Scott E. Curtis

Prognostic value of the dobutamine test in patients with sepsis syndrome and normal lactate values: a prospective, multicenter study.

To determine the oxygen supply (Vo2) and uptake (Vo2) responses to a 60-min dobutamine infusion in critically ill septic patients without circulatory shock and with normal blood lactate concentrations. Also, to determine whether these responses would predict outcome. Design:Prospective, cohort study. Setting:Five intensive care units in university-affiliated, city hospitals. Patients:Fifty critically ill patients with sepsis syndrome were studied from April 1990 to August 1991. Interventions:Pulmonary artery catheteriza-tion; fluid loading if pulmonary artery occlusion pressure was <10 mm Hg; and 10 μg/min/kg dobutamine infusion for 60 mins. Measurements and Main Results:Cardiac in-dex, Vo2, Vo2, and oxygen extraction ratio were determined immediately before and 1 hr after the onset of the dobutamine test. Using receiver operating characteristic curves, responders to the dobutamine infusion were identified by a >15% increase in Vo2 from the time immediately before to 1 hr after the onset of the dobutamine test. We identified 23 responders and 27 nonresponders. Groups differed significantly in age (responders 46 yrs vs. nonresponders 55 yrs) and associated chronic disease (responders one cancer vs. nonresponders six cancers). Significant changes in responders were: a) cardiac index increased 42.9%; b) systemic vascular resistance decreased 20.7%; and c) Vo2 increased 39.1% while Vo2 increased 40.8%, with no changes in oxygen extraction or blood lactate concentration. Significant changes in nonresponders were: a) cardiac index increased 14.2%; b) Vo2 increased 13.2%; and c) oxygen extraction decreased from 0.26 to 0.22. Lactate concentration increased significantly by 25.1% in nonresponders. The mortality rate in responders (8.7%) was significantly less than that rate in nonresponders (44.4%). Conclusions:Most of these septic patients without shock or hyperlactatemia responded to dobutamine infusion in one of two ways: with little increase in Vo2 and no increase in Vo2, or with significant increases in both Vo2 and Vo2 The latter response is typical of healthy volunteers given dobutamine. Because of the calorigenic effect of dobutamine, our results imply nothing about the presence or absence of oxygen supply limitation. Still, patients who had increases in Vo2 and Vo2 had a much higher survival rate than patients who did not. We speculate that the inability of some patients to respond to dobutamine and the associated higher mortality rate may be related to β-adrenoreceptor dysfunction. (Crit Care Med 1993; 21:1868–1875)

Experimental models of pathologic oxygen supply dependency.

Pathologic oxygen supply dependency is an abnormal situation in which oxygen uptake (Vo2) varies directly with oxygen delivery. Its presence in patients with adult respiratory distress syndrome and/or sepsis has been associated with particularly high mortality rates that may be the result of tissue hypoxia that causes multiple organ failure. The evidence for this association has been indirect because we cannot use invasive methods that would be necessary to verify or disprove the hypothesis. Because further progress will depend on the development of adequate animal models of pathologic oxygen supply dependency, we have attempted to evaluate some of the available information in this area as well as the likelihood that tissue hypoxia will prove to be the precipitating factor. In anesthetized dogs injected or infused with endotoxin, many of the features of pathologic oxygen supply dependency have been successfully produced. These features include defective peripheral oxygen extraction, increased oxygen demand, and increased lactate levels. Regional measurements have shown that gut Vo2 decreases before other areas, particularly skeletal muscle. Lactate measurements alone were shown not to be sufficient proof of tissue hypoxia. More direct measurements of actual energy states and tissue Po2 are indicated for future research efforts.

Systemic and regional oxygen uptake and delivery and lactate flux in endotoxic dogs infused with dopexamine.

ObjectiveTo test whether dopexamine, a dopaminergic and β2-adrenergic receptor agonist, would: a) direct a greater share of cardiac output to gut than to muscle when used to increase systemic oxygen delivery (Do2) in endotoxic dogs; and b) enhance the ability of peripheral tissues to extract oxygen. DesignTwo groups of eight dogs infused for 1 hr with 2 mg/kg Escherichia coli endotoxin. One group was continually infused with dopexamine (12 μg/min.kg) and the other group was not (control group). After 2 hrs, oxygen extracting ability was challenged by changing inspired gas to 12% oxygen for 30 mins. SubjectsAnesthetized, paralyzed, pumpventilated mongrel dogs. InterventionsDonor RBCs and dextran used during endotoxin infusion to maintain cardiac output while preserving hematocrit near 40%. Measurements and Main ResultsIn the dopexamine-treated group, cardiac output, systemic Do2, and oxygen consumption (Vo2) were higher than in the control group during the first 90 mins, but were not thereafter. Gut and muscle blood flow did not differ between groups, but the fraction of cardiac output going to each region tended to be less in the dopexamine-treated dogs. Arterial lactate values increased to about 6 mmol/L in all dogs. In both groups, limb muscle first produced lactate but then took up lactate after the first hour. The gut in controls converted from lactate uptake in the first hour to producing about 20 μmol/min.100 g, whereas the gut never produced lactate in the dopexamine-treated group. During hypoxia, systemic Do2 and Vo2 decreased only in the dopexamine-treated group, even though oxygen extraction was only slightly above 40%. Oxygen extraction was not demonstrably improved by dopexamine treatment. ConclusionsDopexamine temporarily increased systemic Do2 and Vo2 in volume-expanded endotoxic dogs during normoxia and may have caused gut mucosa to be preferentially perfused and thus to be kept better oxygenated. (Crit Care Med 1991; 19:1552)

