Alwin E. Goetz

Reliability of a new algorithm for continuous cardiac output determination by pulse-contour analysis during hemodynamic instability.

Objective The method of determining continuous cardiac output (CO) with beat-to-beat pulse-contour analysis calibrated by transthoracic thermodilution is gaining much wider clinical acceptance. However, some questions have been raised regarding the reliability of this method during periods of profound hemodynamic instability. We validated the original calculation of pulse-contour analysis and a new, improved algorithm against thermodilution-derived measurements of CO in patients with changes of CO >20%. Design Comparative study. Setting Cardiac surgical intensive care unit of a university hospital. Patients Twenty-four patients after cardiac surgery who experienced changes of CO >±20% during their postoperative course. Interventions CO was measured by transthoracic thermodilution and pulse-contour analysis (PiCCO, PULSION Medical Systems, Munich, Germany) at serial intervals every 60 mins during study periods of 8–44 hrs. During this time, no recalibration of the pulse-contour computer was performed. Measurements and Main Results A total of 517 simultaneous measurements of thermodilution CO and pulse-contour CO measured by the two different algorithms were compared by regression, structural regression, and Bland-Altman analyses. Mean change of CO was 40% ± 27% (range, 20% to 139%), range of systemic vascular resistance was 450–2360 dyne·sec/cm5. Correlation of the original pulse-contour algorithm to thermodilution CO was r = .76, with p = .027; bias was 0.08 L/min, with 1.8 L/min single sd. Correlation of the improved pulse-contour algorithm to thermodilution CO was r = .88, with p = .0001; bias was 0.2 L/min, with 1.2 L/min single sd. Mean CO by the new pulse-contour algorithm did not differ significantly from CO by thermodilution during the study period. The difference between the methods was not influenced by variations of heart rate or arterial pressure. Conclusions CO measurement by arterial pulse-contour analysis based on a new, improved algorithm is reliable, even in patients with profound changes of CO and during periods of hemodynamic instability.

Usefulness of left ventricular stroke volume variation to assess fluid responsiveness in patients with reduced cardiac function.

ObjectiveStroke volume variation as measured by the analysis of the arterial pressure waveform enables prediction of volume responsiveness in ventilated patients with normal cardiac function. The aim of this study was to investigate the ability of monitoring stroke volume variation to predict volume responsiveness and to assess changes in preload in patients with reduced left ventricular function after cardiac surgery. DesignProspective study. SettingUniversity hospital. PatientsFifteen mechanically ventilated patients with a left ventricular ejection fraction <0.35 (study group) and 15 patients with an ejection fraction >0.50 (control group) after coronary artery bypass grafting following admission to the intensive care unit. InterventionsVolume loading with 10 mL of hetastarch 6% times body mass index. If stroke volume index increased >5%, successive volume loading was performed until no further increase in stroke volume index was reached. Measurements and Main ResultsStroke volume variation, central venous pressure, pulmonary artery occlusion pressure (PAOP), and left ventricular end-diastolic area index (LVEDAI) were measured at baseline and immediately after each volume loading step. In both groups, stroke volume variation at baseline correlated significantly with changes in stroke volume index caused by volume loading (p < .01). Further, changes in stroke volume variation as a result of volume loading correlated significantly with the concomitant changes in stroke volume index in both groups (p < .01). Using receiver operating characteristic analysis, in the study group areas under the curve for stroke volume variation, PAOP, central venous pressure, and LVEDAI did not differ significantly. In the control group, the area under the curve for stroke volume variation was statistically larger than for PAOP, central venous pressure, and LVEDAI. ConclusionsContinuous and real-time monitoring of stroke volume variation by pulse contour analysis can predict volume responsiveness and allows real-time assessment of the hemodynamic effect of volume expansion in patients with reduced left ventricular function after cardiac surgery.

