[Local administration of amphotericin B by VAC instillation: Therapeutic aid in the treatment of mucormycosis]. / Application locale d'amphotéricine B par VAC instillation : aide thérapeutique dans le traitement de la mucormycose.

Mucormycosis is a rare and serious fungal infection, occurring mainly in immunocompromised, diabetic, polytrauma or burn patients. Current standard treatments include iterative carcinological surgical trimming, systemic treatment with liposomal amphotericin B and second-line Posaconazole or Isavuconazole. We report the case of a 37-year-old female patient with no previous medical history who developed a disseminated mucormycosis, with an estimated 25 % loss of skin substance and major decay of the chest wall. In addition to standard treatment, local instillations of amphotericin B using the VAC Veraflow® system were performed. We believe that local instillations of amphotericin B by VAC could improve the functional prognosis of patients with skin involvement.

Monitoring of circulating monocyte HLA-DR expression in a large cohort of intensive care patients: relation with secondary infections.

INTRODUCTION: The reports of an early and profound acquired immunodepression syndrome (AIDs) in ICU patients had gained sufficient credence to modify the paradigm of acute inflammation. However, despite several articles published on AIDs and its assessment by monocytic HLA-DR monitoring, several missing informations remained: 1-Which patients' are more prone to benefit from mHLA-DR measurement, 2-Is the nadir or the duration of the low mHLA-DR expression the main parameter to consider? 3-What are the compared performances of leukocytes' count analyses (lymphocyte, monocyte). MATERIAL AND METHOD: We conducted an observational study in a surgical ICU of a French tertiary hospital. A first mHLA-DR measurement (fixed flow cytometry protocol) was performed within the first 3 days following admission and a 2nd, between day 5 and 10. The other collected parameters were: SAPS II and SOFA scores, sex, age, comorbidities, mortality and ICU-acquired infections (IAI). The associations between mHLA-DR and outcomes were tested by adjusted Fine and Gray subdistribution competing risk models. RESULTS: 1053 patients were included in the study, of whom 592 had a 2nd mHLA-DR measurement. In this cohort, 223 patients (37.7%) complicated by IAI. The initial decrement in mHLA-DR was not associated with the later occurrence of IAI, (p = 0.721), however, the persistence of a low mHLA-DR (< 8000 AB/C), measured between day 5 and day 7, was associated with the later occurrence of IAI (p = 0.01). Similarly, a negative slope between the first and the second value was significantly associated with subsequent IAI (p = 0.009). The best performance of selected markers was obtained with the combination of the second mHLA-DR measurement with SAPSII on admission. Persisting lymphopenia and monocytopenia were not associated with later occurrence of IAI. CONCLUSION: Downregulation of mHLA-DR following admission is observed in a vast number of patients whatever the initial motif for admission. IAI mostly occurs among patients with a high severity score on admission suggesting that immune monitoring should be reserved to the most severe patients. The initial downregulation did not preclude the later development of IAI. A decreasing or a persisting low mHLA-DR expression below 8000AB/C within the first 7 days of ICU admission was independently and reliably associated with subsequent IAI among ICU patients with performances superior to leukocyte subsets count alone.

[Process, procedure and requested conditions for academic appointment in anesthesia and intensive care]. / Processus, procédures et critères d'évaluation conduisant à la mise sur la liste d'aptitude aux fonctions de Maître de conférences des universités--praticien hospitalier (MCU-PH) et de professeur des universités--praticien hospitalier (PU-PH) en anesthésie-réanimation.

Since several decades, anesthesia care and intensive care, as well, are engaged in the way of excellence in clinical care and research. This requirement is also applied for the selection of professor and academic workers. The goals of this article are twice: first to diffuse this knowledge at the medical community and second to describe in details the long process leading to the final appointment.

Is monocyte HLA-DR expression monitoring a useful tool to predict the risk of secondary infection?

