Risk Stratification for Supratherapeutic Peak Anti-Xa Levels in Adult Patients on Therapeutic Enoxaparin.

BACKGROUND: The American Society of Hematology Guidelines for the management of venous thromboembolism recommend against the use of anti-Xa monitoring for assessing enoxaparin dosing based on a low level of evidence associating supratherapeutic levels with an increased risk of bleeding. However, institutions still utilize anti-Xa levels in select patient populations with altered volume of distribution and/or excretion to monitor and adjust therapy. OBJECTIVE: The primary objective of this study was to identify risk factors associated with supratherapeutic peak anti-Xa levels (≥1.10 IU/mL) for patients receiving therapeutic enoxaparin. METHODS: This was a retrospective single-center study performed at an academic tertiary care hospital. Patients who received enoxaparin at 1 mg/kg twice daily and peak anti-Xa monitoring were separated into supratherapeutic and therapeutic/subtherapeutic cohorts. RESULTS: A total of 436 patients were screened, and 215 were included, with a mean age of 62 years. There were 108 in the therapeutic/subtherapeutic cohort and 107 in the supratherapeutic cohort. Acute kidney injury (AKI), body mass index (BMI), weight, female sex, intensive care unit (ICU) service, Sequential Organ Failure Assessment (SOFA) score ≥4, and creatinine clearance at the time of peak anti-Xa level collection were associated with supratherapeutic anti-Xa levels in univariate models. Adjusted logistic regression models were created and identified BMI in the 30 to 34.9 kg/m2 (odds ratio [OR] 4.35; 95% confidence interval [CI] 1.70-11.13, P < 0.005) and ≥35 kg/m2 (OR 6.75; 95% CI 3.05-14.94, P < 0.005) and AKI (OR 2.62; 95% CI 1.04-6.62, P = 0.042) as significant risk factors for supratherapeutic anti-Xa levels. CONCLUSION AND RELEVANCE: Our study identified BMI ≥ 30 kg/m2, AKI, female sex, ICU service, SOFA score ≥4, and creatinine clearance as risk factors for supratherapeutic anti-Xa levels in patients receiving 1 mg/kg twice daily dosing of enoxaparin. Further research should be done to provide evidence for the association between anti-Xa levels and bleeding risk.

Comparison of Fixed Dosing vs Train of Four Titration of Cisatracurium in COVID-19 ARDS Patients.

Background: Early neuromuscular blockade with cisatracurium has been associated with improved outcomes in moderate-severe acute respiratory distress syndrome (ARDS). Previous studies have demonstrated increased drug utilization without benefits in oxygenation using fixed dose cisatracurium compared to train-of-four (TOF) titration. Objective: We sought to compare a novel, lower fixed dose cisatracurium protocol to TOF titration evaluating the impact on PaO2:FiO2 ratio (P/F). Methods: We conducted a single-center retrospective cohort study comparing fixed dose cisatracurium to TOF titration. We included patients aged 18-89 treated for COVID-19 ARDS with a baseline P/F≤200 who received a cisatracurium infusion for ≥12 h. The primary outcome was change in P/F at 48 h from baseline. Secondary outcomes included change in P/F at 24 h and 7 days, need for mechanical ventilation at day 28, and cisatracurium utilization. Results: Analyses included 125 patients (fixed dose = 65, TOF = 60). Severe ARDS was common with a baseline median P/F of 73.7 vs 79.5, P = .133. The change in P/F at 48 h was larger in the TOF cohort in the adjusted analysis (24.9 vs 70.8, P < .005). The rate and total cumulative dose of cisatracurium were higher in the fixed dose cohort (5 vs 3 mcg/kg/min, P < .001; 1034 vs 612 mg, P < .001) despite similar infusion durations (44.1 h vs 48.5 h, P = .642). Conclusions: Patients in the TOF cisatracurium cohort had improved P/F at 48 h compared to the fixed dose cohort, while also using only 60% of the cumulative dose. Future directions should include analysis of the implications of increased cisatracurium exposure on patient outcomes.

