Bacterial Septic Shock Research Articles

Mannose-Binding Lectin-Deficient Donors Increase the Risk of Bacterial Infection and Bacterial Infection-Related Mortality After Liver Transplantation.

Mannose-binding lectin (MBL) is synthesized by the liver and binds to microbes. MBL2 gene polymorphisms produce intermediate/low/null or normal MBL serum levels (MBL-deficient or MBL-sufficient phenotypes, respectively). We aimed to evaluate the incidence and severity of infection, rejection, and survival within 1 year after liver transplantation (LT) according to donor and recipient MBL2 gene polymorphisms. A repeated-event analysis for infection episodes (negative binomial regression, Andersen-Gill model) was performed in 240 LTs. Four hundred twenty-eight infectious episodes (310 bacterial, 15 fungal, 65 cytomegalovirus [CMV]-related, and 38 viral non-CMV-related episodes) and 48 rejection episodes were recorded. The main bacterial infections were urinary (n = 82, 26%) and pneumonia (n = 69, 22%). LT recipients of MBL-deficient livers had a higher risk of bacterial infection (incidence rate ratio [IRR] 1.48 [95% confidence interval 1.04-2.09], p = 0.028), pneumonia (IRR 2.4 [95% confidence interval 1.33-4.33], p = 0.013), and septic shock (IRR 5.62 [95% confidence interval 1.92-16.4], p = 0.002) compared with recipients of MBL-deficient livers. The 1-year bacterial infection-related mortality was higher in recipients of MBL-deficient versus MBL-sufficient livers (65.8% vs. 56.1%, respectively; p = 0.0097). The incidence of rejection, viral, or fungal infection was similar in both groups. Recipient MBL2 genotype did not significantly increase the risk of bacterial infection. LT recipients of MBL-deficient livers have a higher risk of bacterial infection, pneumonia, septic shock, and 1-year bacterial infection-related mortality after LT.

Diagnostic accuracy of procalcitonin, neutrophil-lymphocyte count ratio, C-reactive protein, and lactate in patients with suspected bacterial sepsis.

BackgroundEarly recognition is a key factor to achieve improved outcomes for septic patients. Combinations of biomarkers, as opposed to single ones, may improve timely diagnosis and survival. We investigated the performance characteristics of sepsis biomarkers, alone and in combination, for diagnosis of verified bacterial sepsis using Sepsis-2 and Sepsis-3 criteria, respectively.MethodsProcalcitonin (PCT), neutrophil-lymphocyte count ratio (NLCR), C-reactive protein (CRP), and lactate were determined in a total of 1,572 episodes of adult patients admitted to the emergency department on suspicion of sepsis. All sampling were performed prior to antibiotic administration. Discriminant analysis was used to construct two composite biomarkers consisting of linear combinations of the investigated biomarkers, one including three selected biomarkers (i.e., NLCR, CRP, and lactate), and another including all four (i.e., PCT, NLCR, CRP, and lactate). The diagnostic performances of the composite biomarkers as well as the individual biomarkers were compared using the area under the receiver operating characteristic curve (AUC).ResultsFor diagnosis of bacterial sepsis based on Sepsis-3 criteria, the AUC for PCT (0.68; 95% CI 0.65–0.71) was comparable to the AUCs for the both composite biomarkers. Using the Sepsis-2 criteria for bacterial sepsis diagnosis, the AUC for the NLCR (0.68; 95% CI 0.65–0.71) but not for the other single biomarkers, was equal to the AUCs for the both composite biomarkers. For diagnosis of severe bacterial sepsis or septic shock based on the Sepsis-2 criteria, the AUCs for both composite biomarkers were significantly greater than those of the single biomarkers (0.85; 95% CI 0.82–0.88 for the composite three-biomarker, and 0.86; 95% CI 0.83–0.89 for the composite four-biomarker).ConclusionsCombinations of biomarkers can improve the diagnosis of verified bacterial sepsis in the most critically ill patients, but in less severe septic conditions either the NLCR or PCT alone exhibit equivalent performance.

Role of VA ECMO in septic shock: Does it work?

The use of mechanical circulatory assistance remains controversial during refractory septic shock in adults. 1 However, a profound myocardial dysfunction can occur during bacterial septic shock. 2–4 In this context, extracorporeal membrane oxygenation (ECMO) is highly effective as salvage therapy for children with refractory septic shock. 5,6 We reported the largest cohort of adults who received VA-ECMO for refractory cardiovascular dysfunction in the context of severe bacterial septic shock. 5 Despite multiorgan failure at ECMO initiation and simplified acute physiology score (SAPS) 3-predicted mortality of 79%, >70% of these patients survived with complete recovery of cardiac function. The hemodynamic profile we describe herein (low cardiac index, elevated filling pressure, profound myocardial depression, and elevated systemic vascular resistance) is certainly a rare entity in the spectrum of septic shock, which resembles that of the classic paradigm of cardiogenic shock. In this setting, the infusion o...

