Plasma cholinesterase correlations in acute surgical and critical illness.

AIM: The properties of plasma cholinesterase (CHE) are partly undiscovered. Equally unknown are the correlations between changes in CHE and other blood variables during the acute phase response related to acute surgical and critical illness. METHODS: Data from 432 measurements of CHE and other variables performed in 92 patients were systematically evaluated and processed by regression analysis. RESULTS: There was a strong direct correlation between CHE and albumin (r=0.77, P<0.0001). CHE was also directly correlated to cholesterol, iron binding capacity, hematocrit, prothrombin activity, and inversely correlated to bilirubin and to presence of sepsis or liver dysfunction (P<0.0001 for all). Postoperatively CHE decreased to about 60% of the preoperative value, remaining directly related to it (r=0.69, P<0.0001), and decreasing further in the presence of sepsis or liver dysfunction, with slow reversal of the decrease during recovery from illness. In parenterally fed septic patients the decrease in CHE was moderated by increasing the amino acid dose (P<0.0001). CONCLUSION: In acute surgical and critical illness CHE mostly behaves as a negative acute phase reactant, independently of the modifications related to other already known factors. This should be taken into account when interpreting the implications of decreased CHE in the clinical setting.

Plasma amino acids of the transsulfuration pathway and plasma lactate in septic patients.

OBJECTIVES: In sepsis increasing plasma lactate, even if unrelated to hypoperfusion and hypoxia, is a cause of concern. Among the patterns associated with increasing lactate, several plasma amino acid (AA) abnormalities, more in particular those of sulfur AAs, have remained unexplored, and their assessment has been the purpose of our study. MATERIALS AND METHODS: A systematic and detailed analysis of 183 simultaneous determinations of plasma AA-grams and lactate, from 12 trauma surgery patients who had developed sepsis, was performed. Sepsis severity ranged from moderate to extreme illness. Correlations between changes in lactate and in AA levels were assessed by regression analysis. RESULTS: Increasing lactate was related to increasing alanine, proline, asparagine, tyrosine, cystathionine, histidine, glutamine, citrulline, methionine, phenylalanine and hydroxyproline (r from 0.62 to 0.36, p < 0.001 for all) and to decreasing taurine (r = -0.62, p < 0.001). Furthermore, increasing lactate was strongly related to increasing cystathionine/taurine ratio (r = 0.77, p < 0.001). These correlations were independent of the simultaneous relationship found between increasing lactate and decreasing mixed venous O2 tension. CONCLUSIONS: The overall findings and the correlation with the cystathionine/taurine ratio support the hypothesis that increasing lactate in sepsis may be paralleled by impaired hepatic AA transsulfuration. Because this may disable antioxidant protection by limiting glutathione and taurine availability, the metabolic perturbations associated with septic hyperlactatemia may include enhanced exposure to oxidative stress.

The relationship between albumin, other plasma proteins and variables, and age in the acute phase response after liver resection in man.

A large series of plasma albumin (ALB, g/dl) and simultaneous blood and clinical measurements were prospectively performed on 92 liver resection patients, and processed to assess the correlations between ALB, other plasma proteins, additional variables and clinical events. The measurements were performed preoperatively and at postoperative day 1, 3 and 7 in all patients, and subsequently only in those who developed complications or died. In patients who recovered normally ALB was 4.3 +/- 0.4 g/dl (mean +/- SD) preoperatively, 3.7 +/- 0.7 at day 1 and 3, and 3.9 +/- 0.4 at day 7. In patients with complications its decrease was more prolonged. In non-survivors it was 3.4 +/- 0.4 preoperatively, 3.0 +/- 0.4 at day 1, and then decreased further. Regression analysis showed direct correlations between ALB and pseudo-cholinesterase (CHE, U/l, nv 5300-13000), cholesterol (CHOL, mg/dl), iron binding capacity (IBC, mg/dl), prothrombin activity (PA, % of standard reference) and fibrinogen, an inverse correlation with blood urea nitrogen (BUN, mg/dl) for any given creatinine level (CREAT, mg/dl), and weaker direct correlations with hematocrit, other variables and dose of exogenous albumin. An inverse relationship found between ALB and age (AGE, years) became postoperatively (POSTOP) also a function of outcome, showing larger age-related decreases in ALB associated with complications (COMPL: sepsis, liver insufficiency) or death (DEATH). Main overall correlations: CHE = 287.4(2.014)(ALB), r = 0.73; CHOL = 16.5(1.610)(ALB) (1.001)(ALKPH), r = 0.71; IBC = 68.6(1.391)(ALB), r = 0.64; PA = 13.8 + 16.0(ALB), r = 0.51; BUN = 21.3 + 20.2(CREAT) - 6.2(ALB), r = 0.91; ALB = 5.0-0.013(AGE) - {0.5 + 0.003(AGE)( COMPL ) + 0.012(AGE)( DEATH )}( POSTOP ), r = 0.74 [p < 0.001 for each regression and each coefficient; ALKPH = alkaline phosphatase, U/l, nv 98-279, independent determinant of CHOL; discontinuous variables in italics label the change in regression slope or intercept associated with the corresponding condition]. These results suggest that altered albumin synthesis (or altered synthesis unable to compensate for albumin loss, catabolism or redistribution) is an important determinant of hypoalbuminemia after hepatectomy. The correlations with age and postoperative outcome support the concept that hypoalbuminemia is a marker of pathophysiologic frailty associated with increasing age, and amplified by the challenges of postoperative illness.

