Predictive Factors for Death After Snake Envenomation in Myanmar.

INTRODUCTION: Factors predictive for death from snake envenomation vary between studies, possibly due to variation in host genetic factors and venom composition. This study aimed to evaluate predictive factors for death from snake envenomation in Myanmar. METHODS: A prospective study was performed among adult patients with snakebite admitted to tertiary hospitals in Yangon, Myanmar, from May 2015 to August 2016. Data including clinical variables and laboratory parameters, management, and outcomes were evaluated. Multivariate regression analysis was performed to evaluate factors predictive for death at the time of presentation to the hospital. RESULTS: Of the 246 patients with snake envenomation recruited into the study, 225 (92%) survived and 21 (8%) died during hospitalization. The snake species responsible for a bite was identified in 74 (30%) of the patients; the majority of bites were from Russell's vipers (63 patients, 85%). The independent factors predictive for death included 1) duration from bite to arrival at the hospital >1 h (odds ratio [OR]: 9.0, 95% confidence interval [CI]: 1.1-75.2; P=0.04); 2) white blood cell counts >20 ×103 cells·µL-1 (OR: 8.9, 95% CI: 2.3-33.7; P=0.001); and 3) the presence of capillary leakage (OR: 3.7, 95% CI: 1.2-11.2; P=0.02). A delay in antivenom administration >4 h increases risk of death (11/21 deaths). CONCLUSIONS: Patients who present with these independent predictive factors should be recognized and provided with early appropriate intervention to reduce the mortality rate among adults with snake envenomation in Myanmar.

Capillary leak syndrome in Daboia russelii bite-a complication associated with poor outcome.

Background: Capillary leak syndrome (CLS) has been previously observed as a complication of Daboia russelii bite but not clearly defined or studied in length. This observational case-control study evaluates the mortality along with associated clinical and laboratory features. Methods: Twenty-five patients who developed CLS were compared with 25 patients without CLS following Daboia russelii (Russell's viper) bite. Results: Development of CLS is associated with a significantly high risk of mortality; 11 (44%) patients with CLS died compared with 1 (4%) control (odds ratio 18.8 [95% confidence interval 2.2 to 161.99], p=0.002). Disease-defining manifestations included myalgia (22 [88%]), thirst (20 [80%]), parotid swelling (15 [60%]), conjunctival chemosis (19 [76%]) and hypotension (22 [88%]), which were unobserved in controls. Although several clinical and laboratory parameters were found to be predictive for development of CLS in univariate analysis, none of them had independent predictive value in multivariate analysis. Similarly, development of parotid swelling was the only factor with independent predictive value for mortality in multivariate analysis. Even though the number of vials of snake antivenom used is more in CLS, it seems unlikely to improve the mortality in CLS. Conclusions: This study proves that CLS is a well-defined complication of Russell's viper bite with high mortality but with clear predictors for the development of CLS and mortality.

[Clinical analysis of 34 cases with sepsis and systemic capillary leak syndrome].

