Early prognostic factors in septic shock cancer patients: a prospective study with a proteomic approach.

BACKGROUND: Organ failures are the main prognostic factors in septic shock. The aim was to assess classical clinico-biological parameters evaluating organ dysfunctions at intensive care unit admission, combined with proteomics, on day-30 mortality in critically ill onco-hematology patients admitted to the intensive care unit for septic shock. METHODS: This was a prospective monocenter cohort study. Clinico-biological parameters were collected at admission. Plasma proteomics analyses were performed, including protein profiling using isobaric Tag for Relative and Absolute Quantification (iTRAQ) and subsequent validation by ELISA. RESULTS: Sixty consecutive patients were included. Day-30 mortality was 47%. All required vasopressors, 32% mechanical ventilation, 33% non-invasive ventilation and 13% renal-replacement therapy. iTRAQ-based proteomics identified von Willebrand factor as a protein of interest. Multivariate analysis identified four factors independently associated with day-30 mortality: positive fluid balance in the first 24 h (odds ratio = 1.06, 95% CI = 1.01-1.12, P = 0.02), severe acute respiratory failure (odds ratio = 6.14, 95% CI = 1.04-36.15, P = 0.04), von Willebrand factor plasma level > 439 ng/ml (odds ratio = 9.7, 95% CI = 1.52-61.98, P = 0.02), and bacteremia (odds ratio = 6.98, 95% CI = 1.17-41.6, P = 0.03). CONCLUSION: Endothelial dysfunction, revealed by proteomics, appears as an independent prognostic factor on day-30 mortality, as well as hydric balance, acute respiratory failure and bacteremia, in critically ill cancer patients admitted to the intensive care unit. Endothelial failure is underestimated in clinical practice and represents an innovative therapeutic target.

Oblique contractional reactivation of inherited heterogeneities: Cause for arcuate orogens.

We use lithospheric-scale analog models to study the reactivation of pre-existing heterogeneities under oblique shortening and its relation to the origin of arcuate orogens. Reactivation of inherited rheological heterogeneities is an important mechanism for localization of deformation in compressional settings and consequent initiation of contractional structures during orogenesis. However, the presence of an inherited heterogeneity in the lithosphere is in itself not sufficient for its reactivation once the continental lithosphere is shortened. The heterogeneity orientation is important in determining if reactivation occurs and to which extent. This study aims at giving insights on this process by means of analog experiments in which a linear lithospheric heterogeneity trends with various angles to the shortening direction. In particular, the key parameter investigated is the orientation (angle α) of a strong domain (SD) with respect to the shortening direction. Experimental results show that angles α ≥ 75° (high obliquity) allow for reactivation along the entire SD and the development of a linear orogen. For α ≤ 60° (low obliquity) the models are characterized by the development of an arcuate orogen, with the SD remaining partially non-reactivated. These results provide a new mechanism for the origin of some arcuate orogens, in which orocline formation was not driven by indentation or subduction processes, but by oblique shortening of inherited heterogeneities, as exemplified by the Ouachita orogen of the southern U.S.

Severity of Acute Respiratory Distress Syndrome in haematology patients: long-term impact and early predictive factors.

Severe forms of acute respiratory distress syndrome in patients with haematological diseases expose clinicians to specific medical and ethical considerations. We prospectively followed 143 patients with haematological malignancies, and whose lungs were mechanically ventilated for more than 24 h, over a 5-y period. We sought to identify prognostic factors of long-term outcome, and in particular to evaluate the impact of the severity of acute respiratory distress syndrome in these patients. A secondary objective was to identify the early (first 48 h from ICU admission) predictive factors for acute respiratory distress syndrome severity. An evolutive haematological disease (HR 1.71; 95% CI 1.13-2.58), moderate to severe acute respiratory distress syndrome (HR 1.81; 95% CI 1.13-2.69) and need for renal replacement therapy (HR 2.24; 95% CI 1.52-3.31) were associated with long-term mortality. Resolution of neutropaenia during ICU stay (HR 0.63; 95% CI 0.42-0.94) and early microbiological documentation (HR 0.62; 95% CI 0.42-0.91) were associated with survival. The extent of pulmonary infiltration observed on the first chest X-ray and the diagnosis of invasive fungal infection were the most relevant early predictive factors of the severity of acute respiratory distress syndrome.