First case of Arthrographis kalrae fungemia in a patient with cystic fibrosis

Arthrographis kalrae is a hyalin fungus. It is a saprophyte of the environment, mainly found in soil and compost. In recent years, cases of opportunistic infections attributed to this pathogen have been described. Our patient was a 19-year-old woman with cystic fibrosis. She presented a bacterial and fungal pulmonary colonization with Aspergillus fumigatus and Arthrographis. kalrae. After her lung transplantation, she developed an A. kalrae fungemia, treated with caspofungin 50mg/day associated to liposomal amphotericin B i.v. 3mg/kg/day. The patient died 8 months after her transplantation as the result of a bacterial septic shock.

Gastrointestinal Leakage Detected by Serum (1→3)-β-D-Glucan in Mouse Models and a Pilot Study in Patients with Sepsis.

Gastrointestinal (GI) leakage is believed to exacerbate sepsis and new, validated markers of GI barrier performance might benefit clinical decision-making. Serum (1→3)-β-D-glucan (BG) was evaluated as a potential GI leakage marker. Serum BG was tested in several mouse models of GI leakage, including dextran sulfate solution (DSS) administration, endotoxin (LPS) injection, and cecal ligation and puncture sepsis (CLP). Serum BG titer was also evaluated in patients with sepsis and septic shock, for comparison.With 0.75% DSS administration, BG increased only after oral administration of heat-killed C. albicans, but increased spontaneously with 1.5% DSS. In the LPS and CLP models, BG increased as early as 1 h and at 12 h after LPS administration and surgery, respectively. GI leakage was confirmed by orthogonal validation methods including FITC-dextran oral administration in the DSS, LPS, and CLP models and, in the DSS model, with urine sucralose after oral administration and serum endotoxemia. IL-6 increased in parallel with serum BG. Serum BG or IL-6, at 18 h, anticipated sepsis mortality in the CLP model.Analysis of serum BG from patients with febrile neutropenic sepsis (N = 49) and febrile non-neutropenic sepsis (N = 39) demonstrated BG elevation. Patients with bacterial septic shock had serum BG titers similar to levels observed in invasive fungal disease, regardless of febrile neutropenia. Serum BG was lower in less severe cases of bacterial sepsis. Elevated serum IL-6 was associated with GI leakage and elevated serum BG.Serum BG may have potential as a sepsis/septic shock biomarker and further study in this context is warranted.

Risk Factors and Vaccine Failure Associated With Influenza Related Death in Severe Cases in Greece During the 2014-15 Season

Background We examined risk factors for influenza related death in all severe cases in Greece during the 2014-15 influenza season. Methods A national severe influenza surveillance network includes reporting to the Hellenic Ctr for Disease Control & Prevention (HCDCP) of all laboratory-confirmed influenza cases admitted to ICU &/or in-hospital deaths of influenza patients. Each case is followed up daily, with a structured questionnaire until discharged. We evaluated risk factors for death using univariate & multivariate analyses. Results 248 cases were recorded (median age 67 yrs, 54.7% male, 87.1% high risk pts with comorbidities). Influenza A was noted in 56.5%. 111 deaths were recorded (median age 57 yrs, 55% male). In 64 (57.7%) deaths, influenza A was diagnosed [A(H1N1): 36%, A(H3N2): 64%]. 99/111 (89.2%) deaths occurred in pts with immunization indications; 15 were immunized. ARDS (OR 3.43 (95%CI 1.27 9.3) p=0.006), renal insufficiency (OR 3.9; 95% CI 1.4-11.3, p = 0.01), occurrence of secondary bacterial infection & septic shock (OR 4.4; 95% CI 1.2-16.4, p=0.015) were risk factors for death. Influenza A cases did not differ from B regarding age, comorbidities, rates of intubation or death. Within 31 vaccinated cases influenza A was more prevalent to B (77.4% vs. 22.6%, p=0.06). Conclusion ARDS, renal insufficiency & the presence of secondary infections or septic shock were risk factors for death in a mixed A & B season. Influenza B did not differ from A in the risk for complications & death. Vaccine failures were noted especially among serious influenza A cases, consistent with the reported drift of A(H3N2). Sotirios Tsiodras, MD, DSc University of Athens Med. Sch. Athens, Greece 1 Rimini Street 12462 Athens, Greece Tel: 0030 210 58 31 641 Tel (2nd): 0030 693 26 65 820 FAX: 0030 210 53 26 446 e-mail: tsiodras@med.uoa.gr

Abstract 4286: Development of a safe and effective systemically administered multiple Toll-like receptor (TLR) agonist for anti-tumor immunotherapy

