A pilot study in intraparenchymal therapy delivery in the prostate: a comparison of delivery with a porous needle vs standard needle.

BACKGROUND: New biologic therapies directly injected into the prostate are in clinical trials for prostatic diseases. There is a need to understand distribution of injected therapies as a function of prostatic anatomy, physiology, and device design. METHODS: A needle with a porous length of customizable-length was tested and its performance compared with a standard needle. Injections of magnetic resonance contrast reagent were placed into ex-vivo human prostates after surgical excision in standard of care therapy for invasive bladder cancer patients. Magnetic resonance images were acquired using sequences to quantify volume delivered, distributed, and backflow. RESULTS: Magnetic resonance images analysis revealed heterogeneity distribution with injection into the specimens. There was low resistance to flow along ductal pathways and high resistance to flow into glandular nodules and smooth muscle/fibrous parenchyma. Data confirm previous studies showing injection loss via urethra backflow, urethra, and prostatic ducts. Tissue fraction of dose was significantly higher with porous needle compared with standard needle (p = .03). We found that a greater volume of distribution divided by the amount infused (Vd/Vi) increased by 80% with the porous needle, though no statistically significant association due to small sample size. CONCLUSIONS: This study demonstrated that prostatic tissue is anatomically heterogenic and limits distribution of needle injection. There is greater distribution in the ex-vivo prostate using a porous needle. The complexity of intra prostatic flow pathways suggests preoperative imaging and pre-treatment planning will enhance therapy.

Large-Volume Infusions into the Brain: A Comparative Study of Catheter Designs.

BACKGROUND/AIMS: "Whole-brain" infusions have emerged as a potential need with the promise of disease-modifying therapies for neurodegenerative diseases. In addition, several current clinical trials in brain cancer utilize direct delivery of drugs that are required to fill large volumes. Such requirements may not be well served by conventional single port catheters with their "point source" of delivery. Our aim is to examine infusions into large volumes of heterogeneous tissue, aiming for uniformity of distribution. METHODS: A porous catheter (porous brain infusion catheter, PBIC), designed by Twin Star TDS LLC, for brain infusions was developed for this study and compared with another convection-enhanced delivery catheter (SmartFlowTM NGS-NC-03 from MRI Interventions, a step end-port catheter, SEPC) in current use in clinical trials. The studies were in vivo in porcine brain. A total of 8 pigs were used: the size of the pig brain limited the porous length to 15 mm. The placements of the tips of the two catheters were chosen to be the same (at the respective brain hemispheres). RESULTS: The PBIC and SEPC both performed comparably and well, with the PBIC having some advantage in effecting larger distributions: p ∼ 0.045, with 5 infusions from each. CONCLUSIONS: Given the performance of the PBIC, it would be highly appropriate to use the device for therapeutic infusions in human clinical trials to assess its capability for large-volume infusions.

Hypertonic saline reduces intracranial hypertension in the presence of high serum and cerebrospinal fluid osmolalities.

BACKGROUND: Osmotherapy has been the cornerstone in the management of patients with elevated intracranial pressure (ICP) following traumatic brain injury (TBI). Several studies have demonstrated that hypertonic saline (HTS) is a safe and effective osmotherapy agent. This study evaluated the effectiveness of HTS in reducing intracranial hypertension in the presence of a wide range of serum and cerebrospinal fluid (CSF) osmolalities. METHODS: Forty-two doses of 23.4% saline boluses for treatment of refractory intracranial hypertension were reviewed retrospectively. Thirty milliliters of 23.4% NaCl was infused over 15 min for intracranial hypertension, defined as ICP >20 mmHg. The CSF and serum osmolalities from frozen stored samples were measured with an osmometer. The values of serum sodium, hourly ICP, blood urea nitrogen (BUN), and creatinine were obtained directly from the medical records. RESULTS: The serum and CSF osmolalities correlated very closely to serum sodium (r > 0.9, P < 0.0001). The reduction in ICP from the baseline (measured from either the mean ICP or the lowest ICP measurement in the first 6 h after bolus HTS treatment) was statistically significant regardless of serum osmolality. The mean reduction from baseline to follow-up values was 8.8 mm Hg (P < 0.0001). The decrease in ICP was as evident with serum osmolalities >320 as it was at ≤320. CONCLUSION: This study demonstrates that 23.4% HTS bolus is effective for the reduction of elevated ICP in patients with severe TBI even in the presence of high serum and CSF osmolalities.

