Case report and review: Angiosarcoma with thrombocytopenia after total hip arthroplasty.

Total hip arthroplasty (THA) is a common treatment for osteoarthritis and is also performed for other conditions, such as secondary arthritis due to developmental dysplasia of the hip. Various THA types may be complicated by osteolysis and an inflammatory pseudotumor due to an adverse reaction to metal debris. Rarely, THA has been associated with malignant tumors, but their causality remains unclear. In this case report, we describe a female patient with developmental dysplasia of the hip. She had undergone left metal-on-polyethylene THA, acetabular revision of the THA, and left total knee arthroplasty. In addition, she had a history of dyslipidemia and telangiectasia of the eyes, anemia, hiatal hernia, and pleuritis. A THA-associated mass (suspected to be a pseudotumor) had been detected during a previous hospital admission due to pleuritis. She was hospitalized due to swelling in her left lower limb, fatigue, and bruises. A clinical examination revealed anemia, thrombocytopenia, and growth of the suspected pseudotumor. Within 6 weeks, she presented with bleeding of the oral mucosa, hemoptysis, melena, severe thrombocytopenia that did not respond to treatment, elevated D-dimer and C-reactive protein levels, severe pain, increased osteolysis, and fractures around the THA. Infection or malignancy was suspected, but two trocar biopsies suggested an inflammatory pseudotumor. Since her anemia and thrombocytopenia were considered to have been caused by an inflammatory process within the suspected pseudotumor, her suspected pseudotumor and all THA components were surgically removed. However, she developed severe alveolar hemorrhaging and hypoxia and died 2 weeks after her surgery. Histopathological analysis of her surgical and autopsy samples revealed highly malignant angiosarcoma. Although individual cases of malignancies associated with THA have been reported, the literature lacks a clear association between THA and increased cancer risk. Most pseudotumors are non-malignant. The patient's case presented in this report exemplifies the challenges to the differential diagnosis of a THA-associated pseudotumor and rare angiosarcoma. Atypically rapid tumor growth, severe osteolysis, and deterioration in the general wellbeing suggest a malignant disease.

Anesthesia Method, Tourniquet Use, and Persistent Postsurgical Pain after Total Knee Arthroplasty: A Prespecified Secondary Analysis of a Randomized Trial.

BACKGROUND: Persistent postsurgical pain after total knee arthroplasty is a common problem and a major reason for patient dissatisfaction. This secondary analysis aimed to investigate the effects of anesthesia (spinal vs. general) and tourniquet use on persistent pain after total knee arthroplasty. METHODS: In this secondary analysis of a previously presented parallel, single-center, randomized trial, 404 patients scheduled for total knee arthroplasty were randomized to spinal versus general anesthesia and no-tourniquet versus tourniquet groups. Patients assessed pain using the Brief Pain Inventory-short form preoperatively and 3 and 12 months postoperatively. The prespecified main outcome was the change in "average pain" measured with numerical 0 to 10 rating scale 1 yr postoperatively. The threshold for clinical importance between groups was set to 1.0. RESULTS: The change in average pain scores 1 yr postoperatively did not differ between the spinal and general anesthesia groups (-2.6 [SD 2.5] vs. -2.3 [SD 2.5], respectively; mean difference, -0.4; 95% CI, -0.9 to 0.1; P = 0.150). The no-tourniquet group reported a smaller decrease in the average pain scores than the tourniquet group (-2.1 [SD 2.7] vs. -2.8 [SD 2.3]; mean difference, 0.6; 95% CI, 0.1 to 1.1; P = 0.012). After 1 yr, the scores concerning the mean of four pain severity variables (numerical rating scale) decreased more in the spinal than in the general anesthesia group (-2.3 [SD 2.2] vs. -1.8 [SD 2.1]; mean difference, -0.5; 95% CI, -0.9 to -0.05; P = 0.029) and less in the no-tourniquet than in the tourniquet group (-1.7 [SD 2.3] vs. -2.3 [SD 2.0]; mean difference, 0.6; 95% CI, 0.2 to 1.0; P = 0.005). None of the differences in pain scores reached the threshold for clinical importance. CONCLUSIONS: The type of anesthesia (spinal vs. general) or tourniquet use has no clinically important effect on persistent postsurgical pain after total knee arthroplasty.

Intravenous patient-controlled analgesia vs nurse administered oral oxycodone after total knee arthroplasty: a retrospective cohort study.