Abstract Summary We have developed methods for detoxification and killing of Gram-negative bacteria, which significantly reduce both lipopolysaccharide (LPS) and non-LPS-mediated endotoxin activity and pyrogenicity, without compromising stimulation of anti-tumor immune responses. Background The field of cancer immunotherapy was founded in the late 1800s, based on the observation of tumor regression in the setting of bacterial infection. This was reproduced with intentionally administered live bacteria, but the approach was not safe due to infection and septic shock. A mixture of heat killed bacteria (Coley's toxins) produced long-term responses in advanced cancer patients over 100 years, but was apparently too toxic for safe intravenous (iv) administration at effective doses. In addition, lack of understanding of efficacy and toxicity mechanisms prevented optimization. Discovery of the role of TLRs in immune function has provided a mechanistic rationale for reconsideration of this approach. Gram-negative bacteria were required for the anti-tumor activity of Coley's toxins, due to the presence of multiple TLR agonists, including LPS, which is not produced by Gram-positive bacteria. However, too much TLR activation can over-stimulate the immune system, leading to toxicity. Attempts to produce live, attenuated Gram-negative bacteria for systemic cancer therapy have not been successful. A Phase 1 trial of one product produced dose-limiting symptoms of bacterial infection and septic shock, without evidence of antitumor activity. These historical observations suggest that a killed and appropriately attenuated Gram-negative product might produce significant anti-tumor activity if it could be administered safely iv. Methods and Results Non-pathogenic Gram-negative bacteria were treated with polymyxin B and glutaraldehyde. Endotoxin activity and pyrogenicity were quantified using Limulus amebocyte lysate (LAL) and rabbit pyrogenicity assays. Bacterial integrity was assessed by EM. Antitumor activity was determined using syngeneic tumors in mice. Treatment was found to kill the bacteria and reduce LPS-mediated endotoxin activity by ≥12-fold and non-specific pyrogenicity by ≥30-fold, with retention of cell integrity. The first product, DB103, was approximately 2,500-fold less toxic in mice than a previously described live, attenuated preparation, and produced significant dose-dependent in vivo antitumor activity at non-toxic doses. DB103 was also additive or synergistic in vivo when combined with each of four different established antitumor immunotherapies, including IL-2, metronomic cyclophosphamide, and anti-CTLA-4 or anti-GITR antibodies. Conclusions We have developed a multiple TLR agonist that can be safely and effectively administered systemically alone or in combination with a wide variety of existing anti-tumor immunotherapies. Citation Format: Michael J. Newman. Development of a safe and effective systemically administered multiple Toll-like receptor (TLR) agonist for anti-tumor immunotherapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4286. doi:10.1158/1538-7445.AM2015-4286

Management of bacterial severe sepsis and septic shock

Bacterial sepsis is a leading cause of pediatric morbidity and mortality worldwide. Early diagnosis, a coordinated and aggressive approach to initial resuscitation, and timely and appropriate antibiotic therapy are paramount to improving outcomes of these dangerous infections. The basic tenants of initial and ongoing resuscitation include rapid isotonic intravenous fluid boluses with reassessment for physiologic response, empiric broad-spectrum antibiotics directed to cover suspected sources of infection, source control, vasoactive infusions, supportive critical care and monitoring of response to therapy. In addition to resuscitation of bacterial sepsis, this article will review approaches to empiric antibiotic choice in septic shock, and detail definitive management of infections caused by several specific organisms, including Staphylococcus aureus , group A Streptococcus, Pseudomonas aeruginosa, Mycobacterium tuberculosis , and Clostridium difficile . Lastly, management of several common pediatric infections, including community acquired bacterial pneumonia and bacterial meningitis, will be reviewed.