The relationship between oxygen extraction and venous pH in sepsis.

This study was performed to quantify the impact of Haldane effect (HE) on the relationship between O2 extraction (O2Ex; mL O2/dL blood) and venous pH in 247 measurements performed in 91 septic patients (73 patients with intra-abdominal sepsis, 11 with retroperitoneal abscesses, 6 with severe cholangitis, and 1 with gangrenous fasclitis). The severity of sepsis varied from relatively compensated to extremely diseased conditions. This allowed a detailed assessment of the impact of HE over a wide range of cardiorespiratory and metabolic abnormalities. A recently developed model was used to quantify blood CO2 exchange and Haldane relationships and, in particular, the buffering of venous pH allowed by O2Ex (O2-linked H+ binding) on the basis of arterial and mixed venous blood gas measurements. Arterio-venous pH difference (a-vDpH) was .033 +/- .024 (mean +/- SD). It increased with venoarterial CO2 concentration difference (v-aDCO2; mL CO2/dL blood), but the increase was moderated by a simultaneous increase in O2Ex, as the likely consequence of HE: a-vDpH = .006 + .017 (v-aDCO2) - .009 (O2Ex) [r2 = .96, p < < .001]. To confirm this, the moderation of a-vDpH allowed by the HE (DpH) was calculated. A first component, due to O2-linked H+ binding, had a value of .016 +/- .012, and a second component, due to the Haldane-mediated reduction in venous CO2 tension and plasma carbonic acid concentration, had a value of .019 +/- .006. Their sum (total DpH) was .033 +/- .017 and was related directly and strongly to O2Ex: DpH = -.002 + .009 (O2Ex) [r2 = .85, p < < .001], thus confirming the quantitative impact of HE in moderating the decrease in venous pH relative to arterial pH. The loss of this effect was responsible for the larger decreases in venous pH observed in hypodynamic patients developing impaired O2Ex. These results allow an easy quantification of the Haldane component, separated from the other components affecting pH, and are also useful for assessing the protective role exerted by HE against excessive decreases in venous pH in circulatory failure.

Pathophysiologic correlates of hypocholesterolemia in critically ill surgical patients.

OBJECTIVE: To assess correlates of hypocholesterolemia in moderate to critical surgical illness. DESIGN: Prospective analysis of laboratory and clinical data. SETTING: Department of surgery in a university hospital. PATIENTS: 135 patients undergoing uncomplicated abdominal surgery or with sepsis, liver failure, hemorrhage, severe cholestasis, or multiple organ dysfunction syndrome (MODS). INTERVENTIONS: Surgical and/or medical therapy according to clinical status. MEASUREMENTS AND MAIN RESULTS: Determinations of total cholesterol, additional variables, and clinical data. Cholesterol decreased after surgery, in sepsis, liver failure, acute hemorrhage, and MODS and increased in cholestasis. Hypocholesterolemia correlated with decreases in plasma proteins and indices of hepatic protein synthetic adequacy, with hemodilution from blood loss, and was moderated or prevented by cholestasis. CONCLUSIONS: These results help to explain the dynamics of the development, clinical relevance, and negative prognostic value of hypocholesterolemia in critical illness.

