Hemodynamic support in septic shock.
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Blood Transfusion↗
Biomedical subjects
J L Vincent
Publications and source records attributed to J L Vincent.
Doctors' perceptions of the effects of interventions tested in prospective, randomised, controlled, clinical trials: results of a survey of ICU physicians.
OBJECTIVES: To establish a list of therapeutic interventions considered by intensive care unit (ICU) physicians to have been tested by prospective, randomised, controlled clinical trials (RCTs) in critically ill patients, and to survey the perceptions of the same physicians on the therapeutic effect of these interventions as evaluated by RCT. DESIGN AND SETTING: Self-applied questionnaire in an International Symposium of Intensive Care and Emergency Medicine, Brussels, Belgium. PARTICIPANTS: All 3250 registrants at the symposium. MEASUREMENTS AND RESULTS: There were 527 questionnaires completed, and 446 were suitable for analysis. Respondents were asked to list the therapeutic interventions used in intensive care medicine which they believed have been shown by RCTs to improve survival. Using a 5-point Likert scale, respondents were then asked to rate their assessment of the effectiveness of each intervention they listed and, using a 3-point scale, to select their level of confidence in those assessments. A total of 512 interventions were identified by the respondents as having been tested by RCT. Analysing the 42 interventions quoted more than 12 times, 31 were believed by the respondents to have been shown to have a beneficial effect, and 11 to have a harmful effect. Many of the interventions noted have not in fact been subjected to RCT. CONCLUSIONS: Many interventions that have not been tested by RCT were believed to have been tested; conversely, some interventions actually tested by RCT were not mentioned. Few interventions used in the ICU have actually been shown by RCT to have a positive effect on outcome.
Adult↗
A multi-centre, double-blind, placebo-controlled study of liposomal prostaglandin E1 (TLC C-53) in patients with acute respiratory distress syndrome.
OBJECTIVE: To evaluate the safety of liposomal PGE1 (TLC C-53) in patients with acute respiratory distress syndrome (ARDS), and determine its efficacy in improving oxygenation and reducing ventilator dependency. DESIGN: A multi-centre, randomized, double-blind, placebo-controlled clinical study. SETTING: Thirty-one hospitals in six European countries. PATIENTS: One hundred two patients with ARDS. INTERVENTIONS: Patients were randomized in a 2:1 ratio to receive infusions of either the study drug TLC C-53 or placebo. Infusions were given over 60 min every 6 h for 7 days. The dose of study drug started at 0.6 microg/kg per h, rising over 24 h to a maximum dose of 1.8 microg/kg per h. MEASUREMENTS AND MAIN RESULTS: Seventy patients received the study drug and 32 placebo. Sixty-nine patients (47 treatment, 22 placebo) completed the study protocol. Patients were monitored for changes in the PaO2/FIO2 ratio, changes in lung compliance, time to off-ventilator and 28-day mortality, in addition to basic haematological and haemodynamic parameters. There were no significant differences in demographics and baseline characteristics between the two groups. There were no differences in the time to off-ventilation (16 days with treatment, 16.6 days with placebo, p=0.94) or in 28-day mortality (30% with treatment, 28% with placebo, p=0.78). There was a difference in the time to achieve a PaO2/FIO2 ratio above 300 in favour of TLC C-53 (10.3 versus 26.5 days) but this was not statistically significant (p=0.23). CONCLUSIONS: TLC C-53 was generally well-tolerated but failed to reduce mortality or duration of mechanical ventilation.
Aged↗
Ceftazidime- and imipenem-induced endotoxin release during treatment of gram-negative infections.
To determine whether ceftazidime and imipenem, which target two different penicillin-binding proteins, result in different amounts of endotoxin and cytokine release in patients with gram-negative infection, plasma endotoxin, interleukin-6, and tumor necrosis factor alpha were measured during the first 24 h of antibiotic therapy in 27 patients with gram-negative infection who had been randomized to receive either ceftazidime 2 g t.i.d. (n=12) or imipenem/cilastatin 1 g t.i.d. (n=15). The source of infection was the digestive tract (n=13), the urinary tract (n=5), the respiratory tract (n=2), soft tissue (n=2), i.v. line (n=2), or other (n=3). After the first antibiotic injection, a significant increase in the median concentration of plasma interleukin-6 and plasma tumor necrosis factor alpha was noted, without significant differences related to the antibiotic administered. Antibiotic-induced endotoxemia was detectable in nine patients (including 7 with bacteremia). In conclusion, ceftazidime and imipenem had similar effects on endotoxin and cytokine release during the treatment of gram-negative infections.
