Effects of simulated sample sizes on mortality estimates-Protocol for a study in 3 randomised ICU trials.

BACKGROUND: An increasing number of trials are stopped earlier than originally planned. It has been suggested that trials stopped pre-maturely overestimate the treatment effect. With the outlined observational study, we aim to simulate the results of stopping trials before they reach their planned sample size to assess the effects on mortality estimates. METHODS AND STATISTICS: Based on 3 international, randomised clinical trials (RCTs) in critical care: Scandinavian Starch for Severe Sepsis and Septic Shock (6S) trial, the Transfusion Requirements in Septic Shock (TRISS) trial and the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial, we will estimate relative risks with 95% confidence intervals for the primary outcome 90-day mortality after the inclusion of each individual patient in each RCT. This will be presented graphically with the primary outcome as a function of the number of included patients. DISCUSSION: The outlined study will provide important knowledge about the effects of stopping critical care trials early. This may have important implications for patients, relatives, clinicians, researchers, guideline committee members and policy makers. ETHICS AND DISSEMINATION: We will use data from consenting patients enrolled in RCTs approved by the relevant ethical committees; this study requires no further permissions. We will report the results in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement and submit the final approved manuscript to a peer-reviewed journal.

Timing of onset of gastrointestinal bleeding in the ICU: Protocol for a preplanned observational study.

BACKGROUND: Critically ill patients are at risk of gastrointestinal bleeding, but clinically important gastrointestinal bleeding is rare. The majority of intensive care unit (ICU) patients receive stress ulcer prophylaxis (SUP), despite uncertainty concerning the balance between benefit and harm. For approximately half of ICU patients with gastrointestinal bleeding, onset is early, ie within the first two days of the ICU stay. The aetiology of gastrointestinal bleeding and consequently the balance between benefit and harm of SUP may differ between patients with early vs late gastrointestinal bleeding. METHODS: This is a protocol and statistical analysis plan for a preplanned exploratory substudy of the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) randomized clinical trial, comparing intravenous pantoprazole (40 mg once daily) with placebo in 3350 acutely ill adult ICU patients. We will describe baseline characteristics and assess the time to onset of the first clinically important episode of GI bleeding accounting for survival status and allocation to SUP or placebo. In addition, we will describe differences in therapeutic and diagnostic procedures used in patients with clinically important gastrointestinal bleeding according to early vs late bleeding and 90-day vital status. CONCLUSIONS: The study outlined in this protocol will provide detailed information on patient characteristics and the timing of onset of gastrointestinal bleeding in the patients enrolled in the SUP-ICU trial. This may provide additional knowledge and incentives for future studies on which patients benefit from SUP.

Stress ulcer prophylaxis in adult intensive care unit patients - a protocol for a systematic review.

BACKGROUND: In the intensive care unit (ICU), stress ulcer prophylaxis with proton pump inhibitors or histamine-2-receptor antagonists is standard of care although gastrointestinal bleeding remains uncommon. It remains unknown whether its use is associated with benefits or harms and the quality of evidence supporting the use of stress ulcer prophylaxis has been questioned. Accordingly, the objective of this systematic review was to critically assess the evidence from randomized clinical trials on the benefits and harms of stress ulcer prophylaxis vs. placebo or no prophylaxis in adult ICU patients. METHODS: We will systematically search for randomized clinical trials in major international databases. Two authors will independently screen and select trials for inclusion, extract data and assess the methodological quality using the Cochrane risk of bias tool. Any disagreement will be resolved by consensus. We will perform conventional meta-analyses using Review Manager, and STATA 15, and we will assess the risk of random errors using Trial Sequential Analysis. Also, we will assess and report the overall quality of evidence for all outcomes according to GRADE. DISCUSSION: The evidence on the benefits and harms of stress ulcer prophylaxis in adult ICU patients is unclear and an updated systematic review is warranted as new trials have been published. To control risks of systematic and random errors, we will use Cochrane and GRADE methodology and Trial Sequential Analysis. Our ambition with this systematic review is to provide updated, reliable and precise data to better inform decision makers on the use of stress ulcer prophylaxis in adult ICU patients.

Development and internal validation of the Simplified Mortality Score for the Intensive Care Unit (SMS-ICU).

