Cefepime-induced neurotoxicity: an underestimated complication of antibiotherapy in patients with acute renal failure.

OBJECTIVES: To describe five new cases of life-threatening cefepime-induced neurotoxicity observed in a 2-year period. SETTING: A university intensive care unit. PATIENTS: Five patients recently treated with cefepime, admitted for seizures and coma. All suffered from acute renal failure, induced by sepsis and combined aminoside therapy, or by cefepime itself in one case. INTERVENTIONS: All patients underwent hemodialysis, which led to complete neurological improvement in four of them. One patient remained comatose and subsequently died. MEASUREMENTS: Blood and CSF cefepime levels were measured by high performance liquid chromatography before and after hemodialysis. CONCLUSION: The frequency of cefepime-induced neurotoxicity is probably underestimated. Monitoring of renal function and close neurological survey in treated patients should allow an early diagnosis of this complication. Urgent hemodialysis seems the best therapeutic method to obtain a rapid neurological improvement.

Escherichia coli endotoxin reduces cytochrome aa3 redox status in pig skeletal muscle.

OBJECTIVE: To assess the effect of endotoxin on cytochrome aa3 (Caa3) redox status in a controlled blood flow preparation of pig isolated hindlimb, at a constant oxygen delivery (Do2limb) (constant flow period) and during progressive ischemia (decreasing flow period). DESIGN: Randomized, controlled experimental study. SETTING: University hospital experimental laboratory. SUBJECTS: Ten piglets. INTERVENTIONS: Hindlimb blood flow was restricted to the femoral vessels. The arterial femoral blood flow coming from the carotid artery was controlled by a roller occlusive pump. The femoral venous blood flow was returned to the jugular vein. During the first 100 mins, the hindlimb blood flow was maintained at a normal level and then decreased stepwise. Animals were randomized to receive 150 microg/kg endotoxin lipopolysaccharide (LPS; n = 5) or saline (control; n = 5). MEASUREMENTS AND MAIN RESULTS: Hindlimb muscle Caa3 redox status was monitored by near-infrared spectroscopy. Hindlimb Do2limb and oxygen consumption (Vo2limb) were calculated. In the LPS group, a rapid reduction of Caa3 redox status was observed after LPS administration, whereas the hindlimb blood flow remained normal with no change in Do2limb and Vo2limb. A progressive simultaneous decrease in Do2limb and Vo2limb was observed during the decreasing flow period with no further reduction in Caa3 redox status. In the control group, no change was observed in Caa3, Do2limb, or Vo2limb during the constant flow period. During the decreasing flow period, Caa3 redox status was reduced as Do2limb and Vo2limb decreased. CONCLUSION: Our results suggest that endotoxin may induce a reduction of Caa3 redox status independently of Do2 and Vo2.

Redox status of cytochrome a,a3: a noninvasive indicator of dysoxia in regional hypoxic or ischemic hypoxia.

OBJECTIVE: Multiwavelength near infrared (NIR) spectrophotometry can monitor the redox state of cytochrome a,a3 (cyt a,a3) in vivo. Because cyt a,a3 is the most immediate reductant of oxygen, this technique has been proposed to evaluate tissue oxygenation. The purpose of this study was to examine the relationship between cyt a,a3 oxidation level as an indicator of dysoxia and oxygen uptake (VO2) when oxygen delivery (DO2) was progressively lowered in an in situ vascularly isolated hindlimb. DESIGN: Prospective, randomized, laboratory study. SETTING: University research laboratory. SUBJECTS: Fourteen pigs. INTERVENTIONS: Measurement of critical values for both VO2 and cyt a,a3 oxidation during ischemic and hypoxic hypoxia. MEASUREMENTS AND MAIN RESULTS: The right hindlimb of anesthetized, paralyzed, and ventilated pigs was subjected to progressive ischemic or hypoxic hypoxia for 100 mins by ten stepwise decreases in DO2. In ischemic hypoxia (n = 7), arterial inflow (Q) from a pump-membrane oxygenator system was lowered from 50 to 0 mL/min, with PaO2 maintained at 100 mm Hg. In hypoxic hypoxia (n = 6), PaO2 was lowered from 100 mm Hg to 0 mm Hg. Hindlimb DO2 was calculated as the product of Q and arterial oxygen content, and VO2 as the product of Q and arteriovenous difference. The cyt a,a3 oxidation level was measured every 10 secs with a four-wavelength spectrophotometer. These parameters were measured 9 mins after each change of DO2. Critical values for both VO2 and cyt a,a3 oxidation level as a function of DO2 were determined in each animal by dual linear regression analysis. In ischemic and hypoxic hypoxia, a strong correlation was found between cyt a,a3 oxidation level and VO2 in both ischemic and hypoxic hypoxia (r2 =.90 and .87, respectively). Hindlimb vascular resistance increased in ischemic hypoxia and decreased in hypoxic hypoxia when DO2 reached critical DO2. CONCLUSIONS: From these results, we concluded that monitoring the cyt a,a3 redox state by NIR spectrophotometry is, in this experimental setting, a sensitive indicator of dysoxia during regional hypoxic or ischemic hypoxia.

