The effect of dobutamine infusion on splanchnic blood flow and oxygen transport in patients with acute pancreatitis

Objectives: To measure the blood flow distribution and oxygen transport in pancreatitis and to evaluate the regional effects of increased systemic blood flow. Design: Nonrandomized controlled trial. Setting: A general intensive care unit in a tertiary care center. Patients: 10 patients with pancreatitis requiring mechanical ventilation were studied after fluid resuscitation, and for the response to dobutamine, the patients served as their own controls. For the baseline, 11 patients scheduled for elective abdominal surgery served as a control group. Interventions: Systemic and regional hemodynamics were measured after fluid resuscitation to predefined hemodynamic endpoints. In patients with pancreatitis, the measurement was repeated after cardiac output had been increased by at least 25 % by dobutamine. Measurements and results: Hepatosplanchnic blood flow was estimated using regional catheterization and the dye dilution method. In patients with pancreatitis, the cardiac index did not differ from that of the control group (3.9 ± 0.8 vs 4.1 ± 0.7 l · min^–1· m^–2;NS). Accordingly, there was no difference in the splanchnic blood flow (1.1 ± 0.4 vs 1.2 ± 0.5 l · min^–1· m^–2;NS). Systemic and splanchnic oxygen consumption was increased in patients with pancreatitis (179 ± 25 vs 147 ± 27 ml · min^–1· m^–2, p < 0.05 and 68 ± 15 vs 49 ± 19 ml · min^–1· m^–2, p < 0.05), and systemic and splanchnic oxygen extraction was higher (0.34 ± 0.08 vs23 ± 0.05, p < 0.01 and 0.46 ± 0.18 vs 0.28 ± 0.08, p < 0.05, respectively). Dobutamine had inconsistent effects on splanchnic blood flow: in individual patients, splanchnic blood flow even decreased substantially. Conclusions: In severe pancreatitis, oxygen consumption is increased in the splanchnic region; increased splanchnic oxygen demand is not always met by adequately increased blood flow. Increasing the systemic blood flow with dobutamine does not improve perfusion in the splanchnic bed. Received: 24 September 1996 Accepted: 5 May 1997     

Effect of enteral versus parenteral feeding on hepatic blood flow and steady state propofol pharmacokinetics in ICU patients

Objective: The main objective of this study was to evaluate the effect of switching from parenteral to enteral feeding on liver blood flow and propofol steady-state blood concentrations in patients in the intensive care unit (ICU). Design and patients: Steady-state blood concentrations of propofol were measured in eight ICU patients before (on days D –3, D –2, and D –1) and after (on days D + 1, D + 2, and D + 3) switching from parenteral to enteral feeding (on day D0). All patients received a continuous intravenous infusion of propofol (4.5 mg · kg^–1· h^–1) from several days before the start of the study, continuing throughout the experimental period. Hepatic blood flow was estimated by measuring steady-state D-sorbitol hepatic clearance. Results: Hepatic blood flow was high and was not affected by switching from parenteral to enteral feeding: 33 ± 8 ml · min^–1· kg^–1 (mean ± SD) and 33 ± 10 ml · min^–1· kg^–1 on D-3 and D –1, respectively, as compared to 37 ± 11 ml · min^–1· kg^–1 and 34 ± 8 ml · min^–1· kg^–1 on days D + l and D + 3, respectively. Systemic clearance of propofol was much higher than liver blood flow with average values on the six observation days ranging from 74.0 to 81.2 ml · min^–1· kg^–1 and was not affected by switching from parenteral to enteral feeding. Conclusions: Liver blood flow and systemic clearance of propofol were not affected by switching from parenteral to enteral feeding in the eight ICU patients studied. Extrahepatic clearance accounted for at least two thirds of the overall systemic clearance of propofol. Received: 18 July 1997 Accepted: 1 April 1998     

Use of an artificial oxygen carrier in isolated rat liver perfusion: first demonstration of net glucose uptake at physiological portal glucose concentrations using a hemoglobin-free perfusate

A defect in isolated perfused rat-liver (IPRL) preparations has been proposed to explain discrepancies between in vivo and in vitro findings regarding hepatic glucose metabolism. The aim of the present study was to investigate whether a preparation of IPRL using a synthetic hemoglobin-free perfusate was capable of net glucose uptake and glycogen deposition at physiological portal substrate concentrations. Livers from fed anaesthetized rats were perfused in a recirculating system using a fluorocarbon emulsion as artificial oxygen carrier. Depending on the prevailing glucose concentration, livers exhibited net glucose uptake or release with a threshold value of 5.5–6.0 mM glucose. Net glucose uptake was associated with net glycogen deposition (+0.23 to +0.59 μmol C₆ min⁻¹g⁻¹). From 5.8 mM (n=3) and 10.0 mM (n=8), initial concentration glucose levels fell to 5.3±0.2 mM after 210 min (n=3) and 6.3±0.9 mM after 120 min (n=8), respectively. This was equivalent to a net glucose uptake of −0.16 and −0.45 μmol min⁻¹g⁻¹. Anoxia reversibly switched hepatic glucose balance from net uptake (−0.42 μmol min⁻¹g⁻¹) to release (+0.69 μmol min⁻¹g⁻¹) followed by net uptake (−0.50 μmol min⁻¹g⁻¹) after reinstitution of aerobic conditions. We conclude that the composition of perfusion media might play a pivotal role for studies of glucose metabolism in the isolated perfused rat liver. In our experimental model, using a hemoglobin-free synthetic medium, net glucose uptake was readily demonstrated at physiological portal substrate concentrations similar to the in vivo situation.     