Cardiac output during liquid (perfluorocarbon) breathing in newborn piglets

Background and MethodsLiquid ventilation using perfluorocarbons is a new technique for ventilation of infants with restrictive lung disease. However, this method of ventilation has been shown to impair cardiac output (&OV0422;t) in several animal species, casting doubt as to its feasibility. This study tested whether &OV0422;t could be maintained during liquid breathing by intravascular volume expansion. Seven piglets were carefully hydrated, instrumented for continuous &OV0422;t measurement, and subjected to 2 hr of liquid breathing. Paco2 was maintained at 40 to 50 torr (5.3 to 6.7 kPa), and Pao2 >80 torr (>10.7 kPa). Additional colloid was given during liquid breathing if &OV0422;t decreased to <90% of preliquid breathing values. ResultsFour piglets maintained &OV0422;t throughout the liquid breathing trial with maintenance fluids only. Three piglets each required one 10 mL/kg fluid bolus for &OV0422;t 82% to 89% of the baseline value, after which &OV0422;t rapidly increased to >90% of baseline. Oxygen consumption and serum lactate levels remained normal throughout liquid breathing. Conclusion&OV0422;t is readily maintained during liquid breathing in properly hydrated animals. (Crit Care Med 1991; 19:225)

Effects of progressive intratracheal administration of perflubron during conventional gas ventilation in anesthetized dogs with oleic acid lung injury.

The respiratory distress syndrome of prematurity (RDS) is due to immaturity of alveolar type II cells which fail to produce adequate surfactant. The resultant increase in alveolar surface tension leads to both alveolar flooding and alveolar collapse, decreased compliance, and increased shunt with hypoxemia. Exogenous replacement of surfactant has reduced morbidity and mortality from RDS, though the most premature infants often fail to respond. Another possible therapy for RDS is liquid breathing (LB). Introduced by Kylstra et al. (1962), LB refers to a ventilatory mode in which the lungs are filled with a liquid perfluorocarbon (PFC) or hyperbarically oxygenated saline to functional residual capacity (FRC) followed by tidal ventilation with additional liquid. Using PFC’s with surface tensions of ≈ 15 dynes/cm, Shaffer et al. (1983a, 1983b) showed markedly improved arterial oxygenation during LB compared to gas ventilation in surfactant-deficient, very premature lambs. Interestingly, even after drainage of PFC from the lungs of these lambs, persistent improvements in FRC, compliance, and gas exchange were seen, suggesting that residual PFC coating the alveoli improved alveolar surface tension.

Effect of Continuous Rotation on the Efficacy of Partial Liquid (Perflubron) Breathing in Canine Acute Lung Injury

Perfluorocarbons are liquids characterized by relatively low surface tension (10 to 20 dyne/cm) and high oxygen solubility (Clark, 1985). Liquid breathing can significantly improve gas exchange in animals with acute lung injury or surfactant deficiency (Calderwood et al., 1973; Shaffer et al., 1976, 1983a, 1983b, 1984). In several of the studies by Shaffer et al. (1976, 1983a, 1984), after drainage of most perfluorocarbon from the lung and conversion to gas breathing, improvements in arterial PO2 and lung mechanics persisted, suggesting that residual perfluorocarbon in the lung may have functioned as an artificial surfactant. The use of gas breathing combined with partial lung doses of perfluorocarbon has recently received increased attention, with positive results seen both in animal models of restrictive lung disease and in premature human infants (Curtis et al., 1993a; Greenspan et al., 1990; Richman et al., 1993; Tiitiincii et al., 1993). We previously tested the effects of sequential doses of perflubron (LiquiVent’’, Alliance Pharmaceutical Inc.) from one-sixth of FRC up to full FRC in dogs with severe oleic acid induced lung injury (Curtis et al., 1993b). Moderate improvements in PaO2 occurred after 50% lung filling, with the largest increases in PaO2 seen after complete lung filling. We speculated that, similar to the situation seen with bolus surfactant administration (Lewis et al., 1993), perflubron may not be homogeneously distributed in acutely injured lungs. The high density of perflubron (1.9 g/ml) would also favor a selectively dependent distribution. This study tested the hypothesis that continuous physical rotation of the subject would improve distribution of perflubron within the lungs, and produce greater improvements of PaO2 and compliance at smaller perflubron doses. To achieve this rotation, a mechanical bed commonly used in intensive care settings (to prevent the complications of immobility (Choi, 1992)) was employed. Rotated, oleic-acid injured dogs did (R/PFB) or did not (R/CON) receive serial doses of perflubron and were compared to our two previously studied non-rotated groups (NR/CON and NR/PFB).