Novel In Situ Collection of Tumor Interstitial Fluid from a Head and Neck Squamous Carcinoma Reveals a Unique Proteome with Diagnostic Potential.

INTRODUCTION: Tumors lack normal drainage of secreted fluids and consequently build up tumor interstitial fluid (TIF). Unlike other bodily fluids, TIF likely contains a high proportion of tumor-specific proteins with potential as biomarkers. METHODS: Here, we evaluated a novel technique using a unique ultrafiltration catheter for in situ collection of TIF and used it to generate the first catalog of TIF proteins from a head and neck squamous cell carcinoma (HNSCC). To maximize proteomic coverage, TIF was immunodepleted for high abundance proteins and digested with trypsin, and peptides were fractionated in three dimensions prior to mass spectrometry. RESULTS: We identified 525 proteins with high confidence. The HNSCC TIF proteome was distinct compared to proteomes of other bodily fluids. It contained a relatively high proportion of proteins annotated by Gene Ontology as "extracellular" compared to other secreted fluid and cellular proteomes, indicating minimal cell lysis from our in situ collection technique. Several proteins identified are putative biomarkers of HNSCC, supporting our catalog's value as a source of potential biomarkers. CONCLUSIONS: In all, we demonstrate a reliable new technique for in situ TIF collection and provide the first HNSCC TIF protein catalog with value as a guide for others seeking to develop tumor biomarkers. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12014-010-9050-3) contains supplementary material, which is available to authorized users.

Surgical debridement and adjunctive hyperbaric oxygen in cervical necrotizing fasciitis.

OBJECTIVE: To review our management of cervical necrotizing fasciitis (CNF) with the use of adjunctive hyperbaric oxygen therapy (HBO). STUDY DESIGN: Case series with chart review. SUBJECTS AND METHODS: Evaluation of ten patients with CNF between 2001 to 2006. RESULTS: There were five male and six female patients. Mean age was 43 +/- 11 years. Eight cases resulted from an odontogenic source. Comorbidities included diabetes mellitus, hypertension, and substance abuse. All patients had computed tomography scans performed, received intravenous antibiotics, and underwent surgical debridement. Eight patients underwent surgery within 24 hours. The average number of debridements was 2.2 +/- 0.8. Hospitalization was twice as long for diabetic patients (15.5 +/- 8.16 days) compared with nondiabetic patients (7.5 +/- 1.6 days, P = 0.029). Nine patients had HBO therapy. Combined data revealed a possible decrease in length of hospitalization with HBO therapy (P < 0.001). No mortality was documented. CONCLUSION: In addition to early and aggressive medical management and surgical debridement, this study suggests that HBO therapy is a beneficial adjunct by potentially decreasing length of hospitalization. Randomized trials are still needed to demonstrate its efficacy.

Diagnosis and treatment of deep neck space abscesses.

OBJECTIVE: To review our experience with deep neck abscesses and identify unique trends in our patient population. STUDY DESIGN: Case series with chart review. SUBJECTS AND METHODS: Evaluation of patients with deep neck space abscesses between 2001 and 2006. Peritonsillar abscess, superficial craniocervical infection, and salivary gland infections were excluded from selection of study population. A total of 106 cases were reviewed. RESULTS: Dental infections were the most common cause of deep neck abscesses (49.1%). Comorbidities included substance abuse (53.7%), psychiatric illness (10.4%), hypertension (9.4%), head and neck cancer (6.6%), and diabetes mellitus (5.7%). All patients received systemic antibiotics, eight patients required tracheotomy, 85 patients underwent surgical drainage in the operating room, and 11 had bedside drainage. Median and lower quartile of time in hospital was 2 and 3 days, respectively, whereas upper quartile was 4 days (range, 1 to 27 days). Patients with comorbidities or concurrent illness tended to stay longer (P<0.05, Mann-Whitney test). There were six complications and no mortality. CONCLUSION: Substance abuse and poor orodental hygiene are important predisposing factors to deep neck abscesses. Appropriate management continues to favor a combination of early surgical drainage and systemic antibiotics.

