Nitrogen-sparing mechanisms of singly administered branched-chain amino acids in the injured rat.

Previous studies have demonstrated that the in vivo nitrogen-conserving quality of amino acid solutions might be improved by increasing the percentage of branched-chain amino acids (BCAA) and that infusion of a solution consisting only of the three BCAA-valine, leucine, and isoleucine-in the postoperative period resulted in nitrogen equilibrium. To clarify which of the properties ascribed to the BCAA is responsible for the improved postoperative nitrogen conserving quality, we infused rats undergoing laparotomy and jugular vein cannulation with each of the BCAA or alanine separately. Twenty-four hours before the were killed 5 microCi 14C-tyrosine was added to the infusate to determine total body protein degradation and fractional synthesis rate in liver and muscle. All four amino acid-containing solutions conserved nitrogen as compared with 6.5% dextrose. Fractional synthesis of rate mixed liver protein was significantly increased in all groups receiving BCAA. Only the infusion of valine significantly increased muscle protein synthesis. Total body protein breakdown rate was similarly decreased in all groups receiving amino acids (alanine, valine, leucine, or isoleucine). Total body protein breakdown correlated significantly with the nitrogen balance. The protein-sparing mechanisms of the BCAA in the post-traumatic period are mediated through reduction in whole body protein breakdown, as well as by increasing protein synthesis in both liver and muscle protein. These results appear specific for the BCAA as isonitrogenous amounts of alanine do not give similar results.

Blood-brain barrier derangement in uremic encephalopathy.

A disturbance of cerebral neurotransmitters and an accumulation of octopamine, a putative false neurotransmitter, have been found in patients with uremic encephalopathy who manifest disorientation, somnolence, asterixis, and coma--symptoms also seen in portal systemic encephalopathy (PSE). Altered plasma concentrations of the neutral amino acids (NAAs) and increased blood-brain NAA transport may play a role in PSE, and in the present study plasma amino acid concentrations and blood-brain barrier NAA transport were investigated in rats with acute and chronic uremia. Acute uremia was produced by unilateral nephrectomy and occlusion of the renal artery of the remaining kidney for 70 minutes; the animals were studied 24 hours later. Chronic uremia was produced by unilateral nephrectomy and 70% to 80% devascularization of the remaining kidney; these animals were studied 2 weeks later. Brain uptake was studied with the technique of Oldendorf, and blood and brain amino acids (AAs) were measured. The blood urea nitrogen (BUN) level in rats with acute uremia increased to 108 mg/dl, in rats with chronic uremic 54 mg/dl, and in sham-operated rats 22 mg/dl. In both uremic groups there was a decrease in plasma branched-chain AAs. In the brain these AA levels were normal, while levels of phenylalanine, tyrosine, and histidine were increased in uremic rats.

Chemical phlebothrombosis of large veins. A not uncommon complication of total parenteral nutrition.

Thrombosis of large veins during total parenteral nutrition (TPN) is considered uncommon. Recently, clinical and phlebographic evidence of large-vein thrombosis were encountered in five patients among 200 consecutive patients receiving TPN. The symptoms, signs, and phlebographic findings occurred within one to two days, sometimes as early as a few hours after cannulation. It is suggested that thrombosis of large veins during TPN is not uncommon and is the result of chemical phlebothrombosis due to a hypersensitivity reaction of the venous wall to the polyvinyl catheter material. Early removal of the offending catheter is advocated.

Systolic properties of normal and septic isolated rat hearts. The effect of branched chain amino acids.

Systolic properties and coronary flow were studied in Langendorff preparations of normal and septic rat hearts paced at 100, 200, 300, and 400 beats per minute. In addition, the effects of amino acid formulations differing in their branched chain amino acid (BCAA) concentration in normal and septic rat hearts were investigated. Our experiments demonstrated the following: in the normal isolated rat heart, Krebs plus glucose and Krebs plus glucose plus 42% BCAA are most effective in maintaining systolic properties, while Krebs plus glucose plus 15% or 100% BCAA were considerably less effective. Sepsis results in a significant decrease in the systolic properties of the isolated rat heart, and in a loss of the negative linear correlation between contractility and heart rate, probably the result of a diminishing intracellular load of contractile calcium. In the isolated septic rat heart, mechanical washout during perfusion has a beneficial effect, suggesting the presence of a myocardial depressant substance in sepsis. The use of a balanced amino acid mixture containing 42% BCAA exerts the greatest benefit in maintaining systolic properties and in improving coronary flow in the isolated septic rat heart.

