Azithromycin and Septic Shock Outcomes.

Introduction: Although there is evidence describing the immunomodulatory effects of macrolide antibiotics, there is little literature exploring the clinical effects these properties may have and their impact on measurable outcomes. Objective: The purpose of this study was to determine if empiric antimicrobial regimens containing azithromycin shorten time to shock resolution. Methods: A retrospective study was performed in adults with septic shock admitted to intensive care units (ICUs) of 3 university-affiliated, urban teaching hospitals between June 2012 and June 2016. Eligible patients with septic shock required treatment with norepinephrine as the first-line vasopressor for a minimum of 4 hours and received at least 48 hours of antimicrobial treatment from the time of shock onset. Propensity scores were utilized to match patients who received azithromycin to those who did not. Results: A total of 3116 patients met initial inclusion criteria. After propensity score matching, 258 patients were included, with 124 and 134 patients in the azithromycin and control groups, respectively. Median shock duration was similar in patients treated with or without azithromycin (45.6 hr vs 59.7 hr, P = .44). In-hospital mortality was also similar (37.9% vs 38.1%, P = .979). There were no significant differences in mechanical ventilation duration, ICU length of stay (LOS), or hospital LOS. Conclusions: In patients admitted to the ICU with septic shock, empiric azithromycin did not have a significant effect on shock duration, mechanical ventilation duration, ICU LOS, hospital LOS, or in-hospital mortality.

Incidence and risk factors of COVID-19 associated pneumothorax.

BACKGROUND: Pneumothorax has been increasingly observed among patients with coronavirus disease-2019 (COVID-19) pneumonia, specifically in those patients who develop acute respiratory distress syndrome (ARDS). In this study, we sought to determine the incidence and potential risk factors of pneumothorax in critically ill adults with COVID-19. METHOD: This retrospective cohort study included adult patients with laboratory-confirmed SARS-CoV-2 infection admitted to one of the adult intensive care units of a tertiary, academic teaching hospital from May 2020 through May 2021. RESULTS: Among 334 COVID-19 cases requiring ICU admission, the incidence of pneumothorax was 10% (33 patients). Patients who experienced pneumothorax more frequently required vasopressor support (28/33 [84%] vs. 191/301 [63%] P = 0.04), were more likely to be proned (25/33 [75%] vs. 111/301 [36%], P<0.001), and the presence of pneumothorax was associated with prolonged duration of mechanical ventilation; 21 (1-97) versus 7 (1-79) days, p<0.001 as well as prolonged hospital length of stay (29 [9-133] vs. 15 [1-90] days, P<0.001), but mortality was not significantly different between groups. Importantly, when we performed a Cox proportional hazard ratio (HR) model of multivariate parameters, we found that administration of tocilizumab significantly increased the risk of developing pneumothorax (HR = 10.7; CI [3.6-32], P<0.001). CONCLUSION: Among 334 critically ill patients with COVID-19, the incidence of pneumothorax was 10%. Presence of pneumothorax was associated with prolonged duration of mechanical ventilation and length of hospital stay. Strikingly, receipt of tocilizumab was associated with an increased risk of developing pneumothorax.

Evaluation of dosing strategies and trough concentrations of vancomycin in patients undergoing continuous venovenous hemofiltration.