Objective: To study the clinical characteristics of sepsis with systemic capillary leak syndrome(SCLS) and to evaluate the therapeutic effect and clinical significance of fluid therapy adjusted timely in these patients. Methods: The clinical data of 34 patients with sepsis and SCLS in the Department of Hepatobiliary Surgery ICU of General Hospital of People's Liberation Army General Hospital from July 2014 to January 2016 were retrospectively analyzed.There were 21 males and 13 females, aged from 21 to 74 years, with an average age of 56.3 years.Primary disease as follows: 18 cases with severe acute pancreatitis, 7 postoperative cases of subtotal hepatectomy, 5 postoperative cases of pancreatoduodenectomy, 4 postoperative cases of cholelithiasis.These patients were divided into survival group and death group according to their 28-day survival status.The clinical data including C-reactive protein(CRP), platelets (PLT), brain natriuretic peptide (BNP), the level of arterial blood lactic acid(LAC), oxygenation index(PaO2/FiO2, OI), net fluid balance(NFB) and norepinephrine dosage(NE) were collected and compared between two groups at three different intervals(day 1-3, day 4-6, day 7-9). The measurement data and numeration data were statistically analyzed with t test and χ2 test respectively to explore the inherent characteristics of the disease evolution and its clinical significance. Results: The survival group (n=23)and the death group(n=11)had no significant difference in the characteristics of basic clinical characters.The condition of the survival group and the death group were both in progress in 1-3 days period manifested as increased CRP(t=-0.473, P=0.640) and BNP levels(t=0.140, P=0.895), decreased PLT counts(t=-0.505, P=0.620) in the inflammatory response, decreased LAC(t=-1.008, P=0.320) and OI level (t=-2.379, P=0.020)in tissue perfusion index, and positive fluid balance(NFB: t=0.910, P=0.370), required NE(t=-0.853, P=0.400) to maintain effective perfusion pressure with systemic edema in both groups.There was no significant difference of all these clinical parameters between the two groups.The patients' condition of the survival group reached a plateau phase, whereas all relative indicators of the death group implied significant aggravation and deterioration of systemic infection(CRP: t=-3.438, P=0.000; PLT: t=1.649, P=0.110; BNP: t=-10.612, P=0.000), tissue perfusion (LAC: t=-11.305, P=0.000; OI: t=2.743, P=0.010)and tissue edema NFB(t=-4.257, P=0.000) and NE(t=-7.956, P=0.000) in 4-6 days period.In the last 7-9 days period the patients' condition of the survival group took a turn for improvement, yet the condition of the death group continued to deteriorate, refractory septic shock developed and multiple organ dysfunction syndrome followed afterwards inevitably(CRP: t=-10.036, P=0.000; PLT: t=6.061, P=0.000; BNP: t=-10.119, P=0.000; LAC: t=-24.466, P=0.000; OI: t=13.443, P=0.010; NFB: t=-8.345, P=0.000; NE: t=-7.121, P=0.000). Conclusions: The condition of patient with sepsis and SCLS would be improved markedly at the critical turning point around 7-9 days period since the effective systemic treatment began.If the infection does not be significantly constrolled and SCLS still remains in a sustained extravasation period in 7-9 days, the prognosis of these patients may be worse and the mortality may be higher than that of the patients mentioned before.

Intravenous Immunoglobulins Improve Survival in Monoclonal Gammopathy-Associated Systemic Capillary-Leak Syndrome.

BACKGROUND: Monoclonal gammopathy-associated systemic capillary-leak syndrome, also known as Clarkson disease, is a rare condition characterized by recurrent life-threatening episodes of capillary hyperpermeability in the context of a monoclonal gammopathy. This study was conducted to better describe the clinical characteristics, natural history, and long-term outcome of monoclonal gammopathy-associated systemic capillary-leak syndrome. METHODS: We conducted a cohort analysis of all patients included in the European Clarkson disease (EurêClark) registry between January 1997 and March 2016. From diagnosis to last follow-up, studied outcomes (eg, the frequency and severity of attacks, death, and evolution toward multiple myeloma) and the type of preventive treatments administered were monitored every 6 months. RESULTS: Sixty-nine patients (M/F sex ratio 1:1; mean ± SD age at disease onset 52 ± 12 years) were included in the study. All patients had monoclonal gammopathy of immunoglobulin G type, with kappa light chains in 47 (68%). Median (interquartile range) follow-up duration was 5.1 (2.5-9.7) years. Twenty-four patients (35%) died after 3.3 (0.9-8) years. Fifty-seven (86%) patients received at least one preventive treatment, including intravenous immunoglobulins (IVIg) n = 48 (73.8%), theophylline n = 22 (33.8%), terbutaline n = 22 (33.8%), and thalidomide n = 5 (7.7%). In the 65 patients with follow-up, 5- and 10-year survival rates were 78% (n = 35) and 69% (n = 17), respectively. Multivariate analysis found preventive treatment with IVIg (hazard ratio 0.27; 95% confidence interval, 0.10-0.70; P = .007) and terbutaline (hazard ratio 0.35; 95% confidence interval, 0.13-0.96; P = .041) to be independent predictors of mortality. CONCLUSIONS: We describe the largest cohort to date of patients with well-defined monoclonal gammopathy-associated systemic capillary-leak syndrome. Preventive treatment with IVIg was the strongest factor associated with survival, suggesting the use of IVIg as the first line in prevention therapy.

