Intra- and inter-individual variation of BIS-index and Entropy during controlled sedation with midazolam/remifentanil and dexmedetomidine/remifentanil in healthy volunteers: an interventional study

INTRODUCTION: We studied intra-individual and inter-individual variability of two online sedation monitors, BIS and Entropy, in volunteers under sedation. METHODS: Ten healthy volunteers were sedated in a stepwise manner with doses of either midazolam and remifentanil or dexmedetomidine and remifentanil. One week later the procedure was repeated with the remaining drug combination. The doses were adjusted to achieve three different sedation levels (Ramsay Scores 2, 3 and 4) and controlled by a computer-driven drug-delivery system to maintain stable plasma concentrations of the drugs. At each level of sedation, BIS and Entropy (response entropy and state entropy) values were recorded for 20 minutes. Baseline recordings were obtained before the sedative medications were administered. RESULTS: Both inter-individual and intra-individual variability increased as the sedation level deepened. Entropy values showed greater variability than BIS(R) values, and the variability was greater during dexmedetomidine/remifentanil sedation than during midazolam/remifentanil sedation. CONCLUSIONS: The large intra-individual and inter-individual variability of BIS and Entropy values in sedated volunteers makes the determination of sedation levels by processed electroencephalogram (EEG) variables impossible. Reports in the literature which draw conclusions based on processed EEG variables obtained from sedated intensive care unit (ICU) patients may be inaccurate due to this variability. TRIAL REGISTRATION: clinicaltrials.gov Nr. NCT00641563.

Hemodynamic variables and mortality in cardiogenic shock: a retrospective cohort study

INTRODUCTION: Despite the key role of hemodynamic goals, there are few data addressing the question as to which hemodynamic variables are associated with outcome or should be targeted in cardiogenic shock patients. The aim of this study was to investigate the association between hemodynamic variables and cardiogenic shock mortality. METHODS: Medical records and the patient data management system of a multidisciplinary intensive care unit (ICU) were reviewed for patients admitted because of cardiogenic shock. In all patients, the hourly variable time integral of hemodynamic variables during the first 24 hours after ICU admission was calculated. If hemodynamic variables were associated with 28-day mortality, the hourly variable time integral of drops below clinically relevant threshold levels was computed. Regression models and receiver operator characteristic analyses were calculated. All statistical models were adjusted for age, admission year, mean catecholamine doses and the Simplified Acute Physiology Score II (excluding hemodynamic counts) in order to account for the influence of age, changes in therapies during the observation period, the severity of cardiovascular failure and the severity of the underlying disease on 28-day mortality. RESULTS: One-hundred and nineteen patients were included. Cardiac index (CI) (P = 0.01) and cardiac power index (CPI) (P = 0.03) were the only hemodynamic variables separately associated with mortality. The hourly time integral of CI drops <3, 2.75 (both P = 0.02) and 2.5 (P = 0.03) L/min/m2 was associated with death but not that of CI drops <2 L/min/m2 or lower thresholds (all P > 0.05). The hourly time integral of CPI drops <0.5-0.8 W/m2 (all P = 0.04) was associated with 28-day mortality but not that of CPI drops <0.4 W/m2 or lower thresholds (all P > 0.05). CONCLUSIONS: During the first 24 hours after intensive care unit admission, CI and CPI are the most important hemodynamic variables separately associated with 28-day mortality in patients with cardiogenic shock. A CI of 3 L/min/m2 and a CPI of 0.8 W/m2 were most predictive of 28-day mortality. Since our results must be considered hypothesis-generating, randomized controlled trials are required to evaluate whether targeting these levels as early resuscitation endpoints can improve mortality in cardiogenic shock.