OBJECTIVES: Severe post-operative pain is common after total knee arthroplasty. Patient-controlled analgesia is an alternative method of pain management, whereby a patient administers his or her own pain medication. Patients seem to prefer this method over nurse-administered analgesia. However, it remains unclear whether patients using patient-controlled analgesia devices use higher or lower doses of opioids compared to patients treated with oral opioids. METHODS: This retrospective study examined 164 patients undergoing total knee arthroplasty. Post-operatively, 82 patients received oxycodone via intravenous patient-controlled analgesia devices, while the pain medication for 82 patients in the control group was administered by nurses. The main outcome measure was the consumption of intravenous opioid equivalents within 24 h after surgery. Secondary outcome measures were the use of anti-emetic drugs and the length of stay. Furthermore, we evaluated opioid-related adverse event reports. RESULTS: The consumption of opioids during the first 24 h after surgery and the use of anti-emetic drugs were similar in both groups. The median opioid dose of intravenous morphine equivalents was 41.1 mg (interquartile range (IQR): 29.5-69.1 mg) in the patient-controlled analgesia group and 40.5 mg (IQR: 32.4-48.6 mg) in the control group, respectively. The median length of stay was 2 days (IQR: 2-3 days) in the patient-controlled analgesia group and 3 days (IQR: 2-3 days) in the control group (p=0.02). The use of anti-emetic drugs was similar in both groups. CONCLUSIONS: The administration of oxycodone via intravenous patient-controlled analgesia devices does not lead to increased opioid or anti-emetic consumptions compared to nurse-administered pain medication after total knee arthroplasty. Patient-controlled analgesia might lead to shortened length of stay.

Effects of anaesthesia method and tourniquet use on recovery following total knee arthroplasty: a randomised controlled study.

BACKGROUND: We investigated the effects of spinal and general anaesthesia and surgical tourniquet on acute pain and early recovery after total knee arthroplasty (TKA). METHODS: Patients (n=413) were randomised to four parallel groups: spinal anaesthesia with or without tourniquet, and general anaesthesia with or without tourniquet. The primary outcome was patient-controlled i.v. oxycodone consumption over 24 postoperative hours. RESULTS: Results from 395 subjects were analysed. Median i.v. oxycodone consumption did not differ between the four groups (spinal anaesthesia without [36.6 mg] and with tourniquet [38.0 mg], general anaesthesia without [42.3 mg] and with tourniquet [42.5 mg], P=0.42), between spinal (37.7 mg) and general anaesthesia (42.5 mg) groups (median difference -3.1, 95% confidence interval [CI] -7.4 to 1.2, P=0.15) and between tourniquet and no-tourniquet groups (40.0 vs 40.0 mg, median difference -0.8, CI -5.1 to 3.5, P=0.72). Vomiting incidence was higher with spinal than with general anaesthesia (21% [42/200] vs 13% [25/194], CI 1.05 to 3.1, P=0.034). The mean haemoglobin decrease was greater without than with tourniquet (-3.0 vs -2.5 g dl-1, mean difference -0.48, CI -0.65 to -0.32, P<0.001). No differences were observed in pain, pain management, incidences of blood transfusions, in-hospital complications, or length of hospital stay. CONCLUSIONS: For TKA, spinal and general anaesthesia with or without tourniquet did not differ in 24-h postoperative opioid consumption, pain management, blood transfusions, in-hospital complications, and length of hospital stay. Vomiting incidence was higher in the spinal than in the general anaesthesia group. Tourniquet use caused smaller decreases in haemoglobin levels. CLINICAL TRIAL REGISTRATION: EudraCT 2016-002035-15.

Neuraminidase Inhibitors and Hospital Length of Stay: A Meta-analysis of Individual Participant Data to Determine Treatment Effectiveness Among Patients Hospitalized With Nonfatal 2009 Pandemic Influenza A(H1N1) Virus Infection.

BACKGROUND: The effect of neuraminidase inhibitor (NAI) treatment on length of stay (LoS) in patients hospitalized with influenza is unclear. METHODS: We conducted a one-stage individual participant data (IPD) meta-analysis exploring the association between NAI treatment and LoS in patients hospitalized with 2009 influenza A(H1N1) virus (A[H1N1]pdm09) infection. Using mixed-effects negative binomial regression and adjusting for the propensity to receive NAI, antibiotic, and corticosteroid treatment, we calculated incidence rate ratios (IRRs) and 95% confidence intervals (CIs). Patients with a LoS of <1 day and those who died while hospitalized were excluded. RESULTS: We analyzed data on 18 309 patients from 70 clinical centers. After adjustment, NAI treatment initiated at hospitalization was associated with a 19% reduction in the LoS among patients with clinically suspected or laboratory-confirmed influenza A(H1N1)pdm09 infection (IRR, 0.81; 95% CI, .78-.85), compared with later or no initiation of NAI treatment. Similar statistically significant associations were seen in all clinical subgroups. NAI treatment (at any time), compared with no NAI treatment, and NAI treatment initiated <2 days after symptom onset, compared with later or no initiation of NAI treatment, showed mixed patterns of association with the LoS. CONCLUSIONS: When patients hospitalized with influenza are treated with NAIs, treatment initiated on admission, regardless of time since symptom onset, is associated with a reduced LoS, compared with later or no initiation of treatment.

