The effect of intraoperative intrathecal opioid administration on the length of stay and postoperative pain control for patients undergoing lumbar interbody fusion.

PURPOSE: In an effort to control postoperative pain more effectively in spinal fusion patients, intraoperative intrathecal morphine (ITM) administration is gaining popularity and acceptance with clinicians. This study seeks to determine the impact of intraoperative intrathecal opioid (ITO) administration following lumbar fusion surgery on postoperative pain and length of hospitalization as primary outcomes. Secondary outcomes will investigate postoperative opioid intake and side effects. METHODS: The retrospective analysis of collected data was performed. The study compared patients undergoing one- or two-level transforaminal interbody fusions between 2019 and 2021 who intraoperatively received two different ITO doses (n = 89) vs. the reference group (n = 48) that did not receive ITO. The patients in the ITO group received either 0.2 mg (n = 44) of duramorph or 0.2 mg duramorph + 50 mcg fentanyl (n = 45). The effect of ITO was evaluated for the first four postoperative days (POD) on pain scores (visual analog scale), length of stay (LOS, hours) and opioid requirement (MED, morphine equivalent dose). RESULTS: In the ITO group, a significant reduction of postoperative pain scores (t(99) = 4.3, p < 0.001) and opioid intake (t(70) = 2.49, p = 0.015) was noted on POD1. Cohen's d effect sizes were 0.76 and 0.50, meaning that postoperative pain and MED intake were reduced by about ¾ to ½ standard deviations (SD) in the ITO group. Further, multivariate regression models revealed that ITO administration predicted lower postoperative pain scores for the two PODs (ß = - 0.83, p < 0.001; ß = - 0.63, p = 0.022) and MED intake for the first two PODs (ß = - 20.8, p = 0.047; ß = - 16.4, p = 0.030). Mean LOS was 15.4 h less in the ITO group (mean ± SD, 63.4 ± 37.1 vs. 78.8 ± 39.6, p = 0.10). CONCLUSIONS: In conclusion, our study provides results in a large sample of patients undergoing transforaminal lumbar fusions. The results demonstrated that ITO administration is effective in reducing POD1 pain scores and POD1-2 opioid requirement while not increasing the risk of any opioid-related side effects.

Prospective, Randomized, Blinded Clinical Trial Comparing PEEK and Allograft Spacers in Patients Undergoing Anterior Cervical Discectomy and Fusion Surgeries.

STUDY DESIGN: Prospective, randomized, blinded clinical trial. OBJECTIVE: To examine clinical and radiological outcomes in patients undergoing anterior cervical discectomy and fusion (ACDF) surgeries randomized to receive either polyether-ether-ketone (PEEK) or structural bone allografts. SUMMARY OF BACKGROUND DATA: The biomechanical qualities as well as osteoconductive, osteogenic, and osteoinductive properties of various graft materials have been previously evaluated. There remain questions, however, as to whether there are any clinical and/or radiographic outcome differences in the selection of interbody graft types for ACDF. METHODS: Patients undergoing one- to three-level ACDF with single anterior plate fixation were randomized (1:1 ratio) to receive either cortical allograft or PEEK interbody spacers. Radiographic and clinical outcomes were assessed at 3, 6, 12, and 24 months with an additional postoperative radiographic assessment. RESULTS: A total of 120 patients were enrolled and randomized. Comparing clinical outcomes, no differences in arm or neck pain scores were noted; however, there was a statistically significant (≤0.041) improvement in SF-36 PCS scores for the allograft group at all follow-up time points and a tendency toward lower disability scores. Overall, evidence of radiographic fusion was achieved in 87 (91.6%) patients: five (10.2%) and three (6.5%) patients had pseudoarthrosis (P = 0.72) in the PEEK and allograft groups, respectively. At 24 months' follow-up time, any cervical or segmental alignment restoration achieved with surgery was lost and no statistically significant changes were detected when all levels of surgery were included. Likewise, there were no statistically significant differences between the groups for anterior or posterior body height measurements at the 24 months' follow-up. Approximately 20% of patients had anterior and posterior subsidence, all grade 0 regardless of the group assignment. CONCLUSION: Comparable radiographic outcomes were observed for patients undergoing one- to three-level PEEK versus allograft-assisted ACDF surgeries. Although MCID comparisons suggest that allograft and PEEK-treated patients have similar clinical outcomes, testing that incorporates the magnitude of the change suggests that there may be a statistically significant greater magnitude of improvement for the allograft group patients, but further studies with a larger sample size would be helpful to determine if a true effect exists.

Lower transfer factor of the lung for carbon monoxide in women with a patent foramen ovale.

