Three-dimensional vertebral shape changes confirm growth modulation after anterior vertebral body tethering for idiopathic scoliosis.

PURPOSE: To evaluate three-dimensional (3D) vertebra and disk shape changes over 2 years following anterior vertebral body tether (AVBT) placement in patients with idiopathic scoliosis (IS). METHODS: Patients with right thoracic IS treated with AVBT were retrospectively evaluated. 3D reconstructions were created from biplanar radiographs. Vertebral body and disk height (anterior, posterior, left and right) and shape (wedging angle) were recorded over the three apical segments in the local vertebral reference planes. Changes in height and wedging were measured through 2 years postoperatively. Change in patient height was correlated with changes in the spine dimensions. RESULTS: Forty-nine patients (Risser 0-3, Sanders 2-4) were included. The mean age was 12.2 ± 1.4 years (range 8-14). The mean coronal curve was 51 ± 10° preoperatively, 31 ± 9° at first postoperative time point and 27 ± 11° at 2-year follow-up (p < 0.001). The mean patient height increased 8 cm by 2 years (p < 0.001). The left side of the spine (vertebra + disc) grew in height by 2.2 mm/level versus 0.7 mm/level on the right side (p < 0.001). This differential growth was composed of 0.5 mm/vertebral level and 1.0 mm/disk level. Evaluation of the change in disk heights showed significantly decreased height anteriorly (- 0.4 mm), posteriorly (- 0.3 mm) and on the right (- 0.5 mm) from FE to 2 years. Coronal wedging reduced 2.3°/level with 1.1°/vertebral level change and 1.2°/disk level. There was no differential growth in the sagittal plane (anterior/posterior height). Patient height change moderately correlated with 3D measures of vertebra + disk shape changes. CONCLUSIONS: Three-dimensional analysis confirms AVBT in skeletally immature patients results in asymmetric growth of the apical spine segments. The left (untethered) side length increased more than 3 × than the right (tethered) side length with differential effects observed within the vertebral bodies and disks, each correlating with overall patient height change.

Arthroscopic Shoulder Stabilization in High School Football Players.

Background: Destabilizing shoulder injuries are common in high school American football players; however, the rate of recurrent glenohumeral instability and return to play after arthroscopic labral stabilization surgery remains unknown. Purpose/Hypothesis: The purpose of this study was to determine the rate of recurrent instability on return to competitive high school football after arthroscopic shoulder labral stabilization and capsulorrhaphy procedures. It was hypothesized that the instability rate would be greater in players with more years of eligibility remaining (YER) to play at the high school level. Study Design: Case series; Level of evidence, 4. Methods: Consecutive male high school football players with at least 1 YER who sustained at least 1 anterior traumatic inseason shoulder instability episode and underwent arthroscopic stabilization between 2012 and 2017 were identified. Patients and/or families were contacted by phone to discuss (1) recurrent instability episodes and (2) return to competitive sport and/or recreational athletic activity. Statistical analysis was conducted using chi-square tests to compare recurrent shoulder instability with return to play and YER. Results: A total of 45 football players aged 14 to 17 years were included, with a mean follow-up of 4.1 years. Most patients (60%) chose not to return to competitive football, due mainly to fear of recurrent injury. Overall, the recurrent instability rate was 15.6% (7/45). The instability rate in players who returned to football was 16.7%, with 66.7% requiring revision surgery. The instability rate in patients who did not return to football was 14.8%, with no revision procedures required. In players who returned to football, the instability rate in YER group 4 was significantly higher than that in YER groups 1 to 3 (42% vs 10.5%, respectively, P = .03), with each year of play conferring an additional 10% risk of reinjury. There was a significant difference in the type of recurrent instability in players who returned to any sport versus those who did not (P = .029). Conclusion: High school football players who returned to competitive play after arthroscopic shoulder stabilization surgery experienced a higher rate of recurrent instability that was dependent on their YER. Over half of the players chose not to return to football, with fear of reinjury being the most common reason.

