Michael A. Marano

Total parenteral nutrition and bowel rest modify the metabolic response to endotoxin in humans.

Intestinal mucosal atrophy, as induced by total parenteral nutrition (TPN) and/or prolonged bowel rest, is hypothesized to enhance bowel endotoxin (LPS) translocation and may alter host responses to infection. To examine the effect of TPN-induced bowel atrophy on the response to LPS, 12 healthy volunteers were randomized to receive either enteral feedings (ENT, n = 6) or seven days of TPN without oral intake (TPN, n = 6). Enteral or TPN feedings were terminated 12 hours before the study period when a constant dextrose infusion (50 mg/kg/hour) was initiated and continued throughout the subsequent study period. After placement of arterial, hepatic vein, and femoral vein catheters, metabolic parameters were determined before and for six hours after an intravenous E. coli LPS challenge (20 U/kg). Subsequent peak levels of arterial glucagon (ENT, 189 +/- 39 pg/mL; TPN, 428 +/- 48; p less than 0.01), arterial epinephrine (ENT, 236 +/- 52 pg/mL; TPN, 379 +/- 49; p less than 0.05) and hepatic venous cachectin/tumor necrosis factor (cachectin/TNF) (ENT, 250 +/- 56 pg/mL; TPN, 479 +/- 136; p less than 0.05) were significantly higher in the TPN group than in the ENT group. The extremity efflux of lactate (ENT, -16 +/- 4 micrograms/min-100cc tissue; TPN, -52 +/- 13; t = 2 hours; p less than 0.05) and of amino acids (ENT, -334 +/- 77 nmol/min-100cc tissue; TPN, -884 +/- 58; t = 4 hours; p less than 0.05) were higher in the TPN subjects after the endotoxin challenge. Circulating C-reactive Protein (CRP) levels measured 24 hours postendotoxin were also significantly higher in the TPN subjects (ENT, 1.7 +/- 0.2 mg/dL; TPN, 3.2 +/- 0.3; p less than 0.01). Hence the counter-regulatory hormone and splanchnic cytokine responses to LPS were enhanced after TPN and bowel rest. This is associated with a magnified acute-phase response, peripheral amino acid mobilization, and peripheral lactate production. Thus antecedent TPN may influence the metabolic alterations seen in infection and sepsis via both an exaggerated counter-regulatory hormone response as well as an enhanced systemic and splanchnic production of cytokines.

Peripheral blood leukocyte kinetics following in vivo lipopolysaccharide (LPS) administration to normal human subjects. Influence of elicited hormones and cytokines.

Lipopolysaccharide (LPS, endotoxin) administration to human subjects elicits significant elevations in plasma cachectin/TNF, epinephrine, and cortisol. This study examined the temporal relationship between changes in blood leukocyte subsets and plasma mediators following endotoxin administration to normal human subjects. A five-minute intravenous infusion of purified LPS (20 units/kg Escherichia coli) was administered to 12 healthy volunteers. Blood samples were obtained at varying intervals after infusion and analyzed for differential cell counts and lymphocyte subsets (CD2, CD3, CD4, CD8, CD20, and HLA-DR) by flow microfluorimetry, and also assayed for plasma cachectin/TNF, epinephrine, and cortisol. Plasma cachectin/TNF was significantly elevated at 75 and 90 minutes after infusion with a peak concentration of 261 +/- 115 pg/ml noted 75 minutes after infusion. A significant plasma epinephrine elevation of 181 +/- 75 pg/ml was demonstrated one hour after infusion, while significant elevations in plasma cortisol were noted from one to five hours after infusion with a peak level of 34 +/- 3 micrograms/dl three hours after infusion. A profound monocytopenia (p less than 0.01) was noted one hour after infusion. Temporally associated with the rise in plasma cortisol was a reversal of the early granulocytopenia to a significant granulocytosis (p less than 0.01 versus preinfusion mean), whereas a marked lymphocytopenia (p less than 0.01) was observed from one to six hours after infusion. During the period of hypercortisolemia, CD2, CD3, and CD4 lymphocyte percentages were decreased (p less than 0.01) while CD20 and HLA-DR lymphocyte percentages were increased (p less than 0.01). There was a small percentage decrease in CD8 lymphocytes from one to 24 hours after infusion (p less than 0.01), although relative to the one-hour nadir, there was a significant rise in the percentage during the time of elevated plasma cortisol concentrations. A six-hour infusion of epinephrine (30 ng/kg/min) administered to six healthy volunteers resulted in a monocytosis (p less than 0.05) and granulocytosis (p less than 0.01) without a change in lymphocyte number or lymphocyte subset percentage. Previous reports have shown that in vivo corticosteroid infusion causes a prominent granulocytosis, monocytopenia, and lymphocytopenia with a decrease in the percentages of CD3 and CD4 lymphocytes. The peripheral blood leukocyte dynamics documented in the current study are similar to patterns observed following in vivo corticosteroid administration. This study suggests that the acute adrenocortical response to endotoxemia primarily mediates the subsequent changes in leukocyte subsets.

