Nadia Anguel

Passive leg raising predicts fluid responsiveness in the critically ill.

Objective:Passive leg raising (PLR) represents a “self-volume challenge” that could predict fluid response and might be useful when the respiratory variation of stroke volume cannot be used for that purpose. We hypothesized that the hemodynamic response to PLR predicts fluid responsiveness in mechanically ventilated patients. Design:Prospective study. Setting:Medical intensive care unit of a university hospital. Patients:We investigated 71 mechanically ventilated patients considered for volume expansion. Thirty-one patients had spontaneous breathing activity and/or arrhythmias. Interventions:We assessed hemodynamic status at baseline, after PLR, and after volume expansion (500 mL NaCl 0.9% infusion over 10 mins). Measurements and Main Results:We recorded aortic blood flow using esophageal Doppler and arterial pulse pressure. We calculated the respiratory variation of pulse pressure in patients without arrhythmias. In 37 patients (responders), aortic blood flow increased by ≥15% after fluid infusion. A PLR increase of aortic blood flow ≥10% predicted fluid responsiveness with a sensitivity of 97% and a specificity of 94%. A PLR increase of pulse pressure ≥12% predicted volume responsiveness with significantly lower sensitivity (60%) and specificity (85%). In 30 patients without arrhythmias or spontaneous breathing, a respiratory variation in pulse pressure ≥12% was of similar predictive value as was PLR increases in aortic blood flow (sensitivity of 88% and specificity of 93%). In patients with spontaneous breathing activity, the specificity of respiratory variations in pulse pressure was poor (46%). Conclusions:The changes in aortic blood flow induced by PLR predict preload responsiveness in ventilated patients, whereas with arrhythmias and spontaneous breathing activity, respiratory variations of arterial pulse pressure poorly predict preload responsiveness.

Cardiac filling pressures are not appropriate to predict hemodynamic response to volume challenge.

Objective: Values of central venous pressure of 8–12 mm Hg and of pulmonary artery occlusion pressure of 12–15 mm Hg have been proposed as volume resuscitation targets in recent international guidelines on management of severe sepsis. By analyzing a large number of volume challenges, our aim was to test the significance of the recommended target values in terms of prediction of volume responsiveness. Design: Retrospective study. Setting: A 24‐bed medical intensive care unit. Patients: All consecutive septic patients monitored with a pulmonary artery catheter who underwent a volume challenge between 2001 and 2004. Intervention: None. Measurements and Main Results: A total of 150 volume challenges in 96 patients were reviewed. In 65 instances, the volume challenge resulted in an increase in cardiac index of ≥15% (responders). The pre‐infusion central venous pressure was similar in responders and nonresponders (8 ± 4 vs. 9 ± 4 mm Hg). The pre‐infusion pulmonary artery occlusion pressure was slightly lower in responders (10 ± 4 vs. 11 ± 4 mm Hg, p < .05). However, the significance of pulmonary artery occlusion pressure to predict fluid responsiveness was poor and similar to that of central venous pressure, as indicated by low values of areas under the receiver operating characteristic curves (0.58 and 0.63, respectively). A central venous pressure of <8 mm Hg and a pulmonary artery occlusion pressure of <12 mm Hg predicted volume responsiveness with a positive predictive value of only 47% and 54%, respectively. With the knowledge of a low stroke volume index (<30 mL·m−2), their positive predictive values were still unsatisfactory: 61% and 69%, respectively. When the combination of central venous pressure and pulmonary artery occlusion pressure was considered instead of either pressure alone, the degree of prediction of volume responsiveness was not improved. Conclusion: Our study demonstrates that cardiac filling pressures are poor predictors of fluid responsiveness in septic patients. Therefore, their use as targets for volume resuscitation must be discouraged, at least after the early phase of sepsis has concluded.

High versus Low Blood-Pressure Target in Patients with Septic Shock

BACKGROUND The Surviving Sepsis Campaign recommends targeting a mean arterial pressure of at least 65 mm Hg during initial resuscitation of patients with septic shock. However, whether this blood-pressure target is more or less effective than a higher target is unknown. METHODS In a multicenter, open-label trial, we randomly assigned 776 patients with septic shock to undergo resuscitation with a mean arterial pressure target of either 80 to 85 mm Hg (high-target group) or 65 to 70 mm Hg (low-target group). The primary end point was mortality at day 28. RESULTS At 28 days, there was no significant between-group difference in mortality, with deaths reported in 142 of 388 patients in the high-target group (36.6%) and 132 of 388 patients in the low-target group (34.0%) (hazard ratio in the high-target group, 1.07; 95% confidence interval [CI], 0.84 to 1.38; P=0.57). There was also no significant difference in mortality at 90 days, with 170 deaths (43.8%) and 164 deaths (42.3%), respectively (hazard ratio, 1.04; 95% CI, 0.83 to 1.30; P=0.74). The occurrence of serious adverse events did not differ significantly between the two groups (74 events [19.1%] and 69 events [17.8%], respectively; P=0.64). However, the incidence of newly diagnosed atrial fibrillation was higher in the high-target group than in the low-target group. Among patients with chronic hypertension, those in the high-target group required less renal-replacement therapy than did those in the low-target group, but such therapy was not associated with a difference in mortality. CONCLUSIONS Targeting a mean arterial pressure of 80 to 85 mm Hg, as compared with 65 to 70 mm Hg, in patients with septic shock undergoing resuscitation did not result in significant differences in mortality at either 28 or 90 days. (Funded by the French Ministry of Health; SEPSISPAM ClinicalTrials.gov number, NCT01149278.).

Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: a multicentre randomised controlled trial

BACKGROUND Critically ill patients often require emergency intubation. The use of etomidate as the sedative agent in this context has been challenged because it might cause a reversible adrenal insufficiency, potentially associated with increased in-hospital morbidity. We compared early and 28-day morbidity after a single dose of etomidate or ketamine used for emergency endotracheal intubation of critically ill patients. METHODS In this randomised, controlled, single-blind trial, 655 patients who needed sedation for emergency intubation were prospectively enrolled from 12 emergency medical services or emergency departments and 65 intensive care units in France. Patients were randomly assigned by a computerised random-number generator list to receive 0.3 mg/kg of etomidate (n=328) or 2 mg/kg of ketamine (n=327) for intubation. Only the emergency physician enrolling patients was aware of group assignment. The primary endpoint was the maximum score of the sequential organ failure assessment during the first 3 days in the intensive care unit. We excluded from the analysis patients who died before reaching the hospital or those discharged from the intensive care unit before 3 days (modified intention to treat). This trial is registered with ClinicalTrials.gov, number NCT00440102. FINDINGS 234 patients were analysed in the etomidate group and 235 in the ketamine group. The mean maximum SOFA score between the two groups did not differ significantly (10.3 [SD 3.7] for etomidate vs 9.6 [3.9] for ketamine; mean difference 0.7 [95% CI 0.0-1.4], p=0.056). Intubation conditions did not differ significantly between the two groups (median intubation difficulty score 1 [IQR 0-3] in both groups; p=0.70). The percentage of patients with adrenal insufficiency was significantly higher in the etomidate group than in the ketamine group (OR 6.7, 3.5-12.7). We recorded no serious adverse events with either study drug. INTERPRETATION Our results show that ketamine is a safe and valuable alternative to etomidate for endotracheal intubation in critically ill patients, and should be considered in those with sepsis. FUNDING French Ministry of Health.

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.

Extravascular lung water is an independent prognostic factor in patients with acute respiratory distress syndrome.

