Straws Don't Suck: Are Straws Dangerous after Endoscopic Skull Base Surgery?

Objective Patients undergoing endoscopic endonasal surgery have historically been restricted from using straws postoperatively, due to the concern that this activity generates negative pressure. The objective of this study is to evaluate the pressure dynamics in the sinonasal cavity associated with the use of a straw. Methods Intracranial pressure catheters were placed in the nasal cavity of 20 healthy individuals. Pressure measurements were then recorded while participants drank liquids of different viscosities from a cup and from a straw. Measurements were recorded with and without subjects occluding their nose to simulate postoperative nasal obstruction. Results The average pressure in the nasal cavity while drinking water from a cup was -0.86 cmH 2 O, from a straw was -1.09 cmH 2 O, and while occluding the nose and using a straw was -0.81 cmH 2 O. The average pressure in the nasal cavity while drinking a milkshake from a cup was -0.98 cmH 2 O, from a straw was -1.88 cmH 2 O, and while occluding the nose and using a straw was -1.37 cmH 2 O. There was no statistically significant difference in pressure measurements when comparing either task or consistency ( p > 0.05). Conclusion Straw use is not associated with the generation of significant negative pressure in the nasal cavity. The pressure generated when drinking from a straw is not significantly different from that of drinking from a cup. This data suggest that straw use may be safe for patients following endoscopic skull base surgery, but further investigation is warranted.

Tolerance of Continuous Positive Airway Pressure After Sinonasal Surgery.

OBJECTIVES/HYPOTHESIS: For patients with obstructive sleep apnea (OSA) undergoing sinonasal surgery, there is a lack of consensus on the risk and appropriate postoperative use of continuous positive airway pressure (CPAP). The aim of this study was to assess the tolerability of restarting CPAP on postoperative day one. STUDY DESIGN: Prospective cohort study. METHODS: A prospective study on patients with OSA on CPAP who required a septoplasty/turbinectomy and/or functional endoscopic sinus surgery (FESS) was performed. Data from the memory card of a patient's CPAP machine and subjective information were obtained on the day of surgery and at scheduled follow-up visits. All subjects were instructed to restart CPAP on the first postoperative night. RESULTS: A total of 14 patients were analyzed; nine underwent FESS and five had a septoplasty/turbinectomy. There were no postoperative complications encountered. The only significant change in the first postoperative week was a reduction in the percentage of nights used over 4 hours (P < .05). By the third postoperative visit, average 22-item Sino-Nasal Outcome Test, Nasal Obstruction Symptom Evaluation, and CPAP tolerance scores improved from preoperative values. CPAP pressures, residual apnea-hypopnea index, and number of hours and mean percentage of nights used remained stable throughout the study period. CONCLUSIONS: Both quality-of-life and CPAP outcomes improved or remained the same when restarting CPAP immediately postoperatively. Combined with a lack of significant complications, this study suggests that CPAP is well-tolerated when restarted the day after a septoplasty/turbinectomy or FESS. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E1013-E1018, 2021.

Qualitative Assessment of the Effect of Continuous Positive Airway Pressure on the Nasal Cavity.

BACKGROUND: For patients with obstructive sleep apnea (OSA), there is a lack of knowledge regarding the impact of continuous positive airway pressure (CPAP) on the nasal cavity. There is a significant need for evidence-based recommendations regarding the appropriate use of CPAP following endoscopic sinus and skull base surgery. OBJECTIVE: The goal of this study is to translate a previously developed cadaveric model for evaluating CPAP pressures in the sinonasal cavity by showing safety in vivo and quantifying the effect of positive pressurized air flow on the nasal cavity of healthy individuals where physiologic effects are at play. METHODS: A previously validated cadaveric model using intracranial sensor catheters has proved to be a reliable technique for measuring sinonasal pressures. These sensors were placed in the nasal cavity of 18 healthy individuals. Pressure within the nose was recorded at increasing levels of CPAP. RESULTS: Overall, nasal cavity pressure was on average 85% of delivered CPAP. The amount of pressure delivered to the nasal cavity increased as the CPAP increased. The percentage of CPAP delivered was 77% for 5 cmH2O and increased to 89% at 20 cmH2O. There was a significant difference in mean intranasal pressures between all the levels of CPAP except 5 cmH2O and 8 cmH2O (P < .001). CONCLUSION: On average, only 85% of the pressure delivered by CPAP is transmitted to the nasal cavity. Higher CPAP pressures delivered a greater percentage of pressurized air to the nasal cavity floor. Our results are comparable to the cadaver model, which demonstrated similar pressure delivery even in the absence of anatomic factors such as lung compliance, nasal secretions, and edema. This study demonstrates the safety of using sensors in the human nasal cavity. This technology can also be utilized to evaluate the resiliency of various repair techniques for endoscopic skull base surgery with CPAP administration.

