A Retrospective Cohort Analysis of Analgosedation Requirements in COVID-19 Compared to Non-COVID-19 Extracorporeal Membrane Oxygenation Patients.

BACKGROUND: Reports have described increased sedation requirements in patients with acute respiratory distress syndrome (ARDS) while on extracorporeal membrane oxygenation (ECMO) and for intubated COVID-19 patients. Thus, the objective of this study was to assess the analgosedation requirements of COVID-19 patients receiving ECMO compared to non-COVID-19 ECMO patients. METHODS: This retrospective, observational cohort study included adult patients with ARDS requiring venovenous or venopulmonary arterial ECMO admitted to a single intensive care unit from January 2017 to December 2021. Patients were categorized as COVID-19 ECMO or non-COVID-19 ECMO. The primary outcome was median daily dosing of parenteral analgosedative medications. Pertinent secondary outcomes included incidence of extubation or tracheostomy and change in sedation following tracheostomy or addition of oral agents. RESULTS: A total of 109 patients were evaluated; 63 COVID-19 ECMO patients and 46 non-COVID ECMO patients. The primary outcome was statistically higher in the COVID-19 compared to non-COVID-19 patients for propofol (4131.0 mg vs 2704.8 mg, P < .001), dexmedetomidine (1581.4 mcg vs 1081.3 mcg, P = .016), and parenteral morphine equivalents ([PME], 209.3 mg vs 154.1 mg, P = .027), but only propofol remained significant after adjustment for weight (31.1 mcg/kg/day vs 37.7 mcg/kg/day, P = .014). COVID-19 was significantly associated with increased propofol and PME requirements after adjustment for confounders on linear regression analysis. COVID-19 patients had more days with non-zero dose for propofol (8 days vs 7 days), dexmedetomidine (13 days vs 8.5 days), and PME (17 days vs 8.5 days). The only interventions that were associated with reductions in propofol dose were tracheostomy and antipsychotics. CONCLUSIONS: COVID-19 patients on ECMO had significantly longer durations and higher doses of propofol, dexmedetomidine, and parenteral opioids over the first 28 days of cannulation. The only interventions that were associated with statistical reductions in propofol were antipsychotics and tracheostomy.

Comparison of Outcomes in Patients Requiring Mechanical Circulatory Support Who Received Cangrelor in Addition to Anticoagulation Versus Anticoagulation Alone.

OBJECTIVES: To evaluate the safety of cangrelor administered concurrently with heparin or bivalirudin in patients on mechanical circulatory support. DESIGN: A single-center, retrospective cohort study of adult patients consecutively admitted between January 2016 and October 2020. SETTING: A tertiary medical center. PARTICIPANTS: Adult patients admitted to the cardiovascular intensive care unit put on mechanical circulatory support for acute myocardial infarction (AMI) or non-AMI indications. Patients who received cangrelor underwent percutaneous coronary intervention with stenting during the index event or within the last year. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the incidence of major bleeding, defined by the Extracorporeal Life Support Organization criteria, in patients with mechanical circulatory support receiving cangrelor plus anticoagulation with heparin or bivalirudin with or without aspirin versus patients who did not receive cangrelor. Sixty-eight patients were included in the study. Twenty-nine patients received cangrelor, and 39 did not. Cangrelor was not associated with an increase in major bleeding; however, the CI was wide (adjusted hazard ratio 1.93, 95% CI 0.61-6.11; p = 0.262). CONCLUSIONS: Patients receiving cangrelor did not appear to be at higher risk of major bleeding compared to patients not receiving cangrelor. Larger trials should be conducted to better evaluate the safety of cangrelor in patients with mechanical circulatory support.

Prospective Observational Evaluation of Predatory Journals in Critical Care Pharmacy Practice: Defining Characteristics Associated With Receiving Unsolicited Invitations to Publish.

