Lawrence J. Hak

Measured energy expenditure of tube-fed patients with severe neurodevelopmental disabilities

OBJECTIVE To determine measured resting energy expenditure (REE) of nonambulatory tube-fed patients with severe neurological neurodevelopmental disabilities. METHODS Twenty patients were prospectively studied. Only steady state indirect calorimetry measurements were taken. All measurements were conducted using a canopy system. Nutritional needs were met entirely by enteral feedings via a permanent ostomy. RESULTS REE was widely distributed from 16 kcals/kg/day to 39 kcals/kg/day. The mean REE (888+/-176 kcals/day) of the patients was significantly (p<0.01) lower than predicted as estimated by the Harris-Benedict equations (1081+/-155 kcals/day) and World Health Organization equations (1194+/-167 kcals/day). Fat-free mass (FFM) was the best parameter for predicting REE. Two predictive equations were developed that are not significantly biased and more precise (< or =15% error) than conventional predictive formulas. CONCLUSION Conventional formulas for estimating energy expenditure are inaccurate and generally overestimate measured energy expenditure of nonambulatory patients with severe developmental disabilities.

Recovery from ischemic acute renal failure is improved with enteral compared with parenteral nutrition

OBJECTIVE To compare measurements of renal function after acute ischemic renal failure in rats fed enterally or parenterally. DESIGN Prospective, randomized, animal trial. SETTING University research laboratory. SUBJECTS Male Sprague-Dawley rats (n = 21). INTERVENTIONS Animals were randomized to receive isocaloric (160 nonprotein kcal/kg/day), or isonitrogenous (1.4 g of nitrogen/kg/day [100 mmol/kg/day]) enteral (n = 10), or parenteral nutrition (n = 11) through either a gastrostomy tube or a catheter placed in the jugular vein. After the animals received 7 days of assigned feedings, baseline blood samples were collected. A right nephrectomy and 45-min left renal pedicle occlusion were then performed. One hour after the ischemic injury, assigned feedings were resumed and continued for 3 days. After ischemic injury, daily blood samples were obtained and 24-hr urine collections were performed. On day 11, animals were killed and the kidney was harvested and fixed for subsequent microscopic examination. MEASUREMENTS AND MAIN RESULTS Urine was analyzed for concentrations of total urea nitrogen, creatinine, protein, and calcium. Serum was analyzed for creatinine and urea nitrogen concentrations. Fixed kidney sections were examined for mitotic figures, tubular calcifications, and casts using light microscopy by an investigator blinded to the nutritional regimen. Data are presented as mean +/- SD or median (range). Percent increase in creatinine clearance from the nadir on day 9 to day 11 was approximately 2.5-fold greater in the enteral compared with the parenteral nutrition group (490 +/- 221% vs. 208 +/- 130%; p = .003). Histologic evaluation demonstrated greater dystrophic tubular calcifications per ten high-power fields in the parenteral compared with the enteral nutrition group (50 [four to 85] vs. three [0 to 37]; p = .001). No differences in urine calcium concentration or 24-hr calcium excretion were seen. CONCLUSION Rats given continuous enteral nutrition 7 days before and for 3 days after ischemic acute renal failure have improved renal function compared with rats given parenteral nutrition.

Alterations in N-Acetylation of 3-Methylhistidine in Endotoxemic Parenterally Fed Rats

N-methylhistidine (3-meH) is endogenously released during muscle catabolism and serves as a marker of protein turnover. In rats > 85% of 3-meH is excreted in the urine as the N-acetyl derivative. It has been reported that the percent of non-acetylated 3-meH (NA-3-meH) varies minimally with stress. To further evaluate these reports we randomized 39 male Sprague-Dawley rats (157-213 g) to receive parenteral nutrition only (PN) or PN plus continuous infusion of Escherichia coli 026:B6 lipopolysaccharide at 6 (LPS-6) or 12 (LPS-12) mg.kg-1.d-1 for 48 h. All animals received isocaloric and isonitrogenous PN 24 h before and throughout the study with water ad libitum. Total 3-meH excretion was significantly increased (P < 0.05) in the LPS-6 (470 +/- 136 micrograms/48 h) and LPS-12 (557 +/- 171 micrograms/48 h) groups versus the PN (331 +/- 126 micrograms/48 h) group. NA-3-meH differed significantly between the LPS-12 (218 /+- 89 micrograms/48 h, LPS-6 (94 +/- 48 micrograms/48 h), and PN (39 +/- 12 micrograms/48 h) groups (P < 0.05). Percent NA-3-meH increased significantly from 12.7 +/- 3.9% in the PN group to 19.8 +/- 8.0 and 39.9 +/- 12.8% in the LPS-6 and LPS-12 groups, respectively (P < 0.05). No significant changes in acetyl 3-meH were found between groups. These data suggest that either saturation or inhibition of acetylation pathways occurs with increasing levels of stress. Due to the disproportionate increases in NA-3-meH and percent NA-3-meH during endotoxemia, only total 3-meH should be used as an indicator of protein turnover in rats.

