Droxidopa or Atomoxetine for Refractory Hypotension in Critically Ill Cardiothoracic Surgery Patients.

OBJECTIVE: To evaluate the effects of droxidopa or atomoxetine on intravenous (IV) vasoactive agent discontinuation in cardiothoracic intensive care unit (ICU) patients with hypotension refractory to midodrine. DESIGN: Single-center, retrospective cohort study. SETTING: Tertiary- and quaternary-care university teaching hospital. PARTICIPANTS: Included patients who received at least 4 consecutive doses of droxidopa or atomoxetine and remained on concurrent midodrine. Patients were excluded if they received study medication before admission, had clinical deterioration after study medication initiation requiring additional vasoactives/escalation of IV vasoactive dosage for at least 12 hours, had a diagnosis of hepatorenal syndrome, were prisoners, or were pregnant. INTERVENTIONS: Droxidopa, atomoxetine, or both. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was time to discontinuation of IV vasoactive agents after initiation of study medication, analyzed using a Kaplan-Meier estimate with the Wilcoxon method, censoring death within 24 hours of the last dose of study medication. No adjustment for repetitive analyses was made, as the analysis was hypothesis-generating. Of the 72 charts reviewed, 45 patients met inclusion criteria (18 atomoxetine, 17 droxidopa, and 10 both). There were no differences in median time to discontinuation of IV vasoactive agents (21.9 days v 8.0 days v 13.9 days, respectively; p = 0.259) or ICU or hospital length of stay between groups. A higher percentage of patients who survived to hospital discharge received both study medications or droxidopa alone (90% v 76.5%) than atomoxetine alone (44.4%, p = 0.028). CONCLUSIONS: Droxidopa and atomoxetine are oral vasoactive agents with potential mechanisms to facilitate IV vasopressor weaning for patients in the ICU with hypotension refractory to midodrine, but further prospective research is needed.

Incidence and associated risk factors for systemic drug levels with inhaled aminoglycoside therapy.

OBJECTIVES: To characterize the incidence of and risk factors for a detectable drug level (DDL) in patients that received inhaled aminoglycoside therapy. METHODS: This retrospective, single-centre study included adult patients who received at least one dose of an inhaled aminoglycoside with a drug level during inpatient hospitalization. Patients were excluded if they received an aminoglycoside intravenously within 7 days or if the drug level was not drawn within 4 h of the next dose. A repeated measures logistic regression model evaluated the association between potential risk factors and a DDL. RESULTS: Among 286 drug levels, 88 (30.8%) drug levels were detectable. In multivariable analysis, cystic fibrosis (CF) (OR: 3.03; 95% CI: 1.10-8.35), chronic kidney disease (CKD) (OR: 4.25; 95% CI: 1.84-9.83), lung transplant recipient (OR: 3.08; 95% CI: 1.09-8.73), mechanical ventilation (OR: 2.99; 95% CI: 1.25-7.15) and tobramycin (OR: 5.26; 95% CI: 2.35-11.78) were associated with higher odds of a DDL. Among those with a DDL, inhaled aminoglycoside type and drug level concentration were not associated with acute kidney injury (P = 0.161). CONCLUSIONS: Among 286 drug levels identified among inpatients receiving inhaled aminoglycoside therapy, 88 (30.8%) unique drug levels were detectable. Based on the results of this study, periodic trough concentrations should be considered for patients receiving inhaled aminoglycoside therapy with CF, CKD, lung transplantation, mechanical ventilation or tobramycin.

Renal Dysfunction and Arrhythmia Association in Patients Receiving Milrinone After Cardiac Surgery.

