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Context: Tracheotomy is used to replace endotracheal intubation in patients requiring prolonged ventilation; however, there is considerable variability in the time considered optimal for performing tracheotomy. This is of clinical importance because timing is a key criterion for performing a tracheotomy and patients who receive one require a large amount of health care resources. Objective: To determine the effectiveness of early tracheotomy (after 6-8 days of laryngeal intubation) compared with late tracheotomy (after 13-15 days of laryngeal intubation) in reducing the incidence of pneumonia and increasing the number of ventilator-free and intensive care unit (ICU)-free days. Design, Setting, and Patients: Randomized controlled trial performed in 12 Italian ICUs from June 2004 to June 2008 of 600 adult patients enrolled without lung infection, who had been ventilated for 24 hours, had a Simplified Acute Physiology Score II between 35 and 65, and had a sequential organ failure assessment score of 5 or greater. Intervention: Patients who had worsening of respiratory conditions, unchanged or worse sequential organ failure assessment score, and no pneumonia 48 hours after inclusion were randomized to early tracheotomy (n=209; 145 received tracheotomy) or late tracheotomy (n=210; 119 received tracheotomy). Main Outcome Measures: The primary endpoint was incidence of ventilator-associated pneumonia; secondary endpoints during the 28 days immediately following randomization were number of ventilator-free days, number of ICU-free days, and number of patients in each group who were still alive. Results: Ventilator-associated pneumonia was observed in 30 patients in the early tracheotomy group (14%; 95% confidence interval [CI], 10%-19%) and in 44 patients in the late tracheotomy group (21%; 95% CI, 15%-26%) (P=.07). During the 28 days immediately following randomization, the hazard ratio of developing ventilator-associated pneumonia was 0.66 (95% CI, 0.42-1.04), remaining connected to the ventilator was 0.70 (95% CI, 0.56-0.87), remaining in the ICU was 0.73 (95% CI, 0.55-0.97), and dying was 0.80 (95% CI, 0.56-1.15). Conclusion: Among mechanically ventilated adult ICU patients, early tracheotomy compared with late tracheotomy did not result in statistically significant improvement in incidence of ventilator-associated pneumonia. Trial Registration: clinicaltrials.gov Identifier: NCT00262431. ©2010 American Medical Association. All rights reserved.

This paper describes an automated method for extracting the apparent positions of fiducial points from 2D or 3D images of a phantom. We consider a 3D-lattice phantom for two main reasons: first, ease of manufacture and isotropy of its structure with respect to coordinate projections; second, a connected structure allowing to uniquely assess the adjacency relationship between fiducial points even if geometric distortions arising from main magnet inhomogeneity and gradient fields non-linearity is severe as observed in open-bore systems. In order to validate our proposed method and compare different choices for the parameters of our phantom (i.e. number and distance between grids and thickness of its branches) we developed in-house a software for simulating 2D or 3D volume images of the phantom, using customizable MRI sequence parameters and Spherical Harmonic Coefficients for the fields. We deem worthy of note that using simulated images is the only way to evaluate the estimated position error, since it allows to compare the estimates to their theoretical counterparts. Furthermore, the use of simulated images allows to evaluate the robustness of the method with respect to image quality in terms of Signal-to-Noise Ratios and geometric distortion, and allows to evaluate different phantom geometries without having to manufacture them. The proposed method can be easily extended to phantoms having an arbitrary overall shape, as long as it is a fully connected structure. Specifically, it is easy to design a phantom with fiducial points laying outside of the homogeneity sphere, so that indirect measurement of the fields becomes possible, for example by using the recent method proposed by Acquaviva et al. To the best of our knowledge, the proposed method outperforms other state-of-the-art methods, with an average positioning offset of 0.052 mm (with a 0.99 quantile of 0.12 mm) when working on images featuring a differential Signal-to-Noise Ratio within Region-of-Interest (ROI) equal to 105 (20.2 dB) and a ROI-to-background SNR of 20 dB. Estimating the positions of 6859 fiducial points in a volume, our highest density case, was carried out in less than 30 min on a desktop personal computer.

