Discordance Between Respiratory Drive and Sedation Depth in Critically Ill Patients Receiving Mechanical Ventilation.

OBJECTIVES: In mechanically ventilated patients, deep sedation is often assumed to induce "respirolysis," that is, lyse spontaneous respiratory effort, whereas light sedation is often assumed to preserve spontaneous effort. This study was conducted to determine validity of these common assumptions, evaluating the association of respiratory drive with sedation depth and ventilator-free days in acute respiratory failure. DESIGN: Prospective cohort study. SETTING: Patients were enrolled during 2 month-long periods in 2016-2017 from five ICUs representing medical, surgical, and cardiac specialties at a U.S. academic hospital. PATIENTS: Eligible patients were critically ill adults receiving invasive ventilation initiated no more than 36 hours before enrollment. Patients with neuromuscular disease compromising respiratory function or expiratory flow limitation were excluded. INTERVENTIONS: Respiratory drive was measured via P0.1, the change in airway pressure during a 0.1-second airway occlusion at initiation of patient inspiratory effort, every 12 ± 3 hours for 3 days. Sedation depth was evaluated via the Richmond Agitation-Sedation Scale. Analyses evaluated the association of P0.1 with Richmond Agitation-Sedation Scale (primary outcome) and ventilator-free days. MEASUREMENTS AND MAIN RESULTS: Fifty-six patients undergoing 197 bedside evaluations across five ICUs were included. P0.1 ranged between 0 and 13.3 cm H2O (median [interquartile range], 0.1 cm H2O [0.0-1.3 cm H2O]). P0.1 was not significantly correlated with the Richmond Agitation-Sedation Scale (RSpearman, 0.02; 95% CI, -0.12 to 0.16; p = 0.80). Considering P0.1 terciles (range less than 0.2, 0.2-1.0, and greater than 1.0 cm H2O), patients in the middle tercile had significantly more ventilator-free days than the lowest tercile (incidence rate ratio, 0.78; 95% CI, 0.65-0.93; p < 0.01) or highest tercile (incidence rate ratio, 0.58; 95% CI, 0.48-0.70; p < 0.01). CONCLUSIONS: Sedation depth is not a reliable marker of respiratory drive during critical illness. Respiratory drive can be low, moderate, or high across the range of routinely targeted sedation depth.

Treatment of adults with intracranial hemorrhage on apixaban or rivaroxaban with prothrombin complex concentrate products.

To analyze the efficacy and safety of activated prothrombin complex concentrates (aPCC) and four-factor prothrombin complex concentrates (4F-PCC) to prevent hematoma expansion in patients taking apixaban or rivaroxaban with intracranial hemorrhage (ICH). In this multicenter, retrospective study, sixty-seven ICH patients who received aPCC or 4F-PCC for known use of apixaban or rivaroxaban between February 2014 and September 2018 were included. The primary outcome was the percentage of patients who achieved excellent/good or poor hemostasis after administration of aPCC or 4F-PCC. Secondary outcomes included hospital mortality, thromboembolic events during admission, and transfusion requirements. Excellent/good hemostasis was achieved in 87% of aPCC patients, 89% of low-dose 4F-PCC [< 30 units per kilogram (kg)], and 89% of high-dose 4F-PCC (≥ 30 units per kg). There were no significant differences in excellent/good or poor hemostatic efficacy (p = 0.362). No differences were identified in transfusions 6 h prior (p = 0.087) or 12 h after (p = 0.178) the reversal agent. Mortality occurred in five patients, with no differences among the groups (p = 0.838). There were no inpatient thromboembolic events. Both aPCC and 4F-PCC appear safe and equally associated with hematoma stability in patients taking apixaban or rivaroxaban who present with ICH. Prospective studies are needed to identify a superior reversal agent when comparing andexanet alfa to hospital standard of care (4F-PCC or aPCC) and to further explore the optimal dosing strategy for patients with ICH associated with apixaban or rivaroxaban use.

Outcomes of Inpatient Administration of Restricted Antineoplastic Medications at a Large Academic Medical Institution.