OBJECTIVE: The altered pharmacokinetics of milrinone in renal impairment could result in an increased risk of cardiac arrhythmias. This study aimed to determine if there is an association between new-onset arrhythmias and renal impairment after cardiac surgery following milrinone administration. DESIGN: A retrospective cohort study. SETTING: A single-center tertiary care hospital. PARTICIPANTS: Adult patients who received a milrinone infusion in the intensive care unit (ICU) setting after coronary artery bypass graft, valvuloplasty, annuloplasty, or a combination of these surgeries from July 1, 2014 to July 1, 2021. Renal impairment was defined using a creatinine clearance <60 mL/min, calculated using the Cockcroft-Gault equation. INTERVENTIONS: Patients received a weight-based continuous intravenous infusion of milrinone. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the presence of new arrhythmias after the initial administration of a weight-based continuous intravenous infusion of milrinone postcardiac surgery. Of the 197 patients who met inclusion, there was no difference in the presence of new arrhythmias (42.9% v 40.3%, p = 0.76) or in the time to first new arrhythmia from milrinone initiation in those with renal impairment compared to those without renal impairment (29.1 hours v 33.3 hours, p = 0.54). Patients with renal impairment had a longer hospital stay than patients without renal impairment (17.5 days v 13.9 days, p = 0.016). Arrhythmia type, length of ICU stay, ICU mortality, and hospital mortality were not different between the cohorts. CONCLUSIONS: There was no association between new arrhythmias, milrinone, and renal impairment in patients postcardiac surgery.

Effect of Initial Anticoagulation Targets on Bleeding and Thrombotic Complications for Patients With Acute Respiratory Distress Syndrome Receiving Extracorporeal Membrane Oxygenation.

OBJECTIVE: To evaluate the effect of anticoagulation targets and intensity on bleeding events, thrombotic events, and transfusion requirements in patients with acute respiratory distress syndrome (ARDS) receiving venovenous extracorporeal membrane oxygenation (ECMO) and continuous-infusion heparin. DESIGN: A retrospective cohort study. SETTING: At a single-center, large academic medical center. PARTICIPANTS: One hundred thirty-six critically ill patients. INTERVENTIONS: The following three therapeutic targets were implemented over time and evaluated: (1) no protocol (September 2013-August 2016): no standardized anticoagulation protocol or transfusion thresholds; (2) <50 seconds (September 2016-January 2018): standardized activated partial thromboplastin time (aPTT) goal of <50 seconds, maximum heparin infusion rate of 1,200 units/h, transfusion threshold of hemoglobin (Hgb) <8 g/dL; and (3) 40-to-50 seconds (February 2018-December 2019): aPTT goal of 40-to-50 sec, no maximum heparin infusion rate, transfusion threshold of Hgb <7 g/dL. MEASUREMENTS AND MAIN RESULTS: Continuous variables were compared using the Kruskal-Wallis test, and categorical variables were compared using Fisher exact tests. The primary endpoint, an incidence of at least 1 bleeding event, was highest in the no-protocol group though not statistically different among groups (39.3% v 26.7% v 34%, p = 0.5). Thrombotic complications were similar. The median units of packed red blood cells transfused were highest in the no-protocol group (3 v 2 v 0.5, p < 0.001). CONCLUSION: Anticoagulation protocols standardizing aPTT goals to <50 or 40-to-50 seconds may be a reasonable strategy for patients receiving venovenous ECMO for ARDS. More restrictive hemoglobin transfusion thresholds, in combination with lower aPTT targets, may be associated with a reduction in transfusion requirements.

The Predictive Value of the 4Ts and HEP Score at Recommended Cutoffs in Patients With Mechanical Circulatory Support Devices.