Rate of rhinosinusitis and sinus surgery following a minimally destructive approach to endoscopic transsphenoidal hypophysectomy.

BACKGROUND: There remains considerable variation in the extent of sinonasal preservation during the approach for endoscopic transsphenoidal hypophysectomy (TSH). We advocate for a minimally destructive approach utilizing turbinate lateralization, small posterior septectomy, no ethmoidectomy, and preservation of nasoseptal flap (NSF) pedicles bilaterally. Due to these factors, this approach may affect the rates of postoperative rhinosinusitis. The objective of this study is to define the rates of postoperative rhinosinusitis in patients undergoing this approach. METHODS: Single institution, retrospective chart review of patients undergoing TSH from 2005 to 2018. RESULTS: A total of 415 patients were identified and 14% developed an episode of postoperative rhinosinusitis within 3 months. These patients were significantly more likely to have had a history of recurrent acute or chronic rhinosinusitis. Most cases were sphenoethmoidal sinusitis managed with 1 to 2 courses of antibiotics. Of patients with postoperative rhinosinusitis, most did not undergo NSF. Average follow-up was 38 months. Six patients (1.4%) underwent post-TSH functional endoscopic sinus surgery (FESS). Average time from TSH to FESS was 26.3 months. Two of these patients had a history of prior chronic rhinosinusitis without polyposis. Two patients underwent revision TSH for recurrent tumor as the primary indication for surgery at time of FESS. Twenty-two-item Sino-Nasal Outcome Test (SNOT-22) scores generally increased immediately postoperatively, but frequently decreased below preoperative level by the time of last follow-up, regardless of whether patients developed rhinosinusitis. CONCLUSION: Sinonasal preservation during TSH is associated with a low rate of postoperative rhinosinusitis requiring FESS and excellent long-term patient reported outcomes. We continue to advocate for sinonasal preservation during pituitary surgery.

Adenosine-induced transient hypotension for carotid artery injury during endoscopic skull-base surgery: case report and review of the literature.

BACKGROUND: As the management of ventral skull-base pathology has transitioned from open to endonasal treatment, there has been an increased focus on the prevention and endoscopic endonasal management of internal carotid artery (ICA) and major vascular injury. The use of adenosine to induce transient hypotension or flow arrest has been previously described during intracranial aneurysm surgery; however, there have been no reports of the technique being used during endonasal skull-base surgery to achieve hemostasis following major vascular injury. METHODS: Case report (n = 1) and literature review. RESULTS: A 25-year-old female underwent attempted endoscopic endonasal resection of an advanced right-sided chondrosarcoma. During resection of the tumor, brisk arterial bleeding was encountered consistent with focal injury to the right cavernous ICA. Stable vascular hemostasis could not be achieved with tamponade. An intravenous bolus dose of adenosine was administered to induce a transient decrease in systemic blood pressure and facilitate placement of the muscle patch over the direct site of vascular injury. The patient subsequently underwent endovascular deconstruction of the right ICA. CONCLUSION: This is the first reported use of adenosine to induce transient hypotension for a major vascular injury sustained during endonasal skull-base surgery. Based on well-established safety data from neurosurgical application, adenosine has the potential to be used as a safe and effective adjunctive technique in similar endonasal circumstances and may represent an additional tool in the armamentarium of the skull-base surgeon. Surgeons should consider having adenosine available when a risk of ICA injury is anticipated.

