Prophylactic tranexamic acid use in non-cardiac surgeries at high risk for transfusion.

BACKGROUND: Tranexamic acid (TXA) reduces transfusion in a wide range of surgical populations, although its real-world use in non-cardiac surgeries has not been well described. The objective of this study was to describe prophylactic TXA use in non-cardiac surgeries at high risk for transfusion. METHODS: This is a retrospective cohort study of all adult patients undergoing major non-cardiac surgery at ≥5% risk of perioperative transfusion at five Canadian hospitals between January 2014 and December 2016. Canadian Classification of Health Interventions procedure codes within the Discharge Abstract Database were linked to transfusion and laboratory databases. TXA use was ascertained electronically from The Ottawa Hospital Data Warehouse and via manual chart review for Winnipeg hospitals. For each surgery, we evaluated the percentage of patients who received TXA as well as the specifics of TXA dosing and administration. RESULTS: TXA use was evaluable in 14 300 patients. Overall, 17% of surgeries received TXA, ranging from 0% to 68% among individual surgeries. TXA use was more common in orthopaedic (n = 2043/4942; 41%) and spine surgeries (n = 239/1322; 18%) compared to other surgical domains (n = 109/8036; 1%). TXA was commonly administered as a bolus (n = 2097/2391; 88%). The median TXA dose was 1000 mg (IQR 1000-1000 mg). CONCLUSION: TXA is predominantly used in orthopaedic and spine surgeries, with little uptake in other non-cardiac surgeries at high risk for red blood cell transfusion. Further studies are needed to evaluate the effectiveness and safety of TXA and to understand the barriers to TXA administration in a broad range of non-cardiac surgeries.

Antimicrobial Prophylaxis for Patients Undergoing Cardiac Surgery: Intraoperative Cefazolin Concentrations and Sternal Wound Infections.

This study characterizes the pharmacodynamics of antimicrobial prophylaxis and sternal wound infections following cardiac surgery. Duration of surgery and cefazolin plasma concentration during wound closure were independently associated with surgical site infection at 30 days. Furthermore, a duration of surgery of >346 min and a total cefazolin closure concentration of <104 mg/liter were significant thresholds for an increased risk of infection. This study provides new data that informs dosing strategies for effective antimicrobial prophylaxis (AP) in patients undergoing cardiac surgery with cardiopulmonary bypass.

Limitations of ceftriaxone compared with cefazolin against MSSA: an integrated pharmacodynamic analysis.

Objectives: Despite the convenience of once-daily dosing, the use of ceftriaxone for Staphylococcus aureus infections has significant limitations, including scarce clinical evidence and increasingly questionable pharmacodynamic activity. Our goal was to conduct an integrated pharmacokinetic-pharmacodynamic analysis of the appropriateness of ceftriaxone compared with cefazolin for treating serious MSSA infections. Methods: Ceftriaxone and cefazolin activity against five clinical MSSA isolates was characterized in an in vitro pharmacodynamic model. Monte Carlo simulations were then used to evaluate various dosing regimens of ceftriaxone and cefazolin based on relevant patient pharmacokinetic data, significant pharmacodynamic targets derived from the in vitro studies (55%ƒT>MIC for bacteriostasis, 75%ƒT>MIC for 1 log10 bacterial kill, 100%ƒT>MIC for ≥3 log10 bacterial kill) and MIC distributions for MSSA from national surveillance data. Results: Ceftriaxone at 1 g once daily had poor activity against MSSA with net bacterial growth predicted in 76% of simulated subjects. The standard 2 g of ceftriaxone once daily had predicted bacterial growth or bacteriostasis in 54% of cases with bactericidal effects in only 17%. Cefazolin at 2 g once daily was notably similar to ceftriaxone in expected target attainments. Cefazolin at 2 g twice daily demonstrated maximal pharmacodynamic activity with bactericidal effects in 97% of simulated subjects. Conclusions: Given the limited activity of ceftriaxone against S. aureus, particularly for serious infections when bacterial kill is desired, the convenience of once-daily dosing should be weighed against the risks of using an overly broad, suboptimal therapy. Cefazolin warrants further consideration, particularly as optimal pharmacodynamics against MSSA may be achieved with twice-daily dosing in most patients.