Oxygen supply dependency can characterize septic shock

Objective: To demonstrate that oxygen consumption (VO₂) can be dependent on oxygen delivery (DO₂) during hemodynamic instability and independent of DO₂ following stabilization. Design: We retrospectively reviewed hemodynamic and blood gas data collected from ten patients in whom DO₂ was acutely altered during an episode of septic shock (phase A) and after recovery from this episode (phase B). Setting: General intensive care unit of a university hospital. Patients: 10 critically ill adult patients (aged 55 ± 19 years). Interventions: DO₂ was altered by fluid challenge, administration of vasoactive agents, or application of positive end-expiratory pressure. Results: In phase A, changes in VO₂ (121 ± 32 vs 165 ± 36 ml/min · m²; p < 0.001) paralleled changes in DO₂ (415 ± 153 vs 607 ± 217 ml/min · m²; p < 0.001), but oxygen extraction (O₂ER) remained stable (31.9 ± 11.2 vs. 30.2 ± 8.9 %; NS). In phase B, changes in DO₂ (412 ± 118 vs 526 ± 152 ml/min · m²; p < 0.001) were associated with opposite changes in O₂ER (36.1 ± 4.2 vs 28.9 ± 4.9 %; p < 0.001), and VO₂ was unchanged (147 ± 35 vs 149 ± 33 ml/min · m²; NS). The mean VO₂/DO₂ slope was greater in phase A than in phase B (0.26 ± 0.09 vs. 0.08 ± 0.08; p < 0.004). Blood lactate levels were higher in phase A than in phase B (3.3 ± 1.8 vs 1.6 ± 0.6 mEq/l; p < 0.05). Conclusions: Oxygen supply independency and dependency can be found at different times in the same critically ill patient. Our findings are consistent with the concept that VO₂/DO₂ dependency is a marker of septic shock. Interventions to increase DO₂ are probably justified when this phenomenon is present. Received: 17 February 1997 Accepted: 6 November 1997     

Accuracy and reproducibility of long-term implanted transit-time ultrasound flow probes in dogs

Objective: To assess the accuracy and reproducibility of long-term implanted ultrasound transit-time flow probes for measuring cardiac output. Design: Prospective animal study. Settings: Animal research laboratory in a university department. Animals: Eleven anaesthetised dogs, 24–34 kg. Measurements and results: Flow probes (16–24 mm S-series, Transonic) were implanted around the pulmonary artery for a mean duration of 22 months (range 6–47 months). Comparisons (n = 147) were made between cardiac output thus obtained and that measured by the direct Fick principle using oxygen uptake (Deltatrac II Metabolic Monitor) and the arterial to mixed venous oxygen content difference measured by a galvanic cell (Lex-O₂-Con-TL). Measurements were made either during baseline conditions or during pharmacologically altered cardiac output (range 22–180 ml · kg^–1· min^–1). Regardless of the intervention, the two methods yielded the same results in half of the dogs. In the others, however, cardiac output was underestimated by the flow probes by up to 38 % (probably because of non-perpendicular position of the probe towards the vessel). This difference was constant for the whole range of cardiac output studied and remained constant over the entire observation period for each individual dog, so that a correction factor was used. Thereafter, the mean difference between the two methods was –1.1 ml · kg^–1· min^–1 with a precision (SD) of 14.2 ml · kg^–1· min^–1 for all experiments. Conclusions: After in vivo calibration, ultrasound transit-time flow probes measure cardiac output precisely for several years, regardless of the intervention. Received: 1 October 1999 Final revision received: 6 January 2000 Accepted: 4 February 2000     

Hypercapnia induces a concentration-dependent increase in gastric mucosal oxygenation in dogs

