Sepsis severity is the major determinant of circulating thrombopoietin levels in septic patients

OBJECTIVE: To measure serum thrombopoietin levels and to investigate their relationship with platelet counts and other potential determinants in septic patients. DESIGN: Prospective study comparing septic patients and healthy volunteers. SETTING: General intensive care units in two tertiary university hospitals. PATIENTS: A total of 152 consecutive septic patients (69 with sepsis, 24 with severe sepsis, and 59 with septic shock). Twenty-two healthy volunteers served as control subjects. Sepsis severity was determined by grading septic patients in those having sepsis, severe sepsis, and septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: After blood sampling, platelet counts, and serum thrombopoietin, interleukin-6 and C-reactive protein levels were measured. Platelets did not decrease in patients with sepsis, but they significantly decreased in patients with severe sepsis and septic shock (p <.01 vs. controls and sepsis). In contrast, thrombopoietin levels (median [range]) increased in patients with sepsis (159 [34-1272] pg/mL) compared with controls (57 [33-333] pg/mL, p <.001), exhibiting further significant increase in patients with severe sepsis and septic shock (461 [73-1550] and 522 [45-2313] pg/mL, respectively, p <.001 vs. sepsis). In multiple regression analysis, thrombopoietin levels were independently related only to sepsis severity (higher in patients with increased sepsis severity, p <.001) and platelet counts (higher in patients with lower platelet counts, p =.004). Sepsis severity accounted for most of the variance explained by the model. Thrombopoietin was significantly related to interleukin-6 (r =.26) and C-reactive protein (r =.37, p <.001 for both). In serial measurements, interleukin-6 peak values constantly preceded those of thrombopoietin, whereas peaks in thrombopoietin levels coincided with clinical episodes of septic shock. CONCLUSIONS: Sepsis severity is the major determinant of elevated thrombopoietin levels in septic patients, whereas platelet count is a secondary determinant. Thrombopoietin represents a potential marker of sepsis severity.     

New insights into the mechanisms involved in B-type natriuretic peptide elevation and its prognostic value in septic patients

Introduction

Elevated plasma B-type natriuretic peptide (BNP) levels in patients with critical sepsis (severe sepsis and septic shock) may indicate septic cardiomyopathy. However, multiple heterogeneous conditions may also be involved in increased BNP level. In addition, the prognostic value of BNP in sepsis remains debatable. In this study, we sought to discover potential independent determinants of BNP elevation in critical sepsis. The prognostic value of BNP was also evaluated.

Methods

In this observational study, we enrolled mechanically ventilated, critically septic patients requiring hemodynamic monitoring through a pulmonary artery catheter. All clinical, laboratory and survival data were prospectively collected. Plasma BNP concentrations were measured daily for five consecutive days. Septic cardiomyopathy was assessed on day 1 on the basis of left and right ventricular ejection fractions (EF) derived from echocardiography and thermodilution, respectively. Mortality was recorded at day 28.

Results

A total of 42 patients with severe sepsis (N = 12) and septic shock (N = 30) were ultimately enrolled. Daily BNP levels were significantly elevated in septic shock patients compared with those with severe sepsis (P ≤0.002). Critical illness severity (assessed by Acute Physiology and Chronic Health Evaluation II and maximum Sequential Organ Failure Assessment scores), and peak noradrenaline dose on day 1 were independent determinants of BNP elevation (P <0.05). Biventricular EFs were inversely correlated with longitudinal BNP measurements (P <0.05), but not independently. Pulmonary capillary wedge pressures (PCWP) and volume expansion showed no correlation with BNP. In septic shock, increased central venous pressure (CVP) and CVP/PCWP ratio were independently associated with early BNP values (P <0.05).Twenty-eight-day mortality was 47.6% (20 of 42 patients). Daily BNP values poorly predicted outcome; BNP on day 1 > 800 pg/ml (the best cutoff point) fairly predicted mortality, with a sensitivity%, specificity% and area under the curve values of 65, 64 and 0.70, respectively (95% confidence interval = 0.54 to 0.86; P = 0.03). Plasma BNP levels declined faster in survivors than in nonsurvivors in both critical sepsis and septic shock (P ≤0.002). In septic shock, a BNP/CVP ratio >126 pg/mmHg/ml on day 2 and inability to reduce BNP <500 pg/ml implied increased mortality (P ≤0.036).

