Reconsidering Dexmedetomidine for Sedation in the Critically Ill: Implications of the SPICE III Trial.

Dexmedetomidine is a sedative agent that has gained popularity for use in the intensive care unit over the past 20 years. Guidelines recommend dexmedetomidine as a first-line agent to achieve light sedation in mechanically ventilated adults. Recently, the SPICE III (Sedation Practice in Intensive Care Evaluation III) trial was published. This was a randomized controlled trial comparing initial sedation with dexmedetomidine with usual care sedation in adult patients receiving mechanical ventilation. The results of this trial have both validated and contradicted previous findings about dexmedetomidine. This editorial examines the merits of the SPICE III trial and the role of dexmedetomidine in practice following its publication.

Evaluation of Intravenous Phenytoin and Fosphenytoin Loading Doses: Influence of Obesity and Sex.

BACKGROUND: Recommended loading doses (LDs) of phenytoin and fosphenytoin range from 10 to 25 mg/kg. Few studies have examined the LD requirements in male versus female patients and in patients who are obese. OBJECTIVES: To examine the influence of obesity and sex on phenytoin LDs. METHODS: This was a retrospective cohort study comparing free phenytoin or fosphenytoin serum concentrations following LDs in male versus female and nonobese versus obese patients. An equation used for determining LDs in obese patients was evaluated. RESULTS: There were 141 nonobese and 54 obese patients. When adjusted for total body weight, the obese cohort received a smaller LD than the nonobese cohort (17 mg/kg, interquartile range [IQR] = 14.9-20.0, vs 20 mg/kg, IQR = 18.6-20.0, respectively; P < 0.001). There was no difference between the 2 cohorts in the measured free phenytoin concentration following the LD (obese: 1.7 µg/mL [IQR = 1.4-2.0]; nonobese: 1.8 µg/mL [IQR = 1.5-2.1]; P = 0.16). In the obese cohort, men received a significantly lower weight-based phenytoin dose compared with women (15 mg/kg [IQR = 14.0-19.2], vs 19.9 mg/kg [IQR = 15.0-20.0], respectively; P = 0.008). Postload free phenytoin concentrations were similar between the 2 groups (male: 1.6 µg/mL [IQR = 1.2-2.1]; female: 1.7 µg/mL [IQR = 1.4-2.0]; P = 0.24). Conclusion and Relevance: Phenytoin and fosphenytoin LDs of at least 15 mg/kg of actual body weight are more likely to lead to desired free phenytoin concentrations. Obese female patients need a larger weight-based dose than male patients to achieve similar postload phenytoin concentrations.

Evaluation of Vancomycin Dosing in Patients With Cirrhosis: Beginning De-Liver-ations about a New Nomogram.

Background: Reduced hepatic production of creatinine precursors in patients with decompensated cirrhosis leads to falsely low serum creatinine values. Therefore, when performing empiric dosing of vancomycin, an overestimation of creatinine clearance may result in significantly supratherapeutic vancomycin levels and increased risks of nephrotoxicity. Objective: The objective of the study is to evaluate vancomycin dosing requirements in patients with cirrhosis stratified by Child-Pugh Score, with subsequent comparison with doses that are recommended in the previously published and validated Kullar nomogram. Methods: A retrospective evaluation of patients with cirrhosis who received vancomycin for at least 3 full days and had at least 1 serum concentration drawn. Vancomycin daily dose and corresponding serum concentration were collected with patients stratified by Child-Pugh Score for comparison. Each patient had their vancomycin dose compared with the dose suggested by a published nomogram. Results: A total of 201 courses of vancomycin were followed. There were no significant differences between the Child-Pugh cohorts with respect to initial vancomycin dosing. There was also no significant difference in the median initial vancomycin trough concentration between the 3 cohorts (Child-Pugh A: 13.7 µg/mL [interquartile range, IQR: 10.4-22.1]; Child-Pugh B: 20.2 µg/mL [IQR: 15.1-25.9]; Child-Pugh C: 19.3 µg/mL [IQR: 14.9-25.2, P = .08]. The median vancomycin dose using the Kullar nomogram would have been 3.0 g/day (IQR: 2.0-3.75, P < .001), but the median dose actually used in this patient population was significantly less at 2.0 g/day. Nonetheless, the median vancomycin trough concentration in the entire patient population was 19.8 µg/mL (IQR: 15.4-25.9). Conclusion: In patients with cirrhosis, there was a high incidence of supratherapeutic vancomycin serum concentrations despite the fact that dosing was significantly less than that suggested by the published Kullar nomogram.

