Functional outcome of prolonged refractory status epilepticus.

INTRODUCTION: To characterize etiology, clinical course and outcomes of patients in prolonged refractory status epilepticus (PRSE) and looking for prognostic factors. METHODS: Retrospective study conducted in patients hospitalized from January 1, 2001 to December 31, 2011 in 19 polyvalent intensive care units in French university and general hospitals. Patients were adults with a generalized convulsive refractory status epilepticus that lasted more than seven days, despite treatment including an anesthetic drug and mechanical ventilation. Patients with anoxic encephalopathy were excluded. Follow-up phone call was used to determine functional outcome using modified Rankin Scale (mRS) with mRS 0-3 defining good and mRS 4-6 poor outcome. RESULTS: 78 patients (35 female) were included. Median age was 57 years. Causes of status epilepticus were various, mainly including prior epilepsy (14.1%), CNS infection (12.8%), and stroke (12.8%). No etiology was found in 27 (34.6%) patients. PRSE was considered controlled in only 53 (67.9%) patients after a median duration of 17 (IQR 12-26) days. The median length of ICU stay was 28 (19-48) days. Forty-one (52.5%) patients died in the ICU, 26 from multiple organ failure, 8 from care withdrawal, 2 from sudden cardiac arrest, 1 from brain death and 4 from unknown causes. PRSE was previously resolved in 20 patients who died in the ICU. At one-year follow-up, there were 12 patients with good outcome and 58 with poor outcome and 8 lost of follow-up. On multivariate analysis, only vasopressor use was a predictor of poor outcome (OR 6.54; 95%CI 1.09-39.29; p = 0.04). CONCLUSION: Poor outcome was observed in about 80% of this population of PRSE. Most patients died from systemic complications linked to their ICU stay. Some patients can recover satisfactorily over time though we did not identify any robust factor of good outcome.

Relevance of the ISGLS definition of posthepatectomy liver failure in early prediction of poor outcome after liver resection: study on 680 hepatectomies.

OBJECTIVE: To assess the relevance of the International Study Group of Liver Surgery (ISGLS) definition of posthepatectomy liver failure compared with 2 well-established criteria, 50-50 and PeakBili>7, as early predictors of posthepatectomy outcome. BACKGROUND: There is limited data on the postoperative use of ISGLS definition of posthepatectomy liver failure as early predictor of outcome. METHODS: Between 2007 and 2012, a total of 680 hepatectomies were analyzed from a prospective database. The value of each definition for prediction of 3-month major complications (Clavien III-V) and mortality was assessed either within 10 days of surgery or on postoperative day 5. RESULTS: Three-month major morbidity and mortality rates were 16.5% and 4.4%, respectively. Within 10 days, 79 patients fulfilled ISGLS definition compared with 24 for 50-50 and 44 for PeakBili>7 criteria. Sensitivities of ISGLS definition and 50-50 and PeakBili>7 criteria for prediction of major morbidity and mortality were 35.8, 17.4, 24.8% and 56.7, 36.7, 56.7%, respectively. Patients with no positive score had a risk of death or major complication below 5% and 15%, respectively. In patients with a positive score, the ISGLS definition was the least relevant to predict major complications and mortality (positive predictive values of 49.4% and 21.8% vs 79.2% and 47.8% for 50-50 and 61.4% and 40.5% for PeakBili>7 criteria). The relative risk of death was 6.9 (95% confidence interval, 3.1-15.4) if the ISGLS definition was evaluated on postoperative day 5 versus 21.1 (95% confidence interval, 7.7-57.7) for 50-50 and 21.7 (95% confidence interval, 7.4-63.3) for PeakBili>7 criteria. CONCLUSIONS: ISGLS definition was less discriminatory than 50-50 and PeakBili>7 criteria in identifying patients at risk of posthepatectomy major complications or death.

A composite score combining procalcitonin, C-reactive protein and temperature has a high positive predictive value for the diagnosis of intensive care-acquired infections.

