Fluid resuscitation in major burns

BACKGROUND: The Parkland formula is established as the "gold standard" for initial fluid resuscitation for major burns. The purpose of this study was to review our fluid resuscitation practice for major burns to determine whether anecdotal observations of significant variations from the Parkland formula were wide spread and whether any difference could be used as a basis for a revision of fluid resuscitation in major burns. METHODS: A retrospective review of 127 presentations to The Alfred Burns Unit with total body surface area (TBSA) affected > or =15% was conducted. A retrospective review of the resuscitation data from these patients was compared with the Parkland formula as well as other studies. RESULTS: A total of 49 patients with complete data on fluid administration and uncomplicated burns were included in the analysis. Significantly larger volumes of fluid (5.58 mL/kg per %TBSA) were given to these patients in the first 24 h than predicted by the Parkland formula. Mean arterial pressure, pulse rate and urine output were at satisfactory levels. Clinically evident complications from fluid administration were minimal. Mortality was similar to that in other centres. CONCLUSION: Fluid resuscitation volumes significantly higher than those predicted by the Parkland formula were given, without adverse consequences. This retrospective review supports a prospective, multicentre, randomized, controlled study comparing this study with the Parkland formula, resulting in a better guide to initial fluid resuscitation in major burns.     

Shape imposed by secondary structure of a polypeptide affects its free diffusion through liquid-filled pores

The purpose of the present study was to investigate the effect of secondary structure of three model polypeptides on their apparent permeability (P(app)) across a synthetic, microporous membrane. Poly-L-lysine (PL), poly-L-glutamate (PGlu), and poly-L-lysine-L-phenylalanine (1:1) (PLP) were selected because a solution environment in which their predominant secondary structure is random coil (RC), alpha-helix, and beta-sheet, respectively, is easily achieved. The conformation of each polypeptide was verified by circular dichroism (CD). Diffusion studies were conducted under sink conditions at 25 degrees C across a microporous polyester membrane using a donor concentration of 0.02 mM for each model polypeptide. NMR was utilized to obtain a second estimation of the diffusion coefficient for each polypeptide. The equivalent hydrodynamic radii (R(e)) of the three model polypeptides were calculated using the values of the diffusion coefficient obtained by both NMR and the classic in vitro diffusion studies. The viscosity of each polypeptide solution was also determined to investigate the effect of viscosity on the aqueous diffusion coefficient. Statistical analysis demonstrated a significant (P < 0.05) difference in both P(app) and the aqueous diffusion coefficient (D(aq)), as well as the calculated R(e) values, between all three model polypeptides and there was no significant (P > 0.05) difference in the viscosity of the polypeptide solutions. Values of D(aq) and R(e) calculated from the diffusion studies were in relatively close agreement to those obtained using NMR. The logarithm of P(app) was highly correlated (r = -0.961) with the values of R(e) calculated from NMR (R(e (NMR))) rather than the mw of the polypeptides (r = 0.681). Values of the Perrin or shape factor which deviate substantially from unity are suggestive of a non-spherical or ellipsoid shape and were 1.22 +/- 0.20, 1.55 +/- 0.11, and 2.38 +/- 0.20 for PGlu, PL, and PLP, respectively. In conclusion, the observed difference in the membrane transport/diffusion of the three model polypeptides is suggested to be due to the shape associated with the secondary structure of each macromolecule, rather than the polypeptide's mw or the viscosity of the dilute polypeptide solution.     