Effects of a combined antithrombin III and protein C supplementation in porcine acute endotoxic shock.

Antithrombin III (ATIII) and protein C (PC) are major inhibitors of the coagulation cascade and might regulate the cytokine network. We tested the possibility that a combined supplementation using these two inhibitors might have synergistic effects on sepsis-induced disseminated intravascular coagulation and shock. Hemodynamics, coagulation parameters, tumor necrosis factor (TNF) alpha, and interleukin 6 levels were measured in pigs submitted to a bolus infusion of Escherichia coli endotoxin (lipopolysaccharide). Four groups were studied: control lipopolysaccharide, ATIII (100 IU/kg), PC (50 IU/kg), and ATIII-PC (same doses). The endotoxin infusion resulted in a typical hypokinetic shock with disseminated intravascular coagulation in all animals. Compared with the control group, a significant improvement in mean arterial pressure and systemic vascular resistance was observed in the PC and ATIII-PC groups. The increase in lactate levels was almost completely blunted in the PC group. A significant lesser increase in TNFalpha levels was observed in the ATIII-PC group. No effects were seen on interleukin 6 levels. Coagulation and fibrinolysis parameters were not improved by ATIII and/or PC, except for a lesser decrease in prothrombin time in the ATIII-PC group. We conclude that in this acute endotoxic model, a combined supplementation using PC and ATIII concentrates has favorable effects on hemodynamic parameters and TNFalpha levels, independently from the anticoagulant actions of these inhibitors.

Effects of inter-alpha-inhibitor in experimental endotoxic shock and disseminated intravascular coagulation.

We investigated the effects of human inter-alpha-inhibitor (I alpha I) on hemodynamics, oxygenation, and coagulation parameters in a porcine model of endotoxic shock. Four groups of six animals were studied: (1) control, (2) I alpha I group receiving 30 mg/kg I alpha I over 30 min, (3) LPS group receiving 5 micrograms.kg/min Escherichia coli endotoxin over 30 min, and (4) LPS + I alpha I group receiving 30 min after endotoxin 30 mg/kg/30 min I alpha I. We measured hemodynamic and oxygenation parameters, usual coagulation markers and plasma levels of thrombin-antithrombin complexes, antithrombin III activity, plasminogen activator tissue type, plasminogen activator inhibitor type 1, von Willebrand factor, tumor necrosis factor-alpha, and I alpha I at baseline and at 30, 60, 90, 120, 180, 240, and 300 min. In the I alpha I group, plasma I alpha I levels reached 447 +/- 23 mg/L just after injection and 287 +/- 39 mg/L at 300 min. I alpha I half-life was 7.3 +/- 1.9 h. In the IPS + I alpha I group, I alpha I plasma levels decreased more rapidly, reaching 260 mg/L at 300 min. Compared with the LPS group, administration of I alpha I normalized the mean arterial pressure and cardiac index, improved the LPS-induced pulmonary hypertension, and resulted in the blunted increase in blood lactate and oxygen extraction ratio. A significant decrease in thrombin-antithrombin complexes and plasminogen activator inhibitor type 1 levels were observed. There was no significant difference in plasma tumor necrosis factor-alpha levels. We concluded that in this hypodynamic model of endotoxin shock, I alpha I administration resulted in a marked improvement in the hemodynamic, oxygenation, and coagulation parameters.

Effects of N omega-nitro-L-arginine methyl ester on the endotoxin-induced disseminated intravascular coagulation in porcine septic shock.