BACKGROUND: Restricting oncology and hematology medications to outpatient infusion centers may be considered when infrequent administration is required, a low risk of serious adverse effects exists, or when prompt amelioration of a condition is not expected. At the University of California, San Diego (UCSD), we created a new formulary status for medications designated "formulary, outpatient-restricted use only." This designation could optimize payer reimbursement, as well as improve patient comfort, by negating the need for inpatient admission. When the inpatient administration of a restricted medication is requested at UCSD, there ensues a loosely defined review process involving an informal conversation between the requesting prescriber and the oncology pharmacy and therapeutics (P&T) chair. Patient outcomes associated with this formulary status and informal request process are limited. The purpose of this study is to describe the use of formulary, outpatient-restricted oncology and hematology medications in the inpatient setting at a single-center, academic, and comprehensive cancer center. METHODS: A retrospective chart review was conducted between January 1, 2015 and May 1, 2017. The primary outcome was to determine the percentage of formulary, outpatient-restricted oncology or hematology medications that were administered in the inpatient setting and continued to the outpatient setting. Secondary outcomes included overall survival, hospice enrollment, disease progression status, level of evidence supporting the medication usage, and cost. RESULTS: Twenty-three patients and 24 outpatient-restricted medications met the inclusion criteria. Thirteen (54%) medications were continued upon discharge and eight (33%) were not continued in the outpatient setting. Five of those eight medications were discontinued as a result of patient death. CONCLUSION: In this single-center study, approximately one-third of the outpatient-restricted medications were not continued upon discharge. The findings suggest that our informal approval process could result in the suboptimal use of formulary outpatient-restricted medications for oncology and hematology indications. A more formalized request process might lead to the more effective utilization of these medications.

A Retrospective Review of Hospitalized Patients Receiving a Higher than Maximum Dose of Acetaminophen.

BACKGROUND: Although the 3 to 4 gram per 24 hours dose recommended for daily use are generally safe, case reports and some series raise concerns about nonacute excessive doses in some individuals. OBJECTIVE: To assess the safety of dosing more than 4 grams of acetaminophen in a 24-hour period in hospitalized patients and develop a method to evaluate the ongoing practice of acetaminophen dosing. Methods: We performed a retrospective chart review of supratherapeutic doses of acetaminophen over a 2-year period. Outcomes included death and the need for liver transplant. A "best practices alert" (BPA) was then developed in our EMR when more than 4 grams of acetaminophen was either prescribed or administered in a 24- hour period. Twelve months of alerts were then retrospectively reviewed and evaluated. RESULTS: 152 cases of dosing more than 4 grams were initially identified. No cases of death related to liver failure or liver transplant were found in any of these patients. 482 cases were identified after a BPA was put in place where the alert was overridden. There were no deaths and no cases that required liver transplantation due to liver failure. The majority of overrides were due to the allowed window of timing for nursing administration of acetaminophen for scheduled doses and overlap with as needed dosing. CONCLUSION: Supratherapeutic dosing of acetaminophen in our patients did not lead to death or liver transplant. A BPA in our EMR has allowed better evaluation of patterns of acetaminophen use at our university health system.

A multicenter retrospective study evaluating the impact of desmopressin on hematoma expansion in patients with antiplatelet-associated intracranial hemorrhage.

INTRODUCTION: Antiplatelet medications interfere with hemostasis which can contribute to increased risk of hematoma expansion and potentially worse outcomes in patients presenting with intracranial hemorrhages (ICH). Current Neurocritical Care Society guidelines recommend desmopressin (DDAVP) in patients with antiplatelet-associated ICH with evidence limited by small cohorts. MATERIALS AND METHODS: Patients were included in our multi-center, retrospective study if they had computed tomographic (CT) scan confirmed ICH and were taking antiplatelet medications. Patients were excluded if hospital length of stay was <24 h, administered DDAVP dose was <0.3 µg/kg, no follow-up head CT scan was performed within the first 24 h after baseline, major neurosurgical intervention was performed in between CT scans, or the injury was an acute on chronic ICH. The primary outcome was incidence of hematoma expansion (defined as >20 % increase from baseline). Secondary outcomes were incidence of thrombotic complications within 7 days, largest absolute decrease in serum sodium within the first 24 h, and patient disposition. RESULTS: Among the 209 patients included in the study, 118 patients received DDAVP while 91 did not. The frequency of hematoma expansion was similar between patients who received DDAVP and those who did not (16.1 % vs 17.6 %; P = 0.78). No difference in secondary outcomes was observed between the two groups. CONCLUSIONS: These findings in conjunction with recently published literature may suggest minimal benefit or harm with DDAVP treatment. However, further study could elucidate any potential impact on long-term function outcomes.

