Decreased in vitro fluoroquinolone concentrations after admixture with an enteral feeding formulation.

BACKGROUND: The purpose of this study was to determine if mixing of fluoroquinolones with a common enteral feeding formulation, Ensure (Ross Products Division, Abbott Laboratories, Columbus, OH), would alter the measured in vitro quinolone concentrations over a 24-hour period. METHODS: Tablets of ciprofloxacin (500 mg), levofloxacin (500 mg), and ofloxacin (300 mg) were crushed and mixed with 240 mL of Ensure, water and calcium chloride (500 mg/L), water and magnesium chloride (200 mg/L), water and calcium chloride and magnesium chloride, and water alone. Fluoroquinolone concentrations of the mixtures were measured, via high-performance liquid chromatography, at baseline and serially over 24 hours. Experiments were performed in duplicate, at three temperatures (5 degrees C, 25 degrees C, and 37 degrees C). RESULTS: Average decreases of 82.5% +/- 1.5% for ciprofloxacin, 61.3% +/- 5.2% for levofloxacin, and 45.7% +/- 10.1% for ofloxacin (mean +/- 95% CI) were observed in vitro for Ensure over the two experimental sets at baseline. Serial analysis revealed no further significant change in any of the quinolone concentrations over the remaining 24-hour period. No significant decrease was noted with the quinolones when mixed in water and calcium, water and magnesium, water and calcium and magnesium, or water alone. This phenomenon appears to be unaffected by time and temperature. CONCLUSIONS: These data suggest there is an immediate and significant loss of fluoroquinolone when mixed with Ensure. An explanation for the loss of fluoroquinolone remains unclear.

Determination of quinolone antibiotics in growth media by reversed-phase high-performance liquid chromatography.

A simple, accurate, precise, and versatile high-performance liquid chromatographic (HPLC) method was developed and validated for the determination of three quinolone antibodies in Mueller-Hinton broth. The fluoroquinolone agents studied were ciprofloxacin, ofloxacin, and sparfloxacin; other quinolone agents have been identified using this method but not validated in this matrix (levofloxacin, clinafloxacin, temafloxacin, and trovafloxacin). In addition, several other biological growth mediums have been investigated (human serum, human urine, Todd-Hewitt growth media, Ensure enteral feeding solution, and Haemophilus growth media). This method uses UV detection (280 nm), a simple, one-step protein precipitation extraction, and separation using a C18 column with an isocratic, ion-pairing mobile phase. An appropriate internal standard was obtained by using another quinolone antibiotic of differing retention time. The calibration curves were linear (r2> or =0.999) over a concentration range of 0.0625-20.0 microg/ml with a lower limit of quantification of 0.1 microg/ml. The intra-day and inter-day coefficients of variation were less than 15%.

Lorazepam stability in parenteral solutions for continuous intravenous administration.

OBJECTIVE: To determine the stability of lorazepam over a 24-hour period when prepared in polyvinyl chloride (PVC) bags at initial concentrations of 0.08 and 0.5 mg/mL. DESIGN: Each concentration was studied at room (21 degrees C) and refrigerator (4 degrees C) temperatures in dextrose 5% (D5W) and NaCl 0.9% solutions. Duplicate test solution admixtures were prepared for each lorazepam concentration, diluent, and temperature. At 0, 1, 4, 8, and 24 hours, duplicate samples were obtained for visual inspection, pH determination, and concentration determination by stability-indicating, reverse-phase HPLC analysis. Compared with baseline, peaks for lorazepam degradation products were not found on any of the study chromatograms. RESULTS: In D5W and NaCl 0.9% solutions, lorazepam loss in excess of 10% by HPLC analysis occurred for concentrations of 0.08 and 0.5 mg/mL at 1 and 4 hours, respectively. CONCLUSIONS: These data suggest that significant loss of lorazepam occurs as the probable result of sorption to PVC bags when admixed in both D5W and NaCl 0.9% solutions at 21 and 4 degrees C.

Early enteral feeding does not attenuate metabolic response after blunt trauma.