Randomised controlled study comparing general and spinal anaesthesia with and without a tourniquet on the outcomes of total knee arthroplasty: study protocol.

INTRODUCTION: Total knee arthroplasty is a highly effective treatment for end-stage knee osteoarthritis, and it is usually performed under spinal or general anaesthesia with or without a surgical tourniquet. Some debate about the preferred mode of anaesthesia regarding patient outcomes remains. The aim of this study, which compares general and spinal anaesthesia with and without a tourniquet on the outcomes of total knee arthroplasty, is to determine the optimal type of anaesthesia regimen and assess the effect of a tourniquet on the patient's recovery following total knee arthroplasty. METHODS AND ANALYSIS: This study is a randomised, controlled, parallel-group, four-arm study comparing spinal and general anaesthesia with and without a tourniquet in 400 patients undergoing fast-track total knee arthroplasty, with a 12-month follow-up. The primary outcome is cumulative intravenous oxycodone consumption by patient-controlled analgesia during the first 24 postoperative hours. Secondary outcomes include postoperative nausea and vomiting, the length of hospital stay, the duration of the surgery, blood loss, demand for surgical unit resources, complications, readmissions, postoperative knee function, range of motion, health-related quality of life, prolonged pain and mortality. ETHICS AND DISSEMINATION: This study's protocol is in accordance with the declaration of Helsinki. The results of this study will be disseminated in international peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03364088; Pre-results.

The predictive value of NT-proBNP and hs-TnT for risk of death in cardiac surgical patients.

BACKGROUND: European System for Cardiac Operative Risk Evaluation II (EuroSCORE II) is used for risk stratification before cardiac surgery, but whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT) may add prognostic information to EuroSCORE II is not known. METHODS: Preoperative (n=640) and postoperative (n=629) blood samples were available from cardiac surgical patients with 961-day follow-up (FINNAKI Heart study; cohort #1). The accuracy of a parsimonious risk model with NT-proBNP measurements was also tested in 90 patients with respiratory failure after cardiac surgery (FINNALI study; cohort #2). RESULTS: Sixty-one patients (9.5%) died during follow-up in cohort #1. Preoperative NT-proBNP and hs-TnT concentrations correlated (rho=0.58; p<0.001) and were higher in non-survivors compared to survivors: median 2027 (Q1-3 478-5387) vs. 373 (134-1354) ng/L [NT-proBNP] and 39 (16-191) vs. 13 (8-32) ng/L [hs-TnT]; p<0.001 for both. Preoperative NT-proBNP concentrations were associated with time to death after adjustment for EuroSCORE II (HR [lnNT-proBNP] 1.33 [95% CI 1.08-1.64]), p=0.008 and reclassified patients on top of EuroSCORE II (net reclassification index 0.39 [95% CI 0.14-0.64], p=0.003). Pre- and postoperative NT-proBNP concentrations were closely correlated (rho=0.80, p<0.001) and postoperative NT-proBNP concentrations were also associated with long-term mortality after adjustment for EuroSCORE II. A parsimonious risk model that included age, creatinine clearance, chronic pulmonary disease, and NT-proBNP measurements provided comparable prognostic accuracy as EuroSCORE II in cohort #1 and #2 for risk of long-term mortality. hs-TnT measurements did not add to NT-proBNP measurements CONCLUSION: NT-proBNP measurements could improve and simplify risk prediction in cardiac surgical patients.

Circulating chromogranin B levels in patients with acute respiratory failure: data from the FINNALI Study.