Leptospirosis: complications, causes of death and pathomorphogenesis

The purpose of the study The improvement the diagnosis and prognosis of the course of leptospirosis on the basis of the study of characteristics of clinical picture and pathomorphogenesis, determination of the main causes of lethal outcomes at different stages of the disease, in dependence on the level of the management of specialized medical care. Materials and methods There were analyzed medical records and autopsy protocols of 168 patients who died from leptospirosis in the Krasnodar region in 1969-2014 and medical records of 125 patients with both severe course of leptospirosis and the development of multiple organ insufficiency. 4 groups were considered: 1st -patients died in 1969-1988 before applying of efferent methods therapy, 86 lethal cases; 2nd - patients died in 1989-1997, application of hemosorption and hemofiltration, 31 cases; 3rd - 1998-2008, the use of plasmapheresis and immunocorrectors, 33 cases; 4-th group of 18 patients who died in 2009-2014, up-to-date medical assistance. There was studied autopsy material in 55 patients. The etiological role of L.icterohaemorrhagiae was proved in 75% of lethal cases, L.grippotyphosa - in 16.7%, L.sejroe (Mus 24) - in 8.3%. The results of the study In the initial period at the 3-5 days of illness life-threatening events are toxic shock and hemorrhagic syndrome. In the period of the height of disease (2-3 weeks) polyorganic failure in form of acute renal and hepatic insufficiency , and also combination of hemorrhagic syndrome with acute respiratory distress syndrome assume a great significance Starting From the 4th week, the first place in the risk of the development of the unfavorable outcome is occupied by secondary bacterial complications, sepsis and septic shock. Pathomorphological changes at leptospirosis correspond to organ-system lesions typical for Systemic inflammatory response syndrome - SIRS . Multiple organ dysfunction formed in the height of leptospirosis is a consequence not only of the alternative effect of leptospira and its toxins, but the result of immunopathological reactions of systemic inflammation. At the present time of the observation the lethal outcome occurs in average on the 17,9±2,30 day of illness, the average patient day in reanimation unit is prolonged up to 11,2±2,43. DIC and acute respiratory distress syndrome as a components of multiple organ failure, and at the later stages of the disease - pneumonia and sepsis, indicate to the negative forecast. Risk factors for the unfavorable outcome include late hospitalization and the increased percentage of comorbidity (61%). For the determination of the severity and the prognosis of the course of the disease it is worth to use SIRS criteria and Sepsisrelated Organ Failure (SOFA) rating scale of organ dysfunction. The development of lethal outcome with a probability of 70% is determined in cases with the failure of 4 or more functional systems. The total Score on a SOFA scale in lethal outcomes is 18.7 scores at the first week of illness, and 14.5 scores at the 5-6th weeks. Conclusion The main causes of lethal outcomes leptospirosis are determined by the stage of pathogenesis, depend of the stage of the disease and methods of therapy. The treatment of patients with leptospirosis should be carried out in specialized infectious hospitals with ICUs equipped for efferent methods of detoxification.

Analysis of correlation between inflammatory parameters and severity of sepsis caused by bacterial bloodstream infection in septic patients

To discuss the differences of inflammatory parameters such as procalcitonin (PCT), C-reactive protein (CRP), endotoxin, white blood cell (WBC), neutrophil ratio (Neut%) in blood of septic patients caused by bacterial bloodstream infection, and their correlation with the severity of disease. 292 septic patients with positive blood culture were enrolled in Beijing Shijitan Hospital Affiliated to Capital Medical University from February 2012 to March 2015, and their gender, age, acute physiology and chronic health evaluation II (APACHEII) score, bacterial species and other general information were retrospectively collected. The differences in inflammatory parameters (PCT, CRP, endotoxin, WBC, Neut%) in septic patients caused by bacterial bloodstream infection were compared, their correlations with APACHEII scores within 24 hours were analyzed, and their diagnostic efficacies were also analyzed. (1) It was shown by Pearson correlation coefficients that positively statistical correlation was found between PCT (r=0.638), CRP (r=0.620), endotoxin (r=0.284), WBC (r=0.209) and APACHE II score (all P=0.000) in bacterial bloodstream infective patients (n=292), and positively statistical correlation was found between PCT (r=0.626), CRP (r=0.616), Neut% (r=0.297) and APACHE II score (all P<0.01 ) in Gram positive bacterial (G+) group (n=86), and positively statistical correlation was shown between PCT (r=0.631), CRP (r=0.616), endotoxin (r=0.301), WBC (r=0.226 ) and APACHE II score (all P<0.01) in Gram negative bacterial (G-) group (n=206). (2) It was shown that PCT and CRP of both G+/G- bacterial severe sepsis and septic shock subgroup were significantly higher than those of sepsis subgroup, respectively [G+ group: PCT (μg/L):0.92 (0.38, 4.75) vs. 0.43 (0.22, 1.00), CRP (mg/L): 118.45±62.60 vs. 57.97±32.41; G- group: PCT (μg/L):6.92 (1.94, 25.90) vs. 1.28 (0.27, 4.12), CRP (mg/L): 130.99±60.18 vs. 49.18±26.87, all P<0.01], and the endotoxin and WBC in G- bacterial severe sepsis and septic shock subgroup were significantly higher than those of sepsis subgroup [endotoxin (ng/L): 19.40 (9.62, 33.87) vs. 10.00 (5.00, 18.52), WBC (×10(9)/L): 12.13±6.72 vs. 9.61±5.01, both P<0.01]. The PCT and endotoxin in G- bacterial severe sepsis and septic shock subgroup were significantly higher than those in G+ severe sepsis and septic shock subgroup [PCT (μg/L): 6.92 (1.94, 25.90) vs. 0.92 (0.38, 4.75), endotoxin (ng/L): 19.40 (9.62, 33.87) vs. 2.56 (1.11, 4.01), both P<0.01]. (3) The diagnostic efficacy of inflammatory parameters for severe sepsis and septic shock subgroup were: PCT area under receiver operating characteristic (ROC) curve (AUC)=0.683, the cut-off point=0.55 μg/L, sensitivity 63.2%, specificity 69.0%; CRP AUC=0.802, the cut-off point=92.25 mg/L, sensitivity 73.7%, specificity 86.2%; WBC AUC=0.614, the cut-off point=7.35×10(9)/L, sensitivity 75.4%, specificity 48.3%; Neut% AUC=0.622, the cut-off point=0.882, sensitivity 43.9%, specificity 79.3% in G+ group. At the same time, it was shown that PCT AUC=0.780, the cut-off point=6.80 μg/L, sensitivity 51.0%, specificity 93.9%; CRP AUC=0.907, the cut-off point=90.10 mg/L, sensitivity 73.2%, specificity 95.9%; endotoxin AUC=0.694, the cut-off point=17.54 ng/L, sensitivity 57.3%, specificity 75.5%; WBC AUC=0.611, the cut-off point=10.54×10(9)/L, sensitivity 54.1%, specificity 69.4%; Neut% AUC=0.621, the cut-off point=0.843, sensitivity 65.6%, specificity 61.2% in G- group. The plasma PCT and CRP have the best correlation between inflammatory parameters and severity of disease in bloodstream infective sepsis patients. CRP has the best diagnostic effect in severe sepsis/septic shock patients with bloodstream infection.