Intrawound Vancomycin Powder Reduces Delayed Deep Surgical Site Infections Following Posterior Spinal Fusion for Adolescent Idiopathic Scoliosis.

STUDY DESIGN: Retrospective. OBJECTIVE: Evaluate whether the use of vancomycin powder (VP) placed in the surgical site prior to wound closure prevents delayed deep surgical site infections (DDI). SUMMARY OF BACKGROUND DATA: DDI after posterior spinal fusion (PSF) in adolescent idiopathic scoliosis (AIS) patients remains a significant major complication. The use of VP to prevent acute surgical site infection has been reported but the impact on DDI is unknown. METHODS: AIS patients treated over the past 20 years with PSF/instrumentation from a large muti-center registry were reviewed. Patients were divided into two groups: intraoperative vancomycin powder placed in the wound (VP) or no antibiotics placed in the wound (NVP). DDI was defined as an infection that occurred >90 days after surgery and required surgical intervention in the operating room. Patients who developed a DDI had secondary verification of VP use or not. Chi square and Kaplan-Meier (K-M) survivorship analyses were used to compare demographics and incident rate of DDI between groups. RESULTS: 4145 cases met inclusion for this study. A total of 43 DDI cases were identified (1.0%). The incidence of DDI for the VP group was 0.2% (4/2111), and 1.9% (39/2034) in the NVP group (P<0.001). Given the difference in follow-up for the 2 groups a Cumulative Survival and Kaplan-Meier analysis revealed the VP group had significantly better "survival" (no DDI) than the NVP group (P<0.001). CONCLUSION: DDIs are significant, adverse events that can greatly complicate patient recovery after PSF for AIS, including rehospitalization. This study found that patients who received VP intraoperatively were 10 times less likely to develop a DDI than those who did not receive VP. Although other advances/changes in surgical techniques may contribute to the significant decrease in infections found in the more recent VP cohort, VP should be considered as a prophylactic measure.

Intermediate Outcomes of Medial Ulnar Collateral Ligament Reconstruction Using Gracilis Allograft in Adolescent Patients.

Background: Autograft palmaris has been the primary choice for the reconstruction of the medial ulnar collateral ligament (UCL) in the elbow. Agenesis of the palmaris tendon is not rare, and outcomes of allograft reconstruction in the breadth of athlete types found in the adolescent population are lacking. Hypothesis: Allograft tendon reconstruction of the medial UCL in the young elbow would have low failure rates and satisfactory outcome scores. Study Design: Case series; Level of evidence, 4. Methods: The records of patients who underwent allograft medial UCL reconstruction (UCLR) by a single surgeon between 2009 and 2019 were reviewed. Patient-reported outcome scores in adolescent patients obtained at a minimum 4-year follow-up (for intermediate assessment) were recorded, with no exclusion according to sex or sport type. Outcomes included the Timmerman-Andrews score, the Single Assessment Numeric Evaluation (SANE), and the Conway-Jobe score. Results: Of 29 patients who underwent allograft UCLR, 10 adolescents (40% women; mean age at surgery, 15.8 years [age range, 15-17 years]) met the inclusion criteria and were included in the study. The mean follow-up was 8 years (range, 4.3-11.9 years). There were 4 overhead athletes (baseball, water polo) and 6 impact sports athletes (motocross, gymnastics, wrestling, and soccer). The mean SANE score was 86.3, and the mean subjective Timmerman-Andrews score was 92.5. The Conway-Jobe score was "excellent" in 7 of 10 participants; nonetheless, 3 elected not to return to sport (2 for reasons unrelated to the elbow). No patients experienced loss of range of motion, contracture, or ulnar nerve neuropathy. There was 1 patient with early failure (10%) who required revision reconstruction . Conclusion: Allograft reconstruction for medial UCL instability in adolescent patients from sport and trauma mechanisms demonstrated excellent patient-reported functional scores in this study. If the patient and surgeon desire to avoid autograft morbidity or agenesis of the palmaris longus, allograft tendon UCLR appears viable for both the throwing and the high-impact adolescent athlete, regardless of sex.

