Temporal assessment of Candida risk factors in the surgical intensive care unit.

HYPOTHESIS: Risk factors for Candida infection in surgical intensive care units (SICUs) change over time. Risk factor progression may influence Candida colonization and infection. DESIGN: Multicenter cohort survey. SETTING: Three urban teaching institutions. PATIENTS: A total of 301 consecutively admitted patients in SICUs for 5 or more days. MAIN OUTCOME MEASURES: Assessment of patients on SICU days 1, 3, 4, 6, and 8 and SICU discharge for risk factors, Candida colonization, and antifungal use. Candida colonization status was categorized as noncolonized (NC), locally colonized (LC) if 1 site was involved, and disseminated infection (DI) if 2 or more sites or candidemia were involved. RESULTS: The most frequent risk factors in the 301 patients enrolled were presence of peripheral and central intravenous catheters, bladder catheters, mechanical ventilation, and lack of enteral or intravenous nutrition. Early risk factors included total parenteral nutrition or central catheter at SICU day 1 and previous SICU admissions or surgical procedures. Peak number of risk factors (mean +/- SD) were as follows: 7.2 +/- 2.6 in NC (n = 229), 9.2 +/- 2.3 in LC (n = 45), and 9.2 +/- 2.6 in DI (n = 27). These numbers were reached at day 8 in the NC and LC groups and day 4 in the DI group. The LC and DI groups had more risk factors on each SICU day than the NC group and longer median SICU length of stay (28 days in the DI group vs 11 and 19 days in the NC and LC groups, respectively). Antifungal therapy, while used most frequently in the DI group, was initiated later for this group than in NC and LC groups. CONCLUSIONS: Risk factors for Candida infection in SICU patients change over time. Patients with DI demonstrate a greater number of and more rapid increase in risk factors than patients in the LC and NC groups. Presence of early risk factors at the time of SICU admission, a high incidence of risk factors, or a rapid increase in risk factors should prompt clinicians to obtain surveillance fungal cultures and consider empirical antifungal therapy.

Yeast Mps1p phosphorylates the spindle pole component Spc110p in the N-terminal domain.

The yeast spindle pole body (SPB) component Spc110p (Nuf1p) undergoes specific serine/threonine phosphorylation as the mitotic spindle apparatus forms, and this phosphorylation persists until cells enter anaphase. We demonstrate that the dual-specificity kinase Mps1p is essential for the mitosis-specific phosphorylation of Spc110p in vivo and that Mps1p phosphorylates Spc110p in vitro. Phosphopeptides generated by proteolytic cleavage were identified and sequenced by mass spectrometry. Ser(60), Thr(64), and Thr(68) are the major sites in Spc110p phosphorylated by Mps1p in vitro, and alanine substitution at these sites abolishes the mitosis-specific isoform in vivo. This is the first time that phosphorylation sites of an SPB component have been determined, and these are the first sites of Mps1p phosphorylation identified. Alanine substitution for any one of these phosphorylated residues, in conjunction with an alanine substitution at residue Ser(36), is lethal in combination with alleles of SPC97, which encodes a component of the Tub4p complex. Consistent with a specific dysfunction for the alanine substitution mutations, simultaneous mutation of all four serine/threonine residues to aspartate does not confer any defect. Sites of Mps1p phosphorylation and Ser(36) are located within the N-terminal globular domain of Spc110p, which resides at the inner plaque of the SPB and binds the Tub4p complex.

Pharmacokinetics of aztreonam in critically ill surgical patients.

The pharmacokinetics of aztreonam in critically ill surgical patients with serious gram-negative infections were studied. Blood samples were taken before and at 30 minutes, 2.5 hours, and 5 hours after a dose of aztreonam 2 g i.v. every six hours. All patients had received at least two aztreonam doses before the dosage interval being studied. Aztreonam concentrations were measured by high-performance liquid chromatography. Aztreonam's pharmacokinetics, the severity of illness, and patient outcomes were examined. A total of 28 patients with 111 serum aztreonam concentrations were included in the analysis. The patients were young (mean age, 35 years) and predominantly male. The mean APACHE II score was 19.3, and 22 patients had sepsis. Four patients died. The mean volume of distribution (V) of 0.35 L/ kg was nearly twice the previously reported steady-state value for healthy volunteers (0.18 L/kg) and was highly variable. A slightly higher than normal mean V, 0.22 L/ kg, was seen in a subset of six patients whose infection occurred earlier in their intensive care and who had lower APACHE II scores. While with some antibiotics the elevated V would imply difficulty in achieving therapeutic drug levels, 99 (89%) of the 111 concentrations were at or above the in vitro susceptibility breakpoint of 8 micrograms/mL. Despite observations of markedly increased and highly variable V in critically ill surgical patients, a standard dosage of aztreonam was usually sufficient to maintain adequate serum drug levels.

