Alemtuzumab-induced immune-mediated thrombotic thrombocytopenic purpura: A newly described drug-related autoimmune disease.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening disease that may result from drug exposure. We report a case of iTTP occurring in a 39-year-old patient, 45 months following introduction of the anti-CD52 lymphoid cell depleting monoclonal antibody alemtuzumab, to treat a relapsing-remitting multiple sclerosis. Treatment consisted in plasma exchange, corticosteroids and caplacizumab, allowing clinical remission 3 months after the diagnosis, attested by the absence of thrombocytopenia and recovery of ADAMTS-13 activity. As other autoimmune disorders, iTTP may occur following alemtuzumab. This diagnosis should be suspected in patients with features of thrombotic microangiopathy following this treatment.

A 2-year multicenter, observational, prospective, cohort study on extracorporeal CO2 removal in a large metropolis area.

BACKGROUND: Extracorporeal carbon dioxide removal (ECCO2R) is a promising technique for the management of acute respiratory failure, but with a limited level of evidence to support its use outside clinical trials and/or data collection initiatives. We report a collaborative initiative in a large metropolis. METHODS: To assess on a structural basis the rate of utilization as well as efficacy and safety parameters of 2 ECCO2R devices in 10 intensive care units (ICU) during a 2-year period. RESULTS: Seventy patients were recruited in 10 voluntary and specifically trained centers. The median utilization rate was 0.19 patient/month/center (min 0.04; max 1.20). ECCO2R was started under invasive mechanical ventilation (IMV) in 59 patients and non-invasive ventilation in 11 patients. The Hemolung Respiratory Assist System (Alung) was used in 53 patients and the iLA Activve iLA kit (Xenios Novalung) in 17 patients. Main indications were ultraprotective ventilation for ARDS patients (n = 24), shortening the duration of IMV in COPD patients (n = 21), preventing intubation in COPD patients (n = 9), and controlling hypercapnia and dynamic hyperinflation in mechanically ventilated patients with severe acute asthma (n = 6). A reduction in median V T was observed in ARDS patients from 5.9 to 4.1 ml/kg (p <0.001). A reduction in PaCO2 values was observed in AE-COPD patients from 67.5 to 51 mmHg (p< 0.001). Median duration of ECCO2R was 5 days (IQR 3-8). Reasons for ECCO2R discontinuation were improvement (n = 33), ECCO2R-related complications (n = 18), limitation of life-sustaining therapies or measures decision (n = 10), and death (n = 9). Main adverse events were hemolysis (n = 21), bleeding (n = 17), and lung membrane clotting (n = 11), with different profiles between the devices. Thirty-five deaths occurred during the ICU stay, 3 of which being ECCO2R-related. CONCLUSIONS: Based on a registry, we report a low rate of ECCO2R device utilization, mainly in severe COPD and ARDS patients. Physiological efficacy was confirmed in these two populations. We confirmed safety concerns such as hemolysis, bleeding, and thrombosis, with different profiles between the devices. Such results could help to design future studies aiming to enhance safety, to demonstrate a still-lacking strong clinical benefit of ECCO2R, and to guide the choice between different devices. TRIAL REGISTRATION: ClinicalTrials.gov: Identifier: NCT02965079 retrospectively registered https://clinicaltrials.gov/ct2/show/NCT02965079.

Cystic fibrosis mouse model-dependent intestinal structure and gut microbiome.

