Jean Dellamonica

Fever control using external cooling in septic shock: a randomized controlled trial.

RATIONALE Fever control may improve vascular tone and decrease oxygen consumption, but fever may contribute to combat infection. OBJECTIVES To determine whether fever control by external cooling diminishes vasopressor requirements in septic shock. METHODS In a multicenter randomized controlled trial, febrile patients with septic shock requiring vasopressors, mechanical ventilation, and sedation were allocated to external cooling (n = 101) to achieve normothermia (36.5-37°C) for 48 hours or no external cooling (n = 99). Vasopressors were tapered to maintain the same blood pressure target in the two groups. The primary endpoint was the number of patients with a 50% decrease in baseline vasopressor dose after 48 hours. MEASUREMENTS AND MAIN RESULTS Body temperature was significantly lower in the cooling group after 2 hours of treatment (36.8 ± 0.7 vs. 38.4 ± 1.1°C; P < 0.01). A 50% vasopressor dose decrease was significantly more common with external cooling from 12 hours of treatment (54 vs. 20%; absolute difference, 34%; 95% confidence interval [95% CI], -46 to -21; P < 0.001) but not at 48 hours (72 vs. 61%; absolute difference, 11%; 95% CI, -23 to 2). Shock reversal during the intensive care unit stay was significantly more common with cooling (86 vs. 73%; absolute difference, 13%; 95% CI, 2 to 25; P = 0.021). Day-14 mortality was significantly lower in the cooling group (19 vs. 34%; absolute difference, -16%; 95% CI, -28 to -4; P = 0.013). CONCLUSIONS In this study, fever control using external cooling was safe and decreased vasopressor requirements and early mortality in septic shock.

Complex partial status epilepticus revealing anti-NMDA receptor encephalitis

Encephalitis with anti-NMDA receptor antibodies is a recently-recognised form of paraneoplastic encephalitis characterized by a prodromal phase of unspecific illness with fever resembling viral disease, followed by memory loss, psychiatric features, seizures, disturbed consciousness, prominent abnormal movements and autonomic imbalance. Association with ovarian teratoma is common. Neurological outcome can be good, especially when surgery is performed at an early stage. Here, we report a case of anti-NMDA receptor encephalitis associated with ovarian teratoma presenting with inaugural complex partial status epilepticus. The nature of abnormal movements at early stages was unclear and abnormal movements were misinterpreted as the recurrence of partial epileptic seizures. Despite its rarity, all clinicians treating epilepsy and movement disorders should be familiar with anti-NMDA receptor encephalitis, that appears to be a very severe but curable disease.

Transthoracic Echocardiography with Doppler Tissue Imaging predicts weaning failure from mechanical ventilation: evolution of the left ventricle relaxation rate during a spontaneous breathing trial is the key factor in weaning outcome.

IntroductionThere is growing evidence to suggest that transthoracic echocardiography (TTE) should be used to identify the cardiac origin of respiratory weaning failure. The aims of our study were: first, to evaluate the ability of transthoracic echocardiography, with mitral Doppler inflow E velocity to annular tissue Doppler Ea wave velocity (E/Ea) ratio measurement, to predict weaning failure from mechanical ventilation in patients, including those with atrial fibrillation; and second, to determine whether the depressed left ejection fraction and/or diastolic dysfunction participate in weaning outcome.MethodsThe sample included patients on mechanical ventilation for over 48 hours. A complete echocardiography was performed just before the spontaneous breathing trial (SBT) and 10 minutes after starting the SBT. Systolic dysfunction was defined by a left ventricle ejection fraction under 50% and relaxation impairment by a protodiastolic annulus mitral velocity Ea under or equal to 8 cm/second.ResultsA total of 68 patients were included. Twenty failed the weaning process and the other 48 patients succeeded. Before the SBT, the E/Ea ratio was higher in the failed group than in the successful group. The E/Ea measured during the SBT was also higher in the failed group. The cut-off value, obtained from receiver operating characteristics (ROC) curve analysis, to predict weaning failure gave an E/Ea ratio during the SBT of 14.5 with a sensitivity of 75% and a specificity of 95.8%. The left ventricular ejection fraction did not differ between the two groups whereas Ea was lower in the failed group. Ea increased during SBT in the successful group while no change occurred in the failed group.ConclusionsMeasurement of the E/Ea ratio with TTE could predict weaning failure. Diastolic dysfunction with relaxation impairment is strongly associated with weaning failure. Moreover, the impossibility of enhancing the left ventricle relaxation rate during the SBT seems to be the key factor of weaning failure. In contrast, the systolic dysfunction was not associated with weaning outcome.