STUDY OBJECTIVE: Recommendations regarding vancomycin dosing in critically ill patients on continuous venovenous hemofiltration (CVVH) are limited. The purpose of this study was to evaluate current dosing practices of pharmacists for patients treated with CVVH, develop guidelines for optimal dosing and monitoring of vancomycin to improve target trough attainment, and reduce pharmacist workload. DESIGN: A retrospective cohort study. was performed of critically ill adult patients from January 2015 to December 2018. Patients were included if they received vancomycin during CVVH for at least 48 h. Patients with significant residual kidney function, defined as daily urine output >400 ml or significant fluctuations (≥1000 ml/h in a 24-h period) in their hemofiltration rates, were excluded. Interruptions in CVVH up to 6 h/day were permitted. Dosing strategies with two dosing categories were defined: (1) dosing based on random serum levels (dosing by level, DBL) or (2) scheduled vancomycin dosing (SD). SETTING: Academic medical center in Detroit, Michigan. PATIENTS: Critically ill adult patients. MEASUREMENTS AND MAIN RESULTS: During the study period, 942 patients were evaluated and 200 met inclusion criteria, for a total of 586 serum vancomycin levels. There were 141 patients with 443 random vancomycin serum levels in the DBL group and 59 patients with143 vancomycin trough levels in the SD group. Mean vancomycin trough levels were similar between groups (17.1 ± 6 vs. 16.5 ± 4 mcg/ml) for the DBL and SD groups, respectively. For the primary end point of overall target trough achievement of 15-20 mcg/ml, significantly more trough levels in the SD group were in the 15-20 mcg/ml range compared with the DBL group, 50% vs. 38%; p < 0.001, respectively. When target trough range was extended to 10-20 mcg/ml, success rates were similar between groups (74% DBL vs. 82% SD, p = 0.021). The number of interventions required by the pharmacist, including notes per day and orders per day, were reduced by approximately 50% when the SD strategy was utilized. Scheduled vancomycin dosing regimens of 15-22 mg/kg every 12-24 h were required to yield trough levels in the 15-20 mcg/ml range. CONCLUSIONS: Target vancomycin trough achievement of 15-20 mcg/ml occurred more frequently when vancomycin was scheduled at a dose of 15-22 mg/kg every 12-24 h based on ultrafiltration rate and may alleviate the time and cost associated with frequent vancomycin serum monitoring.

Prophylactic unfractionated heparin and hemorrhage in neurocritically ill underweight patients: A case series and review of the literature.

PURPOSE: Three cases of major bleeding associated with thromboprophylactic unfractionated heparin (UFH) therapy in underweight neurocritically ill patients are reported. SUMMARY: Three underweight patients (body mass index of <18.5 kg/m2) were treated in the intensive care unit with major bleeds associated with UFH thromboprophylaxis. Two of the patients, a 76-year-old female and a 56-year-old female, had hemorrhages on presentation; the third patient, a 29-year-old male, developed bleeding during his admission. All 3 patients had past medical histories consisting of acute neurologic conditions within 6 weeks of presentation, including subdural hematoma, subarachnoid hemorrhage, and obstructive hydrocephalus secondary to a brain mass. All hemorrhages developed following the receipt of prophylactic UFH at doses of 5,000 units every 8 to 12 hours, which translated to high weight-based dosages (>300 units/kg/d). Additionally, hemorrhages were associated with prolonged activated partial thromboplastin time, which declined following heparin discontinuation. The major bleeds following UFH administration included an acute on chronic subdural hematoma, acute rectus sheath hematoma, and cerebellar hematoma. Stabilization of the subdural hematoma was achieved without the use of protamine and the patient was discharged in stable condition. The other 2 patients expired secondary to their hemorrhagic events. Naranjo nomogram scores for the patients indicated that heparin was the probable cause of bleed in 2 cases and a possible cause in 1 case. CONCLUSION: Three major hemorrhages developed following the administration of UFH. Underweight patients with neurologic injury may require increased clinical vigilance, reduced doses, and pharmacodynamic monitoring to improve safety outcomes associated with thromboprophylaxis.

Use of phenytoin for treatment of tacrolimus toxicity with superimposed sepsis.

