Efficacy of ornithine-alpha-ketoglutarate (OKGA) as a dietary supplement in growing rats

New substrates of potential benefit to critically ill patients receiving traditional nutritional support have been suggested to meet organ or tissue specific needs. The addition of an anabolic stimulus during nutritional support therefore appears to be a reasonable adjunct to augment protein synthesis. The purpose of this investigation was to evaluate the efficacy of the neutral salt ornithine alphaketoglutarate (OKGA) as a dietary supplement to promote growth in young rats by enhancing protein metabolism. A group of 16 male Sprague-Dawley rats (150-170g) were housed in individual metabolic cages and after dark-light cycle adaptation were fed ad libitum an oral liquid diet for 7 days. Half of the animals were given the control diet and the other half was fed a test diet. This isonitrogenous test diet contained the control diet with 2.3% of nitrogen (N) replaced by N from OKGA. Daily weight, food intake and urinary excretions of N, creatinine, urea, orotic acid, polyamines and amino-acids were determined. At the end of 7 days of free-feeding, the rats were sacrificed and blood was collected for free amino-acids. Rats fed the OKGA supplemented diet consumed 16% more diet, retained 11% more nitrogen and gained 15% more weight. The accelerated protein metabolism is reflected in the changes in plasma and urinary free amino-acid levels. Enhanced protein anabolism is evident from the increased urinary excretion of polyamines in the OKGA fed rats. The increased ratio of urinary urea N to total N and the decreased orotic acid excretion in OKGA fed rats suggests thata NH(4)(+) was efficiently diverted through urea cycle. It is concluded that in growing rats, supplementing isonitrogenous diet with OKGA significantly stimulates food intake compared to controls. This results in better weight gain and improvement in protein metabolism.     

Surgical device exchange provides improved clinical outcomes compared to medical therapy in treating continuous-flow left ventricular assist device thrombosis

The purpose of this study is to compare clinical outcomes of left ventricular assist device (LVAD) patients with device thrombosis who underwent device exchange (DE) or medical therapy (MT) alone. Consecutive patients undergoing LVAD implant between July 2008 and December 2017 were included. Device thrombosis was diagnosed with comprehensive assessments including ramp test, laboratory data, device parameters, and clinical presentations. First, MT was initiated in all patients. After MT, DE was considered if device thrombosis was refractory to initial MT, and it caused end-organ impairment and/or hemodynamic instability. Among 319 consecutive LVAD patients, 43 patients (13.5%) were diagnosed with device thrombosis. DE was performed in 28 patients (DE group); device explant was performed in 1 patient. MT was continued in 14 patients (MT group). In-hospital mortality was significantly lower in the DE group than the MT group (3.6% [1/28] vs. 28.6% [4/14], P = .0184). One-year survival was significantly better in the DE group (74.0% vs. 30.1%; log-rank = .001), and freedom from cerebrovascular accident (CVA) at 1 year was greater in the DE group (87.1% vs. 47.7%; log-rank = .004). DE was associated with improved 1-year survival and fewer CVAs. Surgical intervention, if feasible, is recommended for LVAD device thrombosis.     

Optimal cannula positioning of HeartMate 3 left ventricular assist device

Cannula position in HeartMate II and HeartWare left ventricular assist devices (LVADs) is associated with clinical outcome. This study aimed to investigate the clinical implication of the device positioning in HeartMate 3 LVAD cohort. Consecutive patients who underwent HeartMate 3 LVAD implantation were followed for one year from index discharge. At index discharge, chest X-ray parameters were measured: (a) cannula coronal angle, (b) height of pump bottom, (c) cannula sagittal angle, and (d) cannula lumen area. The association of each measurement of cannula position with one-year clinical outcomes was investigated. Sixty-four HeartMate 3 LVAD patients (58 years old, 64% male) were enrolled. In the multivariable Cox regression model, the cannula coronal angle was a significant predictor of death or heart failure readmission (hazard ratio 1.27 [1.01-1.60], P = .045). Patients with a cannula coronal angle ≤28° had lower central venous pressure (P = .030), lower pulmonary capillary wedge pressure (P = .027), and smaller left ventricular size (P = .019) compared to those with the angle >28°. Right ventricular size and parameters of right ventricular function were also better in the narrow angle group, as was one-year cumulative incidence of death or heart failure readmission (10% vs. 50%, P = .008). Narrow cannula coronal angle in patients with HeartMate 3 LVADs was associated with improved cardiac unloading and lower incidence of death or heart failure readmission. Larger studies to confirm the implication of optimal device positioning are warranted.     

Altered tissue polyamine levels due to ornithine-alpha-ketoglutarate in traumatized growing rats.