Vertebral body tethering for Lenke 1A curves: the lumbar modifier predicts less optimal outcomes.

INTRODUCTION: The addition of the L4 "AR" and "AL" lumbar modifier for Lenke 1A idiopathic scoliosis (IS) has been shown to direct treatment in posterior spinal fusion; however, its utility in vertebral body tethering (VBT) has yet to be evaluated. METHODS: A review of a prospective, multicenter database for VBT in IS was performed for patients with Lenke 1A deformities and a minimum of 2 years follow-up. Patients were categorized by their lumbar modifier (AR vs AL). Less optimal VBT outcome (LOVO) was defined as a final coronal curve > 35°, lumbar adding-on, or revision surgery for deformity progression or adding-on. RESULTS: Ninety-nine patients met inclusion criteria (81% female, mean 12.6 years), with 55.6% being AL curves. Overall, there were 23 instances of tether breakage (23.3%) and 20 instances of LOVO (20.2%). There was a higher rate of LOVO in AR curves (31.8% vs 10.9%, P = 0.01). Patients with LOVO had greater preoperative deformity, greater apical translation, larger coronal deformity on first erect radiographs, and less coronal deformity correction. Failure to correct the deformity < 30° on first erect was associated with LOVO, as was LIV selection short of the last touch vertebra (TV). Independent risk factors for LOVO included AR curves (OR 3.4; P = 0.04) and first erect curve magnitudes > 30 degrees (OR 6.0; P = 0.002). DISCUSSION: There is a 20.2% rate of less optimal VBT following VBT for Lenke 1A curves. AR curves are independently predictive of less optimal outcomes following VBT and require close attention to LIV selection. Surgeons should consider achieving an initial coronal correction < 30 degrees and extending the LIV to at least the TV to minimize the risk of LOVO.

Breaking the Rules in Three Dimensions: What to Expect After a Thoracic-only Fusion With Structural Thoracic and Thoracolumbar Curves.

OBJECTIVE: Despite guidelines to fuse both thoracic and thoracolumbar/lumbar (TH/L) curves in patients with structural curves in both regions, a thoracic-only fusion allows preservation of lumbar motion segments. The purpose of this study was to assess the 2-year postoperative three-dimensional (3D) radiographic and clinical outcomes of patients with double or triple major (thoracic curves >TH/L curves) structural curves who underwent a thoracic-only fusion. METHODS: A prospective adolescent idiopathic scoliosis registry was queried for double or triple major curves undergoing thoracic-only posterior fusion and a minimum 2-year follow-up. 3D reconstructions were generated from bi-planar radiographs. Paired sample t tests were used to assess differences in the coronal, sagittal, and axial planes pre and postoperatively, as well as Scoliosis Research Society Questionnaire-22 scores. Pearson correlations were utilized to identify variables related to spontaneous lumbar derotation. RESULTS: Twenty-two patients met the inclusion criteria. Both thoracic [61 ± 10 degrees to 20 ± 9 degrees ( P < 0.001)] and lumbar curves [41 ± 7 degrees to 22±7 degrees ( P < 0.001)] had significant coronal improvement and T5 to T12 kyphosis improved from 7 ± 14 degrees to 23 ± 8 degrees ( P < 0.001). The thoracic apical translation was significantly improved postoperatively (4.7 ± 1.5 to 0.5 ± 1 cm, P < 0.001), but the lumbar apical translation was unchanged (-1.7 ± 0.6 to -1.7±0.8 cm, P = 0.94). Scoliosis Research Society Questionnaire-22 scores significantly improved by 2 years postoperative. CONCLUSIONS: Unlike the 3D correction observed in nonstructural TH/L curves after thoracic-only fusion, patients with double or triple major curves demonstrated only spontaneous coronal correction of the lumbar curve, whereas the sagittal and axial planes were not significantly improved. These radiographic parameters did not negatively affect subjective or clinical outcomes at minimum 2-year follow-up. LEVEL OF EVIDENCE: Level IV-therapeutic.