OBJECTIVES: Nitric oxide is known to prevent platelet aggregation and clot formation. Inhibitors of nitric oxide synthase might promote or enhance endotoxin disseminated intravascular coagulation. The present study was designed to evaluate the effects of the arginine analog, N omega-nitro-L-arginine methyl ester (L-NAME), on the endotoxin-induced disseminated intravascular coagulation in a porcine model of septic shock. DESIGN: Prospective, comparative, experimental study. SETTING: Laboratory at a large university hospital. SUBJECTS: Sixteen female piglets, weighing 20 to 28 kg. INTERVENTIONS: Three groups of animals were studied: a control group (n = 6); a lipopolysaccharide (LPS)-treated group (n = 5) receiving Escherichia coli endotoxin (5 micrograms/kg/min over 30 mins); and an LPS + L-NAME group (n = 5) receiving endotoxin and, 1 hr after, a bolus of L-NAME (25 mg/kg). MEASUREMENTS AND MAIN RESULTS: Hemodynamic changes, usual coagulation parameters, and plasma concentrations of thrombin-antithrombin complexes, antithrombin III activity (At III), tissue plasminogen activator, plasminogen activator inhibitor type 1, and von Willebrand factor were measured at baseline, and at 30, 60, 90, 120, 180, 240, and 300 mins. After euthanasia or death, lungs and kidneys were withdrawn for histologic study. The extent of microvascular thrombosis was assessed by a semiquantitative disseminated intravascular coagulation score. In both septic endotoxin group, administration of LPS resulted in hemodynamic changes typical of severe septic shock, with disseminated intravascular coagulation and histologic changes characterized by adult respiratory distress syndrome and kidney microthrombosis. L-NAME administration normalized mean arterial pressure with a dramatic increase in systemic vascular resistances and a marked decrease in cardiac index. The changes in usual coagulation parameters, AT III, tissue plasminogen activator, and plasminogen-activator inhibitor type 1 concentrations were not different between both septic groups. However, in the LPS + L-NAME group, thrombin-antithrombin complexes and von Willebrand factor were higher and associated with a higher histologic disseminated intravascular coagulation score. CONCLUSION: In this model of endotoxin septic shock, L-NAME administration resulted in histologic and coagulation changes consistent with an increased activation of intravascular coagulation.

ATP-sensitive K+ channel blockade impairs O2 extraction during progressive ischemia in pig hindlimb.

Tissues maintain O2 consumption (VO2) when blood flow and O2 delivery (DO2) are decreased by better matching of blood flow to meet local cellular O2 demand, a process that increases extraction of available O2. This study tested the hypothesis that ATP-sensitive K+ channels play a significant role in the response of pig hindlimb to ischemia. We pump perfused the vascularly isolated but innervated right hindlimb of 14 anesthetized pigs with normoxic blood while measuring hindlimb DO2, VO2, perfusion pressure, and cytochrome aa3 redox state. In one-half of the pigs, the pump-perfused hindlimb was also infused with 10 micrograms.min-1.kg-1 of glibenclamide, a potent blocker of ATP-sensitive K+ channels. Control animals were infused with 5% glucose solution alone. Blood flow was then progressively reduced in both groups in 10 steps at 10-min intervals. Glibenclamide had no effect on any preischemic hindlimb or systemic measurements. Hindlimb VO2 and cytochrome aa3 redox state began to decrease at a significantly higher DO2 in glibenclamide-treated compared with control pigs. At this critical DO2, the O2 extraction ratio (VO2/DO2) was 53 +/- 4% in the glibenclamide group and 73 +/- 5% in the control group (P < 0.05). Hindlimb vascular resistance increased significantly with ischemia in the glibenclamide group but did not change in the control group. We conclude that ATP-sensitive K+ channels may be importantly involved in the vascular recruitment response that tried to meet tissue O2 needs as blood flow was progressively reduced in the pig hindlimb.

Use of capnography in diagnosis of pulmonary embolism during acute respiratory failure of chronic obstructive pulmonary disease.

