Peri-operative adrenocortical response to low-dose (1 microg) ACTH and relation to postoperative complications in patients undergoing elective abdominal surgery

BACKGROUND: To test the hypothesis that reduced responsiveness to adrenocorticotropin (ACTH) stimulation before elective major abdominal surgery is associated with an increased incidence of postoperative complications. METHODS: A low-dose (1 microg) ACTH test was performed the day before surgery, during the operation, on the first postoperative day, and before discharge from the hospital in 77 patients undergoing major abdominal surgery (age 62 [47;69] yrs [median, quartiles]; 30 female). Thirty-one patients undergoing minor, non-abdominal surgery (mostly inguinal hernia repair) (age 57 [40;66] yrs; 14 female) served as controls with minor surgical stress. A stimulated plasma cortisol concentration >or=500 nmol/l or an increment of >or=200 nmol/l in response to 1 microg ACTH was defined as normal. Scores for surgical stress and comprehensive risk, postoperative complications, and length of hospital stay (LOS) were assessed. RESULTS: On the day before major abdominal surgery, basal and stimulated plasma cortisol were 242 (165;299) nmol/l and 497 (404;568) nmol/l, respectively. Eighteen (23%) patients had an abnormal ACTH test, and 7 of these (39%) had complications versus 25 (42%) of the 59 patients with normal ACTH tests (P = .992). Surgical stress, comprehensive risk, and intra- and postoperative basal cortisol levels were higher and the response to ACTH stimulation smaller in patients with major abdominal compared to minor surgery. The peri-operative course of ACTH responses was not associated with complications or LOS in abdominal surgery patients. CONCLUSION: In patients scheduled for abdominal surgery, pre-operatively reduced adrenal response to stimulation with 1 microg ACTH is common but not associated with postoperative complications.

Hypoxia inducible factor-1 alpha induction by tumour necrosis factor-alpha, but not by toll-like receptor agonists, modulates cellular respiration in cultured human hepatocytes

BACKGROUND/AIMS: Genes encoding for some of the mitochondrial proteins are under the control of the transcriptional factor hypoxia inducible factor-1 alpha (HIF-1 alpha), which can accumulate under normoxic conditions in inflammatory states. The aim of this study was to evaluate the effects of cobalt chloride (CoCl(2), a hypoxia mimicking agent), tumour necrosis factor-alpha (TNF-alpha) and toll-like receptor (TLR) -2, -3 and -4 agonists on HIF-1 alpha accumulation, and further on HIF-1 alpha-mediated modulation of mitochondrial respiration in cultured human hepatocytes. METHODS: The human hepatoma cell line HepG2 was used in this study. Cells were treated with CoCl(2), TNF-alpha and TLR-2, -3 and -4 agonists. HIF-1 alpha was determined by Western blotting and mitochondrial respiration in stimulated cells by high-resolution respirometry. RESULTS: CoCl(2), TNF-alpha and TLR agonists induced the expression of HIF-1 alpha in a time-dependent fashion. TNF-alpha and CoCl(2), but not TLR agonists, induced a reduction in complex I-, II- and IV-dependent mitochondrial oxygen consumption. TNF-alpha-associated reduction of cellular oxygen consumption was abolished through inhibition of HIF-1 alpha activity by chetomin (CTM). Pretreatment with cyclosporine A prevented CoCl(2)-induced reduction of complex I- and II-dependent mitochondrial oxygen consumption and TNF-alpha-induced reduction of complex-I-dependent respiration, implicating the involvement of the mitochondrial permeability transition pore openings. TNF-alpha and TLR-2, -3 and -4 agonists induced the expression of vascular endothelial growth factor, which was partially abolished by the blockage of HIF-1 alpha with CTM. CONCLUSIONS: The data suggest that HIF-1 alpha modulates mitochondrial respiration during CoCl(2) and TNF-alpha stimulation, whereas it has no effect when induced with TLR-2, -3 and -4 agonists.

Thromboelastometry for the assessment of coagulation abnormalities in early and established adult sepsis: a prospective cohort study

INTRODUCTION: The inflammatory response to an invading pathogen in sepsis leads to complex alterations in hemostasis by dysregulation of procoagulant and anticoagulant factors. Recent treatment options to correct these abnormalities in patients with sepsis and organ dysfunction have yielded conflicting results. Using thromboelastometry (ROTEM(R)), we assessed the course of hemostatic alterations in patients with sepsis and related these alterations to the severity of organ dysfunction. METHODS: This prospective cohort study included 30 consecutive critically ill patients with sepsis admitted to a 30-bed multidisciplinary intensive care unit (ICU). Hemostasis was analyzed with routine clotting tests as well as thromboelastometry every 12 hours for the first 48 hours, and at discharge from the ICU. Organ dysfunction was quantified using the Sequential Organ Failure Assessment (SOFA) score. RESULTS: Simplified Acute Physiology Score II and SOFA scores at ICU admission were 52 +/- 15 and 9 +/- 4, respectively. During the ICU stay the clotting time decreased from 65 +/- 8 seconds to 57 +/- 5 seconds (P = 0.021) and clot formation time (CFT) from 97 +/- 63 seconds to 63 +/- 31 seconds (P = 0.017), whereas maximal clot firmness (MCF) increased from 62 +/- 11 mm to 67 +/- 9 mm (P = 0.035). Classification by SOFA score revealed that CFT was slower (P = 0.017) and MCF weaker (P = 0.005) in patients with more severe organ failure (SOFA >or= 10, CFT 125 +/- 76 seconds, and MCF 57 +/- 11 mm) as compared with patients who had lower SOFA scores (SOFA <10, CFT 69 +/- 27, and MCF 68 +/- 8). Along with increasing coagulation factor activity, the initially increased International Normalized Ratio (INR) and prolonged activated partial thromboplastin time (aPTT) corrected over time. CONCLUSIONS: Key variables of ROTEM(R) remained within the reference ranges during the phase of critical illness in this cohort of patients with severe sepsis and septic shock without bleeding complications. Improved organ dysfunction upon discharge from the ICU was associated with shortened coagulation time, accelerated clot formation, and increased firmness of the formed blood clot when compared with values on admission. With increased severity of illness, changes of ROTEM(R) variables were more pronounced.

Arterial blood pressure during early sepsis and outcome

OBJECTIVE: To evaluate the association between arterial blood pressure (ABP) during the first 24 h and mortality in sepsis. DESIGN: Retrospective cohort study. SETTING: Multidisciplinary intensive care unit (ICU). PATIENTS AND PARTICIPANTS: A total of 274 septic patients. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Hemodynamic, and laboratory parameters were extracted from a PDMS database. The hourly time integral of ABP drops below clinically relevant systolic arterial pressure (SAP), mean arterial pressure (MAP), and mean perfusion pressure (MPP = MAP - central venous pressure) levels was calculated for the first 24 h after ICU admission and compared with 28-day-mortality. Binary and linear regression models (adjusted for SAPS II as a measure of disease severity), and a receiver operating characteristic (ROC) analysis were applied. The areas under the ROC curve were largest for the hourly time integrals of ABP drops below MAP 60 mmHg (0.779 vs. 0.764 for ABP drops below MAP 55 mmHg; P < or = 0.01) and MPP 45 mmHg. No association between the hourly time integrals of ABP drops below certain SAP levels and mortality was detected. One or more episodes of MAP < 60 mmHg increased the risk of death by 2.96 (CI 95%, 1.06-10.36, P = 0.04). The area under the ROC curve to predict the need for renal replacement therapy was highest for the hourly time integral of ABP drops below MAP 75 mmHg. CONCLUSIONS: A MAP level > or = 60 mmHg may be as safe as higher MAP levels during the first 24 h of ICU therapy in septic patients. A higher MAP may be required to maintain kidney function.