Open-access publishing promotes accessibility to scholarly research at no cost to the reader. The emergence of predatory publishers, which exploit the author-pay model by charging substantial publication fees for publication in journals with questionable publishing processes, is on the rise. Authors are solicited through aggressive marketing tactics, though who is targeted is not well described. The purpose of this study was to identify characteristics associated with critical care pharmacists that make them targets of unsolicited invitations to publish. A prospective, observational study of critical care pharmacists was performed. Participants archived emails received by their professional email that were unsolicited invitations to submit their original work for publication in a journal (unsolicited journals). Variables were evaluated to determine which were associated with unsolicited invitations; these were compared to legitimate journals, defined as all PubMed-indexed journals in which the participants were previously published. Twenty-three pharmacist participants were included, all of whom were residency and/or fellowship trained and practicing in an academic medical center. Participants had a median of 7 years of experience since their post-graduate training, 6 years since their last change in professional email address, and 2 years since their first PubMed-indexed publication. From these participants, 136 unsolicited and 59 legitimate journals were included. The average number of invitations increased 1.04 (95% CI, 1.02-1.05) times for every additional PubMed-indexed publication (P < .001). Most unsolicited journals were considered predatory. Legitimate and unsolicited journals differed significantly. The number of previous PubMed-indexed publications strongly correlates with the likelihood of critical care pharmacists receiving unsolicited publication invitations, often from predatory journal.

Fluctuating Voriconazole Concentrations during Extracorporeal Membrane Oxygenation.

BackgroundPatients requiring extracorporeal membrane oxygenation (ECMO) demonstrate complex drug pharmacokinetics due to alterations in clearance and volume of distribution, necessitating close therapeutic drug monitoring. Case Report: A 19-year-old Caucasian female with no past medical history was transferred from an outside hospital and admitted to the intensive care unit for acute respiratory distress syndrome secondary to a fresh water drowning event. The patient decompensated, requiring veno-arterial ECMO, which was subsequently changed to veno-venous ECMO. She was diagnosed with a Scedosporium apiospermum fungal pneumonia and was started on voriconazole. Throughout the course of antifungal therapy, the patient's voriconazole concentrations were labile, ranging from subtherapeutic, requiring dose increases to twice the labeled therapeutic dose, followed by subsequent supratherapeutic concentrations, requiring dose reductions. Conclusion: Our findings demonstrate how voriconazole drug concentrations can be unpredictable when administered during ECMO and the importance of close monitoring of drug concentrations. More studies are needed to provide sufficient guidance on administering voriconazole in critically ill patients receiving ECMO.

Heparin Monitoring with an Anti-Xa Protocol Compared to Activated Clotting Time in Patients on Temporary Mechanical Circulatory Support.

BACKGROUND: Temporary mechanical circulatory support (tMCS) devices are used for patients with severe cardiac or respiratory failure; however, these patients are at high risk for clotting and bleeding. The best method to monitor heparin in these patients has not been established. OBJECTIVE: To determine the risks for bleeding and clotting while monitoring heparin with either anti-Xa or activated clotting time (ACT) in tMCS patients. METHODS: A retrospective cohort study was conducted on tMCS patients who received heparin adjusted according to an anti-Xa or ACT protocol. The primary outcome was incidence of major bleeding. Pertinent secondary outcomes were individual components of the primary outcome, clotting events, and time to therapeutic range. RESULTS: There were 103 patients included in the study: 53 in the ACT group and 50 in the anti-Xa group. Overall, there were 30 (56.6%) patients with major bleeding in the ACT group, compared with 16 (32%) patients in the anti-Xa group (P = 0.017). An anti-Xa-based protocol was associated with a decreased hazard of major bleeding (hazard ratio = 0.388 [0.215-0.701]; P = 0.002) in the univariate analysis. In the multivariable analysis, an anti-Xa protocol remained associated with a significantly lower hazard of bleeding. Findings were similar when broken down into more discrete subgroups of the entire cohort, extracorporeal membrane oxygenation life support (ECMO), and non-ECMO groups. CONCLUSION AND RELEVANCE: Anti-Xa monitoring was associated with a lower hazard of bleeding during tMCS compared to an ACT-based protocol. Further studies should evaluate if anti-Xa monitoring should be preferentially used in tMCS.

Argatroban Versus Bivalirudin in the Treatment of Suspected or Confirmed Heparin-Induced Thrombocytopenia.

BACKGROUND: Argatroban and bivalirudin are direct thrombin inhibitors (DTIs) used for the treatment of heparin-induced thrombocytopenia (HIT). The purpose of this study was to determine whether either agent offered an advantage in efficacy and ability to remain within the targeted therapeutic anticoagulation range. METHODS: This was a single-center, retrospective, observational cohort study at a large academic medical center. The primary efficacy outcome was time to therapeutic anticoagulation, defined as total number of hours to achieve 2 consecutive activated partial thromboplastin time (aPTT) values in goal range. RESULTS: A total of 91 patients were included in the analysis. Average time to initial therapeutic anticoagulation was 4.71 hours and 9.8 hours for the argatroban and bivalirudin groups, respectively (P < .01). CONCLUSIONS: Argatroban may be advantageous compared to bivalirudin in achieving initial therapeutic anticoagulation goals among patients with suspected or confirmed HIT.