NEW FINDINGS: What is the central question of this study? Do individuals with a patent foramen ovale (PFO+ ) have a lower lung transfer factor for carbon monoxide than those without (PFO- )? What is the main finding and its importance? We found a lower rate constant for carbon monoxide uptake in PFO+ compared with PFO- women, which was physiologically relevant (≥0.5 z-score difference), but not for PFO+ versus PFO- men. This suggests that factors independent of the PFO are responsible for our findings, possibly inherent structural differences in the lung. ABSTRACT: The transfer factor of the lung for carbon monoxide (TLCO ) measure assumes that all cardiac output flows through the pulmonary circuit. However, right-to-left blood flow through a shunt can result in a lower transfer factor than predicted. A patent foramen ovale (PFO) is a potential source of right-to-left shunt that is present in ∼35% of the population, but the effect of PFO on TLCO is unknown. We sought to determine the effect of PFO on the TLCO . We conducted a retrospective analysis of TLCO data from 239 (101 women) participants. Anthropometrics and lung function, including spirometry, plethysmography and TLCO , were compiled from our previously published work. Women, but not men, with a PFO had a significantly lower TLCO and rate constant for carbon monoxide uptake (KCO ) (percentage of predicted and z-score) than women without a PFO. Women and men with a PFO had normal alveolar volumes that did not differ from those without a PFO. Correcting the data for haemoglobin in a subset of subjects did not change the results (n = 58; 25 women). The lower KCO in women with versus without a PFO was physiologically relevant (≥0.5 z-score difference). There was no effect of PFO in men. This suggests that factors independent of the PFO are responsible for our findings, possibly inherent structural differences in the lung.

Prospective, randomized, double-blinded clinical trial comparing PEEK and allograft spacers in patients undergoing transforaminal lumbar interbody fusion surgeries.

BACKGROUND CONTEXT: Allograft and polyether-ether-ketone (PEEK) radiographic, biomechanical, histological properties have been extensively studied and both spacers have their advantages and shortcomings. There are no comparative randomized or double-blinded spinal fusion clinical trials reported to date. PURPOSE: The study's primary objective was to prospectively investigate clinical and radiological outcomes in patients undergoing lumbar interbody fusions and randomized to receive either PEEK or structural bone allografts. STUDY DESIGN/ SETTING: A prospective, randomized, double-blinded clinical trial was initiated at a single center. PATIENT SAMPLE: A total of 138 patients were enrolled, randomized and 121 patients completed the study. OUTCOME MEASURES: The primary clinical outcome parameters were scored from standardized patient-reported questionnaires. The severity of lower back and leg pain was evaluated using the 11-point Visual Analog Scale (VAS). The Oswestry Disability Questionnaire was used to evaluate chronic disability and activities of daily living. Health-related quality of life and functional outcomes were assessed using Health-related Quality of Life Questionnaire (SF-36 v2). Two scores within the scoring algorithm were analyzed: Physical Component (PCS) and Mental Component Summary (MCS). The primary radiological outcomes included restoration and maintenance of vertebral body height, lumbar sagittal and segmental alignment, and fusion status. METHODS: All patients were followed for 2 years ± 2 months; radiographic and clinical outcomes were assessed at 3, 6, 12 and 24 months with an additional follow-up at 3 weeks for radiographic assessment. RESULTS: A total of 138 patients undergoing transforaminal lumbar interbody fusions (TLIF) were randomized (1:1) to receive either cortical allograft or PEEK interbody lordotic spacers. Although no differences were detected between the allograft and PEEK patient groups at any of the follow-up time points, there was a highly significant (p<.0001) improvement in all clinical outcome measures. Overall, evidence of radiographic fusion was achieved in 118 (97.5%) patients at the 24 months follow-up. Three patients, all in the allograft group, had pseudoarthrosis and underwent revision surgeries. Postoperative improvement of sagittal alignment, anterior (ABH) or posterior body height (PBH) was initially achieved, but it was mainly lost or reduced at the final follow-up and there were no statistically significant differences between the groups. At the end of the study, improvement and maintenance of lumbar lordosis were achieved in 43.3% and 49.2% patients and segmental alignment in 38.3% and 36.1% for the allograft and PEEK patient groups, respectively. Similarly, ABH was improved and maintained in 28.3% and 36.1% patients and PBH in 28.3% and 44.3% for the allograft and PEEK groups, respectively. CONCLUSIONS: Although allograft-assisted surgeries may have reduced fusion rates, the study findings demonstrated that TLIF surgery with two different types of cages and in conjunction with rhBMP-2 resulted in similar radiological or clinical outcomes and a highly statistically significant improvement in all clinical outcome measures at the end of the study regardless of the randomization group.

No effect of patent foramen ovale on acute mountain sickness and pulmonary pressure in normobaric hypoxia.

