the indication for use (32.3%). Conclusion: Although most critical care practitioners report feeling comfortable using ketamine, there are many inconsistencies in practice regarding dose, duration, and reasons to avoid or limit ketamine use. Further educational tools may be targeted at practitioners to improve appropriate ketamine use.

Evaluation of Vasopressor Exposure and Mortality in Patients With Septic Shock.

OBJECTIVES: The objectives of this study were to: 1) determine the association between vasopressor dosing intensity during the first 6 hours and first 24 hours after the onset of septic shock and 30-day in-hospital mortality; 2) determine whether the effect of vasopressor dosing intensity varies by fluid resuscitation volume; and 3) determine whether the effect of vasopressor dosing intensity varies by dosing titration pattern. DESIGN: Multicenter prospective cohort study between September 2017 and February 2018. Vasopressor dosing intensity was defined as the total vasopressor dose infused across all vasopressors in norepinephrine equivalents. SETTING: Thirty-three hospital sites in the United States (n = 32) and Jordan (n = 1). PATIENTS: Consecutive adults requiring admission to the ICU with septic shock treated with greater than or equal to 1 vasopressor within 24 hours of shock onset. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Out of 1,639 patients screened, 616 were included. Norepinephrine (93%) was the most common vasopressor. Patients received a median of 3,400 mL (interquartile range, 1,851-5,338 mL) during the 24 hours after shock diagnosis. The median vasopressor dosing intensity during the first 24 hours of shock onset was 8.5 µg/min norepinephrine equivalents (3.4-18.1 µg/min norepinephrine equivalents). In the first 6 hours, increasing vasopressor dosing intensity was associated with increased odds ratio of 30-day in-hospital mortality, with the strength of association dependent on concomitant fluid administration. Over the entire 24 hour period, every 10 µg/min increase in vasopressor dosing intensity was associated with an increased risk of 30-day mortality (adjusted odds ratio, 1.33; 95% CI, 1.16-1.53), and this association did not vary with the amount of fluid administration. Compared to an early high/late low vasopressor dosing strategy, an early low/late high or sustained high vasopressor dosing strategy was associated with higher mortality. CONCLUSIONS: Increasing vasopressor dosing intensity during the first 24 hours after septic shock was associated with increased mortality. This association varied with the amount of early fluid administration and the timing of vasopressor titration.

Effects From Continuous Infusions of Dexmedetomidine and Propofol on Hemodynamic Stability in Critically Ill Adult Patients With Septic Shock.

PURPOSE: To compare the development of clinically significant hemodynamic event (ie, hypotension or bradycardia) in adults with septic shock receiving either propofol or dexmedetomidine. MATERIALS AND METHODS: A retrospective cohort study of adults with septic shock admitted to an intensive care unit (ICU) at an academic medical center between July 2013 and July 2017. RESULTS: Patients in the propofol (n = 35) and dexmedetomidine (n = 37) groups developed a clinically significant hemodynamic event at similar frequencies (31.4 vs 29.7%, P = .99). All patients with an event experienced hypotension, whereas 2 (5.4%) patients in the dexmedetomidine group also experienced bradycardia. Most patients in both groups (70% vs 90%) received an escalating sedative dose, and almost half (42.9%) in the dexmedetomidine group had the sedative dosage increased more frequently than every 30 minutes. Patients in both groups had similar ICU (24.1 vs 24.3 days, P = .98) and hospital (37.9 vs 29.7 days, P = .29) lengths of stay. There was no difference in median time to hemodynamic event between the groups (propofol 1 hour [interquartile range, IQR: 0.5-9.9] vs dexmedetomidine 2 hours [IQR: 1.5-11.1 hours], P = .85). CONCLUSION: Patients with septic shock receiving propofol or dexmedetomidine experienced similar rates of clinically significant hemodynamic events. Most patients did not experience an event and those who did most frequently did so in the first couple of hours of therapy.

Norepinephrine and Vasopressin Compared With Norepinephrine and Epinephrine in Adults With Septic Shock.

