Konstantinos Mandragos

Early alterations of the innate and adaptive immune statuses in sepsis according to the type of underlying infection

IntroductionAlthough major changes of the immune system have been described in sepsis, it has never been studied whether these may differ in relation to the type of underlying infection or not. This was studied for the first time.MethodsThe statuses of the innate and adaptive immune systems were prospectively compared in 505 patients. Whole blood was sampled within less than 24 hours of advent of sepsis; white blood cells were stained with monoclonal antibodies and analyzed though a flow cytometer.ResultsExpression of HLA-DR was significantly decreased among patients with severe sepsis/shock due to acute pyelonephritis and intraabdominal infections compared with sepsis. The rate of apoptosis of natural killer (NK) cells differed significantly among patients with severe sepsis/shock due to ventilator-associated pneumonia (VAP) and hospital-acquired pneumonia (HAP) compared with sepsis. The rate of apoptosis of NKT cells differed significantly among patients with severe sepsis/shock due to acute pyelonephritis, primary bacteremia and VAP/HAP compared with sepsis. Regarding adaptive immunity, absolute counts of CD4-lymphocytes were significantly decreased among patients with severe sepsis/shock due to community-acquired pneumonia (CAP) and intraabdominal infections compared with sepsis. Absolute counts of B-lymphocytes were significantly decreased among patients with severe sepsis/shock due to CAP compared with sepsis.ConclusionsMajor differences of the early statuses of the innate and adaptive immune systems exist between sepsis and severe sepsis/shock in relation to the underlying type of infection. These results may have a major impact on therapeutics.

Health-related quality of life and disability in survivors of multiple trauma one year after intensive care unit discharge.

Dimopoulou I, Anthi A, Mastora Z, Theodorakopoulou M, Konstandinidis A, Evangelou E, Mandragos K, Roussos C: Health-related quality of life and disability in survivors of multiple trauma one year after intensive care unit discharge. Am J Phys Med Rehabil 2004;83:171–176. ObjectiveTo evaluate health-related quality of life and disability in multiple-trauma patients requiring intensive care unit management. DesignA total of 87 survivors of multiple trauma, with a median age of 31 yrs and a median Injury Severity Score of 22, were enrolled in the present study. The Nottingham Health Profile, Glasgow Outcome Scale, and Rosser Disability Scale were used to assess the functional consequences of trauma 1 yr after intensive care unit discharge. ResultsA total of 64 of 87 patients had a problem in at least one of the six domains related to subjective health status. The most prevalent complaint was related to somatic subdimensions, but emotional functioning was also affected. Nottingham Health Profile part 2 showed that 63 of the survivors experienced problems in at least one of the daily activities. Of particular importance, inability to work was reported by 47% of the patients. Fifty-nine percent experienced moderate-to-severe disability as evaluated by Glasgow Outcome Scale and Rosser Disability Scale. High aggregate injury severity score along with severe head trauma were independent predictors of poor health-related quality of life and disability. ConclusionsThe majority of survivors of major trauma exhibit considerable levels of disability and impairment in health-related quality of life. Global injury severity score and degree of brain trauma determine functional limitations. This information may help in organizing long-term rehabilitation of multiple-trauma patients.

High prevalence of decreased cortisol reserve in brain-dead potential organ donors.

ObjectiveTo investigate the adrenocortical function in brain-dead patients, potential organ donors. DesignProspective study. SettingIntensive care units in two teaching hospitals. PatientsA total of 37 patients (28 men, nine women) with severe brain injury, having a mean age of 42 ± 18 yrs, were included in the study. Group A consisted of 20 brain-injured patients who did not deteriorate to brain death. Group B included 17 brain-injured patients who were brain dead; of these, ten patients developed brain death during ICU stay and seven patients were admitted to the ICU after clinical brain death. InterventionsIn all patients (group A and group B), a morning blood sample was obtained at admission to the ICU to determine baseline plasma cortisol. Subsequently, 1 &mgr;g of corticotropin (adrenocorticotropic hormone, Synacthen) was administered intravenously, and a blood sample was taken 30 mins after the injection. In group B patients who became brain dead while being treated in the ICU (n = 10), the same procedure was repeated the morning after the confirmation of brain death. Patients having a cortisol level of at least 18 &mgr;g/dL after the administration of adrenocorticotropic hormone were defined as responders. Measurements and Main ResultsAfter the occurrence of brain death, group B patients had significantly lower values for baseline (8.5 ± 6.2 vs. 17.0 ± 6.6 &mgr;g/dL, p < .001) and stimulated (16.9 ± 6.3 vs. 23.9 ± 5.7 &mgr;g/dL, p = .001) plasma cortisol compared with group A patients. Thirteen group B patients (76%) and two group A patients (10%) were nonresponders to adrenocorticotropic hormone (p < .001). In group B patients, baseline and stimulated cortisol concentrations were significantly related (r = .71, p = .001), whereas there was no correlation between baseline cortisol and the increment in cortisol (r = −.37, p = .15). Mean hormonal data of the ten brain-dead patients studied at admission in the ICU and after the occurrence of brain death were the following: baseline plasma cortisol (23.5 ± 11.4 vs. 6.8 ± 4.2 &mgr;g/dL, p = .003) and stimulated serum cortisol (28.8 ± 9.9 vs. 16.3 ± 4.3 &mgr;g/dL, p = .008). ConclusionsAdrenal cortisol secretion after dynamic stimulation is deficient in a substantial proportion of brain-dead potential organ donors.

