A Multicenter, Retrospective Outcome Analysis of Vancomycin Area Under the Curve versus Trough-Based Dosing Strategies in Patients with Burn OR Inhalational Injuries (MONITOR).

Vancomycin is a glycopeptide antibiotic that requires close therapeutic monitoring. Prolonged exposure to elevated concentrations increases risk for serious adverse effects such as nephrotoxicity. However, sub-therapeutic concentrations may lead to bacterial resistance and clinical failure or death. The most recent Infectious Diseases Society of America (IDSA) publication regarding therapeutic monitoring of vancomycin recommends utilizing area under the curve (AUC)-based monitoring to maximize clinical success. Despite the guideline recommendation for AUC-guided dosing, many institutions still use trough-only monitoring in their practices, including those caring for patients with acute burn injuries. Following burn injury, patients are at a higher risk for infections, multi-organ failure, and pharmacokinetic alterations. The primary objective of this multi-center retrospective study is to determine optimal therapeutic monitoring of vancomycin by comparing clinical success between AUC vs. trough-based monitoring in burn patients. MONITOR was a multicenter, retrospective study of patients with thermal or inhalation injury admitted to one of 13 burn centers from 1/1/17 to 8/31/22 who received vancomycin. Demographic and clinical course data, including acute kidney injury (AKI) incidence and clinical success were obtained. Patients were evaluated for clinical success and grouped according to method of monitoring and adjusting doses: AUC vs. trough-based monitoring. Clinical success was a composite definition and lack of meeting any 1 of 5 criteria: 1) persistent infection, 2) relapse, 3) antibiotic failure (clinical worsening), 4) AKI, 5) death. Five-hundred seventeen vancomycin courses were assessed from 485 patients. There was no difference in the rate of clinical success between AUC monitored and the trough-only monitored groups. Incidence of AKI was higher in the trough-only group; however, was not statistically significant after controlling for renal function on admission, past medical history of chronic kidney disease (CKD), and concomitant nephrotoxins.

Acute decompensation of patient following an outpatient CT-guided needle biopsy: A case report.

A 74-year-old female with history of type 2 diabetes, hypertension, and uterine adenocarcinoma presented for CT-guided lung biopsy that was ultimately complicated by an arterial air embolus requiring intensive care. Systemic air embolism is a very rare event but can be devastating. Prompt recognition can be difficult due to an often-vague presentation but is essential and should be considered upon rapid deterioration of a patient's status following high risk procedures. Hyperbaric oxygen therapy is preferred; however, if this is unavailable, additional treatments are predominately supportive care with 100% supplemental oxygen, rapid volume expansion, and ionotropic medications as needed.

Prevention of Venous Thromboembolism in Microvascular Surgery Patients Using Weight-Based Unfractionated Heparin Infusions.

BACKGROUND: Unfractionated heparin infusions are commonly used in microvascular surgery to prevent microvascular thrombosis. Previously, fixed-dose heparin infusions were believed to provide sufficient venous thromboembolism (VTE) prophylaxis; however, we now know that this practice is inadequate for the majority of patients. Anti-factor Xa (aFXa) level is a measure of unfractionated heparin efficacy and safety. This study evaluated the pharmacodynamics of weight-based dose heparin infusions and the impacts of real-time aFXa-guided heparin dose adjustments. METHODS: This prospective clinical trial enrolled adult microvascular surgery patients who received a weight-based heparin dose following a microsurgical procedure. Steady-state aFXa levels were monitored, and patients with out-of-range levels received dose adjustments. The study outcomes assessed were aFXa levels at a dose of heparin 10 units/kg/hour, time to adequate aFXa level, number of dose adjustments required to reach in-range aFXa levels, and clinically relevant bleeding and VTE at 90 days. RESULTS: Twenty-one patients were prospectively recruited, and usable data were available for twenty patients. Four of twenty patients (20%) had adequate prophylaxis at a heparin dose of 10 units/kg/hour. Among patients who received dose adjustments and achieved in-range aFXa levels, the median number of dose adjustments was 2 and the median weight-based dose was 11 units/kg/hour. The percentage of patients with in-range levels was significantly increased (65 vs. 15%, p = 0.0002) as a result of real-time dose adjustments. The rate of VTE at 90 days was 0%, and clinically relevant bleeding rate at 90 days was 15%. CONCLUSION: Weight-based heparin infusions at a rate of 10 units/kg/hour provide a detectable level of anticoagulation for some patients following microsurgical procedures, but most patients require dose adjustment to ensure adequate VTE prophylaxis.

