Effect of Early High-Dose Vitamin D3 Repletion on Cognitive Outcomes in Critically Ill Adults.

BACKGROUND: Long-term cognitive impairment frequently occurs after critical illness; no treatments are known to improve long-term cognition. RESEARCH QUESTION: Does a single high-dose (540,000 International Units) enteral treatment of vitamin D3 given shortly after hospital admission in critically ill patients who are vitamin D deficient improve long-term global cognition or executive function? STUDY DESIGN AND METHODS: This study evaluated long-term cognitive outcomes among patients enrolled in a multicenter, blinded, randomized clinical trial comparing vitamin D3 treatment vs placebo in critically ill adults with vitamin D deficiency. Global cognition was measured by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Executive function was measured with a composite score derived from three Delis-Kaplan Executive Function System subscales. Outcomes were assessed at a median of 443 days (interquartile range, 390-482 days) after randomization and were compared using multivariate proportional odds regression. Adjusted ORs of > 1.0 would indicate better outcomes in the vitamin D3 group compared with the placebo group. RESULTS: Ninety-five patients were enrolled, including 47 patients randomized to vitamin D3 treatment and 48 patients randomized to placebo. The adjusted median RBANS score at follow-up was 79.6 (95% CI, 73.0-84.0) in the vitamin D3 group and 82.1 (95% CI, 74.7-84.6) in the placebo group (adjusted OR, 0.83; 95% CI, 0.50-1.38). The adjusted median executive function composite scores were 8.1 (95% CI, 6.8-9.0) and 8.7 (95% CI, 7.4-9.3), respectively (adjusted OR, 0.72; 95% CI, 0.36-1.42). INTERPRETATION: In vitamin D-deficient, critically-ill adults, a large dose of enteral vitamin D3 did not improve long-term global cognition or executive function. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03733418; URL: www.clinicaltrials.gov.

A Randomized Trial Comparing Antibiotics with Appendectomy for Appendicitis.

BACKGROUND: Antibiotic therapy has been proposed as an alternative to surgery for the treatment of appendicitis. METHODS: We conducted a pragmatic, nonblinded, noninferiority, randomized trial comparing antibiotic therapy (10-day course) with appendectomy in patients with appendicitis at 25 U.S. centers. The primary outcome was 30-day health status, as assessed with the European Quality of Life-5 Dimensions (EQ-5D) questionnaire (scores range from 0 to 1, with higher scores indicating better health status; noninferiority margin, 0.05 points). Secondary outcomes included appendectomy in the antibiotics group and complications through 90 days; analyses were prespecified in subgroups defined according to the presence or absence of an appendicolith. RESULTS: In total, 1552 adults (414 with an appendicolith) underwent randomization; 776 were assigned to receive antibiotics (47% of whom were not hospitalized for the index treatment) and 776 to undergo appendectomy (96% of whom underwent a laparoscopic procedure). Antibiotics were noninferior to appendectomy on the basis of 30-day EQ-5D scores (mean difference, 0.01 points; 95% confidence interval [CI], -0.001 to 0.03). In the antibiotics group, 29% had undergone appendectomy by 90 days, including 41% of those with an appendicolith and 25% of those without an appendicolith. Complications were more common in the antibiotics group than in the appendectomy group (8.1 vs. 3.5 per 100 participants; rate ratio, 2.28; 95% CI, 1.30 to 3.98); the higher rate in the antibiotics group could be attributed to those with an appendicolith (20.2 vs. 3.6 per 100 participants; rate ratio, 5.69; 95% CI, 2.11 to 15.38) and not to those without an appendicolith (3.7 vs. 3.5 per 100 participants; rate ratio, 1.05; 95% CI, 0.45 to 2.43). The rate of serious adverse events was 4.0 per 100 participants in the antibiotics group and 3.0 per 100 participants in the appendectomy group (rate ratio, 1.29; 95% CI, 0.67 to 2.50). CONCLUSIONS: For the treatment of appendicitis, antibiotics were noninferior to appendectomy on the basis of results of a standard health-status measure. In the antibiotics group, nearly 3 in 10 participants had undergone appendectomy by 90 days. Participants with an appendicolith were at a higher risk for appendectomy and for complications than those without an appendicolith. (Funded by the Patient-Centered Outcomes Research Institute; CODA ClinicalTrials.gov number, NCT02800785.).