BACKGROUND: Nosocomial infection diagnosis in the intensive care unit (ICU) remains a challenge. We compared routine measurements of procalcitonin (PCT), C-reactive protein (CRP), white blood cell count (WBC) and temperature in the detection of ICU-acquired infections. METHOD: Prospective observational cohort study in a University hospital Medicosurgical ICU. All patients admitted to the ICU ≥ 5 days (n = 141) were included into two groups, either infected (documented infection, n = 25) or non-infected (discharged from the ICU without diagnosis of infection, n = 88). RESULTS: PCT, CRP, WBC and temperature progression from day -4 (D-4) to day 0 (D0) (day of infection diagnosis or ICU discharge) was analysed. Differences (Δ) were calculated as D0 levels minus the lowest preceding value. D0 PCT and CRP were significantly increased in infected compared to non-infected patients (median, 1st and 3rd quartiles): 3.6 ng/mL (0.92-25) for PCT, 173 mg/L (126-188) for CRP versus 0.02 ng/mL (0.1-0.9) and 57 mg/mL (31-105) respectively (p < 0.0001). In multivariate analysis, D0 temperature > 38.6°C, PCT > 1.86 ng/mL, and CRP > 88 mg/L, performed well (AUCs of 0.88, 0.84, and 0.88 respectively). The sensitivity/specificity profiles of each marker (76%/94% for temperature, 68%/91% for PCT, and 92%/70% for CRP) led to a composite score (0.068 × D0 PCT + 0.005 × D0 CRP + 0.7 × temperature) more highly specific than each component (AUC of 0.90 and sensitivity/specificity of 80%/97%). CONCLUSION: Combining CRP, PCT and temperature is an approach which may increase of nosocomial infection detection in the ICU.

Severe sepsis, coagulation, and fibrinolysis: dead end or one way?

It was suggested more than 30 yrs ago that inhibition of the clotting cascade by natural anticoagulants could decrease the high mortality observed in patients suffering from severe sepsis and septic shock. Unfortunately, this therapeutic "paradigm" has led to a dead end, illustrated by the failure of all randomized trials and the recent withdrawal of recombinant activated protein C. Should we now definitely give up trying to treat septic coagulation disturbances or is there any therapeutic alternative?

Decompressive surgery for malignant middle cerebral artery infarcts: the results of randomized trials can be reproduced in daily practice.

BACKGROUND: In clinical randomized controlled trials (RCTs), decompressive surgery (DS) for malignant middle cerebral artery (MMCA) infarcts leads to a 50% absolute risk reduction in mortality, and improves the 1-year functional outcome. The reproducibility of these results in routine practice has never been evaluated. The purpose of this study was to test the hypothesis that the results of DS for MMCA in practice are similar to those observed in the surgical group of RCTs. METHODS: We prospectively included the first 31 patients who underwent DS for MMCA. They were screened based on similar criteria as in the meta-analysis. The primary outcome was a modified Rankin Scale (mRS) score of ≤4, and secondary outcomes were mRS of ≤3 and death at 1 year. RESULTS: Thirty-one patients underwent DS for MMCA. The 1-year mRS was ≤4 in 22 patients (71.0%) and ≤3 in 16 (51.6%). Seven patients died (22.6%). CONCLUSION: This observational study showed that DS for MMCA in a center without previous experience provides similar results as those obtained in the surgical arm of RCTs.

A simple functional marker to predict the need for prolonged mechanical ventilation in patients with Guillain-Barré syndrome.

INTRODUCTION: Patients suffering from Guillain-Barré syndrome (GBS) may frequently develop an acute respiratory failure and need ventilatory support. Immune therapy using plasma exchange or immunoglobulins has modified the natural course of the disease and by decreasing the length of the plateau phase, may induce a rapid improvement in ventilatory function. However a substantial proportion of patients still require prolonged mechanical ventilation (MV) and tracheotomy. The present study was designed to search for simple functional markers that could predict the need for prolonged MV just after completion of immune therapy. METHODS: We analyzed the data collected in a cohort of patients with GBS admitted to the intensive care unit (ICU) of our university hospital between 1996 and 2009. Demographic, clinical, biological and electrophysiologic data, results of sequential spirometry, and times of endotracheal intubation, tracheotomy, and MV weaning were prospectively collected for all patients. Sequential daily neurological testing used standardized data collection by the same investigators all along the study period. Results were compared by single and multiple regression analysis at admission to ICU and at the end of immune therapy, according to the need and duration of MV (≤ or > 15 days). RESULTS: Sixty-one patients with severe GBS were studied. Sixty-six percent required MV (median length: 24 days). The lack of foot flexion ability at ICU admission and at the end of immunotherapy was significantly associated with MV length > 15 days (positive predictive value: 82%; odds ratio: 5.4 [1.2 - 23.8] and 82%; 6.4 [1.4 - 28.8], respectively). The association of a sciatic nerve motor conduction block with the lack of foot flexion at the end of immunotherapy was associated with prolonged MV with a 100% positive predictive value. CONCLUSIONS: In patients admitted to ICU with Guillain-Barré syndrome and acute respiratory failure, the lack of foot flexion ability at the end of immune therapy predicts a prolonged duration of MV. Combined with a sciatic motor conduction block, it may be a strong argument to perform an early tracheotomy.

