PURPOSE:To evaluate the effect induced on gas exchange and on urea excretion by glucose and insulin infusion in injured patients. The magnitude and time necessary for the full development of the metabolic effect were investigated. METHODS:Six injured patients were investigated. During the first 24 hours, the fasting period, patients received 1 mg/kg*min of glucose; during the second 24 hours, the treatment period, infusion was increased to about the 95% of the energy production rate; during the last 8 hours, (stop period) the infusion rate was again set to 1 mg/kg*min. Gas exchange was determined in two consecutive 12-hour series, for 30 minutes every hour, either during a stabilized treatment or after its variation. Urea excretion was determinated on 4-hour samples. RESULTS:With respect to the fasting period, during the last 4 hours of the treatment period, the energy production rate did not vary; urea excretion (-25%) and oxygen consumption (-9%) decreased significantly. Carbon dioxide production (+16%), total respiratory quotient, and minute ventilation (+5%) increased significantly. Carbon dioxide production varied linearly with time (glucose infusion +1.74 mL/min*m2*h, P < .05; glucose withdrawal -1.89 mL/min*m2*h, P < .01). Minute ventilation decreased only during the withdrawal period by 65 mL/min*m2*h (P < .05). CONCLUSIONS:The infusion of glucose and insulin, in an amount slightly lower than the metabolic expenditure, leads to a consistently reduced amino acid catabolism and to a decreased oxygen consumption, without affecting energy requirements. Although it leads to an increase of carbon dioxide production, the measured change is so small and slow that it is not harmful unless there is severe respiratory insufficiency.

OBJECTIVE:We investigated the amino acid (AA) tolerance during Total Parenteral Nutrition (TPN) in adult patients undergone liver transplant (LTX).DESIGN:The treatment (Glucose and AA), induced on the 2nd postoperative day, was later maintained with 27 kcal/kg Ideal Body Weight (IBW) as glucose and 0.12 (12 patients: protocol #1), 0.18 (10 patients: protocol #2) and 0.25 g nitrogen (N)/kg IBW (13 patients: protocol #3) till end of the 6th postoperative day. The N intake was sequentially modified in protocol #2 and #3 to increase the supply of the amino acid (AA) that resulted in an infusion plasma level below the expected "normal" range (between 1 and 1.6 times the overnight fasting plasma level of volunteer).PATIENTS:35 consecutive adult patients without diabetes and organ failures for the entire study period.MEASUREMENTS:Plasma AA profile was measured before LTX and at the last TPN day under continuous infusion. During #1 and #2 protocol, many AA resulted below or at the lower range of the norm while, during 0.25 gN/kg IBW infusion, the majority of the administered AA significantly increased with respect to reference values. Nevertheless, they remained in the "normal" plasma range indicating that they were supplied in an optimal amount (particularly the aromatic and sulphurated ones, potentially toxic if liver function is impaired, and the branched chain AA (BCAA) given at consistent dosage: 0.5 g/kg). Arginine resulted significantly increased (Arg: 1.9 times the reference) and cystine (Cys: 0.45), serine (Ser: 0.8) and taurine (Tau: 0.85) remained significantly lower than "normal" as well as the not administered citrulline (Cit: 0.58) and alfa amino butyric acid (Aba: 0.41). The AA (and calorie) load almost balanced the N losses during the 5th (0.411 +/- 0.038) and 6th study day (0.305 +/- 0.019 gN/kg).CONCLUSIONS:0.25 gN/kg could be considered the minimum N load in the uncomplicated adult LTX recipients, for reassuring a balanced plasma AA pattern and body N turnover in the early postoperative phase.