Vertical Stenosis as a Morphological Risk Factor for Anterior Cruciate Ligament Ruptures in Children: A Magnetic Resonance Imaging-Based Comparison.

BACKGROUND: There are known anatomic variations that may lead to traumatic disruption of the anterior cruciate ligament (ACL) identified within adult and adolescent patients. PURPOSE/HYPOTHESIS: The purpose of this study was to compare the parameters of pediatric knees diagnosed with and without an ACL injury by magnetic resonance imaging. The hypothesis was that children with ACL abnormalities would demonstrate an equivalent notch width index (NWI), but a larger notch height index (NHI), in comparison with age-matched patients without ACL abnormalities, suggesting an association with congenital morphology. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A retrospective comparison cohort study of pediatric knees was performed by evaluating those with a confirmed ACL rupture/deficiency and those with a benign diagnosis on magnetic resonance imaging. Overall, 6 osseous and cartilaginous measurements and 3 ratios (2 newly described) were determined. They were then grouped for statistical purposes by age: children aged 5 to 11 years and adolescents aged 12 to 19 years. RESULTS: A total of 119 (49 children) consecutive patients with an ACL injury and 139 (72 children) healthy patients met inclusion criteria. The interaction between ACL status and age was significant for condylar measurements (P≤ .001), tibial spine height (P = .003), vertical space above tibial spine (P≤ .001), and NWI (P≤ .001) by 2-way analysis of variance. Although the NHI (P < 0.001) and tibial spine prominence (P = 0.039) demonstrated stenosis in the adolescent group, they did not have significant interactions with age and ACL status (P > 0.05). Regarding the transcondylar width, only the children's group had a significant difference regarding ACL status (P < .001), and the mean values in the children's group with ACL tears were nearly identical to those in the adolescent group both with and without ACL tears. The children's group with ACL tears also had a significantly larger tibial spine height compared with healthy children (P < .001). CONCLUSION: Children, similar to adolescents, demonstrated the effect of the NWI on the risk of ACL tears, but only the adolescent group demonstrated stenosis with the NHI. The morphology of the knee in a child at risk for ACL rupture was not the same as that of an adolescent when considering all dimensions, but it did seem that it was more adolescent-like than child-like at the time of an ACL rupture, refuting the idea of congenital hypoplasia as a common cause.

Inhaled nitric oxide improves ventilatory efficiency and exercise capacity in patients with mild COPD: A randomized-control cross-over trial.