Activation of Toll-like receptors (TLR) seems to be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). Upon TLR activation the release of defensins, including human beta defensin 2 (HBD-2), may occur. In this study, we explored the innate responses in patients with respiratory failure, with and without COPD, requiring intubation and mechanical ventilation. Mini-bronchoalveolar lavage (mini-BAL) samples were collected from nonsmoker subjects without COPD (n = 10), smokers without COPD (n = 6), and smokers with COPD (n = 15). TLR4, TLR2, and HBD-2 expression was evaluated by immunocytochemistry; interleukin (IL)-8, IP-10, and HBD-2 concentrations were evaluated by enzyme-linked immunosorbent assay; chemotactic activity toward neutrophils and lymphocytes; and cell apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling [TUNEL] and by flow cytometry with anti-TLR4 and with HBD-2 depleted and not depleted mini-BAL). COPD mini-BAL showed increased neutrophil numbers, reduced neutrophil apoptosis, increased TLR4 and HBD-2 expression, increased neutrophil chemotactic activity, reduced IP-10 concentrations, and reduced lymphocyte chemotactic activity compared with those in nonsmoker subjects without COPD. In the smokers without COPD the mini-BAL showed reduced TLR4 and HBD-2 expression, higher IP-10 concentrations, and higher chemotactic activity than in patients with COPD. The blocking of TLR4 activation and HBD-2 depletion increased neutrophil apoptosis. No differences were observed for TLR2 expression and IL-8 concentrations. This study strengthens the contribution of TLR4 to promoting airway neutrophilia in COPD.

The use of supplemental doses of opioids is commonly suggested to manage breakthrough pain. A comparative study of intravenous morphine (IV-MO) and oral transmucosal fentanyl citrate (OTFC) given in doses proportional to the basal opioid regimen was performed in 25 cancer patients receiving stable opioid doses. For each episode, when it occurred and 15 and 30 min after the treatment, pain intensity and opioid-related symptoms were recorded. Fifty-three couples of breakthrough events, each treated with IV-MO and OTFC, were recorded. In episodes treated with IV-MO, pain intensity decreased from a mean of 6.9 to 3.3 and to 1.7 at T1 and T2, respectively. In episodes treated with OTFC, pain intensity decreased from a mean of 6.9 to 4.1 and to 2.4 at T1 and T2, respectively. Statistical differences between the two treatments were found at T1 (P=0.013), but not at T2 (P=0.059). Adverse effects were comparable and were not significantly related with the IV-MO and OTFC doses. Intravenous morphine and OTFC in doses proportional to the scheduled daily dose of opioids were both safe and effective, IV-MO having a shorter onset than OTFC. Future comparative studies with appropriate design should compare titration methods and proportional methods of OTFC dosing.

This randomized controlled study evaluated the role of corticosteroids as adjuvants to opioid therapy in 76 advanced cancer patients with pain who requiring strong opioids. Patients were divided in 2 groups. Group O received conventional opioid treatment. Group OS received dexamethasone (8 mg orally) along with conventional treatment. Pain and symptom intensity, sense of well-being, and opioid escalation index and distress score were recorded at weekly intervals until death. No differences in pain intensity, opioid consumption, and opioid escalation index were found in 66 patients who survived 33 to 37 days. Corticosteroids did not provide significant additional analgesia to opioids, but persistently decreased opioid-related gastrointestinal symptoms for the patients with limited survival and improved the sense of well-being for some weeks. Corticosteroidrelated toxicity was minimal. Further studies with an increased sample size are necessary to detect any minimal difference in analgesia between the two groups.

OBJECTIVES: To determine the efficacy and safety of different opioids used in doses proportional to the basal opioid regimen for the management of breakthrough pain (BP). METHODS: In 66 patients consecutive patients admitted to a pain relief and palliative care unit, the efficacy and safety of different opioids used in doses proportional to the basal opioid regimen for the management of breakthrough pain (BP) were assessed. The choice of the opioid to be administered as rescue medication was based on the characteristics of patients, clinical stability, compliance, preference, and so on. For each episode, nurses were instructed to routinely collect changes in pain intensity and emerging problems when pain became severe (T0), and to re-assess the patient 15 minutes after the opioid given as a rescue medication (T15). RESULTS: Six hundred twenty four episodes of BP were recorded during admission. Intravenous morphine (IV-MO) and oral transmucosal fentanyl (OTFC) were most frequently administered. Of 503 events available, 427 episodes were defined as successfully treated, while 76 episodes required a further administration of opioids. Pain intensity significantly decreased at T15 in all the groups (P

