CAR-T cell: Toxicities issues: Mechanisms and clinical management.

CAR-T cells are modified T cells expressing a chimeric antigen receptor targeting a specific antigen. They have revolutionized the treatment of B cell malignancies (aggressive lymphomas, B-ALL), and this has raised hopes for application in many other pathologies (myeloma, AML, solid tumors, etc.). However, these therapies are associated with novel and specific toxicities (cytokine release syndrome and neurotoxicity). These complications, although mostly managed in a conventional hospitalization unit, can sometimes be life threatening, leading to admission of patients to the intensive care unit. Management relies mainly on anti-IL6R (tocilizumab) and corticosteroids. However, the optimal treatment regimen is still a matter of debate, and the management of the most severe forms is even less well codified. In addition to CRS and ICANS, infections, cytopenia and hypogammaglobulinemia are other frequent complications. This article reviews the mechanisms, risk factors, clinical presentation, and management of these toxicities.

Does inferior vena cava respiratory variability predict fluid responsiveness in spontaneously breathing patients?

INTRODUCTION: We have almost no information concerning the value of inferior vena cava (IVC) respiratory variations in spontaneously breathing ICU patients (SBP) to predict fluid responsiveness. METHODS: SBP with clinical fluid need were included prospectively in the study. Echocardiography and Doppler ultrasound were used to record the aortic velocity-time integral (VTI), stroke volume (SV), cardiac output (CO) and IVC collapsibility index (cIVC) ((maximum diameter (IVCmax)- minimum diameter (IVCmin))/ IVCmax) at baseline, after a passive leg-raising maneuver (PLR) and after 500 ml of saline infusion. RESULTS: Fifty-nine patients (30 males and 29 females; 57 ± 18 years-old) were included in the study. Of these, 29 (49 %) were considered to be responders (≥10 % increase in CO after fluid infusion). There were no significant differences between responders and nonresponders at baseline, except for a higher aortic VTI in nonresponders (16 cm vs. 19 cm, p = 0.03). Responders had a lower baseline IVCmin than nonresponders (11 ± 5 mm vs. 14 ± 5 mm, p = 0.04) and more marked IVC variations (cIVC: 35 ± 16 vs. 27 ± 10 %, p = 0.04). Prediction of fluid-responsiveness using cIVC and IVCmax was low (area under the curve for cIVC at baseline 0.62 ± 0.07; 95 %, CI 0.49-0.74 and for IVCmax at baseline 0.62 ± 0.07; 95 % CI 0.49-0.75). In contrast, IVC respiratory variations >42 % in SBP demonstrated a high specificity (97 %) and a positive predictive value (90 %) to predict an increase in CO after fluid infusion. CONCLUSIONS: In SBP with suspected hypovolemia, vena cava size and respiratory variability do not predict fluid responsiveness. In contrast, a cIVC >42 % may predict an increase in CO after fluid infusion.

Use of aztreonam in association with cefepime for the treatment of nosocomial infections due to multidrug-resistant strains of Pseudomonas aeruginosa to ß-lactams in ICU patients: A pilot study.

OBJECTIVES: Resistance to all ß-lactams is emerging among Pseudomonas aeruginosa (PA) clinical isolates. Aztreonam and cefepime act synergistically in vitro against AmpC overproducing PA isolates. The objective of this study was to evaluate the clinical efficacy of this treatment in ICU patients infected with multidrug-resistant PA. MATERIAL AND METHODS: Retrospective study (2 years, 2 ICUs) in a tertiary university hospital. Inclusion criteria were proven infection with evidence of a bacterial strain of PA resistant to all ß-lactams and treated with the association of at least aztreonam plus cefepime. Treatment was considered effective for pneumonia using CPIS scores at the end of treatment and for other infections, using the SOFA score and signs of infection improvement at the end of treatment. Infectious episodes were classified as cure or failure. RESULTS: Thirteen patients were included (10 nosocomial pneumonia, 3 nosocomial intra-abdominal infections). The median [25th-75th percentiles] admission SAPS2 score was 54 [51-69] and the median SOFA score at the beginning of infection was 7 [4-8]. The median CPIS scores for pneumonia at the beginning and end of treatment were 9 [7-10.5] and 2 [0.75-5.5]. The duration of treatment with the combination of aztreonam plus cefepime was 14 days [9.5-16]. Nine episodes were classified as cures and 4 as failures, indicating a clinical efficacy of 69.2%. Overall mortality was 38.5%. DISCUSSION: These data suggest that the association of cefepime plus aztreonam could be an attractive alternative in the treatment of infections with multidrug-resistant PA to all ß-lactams with a clinical efficacy rate of 69%.