Conclusions

The severity of critical illness, rather than septic cardiomyopathy, is probably the major determinant of BNP elevation in patients with critical sepsis. Daily BNP values are of limited prognostic value in predicting 28-day mortality; however, fast BNP decline over time and a decrease in BNP <500 pg/ml may imply a favorable outcome.     

Oligoclonal Immunoglobulin Bands in Serum in Association with Chronic Viral Hepatitis

We studied serum immunoglobulins in 54 patients with chronic viral hepatitis. The majority had hyperglobulinemia, with immunoglobulin G (IgG) being elevated the most. High resolution protein electrophoresis revealed the presence of oligoclonal bands within the gamma-globulin region of the electrophoretic pattern (oligoclonal immunoglobulin bands) in 32 (59%) patients. Between two and seven bands were noted in each sample. In order to analyze the significance of this observation, we performed stepwise discriminant analysis of clinical, demographic, serological, and serum biochemical features in patients with and without detectable oligoclonal immunoglobulin bands. The patient's ages and serum immunoglobulin G levels were found to be important predictors of the presence of oligoclonal immunoglobulin bands. No correlation was found with the type of hepatitis, disease severity, or duration of hepatitis. On follow-up, serum samples were retested in 20 patients, over 5 to 60 months. Significant change was noted in only one patient in whom oligoclonal immunoglobulin bands (initially very prominent) became progressively weaker and finally disappeared over a 5-yr period. This was associated with an improvement in his hepatitis after loss of hepatitis following loss of hepatitis B e antigen from serum. These observations suggest that the determination of oligoclonal immunoglobulin bands in serum may be a useful marker to study the course and activity of chronic viral hepatitis in selected patients.     

Hypoxaemic reperfusion ameliorates the histopathological changes in the pig brain after a severe global cerebral ischaemic insult

BACKGROUND AND PURPOSE: We have recently shown that hypoxaemic reperfusion, after an ischaemic brain insult, improves neurological outcome and decreases lipid peroxidation. In the present study, we investigated the effect of hypoxaemic reperfusion on brain histopathological changes. METHODS: Sixteen pigs subjected to a 10-min global cerebral ischaemia were either hypoxaemically (PaO2 = 35 mmHg, hypoxaemic reperfusion (HR) group, n = 8) or hyperoxaemically (PaO2 > 300 mmHg, control (C) group, n = 8) reperfused. The brains were removed 24 h after reperfusion and six neuropathological abnormalities were evaluated blindly and scored semi-quantitatively (0: normal to 3: severe injury) on eight representative regions of the brain. The overall cumulative score of the abnormalities and their regional prevalence, as well as the neurological outcome, were compared between the two groups. RESULTS: The neuronal degeneration, assessed in terms of cumulative score (P = 0.002) and regional prevalence (P = 0.025 to P = 0.041), was lower in the HR group than in the C group. Spongy degeneration attained statistically significant difference only in cerebellum (P = 0.002) and inflammation only in hippocampus (P = 0.046) but the difference in the cumulative score of these abnormalities was not statistically significant. The difference of the three neurological assessments over time was statistically significant between the two groups, i.e. after resuscitation (P = 0.001), at 8 h (P = 0.006) and at 24 h (P = 0.001) after reperfusion. CONCLUSIONS: Hypoxaemic reperfusion during resuscitation from a severe global ischaemic cerebral insult is associated with statistically significantly fewer histopathological changes of the brain than in controls. This is associated with a superior neurological outcome.     

Carboplatin and paclitaxel versus cisplatin, paclitaxel and doxorubicin for first-line chemotherapy of advanced ovarian cancer: a Hellenic Cooperative Oncology Group (HeCOG) study

IntroductionThe combination of Carboplatin and Paclitaxel is considered the standard of care as initial chemotherapy for Advanced Ovarian Cancer (AOC). We compared this regimen with the combination of Cisplatin, Paclitaxel and Doxorubicin.Patients and methodsPatients with AOC were randomised to either six courses of Paclitaxel 175 mg/m² plus Carboplatin 7AUC or Paclitaxel at the same dose plus Cisplatin 75 mg/m² plus Doxorubicin 40 mg/m².ResultsAnalysis was performed on 451 patients. The treatment groups were well balanced with regard to patient and disease characteristics. Performance status (PS) was better in the anthracycline arm. In terms of severe toxicity, the only significant difference between the two groups was the development of febrile neutropaenia in the anthracycline arm. Overall response rate was similar in both groups. With a median follow-up of 57.5 months, a marginal significance towards improved Progression-Free Survival (PFS) was noted in favour of the anthracycline arm, whilst there was no difference in overall survival. In multivariate analysis the hazard of disease progression at any time was significantly decreased by 25.5% for patients of the anthracycline arm.ConclusionThe combination of Cisplatin, Paclitaxel and Doxorubicin demonstrates a marginal PFS improvement, but no additional survival benefit when compared with the standard Carboplatin/Paclitaxel regimen.     