Background: The optimal adjuvant vasopressor to norepinephrine in septic shock remains controversial. Objective: To compare durations of shock-free survival between adjuvant vasopressin and epinephrine. Methods: A retrospective, single-center, matched cohort study of adults with septic shock refractory to norepinephrine was conducted. Patients receiving norepinephrine not at target mean arterial pressure (MAP; 65 mm Hg) were initiated on vasopressin or epinephrine to raise MAP to target. Vasopressin-exposed patients were matched to epinephrine-exposed patients using propensity scores. Mortality outcomes were examined using multivariable Poisson regression with robust variance estimation. Results: Of 166 patients, 96 (entire cohort) were included in the propensity score-matched cohort. Shock-free survival durations in the first 7 days were similar between epinephrine- and vasopressin-exposed patients in the matched cohort (median = 13.2 hours, interquartile range [IQR] = 0-121.0, vs median = 41.3 hours, IQR = 0-125.9; P = 0.51). Seven- and 28-day mortality rates were similar in the matched cohort (7-day: 47.9% vs 39.6%, P = 0.35; 28-day: 56.3% vs 58.3%, P = 0.84). Mortality rates were similar between epinephrine- and vasopressin-exposed patients in propensity score-matched regression models with and without adjustments at 7 (relative risk [RR] = 1.28, 95% CI = 0.92-1.79; RR = 1.21, 95% CI = 0.81-1.81) and 28 days (RR = 1.04, 95% CI = 0.81-1.34; RR = 0.96, 95% CI = 0.69-1.34). Conclusion and Relevance: Shock-free survival durations were similar in matched epinephrine- and vasopressin-exposed groups. Adjuvant epinephrine or vasopressin alongside norepinephrine to raise MAP to target requires further investigation.

Physician agreement on the diagnosis of sepsis in the intensive care unit: estimation of concordance and analysis of underlying factors in a multicenter cohort.

BACKGROUND: Differentiating sepsis from the systemic inflammatory response syndrome (SIRS) in critical care patients is challenging, especially before serious organ damage is evident, and with variable clinical presentations of patients and variable training and experience of attending physicians. Our objective was to describe and quantify physician agreement in diagnosing SIRS or sepsis in critical care patients as a function of available clinical information, infection site, and hospital setting. METHODS: We conducted a post hoc analysis of previously collected data from a prospective, observational trial (N = 249 subjects) in intensive care units at seven US hospitals, in which physicians at different stages of patient care were asked to make diagnostic calls of either SIRS, sepsis, or indeterminate, based on varying amounts of available clinical information (clinicaltrials.gov identifier: NCT02127502). The overall percent agreement and the free-marginal, inter-observer agreement statistic kappa (κ free) were used to quantify agreement between evaluators (attending physicians, site investigators, external expert panelists). Logistic regression and machine learning techniques were used to search for significant variables that could explain heterogeneity within the indeterminate and SIRS patient subgroups. RESULTS: Free-marginal kappa decreased between the initial impression of the attending physician and (1) the initial impression of the site investigator (κ free 0.68), (2) the consensus discharge diagnosis of the site investigators (κ free 0.62), and (3) the consensus diagnosis of the external expert panel (κ free 0.58). In contrast, agreement was greatest between the consensus discharge impression of site investigators and the consensus diagnosis of the external expert panel (κ free 0.79). When stratified by infection site, κ free for agreement between initial and later diagnoses had a mean value + 0.24 (range - 0.29 to + 0.39) for respiratory infections, compared to + 0.70 (range + 0.42 to + 0.88) for abdominal + urinary + other infections. Bioinformatics analysis failed to clearly resolve the indeterminate diagnoses and also failed to explain why 60% of SIRS patients were treated with antibiotics. CONCLUSIONS: Considerable uncertainty surrounds the differential clinical diagnosis of sepsis vs. SIRS, especially before organ damage has become highly evident, and for patients presenting with respiratory clinical signs. Our findings underscore the need to provide physicians with accurate, timely diagnostic information in evaluating possible sepsis.