Mice with a null mutation in the cystic fibrosis transmembrane conductance regulator (Cftr) gene show intestinal structure alterations and bacterial overgrowth. To determine whether these changes are model-dependent and whether the intestinal microbiome is altered in cystic fibrosis (CF) mouse models, we characterized the ileal tissue and intestinal microbiome of mice with the clinically common ΔF508 Cftr mutation (FVB/N Cftr(tm1Eur)) and with Cftr null mutations (BALB/c Cftr(tm1UNC) and C57BL/6 Cftr(tm1UNC)). Intestinal disease in 12-week-old CF mice, relative to wild-type strain controls, was measured histologically. The microbiome was characterized by pyrosequencing of the V4-V6 region of the 16S rRNA gene and intestinal load was measured by RT-PCR of the 16S rRNA gene. The CF-associated increases in ileal crypt to villus axis distention, goblet cell hyperplasia, and muscularis externa thickness were more severe in the BALB/c and C57BL/6 Cftr(tm1UNC) mice than in the FVB/N Cftr(tm1Eur) mice. Intestinal bacterial load was significantly increased in all CF models, compared to levels in controls, and positively correlated with circular muscle thickness in CF, but not wild-type, mice. Microbiome profiling identified Bifidobacterium and groups of Lactobacillus to be of altered abundance in the CF mice but overall bacterial frequencies were not common to the three CF strains and were not correlative of major histological changes. In conclusion, intestinal structure alterations, bacterial overgrowth, and dysbiosis were each more severe in BALB/c and C57BL/6 Cftr(tm1UNC) mice than in the FVB/N Cftr(tm1Eur) mice. The intestinal microbiome differed among the three CF mouse models.

Comparison of pulse contour analysis by Pulsioflex and Vigileo to measure and track changes of cardiac output in critically ill patients.

BACKGROUND: We compared the new Pulsioflex and the Vigileo devices to measure cardiac index (CI) in critically ill patients. Both devices measure CI by pulse-contour analysis. The Pulsioflex device also allows an auto-calibration (not based on thermodilution). METHODS: Patients were included if we administered fluids (20 patients), reduced (20 patients), or increased (20 patients) the dose of norepinephrine. Before and after interventions, we measured CI provided by the Vigileo (CIVig) and Pulsioflex (CIPfx) devices before and after its auto-calibration. CI measured by transpulmonary thermodilution (CIthermo) was used as the reference. RESULTS: Considering absolute values of CI (n=120), the percentage error was 59% for CIVig vs CIthermo and 40% for CIthermo vs CIPfx. Auto-calibrating CIPfx after interventions did not improve the percentage error between CIPfx and CIthermo (39%). Considering the fluid-induced changes in CI, the coefficient of correlation with changes in CIthermo was 0.50 for CIVig, and 0.73 for CIPfx (P=0.27). It was not significantly improved if CIPfx was auto-calibrated (r=0.64). Considering the norepinephrine-induced changes in CI, the coefficient of correlation with changes in CIthermo was 0.41 for CIVig. It tended to be better for CIPfx (r=0.71, P=0.07). It was not significantly improved by auto-calibration (r=0.53). CONCLUSIONS: The Pulsioflex did not reliably estimate the absolute values of CI. For tracking fluid-induced changes in CI, the Pulsioflex was reliable, and also the Vigileo. For tracking norepinephrine-induced changes in CI, it was also reliable and tended to be better than the Vigileo. Auto-calibration allowed by the system did not improve its reliability.

Hemolysis and schistocytosis in the emergency department: consider pseudothrombotic microangiopathy related to vitamin B12 deficiency.

