Analysis of purine receptor expression and functionality in alveolar epithelial cells.

Despite its fundamental role in providing an extensive surface for gas exchange, the alveolar epithelium (AE) serves as an immunological barrier through, e.g., the release of proinflammatory cytokines and secretion of surfactant to prevent alveolar collapse. Thus, AE is important for sustaining lung homeostasis. Extracellular ATP secreted by alveolar epithelial cells (AECs) is involved in physiological and pathological conditions and acts mainly through the activation of purine receptors (P2Rs). When studying P2R-mediated processes, primary isolated type II AECs (piAECs) still represent the gold standard in in vitro research, although their preparation is time-consuming and requires the sacrifice of many animals. Hence, cultivated immortalized and tumor-derived AEC lines may constitute a valuable alternative. In this work, we examined P2R expression and functionality in piAECs, in immortalized and tumor-derived AEC lines with the purpose of gaining a better understanding of purinergic signaling in different cell systems and assisting researchers in the choice of a suitable cell line with a certain P2R in demand. We combined mRNA and protein analysis to evaluate the expression of P2R. For pharmacological testing, we conducted calcium ([Ca2+]) measurements and siRNA receptor knockdown. Interestingly, the mRNA and protein levels of P2Y2, P2Y6, and P2X4 were detected on all cell lines. Concerning functionality, P2XR could be narrowed to L2 and piAECs while P2YR were active in all cell lines.

Dead space ventilation promotes alveolar hypocapnia reducing surfactant secretion by altering mitochondrial function.

BACKGROUND: In acute respiratory distress syndrome (ARDS), pulmonary perfusion failure increases physiologic dead space ventilation (VD/VT), leading to a decline of the alveolar CO2 concentration [CO2]iA. Although it has been shown that alveolar hypocapnia contributes to formation of atelectasis and surfactant depletion, a typical complication in ARDS, the underlying mechanism has not been elucidated so far. METHODS: In isolated perfused rat lungs, cytosolic or mitochondrial Ca2+ concentrations ([Ca2+]cyt or [Ca2+]mito, respectively) of alveolar epithelial cells (AECs), surfactant secretion and the projected area of alveoli were quantified by real-time fluorescence or bright-field imaging (n=3-7 per group). In ventilated White New Zealand rabbits, the left pulmonary artery was ligated and the size of subpleural alveoli was measured by intravital microscopy (n=4 per group). Surfactant secretion was determined in the bronchoalveolar lavage (BAL) by western blot. RESULTS: Low [CO2]iA decreased [Ca2+]cyt and increased [Ca2+]mito in AECs, leading to reduction of Ca2+-dependent surfactant secretion, and alveolar ventilation in situ. Mitochondrial inhibition by ruthenium red or rotenone blocked these responses indicating that mitochondria are key players in CO2 sensing. Furthermore, ligature of the pulmonary artery of rabbits decreased alveolar ventilation, surfactant secretion and lung compliance in vivo. Addition of 5% CO2 to the inspiratory gas inhibited these responses. CONCLUSIONS: Accordingly, we provide evidence that alveolar hypocapnia leads to a Ca2+ shift from the cytosol into mitochondria. The subsequent decline of [Ca2+]cyt reduces surfactant secretion and thus regional ventilation in lung regions with high VD/VT. Additionally, the regional hypoventilation provoked by perfusion failure can be inhibited by inspiratory CO2 application.

Asymmetric and Symmetric Dimethylarginines are Markers of Delayed Cerebral Ischemia and Neurological Outcome in Patients with Subarachnoid Hemorrhage.

BACKGROUND: Delayed cerebral ischemia (DCI) is the major cause of lethality and neuronal damage in patients who survived the primary subarachnoid hemorrhage (SAH). Asymmetric and symmetric dimethylarginines (ADMA and SDMA) inhibit nitric oxide production from L-arginine via distinct mechanisms. Elevated ADMA levels are associated with vasospasm after SAH. We aimed to study the time course of ADMA and SDMA in plasma and ventricular cerebrospinal fluid (CSF) and their associations with DCI and outcome. METHODS: We measured ADMA and SDMA in 34 SAH patients with an external ventricular drain at admission and on days 3, 6, 8, 12, and 15 and followed them up for clinical status and neurological outcome until 30 days post-discharge. DCI was defined as the appearance of new infarctions on cerebral computed tomography or magnetic resonance imaging. RESULTS: ADMA and SDMA plasma concentrations did not differ significantly at baseline between patients who suffered DCI (N = 14; 41%) and not; however, plasma ADMA reached a peak on days 8 and 15 after hemorrhage in patients with DCI (0.81-0.91 µmol/l). Baseline plasma L-arginine/ADMA ratio was significantly lower in patients with DCI (57.1 [34.3; 70.8] vs. 68.7 [55.7; 96.2]; p < 0.05). ADMA and SDMA concentrations in CSF were significantly higher in patients with DCI than without. In multivariable-adjusted linear regression models, CSF ADMA was negatively associated with the incidence of DCI (OR 0.03 [0.02-0.70]; p = 0.04), whereas CSF SDMA on the day of hemorrhage predicted poor neurological outcome until 30 days after discharge (OR 22.4 [1.21-416.02]; p = 0.04). CONCLUSIONS: Our study shows that ADMA and the L-arginine/ADMA ratio are associated with the incidence of DCI after SAH. By contrast, SDMA was associated with initial neuronal damage and poor neurological outcome after SAH. These data support the hypothesis that ADMA and L-arginine affect the pathophysiology of cerebral ischemia after SAH, while SDMA is a biomarker of neurological outcome after SAH.

