Julien Maizel

Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis: The CRYSTMAS study

Introduction Inadequate initial treatment and delayed hemodynamic stabilization (HDS) may be associated with increased risk of death in severe sepsis patients. Methods In order to compare the hemodynamic efficacy and safety of 6% HES 130/0.4 and NaCl 0.9% for HDS in patients with severe sepsis, we designed a prospective, multicenter, active-controlled, double-blind, randomized study in intensive care units. Results 174 out of 196 patients reached HDS (88 and 86 patients for HES and NaCl, respectively). Significantly less HES was used to reach HDS vs. NaCl (1,379 ±886 ml in the HES group and 1,709 ±1,164 ml in the NaCl group (mean difference = -331± 1,033, 95% CI -640 to -21, P = 0.0185). Time to reach HDS was 11.8 10.1 hours vs. 14.3 ±11.1 hours for HES and NaCl, respectively. Total quantity of study drug infused over four consecutive days, ICU and hospital LOS, and area under the curve of SOFA score were comparable. Acute renal failure occurred in 24 (24.5%) and 19 (20%) patients for HES and NaCl, respectively (P = 0.454). There was no difference between AKIN and RIFLE criteria among groups and no difference in mortality, coagulation, or pruritus up to 90 days after treatment initiation. Conclusion Significantly less volume was required to achieve HDS for HES vs. NaCl in the initial phase of fluid resuscitation in severe sepsis patients without any difference for adverse events in both groups. ClinicalTrials.gov NCT00464204

Echocardiographic diagnosis of pulmonary artery occlusion pressure elevation during weaning from mechanical ventilation

Objective:Weaning-induced pulmonary edema is a cause of weaning failure in high-risk patients. The diagnosis may require pulmonary artery catheterization to demonstrate increased pulmonary artery occlusion pressure (PAOP) during weaning. Transthoracic echocardiography can estimate left ventricular filling pressures using early (E) and late (A) peak diastolic velocities measured with Doppler transmitral flow, and tissue Doppler imaging of mitral annulus velocities including early (Ea) peak diastolic velocity. We tested the hypothesis that E/A and E/Ea could be used to detect weaning-induced PAOP elevation defined by a PAOP ≥18 mm Hg during a spontaneous breathing trial (SBT). Measurements and Main Results:We included 39 patients who previously failed two consecutive SBTs. A third SBT was performed over a maximum 1-hour period using a T-piece. The PAOP, E/A, and E/Ea were measured before and during this SBT. Receiver operating characteristic curves were constructed to determine the optimal sensitivity and specificity values of E/A and E/Ea obtained at the end of the SBT for predicting a weaning-induced PAOP elevation. Weaning-induced PAOP elevation occurred in 17 patients. A value of E/A >0.95 at the end of the SBT predicted weaning-induced PAOP elevation with a sensitivity of 88% and a specificity of 68%. A value of E/Ea >8.5 at the end of the SBT predicted weaning-induced PAOP elevation with a sensitivity of 94% and a specificity of 73%. The combination of E/A >0.95 and E/Ea >8.5 predicted a weaning-induced PAOP elevation with a sensitivity of 82% and a specificity of 91%. Conclusion:At the end of an SBT, the combination of E/A >0.95 and E/Ea >8.5 measured with transthoracic echocardiography allowed an accurate noninvasive detection of weaning-induced PAOP elevation.

Early administration of norepinephrine increases cardiac preload and cardiac output in septic patients with life-threatening hypotension

