Monique Dehoux

Use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial

BACKGROUND Reduced duration of antibiotic treatment might contain the emergence of multidrug-resistant bacteria in intensive care units. We aimed to establish the effectiveness of an algorithm based on the biomarker procalcitonin to reduce antibiotic exposure in this setting. METHODS In this multicentre, prospective, parallel-group, open-label trial, we used an independent, computer-generated randomisation sequence to randomly assign patients in a 1:1 ratio to procalcitonin (n=311 patients) or control (n=319) groups; investigators were masked to assignment before, but not after, randomisation. For the procalcitonin group, antibiotics were started or stopped based on predefined cut-off ranges of procalcitonin concentrations; the control group received antibiotics according to present guidelines. Drug selection and the final decision to start or stop antibiotics were at the discretion of the physician. Patients were expected to stay in the intensive care unit for more than 3 days, had suspected bacterial infections, and were aged 18 years or older. Primary endpoints were mortality at days 28 and 60 (non-inferiority analysis), and number of days without antibiotics by day 28 (superiority analysis). Analyses were by intention to treat. The margin of non-inferiority was 10%. This trial is registered with ClinicalTrials.gov, number NCT00472667. FINDINGS Nine patients were excluded from the study; 307 patients in the procalcitonin group and 314 in the control group were included in analyses. Mortality of patients in the procalcitonin group seemed to be non-inferior to those in the control group at day 28 (21.2% [65/307] vs 20.4% [64/314]; absolute difference 0.8%, 90% CI -4.6 to 6.2) and day 60 (30.0% [92/307] vs 26.1% [82/314]; 3.8%, -2.1 to 9.7). Patients in the procalcitonin group had significantly more days without antibiotics than did those in the control group (14.3 days [SD 9.1] vs 11.6 days [SD 8.2]; absolute difference 2.7 days, 95% CI 1.4 to 4.1, p<0.0001). INTERPRETATION A procalcitonin-guided strategy to treat suspected bacterial infections in non-surgical patients in intensive care units could reduce antibiotic exposure and selective pressure with no apparent adverse outcomes. FUNDING Assistance Publique-Hôpitaux de Paris, France, and Brahms, Germany.

Cardiac troponin I is an independent predictor of in-hospital death after adult cardiac surgery.

Background Although myocardial injury during cardiac surgery is associated with impaired clinical outcome, little is known about the prognostic value of cardiac troponin I (cTnI), a cardiac-specific biologic marker. The purpose of this prospective study was to evaluate the prognostic value of cTnI concentrations measured 20 h after the end of surgery in adult patients undergoing coronary artery bypass grafting or conventional valve surgery. Methods Baseline and perioperative characteristics of 502 consecutive patients undergoing conventional heart surgery during a 1-yr period were collected. In-hospital death (n = 28) and major clinical outcomes, e.g., low cardiac output, ventricular arrhythmia, and renal failure, were recorded. Results Multivariate analysis, using a stepwise logistic regression, showed that cTnI concentration was an independent predictor of in-hospital mortality (for cTnI concentration > 13 ng/ml, odds ratio = 6.7 [95% confidence interval, 2.3–19.3]), as were diabetes, altered preoperative cardiac function, emergent surgery, cardiopulmonary bypass duration, postoperative Pao2 level and total chest drainage volume. Further, elevated cTnI concentrations were associated with a cardiac cause of death and with major clinical outcomes. Conclusions Our results demonstrated that cTnI concentration measured 20 h after the end of surgery is an independent predictor of in-hospital death after cardiac surgery. In addition, elevated concentrations of cTnI are associated with a cardiac cause of death and with major postoperative complications.