Transient and Persistent Acute Kidney Injury and the Risk of Hospital Mortality in Critically Ill Patients: Results of a Multicenter Cohort Study

Objective:To assess the prognostic impact of transient and persistent acute kidney injury in critically ill patients. Design:Retrospective analysis of prospectively collected patient data Setting:Six hospital ICUs. Patients:Critically-ill patients with ICU stay longer than three days. Intervention:None. Measurements and Main Results:Assessment of hospital survival with respect to acute kidney injury duration. A total of 447 patients were included in this study, including 283 patients (63.3%) with an acute kidney injury at admission (175 and 108 patients with persistent and transient acute kidney injury, respectively). Patients with persistent acute kidney injury more frequently had stage 3 acute kidney injury (42.9% vs 30.6%; p = 0.04). Hospital survival was 76.2% (n = 125) in patients without acute kidney injury, 70.4% (n = 76) in patients with transient acute kidney injury, and 61.1% (n = 107) in patients with persistent acute kidney injury. After adjustment for confounding factors, the factors associated with lower hospital survival were the need for vasopressors (odds ratio, 0.65; 95% CI, 0.43–0.98) and the presence of persistent acute kidney injury (odds ratio, 0.58; 95% CI, 0.36–0.95). When included in the final model, stage 3 acute kidney injury was independently associated with a lower hospital survival (odds ratio, 0.83; 95% CI, 0.70–0.98), and persistent acute kidney injury was no longer associated with outcome. Conclusion:Two thirds of the critically ill patients with acute kidney injury have persistent acute kidney injury. Although mortality increased progressively with the duration of acute kidney injury, we found no independent association between this duration and patient outcome when the acute kidney injury severity is taken into account. Our results suggest that the classical “prerenal acute kidney injury” and “acute tubular necrosis” paradigm might be of limited interest from a pathophysiological or prognostic point of view.

Hyperoxia and hypertonic saline in patients with septic shock (HYPERS2S): a two-by-two factorial, multicentre, randomised, clinical trial

BACKGROUND There is insufficient research into the use of mechanical ventilation with increased inspiratory oxygen concentration (FiO2) and fluid resuscitation with hypertonic saline solution in patients with septic shock. We tested whether these interventions are associated with reduced mortality. METHODS This two-by-two factorial, multicentre, randomised, clinical trial (HYPERS2S) recruited patients aged 18 years and older with septic shock who were on mechanical ventilation from 22 centres in France. Patients were randomly assigned 1:1:1:1 to four groups by a computer generated randomisation list stratified by site and presence or absence of acute respiratory distress syndrome by use of permuted blocks of random sizes. Patients received, in an open-labelled manner, mechanical ventilation either with FiO2 at 1·0 (hyperoxia) or FiO2 set to target an arterial haemoglobin oxygen saturation of 88-95% (normoxia) during the first 24 h; patients also received, in a double-blind manner, either 280 mL boluses of 3·0% (hypertonic) saline or 0·9% (isotonic) saline for fluid resuscitation during the first 72 h. The primary endpoint was mortality at day 28 after randomisation in the intention-to-treat population. This study was registered with ClinicalTrials.gov, number NCT01722422. FINDINGS Between Nov 3, 2012, and June 13, 2014, 442 patients were recruited and assigned to a treatment group (normoxia [n=223] or hyperoxia [n=219]; isotonic [n=224] or hypertonic [n=218]). The trial was stopped prematurely for safety reasons. 28 day mortality was recorded for 434 patients; 93 (43%) of 217 patients had died in the hyperoxia group versus 77 (35%) of 217 patients in the normoxia group (hazard ratio [HR] 1·27, 95% CI 0·94-1·72; p=0·12). 89 (42%) of 214 patients had died in the hypertonic group versus 81 (37%) of 220 patients in the isotonic group (HR 1·19, 0·88-1·61; p=0·25). We found a significant difference in the overall incidence of serious adverse events between the hyperoxia (185 [85%]) and normoxia groups (165 [76%]; p=0·02), with a clinically relevant doubling in the hyperoxia group of the number of patients with intensive care unit-acquired weakness (24 [11%] vs 13 [6%]; p=0·06) and atelectasis (26 [12%] vs 13 [6%]; p=0·04) compared with the normoxia group. We found no statistical difference for serious adverse events between the two saline groups (p=0·23). INTERPRETATION In patients with septic shock, setting FiO2 to 1·0 to induce arterial hyperoxia might increase the risk of mortality. Hypertonic (3%) saline did not improve survival. FUNDING The French Ministry of Health.