Bacteremia↗
Inotrope/vasopressor support in sepsis-induced organ hypoperfusion.
Vasoactive agents are commonly required in the management of septic shock not only to restore a sufficient tissue perfusion pressure but also to increase blood flow and oxygen delivery to the organs. Importantly, vasoactive agents are no substitute for fluid therapy. Defining end points for therapy remains difficult. These should be, above all, clinical. Even though the gut may play an important role in the development of multiple organ failure, the use of gastric tonometry to guide therapy cannot be recommended at this time. Study of the microcirculation at the bedside with orthogonal polarization spectral imaging may be helpful in the future. Adrenergic agents are the preferred agents for hemodynamic stabilization. Dopamine and norepinephrine are the drugs of choice to increase arterial pressure. Dobutamine remains the agent of choice to increase blood flow to the organs, including the gut and the kidneys. Many questions remain unanswered with respect to optimal hemodynamic management of septic shock.
Journal Article↗
Sedative and analgesic practice in the intensive care unit: the results of a European survey.
Sedation and analgesia are important aspects of patient care on the intensive care unit (ICU), yet relatively little information is available on common sedative and analgesic practice. We sought to assess international differences in the prescription of sedative and analgesic drugs in western European ICUs by means of a short, self-administered questionnaire. Six hundred and forty-seven intensive care physicians from 16 western European countries replied to the questionnaire. Midazolam was used as a sedative often or always by 63% of respondents and propofol by 35%. There were considerable international variations, with midazolam being preferred over propofol in France, Germany, the Netherlands, Norway and Austria. For analgesia, the drugs most commonly used were morphine (33%), fentanyl (33%) and sufentanil (24%). Morphine was preferred over fentanyl and sufentanil in Norway, UK and Ireland, Sweden, Switzerland, the Netherlands, and Spain and Portugal. Fentanyl was preferred in France, Germany and Italy. Sufentanil was preferred in Belgium and Luxemburg and in Austria. Multivariate analysis showed that the combination of midazolam with fentanyl was most often used in France; propofol with morphine in Sweden, the UK and Ireland, and Switzerland; midazolam with morphine in Norway; and propofol with sufentanil in Belgium and Luxemburg, Germany and Italy. The use of a sedation scale varied from 72% in the UK and Ireland to 18% in Austria. When used, the most common sedation scale was the Ramsay scale. This study demonstrates substantial international differences in sedative and analgesic practices in western European ICUs.
Analgesia↗
The hepatosplanchnic area is not a common source of lactate in patients with severe sepsis.
OBJECTIVE: To investigate the role of the splanchnic region in the hyperlactatemia of septic patients. DESIGN: Prospective, observational study. SETTING: Thirty-one-bed mixed medicosurgical intensive care unit. PATIENTS: Ninety invasively monitored and mechanically ventilated patients with severe sepsis. MEASUREMENTS AND MAIN RESULTS: Splanchnic lactate balance was measured in all patients. Splanchnic blood flow was determined by using the primed continuous indocyanine green infusion technique in 69 patients. In 71 patients, gastric mucosal Pco2 and the Pco2 gap (the difference between gastric and arterial Pco2) also were determined by using gas tonometry with an automated gas analyzer. In each patient, arterial, mixed-venous, and hepatic venous blood samples were obtained to determine hemoglobin oxygen saturations and lactate concentrations. Arterial and hepatic venous lactate concentrations were determined in triplicate and were averaged, and the arterial hepatic venous difference in lactate and lactate consumption were calculated. The splanchnic region produced lactate in only six of the 90 patients. Mean arterial pressure, cardiac index, arterial lactate, hepatic venous oxygen saturation, and catecholamine use were similar in the six patients with splanchnic lactate production and in the 84 others. The arterial hepatic venous differences in lactate and splanchnic lactate consumption were related directly to arterial lactate concentrations (y = 0.073x + 0.209, r(2) =.06, p <.05, and y = 0.06x + 0.183, r(2) =.08, p <.05, respectively) but were not related to Pco2 gap, to the gradient between mixed-venous and hepatic venous oxygen saturations, or to bilirubin concentrations. CONCLUSIONS: Splanchnic lactate release is uncommon in septic patients, even when hyperlactatemia is severe.