Downregulation of the immune response is common among Intensive Care Unit (ICU) patients after an acute inflammatory injury, whether it was septic or not. Such a modification could be seen as an adaptation to attenuate the effects of the inflammatory storm on tissues, but it exposes the subject to the risk of nosocomial infection and impairs recovery processes. The intensity of immunity downregulation is difficult to characterize, since clinical presentation is silent and non-specific, which urges the use of tools for immune monitoring. This review focuses on the use of monocyte HLA-DR expression to detect immune hyporesponsiveness and to select the appropriate immunomodulating therapy, as well as the efficiency of this technique in controlling secondary infections.

Anti-inflammatory profile of circulating immune cells after surgery for seizure.

AIM: The central nervous system has been described as the coordinator of the inflammatory response to infection through the hypothalamo-pituitary axis and the autonomic nervous system. Brain lesions have been associated with impaired immunity and postoperative infections. We studied alterations of the inflammatory response in relation to neurohormonal patterns after neurosurgery for seizure. METHODS: Nine patients were studied before, during and immediately after operation, and then on days 1, 2 and 4 post-operatively. Monocyte HLA-DR (mHLA-DR) expression and plasma interleukin (IL)-10, IL-12 and MIF were measured ex vivo and after an in vitro 6-h our lipopolysaccharide (LPS) stimulation of whole blood. Corticotropin (ACTH), cortisol, arginine vasopressin, prolactin, epinephrine and norepinephrine were quantified in plasma. The effect of plasma mediators on LPS stimulation was studied by replacing plasma with standard culture medium. RESULTS: Surgery resulted in decreased ex vivo mHLA-DR expression, but no change in IL-10 or IL-12 plasma levels. mHLA-DR was low in LPS culture over the 4 postoperative days, whereas IL-10 release was increased and not counterbalanced by IL-12p40 production. The hormonal plasma pattern showed increased prolactin during anesthesia and peaks of cortisol, ACTH and arginine vasopressin during waking, but no alteration in catecholamine levels. mHLA-DR expression in LPS culture was not modified by plasma replacement, except immediately after surgery. CONCLUSION: Postoperatively, mHLA-DR expression was associated with an anti-inflammatory phenotype of whole blood. The anti-inflammatory profile was not related to the plasma mediators measured, suggesting that neural control might take place upstream in the circulation, at the level of progenitors in bone marrow.

Neurosurgery and elderly: analysis through the years.

The aging of the population in westernized countries constitutes an important issue for the health systems struggling with limited resources and increasing costs. Morbidity and mortality rates reported for neurosurgical procedures in the elderly vary widely. The lack of data on risk benefit ratios may result in challenging clinical decisions in this expanding group of patients. The aim of this paper is to analyze the elderly patients cohort undergoing neurosurgical procedures and any trend variations over time. The medical records of elderly patients (defined as an individual of 70 years of age and over) admitted to the Neurosurgical and Neuro-ICU Departments of a major University Hospital in Paris over a 25-year period were retrospectively reviewed. The analysis included: (1) number of admissions, (2) percentage of surgically treated patients, (3) type of procedures performed, (4) length of hospital stay, and (5) mortality. The analysis showed a progressive and significant increase in the proportion of elderly presenting for neurosurgical elective and/or emergency procedures over the last 25 years. The number of procedures on patients over 70 years of age increased significantly whereas the mortality dropped. Though the length of hospital stay was reduced, it remained significantly higher than the average stay. The types of procedures also changed over time with more craniotomies and endovascular procedures being performed. Age should not be considered as a contraindication for complex procedures in neurosurgery. However, downstream structures for postoperative elderly patients must be further developed to reduce the mean hospital stay in neurosurgical departments because this trend is likely to continue to grow.

Expression of monocyte human leukocyte antigen-DR in relation with sepsis severity and plasma mediators.