Early diastolic dysfunction is associated with intensive care unit mortality in cancer patients presenting with septic shock.

BACKGROUND: Cancer patients present a high risk of sepsis and are exposed to cardiotoxic drugs during chemotherapy. Myocardial dysfunction is common during septic shock and can be evaluated at bedside using echocardiography. The aim of this study was to identify early cardiac dysfunctions associated with intensive care unit (ICU) mortality in cancer patients presenting with septic shock. METHODS: Seventy-two cancer patients admitted to the ICU underwent echocardiography within 48 h of developing septic shock. History of malignancies, anticancer treatments, and clinical characteristics were prospectively collected. RESULTS: ICU mortality was 48%. Diastolic dysfunction (e' ≤8 cm s(-1)) was an independent echocardiographic parameter associated with ICU mortality {odds ratio (OR) 7.7 [95% confidence interval (CI), 2.58-23.38]; P<0.001}. Overall, three factors were independently associated with ICU mortality: sepsis-related organ failure assessment score at admission [OR 1.35 ( 95% CI, 1.05-1.74); P=0.017], occurrence of diastolic dysfunction [OR 16.6 (95% CI, 3.28-84.6); P=0.001], and need for conventional mechanical ventilation [OR 16.6 (95% CI, 3.6-77.15); P<0.001]. Diastolic dysfunction was not associated with exposure to cardiotoxic drugs. CONCLUSIONS: Early diastolic dysfunction is a strong and independent predictor of mortality in cancer patients presenting with septic shock. It is not associated with exposure to cardiotoxic drugs. Further studies incorporating monitoring of diastolic function and therapeutic interventions improving cardiac relaxation need to be evaluated in cancer patients presenting with septic shock.

Critically ill cancer patients in the intensive care unit: short-term outcome and 1-year mortality.

BACKGROUND: The short-term survival of critically ill patients with cancer has improved over time. Studies providing long-term outcome for these patients are scarce. METHODS: We prospectively analyzed outcomes and rates of successful discharge of 111 consecutive critically ill cancer patients admitted to intensive care unit (ICU) in 2008 and identified factors influencing these results. RESULTS: ICU mortality was 32% and hospital mortality was 41%. None of the characteristics of the malignancy nor age or neutropenia were significantly different between survivors and others. Two variables were independently associated with ICU mortality: high Logistic Organ Dysfunction score on day 7 and a diagnosis of viral infection and/or reactivation. The 1-year mortality rate for ICU survivors was 58% and was significantly lower in patients with a diagnosis of acute leukemia or multiple myeloma. CONCLUSION: Organ failure scores on day 7 can predict outcome for cancer patients in the ICU. Viral infection and reactivation appear to worsen the prognosis. One-year mortality rate is high and depends on the malignancy.

HLA-DR and B7-2 (CD86) monocyte expressions after major cancer surgery: profile in sepsis.

AIM: HLA-DR monocyte expression may be affected by major surgery. A potential mechanism for monocyte activation is the engagement of costimulatory receptors (B7-2 or CD-86). The aim of the present study was to determine the possible role of monocyte HLA-DR and B7-2 molecules in the occurrence of postoperative sepsis after major cancer surgery. METHODS: This was an observational study in 25 consecutive patients undergoing major elective surgery. Flow cytometry measures were used to determine the expression of HLA-DR and its costimulatory receptors before (day 0) and after surgery (day 1 and day 2). RESULTS: After surgery, the rate of monocytes expressing HLA-DR decreased significantly in all the patients. As compared with day 0, the rate of monocytes expressing B7-2 decreased in all the patients (P<0.03). In the septic group, it remained significantly decreased postoperatively. In the non-septic group, it reached baseline levels at day 2. CONCLUSION: Results suggest a key role for costimulatory molecules in modulating inflammatory response in the context of subsequent postoperative sepsis after major cancer surgery. These molecules may be involved, in association with HLA-DR, in postoperative monocyte dysfunction.

Reduced interleukin-12 release from stimulated monocytes in patients with sepsis after major cancer surgery.