Dynamic arterial elastance predicts mean arterial pressure decrease associated with decreasing norepinephrine dosage in septic shock.

INTRODUCTION: Gradual reduction of the dosage of norepinephrine (NE) in patients with septic shock is usually left to the physician's discretion. No hemodynamic indicator predictive of the possibility of decreasing the NE dosage is currently available at the bedside. The respiratory pulse pressure variation/respiratory stroke volume variation (dynamic arterial elastance (Eadyn)) ratio has been proposed as an indicator of vascular tone. The purpose of this study was to determine whether Eadyn can be used to predict the decrease in arterial pressure when decreasing the NE dosage in resuscitated sepsis patients. METHODS: A prospective study was carried out in a university hospital intensive care unit. All consecutive patients with septic shock monitored by PICCO2 for whom the intensive care physician planned to decrease the NE dosage were enrolled. Measurements of hemodynamic and PICCO2 variables were obtained before/after decreasing the NE dosage. Responders were defined by a >15% decrease in mean arterial pressure (MAP). RESULTS: In total, 35 patients were included. MAP decreased by >15% after decreasing the NE dosage in 37% of patients (n = 13). Clinical characteristics appeared to be similar between responders and nonresponders. Eadyn was lower in responders than in nonresponders (0.75 (0.69 to 0.85) versus 1 (0. 83 to 1.22), P <0.05). Baseline Eadyn was correlated with NE-induced MAP variations (r = 0.47, P = 0.005). An Eadyn less than 0.94 predicted a decrease in arterial pressure, with an area under the receiver-operating characteristic curve of 0.87 (95% confidence interval (95% CI): 0.72 to 0.96; P <0.0001), 100% sensitivity, and 68% specificity. CONCLUSIONS: In sepsis patients treated with NE, Eadyn may predict the decrease in arterial pressure in response to NE dose reduction. Eadyn may constitute an easy-to-use functional approach to arterial-tone assessment, which may be helpful to identify patients likely to benefit from NE dose reduction.

Improvement of left ventricular relaxation as assessed by tissue Doppler imaging in fluid-responsive critically ill septic patients.

PURPOSE: Left ventricular (LV) diastolic function is often impaired in critically ill septic patients. The peak velocity of the mitral annulus early wave during diastole (E'), measured by Doppler echocardiography, is a major tool to evaluate LV relaxation, the ATP-dependent part of diastole. The authors hypothesized that if volume expansion (VE) is followed by an increase in stroke volume (SV) ("adequate" VE), LV relaxation and consequently E' may be increased. METHODS: This was a prospective study in which 83 mechanically ventilated septic patients with circulatory failure were enrolled. Doppler echocardiography was performed before and after the infusion of 500 ml of saline over 20 min. Patients were then classified into two groups according to their response to VE: responders (R) were those in whom SV increased by at least 15 %; all others were considered to be non-responders (NR). SV, mitral flow early wave velocity (E), E' and the E/E' ratio were measured before and after VE. VE-induced variations (∆) in all parameters were compared in R and NR. Patients with an E' < 0.12 m/s were considered to have LV diastolic dysfunction. RESULTS: Fifty-nine patients (71 %) were R and 24 (29 %) were NR. Fifty-six percent of R patients and 58 % of NR patients had LV diastolic dysfunction. For patients with LV diastolic dysfunction (n = 47), ∆E' was significantly higher in the R group (29 ± 5 vs. 5 ± 8 %; p = 0.01) whilst ∆E/E' was higher in the NR group (35 ± 9 vs. 2 ± 6 %; p = 0.02). CONCLUSIONS: E' maximal velocity increased with adequate VE, suggesting an improvement of LV relaxation with the correction of hypovolaemia in patients with septic shock.