Protocol: inspiratory muscle training for promoting recovery and outcomes in ventilated patients (IMPROVe): a randomised controlled trial

Introduction: Inspiratory muscle weakness is a known consequence of mechanical ventilation and a potential contributor to difficulty in weaning from ventilatory support. Inspiratory muscle training (IMT) reduces the weaning period and increases the likelihood of successful weaning in some patients. However, it is not known how this training affects the residual inspiratory muscle fatigability following successful weaning nor patients' quality of life or functional outcomes. Methods and analysis: This dual centre study includes two concurrent randomised controlled trials of IMT in adult patients who are either currently ventilator-dependent (>7 days) (n=70) or have been recently weaned from mechanical ventilation (>7 days) in the past week (n=70). Subjects will be stable, alert and able to actively participate and provide consent. There will be concealed allocation to either treatment (IMT) or usual physiotherapy (including deep breathing exercises without a resistance device). Primary outcomes are inspiratory muscle fatigue resistance and maximum inspiratory pressures. Secondary outcomes are quality of life (Short Form-36v2, EQ-5D), functional status (Acute Care Index of Function), rate of perceived exertion (Borg Scale), intensive care length of stay (days), post intensive care length of stay (days), rate of reintubation (%) and duration of ventilation (days). Ethics and dissemination: Ethics approval has been obtained from relevant institutions, and results will be published with a view to influencing physiotherapy practice in the management of long-term ventilator-dependent patients to accelerate weaning and optimise rehabilitation outcomes

A Comparison of Miltefosine and Sodium Stibogluconate for Treatment of Visceral Leishmaniasis in an Ethiopian Population with High Prevalence of HIV Infection.

BACKGROUND: Antimonials are the mainstay of visceral leishmaniasis (VL) treatment in Africa. The increasing incidence of human immunodeficiency virus (HIV) coinfection requires alternative safe and effective drug regimens. Oral miltefosine has been proven to be safe and effective in the treatment of Indian VL but has not been studied in Africa or in persons with HIV and VL coinfection. METHODS: We compared the efficacy of miltefosine and sodium stibogluconate (SSG) in the treatment of VL in persons in Ethiopia. A total of 580 men with parasitologically and/or serologically confirmed VL were randomized to receive either oral miltefosine (100 mg per day for 28 days) or intramuscular SSG (20 mg/kg per day for 30 days). RESULTS: The initial cure rate was 88% in both treatment groups. Mortality during treatment was 2% in the miltefosine group, compared with 10% in the SSG group. Initial treatment failure was 8% in the miltefosine group, compared with 1% in the SSG group. Among the 375 patients (65%) who agreed to HIV testing, HIV seroprevalence was 29%. Among patients not infected with HIV, initial cure, mortality, and initial treatment failure rates were not significantly different (94% vs. 95%, 1% vs. 3%, and 5% vs. 1% for the miltefosine and SSG groups, respectively). Initial treatment failure with miltefosine occurred in 18% of HIV-coinfected patients, compared with treatment failure in 5% of non-HIV-infected patients. At 6 months after treatment, 174 (60%) of the 290 miltefosine recipients and 189 (65%) of the 290 SSG recipients experienced cure; 30 (10%) of 290 in the miltefosine group and 7 (2%) of 290 in the SSG group experienced relapse, and the mortality rate was 6% in the miltefosine group, compared with 12% in the SSG group. HIV-infected patients had higher rates of relapse (16 [25%] of 63 patients), compared with non-HIV-infected patients (5 [5%] of 131). CONCLUSIONS: Treatment with miltefosine is equally effective as standard SSG treatment in non-HIV-infected men with VL. Among HIV-coinfected patients, miltefosine is safer but less effective than SSG

Stimulation programs for pediatric drug research – do children really benefit?

Most drugs that are currently prescribed in pediatrics have not been tested in children. Pediatric drug studies are stimulated in the USA by the pediatric exclusivity provision under the Food and Drug Administration Modernization Act (FDAMA) that grants patent extensions when pediatric labeling is provided. We investigated the effectiveness of these programs in stimulating drug research in children, thereby increasing the evidence for safe and effective drug use in the pediatric population. All drugs granted pediatric exclusivity under the FDAMA were analyzed by studying the relevant summaries of medical and clinical pharmacology reviews of the pediatric studies or, if these were unavailable, the labeling information as provided by the manufacturer. A systematic search of the literature was performed to identify drug utilization patterns in children. From July 1998 to August 2006, 135 drug entities were granted pediatric exclusivity. Most frequent drug groups were anti-depressants and mood stabilizers, ACE inhibitors, lipid-lowering preparations, HIV antivirals, and non-steroidal anti-inflammatory and anti-rheumatic drugs. The distribution of the different drugs closely matched the distribution of these drugs over the adult market, and not the drug utilization by children

