Ventilator-associated pneumonia and bloodstream infections in intensive care unit cancer patients: a retrospective 12-year study on 3388 prospectively monitored patients.

PURPOSE: Some publications suggest high rates of healthcare-associated infections (HAIs) and of nosocomial pneumonia portending a poor prognosis in ICU cancer patients. A better understanding of the epidemiology of HAIs in these patients is needed. METHODS: A retrospective analysis of all the patients hospitalized for ≥ 48 h during a 12-year period in the 12-bed ICU of the Gustave Roussy hospital, monitored prospectively for ventilator-associated pneumonia (VAP) and bloodstream infection (BSI) and for use of medical devices. RESULTS: During 3388 first stays in the ICU, 198 cases of VAP and 103 primary, 213 secondary, and 77 catheter-related BSIs were recorded. The VAP rate was 24.5/1000 ventilator days (95% confidence interval [CI] 21.2-28.0); the catheter-related BSI rate was 2.3/1000 catheter days (95% CI 1.8-2.8). The cumulative incidence during the first 25 days of exposure was 58.8% (95% CI 49.1-66.6%) for VAP, 8.9% (95% CI, 6.2-11.5%) for primary, 15.1% (95% CI 11.6-18.5%) for secondary and 5.0% (95% CI 3.2-6.8%) for catheter-related BSIs. VAP or BSIs were not associated with a higher risk of ICU mortality. CONCLUSIONS: This is the first study to report HAI rates in a large cohort of critically ill cancer patients. Although both the incidence of VAP and the rate of BSI are higher than in general ICU populations, this does not impact patient outcomes. The occurrence of device-associated infections is essentially due to severe medical conditions in patients and to the characteristics of malignancy.

Differential time to positivity of central and peripheral blood cultures is inaccurate for the diagnosis of Staphylococcus aureus long-term catheter-related sepsis.

OBJECTIVES: Differential time to positivity of cultures of blood drawn simultaneously from central venous catheter and peripheral sites is widely used to diagnose catheter-related bloodstream infections without removing the catheter. However, the accuracy of this technique for some pathogens, such as Staphylococcus aureus, is debated in routine practice. METHODS: In a 320-bed reference cancer centre, the charts of patients with at least one blood culture positive for S. aureus among paired blood cultures drawn over a six-year period were studied retrospectively. Microbiological data were extracted from the prospectively compiled database of the microbiology unit. Data concerning the 149 patients included were reviewed retrospectively by independent physicians blinded to the absolute and differential times to positivity, in order to establish or refute the diagnosis of catheter-related sepsis. Due to missing data, 48 charts were excluded, so 101 cases were actually analysed. The diagnosis was established in 62 cases, refuted in 15 cases and inconclusive in the remaining 24 cases. RESULTS: For the 64 patients with both central and peripheral positive blood cultures, the differential positivity time was significantly greater for patients with catheter-related bloodstream infections due to S. aureus (P<0.02). However, because of the high number of false-negative cases, the classic cut-off limit of 120 min showed 100% specificity but only 42% sensitivity for the diagnosis of catheter-related bloodstream infection due to S. aureus. CONCLUSIONS: These results strongly suggest that despite its high specificity, the differential time to positivity may not be reliable to rule out catheter-related bloodstream infection due to S. aureus.

Zinc transport and metallothionein induction in primary cultures of rabbit kidney proximal cells.