Theory of porous catheters and their applications in intraparenchymal infusions.

Multiport catheters and catheters with a porous surface have been proposed for intraparenchymal infusions of therapeutics in fluid suspensions. Target diseases include brain cancer and serious neurodegenerative diseases, as well as peripheral tumors, for example in the prostate and the liver. We set up the theory for infusions from such devices, in particular the fluid flow equations which demand a coupling between the flow within the catheter and that in tissue. (Such a coupling is not necessary in the theory of infusion from single port catheters.) The new feature of such catheters, treated by our model, is revealed by infusions into inhomogeneous media. Multiport designs have the potential to overcome the limitation of single port catheters, for which the path of the fluid leaving the port is dominated by the inhomogeneities. We solve these equations for some simple cases to illustrate the key design features of porous catheters that show such advantages. The mathematics required for numerical solution with more realistic assumptions is also developed. We confirm the robustness of such catheters, when the ports are sufficiently resistive, against leakage paths that would compromise the infusions from catheters with one or a few large ports. The methods of this paper can be incorporated into a larger planning system for intraparenchymal infusions involving such devices.

Computed tomography scan does not correlate with patient experience of nasal obstruction.

OBJECTIVES/HYPOTHESIS: Third-party payors have begun to demand imaging studies to document septal deviation prior to authorizing septoplasties. This study aims to determine whether septal deviation findings on computed tomography (CT) correlate with symptoms of nasal obstruction as determined by the Nasal Obstruction Symptom Evaluation (NOSE) scale. STUDY DESIGN: Prospective and retrospective chart review. METHODS: Patients 18 years or older undergoing CT scans, which included the nasal septum, were asked to complete a NOSE scale survey and report the laterality of any possible obstruction. Coronal CT images of subjects were graded by two blinded otolaryngologists and two blinded neuroradiologists using a grading system devised by the authors. RESULTS: Seventy-three subjects met inclusion/exclusion criteria. Interobserver reliability about the degree of septal deviation on CT scans was moderately good to substantial (κ values, 0.43 to 0.72). There was poor correlation between NOSE scores and degree of deviation on CT scans (Kendall's τ, 0.031 to 0.045; P values all >.05). There was poor concordance between the side of symptoms that patients reported and the side that observers thought was most deviated on CT. CONCLUSIONS: There is little correlation between septal deviation findings on CT scans and symptoms of nasal obstruction. The results do not support a role for CT scans as either a clinically meaningful or necessary test to investigate uncomplicated nasal obstruction. LEVEL OF EVIDENCE: 4.

Effect of tissue ultrafiltration on skin flap survival.

OBJECTIVE: Tissue ultrafiltration (TUF) is a method of reducing tissue edema by removal of interstitial fluid. Considering the deleterious effects of edema on microcirculation and tissue viability, the effect of TUF on skin flap survival was tested. STUDY DESIGN AND SETTING: Survival of modified McFarlane skin flaps was determined in 40 Sprague-Dawley rats. In 20 treated animals, four 5-cm ultrafiltration catheters were placed in the subdermal plane of the distal flap 24 hours after flap elevation and connected to a down-regulated vacuum manifold for 8 hours. No catheters were placed in the control group. RESULTS: Skin flap survival was improved in the experimental group (87.2 +/- 1.6) over the control group (76.7 +/- 2.2). DISCUSSION: TUF effectively improved skin flap survival. These results provide evidence of the causal effect of edema on tissue viability. The relative ease of use of TUF would allow cost-effective clinical application of this technique.

The effect of capillary ultrafiltration probes on skin flap edema.

