Peter F. Dunn

Adenovirus-mediated gene transfer into normal rabbit arteries results in prolonged vascular cell activation, inflammation, and neointimal hyperplasia.

Adenovirus vectors are capable of high efficiency in vivo arterial gene transfer, and are currently in use as therapeutic agents in animal models of vascular disease. However, despite substantial data on the ability of viruses to cause vascular inflammation and proliferation, and the presence in current adenovirus vectors of viral open reading frames that are translated in vivo, no study has examined the effect of adenovirus vectors alone on the arterial phenotype. In a rabbit model of gene transfer into a normal artery, we examined potential vascular cell activation, inflammation, and neointimal proliferation resulting from exposure to replication-defective adenovirus. Exposure of normal arteries to adenovirus vectors resulted in: (a) pronounced infiltration of T cells throughout the artery wall; (b) upregulation of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in arterial smooth muscle cells; (c) neointimal hyperplasia. These findings were present both 10 and 30 d after gene transfer, with no evidence of a decline in severity over time. Adenovirus vectors have pleiotropic effects on the arterial wall and cause significant pathology. Interpretation of experimental protocols that use adenovirus vectors to address either biological or therapeutic issues should take these observations into account. These observations should also prompt the design of more inert gene transfer vectors.

Established immunity precludes adenovirus-mediated gene transfer in rat carotid arteries. Potential for immunosuppression and vector engineering to overcome barriers of immunity.

Preclinical arterial gene transfer studies with adenoviral vectors are typically performed in laboratory animals that lack immunity to adenovirus. However, human patients are likely to have prior exposures to adenovirus that might affect: (a) the success of arterial gene transfer; (b) the duration of recombinant gene expression; and (c) the likelihood of a destructive immune response to transduced cells. We confirmed a high prevalence (57%) in adult humans of neutralizing antibodies to adenovirus type 5. We then used a rat model to establish a central role for the immune system in determining the success as well as the duration of recombinant gene expression after adenovirus-mediated gene transfer into isolated arterial segments. Vector-mediated recombinant gene expression, which was successful in naive rats and prolonged by immunosuppression, was unsuccessful in the presence of established immunity to adenovirus. 4 d of immunosuppressive therapy permitted arterial gene transfer and expression in immune rats, but at decreased levels. Ultraviolet-irradiated adenoviral vectors, which mimic advanced-generation vectors (reduced viral gene expression and relatively preserved capsid function), were less immunogenic than were nonirradiated vectors. A primary exposure to ultraviolet-irradiated (but not nonirradiated) vectors permitted expression of a recombinant gene after redelivery of the same vector. In conclusion, arterial gene transfer with current type 5 adenoviral vectors is unlikely to result in significant levels of gene expression in the majority of humans. Both immunosuppression and further engineering of the vector genome to decrease expression of viral genes show promise in circumventing barriers to adenovirus-mediated arterial gene transfer.

Seeding of Vascular Grafts With Genetically Modified Endothelial Cells Secretion of Recombinant TPA Results in Decreased Seeded Cell Retention In Vitro and In Vivo

BACKGROUND Seeding of small-diameter vascular grafts with endothelial cells (ECs) genetically engineered to secrete fibrinolytic or antithrombotic proteins offers the potential to improve graft patency rates. METHODS AND RESULTS Sheep venous ECs were transduced with a retroviral vector encoding human tissue plasminogen activator (TPA). The ECs were seeded onto 4-mm-ID synthetic (Dacron) grafts. Retention of the seeded ECs was measured 2 hours after placement of the seeded grafts both in vitro in a nonpulsatile flow system and in vivo (in sheep) as femoral and carotid interposition grafts. On exposure to flow in vitro, ECs transduced with TPA were retained at a significantly lower rate (median, 67%) than either untransduced ECs (81%) or ECs transduced with a control retroviral vector producing beta-galactosidase (beta-Gal) (80%) (P < .05 for TPA versus either control). On implantation in vivo, ECs transduced with TPA were retained at a very low rate (median, 0%), significantly less than the retention of ECs transduced with the beta-Gal vector (32%; P < .00001). Decreased in vivo retention of ECs transduced with TPA correlated modestly with increased in vitro cellular passage level (r2 = .48; P < .0001) but not with in vivo blood flow rate (P = .45). Addition of the protease inhibitor aprotinin to the cell culture and graft perfusion media resulted in a significant (P < .05) increase in in vitro retention of ECs transduced with TPA. CONCLUSIONS Increased TPA expression significantly decreases seeded EC adherence in vitro and in vivo. Gene therapy strategies for decreasing graft thrombosis may require expression of antithrombotic molecules that lack proteolytic activity.