APACHE↗
Cultural differences in end-of-life care.
The exact time of death for many intensive care unit patients is increasingly preceded by an end-of-life decision. Such decisions are fraught with ethical, religious, moral, cultural, and legal difficulties. Key questions surrounding this issue include the difference between withholding and withdrawing, when to withhold/withdraw, who should be involved in the decision-making process, what are the relevant legal precedents, etc. Cultural variations in attitude to such issues are perhaps expected between continents, but key differences also exist on a more local basis, for example, among the countries of Europe. Physicians need to be aware of the potential cultural differences in the attitudes not only of their colleagues, but also of their patients and families. Open discussion of these issues and some change in our attitude toward life and death are needed to enable such patients to have a pain-free, dignified death.
Attitude to Death↗
Effects of alpha - and beta -adrenergic stimulation on hepatosplanchnic perfusion and oxygen extraction in endotoxic shock.
OBJECTIVE: To examine the effects of adrenergic stimulation on hepatosplanchnic perfusion, oxygen extraction, and tumor necrosis factor-alpha production during endotoxic shock. DESIGN: In vivo, prospective, randomized, controlled, repeated-measures, experimental study. SETTING: Experimental physiology laboratory in a university teaching hospital. SUBJECTS: Twenty-one anesthetized and mechanically ventilated dogs. INTERVENTIONS: An intrapericardial catheter was positioned. Catheters for blood sampling were inserted into the right femoral artery, hepatic vein, portal vein, and pulmonary artery. Ultrasonic flow probes were placed around the portal vein, the hepatic artery, the mesenteric artery, the left renal artery, and the left femoral artery. Animals received 2 mg/kg of Escherichia coli endotoxin, followed by fluid resuscitation. Seven dogs received intravenous isoproterenol (0.1 microg/kg x min(-1)), seven received phenylephrine (1 microg/kg x min(-1)), and seven served as controls. Thirty minutes later, cardiac tamponade was introduced to study organ perfusion and tissue oxygen extraction capabilities. MAIN RESULTS: The isoproterenol group had a higher cardiac index and stroke index and lower systemic vascular resistance than the other groups. The phenylephrine group had a higher arterial pressure but a lower cardiac index than the isoproterenol group. The isoproterenol group had a higher hepatic artery blood flow than the other groups and a higher portal and mesenteric flow than the control group. Liver and gut mucosal blood flow was greater in the isoproterenol than in the phenylephrine group. The isoproterenol group had a lower global critical oxygen delivery than the other groups (8.8 +/- 1.3 vs. 13.1 +/- 2.0 (control) and 11.8 +/- 3.3 mL/kg x min(-1) (phenylephrine); both p < .05) and a higher liver critical oxygen extraction ratio than the control group. Isoproterenol tended to attenuate, but phenylephrine significantly increased, blood tumor necrosis factor levels. CONCLUSIONS: During endotoxic shock, beta-stimulation can improve hepatosplanchnic perfusion and enhance tissue oxygen extraction capabilities, whereas alpha-stimulation does not. In addition, alpha-adrenergic stimulation can increase tumor necrosis factor levels.
Adrenergic alpha-Agonists↗
Randomized, placebo-controlled trial of the anti-tumor necrosis factor antibody fragment afelimomab in hyperinflammatory response during severe sepsis: The RAMSES Study.