Noninvasive Measurement of Regional Cerebral Blood Flow by Near-Infrared Spectroscopy and Indocyanine Green

Clinicians lack a practical method for measuring CBF rapidly, repeatedly, and noninvasively at the bedside. A new noninvasive technique for estimation of cerebral hemodynamics by use of near-infrared spectroscopy (NIRS) and an intravenously infused tracer dye is proposed. Kinetics of the infrared tracer indocyanine green were monitored on the intact skull in pigs. According to an algorithm derived from fluorescein flowmetry, a relative blood flow index (BFI) was calculated. Data obtained were compared with cerebral and galeal blood flow values assessed by radioactive microspheres under baseline conditions and during hemorrhagic shock and resuscitation. Blood flow index correlated significantly (rs = 0.814, P < 0.001) with cortical blood flow but not with galeal blood flow (rs = 0.258). However, limits of agreement between BFI and CBF are rather wide (± 38.2 ± 6.4 mL 100 g−1 min−1) and require further studies. Data presented demonstrate that detection of tracer kinetics in the cerebrovasculature by NIRS may serve as valuable tool for the noninvasive estimation of regional CBF. Indocyanine green dilution curves monitored noninvasively on the intact skull by NIRS reflect dye passage through the cerebral, not extracerebral, circulation.

Stress doses of hydrocortisone reduce severe systemic inflammatory response syndrome and improve early outcome in a risk group of patients after cardiac surgery.

ObjectiveSevere systemic inflammation with a vasodilatory syndrome occurs in about one third of all patients after cardiac surgery with cardiopulmonary bypass. Hydrocortisone has been used successfully to reverse vasodilation in septic patients. We evaluated if stress doses of hydrocortisone attenuate severe systemic inflammatory response syndrome in a predefined risk group of patients after cardiac surgery with cardiopulmonary bypass. DesignRandomized, nonblinded, controlled trial. SettingAnesthesiologic intensive care unit for cardiac surgical patients of an university hospital. PatientsAfter a risk analysis, we enrolled 91 patients into a prospective randomized trial. Patients were included according to the evaluated criteria (preoperative ejection fraction, duration of cardiopulmonary bypass, type of surgery). InterventionsThe treatment group received stress doses of hydrocortisone perioperatively: 100 mg before induction of anesthesia, then 10 mg/hr for 24 hrs, 5 mg/hr for 24 hrs, 3 × 20 mg/day, and 3 × 10 mg/day. Measurements and Main ResultsWe measured various laboratory (e.g., lactate) and clinical variables (e.g., duration of ventilation and length of stay in the intensive care unit), characterizing the patients’ outcome. The two study groups did not differ regarding age, preoperative medication, duration of the cardiopulmonary bypass, and type of surgery. The patients in the treatment group had significantly lower concentrations of IL-6 and lactate, higher antithrombin III concentration, lower need for circulatory and ventilatory support and for transfusions, lower Therapeutic Intervention Scoring System values, and shorter length of stay in the intensive care unit and in the hospital. The mortality rate did not differ significantly between the groups. ConclusionsAlthough we acknowledge the limitations of a nonblinded interventional trial, stress doses of hydrocortisone seem to attenuate systemic inflammation in a predefined risk group of patients after cardiac surgery with cardiopulmonary bypass and improve early outcome.

INDOCYANINE GREEN: INTRACELLULAR UPTAKE AND PHOTOTHERAPEUTIC EFFECTS IN VITRO

Indocyanine green (ICG; absorption peak in human plasma 805 nm) was investigated for ICG-mediated phototherapy in vitro. The cellular uptake of ICG (1 microM-50 microM) into HaCaT keratinocytes after an incubation period of 24 h increased up to an intracellular ICG concentration of 12.1 +/- 1.3 nmol per 10(6) cells. To examine dose dependent phototoxic effects in vitro, keratinocytes were incubated with 0 microM-50 microM ICG for 24 h and irradiated by a diode laser (805 nm) with different energy densities (0, 12, 24, 48 J cm-2). All applied ICG concentrations except for 5 microM yielded a cell killing effect in combination with irradiation depending significantly on ICG concentration and light dose. Cell viability for dark control and cells incubated with 50 microM ICG and irradiated with 48 J cm-2 was 0.82 +/- 0.15 and 0.07 +/- 0.02, respectively. Sodium azide (100 mM), a quencher of reactive oxygen species, inhibited significantly the cell killing using 50 microM ICG and 24 J cm-2. Taken together, photoactivation of ICG by irradiation with a diode laser was shown to induce effectively cell killing of HaCaT keratinocytes. Moreover, this effect was inhibited by sodium azide, thus irradiation of ICG might induce a photodynamic reaction.