NEW FINDINGS: What is the central question to this study? Is there a relationship between a patent foramen ovale and the development of acute mountain sickness and an exaggerated increase in pulmonary pressure in response to 7-10 h of normobaric hypoxia? What is the main finding and its importance? Patent foramen ovale presence did not increase susceptibility to acute mountain sickness or result in an exaggerated increase in pulmonary artery systolic pressure with normobaric hypoxia. This suggests hypobaric hypoxia is integral to the increased susceptibility to acute mountain sickness previously reported in those with patent foramen ovale, and patent foramen ovale presence alone does not contribute to the hypoxic pulmonary pressor response. ABSTRACT: Acute mountain sickness (AMS) develops following rapid ascent to altitude, but its exact causes remain unknown. A patent foramen ovale (PFO) is a right-to-left intracardiac shunt present in ∼30% of the population that has been shown to increase AMS susceptibility with high altitude hypoxia. Additionally, high altitude pulmonary oedema (HAPE) is a severe type of altitude illness characterized by an exaggerated pulmonary pressure response, and there is a greater prevalence of PFO in those with a history of HAPE. However, whether hypoxia per se is causing the increased incidence of AMS in those with a PFO and whether a PFO is associated with an exaggerated increase in pulmonary pressure in those without a history of HAPE is unknown. Participants (n = 36) matched for biological sex (18 female) and the presence or absence of a PFO (18 PFO+) were exposed to 7-10 h of normobaric hypoxia equivalent to 4755 m. Presence and severity of AMS was determined using the Lake Louise AMS scoring system. Pulmonary artery systolic pressure, cardiac output and total pulmonary resistance were measured using ultrasound. We found no significant association of PFO with incidence or severity of AMS and no association of PFO with arterial oxygen saturation. Additionally, there was no effect of a PFO on pulmonary pressure, cardiac output or total pulmonary resistance. These data suggest that hypobaric hypoxia is necessary for those with a PFO to have increased incidence of AMS and that presence of PFO is not associated with an exaggerated pulmonary pressor response.

Local Retropharyngeal Space Anesthetic for Dysphagia Reduction after Anterior Cervical Discectomy and Fusion Surgery: A Single-Center, Prospective, Randomized, Double-Blinded, Placebo-Controlled Clinical Trial.

OBJECTIVE: The main objective of this study was to analyze the ability of local anesthetic instillation into the retropharyngeal space to reduce dysphagia symptoms and occurrence rates in patients undergoing anterior cervical discectomy and fusion (ACDF) procedures. METHODS: A single-center, prospective, randomized, double-blinded, and placebo-controlled clinical study was performed. We enrolled patients undergoing one- or two-level ACDF procedures for cervical degenerative disc disease with disc herniation, radiculopathy and/or myelopathy symptoms. The patients were randomly assigned (1:1 ratio) to receive either 0.5% bupivacaine hydrochloride or 0.9% NaCl solution. RESULTS: Forty-three (74%) and 41 (77%) of patients reported dysphagia symptoms at the time of discharge in the investigational and control groups, respectively. There were no statistically significant differences in duration of dysphagia symptoms, Swallowing-Quality of Life (SWAL-QOL) survey or pain scores between the investigational and control patient groups at any of the follow-up time points. Controlling for independent variables, only younger age significantly predicted dysphagia symptoms at discharge, 2-week, and 3-month follow-ups (P ≤ 0.03; R ≥ -0.038; OR 0.96, 95% CI 0.93-0.99. Female sex was associated with lower SWAL-QOL scores at discharge (P = 0.046; R = 0.87; OR 2.38, 95% CI 1.02-5.56). A total of 8 (13.8%) and 6 (11.3%) patients in the investigational and control groups, respectively, were referred to a specialist or underwent speech therapy for their dysphagia symptoms. There were no adverse reactions to the study drug observed. CONCLUSIONS: Local retropharyngeal space anesthetic instillation did not reduce dysphagia symptoms or occurrence rates in patients undergoing anterior discectomy and fusion surgeries.

Impaired pulmonary gas exchange efficiency, but normal pulmonary artery pressure increases, with hypoxia in men and women with a patent foramen ovale.

