A prospective, randomized trial of intravenous fat emulsion administration in trauma victims requiring total parenteral nutrition.

OBJECTIVE: Intravenous fat infusions are a standard component of total parenteral nutrition (TPN). We studied the effects of withholding fat infusions in trauma patients requiring TPN. DESIGN: Polytrauma patients receiving TPN were randomized to receive a standard fat emulsion dose (L) or to have fat infusions withheld (NL) for the first 10 days of TPN. The two groups received the same amino acid and carbohydrate dose (isonitrogenous, nonisocaloric). MATERIALS AND METHODS: Clinical outcome parameters were measured. T-cell function was assessed by measuring lymphokine activated killer and natural killer cell activity. MEASUREMENTS AND MAIN RESULTS: Demographics including Injury Severity Score (27 +/- 8; 30 +/- 9) and APACHE II scores (23 +/- 6; 22 +/- 5) were similar for the L (n = 30) and NL (n = 27) groups, respectively. Differences (p < 0.05) were found in length of hospitalization (L = 39 +/- 24; NL = 27 +/- 16), intensive care unit length of stay (L = 29 +/- 22; NL = 18 +/- 12), and days on mechanical ventilation (L = 27 +/- 21; NL = 15 +/- 12). The L group had a higher number of infections (72 in 30) than the NL group (39 in 27) and T-cell function was depressed in this group. CONCLUSIONS: Intravenous fat emulsion infusions during the early postinjury period increased susceptibility to infection, prolonged pulmonary failure, and delayed recovery in critically injured patients. It is not clear whether the improved outcome in the NL group was directly related to withholding the fat infusions or due to the hypocaloric nutritional regimen (underfeeding) these patients received.

Use of continuous infusion of histamine2-receptor antagonists in critically ill patients.

Certain clinical situations require the use of a histamine2 (H2)-receptor antagonist to reduce gastric-acid volume and concentration or an antacid to act as a buffering agent. Presently, there are three H2-receptor antagonists available for iv use: cimetidine, ranitidine, and famotidine. Conventional therapy dictates that the H2-receptor antagonist be given by intermittent intravenous infusion, resulting in peaks and valleys of acid secretory control. Antacids, although capable of providing adequate gastric acidity control, must be administered frequently, often hourly, and thus require excessive nursing time. Presented here is a review of the rationale for the use of an H2-receptor antagonist by continuous infusion.

Current concepts in clinical therapeutics: peptic ulcer disease.

The epidemiology, pathophysiology, diagnosis, clinical presentation, and treatment of peptic ulcer disease (PUD) are reviewed. PUD occurs commonly, with about 4 million Americans affected in a year. Cigarette smoking, aspirin use, and prolonged corticosteroid use are associated with PUD. The disease's etiology is multifactorial; the long-held assumption that ulcers develop solely because of increased gastric acid secretion is no longer valid. Although duodenal ulcer patients are frequently hypersecretors of acid, gastric ulcer patients more commonly have defective mechanisms for protecting the mucosal lining from acid, pepsin, and other agents. PUD is best diagnosed using an upper gastrointestinal roentgenographic series or using endoscopy. The clinical presentations, which involve epigastric abdominal pain that is relieved by food, milk, or antacids, may aid in diagnosis but are not usually definitive. Treatment is designed to relieve symptoms, heal the ulcer, prevent recurrences, and prevent complications. Of the four currently available drug treatments (cimetidine, ranitidine, antacids, and sucralfate), the treatment of first choice is cimetidine or ranitidine for four or six weeks, respectively, for duodenal and gastric ulcer patients. Antacids should be used as needed for pain, and the patient should be reassessed at the end of this period. For most patients, neither cimetidine nor ranitidine is demonstrably superior to one another. Several agents are under investigation in the U.S., including other H2-receptor antagonists (famotidine and nizatidine), proton-pump inhibitors (omeprazole), prostaglandins (misoprostol, arbasprostil, enprostil, and trimoprostil), antimuscarinic agents (pirenzepine), and tricyclic antidepressants (doxepin and trimipramine). peptic ulcer disease is an important disease. It is best treated with H2-receptor antagonists supplemented with antacids as needed for pain.

A dosage alternative for H2-receptor antagonists--constant infusion.