Aminoglycoside levels in critically ill surgical patients: the implications of physiologic criteria of sepsis.

We retrospectively reviewed medical records and computerized critical care data for 40 consecutive critically ill surgical patients receiving "standard" doses (1.5 to 2.0 mg/kg loading dose and 3 to 5 mg/kg/day) of gentamicin or tobramycin for gram-negative infections. End points measured were serum drug levels and clearance of infection. Therapeutic serum aminoglycoside levels were achieved within 48 hours of therapy by only 7 patients (17.5%). Among the remaining 33 patients, significantly fewer septic than nonseptic patients had clearance of their infection (11% vs 92%). Specific physiologic criteria of sepsis may be used to identify critically ill patients who will most likely benefit from aggressive initial aminoglycoside dosing when these drugs are used to treat gram-negative infections.

In-flight radiation measurements on STS-60.

A joint investigation between the United States and Russia to study the radiation environment inside the Space Shuttle flight STS-60 was carried out as part of the Shuttle-Mir Science Program (Phase 1). This is the first direct comparison of a number of different dosimetric measurement techniques between the two countries. STS-60 was launched on 3 February 1994 in a nearly circular 57 degrees x 353 km orbit with five U.S. astronauts and one Russian cosmonaut for 8.3 days. A variety of instruments provided crew radiation exposure, absorbed doses at fixed locations, neutron fluence and dose equivalent, linear energy transfer (LET) spectra of trapped and galactic cosmic radiation, and energy spectra and angular distribution of trapped protons. In general, there is good agreement between the U.S. and Russian measurements. The AP8 Min trapped proton model predicts an average of 1.8 times the measured absorbed dose. The average quality factor determined from measured lineal energy, y, spectra using a tissue equivalent proportional counter (TEPC), is in good agreement with that derived from the high temperature peak in the 6LiF thermoluminescent detectors (TLDs). The radiation exposure in the mid-deck locker from neutrons below 1 MeV was 2.53 +/- 1.33 microSv/day. The absorbed dose rates measured using a tissue equivalent proportional counter, were 171.1 +/- 0.4 and 127.4 +/- 0.4 microGy/day for trapped particles and galactic cosmic rays, respectively. The combined dose rate of 298.5 +/- 0.82 microGy/day is about a factor of 1.4 higher than that measured using TLDs. The westward longitude drift of the South Atlantic Anomaly (SAA) is estimated to be 0.22 +/- 0.02 degrees/y. We evaluated the effects of spacecraft attitudes on TEPC dose rates due to the highly anisotropic low-earth orbit proton environment. Changes in spacecraft attitude resulted in dose-rate variations by factors of up to 2 at the location of the TEPC.

Piperacillin-tazobactam pharmacokinetics in patients with intraabdominal infections.