Low Anti-Factor Xa Level Predicts 90-Day Symptomatic Venous Thromboembolism in Surgical Patients Receiving Enoxaparin Prophylaxis: A Pooled Analysis of Eight Clinical Trials.

OBJECTIVE: To examine the relationship between enoxaparin dose adequacy, quantified with anti-Factor Xa (aFXa) levels, and 90-day symptomatic venous thromboembolism (VTE) and postoperative bleeding. SUMMARY BACKGROUND DATA: Surgical patients often develop "breakthrough" VTE events-those which occur despite receiving chemical anticoagulation. We hypothesize that surgical patients with low aFXa levels will be more likely to develop 90-day VTE, and those with high aFXa will be more likely to bleed. METHODS: Pooled analysis of eight clinical trials (N = 985) from a single institution over a 4 year period. Patients had peak steady state aFXa levels in response to a known initial enoxaparin dose, and were followed for 90 days. Survival analysis log-rank test examined associations between aFXa level category and 90-day symptomatic VTE and bleeding. RESULTS: Among 985 patients, 2.3% (n = 23) had symptomatic 90-day VTE, 4.2% (n = 41) had 90-day clinically relevant bleeding, and 2.1% (n = 21) had major bleeding. Patients with initial low aFXa were significantly more likely to have 90-day VTE than patients with adequate or high aFXa (4.2% vs 1.3%, P = 0.007). In a stratified analysis, this relationship was significant for patients who received twice daily (6.2% vs 1.5%, P = 0.003), but not once daily (3.0% vs 0.7%, P = 0.10) enoxaparin. No association was seen between high aFXa and 90-day clinically relevant bleeding (4.8% vs 2.9%, P = 0.34) or major bleeding (3.6% vs 1.6%, P = 0.18). CONCLUSIONS: This manuscript establishes inadequate enoxaparin dosing as a plausible mechanism for breakthrough VTE in surgical patients, and identifies anticoagulant dose adequacy as a novel target for process improvement measures.

Double-Blind Randomized Clinical Trial to Examine the Pharmacokinetic and Clinical Impacts of Fixed Dose versus Weight-based Enoxaparin Prophylaxis: A Methodologic Description of the FIxed or Variable Enoxaparin (FIVE) Trial.

Venous thromboembolism is an important patient safety in plastic surgery, and multiple clinical trials in the past 10 years have provided increased understanding of the risks and benefits of venous thromboembolism prevention strategies. This paper provides an exhaustive discussion of the rationale behind and methodology for an in progress randomized double-blind clinical trial in plastic surgery inpatients, in which the 2 study arms are enoxaparin 40 mg twice daily and enoxaparin 0.5 mg/kg twice daily. The trial's primary aims are to: (1) demonstrate whether enoxaparin 0.5 mg/kg twice daily is superior to enoxaparin 40 mg twice daily for the pharmacokinetic endpoint of overanticoagulation (anti-Factor Xa > 0.4 IU/mL) and (2) demonstrate whether enoxaparin 0.5 mg/kg twice daily is not inferior to enoxaparin 40 mg twice daily for the pharmacokinetic endpoint of underanticoagulation (anti-Factor Xa < 0.2 IU/mL). The results of this trial will provide Level I evidence to help guide plastic surgeon's choice of postoperative prophylactic anticoagulation.

Assessment of Anti-Factor Xa Levels of Patients Undergoing Colorectal Surgery Given Once-Daily Enoxaparin Prophylaxis: A Clinical Study Examining Enoxaparin Pharmacokinetics.