Ischemia-Modified Albumin in Acute Stroke

Background: Ischemia-modified albumin (IMA)is a new biological marker of ischemia. Previous studies have found increased serum IMA levels after myocardial ischemia, but no study has investigated the possibility that stroke modifies IMA blood levels. Materials and Methods: We studied 118 consecutive patients presenting within 3 h of the onset of an acute neurological deficit [84 brain infarctions (BI), 18 brain hemorrhages (ICH) and 16 transient ischemic attacks lasting less than 1 h or epileptic seizures]. Serum samples were obtained for all patients at initial presentation and repeated only in patients with stroke at 6, 12 and 24 h. IMA was measured by the albumin-cobalt-binding test (Ischemia Technologies, Denver, Colo., USA). Results: The initial median IMA (bootstrap 95% confidence interval, CI) was 83 U/ml (79–86) and 86 U/ml (75–90) in patients with BI and ICH, respectively (p = 0.76), and was 73 U/ml (58–79) in others (p = 0.003 compared with BI, and p = 0.017 with ICH). Baseline IMA levels correlated with the National Institutes of Health Stroke Scale [Spearman correlation coefficient: 0.34 (p = 0.002) in BI, 0.61 (p = 0.008) in ICH]. During the first 24 h, IMA levels increased in BI patients (median, 9.1%; bootstrap 95% CI, 5.2–11.5), whereas no change was observed in ICH patients (median, 1.2%; bootstrap 95% CI, –7.8 to 6.8). Conclusions: IMA blood levels may be a biomarker for early identification of acute stroke. Further studies are required to investigate the role of IMA in the early detection of acute stroke.

Cardiac troponin I in diagnosis of perioperative myocardial infarction after cardiac surgery

OBJECTIVE The diagnosis of perioperative myocardial infarction (PMI) after cardiac surgery remains an important issue. The present study was designed to determine the relevance of the measurement of serum cardiac troponin I (cTnI, a biochemical marker with high cardiospecificity. Therefore, cTnI was compared with creatine kinase-MB (CK-MB) mass and to the other classical signs of myocardial infarction after cardiac surgery. DESIGN A prospective study. SETTING A university hospital. PARTICIPANTS Forty-one patients undergoing coronary artery bypass grafting (CABG) (n = 17) or valvular replacement (n = 24). These patients were separated into three groups according to postoperative complications: group 1, Q-wave PMI (n = 5); group 2, nonspecific changes (non-Q wave) on the electrocardiogram (ECG) and/or need of inotropic support (n = 12); group 3, no postoperative complication (n = 24). INTERVENTIONS Postoperative follow-up consisted of serial determination of different biochemical markers (CK, CK-MB, cTnI), ECGs, and echocardiography. Blood samples were drawn before (H0) and 3 (H3), 12 (H12), 20 (H20), 24 (H24), and 48 (H48) hours after the onset of cardiopulmonary bypass (CPB). MEASUREMENTS AND MAIN RESULTS In all patients in group 3, CK-MB and cTnI concentrations increased, and peaked at H12 after CPB (13.4 +/- 7.7 and 7.1 +/- 4.1 micrograms/L for CK-MB and cTnI, respectively). In group 1, cTnI concentrations were significantly higher than in group 3 from H12 until H48 (p < 0.002), peaked later (H24; 59.0 +/- 38.8 micrograms/L), and remained in plateau. In group 2, cTnI peak concentrations were significantly different than in groups 1 and 3 (26.2 +/- 14.8 micrograms/L) and occurred at H24 (as in patients with Q-wave PMI). CONCLUSION A cTnI concentration less than 15 micrograms/L (mean + 2 standard deviations [SDs] of peak cTnI in group 3) within 24 to 48 hours after cardiac surgery is highly suggestive of the absence of perioperative myocardial necrosis. Because of its higher cardiospecificity than CK-MB mass, and its prolonged release after myocardial necrosis, cTnI might be a useful tool in the diagnosis of PMI after cardiac surgery.

Plasma brain natriuretic peptide and cardiac troponin I concentrations after adult cardiac surgery: association with postoperative cardiac dysfunction and 1-year mortality.