Primary cultures of isolated rabbit renal proximal cells were grown on collagen-coated permeable supports. The confluent epithelia were polarized, making possible the measurement of uptakes and effluxes across the apical and the basolateral membranes. Uptakes of 65Zn were assessed under initial rate conditions, after 0.5 min incubation. The kinetic parameters of apical uptake were a Jmax of 25.1 +/- 5.3 pmol min-1 (micrograms DNA)-1, a Km of 43.3 +/- 7.3 microM and an unsaturable constant of 0.105 +/- 0.029 (n = 7) at 37 degrees C. Cadmium competitively inhibited the zinc uptake, with a Ki value of 24.5 +/- 7.3 microM. Basolateral uptake was characterized by a high capacity (Jmax = 227.9 +/- 46.6 pmol min-1 (micrograms DNA)-1) and an affinity similar to that of the apical uptake (Km = 35.4 +/- 14.2 microM). Cadmium had no effect on the basolateral zinc uptake. Effluxes across the basolateral face of the epithelium always exceeded those across the apical face. Excess zinc in the culture medium induced the synthesis of metallothionein in the epithelia, as judged by the rate of [35S]cysteine incorporation into a fraction of cytosolic proteins. Metallothionein induction did not appear to modify the kinetic parameters of the apical zinc uptake. These data suggest that separate saturable transport systems are responsible for the apical and basolateral zinc uptakes in proximal renal cells. Induction of metallothionein had no apparent effect on apical zinc uptake in this system.

Prognostic factors for neutropenic patients in an intensive care unit: respective roles of underlying malignancies and acute organ failures.

The admission of neutropenic patients to an intensive care unit (ICU) is still controversial, especially if mechanical ventilation is required. To avoid useless stays in ICU, the evaluation of the respective role of the underlying malignancy and acute organ failures might be useful for better definition of the categories of patients who could benefit from aggressive ICU support. For this purpose, we carried out a retrospective study of the charts of 107 consecutive neutropenic patients admitted to an ICU in a comprehensive cancer centre over a four-year period. The following characteristics were recorded within 24 h of admission: patient data, characteristics of neutropenia and the underlying malignancy, the type and number of organ system failures (OSFs) and simplified acute physiological scores (SAPS and SAPS II). The impact of each variable on outcome in the ICU was studied by univariate and multivariate (logistic regression) analysis. 59 patients died in the ICU (mortality rate: 55%). Patients with a haematological malignancy (n = 57, 53%) were more likely to experience respiratory failure, an underlying malignancy deemed rapidly fatal, and to have longer lasting neutropenia than patients with a solid tumour (n = 50, 47%). However, the mortality rate did not differ in the two groups (haematological malignancy 61% versus solid tumour 48%, p = 0.16). Respiratory and cardiovascular organ failure (p < 0.001 for both) correlated with mortality in the ICU. In the multiple logistic regression model, only the number of organ system failures and respiratory failure remained predictive of ICU mortality. In conclusion, the characteristics of the underlying malignancy are not relevant when deciding whether or not neutropenic patients should be admitted to an ICU. The main risk factors for death in an ICU are the number of organ failures on admission, and among them the presence of respiratory failure.

Acute lung injury complicating imported Plasmodium falciparum malaria.

STUDY OBJECTIVE: To characterize adult patients with acute lung injury complicating severe imported Plasmodium falciparum malaria. DESIGN AND SETTING: Retrospective study of patients with severe P falciparum malaria admitted to the medical ICU of a university hospital infectious diseases department. PATIENTS: Forty adults with complicated malaria, with (group 1, 12 patients) or without (group 2, 28 patients) acute lung injury. RESULTS: Patients with acute lung injury had a higher simplified acute physiology score on admission (24.2 +/- 3.2 vs 13.7 +/- 0.7 in group 2, p < 0.0001) and a longer time interval to adequate antimalarial therapy (8.8 +/- 2.5 vs 4.9 +/- 0.6 days in group 2, p = 0.046). Of the nine group 1 patients given mechanical ventilation, eight had a PaO2/FIO2 < or = 200 mm Hg. Two patients with moderate hypoxemia received oxygen through a nasal tube and one received continuous positive airway pressure via a face mask. Acute renal failure, unrousable coma, metabolic acidosis, and shock were significantly more common among group 1 patients. The number of complications of malaria was significantly higher in patients with acute lung injury (4.7 +/- 0.5 vs 1.6 +/- 0.1 in group 2, p < 0.0001). Five patients, including four with acute lung injury, had evidence of bacterial infection (pneumonia or primary bacteremia) at ICU admission. Four patients with acute lung injury died (33%) vs one patient without acute lung injury (4%, p = 0.022). CONCLUSIONS: Acute lung injury is more likely to occur in patients with extremely severe, multisystemic P falciparum malaria. In patients with acute lung injury and septic shock, bacterial coinfection should be suspected and treated empirically since it contributes substantially to early mortality.