BACKGROUND: Major cancer surgery is a high-risk situation for sepsis in the post-operative period. The aim of this study was to assess the relation between the monocyte production of IL-12 and the development of post-operative sepsis in patients undergoing major cancer surgery. METHODS: In 19 patients undergoing major cancer surgery, the production of cytokines by basal and lipolysaccharide (LPS)-stimulated monocytes was measured before and after (from day 1 to day 3 and day 7) surgery. Seven of them developed a post-operative sepsis. Ten healthy volunteers were used as controls for the assessment of pre-operative values. RESULTS: Before surgery, the production of interleukin (IL)-12 p40 by LPS-stimulated monocytes was similar in the patients and the healthy volunteers. The production of IL-12 p40 by unstimulated monocytes was higher in the patients than in the healthy volunteers. IL-12 production did not differ between the septic and the non-septic patients. After surgery, the production of IL-12 p40 was dramatically reduced in the LPS-stimulated monocytes of the septic patients from day 1 to day 3, as compared with that of the non-septic patients. Before surgery, the production of IL-6, IL-10, and IL-1 receptor antagonist (IL-1ra) in the patients was significantly higher than that of the healthy volunteers for both stimulated and unstimulated monocytes. After surgery, the production of these cytokines by both stimulated and unstimulated monocytes of the septic patients was similar to that of the non-septic patients. Intragroup analysis showed significant changes for IL-6, IL-10, and IL-1ra under all conditions, with the exception of changes in unstimulated monocytes of septic patients that were not significant for IL-10 release. CONCLUSION: After surgery, the septic patients showed drastic failure to up-regulate monocyte LPS-stimulated production of IL-12 p40.

Predictive perioperative factors for developing severe sepsis after major surgery.

BACKGROUND: Early identification of high-risk patients undergoing major surgery can result in an aggressive management affecting the outcome. METHODS: We designed a prospective cohort study of 93 adult patients undergoing major oncological surgery to identify the predictive risk factors for developing postoperative severe sepsis. RESULTS: Nineteen of 93 patients developed a severe sepsis after surgery; seven of the septic patients died in intensive care unit. Multivariate analysis discriminated preoperative and postoperative (first and second day after surgery) predictive risk factors. The postoperative severe sepsis was independently associated with preoperative factors like male gender (OR 4.7, 95% CI between 1.5 and 15.5, P<0.01) and Charlson co-morbidity index (OR 1.3, 95% CI between 1.07 and 1.6, P<0.01). After the surgery, the presence of systemic inflammatory response syndrome (OR 4.0, 95% CI between 1.02 and 15.7, P<0.05) and a logistic organ dysfunction score on day 2 (OR 3.3, 95% CI between 1.9 and 5.7, P<0.001) were found as independent predictive factors. CONCLUSION: We have shown that some of the markers that can be easily collected in the preoperative or postoperative visits can be used to screen the patients at high risk for developing severe sepsis after major surgery.

Procalcitonin, interleukin 6 and systemic inflammatory response syndrome (SIRS): early markers of postoperative sepsis after major surgery.

BACKGROUND: Patients who undergo major surgery for cancer are at high risk of postoperative sepsis. Early markers of septic complications would be useful for diagnosis and therapeutic management in patients with postoperative sepsis. The aim of this study was to investigate the association between early (first postoperative day) changes in interleukin 6 (IL-6), procalcitonin (PCT) and C-reactive protein (CRP) serum concentrations and the occurrence of subsequent septic complications after major surgery. METHODS: Serial blood samples were collected from 50 consecutive patients for determination of IL-6, PCT and CRP serum levels. Blood samples were obtained on the morning of surgery and on the morning of the first postoperative day. RESULTS: Sixteen patients developed septic complications during the first five postoperative days (group 1), and 34 patients developed no septic complications (group 2). On day 1, PCT and IL-6 levels were significantly higher in group 1 (P-values of 0.003 and 0.006, respectively) but CRP levels were similar. An IL-6 cut-off point set at 310 pg ml(-1) yielded a sensitivity of 90% and a specificity of 58% to differentiate group 1 patients from group 2 patients. When associated with the occurrence of SIRS on day 1 these values reached 100% and 79%, respectively. A PCT cut-off point set at 1.1 ng ml(-1) yielded a sensitivity of 81% and a specificity of 72%. When associated with the occurrence of SIRS on day 1, these values reached 100% and 86%, respectively. CONCLUSIONS: PCT and IL-6 appear to be early markers of subsequent postoperative sepsis in patients undergoing major surgery for cancer. These findings could allow identification of postoperative septic complications.