Objective  To clarify the effects of hypercapnia (increased PaCO₂) on gastric mucosal oxygenation during anaesthesia in dogs. Design  Prospective, controlled animal study. Setting  Experimental research laboratory of an university hospital. Subjects  Six chronically instrumented dogs. Interventions  Dogs were anaesthetized (sevoflurane 1.5 MAC), mechanically ventilated (etCO₂ = 35 mmHg) and randomly assigned to the following protocols: in a first series, ventilation was adjusted to increase etCO₂ to 45, 55, 65 and 70 mmHg. In a second series, animals were ventilated to achieve 70 mmHg of etCO₂, which was maintained for 120 min to test if effects are transient or prolonged and to achieve a similar time course in both protocols. Measurements and main results  Gastric mucosal oxygenation (μHbO₂) was assessed continuously by tissue reflectance spectrophotometry. Mean arterial blood pressure (MAP) and cardiac output (CO) were continuously measured. Blood was sampled for blood gas analysis and lactate concentration. Hypercapnia increased gastric mucosal oxygenation concentration dependently from 48 ± 6% (35 mmHg etCO₂) to 51 ± 4, 54 ± 5, 56 ± 5 and 59 ± 3% (etCO₂ 45, 55, 65 and 70 mmHg, respectively). This reflected changes in CO (68 ± 16, 74 ± 16, 82 ± 12, 91 ± 11 and 97 ± 16 ml kg⁻¹ min⁻¹, respectively) and systemic oxygen delivery (10 ± 2, 11 ± 3, 13 ± 2, 14 ± 2 and 14 ± 2 ml kg⁻¹ min⁻¹, respectively). These effects persisted for 2 h (μHbO₂ 53 ± 6 vs. 64 ± 4%, CO 73 ± 16 vs. 92 ± 15 ml kg⁻¹ min⁻¹, DO₂ 12 ± 4 vs. 14 ± 3 ml kg⁻¹ min⁻¹, etCO₂ 35 and 70 mmHg, respectively). Conclusions  Hypercapnia increased systemic and regional oxygenation. If this experimental finding may be transferred to the clinical setting, permissive hypercapnia might be used to augment the oxygenation of the splanchnic region, e.g. gastrointestinal mucosa. Ingo Schwartges, Lothar A. Schwarte have contributed equally to this work. Parts of the study have been presented as an abstract (ESICM Congress 2005, ESICM Poster Award 2005, Intesive Care Medicine, Volume 31, Supplement 1/September 2005, p151 No. 578). This article is discussed in the editorial available at: doi:     

Effects of 15-deoxy-Δ12,14-prostaglandin-J2 during hyperdynamic porcine endotoxemia

Objective To investigate the hemodynamic and metabolic effects of the peroxisome proliferator-activated receptor (PPAR)-γ ligand and nuclear-factor (NF)-κ B inhibitor 15-deoxy-Δ^12,14-prostaglandin-J₂ (15d-PGJ₂) during long-term, hyperdynamic porcine endotoxemia.Design Prospective, randomized, controlled experimental study with repeated measures.Setting Investigational animal laboratory.Subjects 19 anesthetized, mechanically ventilated and instrumented pigs.Interventions At 12 h of continuous intravenous endotoxin and hydroxyethylstarch to keep mean arterial pressure (MAP) > 60 mmHg, swine randomly received vehicle (control group, n = 10) or 15-deoxy-Δ^12,14-prostaglandin-J₂ (15d-PGJ₂ group, n = 9; 1 μg kg⁻¹ min⁻¹loading dose during 1 h; thereafter,0.25 μg kg⁻¹ min⁻¹ for 11 h).Measurements and results Hemodynamic, metabolic and organ function parameters were assessed together with parameters of nitric oxide production and oxidative stress. 15d-PGJ₂ prevented the endotoxin-induced progressive hypotension, due to a positive inotropic effect, which resulted in a significantly higher blood pressure during the treatment phase and prevented the rise in hepatic vein alanine-aminotransferase activity. It did not affect, however, any other parameter of organ function nor of nitric oxide production, proinflammatory cytokine release or lipid peroxidation (8-isoprostane).Conclusions 15d-PGJ₂ stabilized systemic hemodynamics, due to improved myocardial performance, and resulted in an only transient effect on alanine-aminotransferase activity, without further beneficial effect on endotoxin-induced metabolic and organ function derangements. Low tissue 15d-PGJ₂ concentrations and/or the delayed drug administration may explain these findings.B. Hauser and J. Kick equally contributed to this work. Presented in abstract form at the 11th Congress of the European Shock Society, Vienna, January 27–30, 2005     

Comparison of norepinephrine and dobutamine to epinephrine for hemodynamics, lactate metabolism, and gastric tonometric variables in septic shock: a prospective, randomized study