A 40-year-old woman with a history of chronic graft-versus-host-disease on immunosuppression with tacrolimus presented to the hospital with somnolence, confusion and muscle cramps over a few days. She was found to have hypertension, hyperglycaemia and acute kidney injury with an elevated blood tacrolimus level of greater than 120 ng/mL (reference range 5-15 ng/mL). Discontinuation of tacrolimus with concomitant administration of intravenous phenytoin led to the successful reduction of elevated tacrolimus concentrations and the resolution of her symptoms. Tacrolimus is metabolised by the cytochrome P (CYP) 450 3A enzyme system, and utilisation of CYP 3A inducers to accelerate its clearance may be used as a successful therapy to treat tacrolimus toxicity.

Early Experiences With PEGylated Carboxyhemoglobin Bovine in Anemic Jehovah's Witnesses: A Case Series and Review of the Literature.

Jehovah's Witnesses (JW) represent a complex patient population due to their refusal to accept blood transfusions on religious grounds. Pharmacologic management of anemic JW patients is limited to stimulation of hematopoiesis by iron and erythropoietin supplementation and reduction of blood loss by prothrombin complex concentrates (PCCs). Hemoglobin-based oxygen carriers (HBOCs) represent the only pharmacologic modality for JW patients capable of acutely increasing a patient's oxygen carrying capacity in the setting of organ failure, yet clinical safety and efficacy data are lacking in this population. We report 3 cases in which the HBOC, PEGylated carboxyhemoglobin bovine (Sanguinate®), was requested under emergent circumstances for severely anemic (hemoglobin <5 g/dL) JW patients who refused blood transfusions. Two patients received PEGylated carboxyhemoglobin infusions for severe anemia, while the third patient died prior to receiving the medication. One patient who received Sanguinate died after 5 units of medication. The other patient's hemoglobin recovered and she was discharged in stable condition. This series demonstrates the complex nature of the critically anemic JW population and highlights the clinical considerations of using HBOCs in clinical practice and the critical need for further research before they can be broadly recommended.

Pharmacotherapy in Acutely Anemic Jehovah's Witnesses: An Evidence-Based Review.

OBJECTIVE: To determine the pharmacological treatment methods available to anemic Jehovah's Witnesses (JW). DATA SOURCES: MEDLINE and PubMed were searched from inception through February 2018 using the search terms Jehovah's Witnesses, treatment, erythropoietin, hemoglobin-based oxygen carrier, Sanguinate, Hemopure, bleeding, and anemia. STUDY SELECTION AND DATA EXTRACTION: All clinical trials, cohort studies, case-control studies, and observational trials involving pharmacotherapy in anemic JW patients were evaluated. Case reports and bibliographies were also analyzed for inclusion. DATA SYNTHESIS: Two studies involving the use of erythropoietin (EPO) and one study involving recombinant factor VIIa were included. Information was also included from other pharmacotherapeutic modalities that had case report data only. Current published evidence is limited with regard to evidence-based management of JW patients. High-dose EPO, intravenous iron supplementation, and hemostatic agents have demonstrated good clinical outcomes in case reports. EPO doses as high as 40 000 units daily have been advocated by some experts; however, pharmacokinetic studies do not support dose-dependent effects. Hemoglobin-based oxygen carriers (HBOCs) are currently not Food and Drug Administration approved. They are available through expanded access programs and may represent a lifesaving modality in the setting of severe anemia. CONCLUSIONS: There are currently not enough data to make definitive recommendations on the use of pharmacological agents to treat severe anemia in the JW population. Further evidence utilizing EPO and HBOCs will be beneficial to guide therapy.

Assessment of an Extended Interval Fondaparinux Dosing Regimen for Venous Thromboembolism Prophylaxis in Critically Ill Patients with Severe Renal Dysfunction Using Antifactor Xa Levels.