Possible correlation of sirolimus plasma concentration with sinusoidal obstructive syndrome of the liver in patients undergoing myeloablative allogeneic hematopoietic cell transplantation.

STUDY OBJECTIVES: To determine the frequency of sinusoidal obstructive syndrome (SOS) in patients undergoing allogeneic hematopoietic cell transplantation who received graft-versus-host disease (GVHD) prophylaxis with sirolimus and tacrolimus, and to assess whether the occurrence of SOS correlates with immunosuppressant levels. DESIGN: Retrospective cohort study. SETTING: Hematopoietic cell transplant unit at an academic medical center. PATIENTS: Fifty-nine adults who received myeloablative preparative regimens for transplantation of any hematologic malignancy and received sirolimus and tacrolimus for GVHD prophylaxis between January 1, 2007, and May 1, 2009; all donors and transplant recipients were human leukocyte antigen (HLA) matched for at least HLA-A, -B, -C, and -DRB1. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the occurrence of SOS after hematopoietic cell transplantation. Plasma concentrations of sirolimus and tacrolimus and the summative levels of sirolimus and tacrolimus were then compared in patients who developed SOS with those who did not develop SOS. Trough levels were measured from blood samples collected 30-60 minutes before the morning doses of sirolimus and tacrolimus on days 0-35, or until the development of SOS. Of the 59 patients, 12 (20%) developed SOS. The mean sirolimus level was significantly higher in patients who developed SOS relative to those who did not develop SOS (10.5 vs 8.7 ng/ml, p=0.003). The mean summative trough level of sirolimus and tacrolimus was also significantly higher in those who developed SOS compared with those who did not (19.7 vs 17.1 ng/ml, p=0.003). The mean ± SD time to the occurrence of SOS was 28 ± 8.7 days. The median time to death was 101 days for patients who developed SOS compared with 433 days for patients who did not develop SOS (p=0.002). CONCLUSION: Sirolimus plasma concentration may correlate with the development of delayed SOS; however, further research is needed to prospectively evaluate the role of sirolimus exposure in the pathogenesis of SOS.

Systemic steroids in severe sepsis and septic shock.

Despite more than 5 decades of study and debate, the role of corticosteroid treatment in patients with severe sepsis and septic shock remains controversial. Data support a beneficial effect on systemic blood pressure in patients with septic shock. However, the ability of corticosteroid therapy to improve mortality in patients with severe sepsis and septic shock remains controversial, with contradictory results from recent large multicenter clinical trials. Although it appears clear that high-dose corticosteroid treatment provides no benefit and possibly harm in septic patients, the experimental design flaws and biases of recent low-dose (physiologic) steroid treatment trials limit their ability to provide adequate answers to the important questions of which septic patients should be treated, how much steroid to give, and the optimum duration of treatment. Unfortunately, the answer to these important questions is not readily evident based on the current evidence or the application of metaanalysis to the available clinical data. This concise evidence-based review highlights the strengths and weaknesses of the current data to inform the practicing clinician as to which patients are likely to derive significant benefit from corticosteroid treatment, while we await more definitive guidance from future multicenter, prospective, randomized, controlled trials designed to better answer these important therapeutic questions.

An evaluation of hepatotoxicity and nephrotoxicity of liposomal amphotericin B (L-AMB).