Importance: Between 4% and 12% of patients undergoing colorectal surgery and receiving enoxaparin, 40 mg per day, have a postoperative venous thromboembolism (VTE) event. An improved understanding of why "breakthrough" VTE events occur despite guideline-compliant prophylaxis is an important patient safety question. Objective: To determine the proportion of patients undergoing colorectal surgery who received adequate anticoagulation based on peak anti-factor Xa (aFXa) levels while receiving enoxaparin at 40 mg per day. Design, Setting, and Participants: This prospective, nonrandomized clinical trial was conducted between February 2017 and July 2018 with 90-day follow-up at a quaternary academic medical center in the Intermountain West and included patients undergoing colorectal surgery who had surgery after receiving general anesthesia, were admitted for at least 3 days, and received enoxaparin, 40 mg once daily. Interventions: All patients had aFXa levels measured after receiving enoxaparin 40 mg per day. Patients whose aFXa level was out of range entered the trial's interventional arm where real-time enoxaparin dose adjustment and repeated aFXa measurement were performed. Main Outcomes and Measures: Primary outcome: in-range peak aFXa levels (goal range, 0.3-0.5 IU/mL) with enoxaparin, 40 mg per day. Secondary outcomes: (1) in-range trough aFXa levels (goal range, 0.1-0.2 IU/mL) and (2) the proportion of patients with in-range peak aFXa levels from enoxaparin, 40 mg once daily, vs the real-time enoxaparin dose adjustment protocol. Results: Over 16 months, 116 patients undergoing colorectal surgery (65 women [56.0%]; 99 white individuals [85.3%], 13 Hispanic or Latino individuals [11.2%], and 4 Pacific Islander individuals [3.5%]; mean [range] age, 52.1 [18-85] years) were enrolled. Among 106 patients (91.4%) whose peak aFXa level was appropriately drawn, 72 (67.9%) received inadequate anticoagulation (aFXa < 0.3 IU/mL) with enoxaparin, 40 mg per day. Weight and peak aFXa levels were inversely correlated (r2 = 0.38). Forty-seven patients (77%) had a trough aFXa level that was not detectable (ie, most patients had no detectable level of anticoagulation for at least 12 hours per day). Real-time enoxaparin dose adjustment was effective. Patients were significantly more likely to achieve an in-range peak aFXa with real-time dose adjustment as opposed to fixed dosing alone (85.4% vs 29.2%, P < .001). Conclusions and Relevance: This study supports the finding that most patients undergoing colorectal surgery receive inadequate prophylaxis from enoxaparin, 40 mg once daily. These findings may explain the high rate of "breakthrough" VTE observed in many clinical trials. Trial Registration: ClinicalTrials.gov identifier: NCT02704052.

Adequacy of Fixed-Dose Heparin Infusions for Venous Thromboembolism Prevention after Microsurgical Procedures.

BACKGROUND: In microvascular surgery, patients often receive unfractionated heparin infusions to minimize risk for microvascular thrombosis. Patients who receive intravenous (IV) heparin are believed to have adequate prophylaxis against venous thromboembolism (VTE). Whether a fixed dose of IV heparin provides detectable levels of anticoagulation, or whether the "one size fits all" approach provides adequate prophylaxis against VTE remains unknown. This study examined the pharmacodynamics of fixed-dose heparin infusions and the effects of real-time, anti-factor Xa (aFXa) level driven heparin dose adjustments. METHODS: This prospective clinical trial recruited adult microvascular surgery patients placed on a fixed-dose (500 units/h) unfractionated heparin infusion during their initial microsurgical procedure. Steady-state aFXa levels, a marker of unfractionated heparin efficacy and safety, were monitored. Patients with out-of-range aFXa levels received protocol-driven real-time dose adjustments. Outcomes of interest included aFXa levels in response to heparin 500 units/h, number of dose adjustments required to achieve goal aFXa levels, time to reach goal aFXa level, and 90-day clinically relevant bleeding and VTE. RESULTS: Twenty patients were recruited prospectively. None of 20 patients had any detectable level of anticoagulation in response to heparin infusions at 500 units/h. The median number of dose adjustments required to reach goal level was five, and median weight-based dose to reach goal level was 11.8 units/kg/h. Real-time dose adjustments significantly increased the proportion of patients with in-range levels (60 vs. 0%, p = 0.0001). The 90-day VTE rate was 5% and 90-day clinically relevant bleeding rate was 5%. CONCLUSIONS: Fixed-dose heparin infusions at a rate of 500 units/h do not provide a detectable level of anticoagulation after microsurgical procedures and are insufficient for the majority of patients who require VTE prophylaxis. Weight-based heparin infusions at 10 to 12 units/kg/h deserve future study in patients undergoing microsurgical procedures to increase the proportion of patients receiving adequate VTE prophylaxis.