Effect of Pentoxifylline on Nitrogen Balance and 3-Methylhistidine Excretion in Parenterally Fed Endotoxemic Rats

Pentoxifylline interrupts early gene activation for tumor necrosis factor, interleukin-1, and interleukin-6 production and improves survival from experimental sepsis. These effects can alter nitrogen loss during critical illness. To determine the dose-dependent influence of pentoxifylline on nitrogen loss, 44 male Sprague-Dawley rats (220 to 265 g) were randomized to receive parenteral nutrition only (PN), PN plus continuous infusion of Escherichia coli 026:B6 lipopolysaccharide (LPS) at 9 mg x kg(-1) x d(-1), or PN plus LPS plus a continuous infusion of pentoxifylline at either 25 (PEN25) or 100 mg x kg(-1) x d(-1) (PEN100) for 48 h. Before randomization, all animals underwent intravenous cannulation and 40 h of PN adaptation. All animals received isocaloric, isonitrogenous PN (160 kcal x kg(-1) x d(-1) and 1.0 gN x kg(-1) x d(-1)) and were kept nil per os except for water ad libitum. Administration of LPS significantly worsened nitrogen balance for all three groups compared with PN control; however, pentoxifylline only modestly improved nitrogen balance compared with LPS (206 +/- 255, -497 +/- 331, -332 +/- 329, and -310 +/- 383 mg/48hr for the PN, LPS, PEN25, and PEN100 groups, respectively; P < 0.001). Pentoxifylline did not significantly change 3-methylhistidine urinary excretion compared with LPS (573 +/- 180, 705 +/- 156, 780 +/- 326, and 683 +/- 266 microg/48 h for the PN, LPS, PEN25, and PEN100 groups, respectively, P not significant). Pentoxifylline, given in therapeutic doses after an endotoxin challenge, modestly, but not significantly, improved nitrogen balance. Urinary 3-methylhistidine excretion was not influenced by pentoxifylline. A dose-dependent effect by pentoxifylline on these markers was not evident.

Dose-dependent effect of octreotide on nitrogen retention and glucose homeostasis in response to endotoxemia in parenterally fed rats.

OBJECTIVE This study compared the effect of different doses of octreotide on glucose and protein homeostasis in rats receiving concomitant lipopolysaccharide and parenteral nutrition infusions. METHODS Sixty-six male Sprague Dawley rats (185 to 220 g) were randomized to receive parenteral nutrition only (PN), PN plus continuous infusion of Escherichia coli 026:B6 lipopolysaccharide at 6 mg/kg/day (LPS), PN plus LPS plus octreotide at 10 micrograms/kg/day (LPS + Oct 10), 100 micrograms/kg/day (LPS + Oct 100), or 1000 micrograms/kg/day (LPS + Oct 1000) for 48 hours. Prior to randomization all animals received isocaloric and isonitrogenous PN (170 kcal/kg/day as glucose and 1.1 g N/kg/day) and were kept nil per os except for water ad libitum. Nitrogen balance, urinary 3-methylhistidine/creatinine ratio, serum glucose concentration, and incidence of glycosuria were compared between groups. Serum urea nitrogen (SUN) changes were incorporated into the cumulative 48 hour nitrogen balance. ANOVA, Duncans multiple range test, and Fishers Exact Test were used for statistical analysis. RESULTS Nitrogen balance (mg/48 hours) was significantly lower in all four groups receiving LPS +/- Oct when compared to the control group receiving PN alone. SUN (mg/dL) was significantly higher in all four groups receiving LPS +/- Oct when compared to control. There were no statistically significant differences in nitrogen balance or SUN among the four groups receiving LPS +/- Oct. The ratio of urinary 3-methylhistidine/ creatinine was significantly higher in the LPS + Oct 1000 group compared to the PN group (0.77 +/- 0.37 vs. 0.42 +/- 0.24, p < 0.05). Serum glucose concentrations and incidence of glycosuria among the five groups were not significantly different. CONCLUSIONS Endotoxin significantly reduces nitrogen balance compared to controls fed PN. Octreotide does not significantly improve nitrogen retention or glucose homeostasis in endotoxemic parenterally fed rats.