Objective:Acute respiratory distress syndrome might be associated with an increase in extravascular lung water index and pulmonary vascular permeability index, which can be measured by transpulmonary thermodilution. We tested whether extravascular lung water index and pulmonary vascular permeability index are independent prognostic factors in patients with acute respiratory distress syndrome. Design:Retrospective study. Setting:Medical intensive care unit. Patients:Two hundred consecutive acute respiratory distress syndrome patients (age = 57 ± 17, Simplified Acute Physiology Score II = 57 ± 20, overall day-28 mortality = 54%). Measurements:Extravascular lung water index and pulmonary vascular permeability index were collected (PiCCO device, Pulsion Medical Systems) at each day of the acute respiratory distress syndrome episode. Main Results:The maximum values of extravascular lung water index and pulmonary vascular permeability index recorded during the acute respiratory distress syndrome episode (maximum value of extravascular lung water index and maximum value of pulmonary vascular permeability index, respectively) were significantly higher in nonsurvivors than in survivors at day-28 (mean ± SD: 24 ± 10 mL/kg vs. 19 ± 7 mL/kg of predicted body weight, p < 0.001 [t-test] for maximum value of extravascular lung water index and median [interquartile range]: 4.4 [3.3–6.1] vs. 3.5 [2.8–4.4], p = 0.001 for maximum value of pulmonary vascular permeability index, Wilcoxon’s test). In multivariate analyses, maximum value of extravascular lung water index or maximum value of pulmonary vascular permeability index, Simplified Acute Physiology Score II, maximum blood lactate, mean positive end-expiratory pressure, mean cumulative fluid balance, and the minimal ratio of arterial oxygen pressure over the inspired oxygen fraction were all independently associated with day-28 mortality. A maximum value of extravascular lung water index >21 mL/kg predicted day-28 mortality with a sensitivity of (mean [95% confidence interval]) 54% (44–63)% and a specificity of 73% (63–82)%. The mortality rate was 70% in patients with a maximum value of extravascular lung water index >21 mL/kg and 43% in the remaining patients (p = 0.0003). A maximum value of pulmonary vascular permeability index >3.8 predicted day-28 mortality with a sensitivity of (mean [95% confidence interval]) 67% (57–76)% and a specificity of 65% (54–75)%. The mortality rate was 69% in patients with a maximum value of pulmonary vascular permeability index >3.8 and 37% in the group with a maximum value of pulmonary vascular permeability index ⩽3.8 (p < 0.0001). Conclusions:Extravascular lung water index and pulmonary vascular permeability index measured by transpulmonary thermodilution are independent risk factors of day-28 mortality in patients with acute respiratory distress syndrome.

Estimating cardiac filling pressure in mechanically ventilated patients with hyperinflation

ObjectiveWhen 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 × 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. DesignProspective study. SettingMedical intensive care unit of a university hospital. PatientsWe 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). InterventionTransient airway disconnection. Measurements and Main ResultsIn 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). ConclusionsIndexing 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.

Lactate and Venoarterial Carbon Dioxide Difference/Arterial-Venous Oxygen Difference Ratio, but Not Central Venous Oxygen Saturation, Predict Increase in Oxygen Consumption in Fluid Responders*

Objectives:During circulatory failure, the ultimate goal of treatments that increase cardiac output is to reduce tissue hypoxia. This can only occur if oxygen consumption depends on oxygen delivery. We compared the ability of central venous oxygen saturation and markers of anaerobic metabolism to predict whether a fluid-induced increase in oxygen delivery results in an increase in oxygen consumption. Design:Prospective study. Setting:ICU. Patients:Fifty-one patients with an acute circulatory failure (78% of septic origin). Measurements:Before and after a volume expansion (500mL of saline), we measured cardiac index, o2- and Co2-derived variables and lactate. Main Results:Volume expansion increased cardiac index ≥15% in 49% of patients (“volume-responders”). Oxygen delivery significantly increased in these 25 patients (+32% ± 16%, p < 0.0001). An increase in oxygen consumption ≥15% concomitantly occurred in 56% of these 25 volume-responders (+38% ± 28%). Compared with the volume-responders in whom oxygen consumption did not increase, the volume-responders in whom oxygen consumption increased ≥15% were characterized by a higher lactate (2.3 ± 1.1 mmol/L vs. 5.5 ± 4.0 mmol/L, respectively) and a higher ratio of the veno-arterial carbon dioxide tension difference (P(v − a)Co2) over the arteriovenous oxygen content difference (C(a − v)o2). A fluid-induced increase in oxygen consumption greater than or equal to 15% was not predicted by baseline central venous oxygen saturation but by high baseline lactate and (P(v − a)Co2/C(a − v)o2 ratio (areas under the receiving operating characteristics curves: 0.68 ± 0.11, 0.94 ± 0.05, and 0.91 ± 0.06). In volume-nonresponders, volume expansion did not significantly change cardiac index, but the oxygen delivery decreased due to a hemodilution-induced decrease in hematocrit. Conclusions:In volume-responders, unlike markers of anaerobic metabolism, central venous oxygen saturation did not allow the prediction of whether a fluid-induced increase in oxygen delivery would result in an increase in oxygen consumption. This suggests that along with indicators of volume-responsiveness, the indicators of anaerobic metabolism should be considered instead of central venous oxygen saturation for starting hemodynamic resuscitation.