Enteral feeding very early after trauma has been hypothesized to attenuate the stress response and to improve patient outcome. We tested this hypothesis in a prospective, randomized clinical trial in patients with blunt trauma. Following resuscitation and control of bleeding, 52 patients were randomized to receive early feedings (target, < 24 hours) or late feedings (target, 72 hours). Feeding was given via nasoduodenal feeding tubes. A rapid advance technique was used to achieve full volume and strength within 24 hours (goal, 1.5 g protein/kg.day). Patients who underwent at least 5 days of therapy were considered to have completed the study: 38 in all, 19 in each feeding group. Patients were similar in age, gender, Injury Severity Score, and mean PaO2/FiO2 ratio. The early group, however, had more patients with a PaO2/FiO2 < 150. After feeding began, the amount fed per day was the same in both groups. We found no significant differences in metabolic responses as measured by plasma lactate and urinary total nitrogen, catecholamines, and cortisol. Both groups achieved nitrogen retention. In addition, we found no significant differences in intensive care unit (ICU) days, ventilator days, organ system failure, specific types of infections, or mortality, although the early group had a greater number of total infections. In this study, early enteral feeding after blunt trauma neither attenuated the stress response nor altered patient outcome.

Nitrogen balance studies in clinical nutrition.

Nutrition support is recognized as an important cofactor in altering morbidity and mortality of hospitalized patients. Paramount in delivering proper nutrition support is the accurate determination of baseline metabolic and nutritional status, thus influencing necessary protein requirements. After nutritional intervention, routine laboratory monitoring is used to measure the efficacy and to reassess metabolic stress level. Accurate determination of nitrogen excretion (and nitrogen balance) remains the standard in prescribing and monitoring the protein and nutritional treatment regimen. This article examines nitrogen excretion determinations in the clinical setting, including proper collection techniques, laboratory measurements, and analyses and their effect upon nitrogen balance studies.

Inaccuracy of nitrogen balance determinations in thermal injury with calculated total urinary nitrogen.

Many burn centers use nitrogen balance studies to estimate the adequacy of nutritional support. Nitrogen loss includes the sum of urinary urea nitrogen, nonurea urinary nitrogen, and losses from skin, wound, and stool. Urinary urea nitrogen is often used to calculate total urinary nitrogen by multiplying the urinary urea nitrogen by a factor of 1.25 to account for nonurea urinary nitrogen. This formula is appropriate when applied to a nonstressed individual who has fasted overnight but is not appropriate for patients who have undergone surgery or experienced trauma. We have undertaken this study to assess the predictability of this formula in patients with thermal injuries. Twenty-seven patients with major thermal injuries had random 24-hour urine collections, which were analyzed for both urinary urea nitrogen and total urinary nitrogen. In these patients with burns we found that urinary urea nitrogen represented approximately 65% of the directly measured total urinary nitrogen rather than 80% as assumed by the formula. This increase in the nonurea nitrogen loss is greater than that found after surgery or trauma. Individual measurements may underestimate losses by 20% to 60%. Directly measured total urinary nitrogen should replace calculated total urinary nitrogen as the index of urine nitrogen losses for nitrogen balance studies in patients with burns.

Amino acid alterations and encephalopathy in the sepsis syndrome.

OBJECTIVE: To evaluate the role of amino acid profiles in septic encephalopathy. DESIGN: Retrospective analysis. SETTING: Medical wards and medical ICU of a university hospital. PATIENTS: Patients with infections and normal mental status were compared with patients with septic shock and altered sensorium. INTERVENTIONS: Plasma amino acid levels and Acute Physiology and Chronic Health Evaluation (APACHE II) scores were determined. MEASUREMENTS AND MAIN RESULTS: Patients with septic shock and altered sensorium had higher circulating concentrations of ammonia (425 +/- 55 vs. 127 +/- 7 mmol/L) and the aromatic amino acids phenylalanine (122 +/- 19 vs. 74 +/- 3 mmol/L) and tryptophan (97 +/- 7 vs. 32 +/- 13 mmol/L), and lower levels of the branch-chain amino acid isoleucine (48 +/- 7 vs. 68 +/- 5 mmol/L) than patients with infections and normal sensorium (p less than .05). Aromatic amino acid levels correlated with APACHE II scores (R2 = .4, p less than .001) and mortality. APACHE II scores were higher in the septic shock patients (30 +/- 2 vs. 8 +/- 1, p less than .001), and these patients had a higher mortality rate (71% vs. 12%, p less than .01). Patients with septic shock who died had higher levels of ammonia (524 +/- 58 vs. 227 +/- 40 mmol/L, p less than .05) and sulfur-containing amino acids (172 +/- 31 vs. 61 +/- 7 mmol/L, p less than .05) than patients who survived. CONCLUSIONS: Plasma amino acid profiles appear to be important in septic encephalopathy and the severity of septic disease.