Knowledge of appropriate acetaminophen use: A survey of college-age women.

OBJECTIVES: To evaluate college-age women's knowledge of appropriate doses and potential toxicities of acetaminophen, competency in interpreting Drug Facts label dosing information, and ability to recognize products containing acetaminophen. METHODS: In this cross-sectional prospective study, a 20-item written survey was provided to female college students at a University of Michigan fundraising event in March 2015. RESULTS: A total of 203 female college students, 18-24 years of age, participated in the study. Pain was experienced on a daily or weekly basis by 22% of the subjects over the previous 6 months, and 83% reported taking acetaminophen. The maximum 3-gram daily dose of extra-strength acetaminophen was correctly identified by 64 participants; an additional 51 subjects indicated the generally accepted 4 grams daily as the maximum dose. When provided with the Tylenol Drug Facts label, 68.5% correctly identified the maximum amount of regular-strength acetaminophen recommended for a healthy adult. Hepatotoxicity was associated with high acetaminophen doses by 63.6% of participants, significantly more than those who selected distracter responses (P < 0.001). Knowledge of liver damage as a potential toxicity was correlated with age 20 years and older (P < 0.001) but was independent from race and ethnicity and level of alcohol consumption. Although more than one-half of the subjects (58.6%) recognized that Tylenol contained acetaminophen, fewer than one-fourth correctly identified other acetaminophen-containing products. CONCLUSION: Despite ongoing educational campaigns, a large proportion of the college-age women who participated in our study did not know and could not interpret the maximum recommended daily dose from Drug Facts labeling, did not know that liver damage was a potential toxicity of acetaminophen, and could not recognize acetaminophen-containing products. These data suggest a continued role for pharmacists in educational efforts targeted to college-age women.

Angiotensin II Brings More Questions Than Answers.

The approval of synthetic human angiotensin II (Giapreza, LaJolla Pharmaceuticals) by the FDA in December 2017 provides clinicians with a new tool in the treatment of distributive shock. Angiotensin II (ATII) was approved based on the results of the ATHOS-3 trial. In this trial, patients who received angiotensin II were more likely to achieve a mean arterial pressure of 75 mmHg or an increase in mean arterial pressure of 10 mmHg above that seen in patients who received a placebo. However, the results of ATHOS-3 also highlighted important concerns about thrombotic and infectious complications associated with ATII. Given that the cost of medication acquisition is approximately $1,500 per vial, practitioners must also decide how to implement ATII into practice in the most cost-effective manner. This commentary examines the current controversies surrounding both the safety and efficacy of ATII.

Vasopressor and Inotropic Management Of Patients With Septic Shock.

Numerous studies have evaluated the role of vasopressors and inotropes in the management of septic shock. This review assesses available evidence for the use of specific vasopressors in the management of septic shock. Use of adjunctive vasopressor therapy is also evaluated, examining the potential value of individual agents. Lastly, inotropic agents are evaluated for use in patients with myocardial dysfunction.

Retrospective analysis of azithromycin versus fluoroquinolones for the treatment of legionella pneumonia.