IntroductionWe sought to examine the cardiac consequences of early administration of norepinephrine in severely hypotensive sepsis patients hospitalized in a medical intensive care unit of a university hospital.MethodsWe included 105 septic-shock patients who already had received volume resuscitation. All received norepinephrine early because of life-threatening hypotension and the need to achieve a sufficient perfusion pressure rapidly and to maintain adequate flow. We analyzed the changes in transpulmonary thermodilution variables associated with the increase in mean arterial pressure (MAP) induced by norepinephrine when the achieved MAP was ≥65 mm Hg.ResultsNorepinephrine significantly increased MAP from 54 ± 8 to 76 ± 9 mm Hg, cardiac index (CI) from 3.2 ± 1.0 to 3.6 ± 1.1 L/min/m2, stroke volume index (SVI) from 34 ± 12 to 39 ± 13 ml/m2, global end-diastolic volume index (GEDVI) from 694 ± 148 to 742 ± 168 ml/m2, and cardiac function index (CFI) from 4.7 ± 1.5 to 5.0 ± 1.6 per min. Beneficial hemodynamic effects on CI, SVI, GEDVI, and CFI were observed in the group of 71 patients with a baseline echocardiographic left ventricular ejection fraction (LVEF) >45%, as well as in the group of 34 patients with a baseline LVEF ≤45%. No change in CI, SVI, GEDVI, or CFI was observed in the 17 patients with baseline LVEF ≤45% for whom values of MAP ≥75 mm Hg were achieved with norepinephrine.ConclusionsEarly administration of norepinephrine aimed at rapidly achieving a sufficient perfusion pressure in severely hypotensive septic-shock patients is able to increase cardiac output through an increase in cardiac preload and cardiac contractility. This effect remained in patients with poor cardiac contractility except when values of MAP ≥75 mm Hg were achieved.

Norepinephrine increases cardiac preload and reduces preload dependency assessed by passive leg raising in septic shock patients

Objective:To assess the effects of norepinephrine on cardiac preload, cardiac index, and preload dependency during septic shock. Design:Prospective interventional study. Setting:Medical Intensive Care Unit. Patients:We included 25 septic shock patients (62 ± 13 yrs old, Simplified Acute Physiology Score II 53 ± 12, lactate 3.5 ± 2.1 mmol/L, all receiving norepinephrine at baseline at 0.24 [25%–75% interquartile range: 0.12–0.48] &mgr;g/kg/min) with a positive passive leg raising test (defined by an increase in cardiac index ≥10%) and a diastolic arterial pressure ≤40 mm Hg. Interventions:We performed a passive leg raising test (during 1 min) at baseline. Immediately after, we increased the dose of norepinephrine (to 0.48 [0.36–0.71] &mgr;g/kg/min) and, when the hemodynamic status was stabilized, we performed a second passive leg raising test (during 1 min). We finally infused 500 mL saline. Measurements and Main Results:Increasing the dose of norepinephrine significantly increased central venous pressure (+23% ± 12%), left ventricular end-diastolic area (+9% ± 6%), E mitral wave (+19% ± 23%), and global end-diastolic volume (+9% ± 6%). Simultaneously, cardiac index significantly increased by 11% ± 7%, suggesting that norepinephrine had recruited some cardiac preload reserve. The second passive leg raising test increased cardiac index to a lesser extent than the baseline test (13% ± 8% vs. + 19% ± 6%, p < .05), suggesting that norepinephrine had decreased the degree of preload dependency. Volume infusion significantly increased cardiac index by 26% ± 15%. However, cardiac index increased by <15% in four patients (fluid unresponsive patients) while the baseline passive leg raising test was positive in these patients. In three of these four patients, the second passive leg raising test was also negative, i.e., the second passive leg raising test (after norepinephrine increase) predicted fluid responsiveness with a sensitivity of 95 [76–99]% and a specificity of 100 [30–100]%. Conclusions:In septic patients with a positive passive leg raising test at baseline suggesting the presence of preload dependency, norepinephrine increased cardiac preload and cardiac index and reduced the degree of preload dependency.

Echocardiographic measurement of ventricular function.