Starvation leads to decreased levels of mRNA for myofibrillar proteins

Malnutrition is a common complicating factor in surgical illness. To investigate the cellular changes and mechanisms responsible for the protein wasting associated with nutritional deprivation, Sprague-Dawley rats were subjected to total protein-calorie starvation for 3 (n = 12) or 5 days (n = 12) and compared to freely fed animals monitored for 3 (n = 8) or 5 (n = 8) days. Gastrocnemius protein and RNA content and levels of mRNA coding for the myofibrillar proteins myosin heavy chain, myosin light chain, and alpha-actin were measured. Starvation resulted in a significant decrease in gastrocnemius mass and protein content, and was associated with decreases in mRNA levels for the three myofibrillar proteins assayed. We conclude that changes in mRNA levels for these proteins likely contribute to the loss of peripheral protein which occurs during total nutritional deprivation. In addition, the changes in mRNA levels for these three structural proteins appear to be coordinate, suggesting that transcription of no single myofibrillar protein is rate-limiting in the regulation of skeletal muscle protein content.

Pediatric burns. An overview.

This article describes the management of burn injuries in children. It begins with an epidemiologic description of pediatric burns. Attention is given to emergency care, burn wound evaluation, operative management, and rehabilitative goals.

Hepatocellular membrane function during chronic burn injury

Hepatocellular membrane dysfunction, as indicated by depolarization of the membrane potential, occurs after acute injury and early bacteremia. To determine whether hepatocellular membrane dysfunction occurs in the setting of ongoing thermal injury and infection, Wistar rats were divided into four groups: (1) sham-burned, freely fed controls (FF); (2) rats sustaining approximately 30% total body surface area dorsal full-thickness scald burn (Burn); (3) rats sustaining burns as in group 2 followed by immediate inoculation of 1 x 10(8) CFU Pseudomonas aeruginosa (Burn/Inf); and (4) sham-burned rats pair-fed to the food intake of the Burn/Inf group (PF). On the third and seventh days postburn, body and liver weights were determined. In vivo hepatocellular transmembrane potentials were measured and hepatic ATP, RNA, DNA, and protein contents were assayed. By Day 7, despite greater weight loss in the Burn/Inf group than due to starvation alone (P less than 0.01 Burn/Inf vs FF and PF), hepatic mass was conserved. This was associated with hyperpolarization of the hepatic transmembrane potential (-46.6 +/- 1.5 vs -32.1 +/- 0.6 mV, Burn/Inf vs FF, P less than 0.01) and increases in RNA (141 +/- 9 vs 91 +/- 4 mg/liver, Burn/Inf vs FF, P less than 0.01) and DNA (37 +/- 5 vs 22 +/- 2 mg/liver, Burn/Inf vs FF, P less than 0.05) contents, with no change in ATP or hepatic protein contents. There was a significant hypercorticosteronemia observed in the Burn/Inf group (43 +/- 9 vs 2.8 +/- 0.7 micrograms/dl, Burn/Inf vs FF, P less than 0.01). This hepatic membrane hyperpolarization and augmented RNA content were not secondary to burn or starvation alone as the response in these groups was significantly less than that of the Burn/Inf group. It is suggested that this hepatic membrane hyperpolarization is one mechanism by which hepatic function is maintained during ongoing burn infection in the rat.

Interleukin-1 and Interleukin-6 Synergize to Increase Plasma Amyloid P and C3 Concentrations in the Mousea

Following inflammation, trauma, or infection, significant changes occur in the pattern of protein synthesis by the liver. Increased synthesis of a variety of hepatic “acute phase reactant proteins” is presumed to play an integral role in how the host responds to tissue damage or invading pathogen.’ The increased hepatic protein synthesis seen during inflammation is presumed to be regulated by several cytokines, including interleukin1, interferon-beta, /interleukin6, and tumor necrosis factor-alpha (cachectin). However, controversy exists regarding the quantitative and qualitative importance of these three cytokines in inducing the individual plasma protein responses. Although initial studies emphasized the importance of interleukin-1 as the primary inducer of the hepatic acute phase response,’ more recent studies have emphasized interleukin-6’ and, to a lesser extent, tumor necrosis fa~tor -a lpha .~ .~ Therefore, the present study was undertaken to evaluate the induction of two murine acute phase proteins-amyloid P and the third component