Effect of Sustained Endotoxemia on α1‐Adrenergic Responsiveness in Parenterally Fed Rats

We investigated the effect of endotoxemia on α1‐adrenergic receptor‐mediated smooth muscle contraction as measured by mean arterial pressure (MAP) in response to incremental doses of a vasopressor. Twelve male Sprague‐Dawley rats were randomized to receive parenteral nutrition alone (PN) or in combination with a continuous infusion of endotoxin (PN‐LPS) for 48 hours. Incremental doses of phenylephrine were given and peak MAP response was recorded. The endotoxin group had a decreased rise in MAP with the same dose of phenylephrine compared with the control group (59 ± 14 and 99 ± 12 mm Hg, respectively, p<0.001). However, the baseline MAP was higher in the endotoxin group (102 ± 18 and 71 ± 7 mm Hg, respectively, p<0.002). The overall maximum effect was the same for both groups (161 ± 16 and 170 ± 8 mm Hg, respectively, p=NS). These data indicate that sustained endotoxemia does not result in desensitization of α1‐adrenergic responsiveness. Other mechanisms are responsible for the ineffectiveness of vasopressors during advanced sepsis.

The effect of α-adrenergic antagonism upon nitrogen loss during endotoxemia☆

Sixty male Sprague-Dawley rats were randomized to receive parenteral nutrition (PN) only; PN plus continuous infusion of Escherichia coli 026:B6 lipopolysaccharide (PN + LPS) at 6 mg·kg−1·d−1; or PN plus LPS plus a continuous infusion of the α-adrenergic antagonist phentolamine (PN + LPS + PHEN) at 5 mg·kg−1·d−1 or 20 mg·kg−1·d−1 for 48 h. All animals received isocaloric, isonitrogenous PN. LPS significantly lowered nitrogen balance (mmol/48 h) from PN control; however, addition of PHEN substantially worsened nitrogen balance compared with LPS (14.2 ± 3, 2.4 ± 5.2, −1.6 ± 4.5, −0.8 ± 5.4, for the PN, PN + LPS, PN + LPS + PHEN5 and PN + LPS + PHEN20 groups, respectively; P < 0.0001). Urinary 3-methylhistidine/creatinine ratio (3-meH/creat) paralleled the nitrogen balance data (0.30 ± 0.09, 0.45 ± 0.12, 0.51 ± 0.14, 0.60 ± 0.12, respectively; P < 0.0001). The high-dose PHEN resulted in 82 ± 9% blockade. To ascertain if any beneficial effect upon body protein loss is achieved during severe stress, 30 rats were given PN + LPS at 12 mg·kg−1·d−1 or PN + LPS12 + PHEN20. These data showed similar changes in nitrogen balance and 3-methyhistidine/creatinine with the use of PHEN during severe endotoxemia. α-adrenergic antagonism with PHEN worsens body protein loss as measured by nitrogen balance and 3-methylhistadine/creatinine in PN-fed endotoxemic rats.

Comparison of azathioprine (AZA) and 6-mercaptopurine (6-MP) plasma concentrations after administration of aza solution into the stomach jejunum, or cecum

AZA is used in the treatment of patients with refractory inflammatory bowel disease. Its use, however, has been limited by its delayed onset of action and toxicity associated with long term use. Van Os et ai (Gut 1996) reported reduced bioavailability of 6-MP after colonic administration of azathioprine, suggesting the possibility that if a local therapeutic effect occurs, this may result in reduced systemic side effects. The purpose of this study was to compare the systemic exposure to 6-MP following administration of AZA to different absorption sites. Six healthy male volunteers who had normal thiopurine methyltransferase activity, received three doses of Imuran (50mg injectable) via an oral-enteric tube directly into the stomach (S), jejunum (J), or cecum (C), separated by 24 hours. Plasma concentrations of AZA and 6-MP at various times were quantified by HPLC; area under the plasma concentration, time curve (AUC) and mean residence time (MRT) were determined by statistical moment theory. Mean -+ SD results were: