Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness

BACKGROUND: There are conflicting data on the effects of antipsychotic medications on delirium in patients in the intensive care unit (ICU). METHODS: In a randomized, double-blind, placebo-controlled trial, we assigned patients with acute respiratory failure or shock and hypoactive or hyperactive delirium to receive intravenous boluses of haloperidol (maximum dose, 20 mg daily), ziprasidone (maximum dose, 40 mg daily), or placebo. The volume and dose of a trial drug or placebo was halved or doubled at 12-hour intervals on the basis of the presence or absence of delirium, as detected with the use of the Confusion Assessment Method for the ICU, and of side effects of the intervention. The primary end point was the number of days alive without delirium or coma during the 14-day intervention period. Secondary end points included 30-day and 90-day survival, time to freedom from mechanical ventilation, and time to ICU and hospital discharge. Safety end points included extrapyramidal symptoms and excessive sedation. RESULTS: Written informed consent was obtained from 1183 patients or their authorized representatives. Delirium developed in 566 patients (48%), of whom 89% had hypoactive delirium and 11% had hyperactive delirium. Of the 566 patients, 184 were randomly assigned to receive placebo, 192 to receive haloperidol, and 190 to receive ziprasidone. The median duration of exposure to a trial drug or placebo was 4 days (interquartile range, 3 to 7). The median number of days alive without delirium or coma was 8.5 (95% confidence interval [CI], 5.6 to 9.9) in the placebo group, 7.9 (95% CI, 4.4 to 9.6) in the haloperidol group, and 8.7 (95% CI, 5.9 to 10.0) in the ziprasidone group (P=0.26 for overall effect across trial groups). The use of haloperidol or ziprasidone, as compared with placebo, had no significant effect on the primary end point (odds ratios, 0.88 [95% CI, 0.64 to 1.21] and 1.04 [95% CI, 0.73 to 1.48], respectively). There were no significant between-group differences with respect to the secondary end points or the frequency of extrapyramidal symptoms. CONCLUSIONS: The use of haloperidol or ziprasidone, as compared with placebo, in patients with acute respiratory failure or shock and hypoactive or hyperactive delirium in the ICU did not significantly alter the duration of delirium. (Funded by the National Institutes of Health and the VA Geriatric Research Education and Clinical Center; MIND-USA ClinicalTrials.gov number, NCT01211522 .)

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials

Coding defect and a TATA box mutation at the bilirubin UDP-glucuronosyltransferase gene cause Crigler-Najjar type I disease

AbstractMutations at the bilirubin UDP-glucuronosyltransferase (transferase) gene in a severely hyperbilirubinemic Crigler-Najjar (CN) type I individual was compared with that in a moderately hyperbilirubinemic CN II individual. The CN-I (CF) patient in this study sustained a TATA box insertional mutation which was paired with a coding defect at the second allele, unlike all coding defects previously seen in CN-I patients. The sequence of the mutant TATA box, [A(TA)8A], also seen in the CN-II patient, was compared with that at the wild-type box, [A(TA)7A]. Transcriptional activity with [A(TA)8A] was 10–15% that with the wild-type box when present in the −1.7 kb upstream regulatory region (URR) of the bilirubin transferase UGT1A1 gene which was fused to the chloramphenicol acetyl transferase reporter gene, pCAT 1.7H, and transfected into HepG2 cells. Also, a construct with a TA deletion, [A(TA)6A], was prepared and used as a control; transcriptional activity was 65% normal. The coding region defect, R336W, seen in CF (CN-I) was placed in the bilirubin transferase UGT1A1 [HUG-Br1] cDNA, and its corresponding protein was designated UGT1A1*32. The UGT1A1*32 protein supported 0–10% normal bilirubin glucuronidation when expressed in COS-1 cells. The I294T coding defect seen at the second allele in SM (CN-II) generated the UGT1A1*33 mutant protein which supported 40–55% normal activity with a normal Km (2.5 μM) for bilirubin. The hyperbilirubinemia seen in SM decreased in response to phenobarbital treatment, unlike that seen in CF. Parents of the patients were carriers of the respective mutations uncovered in the offspring. The TATA box mutation paired with a deleterious missense mutation is, therefore, completely repressive in the CN-I patient, and is responsible for a lethal genotype/phenotype; but when homozygous, i.e. paired with itself, as previously reported in the literature, it is far less repressive and generates the mild Gilbert’s phenotype

A glimpse of the ‘natural history’ of established Type 2 (non-insulin dependent) diabetes mellitus from the spectrum of metabolic and hormonal responses to a mixed meal at the time of diagnosis