AIM: After an initial septic hit, the immune response to a new antigen changes as time progresses, with an unpredictable efficiency. The aim of this study was to characterize the monocyte functional phenotype by HLA-DR expression in septic patients at the onset of sepsis and during recovery in relation to organ failure and plasma mediators. METHODS: Twenty-six patients were analyzed as either single organ failure at worst (SOF) or multiple organ failure (MOF) over 14 days. Twelve patients received immunosuppressive (IS) drugs before sepsis. We measured: 1) monocyte HLA-DR expression (mHLA-DR); 2) plasma pro-inflammatory mediators (IL-12p40, macrophage Migration Inhibitory Factor [MIF]); 3) plasma anti-inflammatory mediators (IL-10, cortisol); and 4) in vitro lipopolysaccharide (LPS) stimulated mHLA-DR in 6-hour whole blood culture or after plasma replacement with standard milieu. RESULTS: mHLA-DR expression was equally decreased in patients who were treated with IS drugs as those who were not. Despite the difference in severity, SOF patients showed a similar profound mHLA-DR downregulation as MOF patients at day 0, but tended to recover earlier. MOF patients presented higher plasma IL-10 and cortisol levels than SOF patients but similar plasma IL-12p40 and MIF levels. In vitro LPS stimulation showed an impaired mHLA-DR response in both groups. Plasma replacement by milieu elicited a slight improvement in the response to LPS in SOF but not MOF patients. CONCLUSIONS: At the onset of sepsis, an initial low mHLA-DR was not related to any prior IS drug regimen, the severity of the sepsis or the outcome. The duration of mHLA-DR downregulation could be related to plasma factors in SOF, while other mechanisms may be implicated in MOF evolution.

Accelerated in vitro differentiation of blood monocytes into dendritic cells in human sepsis.

Summary Sepsis-induced immune depression is characterized by infection susceptibility and monocyte early deactivation. Because monocytes are precursors for dendritic cells (DC), alterations in their differentiation into DC may contribute to defective immune responses in septic patients. We therefore investigated the ability of monocytes to differentiate into functional DC in vitro in patients undergoing surgery for peritonitis. Monocytes from 20 patients collected immediately after surgery (D0), at week 1 and at weeks 3-4 and from 11 control donors were differentiated into immature DC. We determined the phenotype of monocytes and derived DC, and analysed the ability of DC to respond to microbial products and to elicit T cell responses in a mixed leucocyte reaction (MLR). We show that, although monocytes from septic patients were deactivated with decreased responses to lipopolysaccharide (LPS) and peptidoglycan and low human leucocyte antigen D-related (HLA-DR) expression, they expressed the co-stimulatory molecule CD80, CD40 and CCR7. Monocytes collected from patients at D0 and week 1 differentiated faster into DC with early loss of CD14 expression. Expression of HLA-DR increased dramatically in culture to reach control levels, as did responses of DC to LPS and peptidoglycan. However, although patient and control immature DC had similar abilities to induce T cell proliferation in MLR, maturation of DC derived from patients did not increase T cell responses. These results show that circulating monocytes from septic patients express markers of activation and/or differentiation despite functional deactivation, and differentiate rapidly into phenotypically normal DC. These DC fail, however, to increase their T cell activation abilities upon maturation.

Assessment of immunological status in the critically ill.

The systemic inflammatory response (SIRS) results from various types of injuries such as severe infection, trauma, ischemia-reperfusion and major surgery including cardiac surgery with cardio-pulmonary bypass. This response involves immune cell activation and a complex network of proinflammatory cytokines, which may induce multiple organ failure when uncontrolled. The monocyte plays a central role in the response to infection with the release of TNF, IL-1, and IL-12. In addition, monocytes present antigens to T lymphocytes. An optimal antigen presentation requires the expression of MHC class II HLA-DR on monocytes surface and of co-stimulatory molecules such as CD54 on monocytes and LFA-1 on lymphocytes. It has become increasingly apparent that the pro-inflammatory response is balanced by concomitant anti-inflammatory mechanisms that results in monocyte deactivation, characterized by a decrease in HLA-DR expression and the release of anti-inflammatory cytokines such as IL-10. This counterregulatory response, if prolonged or predominant, may predispose the patient to a higher risk of infection. Further studies need to be conducted to precise: 1) the intensity of depression of the surface molecule expression assessing monocyte function, such as HLA DR and CD54; 2) the level of IL-10 and IL-12 release in patients with severe sepsis; 3) the immunomodulating effects of frequently used treatments in these patients with severe sepsis and in surgical patients; 4) the time course of recovery; 5) if the monitoring of HLA-DR, CD54, IL-10 and IL-12 will better predict the clinical outcome than clinical parameters.