Platelet reactivity testing in peripheral artery disease.

PURPOSE: Oral antiplatelet therapy is routinely used to prevent adverse cardiovascular events in patients with peripheral artery disease (PAD). Several laboratory tests are available to quantify the degree of platelet inhibition following antiplatelet therapy. This article aims to provide a review of the literature surrounding platelet functional testing in patients with PAD receiving oral P2Y12 inhibitors and to offer guidance to clinicians for the use and interpretation of these tests. SUMMARY: A literature search of PubMed and the Web of Science Core Collection database was conducted. All studies that performed platelet function testing and reported clinical outcomes in patients with PAD were included. Evaluation of the data suggests that, among the available testing strategies, the VerifyNow platelet reactivity unit (PRU) test is the most widely used. Despite numerous investigations attempting to define a laboratory threshold indicating suboptimal response to antiplatelet therapy, controversy exists about which PRU value best correlates with cardiovascular outcomes (ie, mortality, stent thrombosis, etc). In the PAD literature, the most commonly used PRU thresholds are 208 or higher and 235 or higher. Nonetheless, adjusting antiplatelet regimens based on suboptimal P2Y12 reactivity values has yet to be proven useful in reducing the incidence of adverse cardiovascular outcomes. This review examines platelet function testing in patients with PAD and discusses the interpretation and application of these tests when monitoring the safety and efficacy of P2Y12 inhibitors. CONCLUSION: Although platelet functional tests may be simple to use, clinical trials thus far have failed to show benefit from therapy adjustments based on test results. Clinicians should be cautioned against relying on this test result alone and should instead consider a combination of laboratory, clinical, and patient-specific factors when adjusting P2Y12 inhibitor therapy in clinical practice.

Dexmedetomidine as add-on sedation to reduce continuous infusion sedative use in mechanically ventilated patients.

PURPOSE: To characterize the impact of add-on dexmedetomidine therapy on baseline continuous infusion sedative use. METHODS: A retrospective, single-center, chart review-based study was conducted to assess outcomes of and potential predictors of response to add-on dexmedetomidine therapy in mechanically ventilated intensive care unit (ICU) patients who were already receiving continuous infusions of sedatives. Patients were defined as complete, partial, or nonresponders to add-on dexmedetomidine therapy if initial sedative infusion rates were reduced by 100%, by 50% to 99%, and by less than 50%, respectively, at 6 and 24 hours after initiation of dexmedetomidine. RESULTS: Among the 100 patients included in the study sample, there were 54 complete responders, 21 partial responders, and 25 nonresponders to dexmedetomidine add-on therapy at 6 hours after dexmedetomidine initiation; at 24 hours, there were 65 complete and 12 partial responders and 23 nonresponders. Of the variables tested (ie, baseline characteristics, opioid and antipsychotic use, hemodynamic parameters), none differentiated between complete or partial responders and nonresponders. Ventilator time, ICU length of stay (LOS), and hospital LOS after add-on dexmedetomidine therapy initiation were shorter among both partial responders and complete responders vs nonresponders (median, 1.1 days vs 4.1 days [P = 0.01], 7.0 days vs 14.1 days [P = 0.20], and 11.0 vs 17.0 days [P = 0.58], respectively), with only ventilator time being significantly different. CONCLUSION: Add-on dexmedetomidine therapy can obviate or reduce the need for alternate sedation in as many as 75% of mechanically ventilated ICU patients. However, the addition of dexmedetomidine does not allow the reduction of alternate sedation in a substantial minority of patients, and failure to respond to dexmedetomidine can be identified as early at 6 hours after add-on therapy initiation. In the absence of clear predictors of response to dexmedetomidine, these data suggest empiric trials of dexmedetomidine can be considered but should be time-limited.

