Improving the immediate management of neutropenic sepsis in the UK: lessons from a national audit

Recent disquiet at inadequacies in the immediate management of neutropenic sepsis in the UK led to a new, gold standard 'door-to-needle' time of 1 h for the administration of intravenous antibiotics. The aim of this audit was to identify whether that target is being met nationally, the potential barriers to its achievement, and concrete recommendations for how to overcome these. We also sought to establish the degree of regional heterogeneity in current local management protocols. Questionnaires were sent to haematologists across the UK to determine their unit's immediate management of patients presenting from the community with possible neutropenic sepsis. Local protocols and audits were also requested. Data covering 95 different hospitals were received, covering a combined catchment area of nearly 30 million people. There were marked regional inconsistencies in the definition of 'neutropenic sepsis' and almost every aspect of its immediate management. Only 26% of audited patients (n=627) received intravenous antibiotics within the target time of 1 h. Median door-to-needle times ranged from 30 min to 4 h. Long delays of over 5 h were not uncommon.     

Guidelines for supportive care in multiple myeloma 2011

Supportive care plays an increasingly important role in the modern management of multiple myeloma. While modern treatments have significantly prolonged overall and progression free survival through improved disease control, the vast majority of patients remain incurable, and live with the burden of the disease itself and the cumulative side effects of treatments. Maintenance of quality of life presents challenges at all stages of the disease from diagnosis through the multiple phases of active treatment to the end of life. Written on behalf of the British Committee for Standards in Haematology (BCSH) and the UK Myeloma Forum (UKMF), these evidence based guidelines summarize the current national consensus for supportive and symptomatic care in multiple myeloma in the following areas; pain management, peripheral neuropathy, skeletal complications, infection, anaemia, haemostasis and thrombosis, sedation, fatigue, nausea, vomiting, anorexia, constipation, diarrhoea, mucositis, bisphosphonate-induced osteonecrosis of the jaw, complementary therapies, holistic needs assessment and end of life care. Although most aspects of supportive care can be supervised by haematology teams primarily responsible for patients with multiple myeloma, multidisciplinary collaboration involving specialists in palliative medicine, pain management, radiotherapy and surgical specialities is essential, and guidance is provided for appropriate interdisciplinary referral. These guidelines should be read in conjunction with the BCSH/UKMF Guidelines for the Diagnosis and Management of Multiple Myeloma 2011.     

The critical role of kinase activity of interleukin‐1 receptor–associated kinase 4 in animal models of joint inflammation

Objective

We have previously reported that the kinase activity of interleukin‐1 receptor–associated kinase 4 (IRAK‐4) is important for Toll‐like receptor and interleukin‐1 receptor signaling in vitro. Using mice devoid of IRAK‐4 kinase activity (IRAK‐4 KD mice), we undertook this study to determine the importance of IRAK‐4 kinase function in complex disease models of joint inflammation.

Methods

IRAK‐4 KD mice were subjected to serum transfer–induced (K/BxN) arthritis, and migration of transferred spleen lymphocytes into joints and cartilage and bone degradation were assessed. T cell response in vivo was tested in antigen‐induced arthritis (AIA) by measuring the T cell–dependent antigen‐specific IgG production and frequency of antigen‐specific T cells in the spleen and lymph nodes. T cell allogeneic response was tested in vitro by mixed lymphocyte reaction (MLR).

Results

Lipopolysaccharide‐induced local neutrophil influx into subcutaneous air pouches was impaired in IRAK‐4 KD mice. These mice were also protected from inflammation in the K/BxN and AIA models, as shown by reduced swelling of joints. Histologic analysis of joints of K/BxN serum–injected mice revealed that bone erosion, osteoclast formation, and cartilage matrix proteoglycan loss were reduced in IRAK‐4 KD mice. Assessment of T cell response by MLR, by frequency of antigen‐specific clones, and by production of antigen‐specific IgG did not reveal substantial differences between IRAK‐4 KD and wild‐type mice.

Conclusion

These results demonstrate that IRAK‐4 is a key component for the development of proarthritis inflammation, but that it is not crucial for T cell activation. Therefore, the kinase function of IRAK‐4 appears to be an attractive therapeutic target in chronic inflammation.