Twelve healthy, unpremedicated women scheduled for total abdominal hysterectomy were given either isoflurane (n = 6) or halothane (n = 6) anaesthesia. They all general anaesthesia for a period of 3 h, with surgery being carried out only in the last hour. The anaesthesia consisted of thiopentone, pancuronium and a mixture of oxygen–enriched air (Fio 2 = 34%) supplemented with 1 MAC of either isoflurane or halothane. The patients were maintained normothermic, and with an arterial Sao 2 above 95% throughout the period of the study. The following measurements were made before, during and after anaesthesia (with and without surgery): oxygen consumption (Vo 2 ), carbon dioxide production (Vco 2 ); circulating concentrations of various hormones (insulin, growth hormone and Cortisol); various metabolites; selected amino acids and albumin; forearm arterio–venous concentration difference of glucose, lactate, free fatty–acids and selected amino acids (four patients in each group). Whole body Vo 2 decreased significantly by over 20% during anaesthesia (with or without surgery), P < 0.05). Although the circulating concentration of most amino acids showed little or no change during anaesthesia alone, there was a tendency for the flux of most metabolites to decrease, and this persisted during surgery ( P < 0.05). During anaesthesia alone there was a twofold reduction in the plasma Cortisol concentration ( P < 0.05), and a decrease in albumin concentration ( P < 0.01). With the onset of surgery, plasma Cortisol concentration increased rapidly (in association with several other hormones and metabolites) but hypoalbuminemia persisted.

Ten-three patients were investigated during the early postoperative phase after orthotopic liver transplantation to assess the adequacy of the amino acid (AA) supply during both parenteral (days 1-5) and enteral (days 6-9) nutrition. Plasma AA profile was determined preoperatively, on day 4 and 5 during TPN and on day 8 and 9 during EN, urea production rate was measured every day. Calories input was 28 kcal.kg-.day as glucose, nitrogen intake was 0.25 g.kg- day, supplying individual AA on the basis of previous studies. Urea nitrogen production during TPN (9-11 gN/m2.day) outlines the ability of the transplanted liver to manage the overall nitrogen load. Individual AA plasma profile was considered the expression of an adequate input when comprised between 1 and 1.5 times the normal value, in this respect we obtained adequate levels of all essential AAs. Particularly phenylalanine, methionine and branched chain AA, critical during liver failure, were kept in this range by supplying 68, 48 and 500 mg.kg-1.day. According to AA profile the supply of cystine and tyrosine (conditionally essential AAs), and of histidine, taurine, proline and serine could be safely increased. Not given dispensable AAs (glutamine, asparagine, citrulline and alfa amino butyric) showed a plasma level below the norm and should be added to the diet.

In 16 critically ill patients with full-blown stress reaction and without severe organ failure, we studied the kinetics of the arterial plasma amino acid (aa) profile during the first 48 h of total parenteral nutrition (TPN) in order to assess the time necessary to reach the steady-state condition during infusion. Each patient was treated with one of three different amino acid solutions giving, with the same nitrogen load, different intakes of individual amino acids. We found four different responses to the administered amino acids. Some amino acids showed a different trend depending on the dose given. At lower doses a steady state was achieved sooner. Plasma levels of amino acids not supplied in the TPN were unaffected or decreased, achieving a steady state at various times during the study period. We conclude that, in critically ill patients, stable arterial plasma amino acid concentrations are obtained within 24 h of starting TPN. In such patients, valid studies of the effect of amino acid solutions may therefore be carried out over short periods of time, thereby minimizing errors due to a fluctuating and unstable clinical state.

A plasmatic concentration for each aminoacid, between 1 and 1.5 times the normal value in fasting healthy subjects, is considered as an optimal target during total parenteral nutrition (TPN) in malnourished patients. We have analyzed the correlation between the aminoacid input and the aminoacid plasmatic concentration during TPN at different aminoacid composition. By exponential regression curves we then calculated the input required to keep each aminoacid plasma concentration in the optimal range.