NEW FINDINGS: What is the central question of this study? Do individuals with a patent foramen ovale (PFO+ ) have a larger alveolar-to-arterial difference in PO2 ( A-aDO2 ) than those without (PFO- ) and/or an exaggerated increase in pulmonary artery systolic pressure (PASP) in response to hypoxia? What is the main finding and its importance? PFO+ had a greater A-aDO2 while breathing air, 16% and 14% O2 , but not 12% or 10% O2 . PASP increased equally in hypoxia between PFO+ and PFO- . These data suggest that PFO+ may not have an exaggerated acute increase in PASP in response to hypoxia. ABSTRACT: Patent foramen ovale (PFO) is present in 30-40% of the population and is a potential source of right-to-left shunt. Accordingly, those with a PFO (PFO+ ) may have a larger alveolar-to-arterial difference in PO2 ( A-aDO2 ) than those without (PFO- ) in normoxia and with mild hypoxia. Likewise, PFO is associated with high-altitude pulmonary oedema, a condition known to have an exaggerated pulmonary pressure response to hypoxia. Thus, PFO+ may also have exaggerated pulmonary pressure increases in response to hypoxia. Therefore, the purposes of the present study were to systematically determine whether or not: (1) the A-aDO2 was greater in PFO+ than in PFO- in normoxia and mild to severe hypoxia and (2) the increase in pulmonary artery systolic pressure (PASP) in response to hypoxia was greater in PFO+ than in PFO- . We measured arterial blood gases and PASP via ultrasound in healthy PFO+ (n = 15) and PFO- (n = 15) humans breathing air and 30 min after breathing four levels of hypoxia (16%, 14%, 12%, 10% O2 , randomized and balanced order) at rest. The A-aDO2 was significantly greater in PFO+ compared to PFO- while breathing air (2.1 ± 0.7 vs. 0.4 ± 0.3 Torr), 16% O2 (1.8 ± 1.2 vs. 0.7 ± 0.8 Torr) and 14% O2 (2.3 ± 1.2 vs. 0.7 ± 0.6 Torr), but not 12% or 10% O2 . We found no effect of PFO on PASP at any level of hypoxia. We conclude that PFO influences pulmonary gas exchange efficiency with mild hypoxia, but not the acute increase in PASP in response to hypoxia.

The Impact of Preventative Multimodal Analgesia on Postoperative Opioid Requirement and Pain Control in Patients Undergoing Lumbar Fusions.

STUDY DESIGN: A prospective observational study with a historical reference group. OBJECTIVES: The main objectives of this study were to determine the impact of preventative multimodal analgesia (PMA) on postoperative opioid requirements and analgesic effectiveness in patients undergoing lumbar fusion surgery. SUMMARY OF BACKGROUND DATA: PMA addresses the multiple pathways of acute and chronic pain by interfering with peripheral and central sensitization and should provide a way to achieve safer and more effective pain management with reduced opioid medication use. MATERIALS AND METHODS: This study compared postoperative opioid requirement and analgesic effect in a total of 101 patients undergoing elective, 1-level or 2-level transforaminal lumbar interbody fusion surgeries for symptomatic lumbar degenerative disk disease. The PMA patient group included 51 consecutive patients who received 1000 mg of acetaminophen, 300-900 mg of gabapentin, and 200-400 mg of celecoxib 1 hour before their index procedure. The reference group included 50 patients who received 15 mg of morphine-equivalent dose (MED) preoperatively.Multiple linear regression was used to evaluate the effect of PMA on postoperative pain and MED over 4 postoperative days, while controlling for all variables likely to influence these outcomes, including age, sex, baseline opioid use, duration of surgery, postoperative intrathecal morphine use and the administration of muscle relaxants and anticonvulsants. RESULTS: The differences in opioid requirement and postoperative pain scores were statistically significant on all 4 postoperative days. The effect size varied from -0.54 to -0.99 (34.8%-54.2% MED reduction) for the postoperative opioid requirement and from -0.59 to -1.16 (28.9%-37.3% visual analog scale reduction) for postoperative pain indicating that these measures were reduced by about ½ to 1 SD in the PMA patient group. CONCLUSIONS: PMA is a highly effective and safe method for postoperative pain management in patients undergoing elective lumbar fusion surgeries by improving pain control and reducing opioid requirement. LEVEL OF EVIDENCE: Level III.

Prospective randomized feasibility study comparing manual vs. automatic position-adaptive spinal cord stimulation with surgical leads.

BACKGROUND: The majority of patients experience uncomfortable stimulation associated with posture changes, especially when lying down. The spinal cord moves within the intrathecal space in response to positional changes affecting the size of the stimulated area accordingly and causing overstimulation or understimulation. To accommodate for positional changes, patients have to manually adjust the stimulation parameters; therefore, an automatic position-adaptive SCS was designed to address these issues. The primary objective of this study was to establish the extent of position-related variations in SCS stimulation parameters experienced by chronic pain patients implanted with surgical, laminectomy-type leads under both automatic and manual SCS conditions. METHODS: A total of 18 patients completed a single-center, prospective, non-blinded, randomized (1:1), feasibility clinical study with a two-arm crossover design. All patients undergoing SCS treatment for chronic refractory back and or leg pain associated with failed back surgery, post-laminectomy, or radicular pain syndromes that were refractory to conservative and surgical interventions were eligible for enrollment. After the manual stimulation mode, the patients were randomized to one of two study arms: manual or automatic position-adaptive stimulation and then crossed over to a different arm. All patients were followed for a total of 5 months (± 2 weeks). RESULTS: Analysis indicated statistically significant differences between therapeutic and threshold stimulation intensity for the supine position compared with all other body positions when using either automatic position-adaptive stimulation or manual stimulation, except for threshold amplitudes in the prone position for automatic stimulation. CONCLUSION: Similar variations were reported for manual and automatic stimulation intensity in response to positional changes.