Regional brain amino acid and neurotransmitter derangements during abdominal sepsis and septic encephalopathy in the rat. The effect of amino acid infusions.

Regional amino acids and brain neurotransmitters were studied in 33 normal and 32 rats with sepsis (induced by cecal ligation and puncture) infused with different amino acid formulations. The brain amino acid pattern during sepsis showed increased concentrations of most essential and six of the nonessential amino acids. The most consistent finding was the accumulation of indoleamines in all six brain regions studied during sepsis; increased brain tryptophan levels presumably resulted in enhanced metabolism of serotonin (5HT), increased production of 5-hydroxyindoleacetic acid (5HIAA), and a high 5HT/5HIAA ratio. Infusion of branched-chain amino acid-enriched formulas restored brain amino acid and neurotransmitter profiles, decreasing levels of tryptophan, tyrosine, 5HIAA, and 5HT/5HIAA ratios while increasing norepinephrine levels in some regions. These alterations in brain neurotransmitter metabolism may be at least partially responsible for the development of septic encephalopathy.

Resting energy expenditure of host and tumor is similar in rats with methylcholanthrene-induced sarcoma.

In the present study we assessed the resting energy expenditure of 30 free-feeding control and methylcholanthrene-induced sarcoma-bearing rats prior to and following surgical removal of the tumor. Tumor-bearing rats demonstrated carcass wasting and massive tumor growth. The resting energy expenditure data in our model suggest that neither the presence and growth of a tumor nor its removal significantly change resting energy expenditure beyond the normal range for non-tumor-bearing rats. We suggest that in the partition of energy costs between host and tumor, both carry a similar input, proportional to their relative weight, into the total combined resting energy expenditure of host and tumor.

Muscle prostaglandin production in the rat. Effect of abdominal sepsis and different amino acid formulations.

Recent in vitro studies attribute regulatory functions to prostaglandins (PGs) in muscle protein metabolism, particularly enhancing proteolysis. In the present study, the amount of muscle PG production from endogenous precursors was determined in control and septic animals (cecal ligation and puncture) that were infused with 5% dextrose or dextrose with three amino acid formulations differing in their branched-chain amino acid (BCAA) content. We could not detect any differences in prostaglandin E, 6-keto-prostaglandin F1 alpha, and thromboxane B2 production between control and septic animals. Furthermore, the infusion of BCAAs, which have previously been shown to be nitrogen sparing following injury, did not influence the production of any of the PGs studied in either control or septic muscle. It is likely that the effects of the BCAAs on muscle synthesis and degradation are independent of the PGs.

The effect of indomethacin on muscle and liver protein synthesis and on whole-body protein degradation during abdominal sepsis in the rat.

It has been recently suggested that increased muscle protein degradation during injury or infection is at least partially mediated by the increased production of prostaglandin E2 in muscle, and some have suggested that cyclooxygenase inhibitors might decrease protein loss in injured or septic patients. In these experiments, fractional synthesis rates of mixed muscle and liver protein and whole-body tyrosine flux were measured by constant intravenous infusion of tyrosine labeled with carbon 14 in 17 rats with sham operations and 15 severely septic rats with or without indomethacin treatment (20 mg/kg/d). Fractional synthesis rates in muscle and liver were decreased in late sepsis and were lowest in the septic group receiving indomethacin. Unlike the fractional synthesis rate, which was affected by indomethacin in septic rats only, tyrosine flux was significantly lower in indomethacin-treated rats with sham operations and those with sepsis. Although indomethacin reduced total-body protein breakdown during sepsis, it was also associated with lower plasma albumin levels and with decreased protein synthesis in muscle and liver at a time when the survival of the septic host may be dependent on its ability to produce new protein for a variety of vital functions. These results do not support the use of indomethacin in sepsis.

Coupling among interstitial cells of Cajal in the human ileum.