Diagnostic accuracy of early urinary index changes in differentiating transient from persistent acute kidney injury in critically ill patients: multicenter cohort study

IntroductionUrinary indices have limited effectiveness in separating transient acute kidneyinjury (AKI) from persistent AKI in ICU patients. Their time-course may vary withthe mechanism of AKI. The primary objective of this study was to evaluate thediagnostic value of changes over time of the usual urinary indices in separatingtransient AKI from persistent AKI.MethodsAn observational prospective multicenter study was performed in six ICUs involving244 consecutive patients, including 97 without AKI, 54 with transient AKI, and 93with persistent AKI. Urinary sodium, urea and creatinine were measured at ICUadmission (H0) and on 6-hour urine samples during the first 24 ICU hours (H6, H12,H18, and H24). Transient AKI was defined as AKI with a cause for renalhypoperfusion and reversal within 3 days.ResultsSignificant increases from H0 to H24 were noted in fractional excretion of urea(median, 31% (22 to 41%) and 39% (29 to 48%) at H24, P < 0.0001),urinary urea/plasma urea ratio (15 (7 to 28) and 20 (9 to 40), P <0.0001), and urinary creatinine/plasma creatinine ratio (50 (24 to 101) and 57 (29to 104), P = 0.01). Fractional excretion of sodium did not changesignificantly during the first 24 hours in the ICU (P = 0.13). Neitherurinary index values at ICU admission nor changes in urinary indices between H0and H24 performed sufficiently well to recommend their use in clinical setting(area under the receiver-operating characteristic curve ≤0.65).ConclusionAlthough urinary indices at H24 performed slightly better than those at H0 indifferentiating transient AKI from persistent AKI, they remain insufficientlyreliable to be clinically relevant.

The early phase of human sepsis is characterized by a combination of apoptosis and proliferation of T cells

PURPOSE T cell activation as well as unresponsiveness has been described in separate studies in sepsis. Our aim was to establish the coexistence of both T cell fate in human sepsis. PATIENTS AND METHODS This is a cross-sectional study of 48 patients presenting with severe sepsis or septic shock and 15 healthy controls. Cytofluorometric techniques were used to quantify T cell activation, apoptosis, proliferation, expression of costimulatory molecules, and cytokine secretion. RESULTS Patients with sepsis were characterized by a significant increase in the percentage of activated T cell subsets, as measured using CD69 marker, compared with healthy controls (P<.05). T cell proliferation as measured through Ki67 expression was obvious in infected patients for both CD4 and CD8 T cell subsets compared with controls (P ≤.006). T cell subset apoptosis as measured using Hoechst dye was also increased in infected patients compared with controls (P ≤.002). CD4 T cell proliferation was correlated with interleukin 2 secretion (R(2)=0.84, P<.001), whereas up-regulation of CD4 T cell apoptosis was correlated with CTLA-4 expression (R(2)=0.24, P=.001). No such similar relationship was observed for CD8(+) T cells. CONCLUSIONS Concomitant T cell proliferation and T cell apoptosis are observed in human sepsis, being related to a different pathway.

Bedside adjustment of proportional assist ventilation to target a predefined range of respiratory effort.

Objectives:During proportional assist ventilation with load-adjustable gain factors, peak respiratory muscle pressure can be estimated from the peak airway pressure and the percentage of assistance (gain). Adjusting the gain can, therefore, target a given level of respiratory effort. This study assessed the clinical feasibility of titrating proportional assist ventilation with load-adjustable gain factors with the goal of targeting a predefined range of respiratory effort. Design:Prospective, multicenter, clinical observational study. Settings:Intensive care departments at five university hospitals. Patients:Patients were included after meeting simple criteria for assisted mechanical ventilation. Interventions:Patients were ventilated in proportional assist ventilation with load-adjustable gain factors. The peak respiratory muscle pressure, estimated in cm H2O as (peak airway pressure – positive end-expiratory pressure) × [(100 – gain)/gain], was calculated from a grid at the bedside. The gain adjustment algorithm was defined to target a peak respiratory muscle pressure between 5 and 10 cm H2O. Additional recommendations were available in case of hypoventilation or hyperventilation. Results:Fifty-three patients were enrolled. Median time spent under proportional assist ventilation with load-adjustable gain factors was 3 days (interquartile range, 1–5). Gain was adjusted 1.0 (0.7–1.8) times per day, according to the peak respiratory muscle pressure target range in 91% of cases and because of hypoventilation or hyperventilation in 9%. Thirty-four patients were ventilated with proportional assist ventilation with load-adjustable gain factors until extubation, which was successful in 32. Eighteen patients required volume assist-controlled reventilation because of clinical worsening and need for continuous sedation. One patient was intolerant to proportional assist ventilation with load-adjustable gain factors. Conclusions:This first study assessing the clinical feasibility of titrating proportional assist ventilation with load-adjustable gain factors in an attempt to target a predefined range of effort showed that adjusting the level of assistance to maintain a predefined boundary of respiratory muscle pressure is feasible, simple, and often sufficient to ventilate patients until extubation.

