Author Correction: Characterization of Retinal Ganglion Cell and Optic Nerve Phenotypes Caused by Sustained Intracranial Pressure Elevation in Mice.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Characterization of Retinal Ganglion Cell and Optic Nerve Phenotypes Caused by Sustained Intracranial Pressure Elevation in Mice.

Elevated intracranial pressure (ICP) can result in multiple neurologic sequelae including vision loss. Inducible models of ICP elevation are lacking in model organisms, which limits our understanding of the mechanism by which increased ICP impacts the visual system. We adapted a mouse model for the sustained elevation of ICP and tested the hypothesis that elevated ICP impacts the optic nerve and retinal ganglion cells (RGCs). ICP was elevated and maintained for 2 weeks, and resulted in multiple anatomic changes that are consistent with human disease including papilledema, loss of physiologic cupping, and engorgement of the optic nerve head. Elevated ICP caused a loss of RGC somas in the retina and RGC axons within the optic nerve, as well as a reduction in both RGC electrical function and contrast sensitivity. Elevated ICP also caused increased hypoxia-inducible factor (HIF)-1 alpha expression in the ganglion cell layer. These experiments confirm that sustained ICP elevation can be achieved in mice and causes phenotypes that preferentially impact RGCs and are similar to those seen in human disease. With this model, it is possible to model human diseases of elevated ICP such as Idiopathic Intracranial Hypertension and Spaceflight Associated Neuro-ocular Syndrome.

Emergency Medical Considerations in a Space-Suited Patient.

INTRODUCTION: The Stratex Project is a high altitude balloon flight that culminated in a freefall from 41,422 m (135,890 ft), breaking the record for the highest freefall to date. Crew recovery operations required an innovative approach due to the unique nature of the event as well as the equipment involved. The parachutist donned a custom space suit similar to a NASA Extravehicular Mobility Unit (EMU), with life support system mounted to the front and a parachute on the back. This space suit had a metal structure around the torso, which, in conjunction with the parachute and life support assembly, created a significant barrier to extraction from the suit in the event of a medical emergency. For this reason the Medical Support Team coordinated with the pressure suit assembly engineer team for integration, training in suit removal, definition of a priori contingency leadership on site, creation of color-coded extraction scenarios, and extraction drills with a suit mock-up that provided insight into limitations to immediate access. This paper discusses novel extraction processes and contrasts the required medical preparation for this type of equipment with the needs of the prior record-holding jump that used a different space suit with easier immediate access. Garbino A, Nusbaum DM, Buckland DM, Menon AS, Clark JB, Antonsen EL. Emergency medical considerations in a space-suited patient. Aerosp Med Hum Perform. 2016; 87(11):958-962.

Crew Recovery and Contingency Planning for a Manned Stratospheric Balloon Flight - the StratEx Program.

The StratEx program used a self-contained space suit and balloon system to loft pilot Alan Eustace to a record-breaking altitude and skydive from 135,897 feet (41,422 m). After releasing from the balloon and a stabilized freefall, the pilot safely landed using a parachute system based on a modified tandem parachute rig. A custom spacesuit provided life support using a similar system to NASA's (National Aeronautics and Space Administration; Washington, DC USA) Extravehicular Mobility Unit. It also provided tracking, communications, and connection to the parachute system. A recovery support team, including at least two medical personnel and two spacesuit technicians, was charged with reaching the pilot within five minutes of touchdown to extract him from the suit and provide treatment for any injuries. The team had to track the flight at all times, be prepared to respond in case of premature release, and to operate in any terrain. Crew recovery operations were planned and tailored to anticipate outcomes during this novel event in a systematic fashion, through scenario and risk analysis, in order to minimize the probability and impact of injury. This analysis, detailed here, helped the team configure recovery assets, refine navigation and tracking systems, develop procedures, and conduct training. An extensive period of testing and practice culminated in three manned flights leading to a successful mission and setting the record for exit altitude, distance of fall with stabilizing device, and vertical speed with a stabilizing device. During this mission, recovery teams reached the landing spot within one minute, extracted the pilot, and confirmed that he was not injured. This strategy is presented as an approach to prehospital planning and care for improved safety during crew recovery in novel, extreme events. Menon AS , Jourdan D , Nusbaum DM , Garbino A , Buckland DM , Norton S , Clark JB , Antonsen EL . Crew recovery and contingency planning for a manned stratospheric balloon flight - the StratEx program. Prehosp Disaster Med. 2016;31(5):524-531.

Acute hypercarbia increases the lower limit of cerebral blood flow autoregulation in a porcine model.

OBJECTIVES: In the present study, our objective was to determine if hypercarbia would alter cerebral blood flow (CBF) autoregulation and reduce the ability of cerebrovascular reactivity monitoring to identify the lower limit of cerebrovascular autoregulation (LLA). METHODS: Anaesthetised juvenile pigs were assigned between two groups: normocarbia (control group, n = 10) or hypercarbia [high carbon dioxide (CO2) group, n = 8]. Normocarbia subjects were maintained with an arterial CO2 of 40 Torr, while the hypercarbia subjects had an increase of inspired CO2 to achieve an arterial pCO2 of >80 Torr. Gradual hypotension was induced by continuous haemorrhage from a catheter in the femoral vein, and the LLA was determined by monitoring cortical laser Doppler flux (LDF). Vascular reactivity monitoring was performed using the pressure reactivity index (PRx) and haemoglobin volume index (HVx). RESULTS: There were no sustained differences in ICP between groups. Autoregulation was present in both groups, despite elevation in pCO2.The control group had an average LLA of 45 mmHg (95% CI: 43-47 mmHg) and the high CO2 group had a LLA of 75 mmHg (95% CI: 73-77 mmHg). The detected LLA for each subject correlated with the level of pCO2 (spearman R = 0.8243, P < 0.0001). Both the PRx and HVx accurately detected the LLA despite the presence of hypercarbia. DISCUSSION: Hypercarbia without acidosis increases the observed LLA independent of alterations in ICP. Elevations in CO2 can impair cerebrovascular autoregulation, but if there is a sufficient increase in blood pressure above the CO2 altered LLA, then autoregulation persists.

Elevated intracranial pressure causes optic nerve and retinal ganglion cell degeneration in mice.

The purpose of this study was to develop a novel experimental system for the modulation and measurement of intracranial pressure (ICP), and to use this system to assess the impact of elevated ICP on the optic nerve and retinal ganglion cells (RGCs) in CD1 mice. This system involved surgical implantation of an infusion cannula and a radiowave based pressure monitoring probe through the skull and into the subarachnoid space. The infusion cannula was used to increase ICP, which was measured by the probe and transmitted to a nearby receiver. The system provided robust and consistent ICP waveforms, was well tolerated, and was stable over time. ICP was elevated to approximately 30 mmHg for one week, after which we assessed changes in optic nerve structure with transmission electron microscopy in cross section and RGC numbers with antibody staining in retinal flat mounts. ICP elevation resulted in optic nerve axonal loss and disorganization, as well as RGC soma loss. We conclude that the controlled manipulation of ICP in active, awake mice is possible, despite their small size. Furthermore, ICP elevation results in visual system phenotypes of optic nerve and RGC degeneration, suggesting that this model can be used to study the impact of ICP on the visual system. Potentially, this model can also be used to study the relationship between ICP and IOP, as well diseases impacted by ICP variation such as glaucoma, idiopathic intracranial hypertension, and the spaceflight-related visual impairment intracranial pressure syndrome.

Prolonged elevation of intraocular pressure results in retinal ganglion cell loss and abnormal retinal function in mice.

The purpose of this study was to assess the impact of prolonged intraocular pressure (IOP) elevation on retinal anatomy and function in a mouse model of experimental glaucoma. IOP was elevated by anterior chamber injection of a fixed combination of polystyrene beads and sodium hyaluronate, and maintained via re-injection after 24 weeks. IOP was measured weekly with a rebound tonometer for 48 weeks. Histology was assessed with a combination of retrograde labeling and antibody staining. Retinal physiology and function was assessed with dark-adapted electroretinograms (ERGs). Comparisons between bead-injected animals and various controls were conducted at both 24 and 48 weeks after bead injection. IOP was elevated throughout the study. IOP elevation resulted in a reduction of retinal ganglion cell (RGCs) and an increase in axial length at both 24 and 48 weeks after bead injection. The b-wave amplitude of the ERG was increased to the same degree in bead-injected eyes at both time points, similar to previous studies. The positive scotopic threshold response (pSTR) amplitude, a measure of RGC electrical function, was diminished at both 24 and 48 weeks when normalized to the increased b-wave amplitude. At 48 weeks, the pSTR amplitude was reduced even without normalization, suggesting more profound RGC dysfunction. We conclude that injection of polystyrene beads and sodium hyaluronate causes chronic IOP elevation which results in phenotypes of stable b-wave amplitude increase and progressive pSTR amplitude reduction, as well as RGC loss and axial length elongation.

A case of survival after cardiac arrest and 3½ hours of resuscitation.

Although survival rates after cardiac arrest remain low, new techniques are improving patients' outcomes. We present the case of a 40-year-old man who survived a cardiac arrest that lasted approximately 3½ hours. Resuscitation was performed with strict adherence to American Heart Association/American College of Cardiology Advanced Cardiac Life Support guidelines until bedside extracorporeal membrane oxygenation could be placed. A hypothermia protocol was initiated immediately afterwards. The patient had a full neurologic recovery and was bridged from dual ventricular assist devices to a total artificial heart. On hospital day 160, he underwent orthotopic heart and cadaveric kidney transplantation. On day 179, he was discharged from the hospital in ambulatory condition. To our knowledge, this is the only reported case in which a patient survived with good neurologic outcomes after a resuscitation that lasted as long as 3½ hours. Documented cases of resuscitation with good recovery after prolonged arrest give hope for improved overall outcomes in the future.

Optic nerve sheath diameter measurement techniques: examination using a novel ex-vivo porcine model.

BACKGROUND: Ultrasound (U/S) and MRI measurements of the optic nerve sheath diameter (ONSD) have been proposed as intracranial pressure measurement surrogates, but these methods have not been fully evaluated or standardized. The purpose of this study was to develop an ex-vivo model for evaluating ONSD measurement techniques by comparing U/S and MRI measurements to physical measurements. METHODS: The left eye of post mortem juvenile pigs (N = 3) was excised and the subdural space of the optic nerve cannulated. Caliper measurements and U/S imaging measurements of the ONSD were acquired at baseline and following 1 cc saline infusion into the sheath. The samples were then embedded in 0.5% agarose and imaged in a 7 Tesla (7T) MRI. The ONSD was subsequently measured with digital calipers at locations and directions matching the U/S and direct measurements. RESULTS: Both MRI and sonographic measurements were in agreement with direct measurements. U/S data, especially axial images, exhibited a positive bias and more variance (bias: 1.318, 95% limit of agreement: 8.609) compared to MRI (bias: 0.3156, 95% limit of agreement: 2.773). In addition, U/S images were much more dependent on probe placement, distance between probe and target, and imaging plane. CONCLUSIONS: This model appears to be a valid test-bed for continued scrutiny of ONSD measurement techniques. In this model, 7T MRI was accurate and potentially useful for in-vivo measurements where direct measurements are not available. Current limitations with ultrasound imaging for ONSD measurement associated with image acquisition technique and equipment necessitate further standardization to improve its clinical utility.

Intracranial pressure and optic nerve sheath diameter as cephalic venous pressure increases in swine.

BACKGROUND: Nontraumatic, nonhydrocephalic increases in intracranial pressure (ICP) are often difficult to diagnose and may underlie spaceflight-related visual changes. This study looked at the utility of a porcine animal model of increasing cephalic venous pressure to mimic acute changes in ICP and optic nerve sheath diameter (ONSD) from cephalic venous fluid shifts observed during spaceflight. METHODS: Anesthetized juvenile piglets were assigned to groups of either naïve (N = 10) or elevated superior vena cava pressure (SVCP; N = 20). To elevate SVCP, a 6F custom latex balloon catheter was inserted and inflated to achieve SVCP of 20 and 40 mmHg for 1 h at each pressure. In both groups, serial measurements of ICP, internal jugular pressure (IJP), and external jugular pressure (EJP) were made hourly for 3 h, and ONSD of the right eye was measured hourly by ultrasound (US). RESULTS: There was a significant linear correlation between IJP and ICP (slope: 0.9614 +/- 0.0038, r = 0.9683). With increasing SVCP, resulting ONSD was also well correlated with the ICP (slope: 0.0958 +/- 0.0061, r = 0.7841). The receiver operating characteristic curve for ONSD in diagnosing elevated ICP had an area under the curve of 0.9632 with a sensitivity and specificity of 92% and 91%, respectively, for a cutoff of 5.45 mm. CONCLUSIONS: Increases in SVCP result in ICP changes that are well correlated with alteration in ONSD. These changes are consistent with observed ONSD changes monitored during spaceflight.