Evaluation of cefazolin antimicrobial prophylaxis during cardiac surgery with cardiopulmonary bypass.

Objectives: Although clinical practice guidelines recommend standard cefazolin antimicrobial prophylaxis (AP) dosing for cardiac surgery, limited data exist as to whether adequate concentrations are achieved in this patient population. The goal of our study was to characterize intraoperative cefazolin concentrations particularly at wound closure with regards to maintaining target cefazolin closure concentrations ≥40 mg/L. Methods: Adults undergoing cardiac surgery with cardiopulmonary bypass (CPB) and receiving cefazolin AP according to protocol were studied. Blood samples were collected after the preoperative cefazolin dose, prior to intraoperative cefazolin doses and at wound closure. Intraoperative trough and closure concentrations were characterized and evaluated against a target threshold of ≥ 40 mg/L (≥8 mg/L unbound, assuming 80% protein binding). Results: Fifty-five subjects (64.9 ±âŸ10.4 years, 89.7 ±âŸ16.5 kg, CLCR >50 mL/min/72 kg) completed the study. Total cefazolin concentrations were <40 mg/L in 40% (12 of 30) of intraoperative trough samples and 9.8% (5 of 51) of closure samples. Below-target concentrations at some time during surgery were documented in 30.9% (17 of 55) of subjects. In multivariate analyses, lower body weight (P = 0.027) and shorter duration of surgery (P = 0.045) were significant predictors of closure concentrations <40 mg/L. A total cefazolin exposure (preoperative and intraoperative doses) of ≥ 7.6 mg/kgdosing weight for every hour of surgery (intermittent dosing) was required to achieve target closure concentrations. Conclusions: The standard cefazolin AP regimen was not reliable in maintaining target closure concentrations ≥40 mg/L in patients with normal renal function undergoing elective cardiac surgery with CPB. The findings supported a cefazolin AP regimen consisting of at least 2 g preoperatively and every 3 h during surgery.

No role for patient body weight on renal function assessment for drug dosing.

Objectives: To evaluate the ability of body-weight-driven renal function assessment (RFA) formulae to predict on-target elimination rate ranges for gentamicin in patients with varying degrees of renal function. Methods: A 6 year retrospective pharmacokinetic study was conducted at a university teaching hospital. Results: A total of 85 patients met the inclusion criteria and 127 pharmacokinetic files were analysed from patients on medical-surgical wards (53%) and medical-surgical ICUs (13%) receiving intravenous gentamicin for treatment, as well as those for patients receiving it for surgical prophylaxis (34%). Each RFA formula was examined against standard dosing tables for gentamicin. A table of acceptable elimination rates was generated using a traditional peak of 8 mg/L and trough between 0.5 and 2 mg/L associated with each of the dosing interval extensions. The ability of each RFA formula to select on-target elimination rates was evaluated. The RFA formula assuming a normalized body weight of 72 kg and a modified creatinine reagent adjustment factor of 90% provided the most accurate on-target elimination rate selection. This method was superior to dosing interval selection based on the Modification in Diet Renal Disease (MDRD) formula, Sanford's guide method, as well as the Cockcroft-Gault formulae using total body weight, ideal body weight or lean body weight ( P < 0.0001). Conclusions: Based on the use of gentamicin as a surrogate guide for renally adjusted drugs, these results support dosing interval selection based on a normalized body weight method and a formula reagent adjustment factor of 90% within the Cockcroft-Gault formula.

Comparison of Fentanyl and Morphine in the Prehospital Treatment of Ischemic Type Chest Pain.