Impact of initial fluid resuscitation volume on clinical outcomes in patients with heart failure and septic shock.

Background: Fluid resuscitation is a key treatment for sepsis, but limited data exists in patients with existing heart failure (HF) and septic shock. The objective of this study was to determine the impact of initial fluid resuscitation volume on outcomes in HF patients with reduced or mildly reduced left ventricular ejection fraction (LVEF) with septic shock. Methods: This multicenter, retrospective, cohort study included patients with known HF (LVEF ≤50%) presenting with septic shock. Patients were divided into two groups based on the volume of fluid resuscitation in the first 6 h; <30 mL/kg or ≥30 mL/kg. The primary outcome was a composite of in-hospital mortality or renal replacement therapy (RRT) within 7 days. Secondary outcomes included acute kidney injury (AKI), initiation of mechanical ventilation, and length of stay (LOS). All related data were collected and compared between the two groups. A generalized logistic mixed model was used to assess the association between fluid groups and the primary outcome while adjusting for baseline LVEF, Acute Physiology and Chronic Health Evaluation (APACHE) II score, inappropriate empiric antibiotics, and receipt of corticosteroids. Results: One hundred and fifty-four patients were included (93 patients in <30 mL/kg group and 61 patients in ≥30 mL/kg group). The median weight-based volume in the first 6 h was 17.7 (12.2-23.0) mL/kg in the <30 mL/kg group vs. 40.5 (34.2-53.1) mL/kg in the ≥30 mL/kg group (P <0.01). No statistical difference was detected in the composite of in-hospital mortality or RRT between the <30 mL/kg group compared to the ≥30 mL/kg group (55.9% vs. 45.9%, P=0.25), respectively. The <30 mL/kg group had a higher incidence of AKI, mechanical ventilation, and longer hospital LOS. Conclusions: In patients with known reduced or mildly reduced LVEF presenting with septic shock, no difference was detected for in-hospital mortality or RRT in patients who received ≥30 mL/kg of resuscitation fluid compared to less fluid, although this study was underpowered to detect a difference. Importantly, ≥30 mL/kg fluid did not result in a higher need for mechanical ventilation.

EARLY INITIATION OF VASOPRESSIN REDUCES ORGAN FAILURE AND MORTALITY IN SEPTIC SHOCK.

ABSTRACT: Purpose : The aim of the study is to determine whether initiating vasopressin earlier in septic shock reduces organ dysfunction and in-hospital all-cause mortality. Methods : This multicenter, retrospective, cohort study evaluated patients admitted to the medical intensive care unit between October 2011 and August 2018 with septic shock who received vasopressin within 48 hours of shock onset. The primary composite outcome was the proportion of patients with a change in the Sequential Organ Failure Assessment score greater than 3 from baseline to 72 hours after initiation of vasopressin and/or in-hospital all-cause mortality. Secondary outcomes included time to hemodynamic stability, acute kidney injury, and intensive care unit length of stay. Results : A total of 385 patients included in the final evaluation with a mean Acute Physiology and Chronic Health Evaluation II score of 31 and a mean baseline Sequential Organ Failure Assessment score of 13. Median time to initiation of vasopressin after norepinephrine was 7.3 hours. The primary composite outcome was significantly reduced in patients who had vasopressin initiated earlier in septic shock (odds ratio = 1.08, 95% confidence interval = 1.03-1.13, P < 0.001). After controlling for baseline data in a multivariable regression model the primary outcome remained statistically significant (odds ratio = 1.04, 95% confidence interval = 1.02-1.07, P = 0.001). Conclusions : Early initiation of vasopressin in septic shock may reduce the risk of in-hospital all-cause mortality and/or organ dysfunction.

Assessment of fluid resuscitation on time to hemodynamic stability in obese patients with septic shock.