BACKGROUND: Legionella is often associated with life-threatening pneumonia that is responsible for significant morbidity and mortality. Fluoroquinolones (FQ) have demonstrated improved clinical outcomes or decreased complications compared with clarithromycin and erythromycin. However, there is limited data comparing outcomes of FQ to azithromycin (AZM), which exhibits better Legionella activity than erythromycin and clarithromycin. METHODS: This single-center retrospective study compared clinical outcomes of patients with Legionella pneumonia (LP) treated with AZM versus FQ from January 1999 to May 2011. RESULTS: A total of 41 patients were included in the analysis; 21 received FQ and 20 received AZM. Demographics, comorbidities, and disease severity were similar between groups. Mortality (9.5% vs. 5%, P > 0.99), time to clinical stability (15.89 days vs. 10.26 days, P = 0.09), length of hospitalization (19.29 days vs. 11.35 days, P = 0.06), and presentation of any complication (85.7% vs. 90%, P > 0.99) were similar between the FQ and AZM groups, respectively. CONCLUSION: Azithromycin appears to have clinical efficacy similar to FQ for the treatment of Legionella pneumonia.

Apparent argatroban resistance in a patient with elevated factor VIII levels.

OBJECTIVE: To report a case in which there was a lack of activated partial thromboplastin time (aPTT) correlation with plasma argatroban concentrations in a patient with elevated factor VIII levels who was diagnosed with heparin-induced thrombocytopenia (HIT). CASE SUMMARY: A 59-year-old female with a history significant for basal cell carcinoma was transferred from an outside hospital and underwent resection of a third ventricle mass. The postoperative hospital course was complicated by subdural hematoma, HIT, and pulmonary embolism. Upon initiation of argatroban, we faced difficulty in maintaining therapeutic aPTT values despite administration of significantly higher than usual doses of argatroban (up to 7 µg/kg/min). A coagulation abnormality was suspected and an argatroban concentration was obtained; results showed an elevated level of 2.2 µg/mL (therapeutic range 0.4-1.2), with a corresponding aPTT of 53.1 seconds. A coagulopathy workup revealed an excess of factor VIII activity. Thereafter, argatroban concentrations were used for dose adjustments and the infusion was titrated to a final rate of 2.75 µg/kg/min. DISCUSSION: The lack of correlation of aPPT values with argatroban administration has not been described in the literature and, to our knowledge, similar cases have not been reported. We were unable to achieve an increase in aPTT, despite aggressive argatroban dosing in a patient with increased factor VIII activity. A definitive mechanism for this is not entirely known; however, it is thought to be secondary to contributing underlying causes such as excessive clotting factors, circulating inflammatory proteins, or other aspects. CONCLUSIONS: With the initiation of argatroban therapy, particular attention should be given to ensure that aPTTs correlate with dosing to prevent life-threatening bleeding complications. Excessive argatroban dosing requirements should prompt further investigation into potential confounders such as elevated factor VIII levels.

Association Between Sedative Medication Administration and Delirium Development in a Medical Intensive Care Unit.

Background: Delirium develops frequently in intensive care unit (ICU) patients. Societal guidelines have suggested that benzodiazepines may cause delirium. This study investigates if a change in sedation administration use over time is associated with changes in delirium incidence. Methods: This was a retrospective cohort study conducted over a 4 year time period in a medical ICU. All data was abstracted from a local data warehouse. The primary outcome of the study was the association between annual cumulative benzodiazepine use and incidence of delirium during the study period. Data was analyzed using descriptive characteristics and Spearman's correlation coefficient. Additionally, multivariate logistic regression was performed to identify independent risk factors for delirium development. Results: From 2015 to 2018, annual total benzodiazepine administration decreased from 62,215 mg to 18,105 mg lorazepam equivalents (p = <.01). The cumulative dose of dexmedetomidine increased, with 657,262 mcg administered in 2015 and 1,476,951 mcg in 2018 (p < .01). No differences in annual delirium incidence were found. Risk factors that were significantly correlated with delirium following multivariate logistic regression included acute respiratory distress syndrome, renal failure, hepatic failure, septic shock, severe alcohol withdrawal, vasopressor use, corticosteroid use, benzodiazepine use, antipsychotic use, opiate use, and propofol use. Conclusions: A profound change in sedation medication paradigm did not influence delirium rates in a medical ICU.

Vancomycin versus linezolid in the treatment of methicillin-resistant Staphylococcus aureus nosocomial pneumonia: implications of the ZEPHyR trial.