In the treatment of acute coronary syndromes, reduction of sympathetic stress and catecholamine release is an important therapeutic goal. One method used to achieve this goal is pain reduction through the systemic administration of analgesia. Historically, morphine has been the analgesic of choice in ischemic cardiac pain. This randomized double-blind controlled trial seeks to prove the utility of fentanyl as an alternate first-line analgesic for ischemic-type chest pain in the prehospital setting. Successive patients who were treated for suspected ischemic chest pain in the emergency medical services system were considered eligible. Once chest pain was confirmed, patients received oxygen, aspirin, and nitroglycerin therapy. If the ischemic-type chest pain continued the patient was randomized in a double-blinded fashion to treatment with either morphine or fentanyl. Pain scale scores, necessity for additional dosing, and rate of adverse events between the groups were assessed every 5 minutes and were compared using t-testing, Fisher's Exact test, or Analysis of Variance (ANOVA) where appropriate. The primary outcome of the study was incidence of hypotension and the secondary outcome was pain reduction as measured by the visual analog score and numeric rating score. A total of 207 patients were randomized with 187 patients included in the final analysis. Of the 187 patients, 99 were in the morphine group and 88 in the fentanyl group. No statistically significant difference between the two groups with respect to hypotension was found (morphine 5.1% vs. fentanyl 0%, p = 0.06). Baseline characteristics, necessity for additional dosing, and other adverse events between the two groups were not statistically different. There were no significant differences between the changes in visual analog scores and numeric rating scale scores for pain between the two groups (p = 0.16 and p = 0.15, respectively). This study supports that fentanyl and morphine are comparable in providing analgesia for ischemic-type chest pain. Fentanyl appears to be a safe and effective alternative to morphine for the management of chest pain in the prehospital setting.

Preoperative therapeutic apheresis for severe medically refractory amiodarone-induced thyrotoxicosis: a case report.

INTRODUCTION: Amiodarone is associated with thyroid dysfunction and life-threatening thyrotoxicosis. In medically refractory cases, or where medical therapy is contraindicated, thyroidectomy may be required. To decrease perioperative thyroid storm and to reduce overall surgical risk, apheresis may be considered preoperatively to restore euthyroidism. CASE DESCRIPTION: We report a 46-year-old female with a history of cardiac arrhythmia and tachycardia-induced cardiomyopathy for which she received amiodarone. Months after discontinuation of amiodarone, the patient presented with wide complex tachycardia and symptoms of thyrotoxicosis. Laboratory testing confirmed severe thyrotoxicosis which was subsequently refractory to medical therapy. Total thyroidectomy was required. Following a total of 10 apheresis treatments, thyroid hormone levels were reduced to near normal levels and the patient's symptoms improved. Thyroidectomy was performed without intraoperative or postoperative complication. DISCUSSION: In the setting of life-threatening, medically refractory amiodarone-induced thyrotoxicosis, therapeutic apheresis can effectively reduce thyroid hormone levels and restore a state of clinical and biochemical euthyroidism.

Comparative simulation of intraperitoneal aminoglycoside regimens for patients with peritonitis on automated peritoneal dialysis.

BACKGROUND: Intraperitoneal (IP) aminoglycosides (AGs) continue to be the cornerstone of empiric management of peritonitis. AG dosing during automated peritoneal dialysis (APD), however, has not been well studied in patients with peritonitis. We sought to identify differences in AG exposure in the peritoneum and plasma for two different dosing regimens with little supporting evidence in patients on APD with peritonitis. METHODS: A retrospective design that utilised the peritoneal and plasma concentration-time data from a prior study of 18 continuous ambulatory peritoneal dialysis (CAPD) patients with peritonitis to generate an in silico peritoneal and plasma PK model. This model was then used to compare via simulation using Phoenix© WinNonlin Software with IP AG dosing for a loading-dose regimen (1.5 mg/kg first dose) versus a fixed-dose regimen (0.6 mg/kg/d) in patients on APD with peritonitis. RESULTS: Outcome measures were (1) percentage of time where peritoneal peak concentrations/minimal inhibitory concentration (MIC) ratio >10, (2) AUC/MIC > 74 and (3) plasma Cmin concentrations. Both regimens resulted in > 90% optimal peak/MIC ratio and AUC/MIC ratios on days 1 and 5 of the dose protocol. The loading-dose regimen resulted in IP exposures that were 2.5 times greater in the peritoneal compartment on day 1. By day 5, both protocols resulted in similar accumulation of AG plasma Cmin concentrations of 2.5-3.4 mg/L versus 2.4-3.3 mg/L, respectively, for the loading-dose regimen versus fixed-dose regimen. CONCLUSIONS: The current international guidelines for the treatment of peritoneal dialysis-associated peritonitis can continue to recommend the fixed-dose regimen for those on APD with the addition of plasma Cmin monitoring after 3 days to assess for drug accumulation.