PURPOSE: Assess time to hemodynamic stability (HDS) in obese patients with septic shock who received <30 vs. ≥30 ml/kg of initial fluid resuscitation based on actual body weight (ABW). MATERIALS AND METHODS: Multicenter, retrospective, cohort analysis of 322 patients. RESULTS: Overall 216 (67%) patients received <30 ml/kg of initial fluid resuscitation. Initial fluid received was lower in the <30 ml/kg vs. ≥30 ml/kg group (16 vs. 37 ml/kg). The ≥30 ml/kg group had shorter time to HDS (multivariable p = 0.038) and lower riskof in-hospital death (multivariable p = 0.038). An exploratory subgroup analysis (n = 227) was performed, classifying patients by dosing strategy [ABW, adjusted body weight (AdjBW), ideal body weight (IBW)] based on fluid received at 3 h divided by 30 ml/kg. ABW dosed patients had a shorter time to HDS (multivariable p = 0.013) and lower risk of in-hospital death (multivariable p = 0.008) vs. IBW. Similar outcomes were observed between ABW vs. AdjBW. CONCLUSIONS: Obese patients given ≥30 ml/kg based on ABW had a shorter time to HDS and a lower risk of in-hospital death. Exploratory results suggest improved outcomes resuscitating by ABW vs. IBW; ABW showed no strong benefit over AdjBW. Further prospective studies are needed to confirm the optimal fluid dosing in obese patients.

Impact of Serum Phosphate in Mechanically Ventilated Patients With Severe Sepsis and Septic Shock.

BACKGROUND: Hypo- and hyperphosphatemia are common in severe sepsis and septic shock. Published outcome data in patients with phosphate derangements primarily focus on hypophosphatemia and the general critically ill population. This study aimed to determine the impact of serum phosphate on clinical outcomes in patients with severe sepsis and septic shock. METHODS: A retrospective cohort analysis of adult mechanically ventilated patients with severe sepsis or septic shock was performed. Patients were randomly selected from an internal intensive care unit (ICU) database at an academic medical center in the United States and screened for inclusion and exclusion criteria. Time-weighted phosphate was calculated using all phosphate measurements obtained during ICU admission. The associations between time-weighted phosphate and duration of mechanical ventilation, 28-day mortality, and ICU and hospital length of stay were evaluated using linear or logistic regression as appropriate. RESULTS: One-hundred ninety-seven patients were evaluated: 33 were categorized as hypophosphatemia, 123 as normophosphatemia, and 41 as hyperphosphatemia. Patients with time-weighted hyperphosphatemia had a higher Simplified Acute Physiology Score III score and incidence of septic shock. Significantly higher rates of 28-day mortality were observed among those with time-weighted phosphate levels above 3.5 mg/dL. However, both time-weighted hypo- and hyperphosphatemia were associated with decreased duration of mechanical ventilation. For every 0.5 mg/dL increase in time-weighted phosphate referent values from 4.0 to 6.0, the duration of mechanical ventilation decreased by 8% to 26%. For every 0.5 mg/dL decrease in time-weighted phosphate referent values from 3.0 to 1.0, significant decreases in duration of mechanical ventilation ranged from 14% to 41%. CONCLUSION: Time-weighted hyperphosphatemia may be associated with increased mortality in mechanically ventilated patients with severe sepsis or septic shock. However, time-weighted hypo- and hyperphosphatemia were associated with decreased duration of mechanical ventilation. Future studies should further describe the impact of hypo- and hyperphosphatemia on clinical outcomes among critically ill patients with severe sepsis or septic shock.

Review of Continuous Infusion Neuromuscular Blocking Agents in the Adult Intensive Care Unit.

The use of continuous infusion neuromuscular blocking agents remains controversial. The clinical benefit of these medications may be overshadowed by concerns of propagating intensive care unit-acquired weakness, which may prolong mechanical ventilation and impair the inability to assess neurologic function or pain. Despite these risks, the use of neuromuscular blocking agents in the intensive care unit is indicated in numerous clinical situations. Understanding pharmacologic nuances and clinical roles of these agents will aid in facilitating safe use in a variety of acute disease processes. This article provides clinicians with information regarding pharmacologic differences, indication for use, adverse effects, recommended doses, ancillary care, and monitoring among agents used for continuous neuromuscular blockade.