Septic shock due to toxoplasmosis in patients infected with the human immunodeficiency virus.

PURPOSE: To describe the presentation and clinical course of septic shock due to Toxoplasma gondii in patients infected with the human immunodeficiency virus (HIV). PATIENTS AND METHODS: From April 1988 to February 1992, nine HIV-infected patients were admitted because of predominant septic shock (7 patients) or developed septic shock in the ICU (2 patients). The recent CD4+ cell count ranged from 2 to 84 x 10(6)/L. RESULTS: The main clinical features were (1) a history of fever for longer than 15 days, with a recent increase to more than 39.5 degrees C; (2) a recent history of dyspnea (< 15 days, 8 cases; < 7 days, 3 cases); and (3) recent onset of thrombocytopenia (6 of 9 cases). All patients were in shock (hyperkinetic profile in 6 of 7; hypokinetic in 1 of 7), and 8 of 9 were in respiratory distress (ratio of PaO2 over fractional concentration of oxygen in the inspired gas of 117 +/- 23; range, 88 to 155). Chest roentgenograms revealed diffuse alveolar infiltrates in six of nine cases. The serum lactate dehydrogenase (LDH) activity was 6,510 +/- 5,080 IU/L (range, 1,010 to 15,450 IU/L). Serologic tests for T gondii were negative in two cases. Toxoplasma gondii was isolated from lung (9/9), bone marrow (5/7), or blood (2/2). One, 3, and 2 patients had brain, ocular, and myocardial involvement, respectively. No other microbial pathogens were isolated. Seven patients died, 5 less than 3 days after admission. CONCLUSION: Disseminated toxoplasmosis can cause septic shock in HIV-infected patients. In two cases, the disease was probably a primary infection. The association of high fever, acute dyspnea, recent onset of thrombocytopenia, and a very high level of LDH activity is suggestive of disseminated toxoplasmosis.

Severe tuberculosis in patients with human immunodeficiency virus infection.

Tuberculosis has now been well documented as a complication of infection with human immunodeficiency virus (HIV), but no studies concern patients requiring admission to the ICU. We report 12 cases of severe disseminated tuberculosis in patients who were seropositive for HIV. Eight patients had diffuse pulmonary involvement responsible for acute respiratory failure, 7 of whom required mechanical ventilation. Four developed septic shock, and in 3 blood cultures were positive for M. tuberculosis. Four patients had central nervous system involvement, with coma requiring mechanical ventilation 3 times. Rapid diagnosis was permitted in 10 patients by acid-fast smears of pulmonary specimens (8 patients) and/or tissue biopsies (4 patients). Seven patients died despite intensive therapy; autopsy was performed in 4 patients, showing disseminated tuberculosis. On the basis of this report, tuberculosis in HIV infection may present as an overwhelming systemic disease and thus requires an aggressive diagnostic and therapeutic approach.

Short-term effects of methylene blue on hemodynamics and gas exchange in humans with septic shock.