Survey of Nurses' Experiences Applying The Joint Commission's Medication Management Titration Standards.

BACKGROUND: Critical care nurses titrate continuous infusions of medications to achieve clinical end points. In 2017, The Joint Commission (TJC) placed restrictions on titration practice, decreasing nurses' autonomous decision-making. OBJECTIVES: To describe the practice and perceptions of nurses regarding the 2017 TJC accreditation/regulatory standards for titration of continuous medication infusions. METHODS: A survey of nurses' experiences titrating continuous medication infusions was developed, validated, and distributed electronically to members of the American Association of Critical-Care Nurses. RESULTS: The content validity index for the survey was 1.0 for relevance and 0.95 for clarity. A total of 781 nurses completed the survey; 625 (80%) perceived titration standards to cause delays in patient care, and 726 (93%) experienced moral distress (mean [SD], 4.97 [2.67]; scale, 0-10). Among respondents, 33% could not comply with titration orders, 68% reported suboptimal care resulting from pressure to comply with orders, 70% deviated from orders to meet patient needs, and 84% requested revised orders to ensure compliance. Suboptimal care and delays in care significantly and strongly (regression coefficients ≥0.69) predicted moral distress. CONCLUSIONS: Critical care nurses perceive TJC medication titration standards to adversely impact patient care and contribute to moral distress. The improved 2020 updates to the standards do not address delays and inability to comply with orders, leading to moral distress. Advocacy is indicated in order to mitigate unintended consequences of TJC medication management titration standards.

Characteristics of Hospitalized Patients Screening Positive for Delirium.

BACKGROUND: Delirium in the hospitals leads to worse outcomes for patients. There were no previous studies that characterize patients with delirium from multiple hospital locations. OBJECTIVE: To describe patient characteristics screening positive for delirium and identify any correlations with hospital location and medication use. DESIGN, SETTINGS, PATIENTS: Retrospective chart review of 227 hospitalized patients from a large, academic, tertiary referral, 2-campus health system. Patients were ≥18 years old and had delirium for at least ≥24 hours. Validated delirium screening tools were utilized. MEASUREMENTS: Patients' demographics, inpatient stay information, delirium episodes characteristics, drugs, and palliative and psychiatry teams' involvement. RESULTS: Most patients were older with a mean age of 64.1 years. The most common primary diagnoses were infection, cardiac, and pulmonary. Average length of delirium was 7.2 days (standard deviation [SD] = 8.2), and average length of stay (LOS) was 18.7 days (median = 10.5, SD = 35.1, 95% confidence interval = 14.1-23). Thirty-day readmission rate was 24.8% (65/262 hospitalizations); 12.8% of patients died in the hospital (29/227). Around one-third of hospitalizations had involvement of palliative care, palliative psychiatry, or general psychiatry team. There was a decrease in the number of medications administered 24 hours after the first recording of delirium compared to the immediate preceding 48 hours. Those hospitalizations where delirium first occurred in the intensive care unit (ICU) did have a longer LOS (average = 22.9, SD = 45.7) than those where delirium first occurred outside the ICU (average = 14.8, SD = 20.5). Patients were likely to have received an opioid within 48 hours in 51% of hospitalizations and to have received benzodiazepines in 16% of hospitalizations. CONCLUSION: In our study, we found that delirium significantly impacted length of delirium episode, number of episodes of delirium, length of hospital admission, and mortality. The population most sensitive to the impacts of delirium were elderly patients.

Acute reversal of dabigatran with Idarucizumab for intravenous thrombolysis as acute stroke treatment.

Intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) for acute ischemic stroke (AIS) is contraindicated in patient taking either Factor Xa inhibitors or direct thrombin inhibitors. Idarucizumab completely reverses the biologic effect of dabigatran within minutes. Intravenous rt-PA treatment results in a significant benefit in functional outcome when administered 3-4.5 h after stroke onset or last seen normal time. There is little reported data and no large-scale studies of the reversal of dabigatran with Idarucizumab for the purpose of treating AIS with IV rt-PA. We describe the case of a 73 year old male with AIS and active dabigatran use. Idarucizumab was administered per an approved medical center protocol and the patient was subsequently treated with IV rt-PA. The patient had a severe stroke with no other contraindications to IV rt-PA other than dabigatran use. The patient was administered Idarucizumab and IV rt-PA was given. Within 24 h of treatment, the patient had minimal stroke deficits. Imaging revealed a right middle cerebral artery patchy infarct. The patient was restarted on dabigatran therapy for his atrial fibrillation and was discharged to a skilled nursing facility for rehabilitation. The patient did not experience any symptomatic or asymptomatic intracranial hemorrhage after treatment or through day 90. Though no randomized evidence exists for the risk of IV rt-PA after dabigatran reversal with Idarucizumab, the case experiences are mounting. This case of successful stroke treatment after reversal adds to the anecdotal literature and supports the study of dabigatran reversal with Idarucizumab for thrombolysis in AIS.

Four-Factor Prothrombin Complex Concentrate for Coagulopathy Reversal in Patients With Liver Disease.

A 4-factor prothrombin complex concentrate (4F-PCC, Kcentra®) was recently approved in the United States for the reversal of vitamin K antagonist-associated major bleeding, but it is often used to reverse coagulopathy in patients with liver disease (LD). This single-center, retrospective study analyzed the efficacy and safety of 4F-PCC administered in patients with and without LD. Prothrombin time/International Normalized Ratio (PT/INR) reversal with 4F-PCC was attempted in 85 patients; LD was documented in 31 patients. Coagulopathy reversal and hemostasis with 4F-PCC were inferior in patients with LD compared to patients without LD. Coagulopathy reversal, defined as INR = 1.5 after 4F-PCC administration, was achieved in 6 (19.4%) LD patients, compared to 44 (81.5%) non-LD patients ( p < 0.01). Hemostasis was achieved in 6 LD patients (19.4%) compared to 23 non-LD patients (42.6%) ( p = 0.03). Thromboembolic events occurred in 1 LD patient (3.2%) and 8 non-LD patients (14.8%) ( p = 0.15). Mortality was 51.6% in LD patients and 18.5% in non-LD patients ( p < 0.01). These observations suggest that the efficacy of 4F-PCC is suboptimal to correct coagulopathy and hemostasis in patients with LD, who have high rates of in-hospital mortality due to sequelae of LD. The incidence of thromboembolic events appeared comparable, suggesting that 4F-PCC does not cause undue thromboembolism in LD patients. In conclusion, 4F-PCC appears to be safe in LD patients when administered judiciously; however, further studies are necessary to optimize its use and elucidate its hemostatic potential in this patient population.

Saccharomyces cerevisiae RRM3, a 5' to 3' DNA helicase, physically interacts with proliferating cell nuclear antigen.

Proliferating cell nuclear antigen (PCNA) plays an essential role in eukaryotic DNA replication, and numerous DNA replication proteins have been found to interact with PCNA through a conserved eight-amino acid motif called the PIP-box. We have searched the genome of the yeast Saccharomyces cerevisiae for open reading frames that encode proteins with putative PIP-boxes and initiated testing of 135 novel candidates for their ability to interact with PCNA-conjugated agarose beads. The first new PCNA-binding protein identified in this manner is the 5' to 3' DNA helicase RRM3. Yeast two-hybrid tests show that N-terminal deletions of RRM3, which remove the PIP-box but leave the helicase motifs intact, abolish the interaction with PCNA. In addition, mutating the two phenylalanine residues in the PIP-box to alanine or aspartic acid reduces binding to PCNA, confirming that the PIP-box in RRM3 is responsible for interaction with PCNA. The results presented here suggest that the RRM3 helicase functions at the replication fork.