Fibrodysplasia Ossificans Progressiva and Pregnancy: A Case Series and Review of the Literature.

Objective: To evaluate maternal and fetal outcomes in pregnant patients with fibrodysplasia ossificans progressiva (FOP; OMIM#135100), an ultrarare genetic disorder characterized by progressive heterotopic ossification of soft tissues and cumulative disability. Methods: This is a retrospective case series of three patients with FOP who were admitted to Grady Memorial Hospital in Atlanta, Georgia, from to February 2011 to July 2021. Results: Three women delivered preterm infants at our institution. These cases posed unique anesthetic and obstetric technical challenges, particularly when securing the airway and performing cesarean delivery. Importantly, each patient received perioperative glucocorticoids for prevention of further heterotopic ossification. Conclusion: FOP is a unique clinical diagnosis encountered by obstetricians and requires multidisciplinary management for optimal outcomes.

Gene Therapy for Fibrodysplasia Ossificans Progressiva: Feasibility and Obstacles.

Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disease, in which soft connective tissue is converted into heterotopic bone through an endochondral ossification process. Patients succumb early as they gradually become trapped in a second skeleton of heterotopic bone. Although the underlying genetic defect is long known, the inherent complexity of the disease has hindered the discovery of effective preventions and treatments. New developments in the gene therapy field have motivated its consideration as an attractive therapeutic option for FOP. However, the immune system's role in FOP activation and the as-yet unknown primary causative cell, are crucial issues which must be taken into account in the therapy design. While gene therapy offers a potential therapeutic solution, more knowledge about FOP is needed to enable its optimal and safe application.

Surgical and Radiological Management of Complicated Uterine Leiomyoma Aided by 3D Models in a Patient with Fibrodysplasia Ossificans Progressiva.

BACKGROUND Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of the connective tissue. Over time, patients with FOP experience decreased range of motion in the joints and the formation of a second skeleton, limiting mobility. Patients with FOP are advised to avoid any unwarranted surgery owing to the risk of a heterotopic ossification flare-up. For patients who do require a surgical procedure, a multidisciplinary team is recommended for comprehensive management of the patient's needs. CASE REPORT A 27-year-old woman with FOP underwent a hysterectomy for removal of a suspected necrotic uterine fibroid. To aid in presurgical planning and management, patient-specific 3-dimensional (3D) models of the patient's tracheobronchial tree, thorax, and lumbosacral spine were printed from the patient's preoperative computed tomography (CT) imaging. The patient required awake nasal fiberoptic intubation for general anesthesia and transversus abdominus plane block for regional anesthesia. Other anesthesia modalities, including spinal epidural, were ruled out after visualizing the patient's anatomy using the 3D model. Postoperatively, the patient was started on a multi-modal analgesic regimen and a course of steroids, and early ambulation was encouraged. CONCLUSIONS Patients with FOP are high-risk surgical patients requiring the care of multiple specialties. Advanced visualization methods, including 3D printing, can be used to better understand their anatomy and locations of heterotopic bone ossification that can affect patient positioning. Our patient successfully underwent supracervical hysterectomy and bilateral salpingectomy with no signs of fever or sepsis at follow-up.

When Limb Surgery Has Become the Only Life-Saving Therapy in FOP: A Case Report and Systematic Review of the Literature.

Fibrodysplasia ossificans progressiva (FOP) is a rare disease in which heterotopic ossification (HO) is formed in muscles, tendons and ligaments. Traumatic events, including surgery, are discouraged as this is known to trigger a flare-up with risk of subsequent HO. Anesthetic management for patients with FOP is challenging. Cervical spine fusion, ankylosis of the temporomandibular joints, thoracic insufficiency syndrome, restrictive chest wall disease, and sensitivity to oral trauma complicate airway management and anesthesia and pose life-threatening risks. We report a patient with FOP suffering from life-threatening antibiotic resistant bacterial infected ulcers of the right lower leg and foot. The anesthetic, surgical and postoperative challenges and considerations are discussed. In addition, the literature on limb surgeries of FOP patients is systemically reviewed. The 44 year-old female patient was scheduled for a through-knee amputation. Airway and pulmonary evaluation elicited severe abnormalities, rendering standard general anesthesia a rather complication-prone approach in this patient. Thus, regional anesthesia, supplemented with intravenous analgosedation and N2O-inhalation were performed in this case. The surgery itself was securely planned to avoid any unnecessary tissue damage. Postoperatively the patient was closely monitored for FOP activity by ultrasound and [18F]PET/CT-scan. One year after surgery, a non-significant amount of HO had formed at the operated site. The systematic review revealed seventeen articles in which thirty-two limb surgeries in FOP patients were described. HO reoccurrence was described in 90% of the cases. Clinical improvement due to improved mobility of the operated joint was noted in 16% of the cases. It should be noted, though, that follow-up time was limited and no or inadequate imaging modalities were used to follow-up in the majority of these cases. To conclude, if medically urgent, limb surgery in FOP is possible even when general anesthesia is not preferred. The procedure should be well-planned, alternative techniques or procedures should be tested prior to surgery and special attention should be paid to the correct positioning of the patient. According to the literature recurrent HO should be expected after surgery of a limb, even though it was limited in the case described.

Self-reported baseline phenotypes from the International Fibrodysplasia Ossificans Progressiva (FOP) Association Global Registry.

A global, patient-reported registry has been established to characterize the course of disease and track clinical outcomes in patients with fibrodysplasia ossificans progressiva (FOP), an ultra-rare genetic condition of progressive heterotopic ossification (HO) that results in ankylosis of joints and renders most affected individuals immobile by the second decade of life. Here, we present baseline phenotypes on 299 patients (median age 21 years; range 0.1 to 78 years) from 54 countries based on aggregate data from the International FOP Association (IFOPA) Global Registry (the "FOP Registry"). The mean current age of the patients is 23.7 years (range, 0.1 to 78 years). Baseline characteristics are presented for FOP diagnosis, HO, flare-ups and precedent events, system-based prevalent symptomatology, encounters with medical and dental care providers, Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale scores, physical function, as well as the use of aids, assistive devices, and adaptations. Correlations of PROMIS Global Health scores with HO burden and physical function are calculated. Associations of joint mobility with PROMIS Global Health scores, physical function, and use of aids, assistive devices, and adaptations are summarized. Overall, the FOP Registry database contains a broad sample of the global FOP patient population, providing a useful tool for expanding knowledge of FOP, designing clinical trials and facilitating evidence-based decisions about the optimal monitoring and management of affected individuals.

Special considerations for clinical trials in fibrodysplasia ossificans progressiva (FOP).

Clinical trials for orphan diseases are critical for developing effective therapies. One such condition, fibrodysplasia ossificans progressiva (FOP; MIM#135100), is characterized by progressive heterotopic ossification (HO) that leads to severe disability. Individuals with FOP are extremely sensitive to even minor traumatic events. There has been substantial recent interest in clinical trials for novel and urgently-needed treatments for FOP. The International Clinical Council on FOP (ICC) was established in 2016 to provide consolidated and coordinated advice on the best practices for clinical care and clinical research for individuals who suffer from FOP. The Clinical Trials Committee of the ICC developed a focused list of key considerations that encompass the specific and unique needs of the FOP community - considerations that are endorsed by the entire ICC. These considerations complement established protocols for developing and executing robust clinical trials by providing a foundation for helping to ensure the safety of subjects with FOP in clinical research trials.

The HYSLAR trial: a prospective randomized controlled trial of the use of a restrictive fluid regimen with 3% hypertonic saline versus lactated Ringers in patients undergoing pancreaticoduodenectomy.