Combined Dietary Nitrate and Exercise Intervention in Peripheral Artery Disease: Protocol Rationale and Design.

BACKGROUND: Peripheral artery disease (PAD) is caused by atherosclerotic occlusions in the legs. It affects approximately 8-12 million people in the United States alone, one-third of whom suffer from intermittent claudication (IC), defined as ischemic leg pain that occurs with walking and improves with rest. Patients with IC suffer a markedly impaired quality of life and a high perception of disability. Improving pain-free walking time is a primary goal of rehabilitation in this population. OBJECTIVE: The nitric oxide (NO)-PAD trial is designed to compare the effects that 12 weeks of supervised exercise training, in combination with a high inorganic nitrate-content (beetroot [BR] juice) beverage or placebo (PL) beverage, has on clinical outcomes of exercise and functional capacity in two groups of PAD+IC patients: exercise training plus beetroot (EX+BR) and exercise training plus placebo (EX+PL). The primary aims of this randomized controlled, double-blind pilot study are to determine group differences following 12 weeks of EX+BR versus EX+PL in the changes for (1) exercise capacity: pain-free walking time (claudication onset time, COT), peak walk time (PWT), and maximal exercise capacity (peak oxygen uptake, VO2peak) during a maximal-graded cardiopulmonary exercise test (max CPX) and (2) functional capacity: 6-minute walk (6MW) distance. The secondary aims will provide mechanistic insights into the exercise outcome measures and will include (1) gastrocnemius muscle oxygenation during exercise via near-infrared spectroscopy (NIRS); (2) gastrocnemius muscle angiogenesis: capillaries per unit area and per muscle fiber, and relative fraction of type I, IIa, IIb, and IId/x fibers; and (3) vascular health/function via brachial artery flow-mediated dilation, lower-limb blood flow via plethysmography, and pulse wave velocity and reflection. METHODS: A total of 30 subjects between 40 and 80 years of age with PAD who are limited by IC will undergo exercise training 3 days per week for 12 weeks (ie, 36 sessions). They will be randomized to either the EX+BR or EX+PL group where participants will consume a beverage high in inorganic nitrate (4.2 mmol) or a low-nitrate placebo, respectively, 3 hours prior to each training session. RESULTS: Data collection from this study has been completed and is in the process of analysis and write-up. While the study is too underpowered-EX+BR, n=11; EX+PL, n=13-to determine between-group differences in the primary outcomes of COT, PWT, and 6MW, preliminary observations are promising with Cohen d effect sizes of medium to large. CONCLUSIONS: Exercise training is currently the most effective therapy to increase functional capacity in PAD+IC. If the addition of inorganic nitrate to an exercise regimen elicits greater benefits, it may redefine the current standard of care for PAD+IC. TRIAL REGISTRATION: ClinicalTrials.gov NCT01684930; https://clinicaltrials.gov/ct2/show/NCT01684930 (Archived by WebCite at http://www.webcitation.org/6raXFyEcP).

A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer.

Local recurrence is a common cause of treatment failure for patients with solid tumors. Intraoperative detection of microscopic residual cancer in the tumor bed could be used to decrease the risk of a positive surgical margin, reduce rates of reexcision, and tailor adjuvant therapy. We used a protease-activated fluorescent imaging probe, LUM015, to detect cancer in vivo in a mouse model of soft tissue sarcoma (STS) and ex vivo in a first-in-human phase 1 clinical trial. In mice, intravenous injection of LUM015 labeled tumor cells, and residual fluorescence within the tumor bed predicted local recurrence. In 15 patients with STS or breast cancer, intravenous injection of LUM015 before surgery was well tolerated. Imaging of resected human tissues showed that fluorescence from tumor was significantly higher than fluorescence from normal tissues. LUM015 biodistribution, pharmacokinetic profiles, and metabolism were similar in mouse and human subjects. Tissue concentrations of LUM015 and its metabolites, including fluorescently labeled lysine, demonstrated that LUM015 is selectively distributed to tumors where it is activated by proteases. Experiments in mice with a constitutively active PEGylated fluorescent imaging probe support a model where tumor-selective probe distribution is a determinant of increased fluorescence in cancer. These co-clinical studies suggest that the tumor specificity of protease-activated imaging probes, such as LUM015, is dependent on both biodistribution and enzyme activity. Our first-in-human data support future clinical trials of LUM015 and other protease-sensitive probes.