PURPOSE: Circulating chromogranin B (CgB) levels are increased in situations characterized by systemic and myocardial stress, but whether CgB provides prognostic information in patients with acute respiratory failure (ARF) is unknown. METHODS: We included 584 patients with ARF, defined as ventilatory support >6 h, and with blood samples available on Intensive Care Unit (ICU) admission and day 3 (n = 479). CgB levels were measured by radioimmunoassay and follow-up was 90 days. RESULTS: One-hundred-sixty-nine patients (29%) died during follow-up. Admission CgB levels separated non-survivors from survivors: median 1234 (Q1-3 989-1742) vs. 917 (753-1224) pmol/L, respectively, p < 0.001. CgB levels on ICU admission (logarithmically transformed) were associated with time to death after adjustment for established risk indices available on ICU admission, including N-terminal pro-B-type natriuretic levels: HR 2.62 (95%C.I. 1.82-3.77), p < 0.001. Admission CgB levels also improved prognostication on top of SOFA and SAPS II scores as assessed by Cox regression analyses and the category-free net reclassification index. The area under the curve (AUC) for admission CgB levels to separate survivors and non-survivors was 0.72 (95%CI 0.67-0.76), while the AUC on day 3 was 0.60 (0.54-0.66). CONCLUSIONS: CgB levels measured on ICU admission provided additional prognostic information to established risk indices in ARF patients.

Prognostic Value of Secretoneurin in Patients with Acute Respiratory Failure: Data from the FINNALI Study.

BACKGROUND: We examined whether secretoneurin (SN), a biomarker associated with cardiomyocyte Ca(2+) handling, provides prognostic information in patients with acute respiratory failure (ARF). METHODS: We included 490 patients with ARF, defined as ventilatory support >6 h, with blood samples available on admission to the intensive care unit (ICU). SN concentrations were measured by RIA. RESULTS: A total of 209 patients (43%) were hospitalized with cardiovascular (CV)-related ARF, and 90-day mortality rates were comparable between CV- and non-CV-related ARF (n = 281): 31% vs 24%, P = 0.11. Admission SN concentrations were higher in nonsurvivors than in survivors in both CV-related (median 148 [quartile 1-3, 117-203] vs 108 [87-143] pmol/L, P < 0.001) and non-CV-related ARF (139 [115-184] vs 113 [91-139] pmol/L, P < 0.001). In patients with CV-related ARF, SN concentrations on ICU admission were associated with 90-day mortality [odds ratio (OR) 1.97 (95% CI, 1.04-3.73, P = 0.04)] after adjusting for established risk indices, including N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentrations. SN also improved patient classification in CV-related ARF as assessed by the net reclassification index: 0.32 (95% CI, 0.04-0.59), P = 0.03. The area under the curve (AUC) of SN to predict mortality in patients with CV-related ARF was 0.72 (95% CI, 0.65-0.79), and the AUC of NT-proBNP was 0.64 (0.56-0.73). In contrast, SN concentrations on ICU admission did not provide incremental prognostic value to established risk indices in patients with non-CV-related ARF, and the AUC was 0.67 (0.60-0.75). CONCLUSIONS: SN concentrations measured on ICU admission provided incremental prognostic information to established risk indices in patients with CV-related ARF, but not in patients with non-CV-related ARF.

Prognostic Value of Secretoneurin in Critically Ill Patients With Infections.

OBJECTIVES: Secretoneurin is produced in neuroendocrine cells, and the myocardium and circulating secretoneurin levels provide incremental prognostic information to established risk indices in cardiovascular disease. As myocardial dysfunction contributes to poor outcome in critically ill patients, we wanted to assess the prognostic value of secretoneurin in two cohorts of critically ill patients with infections. DESIGN: Two prospective, observational studies. SETTING: Twenty-four and twenty-five ICUs in Finland. PATIENTS: A total of 232 patients with severe sepsis (cohort #1) and 94 patients with infections and respiratory failure (cohort #2). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We measured secretoneurin levels by radioimmunoassay in samples obtained early after ICU admission and compared secretoneurin with other risk indices. In patients with severe sepsis, admission secretoneurin levels (logarithmically transformed) were associated with hospital mortality (odds ratio, 3.17 [95% CI, 1.12-9.00]; p = 0.030) and shock during the hospitalization (odds ratio, 2.17 [1.06-4.46]; p = 0.034) in analyses that adjusted for other risk factors available on ICU admission. Adding secretoneurin levels to age, which was also associated with hospital mortality in the multivariate model, improved the risk prediction as assessed by the category-free net reclassification index: 0.35 (95% CI, 0.06-0.64) (p = 0.02). In contrast, N-terminal pro-B-type natriuretic peptide levels were not associated with mortality in the multivariate model that included secretoneurin measurements, and N-terminal pro-B-type natriuretic peptide did not improve patient classification on top of age. Secretoneurin levels were also associated with hospital mortality after adjusting for other risk factors and improved patient classification in cohort #2. In both cohorts, the optimal cutoff for secretoneurin levels at ICU admission to predict hospital mortality was ≈ 175 pmol/L, and higher levels were associated with mortality also when adjusting for Simplified Acute Physiology Score II and Sequential Organ Failure Assessment scores. CONCLUSIONS: Secretoneurin levels provide incremental information to established risk indices for the prediction of mortality and shock in critically ill patients with severe infections.