Neuropathic pain (NP) is a difficult issue, particularly in cancer which is a dynamic condition where multiple pain etiologies are concomitantly present. Cancer pain is often labeled as mixed mechanism pain and is not easily classified as exclusively nociceptive or NP. The aim of this study was to explore the value of evaluation tools such as Neuropathic Pain Questionnaire (NPQ), complete and short form (NPQ-SF), Leeds Assessment of Neuropathic Signs and Symptoms (LANSS) and Neuropathic Pain Symptom Inventory (NPSI). The secondary outcome was to evaluate the response to opioid titration, according to the hierarchical classification of definite, possible and unlikely NP. A consecutive sample of patients referred for treatment of cancer-related pain were eligible for participation in the study. The inclusion criterion was uncontrolled cancer pain requiring adjustment of opioid therapy. Patients were clinically classified into tertiles based according to graded evidence of nervous system lesion: definite NP, possible NP, or unlikely NP. Pain and symptoms intensities were measured before (T0) and at the end of opioid titration (T1). Patients were titrated with escalating doses of opioids, supported by symptomatic drugs, changing the route of administration, or by opioid switching according to the clinical response. At T1 the opioid response was clinically graded from 1 to 4. Opioid escalation index was calculated. A single independent investigator, blinded to the clinical assessment and treatment, collected data from NPQ, NPQ-SF, LANSS Pain Scale, and NPSI. One hundred and sixty-seven patients concluded the study. Sixty, thirty-six, and seventy-one patients were clinically assessed as having definite NP, possible NP, or unlikely NP, respectively. A relationship between the values of the assessment tools and clinician rating was found. Patients with the highest values of assessment tools were also more likely to be clinically labeled as definite NP, although sensibility and specificity were low. Patients with a clinical diagnosis of definite NP, possible NP, or unlikely NP showed significant differences in opioid response (P.0005). Patients with "unlikely NP" had a lower pain intensity at T1 (P.05), and patients with "definite NP" required more intensive treatment. Patients requiring more aggressive treatment showed significantly higher values of Opioid Escalation Index (OEI)mg.Screening tools may provide a basis to suggest a common language in cancer pain syndromes. A hierarchical grouping seems to be more flexible and fits cancer patient characteristics. This study also confirms that opioids are clinically effective in "definite NP" conditions although a more aggressive treatment requiring careful utilization of opioids and symptomatic drugs is strictly necessary.

The aim of this article is to describe the clinical activity and medical intervention of an acute model of palliative care unit (APC), as well as the reimbursement procedures and economic viability. A sample of 504 patients admitted at an APC in 1 year was surveyed. Indications for admission, pain and symptom intensity, analgesic treatments, procedures, instrumental examinations and modalities of discharge were recorded. For each patient, tariff for reimbursement was calculated according to the existent disease related grouping (DRG) system. The mean age was 62 years, and 246 patients were males. The mean hospital stay was 5.4 days. Pain control was the most frequent indication for admission. All patients had laboratory tests and several instrumental examinations. Almost all patients were prescribed one or more opioids at significant doses, and different routes of administration, as well as medication as needed. 59 patients received blood cell transfusions and 34 interventional procedures. Only 40 patients died in the unit, 11 of them being sedated at the end of life. Treatment efficacy was considered optimal and mild in 264 and 226 patients respectively. A mean of 3019 euros for admission was reimbursed by the Health Care System. APCs are of paramount importance within an oncological department, as they provide effective and intensive treatments during the entire course of disease, providing a simultaneous and integrated approach. Our findings also suggest both a cost and quality incentive for oncological departments to develop APC.

The aim of this study was to compare the analgesic and adverse effects, doses, as well as cost of opioid drugs, supportive drug therapy and other analgesic drugs in patients treated with oral sustained-release morphine, transdermal fentanyl, and oral methadone.One hundred and eight cancer patients, no longer responsive to opioids for moderate pain, were selected to randomly receive initial daily doses of 60 mg of oral sustained-release morphine, 15 mg of oral methadone, or 0.6 mg (25 microg/h) of transdermal fentanyl. Oral morphine was used as breakthrough pain medication during opioid titration. Opioid doses, pain intensity, adverse effects, symptomatic drugs, were recorded at week intervals for 4 weeks. Costs of opioid therapy, supportive drugs, and other analgesic drugs were also evaluated.Seventy patients completed the 4 weeks period of study. Five, five, and four patients, treated with oral morphine, transdermal fentanyl, and oral methadone, respectively, required opioid switching. No differences in pain and symptom intensity were observed. Opioid escalation index was significantly lower in patients receiving methadone (p0.0001), although requiring up and down changes in doses. At the doses used, methadone was significantly less expensive (p0.0001), while the use and costs of supportive drugs and other analgesics were similar in the three groups. No relevant differences in adverse effects were observed among the groups during either the titration phase and chronic treatment.All the three opioids used as first-line therapy were effective, well tolerated, and required similar amounts of symptomatic drugs or co-analgesics. Methadone was significantly less expensive, but required more changes, up and down, of the doses, suggesting that dose titration of this drug requires major clinical expertise.