The Clinical Picture of Severe Systemic Capillary-Leak Syndrome Episodes Requiring ICU Admission.

OBJECTIVE: Systemic capillary-leak syndrome is a very rare cause of recurrent hypovolemic shock. Few data are available on its clinical manifestations, laboratory findings, and outcomes of those patients requiring ICU admission. This study was undertaken to describe the clinical pictures and ICU management of severe systemic capillary-leak syndrome episodes. DESIGN, SETTING, PATIENTS: This multicenter retrospective analysis concerned patients entered in the European Clarkson's disease (EurêClark) Registry and admitted to ICUs between May 1992 and February 2016. MEASUREMENTS AND MAIN RESULTS: Fifty-nine attacks occurring in 37 patients (male-to-female sex ratio, 1.05; mean ± SD age, 51 ± 11.4 yr) were included. Among 34 patients (91.9%) with monoclonal immunoglobulin G gammopathy, 20 (58.8%) had kappa light chains. ICU-admission hemoglobin and proteinemia were respectively median (interquartile range) 20.2 g/dL (17.9-22 g/dL) and 50 g/L (36.5-58.5 g/L). IV immunoglobulins were infused (IV immunoglobulin) during 15 episodes (25.4%). A compartment syndrome developed during 12 episodes (20.3%). Eleven (18.6%) in-ICU deaths occurred. Bivariable analyses (the 37 patients' last episodes) retained Sequential Organ-Failure Assessment score greater than 10 (odds ratio, 12.9 [95% CI, 1.2-140]; p = 0.04) and cumulated fluid-therapy volume greater than 10.7 L (odds ratio, 16.8 [1.6-180]; p = 0.02) as independent predictors of hospital mortality. CONCLUSIONS: We described the largest cohort of severe systemic capillary-leak syndrome flares requiring ICU admission. High-volume fluid therapy was independently associated with poorer outcomes. IV immunoglobulin use was not associated with improved survival; hence, their use should be considered prudently and needs further evaluation in future studies.

Snake bite mortality in children: beyond bite to needle time.

OBJECTIVE: To study the clinical characteristics and predictors of mortality from snake bite envenomation in children. DESIGN: Prospective observational study with a one-group cohort design. SETTING: Paediatric intensive care unit of a tertiary care hospital in South India. SUBJECTS: The study cohort consisted of 145 children (55 girls and 90 boys) <12 years of age with snake bite envenomation. METHODS: Demographic and clinical details were recorded in a semistructured pro forma. Children were treated with polyvalent antisnake venom (ASV) as per WHO protocol. Details of treatment, complications and outcomes were recorded. Univariate analysis was done to identify statistical significance, and those variables found to be significant were analysed using binary logistic regression. RESULTS: Russell's viper was the most common offending snake followed by hump-nosed pit viper. Features of haemotoxicity, neurotoxicity and combined haemotoxicity and neurotoxicity occurred in 68 (47%), 39 (26.9%) and 9 (6%) children, respectively. Acute kidney injury (AKI) occurred in 36 (25%) children. The mortality rate was 10.3%. On univariate analysis, nocturnal bites, severe leucocytosis on day 1, AKI, capillary leak syndrome and a need for more than 20 vials of ASV were significantly associated with mortality. On multivariate analysis, only severe leucocytosis on day 1 (OR 35.29; 95% CI 1.37 to 911.89) and AKI (OR 35.05 95% CI 1.74 to 706.93) were found to be independent predictors of mortality. CONCLUSIONS: This study has identified two hitherto unrecognised risk factors-severe leucocytosis on day 1 and capillary leak syndrome. These findings need to be taken into consideration when planning management strategies for snake bite envenomation in children.