Integrating pharmacokinetics, pharmacodynamics and MIC distributions to assess changing antimicrobial activity against clinical isolates of Pseudomonas aeruginosa causing infections in Canadian hospitals (CANWARD).

OBJECTIVES: To study antimicrobial pharmacodynamic (PD) activity over time against clinical isolates of Pseudomonas aeruginosa in Canadian hospitals. METHODS: Integrated pharmacokinetic (PK)/PD analyses with Monte Carlo simulations were used to study cefepime, meropenem, piperacillin/tazobactam, ciprofloxacin, amikacin, gentamicin and colistin. Profiles of P. aeruginosa infections were modelled using CANWARD data from January 2007 to June 2012 inclusive. The probability of target attainment (PTA) was the proportion of cases achieving a %ƒT>MIC ≥ 50% for cefepime, meropenem and piperacillin/tazobactam, an ƒAUC/MIC ≥ 90 for ciprofloxacin and the aminoglycosides, and a total AUC/MIC ≥ 60 for colistin. RESULTS: Some 2126 P. aeruginosa isolates were identified. There were no significant trends over time in the PTA for cefepime (0.93-1.0), meropenem (0.89-0.92) or piperacillin/tazobactam (0.74-0.79) (data shown for the highest recommended doses). The PD activity for ciprofloxacin (PTA 0.48-0.64) was variable. There were notable improvements in the PTA for amikacin (from 0.21 to 0.55, P = 0.027), gentamicin (from 0.10 to 0.51, P = 0.035) and colistin (from 0.04 to ~0.20, P = 0.05), which were not reliably detected by MIC indices. There was a decline over time in the PTA for piperacillin/tazobactam from 0.73 to 0.61 against P. aeruginosa isolated from intensive care units (ICUs) (Pearson correlation coefficient -0.99, P = 0.003). Neither MIC50 nor MIC90 detected this reduction in PD activity. CONCLUSIONS: The overall PD activity against P. aeruginosa was stable from 2007 to 2012 for cefepime, meropenem and piperacillin/tazobactam, was variable and unreliable for ciprofloxacin, and improved significantly but remained relatively low for the aminoglycosides and colistin. There was a progressive reduction over time in the PD activity of piperacillin/tazobactam against ICU isolates, which was not detected by simply assessing MIC indices.

Successful treatment of pulmonary blastomycosis with continuously infused amphotericin B deoxycholate after failure with liposomal amphotericin B.

OBJECTIVE: To describe a case of successful treatment of severe pulmonary blastomycosis with amphotericin B deoxycholate after failure of liposomal amphotericin B. CASE SUMMARY: A 35-year-old male was exposed to damp decomposing wood while cleaning his basement. He subsequently developed a cough, malaise, fever, nausea, vomiting, and diarrhea. He was admitted to the hospital and intubated for worsening pulmonary symptoms. Microscopic examination of his sputum indicated Blastomyces dermatitidis. Liposomal amphotericin B was administered for 6 days, but the patient's temperature reached 39.6 °C and his white blood cell (WBC) count reached 52,300/µL. Extensive consolidation of both lungs fields was observed on chest X-ray. Because of progressive clinical deterioration, the treatment was switched to amphotericin B deoxycholate by continuous infusion. That change resulted in clinical improvement, with abrupt reductions (within 48 hours) in temperature and the WBC count. By day 14 of therapy (day 8 of amphotericin B deoxycholate), the chest X-ray showed improvement in diffuse airspace filling. After 16 days of amphotericin B treatment, intravenous followed by oral voriconazole was administered for 3 months. Eight months later the patient's strength had improved significantly, but he still had occasional episodes of shortness of breath. DISCUSSION: The management of blastomycosis is challenging because of the lack of clinically supporting data. The gold standard for severe pulmonary blastomycosis had been amphotericin B deoxycholate; however, improved safety data with liposomal amphotericin B for other fungal infections has suggested this as an effective alternative. This report describes a patient with severe pulmonary blastomycosis failing 6 days of liposomal amphotericin B, yet he tolerated and clinically responded to continuous infusion of amphotericin B deoxycholate. Based on this case report and a simulated pharmacokinetic/pharmaco dynamic analysis, continuous infusion of amphotericin B deoxycholate may be a reasonable option for enhanced efficacy and minimal toxicity in patients with blastomycosis. CONCLUSIONS: Ours is the first case report to use continuous infusion of amphotericin B deoxycholate for the management of pulmonary blastomycosis. These results suggest that liposomal amphotericin B may not be adequate in some patients for the management of B. dermatitidis pulmonary infections.