Immunological Change in a Parasite-Impoverished Environment: Divergent Signals from Four Island Taxa

Dramatic declines of native Hawaiian avifauna due to the human-mediated emergence of avian malaria and pox prompted an examination of whether island taxa share a common altered immunological signature, potentially driven by reduced genetic diversity and reduced exposure to parasites. We tested this hypothesis by characterizing parasite prevalence, genetic diversity and three measures of immune response in two recently-introduced species (Neochmia temporalis and Zosterops lateralis) and two island endemics (Acrocephalus aequinoctialis and A. rimitarae) and then comparing the results to those observed in closely-related mainland counterparts. The prevalence of blood parasites was significantly lower in 3 of 4 island taxa, due in part to the absence of certain parasite lineages represented in mainland populations. Indices of genetic diversity were unchanged in the island population of N. temporalis; however, allelic richness was significantly lower in the island population of Z. lateralis while both allelic richness and heterozygosity were significantly reduced in the two island-endemic species examined. Although parasite prevalence and genetic diversity generally conformed to expectations for an island system, we did not find evidence for a pattern of uniformly altered immune responses in island taxa, even amongst endemic taxa with the longest residence times. The island population of Z. lateralis exhibited a significantly reduced inflammatory cell-mediated response while levels of natural antibodies remained unchanged for this and the other recently introduced island taxon. In contrast, the island endemic A. rimitarae exhibited a significantly increased inflammatory response as well as higher levels of natural antibodies and complement. These measures were unchanged or lower in A. aequinoctialis. We suggest that small differences in the pathogenic landscape and the stochastic history of mutation and genetic drift are likely to be important in shaping the unique immunological profiles of small isolated populations. Consequently, predicting the impact of introduced disease on the many other endemic faunas of the remote Pacific will remain a challenge

Carbon dioxide and oxygen partial pressure measurements in the cerebrospinal fluid in a conventional blood gas analyzer: analysis of bias and precision

Cerebrospinal fluid (CSF) gas tension measurements have been used as a marker of cerebral oxygenation in animal models and in human studies. Discrepancies in the measurement of PCO2 and PO2 in non-blood solutions by standard blood gas analyzers have been described. The CSF is a physiological non-blood fluid with an ability to carry only dissolved O-2 or- CO2. The aim of this experiment was to determine the bias and precision of CSF pCO(2) and pO(2) measurements of a contemporary blood gas analyzer and a continuous gas sensor. CSF from human patients was tonometered to known PCO2 and PO2 using standard calibration gases in a bubble tonometer. Following equilibration, a continuous measurement of the partial pressure of gases in the CSF in the tonometer solution was made using a calibrated Paratrend 7 gas sensor (Biomedical Sensors, Bucks., UK) inserted into the equilibration chamber of the tonometer and continuous CSF pH, PCO2 and PO2 measurements recorded at I-min intervals. After equilibration, a 3-ml CSF sample was aspirated anaerobically from the tonometer and analysed in duplicate using an ABL 620 (Radiometer, Copenhagen) blood gas analyser. The measured pCO(2) and pO(2) from the ABL 620 blood gas analyser and the Paratrend 7 sensor were paired with the expected values to calculate bias and precision. Small offsets in PCO2 and large offsets in PO2 measurement were seen with the ABL 620 blood gas analyser. This study brings into question clinical decisions based on CSF PO2 measurements. The implications for calibrating CSF sensors against CSF gas measurements are discussed. (C) 1997 Elsevier Science B.V

ARC - Augmented renal clearance

In-hospital and intensive care unit mortality rates for sepsis remain un-acceptably high, and have prompted the publication of international guidelines on best practice. Crucial to this is the application of early appropriate antibacterial therapy, in the correct dose. However, antibacterial regimes in this setting have largely been extrapolated from those in healthy volunteers, and fail to consider the unique pathophysiology and treatment provided to this population. As such, augmented renal clearance (ARC) - the enhanced renal elimination of circulating solute - is likely to be one of the more common physiological changes encountered in this setting, although to date remains largely under-appreciated. Significantly this may alter the pharmacokinetics of many routinely prescribed agents in this setting, pre-disposing to sub-therapeutic levels or treatment failure. This review paper examines this phenomenon in detail, providing a summary of the likely underlying mechanisms, those patients at greatest risk, and the implications for antibacterial dosing in the critically ill