Increased splanchnic oxygen extraction because of routine nursing procedures

OBJECTIVE: Multiple organ failure is a common complication of acute circulatory and respiratory failure. We hypothesized that therapeutic interventions used routinely in intensive care can interfere with the perfusion of the gut and the liver, and thereby increase the risk of mismatch between oxygen supply and demand. DESIGN: Prospective, observational study. SETTING: Interdisciplinary intensive care unit (ICU) of a university hospital. PATIENTS: Thirty-six patients on mechanical ventilation with acute respiratory or circulatory failure or severe infection were included. INTERVENTIONS: Insertion of a hepatic venous catheter. MEASUREMENTS AND MAIN RESULTS: Daily nursing procedures were recorded. A decrease of >or=5% in hepatic venous oxygen saturation (Sho2) was considered relevant. Observation time was 64 (29-104) hours (median [interquartile range]). The ICU stay was 11 (8-15) days, and hospital mortality was 35%. The number of periods with procedures/patient was 170 (98-268), the number of procedure-related decreases in Sho2 was 29 (13-41), and the number of decreases in Sho2 unrelated to procedures was 9 (4-19). Accordingly, procedure-related Sho2 decreases occurred 11 (7-17) times per day. Median Sho2 decrease during the procedures was 7 (5-10)%, and median increase in the gradient between mixed and hepatic venous oxygen saturation was 6 (4-9)%. Procedures that caused most Sho2 decreases were airway suctioning, assessment of level of sedation, and changing patients' position. Sho2 decreases were associated with small but significant increases in heart rate and intravascular pressures. Maximal Sequential Organ Failure Assessment scores in the ICU correlated with the number of Sho2 decreases (r: .56; p < 0.001) and with the number of procedure-related Sho2 decreases (r: .60; p < 0.001). CONCLUSIONS: Patients are exposed to repeated episodes of impaired splanchnic perfusion during routine nursing procedures. More research is needed to examine the correlation, if any, between nursing procedures and hepatic venous desaturation.

Effects of endotoxin and catecholamines on hepatic mitochondrial respiration

Catecholamines are frequently used in sepsis, but their interaction with mitochondrial function is controversial. We incubated isolated native and endotoxin-exposed swine liver mitochondria with either dopamine, dobutamine, noradrenaline or placebo for 1 h. Mitochondrial State 3 and 4 respiration and their ratio (RCR) were determined for respiratory chain complexes I, II and IV. All catecholamines impaired glutamate-dependent RCR (p = 0.046), predominantly in native mitochondria. Endotoxin incubation alone induced a decrease in glutamate-dependent RCR compared to control samples (p = 0.002). We conclude that catecholamines and endotoxin impair the efficiency of mitochondrial complex I respiration in vitro.

Better conduct of clinical trials: the control group in critical care trials

OBJECTIVE: To review trial design issues related to control groups. DESIGN: Review of the literature with specific reference to critical care trials. MAIN RESULTS AND CONCLUSIONS: Performing randomized controlled trials in the critical care setting presents specific problems: studies include patients with rapidly lethal conditions, the majority of intensive care patients suffer from syndromes rather than from well-definable diseases, the severity of such syndromes cannot be precisely assessed, and the treatment consists of interacting therapies. Interactions between physiology, pathophysiology, and therapies are at best marginally understood and may have a major impact on study design and interpretation of results. Selection of the right control group is crucial for the interpretation and clinical implementation of results. Studies comparing new interventions with current ones or different levels of current treatments have the problem of the necessity of defining "usual care." Usual care controls without any constraints typically include substantial heterogeneity. Constraints in the usual therapy may help to reduce some variation. Inclusion of unrestricted usual care groups may help to enhance safety. Practice misalignment is a novel problem in which patients receive a treatment that is the direct opposite of usual care, and occurs when fixed-dose interventions are used in situations where care is normally titrated. Practice misalignment should be considered in the design and interpretation of studies on titrated therapies.

Left ventricular torsion abnormalities in septic shock and corrective effect of volume loading: a pilot study