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer.

BACKGROUND: Tramadol is a synthetic, centrally acting analgesic for the treatment of moderate to severe pain. The marketed tramadol is a racemic mixture containing 50% (+)tramadol and 50% (-)tramadol and is mainly metabolized to O-desmethyltramadol (M1) by the cytochrome P450 CYP2D6. Tramadol is generally considered to be devoid of any serious adverse effects of traditional opioid receptor agonists, such as respiratory depression and drug dependence. CASE REPORT: A 22-year-old Caucasian female patient was admitted to our ICU in refractory cardiac arrest requiring extracorporeal membrane oxygenation. This aggressive support allowed resolution of multi-organ dysfunction syndrome. Repeated blood analyses using liquid chromatography-tandem mass spectrometry confirmed high concentrations of both tramadol and its main metabolite O-desmethyltramadol. Genotyping of CYP2D6 revealed the patient to be heterozygous for a duplicated wild-type allele, predictive of a CYP2D6 ultrarapid metabolizer (UM) phenotype, confirmed by calculation of the tramadol/M1 (MR1) metabolic ratio at all time points. DISCUSSION: We here report a case of near-fatal isolated tramadol cardiotoxicity. Because of the inhibition of norepinephrine reuptake, excessive blood epinephrine levels in this CYP2D6R UM patient following excessive tramadol ingestion could explain the observed strong myocardial stunning. This patient admitted intermittent tramadol consumption to gain a "high" sensation. In patients with excessive morphinomimetic effects, levels of tramadol and its main metabolite M1could be measured, ideally combined with CYP2D6 genotyping, to identify individuals at risk of tramadol-related cardiotoxicity. Tramadol treatment could be optimized in these at-risk individuals, consequently improving patient outcome and safety.

Metformin-associated lactic acidosis: a prognostic and therapeutic study.

OBJECTIVES: Metformin-associated lactic acidosis is a rare and serious complication of biguanide treatment. It usually occurs when a precipitating disease induces an acute renal failure and an incidental overdose. Voluntary intoxication is rare. Bicarbonate hemodialysis (HD) is recommended to decrease metformin levels and correct acidosis but its optimal duration has not been determined. This study was designed to document the characteristics and prognostic factors of intentional and incidental metformin overdose and to determine the optimal duration of HD. DESIGN: Ten years retrospective analysis of patients admitted in intensive care unit for metformin-associated lactic acidosis. SETTING: Two intensive care units (50 beds) in a university hospital. MEASUREMENTS AND MAIN RESULTS: Clinical and biological characteristics, organ failures, and sequential metformin levels during HD were recorded. Forty-two patients were included (13 voluntary intoxications and 29 incidental overdoses); 74% of patients were in acute renal failure and needed HD. No death was observed in intentional overdose patients compared with 48.3% mortality in incidental overdose patients. The factors significantly associated with mortality were logistic organ dysfunction system score, pH, plasma lactate, and prothrombin activity. By multivariate analysis, a prothrombin activity <50% was the only independent predictive factor of mortality (relative risk: 59.8; confidence limits: 6.3-568; p < 0.0001). Sequential measurements of metformin levels during HD were consistent with a bicompartmental elimination pattern. A cumulative HD duration of 15 hours was associated with the return of metformin level to the therapeutic normal range. CONCLUSIONS: In our study, the outcome of MALA was uniformly favorable after intentional metformin overdose. The vital prognosis was mainly influenced by the occurrence of multiple organ dysfunctions, the best predictive factor of death being an acute liver dysfunction as assessed by PT activity. Prolonged HD was needed to correct metformin overdose.