The reported glucose and immunoreactive insulin (IRI) responses to oral and intravenous glucose in subjects with Type 2 diabetes have not always been consistent. This may have resulted from variations in the method of glucose administration, the ethnic backgrounds of subjects, the diagnostic criteria applied, the duration of the disease or IRI assay methods. The use of a mixed meal rather than glucose has been shown to provide a more physiological stimulus to the pancreatic &cell due to both glucose and non-glucose secretagogues. We have analysed the metabolic and hormonal responses of 188 newly diagnosed Caucasian subjects with Type 2 diabetes and 38 non-diabetic subjects to a 500 kcal mixed meal. The diabetic subjects were stratified according to fasting plasma glucose (FPG)( 15 mmol/1) and body mass index (BMI) ( 9 mmol/l had progressive falls in IRI AUC to below that of the normal subjects (P < 0.0001 for the trend). Peak IRI concentrations declined progressively with increasing FPG. Despite equivalent glucose exposure simple trends of increasing AUC, IRI with increasing BMI were statistically significant (P < 0.001, P < 0.02, P < 0.001 and P < 0.01, respectively for each FPG group). Both fasting and AUC non-esterified fatty acid concentrations increased significantly with FPG regardless of BMI (P < 0.001 for the trends). These results using a more physiological mixed meal challenge in a large number of recently diagnosed Type 2 diabetic subjects demonstrate a marked and increasing loss of P-cell secretory function with increasing fasting hyperglycaemia aggravated by insulin resistance with increasing obesity

Reduced sampling protocols in estimation of insulin sensitivity and glucose effectiveness using the minimal - model in NIDDM

Recent work in healthy subjects, the aged, and subjects with gestational diabetes or drug-induced insulin resistance using minimal model analysis of the tolbutamide-modified frequently sampled intravenous glucose tolerance test suggested that a reduced sampling regimen of 12 time points produced unbiased and generally acceptable estimates of insulin sensitivity (SI) and glucose effectiveness (SG) compared with a full sampling schedule of 30 time points. We have used data from 26 insulin-modified frequently sampled intravenous glucose tolerance tests in 21 subjects with NIDDM to derive and compare estimates of SI and SG from the full sampling schedule(SI(30),SG(30)) with those estimated from the suggested 12 time points(SI(12), SG(12)) and those estimated with the addition of a 25-min time point (SI(13), SG(13)). Percentage relative errors were calculated relative to the corresponding 30 time-point values. A statistically significant bias of 15% (97% confidence interval from 7.4 to 25.6%, interquartile range 25%) was introduced by the estimation of SI(12) but not SI(13), (1%, 97% confidence interval from -9.4 to 9.3%, interquartile range 21%). Results for SG(12)(-12%, 97% confidence interval from -46.7 to 1.2%, interquartile range 49%) and SG(13)(-5%, 97% confidence interval from -27.8 to 6.8% interquartile range 37%) were statistically equivocal. The precision of estimation of SI(12), SG(12), and SG(13)measured by the interquartile range of the percentage relative errors was poor. The precision of determination measured by the median minima1 model coefficient of variation was 18, 29, and 27% for S, SI(30), SI(12), and SI(13) and 9, 11, and 11% for SG(30), SG(12), and SG(13), respectively. Thus, the application of minimal model analysis to the 12 time-point protocol of the insulin-modified IVGTT for the estimation of SI, and SG, in NIDDM may necessitate an inordinately large number of subjects. Although the 13 time-point protocol may be more acceptable for the assessment of SI, in population studies, we recommend retention of the full sampling schedule where feasible

Intranasal insulin: the effects of three dose regimens on postprandial glycaemic profiles in type II diabetic subjects

In both fasting normal and diabetic subjects, nasally administered insulin achieves significant falls in plasma glucose concentrations. Repeated administration before and during a meal has been necessary to lower postprandial glycaemic excursion in subjects with NIDDM. We have studied the use of Novolin® Nasal which employs a non-irritant, lecithin-based enhancer as a vehicle for human insulin, on postprandial glucose profiles in NIDDM subjects to determine efficacy, optimal dose frequency, and tolerability. Seventeen NIDDM subjects (15 men, 2 women) participated in a randomized, partially blinded, placebo-controlled, crossover trial of three active treatment regimens (nasal insulin, 120 U at 0 min, 60 U at 0 and +20 min or 120 U at +20 min) in relation to a standardized mixed meal given at 0 min. All active treatments significantly reduced postprandial glucose concentrations compared to placebo. lntranasal insulin given at 0 min at a dose of 60 U or 120 U resulted in a 50 % reduction in postprandial incremental glucose compared to placebo over the first 2 h, whereas treatment with 60 U both at 0 and 20 min lead to a 70 % reduction over the 240 min postprandial period. Post-prandial intravenous insulin was the least effective. There were no episodes of symptomatic hypoglycaemia. Local tolerability was excellent with only four reports of transient nasal irritation out of a total of 68 doses. The delivery device was accurate with intra-device CV of delivered dose of 4.8 %. We conclude that nasal insulin is effective in reducing postprandial glycaemia in subjects with NIDDM and is well tolerated. Repeated dosing achieved the greatest reduction in postprandial glycaemic responses to a mixed meal