STUDY OBJECTIVE: To determine the appropriate compartmental and noncompartmental pharmacokinetic parameters for intravenous piperacillin and tazobactam. DESIGN: Sequential selection of patients entered into a randomized, open-label clinical efficacy trial. SETTING: Los Angeles County-University of Southern California Medical Center. PARTICIPANTS: Sequential sample of 18 patients admitted for intraabdominal infections and consented into a comparative antibiotic trial. INTERVENTIONS: Patients received piperacillin 4 g plus tazobactam 500 mg by intravenous intermittent infusion every 8 hours. MEASUREMENTS AND MAIN RESULTS: The estimated noncompartmental pharmacokinetic parameters (mean +/- SD) for piperacillin and tazobactam, respectively, were as follows: maximum concentration in plasma 218.7 +/- 48.9 micrograms/ml and 27.8 +/- 9.1 micrograms/ml; half-life 1.07 +/- 0.22 hours and 1.00 +/- 0.27 hours; elimination rate constant 0.67 +/- 0.13 hr-1 and 0.73 +/- 0.18 hr-1; area under the concentration-time curve from zero hour to infinity 288.5 +/- 71.25 mg.hr/L and 36.3 +/- 9.55 mg.hr/L; total plasma clearance 14.75 +/- 3.93 L/hour and 14.78 +/- 4.39 L/hour; renal clearance 5.69 +/- 1.94 L/hour and 7.85 +/- 3.37 L/hour; volume of distribution at steady state 21.00 +/- 4.18 L and 22.47 +/- 8.27 L; and mean residence time 1.72 +/- 0.29 hours and 1.79 +/- 0.35 hours. CONCLUSION: Our findings were similar to those in other surgical patient models. The two-compartmental model best described piperacillin and tazobactam disposition in our patients. Bayesian analyses of the two-compartment models of piperacillin and tazobactam were able to predict trough, peak, and 2-hour postadministration levels without bias.

On focused association and the analytic surface: clinical opportunities in resolving analytic stalemate.

Focused association is a technique for exploring repetitive noncommunicative phenomena, especially those which occupy center stage during periods of analytic stalemate. This psychological content is studied by a two-part investigation of the particulars of the presenting "surface," involving (1) focusing and (2) association. The technique was originally devised by Freud to access the latent meanings of dreams. The effort departs from free association, calling upon more active analytic teamwork within a transference-countertransference context that is steadily considered and analyzed. The key "unverbal" material arising from this dyadic flux is descriptively preconscious, multimodal, widely variable in form, and not primarily lexical. A frequent finding is that these repeating ad hoc clinical phenomena, often categorized as resistance (especially transference resistance), are highly condensed and defensively rearranged compositions, like dreams, that have been internally structured by processes akin to dreamwork. Approached by focused association, such content yields unconscious derivatives that previously had been sequestered in repetitious, noncommunicative forms. This work allows the analyst to follow Freud's clinical maxim to "start with the surface" and provides relief for the analyst from the temptation to invoke global resistance interpretations when derivative communication and analytic movement have lapsed.

Dosimetric results on EURECA.

Detector packages were exposed on the European Retrievable Carrier (EURECA) as part of the Biostack experiment inside the Exobiology and Radiation Assembly (ERA) and at several locations around EURECA. The packages consist of different plastic nuclear track detectors, nuclear emulsions and thermoluminescence dosimeters (TLDs). Evaluation of these detectors yields data on absorbed dose and particle and linear energy transfer (LET) spectra. Behind a shielding thickness in front of the detectors of 0.09g cm-2 the doses range between 21.26 Gy and 0.87 Gy depending on the location of the dosimeter. Not all measurement can be explained by calculations.

A note on vector flux models for radiation dose calculations.

This paper reviews and extends modelling of anisotropic fluxes for radiation belt protons to provide closed-form equations for vector proton fluxes and proton flux anisotropy in terms of standard omnidirectional flux models. These equations provide a flexible alternative to the data-based vector flux models currently available. At higher energies, anisotropy of trapped proton flux in the upper atmosphere depends strongly on the variation of atmospheric density with altitude. Calculations of proton flux anisotropies using present models require specification of the average atmospheric density along trapped particle trajectories and its variation with mirror point altitude. For an isothermal atmosphere, calculations show that in a dipole magnetic field, the scale height of this trajectory-averaged density closely approximates the scale height of the atmosphere at the mirror point of the trapped particle. However, for the earth's magnetic field, the altitudes of mirror points vary for protons drifting in longitude. This results in a small increase in longitude-averaged scale heights compared to the atmospheric scale heights at minimum mirror point altitudes. The trajectory-averaged scale heights are increased by about 10-20% over scale heights from standard atmosphere models for protons mirroring at altitudes less than 500 km in the South Atlantic Anomaly. Atmospheric losses of protons in the geomagnetic field minimum in the South Atlantic Anomaly control proton flux anisotropies of interest for radiation studies in low earth orbit. Standard atmosphere models provide corrections for diurnal, seasonal and solar activity-driven variations. Thus, determination of an "equilibrium" model of trapped proton fluxes of a given energy requires using a scale height that is time-averaged over the lifetime of the protons. The trajectory-averaged atmospheric densities calculated here lead to estimates for trapped proton lifetimes. These lifetimes provide appropriate time-averaging intervals for equilibrium models of trapped proton fluxes.