Accuracy and precision of end-expiratory lung-volume measurements by automated nitrogen washout/washin technique in patients with acute respiratory distress syndrome

IntroductionEnd-expiratory lung volume (EELV) is decreased in acute respiratory distress syndrome (ARDS), and bedside EELV measurement may help to set positive end-expiratory pressure (PEEP). Nitrogen washout/washin for EELV measurement is available at the bedside, but assessments of accuracy and precision in real-life conditions are scant. Our purpose was to (a) assess EELV measurement precision in ARDS patients at two PEEP levels (three pairs of measurements), and (b) compare the changes (Δ) induced by PEEP for total EELV with the PEEP-induced changes in lung volume above functional residual capacity measured with passive spirometry (ΔPEEP-volume). The minimal predicted increase in lung volume was calculated from compliance at low PEEP and ΔPEEP to ensure the validity of lung-volume changes.MethodsThirty-four patients with ARDS were prospectively included in five university-hospital intensive care units. ΔEELV and ΔPEEP volumes were compared between 6 and 15 cm H2O of PEEP.ResultsAfter exclusion of three patients, variability of the nitrogen technique was less than 4%, and the largest difference between measurements was 81 ± 64 ml. ΔEELV and ΔPEEP-volume were only weakly correlated (r2 = 0.47); 95% confidence interval limits, -414 to 608 ml). In four patients with the highest PEEP (≥ 16 cm H2O), ΔEELV was lower than the minimal predicted increase in lung volume, suggesting flawed measurements, possibly due to leaks. Excluding those from the analysis markedly strengthened the correlation between ΔEELV and ΔPEEP volume (r2 = 0.80).ConclusionsIn most patients, the EELV technique has good reproducibility and accuracy, even at high PEEP. At high pressures, its accuracy may be limited in case of leaks. The minimal predicted increase in lung volume may help to check for accuracy.

Comparison of two strategies for initiating renal replacement therapy in the intensive care unit: study protocol for a randomized controlled trial (AKIKI).

BackgroundThere is currently no validated strategy for the timing of renal replacement therapy (RRT) for acute kidney injury (AKI) in the intensive care unit (ICU) when short-term life-threatening metabolic abnormalities are absent. No adequately powered prospective randomized study has addressed this issue to date. As a result, significant practice heterogeneity exists and may expose patients to either unnecessary hazardous procedures or undue delay in RRT.Methods/designThis is a multicenter, prospective, randomized, open-label parallel-group clinical trial that compares the effect of two RRT initiation strategies on overall survival of critically ill patients receiving intravenous catecholamines or invasive mechanical ventilation and presenting with AKI classification stage 3 (KDIGO 2012). In the ‘early’ strategy, RRT is initiated immediately. In the ‘delayed’ strategy, clinical and metabolic conditions are closely monitored and RRT is initiated only when one or more events (severity criteria) occur, including: oliguria or anuria for more than 72 hours after randomization, serum urea concentration >40 mmol/l, serum potassium concentration >6 mmol/l, serum potassium concentration >5.5 mmol/l persisting despite medical treatment, arterial blood pH <7.15 in a context of pure metabolic acidosis (PaCO2 < 35 mmHg) or in a context of mixed acidosis with a PaCO2 ≥ 50 mmHg without possibility of increasing alveolar ventilation, acute pulmonary edema due to fluid overload despite diuretic therapy leading to severe hypoxemia requiring oxygen flow rate >5 l/min to maintain SpO2 > 95% or FiO2 > 50% under invasive or noninvasive mechanical ventilation.The primary outcome measure is overall survival, measured from randomization (D0) until death, regardless of the cause. The minimum follow-up duration for each patient will be 60 days. Two interim analyses are planned, blinded to group allocation. It is expected that there will be 620 subjects in all.DiscussionThe AKIKI study will be one of the very few large randomized controlled trials evaluating mortality according to the timing of RRT in critically ill patients with AKI classification stage 3 (KDIGO 2012). Results should help clinicians decide when to initiate RRT.Trial registrationClinicalTrials.gov NCT01932190.