Biomedical subjects
Publications and source records attributed to I Giovannini.
An extensive study has been performed of the cardiovascular, respiratory and metabolic effects of buflomedil. The results indicate that the drug, at the administered dose, does not alter the patient physiological stability. An improved perfusion regimen in peripheral tissues and an optimization of cardiac energetics are also directly or indirectly implied in the results.
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Seven hundred and sixty cardiorespiratory studies, from 151 critically ill or high-risk general surgical patients with extrapulmonary (S) or pulmonary (P) sepsis, cirrhotic liver disease (L), or cardiac failure (C), were analyzed to assess the determinants of a simple, easily obtained measure of respiratory oxygen exchange, the respiratory index (RI). The pattern of cardiorespiratory abnormalities was studied and correlated with the change in RI. The most important relations were with shunt (QS/QT), mixed venous O2 (PvO2), VD, and VE. Higher F1O2 and positive end-expiratory pressure (PEEP) were needed as the RI rose, indicating a greater severity of illness. Regression analysis of all types of critically ill patients and surgical controls showed that QS/QT, PvO2, and F1O2 interacted together to explain most of the variability of the RI. The regressions in each homogeneous patient disease category were all highly significant (p less than .0001) but had somewhat similar coefficients and explained the variability in RI to different degrees. The data suggest that patients with extrapulmonary sepsis or cirrhotic liver disease have an increase in RI (over that in controls) primarily due to a large increase in CI at the high QS/QT caused by the ventilation/perfusion (VA/QT) maldistribution characteristic of these diseases. However, patients with P or C have a disproportionate rise in RI at any given QS/QT compared to that in high-flow states alone, suggesting in P a direct alveolar limitation of oxygen exchange over and above any level of VA/QT mismatching, and suggesting in C a disproportionate decrease in PvO2 that magnifies the QS/QT effect even though VA/QT is more uniform.
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The treatment of sepsis involves, in addition to the aggression of the septic focus by antibiotic and surgical means, the support of physiological functions, in particular the metabolic-nutritional support. The Authors base the description of the relevant aspects of metabolic-nutritional support in sepsis on the results of studies performed in their Clinical Research Center and in other Centers.
A quantification of the determinants of arterial hypoxemia was performed in 376 cardiorespiratory measurements obtained from 180 critically ill patients. Statistical analysis showed that pulmonary venous admixture (Qsp/Qt) could explain only 48% of the PaO2 variability in the sample of measurements taken (r2 = 0.48), while the effect of central venous O2 tension (PVO2) brought the total explained PaO2 variability up to 82% (total r2 = 0.82). These findings imply that pulmonary function is not the only determinant of PaO2; the PVO2-mediated effect of other cardiovascular and metabolic determinants must be recognized in the clinical setting.
Cardiorespiratory and metabolic data were collected in 36 septic patients and 80 patients critically ill after nonseptic general surgery or trauma. Septic patients, particularly nonsurviving septics, showed early and sustained increases in metabolic rate, oxygen consumption, cardiac work, and minute ventilatory volume. They had lower levels of respiratory quotient and total peripheral resistance than nonseptic patients. High cardiac work was related to increasing oxygen transport. Both increases in metabolic utilization with high CO2 production, and abnormal increases in VD/VT appeared responsible for the higher minute ventilatory volumes. Respiratory quotient was negatively related to metabolic rate; this relation was modulated by the rate of caloric intake and, in nonseptic patients, was also influenced by the hemodynamic state. These data suggest that poor prognosis in sepsis is characterized by an early sustained stress response with more severe abnormalities in cardiovascular, metabolic, and respiratory function than is seen in the nonseptic stress response. The need for early support of physiologic functions and early and aggressive nutritional intervention is emphasized.