Determinants of recovery from severe posterior reversible encephalopathy syndrome.

Objective Few outcome data are available about posterior reversible encephalopathy syndrome (PRES). We studied 90-day functional outcomes and their determinants in patients with severe PRES. Design 70 patients with severe PRES admitted to 24 ICUs in 2001–2010 were included in a retrospective cohort study. The main outcome measure was a Glasgow Outcome Scale (GOS) of 5 (good recovery) on day 90. Main Results Consciousness impairment was the most common clinical sign, occurring in 66 (94%) patients. Clinical seizures occurred in 57 (81%) patients. Median mean arterial pressure was 122 (105–143) mmHg on scene. Cerebral imaging abnormalities were bilateral (93%) and predominated in the parietal (93%) and occipital (86%) white matter. Median number of brain areas involved was 4 (3–5). Imaging abnormalities resolved in 43 (88%) patients. Ischaemic and/or haemorrhagic complications occurred in 7 (14%) patients. The most common causes were drug toxicity (44%) and hypertensive encephalopathy (41%). On day 90, 11 (16%) patients had died, 26 (37%) had marked functional impairments (GOS, 2 to 4), and 33 (56%) had a good recovery (GOS, 5). Factors independently associated with GOS<5 were highest glycaemia on day 1 (OR, 1.22; 95%CI, 1.02–1.45, p = 0.03) and time to causative-factor control (OR, 3.3; 95%CI, 1.04–10.46, p = 0.04), whereas GOS = 5 was associated with toxaemia of pregnancy (preeclampsia/eclampsia) (OR, 0.06; 95%CI, 0.01–0.38, p = 0.003). Conclusions By day 90 after admission for severe PRES, 44% of survivors had severe functional impairments. Highest glycaemia on day 1 and time to causative-factor control were strong early predictors of outcomes, suggesting areas for improvement.

Arterial pressure allows monitoring the changes in cardiac output induced by volume expansion but not by norepinephrine.

Objective: To evaluate to which extent the systemic arterial pulse pressure could be used as a surrogate of cardiac output for assessing the effects of a fluid challenge and of norepinephrine. Design: Observational study. Setting: Medical intensive care unit. Patients: Patients with an acute circulatory failure who received a fluid challenge (228 patients, group 1) or in whom norepinephrine was introduced or increased (145 patients, group 2). Interventions: We measured the systolic, diastolic, and mean arterial pressure, pulse pressure, and the transpulmonary thermodilution cardiac output before and after the therapeutic interventions. Main Results: In group 1, the fluid challenge significantly increased cardiac output by 24% ± 25%. It significantly increased cardiac output by ≥15% (+35% ± 27%) in 142 patients (“responders”). The fluid-induced changes in cardiac output were correlated with the changes in pulse pressure (r = .56, p < .0001), systolic arterial pressure (r = .55, p < .0001), diastolic arterial pressure (r = .37, p < .0001), and mean arterial pressure (r = .52, p < .0001). At multivariate analysis, changes in pulse pressure were significantly related to changes in stroke volume (multiple r = .52) and to age (r = .12). A fluid-induced increase in pulse pressure of ≥17% allowed detecting a fluid-induced increase in cardiac output of ≥15% with a sensitivity of 65[56–72]% and a specificity of 85[76–92]%. The area under the receiver operating characteristic curves for the fluid-induced changes in mean arterial pressure and in diastolic arterial pressure was significantly lower than for pulse pressure. In group 2, the introduction/increase of norepinephrine significantly increased cardiac output by 14% ± 18%. The changes in cardiac output induced by the introduction/increase in the dose of norepinephrine were correlated with the changes in pulse pressure and systolic arterial pressure (r = .21 and .29, respectively, p = .001) but to a significantly lesser extent than in group 1. Conclusions: Pulse pressure and systolic arterial pressure could be used for detecting the fluid-induced changes in cardiac output, in spite of a significant proportion of false-negative cases. By contrast, the changes in pulse pressure and systolic arterial pressure were unable to detect the changes in cardiac output induced by norepinephrine.