Urinary urea nitrogen: too insensitive for calculating nitrogen balance studies in surgical clinical nutrition.

Urinary urea nitrogen (UUN) has been used as an estimate of total urinary nitrogen (TUN) when calculating nitrogen output for nitrogen balance (NB) studies. UUN is assumed to constitute 80 to 90% of the total nitrogen output; when estimating TUN from UUN, UUN values are multiplied by 1.25 to correct for non-urea nitrogen components. In order to evaluate the validity of estimating total urinary nitrogen output from measured UUN in a clinical setting, 491 UUN:TUN paired studies were performed on 24-hour urine collections in general surgical/trauma patients who had measured TUN outputs ranging from 0.04 to 54.0 g/d. Assessment of 315 NB studies was done to compare NB values of those calculated by using UUN as an estimate of TUN with those calculated from measured TUN. Patients in both studies were subdivided into four stress categories, using TUN/day as the index: less than 5 g, 5-10 g, 10-15 g, and greater than 15 g. On average, 80 to 90% of TUN is represented by the UUN. However, in our patient population the variability ranged from 12 to 112%. If these UUN values are used as estimates for TUN in calculating NB, variations of up to 12 g/d would result. Application of the correction factor of 1.25 is not consistent in correcting for nonurea nitrogen components in this clinical setting. The use of actual rather than estimated TUN may be a more accurate and appropriate method than UUN when calculating NB.

Other aspects of metabolic monitoring in critically ill patients.

Cardiopulmonary monitoring remains the mainstay of intensive-care unit utilization of clinical chemistry resources. Its focus has been on the restoration and maintenance of oxygen transport. Metabolic monitoring, a relatively new area of application for clinical chemistry technology, focuses on cell metabolism and on cell-cell interaction as a mechanism of metabolic regulation. This latter application of monitoring is developing as a result of a better understanding of the pathogenesis of organ dysfunction and disease processes in intensive-care unit patients. Some of the clinical chemistry technologies used include analyses for amino acids and polyunsaturated fatty acids, measurement of cytokine concentration and activity, nutritional assessment and monitoring, more sensitive monitors of liver function, and assessment of altered immunity in critically ill patients. Use of these technologies, along with specific support measures, offers new avenues for decreasing infectious complications and reducing mortality and morbidity of patients in intensive-care units.

Pyrochemiluminescence: real-time, cost-effective method for determining total urinary nitrogen in clinical nitrogen-balance studies.

Total urinary nitrogen (TUN) determinations for nitrogen-balance studies were traditionally performed by the Kjeldahl method, but this method is laborious, hazardous, prone to error, and no longer widely available in most clinical laboratories. During the last several decades, urinary urea nitrogen (UUN) determinations have replaced TUN as an index of urinary nitrogen excretion in many clinical laboratories, owing to its ease of determination, decreased cost, and wide availability. However, the validity of using UUN for estimating nitrogen loss has been questioned in many disease states, owing to wide variations in the proportional amount of urea found in TUN. Chemiluminescence has been proposed as an alternative to the Kjeldahl method for TUN. TUN values obtained from 24-h urine collections measured by both micro-Kjeldahl (x) and Pyrochemiluminescence (y) (Antek Instruments, Inc.) techniques were comparable by linear regression analysis: n = 97; r = 0.996; r2 = 0.992; y = 1.048x - 0.606; P less than 0.001. Automated induction of samples and calculation of results allows up to 42 samples to be run unattended. This dramatically reduces labor and overall costs for TUN determinations, while providing a more accurate and economical assessment of nitrogen excretion than UUN in a clinical setting.