Markers of nitric oxide are associated with sepsis severity: an observational study.

BACKGROUND: Nitric oxide (NO) regulates processes involved in sepsis progression, including vascular function and pathogen defense. Direct NO measurement in patients is unfeasible because of its short half-life. Surrogate markers for NO bioavailability are substrates of NO generating synthase (NOS): L-arginine (lArg) and homoarginine (hArg) together with the inhibitory competitive substrate asymmetric dimethylarginine (ADMA). In immune cells ADMA is cleaved by dimethylarginine-dimethylaminohydrolase-2 (DDAH2). The aim of this study was to investigate whether concentrations of surrogate markers for NO bioavailability are associated with sepsis severity. METHOD: This single-center, prospective study involved 25 controls and 100 patients with surgical trauma (n = 20), sepsis (n = 63), or septic shock (n = 17) according to the Sepsis-3 definition. Plasma lArg, hArg, and ADMA concentrations were measured by mass spectrometry and peripheral blood mononuclear cells (PBMCs) were analyzed for DDAH2 expression. RESULTS: lArg concentrations did not differ between groups. Median (IQR) hArg concentrations were significantly lower in patient groups than controls, being 1.89 (1.30-2.29) µmol/L (P < 0.01), with the greatest difference in the septic shock group, being 0.74 (0.36-1.44) µmol/L. In contrast median ADMA concentrations were significantly higher in patient groups compared to controls, being 0.57 (0.46-0.65) µmol/L (P < 0.01), with the highest levels in the septic shock group, being 0.89 (0.56-1.39) µmol/L. The ratio of hArg:ADMA was inversely correlated with disease severity as determined by the Sequential Organ Failure Assessment (SOFA) score. Receiver-operating characteristic analysis for the presence or absence of septic shock revealed equally high sensitivity and specificity for the hArg:ADMA ratio compared to the SOFA score. DDAH2 expression was lower in patients than controls and lowest in the subgroup of patients with increasing SOFA. CONCLUSIONS: In patients with sepsis, plasma hArg concentrations are decreased and ADMA concentrations are increased. Both metabolites affect NO metabolism and our findings suggest reduced NO bioavailability in sepsis. In addition, reduced expression of DDAH2 in immune cells was observed and may not only contribute to blunted NO signaling but also to subsequent impaired pathogen defense.

Reduction of clinically irrelevant alarms in patient monitoring by adaptive time delays.

The problem of high rates of false alarms in patient monitoring in anesthesiology and intensive care medicine is well known but remains unsolved. False alarms desensitize the medical staff, leading to ignored true alarms and reduced quality of patient care. A database of intra-operative monitoring data was analyzed to find characteristic alarm patterns. The original data were re-evaluated to find relevant events and to rate the severity of these events. Based on this analysis an adaptive time delay was developed that individually delays the alarms depending on the grade of threshold deviation. The conventional threshold algorithm led to 4893 alarms. 3515 (71.84 %) of these alarms were annotated as clinically irrelevant. In total 81.0 % of all clinically irrelevant alarms were caused by only mild and/or brief threshold violations. We implemented the new algorithm for selected parameters. These parameters equipped with adaptive validation delays led to 1729 alarms. 931 (53.85 %) alarms were annotated as clinically irrelevant. 632 alarms indicated the 645 clinically relevant events. The positive predictive value of occurring alarms improved from 28.16 % (conventional algorithm) to 46.15 % (new algorithm). 13 events were missed. The false positive alarm reduction rate of the algorithm ranged from 33 to 86.75 %. The overall reduction was 73.51 %. The implementation of this algorithm may be able to suppress a large percentage of false alarms. The effect of this approach has not been demonstrated but shows promise for reducing alarm fatigue. Its safety needs to be proven in a prospective study.

Dynamic device properties of pulse contour cardiac output during transcatheter aortic valve implantation.

This prospective single-center study aimed to determine the responsiveness and diagnostic performance of continuous cardiac output (CCO) monitors based on pulse contour analysis compared with invasive mean arterial pressure (MAP) during predefined periods of acute circulatory deterioration in patients undergoing transcatheter aortic valve implantation (TAVI). The ability of calibrated (CCO(CAL)) and self-calibrated (CCO(AUTOCAL)) pulse contour analysis to detect the hemodynamic response to 37 episodes of balloon aortic valvuloplasty enabled by rapid ventricular pacing was quantified in 13 patients undergoing TAVI. A "low" and a "high" cut-off limit were predefined as a 15 or 25 % decrease from baseline respectively. We found no significant differences between CCO(CAL) and MAP regarding mean response time [low cut-off: 8.6 (7.1-10.5) vs. 8.9 (7.3-10.8) s, p = 0.76; high cut-off: 11.4 (9.7-13.5) vs. 12.6 (10.7-14.9) s, p = 0.32] or diagnostic performance [area under the receiver operating characteristics curve (AUC): 0.99 (0.98-1.0) vs. 1.0 (0.99-1.0), p = 0.46]. But CCOCAL had a significantly higher amplitude response [95.0 (88.7-98.8) % decrease from baseline] than MAP [41.2 (30.0-52.9) %, p < 0.001]. CCOAUTOCAL had a significantly lower AUC [0.83 (0.73-0.93), p < 0.001] than MAP. Moreover, CCO(CAL) detected hemodynamic recovery significantly earlier than MAP. In conclusion, CCO(CAL) and MAP provided equivalent responsiveness and diagnostic performance to detect acute circulatory depression, whereas CCO(AUTOCAL) appeared to be less appropriate. In contrast to CCO(CAL) the amplitude response of MAP was poor. Consequently even small response amplitudes of MAP could indicate severe decreases in CO.

Individualized early goal-directed therapy in systemic inflammation: is full utilization of preload reserve the optimal strategy?

OBJECTIVES: In severe acute pancreatitis, the administration of fluids in the presence of positive fluid responsiveness is associated with better outcome when compared to guiding therapy on central venous pressure. We compared the effects of such consequent maximization of stroke volume index with a regime using individual values of stroke volume index assessed prior to severe acute pancreatitis induction as therapeutic hemodynamic goals. DESIGN: Prospective, randomized animal study. SETTING: University animal research laboratory. SUBJECTS: Thirty domestic pigs. INTERVENTIONS: After randomization, fluid resuscitation was started 2 hours after severe acute pancreatitis induction and continued for 6 hours according to the respective treatment algorithms. In the control group, fluid therapy was directed by maximizing stroke volume index, and in the study group, stroke volume index assessed prior to severe acute pancreatitis served as primary hemodynamic goal. MEASUREMENTS AND MAIN RESULTS: Within the first 6 hours of severe acute pancreatitis, the study group received a total of 1,935.8 ± 540.7 mL of fluids compared with 3,462.8 ± 828.2 mL in the control group (p < 0.001). Pancreatic tissue oxygenation did not differ significantly between both groups. Vascular endothelial function, measured by flow-mediated vasodilation before and 6 hours after severe acute pancreatitis induction, revealed less impairment in the study group after treatment interval (-90.76% [study group] vs -130.89% [control group]; p = 0.046). Further, lower levels of heparan sulfate (3.41 ± 5.6 pg/mL [study group] vs 43.67 ± 46.61 pg/mL [control group]; p = 0.032) and interleukin 6 (32.18 ± 8.81 pg/mL [study group] vs 77.76 ± 56.86 pg/mL [control group]; p = 0.021) were found in the study group compared with control group. Histopathological examination of the pancreatic head and corpus at day 7 revealed less edema for the study group compared with the control group (1.82 ± 0.87 [study group] vs 2.89 ± 0.33 [control group, pancreatic head]; p = 0.03; 2.2 ± 0.92 [study group] vs 2.91 ± 0.3 [control group, pancreatic corpus]; p = 0.025). CONCLUSIONS: Individualized optimization of intravascular fluid status during the early course of severe acute pancreatitis, compared with a treatment strategy of maximizing stroke volume by fluid loading, leads to less vascular endothelial damage, pancreatic edema, and inflammatory response.

Perioperative glycemic control with a computerized algorithm versus conventional glycemic control in cardiac surgical patients undergoing cardiopulmonary bypass with blood cardioplegia.