Objectives: To compare the effects of norepinephrine and dobutamine to epinephrine on hemodynamics, lactate metabolism, and gastric tonometric variables in hyperdynamic dopamine-resistant septic shock. Design: A prospective, intervention, randomized clinical trial. Setting: Adult medical/surgical intensive care unit in a university hospital. Patients: 30 patients with a cardiac index (CI) > 3.5 l · min^–1· m^–2 and a mean arterial pressure (MAP) ≤ 60 mmHg after volume loading and dopamine 20 μg/kg per min and either oliguria or hyperlactatemia. Interventions: Patients were randomized to receive an infusion of either norepinephrine-dobutamine or epinephrine titrated to obtain an MAP greater than 80 mmHg with a stable or increased CI. Measurements and main results: Baseline measurements included: hemodynamic and tonometric parameters, arterial and mixed venous gases, and lactate and pyruvate blood levels. These measurements were repeated after 1, 6, 12, and 24 h. All the patients fulfilled the therapeutic goals. No statistical difference was found between epinephrine and norepinephrine-dobutamine for systemic hemodynamic measurements. Considering metabolic and tonometric measurements and compared to baseline values, after 6 h, epinephrine infusion was associated with an increase in lactate levels (from 3.1 ± 1.5 to 5.9 ± 1.0 mmol/l; p < 0.01), while lactate levels decreased in the norepinephrine-dobutamine group (from 3.1 ± 1.5 to 2.7 ± 1.0 mmol/l). The lactate/pyruvate ratio increased in the epinephrine group (from 15.5 ± 5.4 to 21 ± 5.8; p < 0.01) and did not change in the norepinephrine-dobutamine group (13.8 ± 5 to 14 ± 5.0). Gastric mucosal pH (pHi) decreased (from 7.29 ± 0.11 to 7.16 ± 0.07; p < 0.01) and the partial pressure of carbon dioxide (PCO₂) gap (tonometer PCO₂– arterial PCO₂) increased (from 10 ± 2.7 to 14 ± 2.7 mmHg; p < 0.01) in the epinephrine group. In the norepinephrine-dobutamine group pHi (from 7.30 ± 0.11 to 7.35 ± 0.07) and the PCO₂ gap (from 10 ± 3.0 to 4 ± 2.0 mmHg) were normalized within 6 h (p < 0.01). The decrease in pHi and the increase in the lactate/pyruvate ratio in the epinephrine group was transient, since it returned to normal within 24 h. Conclusions: Considering the global hemodynamic effects, epinephrine is as effective as norepinephrine-dobutamine. Nevertheless, gastric mucosal acidosis and global metabolic changes observed in epinephrine-treated patients are consistent with a markedly inadequate, although transient, splanchnic oxygen utilization. The metabolic and splanchnic effects of the combination of norepinephrine and dobutamine in hyperdynamic dopamine-resistant septic shock appeared to be more predictable and more appropriate to the current goals of septic shock therapy than those of epinephrine alone. Received: 7 May 1996 Accepted: 30 October 1996     

Pharmacokinetics of milrinone in patients with congestive heart failure during continuous venovenous hemofiltration

Objective: To evaluate the pharmocokinetics of intravenous milrinone in patients with severe congestive heart failure during continuous venovenous hemofiltration (CVVH). Design: Prospective study of patients with congestive heart failure admitted to the intensive care unit (ICU). Setting: ICU between September 1997 and August 1999. Patients and methods: Six patients with severe congestive heart failure during CVVH: all patients received a continuous infusion of milrinone of 0.25 μg · kg^{− 1}· min^{− 1}. The hemodynamics and plasma concentration of milrinone were measured before and after the infusion. Pharmacokinetics were analyzed with one-compartment model featuring constant rate infusion. Results: The steady-state concentration (Css) was 845 ± 135 (mean ± SD) ng/ml, and the half-life time (t_1/2) was 20.1 ± 3.3 h. Cardiac index and stroke volume index after the infusion of milrinone increased significantly compared with pre-infusion levels. Other hemodynamic parameters did not change significantly. All patients died within 1 month after the injection of milrinone because of severe forms of arrhythmia, such as ventricular tachycardia and ventricular fibrillation. Conclusions: We found that the mean Css and the mean t_1/2 of milrinone in subjects during CVVH were much higher and longer than those previously reported for subjects with normal renal function. It is therefore essential to adjust the dose or modify the dosing interval of milrinone during renal replacement therapy for patients with severe congestive heart failure. However, further studies are needed to determine the details of pharmacokinetics of milrinone and therapeutic procedures for patients with severe heart failure during CVVH. Received: 1 December 1999 Final revision received: 9 March 2000 Accepted: 11 April 2000     

Extracorporeal life support in a case of acute carbamazepine poisoning with life-threatening refractory myocardial failure