Case report 752: Normal variant of the acromion simulating grade I acromioclavicular separation.

This case illustrates a developmental variant of the acromion resulting in apparent widening of the acromioclavicular joint space rather than discontinuity of the inferior cortices of the acromioclavicular joint. Had an axillary view not been obtained, an erroneous radiographic diagnosis of grade I acromioclavicular separation might have been suggested.

The in vivo availability of gentamicin when admixed with total nutrient solutions: a comparative study.

The relative in vivo availability of gentamicin when administered by two different intravenous methods was evaluated in patients treated in a surgical intensive care unit in a randomized, prospective, crossover study. Each patient received gentamicin therapy via intravenous piggyback (IVPB) and in-line burette (ILB) methods. In the IVPB method, the drug was mixed in 5% dextrose in water (D5W) and infused intermittently. In the ILB method, the drug was mixed using the patient's total nutrient admixture (TNA) solution as the diluent in an ILB, which was inserted between the TNA bottle and its administration set and infused intermittently. A serial sampling of four sets of serum concentrations of the gentamicin was obtained. Pharmacokinetic parameters (Kel, Vd, and a maximum serum concentration) were calculated from the four sets of concentrations collected per patient. The IVPB method yielded mean values of Kel, Vd, and C1.5mg/kg of 0.13 hr-1, 0.39 liter/kg, and 5.1 micrograms/ml, respectively. The ILB method yielded mean values of Kel, Vd, and C1.5mg/kg of 0.14 hr-1, 0.34 liter/kg, and 5.6 micrograms/ml, respectively. A t-test for paired samples was applied to these mean values. Significant difference was not found (p greater than 0.05). The intermittent infusion of gentamicin, using TNA as the diluent and an ILB, produced equivalent serum concentrations when compared with D5W as the diluent.

Transference neurosis as a waking dream: notes on a clinical enigma.

This paper demonstrates clinically that the interactional features of a transference neurosis are the waking equivalents of a manifest dream. Through analytic investigation of the emerging repetitive extraverbal elements of apparent transference resistance behavior, it is discovered that the systematic analysis of the details of such behavior yields a picture of synthetic construction fundamentally the same as that seen in dreams. By using Freud's technique of systematic dream interpretation, the tightly organized, coded, and camouflaged presence of many key compromise formations determining a neurosis are found to be represented in compact, highly condensed clinical interactions, providing an overall picture of dreamwork in action. The four components of dreamwork are found to be the principal means by which the unconscious genetic and dynamic material is represented in the analytic field.

Pharmacokinetics of parenteral sulbactam in patients with appendicitis.

The distribution and elimination of a new beta-lactamase inhibitor, sulbactam, were characterized in patients with gangrenous or perforated appendicitis. Using a two-compartment model, the distribution volumes for the central and total body were approximately 11 and 25 L, respectively. Sulbactam is rapidly distributed and eliminated with rate constants of about 3.7 and 0.7 h-1, respectively. Mean total body clearance was 311 ml/min. In contrast to previously reported data from normal subjects, surgical patients have more rapid total body clearance and larger steady-state distribution volumes.

Comparison of physician and pharmacist management of anticoagulant therapy of inpatients.

The management of anticoagulant therapy for hospitalized patients by seven certified pharmacist prescribers and one physician was compared. Eighty-one consecutive patients referred to the anticoagulation service were randomly assigned to two groups. For patients in the pharmacist-prescriber group, the physician independently monitored laboratory results and simulated heparin and warfarin doses. The roles of pharmacist and physician were reversed for patients in the physician-prescriber group. According to an established protocol, adjustments in heparin sodium infusion rate were based on activated partial thromboplastin time (PTT); warfarin sodium dosage was adjusted using a proconvertin and prothrombin (P&P) method. Heparin doses, warfarin doses, and clotting-test results were compared for patients in the two prescriber groups; simulated and actual doses also were compared. Patients were observed for complications of anticoagulant therapy. There were no significant differences in the mean heparin and warfarin doses administered to patients in the two prescribed groups. Similarly, PTT and number of days to reach therapeutic P&P were not significantly different. Within each group, the mean prescribed and simulated heparin doses were not significantly different. There were no episodes of major bleeding, but four patients in the pharmacist-prescriber group had minor bleeding. While the results are not applicable to all pharmacists or all settings, the certified pharmacist prescribers in this study adjusted anticoagulant therapy as well as an experienced physician.