Initial vancomycin dosing protocol to achieve therapeutic serum concentrations in patients undergoing hemodialysis.

BACKGROUND: Although recent consensus guidelines proposed more aggressive vancomycin troughs of >10 or 15-20 mg/L for complicated Staphylococcus aureus infections, dosing information to achieve these targets in patients undergoing hemodialysis (HD) is scarce. METHODS: We used Monte Carlo simulation (MCS) methods with a previously published population-pharmacokinetic model and relevant patient demographics to evaluate and revise our existing vancomycin dosing protocol (1000-mg load followed by 500-mg maintenance dose, with doses infused during the last hour of dialysis). A new protocol (1000-mg load followed by 500-mg maintenance dose for patients <70 kg, 1250-mg followed by 750-mg for those 70-100 kg, and 1500-mg followed by 1000-mg for those >100 kg) was developed and prospectively validated to achieve therapeutic serum troughs in patients undergoing high-flux HD. RESULTS: MCSs predicted that our existing protocol would be suboptimal in more than one-third of patients. Simulations predicted that the new vancomycin dosing protocol would achieve maintenance (pre-HD) troughs of 10-20 mg/L in 86.0% of cases including 15-20 mg/L in 35.2%. In prospective validation, the observed postload trough (pre-HD session 2) was 13.5 ± 3.4 mg/L with 76.9% of levels (20 of 26) between 10 and 20 mg/L. The observed maintenance trough was 17.3 ± 4.0 mg/L with 65.5% (19 of 29) between 10 and 20 mg/L and 89.7% (26 of 29) within 10% of the upper limit (ie, 10-22 mg/L). CONCLUSIONS: In this study, a practical vancomycin dosing protocol for patients undergoing HD was developed and prospectively validated to achieve therapeutic serum concentrations in the clinical setting.

Sedation and analgesia usage in severe pandemic H1N1 (2009) infection: a comparison to respiratory failure secondary to other infectious pneumonias.

BACKGROUND: During the 2009 H1N1 pandemic (pH1N1), patients requiring mechanical ventilation for respiratory failure received high doses of sedation and analgesia. OBJECTIVE: To examine sedation and analgesia use among patients with respiratory failure due to severe pH1N1 infection compared to other infectious pneumonias. METHODS: In this observational cohort study of intensive care unit (ICU) patients with respiratory failure, we compared doses of sedatives and analgesics administered to patients with pH1N1, non-pH1N1 viral pneumonia, and adult respiratory distress syndrome (ARDS) secondary to bacterial pneumonia, on days 1, 3, 7, 14, and 28 of ICU admission. Cumulative drug use, daily drug use, and weight-adjusted medication doses were examined. RESULTS: The study population consisted of 37 patients with pH1N1 infection, 22 patients with non-pH1N1 viral pneumonia, and 46 patients with ARDS secondary to bacterial pneumonia. To achieve similar levels of sedation using the Richmond Agitation Sedation Scale, patients with pH1N1 were administered the highest cumulative median doses of fentanyl (11,230 µg; interquartile range [IQR] 3240-21,000), compared to 2400 µg (IQR 130-7130) in viral pneumonia and 2880 µg (IQR 600-6950) in ARDS (p < 0.001). Patients with pH1N1 were also administered the highest cumulative median doses of midazolam at 820 mg (IQR 330-1160), compared to 160 mg (IQR 20-390) in viral pneumonia and 160 mg (IQR 20-480 mg) in ARDS (p < 0.001). The pH1N1 group received the highest median daily fentanyl and midazolam doses on all study days. The pH1N1 group did not differ significantly in cumulative propofol dose compared with the other 2 study groups. CONCLUSIONS: Sedative and analgesic use may be uniquely higher in critically ill patients with pH1N1 infection compared to patients with other infectious pneumonias. This finding may be important for resource planning in future pandemics. Further study is required to explore the underlying mechanisms for potentially higher sedative and analgesic requirements in this patient population.