Pregnancy with severe influenza A (H1N1) related acute respiratory distress syndrome: Report of three cases from a rural critical care unit in India.

Sir, Pregnant women are important medically susceptible subset of the population. Changes in immune function during pregnancy alter a pregnant womans susceptibility to and severity of certain infectious diseases. These alterations are particularly problematic because physicians may hesitate to provide prophylaxis or aggressive treatment to pregnant women because of concerns about effects on the fetus. Because of concerns about the severity of the disease during pregnancy, the Center for Disease Control and Prevention has implemented enhanced surveillance for infection and has placed them in a group that merits priority vaccine administration. Pregnant women were more likely to be hospitalized or admitted to Intensive Care Units (ICU) and were at higher risk of death compared to nonpregnant adults. In critically ill pregnant patients, spectrum of clinical features associated with H1N1 infection includes, rapidly progressive lower respiratory tract disease and acute respiratory distress syndrome (ARDS) with refractory hypoxemia and secondary bacterial infection, septic shock, and multiorgan failure. Increased mortality was seen in patients with ARDS following H1N1 influenza as compared to all other causes of ARDS in Indian settings.[1] We report three pregnant patients with bilateral pneumonia in severe ARDS, admitted in our ICU. Their nasopharyngeal and endotracheal swabs were positive for H1N1. In our experience, we noticed the wide variation in the course of events that the disease displayed during ICU stay [Table 1]. The first Case A Figure 1, the delay in termination of pregnancy and also the delay in starting the antiviral therapy made her more prone to fatal outcome. Whereas in Cases B Figure 2 and C Figure 3, early delivery combined with a lung-protective ventilation strategy provided significantly better fetal and maternal outcomes.[2] We also noticed that prone position ventilation[4] and low-dose methylprednisolone infusion[3,5] improved oxygenation and eventually outcomes in the survivors Figure 4. Table 1 Course of events during Intensive Care Unit stay Figure 1 Timeline of Case A Figure 2 Timeline of Case B Figure 3 Timeline of Case C Figure 4 As there are three patients in the study, we included all the X-rays in one figure (which includes, one at admission and one before discharge/death) Early treatment with antiviral medication is recommended for pregnant women with suspected novel H1N1 infection regardless of the gestational age.[6] Oseltamivir has been used quite extensively in pregnancy with good results, and of most benefit when administered within 48 h of symptom onset and may reduce the incidence of pneumonia in patients with seasonal influenza.[6] In a report of six maternal deaths with H1N1 pandemic influenza, none of these patients had received antiviral within 48 h of onset of symptoms.[7] In conclusion, our experience suggests that pregnant women are at high-risk of complications such as ARDS requiring mechanical ventilation from H1N1 influenza. We also suggest the following. Early termination of pregnancy may result in improvement in the mother's condition. The timing to terminate is a critical decision necessitating proper cooperation with an obstetrician. Antiviral drugs should be started empirically. To follow ARDS net ventilation protocol and prone position ventilation as necessary. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Disseminated tuberculosis presenting as tuberculous peritonitis and sepsis tuberculosa gravissima in a patient with cirrhosis of the liver: A diagnosis of challenge

We report the case of an 81-year-old man diagnosed with liver cirrhosis complicated by spontaneous bacterial peritonitis and septic shock. Mycobacterium tuberculosis complex was isolated from the ascites, sputum, and blood culture 1 month after the patient died. Clinicians should be aware of the unusual diagnosis of sepsis tuberculosa gravissima presenting with tuberculous peritonitis, which is easily misdiagnosed as spontaneous bacterial peritonitis and Gram-negative bacillus sepsis in patients with cirrhosis. Clinicians should cautiously evaluate the patient's sputum, gastric contents, urine, cerebrospinal fluid, and bone marrow for early diagnosis of disseminated tuberculosis in patients with a high degree of suspicion of this diagnosis.