Cost-effective analysis of unilateral vestibular weakness investigation.

OBJECTIVES: To evaluate the cost-effectiveness of obtaining a magnetic resonance imaging (MRI) in patients with abnormal electronystagmography (ENG) or videonystagmography (VNG) results. STUDY DESIGN: Retrospective chart review. SETTINGS: Academic specialty center. PATIENTS: Patients presenting with vertigo between January 1, 2010, and August 30, 2013. METHODS: Patients who fit the following abnormal criteria were included in the study: unilateral caloric weakness (≥20%), abnormal ocular motor testing, and nystagmus on positional testing. Patients with abnormal findings who then underwent MRI with gadolinium were evaluated. RESULTS: Of the 1,996 charts reviewed, there were 1,358 patients who met the inclusion criteria. The average age of these patients was 62 years (12-94 yr). The male:female ratio was approximately 1:2. Of the 1,358 patients, 253 received an MRI with the following pathologies: four vestibular schwannomas, three subcortical/periventricular white matter changes suspicious for demyelinating disease, four acute cerebellar/posterior circulation infarct, two vertebral artery narrowing, one pseudomeningocele of internal auditory canal, and two white matter changes indicative of migraines. The positive detection rate on MRI was 5.5% based on MRI findings of treatable pathologies causing vertigo. Average cost of an MRI is $1,200, thereby making the average cost of identifying a patient with a positive MRI finding $15,180. CONCLUSION: In our study, those patients with a positive MRI had a constellation of symptoms and findings (asymmetric sensorineural hearing loss, tinnitus, vertigo, and abnormal ENG/VNG). Cost-effectiveness can be improved by ordering an MRI only when clinical examination and VNG point toward a central pathology. Clinical examination and appropriate testing should be factored when considering the cost-effectiveness of obtaining an MRI in patients with abnormal ENG/VNG findings.

ClinicalTrials.gov reporting: strategies for success at an academic health center.

The Food and Drug Administration Amendments Act of 2007 (FDAAA 2007, US Public Law 110-98) mandated registration and reporting of results for applicable clinical trials. Meeting these registration and results reporting requirements has proven to be a challenge for the academic research community. Duke Medicine has made compliance with registration and results reporting a high priority. In order to create uniformity across a large institution, a written policy was created describing requirements for clinical trials disclosure. Furthermore, a centralized resource group was formed with three full time staff members. The group not only ensures compliance with FDAAA 2007, it also acts as a resource for study teams providing hands-on support, reporting, training, and ongoing education. Intensive resourcing for results reporting has been crucial for success. Due to implementation of the institutional policy and creation of centralized resources, compliance with FDAAA 2007 has increased dramatically at Duke Medicine for both registration and results reporting. A consistent centralized approach has enabled success in the face of changing agency rules and new legislation.

Recommendations from the Investigational New Drug/Investigational Device Exemption Task Force of the clInical and Translational Science Award Consortium: developing and implementing a sponsor-investigators training program.