BACKGROUND: Hemolytic anemia with thrombocytopenia and schistocytosis is suggestive of thrombotic thrombocytopenic purpura (TTP). However, these features can occur in the context of vitamin B12 deficiency. AIM: To identify simple means of distinguishing between TTP and pseudothrombotic microangiopathies related to vitamin B12 deficiency (pseudo-TMA) at the bedside. DESIGN AND METHODS: Retrospective study of patients with pseudo-TMA compared with patients with TTP. The patients with pseudo-TMA were further compared with other cases of cobalamin deficiency, in order to detect factors associated with microangiopathic hemolysis during vitamin B12 deprivation. RESULTS: Seven patients with pseudo-TMA were compared with six patients with TTP. The pseudo-TMA patients had higher median lactate dehydrogenase (LDH) levels (7310 vs. 1460 IU/l, P = 0.01), a higher platelet count (73 vs.12.5 × 10(9)/l, P = 0.0023), a lower reticulocyte count (13.1 vs. 265.5 × 10(9)/l, P = 0.0012) and a lower neutrophil count (1.3 vs. 5.1 × 10(9)/l, P = 0.0023). When compared with 21 patients with vitamin B12 deficiency and anemia (but no schistocytosis), the pseudo-TMA patients were more likely to present with pernicious anemia [7 out of 21 (33.3%) vs. 5 out of 7 (71.4%), respectively] and had lower vitamin B12 levels (105 vs. 45 µmol/l, respectively). Vitamin supplementation led to hematological improvements in all pseudo-TMA patients. CONCLUSION: In a context of mechanical hemolysis with thrombocytopenia in a patient admitted to the emergency department, very high LDH levels and a low reticulocyte count are strongly suggestive of pseudo-TMA and should prompt the physician to screen for cobalamin deficiency.

Positional cloning reveals strain-dependent expression of Trim16 to alter susceptibility to bleomycin-induced pulmonary fibrosis in mice.

Pulmonary fibrosis is a disease of significant morbidity, with no effective therapeutics and an as yet incompletely defined genetic basis. The chemotherapeutic agent bleomycin induces pulmonary fibrosis in susceptible C57BL/6J mice but not in mice of the C3H/HeJ strain, and this differential strain response has been used in prior studies to map bleomycin-induced pulmonary fibrosis susceptibility loci named Blmpf1 and Blmpf2. In this study we isolated the quantitative trait gene underlying Blmpf2 initially by histologically phenotyping the bleomycin-induced lung disease of sublines of congenic mice to reduce the linkage region to 13 genes. Of these genes, Trim16 was identified to have strain-dependent expression in the lung, which we determined was due to sequence variation in the promoter. Over-expression of Trim16 by plasmid injection increased pulmonary fibrosis, and bronchoalveolar lavage levels of both interleukin 12/23-p40 and neutrophils, in bleomycin treated B6.C3H-Blmpf2 subcongenic mice compared to subcongenic mice treated with bleomycin only, which follows the C57BL/6J versus C3H/HeJ strain difference in these traits. In summary we demonstrate that genetic variation in Trim16 leads to its strain-dependent expression, which alters susceptibility to bleomycin-induced pulmonary fibrosis in mice.

Third-generation FloTrac/Vigileo does not reliably track changes in cardiac output induced by norepinephrine in critically ill patients.

BACKGROUND: The ability of the third-generation FloTrac/Vigileo software to track changes in cardiac index (CI) induced by volume expansion and norepinephrine in critically ill patients is unknown. METHODS: In subjects with circulatory failure, we administered volume expansion (20 subjects) and increased (20 subjects) or decreased (20 subjects) the dose of norepinephrine. We measured arterial pressure waveform-derived CI provided by the third-generation FloTrac/Vigileo device (CI(pw)) and transpulmonary thermodilution CI (CI(td)) before and after therapeutic interventions. RESULTS: Considering the pairs of measurements performed before and after all therapeutic interventions (n=60), a bias between the absolute values of CI(pw) and CI(td) was 0.26 (0.94) litre min(-1) m(-2) and the percentage error was 54%. Changes in CI(pw) tracked changes in CI(td) induced by volume expansion with moderate accuracy [n=20, bias=-0.11 (0.54) litre min(-1) m(-2), r(2)=0.26, P=0.02]. When changes in CI(td) were induced by norepinephrine (n=40), a bias between CI(pw) and CI(td) was 0.01 (0.41) litre min(-1) m(-2) (r(2)=0.11, P=0.04). The concordance rates between changes in CI(pw) and CI(td) induced by volume expansion and norepinephrine were 73% and 60%, respectively. The bias between changes in CI(pw) and CI(td) significantly correlated with changes in total systemic vascular resistance (r(2)=0.41, P<0.0001). CONCLUSIONS: The third-generation FloTrac/Vigileo device was moderately reliable for tracking changes in CI induced by volume expansion and poorly reliable for tracking changes in CI induced by norepinephrine.

