Torben Martinussen

A protocol of no sedation for critically ill patients receiving mechanical ventilation: a randomised trial

BACKGROUND Standard treatment of critically ill patients undergoing mechanical ventilation is continuous sedation. Daily interruption of sedation has a beneficial effect, and in the general intesive care unit of Odense University Hospital, Denmark, standard practice is a protocol of no sedation. We aimed to establish whether duration of mechanical ventilation could be reduced with a protocol of no sedation versus daily interruption of sedation. METHODS Of 428 patients assessed for eligibility, we enrolled 140 critically ill adult patients who were undergoing mechanical ventilation and were expected to need ventilation for more than 24 h. Patients were randomly assigned in a 1:1 ratio (unblinded) to receive: no sedation (n=70 patients); or sedation (20 mg/mL propofol for 48 h, 1 mg/mL midazolam thereafter) with daily interruption until awake (n=70, control group). Both groups were treated with bolus doses of morphine (2.5 or 5 mg). The primary outcome was the number of days without mechanical ventilation in a 28-day period, and we also recorded the length of stay in the intensive care unit (from admission to 28 days) and in hospital (from admission to 90 days). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00466492. FINDINGS 27 patients died or were successfully extubated within 48 h, and, as per our study design, were excluded from the study and statistical analysis. Patients receiving no sedation had significantly more days without ventilation (n=55; mean 13.8 days, SD 11.0) than did those receiving interrupted sedation (n=58; mean 9.6 days, SD 10.0; mean difference 4.2 days, 95% CI 0.3-8.1; p=0.0191). No sedation was also associated with a shorter stay in the intensive care unit (HR 1.86, 95% CI 1.05-3.23; p=0.0316), and, for the first 30 days studied, in hospital (3.57, 1.52-9.09; p=0.0039), than was interrupted sedation. No difference was recorded in the occurrences of accidental extubations, the need for CT or MRI brain scans, or ventilator-associated pneumonia. Agitated delirium was more frequent in the intervention group than in the control group (n=11, 20%vs n=4, 7%; p=0.0400). INTERPRETATION No sedation of critically ill patients receiving mechanical ventilation is associated with an increase in days without ventilation. A multicentre study is needed to establish whether this effect can be reproduced in other facilities. FUNDING Danish Society of Anesthesiology and Intensive Care Medicine, the Fund of Danielsen, the Fund of Kirsten Jensa la Cour, and the Fund of Holger og Ruth Hess.

Effects of capsaicin, green tea and CH-19 sweet pepper on appetite and energy intake in humans in negative and positive energy balance

BACKGROUND & AIMS Bioactive ingredients have been shown to reduce appetite and energy intake. The magnitude of these effects might depend on energy balance why it was investigated how capsaicin, green tea, CH-19 sweet pepper as well as green tea and capsaicin affect appetite and energy intake during respectively negative and positive energy balance. METHODS 27 subjects were randomized to three weeks of negative and three weeks of positive energy balance during which capsaicin, green tea, CH-19 sweet pepper, capsaicin+green tea or placebo was ingested on ten separate test days while the effects on appetite, energy intake, body weight and heart rate were assessed. RESULTS CH-19 sweet pepper and a combination of capsaicin and green tea reduced energy intake during positive energy balance. Capsaicin and green tea suppressed hunger and increased satiety more during negative than during positive energy balance. CONCLUSIONS Bioactive ingredients had energy intake reducing effects when used in combinations and in positive energy balance. Energy balance did not affect possible treatment induced energy intake, but did affect appetite by supporting negative energy balance. Bioactive ingredients may therefore be helpful in reducing energy intake and might support weight loss periods by relatively sustaining satiety and suppressing hunger.

Efficient Estimation of Fixed and Time‐varying Covariate Effects in Multiplicative Intensity Models

The proportional hazards assumption of the Cox model does sometimes not hold in practise. An example is a treatment effect that decreases with time. We study a general multiplicative intensity model allowing the influence of each covariate to vary non-parametrically with time. An efficient estimation procedure for the cumulative parameter functions is developed. Its properties are studied using the martingale structure of the problem. Furthermore, we introduce a partly parametric version of the general non-parametric model in which the influence of some of the covariates varies with time while the effects of the remaining covariates are constant. This semiparametric model has not been studied in detail before. An efficient procedure for estimating the parametric as well as the non-parametric components of this model is developed. Again the martingale structure of the model allows us to describe the asymptotic properties of the suggested estimators. The approach is applied to two different data sets, and a Monte Carlo simulation is presented.