OBJECTIVE: In critical illness, hypoglycemia and hyperglycemia seem to influence outcome. While hypoglycemia can lead to organ dysfunction, hyperglycemia can lead to surgical site infections (SSI). In cardiac surgery, the use of blood cardioplegia is associated with high blood glucose levels. A computer-based algorithm (CBA) for guiding insulin towards normoglycemia might be beneficial. The authors' primary study end-point was the duration in a predefined blood glucose target range of 80 mg/dL to 150 mg/dL. Patients with conventional therapy served as controls. DESIGN: Prospective, randomized trial. SETTING: University hospital. PARTICIPANTS: Seventy-five patients. INTERVENTIONS: The start of therapy was the beginning of cardiopulmonary bypass. Group A: Therapy with CBA and measurement of blood glucose every 30 minutes. Group B: Measurement of blood glucose every 15 minutes using the identical CBA. Group C: Conventional therapy using a fixed insulin dosing scheme. End of therapy was defined as discharge from ICU. MEASUREMENT AND MAIN RESULTS: Glucose administration during cardioplegia did not differ between groups (A: 33 ± 12 g; B: 32 ± 12 g; C: 38 ± 20 g). Glucose levels in groups A and B stayed significantly longer in the target interval compared with group C (A: 75 ± 20%; B: 72 ± 19%; C: 50 ± 34%, p < 0.01 n = 25, respectively). There were no significant differences regarding ICU stay and SSI rates. CONCLUSIONS: Early computer-based insulin therapy allows practitioners to better achieve normoglycemia in patients undergoing major cardiac surgery with the use of blood cardioplegia.

Individually optimized hemodynamic therapy reduces complications and length of stay in the intensive care unit: a prospective, randomized controlled trial.

BACKGROUND: The authors hypothesized that goal-directed hemodynamic therapy, based on the combination of functional and volumetric hemodynamic parameters, improves outcome in patients with cardiac surgery. Therefore, a therapy guided by stroke volume variation, individually optimized global end-diastolic volume index, cardiac index, and mean arterial pressure was compared with an algorithm based on mean arterial pressure and central venous pressure. METHODS: This prospective, controlled, parallel-arm, open-label trial randomized 100 coronary artery bypass grafting and/or aortic valve replacement patients to a study group (SG; n = 50) or a control group (CG; n = 50). In the SG, hemodynamic therapy was guided by stroke volume variation, optimized global end-diastolic volume index, mean arterial pressure, and cardiac index. Optimized global end-diastolic volume index was defined before and after weaning from cardiopulmonary bypass and at intensive care unit (ICU) admission. Mean arterial pressure and central venous pressure served as hemodynamic goals in the CG. Therapy was started immediately after induction of anesthesia and continued until ICU discharge criteria, serving as primary outcome parameter, were fulfilled. RESULTS: Intraoperative need for norepinephrine was decreased in the SG with a mean (±SD) of 9.0 ± 7.6 versus 14.9 ± 11.1 µg/kg (P = 0.002). Postoperative complications (SG, 40 vs. CG, 63; P = 0.004), time to reach ICU discharge criteria (SG, 15 ± 6 h; CG, 24 ± 29 h; P < 0.001), and length of ICU stay (SG, 42 ± 19 h; CG, 62 ± 58 h; P = 0.018) were reduced in the SG. CONCLUSION: Early goal-directed hemodynamic therapy based on cardiac index, stroke volume variation, and optimized global end-diastolic volume index reduces complications and length of ICU stay after cardiac surgery.

Hemodynamic effects of orally administered delta-ALA during radical prostatectomy.

PURPOSE: We investigated hemodynamics in patients receiving delta-Aminolevulinic acid (delta-ALA) to visualize tumor margins prior to radical retro pubic prostatectomy. PATIENTS: Twenty patients undergoing elective open radical retro pubic prostatectomy (RRP). METHODS: Cohort observational study. Ten patients receiving 20 mg/kg of delta-ALA orally prior to surgery (delta-ALA) and 10 patients undergoing RRP without the application of delta-ALA served as a retrospectively matched cohort (CONTROL). MEASUREMENTS: Changes in heart rate (HR), mean arterial blood pressure (MAP), and functional hemodynamic parameters were assessed by electrocardiogram, non-invasive and invasive blood pressure monitoring plus transcardiopulmonary thermodilution. RESULTS: Patients of both groups did not differ in means of age, body mass index, or ASA classification. During surgery, HR and MAP did not differ significantly between both groups. Also, the amount of IV crystalloids and colloids did not differ significantly. In contrast, the amount of vasopressor necessary to maintain MAP within the target range of 70-90 mmHg was significantly higher in delta-ALA when compared to CONTROL (0.08 ± 0.04 µg/kg/min (delta-ALA) vs. 0.03 ± 0.02 µg/kg/min (CONTROL); P < 0.01). Immediately after surgery, patients of delta-ALA showed a significantly higher heart rate (82 ± 18 min(-1) vs. 67 ± 9 min(-1); P < 0.05) compared to patients of CONTROL. Cardiac index, global end-diastolic volume index, and extravascular lung water index were significantly higher after surgery, when compared to baseline values (P < 0.05). CONCLUSIONS: Orally administered delta-ALA prior to open radical prostatectomy induces hemodynamic instability in the perioperative period requiring vasopressor support. Further, an increase of extravascular lung water points toward an increased vascular permeability induced by delta-ALA.