An updated vancomycin dosing protocol for initiating therapy in patients undergoing intermittent high-flux hemodialysis.

PURPOSE: To design an updated vancomycin dosing protocol for initiating therapy in patients undergoing chronic intermittent high-flux hemodialysis (iHFHD) that is congruent with the revised 2020 consensus guidelines for therapeutic drug monitoring (TDM). METHODS: Monte Carlo simulation methods were used to study vancomycin dosing for patients on iHFHD. Vancomycin regimens were constructed as intravenous infusions (for intradialytic administration) of a loading dose and maintenance doses 3 times weekly during subsequent dialysis sessions. Vancomycin plasma concentrations were simulated, and the probability of target attainment (PTA) for a 24-hour area under the time-concentration curve (AUC24) of 400 to 700 mg · h/L was determined. Standardized weight-based (ie, dose-banding) regimens were investigated, and an optimized protocol was selected based on TDM target attainment and practical considerations for use in the dialysis setting. RESULTS: The proposed vancomycin dosing protocol (for intradialytic administration) specifies 3 regimens: (1) a 1,500-mg loading dose and 750-mg maintenance doses for patients weighing 50 kg to 69 kg; (2) a 2,000-mg loading dose and 1,000-mg maintenance doses for patients weighing 70 kg to 89 kg; and (3) a 2,500-mg loading dose and 1,250-mg maintenance doses for patients weighing 90 kg to 110 kg. In a simulated hemodialysis population (n = 5,000), the proposed protocol delivered median (interquartile range [IQR]) loading and maintenance doses of 25.0 (23.4-26.6) mg/kg and 12.5 (11.8-13.3) mg/kg, respectively. The PTA for an AUC24 of 400 to 700 mg · h/L was 74.7% on day 1 and 70.8% on day 8, with less than 10% of values exceeding the target range. CONCLUSION: Our proposed dosing protocol for patients undergoing iHFHD offers an updated and practical approach for initiating vancomycin therapy that can be optimized with early TDM.

Pharmacodynamics of empirical antibiotic monotherapies for an intensive care unit (ICU) population based on Canadian surveillance data.

OBJECTIVES: To evaluate, using Monte Carlo simulation, the pharmacodynamics (PD) of empirical antibiotic monotherapies for serious infections consistent with Canadian intensive care unit (ICU) surveillance data. METHODS: Meropenem, piperacillin/tazobactam and cefepime, along with ceftobiprole, a broad-spectrum cephalosporin active against methicillin-resistant Staphylococcus aureus (MRSA), were tested at standard and highest recommended doses with and without prolonged infusion times (t'). Population pharmacokinetic models were used to simulate antibiotic serum concentrations (n = 5000). Cumulative target attainment (CTA) at >50%, >75% and 100% fT( > MIC) (percentage of time free concentrations exceed the MIC) targets were determined based on ICU surveillance data including 4798 pathogens, most commonly methicillin-susceptible S. aureus (20.1%), Escherichia coli (15.2%) and Pseudomonas aeruginosa (12.3%). RESULTS: With standard doses, ceftobiprole (500 mg every 8 h, t' 2 h) had 0.90 CTA at the >50% fT( > MIC) target while meropenem (1 g every 8 h, t' 0.5 h), piperacillin/tazobactam (3.375 g every 6 h, t' 0.5 h) and cefepime (2 g every 12 h, t' 0.5 h) reached >50% fT( > MIC) in 0.79-0.82 of the population (0.84-0.88 when MRSA was excluded). Piperacillin/tazobactam had the largest reduction in CTA at the >75% and 100% fT( > MIC) targets requiring prolonged infusions to maintain comparable PD. For all agents, prolonged infusions and/or high doses were required to achieve >0.9 CTA at the lowest target, to reach higher targets or to cover less susceptible pathogens such as P. aeruginosa. CONCLUSIONS: This study provides important comparative data on empirical antibiotic monotherapies in an ICU setting including preliminary data on ceftobiprole. Ceftobiprole was most active overall, but similar to meropenem, piperacillin/tazobactam (lowest target only) and cefepime when MRSA was excluded. Prolonged infusions in particular and high doses were effective at improving antibiotic PD.

Neuroleptic malignant syndrome versus serotonin syndrome: the search for a diagnostic tool.