The aim of this study was to prospectively evaluate the frequency, indications, outcomes, and predictive factors associated with opioid switching, using a protocol that had been clinically applied and viewed as effective for many years. A prospective study was carried out on a cohort of consecutive cancer patients who were receiving opioids but had an unacceptable balance between analgesia and adverse effects, despite symptomatic treatment of side effects. The initial conversion ratio between opioids and routes was as follows (mg/day): oral morphine 100=intravenous morphine 33=transdermal fentanyl 1=intravenous fentanyl 1=oral methadone 20=intravenous methadone 16=oral oxycodone 70=transdermal buprenorphine 1.3. The switch was assisted by opioids used as needed, and doses were changed after the initial conversion according to clinical response in an acute care setting. Intensity of pain and symptoms associated with opioid therapy were recorded. A distress score (DS) was calculated as a sum of symptom intensity. A switch was considered successful when the intensity of pain and/or DS, or the principal symptom necessitating the switch, decreased to at least 33% of the value recorded before switching. One hundred eighteen patients underwent opioid substitutions. The indications for opioid switching were uncontrolled pain and adverse effects (50.8%), adverse effects (28.8%), uncontrolled pain (15.2%), and convenience (4.2%). Overall, 103 substitutions were successful. Ninety-six substitutions were successful after the first switching, and a further substitution was successful in seven patients who did not respond to the first switch. The mean time to achieve dose stabilization after switching was 3.2 days. The presence of both poor pain control and adverse effects was related to unsuccessful switching (P

The aim of this prospective cohort study was to confirm the safety of intravenous morphine (IV-M) used in doses proportional to the basal opioid regimen for the management of breakthrough pain and to record the nurse compliance on regularly recording data regarding breakthrough pain treated by IV-M. Over a one-year period, 99 patients received IV-M for breakthrough pain during 116 admissions. The IV-M dose was 1/5 of the oral daily dose, converted using an equianalgesic ratio of 1/3 (IV/oral). For each episode, nurses were instructed to routinely collect changes in pain intensity and emerging problems when pain became severe (T0), and to reassess the patient 15minutes after IV-M injection (T15). Nurses were unaware of the aim of the study and just followed department policy. In total, 945 breakthrough events treated by IV-M were recorded and the mean number of events per patient per admission was eight (95% confidence interval (CI) 6.9-9.5). The mean dose of IV-M was 12mg (95% CI 9-14mg). In the 469 events (49.6%) with a complete assessment, a decrease in pain of more than 33% and 50% was observed in 287 (61.2%) and 115 (24.5%) breakthrough events, respectively. The mean pain intensity decreased from 7.2 (T0) to 2.7 (T15). In eight episodes, no changes in pain intensity were observed and a further dose of IV-M was given. The remaining patients did not require further interventions. No clinical events requiring medical intervention were recorded. In this confirmatory study, IV-M was administered for the management of breakthrough pain in doses proportional to the basal opioid regimen to all patients, including older patients and those requiring relatively large doses. This did not result in life-threatening adverse effects in a large number of patients and was effective in most cases. The role of nurses is of paramount importance in monitoring and collecting data and gathering information for audit purposes on the unit.

The aim of this study was to confirm that the concomitant presence of transdermal fentanyl (TTS FE) and buprenorphine (TTS BU) may be feasible without important consequences, using doses presumed to be equianalgesic. A prospective "N of 1" study was carried out in a sample of volunteers with cancer pain receiving stable doses of TTS FE or TTS BU, with adequate pain and symptom control. In the study design, each patient provided data before and after a switch from one opioid to the other and then back to the previous one. Sixteen patients receiving daily stable doses of 0.6 or 1.2 mg of TTS FE were switched to TTS BU using an FE-BU ratio of 0.6-0.8. After three days, the TTS BU patch was removed and TTS FE patch was placed for another three days. Six patients receiving TTS BU were switched to TTS FE and then rotated back to TTS BU with the same dosing considerations. No statistical differences in changes in pain and symptom intensity during switching and between the two different sequences were observed. No significant changes in rescue doses of oral morphine were reported at the same intervals. Cancer patients receiving stable doses of TTS FE or TTS BU can be safely switched to the alternative transdermal opioid. Further studies should be performed to gather data about the use of TTS BU with other opioids, at different doses, and in different clinical conditions. © 2007 U.S. Cancer Pain Relief Committee.

The use of symptomatic agents has greatly improved the medical treatment of advanced cancer patients with inoperable bowel obstruction. A systematic review of studies of the most popular drugs used in the medical management of inoperable malignant bowel obstruction was performed to assess the effectiveness of these treatments and provide some lines of evidence. Randomized trials that involved patients with a clinical diagnosis of intestinal obstruction due to advanced cancer treated with these drugs were reviewed. Five reports fulfilled inclusion criteria. Three studies compared octreotide (OC) and hyoscine butylbromide (HB), and two studies compared corticosteroids (CSs) and placebo. Globally, 52 patients received OC, 51 patients received HB, 37 patients received CSs, 15 patients received placebo, and 37 patients received both placebo and CSs. On the basis of these few data, the superiority of OC over HB in relieving gastrointestinal symptoms was evidenced in a total of 103 patients. The latter studies had samples more defined in terms of stage and inoperability, and had a shorter survival in comparison with studies of CSs (less than 61 days, most of them less than 20 days). Data on CSs are less convincing, due to the methodological weakness of existing studies. This review confirms the difficulties in conducting randomized controlled trials in this population.