Effects of thoracic epidural anesthesia on survival and microcirculation in severe acute pancreatitis: a randomized experimental trial.

INTRODUCTION: Severe acute pancreatitis is still a potentially life threatening disease with high mortality. The aim of this study was to evaluate the therapeutic effect of thoracic epidural anaesthesia (TEA) on survival, microcirculation, tissue oxygenation and histopathologic damage in an experimental animal model of severe acute pancreatitis in a prospective animal study. METHODS: In this study, 34 pigs were randomly assigned into 2 treatment groups. After severe acute pancreatitis was induced by intraductal injection of glycodesoxycholic acid in Group 1 (n = 17) bupivacaine (0.5%; bolus injection 2 ml, continuous infusion 4 ml/h) was applied via TEA. In Group 2 (n = 17) no TEA was applied. During a period of 6 hours after induction, tissue oxygen tension (tpO2) in the pancreas and pancreatic microcirculation was assessed. Thereafter animals were observed for 7 days followed by sacrification and histopathologic examination. RESULTS: Survival rate after 7 days was 82% in Group 1 (TEA) versus 29% in Group 2: (Control) (P <0.05). Group 1 (TEA) also showed a significantly superior microcirculation (1,608 ± 374 AU versus 1,121 ± 510 AU; P <0.05) and tissue oxygenation (215 ± 64 mmHg versus 138 ± 90 mmHG; P <0.05) as compared to Group 2 (Control). Consecutively, tissue damage in Group 1 was reduced in the histopathologic scoring (5.5 (3 to 8) versus 8 (5.5 to 10); P <0.05). CONCLUSIONS: TEA led to improved survival, enhanced microcirculatory perfusion and tissue oxygenation and resulted in less histopathologic tissue-damage in an experimental animal model of severe acute pancreatitis.

Brief report: leaking esophageal probe may lead to false ventilator settings when guiding positive end-expiratory pressure by transpulmonary pressure.

Esophageal pressure (Pes) is a surrogate for intrapleural pressure. Measuring Pes during mechanical ventilation allows for positive end-expiratory pressure adjustments by transpulmonary pressure (PL), which has been shown to improve oxygenation and outcome in acute respiratory distress syndrome patients. In morbidly obese patients, we saw progressively increasing PL measurements, although airway pressure (Paw), intra-abdominal pressure, and patient position did not change. On further examination, we determined that the gradual increases of PL were artifacts caused by a leak in the pressure probes, which resulted in underestimation of Pes and overestimation of PL as derived from the equation Paw - Pes = PL.

An assessment of global end-diastolic volume and extravascular lung water index during one-lung ventilation: is transpulmonary thermodilution usable?

BACKGROUND: The thermodilution curve assessed by transpulmonary thermodilution is the basis for calculation of global end-diastolic volume index (GEDI) and extravascular lung water index (EVLWI). Until now, it was unclear whether the method is affected by 1-lung ventilation. Therefore, aim of our study was to evaluate the impact of 1-lung ventilation on the thermodilution curve and assessment of GEDI and EVLWI. METHODS: In 23 pigs, mean transit time, down slope time, and difference in blood temperature (ΔTb) were assessed by transpulmonary thermodilution. "Gold standard" cardiac output was measured by pulmonary artery flowprobe (PAFP) and used for GEDIPAFP and EVLWIPAFP calculations. Measurements were performed during normovolemia during double-lung ventilation (M1), 15 minutes after 1-lung ventilation (M2) and during hypovolemia (blood withdrawal 20 mL/kg) during double-lung ventilation (M3) and again 15 minutes after 1-lung ventilation (M4). RESULTS: Configuration of the thermodilution curve was significantly affected by 1-lung ventilation demonstrated by an increase in ΔTb and a decrease in mean transit time and down slope time (all P < 0.04) during normovolemia and hypovolemia. GEDIPAFP was lower after 1-lung ventilation during normovolemia (M1: 459.9 ± 67.5 mL/m(2); M2: 397.0 ± 54.8 mL/m(2); P = 0.001) and hypovolemia (M3: 300.6 ± 40.9 mL/m(2); M4: 275.2 ± 37.6 mL/m(2); P = 0.03). EVLWIPAFP also decreased after 1-lung ventilation in normovolemia (M1: 9.0 [7.3, 10.1] mL/kg; M2: 7.4 [5.8, 8.3] mL/kg; P = 0.01) and hypovolemia (M3: 7.4 [6.3, 9.7] mL/kg; M4: 5.8 [5.2, 7.4]) mL/kg; P = 0.0009). CONCLUSION: Configuration of the thermodilution curve and therefore assessment of GEDI and EVLWI are significantly affected by 1-lung ventilation.

Prediction of volume-responsiveness during one-lung ventilation: a comparison of static, volumetric, and dynamic parameters of cardiac preload.

