Chitosan Sponges to Locally Deliver Amikacin and Vancomycin: A Pilot In Vitro Evaluation

Background

Open orthopaedic wounds are ideal sites for infection. Preventing infection in these wounds is critical for reducing patient morbidity and mortality, controlling antimicrobial resistance and lowering the cost of treatment. Localized drug delivery has the potential to overcome the challenges associated with traditional systemic dosing. A degradable, biocompatible polymer sponge (chitosan) that can be loaded with clinician-selected antibiotics at the point of care would provide the patient and clinician with a desirable, adjunctive preventive modality.

Questions/purposes

We asked (1) if an adaptable, porous chitosan matrix could absorb and elute antibiotics for 72 hours for potential use as an adjunctive therapy to débridement and lavage; and (2) if the sponges could elute levels of antibiotic that would inhibit growth of Staphylococcus aureus and Pseudomonas aeruginosa?

Methods

We fabricated a degradable chitosan sponge that can be loaded with antibiotics during a 60-second hydration in drug-containing solution. In vitro evaluation determined amikacin and vancomycin release from chitosan sponges at six time points. Activity tests were used to assess the release of inhibitory levels of amikacin and vancomycin.

Results

Amikacin concentration was 881.5 μg/mL after 1 hour with a gradual decline to 13.9 μg/mL after 72 hours. Vancomycin concentration was 1007.4 μg/mL after 1 hour with a decrease to 48.1 μg/mL after 72 hours. Zone of inhibition tests were used to verify inhibitory levels of drug release from chitosan sponges. A turbidity assay testing activity of released amikacin and vancomycin indicated inhibitory levels of elution from the chitosan sponge.

Clinical Relevance

Chitosan sponges may provide a potential local drug delivery device for preventing musculoskeletal infections.     

Topical lidocaine improves conditions for laryngeal mask airway insertion

Purpose

We hypothesized that optimal laryngeal mask airway (LMA?) insertion conditions might be achieved with topical lidocaine and a smaller dose of propofol. In this study, insertion conditions after topical lidocaine 40 mg followed by propofol 2 mg·kg^?1 were compared with propofol 2 mg·kg^?1 or propofol 3 mg·kg^?1 alone.

Methods

Ninety patients were recruited for this randomized prospective double-blind study. One group received four sprays of topical lidocaine (40 mg) over the posterior pharyngeal wall followed by propofol 2 mg·kg^?1 (Group 2PL; n = 30). The other two groups received four sprays of 0.9% normal saline followed by propofol 2 mg·kg^?1 (Group 2P; n = 30) or by propofol 3 mg·kg^?1 (Group 3P; n = 30). The frequency of optimal insertion conditions (successful insertion at the first attempt without adverse responses) and side effects were recorded.

Results

The frequency of optimal insertion conditions was greater in Group 2PL (20/30, 67%) and Group 3P (22/30, 73%) than in Group 2P (11/20, 37%) (P = 0.009). In Group 3P, the mean blood pressure was lower than in the other groups prior to LMA-Classic? insertion (P = 0.003) but was similar after insertion. The incidence of apnea was greater in Group 3P patients (17/30, 57%) than in Group 2P (2/30, 7%) or Group 2PL patients (1/30, 3%) (P < 0.001).

Conclusion

Topical lidocaine 40 mg followed by propofol 2 mg·kg^?1 can provide optimal insertion conditions of the LMA-Classic comparable to those of propofol 3 mg·kg^?1, with fewer hemodynamic changes and a lower incidence of apnea.     

Ultrasound guidance for internal jugular vein cannulation: Continuing Professional Development

Purpose

The objective of this continuing professional development module is to describe the role of ultrasound for central venous catheterization and to specify its benefits and limitations. Although ultrasound techniques are useful for all central venous access sites, the focus of this module is on the internal jugular vein approach.

Principal findings

In recent years, several studies were published on the benefits of ultrasound use for central venous catheterization. This technique has evolved rapidly due to improvements in the equipment and technology available. Ultrasound helps to detect the anatomical variants of the internal jugular vein. The typical anterolateral position of the internal jugular vein with respect to the carotid is found in only 9-92% of cases. Ultrasound guidance reduces the rate of mechanical, infectious, and thrombotic complications by 57%, and it also reduces the failure rate by 86%. Cost-benefit analyses show that the cost of ultrasound equipment is compensated by the decrease in the expenses associated with the treatment of complications. In this article, we will review the history of ultrasound guidance as well as the reasons that account for its superiority over the classical anatomical landmark technique. We will describe the equipment needed for central venous catheterization as well as the various methods to visualize with ultrasound.