High-dose intravenous immunoglobulins dramatically reverse systemic capillary leak syndrome.

OBJECTIVE: The objective of this study was to report the dramatic improvement of patients with systemic capillary leak syndrome obtained with high-dose intravenous immunoglobulins. DESIGN: Systemic capillary leak syndrome is a rare and life-threatening disorder characterized by hypotension that can lead to shock, weight gain, hypoalbuminemia, and elevated hematocrit secondary to unexplained episodic capillary fluid extravasation into the interstitial space. Because its cause is unknown, systemic capillary leak syndrome treatment has remained largely supportive. MAIN RESULTS: Intravenous immunoglobulins administration to a patient with refractory systemic capillary leak syndrome yielded dramatic improvement. The patient is still alive 11 yrs after systemic capillary leak syndrome diagnosis and receives intravenous immunoglobulins monthly. Later, based on that result, intravenous immunoglobulins were successfully given to two other patients during the acute phase of systemic capillary leak syndrome. Both are still alive 8 and 1.5 yrs after receiving intravenous immunoglobulins at the onset of each flare. CONCLUSIONS: Intravenous immunoglobulins were effective against systemic capillary leak syndrome symptoms in three patients, but their exact mechanism remains unknown. Their immunomodulatory effect merits further investigation.

Evaluation of BCECF fluorescence ratio imaging to properly measure gastric intramucosal pH variations in vivo.

Our purpose is to evaluate intramucosal gastric pH video imaging by 2('),7(')-bis(carboxyethyl)-5,6-carboxyfluorescein (BCECF) fluorescence ratio techniques. We use a video endoscopic imaging system and BCECF as the pH fluorescent probe. Systemic in vivo pH variations are studied in 10 pigs: five in the control group and five with respiratory acidosis induced through rebreathing. The intramucosal pH of the gastric wall is measured every 5 s and the results demonstrate a good correlation (pearson correlation=0.832) between blood gases pH measurements and pH measured with the video endocopic imaging system. Our results confirm the feasibility of using BCECF fluorescence pH imaging to measure intramucosal pH in vivo.

Extracorporeal membrane oxygenation in severe acute respiratory failure in postpartum woman with rheumatic mitral valve disease: benefit, factors furthering the success of this procedure, and review of the literature.

Pregnancy is a common decompensation factor for women with post-rheumatic mitral disease. However, valvular heart diseases causing severe acute respiratory distress are rare. Use of extracorporeal membrane oxygenation (ECMO) early in the event of cardiorespiratory failure after cardiac surgery may be of benefit. Indeed, ECMO cardiopulmonary bypass (CPB) support could help pulmonary recovery if the mitral pathology is involved. A 31-year-old female patient at 30 weeks of amenorrhea was admitted to the obstetrics department with 40 degrees C hyperthermia and New York Heart Association (NYHA) class 4 dyspnea. The patient's medical history included a post-rheumatic mitral stenosis. Blood gases showed severe hypoxemia associated with hypocapnia. The patient needed to be rapidly intubated and was placed on ventilatory support because of acute respiratory failure. Transesophageal echocardiography showed a severe mitral stenosis, mild mitral insufficiency, and diminished left ventricular function, hypokinetic, dilated right ventricle, and a severe tricuspid regurgitation. An urgent cesarean section was performed. Because of the persistent hemodynamic instability, a mitral valvular replacement and tricuspid valve annuloplasty were performed. In view of the preoperative acute respiratory distress, we decided, at the beginning of the operation, to carry on circulatory support with oxygenation through an ECMO-type CPB at the end of the operation. This decision was totally justified by the unfeasible CPB weaning off. ECMO use led to an efficient hemodynamic state without inotropic drug support. The surgical post-operative course was uneventful. Early use of cardiorespiratory support with veno-arterial ECMO allows pulmonary and right heart recovery after cardiac surgery, thus avoiding the use of inotropic drugs and complex ventilatory support.