OBJECTIVE: The objective of this study was to provide recommendations for provision of training for sponsor and investigators at Academic Health Centers. BACKGROUND: A subgroup of the Investigational New Drug/Investigational Device Exemption (IND/IDE) Task Force of the Clinical and Translational Science Award (CTSA) program Regulatory Knowledge Key Function Committee was assembled to specifically address how clinical investigators who hold an IND/IDE and thus assume the role of sponsor-investigators are adequately trained to meet the additional regulatory requirements of this role. METHODS: The participants who developed the recommendations were representatives of institutions with IND/IDE support programs. Through an informal survey, the task force determined that a variety and mix of models are used to provide support for IND/IDE holders within CTSA institutions. In addition, a CTSA consortium-wide resources survey was used. The participants worked from the models and survey results to develop consensus recommendations to address institutional support, training content, and implementation. RECOMMENDATIONS: The CTSA IND/IDE Task Force recommendations are as follows: (1) Institutions should assess the scope of Food and Drug Administration-regulated research, perform a needs analysis, and provide resources to implement a suitable training program; (2) The model of training program should be tailored to each institution; (3) The training should specifically address the unique role of sponsor-investigators, and the effectiveness of training should be evaluated regularly by methods that fit the model adopted by the institution; and (4) Institutional leadership should mandate sponsor-investigator training and effectively communicate the necessity and availability of training.

Warning letters to sponsor-investigators at academic health centres - the regulatory "canaries in a coal mine".

PURPOSE: This study highlights Warning Letter (WL) findings issued to sponsor-investigators (S-Is) by the Food and Drug Administration (FDA). METHODS: The online index of WLs issued from October 1, 2007 through September 30, 2012 was reviewed [1]. Through a manual screening process, letters were evaluated if specifically issued to 'clinical investigators', 'sponsors' or 'sponsor-investigators'. A particular focus was given to S-Is at Academic Health Centres (AHCs). Each letter was scored for the presence of violations in 40 general regulatory categories. RESULTS: A review of FDA WLs issued over a five-year period (FDA Fiscal Years 2008-2012) revealed that WLs to S-Is represent half of the WLs issued to all sponsors (16 of 32 letters). A review of these letters indicates that S-Is are not aware of, or simply do not meet, their regulatory responsibilities as either investigators or sponsors. In comparing total sponsor letters to those of S-Is, the most cited violation was the same: a lack of monitoring. A review of publicly available inspection data indicates that these 16 letters merely represent the tip of the iceberg. CONCLUSION: This review of the WL database reveals the potential for serious regulatory violations among S-Is at AHCs. Recent translational funding initiatives may serve to increase the number of S-Is, especially among Academic Health Centres (AHCs) [2]; thus, AHCs must become aware of this S-I role and work to support investigators who assume both roles in the course of their research.

Cutaneous endothelin-A receptors elevate post-incisional pain.

The contribution of endothelin-1 (ET-1), acting via endothelin-A receptors (ET(A)), on post-incisional pain was examined in a rat model of incision through the hairy skin of the lumbar dorsum. Post-incisional mechanical hyperesthesia was evaluated by cutaneous trunci muscle reflexes (CTMR) of subcutaneous muscles responding to stimulation with von Frey filaments near the wound (primary responses) and at a distance, especially on the contralateral dorsum (secondary responses, involving spinal circuits). The role of ET(A) was determined by pre-incisional, subcutaneous injection of the selective receptor antagonist BQ-123 at the incision site, 15 min or 24h before surgery. Control incisions showed both primary tactile allodynia and hyperalgesia, and a weaker secondary hyperesthesia, peaking 3-4h after surgery and lasting at least 24h. Primary allodynia, but not hyperalgesia, was dose-dependently suppressed by 15 min pre-incisional BQ-123. In contrast, both secondary allodynia and hyperalgesia were inhibited by local BQ-123. The suppression of primary allodynia by local antagonist disappeared in 24h, but that of secondary hyperesthesia remained strong for at least 24h. Systemically delivered BQ-123 was without effect on any post-incisional hyperesthesia, and if the antagonist was locally injected 24h before surgery there was no difference on hyperesthesia compared to vehicle injected at that time. We conclude that ET-1, released from skin by incision, activates nociceptors to cause primary allodynia and to sensitize spinal circuits through central sensitization. Blockade of ET(A) in the immediate peri-operative period prevents the later development of central sensitization.

Genetic analysis of the requirements for SOS induction by nalidixic acid in Escherichia coli.