Objective To report the efficacy of extracorporeal life support (ECLS) in acute carbamazepine poisoning with sustained refractory myocardial failure and a high degree of conductance disturbances.Design and setting Case report from the toxicological and medical intensive care unit in a university hospital.Patient A 26-year-old man with severe myocardial failure unresponsive to 1.7 μg kg⁻¹ min⁻¹ epinephrine and 1.9 μg kg⁻¹ min⁻¹ norepinephrine (SvO₂, 17.8% and cardiac index, 0.8 l min⁻¹ m⁻²) following a suicidal ingestion of 32 g slow-release carbamazepine.Interventions ECLS (Jostra-Maquet centrifugal pump (Rotaflow) connected to a hollow-fiber membrane oxygenator).Measurements and results ECLS device allowed inotropic drug weaning while maintaining end-organ function and supported the patient until myocardial recovery. The plasma carbamazepine level was 224 μmol/l on admission and peaked at 338 μmol/l 101 h after admission with a prolonged gastrointestinal absorption phase despite multiple doses of activated charcoal. The patient survived and was successfully explanted on day 6. An extensive and regressive thrombosis of the inferior vena cava was noted. Cardiac function totally recovered and at 2-year follow-up. There were no significant sequelae.Conclusions We report a case of life-threatening myocardial failure with conductance disturbances secondary to an acute carbamazepine poisoning, demonstrating the efficacy of ECLS to assist recovery.     

Splanchnic oxygen transport after cardiac surgery: evidence for inadequate tissue perfusion after stabilization of hemodynamics

Objective To evaluate the adequacy of visceral oxygen transport and gastric pH_i after open heart surgery in patients with stable hemodynamics.Design Nonrandomized control trial.Setting A general intensive care unit in a tertiary care center.Patients Sixteen postoperative cardiac surgery patients were studied after stabilization of systemic hemodynamics.Interventions The effect of dobutamine infusion (6 g kg^–1 min^–1) on systemic and regional oxygen transport was studied in ten patients, with six patients serving as controls. Systemic oxygen consumption was measured by indirect calorimetry and splanchnic and femoral blood flow, by continuous infusion of indocyanine green using regional catheters and gastric mucosal pH_i by gastric tonometer.Measurements and results Gastric mucosal acidosis was observed in half of the patients. Dobutamine increased cardiac output (3.2±0.6 vs 4.4±0.7l· min^–1·m^–2;P<0.05), splanchnic blood flow (0.68±0.28 vs 0.91±0.281· min^–1·m^–2;p<0.05) and femoral blood flow (0.25±0.08 vs 0.32±0.11l·min^–1·m^–2;p<0.05). Changes in splanchnic oxygen delivery and consumption were parallel in the two study groups. In response to dobutamine, gastric pH_i did not change (7.30±0.08 vs 7.31±0.06; NS), while in the control group, gastric pH_i tended to decrease (7.32±0.04 vs 7.28±0.06; NS). Systemic oxygen consumption increased in response to dobutamine (141±11 vs 149±11 ml· min^–1·m^–2;P<0.05) but did not change in the control group.Conclusions We conclude that a mismatch between splanchnic oxygen delivery and demand may be present despite stabilization of systemic hemodynamics after cardiac surgery. This is suggested by the parallel changes in splanchnic oxygen delivery and consumption. Dobutamine is likely to improve splanchnic tissue perfusion at this phase.This study was supported in part by the senior researcher's grant no. 1945/3015/92 to Dr. Takala from the Academy of Finland     

Normal values of SvO2 as therapeutic goal in patients with multiple injuries

Objective: To determine whether maintaining normal levels of mixed venous oxygen saturation (SvO₂) in patients with multiple injuries is more relevant to survival than maintaining above-normal levels of oxygen transport. Design: Non-randomised, retrospective control study over a 38-month period. Setting: Multidisciplinary intensive care unit in a university hospital. Patients: 40 patients with multiple injuries divided in to group A (23 patients) and group B (17 patients). Interventions: In group A patients, we maintained normal SvO₂ by manipulation of oxygen transport variables; oxygen delivery (DO₂) was increased only if SvO₂ decreased or the dobutamine test was positive. In group B patients, DO₂ was routinely maintained at above-normal levels by aggressive use of fluids and dobutamine. Measurements and results: In group A we measured SvO₂ continuously and performed the dobutamine test. Oxygen transport-related variables were recorded every 12 h in the first 5 days after injury in both groups, as well as lactate concentrations. Survival was significantly greater in group A than in group B (p<0.01). Multiple organ failure was less frequent in group A than in group B (p<0.01). The average DO₂ in group A was significantly lower than in group B from day 2 onwards (p<0.05–0.01). Average values of DO₂ of 605–688 ml/min per m² were required to maintain normal SvO₂ and aerobic metabolism in group A; 10 patients required dobutamine 2.5–5 μg/kg per min. The average DO₂ in group B was 622 ml/min per m² on day 1 and then it increased to 835 ml/min per m² on day 5 after trauma. Conclusions: Our results indicate that for patients with multiple injuries maintaining normal SvO₂ values and increasing DO₂ only if required are more relevant for survival than routine maintenance of above-normal oxygen transport values. Received: 4 March 1996 Accepted: 28 September 1996     

The effect of iNOS deletion on hepatic gluconeogenesis in hyperdynamic murine septic shock