Current knowledge on the morphology and physiology of interstitial cells of Cajal (ICC) is mostly based on animal studies, and information about the function of these cells in humans is scarce. There is ultrastructural evidence that ICC in the myenteric region (ICC-MP) of the small intestine of several species are connected by gap junctions, but these were not observed in the human small intestine. The aim of the present study was to determine whether functional coupling also exists among ICC-MP in the human ileum. We visualized ICC-MP in live tissues using Nomarski optics, and verified their identity by staining for c-Kit. ICC were injected intracellularly with the fluorescent dye Lucifer yellow, which crosses gap junctions. In most cases the labelled cells had oval somata with two primary processes. At normal pH (7.3-7.4) only 20.2% (21/104) of the injected ICC were coupled to other ICC. However, at pH 7.8-7.9 coupling incidence increased to 74.5% (35/47, P < 0.0001). The injected cells were coupled to one to 35 other ICC. Octanol blocked coupling in all cases. Apparently, gap junctions interconnect ICC in the human small intestine. Coupling was enhanced by a small increase in pH, suggesting that it may be under physiological control.

Direct inhibitory effect of erythromycin on the gallbladder muscle.

Erythromycin, a macrolide antibiotic, stimulates motor activity in various parts of the gastrointestinal tract in humans and animals. This effect of erythromycin resembles that of motilin, a gastrointestinal hormone, in evoking contractions similar to phase 3 activity of the migrating motor complex. Motilin induces contractions in the canine gallbladder but fails to evoke any response, either in vivo or in vitro, in the human gallbladder. Surprisingly, erythromycin stimulates human gallbladder emptying in healthy volunteers and in persons with diabetic autonomic neuropathy. In the present study we examined the effect of erythromycin on chemically and electrically evoked contractions of isolated gallbladders from guinea pigs and humans by use of isometric force measurements. Carbachol, a muscarinic cholinergic agonist, evoked gallbladder contractions that were diminished by erythromycin in a concentration-dependent manner: at 200 micromol/L the contractions were 86% +/- 20% of the control response, at 500 micromol/L they were 63% +/- 21% of control, and at 1000 micromol/L they were 41% +/- 20% of control (P <0.05, N = 10, mean +/- standard deviation). Electrically evoked gallbladder contractions were reduced to 68% +/- 18% of the control response with the addition of 500 micromol/L of erythromycin and to 56% +/- 19% of control after the addition of 1000 micromol/L (P <0.05, N = 8). Guinea pig but not human gallbladders contracted after stimulation with the alpha-adrenergic agonist phenylephrine. Erythromycin reduced these contractions in a concentration-dependent manner but had no effect on gallbladder contractions induced by bradykinin. In human gallbladder strips, erythromycin at 500 micromol/L reduced the contractile response to electrical stimulation to 71% +/- 16% of the control value (N = 10 [5 patients], P <0.01) and the carbachol-evoked contractions to 53% +/- 24% (P <0.01, N = 32). The inhibitory effect of erythromycin persisted in the presence of the nerve blocker tetrodotoxin at 1 micromol/L. It is concluded that erythromycin has a direct inhibitory effect on guinea pig and human gallbladder contractions.

Current controversies in sentinel lymph node biopsy for breast cancer.

Despite the widespread use of sentinel lymph node biopsy (SLNBx) in the surgical management of breast cancer patients, several areas remain controversial. The following controversies are reviewed: Learning curves and validation studies. There clearly is a learning curve, and a completion ALND should be done until adequate proficiency is exhibited, both in terms of identification and false-negative rates. Location of injection. Intradermal injection offers superior identification rates compared with peritumoral injection, with comparable false-negative rates. Subareolar injection is as accurate as peritumoral injection. The value of scintigraphy. Routine scintigraphy does not enhance identification or false-negative rates. Mapping agents. Blue dye and radioactive tracer combined to provide a higher identification rate than either used alone.SLNBx in DCIS. In patients with a high risk of microinvasion, such as large tumors, a mass or high-grade DCIS-SLNBx is justified.SLNBx following neoadjuvant chemotherapy. Although there is evidence that SLNBx after neoadjuvant chemotherapy may be accurate, these data should be applied cautiously. Implications of non axillary SLN, especially internal mammary nodes. Data do not support routine resection of internal mammary sentinel lymph nodes outside a clinical trial. Implications of micrometastases in the sentinel lymph node seen only on immunohistochemistry. Since the significance of such metastases is unclear, decisions regarding treatment of these patients should be individualized. The value of completion axillary lymph node dissection. Is being addressed in clinical trials. Until those studies mature, completion ALND should be performed for patients with SLN metastases, but may be abandoned for patients with a negative SLN.

Candida sepsis during total parenteral nutrition: An endogenous infection indicating the severity of patients' disease state.