Nalidixic acid, the prototype antibacterial quinolone, induces the SOS response by a mechanism that requires the RecBCD nuclease/helicase. A key step inferred for this induction pathway is the conversion of a drug-induced gyrase cleavage complex into a DNA break that can be processed by RecBC. We tried to clarify the nature of this step by searching for additional gene products that are specifically necessary for SOS induction following nalidixic acid treatment. A transposon library of approximately 19,000 insertion mutants yielded 18 mutants that were substantially reduced for SOS induction following nalidixic acid but not UV treatment, and which were also hypersensitive to nalidixic acid. All 18 mutants turned out to have insertions in recB or recC. As expected, recA insertion mutants were uncovered as being uninducible by either nalidixic acid or UV treatment. Insertions in 11 other genes were found to cause partial defects in SOS induction by one or both pathways, providing possible leads in understanding the detailed mechanisms of SOS induction. Overall, these results suggest that nalidixic acid-induced DNA breaks are generated either by RecBC itself, by redundant activities, and/or by an essential protein that could not be uncovered with transposon mutagenesis.

Isolation of SOS constitutive mutants of Escherichia coli.

The bacterial SOS regulon is strongly induced in response to DNA damage from exogenous agents such as UV radiation and nalidixic acid. However, certain mutants with defects in DNA replication, recombination, or repair exhibit a partially constitutive SOS response. These mutants presumably suffer frequent replication fork failure, or perhaps they have difficulty rescuing forks that failed due to endogenous sources of DNA damage. In an effort to understand more clearly the endogenous sources of DNA damage and the nature of replication fork failure and rescue, we undertook a systematic screen for Escherichia coli mutants that constitutively express the SOS regulon. We identified mutant strains with transposon insertions in 42 genes that caused increased expression from a dinD1::lacZ reporter construct. Most of these also displayed significant increases in basal levels of RecA protein, confirming an effect on the SOS system. As expected, this collection includes genes, such as lexA, dam, rep, xerCD, recG, and polA, which have previously been shown to cause an SOS constitutive phenotype when inactivated. The collection also includes 28 genes or open reading frames that were not previously identified as SOS constitutive, including dcd, ftsE, ftsX, purF, tdcE, and tynA. Further study of these SOS constitutive mutants should be useful in understanding the multiple causes of endogenous DNA damage. This study also provides a quantitative comparison of the extent of SOS expression caused by inactivation of many different genes in a common genetic background.

A unique type II topoisomerase mutant that is hypersensitive to a broad range of cleavage-inducing antitumor agents.

Bacteriophage T4 provides a useful model system for dissecting the mechanism of action of antitumor agents that target type II DNA topoisomerases. Many of these inhibitors act by trapping the cleavage complex, a covalent complex of enzyme and broken DNA. Previous analysis showed that a drug-resistant T4 mutant harbored two amino acid substitutions (S79F, G269V) in topoisomerase subunit gp52. Surprisingly, the single amino acid substitution, G269V, was shown to confer hypersensitivity in vivo to m-AMSA and oxolinic acid [Freudenreich, C. H., et al. (1998) Cancer Res. 58, 1260-1267]. We purified this G269V mutant enzyme and found it to be hypersensitive to a number of cleavage-inducing inhibitors including m-AMSA, VP-16, mitoxantrone, ellipticine, and oxolinic acid. While the mutant enzyme did not exhibit altered DNA cleavage site specificity compared to the wild-type enzyme, it did display an apparent 10-fold increase in drug-independent DNA cleavage. This suggests a novel mechanism of altered drug sensitivity in which the enzyme equilibrium has been shifted to favor the cleavage complex, resulting in an increase in the concentration of cleavage intermediates available to inhibitors. Mutations that alter drug sensitivities tend to cluster within two specific regions of all type II topoisomerases. Residue G269 of gp52 lies outside of these regions, and it is therefore not surprising that G269V leads to a unique mechanism of drug hypersensitivity. We believe that this mutant defines a new category of type II topoisomerase mutants, namely, those that are hypersensitive to all inhibitors that stabilize the cleavage complex.