Objective To investigate the role of the inducible nitric oxide synthase activation-induced excess nitric oxide formation on the rate of hepatic glucose production during fully resuscitated murine septic shock. Design Prospective, controlled, randomized animal study. Setting University animal research laboratory. Subjects Male C57Bl/6 and B6.129P2-Nos2^tm1Lau/J (iNOS^−/−) mice. Interventions Fifteen hours after cecal ligation and puncture, anesthetized, mechanically ventilated and instrumented mice (wild-type controls, n = 13; iNOS^−/−, n = 12; wild-type mice receiving 5 mg·kg⁻¹ i.p. of the selective iNOS inhibitor GW274150 immediately after cecal ligation and puncture, n = 8) received continuous i.v. hydroxyethylstarch and norepinephrine to achieve normotensive and hyperdynamic hemodynamics. Measurements and results Measurements were recorded 18, 21 and 24 h after cecal ligation and puncture. Liver microcirculatory perfusion and capillary hemoglobin O₂ saturation (laser Doppler flowmetry and remission spectrophotometry) were well maintained in all groups. Despite significantly lower norepinephrine doses required to achieve the hemodynamic targets, the rate of hepatic glucose production (gas chromatography–mass spectrometry measurements of tissue isotope enrichment during continuous i.v. 1,2,3,4,5,6-¹³C₆-glucose infusion) at 24 h after cecal ligation and puncture was significantly higher in both iNOS^−/− and GW274150-treated mice, which was concomitant with a significantly higher hepatic phosphoenolpyruvate carboxykinase activity (spectrophotometry) in these animals. Conclusions In normotensive, hyperdynamic septic shock, both pharmacologic and genetic deletion of the inducible nitric oxide synthase allowed maintenance of hepatic glucose production, most likely due to maintained activity of the key regulatory enzyme of gluconeogenesis, phosphoenolpyruvate carboxykinase. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. G. Albuszies and J. Vogt contributed equally to this article.     

Haemodynamic changes and skeletal muscle oxygen tension during complete blood exchange with ultrapurified polymerized bovine haemoglobin

Objective: The study investigates the effect of continuous blood exchange with ultrapurified, polymerized bovine haemoglobin (UPBH) in comparison to hetastarch on haemodynamics, oxygen transport and skeletal muscle oxygen tension in a canine model. Design: Sixteen anaesthetized beagle dogs underwent haemodilution with lactated Ringer's to a starting haematocrit of 20 % followed by progressive blood exchange with 6 % hetastarch 200,000/0.5 (HES, group 1) or UPBH (haemoglobin 13 ± 1 g · dl⁻¹, molecular weight (MW) 32–500,000, group 2) to haematocrit target levels of 15 %, 10 % and 5 % or less. Measurements and results: Besides haemodynamics, skeletal muscle tissue oxygen tension (tPO₂) was measured using a polarographic needle probe. In HES-treated animals, heart rate, cardiac output and blood flow were higher while systemic vascular resistance, systemic and regional arterio-venous oxygen difference (avDO₂) and oxygen extraction ratios were lower when compared to the UPBH group. In spite of a higher final haematocrit of 5 % in group 1, in comparison to group 2 with 2 %, final muscular oxygen uptake (4.7 ± 4 vs 10.1 ± 2 ml · min⁻¹) and mean tPO₂ (11.8 ± 2.3 vs 51.1 ± 2.9 mm Hg) were lower in group 1 than in group 2. While tPO₂ histograms were continuously shifted to lower oxygen tensions during progressive haemodilution with HES, UPBH-exchanged animals showed tPO₂ histograms shifted to higher values than baseline. Conclusion: In spite of vasoconstriction, UPBH provided more haemodynamic stability and enhanced skeletal muscle tPO₂ during progressive blood exchange when compared to HES. Received: 30 December 1996 Accepted: 16 June 1997     