Lung-Protective Ventilation With Low Tidal Volumes and the Occurrence of Pulmonary Complications in Patients Without Acute Respiratory Distress Syndrome: A Systematic Review and Individual Patient Data Analysis.

OBJECTIVE: Protective mechanical ventilation with low tidal volumes is standard of care for patients with acute respiratory distress syndrome. The aim of this individual patient data analysis was to determine the association between tidal volume and the occurrence of pulmonary complications in ICU patients without acute respiratory distress syndrome and the association between occurrence of pulmonary complications and outcome in these patients. DESIGN: Individual patient data analysis. PATIENTS: ICU patients not fulfilling the consensus criteria for acute respiratory distress syndrome at the onset of ventilation. INTERVENTIONS: Mechanical ventilation with low tidal volume. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was development of a composite of acute respiratory distress syndrome and pneumonia during hospital stay. Based on the tertiles of tidal volume size in the first 2 days of ventilation, patients were assigned to a "low tidal volume group" (tidal volumes ≤ 7 mL/kg predicted body weight), an "intermediate tidal volume group" (> 7 and < 10 mL/kg predicted body weight), and a "high tidal volume group" (≥ 10 mL/kg predicted body weight). Seven investigations (2,184 patients) were included. Acute respiratory distress syndrome or pneumonia occurred in 23% of patients in the low tidal volume group, in 28% of patients in the intermediate tidal volume group, and in 31% of the patients in the high tidal volume group (adjusted odds ratio [low vs high tidal volume group], 0.72; 95% CI, 0.52-0.98; p = 0.042). Occurrence of pulmonary complications was associated with a lower number of ICU-free and hospital-free days and alive at day 28 (10.0 ± 10.9 vs 13.8 ± 11.6 d; p < 0.01 and 6.1 ± 8.1 vs 8.9 ± 9.4 d; p < 0.01) and an increased hospital mortality (49.5% vs 35.6%; p < 0.01). CONCLUSIONS: Ventilation with low tidal volumes is associated with a lower risk of development of pulmonary complications in patients without acute respiratory distress syndrome.

Severe heart failure and rhabdomyolysis associated with propofol infusion in a burn patient.

The authors report a favorable outcome in an adult burn patient, who developed severe propofol-related infusion syndrome presenting with rhabdomyolysis, acute kidney injury, and right-sided heart failure after a low-dose propofol infusion. Other possible causes for late-onset rhabdomyolysis after burn trauma were ruled out by extensive differential diagnostics. The most distinctive abnormal finding was a Brugada-type ST-segment elevation, reported previously associating with imminent death. The patient survived because of cessation of propofol infusion and continuous renal replacement therapy. ECG recording is important in early detection of propofol-related infusion syndrome. ST elevations in the ECG should lead to the immediate discontinuation of propofol.

Serum activin A and B, and follistatin in critically ill patients with influenza A(H1N1) infection.

BACKGROUND: Activin A and its binding protein follistatin (FS) are increased in inflammatory disorders and sepsis. Overexpression of activin A in the lung causes similar histopathological changes as acute respiratory distress syndrome (ARDS). ARDS and severe respiratory failure are complications of influenza A(H1N1) infection. Interleukin 6 (IL-6), which in experimental studies increases after activin A release, is known to be related to the severity of H1N1 infection. Our aim was to evaluate the levels of activin A, activin B, FS, IL-6 and IL-10 and their association with the severity of respiratory failure in critically ill H1N1 patients. METHODS: A substudy of a prospective, observational cohort of H1N1 patients in Finnish intensive care units (ICU). Clinical information was recorded during ICU treatment, and serum activin A, activin B, FS, IL-6 and IL-10 were measured at admission to ICU and on days 2 and 7. RESULTS: Blood samples from 29 patients were analysed. At the time of admission to intensive care unit, elevated serum levels above the normal range for respective age group and sex were observed in 44% for activin A, 57% for activin B, and 39% for FS. In 13 of the 29 patients, serial samples at all time points were available and in these the highest activin A, activin B and FS were above the normal range in 85%, 100% and 46% of the patients, respectively. No difference in baseline or highest activin A or activin B was found in patients with or without acute lung injury (ALI) or ARDS (P > 0.05 for all). Peak levels of IL-6 were significantly elevated in ALI/ARDS patients. Peak activin A and activin A/FS were associated with ventilatory support free-days, severity of acute illness and length of ICU stay (P < 0.05 for all). CONCLUSIONS: Higher than normal values of these proteins were common in patients with H1N1 infection but we found no association with the severity of their respiratory failure.