BACKGROUND Ventricular torsion is an important component of cardiac function. The effect of septic shock on left ventricular torsion is not known. Because torsion is influenced by changes in preload, we compared the effect of fluid loading on left ventricular torsion in septic shock with the response in matched healthy control subjects. METHODS We assessed left ventricular torsion parameters using transthoracic echocardiography in 11 patients during early septic shock and in 11 age- and sex-matched healthy volunteers before and after rapid volume loading with 250 mL of a Ringer's lactate solution. RESULTS Peak torsion and peak apical rotation were reduced in septic shock (10.2 ± 5.2° and 5.6 ± 5.4°) compared with healthy volunteers (16.3 ± 4.5° and 9.6 ± 1.5°; P = 0.009 and P = 0.006 respectively). Basal rotation was delayed and diastolic untwisting velocity reached its maximum later during diastole in septic shock patients than in healthy volunteers (104 ± 16% vs 111 ± 14% and 13 ± 5% vs 21 ± 10%; P = 0.03 and P = 0.034, respectively). Fluid challenge increased peak torsion in both groups (septic shock, 10.2 ± 5.3° vs 12.6 ± 3.9°; healthy volunteers, 16.3 ± 4.5° vs 18.1 ± 6°; P = 0.01). Fluid challenge increased left ventricular stroke volume in septic shock patients (P = 0.003). CONCLUSIONS Compared with healthy volunteers, left ventricular torsion is impaired in septic shock patients. Fluid loading attenuates torsion abnormalities in parallel with increasing stroke volume. Reduced torsional motion might constitute a relevant component of septic cardiomyopathy, a notion that merits further testing in larger populations.

Different Contribution of Splanchnic Organs to Hyperlactatemia in Fecal Peritonitis and Cardiac Tamponade

Background. Changes in hepatosplanchnic lactate exchange are likely to contribute to hyperlactatemia in sepsis. We hypothesized that septic and cardiogenic shock have different effects on hepatosplanchnic lactate exchange and its contribution to hyperlactatemia. Materials and Methods. 24 anesthetized pigs were randomized to fecal peritonitis (P), cardiac tamponade (CT), and to controls ( per group). Oxygen transport and lactate exchange were calculated during 24 hours. Results. While hepatic lactate influx increased in P and in CT, hepatic lactate uptake remained unchanged in P and decreased in CT. Hepatic lactate efflux contributed 20% (P) and 33% (CT), respectively, to whole body venous efflux. Despite maintained hepatic arterial blood flow, hepatic oxygen extraction did not increase in CT. Conclusions. Whole body venous lactate efflux is of similar magnitude in hyperdynamic sepsis and in cardiogenic shock. Although jejunal mucosal pCO2 gradients are increased, enhanced lactate production from other tissues is more relevant to the increased arterial lactate. Nevertheless, the liver fails to increase hepatic lactate extraction in response to rising hepatic lactate influx, despite maintained hepatic oxygen consumption. In cardiac tamponade, regional, extrasplanchnic lactate production is accompanied by hepatic failure to increase oxygen extraction and net hepatic lactate output, despite maintained hepatic arterial perfusion.

No evidence for a local renin-angiotensin system in liver mitochondria

The circulating, endocrine renin-angiotensin system (RAS) is important to circulatory homeostasis, while ubiquitous tissue and cellular RAS play diverse roles, including metabolic regulation. Indeed, inhibition of RAS is associated with improved cellular oxidative capacity. Recently it has been suggested that an intra-mitochondrial RAS directly impacts on metabolism. Here we sought to rigorously explore this hypothesis. Radiolabelled ligand-binding and unbiased proteomic approaches were applied to purified mitochondrial sub-fractions from rat liver, and the impact of AngII on mitochondrial function assessed. Whilst high-affinity AngII binding sites were found in the mitochondria-associated membrane (MAM) fraction, no RAS components could be detected in purified mitochondria. Moreover, AngII had no effect on the function of isolated mitochondria at physiologically relevant concentrations. We thus found no evidence of endogenous mitochondrial AngII production, and conclude that the effects of AngII on cellular energy metabolism are not mediated through its direct binding to mitochondrial targets.

Effect of sedation level on the prevalence of delirium when assessed with CAM-ICU and ICDSC

Purpose We hypothesized that reduced arousability (Richmond Agitation Sedation Scale, RASS, scores −2 to −3) for any reason during delirium assessment increases the apparent prevalence of delirium in intensive care patients. To test this hypothesis, we assessed delirium using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) and Intensive Care Delirium Screening Checklist (ICDSC) in intensive care patients during sedation stops, and related the findings to the level of sedation, as assessed with RASS score. Methods We assessed delirium in 80 patients with ICU stay longer than 48 h using CAM-ICU and ICDSC during daily sedation stops. Sedation was assessed using RASS. The effect of including patients with a RASS of −2 and −3 during sedation stop (“light to moderate sedation”, eye contact less than 10 s or not at all, respectively) on prevalence of delirium was analyzed. Results A total of 467 patient days were assessed. The proportion of CAM-ICU-positive evaluations decreased from 53 to 31 % (p < 0.001) if assessments from patients at RASS −2/−3 (22 % of all assessments) were excluded. Similarly, the number of positive ICDSC results decreased from 51 to 29 % (p < 0.001). Conclusions Sedation per se can result in positive items of both CAM-ICU and ICDSC, and therefore in a diagnosis of delirium. Consequently, apparent prevalence of delirium is dependent on how a depressed level of consciousness after sedation stop is interpreted (delirium vs persisting sedation). We suggest that any reports on delirium using these assessment tools should be stratified for a sedation score during the assessment.