Assessment of immunological status in the critically ill.

The systemic inflammatory response (SIRS) results from various types of injuries such as severe infection, trauma, ischemia-reperfusion and major surgery including cardiac surgery with cardio-pulmonary bypass. This response involves immune cell activation and a complex network of proinflammatory cytokines, which may induce multiple organ failure when uncontrolled. The monocyte plsys a central role in the response to infection with the release of TNF-alpha, IL-1 beta, and IL-12. In addition, monocytes present antigens to T lymphocytes. An optimal antigen presentation requires the expression of MHC class II HLA-DR on monocytes surface and of costimulatory molecules such as CD54 on monocytes and LFA-1 on lymphocytes. It has become increasingly apparent that the proinflammatory response is balanced by concomitant anti-inflammatory mechanisms that results in monocyte deactivation, characterized by a decrease in HLA-DR expression and the release of anti-inflammatory cytokines such as IL-10. This counterregulatory response, if prolonged or predominant, may predispose the patient to a higher risk of infection. Further studies need to be conducted to precise: i) the intensity of depression of the surface molocule expression assessing monocyte function, such as HLA DR and CD54; ii) the level of IL-10 and IL-12 release in patients with severe sepsis; iii) the immuno-modulating effects of frequently used treatments in these patients with severe sepsis and in surgical patients; iv) the time course of recovery; v) if the monitoring of HLA-DR, CD54, IL-10 and IL-12 will better predict the clinical outcome than clinical parameters.

Somatosensory responses during selective spatial attention: The N120-to-N140 transition.

The somatosensory evoked potential negative components in the 100-150-ms range were studied under conditions where attention was directed either toward or away from the probe stimulus. An N120 component, not sensitive to spatial attention, appeared in all conditions, including the no-task condition. Its distribution was consistent with an origin in the second somatic area. A later N140 response, not recorded in neutral conditions, was highly sensitive to spatial attention and reached its maximum to stimulation of the attended hand; its behavior was consistent with that of a processing negativity. The N140 was bilaterally distributed, but the hemisphere contralateral to stimulation appeared to be involved earlier than the ipsilateral one. Although the exogenous N120 may be influenced by somatosensory awareness and perhaps tactile recognition, the N140 appears linked to the spatial components of attention and results from the activation of several areas in both hemispheres.

Revisiting the oddball paradigm. Non-target vs neutral stimuli and the evaluation of ERP attentional effects.

We recorded topographic mapping of auditory evoked potentials (AEPs) to homogeneous series of tones delivered in the absence of any cognitive task ("neutral condition") and compared them with responses to identical stimuli when they acted as non-targets in an oddball paradigm. With respect to the neutral condition, non-target responses showed an increase in N100 amplitude which was found to depend on two different, but partially overlapping effects. The "early effect" had similar latency and topography as exogenous N100 and may reflect changes in the overall state of alertness since its amplitude declined at the end of the test. The "late effect" affected the N100s descending slope and had features consistent with those of a processing negativity. It was frontally distributed, and topographic mapping revealed a right-sided predominance. Finally, non-target responses exhibited a central positivity (P250) which did not appear in neutral AEPs. P250 shares several features, including latency, amplitude and scalp topography, with the endogenous ERP component commonly labelled "P3a". Non-target P250 could be the result of an attentional shift towards the stimuli, and reflect some aspects of the classification process. We suggest that non-target responses in simple oddball paradigms should be routinely studied along with target responses in order to improve the diagnostic capabilities of cognitive ERPs. Notably, non-target responses may help to decide whether an abnormal target-P300 is related or not to a deficit in the mobilization of attentional resources.