OBJECTIVE: The aim of this study was to investigate the acute effects of methylene blue (MB), an inhibitor of the L-arginine nitric oxide pathway, in patients with septic shock. DESIGN: A prospective, open, single-dose study. SETTING: The medical ICU of a university hospital. PATIENTS: Six patients with severe septic shock. INTERVENTIONS: Complete hemodynamic values were recorded before and 20 min after the infusion of intravenous MB (3 mg kg(-1)). Arterial pressure was then monitored during the next 24 h or until death. MEASUREMENTS AND RESULTS: Methylene blue increased the mean arterial pressure from 69.7 +/- 4.5 to 83.7 +/- 5.1 mmHg (p = 0.028) and the mean pulmonary artery pressure, from 34.3 +/- 7.2 to 38.7 +/- 8.0 mmHg (p = 0.023). Systemic vascular resistance index was increased from 703.1 +/- 120.6 to 903.7 +/- 152.2 dyne.s.cm(-5).m(-2) (p = 0.028) and pulmonary vascular resistance index, from 254.6 +/- 96.9 to 342.2 +/- 118.9 dyne.s.cm(-5) .m(-2) (p = 0.027). The PaO2/FIO2 decreased from 229.2 +/- 54.4 to 162.2 +/- 44.1 mmHg (p = 0.028), without significant modification of intrapulmonary shunting. Heart rate, cardiac index, right atrial pressure, DO2, VO2, oxygen extraction and arterial lactate were essentially unchanged. Sequential measurements of arterial pressure demonstrated a return to baseline level in 2-3 h. All but one patients died, three in shock and two in multiple organ failure. CONCLUSIONS: MB induces systemic and pulmonary vasoconstriction in patients with septic shock, without significant decrease in cardiac index. The worsening of arterial oxygenation following MB injection may limit its use in patients with the adult respiratory distress syndrome. Larger studies are required to determine whether MB improves the outcome of patients with septic shock.

Continuous positive airway pressure by face mask or mechanical ventilation in patients with human immunodeficiency virus infection and severe Pneumocystis carinii pneumonia.

We reviewed the records of 44 patients with AIDS who had 45 episodes of severe Pneumocystis carinii pneumonia (PCP). While 9 patients required intubation and mechanical ventilation (MV) on admission, continuous positive airway pressure (CPAP) by face mask was the initial measure in 36 episodes. There were 25 patients managed with CPAP alone, 23 of whom survived. Among the reasons for delayed intubation and MV (11 patients) was that treatment failure was strongly associated with non-survival, since all 6 such patients died. The in-hospital mortality for severe PCP in this study was 33% overall, and reached 65% for mechanically ventilated patients. The 1-year survival was 43% (95% confidence interval, 28%-58%). These data confirm the improved prognosis for patients with AIDS and severe PCP, and suggest that mask CPAP may be an adequate mean of ventilatory support in this setting.

Shock complicating severe falciparum malaria in European adults.

OBJECTIVE: To study adult patients with severe falciparum malaria who developed shock. DESIGN: Retrospective study from 1987 to 1993. SETTING: Medical intensive care unit in a university hospital. PATIENTS: 14 patients admitted with severe falciparum malaria who developed shock. All received intravenous quinine. MEASUREMENTS AND RESULTS: The mean Simplified Acute Physiology Score II was 59.5 +/- 7.1; 2.6 +/- 0.4 criteria defining severe disease were present on admission in 12 patients; and initial parasitemia was 21 +/- 6%. Twelve patients received inotropic drugs. Pulmonary artery catheterization showed the following results in 7 patients: mean arterial pressure 57 +/- 4 mmHg; pulmonary artery occlusion pressure 11 +/- 1 mmHg; cardiac index 5.5 +/- 0.91.min-1.m-2, and systemic vascular resistance index 783 +/- 122 dyne.s.cm-5.m-2. Seven patients had evidence of bacterial infection at the time of shock. Of the 7 deaths (50%), 5 were due to shock, with documented bacterial infection in all patients and persistent parasitemia in 4. CONCLUSIONS: Shock complicating severe falciparum malaria in adults is associated with peripheral vasodilation and carries a poor prognosis. In falciparum malaria with shock, bacterial coinfection should be suspected immediately and treated empirically with broad-spectrum antibiotics. Nevertheless, Plasmodium falciparum may contribute directly or indirectly to the onset of shock.

Usefulness of a strategy based on bronchoscopy with direct examination of bronchoalveolar lavage fluid in the initial antibiotic therapy of suspected ventilator-associated pneumonia.

