Sonographic evaluation of intravascular volume status in the surgical intensive care unit: a prospective comparison of subclavian vein and inferior vena cava collapsibility index.

BACKGROUND: Traditional methods for intravascular volume status assessment are invasive and are associated significant complications. While focused bedside sonography of the inferior vena cava (IVC) has been shown to be useful in estimating intravascular volume status, it may be technically difficult and limited by patient factors such as obesity, bowel gas, or postoperative surgical dressings. The goal of this investigation is to determine the feasibility of subclavian vein (SCV) collapsibility as an adjunct to IVC collapsibility in intravascular volume status assessment. METHODS: A prospective study was conducted on a convenience sample of surgical intensive care unit patients to evaluate interchangeability of IVC collapsibility index (IVC-CI) and SCV-CI. After demographic and acuity of illness information was collected, all patients underwent serial, paired assessments of IVC-CI and SCV-CI using portable ultrasound device (M-Turbo; Sonosite, Bothell, WA). Vein collapsibility was calculated using the formula [collapsibility (%) = (max diameter - min diameter)/max diameter × 100%]. Paired measurements from each method were compared using correlation coefficient and Bland-Altman measurement bias analysis. RESULTS: Thirty-four patients (mean age 56 y, 38% female) underwent a total of 94 paired SCV-CI and IVC-CI sonographic measurements. Mean acute physiology and chronic health evaluation II score was 12. Paired SCV- and IVC-CI showed acceptable correlation (R(2) = 0.61, P < 0.01) with acceptable overall measurement bias [Bland-Altman mean collapsibility difference (IVC-CI minus SCV-CI) of -3.2%]. In addition, time needed to acquire and measure venous diameters was shorter for the SCV-CI (70 s) when compared to IVC-CI (99 s, P < 0.02). CONCLUSIONS: SCV collapsibility assessment appears to be a reasonable adjunct to IVC-CI in the surgical intensive care unit patient population. The correlation between the two techniques is acceptable and the overall measurement bias is low. In addition, SCV-CI measurements took less time to acquire than IVC-CI measurements, although the clinical relevance of the measured time difference is unclear.

Inducible nitric oxide synthase inhibitor SD-3651 reduces proteinuria in MRL/lpr mice deficient in the NOS2 gene.

Several studies have demonstrated the effectiveness of arginine analog nitric oxide synthase (NOS) inhibitor therapy in preventing and treating murine lupus nephritis. However, MRL/MpJ-FAS (MRL/lpr) mice lacking a functional NOS2 (inducible NOS [iNOS]) gene (NOS2) develop proliferative glomerulonephritis in a fashion similar to their wild-type (wt) littermates. This finding suggests that the effect of arginine analog NOS inhibitors is through a non-iNOS-mediated mechanism. This study was designed to address this hypothesis.NOS2 mice were given either vehicle or a NOS inhibitor (SD-3651) to determine if pharmacological NOS inhibition prevented glomerulonephritis, using wt mice as positive controls. Urine was collected fortnightly to measure albumin. At the time of full disease expression in wt mice, all mice were killed, and renal tissue was examined for light, immunofluorescence, and electron microscopic evidence of disease. Serum was analyzed for anti-double-stranded DNA antibody production.NOS2 mice had higher serum anti-double-stranded DNA antibody antibody levels than those of wt mice. SD-3651 therapy reduced proteinuria, glomerular immunoglobulin G deposition, and electron microscopic evidence of podocytopathy and endothelial cell swelling without affecting proliferative lesions by light microscopy.These studies confirm that genetic iNOS deficiency alone is insufficient to prevent proliferative glomerulonephritis and suggest that iNOS activity may inhibit autoantibody production. These results also suggest that SD-3651 therapy acts via a non-iNOS-mediated mechanism to prevent endothelial cell and podocyte pathology. Studies that elucidate this mechanism could provide a useful drug target for the treatment of nephritis.

Continuous versus bolus tube feeds: Does the modality affect glycemic variability, tube feeding volume, caloric intake, or insulin utilization?

INTRODUCTION: Enteral nutrition (EN) is very important to optimizing outcomes in critical illness. Debate exists regarding the best strategy for enteral tube feeding (TF), with concerns that bolus TF (BTF) may increase glycemic variability (GV) but result in fewer nutritional interruptions than continuous TF (CTF). This study examines if there is a difference in GV, insulin usage, TF volume, and caloric delivery among intensive care patients receiving BTF versus CTF. We hypothesize that there are no significant differences between CTF and BTF when comparing the above parameters. MATERIALS AND METHODS: Prospective, randomized pilot study of critically ill adult patients undergoing percutaneous endoscopic gastrostomy (PEG) placement for EN was performed between March 1, 2012 and May 15, 2014. Patients were randomized to BTF or CTF. Glucose values, insulin use, TF volume, and calories administered were recorded. Data were organized into 12-h epochs for statistical analyses and GV determination. In addition, time to ≥80% nutritional delivery goal, demographics, Acute Physiology and Chronic Health Evaluation II scores, and TF interruptions were examined. When performing BTF versus CTF assessments, continuous parameters were compared using Mann-Whitney U-test or repeated measures t-test, as appropriate. Categorical data were analyzed using Fisher's exact test. RESULTS: No significant demographic or physiologic differences between the CTF (n = 24) and BTF (n = 26) groups were seen. The immediate post-PEG 12-h epoch showed significantly lower GV and median TF volume for patients in the CTF group. All subsequent epochs (up to 18 days post-PEG) showed no differences in GV, insulin use, TF volume, or caloric intake. Insulin use for both groups increased when comparing the first 24 h post-PEG values to measurements from day 8. There were no differences in TF interruptions, time to ≥80% nutritional delivery goal, or hypoglycemic episodes. CONCLUSIONS: This study demonstrated no clinically relevant differences in GV, insulin use, TF volume or caloric intake between BTF and CTF groups. Despite some shortcomings, our data suggest that providers should not feel limited to BTF or CTF because of concerns for GV, time to goal nutrition, insulin use, or caloric intake, and should consider other factors such as resource utilization, ease of administration, and/or institutional/patient characteristics.