     

Using the BOLD MR signal to differentiate the stereoisomers of ketamine in the rat

RATIONALE: Ketamine is a chiral molecule that is reported to model aspects of schizophrenia. OBJECTIVES: To investigate the stereospecificity of the isomers of ketamine using pharmacological magnetic resonance imaging (phMRI) in order to further understand ketamine's pharmacodynamic actions. METHOD: Responses to 25 mg kg-1S(+) isomer, R(-) isomer and racemic ketamine in independent groups of Sprague-Dawley rats were investigated using a prepulse inhibition paradigm, locomotor observations, MRI and 2-deoxyglucose techniques. RESULTS: Racemic ketamine and the S(+) isomer were both capable of disrupting sensorimotor gating as measured using prepulse inhibition and produced a longer period of hyperlocomotion comparative to the R(-) isomer. In contrast, large alterations in the BOLD MR signal were observed with R(-) isomer, whereas S(+) isomer and racemate precipitated more localized BOLD signal changes predominantly in cortical, hippocampal and hindbrain regions. Glucose utilization rates in conscious animals are in agreement with previously published data and verify the BOLD responses in the racemic group. However, no significant changes in glucose utilization were observed in the anesthetized cohort. CONCLUSIONS: Ketamine and its isomers have stereospecific effects on sensorimotor gating and locomotion that correlate with the enantiomer's affinity for the NMDA receptor. It would appear that anesthesia, as required for preclinical MRI procedures, may interact with and potentially attenuate the drug's response. Although analysis of the main effect of isomers in comparison to each other or the racemate offers an alternative analysis method that should be less susceptible to anesthetic interactions, only the R(-) isomer comparative to the racemate offers significant differences of interest.     

Nutrition in patients with cystic fibrosis: a European Consensus.

This document is the result of an European Consensus conference which took place in Artimino, Tuscany, Italy, in March 2001 involving 33 experts on nutrition in patients with cystic fibrosis, organised by the European Cystic Fibrosis Society, and sponsored by Axcan-Scandipharm, Baxter, Dr Falk Pharma, Fresenius, Nutricia, SHS International, Solvay Pharmaceuticals (major sponsor). The purpose of the conference was to develop a consensus document on nutrition in patients with cystic fibrosis based on current evidence.     

The effect of the intrathoracic pressure regulator on hemodynamics and cardiac output

The intrathoracic pressure regulator (ITPR) (CirQLator; Advanced Circulatory Systems Inc, Roseville, Minn) is a novel, noninvasive device intended to increase cardiac output and blood pressure in hypovolemic or cardiogenic shock by generating a continuous low-level intrathoracic vacuum in between positive pressure ventilations. Although there are robust data supporting the benefit of the ITPR in multiple animal models of shock, the device has not been used in humans.The goals of this study were to evaluate both the safety and efficacy of the ITPR in humans. Twenty patients undergoing coronary artery bypass graft surgery were enrolled in this phase 1 study. Intraoperative use of both pulmonary artery pressure monitoring and transesophageal echocardiography (TEE) was required for study inclusion. Hemodynamic variables as well as TEE measurements of left ventricular performance were collected at baseline and after the ITPR device was activated, before surgical incision. Thermodilution cardiac output increased significantly with the application of the ITPR (4.9 vs. 5.5 L/min; P = 0.017). Similarly, cardiac output was measured by TEE (5.1 vs. 5.7 L/min; P = 0.001).There were significant increases in pulmonary artery systolic blood pressures (35 vs. 38 mmHg; P G 0.001) and mean pulmonary artery pressures (24 vs. 26 mmHg; P = 0.008). There were no significant differences in systemic blood pressures, left ventricular volumes, stroke volume, or ejection fraction as measured by TEE. Using two different measurement techniques, application of the ITPR increased cardiac output in normovolemic anesthetized patients who underwent coronary artery bypass graft before sternotomy. These data suggest that the ITPR has the potential to safely and effectively increase cardiac output in humans.     

The RCT means nothing to me!

Research is a cornerstone of evidence based practice with the randomised controlled trial (RCT) regarded as the ‘gold standard’ for evaluating the effectiveness of interventions. However, it is not uncommon for RCT’s to arrive at conflicting conclusions. This conflict might be explained by the quality of the different studies and their inherent risk of bias. Despite this, discussion and debate around methodological issues is limited in physiotherapy specific journals. It is important that clinicians are aware of the inherent risk of bias within studies and what this means for their practice. Hence, this paper presents a clinically focused methodological discussion with the intention of offering a platform upon which readers can develop their understanding of meaningful critical appraisal and hence gain confidence when reading and appraising published RCT’s.     

Red wine contains a potent inhibitor of phenolsulphotransferase.

Many ethanolic drinks, especially red wine, contain potent inhibitors of phenolsulphotransferase. At a dilution of 1/75 from the original beverage, extracts from six types of red wine inhibited human platelet phenolsulphotransferase P by a mean of 99% and human platelet phenolsulphotransferase M by 12%. Such extracts had no significant effect on rat liver monoamine oxidase A or human platelet monoamine oxidase B. The inhibitors, which have not yet been identified, can be extracted into ethyl acetate at acid or neutral pH. Thus, they are not monoamines. Flavonoid phenols are plausible candidates. As phenolsulphotransferase M and P are involved in the metabolism of many phenols, including drugs, the inhibition of these enzymes could result in the enhancement of pharmacological potency and have important clinical consequences.