OBJECTIVES: The aim of this study was to evaluate the ability of static, volumetric, and dynamic parameters of cardiac preload to predict volume responsiveness during one-lung ventilation (OLV). DESIGN: Prospective experimental study. SETTING: Laboratory of the animal facility of the University Medical Center Hamburg-Eppendorf. PARTICIPANTS: Twenty-three German domestic pigs. INTERVENTIONS: Hypovolemia was induced by withdrawing 20 mL/kg body weight (BW) of blood. OLV was established, and the volume withdrawn was re-transfused in 3 volume-loading steps, each consisting of 7 mL/kg BW. An ultrasonic flow probe around the pulmonary artery was used to measure the stroke-volume index (SVI) and to evaluate the volume response. An increase in the SVI of ≥ 15% was considered a positive response. For each measurement time point, central venous pressure (CVP), left atrial pressure (LAP), the global end-diastolic volume index (GEDI), stroke-volume variation (SVV), and pulse-pressure variation (PPV) were recorded. The ability to predict volume responsiveness was assessed using ROC analysis. MEASUREMENTS AND MAIN RESULTS: A total of 69 volume loading steps were performed, 48 of which showed a positive volume response. ROC analysis revealed the following area under the curve (AUC) values: CVP, 0.88; LAP, 0.65; GEDI, 0.75; SVV, 0.78; and PPV, 0.83. A comparison of the areas under the ROC curves did not reveal any statistically significant differences (p>0.05), with the exception of LAP compared with CVP (p = 0.005). CONCLUSIONS: Under these OLV experimental conditions, the volumetric and dynamic parameters of preload, as well as CVP, seemed to be of similar value in predicting volume responsiveness.

Tetrastarch sustains pulmonary microvascular perfusion and gas exchange during systemic inflammation.

OBJECTIVE: According to Fick's law of diffusion, gas exchange depends on the size and thickness of the blood perfused alveolocapillary membrane. Impairment of either one is tenuous. No data are available concerning the impact of hydroxyethyl starches and saline on pulmonary microperfusion and gas exchange during systemic inflammation. DESIGN: Prospective, randomized, controlled experimental study. SETTING: University research laboratory. SUBJECTS: Thirty-two anesthetized rabbits assigned to four groups (n = 8). INTERVENTIONS: Except for the control group, systemic inflammation was induced by lipopolysaccharide. Fluid resuscitation was performed with saline alone or in conjunction with tetrastarch or pentastarch. Pulmonary microcirculation was analyzed at 0 hr and 2 hrs using intravital microscopy. Thickness of the alveolocapillary membrane was measured using electron microscopy. MEASUREMENTS AND MAIN RESULTS: Macrohemodynamics were stable in all groups. In pulmonary arterioles, lipopolysaccharide reduced the erythrocyte velocity and impeded the microvascular decrease of the hematocrit in the saline and pentastarch group. In contrast, infusion of tetrastarch normalized these perfusion parameters. In capillaries, lipopolysaccharide decreased the functional capillary segment density and the capillary perfusion index, which was prevented by both starches. However, compared with saline and pentastarch, treatment with tetrastarch prevented the lipopolysaccharide-induced reduction of the capillary erythrocyte flux and inversely reduced the erythrocyte capillary transit time. Thickening of alveolocapillary septae after lipopolysaccharide application was solely observed in the saline and pentastarch group. In contrast to pentastarch and saline, the application of tetrastarch prevented the lipopolysaccharide-induced increase of the alveoloarterial oxygen difference. CONCLUSIONS: Tetrastarch sustains pulmonary gas exchange during experimental systemic inflammation more effectively than saline and pentastarch by protecting the diffusion distance and the size of the microvascular gas exchange surface. Improved capillary perfusion resulting from tetrastarch therapy, which is typically applied to increase blood pressure, may according to the Ohm's law locally decrease hydrostatic perfusion pressures in the pulmonary microvasculature during systemic inflammation.

Heart-lung interactions measured by electrical impedance tomography.