Risk assessment in sepsis: a new prognostication rule by APACHE II score and serum soluble urokinase plasminogen activator receptor.

IntroductionEarly risk assessment is the mainstay of management of patients with sepsis. APACHE II is the gold standard prognostic stratification system. A prediction rule that aimed to improve prognostication by APACHE II with the application of serum suPAR (soluble urokinase plasminogen activator receptor) is developed.MethodsA prospective study cohort enrolled 1914 patients with sepsis including 62.2% with sepsis and 37.8% with severe sepsis/septic shock. Serum suPAR was measured in samples drawn after diagnosis by an enzyme-immunoabsorbent assay; in 367 patients sequential measurements were performed. After ROC analysis and multivariate logistic regression analysis a prediction rule for risk was developed. The rule was validated in a double-blind fashion by an independent confirmation cohort of 196 sepsis patients, predominantly severe sepsis/septic shock patients, from Sweden.ResultsSerum suPAR remained stable within survivors and non-survivors for 10 days. Regression analysis showed that APACHE II ≥17 and suPAR ≥12 ng/ml were independently associated with unfavorable outcome. Four strata of risk were identified: i) APACHE II <17 and suPAR <12 ng/ml with mortality 5.5%; ii) APACHE II < 17 and suPAR ≥12 ng/ml with mortality 17.4%; iii) APACHE II ≥ 17 and suPAR <12 ng/ml with mortality 37.4%; and iv) APACHE II ≥17 and suPAR ≥12 ng/ml with mortality 51.7%. This prediction rule was confirmed by the Swedish cohort.ConclusionsA novel prediction rule with four levels of risk in sepsis based on APACHE II score and serum suPAR is proposed. Prognostication by this rule is confirmed by an independent cohort.

Early Administration of Hydrocortisone Replacement After the Advent of Septic Shock: Impact on Survival and Immune Response*

Objectives:To investigate the impact of early initiation of hydrocortisone therapy on the clinical course of septic shock and on cytokine release. Design:Prospective study in patients with septic shock treated with low doses of hydrocortisone. Setting:ICUs and general wards. Patients:Over a 2-year period, 170 patients with septic shock treated with low doses of hydrocortisone were enrolled. Blood was sampled from 34 patients for isolation of peripheral blood mononuclear cells and cytokine stimulation before and 24 hours after the start of hydrocortisone. Interventions:None. Measurements and Main Results:After quartile analysis, patients were divided into those with early initiation of hydrocortisone (< 9 hr after vasopressors, n = 46) and those with late initiation of hydrocortisone (> 9 hr after vasopressors, n = 124). After adjusting for disease severity and type of infection, a protective effect of early hydrocortisone administration against unfavorable outcome was found (hazard ratio, 0.20; p = 0.012). Time of discontinuation of vasopressors was earlier among patients with initiation of hydrocortisone within 9 hours. Production of tumor necrosis factor-&agr; was lower among patients who had had hydrocortisone early. Conclusions:In patients receiving hydrocortisone for septic shock, early initiation of treatment was associated with improved survival. This treatment was also associated with attenuated stimulation of tumor necrosis factor-&agr;.

Prediction of prolonged ventilatory support in blunt thoracic trauma patients

ObjectiveTo identify predictors of prolonged (>7 days) mechanical ventilation (MV) in patients with blunt thoracic trauma.DesignProspective analysis of consecutive patients.SettingAdult intensive care unit (ICU) in a teaching, tertiary-care hospital.Patients and participantsSixty-nine patients (53 men, 16 women) with thoracic trauma having a median age of 35 (range 17–85) years and a median injury severity score (ISS) of 29 (range 14–41) were enrolled in the present study. Associated injuries included head–neck (77%), extremities (72%), external (67%), abdomen–pelvis (67%), and face (55%).InterventionsPatient surveillance and data collection.Measurements and resultsThirty-three (48%) of the 69 patients required prolonged ventilatory support, ranging in duration from 8 to 38 (median 18) days. Logistic regression analysis revealed that advancing age (odds ratio=1.04, p=0.04), severity of head injury (odds ratio=1.92, p=0.008), and bilateral thoracic injuries (odds ratio=12.80, p<0.0001) were significant and independent predictors of long-lasting MV. In contrast, gender, injuries affecting the other body regions (face, abdomen–pelvis, extremities, and external), laparotomy in patients with abdominal injury, or PaO2/FIO2 on admission in the ICU, were unrelated to prolonged MV.ConclusionsIn thoracic trauma patients admitted in the ICU, prolonged mechanical ventilation was primarily determined by presence of bilateral chest injuries, age, and degree of neurotrauma. This information may help in planning the long-term care of such patients.