A model for understanding the impacts of demand and capacity on waiting time to enter a congested recovery room.

Background:When a recovery room is fully occupied, patients frequently wait in the operating room after emerging from anesthesia. The frequency and duration of such delays depend on operating room case volume, average recovery time, and recovery room capacity. Methods:The authors developed a simple yet nontrivial queueing model to predict the dynamics among the operating and recovery rooms as a function of the number of recovery beds, surgery case volume, recovery time, and other parameters. They hypothesized that the model could predict the observed distribution of patients in recovery and on waitlists, and they used statistical goodness-of-fit methods to test this hypothesis against data from their hospital. Numerical simulations and a survey were used to better understand the applicability of the model assumptions in other hospitals. Results:Statistical tests cannot reject the prediction, and the model assumptions and predictions are in agreement with data. The survey and simulations suggest that the model is likely to be applicable at other hospitals. Small changes in capacity, such as addition of three beds (roughly 10% of capacity) are predicted to reduce waiting for recovery beds by approximately 60%. Conversely, even modest caseload increases could dramatically increase waiting. Conclusions:A key managerial insight is that there is a sensitive relationship among caseload and number of recovery beds and the magnitude of recovery congestion. This is typical in highly utilized systems. The queueing approach is useful because it enables the investigation of future scenarios for which historical data are not directly applicable.

Physiology of the lateral decubitus position and one-lung ventilation.

OLV is most frequently utilized to provide a quiet field for the performance of many different surgical procedures. In some patients, severe hypoxemia may result, mandating the implementation of other therapies to provide adequate oxygenation. This paper has reviewed the physiological consequences of the lateral position that may contribute to the hypoxemia and the techniques we utilize at our institution for establishing OLV, maintaining OLV, and treating hypoxemia during OLV. Our technique is performed with the goal of maintaining adequate gas exchange and protecting the ventilated lung from potential overdistension and injury. It remains for future study to determine if the use of a lung protective strategy during intraoperative OLV offers any benefit to patients at risk for postoperative lung injury, such as those undergoing major lung resections.

Elective change of surgeon during the OR day has an operationally negligible impact on turnover time

STUDY OBJECTIVE To compare turnover times for a series of elective cases with surgeons following themselves with turnover times for a series of previously scheduled elective procedures for which the succeeding surgeon differed from the preceding surgeon. DESIGN Retrospective cohort study. SETTING University-affiliated teaching hospital. MEASUREMENTS The operating room (OR) statistical database was accessed to gather 32 months of turnover data from a large academic institution. Turnover time data for the same-surgeon and surgeon-swap groups were batched by month to minimize autocorrelation and achieve data normalization. Two-way analysis of variance (ANOVA) using the monthly batched data was performed with surgeon swapping and changes in procedure category as variables of turnover time. Similar analyses were performed using individual surgical services, hourly time intervals during the surgical day, and turnover frequency per OR as additional covariates to surgeon swapping. MAIN RESULTS The mean (95% confidence interval [CI]) same-surgeon turnover time was 43.6 (43.2 - 44.0) minutes versus 51.0 (50.5 - 51.6) minutes for a planned surgeon swap (P < 0.0001). This resulted in a difference (95% CI) of 7.4 (6.8 - 8.1) minutes. The exact increase in turnover time was dependent on surgical service, change in subsequent procedure type, time of day when the turnover occurred, and turnover frequency. CONCLUSIONS The investigated institution averages 2.5 cases per OR per day. The cumulative additional turnover time (far less than one hour per OR per day) for switching surgeons definitely does not allow the addition of another elective procedure if the difference could be eliminated. A flexible scheduling policy allowing surgeon swapping rather than requiring full blocks incurs minimal additional staffed time during the OR day while allowing the schedule to be filled with available elective cases.