Measurement of Neutrophil Content in Brain and Lung Tissue by a Modified Myeloperoxidase Assay

Myeloperoxidase (MPO) activity is assessed for the quantification of neutrophil accumulation in tissues. In particular, it may be used to support in vivo data on leukocyte kinetics obtained by intravital microscopy and to clarify whether phenomena observed on the organ surface reflect the situation of the whole organ microcirculation. Previous measurements of MPO activity were limited by interference with other peroxidases and by inhibition of MPO activity by specific enzymes. To circumvent these limitations, a modified assay was devised that combined a two-step tissue homogenization technique with heat incubation in a continuous photometric measurement. MPO activity was quantified in neutrophils isolated from rat and rabbit whole blood, rat brain and rabbit lung and compared with intravital microscopic data on leukocyte accumulation. The modified assay is characterized by high reproducibility, strong correlation of MPO activity with number of neutrophils and full recovery of neutrophils added to tissue homogenate. MPO activity per neutrophil was 342.9 +/- 11.7 mU/10(6) cells in rats and 40.3 +/- 0.8 mU/10(6) cells in rabbits. MPO activity in tissue was significantly lower in rat brains (18.9 +/- 29.7 mU/g) as compared to rabbit lungs (741 +/- 67 mU/g). Whereas global cerebral ischemia/reperfusion did not increase MPO activity in rat brain (18.1 +/- 26.1 mU/g), intravenous infusion of cobra venom factor (1,447 +/- 407 mU/g) or endotoxin (1,439 +/- 285 mU/g), enhanced MPO activity in rabbit lung. These results parallel microcirculatory data from the organ surface. Therefore they supplement the intravital microscopic observations by demonstrating that these are indeed representative of deeper parenchymal tissue areas.

Beat-to-beat measurement of cardiac output by intravascular pulse contour analysis: A prospective criterion standard study in patients after cardiac surgery

OBJECTIVE To evaluate the accuracy of a new pulse contour method of measuring cardiac output in critically ill patients. DESIGN A prospective criterion standard study. SETTING Cardiac surgery intensive care unit in a university hospital. PARTICIPANTS Nineteen cardiac surgery patients requiring intensive care treatment with pulmonary artery catheters after surgery. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS The pulse contour cardiac output monitor uses transpulmonary bolus thermodilution measurements to calibrate the system. In each patient, the pulse contour cardiac output values were compared with conventional thermodilution. The method described by Bland and Altman and linear regression analysis were used for comparison. The mean difference (bias) +/- standard deviation of differences (precision) was 0.31 +/- 1.25 L/min for pulmonary bolus thermodilution cardiac output versus pulse contour cardiac output and 0.21 +/- 0.73 L/min for pulmonary bolus thermodilution cardiac output versus transpulmonary bolus thermodilution cardiac output. Linear regression (correlation) analyses were pulse contour cardiac output = 0.97 thermodilution + 0.53 (r = 0.88), and transpulmonary cardiac output = 0.87 thermodilution + 1.09 (r = 0.96). There was a small increase 60 minutes after recalibration but not a statistically significant difference between pulse contour cardiac output and pulmonary bolus thermodilution cardiac output (p = 0.52). CONCLUSIONS Bias and precision are acceptable, and the system provides results that agree with conventional thermodilution. This study demonstrates the clinical applicability of the pulse contour cardiac output monitoring system.

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.

Effects of intravenous fat emulsions on lung function in patients with acute respiratory distress syndrome or sepsis