Enteral nutrition does not prevent multiple organ failure syndrome (MOFS) after sepsis.

Gut malnutrition in patients with persistent hypermetabolism is hypothesized to be an important factor in postseptic multiple organ failure syndrome (MOFS). The hypothesis was made that enteral nutrition (EN) started at the onset of hypermetabolism could reduce the incidence of MOFS. Sixty-six patients with persistent hypermetabolism 4 to 6 days after onset of sepsis were prospectively randomized to receive either parenteral nutrition (PN) or enteral nutrition (EN) at 1.5 gm protein/kg/day and 30 nonprotein calories/kg/day; the EN and TPN were of the same composition. There was no reduction in either the incidence of MOFS or mortality attributable to the route of nutrition administration. The PN group tended to have better visceral protein support; the EN group had more gut complications. When analyzed, the type of formula given did have an effect on the nutritional outcome but not on the mortality rate. A formula with a nonprotein-calorie-to-nitrogen ratio of 100:1 was associated with more nitrogen retention, higher levels of visceral proteins, and better gut tolerance. The route of nutrition administration does not seem to affect the incidence of postseptic MOFS or mortality when hypermetabolism is already present and when commercially available nutritional formulas are used. The relationships among the route of nutrition, the type of enteral formula, and the disease process of hypermetabolism and MOFS appear to be complex and require much more investigation before the role of the gut and enteral nutrition can be defined.

Essential fatty acid status in isolated closed head injury.

Abnormal profiles of polyunsaturated fatty acids in the plasma phospholipid fraction were observed in 14 patients with hypermetabolism due to severe isolated closed head injury. Depressed linoleic acid levels were observed within 24 hours along with elevation of oleic acid levels. By one week postinjury, subnormal levels of arachidonic acid were also observed. These data indicate that the metabolic response to injury encompasses changes in the metabolism of polyunsaturated fatty acids which are rapid in onset and qualitatively similar to those seen in mild essential fatty acid deficiency.

Overcoming retention time shifts as a source of error in HPLC analysis.

When used for physiologic fluid analysis, shifts in retention times, even at constant flow rates, can cause integrators to function inadequately as tools for peak identification and thus result in concentration errors. A system capable of data collection, identification, quantification, and long-term storage that primarily uses retention times only for identification of elution sequence is described. Operator identification, aided by manipulation of x and y coordinates of the chromatograph, enhances positive identification of compounds for the experienced chromatographer.

Physiological and metabolic response to isolated closed-head injury. Part 2: Effects of steroids on metabolism. Potentiation of protein wasting and abnormalities of substrate utilization.

In order to determine the effects of steroid administration on the metabolic response to isolated closed-head injury, a longitudinal study was performed. Metabolic indices were prospectively evaluated for the first 5 days postinjury in six patients who received steroids and 10 patients who did not. Patients were carefully screened to eliminate those with associated injuries as well as those with abnormalities due to sepsis. Other than steroid administration, a uniform treatment regimen was used in both groups. Metabolic indices measured on postinjury Days 1, 3, and 5 were analyzed. In addition, data were compared to results in large data banks obtained both from overnight-fasted patients (fasted controls) and from polytrauma victims (stressed controls). Both treatment groups were comparable with respect to age, mean Glasgow Coma Scale scores on admission and on Day 5, and initial intracranial pressure. Metabolic data indicated significantly higher levels of nitrogen excretion and somatic protein mobilization in steroid-treated patients than in patients not receiving steroids. In both groups, glucose levels, the lactate/pyruvate ratio, and branched-chain amino acid levels (all metabolic indices that correlate well with level of stress) initially corresponded to values for stressed controls. By Day 5, values for these variables were similar to fasted controls for the group not receiving steroids. In patients receiving steroids, however, the data remained similar to those for stressed controls. It is concluded that steroids prolong the metabolic abnormalities associated with the initial phase of head injury. In view of inconclusive data regarding benefit from steroid administration, serious questions must be raised regarding the use of these catabolic agents in this setting.