OBJECTIVE: This study investigated whether treatment with the anti-tumor necrosis factor-alpha monoclonal antibody afelimomab would improve survival in septic patients with serum interleukin (IL)-6 concentrations of >1000 pg/mL. DESIGN: Multicenter, double-blind, randomized, placebo-controlled study. SETTING: Eighty-four intensive care units in academic medical centers in Europe and Israel. PATIENTS: A total of 944 septic patients were screened and stratified by the results of a rapid qualitative immunostrip test for serum IL-6 concentrations. Patients with a positive test kit result indicating IL-6 concentrations of >1000 pg/mL were randomized to receive either afelimomab (n = 224) or placebo (n = 222). Patients with a negative IL-6 test (n = 498) were not randomized and were followed up for 28 days. INTERVENTIONS: Treatment consisted of 15-min infusions of 1 mg/kg afelimomab or matching placebo every 8 hrs for 3 days. Standard surgical and intensive care therapy was otherwise delivered. MEASUREMENTS AND MAIN RESULTS: The study was terminated prematurely after an interim analysis estimated that the primary efficacy end points would not be met. The 28-day mortality rate in the nonrandomized patients (39.6%, 197 of 498) was significantly lower (p <.001) than that found in the randomized patients (55.8%, 249 of 446). The mortality rates in the IL-6 test kit positive patients randomized to afelimomab and placebo were similar, 54.0% (121 of 224) vs. 57.7% (128 of 222), respectively. Treatment with afelimomab was not associated with any particular adverse events. CONCLUSIONS: The IL-6 immunostrip test identified two distinct sepsis populations with significantly different mortality rates. A small (3.7%) absolute reduction in mortality rate was found in the afelimomab-treated patients. The treatment difference did not reach statistical significance.
APACHE↗
Clinical expert round table discussion (session 5) at the Margaux Conference on Critical Illness: outcomes of clinical trials in sepsis: lessons learned.
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Anti-Inflammatory Agents↗
Effects of dobutamine on hepato-splanchnic hemodynamics in an experimental model of hyperdynamic endotoxic shock.
Dobutamine infusion has been proposed to increase splanchnic blood flow in septic conditions, but its' effects on liver blood flow and metabolism have not been well defined. We investigated the effects of dobutamine on liver blood flow, metabolism, and pathology in a canine hyperdynamic endotoxic shock model. Twenty-one dogs were anesthetized and paralyzed. After the administration of 2 mg/kg endotoxin, normal saline was infused to restore the pulmonary artery-occluded pressure to 10 mmHg. The dogs were then randomized to receive fluids either alone (n = 7) or combined with a dobutamine infusion at a rate of 5 (n = 7) or 10 microg/kg per min (n = 7). After initial fluid resuscitation, cardiac index (CI) increased from 152+/-48 to 386+/-97 mL/kg per min (P < 0.01) and then slightly decreased with time in the control group, but further increased to 458+/-54 mL/kg per min (P< 0.05) and remained elevated in the group treated with 5 microg/kg per min of dobutamine. Portal vein and hepatic arterial blood flows followed a similar course and increased with fluid resuscitation. Both decreased with time in the control group, but further increased in the dobutamine-treated animals. Liver oxygen delivery (DO2liv) increased with fluids from 2.2+/-2.4 to 3.8+/-1.9 mL/kg per min (P < 0.01) and further increased in the dobutamine-treated animals to 4.1+/-1.2 mL/kg per min. This was associated with an increase in liver oxygen uptake from 1.6+/-1.6 to 2.9+/-1.1 mL/kg per min with fluid resuscitation and a further increase to 4.3+/-1.5 mL/kg per min with dobutamine administration. Lactate consumption and hepatic vein oxygen saturation increased with initial fluid resuscitation and then decreased with time in the control group, but not in the dobutamine-treated animals. Increasing the dose of dobutamine to 10 microg/kg per min did not alter this response. At the end of the experiment, liver tissue samples were obtained for microscopic studies. The histological lesions seen in the control group were unaffected by dobutamine. In conclusion, dobutamine increases liver blood flow and metabolism, but does not affect microscopic findings in this hyperdynamic endotoxic shock model.