OBJECTIVE: This study was designed to determine whether the volume and type of fluid administered for pancreaticoduodenectomy impacts postoperative outcomes. BACKGROUND: Three percent hypertonic saline (HYS) has been suggested as a means of reducing the volume of fluid required to sustain tissue perfusion in the perioperative period. METHODS: Between May 2011 and November 2013, patients undergoing pancreaticoduodenectomy were enrolled in an institutional review board-approved, single-center, prospective, parallel, randomized controlled trial (NCT 01428050), comparing lactated Ringers (LAR) (15 mL/kg/hr LAR intraoperation, 2 mL/kg/hr LAR postoperation) with HYS (9 mL/kg/hr LAR and 1 mL/kg/hr HYS intraoperation, 1 mL/kg/hr HYS postoperation). RESULTS: A total of 264 patients were randomized. Demographic variables between groups were similar. The HYS patients had a significantly reduced net fluid balance (65 vs 91 mL/kg, P = 0.02). The overall complication rate was reduced in the HYS group (43% vs 54%), with a relative risk of 0.79 [95% confidence interval (CI), 0.62-1.02; P = 0.073], factoring stratification for pancreas texture. After adjustment for age and weight, the relative risk was 0.75 [95% CI (0.58-0.96); P = 0.023]. The total number of complications was significantly reduced in the HYS group (93 vs 123), with an incidence rate ratio of 0.74 [95% CI (0.56-0.97); P = 0.027]. After adjustment for age and weight, the incidence rate ratio was 0.69 [95% CI (0.52-0.90); P = 0.0068]. Reoperations, length of stay, readmissions, and 90-day mortality were similar between groups. CONCLUSIONS: A moderately restrictive fluid regimen with HYS resulted in a statistically significant 25% reduction in complications when adjusted for age, weight, and pancreatic texture.

General anesthesia for dental procedures in patients with fibrodysplasia ossificans progressiva: a review of 42 cases in 30 patients.

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is a rare genetic condition characterized by progressive heterotopic ossification of skeletal muscle and soft connective tissues, leading to progressive ankylosis of all joints of the axial and appendicular skeleton. Cervical spine fusion, ankylosis of the temporomandibular joints, thoracic insufficiency syndrome, restrictive chest wall disease, and sensitivity to oral trauma complicate airway management and anesthesia and pose life-threatening risks. METHODS: We conducted a retrospective chart review at 1 institution of patients with FOP who underwent general anesthesia (GA) for dental procedures. RESULTS: Thirty patients underwent 42 general anesthetics. In 35 of 42 cases, GA was induced after the airway was secured by an awake fiberoptic intubation. In 4 of 42 cases, all of them pediatric, GA was first induced with maintenance of spontaneous ventilation, and the trachea was then intubated using a fiberoptic scope. In 2 cases, 1 adult and 1 pediatric, GA was first induced, and the trachea was then intubated using a GlideScope. In 1 case, the patient had a cuffed tracheostomy device in place that was accessed for GA. In 36 of 42 cases, the patients were discharged home on the same day as their dental procedure. No significant postoperative complications were encountered. CONCLUSIONS: GA can be administered safely to patients with FOP for dental procedures with attention to perioperative and airway management using a multidisciplinary approach. An awake nasal fiberoptic intubation should be considered the first choice for airway management. Most patients can be discharged home on the same day as their dental procedure.

Surgical Apgar score predicts perioperative morbidity in patients undergoing pancreaticoduodenectomy at a high-volume center.

OBJECTIVES: Pancreaticoduodenectomy (PD) remains a procedure that carries considerable morbidity. Numerous studies have evaluated factors to predict patients at risk. The aim of this study was to determine whether the surgical Apgar score (SAS) predicts perioperative morbidity and mortality. METHODS: We examined 553 patients undergoing successful PD between January 2000 and December 2010. Postoperative complications were graded using the Clavien scale, and the SAS (range, 0-10) was determined. The Cochran-Armitage test for trend was used to determine the association between grouped SAS scores (0-2, 3-4, 5-6, 7-8, and 9-10) and each of the outcomes. RESULTS: The average patient age was 64 years, and there was an even distribution of males and females. There were 11 perioperative deaths (2%), 186 grade 2 or higher complications (34%), and 86 major complications (grades 3-5, 16%). Additionally, 61 patients developed pancreatic fistulae (11%). Statistical analysis determined that SAS was a significant predictor of grade 2 or higher complications (p < 0.0001), major morbidity (p = 0.01), and pancreatic fistula (p = 0.04) but not mortality (p = 0.20). CONCLUSIONS: We demonstrate that the SAS is a significant predictor of perioperative morbidity for patients undergoing PD. This score should be used to identify patients at higher risk in order to prioritize use of postoperative critical care beds and hospital resources.

Use of a tracheoscopic ventilation tube for endotracheal intubation in the difficult airway.

Difficult endotracheal intubation is a clinical challenge for anesthesiologists and other practitioners of airway management. The use of a tracheoscopic ventilation tube, a novel airway device, for endotracheal intubation during general anesthesia in two patients with difficult airways after unsuccessful direct laryngoscopy is presented.

Validation of a system to detect scheduled drug diversion by anesthesia care providers.

BACKGROUND: We recently described a method to identify drug diversion in the operating room (OR) from automated drug dispensing carts by anesthesia care providers, based on a retrospective outlier analysis of atypical transactions. Such transactions included those occurring on patients after their exit from the OR and on patients whose drugs were not dispensed at the location where the case was performed. In this report, we demonstrate prospectively the utility of our methodology to detect diversion by unsuspected individuals. METHODS: Each month, all transactions involving scheduled drugs by anesthesia care providers are downloaded from the pharmacy database and matched to case records from the anesthesia information management system. The frequency of atypical transactions is determined for each provider, normalized by the number of days they worked in the OR. For individuals who are >2 SDs above the mean for the month for any of the screening queries, a manual examination of their drug transaction logs is performed. Anesthesia records for such providers are examined manually to help determine the likelihood that diversion is taking place, and evidence of escalating activity is considered. Actions taken depend on an assessment of the strength of the evidence that diversion has been occurring. RESULTS: Two unsuspected individuals were identified prospectively as diverting drugs. Two individuals identified as abusing drugs recreationally outside the workplace showed no evidence of drug diversion through examination of the screening reports and transaction logs, and their rehabilitation treatment teams concurred that there was a very low probability of diversion. A final individual who demonstrated suspicious activity by the screening process was determined to have been careless in documentation practices, rather than diverting. CONCLUSIONS: The drug diversion screening methodology previously developed is valid for the prospective detection of unsuspected individuals diverting drugs from the OR. The system also provides material useful in the evaluation of possible diversion by anesthesia providers determined to be abusing drugs outside the workplace.

A description of two surgical and anesthetic management techniques used for a patient with fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a rare and debilitating genetic disorder of skeletal malformations and progressive heterotopic ossification. Flare-ups are episodic, with bone formation in skeletal muscle and connective tissue leading to ankylosis of major joints of the axial and appendicular skeleton. This report outlines the management of a patient with FOP who had ankylosis of the temporomandibular joint and progressive ossification of the neck structures. The patient underwent two different surgical and anesthetic procedures within a 10-year period to manage his oral pain. The authors compare the surgical techniques, osteotomy versus the more conservative buccal approach, anesthesia techniques, and conventional intubation versus sedated fiberoptic intubation. This report emphasizes the importance of a less invasive surgical technique and an appropriate anesthetic management that reduces the risks, cost, and morbidity associated with routine surgical management of patients with FOP.

Development of a staff recall system for mass casualty incidents using cell phone text messaging.

BACKGROUND: After a mass casualty incident (MCI), rapid mobilization of hospital personnel is required because of an expected surge of victims. Risk assessment of our department's manual phone tree recall system revealed multiple weaknesses that would limit an effective response. Because cell phone use is widespread within the department, we developed and tested a staff recall system, based in our anesthesia information management system (AIMS), using Short Message Service (SMS) text messaging. METHODS: We sent test text messages to anesthesia staff members' cell phone numbers, determined the distance from their home to the hospital, and stored this information in our AIMS. Latency testing for the time from transmission of SMS test messages from the server to return of an e-mail reply was determined at 2 different times on 2 different dates, 1 of which was a busy holiday weekend, using volunteers within the department. Two unannounced simulated disaster recall drills were conducted, with text messages sent asking for the anticipated time to return to the hospital. A timeline of available staff on site was determined. Reasons for failure to respond to the disaster notification message were tabulated. RESULTS: Latency data were fit by a log-normal distribution with an average of 82 seconds from message transmission to e-mail reply. Replies to the simulated disaster alert were received from approximately 50% of staff, with 16 projecting that they would have been able to be back at the hospital within 30 minutes on both dates. There would have been 21 and 23 staff in-house at 30 minutes, and 32 and 37 staff in-house at 60 minutes on the first and second test date, respectively, including in-house staff. Of the nonresponders to the alert, 48% indicated that their cell phone was not with them or was turned off, whereas 22% missed the message. CONCLUSIONS: Our SMS staff recall system is likely to be able to rapidly mobilize sufficient numbers of anesthesia personnel in response to an MCI, but actual performance cannot be predicted with confidence. Using our AIMS as the source for contact information and from which to send messages was simple, inexpensive, and easy to implement. Updating contact information, periodic testing, and analysis of responses to simulated disaster alerts are essential for the effective functioning of such a system. However, maintenance of alternative methods of communication is recommended, because there may be more significant message transmission delays and failures during an actual MCI, and not all staff will receive the text message in a timely fashion.

Clinical need for continuous glucose monitoring in the hospital.

Automation and standardization of the glucose measurement process have the potential to greatly improve glycemic control, clinical outcome, and safety while reducing cost. The resources required to monitor glycemia in hospitalized patients have thus far limited the implementation of intensive glucose management to patients in critical care units. Numerous available and up-and-coming technologies are targeted for the hospital patient population. Advantages and limitations of these devices are discussed herewith in.

Adoption of anesthesia information management systems by academic departments in the United States.

BACKGROUND: Information technology has been promoted as a way to improve patient care and outcomes. Whereas information technology systems for ancillary hospital services (e.g., radiology, pharmacy) are deployed commonly, it has been estimated that anesthesia information management systems (AIMS) are only installed in a small fraction of United States (US) operating rooms. In this study, we assessed the adoption of AIMS at academic anesthesia departments and explored the motivations for and resistance to AIMS adoption. METHODS: Members of the Society of Academic Anesthesiology Chairs and the Association of Anesthesiology Program Directors were solicited by e-mail to participate in an online survey of AIMS adoption. Two months after closing the survey, another e-mail was sent with a single question asking for an update to their AIMS implementation status. RESULTS: Surveys were fully completed by 48 (34%) of the 140 Society of Academic Anesthesiology Chairs and Association of Anesthesiology Program Directors departments surveyed, with 72 (51%) providing AIMS status information. Twenty of these 72 departments have an AIMS installed, 12 are currently implementing, 11 have selected but not yet installed, and 18 are planning to purchase an AIMS in 2008 or 2009. Therefore, at least 61 (44%) of all 140 US academic anesthesia departments have committed to AIMS. This estimated adoption rate is conservative because the numerator equals the affirmative responses, whereas the denominator equals the total population of academic departments. Among adopters, the top ranked anticipated benefits from installing an AIMS included improved clinical documentation, improved data collection for clinical research, enhancement of quality improvement programs, and compliance with requirements of regulatory authorities. The hospital provided funding in almost all facilities (90%), with co-funding by the anesthesia group in 35%. CONCLUSIONS: At least 61 or 44% of the 140 US academic departments surveyed in this study have already implemented, are planning to acquire, or are currently searching for an AIMS. Adoption of AIMS technology appears to have reached sufficient momentum within academic anesthesiology departments to result in a fundamental change.

Tonic beta-adrenergic drive provokes proinflammatory and proapoptotic changes in aging mouse heart.