OBJECTIVES: To evaluate (a) the routine accuracy of bronchoalveolar lavage by direct examination (BAL-D) in diagnosing ventilator-associated pneumonia (VAP), and (b) the impact of a diagnostic strategy including clinical judgment, bronchoscopy, and BAL-D on the initial diagnosis and appropriateness of treatment when VAP is suspected. DESIGN AND SETTING: Prospective cohort study in two academic ICUs in Paris, France. PATIENTS AND PARTICIPANTS: Mechanically ventilated patients with suspected VAP underwent bronchoscopy with BAL and protected specimen brush (PSB). BAL-D results were available within 2 h, BAL on culture and PSB results after 24 h, and antibiotic susceptibility after 48 h. At each step in the strategy the senior and the resident in charge of the patient were asked their diagnosis and their therapeutic plan on the basis of presently available data. Definite diagnosis of suspected VAP was based on histology, appearance of cavitation, positive pleural fluid culture, results of PSB and BAL culture, and follow-up. MEASUREMENT AND RESULTS: A total of 110 episodes of suspected VAP were studied; 94 definite diagnoses were made (47 VAP, 47 no VAP). Using a threshold 1% of infected cells, BAL-D discriminated well between patients with and those without VAP (sensitivity 93.6%, specificity 91.5%, area under the receiver-operating characteristic curve 0.953). The senior clinical judgment was correct in 71% cases. It was correct in 78% and 94% of cases after airway visualization and BAL-D findings, respectively. After BAL-D the positive and negative predictive values in diagnosing VAP were 90% and 98%, respectively. However, the therapeutic plan was correct in only 65% using clinical judgment (15 untreated patients, 3 ineffective treatment, 15 useless treatment), 66% using airway visualization (14 untreated VAP, 4 ineffective treatment, 14 useless treatment), and 88% using BAL-D results (1 untreated patients, 6 ineffective, 4 useless), according to definite diagnosis and final antibiotic susceptibility testings. CONCLUSIONS: A strategy based on bronchoscopy and BAL-D generally leads to a rapid and appropriate treatment of nosocomial pneumonia in ventilated patients.

Septic shock in patients with the acquired immunodeficiency syndrome.

OBJECTIVE: To evaluate the prognosis of patients with septic shock admitted to an intensive care unit (ICU), according to their HIV serostatus. DESIGN: Retrospective study. SETTING: Medical ICU of a university hospital. PATIENTS: 76 patients with septic shock admitted to the same ICU, of whom 28 were HIV positive and 48 were HIV negative. MEASUREMENTS AND RESULTS: Severity scores, number and type of organ failures, and survival rates were assessed in the two groups of patients. Glasgow Coma Scale and general severity scores [Acute Physiology and Chronic Health Evaluation II and Simplified Acute Physiology Score (SAPS)] were significantly worse in HIV-infected patients. The total number of organ failures was also higher in the HIV-positive group: 3.7 +/- 0.2 vs 3.1 +/- 0.2 in the HIV-negative group (p < 0.001). On day 28, 21 (46%) HIV-negative patients were dead compared to 26 (93%) patients in the HIV-positive group (p < 0.001). In the multivariate analysis, HIV infection was an independent risk factor for mortality, as were the SAPS score, use of mechanical ventilation, and the McCabe score. CONCLUSIONS: This study reports a considerable excess mortality in HIV-infected patients with septic shock. Although severity of illness was clearly much more pronounced in HIV-positive patients, retroviral infection was independently associated with death. Improving survival in HIV-positive patients with septic shock may require earlier diagnosis and treatment of the causative infection.

Successful rescue in a patient with high dose methotrexate-induced nephrotoxicity and acute renal failure.

We describe the case of a 35-year old male who developed acute renal failure following high dose methotrexate therapy for Burkitt's non Hodgkin lymphoma. Serum methotrexate levels reached 37 micromol/l, and remained higher than 1 micromol/l for more than a week. Folinic acid rescue was intensified to 200-400 mg intravenously every 4 hours. As methotrexate binds markedly to proteins, plasma exchange was initially chosen, 4 sessions being performed from day 2 to day 4. The methotrexate pharmacokinetic profile was not significantly modified during plasma exchange, and serum drug level was 3 micromol/l. Continuous veno-venous hemodiafiltration was therefore performed from day 5 to day 10. This procedure also seemed ineffective, with evidence of low ultrafiltrate clearance. No extrarenal toxicity was observed in our patient. Thus, conventional extrarenal procedures appear to have a limited role in the setting of overexposure to methotrexate. The use of very high doses of folinic acid in our case probably played a major role in the eventual favorable outcome.