Control of gastric acid is accomplished either by buffering it with antacids or by preventing acid secretion with H2-receptor antagonists. Advantages of antacids are their rapid onset of action and the possibility of precisely titrating intragastric pH. In practice, however, they are cumbersome to use because they must be administered frequently (often hourly) and thus require excessive nursing time. In addition, their use often leads to undesirable side effects, such as diarrhea. Cimetidine and ranitidine are H2-receptor antagonists that differ primarily in their potency, ranitidine being four to ten times more potent than cimetidine. With either drug, the patient's intragastric pH falls below 5 by about the fourth hour after the dose. One way to avoid the peaks and valleys of acid secretory control is to use constant infusion. Infusion rates of 50 mg/hr of cimetidine preceded by loading doses of 300 mg of cimetidine often produce a constant intragastric pH above 5. It is essential that intragastric above 5. It is essential that intragastric pH be checked and infusion rates increased or antacids added if pH drops below 5. Bauer used constant infusion of cimetidine in patients with upper gastrointestinal bleeding. He found constant infusion more successful, but his end-point was merely to stabilize the patient before surgery. At UC Davis, we compared constant infusion with intermittent dosing (300 mg of cimetidine every six hours) in patients admitted to the intensive care unit with upper gastrointestinal bleeding.

Clinical use of intravenous phenytoin sodium infusions.

The safety of administering phenytoin sodium by intermittent intravenous infusion was evaluated. Twenty-eight adult patients in a neurosurgical intensive-care unit were studied; most patients had head trauma. Ninety-three doses of phenytoin sodium 300 mg in 0.9% sodium chloride injection 50 ml were administered according to hospital-approved guidelines, which included administration over 30-60 minutes, initiation of infusion within one hour of solution preparation, and use of a 5-microns inline filter. All patients were monitored for adverse reactions and were on continuous ECG monitoring. Analysis of clinical data before and immediately after phenytoin infusions showed no statistically significant change in blood pressure and a small but significant drop in mean heart rate. There were no cases of hypotension, arrhythmias, bradycardia, or phlebitis. Single occurrences of hypertension, nystagmus, and pain at the i.v. site were noted. It is concluded that careful infusion of phenytoin sodium in 0.9% sodium chloride injection is safe. The use of approved written guidelines to govern important factors of preparation and administration are recommended.

Ranitidine: a new H2-receptor antagonist.

The pharmacology, pharmacokinetics, clinical efficacy, adverse reactions, drug interactions, and dosage of ranitidine are reviewed; specific comparisons are made of this new H2-receptor antagonist with the older agent, cimetidine. Ranitidine is a potent inhibitor of gastric acid secretion whose chemical structure lacks the imidazole group previously believed to be essential for H2-receptor blocking activity. The new agent does not bind substantially to the cytochrome P-450 mixed-function oxidase system and does not penetrate the cerebrospinal fluid appreciably. Peak serum ranitidine concentrations occur within one to two hours after oral administration; approximately 50% of an oral dose reaches systemic circulation. There are at least three metabolites of ranitidine, but substantial fractions of both i.v. and oral doses are recovered unchanged in the urine. Ranitidine's duration of action is 8-12 hours. Controlled clinical trials have shown ranitidine to be effective in the treatment of duodenal and gastric ulcers, Zollinger-Ellison syndrome, and prophylaxis against aspiration during anesthesia. Ranitidine has been effective in patients unresponsive to or intolerant of cimetidine. In clinical trials, the incidence of adverse effects from ranitidine has been low; certain rare but serious side effects that have been noted with cimetidine have not been associated with ranitidine therapy. There is no evidence thus far that certain drug-drug interactions observed with cimetidine therapy will occur with ranitidine. Oral adult daily doses of ranitidine are likely to be 300 mg given as the hydrochloride salt in two divided doses. Ranitidine is similar to cimetidine in efficacy but has an apparently safer adverse-effects profile. Ranitidine is likely to be the preferred agent in certain clinical situations.

Crystallization of three phenytoin preparations in intravenous solutions.