Association of arterial blood pressure and vasopressor load with septic shock mortality: a post hoc analysis of a multicenter trial

INTRODUCTION: It is unclear to which level mean arterial blood pressure (MAP) should be increased during septic shock in order to improve outcome. In this study we investigated the association between MAP values of 70 mmHg or higher, vasopressor load, 28-day mortality and disease-related events in septic shock. METHODS: This is a post hoc analysis of data of the control group of a multicenter trial and includes 290 septic shock patients in whom a mean MAP > or = 70 mmHg could be maintained during shock. Demographic and clinical data, MAP, vasopressor requirements during the shock period, disease-related events and 28-day mortality were documented. Logistic regression models adjusted for the geographic region of the study center, age, presence of chronic arterial hypertension, simplified acute physiology score (SAPS) II and the mean vasopressor load during the shock period was calculated to investigate the association between MAP or MAP quartiles > or = 70 mmHg and mortality or the frequency and occurrence of disease-related events. RESULTS: There was no association between MAP or MAP quartiles and mortality or the occurrence of disease-related events. These associations were not influenced by age or pre-existent arterial hypertension (all P > 0.05). The mean vasopressor load was associated with mortality (relative risk (RR), 1.83; confidence interval (CI) 95%, 1.4-2.38; P < 0.001), the number of disease-related events (P < 0.001) and the occurrence of acute circulatory failure (RR, 1.64; CI 95%, 1.28-2.11; P < 0.001), metabolic acidosis (RR, 1.79; CI 95%, 1.38-2.32; P < 0.001), renal failure (RR, 1.49; CI 95%, 1.17-1.89; P = 0.001) and thrombocytopenia (RR, 1.33; CI 95%, 1.06-1.68; P = 0.01). CONCLUSIONS: MAP levels of 70 mmHg or higher do not appear to be associated with improved survival in septic shock. Elevating MAP >70 mmHg by augmenting vasopressor dosages may increase mortality. Future trials are needed to identify the lowest acceptable MAP level to ensure tissue perfusion and avoid unnecessary high catecholamine infusions.

Intensive care medicine in Mongolia's 3 largest cities: outlining the needs

PURPOSE: To evaluate intensive care resources, support, and personnel available in Mongolia's 3 largest cities. MATERIALS AND METHODS: This prospective study was performed as a questionnaire-based survey evaluating intensive care units (ICUs) in Mongolia's 3 main cities. RESULTS: Twenty-one of 31 ICUs participated in the survey. The median number of beds per ICU was 7 (interquartile ranges, 6-10) with 0.7 (0.6-0.9) physicians and 1.5 (0.6-1.8) nurses per bed. A 24-hour physician service was available in 61.9% of the participating ICUs. A median number of 359 patients (250-500) with an average age of 39 (30-49) years were treated annually. Oxygen was available in all ICUs, but only for 60% (17-75) of beds. Pressurized air was available in 33% of the ICUs for 24% (0-15) of beds. Of the ICUs, 52.4% had a lung ventilator serving 20% (0-23) of beds. The most common admission diagnoses were sepsis, stroke, cardiac disease, postoperative or postpartum hemorrhage, and intoxication. Availability of medical equipment, disposables, and drugs was inadequate in all ICUs. CONCLUSIONS: Intensive care medicine in Mongolia's 3 largest cities is an under-resourced and underdeveloped medical specialty. The main problems encountered are insufficient training of staff as well as lack of medical equipment, disposables, and drugs.

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.

Treatment of acute renal failure in the intensive care unit: lower costs by intermittent dialysis than continuous venovenous hemodiafiltration