In 2003, a retrospective trial comparing linezolid versus vancomycin in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) showed improved survival in the linezolid group. This led to the ZEPHyR (Linezolid in the Treatment of Subjects with Nosocomial Pneumonia Proven to Be Due to Methicillin-Resistant Staphylococcus aureus) trial comparing linezolid versus vancomycin for MRSA pneumonia, which showed a benefit for linezolid with respect to clinical response but without a survival advantage. Limitations of the study included unbalanced treatment groups at baseline and number of patients excluded to reach the per-protocol group. Results of the ZEPHyR trial do not support routine use of linezolid for the treatment of MRSA pneumonia.

Combination therapy for the treatment and prevention of hepatic encephalopathy.

OBJECTIVE: To evaluate the efficacy and safety of combination therapy for the treatment and prevention of hepatic encephalopathy (HE). DATA SOURCES: A PubMed MEDLINE search was conducted (1947-June 2012) using the key terms lactulose, lactitol, nonabsorbable disaccharide, metronidazole, rifaximin, neomycin, probiotics, and hepatic encephalopathy. Searches were limited to include articles published in English. STUDY SELECTION AND DATA EXTRACTION: Study selection included published trials, case reports, and case series of humans with HE who were treated with combination therapy of rifaximin, lactulose, lactitol, metronidazole, neomycin, and/or probiotics. DATA SYNTHESIS: Only 6 studies that evaluated the benefits of combination drug therapy in the treatment or prevention of HE were available for review. Four studies addressed the treatment of HE, 2 found no significant difference between lactulose/neomycin versus placebo or rifaximin/lactulose, 1 assessed the use of rifaximin/lactulose without a control group, and the fourth found no significant difference between lactulose/probiotics versus either drug alone, although each group showed improvement from baseline. In the 2 prevention trials, both of which stemmed from the same data, the combination of rifaximin/lactulose was superior to lactulose alone, showing significant improvement in mental status, blood ammonia levels, and health-related quality of life and reductions in HE recurrence and hospitalization. Currently, there are no available clinical studies evaluating dual antibiotic therapy, metronidazole with nonabsorbable disaccharides, or antibiotics with probiotics. CONCLUSIONS: The evidence evaluating the use of combination therapy for the treatment of HE does not support its widespread use. The combination of rifaximin and lactulose may be considered in the treatment of HE and in patients refractory to monotherapy. The combination of rifaximin and lactulose should be considered for the prevention of HE, especially after the second episode of HE recurrence.

Cost analysis before and after implementation of a computerized physician order entry order form for enoxaparin.

OBJECTIVE: The authors sought to analyze the impact of a computerized physician order entry (CPOE) order form for enoxaparin sodium injection (Lovenox) to reduce the daily cost of drug therapy by switching appropriate patients to once-daily enoxaparin administration. METHODS: The study population included patients older than 18 years of age who had been treated with enoxaparin from September 1 to December 31, 2008 (the pre-order form implementation group) and from March 1 to June 30, 2009 (the post-order form implementation group). The wholesale acquisition cost was used to determine the cost of enoxaparin per day. Appropriate dosing was established by chart review. RESULTS: The post-implementation group showed a trend toward a higher cost of enoxaparin therapy per day compared with the pre-implementation group (P = 0.23). There was a non-significant increase in appropriate dosing after implementation of the order form-from 64.5% before implementation to 71.5% after implementation (P = 0.13). In the overall cohort, although the authors controlled for other factors that could influence cost, patients who received the appropriate dose per protocol were 3.2 times more likely (95% confidence interval, 1.8-5.9; P = 0.001) to have lower enoxaparin drug costs per day of therapy. CONCLUSION: The use of a CPOE enoxaparin order form did not reduce the daily cost of therapy.

Continuous infusion of pantoprazole with octreotide does not improve management of variceal hemorrhage.