Inducible nitric oxide synthase inhibitors reduce urinary markers of systemic oxidant stress in murine proliferative lupus nephritis.

BACKGROUND: Proliferative lupus nephritis (PLN) is characterized by increased expression of inducible nitric oxide (NO) synthase (iNOS). Inhibition of iNOS with NG-monomethyl L-arginine (L-NMMA) abrogates renal disease in two models of murine PLN, but the mechanism of this effect is unknown. Reactive oxygen species have both direct and indirect pathogenic effects in inflammatory lesions and are therefore potentially an important therapeutic target in PLN. We hypothesized that inhibition of iNOS activity would reduce ROS production in murine PLN. METHODS: A dose escalation of L-NMMA (0, 20, 100, and 500 mg/kg/day) was performed in New Zealand Black x New Zealand White F1 (NZB/W) mice with active renal disease. Twenty-four-hour urine nitrate + nitrite (NOX) was measured with a chemiluminescence NO analyzer. Twenty-four-hour urine 8-isoprostane F2alpha (8-iso-PGF2alpha) was measured by gas chromatography-negative ion chemical ionization mass spectrometry. MRL-MpJFASlpr (MRL/lpr) and NZB/W mice were divided into three groups and given either L-NMMA, L-N6-iminoethyl-lysine (L-NIL), or distilled water for 2 weeks. Urine NOX and 8-iso-PGF2alpha were determined after 2 weeks. RESULTS: L-NMMA reduced both urine NOX and 8-iso-PGF2alpha levels in a dose-dependent fashion in NZB/W and MRL/lpr mice. Urine NOX and 8-iso-PGF2alpha levels were highly correlated. Both specific (L-NIL) and nonspecific (L-NMMA) iNOS inhibition reduced urine NOX and 8-iso-PGF2alpha levels in both models of murine PLN. CONCLUSION: These findings suggest that iNOS activity is a major source of reactive oxidant stress in these models of murine PLN. Future studies will address the pathogenic role of reactive oxygen stress in PLN.

Oral administration of a decaffeinated green tea (Camellia sinensis) extract did not alter urinary 8-epi-prostaglandin F(2 alpha), a biomarker for in-vivo lipid peroxidation.

Oxidative stress is involved in the pathogenesis of numerous chronic human diseases. The objective of this study was to determine whether administration of a decaffeinated green tea extract providing 844 mg flavonoids daily reduced the urinary excretion of 8-epi-prostaglandin F(2 alpha) (8-epi-PGF(2 alpha)), a product of lipid peroxidation in cellular membranes and of low-density lipoprotein (LDL). Nine healthy male and female subjects were studied at baseline and after 14 days of green tea supplementation. Analysis of urinary 8-epi-PGF(2 alpha) was performed using immunoaffinity extraction-gas chromatography-negative ion chemical ionization-mass spectrometry (GC-NICI-MS). Urinary 8-epi-PGF(2 alpha) concentrations were 0.286+/-0.120 nmol (mmol creatinine)(-1) at baseline and 0.244+/-0.177 nmol mmol(-1) creatinine after green tea supplementation. There were no significant differences in the excretion of urinary 8-epi-PGF(2 alpha) after treatment with green tea. We conclude that 14 days of green tea supplementation did not significantly alter in-vivo lipid peroxidation.

Prospective evaluation of intravascular volume status in critically ill patients: does inferior vena cava collapsibility correlate with central venous pressure?