Intermittent and continuous renal replacement therapies (RRTs) are available for the treatment of acute renal failure (ARF) in the intensive care unit (ICU). Although at present there are no adequately powered survival studies, available data suggest that both methods are equal with respect to patient outcome. Therefore, cost comparison between techniques is important for selecting the modality. Expenditures were prospectively assessed as a secondary end point during a controlled, randomized trial comparing intermittent hemodialysis (IHD) with continuous venovenous hemodiafiltration (CVVHDF). The outcome of the primary end points of this trial, that is, ICU and in-hospital mortality, has been previously published. One hundred twenty-five patients from a Swiss university hospital ICU were randomized either to CVVHDF or IHD. Out of these, 42 (CVVHDF) and 34 (IHD) were available for cost analysis. Patients' characteristics, delivered dialysis dose, duration of stay in the ICU or hospital, mortality rates, and recovery of renal function were not different between the two groups. Detailed 24-h time and material consumption protocols were available for 369 (CVVHDF) and 195 (IHD) treatment days. The mean daily duration of CVVHDF was 19.5 +/- 3.2 h/day, resulting in total expenditures of Euro 436 +/- 21 (21% for human resources and 79% for technical devices). For IHD (mean 3.0 +/- 0.4 h/treatment), the costs were lower (Euro 268 +/- 26), with a larger proportion for human resources (45%). Nursing time spent for CVVHDF was 113 +/- 50 min, and 198 +/- 63 min per IHD treatment. Total costs for RRT in ICU patients with ARF were lower when treated with IHD than with CVVHDF, and have to be taken into account for the selection of the method of RRT in ARF on the ICU.

Septic shock resuscitation: what goals and how to achieve them?

The need to achieve adequate tissue oxygen delivery early in patients with septic shock is well established. However, it is less well recognized that tissue hypoperfusion can exist despite normalization of systemic hemodynamics. Efforts to resuscitate septic patients until adequate tissue perfusion has been achieved can potentially improve outcome. In a multicenter study, 130 patients with septic shock were resuscitated within 12 hours of diagnosis using a protocol including goals for mean arterial and pulmonary artery occluded pressures, urinary output, arterial pH, and hemoglobin goals. They were then randomly assigned to further resuscitation with either a cardiac index (>or= 3 l/minute per m2) or a gastric mucosal pH (>or= 7.32) target. The intensive care unit length of stay and 28-day mortality did not differ between groups, but more patients in the cardiac index group were in the target range, both at baseline and after resuscitation, as compared with the gastric mucosal pH group. In contrast to cardiac index, gastric mucosal pH at baseline and at 24 and 48 hours predicted mortality. Whether other targets for the chosen variables, or different and--in particular--earlier resuscitation efforts would have favored one group cannot be concluded from the data provided.

Evaluation of physical and mental recovery status after elective liver resection

BACKGROUND AND OBJECTIVE: This prospective, clinical pilot trial compared the Short Form 36 Health Survey (SF-36) and a nine-item quality of recovery [Quality of Recovery 9 (QoR-9)] survey to assess the 1-week outcome after liver resection and prediction of postoperative complications from baseline values before liver resection. METHODS: In 19 patients, the SF-36 was recorded preoperatively (baseline) and on postoperative day (POD) 7. SF-36 z-values (means +/- SD) for the physical component summary (PCS) and mental component summary (MCS) were calculated. QoR-9 (score 0-18) was performed at baseline, POD1, POD3, POD5 and POD7. Descriptive analysis and effect sizes (d) were calculated. RESULTS: From baseline to POD7, PCS decreased from -0.38 +/- 1.30 to -2.10 +/- 0.76 (P = 0.002, d = -1.57) and MCS from -0.71 +/- 1.50 to -1.33 +/- 1.11 (P = 0.061, d = -0.46). QoR-9 was significantly lower at POD1, POD3 and POD5 compared with baseline (P < 0.050, d < -2.0), but not at POD7 (P = 0.060, d = -1.08). Baseline PCS was significantly lower with a high effect size in patients with complications (n = 12) compared with patients without complications (n = 7) (-0.76 +/- 1.46 vs. 0.27 +/- 0.56; P = 0.044, d = -0.84) but not baseline MCS (P = 0.831, d = -0.10) or baseline QoR-9 (P = 0.384, d = -0.44). CONCLUSIONS: The SF-36 indicates that liver resection surgery has a higher impact on physical health than on mental health. QoR-9 determines the feasible time course of recovery with a 1-week return to baseline. Preoperative impaired physical health might predict postoperative complications.

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.