Leucine dose response in the reduction of urea production from septic proteolysis and in the stimulation of acute-phase proteins.

The administration of branched-chain amino acids (BCAAs) has been proved useful in reducing both urea nitrogen production and muscle proteolysis in trauma patients with sepsis, but the optimum infusion rate to achieve these effects is still in question. In this prospective randomized study, a group of 16 posttrauma patients with sepsis received a branched chain-enriched (BCAA = 49.4%) amino acid mixture (8 patients; 120 observations) or a standard amino acid infusion (BCAAs = 15.5%; 8 patients; 227 observations). Total calories, percent lipid calories, and amino acid nitrogen administration were not different in the two groups. Each patient was studied at 8-hour intervals for the plasma levels of amino acids, six hepatic acute-phase proteins, albumin, and other metabolic parameters, including urinary urea nitrogen and 3-methylhistidine excretion. The total intake of each amino acid and its clearance were calculated and the dose of leucine during each 8-hour period was related to the leucine clearance, plasma acute-phase protein levels, and the urinary production of urea and 3-methylhistidine, as an indicator of proteolysis. The results show a significant (r2 = 0.691; p less than 0.0001) reduction of urea nitrogen production and proteolysis as a function of the increase in leucine dose. The identification of a critical mean rate of leucine infusion has been derived from the analysis of the significant linear correlation between leucine intake and leucine clearance (r2 = 0.594; p less than 0.0001). Significant positive correlations between the leucine intake dose and the platelet count (r2 = 0.402; p less than 0.0001), the plasma fibrinogen level (r2 = 0.218; p less than 0.0001), and the regression-derived sum of six acute-phase proteins plus albumin (r2 = 0.696; p less than 0.0001) were found. The increase in leucine clearance was progressively less marked above a mean daily leucine intake rate of 1.4 mumol/kg/min, which also appeared to be the dose level that maximized the acute-phase protein and coagulation effects and reduced proteolysis and urea nitrogen production, suggesting that this is a critical BCAA infusion rate at which an optimum leucine effect occurs. From these data a BCAA (leucine) dose nomogram has been derived.

Calculation of venoarterial CO2 concentration difference.

Quantitative relationships in CO2 transport and exchange processes were combined for use as the basic components of an original mathematical model for the calculation of venoarterial blood CO2 concentration difference (v-aDCO2). This is calculated as the sum of the increment in CO2 concentration (CCO2) related to the increase in CO2 tension (delta P) from arterial to venous value at constant O2 saturation (delta CCO2/delta P) and of the increment in CO2 concentration related to the decrease in O2 saturation (delta S) from arterial to venous value at constant CO2 tension (delta CCO2/delta S). The newly developed relationships correlated well with the experimental data from which they were derived (r2 = 0.94-0.99). The results provided by the model compared remarkably well with the results of previously published measurements (r2 = 0.96-0.99). This new model allows one to overcome some of the limitations implicit in previously available methods and provides a useful tool for the assessment and monitoring of hemodynamic, metabolic, and O2-CO2 exchange patterns in whole body and regional vascular beds.

Quantitative assessment of changes in blood CO(2) tension mediated by the haldane effect.

Adequate assessment of circulatory and gas-exchange interactions may involve the quantification of the Haldane effect (HE) and of the changes in blood PCO(2) mediated by changes in Hb-O(2) saturation and O(2)-linked CO(2) binding. This is commonly prevented by the complexity of the involved calculations. To simplify the task, a large series of patient measurements has been processed by regression analysis, thus developing an accurate fit for this quantification (v-a) PCO(2)HE + 0.460 [(a-v) HbO(2)]0.999e0.015(PvCO(2))-0.852(Hct) (n = 247, r(2) = 0. 99, P << 0.001), where (v-a)PCO(2 HE) is the reduction in venous PCO(2) (Pv(CO(2)), Torr) allowed by the chemical binding of CO(2) in blood due to the HE (Torr), (a-v)HbO(2) is the arteriovenous difference in Hb-bound O(2) (ml/dl), and Hct is hematocrit fraction. Values of (v-a)PCO(2 HE) estimated by this expression compared well with the results of previously published experiments. This formula is useful in assessing the impact of HE on Pv(CO(2)) and venoarterial PCO(2) gradient and the survival advantage offered by HE in extreme conditions. Use may be extended to all investigative and clinical settings in which changes in blood O(2) saturation and O(2)-linked CO(2) binding must be converted into the corresponding changes in dissolved CO(2) and PCO(2).