OBJECTIVE: To evaluate the use of urine dopamine and catecholamine concentrations as diagnostic aids in a patient with neuroleptic malignant syndrome (NMS) in the emergency department setting. CASE SUMMARY: A 61-year-old female on multiple medications, including several antipsychotics, rapidly deteriorated, with fever, lead-pipe rigidity, and decreased level of consciousness. The patient died 20 days after initial presentation to an emergency department. The Naranjo probability scale indicated probable causality for NMS due to quetiapine, haloperidol, and risperidone in this patient, whereas the Naranjo scale assigned only possible causality for serotonin syndrome developing with serotonergic agents. Laboratory investigations of blood and urine revealed elevations in dopamine, metanephrines, and epinephrines, as well as trazodone and risperidone. Serotonin metabolites were not elevated. DISCUSSION: NMS is a rare and potentially severe adverse effect associated with the use of antipsychotic medications. It is mainly characterized by hyperthermia, altered mental state, hemodynamic dysregulation, elevated serum creatine kinase, and rigors. It has been associated with multisystem organ failure potentially leading to rhabdomyolysis, acute respiratory distress syndrome, and disseminated intravascular coagulation. The prevalence of this syndrome is associated with the use of neuroleptics. Serotonin syndrome is another adverse drug reaction leading to NMS associated with elevated serotonin. It occurs when multiple serotonergic medications are ingested and is associated with rapid onset of altered mental status, myoclonus, and autonomic instability. Differentiating between NMS and serotonin syndrome can be challenging because of their similar clinical presentation. This case highlights the importance of a diagnostic aid being available to help distinguish between the 2 syndromes. CONCLUSIONS: We propose that laboratory findings that include dopamine and serotonin metabolites can be used as adjuncts to clinical and prescription histories in the diagnosis of NMS. The use of urinary catecholamine as a diagnostic aid in NMS needs further evaluation.

Evaluation of Transfusion Practices in Noncardiac Surgeries at High Risk for Red Blood Cell Transfusion: A Retrospective Cohort Study.

Perioperative bleeding is a major indication for red blood cell (RBC) transfusion, yet transfusion data in many major noncardiac surgeries are lacking and do not reflect recent blood conservation efforts. We aim to describe transfusion practices in noncardiac surgeries at high risk for RBC transfusion. We completed a retrospective cohort study to evaluate adult patients undergoing major noncardiac surgery at 5 Canadian hospitals between January 2014 and December 2016. We used Canadian Classification of Health Interventions procedure codes within the Discharge Abstract Database, which we linked to transfusion and laboratory databases. We studied all patients undergoing a major noncardiac surgery at ≥5% risk of perioperative RBC transfusion. For each surgery, we characterized the percentage of patients exposed to an RBC transfusion, the mean/median number of RBC units transfused, and platelet and plasma exposure. We identified 85 noncardiac surgeries with an RBC transfusion rate ≥5%, representing 25,607 patient admissions. The baseline RBC transfusion rate was 16%, ranging from 5% to 49% among individual surgeries. Of those transfused, the median (Q1, Q3) number of RBCs transfused was 2 U (1, 3 U); 39% received 1 U RBC, 36% received 2 U RBC, and 8% were transfused ≥5 U RBC. Platelet and plasma transfusions were overall low. In the era of blood conservation, we described transfusion practices in major noncardiac surgeries at high risk for RBC transfusion, which has implications for patient consent, preoperative surgical planning, and blood bank inventory management.

The use of antiviral agents for the management of severe influenza.

The clinical course of pandemic H1N1 2009 influenza can be severe, particularly in the very young and patients with comorbidities. Pandemic H1N1 2009 is sensitive to the antiviral agents oseltamivir and zanamivir but is resistant to the M2 inhibitors. Although few clinical data are yet available, treatment of pandemic H1N1 2009 influenza in hospital settings with oseltamivir or zanamivir appears to be beneficial. In hospitalized patients with severe influenza treated with oseltamivir, mortality and length of stay are significantly reduced, and viral load is reduced more quickly than in untreated patients. In patients at high risk treated with oseltamivir or zanamivir, reductions in the risk of complications and mortality after treatment have been demonstrated with oseltamivir and zanamivir, although there are fewer data on the latter. There is no evidence yet that other antiviral agents are effective in severe or pandemic H1N1 2009 influenza. Current World Health Organization guidance strongly recommends the use of oseltamivir for severe or progressive infection with pandemic H1N1 2009, with zanamivir as an alternative if the infecting virus is oseltamivir-resistant. Very little resistance to oseltamivir has been found to date.