Evidence-based medicine criticism / Critique de l'evidence-based medicine

Evidence-based medicine criticism. Evidence-based medicine is now considered as the rule in the practice of clinical medicine. It covers however a lot of issues and limitations, leading to numerous and severe pitfalls. Most are described and discussed in this review.

Critique de l'évidence - based medicine. En 20 ans, la médecine fondée sur la recherche des preuves a imposé ses principes et ses méthodes. Elle a aussi conduit à des dommages, des insuffisances et parfois à la constitution d'une dictature sans contrôle. Cet article décrit les inconvénients majeurs de l'evidence-based medicine dans la pratique clinique.

Patients with ANCA-associated vasculitis admitted to the intensive care unit with acute vasculitis manifestations: a retrospective and comparative multicentric study.

PURPOSE: Data for ANCA-associated vasculitis (AAV) patients requiring intensive care are scarce. METHODS: We included 97 consecutive patients with acute AAV manifestations (new onset or relapsing disease), admitted to 18 intensive care units (ICUs) over a 10-year period (2002-2012). A group of 95 consecutive AAV patients with new onset or relapsing disease, admitted to two nephrology departments with acute vasculitis manifestations, constituted the control group. RESULTS: In the ICU group, patients predominantly showed granulomatosis with polyangiitis and proteinase-3 ANCAs. Compared with the non-ICU group, the ICU group showed comparable Birmingham vasculitis activity score and a higher frequency of heart, central nervous system and lungs involvements. Respiratory assistance, renal replacement therapy and vasopressors were required in 68.0, 56.7 and 26.8% of ICU patients, respectively. All but one patient (99%) received glucocorticoids, 85.6% received cyclophosphamide, and 49.5% had plasma exchanges as remission induction regimens. Fifteen (15.5%) patients died during the ICU stay. The following were significantly associated with ICU mortality in the univariate analysis: the need for respiratory assistance, the use of vasopressors, the occurrence of at least one infection event in ICU, cyclophosphamide treatment, sequential organ failure assessment at admission and simplified acute physiology score II. After adjustment on sequential organ failure assessment or infection, cyclophosphamide was no longer a risk factor for mortality. Despite a higher initial mortality rate of ICU patients within the first hospital stay (p < 0.0001), the long-term mortality of hospital survivors did not differ between ICU and non-ICU groups (18.6 and 20.4%, respectively, p = 0.36). Moreover, we observed no renal survival difference between groups after a 1-year follow-up (82.1 and 80.5%, p = 0.94). CONCLUSION: This study supports the idea that experiencing an ICU challenge does not impact the long-term prognosis of AAV patients.

Management of postintubation tracheobronchial ruptures.

STUDY OBJECTIVES: To determine whether nonoperative management can be applied to iatrogenic postintubation tracheobronchial rupture (TBR). DESIGN: Prospective cohort study. PATIENTS AND INTERVENTIONS: Thirty consecutive patients with TBR complicating intubation between June 1993 and December 2005 entered the study. Patients not receiving mechanical ventilation at time of diagnosis were treated nonsurgically. Patients receiving mechanical ventilation who were judged operable underwent surgical repair, while nonoperable candidates had their TBR bridged by endotracheal tubes. RESULTS: Fifteen patients not requiring mechanical ventilation underwent simple conservative management. TBR length measured 3.85 +/- 1.46 cm (mean +/- SD). Eight TBRs showed full-thickness rupture with frank anterior intraluminal protrusion of the esophagus. In three patients, transient noninvasive positive pressure ventilatory support (NIV) was necessary. All lesions healed without sequelae. Two patients receiving mechanical ventilation underwent surgical repair and died. Thirteen patients receiving mechanical ventilation were considered at high surgical risk, and TBR bridging was attempted as salvage therapy. Complete bridging was achieved in five patients by simply advancing the endotracheal tube distal to the injury. Separate bilateral mainstem endobronchial intubation was necessary in six patients whose TBRs were too close to the carina. Nine of 13 patients (69%) treated with nonoperative therapy completely recovered. CONCLUSION: We conclude that conservative nonoperative therapy should be considered in patients with postintubation TBR who are breathing spontaneously, or when extubation is scheduled within 24 h from the time of diagnosis, or when continued ventilation is required to treat an underlying respiratory status. Surgical repair should be reserved for cases in which NIV or bridging the lesion is technically not feasible.