Substrate supply as determinant of O2 extraction in sepsis and nonseptic trauma.

Metabolic and hemodynamic measurements performed in 72 septic (S) and 40 nonseptic (NS) surgical patients undergoing total parenteral nutrition were analyzed to assess the role of substrate supply as a determinant of O2 extraction (O2Ex). In S, O2Ex was inversely related to cardiac index (CI); at any given CI, significant increases in O2Ex with simultaneous increases in O2 consumption (VO2) were related to increasing doses of amino acids, with a less remarkable effect of fat and no effect of glucose dose. In NS, O2Ex was also inversely related to CI; however, at any given CI, there was no evident substrate-supply dependency of O2Ex, which was more normally related to P50. The increase in VO2 per gram of administered amino acids, at any CI and O2 transport index, was 817 ml in S and 267 ml in NS. These results suggest that the impaired O2Ex and VO2 in S may at least partly reflect abnormalities in substrate utilization and that amino acid support may have a role in modulating these abnormal O2Ex patterns by providing preferential substrate for oxidative metabolism.

Impact of fat and glucose administration on metabolic and respiratory interactions in sepsis.

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.

Cardiorespiratory and metabolic effects of buflomedil: case reports.

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.

A simple method for rapid estimate of pulmonary venous admixture.

Data from 2,298 measurements of pulmonary venous admixture (QS/QT) performed in 733 patients were analyzed and processed in order to develop a method for rapid and reliable estimation of QS/QT by a simplified approach. Formulae and charts were obtained, which are easily suitable for use in all settings, and permit estimation of QS/QT with an 85%-93% control of its variability (r2 = 0.85-0.93, p less than 0.0001) simply on the basis of the measured arterial and central venous O2 tensions or saturations.

[The branched-chain amino acids]. / Gli aminoacidi ramificati.

Branched-chain amino acids (BCAA: leucine, isoleucine and valine) are not just structural constituents of proteins, but have ''pharmacologic'' properties, known for several years: BCAA are catabolized mainly in muscle; can be oxidized with energy production, being nitrogen donors for other amino acids; regulate protein synthesis and degradation; modulate metabolism of neuroactive mediators. These properties make the clinical use of BCAA particularly suitable in critical conditions such as liver cirrhosis, sepsis, surgical or nonsurgical trauma, acute renal failure, acute pancreatitis, cancer, in which energy production from conventional substrates is altered and, at the same time, reduction of protein catabolism and enhancement of synthetic processes is advisable. Recently, the changes of plasma aminoacidograms induced by the administration of high-dose BCAA in sepsis have been better detailed: 1) a tendency to normalization of high levels of proline and of other amino acids transported intracellularly by transport system ''A''; 2) less relevant reduction of the levels of other amino acids; 3) increase of the levels of taurine, glutamate and aspartate; more complex interactions with specific amino acids. These changes, and changes of other variables, reconfirm in part some well-known properties of BCAA, and are also objective indicators of an improvement of the metabolic abnormalities of sepsis induced by BCAA administration. In sepsis and in other stress conditions it is recommended to administer, within balanced parenteral nutritional regimens, AA solutions with a 35-50% BCAA concentration.

[Medium-chain triglycerides in artificial nutrition]. / I trigliceridi a catena media (MCT) in nutrizione artificiale.

Medium Chain Triglycerides (MCT) are lipids which are commonly present in nature, for instance in milk and in some vegetable oils. The MCT molecule is composed of glycerol esterified with saturated linear-chain fatty acids containing 6 to 12 carbon atoms (MCFA: Medium Chain Fatty Acids: C(6:0), esanoic acid; C(8:0), octanoic acid; C(10:0), decanoic acid; C(12:0), dodecanoic acid). MCT for clinical use are currently obtained from vegetable fat through industrial processing. The large interest for MCT in clinical nutrition is due to unique physico-chemical, biochemical and metabolic features, which characterize MCT compared to conventional lipids (LCT: Long Chain Triglycerides). In particular, MCT represent a source of rapidly, fully available and ''high density'' energy, which makes their use very advantageous and suitable in a wide range of clinical situations, from the premature newborn to the adult patient. In addition to the MCT oil, known to physicians and nutritionists since the 1950s, and to the many commercially available MCT-containing compounds for oral-enteral use, in the last years it has become possible also to administer MCT-containing emulsions in parenteral nutrition. This has allowed to improve further knowledge of the effects of MCT, expanding the indications for use, often as a ''first-choice'' substrate in different types of critically ill patients.