Early High-Dose Vitamin D3 for Critically Ill, Vitamin D-Deficient Patients.

BACKGROUND: Vitamin D deficiency is a common, potentially reversible contributor to morbidity and mortality among critically ill patients. The potential benefits of vitamin D supplementation in acute critical illness require further study. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial of early vitamin D3 supplementation in critically ill, vitamin D-deficient patients who were at high risk for death. Randomization occurred within 12 hours after the decision to admit the patient to an intensive care unit. Eligible patients received a single enteral dose of 540,000 IU of vitamin D3 or matched placebo. The primary end point was 90-day all-cause, all-location mortality. RESULTS: A total of 1360 patients were found to be vitamin D-deficient during point-of-care screening and underwent randomization. Of these patients, 1078 had baseline vitamin D deficiency (25-hydroxyvitamin D level, <20 ng per milliliter [50 nmol per liter]) confirmed by subsequent testing and were included in the primary analysis population. The mean day 3 level of 25-hydroxyvitamin D was 46.9±23.2 ng per milliliter (117±58 nmol per liter) in the vitamin D group and 11.4±5.6 ng per milliliter (28±14 nmol per liter) in the placebo group (difference, 35.5 ng per milliliter; 95% confidence interval [CI], 31.5 to 39.6). The 90-day mortality was 23.5% in the vitamin D group (125 of 531 patients) and 20.6% in the placebo group (109 of 528 patients) (difference, 2.9 percentage points; 95% CI, -2.1 to 7.9; P = 0.26). There were no clinically important differences between the groups with respect to secondary clinical, physiological, or safety end points. The severity of vitamin D deficiency at baseline did not affect the association between the treatment assignment and mortality. CONCLUSIONS: Early administration of high-dose enteral vitamin D3 did not provide an advantage over placebo with respect to 90-day mortality or other, nonfatal outcomes among critically ill, vitamin D-deficient patients. (Funded by the National Heart, Lung, and Blood Institute; VIOLET ClinicalTrials.gov number, NCT03096314.).

Impact of transfusion of autologous 7- versus 42-day-old AS-3 red blood cells on tissue oxygenation and the microcirculation in healthy volunteers.

BACKGROUND: Stored red blood cells (RBCs) accumulate biochemical and biophysical changes. Maximum storage duration is based on acceptable in vitro characteristics and 24-hour survival, but not RBC function. Relatively little is known about the impact of RBC storage duration on oxygenation and the microcirculation. STUDY DESIGN AND METHODS: Eight healthy subjects donated a double RBC apheresis, which were prestorage leukoreduced and processed in AS-3. Subjects were transfused 1 unit of RBCs at 7 and 42 days after blood collection. Measurements of percentage of tissue oxygenation in the thenar eminence muscle (StO2) and brain (SctO2) were recorded with Food and Drug Administration-cleared noninvasive devices. Sublingual microvascular blood flow (microcirculatory flow index [MFI]) was quantified before and after RBC transfusion using a video microscope. Raw electronic data for all measurements were analyzed by a blinded observer at a core laboratory. RESULTS: The only pre- versus posttransfusion change observed in measurements of SctO2, StO2, or MFI was a very small increase in SctO2, from 70.4 to 71.8 (means, p=0.032) at 7 days. There was no significant difference in the amount of pre-post change at 7 days versus 42 days for any of the measures. CONCLUSION: Transfusion of 1 unit of 42-day-stored RBCs to healthy subjects has no overt detrimental effect on tissue oxygenation or the microcirculation assessed by clinically available monitors.

Vitamin D insufficiency and sepsis severity in emergency department patients with suspected infection.