Strain-dependent airway hyperresponsiveness and a chromosome 7 locus of elevated lymphocyte numbers in cystic fibrosis transmembrane conductance regulator-deficient mice.

We previously observed the lungs of naive BALB/cJ Cftr(tm1UNC) mice to have greater numbers of lymphocytes, by immunohistochemical staining, than did BALB wild type littermates or C57BL/6J Cftr(tm1UNC) mice. In the present study, we initially investigated whether this mutation in Cftr alters the adaptive immunity phenotype by measuring the lymphocyte populations in the lungs and spleens by FACS and by evaluating CD3-stimulated cytokine secretion, proliferation, and apoptosis responses. Next, we assessed a potential influence of this lymphocyte phenotype on lung function through airway resistance measures. Finally, we mapped the phenotype of pulmonary lymphocyte counts in BALB × C57BL/6J F2 Cftr(tm1UNC) mice and reviewed positional candidate genes. By FACS analysis, both the lungs and spleens of BALB Cftr(tm1UNC) mice had more CD3(+) (both CD4(+) and CD8(+)) cells than did littermates or C57BL/6J Cftr(tm1UNC) mice. Cftr(tm1UNC) and littermate mice of either strain did not differ in anti-CD3-stimulated apoptosis or proliferation levels. Lymphocytes from BALB Cftr(tm1UNC) mice produced more IL-4 and IL-5 and reduced levels of IFN-γ than did littermates, whereas lymphocytes from C57BL/6J Cftr(tm1UNC) mice demonstrated increased Il-17 secretion. BALB Cftr(tm1UNC) mice presented an enhanced airway hyperresponsiveness to methacholine challenge compared with littermates and C57BL/6J Cftr(tm1UNC) mice. A chromosome 7 locus was identified to be linked to lymphocyte numbers, and genetic evaluation of the interval suggests Itgal and Il4ra as candidate genes for this trait. We conclude that the pulmonary phenotype of BALB Cftr(tm1UNC) mice includes airway hyperresponsiveness and increased lymphocyte numbers, with the latter trait being influenced by a chromosome 7 locus.

Rapid and beneficial hemodynamic effects of activated protein C in septic shock patients.

OBJECTIVE: Because recombinant human activated protein C (rhAPC) reduces NO production during sepsis, it could improve the vascular tone. We tested whether rhAPC reduces the dose of norepinephrine required to maintain mean arterial pressure (MAP) in septic shock patients. DESIGN AND SETTING: Retrospective study in intensive care unit of two university hospitals. PATIENTS: Twenty-two septic shock patients with at least two organ failures were retrospectively investigated for MAP and the required dose of norepinephrine before and 24 h after rhAPC administration. A control group of 22 septic shock patients with at least two organ failures who did not receive rhAPC was matched on age, SAPS II, MAP, and norepinephrine dose at the time of the theoretical start of rhAPC. MEASUREMENTS AND RESULTS: The MAP remained stable and similar in the two groups (86+/-16 vs. 89+/-9 mmHg at 24 h). The required dose of norepinephrine increased in the control group (+38%, from -41% to +38%) but decreased in the treated group (-33%, from -74% to +11%). CONCLUSIONS: rhAPC rapidly improved the vascular tone in septic shock patients as assessed by a decrease in the norepinephrine dose required to maintain arterial pressure.

Effects of tidal volume reduction in acute respiratory distress syndrome on gastric mucosal perfusion.