OBJECTIVE: Edema clearly has deleterious effects on the microcirculation and, consequently, cell viability. Prior work from this laboratory demonstrated that hyperosmolar microdialysis can reduce tissue edema, but this method is technically challenging. A new, simpler technique of microdialysis using capillary ultrafiltration probes (CUPs) has been studied to determine if CUP microdialysis is as effective in reducing tissue edema in the same animal model. METHODS: Twenty-four Sprague-Dawley rats were studied using a modified McFarlane skin flap. Microdialysis was accomplished using a catheter constructed of four 4-cm hollow fibers that were connected to polyethylene tubing. Catheters on the experimental side of the flap were attached to a vacuum manifold for 8 hours. The control side was treated in 2 ways. In group 1, catheters were placed but not applied to suction. In group 2, no catheters are placed on the control side. Tissue water content was determined by a biopsy-drying technique. RESULTS: Tissue water content was significantly reduced (by paired t test) in both groups by a mean of 3.2 mL/100 g of wet tissue. CONCLUSION: CUP microdialysis reduced tissue water content as effectively as did hyperosmolar microdialysis, but in a simpler and therefore more cost-effective method. The technique could be easily adapted for clinical application.

Estimation of perilymph concentration of agents applied to the round window membrane by microdialysis.

OBJECTIVE: The round window membrane (RWM) is known to be permeable to various biological substances. Application of biological substances to the RWM has been shown to affect inner ear fluid composition and damage hair cells, resulting in functional changes RWM instillation of gentamicin, a preferentially vestibulotoxic aminoglycoside, is used as a therapeutic treatment for patients with intractable vertigo and is gaining acceptance as a chemical vestibular ablation agent, despite considerable variations in the incidence and severity of hearing loss associated with gentamicin. Clearly, the susceptibility of vestibular and auditory hair cells to the ototoxic effects of gentamicin is not well understood. The aim of this study was to understand the kinetics of urea and methylene blue instilled into the inner ear space through the RWM and to establish a method for determining the optimal dosage for the treatment of inner ear disorders. MATERIAL AND METHODS: We used inner ear microdialysis to quantify changes in perilymph concentration of low molecular weight agents applied to the RWM in a chinchilla model. RESULTS: Preliminary results after placement of a microdialysis probe and application of a low molecular weight marker (urea) to the RWM were extrapolated from a time versus concentration plot from dialysates sampled over a 3-min interval using modifications of standard microdialysis equations for estimation of in vivo recovery. Our data suggest that inner ear microdialysis can be used to measure the pharmacokinetics of a low molecular weight agent within the perilymphatic space without the need for repeated direct sampling. CONCLUSION: Inner ear microdialysis may be a useful method for establishing a therapeutic dosage for ototoxic agents used in the treatment of inner ear disorders.

Morbidity and cost of odontogenic infections.

OBJECTIVE: Cost analysis of deep neck space infections from odontogenic origin and review of the morbidity of potentially preventable complications. STUDY DESIGN: Case series with chart review. SETTING: Level 1 trauma center and academic safety net hospital. SUBJECTS AND METHODS: Patients treated for deep neck space infections due to an odontogenic source between 2001 and 2010 were reviewed. Two hundred patients were included in the study. Ninety-eight patients required inpatient admission. Twelve percent of these patients had difficult airways, and 16% had at least 1 day in the intensive care unit. Cost data were available only for the later 3.5 years of the study period. RESULTS: The overall cost of treatment for these 71 individuals exceeded $1.1 million. CONCLUSION: The cost of treatment for odontogenic infections is staggering. Based on assumptions of the percentage of infections in the metropolitan area captured at Hennepin County Medical Center, extrapolation to the total national cost of inpatient care approaches $200 million annually. This study highlights the importance of access to medical and preventative dental care for the general population and demonstrates the cost benefit that could be achieved through prevention of disease and, therefore, avoidance of its complications.

Efficacy of reductive ventricular osmotherapy in a swine model of traumatic brain injury.