Conclusion

To improve patient safety, we recommend the use of ultrasound for central venous catheterization using the internal jugular approach.     

Characterization of intensive care unit acquired hyponatremia and hypernatremia following cardiac surgery

Purpose

Although intensive care unit (ICU) acquired sodium disturbances are common in critically ill patients, few studies have examined sodium disturbances in patients following cardiac surgery. The objective of this study was to describe the epidemiology of ICU-acquired hyponatremia and hypernatremia in patients following cardiac surgery.

Methods

We identified 6,727 adults (≥18 yr) who were admitted consecutively to a regional cardiovascular intensive care unit (CVICU) from January 1, 2000 to December 31, 2006 and were documented as having normal serum sodium levels (133 to 145 mmol·L^?1) during the first day of ICU admission. ICU-acquired hyponatremia and hypernatremia were defined as a change in serum sodium concentration to <133 mmol·L^?1 or >145 mmol·L^?1, respectively, following ICU day one.

Results

A first episode of ICU-acquired hyponatremia and hypernatremia developed in 785 (12%) and 242 (4%) patients, respectively, (95% confidence interval [CI] 11-12% and 95% CI 3-4%, respectively), with a respective incidence density of 4.2 and 1.3 patients per 100 days of ICU admission (95% CI 4.0-4.5 and 95% CI 1.2-1.5). The incidence of ICU-acquired sodium disturbances varied according to the patients’ demographic and clinical variables for both hyponatremia (age, diabetes, Acute Physiology and Chronic Health Evaluation [APACHE II] score, mechanical ventilation, length of ICU stay, serum glucose level, and serum potassium level) and hypernatremia (APACHE II score, mechanical ventilation, length of hospital stay prior to ICU admission, length of ICU stay, serum glucose level, and serum potassium level). Compared with patients with normal serum sodium levels, hospital mortality was increased in patients with ICU-acquired hyponatremia (1.6% vs 10%, respectively; P < 0.001) and ICU-acquired hypernatremia (1.6% vs 14%, respectively; P < 0.001).

Conclusion

ICU-acquired hyponatremia and hypernatremia are common complications in critically ill patients following cardiac surgery. They are associated with patient demographic and clinical characteristics and an increased risk of hospital mortality.     

Intravenous lidocaine does not reduce length of hospital stay following abdominal hysterectomy

Purpose

Intravenous lidocaine given both intraoperatively and postoperatively decreases pain scores, reduces opioid consumption, and promotes faster return of bowel function following abdominal surgery. The purpose of this trial was to determine if intravenous lidocaine limited to the intraoperative period reduces length of hospital stay and improves functional recovery following abdominal hysterectomy.

Methods

Following Research Ethics Board approval and informed consent, women of American Society of Anesthesiologists’ class I and II undergoing abdominal hysterectomy were assigned randomly to lidocaine and control groups. Lidocaine subjects received an intravenous bolus of 1.5 mg·kg^?1 followed by an infusion of 3 mg·kg^?1·hr^?1, while control subjects received matching placebo. Patients, anesthesiologists, and study personnel were blinded, and anesthesia and multimodal perioperative analgesia were standardized. The primary outcome of this trial was discharge from hospital on or before the second postoperative day (POD2). Additional criteria were assessed for secondary outcomes, i.e., discharge fitness on POD2, length of hospital stay, opioid use, numeric rating scores for pain, quality of recovery, and recovery of bowel function.

Results

Ninety of the 93 women who were recruited completed the study protocol. The characteristics of the patients in both groups were similar—lidocaine group (n = 44) and control group (n = 46)—and no difference was noted between groups in the numbers of women discharged from hospital on POD2 (10 lidocaine, 15 control; P = 0.295). Days to discharge fitness (P = 0.666) and length of hospital stay (P = 0.456) were also similar. Differences in opioid consumption, pain scores, and recovery were neither clinically nor statistically significant.

Conclusion

Intraoperative administration of intravenous lidocaine did not reduce hospital stay or improve objective measures of analgesia and recovery following abdominal hysterectomy. This trial was registered at ClinicalTrials.gov (NCT00382499).     

Gene Expression Profile Prospectively Predicts Peritoneal Relapse After Curative Surgery of Gastric Cancer

Background

Peritoneal relapse is the most common pattern of tumor progression in advanced gastric cancer. Clinicopathological findings are sometimes inadequate for predicting peritoneal relapse. The aim of this study was to identify patients at high risk of peritoneal relapse in a prospective study based on molecular prediction.