Mitochondrial function in sepsis

Background The relevance of mitochondrial dysfunction as to pathogenesis of multiple organ dysfunction and failure in sepsis is controversial. This focused review evaluates the evidence for impaired mitochondrial function in sepsis. Design Review of original studies in experimental sepsis animal models and clinical studies on mitochondrial function in sepsis. In vitro studies solely on cells and tissues were excluded. PubMed was searched for articles published between 1964 and July 2012. Results Data from animal experiments (rodents and pigs) and from clinical studies of septic critically ill patients and human volunteers were included. A clear pattern of sepsis-related changes in mitochondrial function is missing in all species. The wide range of sepsis models, length of experiments, presence or absence of fluid resuscitation and methods to measure mitochondrial function may contribute to the contradictory findings. A consistent finding was the high variability of mitochondrial function also in control conditions and between organs. Conclusion Mitochondrial function in sepsis is highly variable, organ specific and changes over the course of sepsis. Patients who will die from sepsis may be more affected than survivors. Nevertheless, the current data from mostly young and otherwise healthy animals does not support the view that mitochondrial dysfunction is the general denominator for multiple organ failure in severe sepsis and septic shock. Whether this is true if underlying comorbidities are present, especially in older patients, should be addressed in further studies.

Hemodynamic assessment of critically ill patients using a miniaturized transesophageal echocardiography probe.

INTRODUCTION Hemodynamic management in intensive care patients guided by blood pressure and flow measurements often do not sufficiently reveal common hemodynamic problems. Trans-esophageal echocardiography (TEE) allows for direct measurement of cardiac volumes and function. A new miniaturized probe for TEE (mTEE) potentially provides a rapid and simplified approach to monitor cardiac function. The aim of the study was to assess the feasibility of hemodynamic monitoring using mTEE in critically ill patients after a brief operator training period. METHODS In the context of the introduction of mTEE in a large ICU, 14 ICU staff specialists with no previous TEE experience received six hours of training as mTEE operators. The feasibility of mTEE and the quality of the obtained hemodynamic information were assessed. Three standard views were acquired in hemodynamically unstable patients: 1) for assessment of left ventricular function (LV) fractional area change (FAC) was obtained from a trans-gastric mid-esophageal short axis view, 2) right ventricular (RV) size was obtained from mid-esophageal four chamber view, and 3) superior vena cava collapsibility for detection of hypovolemia was assessed from mid-esophageal ascending aortic short axis view. Off-line blinded assessment by an expert cardiologist was considered as a reference. Inter-rater agreement was assessed using Chi-square tests or correlation analysis as appropriate. RESULTS In 55 patients, 148 mTEE examinations were performed. Acquisition of loops in sufficient quality was possible in 110 examinations for trans-gastric mid-esophageal short axis, 118 examinations for mid-esophageal four chamber and 125 examinations for mid-esophageal ascending aortic short axis view. Inter-rater agreement (Kappa) between ICU mTEE operators and the reference was 0.62 for estimates of LV function, 0.65 for RV dilatation, 0.76 for hypovolemia and 0.77 for occurrence of pericardial effusion (all P < 0.0001). There was a significant correlation between the FAC measured by ICU operators and the reference (r = 0.794, P (one-tailed) < 0.0001). CONCLUSIONS Echocardiographic examinations using mTEE after brief bed-side training were feasible and of sufficient quality in a majority of examined ICU patients with good inter-rater reliability between mTEE operators and an expert cardiologist. Further studies are required to assess the impact of hemodynamic monitoring by mTEE on relevant patient outcomes.