BACKGROUND: The presence of osmotic gradients in the development of cerebral edema and the effectiveness of osmotherapy are well recognized. A modification of ventriculostomy catheters described in this article provides a method of osmotherapy that is not currently available. The reductive ventricular osmotherapy (RVOT) catheter removes free water from ventricular cerebrospinal fluid (CSF) by incorporating hollow fibers that remove water vapor, thereby providing osmotherapy without increasing osmotic load. OBJECTIVE: To increase osmolarity in the ventricular CSF through use of RVOT in vivo. METHODS: Twelve Yorkshire swine with contusional injury were randomized to external ventricular drainage (EVD) or RVOT for 12 hours. MR imaging was obtained. Serum, CSF, and brain ultrafiltrate were analyzed. Histology was compared using Fluor-Jade B and hematoxylin and eosin (H & E) stains. RESULTS: With RVOT, CSF osmolality increased from 292 ± 2.7 to 345 ± 8.0 mOsmol/kg (mean ± SE, P = 0.0006), and the apparent diffusion coefficient (ADC) in the injury region increased from 0.735 ± 0.047 to 1.135 ± .063 (P = 0.004) over 24 hours. With EVD controls, CSF osmolarity and ADC were not significantly changed. Histologically, all RVOT pigs showed no evidence of neuronal degeneration (Grade 1/4) compared to moderate degeneration (Grade 2.6 ± .4/4) seen in EVD treated animals (P = 0.02). The difference in intracranial pressure (ICP) by area under the curve approached significance at P = .065 by Mann Whitney test. CONCLUSION: RVOT can increase CSF osmolarity in vivo after experimental traumatic brain injury (TBI). In anticipated clinical use, only a slight increase in CSF osmolarity may be required to reduce cerebral edema.

Implanted upper airway stimulation device for obstructive sleep apnea.

OBJECTIVES/HYPOTHESIS: Previous feasibility studies have shown that electrical stimulation of the hypoglossal nerve can improve obstructive sleep apnea (OSA). The current study examined the safety and preliminary effectiveness of a second generation device, the Upper Airway Stimulation (UAS) system, and identified baseline predictors for therapy success. STUDY DESIGN: Two consecutive open prospective studies. METHODS: UAS systems were implanted in patients with moderate to severe OSA who failed or were intolerant of continuous positive airway pressure (CPAP). The study was conducted in 2 parts. In part 1, patients were enrolled with broad selection criteria. Apnea hypopnea index (AHI) was collected using laboratory-based polysomnography at preimplant and postimplant visits. Epworth Sleepiness Scale (ESS) and Functional Outcomes of Sleep Questionnaire (FOSQ) were also collected. In part 2, patients were enrolled using selection criteria derived from the experience in part 1. RESULTS: In part 1, 20 of 22 enrolled patients (two exited the study) were examined for factors predictive of therapy response. Responders had both a body mass index ≤32 and AHI ≤50 (P < .05) and did not have complete concentric palatal collapse. Part 2 patients (n = 8) were selected using responder criteria and showed an improvement on AHI from baseline, from 38.9 ± 9.8 to 10.0 ± 11.0 (P < .01) at 6 months postimplant. Both ESS and FOSQ improved significantly in part 1 and 2 subjects. CONCLUSIONS: The current study has demonstrated that therapy with upper airway stimulation is safe and efficacious in a select group of patients with moderate to severe OSA who cannot or will not use CPAP as primary treatment.

Compartment syndrome ultrafiltration catheters: report of a clinical pilot study of a novel method for managing patients at risk of compartment syndrome.

OBJECTIVES: To demonstrate that tissue ultrafiltration catheters are safe to place and use in an injured lower extremity, measure tissue pressures as well as the current standard of care, and effectively remove interstitial fluid for analysis of biomarkers. DESIGN: Institutional Review Board-approved, prospective pilot study. SETTING: Metropolitan Level I trauma center. PATIENTS: All patients who presented to the emergency department with a tibial fracture met the inclusion and exclusion criteria and gave informed consent were enrolled. A total of 10 patients were studied. INTERVENTION: All subjects were treated with two types of percutaneous intramuscular catheters in both the anterior and deep posterior compartments of the leg for 24 hours. One catheter was a conventional indwelling intramuscular pressure catheter (Stryker Quick Pressure Monitor, Kalamazoo, MI), whereas the other was an experimental combined pressure monitoring/tissue ultrafiltration catheter (Compartment Monitoring System [CMS] catheter; Twin Star Medical, Inc, Minneapolis, MN). MAIN OUTCOME MEASUREMENTS: Safety of device, intramuscular pressure values, and quantity of fluid removed (from CMS catheter only). RESULTS: No serious device-related complications occurred. There was reasonable correlation between the pressures measured by the CMS and Stryker catheters. Average decrease in intramuscular pressure from baseline to final pressure was 11.3 ± 2.8 mm Hg in the anterior compartment (P = 0.003 by two-tailed paired t test) and 5.9 ± 1.4 mm Hg in the deep posterior compartment (P = 0.01). Ultrafiltrate analysis revealed that lactate dehydrogenase and creatine kinase levels were markedly elevated over serum levels. No patient needed fasciotomy or developed compartment syndrome during the study period. CONCLUSIONS: This pilot study of CMS catheters demonstrates safety of CMS catheter use. Assay of the ultrafiltrate may provide greater sensitivity to muscle injury; further research of this approach is warranted.