Acute Phase Response to Surgery of Varying Intensity in Horses: A Preliminary Study

OBJECTIVE To evaluate the postoperative inflammatory response of horses to elective surgery of varying intensity. STUDY DESIGN Prospective longitudinal study. ANIMALS Horses referred to 2 hospitals for either arthroscopic removal of a unilateral osteochondritic lesion in the tibiotarsal joint (minimal surgical trauma, n=11), correction of recurrent laryngeal neuropathy by laryngoplasty and ventriculectomy (intermediate surgical trauma, n=10) or removal of an ovarian tumor by laparotomy (major surgical trauma, n=5). METHODS Horses had a thorough clinical examination every day. White blood cell (WBC) counts and concentrations of serum amyloid A (SAA), fibrinogen, and iron were assessed in blood samples obtained before, and 1-3, 5, 7, 9, and 11 days after surgery. Differences in levels of the inflammatory markers between the 3 surgical groups were analyzed using repeated measures ANOVA. RESULTS Postoperative concentrations of SAA and fibrinogen were significantly higher in horses that had laparotomy and ovariectomy than in horses that had laryngoplasty and ventriculectomy, or arthroscopy. Iron concentrations decreased to lower levels after intermediate and major surgical trauma than after small surgical trauma. WBC count did not differ between the 3 groups. CONCLUSIONS Levels of SAA, fibrinogen, and iron reflected the intensity of the surgical trauma, whereas WBC count did not. CLINICAL RELEVANCE Postoperative measurements of SAA, fibrinogen, and iron may be useful for comparing surgical trauma associated with new and established surgical techniques. Moreover, knowledge of the normal postoperative acute phase response is essential, if acute phase reactants are to be used for monitoring occurrence of postoperative infections.

Is the Relationship Between BMI and Mortality Increasingly U-Shaped With Advancing Age? A 10-Year Follow-up of Persons Aged 70–95 Years

BACKGROUND In the call for papers (Alley DE, Ferrucci L, Barbagallo M, Studenski SA, Harris TB. A research agenda: the changing relationship between body weight and health in aging. J Gerontol A Biol Sci Med Sci. 2008;63(11):1257-1259.), it is assumed that the association between body mass index (BMI [kilogram per square meter]) and mortality becomes increasingly U-shaped with advancing age. The aim of this study is to examine the association between BMI and mortality and to test whether the association is changing with advancing age for persons aged 70-95 years in Denmark. METHODS The study populations comprised two surveys: the Longitudinal Study of Aging of Danish Twins (LSADT) and the Danish 1905 Cohort Survey. From 1995 to 1999, 4253 individuals aged 70-95 years from the LSADT were interviewed at home. In 1998, 2,262 individuals aged 92-93 years from the 1905 Cohort were interviewed at home. The information in both surveys included self-reported weight and height. With virtually no loss to follow-up, survival was assessed through a 10-year follow-up period, during which 4,664 (72%) of the persons died. RESULTS The association between BMI and mortality is changing with advancing age for people aged 70-95 years. There was a significant decrease in the association between mortality and low BMI with advancing age for both genders (p < or = .03). There was also a tendency for the association between mortality and high BMI to decrease with advancing age for males (p = .06). CONCLUSION In a large contemporary Danish population-based sample, the association of BMI and mortality became decreasingly U-shaped with advancing age for the age range 70-95 years.

Instrumental variable estimation in a survival context

Bias due to unobserved confounding can seldom be ruled out with certainty when estimating the causal effect of a nonrandomized treatment. The instrumental variable (IV) design offers, under certain assumptions, the opportunity to tame confounding bias, without directly observing all confounders. The IV approach is very well developed in the context of linear regression and also for certain generalized linear models with a nonlinear link function. However, IV methods are not as well developed for regression analysis with a censored survival outcome. In this article, we develop the IV approach for regression analysis in a survival context, primarily under an additive hazards model, for which we describe 2 simple methods for estimating causal effects. The first method is a straightforward 2-stage regression approach analogous to 2-stage least squares commonly used for IV analysis in linear regression. In this approach, the fitted value from a first-stage regression of the exposure on the IV is entered in place of the exposure in the second-stage hazard model to recover a valid estimate of the treatment effect of interest. The second method is a so-called control function approach, which entails adding to the additive hazards outcome model, the residual from a first-stage regression of the exposure on the IV. Formal conditions are given justifying each strategy, and the methods are illustrated in a novel application to a Mendelian randomization study to evaluate the effect of diabetes on mortality using data from the Health and Retirement Study. We also establish that analogous strategies can also be used under a proportional hazards model specification, provided the outcome is rare over the entire follow-up.

Increased effect of the ApoE gene on survival at advanced age in healthy and long-lived Danes: two nationwide cohort studies.