Adrenergic beta-Agonists↗
Effects of nucleoside transport inhibition on hepatosplanchnic perfusion, oxygen extraction capabilities, and TNF release during acute endotoxic shock.
We explored the effects of the nucleoside transport inhibitor draflazine on regional blood flow, O2 extraction capabilities, and tumor necrosis factor (TNF) release in acute endotoxic shock. Fourteen anesthetized and mechanically ventilated dogs received 2 mg/kg of Escherichia coli endotoxin and were divided into two groups. Seven dogs received 0.1 mg/kg of draflazine 30 min before endotoxin, and 7 dogs served as a control group. Draflazine decreased arterial pressure without influencing cardiac index. Mesenteric and portal blood flow and ileum mucosal perfusion increased, but renal blood flow dramatically decreased. After endotoxemia, the draflazine-treated dogs had a lesser fall in cardiac index, filling pressures, and left ventricular stroke work index, and a lesser increase in pulmonary vascular resistance. After fluid resuscitation, they had a consistently lower renal blood flow and ileum mucosal perfusion, but a higher mixed venous and hepatic oxygen saturation and arterial pH than the control group. When cardiac index was reduced by tamponade to study the O2 extraction capabilities, renal blood flow and ileum mucosal perfusion remained lower in the draflazine group. Draflazine did not influence whole-body O2 extraction capabilities, but it delayed the occurrence of liver O2 supply dependency as indicated by a significantly lower liver DO2crit (27.7 +/- 3.9 vs. 43.3 +/- 10.8 mL/min) and a higher O2ERcrit (62.7 +/- 9.5 vs. 42.5 +/- 7.1%) than controls (both P< 0.05). On the other hand, draflazine increased intestinal DO2crit (42.4 +/- 15.4 vs. 27.7 +/- 6.5 mL/min, P < 0.05) compared to the control group. TNF levels remained higher in the draflazine group than in the control group, particularly 3 and 4 h after endotoxin administration. We conclude that nucleoside transport inhibition with draflazine does not alter global and hepatosplanchnic hemodynamics but may decrease gut mucosal perfusion and renal blood flow. However, this intervention can improve liver O2 extraction capabilities in acute endotoxic shock.
Animals↗
Normovolemic hemodilution improves oxygen extraction capabilities in endotoxic shock.
We studied the effects of normovolemic hemodilution on tissue oxygen extraction capabilities in a canine model of endotoxic shock. Eighteen anesthetized and mechanically ventilated dogs underwent normovolemic hemodilution with 6% hydroxyethyl starch solution to reach hematocrit (Hct) levels around 40, 30, or 20% before the administration of 2 mg/kg of Escherichia coli endotoxin. Cardiac tamponade was then induced by repeated injections of normal saline into the pericardial sac to reduce cardiac output and study whole body oxygen extraction capabilities. Whole body critical oxygen delivery was lower in the Hct 20% and 30% groups (8.4 +/- 0.4 and 10.4 +/- 0.7 ml. kg(-1). min(-1), respectively) than in the Hct 40% group (12.8 +/- 0.8 ml. kg(-1). min(-1)) (both P < 0.005). The whole body critical oxygen extraction ratio was higher in the Hct 30% and 20% groups (49.1 +/- 8.2 and 55.2 +/- 4.6%, respectively) than in the Hct 40% group (37.1 +/- 4.4 %) (both P < 0.05). Liver critical oxygen extraction ratio was also higher in the Hct 30% and 20% groups than in the Hct 40% group. The arterial lactate concentrations and the gradient between ileum mucosal PCO(2) and arterial PCO(2) were lower in the Hct 20% and 30% groups than in the Hct 40% group. We conclude that, during an acute reduction in blood flow during endotoxic shock in dogs, normovolemic hemodilution is associated with improved tissue perfusion and increased oxygen extraction capabilities.
Animals↗
Incidence of acute renal failure in the intensive care unit.
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Acute Kidney Injury↗
Ventilator associated pneumonia: risk factors and preventive measures.