Clinical and immunological assessment of Mycobacterium vaccae (SRL172) with chemotherapy in patients with malignant mesothelioma

The objectives of this study were to determine the toxicity of intratumoural/intrapleural SRL172 in addition to intradermal SRL172 and standard chemotherapy (mitomycin-C, vinblastine and cisplatin) in patients with malignant mesothelioma. Patients received chemotherapy (mitomycin-C: 8 mg m(-2), vinblastine: 6 mg m(-2), cisplatin 50 mg m(-2)) on a 3-weekly basis for up to six courses. IP SRL172 injections were given 3-weekly prior to chemotherapy and escalated in groups of three patients from 1 microg to 1 mg bacilli in 10-fold increments. Patients were also given ID SRL172 at a dose of 1 mg bacilli 4-weekly. Patients were assessed for toxicity after each course of chemotherapy and for response by CT imaging. Immuno-haematological parameters were analyzed pre-treatment and 1 month after completion of treatment. There was no dose limiting toxicity with IP SRL172 although there was greater toxicity at the highest dose (n=13). There were six out of 16 partial responses (37.5%). Haemato-immunological parameters, measured in seven patients pre and post-therapy, revealed that response rate correlated with a decrease in platelet count and there was an increase in activation of natural killer cells and a decrease in the percentage of IL-4 producing T cells in all tested patients post-treatment. SRL172 can be given safely into tumour deposits and the pleural cavity in patients with malignant mesothelioma and we have established the dose for phase II testing.     

MRI simulation: effect of gradient distortions on three-dimensional prostate cancer plans

PURPOSE: To quantify the dosimetric consequences of external patient contour distortions produced on low-field and high-field MRIs for external beam radiation of prostate cancer. METHODS AND MATERIALS: A linearity phantom consisting of a grid filled with contrast material was scanned on a spiral CT, a 0.23 T open MRI, and a 1.5 T closed bore system. Subsequently, 12 patients with prostate cancer were scanned on CT and the open MRI. A gradient distortion correction (GDC) program was used to postprocess the MRI images. Eight of the patients were also scanned on the 1.5 T MRI with integrated GDC correction. All data sets were fused according to their bony landmarks using a chamfer-matching algorithm. The prostate volume was contoured on an MRI image, irrespective of the apparent prostate location in those sets. Thus, the same target volume was planned and used for calculating the anterior-posterior (AP) and lateral separations. The number of monitor units required for treatment using a four-field conformal technique was compared. Because there are also setup variations in patient outer contours, two different CT scans from 20 different patients were fused, and the differences in AP and lateral separations were measured to obtain an estimate of the mean interfractional separation variation. RESULTS: All AP separations measured on MRI were statistically indistinguishable from those on CT within the interfractional separation variations. The mean differences between CT and low-field MRI and CT and high-field MRI lateral separations were 1.6 cm and 0.7 cm, respectively, and were statistically significantly different from zero. However, after the GDC was applied to the low-field images, the difference became 0.4 +/- 0.4 mm (mean +/- standard deviation), which was statistically insignificant from the CT-to-CT variations. The mean variations in the lateral separations from the low-field images with GDC would result in a dosimetric difference of <1%, assuming an equally weighted four-field 18-MV technique for patient separations up to approximately 40 cm. CONCLUSIONS: For patients with lateral separations <40 cm, a homogeneous calculation simulated using a 1.5 T MRI or a 0.23 T MRI with a gradient distortion correction will yield a monitor unit calculation indistinguishable from that generated using CT simulation.     

Cystometric evaluation of reconstructed classical bladder exstrophy

OBJECTIVE: To evaluate the association of urodynamic variables with continence and upper tract status after reconstruction in patients with classical bladder exstrophy. PATIENTS AND METHODS: Thirty-one patients with bladder exstrophy were assessed 1 year after a modified bladder neck reconstruction. The evaluation included a detailed history, radioisotope renography, voiding cysto-urethrography, ultrasonography and artificial slow-filling cystometry. RESULTS: Fifteen of the 31 patients were satisfactorily continent; their maximum cystometric capacity was higher than that of the incontinent patients. The compliance, assessed as the maximum bladder capacity at a detrusor pressure of < 20 cmH2O, was significantly higher in the continent patients. There was a 45% incidence of unstable contractions in the 31 patients. Persistent sphincteric activity was detected on electromyography in 10 patients during voiding. Twenty-one patients could initiate a detrusor contraction during voiding. The residual volume was significant in nine of the 21 patients who attempted to void. Patients with a high end-fill pressure (> 40 cmH2O) had a significantly higher incidence of unobstructive hydronephrosis than had patients who had an end-fill pressure of < 40 cmH2O. CONCLUSIONS: Bladder abnormalities are common after reconstruction of bladder exstrophy, with poor compliance, small capacity and unstable contractions. These factors hinder any increase in capacity and cause persistent incontinence. Hypocompliance and high end-fill pressure can lead to upper tract damage even in continent patients. Detailed urodynamic evaluation is vital to assess the results and to plan subsequent treatment.     