AltitudeOmics: effect of reduced barometric pressure on detection of intrapulmonary shunt, pulmonary gas exchange efficiency, and total pulmonary resistance.

Blood flow through intrapulmonary arteriovenous anastomoses (QIPAVA) occurs in healthy humans at rest and during exercise when breathing hypoxic gas mixtures at sea level and may be a source of right-to-left shunt. However, at high altitudes, QIPAVA is reduced compared with sea level, as detected using transthoracic saline contrast echocardiography (TTSCE). It remains unknown whether the reduction in QIPAVA (i.e., lower bubble scores) at high altitude is due to a reduction in bubble stability resulting from the lower barometric pressure (PB) or represents an actual reduction in QIPAVA. To this end, QIPAVA, pulmonary artery systolic pressure (PASP), cardiac output (QT), and the alveolar-to-arterial oxygen difference (AaDO2) were assessed at rest and during exercise (70-190 W) in the field (5,260 m) and in the laboratory (1,668 m) during four conditions: normobaric normoxia (NN; [Formula: see text] = 121 mmHg, PB = 625 mmHg; n = 8), normobaric hypoxia (NH; [Formula: see text] = 76 mmHg, PB = 625 mmHg; n = 7), hypobaric normoxia (HN; [Formula: see text] = 121 mmHg, PB = 410 mmHg; n = 8), and hypobaric hypoxia (HH; [Formula: see text] = 75 mmHg, PB = 410 mmHg; n = 7). We hypothesized QIPAVA would be reduced during exercise in isooxic hypobaria compared with normobaria and that the AaDO2 would be reduced in isooxic hypobaria compared with normobaria. Bubble scores were greater in normobaric conditions, but the AaDO2 was similar in both isooxic hypobaria and normobaria. Total pulmonary resistance (PASP/QT) was elevated in HN and HH. Using mathematical modeling, we found no effect of hypobaria on bubble dissolution time within the pulmonary transit times under consideration (<5 s). Consequently, our data suggest an effect of hypobaria alone on pulmonary blood flow. NEW & NOTEWORTHY Blood flow through intrapulmonary arteriovenous anastomoses, detected by transthoracic saline contrast echocardiography, was reduced during exercise in acute hypobaria compared with normobaria, independent of oxygen tension, whereas pulmonary gas exchange efficiency was unaffected. Modeling the effect(s) of reduced air density on contrast bubble lifetime did not result in a significantly reduced contrast stability. Interestingly, total pulmonary resistance was increased by hypobaria, independent of oxygen tension, suggesting that pulmonary blood flow may be changed by hypobaria.

Medical complications and mortality in octogenarians undergoing elective spinal fusion surgeries.

BACKGROUND: The consequences of suffering postoperative complications in elderly undergoing spinal surgeries may be different compared to younger patients. The primary objective of this study was to identify the types and frequency of medical complications and mortality rates in patients 80 years of age or older undergoing elective spinal fusion surgeries for degenerative spinal disease. METHODS: A prospective observational study with a retrospective chart review was performed, which included all consecutive patients ≥80 years old undergoing elective spinal fusion surgeries from May 2012 to August 2015. We identified a total of 95 patients, of which 39 cervical and 56 lumbar surgeries were performed. There were 41 female and 54 male patients with the mean age of 82.8 years (range, 80-91). The perioperative complications were allocated into the following categories: infection, pulmonary, cardiac, gastrointestinal, hematologic, urologic, neurovascular, thromboembolic, and other. Baseline and postoperative clinical outcome scores were compared to evaluate efficacy. RESULTS: The mean follow-up time was 14.8 months (range, 5 days to 37 months) with an overall mortality rate of 8.4%. The 30-day, 90-day, and 1-year mortality rates were 2.1, 2.1, and 4.2%, respectively. There were 53.9 and 71.4% patients with complications in the cervical and lumbar patient groups, respectively. The presence of general comorbidities and the number of intervertebral levels predicted the occurrence of perioperative complications. Also, longer OR times were associated with a higher number of complications per patient and the occurrence of a UTI. Dysphagia was a significant predictor in developing pneumonia and atelectasis. CONCLUSIONS: The incidence of perioperative medical complications and mortality rates in octogenarians undergoing elective spinal surgeries are quite high. The benefits of having surgery must be weighed against the risks of not only surgical but also adverse medical events. An informed decision-making process should include discussion of potential postoperative morbidity specific to this patient population in order to guide patient's acceptance of higher risks and expectations postoperatively. It is also important to identify potential complications and adapt preventive measures in order to help minimize them in this patient population.