OBJECTIVE: This study was conducted with the aim of testing the effects of a reduction in tidal volume (V(T)) on gastric mucosal perfusion using laser-Doppler flowmetry in patients with acute respiratory distress syndrome (ARDS). DESIGN: It was designed as a prospective study. PATIENTS: Seventeen patients with ARDS were enrolled in the study. All patients were mechanically ventilated in volume-controlled mode. Before the start of the protocol, V(T) was set at 9 ml/kg body weight. INTERVENTION: V(T) was reduced to 6 ml/kg body weight. MEASUREMENTS AND RESULTS: Measurements of systemic hemodynamic parameters and gastric mucosal blood flow (GMBF) were obtained before and after reduction of V(T). Cardiac index, heaart rate and pulmonary arterial pressure increased significantly after V(T) reduction. The increase in cardiac output was observed in all patients. However, despite a mean 25% increase in cardiac output after V(T) reduction, no significant increase in mean GMBF was observed, and individual GMBF responses were heterogeneous. CONCLUSION: V(T) reduction in patients with ARDS, despite resulting in an increase in cardiac output, did not change gastric mucosal perfusion. The heterogeneity in the individual response of GMBF to V(T) reduction could be due to opposite direct (i.e., local vasodilatory effect) and indirect (i.e., global sympathetic stimulation) effects of hypercapnia on gut vessels.

Extending inspiratory time in acute respiratory distress syndrome.

OBJECTIVE: To assess the short-term effects of extending inspiratory time by lengthening end-inspiratory pause (EIP) without inducing a clinically significant increase in intrinsic positive end-expiratory pressure (PEEPi) in patients with acute respiratory distress syndrome (ARDS). DESIGN: Controlled, randomized, crossover study. SETTING: Two medical intensive care units of university hospitals. PATIENTS: Sixteen patients with early (< or =48 hrs) ARDS. INTERVENTION: We applied two durations of EIP (0.2 secs and extended) each for 1 hr while keeping all the following ventilatory parameters constant: FIO2, total PEEP (PEEPtot = applied PEEP + PEEPi), tidal volume, inspiratory flow, and respiratory rate. The duration of extended EIP was titrated to avoid an increase of PEEPi of > or =1 cm H2O. MEASUREMENTS AND MAIN RESULTS: Despite an increase in mean airway pressure (20.6 +/- 2.3 vs. 17.6 +/- 2.1 cm H2O, p < .01), extended EIP did not significantly improve PaO2 (93 +/- 21 vs. 86 +/-16 torr [12.40 +/- 2.80 vs. 11.46 +/- 2.13 kPa] with 0.2 secs EIP, NS). However, although the difference in PaO2 between the two EIP durations was <20 torr (<2.66 kPa) in 14 patients, two patients exhibited a >40 torr (>5.33 kPa) increase in PaO2 with extended EIP. Extended EIP decreased PaCO2 (62 +/- 13 vs. 67 +/- 13 torr [8.26 +/- 1.73 vs. 8.93 +/- 1.73 kPa] with 0.2 secs EIP, p < .01), which resulted in a higher pH (7.22 +/- 0.10 vs. 7.19 +/- 0.09 with 0.2 secs EIP, p < .01) and contributed to a slight increase in arterial hemoglobin saturation (94 +/- 3 vs. 93 +/- 3% with 0.2 EIP, p < .01). No significant difference in hemodynamics was observed. CONCLUSION: In patients with ARDS, extending EIP without inducing a clinically significant increase in PEEPi does not consistently improve arterial oxygenation but enhances CO2 elimination.

Estimating cardiac filling pressure in mechanically ventilated patients with hyperinflation.