Purpose of reviewWe review new findings concerning ventricular function in patients in intensive care units with shock or unexplained respiratory distress syndrome analyzed using echocardiography. Recent findingsBedside echocardiography is not only an imaging technique but should be considered as a hemodynamic method. Left-ventricular systolic function can be assessed in daily clinical practice by measuring shortening fraction, fraction area change and ejection fraction. But these indices are dependent on load conditions. Index of myocardial performance can be also used. Rate of left-ventricular pressure increase may be measured from mitral regurgitation. Other indices such a maximal elastance and preload-adjusted maximal power were developed to evaluate myocardial systolic function but are not still used in clinical practice in patients in intensive care. Cardiac output measurement can be calculated easily from aortic annulus diameter and the velocity time integral of aortic blood flow. To complete the assessment of ventricular function, left-ventricular diastolic function and pressure as well as right ventricular size, septal movement and right pressures should be analyzed. SummaryUsing echocardiography the intensivist can examine both the mechanism and the cause of shock or pulmonary edema. It is time to increase the use of this technique in intensive care units.

Early dynamic left intraventricular obstruction is associated with hypovolemia and high mortality in septic shock patients

IntroductionBased on previously published case reports demonstrating dynamic left intraventricular obstruction (IVO) triggered by hypovolemia or catecholamines, this study aimed to establish: (1) IVO occurrence in septic shock patients; (2) correlation between the intraventricular gradient and volume status and fluid responsiveness; and (3) mortality rate.MethodWe prospectively analyzed patients with septic shock admitted to a general ICU over a 28-month period who presented Doppler signs of IVO. Clinical characteristics and hemodynamic parameters as well as echocardiographic data regarding left ventricular function, size, and calculated mass, and left ventricular outflow Doppler pattern and velocity before and after fluid infusions were recorded.ResultsDuring the study period, 218 patients with septic shock were admitted to our ICU. IVO was observed in 47 (22 %) patients. Mortality rate at 28 days was found to be higher in patients with than in patients without IVO (55 % versus 33 %, p < 0.01). Small, hypercontractile left ventricles (end-diastolic left ventricular surface 4.7 ± 2.1 cm2/m2 and ejection fraction 82 ± 12 %), and frequent pseudohypertrophy were found in these patients. A rise ≥12 % in stroke index was found in 87 % of patients with IVO, with a drop of 47 % in IVO after fluid infusion.ConclusionLeft IVO is a frequent event in septic shock patients with an important correlation with fluid responsiveness. The mortality rate was found to be higher in these patients in comparison with patients without obstruction.

Effect of simvastatin in apolipoprotein E deficient mice with surgically induced chronic renal failure.

PURPOSE Patients with a surgically reduced renal mass are at increased risk for progressive renal failure, which often requires renal replacement therapy or kidney transplantation. We investigated the effects of simvastatin supplementation on uremia enhanced atherosclerosis and vascular calcification in apoE(-/-) (apolipoprotein E deficient) mice (Charles Rivers Laboratories, Wilmington, Massachusetts) with or without superimposed chronic kidney disease. MATERIALS AND METHODS The mice were randomly assigned to 4 groups, including 2 groups with normal renal function (simvastatin vs control in 13 mice) and the other 2 with surgically created chronic kidney disease (simvastatin vs control in 18). Simvastatin (100 mg/kg) was administered by daily oral gavage for 4 weeks. RESULTS Simvastatin treatment did not prevent uremia accelerated atherosclerosis in chronic kidney disease apoE(-/-) mice, nor did it retard atherosclerosis progression in control nonchronic kidney disease mice. However, aortic plaques in simvastatin treated chronic kidney disease mice showed significantly less calcification than those in controls with chronic kidney disease (p <0.03). In addition, the increase of aortic nitrotyrosine staining in mice with chronic kidney disease was prevented by simvastatin treatment (p <0.02). Serum total cholesterol was increased to a similar extent in the 2 chronic kidney disease groups compared with that in the nonchronic kidney disease groups. The beneficial effect of simvastatin on uremia enhanced vascular calcification in apoE(-/-) mice with chronic kidney disease was observed despite the absence of changes in uremia accelerated atherosclerosis progression, serum total cholesterol levels or osteopontin and alkaline phosphatase expression. CONCLUSIONS Our observation opens the possibility of a cholesterol independent action of statins on vascular calcification via a decrease in oxidative stress.