The stability of three phenytoin sodium intravenous preparations in two intravenous solutions was compared. Solutions of phenytoin sodium 1.0, 1.5, 4.0. and 10.0 mg/ml were prepared by adding Dilantin, Phenhydan (commercially available in Europe) and Phenytoin Concentrate (available in Europe for research) to 5% dextrose or 0.9% sodium chloride injection. (The two European products contain solubilizers and stabilizers different from those in U.S. formulations.) Four sets of samples were prepared in 10-ml glass blood collection tubes; two sets each were sealed and unsealed. Macroscopic and microscopic observations were made immediately and at various times up to 24 hours. The pH was measured periodically. The three phenytoin sodium preparations also were added to 100-ml polyvinyl chloride bags of 5% dextrose or 0.9% sodium chloride injection in concentrations of 1, 1.5, 4, and 10 mg/ml. Phenytoin concentration was determined spectrophotometrically initially and at 1, 4, 8, 12, and 24 hours. Percent phenytoin crystallization, based on initial concentration, was calculated, and differences among the three phenytoin products were tested using an analysis of variance split-plot factorial design (p less than 0.05). Dilutions of Phenhydan and Phenytoin Concentrate in both solutions were stable (less than 10% crystallization) for at least 24 hours. Percent phenytoin crystallization was significantly greater for Dilantin compared with Phenhydan or Phenytoin Concentrate at each time in 5% dextrose injection and after four hours in 0.9% sodium chloride injection. Phenytoin crystallization was not solely dependent on pH of the solution, concentration, or carbon dioxide absorption. Phenhydan and Phenytoin Concentrate admixtures provided a more suitable environment for phenytoin stability than Dilantin admixtures did.

Relationship between cimetidine plasma levels and gastric acidity in acutely ill patients.

The relationship between cimetidine plasma levels and gastric acidity was studied in acutely ill patients. Patients in surgical intensive care for stress ulcer who were being managed with nasogastric suction were studied. Nine patients (Group 1) received 300 mg of intravenous cimetidine over 30 minutes every six hours. Titratable acidity and pH of gastric aspirates and plasma cimetidine levels were measured at peak (1.5--2.5 hours) and trough (5--6 hours) times following cimetidine administration, in Group 1. Titratable acidity and pH were measured for nine Group 2 patients (control) who did not receive cimetidine. In Group 1, mean gastric acid output was significantly lower (p less than 0.05) and mean pH was significantly higher (p less than 0.005) than in Group 2. In Group 1, plasma cimetidine concentration correlated poorly with gastric pH and gastric acid output (r = 0.21). The study indicates that the correlation between plasma cimetidine levels and gastric acid secretion is poor, but that the cimetidine dosage used suppressed acid output during the entire dosing interval.

A pharmacokinetic analysis of the vagal release of 5-hydroxytryptamine in the cat.

The kinetics of 5-hydroxytryptamine (5-HT) release into the portal system after efferent electrical vagal stimulation were studied in an in vivo model. Blood samples were drawn from cats before, during and after vagal nerve stimulation, and portal plasma levels of 5-HT were measured. Portal plasma concentration of 5-HT rose during stimulation. After termination of stimulation, the plasma levels returned to steady state values and were used to calculate half-life and elimination rate constant. When pharmacokinetic principles were applied, the plasma half-life (T1/2) was determined to be 1.32 min and the elimination rate constant (KE), 0.5246 min-1. Pharmacokinetic principles also were applied to data from earlier in vitro studies using exogenously administered 5-HT, and a half-life of 1.03 min and a KE of 0.67 min-1 were calculated. Therefore, it appears that exogenously administered 5-HT and neurogenically released endogenous 5-HT are metabolized at a similar rate, both having a short half-life.

The effect of propranolol on the serotonin concentration in the portal plasma after vagal nerve stimulation in the cat.

Efferent cervical vagal nerve stimulation in the cat caused a marked increase of the portal plasma 5-HT concentration. This increase was more than two-fold within 15 min of stimulation. After cessation of stimulation portal plasma 5-HT returned to basal levels within 10 min. Treatment with the beta-adrenoceptor antagonist propranolol, in various doses (0.1-2 mg/kg b.wt.), did not abolish but significantly reduced the response to vagal stimulation, particularly during the final part of the stimulation period. The results confirm the existence of a beta-adrenoceptor-mediated release of 5-HT, but also suggest that other mechanisms for 5-HT release may be involved in the response on vagal nerve stimulation.

H2 receptor antagonists.

The uses of the histamine H2 receptor antagonists (H2 antagonists) in the management of peptic ulcer disease and the Zollinger-Ellison syndrome are reviewed. Drugs included in the discussion are burimamide, metiamide and cimetidine. The secretion and the pharmacology of the H2 antagonists are described. A discussion of the clinical use of the H2 receptor antagonists in the treatment of gastric hyperacidity and hypersecretory states, and the side effects encountered is presented. Cimetidine is effective in the treatment of duodenal ulcer, and its use appears promising in Zollinger-Ellison syndrome and gastric ulceration.