BACKGROUND: In search of a standardized noninvasive assessment of intravascular volume status, we prospectively compared the sonographic inferior vena cava collapsibility index (IVC-CI) and central venous pressures (CVPs). Our goals included the determination of CVP behavior across clinically relevant IVC-CI ranges, examination of unitary behavior of IVC-CI with changes in CVP, and estimation of the effect of positive end-expiratory pressure (PEEP) on the IVC-CI/CVP relationship. METHODS: Prospective, observational study was performed in surgical/medical intensive care unit patients between October 2009 and July 2013. Patients underwent repeated sonographic evaluations of IVC-CI. Demographics, illness severity, ventilatory support, CVP, and patient positioning were recorded. Correlations were made between CVP groupings (<7, 7-12, 12-18, 19+) and IVC-CI ranges (<25, 25-49, 50-74, 75+). Comparison of CVP (2-unit quanta) and IVC-CI (5-unit quanta) was performed, followed by assessment of per-unit ΔIVC-CI/ΔCVP behavior as well as examination of the effect of PEEP on the IVC-CI/CVP relationship. RESULTS: We analyzed 320 IVC-CI/CVP measurement pairs from 79 patients (mean [SD] age, 55.8 [16.8] years; 64.6% male; mean [SD] Acute Physiology and Chronic Health Evaluation II, 11.7 [6.21]). Continuous data for IVC-CI/CVP correlated poorly (R = 0.177, p < 0.01) and were inversely proportional, with CVP less than 7 noted in approximately 10% of the patients for IVC-CIs less than 25% and CVP less than 7 observed in approximately 85% of patients for IVC-CIs greater than or equal to 75%. Median ΔIVC-CI per unit CVP was 3.25%. Most measurements (361 of 320) were collected in mechanically ventilated patients (mean [SD] PEEP, 7.76 [4.11] cm H2O). PEEP-related CVP increase was approximately 2 mm Hg to 2.5 mm Hg for IVC-CIs greater than 60% and approximately 3 mm Hg to 3.5 mm Hg for IVC-CIs less than 30%. PEEP also resulted in lower IVC-CIs at low CVPs, which reversed with increasing CVPs. When IVC-CI was examined across increasing PEEP ranges, we noted an inverse relationship between the two variables, but this failed to reach statistical significance. CONCLUSION: IVC-CI and CVP correlate inversely, with each 1 mm Hg of CVP corresponding to 3.3% median ΔIVC-CI. Low IVC-CI (<25%) is consistent with euvolemia/hypervolemia, while IVC-CI greater than 75% suggests intravascular volume depletion. The presence of PEEP results in 2 mm Hg to 3.5 mm Hg of CVP increase across the IVC-CI spectrum and lower collapsibility at low CVPs. Although IVC-CI decreased with increasing degrees of PEEP, this failed to reach statistical significance. While this study represents a step forward in the area of intravascular volume estimation using IVC-CI, our findings must be applied with caution owing to some methodologic limitations. LEVEL OF EVIDENCE: Diagnostic study, level III. Prognostic study, level III.

Bioavailability of metronidazole in rabbits after administration of a rectal suppository.

The bioavailability of metronidazole in rabbits was studied using plasma concentration measurements after the administration of the drug in a hydrophilic (glycerogelatin) suppository form. The peak in the plasma concentration time curve occurred about 1 hour after administration, indicating that the rate of absorption is fast and equivalent to that observed in humans after oral administration. There was rapid elimination of the drug, as indicated by a relatively high elimination rate constant and low plasma half-life. The in vitro dissolution profile of the suppositories further confirms rapid absorption of the drug from the suppositories in the rectum. The presence of Tween 80 enhanced the in vitro release of metronidazole, but the presence of a hydrogenated vegetable oil lubricant (Lubritab) caused retardation in the drug release from the suppositories.

Reduced levels of nitric oxide metabolites in cerebrospinal fluid are associated with equine protozoal myeloencephalitis.

Equine protozoal myeloencephalitis (EPM) is a disease of horses that is primarily associated with infection with the apicomplexan Sarcocystis neurona. Infection with this parasite alone is not sufficient to induce the disease, and the mechanism of neuropathogenesis associated with EPM has not been reported. Nitric oxide (NO) functions as a neurotransmitter, a vasodilator, and an immune effector and is produced in response to several parasitic protozoa. The purpose of this work was to determine if the concentration of NO metabolites (NO(x)(-)) in the cerebrospinal fluid (CSF) is correlated with the development of EPM. CSF NO(x)(-) levels were measured before and after transport-stressed, acclimated, or dexamethasone-treated horses (n = 3 per group) were experimentally infected with S. neurona sporocysts. CSF NO(x)(-) levels were also compared between horses that were diagnosed with EPM after natural infection with S. neurona and horses that did not have clinical signs of disease or that showed no evidence of infection with the parasite (n = 105). Among the experimentally infected animals, the mean CSF NO(x)(-) levels of the transport-stressed group, which had the most severe clinical signs, was reduced after infection, while these values were found to increase after infection in the remaining groups that had less severe signs of EPM. Under natural conditions, horses with EPM (n = 65) had a lower mean CSF NO(x)(-) concentration than clinically normal horses with antibodies (Abs) against S. neurona (n = 15) in CSF, and horses that developed ataxia (n = 81) had a significantly lower mean CSF NO(x)(-) concentration than horses that did not have neurologic signs (n = 24). In conclusion, lower CSF NO(x)(-) levels were associated with clinical EPM, suggesting that measurement of CSF NO(x)(-) levels could improve the accuracy of diagnostic tests that are based upon detection of S. neurona-specific Abs in CSF alone and that reduced NO levels could be causally related to the development of EPM.