[Is a different view on the pathophysiology of sepsis the key for novel therapeutic options?]. / Sepsis: neue Erkenntnisse, andere Perspektiven - neue Therapieoptionen?

Sepsis remains a critical problem in virtually all fields of clinical medicine. Despite intensive scientific and clinical efforts no significant progress has emerged in the fight against sepsis mortality. Solely the algorithm of the "surviving sepsis campaign" has proven to result in significantly enhanced survival of sepsis patients when consequently adopted. Novel research in the field of the complex immunological alterations in sepsis suggests that ongoing immunosuppression is the critical determinant underlying sepsis mortality. Therefore, it was proposed that immunostimulation might be a successful approach to improve outcome in individually selected patients. Others favor a different view on the pathophysiology of sepsis and support the notion that the manifestation of organ failure may be the dominant therapeutic target. Due to the fact that breakdown of the microcirculation and disruption of the microvascular barrier are critical events preceding organ failure, experimental therapeutic efforts to address these events led to promising results. Taken together, in view of the many initially promising experimental data and the failure to translate them into successful clinical therapies, a different view on the pathophysiology of sepsis is warranted to obtain the key for novel therapeutic options.

Effect of preoperational mechanical ventilation on short-term postoperative outcomes in patients with severe tetralogy of Fallot.

BACKGROUND: This study is designed to investigate the effect of preoperational mechanical ventilation on the short-term postoperative outcomes following corrective surgery for severe tetralogy of Fallot (TOF). METHODS: Ninety-two patients (58 males, mean age 20.5±8.5 months) with severe TOF were randomised into study and control groups. In the study group, mechanical ventilation was performed in PEEP/PRVC mode in the intensive care unit to correct blood gas imbalances for the corrective surgery. In the control group, preoperative oxygen supply was provided via face mask or nasal tubes. RESULTS: The postoperative mechanical ventilation time (14.3±1.9 vs 22.5±2.2h, p=0.02), intensive care stay (2.3±1.2 vs 4.7±1.1d, p=0.03) and duration for positive inotropic drug administration (2.5±1.1 vs 4.8±1.2d, p=0.04) in the study group were shorter than those in the control group. The postoperative capillary leak syndrome in the study group was lower than that in the control group (4.3% vs 23.9%, p=0.006). There was no statistically significant difference in the postoperative mortality between the study and control groups (2.1% vs 6.5%, p=0.606). CONCLUSIONS: Preoperational mechanical ventilation in patients with severe forms of TOF was associated with improved short-term outcomes following the corrective surgery. The effect of the preoperational ventilation on postoperative mortality requires further investigation.

Interleukin-6 in sepsis and capillary leakage syndrome.

Bacterial sepsis is one of the most frequent and dreaded causes of death in intensive care units. According to the current understanding of sepsis, bacterial components activate innate immune responses via pattern-recognition receptors that stimulate signaling pathways, thereby leading to activation of NF-κB and the release of cytokines, alarming the organism and coordinating appropriate defense mechanisms. The resulting "cytokine storm" not only restricts bacterial invasion; it also harms the host by triggering a hemodynamic collapse with a drop in blood pressure, which could lead to death. One of the cytokines released during sepsis is interleukin-6 (IL-6). Originally described as a B-cell-stimulating factor, this cytokine has since been shown to have multiple additional functions. Interestingly, there is emerging evidence of IL-6 trans-signaling in the pathogenesis of sepsis. We review recent findings and discuss whether therapeutic interference with IL-6 trans-signaling may be beneficial in this important clinical scenario.