Objective:The purpose of the present study was to evaluate the prognostic implications of perioperative B-type natriuretic peptide (BNP) and cardiac troponin I concentrations in patients undergoing cardiopulmonary bypass for cardiac surgery. Design:Prospective observational study. Setting:Biochemistry laboratory and surgical care unit in a university hospital. Patients:A total of 92 consecutive patients undergoing elective coronary artery (43 patients) or valve surgery (49 patients). Interventions:None. Measurements and Main Results:BNP and cardiac troponin I concentrations were measured before surgery (day 0), and at day 1 after surgery. Postoperative cardiac dysfunction was defined as low cardiac output or hemodynamic instability requiring inotropic support for >24 hrs or congestive heart failure until day 5. One-year survival was also evaluated. Univariate and multivariate analyses were performed. An important BNP secretion was systematically observed after cardiac surgery. Independent predictors of cardiac dysfunction were preoperative New York Health Association class and BNP and cardiac troponin I concentrations measured at day 1. Patients with an elevation of both markers have a 12-fold increased risk of postoperative heart failure. The use of both markers in combination predicted better postoperative heart failure than each one separately. Age, low preoperative left ventricular ejection fraction, and elevated BNP at day 1 (>352 pg/mL) were associated with an increased mortality rate at 1 yr. In multivariate analysis, only left ventricular ejection fraction was significantly associated with 1-yr survival. Conclusions:Postoperative plasma BNP and cardiac troponin I levels are independent predictors of postoperative cardiac dysfunction after cardiac surgery. Simultaneous measurement of BNP and cardiac troponin I improve the risk assessment of postoperative cardiac dysfunction. However, the association between BNP levels and 1-yr outcome was no longer significant after adjustment on left ventricular ejection fraction.

Ectopic respiratory epithelial cell differentiation in bronchiolised distal airspaces in idiopathic pulmonary fibrosis

Background Bronchiolisation of distal airspaces is an unexplained feature of idiopathic pulmonary fibrosis (IPF). The authors sought to identify mechanisms driving the differentiation of mucus cells during the bronchiolisation process. Methods Pathways governing airway mucus cell differentiation include SRY (sex determining region Y)-box 2 (SOX2), Notch, forkhead box A3(FOXA3)/SAM pointed domain containing ETS transcription factor (SPDEF), epidermal growth factor (EGF) and the EGF-related neuregulins NRG1α and NRG1β. Immunostaining for components of those pathways and mucins were performed on lung tissue obtained from patients with IPF (n=20), chronic obstructive pulmonary disease (n=13), idiopathic pulmonary artery hypertension (n=5) and from organ donors (n=6). NRG1α and NRG1β were quantified in bronchoalveolar lavage fluid (BALF) of patients with early IPF (n=20), controls (n=9), and patients with other interstitial pneumonias (n=13). Results In IPF, the bronchiolised and enlarged distal airspaces stained for SOX2 are consistent with epithelial differentiation characteristic of conducting airway epithelium. IPF mucus cells expressed MUC5B but low levels of MUC5AC and MUC2, a profile typical of submucosal glands. Singularly, SPDEF, a transcription factor associated with mucus metaplasia, was rarely detected in mucus cells in IPF. The Notch target, HES1, was present in mucus cells from all groups. NRG1α was detected in serous cells within normal submucosal glands and in epithelial cells lining honeycombing areas in IPF, and was not detected in other patients. NRG1α concentrations were elevated in BALF from patients with early IPF. Conclusion Expression of SOX2 and MUC5B and lack of SPDEF in atypically differentiated cells of bronchiolised distal airspaces are consistent with abnormal programming of airway epithelial cells in IPF. NRG1α may contribute to bronchiolisation of the distal lung seen in IPF.