Methods

RNA samples from 141 primary gastric cancer tissues after curative surgery were profiled using oligonucleotide microarrays covering 30,000 human probes. Firstly, we constructed a molecular prediction system and validated its robustness and prognostic validity by 500 times multiple validation by repeated random sampling in a retrospective set of 56 (38 relapse-free and 18 peritoneal-relapse) patients. Secondly, we applied this prediction to 85 patients of the prospective set to assess predictive accuracy and prognostic validity.

Results

In the retrospective phase, repeated random validation yielded ~68% predictive accuracy and a 22-gene expression profile associated with peritoneal relapse was identified. The prediction system identified patients with poor prognosis. In the prospective phase, the molecular prediction yielded 76.9% overall accuracy. Kaplan–Meier analysis of peritoneal-relapse-free survival showed a significant difference between the “good signature group” and “poor signature group” (log-rank p = 0.0017). Multivariate analysis by Cox regression hazards model identified the molecular prediction as the only independent prognostic factor for peritoneal relapse.

Conclusions

Gene expression profile inherent to primary gastric cancer tissues can be useful in prospective prediction of peritoneal relapse after curative surgery, potentially allowing individualized postoperative management to improve the prognosis of patients with advanced gastric cancer.     

Promoter Methylation of Specific Genes is Associated with the Phenotype and Progression of Colorectal Adenocarcinomas

Background

Promoter methylation of colorectal cancer-related genes were examined with respect to phenotype and tumor progression.

Materials and Methods

We assayed promoter methylation of 11 genes including established CpG island methylator phenotype (CIMP) markers (MLH1, MINT1, MINT2, MINT31, p16 ^INK4a , p14 ^ARF , and CACNA1G) and four genes (COX2, DAPK, MGMT, and APC) frequently methylated in colorectal cancer in 285 patients with sporadic colorectal cancer.

Results

CIMP+ tumors were more than two times more frequent among high-frequency microsatellite instability tumors (MSI-H) than in tumors without MSI (P ≤ .0001–.002). COX2 and DAPK methylation were significantly associated with CIMP+ and MSI. KRAS showed tendency toward more frequent codon 12-13 mutations identified in tumors with APC and p16 ^INK4a methylation than in those with unmethylation (P = .033 and .05, respectively). Additionally, tumors with synchronous adenoma were associated with p16 ^INK4a methylation (P = .004). The p16 ^INK4a methylation was significantly associated with poor overall and disease-free survival in 131 rectal cancer patients who underwent curative operation, according to multivariate analyses (relative risk [RR] = 0.317 and 0.349; P = .033 and .024, respectively). Specifically, in 175 stage II and III patients receiving adjuvant-based fluoropyrimidine chemotherapy, p16 ^INK4a methylation and MINT31 unmethylation showed a significant or tendency toward an association with recurrence and DFS (P = .007–.032).

Conclusions

The study suggests that specific CIMP markers, such as p16 ^INK4a and MINT31, should be further verified as potential epigenetic targets for the design of efficient chemotherapy regimens. We also identified a subset of colorectal cancer, possibly comprising APC methylation-KRAS mutation-p16 ^INK4a methylation.     

Effects of Pulsed Electromagnetic Fields on Human Osteoblastlike Cells (MG-63): A Pilot Study

Background

Although pulsed electromagnetic fields (PEMFs) are used to treat delayed unions and nonunions, their mechanisms of action are not completely clear. However, PEMFs are known to affect the expression of certain genes.

Questions/purposes

We asked (1) whether PEMFs affect gene expression in human osteoblastlike cells (MG63) in vitro, and (2) whether and to what extent stimulation by PEMFs induce cell proliferation and differentiation in MG-63 cultures.

Methods

We cultured two groups of MG63 cells. One group was treated with PEMFs for 18 hours whereas the second was maintained in the same culture condition without PEMFs (control). Gene expression was evaluated throughout cDNA microarray analysis containing 19,000 genes spanning a substantial fraction of the human genome.

Results

PEMFs induced the upregulation of important genes related to bone formation (HOXA10, AKT1), genes at the transductional level (CALM1, P2RX7), genes for cytoskeletal components (FN1, VCL), and collagenous (COL1A2) and noncollagenous (SPARC) matrix components. However, PEMF induced downregulation of genes related to the degradation of extracellular matrix (MMP-11, DUSP4).

Conclusions and Clinical Relevance

PEMFs appear to induce cell proliferation and differentiation. Furthermore, PEMFs promote extracellular matrix production and mineralization while decreasing matrix degradation and absorption. Our data suggest specific mechanisms of the observed clinical effect of PEMFs, and thus specific approaches for use in regenerative medicine.