Possible prognostic significance of a brief rise in parasitaemia following quinine treatment of severe Plasmodium falciparum malaria.

An increase in parasitaemia is not uncommon after initiation of treatment for Plasmodium falciparum malaria, but its exact significance is unknown. The time-course of parasitaemia was assessed retrospectively in 33 patients with severe imported malaria. In 19 patients (group 1) mean parasitaemia (+/- SEM) fell promptly after starting quinine treatment, from 24.9 +/- 4.1% on day 0 to 9.7 +/- 2.3% on day 1 and 1.8 +/- 0.7% on day 2. In 14 other patients (group 2), parasitaemia did not change significantly or increased, with mean parasitaemia (+/- SEM) of 9.5 +/- 2.1% on day 0, 17.2 +/- 2.6% on day 1, and 3.7 +/- 1.8% on day 2. Simplified acute physiology scores on admission (mean +/- SEM) were 17.4 +/- 1.4 in group 1 and 11.7 +/- 1.0 in group 2 (P = 0.006). The mean number of complications of malaria per patient (+/- SEM) was 2.9 +/- 0.5 in group 1 and 1.6 +/- 0.3 in group 2 (P = 0.046). Two group 1 patients died. Initially, more than 95% of peripheral blood parasites were tiny and small rings in both groups, and this distribution was unchanged on day 1, suggesting that the parasitaemia increase in group 2 was not due to release of sequestered mature parasites. In severe falciparum malaria, a rise in parasitaemia after treatment initiation may be of favourable prognostic significance and should not lead to aggressive therapeutic approaches such as exchange transfusion.

Effects of cadmium and copper on zinc transport kinetics by isolated renal proximal cells.

Zinc, cadmium, and copper are known to interact in many transport processes, but the mechanism of inhibition is widely debated, being either competitive or noncompetitive according to the experimental model employed. We investigated the mechanisms of inhibition of zinc transport by cadmium and copper using renal proximal cells isolated from rabbit kidney. Initial rates of 65Zn uptake were assessed after 0.5 min of incubation. The kinetics parameters of zinc uptake obtained at 20 degrees C were a Jmax of 208.0 +/- 8.4 pmol.min-1.(mg protein)-1, a Km of 15.0 +/- 1.5 microM and an unsaturable constant of 0.259 +/- 0.104 (n = 8). Cadmium at 15 microM competitively inhibited zinc uptake. In the presence of 50 microM cadmium, or copper at both 15 and 50 microM, there was evidence of noncompetitive inhibition. These data suggest that zinc and cadmium enter renal proximal cells via a common, saturable, carrier-mediated process. The mechanisms of the noncompetitive inhibition observed at higher concentrations of cadmium or with copper require further investigation, but may involve a toxic effect on the cytoskeleton.

[Peritoneal carcinosis treated by complete excision and immediate postoperative intra-peritoneal chemotherapy. Phase II study in 54 patients]. / Carcinoses péritonéales traitées par exérèse complète et chimiothérapie intra-péritonéale postopératoire immédiate (CIPPI). Etude de phase II portant sur 54 malades.