The aim of this study was to evaluate the kinetics of arterial plasma amino acid profile during the first 48 h of clinical TPN in order to assess the time necessary to reach the steady-state condition during infusion. Each patient was treated with one of three different amino acid solutions yielding, in the same nitrogen intake, different intakes of individual amino acids. We found four different kinetics for the administered amino acids: an increase of plasma levels immediately after the start of the TPN with no variations during the steady period; the same trend with the steady-state obtained after 6-24 h of TPN infusion; no influence at all; a decrease of fasting plasma levels with the steady-state attained variably during the study period. Each given amino acid showed a different trend partly depending on the supply, suggesting that the steady-state was reached sooner for most amino acids, when the supply was larger. With lower intakes, plasma levels were unaffected or decreased. We conclude that in critically ill patients at least 24 h are needed to obtain stable arterial plasma amino acid concentration during TPN with adequate intakes of amino acid. Knowledge offers the possibility for a quick and accurate assessment of the adequacy of a given preparation (tailored for critically ill patients), it reduces the time span of the study and, as a consequence, the influence of varied metabolic conditions.

The equilibrium kinetic of two different amino acid solutions was investigated in ten catabolic patients (Parentamin, Pierrel; HBC, Baxter). Plasma amino acid pattern was determined on arterial samples before TPN and several times over 48 hours of TPN. Nitrogen balance was measured from 24 hours urine collection. Three different cinetic trends were found: a fast modification (diminution or increase), a slow adaptation, or no modification of plasmatic levels, however each amino acid reached a steady state plateau. The adequacy of the infusion of each amino acid was evaluated comparing its steady-state plasma level to the after lunch level in healthy man. This made possible to approximate metabolic needs of each of the infused amino acids and to identify the inadequacy of some metabolic pathways to synthetized non essential amino acids lacking in solutions. This made possible to identify amino acids infused in excess or in defect, and those infused in dose adapt to the metabolic needs of such patients.

Despite consistent improvement in its treatment, amatoxin poisoning still extolls an elevated overall mortality, ranging between 10 and 15%, which approaches 100% when severe (grade 3-4 encephalopathy) hepatic failure supervened. Therefore, the proper treatment of intoxication by amatoxin containing mushrooms, and particularly of its complications, remains a challenge in emergency medicine. Klein and coworkers reviewed the role of liver transplantation in amatoxin poisoning as a useful therapeutic tool for patients with severe impairment of liver function. Their indication for intervention is the presence of any of the following signs: grade 2 encephalopathy or higher; prothrombin time twice than normal, despite fresh frozen plasma infusion; hypoglycemia requiring hypertonic glucose infusion; hyperbilirubinemia (greater than 25 mg/dl). During the past autumn two patients with fulminant hepatic failure due to amatoxin poisoning were referred to our institutions as candidates for liver transplantation, since both satisfied Klein's criteria. However, due to shortage of organ donors it was impossible to transplant them over the following days. Despite they did not receive liver transplantation, both patients wakened from coma, their liver function improved, and they recovered from terminal amatoxin poisoning. After one year, both patients are long-term survivors, in good health and without any sequelae either in brain or liver function.

Body N balance, 3-methylhistidine (MEH) excretion, amino acid (AA) plasma concentration, and fluxes across the leg were investigated both during fasting and during parenteral nutrition of injured patients in order to better understand protein-sparing mechanisms induced by metabolic support in the whole body and in skeletal muscle. Patients were randomized to receive 15 or 30 kcal/kg·day coupled with 0.30 g of N either with standard or branch-chain (BC)-enriched AA solutions. During fasting, patients were highly catabolic (N balance −14.7 ± 1.2 g N/m2·day, MEH excretion 422 ± 25 μmol/m2 · day) and showed a high efflux of AA N from the leg (5.08 ± 2.1 g N/m2 · day) without difference between the groups. During treatment, body N balance (-5.55 ± 0.88, p < .001) and MEH excretion (284 ± 20, p < .001) were significantly reduced without difference among the groups; also, AA N leg efflux (2.64 ± 0.47, p < .001) was reduced. Moreover, considering the effect of calorie load, patients receiving 30 kcal/kg · day showed a lower efflux of total AA N and of some AA considered as markers of muscle protein catabolism, such as phe, lys, met, and glu. The main difference between solutions was in the efflux of BCAA; particularly, val and leu efflux was turned into uptake in the BCAA group. No significant difference among the groups was found in N balance and MEH excretion during treatment. In brief, muscle catabolism was reduced in an amount dependent on glucose and insulin load, but it was not influenced by BCAA supply. Whole body net protein catabolism was reduced through different mechanisms, either an increased visceral N retention or a decreased muscle N loss. However, muscle N loss was never abolished even in the high calorie groups.