Between 1986 and 1989 we encountered 33 episodes of candida sepsis among 1169 patients receiving TPN for a total of 23350 days (2.8% candida infection rate). Total hospital stay averaged 78 (range 10-230) days and patients received TPN for an average of 21.5 (range 3-83) days before developing candida sepsis. Candida sepsis developed in 8 patients (26.6%) hospitalised in an ICU; 6 patients (20%) receiving high doses of glucocorticoids, 5 patients (16.6%) treated by cytotoxic agents; 23 patients (76.6%) received various combinations of broad-spectrum antibiotics. The number of tubes going in or out numbered an average of 3.6/patient (peripheral and/or central I.V.; endotracheal; tracheostomy; urinary catheter; arterial line; abdominal or chest drains). 18 patients underwent 38 (2.1/patient) operative procedures. 20 patients (66%) suffered fron mono- or polymicrobial bacterial sepsis in addition to candida sepsis, 16 of them metachronously. Candida species isolated were C. albicans - 14 patients; C. tropicalis - 6 patients; C. parapsylosis - 6 patients; not specified - 4 patients. In addition to positive blood cultures we found positive candida cultures in urine, peritoneal cavity, chest cavity, wounds, respiratory tract, intravascular catheters, often in more than one site per patient. All patients were treated with Amphotericin at an average dose of 770 mg/patient. Mortality rate in patients with candida sepsis was 33%. TPN associated candida sepsis seems to be an endogenous self-infecting process in a select group of severely injured-infected-depleted-immunosuppressed patients and is thus completely different from the usual exogenous bacterial TPN associated sepsis. The major risk factors for fungaemia and candida sepsis are the combination of severe underlying disease state, multiple surgical interventions and intravascular lines, the use of broad spectrum antibiotics, TPN, injury and malnutrition associated immunosuppression, multiple tubes and catheters, and intra-abdominal or intra-thoracic infection.

Nitrogen sparing effects and mechanisms of branched-chain amino acids in the injured rat.

A series of experiments in a rat injury model were designed to elucidate the role and mechanisms of branched-chain amino acids in the post-injury catabolism. Our results suggest that: 1. Nutritional support can maintain nitrogen equilibrium in the early post-operative state. 2. Branched chain amino acids exert a nitrogen sparing effect and thus prevent or minimise post-operative catabolism. 3. Increasing the amount of infused branched chain amino acids results in nitrogen retention. 4. A balanced amino-acid mixture containing 45 per cent branched chain amino acids seems to be optimal for nutritional support in the post-injury state.

Feeding jejunostomy for post-operative nutritional support.

Enteral feeding by tube jejunostomy, inserted during definitive surgery, was used in 19 adult patients operated upon in a 24 month period. Jejunostomy feeding was associated with a low rate of minor complications enabling delivery of adequate caloric and protein input shortly after major abdominal operations and up to 9 months later. We feel that the insertion of a regular size jejunostomy tube during surgery is a simple, brief and safe procedure which offers efficient and inexpensive nutritional support, and thus has an important role in the post-operative management of selected patients. It is also easily used in the home setting if needed.

Role of total parenteral nutrition in the treatment of Crohn's disease.

We studied 49 patients with severe nonresponsive Crohn's disease receiving 73 courses of total parenteral nutrition (TPN) for a total of 2,153 days (30 +/- 18 days/admission). Forty-five percent of all courses of TPN resulted in patients not being operated on, whereas 55 percent resulted in surgical intervention. Fifty percent of patients who did not undergo operation initially as a result of a successful course of bowel rest and TPN had surgery within 15.4 +/- 13.9 months, whereas 75 percent of patients operated on immediately after a course of TPN did not need additional surgery during a follow-up of 36.1 +/- 31.2 months. Thus, a total of 80 percent of patients underwent gastrointestinal surgery sometime during the study and follow-up periods. TPN has an important role in replenishment of nutritional deficits and perioperative nutritional support; however, from the results of the present study, it is difficult to advocate it as the sole primary therapy for Crohn's disease.

Surgical treatment of gastroesophageal reflux with esophageal stricture in infancy and childhood.

During the past 5 years, 26 infants and children with gastroesophageal reflux were operated on. The results have been highly satisfactory and unattended by serious complications or mortality. Barium fluoroscopy was the most reliable diagnostic method. The indications for operation were persistent vomiting with failure to thrive, recurrent aspiration pneumonia, gastrointestinal bleeding and peptic stricture of the esophagus, not relieved by medical treatment. The high incidence of peptic stricture of the esophagus (50 percent) may reflect delay in diagnosis and medical treatment, which is successful in 60 to 87 percent of the infants with gastroesophageal reflux. Surgical treatment consisted of Nissen fundoplication combined with gastrostomy in cases of esophageal stenosis where dilatations were indicated. Complications related to the operation were minimal. In a follow-up period of 9 months to 5 years, all patients had obtained relief of symptoms of reflux and had excellent nutritional status and normal growth.