Physiology and metabolism in isolated viral septicemia. Further evidence of an organism-independent, host-dependent response.

The hypothesis has been advanced that the human systemic septic response is a function of the host and not of the type of infecting organism. Metabolic and physiologic data from five immunosuppressed transplant recipients with isolated cytomegaloviral sepsis and viremia were prospectively evaluated. Serial cultures obtained from lung, sputum, urine, wound, blood, and invasive lines were positive for virus and negative for bacterial or fungal pathogens. The results were compared with two data banks derived from either victims of multiple trauma without sepsis or surgical patients with early bacterial or fungal sepsis. Statistically significant differences between the patients and the nonseptic reference group were noted for cardiac index, total peripheral resistance, arteriovenous oxygen content difference, oxygen consumption, and levels of triglycerides, proline, phenylalanine, tyrosine, alpha-aminobutyrate, and alanine. No such differences were present for these data compared with the septic reference group. Physiologic data obtained just before death in three patients indicated a failure of oxygen transport. It appears that the systemic septic response to viral agents is indistinguishable by physiologic and metabolic criteria from that resulting from bacterial or fungal agents.

Partial correction by exogenous lipid of abnormal patterns of polyunsaturated fatty acids in plasma phospholipids of stressed and septic surgical patients.

Polyunsaturated fatty acid (PUFA) profiles are abnormal in a variety of clinical conditions that are commonly seen in the surgical intensive care unit. PUFA profiles in the serum phospholipids were studied by capillary gas chromatography in 22 critically ill, hypermetabolic surgical intensive care unit patients. All patients received continuous total parenteral nutrition (TPN) by central vein with trace elements and vitamins. Eleven patients received daily supplementation with 50 gm of safflower oil-based lipid emulsion (TPN + L group). No lipid was administered in the other 11 patients (TPN). Both groups showed deficiencies in 18:2 omega 6 linoleic acid from the time of onset of TPN. In TPN the deficiency was progressive; in the TPN + L group, lipid administration prevented this progression but did not restore 18:2 omega 6 levels to normal. In the TPN group levels of 18:1 omega 9 and its metabolite 20:3 omega 9 (the triene of deficiency) increased over time, consistent with a mild essential fatty acid deficiency. These changes in omega 9 acids were not seen with lipid supplementation. Despite low levels of 18:2 omega 6 in both groups, the levels of omega 6 metabolites were normal or increased. Levels of 20:4 omega 6 (arachidonate) remained normal or slightly decreased in the TPN group but were decreased in the TPN + L group. Levels of arachidonate metabolites, in particular 22:5 omega 6, were increased in the lipid-supplemented group. We concluded that stressed patients receiving TPN develop mild essential fatty acid deficiency that is only partially correctable by lipid supplementation and that administration of supplemental lipid to these patients stimulates arachidonic acid conversion to 22:5 omega 6.

Paranasal sinusitis associated with nasotracheal intubation: a frequently unrecognized and treatable source of sepsis.

Paranasal sinusitis secondary to prolonged nasotracheal intubation represents an infrequently reported source of sepsis. Of 27 nasally intubated patients who developed paranasal sinusitis over a 1-yr period, 17 patients underwent emergency blind nasotracheal intubation post-trauma or shock (group 1) and the remaining ten were intubated electively under operating room or ICU conditions (group 2). Group 1 patients were younger (mean age 33 +/- 6 vs. 57 +/- 5 yr) than those in group 2; they also developed sinusitis more quickly after intubation (mean time 8 +/- 1 vs. 15 +/- 2 days). Diagnosis was confirmed via sinus x-rays (14 cases), computed tomography (five cases), indium scan (two cases), or clinical picture. Cultures were obtained in 14 cases. Staphylococci predominated in group 1, while nosocomial Gram-negative organisms predominated in group 2. Seven patients developed pulmonary infections and two developed systemic sepsis with an organism present on sinus culture. In all cases treatment was successful with antibiotics and tracheostomy or movement of the tube to the oral route. These data indicate that patients nasally intubated are at risk for development of paranasal sinusitis; this diagnosis should be suspected in sepsis of undetermined etiology.