Tonic activation of adrenergic drive has been found to be associated with aging, and its further activation is also seen in aging patients with major surgery or congestive heart failure. Nevertheless, its potential effect on the aging heart remains enigmatic. In the present study, at baseline, significant inflammatory and apoptotic changes were found in the aging mouse (20 months old), as evidenced by increases in inducible nitric oxide synthase (iNOS) expression, myocardial apoptosis in the heart, and C-reactive protein (CRP) release in the circulation. These phenotypic changes in aging animals can be induced in young animals (3 months old) by chronic beta-adrenergic receptor (AR) stimulation with isoproterenol (ISO), and they can be markedly reduced in aging animals by chronic beta-blockade with propranolol. Compared with young animals, chronic beta-AR stimulation with ISO in aging animals induced larger increases in iNOS expression, nitrotyrosine formation in the heart, and nitric oxide (NO) production and CRP release in the circulation; it also accelerated myocardial apoptosis and resulted in an enlarged infarct size when animals were subjected to myocardial ischemia and reperfusion (MI/R). However, the pretreatment of 1400W (N-(3-(aminomethyl) benzyl)acetamidine)-a specific iNOS inhibitor-significantly reduced iNOS-mediated nitrative stress associated with a marked decrease in myocardial apoptosis and infarct size in aging mice. These results demonstrate that tonic activation of the beta-adrenergic system associated with aging induces proinflammatory and proapoptotic changes in the heart and that additional beta-AR stimulation results in an exaggerated nitrative stress, mediated by iNOS, that is associated with more severe myocardial injury in aging mice.

Development of a scheduled drug diversion surveillance system based on an analysis of atypical drug transactions.

BACKGROUND: Drug diversion in the operating room (OR) by anesthesia providers is a recognized problem with significant morbidity and mortality. Use of anesthesia drug dispensing systems in ORs, coupled with the presence of anesthesia or OR information management systems, may allow detection through database queries screening for atypical drug transactions. Although such transactions occur innocently during the course of normal clinical care, many are suspicious for diversion. METHODS: We used a data mining approach to search for possible indicators of diversion by querying our information system databases. Queries were sought that identified our two known cases of drug diversion and their onset. A graphical approach was used to identify outliers, with diversion subsequently assessed through a manual audit of transactions. RESULTS: Frequent transactions on patients after the end of their procedures, and on patients having procedures in locations different from that of the dispensing machine, identified our index cases. In retrospect, had we been running the surveillance system at the time, diversion would have been detected earlier than actually recognized. CONCLUSIONS: Identification of the frequent occurrence of atypical drug transactions from automated drug dispensing systems using database queries is a potentially useful method to detect drug diversion in the OR by anesthesia providers.

Chronic beta-adrenergic receptor stimulation induces cardiac apoptosis and aggravates myocardial ischemia/reperfusion injury by provoking inducible nitric-oxide synthase-mediated nitrative stress.

The present study provides evidence that inducible nitric-oxide synthase (iNOS)-mediated nitrative stress plays a pivotal role in chronic beta-adrenergic receptor (AR) stimulation-induced cardiac damage. In mice, 14 days of isoproterenol (ISO) stimulation via an osmotic minipump induced an up-regulation of iNOS as evidenced by increases in mRNA, protein expression, and immunochemical staining of myocardial iNOS. Serum level of C-reactive protein, an inflammatory mediator, was also markedly increased. Under chronic ISO stimulation, the up-regulated iNOS produced a significantly increased amount of nitric oxide (NO) and its byproduct, peroxynitrite, in the circulation and heart and subsequently resulted in an accelerated myocardial apoptosis. Forty-minute myocardial ischemia (MI) and 24-h reperfusion (R) further increased NO production and peroxynitrite formation and resulted in an enlarged infarct size in mice receiving chronic ISO stimulation. However, the treatment with a selective iNOS inhibitor [N-(3-(aminomethyl) benzyl)acetamidine] (1400W) or the use of a genetic modified animal (iNOS-knockout mice) markedly reduced iNOS-mediated production of NO and formation of peroxynitrite and consequently significantly decreased myocardial apoptosis and infarct size, showing a crucial link between iNOS-mediated nitrative stress and myocardial injury. In conclusion, chronic beta-AR stimulation up-regulates iNOS expression and increases NO production in the heart, which subsequently markedly enhances formation of reactive nitrogen species/peroxynitrite in the heart, thereby eliciting myocardial apoptosis and potentiating MI/R injury.