[Syphilis in Europe in antiquity: the fetus of Costebelle and other new gifts from osteoarchaeology]. / La syphilis en Europe dans l'Antiquité: le foetus de Costebelle et les autres nouvelles données ostéoarcheologiques.

Tomb Nr 1 of the ancient cemetery of Costebelle, attributed to the 4th century AD, contained the skeleton of a pregnant female and that of her foetus in the pelvic cavity. This was aged seven months, was almost complete and showed an exceptional example of bony lesions suggestive of infection. Its etiology suggested the likelihood of early congenital syphilis. This case raises the question of the theory of the importation of venereal disease into Europe, about a 1000 years later, by the crews of Christopher Columbus. The foetus of Costebelle is not an isolated example : other osteo-archaeological findings make a case for the existence of a treponeme (venereal or non venereal) in Europe before 1493.

[Feasibility and tolerance evaluation of 2 routes of preoperative administration of interleukin 2]. / Faisabilité et évaluation de la tolerance de deux schémas d'administration préopératoire d'interleukine 2.

Preoperative interleukin 2 (IL2) administration has been performed, in order to diminish the post-operative immunodepression in cancer patients. The aim of this study was to compare two different ways of preoperative IL2 administration, ie, intravenous (iv) and subcutaneous (sc), in terms of feasibility and tolerance. Nineteen surgical procedures were performed in 18 patients: a) 10 following the administration of 12 IU/m2/24 hours IL2 IV, with a continuous infusion, from day 5 to day 3 before surgery; b) 9 following the administration of 18 IU IL2, in 2 SC injections per day, from day 4 to day 2 before surgery. Tolerance was evaluated by both clinical and biological parameters, before, during, and after surgery. Hyperthermia and capillary leak syndrome were more important in the iv versus sc injection group. Insomnia and digestive troubles were more frequent in the iv injection group as well. However, we noticed few and equivalent cutaneous and respiratory complications in both groups. In conclusion, the tolerance of IL2 was better after sc versus iv injection. However, the toxicity of iv infusion of IL2 was moderate and could be limited by preventive treatments; moreover there was no consequence on the scheduled surgical procedure.

[Training evaluation of the nursing staff in patient-controlled analgesia]. / Evaluation d'un enseignement de l'auto-analgésie au personnel infirmier.

Intravenous patient-controlled analgesia (PCA) is an effective technique to relieve most forms of acute postoperative pain. However it is not easy to apply. An adequate training of the nursing staff has been for a safe and successful use in the recovery room and the wards as well. Our study was aimed to assess such a training. The most common errors during training period included the incorrect preparation of syringes and the inadequate use of i.v. lines. Errors in programming were spontaneously rectified by using a special procedure. Specific acute pain nurse teams were trained. To optimize the pump use and promote safety and efficacy, special protocols and procedures were devised. PCA is now accepted as a normal nurse procedure. There is no longer any resistance against the introduction of PCA in the wards. Training of nursing staff for the use of PCA devices is essential in order to avoid "human errors". PCA has become routine for the management of postoperative pain.

[Foot equipment of diabetic arteriopathy]. / L'appareillage du pied des artéritiques diabétiques.

Surgical appliances have a place of choice in the care of the foot with trophic lesions in diabetics, after partial amputation and as a preventive measure when it is free from trophic disorders. The type of appliance will depend on the footwear and the possibility of wearing orthopedic soles, whatever the stage of the affection. For the foot free from trophic disorders the shoes should be wide fitting, in soft leather and of the seamless type. Made to measure shoes should be reserved for badly deformed feet. The soles should be molded in silicone or polyurethane to distribute weight bearing and to avoid it over zones at risk. Appliances for the foot with trophic lesions should allow the resumption of walking. If the lesions are too extensive an orthosis is performed or a specific type of slipper with molded soles is worn to avoid pressure on the wounds. After amputation of toes a silicone orthoplasty is used to fill the interdigital space to avoid deformity of the other toes. If a front of foot has been amputated a corrected silicone molded sole with false extremity is applied. For a back of foot amputation an orthoprosthesis is made, preferentially in silicone introductible in a regular high sided shoe. In order to fulfil its preventive or temporary role, the appliance should evolve with time and be followed up regularly with close collaboration between the diabetic specialist the podologist and the orthotist.