Association between tidal volume size, duration of ventilation, and sedation needs in patients without acute respiratory distress syndrome: an individual patient data meta-analysis.

PURPOSE: Mechanical ventilation with lower tidal volumes (≤6 ml/kg of predicted body weight, PBW) could benefit patients without acute respiratory distress syndrome (ARDS). However, tidal volume reduction could be associated with increased patient discomfort and sedation needs, and consequent longer duration of ventilation. The aim of this individual patient data meta-analysis was to assess the associations between tidal volume size, duration of mechanical ventilation, and sedation needs in patients without ARDS. METHODS: Studies comparing ventilation with different tidal volume sizes in patients without ARDS were screened for inclusion. Corresponding authors were asked to provide individual participant data. Patients were assigned to three groups based on tidal volume size (≤6 ml/kg PBW, 6-10 ml/kg PBW, or ≥10 ml/kg PBW). Ventilator-free days, alive at day 28, and dose and duration of sedation (propofol and midazolam), analgesia (fentanyl and morphine), and neuromuscular blockade (NMB) were compared. RESULTS: Seven investigations (2,184 patients) were included in the analysis. The number of patients breathing without assistance by day 28 was higher in the group ventilated with tidal volume ≤6 ml/kg PBW compared to those ventilated with tidal volume ≥10 ml/kg PBW (93.1 vs. 88.6%; p = 0.027, respectively). Only two investigations (187 patients) could be included in the meta-analysis of sedation needs. There were neither differences in the percentage of study days that patients received sedatives, opioids, or NMBA nor in the total dose of benzodiazepines, propofol, opioids, and NMBA. CONCLUSIONS: This meta-analysis suggests that use of lower tidal volumes in patients without ARDS at the onset of mechanical ventilation could be associated with shorter duration of ventilation. Use of lower tidal volumes seems not to affect sedation or analgesia needs, but this must be confirmed in a robust, well-powered randomized controlled trial.

Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data.

BACKGROUND: Neuraminidase inhibitors were widely used during the 2009-10 influenza A H1N1 pandemic, but evidence for their effectiveness in reducing mortality is uncertain. We did a meta-analysis of individual participant data to investigate the association between use of neuraminidase inhibitors and mortality in patients admitted to hospital with pandemic influenza A H1N1pdm09 virus infection. METHODS: We assembled data for patients (all ages) admitted to hospital worldwide with laboratory confirmed or clinically diagnosed pandemic influenza A H1N1pdm09 virus infection. We identified potential data contributors from an earlier systematic review of reported studies addressing the same research question. In our systematic review, eligible studies were done between March 1, 2009 (Mexico), or April 1, 2009 (rest of the world), until the WHO declaration of the end of the pandemic (Aug 10, 2010); however, we continued to receive data up to March 14, 2011, from ongoing studies. We did a meta-analysis of individual participant data to assess the association between neuraminidase inhibitor treatment and mortality (primary outcome), adjusting for both treatment propensity and potential confounders, using generalised linear mixed modelling. We assessed the association with time to treatment using time-dependent Cox regression shared frailty modelling. FINDINGS: We included data for 29,234 patients from 78 studies of patients admitted to hospital between Jan 2, 2009, and March 14, 2011. Compared with no treatment, neuraminidase inhibitor treatment (irrespective of timing) was associated with a reduction in mortality risk (adjusted odds ratio [OR] 0·81; 95% CI 0·70-0·93; p=0·0024). Compared with later treatment, early treatment (within 2 days of symptom onset) was associated with a reduction in mortality risk (adjusted OR 0·48; 95% CI 0·41-0·56; p<0·0001). Early treatment versus no treatment was also associated with a reduction in mortality (adjusted OR 0·50; 95% CI 0·37-0·67; p<0·0001). These associations with reduced mortality risk were less pronounced and not significant in children. There was an increase in the mortality hazard rate with each day's delay in initiation of treatment up to day 5 as compared with treatment initiated within 2 days of symptom onset (adjusted hazard ratio [HR 1·23] [95% CI 1·18-1·28]; p<0·0001 for the increasing HR with each day's delay). INTERPRETATION: We advocate early instigation of neuraminidase inhibitor treatment in adults admitted to hospital with suspected or proven influenza infection. FUNDING: F Hoffmann-La Roche.