Effects of Endotoxin on Canine Skeletal Muscle Oxygen Delivery-Uptake Relations During Progressive Hypoxic Hypoxia

Septic patients, who may also have the adult respiratory distress syndrome (ARDS) often show apparent O2 supply dependency with elevated arterial lactate levels even at normal to high rates of O2 delivery (DO2) and appear unable to increase O2 extraction appropriately (Gilbert et al. 1986; Astiz et al. 1987). Cain (1986) has suggested that multiple events in the microcirculation may be responsible for this apparent defect in O2 extraction. These include microembolization and loss of endothelial functions and integrity. If the capillary membrane becomes leaky, then pericapillary edema may ensue and offer a diffusional block to the movement of O2 into tissue. The combination of microembolization and loss of endothelial functions that include microregional vascular control can lead to coexistence of underperfused and overperfused areas in a peripheral tissue, such as skeletal muscle. The outcome of these conditions would be a reduced ability of the tissues to extract O2 from arterial blood and an increased impediment to O2 diffusion.

ENDOTHELIAL AND SYMPATHETIC REGULATION OF VASCULAR TONE IN CANINE SKELETAL MUSCLE

In vitro studies have shown that production of the vasoconstrictor endothelin-1 (ET) is inhibited by NO in porcine aorta (Boulanger & Luscher, 1990) while in vivo studies have shown that the increase in total peripheral resistance following nitric oxide synthase (NOS) inhibition in anesthetized rats is blunted by blockade of endothelin receptors (Nafrialdi et al., 1994; Richard et al., 1995). In order to assess the role of endothelin in the regulation of resting vascular tone in skeletal muscle, it was first necessary to establish that we could effectively inhibit the vasoconstrictor actions of endothelin in our experimental preparation. Endothelin-1 binds to both ETA receptors on vascular smooth muscle producing vasoconstriction (Barnes, 1994) and to ETB receptors on endothelial cells to induce transient vasodilation through stimulation of NO production (Fujitani et al., 1993; Sakurai et al., 1992). The contribution of ETB receptors in the vasoconstrictor response to ET is minimal, but some studies have demonstrated that the ETA receptor antagonists BQ123 and FR139317 were unable to fully prevent or reverse the vasoconstrictor effect of endothelin in (Bird & Waldron, 1993; McMurdo et al., 1993). Because the dilatory action of ET is transient, we elected to focus on the vasoconstrictor action of ET.

Gut and muscle tissue Po2 in endotoxemic dogs during shock and resuscitation

There is indirect evidence that tissue hypoxia occurs in human sepsis and surface measures of muscle tissue PO2 (PtiO2) in hypodynamic endotoxic animals are decreased. This study assessed systemic and regional tissue oxygenation in a more relevant model of hyperdynamic endotoxicosis. We isolated venous outflow from the left hindlimb and a segment of ileum in six anesthetized dogs to measure muscle and gut O2 delivery and uptake (VO2) and lactate flux, gut intramucosal pH (pHi) by tonometry, and PtiO2 by multi-point surface electrodes placed on mucosal and serosal surfaces of gut and on muscle. We then infused Escherichia coli lipopolysaccharide (LPS; 2 mg/kg) over 1 h followed by a 2-h infusion of dextran (0.5 ml.kg-1.min-1). LPS infusion significantly decreased systemic and gut VO2, cardiac output (Q), and blood pressure and increased arterial lactate and gut lactate flux. Resuscitation increased Q to above baseline and restored systemic VO2. In response to LPS and then resuscitation, muscle PtiO2 distribution did not change, suggesting little microcirculatory disturbance, although mean PtiO2 first decreased and then increased. In contrast, gut VO2 and pHi remained low and lactate output remained high, despite restoration of gut blood flow. Gut VO2, lactate flux, pHi, and PtiO2 histograms were consistent with a marked redistribution of blood flow within the gut wall, away from the mucosa and toward the muscularis. These data show that, in hyperdynamic acute endotoxemia, skeletal muscle PtiO2 and VO2 are well maintained, but blood flow within the gut is significantly disturbed with mucosal hypoxia.

Facilitation of Oxygen Transfer by Perflubron in Hemodiluted Dogs

Intentional hemodilution is an alternative to avoid the potential problems associated with blood transfusions. Multipoint measurements of surface PO2 in several organ systems have indicated that moderate hemodilution may actually increase tissue oxygenation (Messmer, 1973). Theoretical analyses, on the other hand, have indicated that hemodilution may hinder oxygen delivery to tissues because of the increased barrier to diffusion offered by an expanded plasma phase (Homer, 1981; Gutierriez, 1986). The explanation in simple terms is that oxygen can be removed faster from the plasma than it can be released from the red blood cell in the tissue capillary. This results from the very low solubility of oxygen in plasma and the resultant slow diffusion in the plasma phase. Homer et al. (1981) suggested that a faster release and better equilibrium between red cell and plasma would be achieved by increasing oxygen solubility in the plasma.