Adequacy of hemostatic resuscitation improves therapeutic efficacy of recombinant activated factor VII and reduces reexploration rate for bleeding in postoperative cardiac surgery patients with refractory hemorrhage.

Background: Excessive bleeding and surgical reexploration are common complications that increase the risk of multi-organ failure and prolonged hospitalization after cardiac surgery. Off-label use of recombinant activated factor VII (rFVIIa) is a recommended treatment for refractory bleeding. Objective: The objective of the study is to determine if the adequacy of hemostatic resuscitation enhances the efficacy of rFVIIa. Methods: This retrospective, observational, cohort study included patients who received rFVIIa for refractory postoperative bleeding after cardiac surgery. Patients were divided into two groups based on the presence or absence of adequate coagulation resuscitation before rFVIIa administration, defined as international ratio (INR) ≤1.5, platelet count ≥100 K/mL, and fibrinogen ≥200 mg/dL. The failure of rFVIIa treatment was defined as surgical reexploration within 24 h, thoracostomy drainage >400 mL/h within 6 h or transfusion of additional blood products or another rFVIIa dose within 6 h after initial rFVIIa dose. Results: Of the 3833 patients, screened who underwent cardiothoracic surgery procedures, 58 patients received rFVIIa for refractory postoperative bleeding. Successful hemostasis with rFVIIa was more likely in patients who were adequately resuscitated compared with those who were not (20 [71.4%] vs. 10 [33.3%], respectively; P = 0.0046). Multiple logistic regression analysis indicated that patients who were adequately resuscitated before rFVIIa were less likely to fail treatment (odds ratio, 0.16; 95% confidence interval [0.04-0.62]; P = 0.007). Conclusions: The therapeutic efficacy of rFVIIa is dependent on the adequacy of hemostatic resuscitation; restoration of normal serum fibrinogen, INR, and platelet counts >100 K/mL may provide an adequate substrate for rFVIIa to be effective in managing refractory postoperative cardiac surgical bleeding.

Methylene Blue Monotherapy Compared With Combination Therapy With Hydroxocobalamin for the Treatment of Refractory Vasoplegic Syndrome: ARetrospective Cohort Study.

OBJECTIVE: To compare the efficacy of methylene blue with combination therapy with hydroxocobalamin in patients experiencing vasoplegic syndrome after cardiac surgery. DESIGN: Retrospective cohort study. SETTING: Tertiary medical center. PARTICIPANTS: Patients who received methylene blue with or without hydroxocobalamin for refractory vasoplegic syndrome rescue therapy. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 0.the ability to maintain mean arterial pressure (MAP) >60 mmHg beyond 1hour after study drug administration. Other pertinent outcomes included MAP at hours 6, 12, and 24 post-administration; both raw and proportional changes of vasopressor doses from baseline at hours 1, 6, 12, and 24 post-administration; and change in pulmonary artery catheter hemodynamics. Overall, 28 doses were administered in 14 patients in the monotherapy group and 17 doses (10 methylene blue, 7 hydroxocobalamin) were administered in 6 patients in the combination therapy group. There were no differences in ability to maintain MAP at 1hour, with 71% of the monotherapy and 82% of combination therapy patients meeting MAP goals (p = 0.49). Pairwise comparisons demonstrated vasopressor reductions at 6, 12, and 24hours in both groups, but only significant reductions at 1hour were observed in the combination therapy group (-0.06 µg/kg/min; p = 0.003) but not in the monotherapy group (-0.015 µg/kg/min; p = 0.14). CONCLUSION: This is the first study to compare methylene blue monotherapy with combination therapy, which suggests there may be an advantage to combination therapy. Further characterization of ideal dosing, timing, and agent selection should be investigated on a larger scale format.

Major publications in the critical care pharmacotherapy literature: January-December 2016.