KEY POINTS: Patients with mild chronic obstructive pulmonary disease (COPD) have an elevated ventilatory equivalent to CO2 production ( V̇E / V̇CO2 ) during exercise, secondary to increased dead space ventilation. The reason for the increased dead space is unclear, although pulmonary microvascular dysfunction and the corresponding capillary hypoperfusion is a potential mechanism. Despite emerging evidence that mild COPD is associated with pulmonary microvascular dysfunction, limited research has focused on experimentally modulating the pulmonary microvasculature during exercise in mild COPD. The present study sought to examine the effect of inhaled nitric oxide (iNO), a selective pulmonary vasodilator, on V̇E / V̇CO2 , dyspnoea and exercise capacity in patients with mild COPD. Experimental iNO increased peak oxygen uptake in mild COPD, secondary to reduced V̇E / V̇CO2 and dyspnoea. This is the first study to demonstrate that experimental manipulation of the pulmonary circulation alone, can positively impact dyspnoea and exercise capacity in mild COPD. ABSTRACT: Patients with mild chronic obstructive pulmonary disease (COPD) have an exaggerated ventilatory response to exercise, contributing to dyspnoea and exercise intolerance. Previous research in mild COPD has demonstrated an elevated ventilatory equivalent to CO2 production ( V̇E / V̇CO2 ) during exercise, secondary to increased dead space ventilation. The reason for the increased dead space is unclear, although pulmonary microvascular dysfunction and the corresponding capillary hypoperfusion is a potential mechanism. The present study tested the hypothesis that inhaled nitric oxide (iNO), a selective pulmonary vasodilator, would lower V̇E / V̇CO2 and dyspnoea, and improve exercise capacity in patients with mild COPD. In this multigroup randomized-control cross-over study, 15 patients with mild COPD (FEV1  =  89 ± 11% predicted) and 15 healthy controls completed symptom-limited cardiopulmonary exercise tests while breathing normoxic gas or 40 ppm iNO. Compared with placebo, iNO significantly increased peak oxygen uptake (1.80 ± 0.14 vs. 1.53 ± 0.10 L·min-1 , P < 0.001) in COPD, whereas no effect was observed in controls. At an equivalent work rate of 60 W, iNO reduced V̇E / V̇CO2 by 3.8 ± 4.2 units (P = 0.002) and dyspnoea by 1.1 ± 1.2 Borg units (P < 0.001) in COPD, whereas no effect was observed in controls. Operating lung volumes and oxygen saturation were unaffected by iNO in both groups. iNO increased peak oxygen uptake in COPD, secondary to reduced V̇E / V̇CO2 and dyspnoea. These data suggest that mild COPD patients demonstrate pulmonary microvascular dysfunction that contributes to increased V̇E / V̇CO2 , dyspnoea and exercise intolerance. This is the first study to demonstrate that experimental manipulation of the pulmonary circulation alone, can positively impact dyspnoea and exercise capacity in mild COPD.

The Effect of Carotid Chemoreceptor Inhibition on Exercise Tolerance in Chronic Heart Failure.

PURPOSE: Chronic heart failure (CHF) is characterized by heightened sympathetic nervous activity, carotid chemoreceptor (CC) sensitivity, marked exercise intolerance and an exaggerated ventilatory response to exercise. The purpose of this study was to determine the effect of CC inhibition on exercise cardiovascular and ventilatory function, and exercise tolerance in health and CHF. METHODS: Twelve clinically stable, optimally treated patients with CHF (mean ejection fraction: 43 ± 2.5%) and 12 age- and sex-matched healthy controls were recruited. Participants completed two time-to-symptom-limitation (TLIM) constant load cycling exercise tests at 75% peak power output with either intravenous saline or low-dose dopamine (2 µg⋅kg-1⋅min-1; order randomized). Ventilation was measured using expired gas data and operating lung volume data were determined during exercise by inspiratory capacity maneuvers. Cardiac output was estimated using impedance cardiography, and vascular conductance was calculated as cardiac output/mean arterial pressure. RESULTS: There was no change in TLIM in either group with dopamine (CHF: saline 13.1 ± 2.4 vs. dopamine 13.5 ± 1.6 min, p = 0.78; Control: saline 10.3 ± 1.2 vs. dopamine 11.5 ± 1.3 min, p = 0.16). In CHF patients, dopamine increased cardiac output (p = 0.03), vascular conductance (p = 0.01) and oxygen delivery (p = 0.04) at TLIM, while ventilatory parameters were unaffected (p = 0.76). In controls, dopamine improved vascular conductance at TLIM (p = 0.03), but no other effects were observed. CONCLUSION: Our findings suggest that the CC contributes to cardiovascular regulation during full-body exercise in patients with CHF, however, CC inhibition does not improve exercise tolerance.

The supine position improves but does not normalize the blunted pulmonary capillary blood volume response to exercise in mild COPD.