Serum MMP-8 and TIMP-1 in critically ill patients with acute respiratory failure: TIMP-1 is associated with increased 90-day mortality.

BACKGROUND: Matrix metalloproteinases (MMPs) likely have an important role in the pathophysiology of acute lung injury. In a recent study, high matrix metalloproteinases (MMP-8) levels in tracheal aspirates of pediatric acute respiratory distress syndrome (ARDS) patients were associated with worse outcome. In patients with sepsis, an imbalance between MMPs and their tissue inhibitors (TIMPs) has been associated with impaired survival. We hypothesized that the elevated systemic MMP-8 and TIMP-1 are associated with worse outcome in acute respiratory failure. METHODS: This was a substudy of the observational FINNALI study conducted in 25 Finnish intensive care units over an 8-week period. All patients older than 16 years requiring mechanical ventilation for >6 hours were included. MMP-8 and TIMP-1 levels were analyzed from blood samples taken on enrollment in the study and 48 hours later. Laboratory analyses were performed by using immunofluorometric assay for MMP-8 and ELISA for TIMP-1. MMP-8 and TIMP-1 levels were compared between 90-day survivors and nonsurvivors. Survival was compared in quartiles based on TIMP-1 levels, and ROC analysis was performed to calculate areas under the curves. The relationship between MMP-8 and TIMP-1 levels and degree of hypoxemia was examined. RESULTS: The final analyses included 563 patients. Admission TIMP-1 levels were higher in nonsurvivors, median 367 ng/mL (interquartile range 199-562), than survivors, median 240 ng/mL (interquartile range 142-412), WMWodds 1.68 (95% confidence interval [CI], 1.43-2.08). MMP-8 levels may have differed between survivors and nonsurvivors, WMWodds 1.20 (95% CI, 1.01-1.43), but no difference was found in the MMP-8/TIMP-1 molar ratio, WMWodds 0.83 (95% CI, 0.67-1.04). Difference in survival between quartiles based on TIMP-1 was significant (log-rank, P < 0.001). ROC analysis produced an area under the curve 0.63 (95% CI, 0.58-0.69) for TIMP-1. TIMP-1 was associated with severity of hypoxemia. TIMP-1 levels were higher in an ARDS subgroup than in the whole cohort, WMWodds 1.65 (95% CI, 1.15-2.44). CONCLUSIONS: MMP-8 levels were possibly higher in 90-day nonsurvivors but performed poorly in predicting outcome. Increased systemic levels of TIMP-1 were associated with more severe hypoxemia and worse outcome in a large cohort of mechanically ventilated critically ill patients and in a subgroup of ARDS patients.

Serum activin A and B levels predict outcome in patients with acute respiratory failure: a prospective cohort study.

INTRODUCTION: 30 day mortality in patients with Acute Respiratory Failure (ARF) is approximately 30%, defined as patients requiring ventilator support for more than 6 hours. Novel biomarkers are needed to predict patient outcomes and to guide potential future therapies. The activins A and B, members of the Transforming Growth Factor ß family of proteins, and their binding protein, follistatin, have recently been shown to be important regulators of inflammation and fibrosis but no substantial data are available concerning their roles in ARF. METHODS: Specific assays for activin A, B and follistatin were used and the results analyzed according to diagnostic groups as well as according to standard measures in intensive care. Multivariable logistic regression was used to create a model to predict death at 90 days and 12 months from the onset of the ARF. RESULTS: Serum activin A and B were significantly elevated in most patients and in most of the diagnostic groups. Patients who had activin A and/or B concentrations above the reference maximum were significantly more likely to die in the 12 months following admission [either activin A or B above reference maximum: Positive Likelihood Ratio [LR+] 1.65 [95% CI 1.28-2.12, P = 0.00013]; both activin A and B above reference maximum: LR + 2.78 [95% CI 1.96-3.95, P < 0.00001]. The predictive model at 12 months had an overall accuracy of 80.2% [95% CI 76.6-83.3%]. CONCLUSIONS: The measurement of activin A and B levels in these patients with ARF would have assisted in predicting those at greatest risk of death. Given the existing data from animal studies linking high activin A levels to significant inflammatory challenges, the results from this study suggest that approaches to modulate activin A and B bioactivity should be explored as potential therapeutic agents.

SuPAR and PAI-1 in critically ill, mechanically ventilated patients.