Acute Adrenal Insufficiency After Large-dose Glucocorticoids for Spinal Cord Injury

A 24- to 48-h course of large-dose glucocorticoid therapy is often used in the acute management of spinal cord injury. We describe a patient who developed adrenal insufficiency (AI) after this protocol. Although a definitive causal relationship between the steroids and AI was not established, their temporal association and the exclusion of other possible etiologies led us to postulate that AI was a complication of the steroid protocol. Clinicians should, therefore, consider AI in patients with spinal cord injury receiving glucocorticoids, a population in whom it may otherwise go undiagnosed and untreated.

Endotracheal tubes and airway appliances.

This chapter will review the development and use of endotracheal tubes and common airway appliances. The first section will review the history and development of endotracheal tubes. The design of modern endotracheal tubes, complications associated with their use, and suggestions for preventing and treating these complications will be presented. In the second section, tracheostomy tubes will be discussed with emphasis on their history, design, and routine care. Some common problems encountered with their use and suggestions for therapies to correct these problems will be discussed.

Systematic Or Block Allocation at a Large Academic Medical Center: Comprehensive Review on a Data-driven Surgical Scheduling Strategy.

Objective: To alleviate the surgical patient flow congestion in the perioperative environment without additional resources. Background: Massachusetts General Hospital experienced increasing overcrowding of the perioperative environment in 2008. The Post-Anesthesia Care Unit would often be at capacity, forcing patients to wait in the operating room. The cause of congestion was traced back to significant variability in the surgical inpatient-bed occupancy across the days of the week due to elective surgery scheduling practices. Methods: We constructed an optimization model to find a rearrangement of the elective block schedule to smooth the average inpatient census by reducing the maximum average occupancy throughout the week. The model was revised iteratively as it was used in the organizational change process that led to an implementable schedule. Results: Approximately 21% of the blocks were rearranged. The setting of study is very dynamic. We constructed a hypothetical scenario to analyze the patient population most representative of the circumstances under which the model was built. For this group, the patient volume remained constant, the average census peak decreased by 3.2% (P < 0.05), and the average weekday census decreased by 2.8% (P < 0.001). When considering all patients, the volume increased by 9%, the census peak increased 1.6% (P < 0.05), and the average weekday census increased by 2% (P < 0.001). Conclusions: This work describes the successful implementation of a data-driven scheduling strategy that increased the effective capacity of the surgical units. The use of the model as an instrument for change and strong managerial leadership was paramount to implement and sustain the new scheduling practices.

Endovascular abdominal aortic aneurysm repair.

Since Parodi’s first report of intraluminal graft implantation for the treatment of an abdominal aortic aneurysm in 1991, repair of abdominal aortic aneurysms (AAAs) through endovascular technology has been used by an increasing number of centers. Where once it was the exclusive domain of major academic medical centers, the procedure has gained widespread acceptance at community hospitals as well. Despite the wellproven and durable technique of open aneurysm repair, the endovascular approach provides a less invasive method of treatment that could reduce risks, provide shorter patient recovery periods, and possibly achieve a cost savings by reduced resource use and decreased length of stay. Although initially developed for use in those deemed unfit for open repair, endovascular exclusion has emerged as a viable option for many patient populations. The intricacies and nuances of endovascular repair present unique issues that the prospective anesthesiologist must address. Although theoretically less invasive, it is still performed on vascular patients who present with significant comorbid issues that the perioperative physician must manage. Most importantly, the multidisciplinary nature of this procedure necessitates a team approach among surgeons, radiology personnel, nurses, and anesthesiologists to ensure optimal patient outcomes.