OBJECTIVES: Despite the increasing utilization of mechanical circulatory support (MCS) devices, the 4Ts and heparin-induced thrombocytopenia (HIT) Expert Probability (HEP) scores have not been validated in patients with suspected HIT requiring MCS. DESIGN: A retrospective cohort study. SETTING: At a tertiary university hospital. PARTICIPANTS: Adults with suspected HIT requiring any MCS. INTERVENTIONS: A diagnostic investigation of HIT. MEASUREMENTS AND MAIN RESULTS: Of the 299 patients included, there were 374 diagnostic investigations of HIT, of which 32 (8.6%) were HIT-probable (heparin PF4 immunoassay optical density ≥1 or positive serotonin release assay). The 4Ts score ≥4 demonstrated a pretest sensitivity of 0.56 (95% confidence interval [CI]: 0.39-0.72) and specificity of 0.8 (95% CI: 0.75-0.83). The HEP score ≥3 demonstrated a pretest sensitivity of 0.31 (95% CI: 0.18-0.49) and specificity of 0.83 (95% CI: 0.79-0.87). The area under the receiver operating characteristic curve for the 4Ts and HEP scores were 0.68 (95% CI: 0.63-0.73) and 0.63 (95% CI: 0.59-0.68), respectively, and were not statistically different (p = 0.21). In patients with an intra-aortic balloon pump, neither the 4Ts nor HEP score had discriminatory ability to differentiate probable HIT. The HEP score had no discriminatory ability in patients with concomitant MCS devices. CONCLUSIONS: The 4Ts and HEP scores have a modest predictive performance for probable HIT in patients requiring MCS devices. A low 4Ts or HEP score does not reliably rule out HIT in patients requiring MCS, and clinical suspicion for HIT should be investigated, utilizing laboratory tests in this population.

Hydroxocobalamin or Methylene Blue for Vasoplegic Syndrome in Adult Cardiothoracic Surgery.

OBJECTIVE: To compare hydroxocobalamin and methylene blue for the treatment of vasopressor-refractory vasoplegic syndrome (VS) after adult cardiac surgery with cardiopulmonary bypass (CPB). DESIGN: A retrospective, propensity-matched, cohort study was performed. The primary endpoints were the percentage change in vasopressor use at 30, 60, and 120 minutes, characterized as both norepinephrine equivalents and vasoactive inotropic score. Eligible patients who received methylene blue were matched 3:1 with patients who received hydroxocobalamin based on sequential organ failure assessment score, preoperative mechanical circulatory support, CPB duration, and use of pre-CPB vasopressors, angiotensin-converting enzyme inhibitors, or beta-blockers. SETTING: A quaternary care academic medical center. PARTICIPANTS: Adult patients who underwent cardiac surgery with CPB from July 2013 to June 2019. INTERVENTIONS: Patients were included who received either hydroxocobalamin (5,000 mg) or methylene blue (median 1.2 mg/kg) for VS in the operating room during the index surgery or in the intensive care unit up to 24 hours after CPB separation. MEASUREMENTS AND MAIN RESULTS: Of the 142 included patients, 120 received methylene blue and 22 received hydroxocobalamin. After matching, 66 patients in the methylene blue group were included in the analysis. Baseline demographics, surgical characteristics, and vasoactive medications were similar between groups. There were no significant between-group differences in percentage change in norepinephrine equivalents or vasoactive inotropic score at each timepoint. CONCLUSIONS: In adult patients undergoing cardiothoracic surgery using CPB with VS, the ability to reduce vasopressor use was similar with hydroxocobalamin compared with methylene blue.

VanA rectal swab screening as a predictor of subsequent vancomycin-resistant enterococcal bloodstream infection in critically ill adults.

OBJECTIVE: To evaluate whether vanA rectal screening for vancomycin-resistant Enterococcus (VRE) predicts vancomycin resistance for patients with enterococcal bloodstream infection (BSI). DESIGN: A retrospective cohort study. SETTING: Large academic medical center. METHODS: The predictive performance of a vanA rectal swab was evaluated in 161 critically ill adults with an enterococcal BSI from January 1, 2007, to September 1, 2014, and who had a vanA rectal swab screening obtained within 14 days prior to blood culture. RESULTS: Of the patients meeting inclusion criteria, 83 (51.6%) were vanA swab positive. Rectal-swab-positive patients were more likely to be younger, to be immunocompromised, to have an indwelling central vascular catheter, and to have a history of MDR bacteria. The vanA rectal swab had sensitivity and negative predictive values of 83.6% and 85.9%, respectively, and specificity and positive predictive values of 71.3% and 67.5%, respectively, for predicting a vancomycin-resistant enterococcal BSI in critically ill adults. CONCLUSIONS: VanA rectal swabs may be useful for antimicrobial stewardship at institutions with VRE screening already in place for infection control purposes. A higher PPV would be warranted to implement a universal vanA screen on all ICU patients.