Multivariable physiologic studies of cardiovascular, respiratory, and metabolic functions were performed in 341 patients (884 studies). Eighty patients had cirrhotic liver disease, 64 had sepsis, 87 had nonseptic cariogenic syndromes, and 110 had nonseptic general surgical or traumatic injury. The group with cirrhosis had the highest cardiac index and ejection fraction. When compared with the group with nonseptic surgery or trauma, vascular tone was reduced in the patients with cirrhosis or sepsis and was lowest in patients with both conditions. Ventricular function was good in the groups with cirrhosis or sepsis, due to the additive effect in reducing vascular tone that allowed ejection fraction to increase, but caused the ratio of alveolar ventilation to perfusion (VA/QT) to fall, resulting in a greater perfusion of a decreased pulmonary vascular bed. The falls in vascular tone and VA/QT in patients with cirrhosis or sepsis result from the reduced oxygen consumption that occurs due to metabolic imbalance (B state). This B state seems to reflect a hepatic inability to metabolize aromatic amino acids, so that levels of tyrosine, phenylalanine, and the false neurotransmitter octopamine increase. These mechanisms are pathologically synergistic when sepsis and cirrhosis occur together.
Detailed serial cardiovascular and respiratory physiologic studies were carried out in 80 patients with cirrhotic liver disease, including 45 cirrhotic patients who underwent portal decompressive surgery on an urgent or elective basis. In surgical cases, death could be predicted from the first postoperative day's pattern of response. Predictors of death were an increase in percent of pulmonary shunt due to a redistribution of the increased pulmonary blood flow, and a disproportionate fall in vascular tone, which permits an increased cardiac ejection fraction even when significant myocardial depression occurs. The etiology of the vascular tone defect seems related to the rise in levels of the false neurotransmitter octopamine, which are shown to increase as oxygen consumption falls in the patho-physiologic hyperdynamic B state, presumably due to a block in the oxidative metabolism of aromatic amino acids.
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The septic response in man appears to be a disease in which the infecting agent induces a state of disordered metabolic control in the host. The abnormal regulation of metabolic pathways causes a diversion of substrate utilization toward gluconeogenesis and ketone body formation and a reduction in oxidative energy-producing metabolism. This state of metabolic insufficiency is reflected in the pattern of cardiorespiratory, vascular, and physiological compensation. The precise magnitude of the resultant physiological compensation and its rate and direction of change can be quantified by the use of physiological state trajectories which also reflect the magnitude of underlying metabolic derrangements. The prognostic and therapeutic implications of these changes are discussed.
Cardiovascular and respiratory parameters were obtained in 374 studies from 151 patients (64 septic or septic shock and 87 with nonseptic cardiogenic syndromes). Cardiac output and related measures, respiratory parameters, pulmonary blood volume (DV/m2), cardiac ejection fraction (EFx), left ventricular end-diastolic volume (LVEDV), peripheral resistance (TPR), pulmonary shunt (QS/QT), physiologic dead space (VD/VT) and mean ventilation perfusion ratios (VA/QT) were calculated. Both physiologic evaluation and multivariable statistical analyses of the data were performed. For a given level of (A-aO2 gradient/PaO2) septic patients have a higher QS/QT than cardiogenic patients. Hyperdynamic septic patients have a larger QS/QT, a greater VD/VT, and a lower VA/QT and TPR than cardiogenics. The decrease in VA/QT and the rise in VD/VT are strong functions of the increased EFx, which raises cardiac index (CI) and reduces LVEDV and the mean dispersion of pulmonary blood volume, thus causing hemodynamic redistribution of flow. QS/QT is mainly a direct function of the increase in CI which also tends to reverse the EFx-mediated rise in VD/VT. The role of the septic mediated decrease in TPR as a contributing pathologic feature and the use of volume infusion to raise LVEDV and VA/QT in high-CI septics with large QS/QT is discussed.