BACKGROUND: Intensive care unit (ICU) mortality prediction scores deteriorate over time, and their complexity decreases clinical applicability and commonly causes problems with missing data. We aimed to develop and internally validate a new and simple score that predicts 90-day mortality in adults upon acute admission to the ICU: the Simplified Mortality Score for the Intensive Care Unit (SMS-ICU). METHODS: We used data from an international cohort of 2139 patients acutely admitted to the ICU and 1947 ICU patients with severe sepsis/septic shock from 2009 to 2016. We performed multiple imputations for missing data and used binary logistic regression analysis with variable selection by backward elimination, followed by conversion to a simple point-based score. We assessed the apparent performance and validated the score internally using bootstrapping to present optimism-corrected performance estimates. RESULTS: The SMS-ICU comprises seven variables available in 99.5% of the patients: two numeric variables: age and lowest systolic blood pressure, and five dichotomous variables: haematologic malignancy/metastatic cancer, acute surgical admission and use of vasopressors/inotropes, respiratory support and renal replacement therapy. Discrimination (area under the receiver operating characteristic curve) was 0.72 (95% CI: 0.71-0.74), overall performance (Nagelkerke's R2 ) was 0.19 and calibration (intercept and slope) was 0.00 and 0.99, respectively. Optimism-corrected performance was similar to apparent performance. CONCLUSIONS: The SMS-ICU predicted 90-day mortality with reasonable and stable performance. If performance remains adequate after external validation, the SMS-ICU could prove a valuable tool for ICU clinicians and researchers because of its simplicity and expected very low number of missing values.

Stress ulcer prophylaxis in the intensive care unit trial: detailed statistical analysis plan.

BACKGROUND: In this statistical analysis plan, we aim to provide details of the pre-defined statistical analyses of the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial. The aim of the SUP-ICU trial is to assess benefits and harms of stress ulcer prophylaxis with a proton pump inhibitor in adult patients in the intensive care unit (ICU). METHODS: The SUP-ICU trial is an investigator-initiated, international, multicentre, randomised, blinded, parallel-group trial of intravenously pantoprazole 40 mg once daily vs. placebo in 3350 acutely ill adult ICU patients at risk of gastrointestinal bleeding. The primary outcome measure is 90-day mortality. Secondary outcomes include the proportion of patients with clinically important gastrointestinal bleeding, pneumonia, Clostridium difficile infection or myocardial ischaemia, days alive without life support, serious adverse reactions, 1-year mortality, and a health economic analysis. Two formal interim analyses will be performed. The statistical analyses will be conducted according to the outlined pre-defined statistical analysis plan. The primary analysis will be a logistic regression analysis adjusted for stratification variables comparing the two intervention groups in the intention-to-treat population. In a secondary analysis, we will additionally adjust the primary outcome for potential random differences in baseline characteristics. The conclusion will be based on the intention-to-treat population. CONCLUSION: Stress ulcer prophylaxis is standard of care in ICUs worldwide, but has never been tested in large high-quality randomised placebo-controlled trials. The SUP-ICU trial will provide important high-quality data on the balance between the benefits and harms of stress ulcer prophylaxis in adult critically ill patients.

Analysis of select folate pathway genes, PAX3, and human T in a Midwestern neural tube defect population.

Neural tube defects (NTDs) are a common birth defect, seen in approximately 1/1,000 births in the United States. NTDs are considered a complex trait where several genes, interacting with environmental factors, create the phenotype. Using a Midwestern NTD population consisting of probands, parents, and siblings from Iowa, Minnesota, and Nebraska, we analyzed a range of candidate genes, including 5,10-methylenetetrahydrofolate reductase (MTHFR), folate receptors-alpha (FOLR1; hereafter abbreviated "FR-alpha") and -beta (FOLR2; hereafter, "FR-beta"), methionine synthase (hereinafter, "MS"), T, the human homolog of the murine Brachyury gene, and the paired-box homeotic gene 3 (PAX3), for association with NTDs. We were unable to demonstrate an association using a previously described Ala-->Val mutation in MTHFR and the majority of our NTD populations. However, we discovered a silent polymorphism in exon 6 of MTHFR which conserved a serine residue and which showed significant association with NTDs in our Iowa population. Analysis of exon 7 of MTHFR then demonstrated an Ala-->Glu mutation which was significantly associated with our Iowa NTD population; however, we could not replicate this result either in a combined Minnesota/ Nebraska or in a California NTD population. Using polymorphic markers for MS, FR-beta, T, and PAX3, we were unable to demonstrate linkage disequilibrium with our NTD populations. A mutation search of FR-alpha revealed one proband with a de novo silent mutation of the stop codon. This work provides a new panel of genetic variants for studies of folate metabolism and supports, in some NTD populations, an association between MTHFR and NTDs.

Hydrosyringomyelia and diastematomyelia detected by MRI in myelomeningocele.

Magnetic resonance imaging of the spine in 45 patients with myelomeningocele revealed hydrosyringomyelia in 24 and diastematomyelia in two. No patient at initial imaging manifested symptoms referable to hydrosyringomyelia; both patients with diastematomyelia had flaccid lower extremities. One patient developed an upper extremity monoparesis which resolved with syringo-peritoneal shunt placement; no other patient manifested symptoms or required surgery. Ventriculoperitoneal shunt malfunction produced reversible distention of the syrinx in another patient who remained asymptomatic.