Commentary: Old Self vs. New Self.

Implantation of deep brain stimulator (DBS) leads for Gilles de Tourette syndrome was first described by Visser-Vanderwalle et al., with a reported 70%-90% decrease in tic frequency. 1 Since that time, several targets, including the basal/ganglia and striatum, have been described. The target remains experimental, and in this case, leads were implanted under an investigator-initiated research protocol. Ms. L. reported an excellent intraoperative reduction in the "urge to tic" that persisted for 15 weeks postoperatively, indicating that the leads were well placed. Furthermore, although her tic frequency has increased, it remains improved from baseline and returns to baseline when stimulation is discontinued. Although her response does not represent what her treatment team would consider the "desired medical/therapeutic outcomes," there is no question that the patient recognizes benefit from her stimulation. In fact, she clearly states that "it's like I've felt a new way and don't want to go back to the old way."

Intrapulmonary arteriovenous anastomoses in humans with chronic obstructive pulmonary disease: implications for cryptogenic stroke?

What is the central question of this study? Do individuals with chronic obstructive pulmonary disease have blood flow through intrapulmonary arteriovenous anastomoses at rest or during exercise? What is the main finding and its importance? Individuals with chronic obstructive pulmonary disease have a greater prevalence of blood flow through intrapulmonary arteriovenous anastomoses at rest than age-matched control subjects. Given that the intrapulmonary arteriovenous anastomoses are large enough to permit venous emboli to pass into the arterial circulation, patients with chronic obstructive pulmonary disease and an elevated risk of thrombus formation may be at risk of intrapulmonary arteriovenous anastomosis-facilitated embolic injury (e.g. stroke or transient ischaemic attack). The pulmonary capillaries prevent stroke by filtering venous emboli from the circulation. Intrapulmonary arteriovenous anastomoses are large-diameter (≥50 µm) vascular connections in the lung that may compromise the integrity of the pulmonary capillary filter and have recently been linked to cryptogenic stroke and transient ischaemic attack. Prothrombotic populations, such as individuals with chronic obstructive pulmonary disease (COPD), may be at increased risk of stroke and transient ischaemic attack facilitated by intrapulmonary arteriovenous anastomoses, but the prevalence and degree of blood flow through intrapulmonary arteriovenous anastomoses in this population has not been fully examined and compared with age-matched healthy control subjects. We used saline contrast echocardiography to assess blood flow through intrapulmonary arteriovenous anastomoses at rest (n = 29 COPD and 19 control subjects) and during exercise (n = 10 COPD and 10 control subjects) in subjects with COPD and age-matched healthy control subjects. Blood flow through intrapulmonary arteriovenous anastomoses was detected in 23% of subjects with COPD at rest and was significantly higher compared with age-matched healthy control subjects. Blood flow through intrapulmonary arteriovenous anastomoses at rest was reduced or eliminated in subjects with COPD after breathing hyperoxic gas. Sixty per cent of subjects with COPD who did not have blood flow through the intrapulmonary arteriovenous anastomoses at rest had blood flow through them during exercise. The combination of blood flow through intrapulmonary arteriovenous anastomoses and potential for thrombus formation in individuals with COPD may permit venous emboli to pass into the arterial circulation and cause stroke and transient ischaemic attack. Breathing supplemental oxygen may reduce this risk in COPD. The link between blood flow through intrapulmonary arteriovenous anastomoses, stroke and transient ischaemic attack is worthy of future investigation in COPD and other populations.

Decreased arterial PO2, not O2 content, increases blood flow through intrapulmonary arteriovenous anastomoses at rest.