The role of the endothelium in the short-term complications of hematopoietic SCT.

In this review, we analyse the role of the endothelium in the development of several complications that appear soon after haematopoietic SCT (HSCT). Once it had been demonstrated that sinusoidal damage is the initiating event of the sinusoidal obstruction syndrome, it was considered that other short-term complications with overlapping clinical manifestations, such as capillary leak syndrome, engraftment syndrome, transplant-associated microangiopathy, diffuse alveolar haemorrhage and idiopathic pneumonia syndrome, could have an endothelial origin. During HSCT, endothelial cells (ECs) are activated and damaged by several factors, including conditioning, cytokines released by damaged tissues, endotoxins translocated through damaged mucosa, drugs used in the procedure, the engraftment, and--in the allogeneic setting--immunological reactions. The different clinical syndromes that occur could be determined by the predominant phenotypic change in the ECs and the location of this change (organ dependant or systemic). Several translational studies have provided evidence of this endothelial dysfunction on the basis of analysis of soluble markers, soluble forms of adhesion molecules, the enumeration of circulating ECs and microparticles, and morphologic and functional changes induced in cultured ECs. This increased knowledge has opened up a wide range of potential pharmacologic interventions to prevent or treat endothelial damage and, consequently, to improve the outcome of patients receiving HSCT.

Grading of severity of the condition in burn patients by serum protein and albumin/globulin studies.

Capillary permeability increases after inflammation with consequent leak of fluid, electrolytes, and proteins. The albumin molecule size being smaller (69 kDa) than the globulin molecule (90-156 kDa) will leak relatively at an early stage of the disease (with moderate increase in capillary pore size) than globulin leading to albumin/globulin reversal. In cases with severe permeability changes with rapid progression to larger pore size with simultaneous leak of both albumin and globulin, albumin/globulin reversal will not occur. In this study estimation the serum protein and albumin/globulin (A/G) ratio at frequent intervals was done to grade the severity of the condition of burn patients by assessing the severity of capillary leak.A total of 61 admitted patients (from March 2002 to December 2004) based on the protein values were divided into 3 groups (group 1: 6-8 g/dL, group 2: 5.1-5.9 g/dL, group 3: < or =5.0 g/dL), and all the patients who showed change in their protein levels during the study were shifted to appropriate group and were classified as group shifters. The mean survival time and mortality of various groups were compared, and A/G ratio of all the expired cases was analyzed.Group 3 patients showed higher mortality (95%) as compared to that in other groups (group 1 and 2: 0% each and group shifters: 30.2%). Median survival time of group 3 was significantly low as compared to that of group 1 (P < 0.0026), group 2 (P < 0.0006), and group shifters (P < 0.0000). In group shifters the mean time (days) required for shifting from one group to other just before death or discharge in survivors was significantly higher than that in expired cases. Of 26 cases expired during the study, initial A/G ratio at the time of first assigning the group was not reversed in 22 cases (84.6%).The study concluded that the severity (indicated by lower serum protein values) and speed (judged by A/G ratio changes and median survival time analysis) of capillary permeability changes were associated with high mortality, and therefore, it is possible to grade the severity of the condition in burn patients.

[Idiopathic capillary leak syndrome]. / Syndrome de fuite capillaire idiopathique.