Increased incidence of clinical hypotension with etomidate compared to ketamine for intubation in septic patients: A propensity matched analysis.

PURPOSE: This study compared the incidence of clinical hypotension between ketamine and etomidate within a 24 hour period following endotracheal intubation. MATERIALS AND METHODS: This single-center, retrospective propensity-matched cohort study included septic patients admitted to our medical intensive care unit who received either etomidate or ketamine for intubation. Clinical hypotension was defined as any one of the following: mean arterial pressure (MAP) decrease >40% compared to baseline and MAP <70 mmHg, MAP <60 mmHg, initiation of a vasopressor, or increase to >30% of the initial vasopressor dose. RESULTS: Patients were matched based on propensity scores determined by demographics and baseline characteristics. A total of 384 (200 etomidate and 184 ketamine) patients were included for analysis with 230 patients (115 in each group) matched. Clinical hypotension was less prevalent in patients who received ketamine as compared to etomidate [51.3% vs. 73% (odds ratio=0.39, 95% confidence interval=0.22-0.67, P=.001]. The etomidate group experienced significantly lower MAPs at time periods 6.1-12 hours (65.1 mmHg vs. 69.3 mmHg, P=.01) and 12.1-24 hours (63.9 mmHg vs. 68.4 mmHg, P=.003). CONCLUSIONS: Ketamine was associated with a lower incidence of clinical hypotension within the 24 hour period following endotracheal intubation in septic patients.

A comparison of severe hemodynamic disturbances between dexmedetomidine and propofol for sedation in neurocritical care patients.

OBJECTIVE: Dexmedetomidine and propofol are commonly used sedatives in neurocritical care as they allow for frequent neurologic examinations. However, both agents are associated with significant hemodynamic side effects. The primary objective of this study is to compare the prevalence of severe hemodynamic effects in neurocritical care patients receiving dexmedetomidine and propofol. DESIGN: Multicenter, retrospective, propensity-matched cohort study. SETTING: Neurocritical care units at two academic medical centers with dedicated neurocritical care teams and board-certified neurointensivists. PATIENTS: Neurocritical care patients admitted between July 2009 and September 2012 were evaluated and then matched 1:1 based on propensity scoring of baseline characteristics. INTERVENTIONS: Continuous sedation with dexmedetomidine or propofol. MEASUREMENTS AND MAIN RESULTS: A total of 342 patients (105 dexmedetomidine and 237 propofol) were included in the analysis, with 190 matched (95 in each group) by propensity score. The primary outcome of this study was a composite of severe hypotension (mean arterial pressure < 60 mm Hg) and bradycardia (heart rate < 50 beats/min) during sedative infusion. No difference in the primary composite outcome in both the unmatched (30% vs 30%, p = 0.94) or matched cohorts (28% vs 34%, p = 0.35) could be found. When analyzed separately, no differences could be found in the prevalence of severe hypotension or bradycardia in either the unmatched or matched cohorts. CONCLUSIONS: Severe hypotension and bradycardia occur at similar prevalence in neurocritical care patients who receive dexmedetomidine or propofol. Providers should similarly consider the likelihood of hypotension or bradycardia before starting either sedative.

Effects of etomidate on vasopressor use in patients with sepsis or severe sepsis: a propensity-matched analysis.

PURPOSE: The safety of single-bolus etomidate to facilitate intubation in septic patients is controversial due to its potential to suppress adrenal steroidogenesis. The purpose of this study was to evaluate the effects of etomidate on the development of shock when used as an induction agent to facilitate intubation in septic patients. METHODS: A multicenter, retrospective, propensity-matched cohort study comparing patients with sepsis or severe sepsis who either received etomidate or did not receive etomidate for intubation was conducted. The primary outcome was the difference in the need for vasopressor support within 72 hours after intubation. Secondary outcomes included the use of multiple vasopressors, intensive care unit length of stay, and in-hospital mortality. RESULTS: A total of 411 patients were analyzed. Eighty-three patients were matched by propensity score. There was no difference in the matched cohort in regards to vasopressor use within 72 hours of intubation (odds ratio, 0.95; 95% confidence interval, 0.52-1.76; P=.88). Furthermore, there were no significant differences observed with regard to secondary outcomes, including in-hospital mortality (P=.76). CONCLUSIONS: The use of etomidate for intubation in septic patients did not increase vasopressor requirements within 72 hours after intubation.