PURPOSE: To summarize select critical care pharmacotherapy guidelines and studies published in 2016. SUMMARY: The Critical Care Pharmacotherapy Literature Update (CCPLU) Group screened 31 journals monthly for relevant pharmacotherapy articles and selected 107 articles for review over the course of 2016. Of those included in the monthly CCPLU, three guidelines and seven primary literature studies are reviewed here. The guideline updates included are as follows: hospital-acquired pneumonia and ventilator-associated pneumonia management, sustained neuromuscular blocking agent use, and reversal of antithrombotics in intracranial hemorrhage (ICH). The primary literature summaries evaluate the following: dexmedetomidine for delirium prevention in post-cardiac surgery, dexmedetomidine for delirium management in mechanically ventilated patients, high-dose epoetin alfa after out-of-hospital cardiac arrest, ideal blood pressure targets in ICH, hydrocortisone in severe sepsis, procalcitonin-guided antibiotic de-escalation, and empiric micafungin therapy. CONCLUSION: The review provides a synopsis of select pharmacotherapy publications in 2016 applicable to clinical practice.

Pharmacist involvement on a rapid response team.

PURPOSE: The effect of a pharmacist on a rapid response team (RRT) was investigated. METHODS: This study evaluated 234 patients before and 157 patients after pharmacist involvement on an RRT. The primary outcome was time to medication administration, with a goal turnaround time of less than 30 minutes. Secondary outcomes included most frequently used medications, readmissions to the intensive care unit (ICU) within 48 hours, number of rapid responses that resulted in ICU admission, length of hospital stay, and survival to hospital discharge. Additionally, pharmacist interventions were tracked in the postinterventional group. RESULTS: The preinterventional group screened 326 rapid response events, of which 234 were included for analysis; during the postinterventional phase, 256 rapid response events were evaluated, of which 157 were included. The primary outcome, median time to medication administration from central pharmacy, was lower in the postinterventional group compared with the preinterventional group (32.0 minutes versus 64.5 minutes, p = 0.004). ICU admission rates following rapid response were not significantly different between the two groups. Additionally, there were no significant differences between rates of medical emergency and survival to hospital discharge. The most common medications administered were metoprolol and naloxone. Pharmacists provided documentation for 90 of 157 (57%) patient cases. In the 90 cases with documentation, 18 (20% of patients) had documented pharmacist interventions, including dosing assistance for 8 cases (44% of interventions). CONCLUSION: The addition of a pharmacist to an RRT reduced time to medication administration, helped improve medication accessibility, and helped optimize medication selection and dosing.

Dimethyltryptamine and other hallucinogenic tryptamines exhibit substrate behavior at the serotonin uptake transporter and the vesicle monoamine transporter.

N,N-dimethyltryptamine (DMT) is a potent plant hallucinogen that has also been found in human tissues. When ingested, DMT and related N,N-dialkyltryptamines produce an intense hallucinogenic state. Behavioral effects are mediated through various neurochemical mechanisms including activity at sigma-1 and serotonin receptors, modification of monoamine uptake and release, and competition for metabolic enzymes. To further clarify the pharmacology of hallucinogenic tryptamines, we synthesized DMT, N-methyl-N-isopropyltryptamine (MIPT), N,N-dipropyltryptamine (DPT), and N,N-diisopropyltryptamine. We then tested the abilities of these N,N-dialkyltryptamines to inhibit [(3)H]5-HT uptake via the plasma membrane serotonin transporter (SERT) in human platelets and via the vesicle monoamine transporter (VMAT2) in Sf9 cells expressing the rat VMAT2. The tryptamines were also tested as inhibitors of [(3)H]paroxetine binding to the SERT and [(3)H]dihydrotetrabenazine binding to VMAT2. Our results show that DMT, MIPT, DPT, and DIPT inhibit [(3)H]5-HT transport at the SERT with K ( I ) values of 4.00 +/- 0.70, 8.88 +/- 4.7, 0.594 +/- 0.12, and 2.32 +/- 0.46 microM, respectively. At VMAT2, the tryptamines inhibited [(3)H]5-HT transport with K ( I ) values of 93 +/- 6.8, 20 +/- 4.3, 19 +/- 2.3, and 19 +/- 3.1 muM, respectively. On the other hand, the tryptamines were very poor inhibitors of [(3)H]paroxetine binding to SERT and of [(3)H]dihydrotetrabenazine binding to VMAT2, resulting in high binding-to-uptake ratios. High binding-to-uptake ratios support the hypothesis that the tryptamines are transporter substrates, not uptake blockers, at both SERT and VMAT2, and also indicate that there are separate substrate and inhibitor binding sites within these transporters. The transporters may allow the accumulation of tryptamines within neurons to reach relatively high levels for sigma-1 receptor activation and to function as releasable transmitters.