OBJECTIVE: When positive end-expiratory pressure (PEEP) is applied, the intracavitary left ventricular end-diastolic pressure (LVEDP) exceeds the LV filling pressure because pericardial pressure exceeds 0 at end-expiration. Under those conditions, the LV filling pressure is itself better reflected by the transmural LVEDP (tLVEDP) (LVEDP minus pericardial pressure). By extension, end-expiratory pulmonary artery occlusion pressure (eePAOP), as an estimate of end-expiratory LVEDP, overestimates LV filling pressure when pericardial pressure is >0, because it occurs when PEEP is present. We hypothesized that LV filling pressure could be measured from eePAOP by also knowing the proportional transmission of alveolar pressure to pulmonary vessels calculated as index of transmission = (end-inspiratory PAOP--eePAOP)/(plateau pressure--total PEEP). We calculated transmural pulmonary artery occlusion pressure (tPAOP) with this equation: tPAOP = eePAOP--(index of transmission x total PEEP). We compared tPAOP with airway disconnection nadir PAOP measured during rapid airway disconnection in subjects undergoing PEEP with and without evidence of dynamic pulmonary hyperinflation. DESIGN: Prospective study. SETTING: Medical intensive care unit of a university hospital. PATIENTS: We studied 107 patients mechanically ventilated with PEEP for acute respiratory failure. Patients without dynamic pulmonary hyperinflation (group A; n = 58) were analyzed separately from patients with dynamic pulmonary hyperinflation (group B; n = 49). INTERVENTION: Transient airway disconnection. MEASUREMENTS AND MAIN RESULTS: In group A, tPAOP (8.5+/-6.0 mm Hg) and nadir PAOP (8.6+/-6.0 mm Hg) did not differ from each other but were lower than eePAOP (12.4+/-5.6 mm Hg; p < .05). The agreement between tPAOP and nadir PAOP was good (bias, 0.15 mm Hg; limits of agreement, -1.5-1.8 mm Hg). In group B, tPAOP (9.7+/-5.4 mm Hg) was lower than both nadir PAOP and eePAOP (12.1+/-5.4 and 13.9+/-5.2 mm Hg, respectively; p < .05 for both comparisons). The agreement between tPAOP and nadir PAOP was poor (bias, 2.3 mm Hg; limits of agreement, -0.2-4.8 mm Hg). CONCLUSIONS: Indexing the transmission of proportional alveolar pressure to PAOP in the estimation of LV filling pressure is equivalent to the nadir method in patients without dynamic pulmonary hyperinflation and may be more reliable than the nadir PAOP method in patients with dynamic pulmonary hyperinflation.

Relation between respiratory changes in arterial pulse pressure and fluid responsiveness in septic patients with acute circulatory failure.

In mechanically ventilated patients with acute circulatory failure related to sepsis, we investigated whether the respiratory changes in arterial pressure could be related to the effects of volume expansion (VE) on cardiac index (CI). Forty patients instrumented with indwelling systemic and pulmonary artery catheters were studied before and after VE. Maximal and minimal values of pulse pressure (Pp(max) and Pp(min)) and systolic pressure (Ps(max) and Ps(min)) were determined over one respiratory cycle. The respiratory changes in pulse pressure (DeltaPp) were calculated as the difference between Pp(max) and Pp(min) divided by the mean of the two values and were expressed as a percentage. The respiratory changes in systolic pressure (DeltaPs) were calculated using a similar formula. The VE-induced increase in CI was >/= 15% in 16 patients (responders) and < 15% in 24 patients (nonresponders). Before VE, DeltaPp (24 +/- 9 versus 7 +/- 3%, p < 0.001) and DeltaPs (15 +/- 5 versus 6 +/- 3%, p < 0.001) were higher in responders than in nonresponders. Receiver operating characteristic (ROC) curves analysis showed that DeltaPp was a more accurate indicator of fluid responsiveness than DeltaPs. Before VE, a DeltaPp value of 13% allowed discrimination between responders and nonresponders with a sensitivity of 94% and a specificity of 96%. VE-induced changes in CI closely correlated with DeltaPp before volume expansion (r(2) = 0. 85, p < 0.001). VE decreased DeltaPp from 14 +/- 10 to 7 +/- 5% (p < 0.001) and VE-induced changes in DeltaPp correlated with VE-induced changes in CI (r(2) = 0.72, p < 0.001). It was concluded that in mechanically ventilated patients with acute circulatory failure related to sepsis, analysis of DeltaPp is a simple method for predicting and assessing the hemodynamic effects of VE, and that DeltaPp is a more reliable indicator of fluid responsiveness than DeltaPs.