Chediak-Higashi syndrome: case report in afro-descendant individual

This is a Chediak-Higashi Syndrome (CHS) case report in afro-descendant individual, male, 3 months old, born from consanguineous union. On admission he had fever for a month, unresolved pneumonia, and hepatosplenomegaly. He evolved to bacterial sepsis, septic shock, and death. CHS presents quantitative and morphological and hematological changes. Abnormal leukocyte inclusions are the pathognomonic finding of the disease; its recognition and differentiation from other leukocyte inclusions is essential for diagnosis and institution of therapy. Early diagnosis of CHS increases the life expectancy of the individual and provides appropriate therapeutic approach for patients affected by the disease.

1038

Introduction: The evidence for the clinical usefulness of procalcitonin (PCT) in adults with bacteremia has grown over the past two decades. In adults admitted with clinical signs of infection, low PCT values (<0.25μg/L) indicate a low probability for bacteremia, whereas elevated PCT values correlate with bacteremia (>1 μg/L) and septic shock (>10 μg/L). PCT guidance for initiation of antibiotics in adults is a growing trend. However, there is little evidence correlating PCT levels with bacteremia in the pediatric population. We examined PCT as a marker of bacteremia in children admitted to the pediatric intensive care unit with clinical signs of infection. Methods: We retrospectively reviewed all <10 yr old children admitted to the Riley Hospital PICU with suspicion of infection over a 6-month period. Only patients who had PCT levels, blood cultures (BCx), RSV assay, and respiratory cultures (RCx) obtained on admission were included. To assess the reliability of using PCT to predict bacteremia, we compared the incidence of bacteremia between those with PCT <1μg/L and those with PCT ≥1μg/L. We also assessed the effect of RSV pneumonia on PCT levels. Results: A total of 65 patients met inclusion criteria. The mean age was 17.6 months (range 0.7 to 45 mo). PCT was <1μg/L in 33 patients (mean 0.3μg/L, SD=0.2). Of these, 3 (9.1%) were bacteremic and 13 (39%) were RSV-positive. On the other hand, 32 patients had a PCT ≥1μg/L (mean 17.3μg/L, SD=8.3). Only 1 (3.1%) of these patients was bacteremic on admission. Sixteen (50%) were RSV-positive. The incidence of bacteremia (9.1 vs. 3.1%) between the two groups (<1 and ≥1μg/L respectively) was not statistically significant (p=0.613). When comparing only non-bacteremic patients, the mean PCT for RSV-negative patients (n=33) was 8.14μg/L (SD=15.11) whereas for RSV-positive (n=24) was 6.70μg/L (SD=12.12). The difference was not statistically significant (p=0.7). Conclusions: PCT levels are not a reliable indicator of bacteremia in children admitted to the PICU with clinical signs of infection. Infection with RSV raises PCT levels to near those typically seen with bacterial septic shock in adults.

Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock

Mortality from sepsis and septic shock remains high. Results of trials on intravenous immunoglobulins (IVIG) as adjunctive therapy for sepsis have been conflicting. This is an update of a Cochrane review that was originally published in 1999 and updated in 2002 and 2010. To estimate the effects of IVIG as adjunctive therapy in patients with bacterial sepsis or septic shock on mortality, bacteriological failure rates, and duration of stay in hospital. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 6), MEDLINE (1966 to December 2012), and EMBASE (1988 to December 2012). We contacted investigators in the field for unpublished data. The original search was performed in 1999 and updated in 2002 and 2008. We included randomized controlled trials comparing IVIG (monoclonal or polyclonal) with placebo or no intervention in patients of any age with bacterial sepsis or septic shock. Two authors independently assessed the studies for inclusion and undertook methodologic quality assessment and data abstraction. We conducted pre-specified subgroup analyses by type of immunoglobulin preparation. We included 43 studies that met our inclusion criteria in this updated review out of 88 potentially eligible studies. The studies included a large polyclonal IVIG trial in neonates that was concluded in 2011 and classified as ongoing in the 2010 version of this review. Pooled analysis of polyclonal and monoclonal IVIG was not done due to clinical heterogeneity. Subgroup analysis of 10 polyclonal IVIG trials (n = 1430) and seven trials on IgM-enriched polyclonal IVIG (n = 528) showed significant reductions in mortality in adults with sepsis compared to placebo or no intervention (relative risk (RR) 0.81; 95% confidence interval (CI) 0.70 to 0.93 and RR 0.66; 95% CI 0.51 to 0.85, respectively). Subgroup analysis of polyclonal IVIG in neonates, which now includes the recently concluded large polyclonal IVIG trial, showed no significant reduction in mortality for standard IVIG (RR 1.00; 95% CI 0.92 to 1.08; five trials, n = 3667) and IgM-enriched polyclonal IVIG (RR 0.57; 95% CI 0.31 to 1.04; three trials, n = 164). Sensitivity analysis of trials with low risk of bias showed no reduction in mortality with polyclonal IVIG in adults (RR 0.97; 95% CI 0.81 to 1.15; five trials, n = 945) and neonates (RR 1.01; 95% CI 0.93 to 1.09; three trials, n = 3561). Mortality was not reduced among patients (eight trials, n = 4671) who received anti-endotoxin antibodies (RR 0.99; 95% CI 0.91 to1.06) while anti-cytokines (nine trials, n = 7893) demonstrated a marginal reduction in mortality (RR 0.92; 95% CI 0.86 to 0.97). Polyclonal IVIG reduced mortality among adults with sepsis but this benefit was not seen in trials with low risk of bias. Among neonates with sepsis, there is sufficient evidence that standard polyclonal IVIG, as adjunctive therapy, does not reduce mortality based on the inclusion of the large polyclonal IVIG trial on neonates. For Ig-M enriched IVIG, the trials on neonates and adults were small and the totality of the evidence is still insufficient to support a robust conclusion of benefit. Adjunctive therapy with monoclonal IVIGs remains experimental.