PURPOSE: SuPAR (soluble urokinase plasminogen activator receptor) and PAI-1 (plasminogen activator inhibitor 1) are active in the coagulation-fibrinolysis pathway. Both have been suggested as biomarkers for disease severity. We evaluated them in prediction of mortality, acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), sepsis and renal replacement therapy (RRT) in operative and non-operative ventilated patients. METHODS: We conducted a prospective, multicenter, observational study. Blood samples and data of intensive care were collected. Mechanically ventilated patients with baseline suPAR and PAI-1 measurements were included in the analysis, and healthy volunteers were analysed for comparison. Receiver operating characteristics (ROC), logistic regression, likelihood ratios and Kaplan-Meier analysis were performed. RESULTS: Baseline suPAR was 11.6 ng/ml (quartiles Q1-Q3, 9.6-14.0), compared to healthy volunteers with suPAR of 0.6 ng/ml (0.5-11.0). PAI-1 concentrations were 2.67 ng/ml (1.53-4.69) and 0.3 ng/ml (0.3-0.4), respectively. ROC analysis for suPAR 90-day mortality areas under receiver operating characteristic curves (AUC) 0.61 (95 % confidence interval (CI): 0.55-0.67), sepsis 0.68 (0.61-0.76), ALI/ARDS 0.64 (0.56-0.73) and RRT 0.65 (0.56-0.73). Patients with the highest quartile of suPAR concentrations had an odds ratio of 2.52 (1.37-4.64, p = 0.003) for 90-day mortality and 3.16 (1.19-8.41, p = 0.02) for ALI/ARDS. In non-operative patients, the AUC's for suPAR were 90-day mortality 0.61 (0.54-0.68), RRT 0.73 (0.64-0.83), sepsis 0.70 (0.60-0.80), ALI/ARDS 0.61 (0.51-0.71). Predictive value of PAI-1 was negligible. CONCLUSIONS: In non-operative patients, low concentrations of suPAR were predictive for survival and high concentrations for RRT and mortality. SuPAR may be used for screening for patients with potentially good survival. The association with RRT may supply an early warning sign for acute renal failure.

[Incidence, treatment and prognosis of acute respiratory failure in Finland--the FINNALI study]. / Akillisen hengitysvajauksen esiintyvyys, hoito ja ennuste Suomessa--FINNALI-tutkimus.

In a cohort study covering whole Finland, the incidence of acute respiratory failure was higher than in previous international studies. The number of patients fulfilling the diagnostic criteria for acute lung injury and acute respiratory failure remained, however, smaller than that reported in international comparative data. The 90-day mortality was 31% and one-year mortality 35%. Recommended airway pressure levels were followed in ventilatory support treatment, but tidal volumes were larger than those in recent therapeutic trials. Patients outcome could probably be further improved by centralizing intensive care services.

One-year mortality, quality of life and predicted life-time cost-utility in critically ill patients with acute respiratory failure.

INTRODUCTION: High daily intensive care unit (ICU) costs are associated with the use of mechanical ventilation (MV) to treat acute respiratory failure (ARF), and assessment of quality of life (QOL) after critical illness and cost-effectiveness analyses are warranted. METHODS: Nationwide, prospective multicentre observational study in 25 Finnish ICUs. During an eight-week study period 958 consecutive adult ICU patients were treated with ventilatory support over 6 hours. Of those 958, 619 (64.6%) survived one year, of whom 288 (46.5%) answered the quality of life questionnaire (EQ-5D). We calculated EQ-5D index and predicted lifetime quality-adjusted life years (QALYs) gained using the age- and sex-matched life expectancy for survivors after one year. For expired patients the exact lifetime was used. We divided all hospital costs for all ARF patients by the number of hospital survivors, and by all predicted lifetime QALYs. We also adjusted for those who died before one year and for those with missing QOL to be able to estimate the total QALYs. RESULTS: One-year mortality was 35% (95% CI 32 to 38%). For the 288 respondents median [IQR] EQ-5D index after one year was lower than that of the age- and sex-matched general population 0.70 [0.45 to 0.89] vs. 0.84 [0.81 to 0.88]. For these 288, the mean (SD) predicted lifetime QALYs was 15.4 (13.3). After adjustment for missing QOL the mean predicted lifetime (SD) QALYs was 11.3 (13.0) for all the 958 ARF patients. The mean estimated costs were 20.739 euro per hospital survivor, and mean predicted lifetime cost-utility for all ARF patients was 1391 euro per QALY. CONCLUSIONS: Despite lower health-related QOL compared to reference values, our result suggests that cost per hospital survivor and lifetime cost-utility remain reasonable regardless of age, disease severity, and type or duration of ventilation support in patients with ARF.