Patients with mild chronic obstructive pulmonary disease (COPD) demonstrate resting pulmonary vascular dysfunction as well as a blunted pulmonary diffusing capacity (DLCO) and pulmonary capillary blood volume (VC) response to exercise. The transition from the upright to supine position increases central blood volume and perfusion pressure, which may overcome microvascular dysfunction in an otherwise intact alveolar-capillary interface. The present study examined whether the supine position normalized DLCO and VC responses to exercise in mild COPD. Sixteen mild COPD participants and 13 age-, gender-, and height-matched controls completed DLCO maneuvers at rest and during exercise in the upright and supine position. The multiple FIO2-DLCO method was used to determine DLCO, VC, and membrane diffusion capacity (DM). All three variables were adjusted for alveolar volume (DLCOAdj, VCAdj, and DMAdj). The supine position reduced alveolar volume similarly in both groups, but oxygen consumption and cardiac output were unaffected. DLCOAdj, DMAdj, and VCAdj were all lower in COPD. These same variables all increased with upright and supine exercise in both groups. DLCOAdj was unaffected by the supine position. VCAdj increased in the supine position similarly in both groups. DMAdj was reduced in the supine position in both groups. While the supine position increased exercise VCAdj in COPD, the increase was of similar magnitude to healthy controls; therefore, exercise VC remained blunted in COPD. The persistent reduction in exercise DLCO and VC when supine suggests that pulmonary vascular destruction is a contributing factor to the blunted DLCO and VC response to exercise in mild COPD.NEW & NOTEWORTHY Patients with mild chronic obstructive pulmonary disease demonstrate a combination of reversible pulmonary microvascular dysfunction and irreversible pulmonary microvascular destruction.

The effect of carotid chemoreceptor inhibition on exercise tolerance in chronic obstructive pulmonary disease: A randomized-controlled crossover trial.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) have an exaggerated ventilatory response to exercise, contributing to exertional dyspnea and exercise intolerance. We recently demonstrated enhanced activity and sensitivity of the carotid chemoreceptor (CC) in COPD which may alter ventilatory and cardiovascular regulation and negatively affect exercise tolerance. We sought to determine whether CC inhibition improves ventilatory and cardiovascular regulation, dyspnea and exercise tolerance in COPD. METHODS: Twelve mild-moderate COPD patients (FEV1 83 ±â€¯15 %predicted) and twelve age- and sex-matched healthy controls completed two time-to-symptom limitation (TLIM) constant load exercise tests at 75% peak power output with either intravenous saline or low-dose dopamine (2 µg·kg-1·min-1, order randomized) to inhibit the CC. Ventilatory responses were evaluated using expired gas data and dyspnea was evaluated using a modified Borg scale. Inspiratory capacity maneuvers were performed to determine operating lung volumes. Cardiac output was estimated using impedance cardiography and vascular conductance was calculated as cardiac output/mean arterial pressure (MAP). RESULTS: At a standardized exercise time of 4-min and at TLIM; ventilation, operating volumes and dyspnea were unaffected by dopamine in COPD patients and controls. In COPD, dopamine decreased MAP and increased vascular conductance at all time points. In controls, dopamine increased vascular conductance at TLIM, while MAP was unaffected. CONCLUSION: There was no change in time to exhaustion in either group with dopamine. These data suggest that the CC plays a role in cardiovascular regulation during exercise in COPD; however, ventilation, dyspnea and exercise tolerance were unaffected by CC inhibition in COPD patients.

The effect of dopamine on pulmonary diffusing capacity and capillary blood volume responses to exercise in young healthy humans.