Safety and Pharmacokinetics of Intravenous Zanamivir Treatment in Hospitalized Adults With Influenza: An Open-label, Multicenter, Single-Arm, Phase II Study

Background. Intravenous zanamivir is a neuraminidase inhibitor suitable for treatment of hospitalized patients with severe influenza. Methods. Patients were treated with intravenous zanamivir 600 mg twice daily, adjusted for renal impairment, for up to 10 days. Primary outcomes included adverse events (AEs), and clinical/laboratory parameters. Pharmacokinetics, viral load, and disease course were also assessed. Results. One hundred thirty patients received intravenous zanamivir (median, 5 days; range, 1–11) a median of 4.5 days (range, 1–7) after onset of influenza; 83% required intensive care. The most common influenza type/subtype was A/H1N1pdm09 (71%). AEs and serious AEs were reported in 85% and 34% of patients, respectively; serious AEs included bacterial pulmonary infections (8%), respiratory failure (7%), sepsis or septic shock (5%), and cardiogenic shock (5%). No drug-related trends in safety parameters were identified. Protocol-defined liver events were observed in 13% of patients. The 14- and 28-day all-cause mortality rates were 13% and 17%. No fatalities were considered zanamivir related. Pharmacokinetic data showed dose adjustments for renal impairment yielded similar zanamivir exposures. Ninety-three patients, positive at baseline for influenza by quantitative polymerase chain reaction, showed a median decrease in viral load of 1.42 log10 copies/mL after 2 days of treatment. Conclusions. Safety, pharmacokinetic and clinical outcome data support further investigation of intravenous zanamivir. Clinical Trials Registration NCT01014988.

Mycobacterium tuberculosis Septic Shock

Septic shock due to Mycobacterium tuberculosis (MTB) is an uncommon but well-recognized clinical syndrome. The objective of this study was to describe the unique clinical characteristics, epidemiologic risk factors, and covariates of survival of patients with MTB septic shock in comparison with other bacterial septic shock. A retrospective nested cohort study was conducted of patients given a diagnosis of MTB septic shock derived from a trinational, 8,670-patient database of patients with septic shock between 1996 and 2007. In the database, 53 patients had been given a diagnosis of MTB shock compared with 5,419 with septic shock associated with isolation of more common bacterial pathogens. Patients with MTB and other bacterial septic shock had in-hospital mortality rates of 79.2% and 49.7%, respectively (P &lt; .0001). Of the cases of MTB shock, all but five patients had recognized respiratory tract involvement. Fifty-five percent of patients (29 of 53) were documented (by direct culture or stain) as having disseminated extrapulmonary involvement. Inappropriate and appropriate initial empirical therapy was delivered in 28 patients (52.8%) and 25 patients (47.2%); survival was 7.1% and 36.0%, respectively (P = .0114). Ten patients (18.9%) did not receive anti-MTB therapy; all died. The median time to appropriate antimicrobial therapy for MTB septic shock was 31.0 h (interquartile range, 18.9-71.9 h). Only 11 patients received anti-MTB therapy within 24 h of documentation of hypotension; six of these (54.5%) survived. Only one of 21 patients (4.8%) who started anti-MTB therapy after 24 h survived (P = .0003 vs &lt; 24 h). Survival differences between these time intervals are not significantly different from those seen with bacterial septic shock due to more common bacterial pathogens. MTB septic shock behaves similarly to bacterial septic shock. As with bacterial septic shock, early appropriate antimicrobial therapy appears to improve mortality.