Ventilator-associated pneumonia (VAP) is a common nosocomial infection associated with considerable morbidity and mortality. Various risk factors for VAP have been identified and include the duration of ICU stay and of mechanical ventilation, a diagnosis of trauma, and severity of illness. Knowledge of these factors can promote early diagnosis and hence treatment. In addition to simple, but very effective, basic hygiene, different preventative strategies have been suggested, and can be divided into those that aim to limit airway colonization, and those that improve host defense mechanisms. Of the former, non-invasive ventilation is effective but not always applicable or available, nursing the patient in the semi-recumbent position is also associated with a reduced incidence of VAP but carries its own problems, stress ulcer prophylaxis remains controversial, and selective digestive decontamination is probably only relevant to certain subgroups of patients. Methods to improve host defense include early nutrition. Immunostimulatory therapies, such as interferon and granulocyte colony stimulating factor, require further research to confirm their place in the prevention or management of VAP.
Anti-Bacterial Agents↗
Microvascular endothelial dysfunction: a renewed appreciation of sepsis pathophysiology.
Severe sepsis, defined as sepsis associated with acute organ dysfunction, results from a generalized inflammatory and procoagulant host response to infection. Coagulopathy in severe sepsis is commonly associated with multiple organ dysfunction, and often results in death. The molecule that is central to these effects is thrombin, although it may also have anticoagulant and antithrombotic effects through the activation of Protein C and induction of prostacyclin. In recent years, it has been recognized that chemicals produced by endothelial cells play a key role in the pathogenesis of sepsis. Thrombomodulin on endothelial cells coverts Protein C to Activated Protein C, which has important antithrombotic, profibrinolytic and anti-inflammatory properties. A number of studies have shown that Protein C levels are reduced in patients with severe infection, or even in inflammatory states without infection. Because coagulopathy is associated with high mortality rates, and animal studies have indicated that therapeutic intervention may result in improved outcomes, it was rational to initiate clinical studies.
Antithrombin III↗
Predictive value of microalbuminuria in medical ICU patients: results of a pilot study.
STUDY OBJECTIVES: To evaluate the predictive value of microalbuminuria in the development of acute respiratory failure (ARF) and multiple organ failure (MOF) in ICU patients. DESIGN: Prospective, observational study. SETTING: A 31-bed, mixed medicosurgical ICU in a university hospital. PATIENTS: All adult medical patients admitted to the ICU over a 2-month period, except those receiving nephrotoxic drugs, or those with urologic trauma resulting in frank hematuria or urinary infection, or with existing chronic renal disease (serum creatinine level > or 2.0 mg/dL). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Urinary samples for microalbumin measurement were collected at hospital admission and at 8, 24, 48, 72, 96, and 120 h after hospital admission. The severity of illness was assessed by the APACHE (acute physiology and chronic health evaluation) II score calculated on the first ICU day, and the degree of organ dysfunction was assessed using the sequential organ failure assessment (SOFA) score. Acute respiratory failure (ARF) was defined as a SOFA respiratory score > or = 3. Patients were separated into two groups according to the trend in microalbuminuria levels over the first 48 h: patients in group 1 had increasing microalbuminuria levels, and patients in group 2 had decreasing microalbuminuria levels. Group 1 included 14 patients in whom microalbuminuria levels increased from 5.2 +/- 2.0 to 19.0 +/- 3.0 mg/dL. Group 2 included 26 patients in whom microalbuminuria levels decreased from 16.4 +/- 4.0 to 7.8 +/- 3.0 mg/dL. The hospital mortality rate was 43% in group 1 and 15% in group 2 (p < 0.05). The APACHE II score and the SOFA score were higher in group 1 than in group 2. The negative predictive value of increasing microalbuminuria was 100% for the development of ARF and 96% for MOF; the positive predictive value of increasing microalbuminuria was 57% for the development of ARF and 50% for MOF. CONCLUSIONS: Accurate identification of patients destined for ARF and MOF development may enable therapeutic strategies to be applied to limit the disease process. Trend analysis of urinary albumin excretion over the first 48 h of an ICU admission may provide a useful means of identifying such patients. Additional studies need to be performed in larger, mixed patient populations to confirm these findings.
APACHE↗