[The choice of substrates in total parenteral nutrition]. / La scelta dei substrati in nutrizione parenterale totale.

This review contains a full outline on the choice of substrates in total parenteral nutrition (NPT). The basic properties of "conventional" substrates (glucose, long chain triglyceride-containing fat, common amino acid mixtures) are used to outline the general principles for NPT support in normal conditions and in stress (surgical and nonsurgical trauma, sepsis). Without taking into account factors which are not strictly metabolic (vascular access, local availability of products, costs), particular attention is then paid to "non-conventional" substrates and substrate mixtures, including some under study, with specific reference to properties and features which may motivate their choice.

[The surgical risk of liver resections for neoplasms in the elderly patient]. / Il rischio operatorio delle resezioni epatiche per neoplasia nel paziente anziano.

For patients who are candidates for surgical resection of the liver, advanced age has, for many years, been considered to be a limiting factor or has precluded intervention. More recently, improvements in diagnostic, surgical and anaesthetic techniques and the increase in the average age of the population have gradually broadened the indications for hepatic resection in elderly patients. The factors for reappraisal of the surgical risk of liver resection in elderly patients are discussed here. Comparative data are also presented on the mortality, morbidity and post-operative changes in blood chemistry parameters in 90 patients who underwent hepatic resection: 33 patients over 65 years of age (group A) and 57 under 65 years (group B). In group A, compared to group B, mortality (3% versus 5%) and the percentage of patients with post-operative complications (27% versus 37%) were not significantly different. The incidence of post-operative complications correlated more closely with specific risk factors (elevated pre-operative "ASA score" from associated disease) than with age itself. Analysis of the regressions did not reveal important relationships between age and changes in the blood chemistry parameters. These results help to support the idea that advanced age alone is not now an absolute contra-indication to major liver resection.

[Use of unconventional lipid substrates in parental nutrition]. / Uso dei substrati lipidici "non convenzionali" in nutrizione parenterale.

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.

Gas in portal circulation and pneumatosis cystoides intestinalis during chemotherapy for advanced rectal cancer.

OBJECTIVES: Acute abdominal symptoms with CT scan evidence of intramural gas in bowel walls (pneumatosis cystoides intestinalis, PCI) and of gas in the portal venous blood (PBG) in patients undergoing chemotherapy may represent a worrisome picture, suggestive of bowel necrosis. This picture remains a major clinical clue and the reporting of new cases may help to share awareness and experience on management. We describe a patient with acute abdominal symptoms and evidence of PCI with PBG under cetuximab, oxaliplatin, tegafur-uracil and folinic acid chemotherapy for metastatic adenocarcinoma of the rectosigmoid junction. METHODS: After admission for mucositis with diarrhea and profound dehydration, and subsequent emergency laparotomy for derotation of an intestinal volvulus, on the tenth postoperative day the patient developed fever and abdominal pain, with CT scan evidence of PCI with PBG. The exam of the abdomen did not suggest major problems requiring emergency surgery, and antibiotic treatment with close monitoring were performed, followed by rapid improvement. RESULTS: Twelve days later, after resumption of oral diet, the patient unexpectedly suffered a spontaneous jejunal microperforation, requiring emergency laparotomy and bowel resection. Pathology showed that the perforation was within an area of ulceration involving the inner superficial layer of the bowel. Subsequently recovery was normal and at present, after 15 months, the patient is well and continuing chemotherapy. CONCLUSIONS: This is probably the first report of PCI with PBG related to intestinal toxicity during cetuximab, oxaliplatin, tegafur-uracil and folinic acid chemotherapy in a patient with advanced rectal carcinoma, followed by delayed small bowel perforation. It provides an example of the challenges involved in the management of this type of patient.