Venous oxygen saturation and lactate gradient from superior vena cava to pulmonary artery in patients with septic shock

Monitoring of central venous oxygen saturation (ScvO2) is considered comparable with mixed venous oxygen saturation (SvO2) in the initial resuscitation phase of septic shock. Our aim was to assess their agreement in septic shock in the intensive care unit setting and the effect of a potential difference in a computed parameter, namely, oxygen consumption (VO2). In addition, we sought for a central venous to pulmonary artery (PA) lactate gradient. We enrolled 37 patients with septic shock who were receiving noradrenaline infusions, and their attending physicians had placed a PA catheter for fluid management. Blood samples were drawn in succession from the superior vena cava, right atrium (RA), right ventricle, and PA. Hemodynamic and treatment parameters were monitored, and data were compared by correlation and Bland-Altman analysis. Mixed venous oxygen saturation was lower than ScvO2 (70.2% +/- 11.4% vs. 78.6% +/- 10.2%; P < 0.001), with a bias of -8.45% and 95% limits of agreement ranging from -20.23% to 3.33%. This difference correlated significantly to the noradrenaline infusion rate and the oxygen consumption and extraction ratio. These lower SvO2 values resulted in computed VO2v higher than the VO2cv (P < 0.001), with a bias of 104.97 mL min(-1) and 95% limits of agreement from -4.12 to 214.07 mL min(-1). Finally, lactate concentration was higher in the superior vena cava and RA than in the PA (2.42 +/- 3.15 and 2.35 +/- 3.16 vs. 2.17 +/- 3.19 mM; P < 0.01 for both comparisons). Thus, our data suggest that ScvO2 and SvO2 are not equivalent in intensive care unit patients with septic shock. Additionally, the substitution of ScvO2 for SvO2 in the calculation of VO2 produces unacceptably large errors. Finally, the decrease in lactate between RA and PA may support the hypothesis that the mixing of RA and coronary sinus blood is at least partially responsible for the difference between ScvO2 and SvO2.     

Exposure to Stress-Dose Steroids and Lethal Septic Shock After In-Hospital Cardiac Arrest: Individual Patient Data Reanalysis of Two Prior Randomized Clinical Trials that Evaluated the Vasopressin–Steroids–Epinephrine Combination Versus Epinephrine Alone

Purpose

Low-dose steroids may reduce the mortality of severely ill patients with septic shock. We sought to determine whether exposure to stress-dose steroids during and/or after cardiopulmonary resuscitation is associated with reduced risk of death due to postresuscitation septic shock.

Methods

We analyzed pooled, individual patient data from two prior, randomized clinical trials (RCTs). RCTs evaluated vasopressin, steroids, and epinephrine (VSE) during resuscitation and stress-dose steroids after resuscitation in vasopressor-requiring, in-hospital cardiac arrest. In the second RCT, 15 control group patients received open-label, stress-dose steroids. Patients with postresuscitation shock were assigned to a Steroids (n?=?118) or No Steroids (n?=?73) group according to an “as-treated” principle. We used cumulative incidence competing risks Cox regression to determine cause-specific hazard ratios (CSHRs) for pre-specified predictors of lethal septic shock (primary outcome). In sensitivity analyses, data were analyzed according to the intention-to-treat (ITT) principle (VSE group, n?=?103; control group, n?=?88).

Results

Lethal septic shock was less likely in Steroids versus No Steroids group, CSHR, 0.40, 95% confidence interval (CI), 0.20–0.82; p?=?0.012. ITT analysis yielded similar results: VSE versus Control, CSHR, 0.44, 95% CI, 0.23–0.87; p?=?0.019. Adjustment for significant, between-group baseline differences in composite cardiac arrest causes such as “hypotension and/or myocardial ischemia” did not appreciably affect the aforementioned CSHRs.

Conclusions

In this reanalysis, exposure to stress-dose steroids (primarily in the context of a combined VSE intervention) was associated with lower risk of postresuscitation lethal septic shock.