KEY POINTS: The mechanism(s) that regulate hypoxia-induced blood flow through intrapulmonary arteriovenous anastomoses (QIPAVA ) are currently unknown. Our previous work has demonstrated that the mechanism of hypoxia-induced QIPAVA is not simply increased cardiac output, pulmonary artery systolic pressure or sympathetic nervous system activity and, instead, it may be a result of hypoxaemia directly. To determine whether it is reduced arterial PO2 (PaO2) or O2 content (CaO2) that causes hypoxia-induced QIPAVA , individuals were instructed to breathe room air and three levels of hypoxic gas at rest before (control) and after CaO2 was reduced by 10% by lowering the haemoglobin concentration (isovolaemic haemodilution; Low [Hb]). QIPAVA , assessed by transthoracic saline contrast echocardiography, significantly increased as PaO2 decreased and, despite reduced CaO2 (via isovolaemic haemodilution), was similar at iso-PaO2. These data suggest that, with alveolar hypoxia, low PaO2 causes the hypoxia-induced increase in QIPAVA , although where and how this is detected remains unknown. ABSTRACT: Alveolar hypoxia causes increased blood flow through intrapulmonary arteriovenous anastomoses (QIPAVA ) in healthy humans at rest. However, it is unknown whether the stimulus regulating hypoxia-induced QIPAVA is decreased arterial PO2 (PaO2) or O2 content (CaO2). CaO2 is known to regulate blood flow in the systemic circulation and it is suggested that IPAVA may be regulated similar to the systemic vasculature. Thus, we hypothesized that reduced CaO2 would be the stimulus for hypoxia-induced QIPAVA . Blood volume (BV) was measured using the optimized carbon monoxide rebreathing method in 10 individuals. Less than 5 days later, subjects breathed room air, as well as 18%, 14% and 12.5% O2 , for 30 min each, in a randomized order, before (CON) and after isovolaemic haemodilution (10% of BV withdrawn and replaced with an equal volume of 5% human serum albumin-saline mixture) to reduce [Hb] (Low [Hb]). PaO2 was measured at the end of each condition and QIPAVA was assessed using transthoracic saline contrast echocardiography. [Hb] was reduced from 14.2 ± 0.8 to 12.8 ± 0.7 g dl(-1) (10 ± 2% reduction) from CON to Low [Hb] conditions. PaO2 was no different between CON and Low [Hb], although CaO2 was 10.4%, 9.2% and 9.8% lower at 18%, 14% and 12.5% O2 , respectively. QIPAVA significantly increased as PaO2 decreased and, despite reduced CaO2, was similar at iso-PaO2. These data suggest that, with alveolar hypoxia, low PaO2 causes the hypoxia-induced increase in QIPAVA . Whether the low PO2 is detected at the carotid body, airway and/or the vasculature remains unknown.

Bilateral deep brain stimulation of the fornix for Alzheimer's disease: surgical safety in the ADvance trial.

OBJECT This report describes the stereotactic technique, hospitalization, and 90-day perioperative safety of bilateral deep brain stimulation (DBS) of the fornix in patients who underwent DBS for the treatment of mild, probable Alzheimer's disease (AD). METHODS The ADvance Trial is a multicenter, 12-month, double-blind, randomized, controlled feasibility study being conducted to evaluate the safety, efficacy, and tolerability of DBS of the fornix in patients with mild, probable AD. Intraoperative and perioperative data were collected prospectively. All patients underwent postoperative MRI. Stereotactic analyses were performed in a blinded fashion by a single surgeon. Adverse events (AEs) were reported to an independent clinical events committee and adjudicated to determine the relationship between the AE and the study procedure. RESULTS Between June 6, 2012, and April 28, 2014, a total of 42 patients with mild, probable AD were treated with bilateral fornix DBS (mean age 68.2 ± 7.8 years; range 48.0-79.7 years; 23 men and 19 women). The mean planned target coordinates were x = 5.2 ± 1.0 mm (range 3.0-7.9 mm), y = 9.6 ± 0.9 mm (range 8.0-11.6 mm), z = -7.5 ± 1.2 mm (range -5.4 to -10.0 mm), and the mean postoperative stereotactic radial error on MRI was 1.5 ± 1.0 mm (range 0.2-4.0 mm). The mean length of hospitalization was 1.4 ± 0.8 days. Twenty-six (61.9%) patients experienced 64 AEs related to the study procedure, of which 7 were serious AEs experienced by 5 patients (11.9%). Four (9.5%) patients required return to surgery: 2 patients for explantation due to infection, 1 patient for lead repositioning, and 1 patient for chronic subdural hematoma. No patients experienced neurological deficits as a result of the study, and no deaths were reported. CONCLUSIONS Accurate targeting of DBS to the fornix without direct injury to it is feasible across surgeons and treatment centers. At 90 days after surgery, bilateral fornix DBS was well tolerated by patients with mild, probable AD. Clinical trial registration no.: NCT01608061 ( clinicaltrials.gov ).

AltitudeOmics: impaired pulmonary gas exchange efficiency and blunted ventilatory acclimatization in humans with patent foramen ovale after 16 days at 5,260 m.