ObjectiveTo investigate whether rapid or slowly infused intravenous fat emulsions affect the ratio of prostaglandin I2/thromboxane A2 in arterial blood, pulmonary hemodynamics, and gas exchange. DesignProspective, controlled, randomized, crossover study. SettingOperative intensive care unit of a university hospital. PatientsEighteen critically ill patients. Ten patients were stratified with severe sepsis, and eight patients had acute respiratory distress syndrome (ARDS). InterventionsPatients were assigned randomly to receive intravenous fat emulsions (0.4 × resting energy expenditure) over 6 hrs (rapid fat infusion) or 24 hrs (slow fat infusion) along with a routine parenteral nutrition regimen, by using a crossover study design. Measurements and Main Results Systemic and pulmonary hemodynamics as well as gas exchange measurements were recorded via respective indwelling catheters. Arterial thromboxane B2 and 6-keto-prostaglandin-F1&agr; plasma concentrations were obtained by radioimmunoassay, and 6-keto-prostaglandin-F1&agr;/thromboxane B2 ratios (P/T ratios) were calculated. Data were collected immediately before and 6, 12, 18, and 24 hrs after onset of fat infusion. In the ARDS group, P/T ratio increased by rapid fat infusion. Concomitantly, pulmonary shunt fraction, alveolar-arterial oxygen tension difference [P(a-a)o2]/Pao2, and cardiac index increased as well, whereas pulmonary vascular resistance and Pao2/Fio2 declined. After slow fat infusion, a decreased P/T ratio was revealed. This was accompanied by decreased pulmonary shunt fraction, lowered P(a-a)o2/Pao2, and increased Pao2/Fio2. Correlations between plasma concentrations of 6-keto-prostaglandin-F1&agr; or thromboxane B2 and measures of respiratory performance could be shown during rapid and slow fat infusion, respectively. In the sepsis group, the P/T ratio remained unchanged at either infusion rate, but pulmonary shunt fraction and P(a-a)o2/Pao2 decreased after rapid fat infusion, whereas Pao2/Fio2 increased. ConclusionPulmonary hemodynamics and gas exchange are related to changes of arterial prostanoid levels in ARDS patients, depending on the rate of fat infusion. In ARDS but not in sepsis patients clear of pulmonary organ failure, a changing balance of prostaglandin I2 and thromboxane A2 may modulate gas exchange, presumably via interference with hypoxic pulmonary vasoconstriction.

Strong and prolonged induction of c-jun and c-fos proto-oncogenes by photodynamic therapy.

Photodynamic therapy (PDT) is currently under investigation in phase II and III clinical studies for the treatment of tumours in superficial localisations. Thus far, the underlying mechanisms of PDT regarding cellular responses and gene regulation are poorly understood. Photochemically generated singlet oxygen (1O2) is mainly responsible for cytotoxicity induced by PDT. If targeted cells are not disintegrated, photo-oxidative stress leads to transcription and translation of various stress response and cytokine genes. Tumour necrosis factor (TNF) alpha, interleukin (IL) 1 and IL-6 are strongly induced by photodynamic treatment, supporting inflammatory action and immunological anti-tumour responses. To investigate the first steps of gene activation, this study focused on the proto-oncogenes c-jun and c-fos, both coding for the transcription factor activator protein 1 (AP-1), which was found to mediate IL-6 gene expression. We here determine the effects of photodynamic treatment on transcriptional regulation and DNA binding of transcription factor AP-1 in order to understand the modulation of subsequent regulatory steps. Photodynamic treatment of epithelial HeLa cells was performed by incubation with Photofrin and illumination with 630 nm laser light in vitro. Expression of the c-jun and c-fos genes was determined by way of Northern blot analysis, and DNA-binding activity of the transcription factor AP-1 was evaluated by electrophoretic mobility shift assay (EMSA). Photofrin-mediated photosensitisation of HeLa cells resulted in a rapid and dose-dependent induction of both genes but preferential expression of c-jun. Compared with the transient expression of c-jun and c-fos by phorbol ester stimulation, photodynamic treatment led to a prolonged activation pattern of both immediate early genes. Furthermore, mRNA stability studies revealed an increased half-life of c-jun and c-fos transcripts resulting from photosensitisation. Although mRNA accumulation after PDT was stronger and more prolonged compared with phorbol ester stimulation, with regard to AP-1 DNA-binding activity, phorbol ester was more efficient. Surprisingly, in addition to the activation of AP-1 DNA-binding via PDT, photodynamic treatment can decrease AP-1 DNA-binding of other strong inducers, such as the protein kinase C-mediated pathway of phorbol esters and the antioxidant pyrrolidine dithiocarbamate (PDTC). This study demonstrates a strong induction of c-jun and c-fos expression by PDT, with prolonged kinetics and mRNA stabilisation as compared with activation by phorbol esters. Interestingly, this observation is not coincident with an overinduction of AP-1 DNA-binding, hence suggesting that post-translational modifications are dominant regulatory mechanisms after PDT that tightly control AP-1 activity in the nucleus thus limiting the risk of deregulated oncogene expression.