The effect of reductive ventricular osmotherapy on the osmolarity of artificial cerebrospinal fluid and the water content of cerebral tissue ex vivo.

The purpose of this study was to explore a novel treatment involving removal of free water from ventricular cerebrospinal fluid (CSF) for the reduction of cerebra]l edema. The hypothesis is that removal of free water from the CSF will increase the osmolarity of the CSF, which will favor movement of tissue-bound water into the ventricles, where the water can be removed. Reductive ventricular osmotherapy (RVOT) was tested in a flowing solution of artificial CSF (aCSF) with two end-points: (1) the effect of RVOT on osmolarity of the CSF, and (2) the effect of RVOT on water content of ex vivo cerebral tissue. RVOT catheters are made up of membranes permeable only to water vapor. When a sweep gas is drawn through the catheter, free water in the form of water vapor is removed from the solution. With RVOT treatment, aCSF osmolarity increased from a baseline osmolarity of 318.8 ± 0.8 mOsm/L to 339.0 ± 3.3 mOsm/L (mean ± standard deviation) within 2 h. After 10 h of treatment, aCSF osmolarity approached an asymptote at 344.0 ± 4.2 mOsm/L, which was significantly greater than control aCSF osmolarity (p <<0.001 by t-test, n = 8). Water content at the end of 6 h of circulating aCSF exposure was 6.4 ± 0.9 g H2O (g dry wt)⁻¹ in controls, compared to 6.1 ± 0.7 g H2O (g dry wt)⁻ after 6 h of RVOT treatment of aCSF (p = 0.02, n = 24). The results support the potential of RVOT as a treatment for cerebral edema and intracranial hypertension.

A preliminary theoretical model of hydrodynamics in the inner ear.

Head movement should create a transient pressure imbalance across the membranous inner ear. We used basic concepts of fluid dynamics to develop a theoretical model of the inner ear. According to this model, two contiguous fluidic systems-the perilymphatic system and the endolymphatic system-are in hydrostatic equilibrium across a compliant membrane. Our model demonstrates that changes in resistance or compliance in one system results in a transient distortion of the membranous inner ear until equilibrium between the two systems is restored. The concept of hydrodynamic pressure changes in the inner ear has received little attention, but it may represent a new approach to understanding the inner ear and treating inner ear diseases.

Interstitial delivery of vascular endothelial growth factor to skin flaps.

OBJECTIVES: To demonstrate the feasibility of using microporous catheters to deliver a growth factor in a skin flap model, and to determine whether removal of excess fluid by ultrafiltration catheters reduces edema. METHODS: In a controlled study at a research laboratory associated with major teaching hospital, vascular endothelial growth factor was delivered to porcine skin flaps by direct infusion using hollow fiber catheters. Treated flaps received either infusion alone or infusion and ultrafiltration via hollow fibers inserted into the distal portion of the flap. Controls had neither type of catheter placed. The main outcome measure was flap survival and edema. RESULTS: Treated anterior flaps were found to have increased survival (mean [SD] increase, 49.9% [9.4%]) compared with control flaps (44.1% [4.5%]) for group (P = .005) and side (P = .01) but not by interaction (P = .14). Water content was significant by analysis of variance for group, position, and interaction (all P < .001, df = 31) for treated (55.3% [9.7%]) and control (61.9% [8.2%]) groups. CONCLUSIONS: This study demonstrated feasibility of using hollow fiber technology to deliver a growth factor to skin flaps. Further study may yield clinical applications for human patients undergoing reconstructive procedures.