OBJECTIVE: Pharmacologic options for venous thromboembolism (VTE) prophylaxis are often limited in critically ill patients due to thrombocytopenia and multisystem organ dysfunction. Fondaparinux offers potential advantages in the critically ill; however, it is currently contraindicated in severe renal dysfunction (SRD). We evaluated anti-factor Xa levels in critically ill patients with SRD who were receiving an extended interval dosing regimen of fondaparinux for VTE prophylaxis. METHODS: A prospective, single-arm, interventional study was conducted at two academic hospitals of the Detroit Medical Center. Eligible patients were in the intensive care unit, had an estimated creatinine clearance of less than 30 ml/minute, and had either acute kidney injury or end-stage renal disease; several patients were taking renal replacement therapy. Fondaparinux was administered at an extended interval dosing regimen of 2.5 mg subcutaneously every 48 hours. Fondaparinux peak and trough anti-factor Xa levels were obtained. Lower extremity venous duplex studies were performed at baseline and study completion to assess for deep vein thrombosis (DVT), and patients were monitored for bleeding complications. RESULTS: Thirty-two patients were enrolled. Patients received a median of four doses (interquartile range two to five) of fondaparinux. Fondaparinux peak (n=98) and trough (n=86) anti-factor Xa levels were 0.36 ± 0.18 mg/L and 0.17 ± 0.11 mg/L (mean ± SD), respectively, and were similar to levels reported in patients with normal renal function receiving conventional once-daily dosing. No lower extremity DVTs or suspected VTE events occurred. Two (6%) patients had significant bleeding events. CONCLUSIONS: In critically ill patients with SRD, an extended interval fondaparinux dosing regimen of 2.5 mg every 48 hours for VTE prophylaxis achieved peak and trough anti-factor Xa levels similar to those reported in noncritically ill patients with normal renal function receiving once-daily fondaparinux. This regimen offers an alternative for patients with SRD when heparinoids must be avoided.

Heparin dosing in critically ill patients undergoing therapeutic hypothermia following cardiac arrest.

PURPOSE: To determine the effects of anticoagulation with intravenous unfractionated heparin (IVUH) during therapeutic hypothermia (TH) post-cardiac arrest. METHODS: Single-center, retrospective, observational trial in the intensive care units of two hospitals within the Detroit Medical Center. Unresponsive survivors of cardiac arrest, receiving treatment doses of IVUH during TH were included. Patients were required to have at least 1 measured activated partial thromboplastin time (aPTT) during TH. Coagulation parameters were collected at 3 distinct temperature phases: baseline, TH, and post-re-warming (±37 °C) target aPTT defined as 1.5-2 times baseline. RESULTS: Forty-six patients received IVUH during TH, with 211 aPTTs. Heparin starting rate was 13±4 units/kg/h. Average baseline, TH and post-TH aPTT were 34±12, 142±48, and 56±17 s, respectively. Using standard dosing strategies, initial aPTT was above the target range in 89% of patients. After re-warming, aPTT significantly decreased (142±48s vs. 56±17 s, p=0.005), and heparin dose significantly increased (7.9±3 vs. 9±4 units/kg/h, p<0.001). There was a significant difference between aPTT among all three groups, and heparin dose between TH and post-TH even after correcting for age, sex, body mass index, heparin rate, and APACHE II score (p<0.001). Three patients experienced a major bleeding event. CONCLUSIONS: Current dosing protocols for IVUH should not be utilized during TH. Heparin requirements are drastically reduced during TH and prolonged interruptions may be required to allow for adequate clearance of UH.

Vascular catheter tip cultures for suspected catheter-related blood stream infection in the intensive care unit: a tradition whose time has passed?