Twice-Daily Enoxaparin among Plastic Surgery Inpatients: An Examination of Pharmacodynamics, 90-Day Venous Thromboembolism, and 90-Day Bleeding.

BACKGROUND: Low anti-factor Xa level, indicative of inadequate enoxaparin dosing, has a significant association with 90-day venous thromboembolism events. The authors examined the pharmacodynamics of enoxaparin 40 mg twice daily and its correlation with anti-factor Xa level, postoperative venous thromboembolism, and bleeding. METHODS: Adult patients were admitted after plastic and reconstructive surgery and received enoxaparin 40 mg twice daily. Peak anti-factor Xa levels, which quantify enoxaparin's antithrombotic effect, were drawn, with a goal level of 0.2 to 0.4 IU/ml. Ninety-day symptomatic venous thromboembolism and clinically relevant bleeding were identified. RESULTS: The authors enrolled 118 patients who received enoxaparin 40 mg twice daily. Of these patients, 9.6 percent had low peak anti-factor Xa levels (<0.2 IU/ml), 62.6 percent had in-range peak anti-factor Xa levels (0.2 to 0.4 IU/ml), and 27.8 percent had high anti-factor Xa levels (>0.4 IU/ml). With enoxaparin 40 mg twice daily, 90.4 percent of patients received at least adequate prophylaxis. Patient weight predicted the rapidity of enoxaparin metabolism. Zero acute 90-day venous thromboembolism occurred. Eight patients (6.8 percent) had clinically relevant 90-day bleeding: clinical consequences ranged from cessation of enoxaparin prophylaxis to transfusion to operative hematoma evacuation. CONCLUSIONS: When enoxaparin 40 mg twice daily is provided, 90 percent of patients receive at least adequate venous thromboembolism prophylaxis (anti-factor Xa level >0.2 IU/ml). However, 27 percent of the overall population is overtreated (anti-factor Xa level >0.4 IU/ml). These pharmacodynamics data likely explain the low rate of 90-day acute venous thromboembolism (0 percent) and the high rate of clinically relevant bleeding (6.8 percent) observed. Future studies are needed to better optimize the risks and benefits of enoxaparin prophylaxis in plastic and reconstructive surgery patients. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Enoxaparin 40 mg per Day Is Inadequate for Venous Thromboembolism Prophylaxis After Thoracic Surgical Procedure.

BACKGROUND: Many patients undergoing thoracic surgical procedures have venous thromboembolism (VTE) events despite the receipt of chemical prophylaxis. Enoxaparin's pharmacologic impact can be quantified by using anti-Factor Xa (aFXa) levels. We hypothesized that enoxaparin 40 mg once daily would be inadequate for most inpatients undergoing thoracic surgical procedures and that a real-time dose adjustment algorithm would be effective. METHODS: This prospective clinical trial enrolled inpatients who were to undergo a thoracic surgical procedure and placed on enoxaparin 40 mg once daily for VTE prophylaxis after surgical procedures. aFXa levels were used to measure the anticoagulant effect of enoxaparin once steady state had been reached. Patients whose aFXa levels were out of range received real-time enoxaparin dose adjustment and had repeat aFXa levels drawn. RESULTS: Ninety-three inpatients undergoing thoracic surgical procedures were prospectively enrolled. The majority of patients (67.4%) had low peak aFXa levels (<0.3 IU/mL), indicative of inadequate enoxaparin prophylaxis, and 30.3% of patients had in-range aFXa levels (0.3 to 0.5 IU/mL). Patient weight had a moderate correlation (r2 0.38) with peak aFXa level. Patient weight, female sex, and preoperative creatinine were independent predictors of peak aFXa in a linear regression model. Real-time, protocol-driven enoxaparin dose adjustment allowed a significantly increased proportion of patients to achieve in-range aFXa levels (30.3% vs 97.6%, p < 0.001). CONCLUSIONS: Enoxaparin 40 mg once daily is inadequate for most inpatients undergoing thoracic surgical procedures, based on a pharmacodynamic study of aFXa levels. Future research should examine the impact of weight-based once daily enoxaparin dosing versus twice daily enoxaparin dosing on prophylaxis adequacy.

