Causes and predictors of nonresponse to treatment of intensive care unit-acquired pneumonia

OBJECTIVE: To prospectively evaluate the predictive factors for the nonresponse to empirical antibiotic treatment and mortality in patients with intensive care unit-acquired pneumonia. DESIGN: A 1-yr prospective cohort of patients with suspicion of intensive care unit-acquired pneumonia. SETTING: Five medical and surgical intensive care units of Hospital Clinic in Barcelona. PATIENTS: A total of 71 patients with intensive care unit-acquired pneumonia were studied. The definition of nonresponse included at least one of the following: failure to improve the Pao2/Fio2 ratio or need of intubation because of pneumonia, persistence of fever or hypothermia and purulent respiratory secretions, worsening of pulmonary infiltrates, or occurrence of septic shock or multiple organ dysfunction not present at onset of pneumonia. INTERVENTIONS: Clinical assessment, including severity scores, blood and quantitative cultures of respiratory secretions, and cytokine measurements in serum and bronchoalveolar lavage at onset of pneumonia and 72 hrs after antimicrobial treatment. MEASUREMENTS AND RESULTS: A total of 44 patients (62%) fulfilled criteria of nonresponse, and at least one cause of nonresponse could be determined in 28 cases (64%): inappropriate treatment in ten (23%), superinfection in six (14%), concomitant foci of infection in 12 (27%), and noninfectious causes in seven cases (16%). The remaining 16 patients with no definite cause of nonresponse presented with septic shock, multiple organ dysfunction, or acute respiratory distress syndrome. Increased levels of interleukin-6 at onset of pneumonia (odds ratio, 9.7; p =.014) was an independent predictor of nonresponse to treatment. Likewise, increased level of interleukin-6 at follow-up (odds ratio, 27; p =.001) was the only independent predictor for hospital mortality. CONCLUSION: Increased systemic inflammatory response was the main predictor of nonresponse to treatment and mortality.     

Neuroimaging of stroke: a review

Advances in neuroimaging technology during the past 30 years have resulted in a virtual explosion in the amount of pathologic information that can be obtained in the clinical stroke setting. This neuroimaging revolution has led to a much better understanding of cerebrovascular and tissue pathology, creating a wide array of opportunities for acute treatment and secondary prevention. Advances include early and accurate detection of ischemic and infarcted tissue and the ability to reveal hypoperfused tissue at risk. Clinicians are increasingly able to noninvasively detect embolic and atherothrombotic intravascular lesions. Vascular lesions associated with stroke can be characterized through endovascular neuroimaging techniques and repaired by various means. In this article, we provide an overview and update on the various techniques used in the neuroimaging of stroke and intracranial hemorrhage, including computed tomography, magnetic resonance imaging, ultrasound, and catheter angiography. We outline the specific role of each modality in clinical practice.     

Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues

Although the heat shock protein 90 (HSP90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) shows clinical promise, potential limitations encourage development of alternative chemotypes. We discovered the 3,4-diarylpyrazole resorcinol CCT018159 by high-throughput screening and used structure-based design to generate more potent pyrazole amide analogues, exemplified by VER-49009. Here, we describe the detailed biological properties of VER-49009 and the corresponding isoxazole VER-50589. X-ray crystallography showed a virtually identical HSP90 binding mode. However, the dissociation constant (K(d)) of VER-50589 was 4.5 +/- 2.2 nmol/L compared with 78.0 +/- 10.4 nmol/L for VER-49009, attributable to higher enthalpy for VER-50589 binding. A competitive binding assay gave a lower IC(50) of 21 +/- 4 nmol/L for VER-50589 compared with 47 +/- 9 nmol/L for VER-49009. Cellular uptake of VER-50589 was 4-fold greater than for VER-49009. Mean cellular antiproliferative GI(50) values for VER-50589 and VER-49009 for a human cancer cell line panel were 78 +/- 15 and 685 +/- 119 nmol/L, respectively, showing a 9-fold potency gain for the isoxazole. Unlike 17-AAG, but as with CCT018159, cellular potency of these analogues was independent of NAD(P)H:quinone oxidoreductase 1/DT-diaphorase and P-glycoprotein expression. Consistent with HSP90 inhibition, VER-50589 and VER-49009 caused induction of HSP72 and HSP27 alongside depletion of client proteins, including C-RAF, B-RAF, and survivin, and the protein arginine methyltransferase PRMT5. Both caused cell cycle arrest and apoptosis. Extent and duration of pharmacodynamic changes in an orthotopic human ovarian carcinoma model confirmed the superiority of VER-50589 over VER-49009. VER-50589 accumulated in HCT116 human colon cancer xenografts at levels above the cellular GI(50) for 24 h, resulting in 30% growth inhibition. The results indicate the therapeutic potential of the resorcinylic pyrazole/isoxazole amide analogues as HSP90 inhibitors.     