Characterisation of left ventricular relaxation in the isolated guinea pig heart

The time constant of left ventricular pressure fall, τ, has frequently been used as a measure of myocardial relaxation in the blood-perfused, ejecting heart. The aim of the present study was to characterise τ in relation to β-adrenergic activation, coronary perfusion pressure and flow as well as cardiac oxygen supply and demand in the isolated, isovolumically beating heart. Therefore, τ was analysed from digitised left ventricular pressure data in a total of 23 guinea pig hearts perfused with saline at constant pressure (60 cmH₂O). The coronary venous adenosine concentration ([ADO]) served as an index of myocardial oxygenation. Isoprenaline (0.4–3.2 nmol l⁻¹) decreased and propranolol (3–9 μmol l⁻¹) increased τ dose-dependently (linear regression τ vs lg ([isoprenaline]),r=0.74; τ vs. lg([propranolol]),r=0.66, bothP<0.05). During graded reductions in cardiac oxygen supply from 96.1±12.6(SEM) to 44.4±4.4 μl min⁻¹ g⁻¹, τ was prolonged from 61.5±12.7 to 109.9±22.6 ms while left ventricular developed pressure (LVDP) decreased from 90.7±7.2 to 40.7±5.1 mmHg. In parallel, [ADO] increased from 23.7±9.1 to 58.0±19.1 pmol ml⁻¹ (P<0.05). Increasing oxygen supply to 165.4±32.4 μl min⁻¹ g⁻¹ augmented LVDP to 102.7±7.3 mmHg but did not change τ or [ADO]. There was a dual response of τ to changes in cardiac oxygen supply or demand. As long as oxygen supply and demand matched, τ remained constant. However, when the oxygen supply was less than 100 μl min⁻¹g⁻¹, left ventricular relaxation was prolonged in parallel to the reduction in oxygen supply. In addition, a close relationship was observed between [ADO] as an indicator of myocardial oxygenation and τ (Spearman correlation,r=0.99,P<0.005). We conclude that the time constant of left ventricular pressure fall, τ, sensitively reflects myocardial relaxation in the isolated, isovolumically beating guinea pig heart. Moreover, in this model left ventricular relaxation is not influenced by alterations in coronary perfusion pressure or flow as long as cardiac oxygen demand is matched by an adequate supply. Rather, relaxation is strictly coupled to myocardial oxygenation as reflected by coronary venous adenosine concentrations.     

Vasopressin or norepinephrine in early hyperdynamic septic shock: a randomized clinical trial

Objective To compare the effects of arginine-vasopressin (AVP) and norepinephrine (NE) on hemodynamic variables, organ dysfunction, and adverse events in early hyperdynamic septic shock.Design and setting Randomized, controlled, open-label trial.Patients and participants Twenty-three patients with early (12 h) hyperdynamic septic shock in two teaching hospitals.Interventions AVP (0.04–0.20 U min^–1, n = 13) as a single agent or NE (0.1–2.8 μg kg^–1 min^–1, n = 10) infusion for 48 h to achieve mean arterial pressure at or above 70 mmHg.Measurements and results Hemodynamic parameters and Sequential Organ Failure Assessment (SOFA) score were measured. AVP and NE equally increased mean arterial pressure over 48 h, but NE was required in 36% of AVP patients at 48 h. Compared to baseline, AVP increased systemic vascular resistance, decreased exposure to NE, decreased cardiac output by decreasing heart rate, increased creatinine clearance, and improved SOFA score. The PrCO₂ – PaCO₂ difference remained stable throughout the study. One AVP patient developed acute coronary syndrome with dose-dependent ECG changes. Three patients in both groups died during their ICU stay.Conclusion In early hyperdynamic septic shock, the administration of high-dose AVP as a single agent fails to increase mean arterial pressure in the first hour but maintains it above 70 mmHg in two-thirds of patients at 48 h. AVP decreases NE exposure, has no effect on the PrCO₂ – PaCO₂ difference, and improves renal function and SOFA score.This work was supported by the Cardiovascular Critical Care research Network FRSQ and departmental funding.     

Plasma lipid and lipoprotein profiles in pre- and post-menopausal middle-aged runners

Summary. Plasma lipid and lipoprotein profiles were compared in middle-aged trained and untrained women before and after menopause. Subjects were assigned to one of four groups: (1) pre-menopausal trained (Pre-T: n= 17, aged 42 ±5 years, body fat 19±5%, training distance 53 ±20 km week^-1, V?o_2max 49 ±4 ml kg^-1 min^-1, mean±SD); (2) pre-menopausal untrained (Pre-UT: n= 26, 42 ±5 years, 24 ±7%, 34 ±6 ml kg^-1 min^-1); (3) post-menopausal trained (Post-T: n= 16, 54 ±3 years, 20 ±4%, 43 ±19 km week^-1, 41 ±5 ml kg^-1 min^-1); and (4) post-menopausal untrained (Post-UT: n= 15, 55 ±3 years, 25 ±6%, 31 ±3 ml kg^-1 min^-1). There were no significant differences in total cholesterol (range 173–194 mg dl^-1), triglyceride (56–72 mg dl^-1), and HDL-cholesterol (HDLC: 76–85 mg dl^-1) among the four groups. LDL-cholesterol (LDLC) in the post-menopausal women (Post-T: 96 ±32 mg dl^-1; Post-UT: 104 ±23 mg dl^-1) tended to be higher than in the premenopausal women (Pre-T: 86 ± 25 mg dl^-1, Pre-UT: 81 ± 23 mg dl^-1). LDLC/HDLC ratio in Post-UT (1·42 ±0·38 unit) was higher than in the pre-menopausal women (Pre-T: 1·03±0·31 unit, P<0·01; Pre-UT: 1·10±0·38 unit, P<0·05), whereas the ratio in Post-T (1·20 ±0·38 unit) was not different from those of the pre-menopausal groups. These results suggest that endurance running protects against the increase in LDLC/HDLC ratio that frequently occurs after menopause.     