Variations in plasma levels of total carnitine (TC), free carnitine (FC), and acyl-carnitine (AC) were studied in 10 patients undergoing orthotopic liver transplantation. The postoperative values were higher than the preoperative ones and positively related to time flow. As exogenous carnitine was not supplied during the study, these data suggested a better biosynthetic activity in the transplanted liver, in spite of standard blood tests results. No positive correlation between carnitine levels and variations in serum transaminases, bilirubin, cholestasis related enzymes, pre-albumin and albumin supply was found. Carnitine plasma levels were not influenced either by nutritional caloric input or by methionine and lysine inputs. Our results show that variations in carnitine plasma levels are a specific and responsive index of functional recovery in the transplanted liver.

Plasma amino acids profile is assumed to be a good index of whole body amino acids balance and in particular to give information on the actual control of the transplanted liver on protein metabolism. Variations in plasma amino acids profile were studied in 12 patients undergoing orthotopic liver transplantation. Total parenteral nutrition (TPN) was maintained at 26.05 +/- 1.53 kcal/kg and 0.117 +/- 0.01 gN/kg until the 7th postoperative day. Following this, an enteral nutrition (EN) was added as to maintain a mixed metabolic therapy at 30.28 +/- 2.76 kcal/kg and 0.198 +/- 0.01 gN/kg. Such a treatment completely satisfied the caloric needs, while nitrogen input was prudently kept low in accordance to the lack of data on the metabolic effectiveness of the transplanted liver. Amino acids profiles showed an early metabolic recovery of the new liver. Therefore nitrogen input could be higher and more adequate to nitrogen needs.

In patients with trauma or sepsis, carnitine is known to be produced to a greater extent; deficient production could impair the energy management that is required in such patients. To clarify the requirements of carnitine after injury, we studied carnitine elimination (in 10 critically ill injured patients) both during fasting and early parenteral nutrition. Increased carnitine (mainly, free) output after injury (9.36 +/- 1.63 mumol/kg p less than 0.02 vs reference) was negatively related to nitrogen balance (p less than 0.05) and positively to 3-methyl-histidine output (p less than 0.01), acting as a market of body mass catabolism. The output of both total and free carnitine progressively decreased (p less than 0.01) throughout the course of total parenteral nutrition. In conclusion, our data definitively suggest that carnitine loss after injury reflects body cell mass wastage and does not necessarily mean an increased need.

The effect of major trauma and sepsis on skeletal muscle, central tissue and whole body nitrogen (N) metabolism was investigated in 5 patients before and during TPN (30 kcal, 0.30 g N kg-1 day-1). Fasting 3-methylhistidine (MEH) urinary excretion was elevated (407.9±67.6 μmol m-2 day-1), muscle and body N balances (NB) were markedly negative (-28.2±4.6 g m-2 day-1 and-15.7±3.1 g m-2 day-1), while central tissue NB was positive (13.0±2.4 g m-2 day-1). TPN effected a reduction in MEH excretion (261.8±27.5 mmol m-2 day-1-p<0.05) and decreased the release of almost all amino acids from muscle tissue, some of them acting as catabolic markers. Muscle (-7.2±1.2 g m-2 day-1-p<0.01) as well as body NB (-4.8±1.4 g m-2 day-1-p<0.01) improved, whilst central tissue NB worsened, even though still positive (3.1±1.6 g m-2 day-1-p<0.05). Gathering fasting and TPN data MEH excretion was significantly related to both body (r=0.89) and muscle (r=0.73) NB, that were highly related to each other (r=0.93), being muscle always worse than body NB. In conclusion, the anticatabolic activity of TPN is confirmed, although our setting did not achieve muscle NB, it was consistently improved and seems to be the major determinant of body NB, in contrast central NB and central N utilization (46.4%±5.4 vs 15.8%±8.4-p<0.05) worsened.