The Impact of Once- versus Twice-Daily Enoxaparin Prophylaxis on Risk for Venous Thromboembolism and Clinically Relevant Bleeding.

BACKGROUND: Venous thromboembolism is a life- or limb-threatening complication that occurs in plastic surgery patients. At present, the optimal dose of enoxaparin that balances the risk of venous thromboembolism and the risk of medication-related adverse drug events-specifically, bleeding-remains unknown. METHODS: This study compared pharmacodynamic and clinical outcomes, including 90-day venous thromboembolism and 90-day clinically relevant bleeding, between two prospectively performed clinical trials whose sole difference was postoperative anticoagulation strategy. Patients in trial 1 received enoxaparin 40 mg once daily for the duration of inpatient stay, and patients in trial 2 received enoxaparin 40 mg twice daily for the duration of inpatient stay. The study also examined the potential impact of a weight-based twice-daily prophylaxis strategy to achieve in-range anti-factor Xa levels. RESULTS: The study compared 94 patients who received once-daily enoxaparin to 118 patients who received twice-daily enoxaparin. Twice-daily enoxaparin was associated with a significant decrease in 90-day acute venous thromboembolism (0 percent versus 5.3 percent; p = 0.012) and a nonsignificant increase in 90-day clinically relevant bleeding (6.8 percent versus 3.2 percent; p = 0.25). Twice-daily enoxaparin at 0.4 to 0.5 mg/kg may allow an increased proportion of patients to avoid both inadequate anticoagulation and overanticoagulation, based on anti-factor Xa levels. CONCLUSIONS: Twice-daily enoxaparin is superior to once-daily enoxaparin for 90-day acute venous thromboembolism risk reduction. Twice-daily enoxaparin may increase clinically relevant bleeding, although observed differences in this study were not significant. Weight-based twice-daily enoxaparin dosing may optimize the risks and benefits of prophylactic anticoagulation after plastic and reconstructive surgery. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

Weight-Based Dosing for Once-Daily Enoxaparin Cannot Provide Adequate Anticoagulation for Venous Thromboembolism Prophylaxis.

BACKGROUND: Surgeons commonly provide enoxaparin prophylaxis to high-risk patients to decrease venous thromboembolism risk. The authors' prior work demonstrated that most patients receive inadequate venous thromboembolism prophylaxis, based on anti-factor Xa level, when enoxaparin 40 mg/day is provided and that peak anti-factor Xa level correlates with weight. This study models a weight-based strategy for daily enoxaparin prophylaxis and its impact on anti-factor Xa levels. METHODS: The authors enrolled plastic surgery patients who received enoxaparin 40 mg/day and had anti-factor Xa levels drawn. The enoxaparin dose of 40 mg was converted to a milligram-per-kilogram dose for each patient. Stratified analysis examined the milligram-per-kilogram dose that produced low, in-range, and high anti-factor Xa levels to identify the appropriate milligram-per-kilogram dose to optimize venous thromboembolism prevention and bleeding events. RESULTS: Among 94 patients, weight-based dosing ranged from 0.28 to 0.94 mg/kg once daily. For peak and trough anti-factor Xa levels, there was nearly complete overlap for milligram-per-kilogram dosing that produced low versus in-range anti-factor Xa levels. For peak anti-factor Xa, there was nearly complete overlap for milligram-per-kilogram dosing that produced in-range versus high anti-factor Xa levels. Mean milligram-per-kilogram dose was not significantly different between patients who did or did not have postoperative venous thromboembolism (0.41 mg/kg versus 0.52 mg/kg; p = 0.085) or clinically relevant bleeding (0.48 mg/kg versus 0.51 mg/kg; p = 0.73). CONCLUSIONS: Alterations in enoxaparin dose magnitude based on patient weight cannot allow a high proportion of patients to achieve appropriate anti-factor Xa levels when once-daily enoxaparin prophylaxis is provided. Future research should examine the impact of increased enoxaparin dose frequency on anti-factor Xa levels, venous thromboembolism events, and bleeding. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Utility of anti-factor Xa monitoring in surgical patients receiving prophylactic doses of enoxaparin for venous thromboembolism prophylaxis.