Endostatin and kidney fibrosis in aging: a case for antagonistic pleiotropy?

A recurring theme of a host of gerontologic studies conducted in either experimental animals or in humans is related to documenting the functional decline with age. We hypothesize that elevated circulating levels of a powerful antiangiogenic peptide, endostatin, represent one of the potent systemic causes for multiorgan microvascular rarefaction and functional decline due to fibrosis. It is possible that during the life span of an organism there is an accumulation of dormant transformed cells producing antiangiogenic substances (endostatin) that maintain the dormancy of such scattered malignant cells. The proof of this postulate cannot be obtained by physically documenting these scattered cells, and it rests exclusively on the detection of sequelae of shifted pro- and antiangiogenic balance toward the latter. Here we compared circulating levels of endostatin in young and aging mice of two different strains and showed that endostatin levels are elevated in the latter. Renal expression of endostatin increased ~5.6-fold in aging animals. This was associated with microvascular rarefaction and progressive tubulointerstitial fibrosis. In parallel, the levels of sirtuins 1 and 3 were significantly suppressed in aging mice in conjunction with the expression of markers of senescence. Treating young mice with endostatin for 28 days showed delayed recovery of circulation after femoral artery ligation and reduced patency of renal microvasculature but no fibrosis. In conclusion, the findings are consistent with the hypothesis on elevation of endostatin levels and parallel microvascular rarefaction and induction of renal fibrosis in aging mice.

Is chest X-ray still necessary after central venous catheter insertion?

markedly improved using NAVA. Although these results are encouraging, especially for the management of patients with difficult dys-synchrony issues, many unanswered questions remain. First, the PS settings in this study used a very low flow cycling setting, which can induce significant cycling delays (with resultant intrinsic positive end-expiratory pressure), especially in patients with airway obstruction, such as patients in this study (8). Thus, the marked improvement in cycle synchrony with NAVA in this study may likely have been exaggerated by the suboptimal PS settings. Similarly, the improved triggering delay seen with NAVA may have been exaggerated by the presence of a PS triggering threshold load due to the imposed intrinsic positive end-expiratory pressure. Second, NAVA requires a complex diaphragmatic electromyographic sensor to be placed in the esophagus. The long-term reliability of this device in the “real world” of critically ill patients is largely unknown. Third, it is important to note that NAVA (like PAV) is a mode driven entirely by patient effort. There are no minimum tidal volumes, airway pressures, or ventilatory rate settings. Thus, patients with unstable or unreliable ventilatory drives (e.g., patients with fluctuating sedation/analgesia needs) are at risk for suboptimal ventilatory support. Finally, given the expense and complexity of this approach, it is not clear which patients will really benefit from the improved synchrony. Most patients receiving conventional interactive modes (e.g., PS) can generally be made comfortable if skilled clinicians are monitoring and adjusting the devices appropriately. Despite my concerns, I am intrigued with an approach to interactive ventilatory support that senses directly neural drive and provides flow and pressure in accordance with that drive. Next-generation systems that assure reliability and can be done with simpler, external sensors could conceivably become the standard of care for future interactive ventilatory support. Imposed loading producing extra sedation needs and resulting iatrogenic weaning delays could thus become a thing of the past. Neil MacIntyre, MD Duke University Medical Center Durham, NC REFERENCES

Assessment of Fluid Requirements: Fluid Responsiveness

Fluid administration is the first-line therapy in many patients with circulatory failure, though many patients may not respond to it. Accordingly, it is important to determine the chances of the patient responding to fluids. Assessing fluid responsiveness with the dynamic approach is based on the Frank–Starling relationship: using either heart–lung interactions or a postural change, an acute and transient change in preload is obtained, which results in an increase in stroke volume (SV) in preload-dependent patients, while it remains unaltered in preload-independent patients. Static estimates of preload (pressures, surfaces, and volumes) are unfortunately of limited value since each patient is characterized by his or her own Frank–Starling relationship, and so it is difficult to predict the response to fluids from a given value of preload.