OBJECTIVE: The clinical value of stroke volume variations to assess intravascular fluid status in critically ill patients is well known. Electrical impedance tomography is a noninvasive monitoring technology that has been primarily used to assess ventilation. We investigated the potential of electrical impedance tomography to measure left ventricular stroke volume variation as an expression of heart-lung interactions. The objective of this study was thus to determine in a set of different hemodynamic conditions whether stroke volume variation measured by electrical impedance tomography correlates with those derived from an aortic ultrasonic flow probe and arterial pulse contour analysis. DESIGN: Prospective animal study. SETTING: University animal research laboratory. SUBJECTS: Domestic pigs, 29-50 kg. INTERVENTIONS: A wide range of hemodynamic conditions were induced by mechanical ventilation at different levels of positive end-expiratory pressure (0-15 cm H2O) and with tidal volumes of 8 and 16 mL/kg of body weight and by hypovolemia due to blood withdrawal with subsequent retransfusion followed by infusions of hydroxyethyl starch. MEASUREMENTS AND MAIN RESULTS: In eight pigs, aortic stroke volume variations measured by electrical impedance tomography were measured and compared to those derived from an aortic ultrasonic flow probe and from arterial pulse contour analysis. Data for four animals were used to develop and train a novel frequency-domain electrical impedance tomography analysis algorithm, while data for the remaining four were used to test the performance of the novel methodology. Correlation of stroke volume variation measured by electrical impedance tomography and that derived from an aortic ultrasonic flow probe was significant (r = 0.69; p < .001), as was the correlation between stroke volume variation measured by electrical impedance tomography and that derived from arterial pulse contour analysis (r = 0.73; p < .001). Correlation of stroke volume variation derived from an aortic ultrasonic flow probe and that derived from arterial pulse contour analysis was significant too (r = 0.82; p < .001). Bland-Altman analysis comparing stroke volume variation measured by electrical impedance tomography and that derived from an aortic ultrasonic flow probe revealed an overall bias of 1.87% and limits of agreement of ± 7.02%; when comparing stroke volume variation measured by electrical impedance tomography and that derived from arterial pulse contour analysis, the overall bias was 0.49% and the limits of agreement were ± 5.85%. CONCLUSION: Stroke volume variation measured by electrical impedance tomography correlated with both the gold standard of direct aortic blood flow measurements of stroke volume variation and pulse contour analysis, marking an important step toward a completely noninvasive monitoring of heart-lung interactions.

Thermodilution-derived indices for assessment of left and right ventricular cardiac function in normal and impaired cardiac function.

OBJECTIVE: The aim of this study was to assess whether thermodilution-derived parameters of right and left ventricular cardiac function (right ventricular ejection fraction, global ejection fraction, cardiac function index) are able to track changes of cardiac contractile function and whether they are influenced by substantial preload reduction. DESIGN: Prospective animal study. SETTING: University-affiliated animal research laboratory. SUBJECTS: Domestic pigs. INTERVENTIONS: Sixteen domestic pigs were studied. Right ventricular ejection fraction, global ejection fraction, and cardiac function index were compared to direct measurement of left ventricular rate of maximum systolic pressure rise and the left ventricular rate of maximum systolic pressure rise corrected to preload. Measurements were done with normal cardiac function during normo- and hypovolemia. Thereafter, cardiac function was impaired by continuous infusion of verapamil and measurements were repeated during normo- and hypovolemia (withdrawal of blood 20 mL kg body weight). MEASUREMENTS AND MAIN RESULTS: With normal cardiac function, hypovolemia led to a significant decrease of right ventricular ejection fraction from 36.7% ± 6.6% to 29.8% ± 5.8% (p < .001), global ejection fraction from 40.5% ± 6.2% to 33.6% ± 7.6% (p < .001), and the left ventricular rate of maximum systolic pressure rise from 2104 ± 390 mm Hg sec to 1297 ± 438 mm Hg sec (p < .001). Cardiac function index (8.92 ± 2.20 min to 7.93 ± 1.54 min) and the left ventricular rate of maximum systolic pressure rise corrected to preload (18.2 ± 4.7 mm Hg sec mL to 15.2 ± 4.3 mm Hg sec mL) did not change significantly. Infusion of verapamil led to a significant reduction of right ventricular ejection fraction, global ejection fraction, cardiac function index, the left ventricular rate of maximum systolic pressure rise, and the left ventricular rate of maximum systolic pressure rise corrected to preload (p < .001). Now, hypovolemia led to a significant decrease of right ventricular ejection fraction (29.1% ± 4.6% to 24.9% ± 5.9%; p < .001), global ejection fraction (37.1% ± 4.7% to 31.9% ± 3.9%; p < .05), cardiac function index (7.58 ± 1.02 to 6.27 ± 1.19 min; p < .05), and the left ventricular rate of maximum systolic pressure rise (733 ± 141 mm Hg sec to 426 ± 108 mm Hg sec; p < .05). Only the left ventricular rate of maximum systolic pressure rise corrected to preload did not change significantly (6.7 ± 1.3 mm Hg sec mL to 4.6 ± 1 mm Hg sec mL; p > .05). CONCLUSIONS: Right ventricular ejection fraction, global ejection fraction, and cardiac function index enable detection of changes in load-independent, intrinsic cardiac contractility. Importantly, they also reflect changes of contractile function caused by substantial decrease of preload, emphasizing the importance of assessing both cardiac contractile function in coherence with cardiac preload to differentiate between reduced intrinsic contractility and hypovolemia.

The wolf is crying in the operating room: patient monitor and anesthesia workstation alarming patterns during cardiac surgery.