BACKGROUND: Between 2% and 10% of the highest risk surgery, patients have a "breakthrough" venous thromboembolism (VTE) event despite receipt of chemoprophylaxis. The goals of this review are to summarize how patient-level factors may predict enoxaparin metabolism and how alterations in enoxaparin dose magnitude and frequency affect both anti-factor Xa (aFXa) levels and downstream VTE events. DATA SOURCES: Relevant articles were identified on PubMed. Fixed-dose prophylaxis provides inadequate enoxaparin prophylaxis for most surgical patients based on anti-factor Xa levels. Inadequate enoxaparin dosing has been correlated with both asymptomatic and symptomatic VTE events. Patient-level factors such as gross weight and extent of injury predict enoxaparin metabolism. Weight-based or weight-tiered dosing regimens-and real-time dose adjustment based on anti-factor Xa levels-allow an increased proportion of patients to have in-range anti-factor Xa levels. CONCLUSIONS: Inadequate enoxaparin dosing may explain why some patients have VTE despite enoxaparin prophylaxis. Ongoing research in the utility of weight-based or anti-factor Xa level driven enoxaparin dosing and dose adjustment is reasonable.

Supratherapeutic anti-factor Xa levels in patients receiving prophylactic doses of enoxaparin: A case series.

INTRODUCTION: Enoxaparin prophylaxis prevents venous thromboembolism in surgical patients. Real time anti-Factor Xa monitoring for surgical patients on enoxaparin prophylaxis is increasingly common. PRESENTATION OF CASES: We report on three cancer patients with therapeutic or supratherapeutic anti-Factor Xa levels while on prophylactic doses of enoxaparin after surgical procedures. In all cases, elevated anti-Factor Xa levels were the result of blood specimens being removed from a heparinized chemoport. DISCUSSION: This case series highlights the importance of peripheral venipuncture or appropriate blood wasting from central access sites for anti-Factor Xa levels. CONCLUSION: Inappropriately drawn anti-Factor Xa levels may contribute to prophylaxis interruption or unnecessary workup for renal or liver failure.

Prevalence of Listeria monocytogenes during production and postharvest processing of cabbage.

From November 1999 to May 2000, analyses of 425 cabbage, 205 water, and 225 environmental sponge samples from four cabbage farms with packing sheds and from two packing sheds in the Rio Grande Valley and Uvalde, Tex., were conducted to determine whether Listeria monocytogenes was present. Samples were tested by the Food and Drug Administration method for the isolation of Listeria spp., and confirmed isolates were DNA fingerprinted by repetitive-element sequence-based polymerase chain reaction (rep-PCR). L monocytogenes was isolated from 3% (26 of 855) of the samples. Twenty of these isolates were obtained from cabbage (7 isolates from farms and 13 from packing sheds). Three isolates were from water samples(two from farms and one from a packing shed), and three were from environmental sponge samples of packing shed surfaces. Rep-PCR-generated fingerprints of 21 of the isolates revealed 18 distinctive banding patterns. Four isolates from environmental sponge samples of conveyor belts and from cabbage samples shared identical banding patterns, suggesting common sources of contamination. These identical environmental isolates suggest that contact with packing shed surfaces may be a source of contamination of cabbage. However, the cabbage samples could have arrived contaminated, since they were not washed.