Esophageal Doppler monitoring predicts fluid responsiveness in critically ill ventilated patients

Objective To test whether fluid responsiveness can be predicted by the respiratory variation in aortic blood flow and/or the flow time corrected for heart rate monitored with esophageal Doppler.Design and setting Prospective study in a 24-bed medical intensive care unit of a university hospital.Patients 38 mechanically ventilated patients with sinus rhythm and without spontaneous breathing activity in whom volume expansion was planned.Interventions The aortic blood flow was measured using an esophageal Doppler monitoring device before and after fluid infusion (500 ml NaCl 0.9% over 10 min). The variation in aortic blood flow over a respiratory cycle between its minimal and maximal values was calculated. The flow time was also measured.Measurements and results Aortic blood flow increased by at least 15% after volume expansion in 20 patients (defined as responders). Before fluid infusion the respiratory variation in aortic flow was higher in responders than in nonresponders (28±12% vs. 12±5%). It significantly decreased after volume expansion (18±11%) in responders only. A respiratory variation in aortic flow before volume expansion of at least 18% predicted fluid responsiveness with a sensitivity of 90% and a specificity of 94%. Flow time increased with fluid infusion in responders and nonresponders. A flow time corrected for heart rate below 277 ms predicted fluid responsiveness with a sensitivity of 55% and a specificity of 94%. The area under the ROC curve generated for variation in aortic blood flow ABF was greater than that generated for flow time.Conclusions The respiratory variation in aortic blood flow reliably predicts fluid responsiveness in patients with sinus rhythm and without breathing activity.     

A contributive result of open-lung biopsy improves survival in acute respiratory distress syndrome patients

OBJECTIVE: The impact of a contributive result of open-lung biopsy on the outcome of patients with acute respiratory distress syndrome (ARDS) has not been extensively investigated. The aim of this study was therefore to determine the rate of contributive open-lung biopsy and whether it improved the prognosis of ARDS patients. DESIGN: Prospective study conducted during an 8-yr period. SETTING: A 14-bed medico-surgical intensive care unit and a 12-bed medical intensive care unit from the same hospital. PATIENTS: One hundred open-lung biopsies were performed in 100 patients presenting ARDS. INTERVENTIONS: Open-lung biopsy was performed after > or = 5 days of evolution of ARDS when there was no improvement in the respiratory status despite negative microbiological samples cultures and potential indication for corticosteroid treatment. MEASUREMENTS AND MAIN RESULTS: Ten patients presented a mechanical complication following open-lung biopsy (two pneumothoraces and eight moderate air leaks). The unique independent factor associated with this complication was the minute ventilation when open-lung biopsy was performed (odds ratio, 1.20; 95% confidence interval, 1.03-1.41; p = .02). Fibrosis was noted in 53 patients but was associated with an infection in 29 of these 53 patients (55%). A contributive result of open-lung biopsy (defined as the addition of a new drug) was noted in 78 patients. Simplified Acute Physiology Score II was the only independent predictive factor of a contributive open-lung biopsy (odds ratio, 0.96; 95% confidence interval, 0.92-0.99; p = .04). Survival was higher in patients with a contributive open-lung biopsy (67%) than in patients in whom open-lung biopsy results did not modify the treatment (14%) (p < .001). The factors predicting survival were a contributive result of open-lung biopsy, female gender, and the Organ System Failures score the day of open-lung biopsy. CONCLUSIONS: The present study shows that open-lung biopsy provided a contributive result in 78% of ARDS patients with a negative bronchoalveolar lavage. Survival of ARDS patients improved when open-lung biopsy was contributive.     

Reproducibility of protected specimen brush and bronchoalveolar lavage conserved at 4 degrees C for 48 hours

OBJECTIVE: Protected specimen brush (PSB) and bronchoalveolar lavage (BAL) are proposed in combination to optimize antimicrobial treatment. Nevertheless, they are only validated for immediate laboratory processing. This study was therefore conducted to determine whether 48 h conservation at a mere 4 degrees C enables good culture reproducibility for both PSB and BAL. DESIGN AND SETTING: Prospective study, evaluation of a conservation procedure for PSB and BAL, from February 1994 to February 1995, in the 12 bed ICU of a general hospital (938 beds). SAMPLES: Ninety-nine PSB and 86 BAL samples, obtained from 100 bronchoscopic procedures, were analyzed. Thresholds were 10(3) and 10(4) cfu/ml for PSB and BAL, respectively. MEASUREMENTS AND RESULTS: Qualitative comparison between the immediate and 48 h procedures were, for PSB, specificity 100%, sensitivity 78%, positive predictive value 100%, negative predictive value 84% and overall accuracy 90%; and for BAL: 100%, 89%, 100%, 89% and 94%. Lowered 10(2) and 10(3) cfu/ml thresholds at the 48 h procedure for PSB and BAL reduce the false negatives from 10 to 3 and 5 to 1, respectively. Microorganism results were comparable for PSB and BAL ( r = 0.63 and 0.67), especially for the most resistant strains: Staphylococcus, Enterobacteriaceae and Pseudomonas. However, there was a decrease in the Neisseria and Haemophilus group ( p < 0.01). CONCLUSION: There is a good culture reproducibility for both PSB and BAL after 48 h conservation at 4 degrees C, especially with lowered thresholds; this technique is therefore appropriate for routine use.