Perforated and gangrenous appendicitis: an analysis of antibiotic failures.

The relationships between resistant pathogens, serum levels of gentamicin, and the outcomes of gangrenous or perforated appendicitis were analyzed in 147 patients. Failure to cure the infection occurred significantly more frequently among patients treated with cefoperazone or cefamandole than among those treated with clindamycin and gentamicin in combination. The failures were associated with recovery of resistant Bacteroides fragilis from intraoperative cultures. Pseudomonas species were also associated with failures, their in vitro susceptibility not correlating with clinical cure. Patients with gentamicin peak serum levels of less than 6 micrograms/ml in the first three days were not more likely to be associated with failure than were patients with higher levels. These clinical observations indicate that antibiotic therapy of intra-abdominal sepsis should include antibiotics with in vitro activity against B fragilis and that precise adjustments of gentamicin levels may not improve outcome. In addition, Pseudomonas species may play a significant role in some of these infections.

Influence of manufacturer lot number on pharmacokinetic manipulation of gentamicin serum concentrations.

A prospective, randomized trial was performed to study the impact of lot variation on pharmacokinetic manipulation of serum gentamicin concentrations. Twenty patients receiving gentamicin were randomized prospectively into two groups. Group I patients had blood samples obtained before and after two doses during their hospital regimen using gentamicin from the same lot number. Group II patients had the samples obtained around two doses using different lot numbers of gentamicin. Pharmacokinetic parameters were calculated assuming a one-compartment model and were compared between the initial and subsequent set of serum concentrations. For Group I, the gentamicin distribution volume (Vd) did not differ (mean change, -0.007 L/kg, or mean absolute percentage change, 20.8%). Group II also did not have a significant mean change in Vd (0.023 L/kg, or mean absolute percentage change, 18.7%). The gentamicin Vd did not appear to change over time whether gentamicin was administered using identical or differing lot numbers.

Altered gentamicin distribution in ascitic patients.

Gentamicin pharmacokinetics were studied in eight patients with ascites. Gentamicin serum levels were measured by radioimmunoassay immediately before, 15 minutes after, and at one and two estimated half-lives after intermittent i.v. infusions of gentamicin. Volumes of distributions (Vd) calculated for the eight patients were significantly larger than mean values reported for the drug in normal patients (p less than 0.025). Vd ranged from 20.2 to 53 liters and correlated poorly with lean and total body weights. In patients with ascites or abnormal extracellular fluid volumes, gentamicin dosage should be based on frequent measurements of serum gentamicin levels and on clinical response.

Improved methods for estimating initial heparin infusion rates.

Two methods of calculating heparin infusion rates for patients with venous thrombotic disease were compared; one method was based on a one-compartment pharmacokinetic model, the other on patient weight. Sixty-eight patients with presumed thromboembolic disease were started on continuous i.v. heparin sodium (porcine) using an infusion pump. Patients were divided into two groups--the infusion rate of Group I was based on patient weight (77 units/kg/4 hrs) and the infusion rate of Group 2 was determined by a pharmacokinetic equation based on a one-compartment heparin model. Heparin effect was measured by an activated partial thromboplastin time (APTT). The initial heparin infusion rate for Group 1 (4,784 +/- 672 units/4 hrs) was significantly greater (p less than 0.039, two-sample t-test) than that for Group 2 (4,413 +/- 779 units/4 hrs), but the variances of the rates were not significantly different (p = 0.40, ratio of variance F-test). Both methods for estimating initial heparin infusion rates gave mean APTT values in the center of the therapeutic range, but the variance in the APTTs of Group 2 patients was significantly smaller (p = 0.004) than that of Group 1. The pharmacokinetic model was more precise and reliable. This model should be valuable for insuring heparin's therapeutic effect without exposing patients to the potential risk of hemorrhage.