Pharmacokinetics and tissue penetration of a single 1,000-milligram, intravenous dose of metronidazole for antibiotic prophylaxis of colorectal surgery.

The levels of metronidazole in serum and tissue penetration of metronidazole were studied after prophylactic administration in 11 patients undergoing elective colorectal surgery. A single dose of 1,000 mg given intravenously was administered before surgery. Adequate drug levels in serum (greater than or equal to MIC for 90% of strains tested [MIC90] for Bacteroides fragilis) were found in all patients throughout the procedure. Mean peak (15-min) and last-determined (24-h) metronidazole levels in serum were 28.8 +/- 8 and 4.2 +/- 1.7 mg/liter, respectively. The beta-phase elimination half-life was 9.5 +/- 2.3 h, and the clearance and apparent volume of distribution were 57 +/- 13 ml/min and 0.7 +/- 0.1 liter/kg, respectively. In the colonic wall at surgical anastomosis, tissue metronidazole levels greater than or equal to MIC90 for B. fragilis were found in 91% of patients. In the abdominal wall fat and epiploic fat, tissue metronidazole levels greater than or equal to MIC90 for B. fragilis were found in 40 to 60% of patients at surgical incision and closure. No anaerobic infection occurred during the study.

[Pharmacokinetics and tissue penetration of single-dose netilmicin used for antibiotic prophylaxis during colo-rectal surgery]. / Pharmacocinétique et diffusion tissulaire de la nétilmicine utilisée en dose unique pour l'antibioprophylaxie en chirurgie colo-rectale.

Pharmacokinetics and tissue penetration of netilmicin were studied after the use of a single dose (6 mg/kg) given for antibioprophylaxis in colo-rectal surgery. Thirteen patients, scheduled for elective surgery, were given 6 mg/kg IV netilmicin over 30 min, together with 1000 mg IV ornidazole. Netilmicin peak serum concentration (10 min after end of infusion) was 24.4 +/- 3.4 mg/l and trough level (24 h) was 0.9 +/- 0.5 mg/l. Plasma elimination half-life was 409 +/- 70 min, le volume apparent volume of distribution was 38 +/- 101 and total body clearance was 0.07 +/- 0.02 ml/min. Adequate netilmicin levels (5 greater than or equal to CMI 90 of involved pathogens Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus) were obtained in 100 per cent of patients in abdominal wall and epiploid fat, at time of opening, and in colonic wall at time of anastomosis. Adequate levels were obtained at time of closure in abdominal wall and epiploid fat in 92 to 100 per cent of patients. In situation of allergy to beta-lactam antibiotics, the use of netilmicin in combination with ornidazole may be recommended.

[Tissue penetration of single-dose cefotetan used for antibiotic prophylaxis in colorectal surgery]. / Pénétration tissulaire du céfotétan utilisé en dose unique pour une antibioprophylaxie en chirurgie colorectale.

Pharmacokinetics and tissue penetration of cefotetan were studied after a single injection of 2 g for antibiotic prophylaxis in colo-rectal surgery. Beta half-life was 4.3 +/- 1 h, total body clearance was 0.74 +/- 0.2 ml/kg/min and volume of distribution was 270 +/- 76 ml/kg. At time of laparotomy, cefotetan concentration was 14.2 +/- 7 micrograms/g in abdominal wall fat and 16.4 +/- 1 micrograms/g in epiploic fat. In the colonic wall, cefotetan concentration was 33.3 +/- 16 micrograms/g. At time of abdominal closure, cefotetan concentrations were 6.3 +/- 3 micrograms/g in the abdominal wall fat and 6.1 +/- 4 micrograms/g in the epiploic fat.