Cytomegalovirus infection: a quantitative prospective study of three hundred twenty consecutive renal transplants.

The quantitative effects of cytomegalovirus (CMV) infection on morbidity and mortality rates were examined in 320 renal transplant cases. With the use of virus cultures and CMV antibody measurements, all patients were studied, regardless of symptoms, from a time before transplantation to at least 1 year, 11 months after transplantation for a maximum of 5 years, 9 months. The posttransplant risk factors of CMV infection--patient age, type of donor (living-related or cadaver), antigen match between donor and recipient, presence of diabetes, and the presence of pretransplant CMV antibody--were evaluated for their relative effects on patient survival, graft survival, fever, and leukopenia. CMV infection was a significant risk factor for these four events. CMV infection occurred in 181 patients after transplantation and accounted for 25% of the deaths, 20% of the graft failures, 30% of the occurrences of fever, and 35% of the occurrences of leukopenia. Unexpectedly, female recipients were at higher risk than men for the adverse effects of CMV infection. Young patients and those receiving their second transplant were at higher risk of graft loss if they had associated CMV infection. CMV infection was most reliably predicted by the presence of pretransplant antibody, indicating that reactivation of endogenous virus was responsible for most infections. The presence of pretransplant antibody offered a small amount of protection against fever, but no protection against death, graft failure, or leukopenia. Simultaneous episodes of CMV infection and transplant rejection, both common posttransplant events, most often occurred by chance.

A trial of vidarabine for cytomegalovirus infection in renal transplant patients.

Vidarabine was evaluated in renal transplant patients as a potential therapeutic agent in cytomegalovirus (CMV) infection. Four patients received vidarabine on an open protocol, then ten additional patients were enrolled in a double-blind protocol. Among the nine patients who received vidarabine, no notable clinical improvement occurred in either the vidarabine- or placebo-treated groups. Thus, vidarabine showed no therapeutic effect in the treatment of CMV infections at the dosages used. Four patients showed dramatic CNS deterioration within several days of the onset of vidarabine therapy. Tremors and myoclonus were common, and one patient had unusual brain pathologic changes with widespread neuronal chromatolysis. The pathologic findings in the brain in the other three patients were complex and included intracerebral hemorrhage, Fabry's disease, coccidioidomycosis meningitis, and cerebral vascular occlusion. Thus, there was no conclusive proof that vidarabine contributed to the sudden neurologic deterioration of these patients.

Experimental otitis media after nasal inoculation of Streptococcus pneumoniae and influenza A virus in chinchillas.

Otitis media developed in 67% of chinchillas inoculated intranasally with type 7 Streptococcus pneumoniae and influenza A virus. Only 4% of chinchillas inoculated with influenza alone and 21% of chinchillas inoculated with S. pneumoniae alone developed otitis media. Among the chinchillas that developed otitis media after inoculation with both pneumococcus and influenza, 73% of the affected ears contained effusion, and 27% of the affected ears showed tympanic membrane inflammation without middle ear effusion obtained on paracentesis. Although a majority of the ears with effusion yielded S. pneumoniae on culture, one-third of the effusions were sterile for aerobic bacteria. This model resembles conditions accompanying otitis media in humans and suggests that respiratory viral infection contributes significantly to the pathogenesis of acute otitis media.

Cytomegalovirus disease in renal allograft recipients: a prospective study of the clinical features, risk factors and impact on renal transplantation.

Fifty-nine renal transplant recipients with overt CMV disease were treated at the University of Minnesota Health Sciences Center between October 1, 1977 and November 15, 1978. In a group of 141 consecutive transplant patients, the incidence of overt CMV disease was 31%. Fifty-three patients (90%) developed clinical manifestations of CMV disease within 4 months of transplantation, and it was during this time period that overt CMV disease was associated with a significantly increased incidence of transplant nephrectomy and death. Fever was the most common presenting symptom (95% of patients), and overt CMV disease was found to be the single most common cause of fever in all hospitalized transplant recipients. Prolonged fever, diffuse pulmonary infiltrates, gastrointestinal bleeding, pancreatitis, transplant nephrectomy and development of other systemic infections were clinical features used to categorize patients according to disease severity. A number of these features were found to be significantly associated with the diagnosis of overt CMV disease. Twelve patients (20%) developed lethal CMV disease characterized by the presence of most of these features, 6 (10%) had severe disease, 9 (15%) had disease of moderate severity and 32 patients (54%) had mild CMV disease with fever being essentially their only clinical finding. Development of secondary systemic infection was most ominous, and occurred before death in 10 of the 12 patients with lethal CMV disease. The only patients to die with serious bacterial, fungal or protozoan infection during the period of this study had concomitant overt CMV disease. Abnormal liver function tests and leukopenia were common, and the degree of abnormality correlated with the severity of CMV disease. Of the multiple factors analyzed for their influence on the risk of developing overt CMV disease, several factors related to the kidney donor (the relationship of the donor to the recipient, HLA matching and CMV serology) appeared to be most important.