Idiopathic capillary leak syndrome (ICLS) is a rare and poorly known condition. Since the first description in 1960, about hundred cases have been reported. A French register that was initiated in 1997 provides a better knowledge of the natural course of the disease and highlights some therapeutic issues. ICLS mainly affects middle-aged adults. The prognosis is poor with a 10-year mortality rate around 34%. Severe crisis and complications occurring in intensive care units account for 80% of the mortality. Diagnosis relies on an almost pathognomonic association: recurrent attacks of hypotension and hemoconcentration with paradoxical hypoalbuminemia. A monoclonal gammopathy is found in about 80% of patients. Physiopathology still remains unclear. Paraprotein toxicity has never been demonstrated. As a result, no evidence-based treatment is available neither for acute crisis nor for prophylaxis. Management of acute episodes is mainly symptomatic. Fluid infusion must be cautious because it can induce complications during the recovery phase. Patient education is a major measure to prevent recurrent attacks. Beta-2 stimulants were reported to reduce the frequency and severity of episodes and were considered as the recommended prophylactic measure. However, early data from the French register suggest that intravenous immunoglobulins are more effective in reducing both frequency and severity of the attacks. Inclusion of patients with ICLS in a register is crucial to improve the knowledge about aetiology and treatment of this disorder.

Prognostic value of a simple evolving disseminated intravascular coagulation score in patients with severe sepsis.

OBJECTIVE: We postulated that the coagulopathy initiated by the inflammatory response to severe sepsis would be reflected by changes in the platelet count and prothrombin time that convey prognostic information. To examine this hypothesis, we looked at the utility of a simple evolving disseminated intravascular coagulation (DIC) score that awarded 1 point for each of the following: a) an absolute platelet count <100 x 10/L; b) a prothrombin time >15.0 secs; c) a 20% decrease in platelets; and d) a >0.3-sec increase in prothrombin time in predicting outcome in patients with severe sepsis. DESIGN: Prospective observational study. SETTING: Intensive care units of university medical center. PATIENTS: Patients were 163 critically ill severe sepsis patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were clinically classified as having capillary leak syndrome (n = 24), multiple organ failure with death from sepsis (n = 37), or multiple organ failure with recovery (n = 57) or as well (n = 45) if they showed rapid improvement in their modified Multiple Organ Dysfunction Syndrome (MODS) score (which did not score for thrombocytopenia). Patients with capillary leak syndrome had the highest Acute Physiology and Chronic Health Evaluation II score, modified MODS, and prothrombin time and the lowest platelet counts, whereas well patients had the most normal values. The simple evolving DIC score increased with worsening clinical class and was associated with worsening organ failure (increased modified MODS). Mortality rate increased from 10% for a simple evolving score of 0 to 73% for a score of 4 (p < .01). Overall, 86% of those with a score < or =1 survived, whereas 85% of those with a score of > or =2 developed multiple organ failure and half of them died from sepsis. CONCLUSIONS: The simple evolving DIC score calculated in the first 48 hrs from two readily available global coagulation markers appears to reflect the severity of the underlying disorder. It can be easily calculated at the bedside and provides useful prognostic information for the patient with severe sepsis.

Histamine improves survival and protects against interleukin-2-induced pulmonary vascular leak syndrome in mice.

The therapeutic efficacy in the treatment of metastatic cancer with high doses of interleukin-2 (IL-2) has been limited by the onset of vascular leak syndrome (VLS) and related toxicities. VLS is characterized by an increase in vascular permeability and severe hypotension resulting in interstitial edema and organ failure. This study explores the protective effects of histamine dihydrochloride (HDC) against IL-2-induced toxicities in mice. Treatment with HDC administered before or after IL-2 (1.25 x 10(6) IU, BID) was shown to protect mice from VLS-related toxicities and mortality in a dose-dependent manner. Survival rates when HDC was added were 56, 75 and 81% at doses of 0.47, 4.7 and 47.0 mg/kg, respectively, compared to 42% survival with IL-2 alone. HDC protected against IL-2-induced macroscopic pulmonary lesions, reduced edema (up to 62% reduction in lung wet/dry weight ratio) and reduced capillary leakage into the lungs as measured by a reduction in Evans Blue dye content. In addition, the systemic effect on serum cytokine levels showed that HDC only moderately lowered IL-2 induced IFN-gamma, IL-6, IL-10, IL-18 and TNF-alpha. Serum levels of IL-1beta, IL-4 and IL-12 were not measurably induced by IL-2 treatment. HDC modulates many cellular functions including regulating cytokines and blocking immune-suppression caused by reactive oxygen species (ROS) generated by the NADPH oxidase. However, the protective effect of HDC on alleviating IL-2-induced pulmonary edema was not related to ROS inhibition. Our data indicate that HDC treatment improves survival and protects against IL-2 induced VLS independent of ROS regulation in mice.