Genetic polymorphisms within tumor necrosis factor gene promoter region: a role for susceptibility to ventilator-associated pneumonia.

Debatable findings exist among various studies regarding the impact of single nucleotide polymorphisms (SNPs) within the promoter region of the tumor necrosis factor (TNF) gene for susceptibility to infections. Their impact was investigated in a cohort of mechanically ventilated patients who developed ventilator-associated pneumonia (VAP). Two-hundred and thirteen mechanically ventilated patients who developed VAP were enrolled. Genomic DNA was extracted and SNPs at the -376, -308 and -238 position of the promoter region of the TNF gene were assessed by restriction fragment length polymorphisms. Monocytes were isolated from 47 patients when they developed sepsis and stimulated by bacterial endotoxin for the production of TNFα and of interleukin-6 (IL-6). Patients were divided into two groups; 166 patients bearing only wild-type alleles of all three studied polymorphisms; and 47 patients carrying at least one A allele of the three studied SNPs. Time between start of mechanical ventilation and advent of VAP was significantly shorter in the second group than in the first group (log-rank: 4.416, p: 0.041). When VAP supervened, disease severity did not differ between groups. Stimulation of TNFα and of IL-6 was much greater by monocytes for patients carrying A alleles. Carriage of at least one A allele of the three studied SNPs at the promoter region of the TNF-gene is associated with shorter time to development of VAP but it is not associated with disease severity. Findings may be related with a role of the studied SNPs in the production of pro-inflammatory cytokines.

Defective cytokine production early after multiple traumas: Modulation in severe sepsis

The exact time frame of multiple trauma-induced immunosuppression and the immune mechanisms mediating transition to severe sepsis are largely unknown. Peripheral blood mononuclear cells were isolated from 69 patients with multiple injuries within the first 24h from injury and from 36 healthy volunteers and stimulated for cytokine production. Circulating endotoxins were measured by the kinetic LAL assay. Measurements were repeated the first 24h of sepsis onset. Patients had defective responses for tumour necrosis factor-alpha (TNFα), interleukin (IL)-10, IL-17 and interferon-gamma (IFNγ) using a broad-panel of bacterial stimuli. Production of IFNγ was pronounced for patients with trauma-related multiple organ failure (MOF). Thirty-six patients developed severe sepsis. At that time, production of TNFα was increased compared to baseline. The increase was greater among non-survivors than among survivors. Enhanced TNFα production on sepsis onset was a main finding of patients without endotoxemia. Immunosuppression of both innate and adaptive cytokine responses appears as early as the first 24h from injury. Transition into severe sepsis due to bacterial superinfection is accompanied by enhanced production of TNFα and this is linked with unfavorable outcome.

Polymicrobial bloodstream infections: Epidemiology and impact on mortality

The aim of this study was to investigate the impact of polymicrobial bloodstream infections (pBSIs) on the outcome of sepsis in an area where antimicrobial resistance is of concern. This was a retrospective analysis of data collected prospectively from patients developing BSI outside of an intensive care unit (non-ICU patients) or after ICU admission. Demographics and clinical characteristics were compared for patients with pBSI versus monomicrobial BSI (mBSI) and following stratification by ICU or non-ICU and severity of sepsis status. Possible risk factors for adverse outcome were explored by multivariate analysis, and outcomes were measured by Cox regression analysis. Among 412 patients with BSI, 47 patients (11.4%) with pBSI were recorded; compared with patients with mBSI, they had significantly higher APACHE II scores and presented more frequently with severe sepsis/septic shock. The all-cause 28-day mortality was significantly higher for pBSI versus mBSI (38.3% vs. 24.7%; P=0.033), whereas appropriateness of treatment was comparable (78.7% vs. 86.6%). Primary bacteraemia by combinations of Enterococcus faecalis, Klebsiella pneumoniae and Acinetobacter baumannii was predominant among pBSIs; in mBSIs, urinary tract infections by Escherichia coli, K. pneumoniae or Pseudomonas aeruginosa predominated. Multivariate analysis demonstrated pBSI as a significant contributor to 28-day mortality (HR=1.86; P=0.039), along with presence of two or more co-morbidities (HR=2.35; P=0.004). In conclusion, pBSIs differed epidemiologically from mBSIs, with the emergence of enterococcal species, and portended an almost two-fold increased risk of 28-day mortality. Prospective studies are warranted to elucidate possibly modifiable factors.

Massive Rupture of a Hepatic Hydatid Cyst Associated with Mechanical Ventilation

UNLABELLED An 80-yr-old woman with a complicated Echinococcus cyst of the liver underwent endotracheal intubation with a simple endotracheal tube and conventional mechanical ventilation that led to massive rupture of the cyst into the bronchi followed by fatal anaphylactic shock. We believe that the currently recommended use of a double-lumen endotracheal tube during surgery in the pulmonary hydatid cysts should be extended to hydatid cysts of the liver with thoracic involvement. IMPLICATIONS We present a case of massive rupture of hepatic Echinococcus cyst associated with mechanical ventilation. We believe that the use of a double-lumen endotracheal tube could be crucial in the management of the hydatid cysts of the liver with thoracic involvement.