Is there a place for preconditioning during cardiac operations in humans

BACKGROUND Activation of the kinase cascade (protein kinase C (PKC), tyrosine kinase (TK), and mitogen-activated protein kinase (MAPK) is a key feature of the transduction pathway, elicited by preconditioning signals and mediating their cardioprotective effects. We assessed whether such an activation occurred during cardiac operations and could thus represent a target for cardioprotective strategies. METHODS A total of 20 patients undergoing coronary artery bypass grafting surgery were studied. During the first 10 minutes of cardiopulmonary bypass (CPB), 10 were treated with sevoflurane (2.5 minimum alveolar concentration), an inhalational anesthetic that mimics preconditioning through a similar activation of the kinase cascade. Ten case-matched patients undergoing 10 minutes of sevoflurane-free CPB served as controls. Right atrial biopsies were taken before and 10 minutes after CPB and were then processed for the measurement of PKC, TK, and p38 MAPK activities by enzyme assay techniques. Troponin I was also monitored over the first 2 postoperative days. RESULTS Compared with pre-CPB values, PKC and p38 MAPK activities (in nanomoles per milligram of protein per minute and arbitrary units, respectively) increased significantly and to the same extent in both groups: PKC, from 20.7+/-0.7 to 29.9+/-3.9 in controls (p = 0.037) and from 18.4+/-1.1 to 23.9+/-1.8 in sevoflurane (p = 0.016); p38 MAPK, from 88.6+/-8.5 to 312.9+/-66.2 in controls (p = 0.005) and from 114.6+/-14.7 to 213.4+/-51.8 in sevoflurane (p = 0.045). Conversely, sevoflurane triggered a significant increase in TK activity (from 68.5+/-1.4 to 83.7+/-2.9 picomoles per milligram of protein per minute p = 0.0015) which did not occur in controls (from 67.5+/-1.9 to 76.8+/-4.2 picomoles per milligram of protein per minute, p = 0.09). Likewise, the peak postoperative value of troponin I was not different between controls and sevoflurane-treated patients (3.4+/-0.6 vs 2.4+/-0.4, p = 0.21). CONCLUSIONS Cardiopulmonary bypass triggers an activation of the kinase cascade that is mechanistically linked to opening of potassium channels. The direct opening of these channels by the anesthetic sevoflurane does not increase kinase activation further, nor does it improve markers of cell necrosis, thus suggesting that pharmacologically targeting potassium channels may overlap the preconditioning-like effects of CPB alone.

The Hedgehog System Machinery Controls Transforming Growth Factor-β–Dependent Myofibroblastic Differentiation in Humans: Involvement in Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a devastating disease of unknown cause. Key signaling developmental pathways are aberrantly expressed in IPF. The hedgehog pathway plays a key role during fetal lung development and may be involved in lung fibrogenesis. We determined the expression pattern of several Sonic hedgehog (SHH) pathway members in normal and IPF human lung biopsies and primary fibroblasts. The effect of hedgehog pathway inhibition was assayed by lung fibroblast proliferation and differentiation with and without transforming growth factor (TGF)-β1. We showed that the hedgehog pathway was reactivated in the IPF lung. Importantly, we deciphered the cross talk between the hedgehog and TGF-β pathway in human lung fibroblasts. TGF-β1 modulated the expression of key components of the hedgehog pathway independent of Smoothened, the obligatory signal transducer of the pathway. Smoothened was required for TGF-β1-induced myofibroblastic differentiation of control fibroblasts, but differentiation of IPF fibroblasts was partially resistant to Smoothened inhibition. Furthermore, functional hedgehog pathway machinery from the primary cilium, as well as GLI-dependent transcription in the nucleus, was required for the TGF-β1 effects on normal and IPF fibroblasts during myofibroblastic differentiation. These data identify the GLI transcription factors as potential therapeutic targets in lung fibrosis.

Keratinocyte growth factor and hepatocyte growth factor in bronchoalveolar lavage fluid in acute respiratory distress syndrome patients.