Effectiveness of Quetiapine as a Sedative Adjunct in Mechanically Ventilated Adults Without Delirium.

BACKGROUND: Quetiapine is an atypical antipsychotic that is commonly used in the Intensive Care Unit (ICU). The utility of quetiapine as a sedative adjunct has not yet been evaluated, but has been described previously in studies evaluating quetiapine for delirium or delirium prophylaxis. OBJECTIVE: To determine if adjunctive use of quetiapine reduces sedative dosage requirements among mechanically ventilated adults without delirium. METHODS: This retrospective intrapatient comparator study included all mechanically ventilated adults admitted to a medical ICU who received quetiapine between July 1, 2013, and July 1, 2018. The primary outcome was the change in sedative dosage requirements over 24 hours following quetiapine initiation. Secondary outcomes included change in sedative dosage requirements 48 hours postquetiapine initiation, opioid dosage requirements 24 hours postquetiapine initiation, percent time at goal for both pain and sedation scores, depth of sedation, and QTc. RESULTS: A total of 57 patients were included in the study cohort. There was no significant difference in 24-hour cumulative doses of propofol (P = 0.10), dexmedetomidine (P = 0.14), or benzodiazepines (P = 0.14). During the 48-hour treatment period, there was a significant increase in dexmedetomidine requirements (P = 0.03). There were no differences in 24-hour opioid dosage requirements, percent time at goal pain or sedation scores, depth of sedation, or QTc following quetiapine initiation. CONCLUSION AND RELEVANCE: Adjunctive use of quetiapine was not associated with a significant reduction in sedative dosage requirements 24 or 48 hours following initiation among mechanically ventilated adults without delirium.

Medication Histories in Critically Ill Patients Completed by Pharmacy Personnel.

BACKGROUND: Although critically ill adults often have extended hospital lengths of stay and are at high risk of having medication-related adverse events, the value of medication histories in these patients remains underreported. OBJECTIVE: To assess the feasibility of performing medication histories in critically ill adults and to establish the frequency of and characterize identified discrepancies. METHODS: This prospective study included patients admitted to 4 intensive care units (ICUs) in a large academic medical center and was conducted in 2 phases. In phase 1, medication histories were conducted over a 5-week period by clinical pharmacists to assess feasibility. In phase 2, medication histories were conducted over a 3-week period by a pharmacy technician. Medication discrepancies, defined as any difference between the documented and pharmacy personnel-identified home medication list, were aggregated in both phases and adjudicated for severity. RESULTS: In phase 1, 127 medication histories were completed (42.3% of admitted patients). Impaired cognition was the most common barrier encountered; however, 76% of patients were able to have a history completed if an attempt was made. In phase 2, a medication history was completed for 176 patients (58.9% of admitted patients). In aggregate, 1155 discrepancies were identified, with 78.2% of patients having a discrepancy. The median number of discrepancies per patient was 3 (interquartile range = 1-5); 11 life-threatening, 101 serious, and 326 significant discrepancies were identified. Conclusion and Relevance: A pharmacy personnel-based medication history program in the ICU is feasible and assists in the discovery of medication discrepancies with the potential for patient harm.

Effectiveness of Vancomycin or Beta-Lactam Therapy in Ampicillin-Susceptible Enterococcus spp. Bloodstream Infections.