OBJECTIVES: The short term prognosis of peritoneal carcinomatosis whose classical treatment is intravenous chemotherapy, is poor (mean survival of 6 months). The aim of this study was to report the results of a phase II prospective study in which peritoneal carcinomatosis was managed with complete reductive surgery associated with treatment of the residual microscopic disease with immediate intraperitoneal postoperative chemotherapy. PATIENTS AND METHODS: Fifty-four patients with peritoneal carcinomatosis from miscellaneous origins, were treated between January 1993 and April 1996. Major peritoneal carcinomatosis was important, clinically evident, but without extraperitoneal localization in 29 cases. It was moderate, fortuitously discovered during a laparotomy for an extraperitoneal recurrence in 25 cases. Immediate intraperitoneal postoperative chemotherapy was carried out continuously during 5 days, with 900 ml/m2 of ringer lactate, with either mitomycine C and 5-fluorouracil, or doxorubicin and platinum, according to histology. The treatment was complete in 91% of cases. RESULTS: Three patients died during the hospitalization (5.5%), and a high morbidity (61%) was observed, with 35% intra-abdominal complications necessitating surgery in 13% of the patients. The postoperative complications were correlated with the extension of the cytoreductive surgery (P < 0.001). After a mean follow-up of 12.3 months, 13 patients died. The 2-year survival rate was 50%. Survival was related to the importance of the peritoneal carcinomatosis (P < 0.01) and was identical for patients with isolated peritoneal carcinomatosis and for patients with moderate peritoneal carcinomatosis associated with resected extra-peritoneal disease. The incidence of recurrence of peritoneal carcinomatosis was 30% at 2 years, showing the efficiency of this new procedure to treat peritoneal carcinomatosis. CONCLUSIONS: Complete cytoreductive surgery with immediate intraperitoneal postoperative chemotherapy is a promising treatment of peritoneal carcinomatosis. However it appears that: a) it is a difficult treatment for patients and for physicians, b) its efficiency will be asserted only with a randomized study (currently ongoing), that only allows to suppress selection bias, c) it is able to cure some groups of peritoneal carcinomatosis (probably 20%), that will be difficult to identify, and d) improvement of immediate intraperitoneal postoperative chemotherapy is possible (mainly with hyperthermia). The main advantage of immediate intraperitoneal postoperative chemotherapy is that, after proving its efficiency, easy widespread use will be assured.

[Optimum quinine therapy in falciparum malaria attacks contracted in Africa]. / Du bon usage thérapeutique de la quinine dans l'accès palustre à P. falciparum contracté en Afrique.

A review about the use of quinine for uncomplicated falciparum malaria contracted in Africa is proposed. The dose of 8 mg/kg of quinine base 3 times a day seems to be admitted by all. On the other way, the duration of treatment fluctuates from 2 to 10 days without evidence of difference in efficacy between 3, 5 and 7 days. The pharmacodynamic and pharmacokinetic properties of quinine are reviewed and suggest that 3, 5 and 7 days are efficient at least on, respectively, 1, 2 and 3 parasite cycles and suggest that a five day treatment may be curative for all kind of patients infested with a quinine-sensitive strain of P. falciparum in Africa.

[Physiopathology of cerebral malaria]. / Physiopathologie du neuropaludisme.

Although simple animal models relevant to human disease are lacking, many recent clinical and experimental studies have focused on the pathophysiology of cerebral malaria. Evidence of sequestration of parasitized erythrocytes is found in the cerebral capillaries of patients dying from cerebral malaria. Cytoadherence of parasitized red blood cells to endothelium is an essential process. However, no correlation was found between in vitro cytoadherence of clinical isolates and the presence of cerebral symptoms. Rosetting is defined by the agglutination of nonparasitized erythrocytes around red cells containing mature forms of the parasite, and probably contributes to the intravascular sequestration of erythrocytes. This phenomenon occurs in vitro, and isolates from patients with cerebral malaria appear to have increased rosetting properties. The excellent recovery of most survivors, even after a deep and lengthy coma, suggests that microvascular obstruction causing cerebral hypoxia is not the main factor contributing to cerebral dysfunction. Raised intracranial pressure with or without cerebral oedema is common in children, and contributes to mortality. The nonspecific immune inflammatory response of the host to the malarial parasite, with release of various mediators, seems to be of paramount importance. Among cytokines, tumor necrosis factor (TNF) appears to be associated with mortality; although plasma levels of TNF are not correlated with neurological dysfunction, this does not exclude a role of this cytokine at a paracrine level. Cytoadherence of parasitized red blood cells to endothelium and concomitant activation of mononuclear blood cells may be responsible for a local synthesis of cytokines, or even neurotransmitters that remain to be identified.