Objectives To determine bronchoalveolar lavage (BAL) fluid concentrations of keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF), two potent growth factors for alveolar type II epithelial cells, in patients with acute respiratory distress syndrome (ARDS). Design Prospective study. Setting An adult trauma/surgical intensive care unit in an urban teaching hospital. Patients A total of 32 ventilated patients with pulmonary infiltrates prospectively identified with ARDS (n = 17) or without ARDS (n = 15), including eight patients with hydrostatic edema (HE), and ten nonventilated patients serving as controls. Interventions None. Measurements and Main Results BAL was performed 2.88 days ± 2.4, 3.5 days ± 2.4, and 2.3 days ± 2.2 after the lung insult in ARDS, HE, and other non-ARDS patients respectively (p = .32). KGF was detected in BAL fluid in 13 of the 17 ARDS patients (median, 31.6 pg/mL), in one patient with HE, and in none of other non-ARDS patients. In ARDS patients, detection of KGF in BAL was associated in BAL fluid with the detection of type III procollagen peptide (PIIIP), a biological marker of fibroproliferation. In ARDS patients, detection of KGF in BAL was associated with death (p = .02). HGF was detected in 15 ARDS patients (median, 855 pg/mL), in seven patients with HE (median, 294 pg/mL;p = .05 for the comparison with ARDS group), in six of other non-ARDS patients (median, 849 pg/mL;p = .32 with ARDS group). HGF concentrations were higher in nonsurvivors than in survivors (p = .01). None of the ten BAL of controls contained either KGF or HGF. Conclusion KGF was detected almost exclusively in BAL fluid from ARDS patients and correlated with a poor prognosis in this group. In contrast, HGF was detected in the BAL fluid from a majority of patients with or without ARDS. Elevated HGF concentrations were associated with a poor prognosis in the overall group.

Halogenated Anesthetics Reduce Interleukin-1β-induced Cytokine Secretion by Rat Alveolar Type II Cells in Primary Culture

Background Alveolar epithelial type II (ATII) cells participate in the intraalveolar cytokine network by secreting cytokines and are widely exposed to volatile anesthetics during general anesthesia. The aim of the current study was to evaluate the effects of halothane, enflurane, and isoflurane on rat ATII cell cytokine secretions in ATII primary cell cultures. Methods Alveolar epithelial type II primary cell cultures were obtained from adult rat lungs. ATII cells were stimulated by recombinant murine interleukin-1&bgr; (rmIL-1&bgr;) to mimic an inflammatory response, and immediately exposed for various duration to different concentration of halothane, enflurane, or isoflurane. Interleukin-6, macrophage inflammatory protein-2 (MIP-2), and monocyte chemoattractant protein-1 (MCP-1) protein concentrations were then measured in cell culture supernatants. Recombinant mIL-1&bgr;-stimulated ATII cells exposed to air served as control. Results Halothane, isoflurane, and enflurane (1 minimum alveolar concentration [MAC], 4 h) decreased rmIL-1&bgr;-stimulated ATII cell secretions of interleukin-6, MIP-2, and MCP-1, but did not modify total protein secretion. Halothane exposure decreased rmIL-1&bgr;-stimulated ATII cell secretions of interleukin-6, MIP-2, and MCP-1 in a dose- and time-dependent manner. Total protein concentrations remained unchanged except at 1.5 MAC of halothane, and no cytotoxic effect could be evidenced by lactate dehydrogenase release. These effects were transient as rmIL-1&bgr;-stimulated ATII cell secretions of interleukin-6 and MIP-2 progressively reached control values between 4 and 24 h after the end of halothane exposure. However, MCP-1 inhibition persisted until 24 h. rmIL-1&bgr;-induced MIP-2 and tumor necrosis factor-&agr; mRNA expression were decreased by 36 and 24%, respectively, after halothane exposure. Conclusions The current study shows that exposure of rmIL-1&bgr;-stimulated ATII cells to volatile anesthetics reversibly alters their cytokine secretion. Therefore, volatile anesthesia, by modulating pulmonary epithelial cell secretion of inflammatory cytokines, might affect the lung inflammatory response.