In chronic obstructive pulmonary disease (COPD) patients, there is a difference between PaCO2 and end-tidal partial pressure of CO2 (PetCO2). This gradient P(a-et)CO2 is due to ventilation/perfusion mismatching and deadspace, and is usually abolished by forced and prolonged expiration. We hypothesized that this gradient might not be canceled by forced expiration in the case of acute respiratory failure (ARF) related to pulmonary embolism (PE). Forty-four adult COPD patients were prospectively entered into this study; they were suspected of having ARF related to PE on the basis of clinical and biological data on admission. Maximum expired partial pressure of CO2 (PemCO2) was measured in mechanically ventilated and sedated patients by an interrupt of mechanical support. CO2 concentration was recorded during the following prolonged and passive expiration. The test was considered valid if an expiratory plateau was obtained. PemCO2 was measured in triplicate. Simultaneously, PaCO2 was measured and the ratio, R = [( 1-PemCO2]/PaCO2) x 100, was calculated. Pulmonary angiography was performed on the same day for all patients. Results showed that 17 patients had PE (PE+) and 17 had no PE (PE-). The two groups were comparable regarding mean age, severity of underlying chronic respiratory disease, PaCO2, PaO2, and hemodynamic data on admission. P(a-em)CO2 and R were significantly different in PE+ and PE- patients at 12 +/- 6.9 torr compared to 1 +/- 2.4 torr and at 28 +/- 14.8% compared to 2 +/- 6.2% (p less than .001), respectively. The positive predictive value of the test was 74%, but the negative predictive value 100% and the specificity was 65%, but sensitivity was 100%.(ABSTRACT TRUNCATED AT 250 WORDS)

Meningococcemia and purpura fulminans in adults: acute deficiencies of proteins C and S and early treatment with antithrombin III concentrates.

It has been recently suggested that an acquired deficiency of proteins C and S could contribute to the pathogenesis of meningococcemic purpura fulminans (PF) in children. Our study was designed to measure the levels of antithrombin III (AT III), protein C, and protein S during adult PF and to determine the effects of an early infusion of high doses of AT III concentrates on clinical and biological alterations of PF. We studied five consecutive adult patients with meningococcemia (type B) and PF. The levels of AT III, protein C (antigen and activity), and protein S (total and free) were measured at admission and 24 h and 1 month later. The treatment included in each case: amoxycillin, dobutamine and high doses of AT III concentrates. All patients survived and were discharged without any sequelae. At admission, biological data were consistent with severely depressed protein C and protein S levels and moderately decreased AT III levels, without any discrepancy between protein C antigen and activity. After 24 h, AT III and protein S levels were within normal ranges, whereas protein C levels were still depressed. These data are consistent with the theory of a particular imbalance in the anticoagulant systems during meningococcemic PF, contrasting with the usual findings observed during septic disseminated intravascular coagulation. The possibility must be considered that high doses of one anticoagulant (AT III concentrates) could compensate for the acute decrease in the other (protein C system).

Computer-assisted evaluation of respiratory data in ventilated critically ill patients.

In intensive care unit, a lot of data are currently available but remain unused by nurses and residents because of complexity of analysis. We have developed a system for interpretation of respiratory data (RESPAID) in order to improve monitoring of patients under respiratory support and also to provide a high level of information. RESPAID is a real-time system which interprets quantitative and qualitative aspects of the usual respiratory data at different levels of information. Initial knowledge base was built from data given by four specialists in intensive care. Major attention was paid to different aspects of the system: monitor interface, user interface and time representation. Data are issued from standard respirators and/or monitors used in the intensive care unit. Informations provided by RESPAID are alarm identification, ventilator settings modification and proposal for physiological evolution of the patient or suspected complication. RESPAID runs on IBM PCAT3 with 1st class shell. It is currently in clinical validation procedure.

Carbon dioxide mandatory ventilation (CO2MV): a new method for weaning from mechanical ventilation. Description and comparative clinical study with I.M.V. and T. tube method in COPD patient.

We describe a new technique specially designed for weaning from mechanical ventilation: carbon dioxide mandatory ventilation (CO2MV). CO2MV is based on feedback between end tidal expired partial pressure of carbon dioxide and ventilatory mode, controlled or spontaneous. In order to evaluate its real interest we performed a randomized prospective study, CO2MV vs Intermittent Mandatory Ventilation (IMV) and T. Tube Method (TTM). Fourty-two adult patients with chronic obstructive pulmonary disease entered this study at the end of acute respiratory failure requiring mechanical ventilatory support. We observed a better stability of arterial blood gas during weaning with CO2MV and an increase in success rate (CO2MV 13/14 - IMV 5/14 - TTM 10/14). From this study CO2MV seems available for weaning of COPD patients. Nevertheless, further studies are required to appreciate its real clinical interest.