Venoarterial Extracorporeal Membrane Oxygenation Support for Refractory Cardiovascular Dysfunction During Severe Bacterial Septic Shock*

Profound myocardial depression can occur during severe septic shock. Although good outcomes of venoarterial extracorporeal membrane oxygenation-treated children with refractory septic shock have been reported, little is known about adults' outcomes. This study was designed to assess the outcomes and long-term health-related quality-of-life of patients supported by venoarterial extracorporeal membrane oxygenation for refractory cardiac and hemodynamic failure during severe septic shock. A retrospective, single-center, observational study and a cross-sectional survey to assess health-related quality of life by the Short Form-36 questionnaire and frequencies of anxiety, depression and posttraumatic stress disorder symptoms by the Hospital Anxiety and Depression Scale and the Impact of Event Scale, respectively. A 26-bed tertiary intensive care unit in a university hospital. We evaluated the outcomes of patients who received venoarterial extracorporeal membrane oxygenation rescue therapy for refractory cardiovascular failure during bacterial septic shock. Results are expressed as medians (range). From January 2008 to September 2011, 14 patients, 45 years old (28-66), seven males, none with a history of left ventricular dysfunction, received venoarterial extracorporeal membrane oxygenation for septic shock refractory to conventional treatment, 24 hours (3-108) after shock onset. All exhibited severe myocardial dysfunction at extracorporeal membrane oxygenation implantation. Left ventricular ejection fraction was 16% (10% to 30%), cardiac index was 1.3 L/min/m (0.7-2.2 ) and systemic resistance vascular index was 3162 (2047-7685). All were receiving high-dose catecholamines and had signs of multiple organ failure: pH 7.16 (6.68-7.39), blood lactate 9 (2-17) mmol/L, PaO2/FIO2 87 (28-364), Simplified Acute Physiology Score III 84 (75-106) and Sepsis-Related Organ Failure Assessment score 18 (8-21). Twelve patients (86%) could be weaned off venoarterial extracorporeal membrane oxygenation after 5.5 days (2-12) days of support and 10 patients (71%) were discharged to home and were alive after a median follow-up of 13 months (3-43). All 10 survivors had normal left ventricular ejection fraction and reported good health-related quality of life at long-term follow-up. Venoarterial extracorporeal membrane oxygenation rescued more than 70% of the patients who developed refractory cardiovascular dysfunction during severe bacterial septic shock. Survivors reported good long-term quality of life. Venoarterial extracorporeal membrane oxygenation might represent a valuable therapeutic option for adults in severe septic shock with refractory cardiac and hemodynamic failure.

Is Toso/IgM Fc receptor (FcμR) expressed by innate immune cells?

Lang et al. have recently published that innate immune cells, including bone-marrow granulocytes and splenic macrophages, express the plasma-membrane protein Toso as a unique regulator of innate immune responses during bacterial infection and septic shock (1). In contrast, we and others have previously reported that the IgM Fc receptor (FcμR), originally designated as Toso or Fas apoptosis inhibitory molecule 3, is expressed only by B-lineage cells in mice and is involved in IgM homeostasis, B-cell survival, and humoral immune responses (2, 3). Because of these conflicting results, we have extensively reexamined the cellular distribution of Toso/FcμR and wish to provide some new results and comments.

Susceptibilidad genética para el desarrollo de la sepsis bacteriana grave y choque séptico

Objective: to present the state of the art of research, so far relate patient’s genetic polymorphism with the development of sepsis, as a diagnostic tool and a novel therapeutic approach for this condition. The concepts given by the research establishing the genetic polymorphism of the individual is relevant to disease progression of the disease and effective response to treatment in the critically ill patient, especially with bacterial sepsis and septic shock. Materials and methods: we reviewed indexed literature linking genetic factors with the development of some diseases of the critically ill patient. Results: the particular characteristics of the disease would be influenced by the genetic background of the patient, determining largely the pathophysiological response. It has revealed the genetic susceptibility of individuals to develop infection. These individuals with a similar treatment did not evolve in the same way, triggering a severe bacterial sepsis and septic shock. The polymorphism in the genes e coding the tumor necrosis factor-α (TNF-α) the interleukins-1 (IL-1), IL-6, IL-10, soluble factor CD-14, Toll like receptors, the inhibitor type 1 plasminogen activator would be associated with the development of severe sepsis and septic shock, particularly TNF-α mutations 308 G/A, PAI-1 4G/4G, IL-6174 G/C. Conclusions: knowledge of the genetic susceptibility of the individual, risk factors and proper functioning of the immune system to help reduce and offset the complications of bacterial sepsis. It is clear that individualized early treatment in patients with sepsis is associated with decreased mortality and a reduction in the deterioration of the inflammatory response.