Amino-acids involved in transsulphuration pathway were studied in the plasma and urine of 49 depleted surgical patients and 36 critically ill, injured patients who received total parenteral nutrition. A minimum B6 intake of 5 mg day−1 was provided to all patients; nitrogen intake was supplied with different amino-acid solutions. A daily methionine load higher than 15–24 mg kg−1, resulted in increased methionine plasma levels and increased urinary loss, both linearly related to methionine intake and notwithstanding the metabolic status of the patients. The increase of methionine load caused the appearance of traces of cystathionine in plasma and the increase of cystathionine urinary loss that were always higher than reference. This increase was linearly related to methionine intake in both patient groups, the slope being significantly higher in the depleted group. It suggests a limiting role of cystathioninase in the transsulphuration pathway. Its activity seems lower in depleted than in catabolic patients. During total parenteral nutrition, in spite of lower than normal cystine plasma values, cystine urinary output was always 2–10 times higher than reference in both patient groups, although cystine urinary loss was linearly related to methionine intake. Taurine and amino-butyrate were not significantly affected by total parenteral nutrition.

The metabolic derangements of injury are known to influence nitrogen (N) requirements whilst less is known about individual amino acid (AA) requirements. This study was designed to investigate prospectively N vs AA requirement in 36 injured patients treated with total parenteral nutrition (TPN). The non-protein caloric input was 30 kcal kg-1 day-1 and three AA solutions were assessed containing the same AAs but in different proportion. Overall N intake was set at 0.35 g N kg-1 day-1 for solution A and B and 0.24 g N kg-1 day-1 for solution C. Solution B was similar to A, both being enriched in branched chain AAs (BCAA: 0.69 g kg-1 day-1 in B compared with 0.55 g kg-1 day-1 in A) while decreased in aromatic and sulphurated forms (1.75 times the normal need). Solution C was designed to maintain a daily input of BCAA similar to A (0.52 g kg-1 day-1) but with the supply of aromatic and sulphurated AA between solutions A and B, the supply of other AAs (lysine, theonine, histidine, arginine, glycine) being dependent on the selected N intake. For all the essential AAs the supply was always greater than normal allowances. Increasing BCAA over 0.55 g kg-1 day-1 did not improve N balance when N intake was 0.35 g kg-1 day-1, whilst nutrition with solution C was unable to maintain N balance. Moreover we found indirect evidence that this N intake, 0.52g kg-1 day-1 was more sparing than 0.37 g kg-1 day-1 of BCAA.

Nitrogen balance, insulin and C peptide profiles were evaluated in 24 normo metabolic malnourished patients during parenteral feeding with three different diets. The nitrogen source and amount were identical (0.22 g/kg/day) but the calorie supply was different: 35 and 50 kcal as glucose or 50 kcal in a mixed system (15 kcal lipid). There were three groups: low (L) and high (H) glucose (G) and H lipid (L). Nitrogen balance in HG subset was higher than HL (0.019 ± 0.012 vs −0.022 ± 0.07, SEM, p < 0.001). The latter did not show any difference with respect to LG (0.006 ± 0.011). Insulin and C peptide plasma levels (limited to H groups) decreased during the study after an early peak; this decrease was significantly related to time in both groups and was significantly higher for both hormones in the HG group. However insulin plasma levels were always higher in the HG group and the better nitrogen balance in this group may be related to the anabolic activity of insulin.