Influence of combined intravenous and oral glucose administration on splanchnic glucose uptake in man

Summary. The influence of intravenous plus oral glucose administration on splanchnic glucose handling was examined in healthy young individuals by combining the hepatic vein catheterization technique with the double glucose tracer method. After 1 h of steady state hyperglycaemia (11·7 Itim ) induced by intravenous glucose alone (hyperglycaemic clamp technique), subjects ingested 89 ± 1 g of glucose, and the hyper-glycaemic plateau was maintained for the subsequent 4 h by adjusting the exogenous glucose infusion rate. Over the 4-h absorptive period, only 51 ± 4 g of oral glucose (i.e. 58 ±4% of the ingested load) appeared in the systemic circulation, while 193 ± 15 g (1·072±0·083 mol) of glucose had to be infused exogenously to sustain the hyperglycaemia. Endogenous glucose production was suppressed by over 60%. Net splanchnic glucose balance switched from a positive value (i.e. net uptake) of 506 ± 2–56 uniol min^-1kg^-1with intravenous glucose alone (0·60 min) to a negative one (i.e. net output) of 12·50 ± 2·44 u. mol min^-1kg^-1during 4 h (60–300 min) of intravenous+oral glucose. The mean rate of splanchnic glucose uptake was estimated to be 6·39 ±4·67 ixmol min^-1kg^-1with intravenous glucose alone, and 8·83 ±4·28 u. mol min^-1kg^-1with intravenous+oral glucose. In either case, the large majority (80–90%) of the glucose appearing in the systemic circulation was disposed of by extrasplanchnic tissues. These results indicate that pre-existing hyperglycaemia and/or hyperinsulinaemia inhibit gastrointestinal glucose absorption, and that oral glucose administration does not result in a major redistribution of intravenous glucose between splanchnic and extrasplanchnic tissues.     

Combination of inhaled nitric oxide and intravenous prostacyclin for successful treatment of severe pulmonary hypertension in a patient with acute respiratory distress syndrome

Objective: To investigate the combination of inhaled nitric oxide (iNO) and intravenously administered prostacyclin (i. v. PGI₂) in a patient with severe pulmonary hypertension and acute respiratory distress syndrome (ARDS). Design: Single case study. Setting: Intensive care unit of a university hospital. Methods: In an ARDS patient with severe pulmonary hypertension, gas exchange and hemodynamics were measured during combined treatment with iNO and i. v. PGI₂. On two subsequent days, a protocol consisting of four 20-min periods was performed: baseline, 10 ppm iNO, 10 ppm iNO plus 4 ng kg⁻¹ min⁻¹, and 4 ng kg⁻¹ min⁻¹ PGI₂ alone. At the end of each period hemodynamic and gas exchange data were obtained. Results: The combination of iNO and i. v. PGI₂ resulted in a marked decrease in pulmonary artery pressure and a concomitant increase in cardiac output which was more pronounced than the effect of either drug alone. During iNO, as well as during the combination of iNO and i. v. PGI₂, oxygenation was improved, whereas during i. v. PGI₂ alone oxygenation was worse than baseline. Conclusion: We conclude that the combination of iNO and i. v. PGI₂ might be more useful than either drug alone when severe pulmonary hypertension leading to impaired right ventricular function is present in ARDS. A systematic study of this observation is warranted. Received: 19 November 1998 Final revision received: 18 February 1999 Accepted: 12 April 1999     

Tracing best PEEP by applying PEEP as a RAMP

Objective: The aim of this study was to show the feasibility of a slow, continuously increasing level of positive end-expiratory pressure (PEEP) (ramp manoeuvre) in selecting best PEEP and to evaluate whether best PEEP, as definded by maximal oxygen transport, coincides with best systemic arterial oxygenation or best compliance. Design: In 11 anaesthetized piglets, PEEP was increased between 0 cmH₂O (zero end-expiratory pressure; ZEEP) and 15 cmH₂O (PEEP₁₅) with a constant rate of 0.67 cmH₂O · min⁻¹. This ramp manoeuvre was performed both under normal conditions and after induction of an experimental lung oedema. During the ramp manoeuvre, haemodynamic and pulmonary variables were monitored almost continuously. Results: During the rise in PEEP, cardiac output declined in a non-linear way. In the series with normal conditions, best PEEP was always found at ZEEP. In the series with experimental lung oedema, best PEEP, as defined by maximum oxygen transport, was found at PEEP_1–6, as defined by maximal compliance, at PEEP_7.5 and by maximal arterial oxygen tension (PaO₂) at PEEP_10–14. Conclusions: Best PEEP according to oxygen transport is lower than best PEEP according to compliance and PaO₂; the use of PEEP as a ramp might prevent unnecessarily high levels of PEEP. Received: 16 June 1997 Accepted: 24 April 1998