[The clinical relevance of subcutaneous-thoracic ratio in preterm newborns as a possibility for quantification of capillary leak syndrome]. / Die klinische Bedeutung der Weichteildicke in Röntgen-Thoraxaufnahmen bei Frühgeborenen mit einem Geburtsgewicht unter 1500 Gramm - eine Quantifizierungsmöglichkeit des Kapillarlecksyndroms.

BACKGROUND: Capillary leak syndrome (CLS) is associated with increased morbidity and mortality in preterm newborns (PN) with sepsis or necrotizing enterocolitis. PATIENTS AND METHODS: In order to provide improved standards for measuring edema and for the definition of CLS, subcutaneous-thoracic ratios (S/T) were calculated from 821 anteroposterior supine chest radiographs of 119 PN with a birth weight below 1500 g. The S/T was computed by 100 % minus ratio of dividing the outer margins of the eighth rib by the total diameter of the thorax at the same position. Birth weight, gestational age, need for assisted ventilation and the position of the diaphragm did not significantly affect S/T. The S/T drifted downwards slightly with postnatal age. RESULTS: To provide normal standards of S/T in PN, the ratio was calculated in percentiles and the higher percentiles correlated with diseases. 771 S/T were lower than 10.1 % (95th percentile), 21 were 10.1 - 12.6 % (97.5th percentile) and 20 were even higher. 3 of the 100 PN (84 %) with an S/T < 10.1 % died because of extreme immaturity. Eight patients (6.7 %) had an S/T between the 95th and the 97.5th percentile in at least one of their radiographs. Four of them had a respiratory distress syndrome and one died. Eleven PN had an S/T > 12.6 %. All of them showed a multiple organ failure and four died. When the SIT was > 15 % the edema became visible. A CLS was diagnosed in two PN with an S/T > 20 %. CONCLUSIONS: The threshold for the capillary leak syndrome was found to be 12.6 % also in reference to the course of diseases. The S/T is a useful tool because it is simple to measure and calculate, and is available from a single frontal film. The ratio can measure objectively the edema and the CLS in PN.

Lethal systemic capillary leak syndrome associated with severe ventilator-induced lung injury: an experimental study.

OBJECTIVE: We report the evolution of severe ventilator-induced lung injury associated with lethal systemic capillary leak syndrome, when sheep were ventilated at a peak inspiratory pressure of 50 cm H2O, at a respiratory rate of 8 breaths.min, with an inspiratory time of 2.5 secs. DESIGN: A prospective laboratory animal study. SETTING: Experimental animal research laboratory. SUBJECTS: Mixed breed sheep. INTERVENTIONS: Sheep were anesthetized, paralyzed, and mechanically ventilated. MEASUREMENTS AND MAIN RESULTS: This sheep model was characterized by a rapidly evolving massive anasarca, hemoconcentration, cardiac dysfunction, multiple system organ failure, and severe ventilator-induced lung injury. Cardiovascular changes and profound hemoconcentration developed within 6 hrs from the start of mechanical ventilation, along with a major decline in pulmonary compliance and deterioration in arterial blood gases. When total static lung compliance decreased to 0.15 mL (cm H2O)(-1) x kg(-1) (7-30 hrs), the sheep were randomized to two groups. Group I received high (recruitive) positive end-expiratory pressure (9-20 cm H2O), adjusted as needed; group II received low (supportive) positive end-expiratory pressure (2-6 cm H2O). Sheep in both groups progressively deteriorated and died with cardiocirculatory failure and multiple system organ failure within 12-24 hrs from start of treatment. CONCLUSIONS: This model of lethal systemic capillary leak syndrome with multiple system organ failure differs greatly from our previous sheep model of acute ventilator-induced lung injury in which sheep were ventilated with a peak inspiratory pressure of 50 cm H2O, a respiratory rate of 4 breaths x min(-1), and an inspiratory time of 1.35 secs, without inducing capillary leak syndrome. The mere change of respiratory rate from 4 to 8 breaths x min(-1), with a near doubling of the inspiratory time to 2.5 secs, although maintaining eucapnia, resulted in lethal systemic capillary leak syndrome and multiple system organ failure with both gross and microscopic pathology of lungs greatly different from our previous model of mechanical ventilation-induced acute respiratory distress syndrome.