Support for higher ciprofloxacin AUC 24/MIC targets in treating Enterobacteriaceae bloodstream infection.

OBJECTIVES: Given concerns regarding optimal therapy for serious Gram-negative infections, the goal was to characterize the pharmacodynamics of ciprofloxacin in the context of treating bloodstream infection. PATIENTS AND METHODS: Data were collected from the medical records of 178 clinical cases. Blood isolates were retrieved and ciprofloxacin MICs were measured. Forty-two cases in which ciprofloxacin was initiated within 24 h of the positive blood culture were used in the pharmacodynamic analysis. RESULTS: Significant factors with regard to treatment failure were low ciprofloxacin AUC(24)/MIC (P < 0.0001), high MIC (P = 0.001), male sex (P = 0.002) and low AUC(24) (P = 0.01). AUC(24)/MIC (P = 0.012) and MIC (P = 0.019) were significant variables in multivariate analyses; however, only the former remained significant (P = 0.038) after excluding two cases with ciprofloxacin-resistant isolates. An AUC(24)/MIC breakpoint of 250 was most significant, with cure rates of 91.4% (32/35) and 28.6% (2/7) in patients with values above and below this threshold, respectively (P = 0.001). The risk of ciprofloxacin treatment failure was 27.8 times (95% confidence interval, 2.1-333) greater in those not achieving an AUC(24)/MIC >or=250 (P = 0.011). Monte Carlo simulation of 5000 study subjects predicted that 0.88 of the population would achieve an AUC(24)/MIC >or=250 with standard-dose ciprofloxacin (400 mg intravenously every 12 h). CONCLUSIONS: This study confirms the pharmacodynamic parameters of ciprofloxacin that are important for optimizing the treatment of serious infections, particularly the benefits of achieving an AUC(24)/MIC >or=250, rather than the conventional target of >or=125. It also shows the relevance of dose selection in optimizing target attainment, with important differences among pathogens, even those with MICs within the susceptible range.

Enteric absorption and pharmacokinetics of oseltamivir in critically ill patients with pandemic (H1N1) influenza.

BACKGROUND: Whether the enteric absorption of the neuraminidase inhibitor oseltamivir is impaired in critically ill patients is unknown. We documented the pharmacokinetic profile of oseltamivir in patients admitted to intensive care units (ICUs) with suspected or confirmed pandemic (H1N1) influenza. METHODS: We included 41 patients 18 years of age and older with suspected or confirmed pandemic (H1N1) influenza who were admitted for ventilatory support to nine ICUs in three cities in Canada and Spain. Using tandem mass spectrometry, we assessed plasma levels of oseltamivir free base and its active metabolite carboxylate at baseline (before gastric administration of the drug) and at 2, 4, 6, 9 and 12 hours after the fourth or later dose. RESULTS: Among the 36 patients who did not require dialysis, the median concentration of oseltamivir free base was 10.4 (interquartile range [IQR] 4.8-14.9) microg/L; the median concentration of the carboxylate metabolite was 404 (IQR 257-900) microg/L. The volume of distribution of the carboxylate metabolite did not increase with increasing body weight (R2=0.00, p=0.87). The rate of elimination of oseltamivir carboxylate was modestly correlated with estimations of creatinine clearance (R2=0.27, p<0.001). Drug clearance in the five patients who required continuous renal replacement therapy was about one-sixth that in the 36 patients with relatively normal renal function. INTERPRETATION: Oseltamivir was well absorbed enterically in critically ill patients admitted to the ICU with suspected or confirmed pandemic (H1N1) influenza. The dosage of 75 mg twice daily achieved plasma levels that were comparable to those in ambulatory patients and were far in excess of concentrations required to maximally inhibit neuraminidase activity of the virus. Adjustment of the dosage in patients with renal dysfunction requiring continuous renal replacement therapy is appropriate; adjustment for obesity does not appear to be necessary.