Epstein-Barr virus antibody responses and clinical illness in renal transplant recipients.

Among 88 renal transplant recipients evaluated for a change in Epstein-Barr virus (EBV) antibody status in the period after transplant, 22 showed a 4-fold rise and eight showed an 8-fold or greater rise in EBV antibody. Among the patients with an 8-fold or greater EBV ANTIBODY RISE, THE OCCURRENCE OF FEVER WAS FREQUENT, ONE PATIENT DEVELOPED A LYMPHOPROLIFERATIVE reaction, and one died with a malignant EBV infection. Patients without pretransplant antibody showed a longer mean time to antibody rise (104 +/- 23 days) than did those patients with pretransplant antibody (19 +/- 7 days). The longer incubation period in patients without pretransplant antibody was in the expected range for primary EBV infections. Both primary and secondary (reactivation) EBV infections occur in renal transplant patients. These infections may be assoicated with prolonged fever, and in unusual circumstances, may cause dramatic lymphoproliferative disease.

Correlation between virus-cell receptor properties of alphaviruses in vitro and virulence in vivo.

Virulent and avirulent clones of Venezuelan, Western, and Eastern equine encephalitis viruses were examined for their in vitro attachment characteristics to the surface of cultured cell monolayers. These attachment characteristics were correlated with in vivo plasma clearance rates and virulence. For the clones investigated, avirulence correlated in vitro with attachment pH optima close to physiologic pH and in vivo with a rapid clearance from plasma. Conversely, virulent clones had lower in vitro attachment pH optima and low plasma clearances in vivo.

Tuberculous joint disease in transplant patients.

Three patients with tuberculosis, all manifesting monarticular joint involvement, among 845 renal allograft recipients at the University of Minnesota are reported on. Clinical symptoms, methods of diagnosis, and optimal antibiotic regimes are discussed. The physician must suspect tuberculous joint disease when confronted with monarticular swelling and pain in the transplant recipient.

Evaluation of zoster immune plasma. Treatment of cutaneous disseminated zoster in immunocompromised patients.

Zoster immune plasma (ZIP) was evaluated for treatment of cutaneous disseminated zoster in immunocompromised hosts. Twenty patients were studied: 13 were enrolled in a double-blind protocol, five received ZIP under an open protocol, and two were observed without receiving a transfusion. In the double-blind study, eight patients actually received ZIP; five were given plasma lacking varicella-zoster virus antibodies (control plasma). The clinical course of zoster in the group given ZIP was the same as that of patients given control plasma or no transfusions. Because ZIP did not alter the clinical course of zoster and because zoster patients produced high-antibody titers without ZIP, we concluded that ZIP is not useful for treatment of cutaneous disseminated zoster and should be reserved for prevention or modification of varicella in exposed, susceptible immunocompromised patients.

Listeria infection in transplant patients. Five cases and a review of the literature.

We report five cases of Listeria monocytogenes infection in renal transplant patients at the University of Minnesota and compare them to 15 additional patients reported on in the United States literature. All patients were noted to have fever, malaise, and nonspecific symptoms of infection. There were no consistent diagnostic laboratory findings except for positive bacteriologic studies. Successful treatment consisted of intravenous penicillin G potassium in most cases (ampicillin sodium was required in two patients). Mortality was low, with only one patient of the 20 (and no Minnesota patients) dying of listeriosis. The time interval from transplant to infection was definitively longer in the Minnesota patients; this may be due to the routine use of sulfisoxazole following renal transplantation. Listeria infection, though mild itself, may herald other infectious processes in the immunoincompetent host.

Specific cell-mediated immune defect in active cytomegalovirus infection of young children and their mothers.

4 young children with active cytomegalovirus (C.M.V.) infection were found, by an in-vitro lymphocyte-proliferation assay, to have a C.M.V.-specific cell-mediated immune defect. These children had antibodies to C.M.V. and were actively shedding C.M.V. in the urine when studied. Their general cellular immune responses were intact, with normal numbers of T lymphocytes and normal in-vitro responses to mitogens and at least one antigen. 3 of the 4 mothers studied shortly after delivery had decreased cell-mediated immunity to C.M.V. These findings suggest that an antigen-specific immune defect facilitates transmission of virus from mother to infant and permits persistence of viral replication in the offspring.