Studies of Nordic twins suggest an increased genetic influence on mortality with age. Contrary to this, the heterogeneity hypothesis predicts that the mortality of individuals carrying a ‘frail’ or ‘risky’ genotype in a population will approach that of noncarriers with age because of selection pressure. The ApoE ε4 allele is associated with an increased mortality risk, and its effect has been suggested to decrease with age. Here, we investigated the effect of ApoE ε4 allele on survival in a sample of the healthiest and long‐lived Danes. The study population comprised Danes born in 1905 and a replicate sample of the 1895 cohort. For the 1905 cohort, a total of 350 carriers and 1256 noncarriers of the ApoE ε4 allele were followed from 1998 until death or end of follow‐up. Cox regression models were used for the analysis. Of the 1606 persons with known ApoE ε4 status in 1998, 1546 had died at the end of the 10‐year follow‐up. Carriers of the ApoE ε4 allele had an increased mortality compared to noncarriers, and the influence of ApoE status on mortality increased in the age interval 92–103. For the covariates sex and independency status, the difference in relative risk of death between groups decreased with advancing age. Our findings of increasing influence of ApoE ε4 allele on mortality with age do not support previous findings of decreased influence ApoE ε4 allele on mortality with age, and alternative models such as the multifactorial threshold models should be considered for understanding the genetic effects on mortality at advanced age.

Cereulide formation by Bacillus weihenstephanensis and mesophilic emetic Bacillus cereus at temperature abuse depends on pre-incubation conditions.

Emetic toxin (cereulide) formation was recently identified in a psychrotolerant species, Bacillus weihenstephanensis [Thorsen, L., Hansen, B.M., Nielsen, K.F., Hendriksen, N.B., Phipps, R.K., Budde, B.B., 2006. Characterization of emetic Bacillus weihenstephanensisis, a new cereulide-producing bacterium. Applied and Environmental Microbiology, 72, 5118-5121.]. Although recent findings indicated B. weihenstephanensis as a cereulide producer only limited information is available regarding environmental conditions affecting cereulide production. In the present study a model agar system was used to compare cereulide production during surface growth of B. weihenstephanensis MC67, and two well known mesophilic cereulide producing Bacillus cereus strains, NC7401 and NS117. Cereulide production was quantified by use of Liquid-Chromatography Mass Spectrometry/Mass Spectrometry. Cereulide production of B. weihenstephanensis MC67 occurred in stationary growth phase, as previously observed for B. cereus, and biomass formation and cereulide formation showed a linear correlation. During incubation at 5 degrees C for 1, 2 and 3 weeks growth was inhibited and as a consequence no detectable cereulide production occurred for any of the three strains. Similar results were obtained for the mesophilic B. cereus strains when incubated at 8 degrees C, whereas B. weihenstephanensis MC67 grew to stationary phase and produced 0.002 microg cereulide/cm(2) agar surface in 1 week. Raising the temperature from 5 degrees C to 25 degrees C for 24 h after 1 week of incubation resulted in growth to stationary phase and production of variable levels of cereulide. B. weihenstephanensis MC67 produced 6.18 microg cereulide/cm(2), B. cereus NS117 0.91 microg cereulide/cm(2) and B. cereus NC7401 0.09 microg cereulide/cm(2). Similar levels of cereulide was produced by the mesophilic strains when raising the temperature from 8 degrees C (instead of from 5 degrees C) to 25 degrees C for 24 h, while a considerably lower level was produced by B. weihenstephanensis MC67 (0.10 microg cereulide /cm(2)). If the temperature was raised from 5 degrees C and 8 degrees C to 25 degrees C for 24 h after an increased incubation time for 2 and 3 weeks, all three strains produced considerably less cereulide. B. weihenstephanensis MC67 produced 100-6000 times less and the mesophilic B. cereus strains produced 9-40 times less cereulide. These results can partly be explained by differences in the growth at the temperature abuse. Effect of chill storage on cereulide production at temperature abuse has not been investigated previously. Results of the present study indicate that storage at 5 and 8 degrees C will not lead to emetic intoxications, however the time at, and choice of chill temperature will determine the amount of cereulide produced in a temperature abuse situation. These results are of relevance for the safety of chilled foods of extended durability.

Diabetes is a strong predictor of mortality during tuberculosis treatment: a prospective cohort study among tuberculosis patients from Mwanza, Tanzania

Strong evidence suggests diabetes may be associated with tuberculosis (TB) and could influence TB treatment outcomes. We assessed the role of diabetes on sputum culture conversion and mortality among patients undergoing TB treatment.

Cox Regression with Incomplete Covariate Measurements using the EM-algorithm

Ibrahim (1990) used the EM‐algorithm to obtain maximum likelihood estimates of the regression parameters in generalized linear models with partially missing covariates. The technique was termed EM by the method of weights. In this paper, we generalize this technique to Cox regression analysis with missing values in the covariates. We specify a full model letting the unobserved covariate values be random and then maximize the observed likelihood. The asymptotic covariance matrix is estimated by the inverse information matrix. The missing data are allowed to be missing at random but also the non‐ignorable non‐response situation may in principle be considered. Simulation studies indicate that the proposed method is more efficient than the method suggested by Paik & Tsai (1997). We apply the procedure to a clinical trials example with six covariates with three of them having missing values.