BACKGROUND: Vital sign monitors and ventilator/anesthesia workstations are equipped with multiple alarms to improve patient safety. A high number of false alarms can lead to a "crying wolf" phenomenon with consecutively ignored critical situations. Systematic data on alarm patterns and density in the perioperative phase are missing. Our objective of this study was to characterize the patterns of alarming of a commercially available patient monitor and a ventilator/anesthesia workstation during elective cardiac surgery. METHODS: We performed a prospective, observational study in 25 consecutive elective cardiac surgery patients. In all patients, identically fixed alarm settings were used. All incoming patient data and all alarms from the patient monitor and the anesthetic workstation were digitally recorded. Additionally, the anesthesia workplace was videotaped from 2 different angles to allow retrospective annotation and correlation of alarms with the clinical situation and assessment of the anesthesiologists' reaction to the alarms. RESULTS: Of the 8975 alarms, 7556 were hemodynamic alarms and 1419 were ventilatory alarms. For each procedure, 359 ± 158 alarms were recorded, representing a mean density of alarms of 1.2/minute. CONCLUSION: Approximately 80% of the total 8975 alarms had no therapeutic consequences. Implementation of procedure-specific settings and optimization in artifact and technical alarm detection could improve patient surveillance and safety.

Detection of right ventricular insufficiency and guidance of volume therapy are facilitated by simultaneous monitoring of static and functional preload parameters.

OBJECTIVE: Acute right ventricular failure (RVF) is a life-threatening condition. This study investigated whether the combination of central venous pressure (CVP) and left ventricular functional preload parameters, such as stroke volume variation (SVV) and pulse pressure variation (PPV), can be used for the detection of acute RVF and for guidance of volume therapy. DESIGN AND SETTING: Experimental study in a university laboratory. PARTICIPANTS: Fifteen anesthetized and ventilated pigs. MEASUREMENTS AND MAIN RESULTS: For the induction of RVF, mean pulmonary artery pressure (MPAP) was increased by 50% with a continuous infusion of a thromboxane-A(2) analog (U46619). Then, blood removal (300 mL) and retransfusion (blood 200 mL + colloid solution 200 mL) were performed. An analysis of volume responders and nonresponders was implemented. Increasing MPAP (25.1 to 37.4 mmHg) led to decreases in mean arterial pressure (72.2 to 60.1 mmHg) and cardiac output (2.8 to 2.3 L/min, p < 0.05). CVP (11.3 to 12.6 mmHg), PPV (13% to 17%), and SVV (11 to 14%) increased significantly (p < 0.05). During volume removal, MPAP (37.4 to 34.1 mmHg), mean arterial pressure (60.1 to 53.2 mmHg), and cardiac output (2.3 to 2.1 L/min) decreased (p < 0.05), whereas PPV and SVV remained unchanged. During volume loading, CVP increased in volume responders and nonresponders; however, PPV decreased in responders only. CONCLUSIONS: Increases of CVP and SVV or PPV are suspicious for RVF. However, SVV and PPV fail to predict volume responsiveness in RVF. Changes in SVV and PPV during a volume-loading maneuver can be used to assess volume responsiveness.

Functional hemodynamic parameters do not reflect volume responsiveness in the immediate phase after acute myocardial ischemia and reperfusion.

OBJECTIVE: Functional preload parameters such as stroke-volume variation (SVV) and pulse-pressure variation (PPV) are superior to filling pressures when assessing volume responsiveness in mechanically ventilated patients. This investigation studied their application in the setting of acute myocardial ischemia and reperfusion (I/R). DESIGN AND SETTING: Experimental animal study in a university laboratory. PARTICIPANTS: Twenty anesthetized and ventilated pigs. INTERVENTIONS: A temporary reduction of preload was obtained by ventilation with a positive end-expiratory pressure of 10 cmH(2)O. Ischemia was induced by temporary occlusion of the left anterior descending coronary artery for 60 minutes and was followed by 30 minutes of reperfusion. MEASUREMENTS AND MAIN RESULTS: Animals were instrumented with an ultrasonic aortic flow probe to monitor stroke volume (SV) and SVV. Arterial pressure and PPV were recorded with a microtip catheter; left ventricular volume and pressure were registered by a conductance catheter. Respective hemodynamic measurements were made before, during, and after PEEP; before and after the induction of I/R. Eleven animals survived I/R and were analyzed. Before I/R, SVV (r = 0.87, p < 0.001) and PPV (r = 0.75, p < 0.05) during PEEP correlated significantly with relative changes in SV caused by the release of PEEP. Changes in SVV (r = 0.82, p < 0.01) and PPV (r = 0.67, p < 0.05) correlated significantly with relative changes in SV. After I/R, neither the relations between changes in SV to SVV or PPV during PEEP nor the relations between changes in SVV or PPV to changes in SV reached significance. CONCLUSIONS: SVV and PPV did not reflect volume responsiveness in an experimental model of acute myocardial I/R.