BACKGROUND: Catheter-related blood stream infections (CR-BSIs) are estimated to occur in 80,000 patients in intensive care units (ICUs) each year in the United States. We sought to determine the clinical utility of vascular catheter cultures in critically ill patients with suspected CR-BSI. METHODS: We reviewed retrospectively all positive (≥15 colony forming units/roll) vascular catheter tip cultures (CTCs) documented over a four-year period in the ICUs of two hospitals. A CR-BSI was defined as matching positive blood and catheter cultures. The time interval between catheter removal and blood culture was recorded. RESULTS: A total of 1,391 CTCs were obtained, of which 468 (34%) were positive and 143 (31% of the positive cultures) were associated with a diagnosis of CR-BSI. In 133 of these 143 cases (93%), the positive blood culture was obtained before or within 24 h after catheter removal and dictated antibiotic therapy. In only 10 of 143 cases (7%) did catheter removal and culture significantly (>1 day) precede the positive blood culture. In 55% of the CR-BSI cases, the catheter was removed empirically and close to the time of blood culture (-1.3±19.0 h). In the remaining 45%, the catheter was removed clinically (after a blood culture was positive), and this action was more remote in time (23.6±19.4 h; p<0.001 vs. empiric removal). Total microbiology laboratory costs for the CTCs were $75,300, and 600 microbiology technician hours were required. CONCLUSION: In an ICU patient population, only about one-third of vascular catheter cultures were positive, and only about one-third of the positive CTCs were associated with CR-BSI. Ninety-three percent of all CR-BSIs were identified by bacteremia either before or coinciding with catheter removal, and the results of the blood culture dictated antimicrobial therapy. Because CTCs rarely changed therapy, they may not be appropriate in the management of suspected CR-BSI in the ICU setting.

Validation of the effectiveness of a vancomycin nomogram in achieving target trough concentrations of 15-20 mg/L suggested by the vancomycin consensus guidelines.

STUDY OBJECTIVE: To assess and validate the effectiveness of a newly constructed vancomycin dosing nomogram in achieving target trough serum concentrations of 15-20 mg/L. DESIGN: Prospective multicenter study. SETTING: Five tertiary care teaching hospitals. PATIENTS: A total of 200 adults who required vancomycin dosages targeted to attain recommended trough vancomycin serum concentrations of 15-20 mg/L. INTERVENTION: The new nomogram, which based dosing on weight and renal function, was used to calculate patients' initial vancomycin dosages. Serum trough concentrations were measured before the fourth or fifth dose, and dosages were adjusted as needed. MEASUREMENTS AND MAIN RESULTS: Median patient age was 56 years (interquartile range [IQR] 49-65 yrs), median weight was 71.2 kg (IQR 63-85 kg), and median creatinine clearance was 66.5 ml/minute (IQR 52-82 ml/min). The median initial vancomycin trough concentration achieved was 17.5 mg/L (IQR 15.0-20.0 mg/L), with 116 patients (58%) achieving the initial target trough of 15-20 mg/L. The median percent error was 13.6%, and the mean ± SD error for predicted versus actual serum trough concentrations was -0.50 ± 0.021 mg/L. One hundred fifty-four patients (77%) eventually achieved the trough target concentration within a median of 2 days. One hundred forty patients (70%) achieved initial troughs of 14-21 mg/L and 160 (80%) achieved troughs of 13-22 mg/L. Nine patients (4.5%) experienced nephrotoxicity while receiving vancomycin, which occurred after a median of 8 days of therapy. The median initial vancomycin trough concentration for these patients was 18.5 mg/L (IQR 15.3-19.3 mg/L), with eight of the nine patients having trough concentrations of 15 mg/L or greater. CONCLUSION: Fifty-eight percent of patients achieved the target trough of 15-20 mg/L (median 17.5 mg/L). The performance of the nomogram improved to 80% when the trough range was adjusted to 13-22 mg/L. Caution should be applied when using this nomogram. The nomogram should not replace clinical judgment, and dosage adjustments should be based on pharmacokinetic-pharmacodynamic targets and clinical response.

Intravenous and inhalational colistin-induced respiratory failure.

The emergence of highly resistant gram-negative pathogens in hospitals around the world has placed emphasis on colistin, a seemingly ancient drug. Respiratory failure from colistin was reported in the years following its release; however, there are no recent reports of colistin-induced respiratory failure. We report a case of intravenous colistin- and, later, inhalational colistin-induced respiratory failure.