Intravenous administration of activated protein C in Pseudomonas-induced lung injury: impact on lung fluid balance and the inflammatory response.

BACKGROUND: Acute lung injury (ALI) induces a coagulation/fibrinolysis imbalance and leads to fibrin deposition. The protein C pathway is an important regulator of the coagulation system and reduces the inflammatory response. The aim of the study was to examine the effects of recombinant human activated protein C (rhAPC) in the early phase of Pseudomonas aeruginosa (Pa)-induced lung injury. METHODS: The study was conducted in vivo on a rat model of Pa-induced ALI. Continuous intravenous (IV) rhAPC was administrated simultaneously with intratracheal (IT) Pa. We instilled into the airspaces a 5% bovine albumin solution with 1 mu(Ci of (125)I-albumin and injected IV 1 mu(Ci of (111)In-albumin to measure lung liquid clearance (LLC) and endothelial injury. Cytokines levels (TNFalpha and IL-6) and thrombin-antithrombin (TAT) complexes were measured in blood and bronchoalveolar lavage fluid (BALF) at 4 hours. Four groups were compared: control (CTR), pneumonia (PNP) receiving IT Pa (0.5 ml/kg of 1 x 10(9) cfu), APC: IV rhAPC (300 microg/kg/h), A-PNP: IT Pa /IV rhAPC. RESULTS: Alveolar-capillary permeability was increased in the PNP versus the CTR group (0.28 +/- 0.08 vs. 0.03 +/- 0.01, p < 0.05). IV rhAPC in Pa-induced ALI led to further injury (0.47 +/- 0.17 vs. 0.28 +/- 0.08, p = 0.2). The LLC was significantly decreased in the A-PNP group compared to PNP group (9.1 +/- (4.3% vs. 33.4 +/- 2.6%, p < 0.05). The lung wet to dry weight ratio was significantly increased in the PNP group (4.62 +/- 0.31) compared to the CTR group (3.87 +/- 0.22, p < 0.05). IV rhAPC administration tends to increase this parameter in Pa-induced ALI (5.80 +/- 0.66, p = 0.07). These findings were associated with a loss of inflammatory response compartmentalization measured by TNFalpha and IL-6 systemic levels. TAT complexes in BALF were increased in the A-PNP group (23.17 +/- 2.89 ng/ml) compared to the CTR group (0.92 +/- 0.17 ng/ml, p < 0.05) and the PNP group (11.06 +/- 2.76 ng/ml, p < 0.05). CONCLUSION: rhAPC reduces LLC following Pa-induced ALI and may influence pulmonary edema formation. The early massive fibrin formation is probably beneficial in ALI limiting both the extent of injury and permeability disorders.

Comparison of Two Diagnostic Scores of Disseminated Intravascular Coagulation in Pregnant Women Admitted to the ICU.

OBJECTIVE: To compare the validity of two previously published diagnostic scores of disseminated intravascular coagulation (DIC) in pregnant women admitted to ICU for an acute thrombotic or hemorrhagic complication of delivery and postpartum. METHODS: This was a population based retrospective study of 154 patients admitted to ICU for severe delivery and postpartum complications in a University Hospital. A recently published score (adapted to physiological changes of pregnancy and based on three components: platelet count, prothrombin time difference and fibrinogen) was compared to the International Society for Thrombosis and Hemostasis (ISTH) score (based on four components: platelet count, fibrinogen, prothrombin time, and fibrin related marker). Both scores were calculated at delivery, ICU admission (day 0), day 1 and day 2 during the postpartum ICU stay. The validity of both scores was assessed by comparison with the consensual and blinded analysis of two experts. The sensitivity, specificity, and area under the curve (AUC) of each score were calculated at each time and overall by generalized linear mixed model. The agreement between the two scores was evaluated by the Kappa coefficient. RESULTS: The new score had a sensitivity of 0.78, a specificity of 0.97 (p <0.01) and a global AUC of 96% while the ISTH score had a sensitivity of 0.31, a specificity of 0.99 and an AUC of 94% (p <0.01). The Kappa coefficient of correlation between both scores was 0.35. The lower sensitivity of the ISTH score was mainly explained by the lack of fibrinogen and fibrin-related peptides thresholds adapted to the physiological changes of coagulation induced by pregnancy. CONCLUSION: The new DIC score seem highly discriminant in the subset of patients admitted to the ICU after delivery for an acute specific complication. The ISTH score is not recommended in pregnant women because of its poor sensitivity.