A phase I study of Foscan-mediated photodynamic therapy and surgery in patients with mesothelioma.

BACKGROUND: Photodynamic therapy (PDT) is a light-based cancer treatment that, in the correct setting, can be delivered intraoperatively as an adjuvant therapy. A phase I clinical trial combining surgical debulking with Foscan-mediated PDT was performed in patients with malignant pleural mesothelioma. The purpose of the study was to define the toxicities and to determine the maximally tolerated dose (MTD) of Foscan-mediated PDT. METHODS: A total of 26 patients completed treatment. Tumor debulking was accomplished with either an extrapleural pneumonectomy (7 patients) or a lung-sparing pleurectomy-decortication (19 patients). Patients were injected with Foscan before surgery, and 652 nm light was delivered intraoperatively after completion of surgical debulking. Four light sensors were placed in the chest, allowing delivery of light to a uniform measured dose throughout the hemithorax. RESULTS: Four dose levels were explored. The MTD was 0.1 mg/kg of Foscan injected 6 days before surgery in combination with 10 J x cm(-2) 652 nm light. Dose limiting toxicity at the next higher dose was a systemic capillary leak syndrome leading to death in 2 of 3 patients treated at that dose. Other PDT-related toxicities included wound burns and skin photosensitivity. In all, 14 patients were treated at the MTD without significant complications. CONCLUSIONS: Foscan-mediated PDT can be safely combined with surgery at the established MTD. Unlike most other surgery-based multimodal treatments for mesothelioma, Foscan-mediated PDT affords the option, in selected patients, of accomplishing tumor debulking with a lung-sparing procedure rather than an extrapleural pneumonectomy. A phase II study is warranted.

Complement activation in relation to capillary leakage in children with septic shock and purpura.

To assess the relationship between capillary leakage and inflammatory mediators during sepsis, blood samples were taken on hospital admission, as well as 24 and 72 h later, from 52 children (median age, 3.3 years) with severe meningococcal sepsis, of whom 38 survived and 14 died. Parameters related to cytokines (interleukin 6 [IL-6] IL-8, plasma phospholipase A2, and C-reactive protein [CRP]), to neutrophil degranulation (elastase and lactoferrin), to complement activation (C3a, C3b/c, C4b/c, and C3- and C4-CRP complexes), and to complement regulation (functional and inactivated C1 inhibitor and C4BP) were determined. The degree of capillary leakage was derived from the amount of plasma infused and the severity of disease by assessing the pediatric risk of mortality (PRISM) score. Levels of IL-6, IL-8, C3b/c, C3-CRP complexes, and C4BP on admission, adjusted for the duration of skin lesions, were significantly different in survivors and nonsurvivors (C3b/c levels were on average 2.2 times higher in nonsurvivors, and C3-CRP levels were 1.9 times higher in survivors). Mortality was independently related to the levels of C3b/c and C3-CRP complexes. In agreement with this, levels of complement activation products correlated well with the PRISM score or capillary leakage. Thus, these data show that complement activation in patients with severe meningococcal sepsis is associated with a poor outcome and a more severe disease course. Further studies should reveal whether complement activation may be a target for therapeutical intervention in this disease.