A patent foramen ovale (PFO), present in ∼40% of the general population, is a potential source of right-to-left shunt that can impair pulmonary gas exchange efficiency [i.e., increase the alveolar-to-arterial Po2 difference (A-aDO2)]. Prior studies investigating human acclimatization to high-altitude with A-aDO2 as a key parameter have not investigated differences between subjects with (PFO+) or without a PFO (PFO-). We hypothesized that in PFO+ subjects A-aDO2 would not improve (i.e., decrease) after acclimatization to high altitude compared with PFO- subjects. Twenty-one (11 PFO+) healthy sea-level residents were studied at rest and during cycle ergometer exercise at the highest iso-workload achieved at sea level (SL), after acute transport to 5,260 m (ALT1), and again at 5,260 m after 16 days of high-altitude acclimatization (ALT16). In contrast to PFO- subjects, PFO+ subjects had 1) no improvement in A-aDO2 at rest and during exercise at ALT16 compared with ALT1, 2) no significant increase in resting alveolar ventilation, or alveolar Po2, at ALT16 compared with ALT1, and consequently had 3) an increased arterial Pco2 and decreased arterial Po2 and arterial O2 saturation at rest at ALT16. Furthermore, PFO+ subjects had an increased incidence of acute mountain sickness (AMS) at ALT1 concomitant with significantly lower peripheral O2 saturation (SpO2). These data suggest that PFO+ subjects have increased susceptibility to AMS when not taking prophylactic treatments, that right-to-left shunt through a PFO impairs pulmonary gas exchange efficiency even after acclimatization to high altitude, and that PFO+ subjects have blunted ventilatory acclimatization after 16 days at altitude compared with PFO- subjects.

Ventilatory and sensory responses in adult survivors of preterm birth and bronchopulmonary dysplasia with reduced exercise capacity.

RATIONALE: Adults born very to extremely preterm, with or without bronchopulmonary dysplasia (BPD), have obstructive lung disease, but it is unknown whether this results in respiratory limitations, such as mechanical constraints to Vt expansion during exercise leading to intolerable dyspnea and reduced exercise tolerance, as it does in patients with chronic obstructive pulmonary disease. OBJECTIVES: To test the hypothesis that adult survivors of preterm birth (≤32 wk gestational age) with (n = 20) and without BPD (n = 15) with reduced exercise capacity demonstrate clinically important respiratory limitations at near-maximal exercise compared with full-term control subjects (n = 20). METHODS: Detailed ventilatory and sensory measurements were made before and during exercise on all patients in the three study groups. MEASUREMENTS AND MAIN RESULTS: During exercise at 90% of peak [Formula: see text]o2 ([Formula: see text]o2peak), inspiratory reserve volume decreased to ∼0.5 L in all groups, but this occurred at significantly lower absolute workloads and [Formula: see text]e in ex-preterm subjects with and without BPD compared with full-term control subjects. Severe dyspnea was present and similar at comparable [Formula: see text]e between all groups, but leg discomfort at comparable workloads was greater in ex-preterm subjects with and without BPD compared with control subjects. At 50 to 90% of [Formula: see text]o2peak, exercise-induced expiratory flow limitation was significantly greater in ex-preterm subjects with BPD compared with ex-preterm subjects without BPD and control subjects. The degree of expiratory flow limitation in ex-preterm subjects with and without BPD was significantly related to neonatal O2 therapy duration. CONCLUSIONS: Severe dyspnea and leg discomfort associated with critical constraints on Vt expansion may lead to reduced exercise tolerance in adults born very or extremely preterm, whether or not their birth was complicated by BPD and despite differences in expiratory flow limitation. In this regard, adults born very or extremely preterm have respiratory limitations to exercise similar to patients with chronic obstructive pulmonary disease.

Pulmonary gas exchange efficiency during exercise breathing normoxic and hypoxic gas in adults born very preterm with low diffusion capacity.

Adults with a history of very preterm birth (<32 wk gestational age; PRET) have reduced lung function and significantly lower lung diffusion capacity for carbon monoxide (DLCO) relative to individuals born at term (CONT). Low DLCO may predispose PRET to diffusion limitation during exercise, particularly while breathing hypoxic gas because of a reduced O2 driving gradient and pulmonary capillary transit time. We hypothesized that PRET would have significantly worse pulmonary gas exchange efficiency [i.e., increased alveolar-to-arterial Po2 difference (AaDO2)] during exercise breathing room air or hypoxic gas (FiO2 = 0.12) compared with CONT. To test this hypothesis, we compared the AaDO2 in PRET (n = 13) with a clinically mild reduction in DLCO (72 ± 7% of predicted) and CONT (n = 14) with normal DLCO (105 ± 10% of predicted) pre- and during exercise breathing room air and hypoxic gas. Measurements of temperature-corrected arterial blood gases, and direct measure of O2 saturation (SaO2), were made prior to and during exercise at 25, 50, and 75% of peak oxygen consumption (V̇o2peak) while breathing room air and hypoxic gas. In addition to DLCO, pulmonary function and exercise capacity were significantly less in PRET. Despite PRET having low DLCO, no differences were observed in the AaDO2 or SaO2 pre- or during exercise breathing room air or hypoxic gas compared with CONT. Although our findings were unexpected, we conclude that reduced pulmonary function and low DLCO resulting from very preterm birth does not cause a measureable reduction in pulmonary gas exchange efficiency.