Massive alveolar thrombin activation in Pseudomonas aeruginosa-induced acute lung injury.

In acute lung injury (ALI), a coagulation/fibrinolysis imbalance leads to fibrin deposition, persistence of which contributes to fibrotic evolution. Our study evaluated the effects of early inhibition of coagulation in Pseudomonas aeruginosa (Pa)-induced ALI through the use of recombinant human antithrombin (rhAT). The study was conducted in vivo on a murine model of Pa-induced ALI. Intravenous rhAT was administered simultaneously with intratracheal Pa. Four experimental groups were compared: CTR, intratracheal saline (0.5 mL/kg)/intravenous saline (1 mL); PNP, intratracheal Pa (0.5 mL/kg of 2 x 10(9) cfu)/intravenous saline; AT, intratracheal saline/intravenous rhAT (500 IU/kg); ATPNP, intratracheal Pa/intravenous rhAT. Epithelial and endothelial permeabilities were evaluated with radiolabeled albumin flux across the alveolar barrier (125I- and 131I-labeled albumin). Thrombin-antithrombin (TAT) complexes levels were used as markers of coagulation activation in blood samples and in BAL fluid. Epithelial and endothelial protein permeability were increased in Pa-induced ALI versus control. Intravenous rhAT administration led to further permeability disorders. Administration of rhAT in Pa ALI led to a rise in TAT complexes in ATPNP blood serum and BAL fluids compared with the other groups. In Pa-induced ALI the administration intravenous rhAT leads to major histologic damage, alveolar capillary barrier injury, and permeability increase. Such effects of the inhibition of thrombin activation by rhAT lead to the hypothesis of a probable beneficial role of early coagulation activation in ALI as a factor limiting both the extent of injury and permeability disorders. Our study suggests that inhibition of this initial procoagulative imbalance is potentially dangerous.

Combined antithrombin and protein C supplementation in meningococcal purpura fulminans: a pharmacokinetic study.

PURPOSE: To document in patients with meningococcal purpura fulminans (PF), the effects of a combined supplementation with antithrombin (AT) and protein C (PC) plasma concentrates and to estimate the pharmacokinetics and dose requirements of each inhibitor. DESIGN: Retrospective study of 15 patients. SETTING. One paediatric and one adult ICU in a university hospital. INTERVENTIONS: In addition to standard intensive care, all patients received a 100 IU/kg loading dose of AT and PC concentrates, followed by a continuous infusion (AT: 100-150 IU.kg.day; PC: 100 IU.kg.day in adults, and 400 IU/kg in infants). MEASUREMENTS: Clinical data, coagulation, and fibrinolysis parameters, AT and PC activities, and free protein S (PS) levels were sequentially measured. Restitution ratio, median increment after supplementation, and half-life of clearance from plasma were calculated for the two plasma substitutes. RESULTS. At admission, all patients had a severe decrease in AT, PC, and PS levels. The supplementation regimen induced a substantial increase in AT and PC activities, peaking at H18 and H48, respectively. The supplementation procedure did not modify free PS levels. The median values of AT and PC restitution ratio, increment in plasma activity observed after 100 IU/kg concentrate, and apparent half-life of clearance from plasma were 0.85 U.ml.U.kg and 0.59 U.ml.U.kg, 23% and 21%, 16 h and 6 h, respectively. CONCLUSION: If AT and PC concentrates are to be given in fulminant meningococcemia, the doses of supplementation should be at least 150 IU/kg AT and 250 IU/kg PC as loading dose and 150 IU/kg AT and 200 IU/kg PC as daily maintenance therapy. Taking into account the individual variability in inhibitor deficiency and restitution ratio, repeated measurements of plasma levels are mandatory to obtain a patient-based adjustment of the supplementation.