Reduced tissue content of vasoactive intestinal peptide in aganglionic colon of Hirschsprung's disease.

The colonic tissue content of immunoreactive vasoactive intestinal peptide was measured in four children with histologically proven Hirschsprung's disease. The concentration of vasoactive intestinal peptide was lower in the aganglionic bowel than in nearby normal bowel. Similar results have been described for another gastrointestinal peptide: substance P. Abnormalities of peptidergic control may contribute to the motility disorder of congenital aganglionic colon.

How conservatively can postoperative small bowel obstruction be treated?

Although postoperative adhesion ileus is the most common cause of small bowel obstruction in adults, its management remains controversial. We retrospectively studied 297 admissions of 227 patients over a period of 14 years to evaluate our conservative approach in managing adhesion ileus. We found that nonoperative therapy of up to 5 days' duration can be used safely for the majority of patients who present with postoperative intestinal obstruction, including those with complete obstruction. In those patients, who responded to conservative treatment, the obstruction resolved within a mean of 22 hours and a maximum of 5 days. A trial of more than 5 days' duration proved ineffective. The conservative approach resulted in a 73% resolution of obstruction with no significant increase in mortality or in the rate of strangulated bowel.

A more liberal approach to the surgical treatment of Crohn's disease.

BACKGROUND: Surgery for Crohn's disease is not intended for cure, but rather to relieve symptoms and treat complications. Perioperative morbidity, the fear of creating short bowel syndrome, and the tendency of the disease to recur convinced many physicians to refer their Crohn's patients for surgery only when life-threatening complications occur. METHODS: This is a retrospective analysis of 47 patients operated on for Crohn's disease between 1989 and 1994. Twenty-six patients were operated on for "classic" indications ("classic" group) and the other 21 were operated on to improve their quality of life ("quality" group). RESULTS: There was no operative or postoperative mortality during a mean follow-up period of 50 (27 to 84) months. All major postoperative complications occurred only in patients operated on for the classic indications (four abscesses, two fistulas, one wound dehiscence, and two small bowel obstructions). During the follow-up period, a total of 13 patients (50%) in the classic group and only 5 patients (24%) in the quality group required reintroduction of medical therapy or additional operations for exacerbations and complications of Crohn's disease. CONCLUSIONS: Our data suggest that surgical intervention intended to improve the quality of life for Crohn's disease patients is safe and effective for carefully selected patients. It does improve quality of life, may prevent life-threatening complications, and offers a lower recurrence rate following surgery.

Water-soluble contrast material has no therapeutic effect on postoperative small-bowel obstruction: results of a prospective, randomized clinical trial.

BACKGROUND: Hyperosmotic water-soluble contrast materials have been fo und to be helpful diagnostic tools in postoperative small-bowel obstruction (POSBO); however, their therapeutic value remains controversial. PATIENTS AND METHODS: A prospective, randomized clinical study was conducted to examine the use of meglumine ioxitalamate as a supplement to the standard conservative treatment of POSBO. Patients with POSBO (n = 50) suitable for a conservative approach were randomized to receive standard conservative treatment with (n = 25) or without (n = 25) the addition of 100 mL of meglumine ioxitalamate via the nasogastric tube (patients with diffuse carcinomatosis and early POSBO were excluded). Both groups were compared for resolution of obstruction, need for surgical relief of obstruction, and complications. RESULTS: Seven (14%) patients required surgery: 3 in the contrast material group and 4 in the control group (P = not significant [NA]. Resolution of symptoms was achieved in nonsurgical patients within an average of 25.7 hours in the contrast material group and 28.7 hours in the control group (P = NS). There was no mortality in this study. In 2 (4%) patients (1 in each group), strangulated bowel was found during surgery, but only the 1 (2%) patient in the contrast material group required bowel resection. No difference was found in the length of hospital stay or rate of complications. There were no complications that could be attributed to the use of the contrast material itself. CONCLUSIONS: Although water-soluble contrast material is a safe and useful diagnostic tool, it offers no advantage as a supplement to the usual conservative treatment of POSBO.