Hepatic and renal functions are important considerations when selecting antifungal therapy. This investigation of liposomal amphotericin B (L-AMB) was conducted to determine the incidence and factors associated with the development of hepatotoxicity and nephrotoxicity. A retrospective chart review was conducted of 100 consecutive patients receiving L-AMB at doses of 1, 3, and 5 mg/kg. Hepatotoxicity was defined as an increase of bilirubin greater than 1.5 mg/dl or AST and ALT greater than three times the normal range. Nephrotoxicity was defined as an increase in serum creatinine of 0.5 mg/dl or an increase of 50% from baseline. Patients were included if they were 18 years of age or older. Patients were excluded if they had developed hepatic or renal dysfunction prior to L-AMB administration. Seventy-five patients were included based upon the predefined inclusion/exclusion criteria. Twenty-one percent (16/75) developed hepatotoxicity based upon the predefined criteria. There were no additive correlates for this adverse effect. Overall, 56% (42/75) of patients developed nephrotoxicity. Seventy-four percent (31/42) were exposed to IV contrast, and 90% (38/42) were receiving nephrotoxins concurrently. Age, cumulative dose, concomitant nephrotoxins, and IV contrast exposure were associated with increased nephrotoxicity (p<0.001). The development of hepatotoxicity was observed; however, no correlates (age, dose escalation, or cumulative dose) were significantly associated with its occurrence. Overall nephrotoxicity with L-AMB was common and often multifactorial. Lipid amphotericin B products are associated with lower rates of nephrotoxicity than conventional amphotericin; however, in this analysis, L-AMB was associated with a high incidence of nephrotoxicity.

Assessing the influence of registered dietitian order-writing privileges on parenteral nutrition use.

Previous studies have examined the influence of a nutrition support team on parenteral nutrition (PN) use; however, the influence of registered dietitian (RD) order-writing privileges on appropriate PN use has yet to be reported. A retrospective cohort was conducted at a single tertiary care urban academic medical center to compare adult PN use before RD order-writing privileges (January 1, 2003 to December 31, 2004, pre-privileges) to after RD order-writing privileges (January 1, 2006 to December 31, 2007, post-privileges). RD order-writing privileges were obtained June 2005; PN patients during the washout period (January 1, 2005 to December 31, 2005) were not included. Descriptive statistics were conducted (N=1,965 patients). Although total hospital admissions increased from the pre-privileges to post-privileges periods (P<0.0001), overall PN use decreased from 1,080 patients during the pre-privileges period to 885 patients during the post-privileges period (P<0.0001). Inappropriate PN use decreased from 482 (45%) to 240 (27%) patients (P<0.0001) during the pre- and post-privileges periods, respectively. Among inappropriate PN use, there was a decrease in PN administration for patients with poor oral intake (130 to 41 patients), pancreatitis (78 to 26 patients), intractable nausea and vomiting (68 to 23 patients), and mucositis (56 to 18 patients; all Ps<0.0003), reflecting a 20% cost savings for PN. No significant differences were found in hospital length of stay, admissions to intensive care units, or other infectious complications between the two periods. RDs with order-writing privileges can decrease inappropriate PN use and costs in a hospital setting. Future studies should continue to highlight the influence of RDs in these advanced practice roles, as well as other members of the nutrition support team, especially with regard to nutrition support delivery and patient outcomes.

Impact of the implementation of a sepsis protocol for the management of fluid-refractory septic shock: A single-center, before-and-after study.

BACKGROUND: Evidence-based guidelines have been published for the acute management of severe sepsis and septic shock. Key goals of institution-driven protocols include timely fluid resuscitation and antibiotic selection, as well as source control. OBJECTIVE: This study assessed the impact of a sepsis protocol on the timeliness of antibiotic administration, the adequacy of fluid resuscitation, and 28-day mortality in patients with fluid-refractory septic shock. METHODS: This was a single-center, before-and-after study (18 months before July 2007 and 18 months after) with prospective data collection evaluating the outcomes of a sepsis protocol in adult patients with fluid-refractory septic shock. All patients received a fluid challenge and antibiotics; those who did not were excluded from this analysis. Preprotocol findings led to the development of the sepsis protocol, which emphasized fluid resuscitation, timely administration of antibiotic therapy, and collection of specimens for culture at the onset of septic shock. In the pre- and postprotocol phases of the study, data were collected prospectively and analyzed for demographic characteristics; Acute Physiology and Chronic Health Evaluation (APACHE) II score; appropriateness of fluid resuscitation; antibiotic use; number of vasopressor, ventilator, and intensive care unit (ICU) days; and 28-day mortality. Outcomes were measured prospectively at any time during the patient's hospital admission. The primary end points were the time to administration of antimicrobial therapy and the appropriateness of fluid resuscitation before and after implementation of the sepsis protocol. RESULTS: A total of 118 patients were included in the analysis: 64 and 54 in the pre- and postprotocol groups, respectively. Patients in the preprotocol group were primarily women (53% [34/64]) and had a mean (SD) age of 61 (15.5) years and a mean APACHE II score of 28 (6.0). Patients in the postprotocol group were primarily men (54% [29/54]) and had a mean age of 52 (18.0) years and a mean APACHE II score of 27 (6.4). Implementation of the sepsis protocol resulted in a greater percentage of patients receiving timely antibiotic therapy (ie, within 4.5 hours of refractory shock; 85% [46/54] vs 56% [36/64]; P = 0.001) and adequate fluid resuscitation (72% [39/54] vs 31% [20/64]; P < 0.001) compared with the preprotocol group. Post hoc analysis found significant decreases in the number of vasopressor days (mean [SD], 3.8 [2.7] to 1.4 [1.5]; P < 0.001), ventilator days (9.1 [12.2] to 2.7 [4.0]; P < 0.001), and ICU days (12.3 [12.6] to 4.9 [3.9]; P < 0.001) in the postprotocol group. In-hospital mortality was not significantly different between the groups (survival 46% [28/61] before vs 54% [33/61] after the protocol). Multivariate analysis for predictors of in-hospital mortality identified an interval between shock and empiric antibiotic administration of >4.5 hours (odds ratio [OR] = 5.54; 95% CI, 1.91-16.07; P < 0.002), vasopressor duration in days (OR = 1.27; 95% CI, 1.01-1.59; P = 0.037), APACHE II score (OR = 1.14; 95% CI, 1.05-1.24; P = 0.003), and type of infection (community vs nosocomial, OR = 0.18; 95% CI, 0.05-0.61; P = 0.006) as significant predictors. The 28-day mortality decreased from 61% (39/64) to 33% (18/54) after implementation of the protocol (P = 0.004). CONCLUSION: Implementation of a sepsis protocol emphasizing early administration of antibiotic therapy and adequate fluid resuscitation was associated with improved clinical outcomes and lower 28-day mortality in patients with fluid-refractory septic shock at this institution.

Comparison of outcomes from daptomycin or linezolid treatment for vancomycin-resistant enterococcal bloodstream infection: A retrospective, multicenter, cohort study.

BACKGROUND: The optimal treatment for bloodstream infections (BSIs) with vancomycin-resistant enterococci (VRE) is unknown. OBJECTIVE: This study examined outcomes in patients treated with daptomycin or linezolid for VRE BSI. METHODS: A retrospective, multicenter, cohort study was performed via chart review. Hospitalized patients treated for VRE BSI with daptomycin or linezolid from September 1, 2003, to June 30, 2007, were identified via pharmacy and microbiology reports at each institution. Patients aged <18 years or with polymicrobial bacteremia were excluded from analysis. Linezolid and daptomycin were included because the participating institutions used either of the 2 agents as first-line treatment for VRE BSI. Univariate and multivariate analyses were performed to determine the effect of drug selection on mortality and duration of BSI. Duration of BSI was defined as the amount of time from the draw date of the first positive blood culture to the draw date of the first finalized negative blood culture. Adverse events were not assessed. RESULTS: One-hundred one patients from 3 participating US hospitals experiencing VRE BSI were identified. Sixty-seven patients were treated with daptomycin and 34 with linezolid. Baseline characteristics appeared comparable between the daptomycin- and linezolidtreated groups, with the exception of shock (P = 0.049), prior vancomycin treatment (P = 0.002), and prior linezolid treatment (P < 0.001), all of which occurred significantly more often in daptomycin-treated patients. Inpatient mortality occurred in 31 daptomycin- and 10 linezolid-treated patients (46.3% vs 29.4%; P = NS). Linear regression found that shock (P = 0.015), infective endocarditis (P = 0.021), and concurrent rifampin or gentamicin treatment (P = 0.01) were associated with prolonged duration of positive cultures. Logistic regression revealed that shock (odds ratio [OR] = 14.24; P = 0.008), infection with Enterococcus faecium (OR = 53.10; P = 0.024), previous linezolid treatment (OR = 6.63; P = 0.031), concurrent rifampin or gentamicin treatment (OR = 6.48; P = 0.046), and a nonline source of infection (OR = 6.67; P = 0.019) were associated with increased mortality. CONCLUSIONS: In this retrospective cohort analysis, there were no significant differences in mortality of VRE BSI between patients receiving daptomycin or linezolid. Underlying comorbidities appeared to best predict outcome; however, given the retrospective nature of this study, larger, prospective, randomized, comparative studies are needed to control for potential biases and determine definitive outcome differences between these 2 antimicrobials.

Efficacy and safety of dopamine versus norepinephrine in the management of septic shock.

The optimum septic shock vasopressor support strategy is currently debated. This study was performed to evaluate the efficacy and safety of norepinephrine (NE) and dopamine (DA) as the initial vasopressor in septic shock patients who were managed with a specific treatment protocol. A prospective, randomized, open-label, clinical trial was used in a medical intensive care unit comparing DA with NE as the initial vasopressor in fluid-resuscitated 252 adult patients with septic shock. If the maximum dose of the initial vasopressor was unable to maintain the hemodynamic goal, then fixed-dose vasopressin was added to each regimen. If additional vasopressor support was needed to achieve the hemodynamic goal, then phenylephrine was added. The primary efficacy end point was all-cause 28-day mortality. Secondary end points included organ dysfunction, hospital and intensive care unit length of stay, and safety (primarily occurrence of arrhythmias). The 28-day mortality rate was 50% (67/134) with DA as the initial vasopressor compared with 43% (51/118) for NE treatment (P = 0.282). There was a significantly greater incidence of sinus tachycardia with DA (24.6%; 33/134) than NE (5.9%; 7/118) and arrhythmias noted with DA treatment (19.4%; 26/134) compared with NE treatment (3.4%; 4/118; P < 0.0001), respectively. Logistic regression analysis identified Acute Physiologic and Chronic Health Evaluation II score (P < 0.0001) and arrhythmia (P < 0.015) as significant predictors of outcome. In this protocol-directed vasopressor support strategy for septic shock, DA and NE were equally effective as initial agents as judged by 28-day mortality rates. However, there were significantly more cardiac arrhythmias with DA treatment. Patients receiving DA should be monitored for the development of cardiac arrhythmias (NCT00604019).

The effect of time to antifungal therapy on mortality in Candidemia associated septic shock.

The timely administration of appropriate antifungal therapy for Candida bloodstream infections (CBSI) improves clinical outcomes. However, little data exist on the effect of antifungal therapy in patients with septic shock and candidemia. We describe antifungal treatment of patients with septic shock due to CBSI and its impact on in-hospital mortality. We retrospectively reviewed medical records of hospitalized patients identified with at least one positive blood culture for Candida between January 2003 and June 2007. All septic shock patients received vasopressor therapy and had candidemia within 72 hours of refractory shock. Data collected included demographics, comorbidities, antibiotic exposure, in-hospital mortality, and intensive care-related factors. Acute Physiology and Chronic Health Evaluation II scores were calculated. Time to antifungal therapy was defined as the interval between time of collection of the first positive Candida blood culture and the time when appropriate antifungal therapy was initiated. Univariate and multivariate analyses were performed to identify variables associated with in-patient mortality. Classification and regression tree analysis was used to identify the mortality breakpoint between early and late antifungal therapy. Septic shock developed in 23% (31 of 135) patients with CBSI. In-hospital mortality was 68%. Nonalbicans Candida spp. accounted for 48% of blood isolates. Appropriate antifungal therapy was administered to 24 patients; 15 (63%) of these patients died. Classification and regression tree analysis revealed that patients who received appropriate antifungal therapy within 15 hours of collecting the first positive Candida blood culture had improved survival (P = 0.03). Early, appropriate antifungal therapy improves survival among patients with septic shock due to CBSI.

An evaluation of amikacin nephrotoxicity in the hematology/oncology population.

Amikacin is an aminoglycoside commonly used to provide empirical double gram-negative treatment for febrile neutropenia and other suspected infections. Strategies of extended-interval and conventional dosing have been utilized extensively in the general medical population; however, data are lacking to support a dosing strategy in the hematology/oncology population. To evaluate amikacin-associated nephrotoxicity in an adult hematology/oncology population, a prospective, randomized, open-label trial was conducted at a university-affiliated medical center. Forty patients with a diagnosis consistent with a hematologic/oncologic disorder that required treatment with an aminoglycoside were randomized to either conventional or extended-interval amikacin. The occurrence of nephrotoxicity by means of an increase in serum creatinine and evaluation of efficacy via amikacin serum concentrations with respective pathogens were assessed. The occurrence of nephrotoxicity was similar between the conventional and extended-interval groups, at 10% and 5%, respectively (P = 1.00). Six patients in the conventional group had a positive culture, compared with none in the extended-interval group (P = 0.002). The occurrence of nephrotoxicity was similar between the two dosing regimens, but the distribution of risk factors was variable between the two groups. Efficacy could not be assessed.

Choice of vasopressor in septic shock: does it matter?

Septic shock is a medical emergency that is associated with mortality rates of 40-70%. Prompt recognition and institution of effective therapy is required for optimal outcome. When the shock state persists after adequate fluid resuscitation, vasopressor therapy is required to improve and maintain adequate tissue/organ perfusion in an attempt to improve survival and prevent the development of multiple organ dysfunction and failure. Controversy surrounding the optimum choice of vasopressor strategy to utilize in the management of patients with septic shock continues. A recent randomized study of epinephrine compared to norepinephrine (plus dobutamine when indicated) leads to more questions than answers.

Recognition and treatment of hyponatremia in acutely ill hospitalized patients.

OBJECTIVE: The objective of this paper was to discuss the diagnosis, pathophysiology, and management of hyponatremia among critically ill, hospitalized patients (eg, after surgery or in the intensive care unit). METHODS: English-language literature published between 1967 and 2006 was searched using several key words (AVP receptor antagonists, hyponatremia, SIADH, conivaptan, tolvaptan, and lixivaptan) and by accessing MEDLINE and ScienceDirect. Meeting abstracts from scientific sessions (American Society of Nephrology Renal Week 2004 and the Endocrine Society's 87th Annual Meeting [2005]) were reviewed. The package insert for conivaptan hydrochloride injection was referenced from . Clinical trials included in this review were randomized and placebo controlled. RESULTS: Based on the literature we researched, hyponatremia is the most common electrolyte disorder encountered in critical care and is associated with a variety of conditions, including congestive heart failure and the syndrome of inappropriate antidiuretic hormone secretion. Because hyponatremia can arise in hypervolemic, euvolemic, and hypovolemic states, clinicians may not recognize its presence and cause. Incorrect management can lead to significant morbidity and mortality. Physicians need to recognize risk factors and symptoms and use appropriate treatment guidelines for hyponatremia. Traditionally, therapy for hyponatremia has been limited by efficacy and safety concerns. Arginine vasopressin (AVP) receptor antagonists, therapeutic agents that promote aquaresis in patients with hyponatremia by targeting V(1a) receptors in the vascular smooth muscle, V(2) receptors in the kidney, or both, are under development. A dual-receptor antagonist targeting both V(1a) and V(2) receptors is now approved for the treatment of euvolemic hyponatremia in hospitalized patients. CONCLUSIONS: Hyponatremia, an electrolyte abnormality found in critically ill patients, can be associated with significant morbidity and mortality. AVP receptor antagonists show promise as effective and tolerable treatments for patients with hyponatremia.