Predictors of severe hypotension in neurocritical care patients sedated with propofol.

INTRODUCTION: Propofol is used extensively in neurocritical care (NCC) due to its pharmacologic properties allowing for facilitation of serial neurologic examinations. Despite widespread use, few studies have identified risk factors for hypotension in these patients. We aimed to determine predictors of hypotension in NCC patients sedated with propofol. METHODS: This retrospective, multicenter study evaluated 237 patients at two academic medical centers, both with dedicated NCC teams led by board-certified neurointensivists. Univariate analyses were performed to determine risk factors associated with severe hypotension during sedation with propofol. Multivariable analysis was performed to determine variables independently associated with hypotension, defined as a mean arterial pressure (MAP) less than 60 mmHg. RESULTS: There was an average maximum reduction in MAP of 28.8 % after propofol initiation in the entire cohort. Severe hypotension developed in 62 (26.2 %) patients to a median nadir MAP of 56 mmHg. Those who developed severe hypotension had a longer median duration of mechanical ventilation (5.0 vs. 3.6 days; p = 0.01) and an increased in-hospital mortality (38.7 vs. 24.0 %; p = 0.03). Multivariable logistic regression analysis identified increasing number of changes to the propofol infusion rate, baseline MAP 60-70 mmHg, and need for renal replacement therapy (RRT) as factors independently associated with hypotension. CONCLUSIONS: Multiple factors predicted hypotension in NCC patients receiving propofol. Clinicians should use propofol cautiously in patients with a lower baseline MAP or receiving RRT. Development of protocols related to the frequency of dose titrations is also recommended to prevent this avoidable complication.

Thromboembolic events during continuous vasopressin infusions: a retrospective evaluation.

BACKGROUND: Published guidelines suggest that vasopressin has a role in shock treatment, although its safety has not been adequately evaluated in a clinical setting. Vasopressin causes platelet aggregation and has been associated with the release of factor VIII coagulant and von Willebrand factor. OBJECTIVE: To compare the incidence of venous thromboembolism (VTE) in patients with a diagnosis of shock who received vasopressin with those who did not receive vasopressin for hemodynamic support. METHODS: A retrospective, single-center, cohort study was conducted at an academic, tertiary care center with 350 patients with a diagnosis of shock. Patients from the intensive care unit were randomly selected and separated into 2 groups for comparison of those receiving only catecholamines with those receiving vasopressin with or without catecholamines for hypotension. Patients with diabetes insipidus or variceal hemorrhage and those with any documented history of VTE were excluded. The primary outcome, VTE occurrence, was defined as a positive Doppler ultrasound, spiral computed tomography, or documented diagnosis in the discharge records. Frequency and type of risk factors for VTE were compared between the 2 study arms. A risk factor modeling approach was performed, using logistic regression to identify potential confounders and effect modifiers in the relationship between vasopressin and VTE. RESULTS: There were 175 patients in each arm of the study. The crude incidence of VTE was 7.4% and 8% in the vasopressin and catecholamine groups, respectively (p = 0.84). No significant difference in the incidence of deep venous thrombosis (vasopressin 5.1%, control 7.4%; p = 0.51) or pulmonary embolism (vasopressin 2.3%, control 0.6%; p = 0.37) was found between groups. After adjusting for covariates, there was no statistically significant difference in the incidence of VTE between the 2 arms (p = 0.72). CONCLUSIONS: This investigation provides initial evidence that vasopressin infusions do not increase the risk of VTE in patients with shock.