Effects of epinephrine, norepinephrine, or the combination of norepinephrine and dobutamine on gastric mucosa in septic shock.

OBJECTIVES: To compare in the same patient with septic shock, respective effects of epinephrine, norepinephrine, and the combination of norepinephrine and dobutamine (5 microg/kg/min) on systemic hemodynamic parameters and gastric mucosal perfusion using gastric tonometry and laser-Doppler flowmetry techniques. DESIGN: Prospective, controlled, randomized, crossover study. SETTING: University hospital intensive care unit. PATIENTS: Twelve patients with septic shock. INTERVENTIONS: Each patient received in a random succession epinephrine, norepinephrine, and norepinephrine plus dobutamine. Dosages of epinephrine and norepinephrine were adjusted to achieve a mean arterial pressure between 70 and 80 mm Hg. A laser-Doppler probe and a tonometer were introduced into the gastric lumen. MEASUREMENTS AND MAIN RESULTS: The increase in gastric mucosal perfusion detected by laser-Doppler flowmetry was higher with epinephrine and the combination of norepinephrine and dobutamine than with norepinephrine alone (p < .05). In addition, the ratio of gastric mucosal perfusion (local oxygen delivery) to systemic oxygen delivery was increased after norepinephrine plus dobutamine as compared with norepinephrine alone and epinephrine (p< .05). Although values of intramucosal pH and gastroarterial PCO2 tended to be higher with norepinephrine plus dobutamine compared with those obtained with norepinephrine and epinephrine, differences were not statistically significant. CONCLUSIONS: For the same mean arterial pressure in patients with septic shock, our study showed that administration of epinephrine increased gastric mucosal perfusion more than norepinephrine administration alone. Addition of dobutamine (5 microg/kg/ min) to norepinephrine improved gastric mucosal perfusion. This result could be explained by a vasodilating effect of dobutamine on gastric mucosal microcirculation.

Inverse ratio ventilation (I/E = 2/1) in acute respiratory distress syndrome: a six-hour controlled study.

To assess the cardiorespiratory effects of a prolonged application of inverse ratio ventilation (IRV), we compared IRV (I/E = 2) with conventional ventilation (CV) (I/E = 0.5), applied for 6 h each in a randomized order, with constant tidal volume (VT) and total positive end-expiratory pressure (PEEP(tot)) in eight patients with acute respiratory distress syndrome (ARDS). After 1 h, IRV resulted in a lower peak inspiratory pressure (PIP) (28.2 +/- 1.5 versus 35.6 +/- 1.7 cm H2O, p < 0.05), an unchanged plateau pressure, and a higher mean airway pressure (MAP) (17.8 +/- 0.8 versus 15.6 +/- 0.5 cm H2O, p < 0.05) than CV. No significant difference in Pa(O2) and shunt fraction (QS/QT) was observed (83 +/- 7 mm Hg and 40 +/- 4% in CV versus 92 +/- 14 mm Hg and 35 +/- 3% in IRV, respectively). The Pa(CO2) was lower in IRV (48 +/- 3 versus 55 +/- 5 mm Hg, p < 0.05). Cardiac index (CI) and oxygen delivery (D(O2)) were lower in IRV (3.7 +/- 0.4 L/min/m2 and 500 +/- 61 ml/min/m2 versus 4.6 +/- 0.5 L/min/m2 and 617 +/- 80 ml/min/m2, respectively, p = 0.05 for both). Regardless of the considered parameter, no significant difference was observed between results after 1, 2, 4, and 6 h in each mode. We conclude that IRV at a ratio that results in a significant intrinsic PEEP does not improve Pa(O2), enhances CO2 elimination, decreases cardiac output (CO), and does not exert any time-dependent effect.