Three hundred measurements of indirect calorimetric and hemodynamic variables were performed in 99 critically ill septic and nonseptic surgical patients. Septics manifested, with respect to nonseptics, higher O2 consumption, metabolic rate and cardiac index, and lower respiratory quotient in the presence of higher glucose infusion rates and glucose infusion rate/metabolic rate ratios. Among septics there was a group of more severely ill patients with signs of multiple organ failure who manifested a dissociated pattern characterized by a tendency to decreased O2 consumption in the presence of increasing cardiac index and central venous O2 partial pressure: they had higher respiratory quotients, with respect to the other septics, for a given glucose infusion rate/metabolic rate ratio. The lower mean respiratory quotient of septics indicates that they depend generally more than nonseptic trauma patients on fat as an energy substrate and confirms a previously obtained evidence of limited hepatic lipogenesis in sepsis. At the same time, however, it is suggested that fat utilization becomes impaired (and hepatic lipogenesis becomes prominent) in sepsis at a stage in which signs of impaired oxidative metabolism and major metabolic abnormalities also develop.
Carnitine is an indispensable factor for the beta-oxidation of medium- and long-chain fatty acids, and it plays a possible role in the oxidation of branched-chain amino acids. Plasma and urinary levels of free carnitine and short-chain acyl-carnitines were studied in 67 surgical patients, after non-septic surgical procedures or during sepsis. The septic state was associated with increased urinary excretion of free carnitine (p less than 0.001), as well as with lower plasma levels of short-chain acyl-carnitines (p less than 0.001); the latter feature correlated with the level of hypermetabolism, as evaluated by the metabolic rate and by the arterial-mixed venous O2 difference. In 26 patients during total parenteral nutrition D, L-acetyl-carnitine was administered (100 mg/kg/24 hrs, in continuous iv infusion) and was associated, in septic patients only, with a significant decrease in the respiratory quotient, suggesting enhanced oxidation of low respiratory quotient substrates (fatty acids and/or branched-chain amino acids). Carnitine supplementation during total parenteral nutrition might be of theoretical benefit in some clinical conditions, such as sepsis, in which the following conditions coexist enhanced utilization of substrates whose oxidation is partially or totally carnitine dependent; prolonged absence of exogenous intake of carnitine (as in long-term total parenteral nutrition); eventual impairment of carnitine synthesis due to hepatic dysfunction; increased, massive urinary loss of carnitine.
Metabolic and respiratory interactions were analyzed in a large group of septic patients (S) and in a reference group of nonseptics (NS) during the iv administration of glucose and fat. In spite of a moderate increase in CO2 production (VCO2) observed during the administration of fat in S, a VCO2-sparing effect of fat, with respect to equicaloric amounts of glucose, was reconfirmed. The relevance of the therapeutic modulation of CO2 production during parenteral nutrition, and the relative impact on the abnormal septic respiratory patterns, were emphasized by analyzing the physiological relationships and mechanisms responsible for the increase in respiratory work in sepsis.
In addition to the classic soybean oil fat emulsion, developed more than 40 years ago and still widely used, emulsions with other lipid substrates are available today for parenteral nutrition; these substrates implement the benefits offered by soybean oil when mixed with it in given proportions. Soybean oil triglycerides are rich in linoleic acid, a long chain omega-6 polyunsaturated fatty acid, which is essential and is an indispensable component of parenteral nutrition. However, very high doses of omega-6 polyunsaturated fatty acids should be avoided, particularly in some critical illnesses. Medium chain triglycerides, long well known to nutritionists and dietitians for their easy intestinal absorption, have become available in parenteral nutrition emulsions in a mixture with soybean oil. Medium chain triglycerides are completely and readily used for energy production and do not interfere significantly in the production of inflammatory mediators, in the composition of cell membranes and in body organ and system functions. Omega-3 polyunsaturated fatty acids, essential fatty acids derived from fish oil, permeate cell structure and affect cell activity with different mechanisms, playing also an important role in the modulation of inflammatory processes. Omega-3 emulsions in parenteral nutrition are currently added as a supplement to other fat emulsions. Knowledge of these "non-conventional" fat emulsions is being continuously improved by investigative work and clinical experience.
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