BACKGROUND: De-escalation to a beta-lactam improves outcomes for patients with a methicillin-susceptible Staphylococcus aureus bloodstream infection (BSI). Whether a similar strategy is appropriate for enterococcal species is less clear. OBJECTIVE: To determine whether definitive antibiotic selection affects outcomes for patients with an ampicillin-susceptible enterococcal BSI. METHODS: This retrospective cohort study included patients over 18 years of age receiving definitive therapy with vancomycin or a beta-lactam for one or more blood cultures positive for Enterococcus spp. isolates between 2007 and 2014. Survival differences were examined using a Kaplan-Meier curve with log-rank test. RESULTS: One-hundred eighty-six patients received definitive therapy with either vancomycin (n = 45, 24.2%) or a beta-lactam (n = 141, 75.8%). The primary outcome, 30-day all-cause mortality, was not different between groups (6.7% vs 7.1%; P = .992). A post hoc analysis of all-cause mortality 1 year after the index BSI was significantly higher in the vancomycin group (51% vs 33%; P = .032). In a Cox proportional hazards regression model, definitive vancomycin was associated with an increased risk of all-cause mortality at 1 year (hazard ratio [HR]: 2.39; 95% confidence interval [CI]: 1.41-4.04). CONCLUSION: For patients with an ampicillin-susceptible enterococcal BSI, definitive therapy with vancomycin or a beta-lactam was not independently associated with a difference in 30-day all-cause mortality. Whether definitive vancomycin is associated with poor long-term outcomes warrants further exploration.

A Pharmacy-Based Electronic Handoff Tool to Reduce Discharge Prescribing of Atypical Antipsychotics Initiated in the Intensive Care Unit: A Quality Improvement Initiative.

PURPOSE: To evaluate whether a pharmacist-initiated electronic handoff tool can reduce the overall, and potentially inappropriate, hospital discharge prescribing rate of atypical antipsychotics (AAP) initiated in AAP-naive critically ill adults. METHODS: This pre-post quality improvement study was initiated in 5 intensive care units (ICUs) at a large academic medical center. An electronic handoff tool (iVent) was utilized in the post-intervention period to enhance pharmacist communication at inpatient transitions of care. RESULTS: Of the 358 included patients, the proportion of hospital survivors with an AAP initiated in the ICU receiving a hospital discharge prescription was not different between the pre- and post-intervention period (28.6% vs 22.2%, P = .12). The proportion of ICU survivors with an AAP continued at the time of ICU transfer to the floor was reduced post-intervention (78.7% vs 66.7%, P = .012). Additionally, the overall proportion of a patient's hospitalization receiving an AAP was also reduced (50.4% vs 42.8%, P = .008). A multivariate logistic regression demonstrated thatutilization of the electronic handoff tool was not associated with a reduction in hospital discharge prescribing of an AAP (odds ratio [OR]: 0.97, 95% confidence interval [CI]: 0.57-1.65). CONCLUSIONS: A pharmacy-initiated electronic handoff tool may reduce the proportion of AAP-naive ICU survivors with an AAP continued at the time of ICU transfer. The handoff tool was not associated with a significant reduction in the discharge prescribing rates of AAPs for hospital survivors, but a clinically meaningful reduction was possibly achieved due to enhanced communication enabled by this tool.

Analgesia and Sedation Requirements in Mechanically Ventilated Trauma Patients With Acute, Preinjury Use of Cocaine and/or Amphetamines.

BACKGROUND: The purpose of this study was to determine whether mechanically ventilated trauma patients with a positive urine drug screen (UDS) for cocaine and/or amphetamines have different opioid analgesic and sedative requirements compared with similar patients with a negative drug screen for these stimulants. METHODS: This retrospective, single-center cohort study at a tertiary care, academic medical and level 1 trauma center in the United States included patients ≥16 years of age who were admitted to an adult intensive care unit with a diagnosis of trauma between 2009 and 2013 with a UDS documented within 24 hours of admission, and were mechanically ventilated for >24 hours. The primary end point was the daily dose of opioid received during mechanical ventilation, expressed as morphine equivalents, for patients presenting with a positive UDS for cocaine and/or amphetamines compared with patients with a negative UDS for these stimulants. Secondary end points included the daily benzodiazepine dose and median infusion rates of propofol and dexmedetomidine received during mechanical ventilation, duration of mechanical ventilation, intensive care unit and hospital length of stay, and in-hospital mortality. Analgesic and sedative goals were similar for the duration of the study period, and both intermittent and continuous infusions of opioids and sedatives were administered to achieve these targets, although a standardized approach was not used. A multivariate logistic regression analysis and a propensity-adjusted model evaluated patient characteristics predictive of a higher median opioid requirement. RESULTS: A total of 150 patients were included in the final analysis. In a univariate analysis, opioid and sedative requirements were similar for patients presenting with a positive UDS for cocaine and/or amphetamines compared with patients with a negative UDS for these stimulants. In the multivariate regression analysis, increasing age and Abbreviated Injury Scale (head and neck) were associated with decreased daily opioid requirements (odds ratio [OR], .95, 95% confidence interval [CI], .93-.97 and OR, .71, 95% CI, .65-.77, respectively), whereas preinjury stimulant use was not predictive of opioid requirements (OR, .88, 95% CI, .40-1.90). In a propensity score--adjusted model, preinjury stimulant use was similarly not predictive of opioid requirements during mechanical ventilation (OR, .97, 95% CI, .44-2.11). CONCLUSIONS: For trauma patients presenting with acute, preinjury use of cocaine and/or amphetamines, analgesic and sedative requirements are variables and may not be greater than those patients presenting with a stimulant-negative UDS to achieve desirable pain control and depth of sedation, although this observation should be interpreted cautiously in light of the wide CI observed in the propensity score--adjusted model. Although unexpected, these findings indicate that empirically increasing analgesic and sedative doses based on positive UDS results for these stimulants may not be necessary.