Decrease of angiotensin-converting enzyme activity after plasma exchange.

We measured sequential changes in serum angiotensin-converting enzyme (ACE) in 12 ICU patients undergoing plasma exchange (PE) with plasma substitutes (albumin-Polygelin). A dramatic decrease in serum ACE activity was observed after each of the 51 PE procedures. Repeated PE procedures resulted in almost a total depletion of serum ACE, which returned to normal ranges in 4 to 10 days. No ACE change was observed during hemodialysis or hemofiltration. ACE activity increased after PE with fresh frozen plasma replacement. ACE changes were compared with IgG, antithrombin III, and fibronectin changes. Extraction ratio comparisons were consistent, with a loss in removed plasma accounting for 50% to 70% of the observed ACE decrease. Plasma zinc levels were not modified after PE. Mixing experiments with increasing volumes of plasma substitutes showed ACE inhibition by Polygelin. In vivo infusion of Polygelin had the same effect. The renin-induced aldosterone response studied in six exchanged patients was consistent with a relative hyperreninemic hypoaldosteronism after repeated PE. These findings may be of clinical relevance during acute hypovolemia and dehydration after PE or Polygelin infusion and in patients with impaired lung endothelial function.

Compared evolution of plasma fibronectin and angiotensin-converting enzyme levels in septic ARDS.

Serum angiotensin converting enzyme (serum ACE) levels and plasma fibronectin levels were measured daily in 46 septic patients during a ten day period. Thirty-eight patients developed ARDS; 28 survived (group 1), ten died (group 2), eight patients had no features of ARDS and survived (group 3). Sequential measurements of ACE and fibronectin levels were compared and plotted against indexes of respiratory impairment: PaO2 max Qs/Qt, static compliance and VD/VA ratio. These indexes were taken as criteria of weaning from controlled ventilation. During ARDS (groups 1 and 2), serum ACE levels decreased and were closely correlated with the severity of lung injury. Persistently decreased levels after eight days were consistent with continuing injury or lack of endothelial repair. On the other hand, plasma fibronectin levels increased throughout the study in survivors (group 1 and 3) and decreased in the group with fatal ARDS only (group 2). These results indicate that serum ACE levels might be a good index of endothelial injury and repair during ARDS and fibronectin a better index for evolution of sepsis and vital prognosis.

Angiotensin-converting enzyme in human adult respiratory distress syndrome.

Angiotensin-converting enzyme (ACE) levels, complement activation, and intravascular coagulation were studied in 36 patients with adult respiratory distress syndrome (ARDS) (17 aseptic, 19 septic), in order to investigate the possible interrelations among ACE, immunologic data, and hematologic findings. The severity of respiratory impairment was assessed with measurements of mechanical and gas exchange functional qualities of the lung. Serial measurements of ACE could be done in 14 patients during an eight-day period. During the first 24 hours, ACE levels were always normal (38 percent) or decreased (62 percent). No difference could be found between patients with septic and aseptic ARDS. Complement activation occurred in 78 percent (28/36) and used, in most cases, the classic pathway with presence of circulating immune complexes. Criteria for intravascular coagulation were present in 58 percent (21/36). No relation between coagulation, complement, and ACE could be found except for the patients with a greater respiratory impairment, who had complement activation, intravascular coagulation, and significantly lower ACE levels. In all patients together, ACE levels had no diagnostic value for aseptic cause of ARDS and a poor prognostic value. Only intravascular coagulation was linked with a higher significant mortality and a greater functional impairment. Serial measurements showed a diphasic evolution of ACE levels, with a maximum decrease between the 72nd and 96th hours and a further normalization (seventh day). The persistence of low levels seemed to be associated with evolutive sepsis or secondary aggravation and fibrosis.

[New method of weaning from respiratory assistance. Ventilation based on carbon dioxide]. / Nouvelle technique de sevrage de l'assistance ventilatoire. Ventilation asservie au gaz carbonique.

The authors describe a new device for weaning from mechanical ventilation, based on continuous measurement of end-expiratory concentration of CO 2 (FCO 2 ET). The spontaneous or controlled mode of ventilation is automatically determined by the level of FCO 2 ET in relation to preselected maximum and minimum thresholds. The authors call this device "CO 2MV".