All cells contain significant amounts of polyamines (PA), and their concentrations are highly regulated. Metabolic activity within a tissue may be reflected in the amount of intracellular PA. Since trauma involves accelerated death and regeneration of tissues, the related levels of PA in extracellular and intracellular fluids may reflect altered protein metabolism. Trauma induces an increased excretion of urinary PA, and the tissues responsible for this whole-body activity are not known. During posttraumatic nutritional management, supplementation with ornithine-alpha-ketoglutarate (OKG) seems to improve nitrogen economy. The present study evaluates the significance of muscle, liver, and intestine PA responses in traumatized (bilateral femur fractures) rats to the feeding of an isonitrogenous liquid diet supplemented with or without OKG. Uninjured control rats were pair-fed with respective traumatized rats. After 2 days of starvation and 4 days of feeding, the traumatized and control rats were killed and the tissues were excised and analyzed. Starvation decreases and refeeding increases urinary PA excretion. Trauma-induced PA response is predominantly seen in muscle tissues, and this may be responsible for parallel increases in PA excretion. Liver PA responses show a varying tendency confirming the increased protein synthetic activity due to trauma. Intestine has the highest intracellular PA levels, and there is a general smaller (statistically insignificant) increase in all the individual PA contents due to trauma. OKG supplementation augments tissue and urine PA responses in control rats; however, in trauma rats muscle PA levels show very little change, although nitrogen retention is significantly better (88% to 77%). Mechanistic studies are needed to evaluate the significances of the time-dependent, injury-induced, individual intracellular PA levels.     

Comparison of hepatic protein synthesis in vivo versus in vitro in the tumor-bearing rat

We have used the model of the freshly isolated hepatocyte to study liver metabolism in a rat tumor model and have reported elevations in the rates of protein synthesis, gluconeogenesis, alanine transport, and oxygen utilization by the tumor-influenced hepatocyte. While the metabolic activity of the isolated hepatocyte has been taken to reflect metabolism in the in vivo state, this assumption has not been validated. In the present study, we measure hepatic protein synthesis in vivo using a flooding dose of tracer amino acid, and in vitro in hepatocytes freshly isolated from tumor-bearing (TB) and pair-fed control rats. Increased protein synthesis was observed for the TB rats using both methods of analysis. However, the degree of stimulation seen in the TB animals was much greater in the in vitro assay than in the in vivo approach, suggesting that absolute protein synthetic rates in vitro must be interpreted with caution when extrapolating to the in vivo state.     

Measured energy expenditure in pediatric intensive care patients

Few data are available on energy requirements of mechanically ventilated, critically ill children. We measured the resting energy expenditure in 18 mechanically ventilated patients between ages 2 and 18 years, using indirect calorimetry. All patients had fractional inspired oxygen concentration less than 0.6, no spontaneous respirations, hemodynamic stability, and no fever or active infection, and were receiving 5% dextrose. All subjects were hypermetabolic, since the measured resting energy expenditure divided by the predicted basal energy expenditure from the Harris-Benedict equations was 1.48 +/- 0.09 (mean +/- SEM). The energy requirements calculated using "injury factors" and "activity factors" adapted for adults is 1.62 times basal energy expenditure. The injury factor for the pediatric multiple trauma patients should be 1.25 compared with 1.35 in adults. In these pediatric intensive care patients 33% +/- 8% of the energy is derived from carbohydrates, 53% +/- 8% from fat, and 14% +/- 2% from protein oxidation. In individual critically ill pediatric patients, energy requirements should be estimated by measuring their resting energy expenditure whenever possible and adding 5% for their activity. In the absence of the actual measurement of resting energy expenditure, the recommended energy requirement is 1.5 times basal energy expenditure. In this acute phase of injury, the daily nitrogen requirement is 250 mg per kilogram of body weight.     

Whole-body protein breakdown and 3-methylhistidine excretion during brief fasting, starvation, and intravenous repletion in man.

Simultaneous whole-body protein breakdown (using 15N-glycine) and urinary 3-methylhistidine (3MH) excretion rates were determined in six hospitalized normal volunteers after 10 days of starvation and a subsequent 10-day period of total parental nutrition (TPN). These data were contrasted to whole-body protein breakdown and urinary 3MH excretion in ten depleted (14.8% body weight loss) patients with benign intraabdominal disease studied in the basal (48 hours without nutrient intake) and intravenously refed states. The rates of whole-body protein breakdown were significantly reduced from basal (brief fasting or starvation) conditions in both normal volunteers (p less than 0.01) and depleted patients (p less than 0.01) during TPN. The rate of protein catabolism normalized for creatinine excretion in patients was higher than that observed in normal subjects during both basal (p less than 0.05) and intravenous feeding conditions. Daily urinary 3MH excretion was reduced during intravenous feeding in both starved normal volunteer (235 +/- 13 mumol/d to 197 +/- 9 mumol/d p less than 0.05) and in depleted patients (209 +/- 31 mumol/d to 140 +/- 35 mumol/d), and an apparent linear relationship between protein breakdown and urinary 3MH, normalized for creatinine excretion, was obtained in both volunteer and patient (r = 0.85) populations during fasting-refeeding. However, separate regression analysis of the protein breakdown and 3MH responses of both volunteer and patient groups under conditions of fasting, starvation, and refeeding revealed significant differences between volunteer and patient populations during intravenous refeeding (p less than 0.01). Further analysis of 3MH excretion in relationship to nitrogen balance during refeeding suggests a complex relationship between urinary 3MH excretion and whole-body protein metabolism that may be partly related to the degree of antecedent malnutrition.     

Current state of intraoperative echocardiography

Intraoperative use of echocardiography is becoming more prevalent and is now considered an essential part of modern cardiac surgery. Echocardiography can be performed intraoperatively using transesophageal, epicardial or epiaortic, and substernal approaches. These techniques have a variety of applications in evaluating myocardial and valvular function, assessing aortic atheroma, and determining adequacy of various kinds of repair and reconstruction. Future applications will most likely involve more compact equipment, the implementation of epicardial and transesophageal real-time three-dimensional echocardiography, and better use of provocative methods of intraoperative testing.