Implications of atypical antipsychotic prescribing in the intensive care unit.

PURPOSE: The purpose of the study was to determine the downstream implications of atypical antipsychotic (AAP) prescribing in the intensive care unit (ICU), including discharge prescribing practices, monitoring, and attributable adverse drug events. MATERIALS AND METHODS: This retrospective cohort study included patients at least 18 years of age admitted to an ICU that received at least 2 doses of an AAP for documented delirium or avoidance of a deliriogenic medication. Exclusion criteria were documentation of an AAP as a home medication or initiation for a psychiatric indication unrelated to delirium (eg, schizophrenia). RESULTS: During the 8-month study period, 156 patients were included and 133 (85.2%) patients survived to hospital discharge. Of the survivors, AAP therapy was continued for 112 (84.2%) patients upon ICU transfer and for 38 (28.6%) patients upon hospital discharge. A majority of these patients had evidence of delirium resolution or no indication for continuation documented at discharge. Of the 127 patients with an electrocardiogram ordered during AAP therapy, QTc prolongation occurred in 49 (31.4%) patients. An adverse drug event leading to drug discontinuation was documented in 16 (10.2%) patients. CONCLUSIONS: Because of significant patient-centered implications, AAPs initiated in the ICU require continued evaluation for indication to avoid prolonged and possibly unnecessary use.

Major publications in the critical care pharmacotherapy literature: January-December 2013.

PURPOSE: Ten recently published articles with important implications for critical care pharmacotherapy are summarized. SUMMARY: The Critical Care Pharmacotherapy Literature Update (CCPLU) group is a national assembly of experienced intensive care unit (ICU) pharmacists across the United States. Group members monitor 25 peer-reviewed journals on an ongoing basis to identify literature relevant to pharmacy practice in the critical care setting. After evaluation by CCPLU group members, selected articles are chosen for summarization and distribution to group members nationwide based on (1) applicability to critical care practice, (2) relevance to pharmacy practitioners, and (3) quality of evidence or research methodology. Hundreds of relevant articles were evaluated by the group during the period January-December 2013, of which 98 were summarized and disseminated nationally to CCPLU group members. Among those 98 publications, 10 deemed to be of particularly high utility to critical care practitioners were included in this review. The 10 articles address topics such as rapid lowering of blood pressure in patients with intracranial hemorrhage, adjunctive therapy to prevent renal injury due to acute heart failure, triple-drug therapy to improve neurologic outcomes after cardiac arrest, and continuous versus intermittent infusion of ß-lactam antibiotics in severe sepsis. CONCLUSION: There were many important additions to the critical care pharmacotherapy literature in 2013, including an updated guideline on the management of myocardial infarction and reports on advances in research focused on improving outcomes in patients with stroke or cardiac arrest and preventing the spread of drug-resistant pathogens in the ICU.