STUDY OBJECTIVE: To assess the effect of a prolonged continuous infusion of pantoprazole on patient outcomes when the drug was combined with standard octreotide therapy in patients with variceal hemorrhage. DESIGN: Retrospective cohort study. SETTING: Large academic hospital. Patients. One hundred thirty adults who received treatment for a documented variceal hemorrhage; 53 patients received standard octreotide therapy plus a prolonged continuous infusion of pantoprazole (continuous-infusion group) and 77 patients received either octreotide alone, octreotide with a short-term (<24 hrs) infusion of pantoprazole, or octreotide with intermittent acid suppression (control group). MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was the number of units of packed red blood cells transfused during hospitalization. Baseline characteristics between the treatment groups were similar. The duration of therapy for variceal hemorrhage was significantly longer in the continuous-infusion group than in the control group. Transfusion requirements for packed red blood cells (mean+/-SD 6.4+/-6.5 vs 5.8+/-6.6 units, p=0.66) and platelets (8.8+/-15.1 vs 5.1+/-11.9 units, p=0.13) were similar for the continuous-infusion group versus the control group. The continuous-infusion group, however, received significantly more units of fresh-frozen plasma than the control group (6.1+/-10.6 vs 2.9+/-6.2 units, p=0.05). There was no significant difference in mortality rate between groups. CONCLUSION: Prolonged continuous infusions of pantoprazole with octreotide seemed to offer no additional benefit compared with octreotide plus short-term infusions of pantoprazole or intermittent acid suppression in the management of acute variceal hemorrhage. Prospective studies should be conducted to evaluate the role of continuously infused proton pump inhibitors in this setting before their use can be advocated.

Incidence of Rebound Hypertension after Discontinuation of Dexmedetomidine.

INTRODUCTION: To date, no studies have evaluated the incidence of rebound hypertension occurring with the discontinuation of long-term (> 72 hrs) dexmedetomidine infusions. Rebound hypertension has been documented in the literature with clonidine, a structurally and pharmacologically similar medication. OBJECTIVES: To compare the incidence of rebound hypertension associated with cessation of dexmedetomidine infusion with other sedative medications. METHODS: This retrospective, matched cohort study evaluated the incidence of rebound hypertension in intensive care unit patients receiving continuous infusions of at least 72 hours in duration of dexmedetomidine, propofol, or midazolam. RESULTS: The study population consisted of 216 patients: 54 treated with dexmedetomidine and 162 treated with propofol or midazolam. Rebound hypertension occurred significantly more often in patients with a history of hypertension (71.1%) than in patients with no prior hypertension (28.9%; p<0.001).There was no difference in incidence of rebound hypertension in the dexmedetomidine or propofol and midazolam arms (16.7% vs 17.9%, p=0.837). The titration timeframe for the dexmedetomidine infusion, defined as the time from peak infusion rate until discontinuation, was significantly shorter in patients with rebound hypertension (median duration, 4 hrs) compared with patients who did not have rebound hypertension (median duration, 17 hrs; p=0.011). CONCLUSION: There was no difference in the incidence of rebound hypertension observed with dexmedetomidine discontinuation compared with propofol or midazolam. Instead, history of hypertension and a shorter weaning duration appear to be associated with increased risk of rebound hypertension regardless of the sedative used.

Amino Acid requirements in critically ill patients with acute kidney injury treated with continuous renal replacement therapy.

Acute kidney injury in critically ill patients is often a complication of an underlying condition such as organ failure, sepsis, or drug therapy. In these patients, stress-induced hypercatabolism results in loss of body cell mass. Unless nutrition support is provided, malnutrition and negative nitrogen balance may ensue. Because of metabolic, fluid, and electrolyte abnormalities, optimization of nutrition to patients with acute kidney injury presents a challenge to the clinician. In patients treated with conventional intermittent hemodialysis, achieving adequate amino acid intake can be limited by azotemia and fluid restriction. With the use of continuous renal replacement therapy (CRRT), however, better control of azotemia and liberalization of fluid intake allow amino acid intake to be maximized to support the patient's metabolic needs. High amino acid doses up to 2.5 g/kg/day in patients treated with CRRT improved nitrogen balance. However, to our knowledge, no studies have correlated increased amino acid intake with improved outcomes in critically ill patients with acute kidney injury. Data from large, prospective, randomized, controlled trials are needed to optimize the dosing of amino acids in critically ill patients with acute kidney injury who are treated with CRRT and to study the safety of high doses and their effects on patient morbidity and survival.