OBJECTIVES: Vitamin D is increasingly recognized as an important mediator of immune function and may have a preventive role in the pathogenesis of sepsis. We sought to evaluate the association between vitamin D status and sepsis severity and hypothesized that vitamin D insufficiency would be associated with increased sepsis severity. METHODS: This was a pilot study of emergency department (ED) patients age ≥ 18 years evaluated for suspected infection at an urban, teaching hospital. The authors measured illness severity using the following assessments at baseline and 24 hours: 1) severe sepsis, defined as suspected infection plus two or more elements of systemic inflammatory response syndrome criteria and acute dysfunction of one or more organ systems; 2) Acute Physiology Age Chronic Health Evaluation (APACHE) II scores; and 3) Sepsis-related Organ Failure Assessment (SOFA) scores. Vitamin D insufficiency was defined as baseline serum 25-hydroxyvitamin D (25OHD) levels <75 nmol/L. RESULTS: Eighty-one patients were enrolled, with a median age of 62 years (interquartile range [IQR] = 48-76 years), 47% were female, and 77% were white. At baseline, 64 (79%) had 25OHD levels of <75 nmol/L, and 43 (53%) had severe sepsis. At 24 hours, 48 (59%) had severe sepsis. Patients with baseline 25OHD levels of <75 nmol/L, compared to patients with 25OHD levels of ≥ 75 nmol/L, were more likely to have severe sepsis (61% vs. 24%; p = 0.006) and SOFA scores ≥ 2 (44% vs. 18%; p = 0.049). Additionally, at 24 hours, those with 25OHD levels of <75 nmol/L were more likely to have severe sepsis (67% vs. 29%; p = 0.005), dysfunction of two or more organ systems (50% vs. 18%; p = 0.02), APACHE II score of ≥ 25 (19% vs. 0%; p = 0.06), and SOFA scores of ≥ 2 (63% vs. 29%; p = 0.02). Additionally, all four patients who died during the index hospitalization had 25OHD levels of <75 nmol/L. CONCLUSIONS: Vitamin D insufficiency was associated with higher sepsis severity in ED patients hospitalized for suspected infection. Larger observational studies, mechanistic studies, and ultimately randomized controlled trials are needed to determine causation and to evaluate if vitamin D supplementation can reduce the risk of sepsis as a preventive or therapeutic strategy.

Do emergency department blood cultures change practice in patients with pneumonia?

STUDY OBJECTIVE: Although it is considered standard of care to obtain blood cultures on patients hospitalized for pneumonia, several studies have questioned the utility and cost-effectiveness of this practice. The objective of this study is to determine the impact of emergency department (ED) blood cultures on antimicrobial therapy for patients with pneumonia. METHODS: We performed a prospective, observational, cohort study of consecutive adult (age > or =18 years) patients treated at an urban university ED between February 1, 2000 and February 1, 2001. Inclusion criteria were radiographic evidence of pneumonia, clinical evidence of pneumonia, and blood culture obtained. Blood cultures were classified as positive, negative, or contaminant based on previously established criteria. Additionally, data were collected on antimicrobial sensitivities, empiric antibiotic therapy, antibiotic changes, and reasons for changes. RESULTS: There were 3,926 ED visits with blood cultures obtained for any reason, of which 3,762 (96%) were available for review. Of these, 414 of 3,762 (11%) patients met pneumonia study inclusion criteria, and blood cultures identified 29 of 414 (7.0%) patients with true bacteremia. In the 414 patients, blood culture results altered therapy for 15 patients (3.6%) with suspected pneumonia, of which 11 (2.7%) patients had their coverage narrowed; only 4 (1.0%) patients had their coverage broadened because of resistance to empiric therapy. For the 11 patients with bacteremia whose therapy was not altered, culture results actually supported narrowing therapy in 8 (1.9%) cases, but this was not done. CONCLUSION: Blood cultures rarely altered therapy for patients presenting to the ED with pneumonia. More discriminatory blood culture use may potentially reduce resource utilization.

Barriers to the use of outpatient enoxaparin therapy in patients with deep venous thrombosis.

OBJECTIVE: To establish a clinical pathway for outpatient enoxaparin therapy in deep venous thrombosis (DVT) and then characterize its implementation and barriers to use. PROCEDURE: Single institution, prospective, observational study of consecutive adult emergency department patients (age > or =18 years) who had a diagnosis of DVT. A clinical pathway was created to facilitate outpatient therapy with enoxaparin, and then all patients with DVT were enrolled and studied. RESULTS: A total of 97/98 (99%) eligible patients were enrolled. Among 97 patients, 29 (30%) were successfully started on the outpatient enoxaparin therapy approach. Of the 68 (70%) patients not started on the outpatient therapy, 19 (20%) patients had contraindications to anticoagulant therapy, 33 (34%) had other indications for hospitalization, 6 (6%) were unable to reliably self-inject, and 10 (10%) patients had a primary care physician or emergency physician who rejected the outpatient approach. CONCLUSIONS: The establishment of an organized DVT pathway for outpatient enoxaparin may facilitate home therapy; however, there will remain reasons that make hospital admission unavoidable in some patients.