Binding of cosalane--a novel highly lipophilic anti-HIV agent--to albumin and glycoprotein

Cosalane is a potent inhibitor of HIV replication with multiple sites of action. The purposes of this study were to (a) determine the extent and nature of cosalane binding to mucin, alpha(1)-acid glycoprotein (AAG), plasma, and human (HSA) and bovine serum (BSA) albumin, and (b) determine the primary site(s) of cosalane binding to HSA. Plasma protein binding of cosalane was studied by a gel filtration technique. Cosalane binding to HSA was also determined in the presence of salicylic acid. Competitive inhibition studies were conducted using warfarin, digitoxin, and diazepam to determine the primary HSA binding site(s) of cosalane. The drug was bound extensively to HSA and BSA and required 500-550 moles to saturate 1 mole of protein. Stoichiometries of cosalane binding to alpha(1)-acid glycoprotein (AAG) and mucin were between 30 and 50 mol/mol of either glycoprotein. The binding isotherm deviated from a rectangular hyperbola, suggesting self-association of the ligand. Salicylic acid decreased cosalane binding to HSA by one order of magnitude. Inhibition studies of cosalane to HSA revealed that the compound binds primarily to warfarin site with a K(i) of 1.24 +/- 0.24 nM. In summary, cosalane binds extensively to serum albumins and to a lesser extent to both AAG and mucin.     

Enhanced pulmonary delivery of insulin by lung lavage fluid and phospholipids

Pulmonary delivery appears to be the most promising non-parenteral route of insulin administration. In this work, we investigated the enhancement of insulin absorption in the presence of phospholipids and lung lavage fluid in vivo and in vitro. In-vitro experiments of insulin uptake by type II cells showed a significantly enhanced absorption in presence of lavage fluid, compared to various buffer preparations. The same trend was obtained with in-vivo studies of tracheal instillation of insulin. The incorporation of phospholipids as absorption enhancers in 1,2-dipalmitoyl phosphatidylcholine (DPPC) dispersion was compared to blank liposomes. A significantly higher blood glucose decrease was observed with a DPPC-insulin physical mixture compared to liposome, suggesting a possible effect of the phospholipid chain physical state on the insulin in-vivo absorption.     

Effect of mono- and di-acylation on the ocular disposition of ganciclovir: physicochemical properties, ocular bioreversion, and antiviral activity of short chain ester prodrugs

A series of short-chain carboxylic mono- and diesters of ganciclovir were synthesized in our laboratory. Physico-chemical properties, i.e., solubility (pH 4.2), partition coefficient in 1-octanol/phosphate buffer (pH 7.4), aqueous stability at various pH values, bioreversion kinetics in various ocular homogenates and effectiveness against various Herpes viruses in vitro were determined. The compounds exhibited a decrease in solubility as the ester length ascended with a corresponding increase in the octanol/buffer partition coefficient values. All of the prodrugs exhibit stability profiles typical of a carboxylic ester with maximum stability at neutral or slight acidic pH (4.0-7.0). Apparent first-order rate constants associated with prodrug to drug hydrolysis in the ocular homogenates varied depending on the size of the promoiety, lipophilicity of the compound, and the ocular tissue studied. The acetyl and butyryl mono and diesters were screened against various Herpes viruses. The monobutyrate ester of ganciclovir exhibits excellent activity against HSV-2 and VZV and provides a very high selectivity index against most of the viruses studied.