NEW FINDINGS: What is the Central question? Does dopamine, a pulmonary vascular vasodilator, contribute to the regulation of pulmonary diffusing capacity and capillary blood volume responses to exercise and exercise tolerance? What are the main findings and their importance? Dopamine appears not to be important for regulating pulmonary diffusing capacity or pulmonary capillary blood volume during exercise in healthy participants. Dopamine blockade trials demonstrated that endogenous dopamine is important for maintaining exercise tolerance; however, exogenous dopamine does not improve exercise tolerance. ABSTRACT: Pulmonary capillary blood volume (Vc ) and diffusing membrane capacity (Dm ) expansion are important contributors to the increased pulmonary diffusing capacity (DLCO ) observed during upright exercise. Dopamine is a pulmonary vascular vasodilator, and recent studies suggest that it may play a role in Vc regulation through changes in pulmonary vascular tone. The purpose of this study was to examine the effect of exogenous dopamine and dopamine receptor-2 (D2 -receptor) blockade on DLCO , Vc and Dm at baseline and during cycle exercise, as well as time-to-exhaustion at 85% of V̇O2peak . We hypothesized that dopamine would increase DLCO , Vc , Dm and time-to-exhaustion, while D2 -receptor blockade would have the opposite effect. We recruited 14 young, healthy, recreationally active subjects ( V̇O2peak 45.8 ± 6.6 ml kg-1  min-1 ). DLCO , Vc and Dm were determined at baseline and during exercise at 60% and 85% of V̇O2peak under the following randomly assigned and double blinded conditions: (1) intravenous saline and placebo pill, (2) intravenous dopamine (2 µg kg-1  min-1 ) and placebo pill, and (3) intravenous saline and D2 -receptor antagonist (20 mg oral metoclopramide). Exogenous dopamine and dopamine blockade had no effect on DLCO , Vc and Dm responses at baseline or during exercise. Dopamine blockade reduced time-to-exhaustion by 47% (P = 0.04), but intravenous dopamine did not improve time-to-exhaustion. While dopamine modulation did not affect DLCO , Vc or Dm , the reduction in time-to-exhaustion with D2 -receptor blockade suggests that endogenous dopamine is important for exercise tolerance.

Pulmonary capillary blood volume response to exercise is diminished in mild chronic obstructive pulmonary disease.

BACKGROUND: Previous work suggests that mild chronic obstructive pulmonary disease (COPD) patients have greater lung dysfunction than previously appreciated from spirometry alone. There is evidence of pulmonary microvascular dysfunction in mild COPD, which may reduce diffusing capacity (DLCO) and increase ventilatory inefficiency during exercise. The purpose of this study was to determine if DLCO, pulmonary capillary blood volume (Vc), and membrane diffusing capacity (Dm) are diminished during exercise in mild COPD, and whether this is related to ventilatory inefficiency and dyspnea. METHODS: Seventeen mild COPD patients (FEV1/FVC: 64 ±â€¯4%, FEV1 = 94 ±â€¯11%pred) and 17 age- and sex-matched controls were recruited. Ten moderate COPD patients were also tested for comparison (FEV1 = 66 ±â€¯7%pred). DLCO, Vc, and Dm were determined using the multiple-fraction of inspired oxygen (FIO2) DLCO method at baseline and during steady-state cycle exercise at 40W, 50%, and 80% of V˙O2peak. Using expired gas data, ventilatory inefficiency was assessed by V˙E/V˙CO2. RESULTS: Compared to controls, mild COPD had lower DLCO at baseline and during exercise secondary to diminished Vc (P < 0.05). No difference in Dm was observed between controls and mild COPD at rest or during exercise. Patients with high V˙E/V˙CO2 (i.e. ≥34) had lower Vc and greater dyspnea ratings compared to control at 40W. Moderate COPD patients were unable to increase Vc with increasing exercise intensity, suggesting further pulmonary vascular impairment with increased obstruction severity. CONCLUSION: Despite relatively minor airflow obstruction, mild COPD patients exhibit a diminished DLCO and capillary blood volume response to exercise, which appears to contribute to ventilatory inefficiency and greater dyspnea.

The carotid chemoreceptor contributes to the elevated arterial stiffness and vasoconstrictor outflow in chronic obstructive pulmonary disease.

KEY POINTS: The reason(s) for the increased central arterial stiffness in chronic obstructive pulmonary disease (COPD) are not well understood. In this study, we inhibited the carotid chemoreceptor with both low-dose dopamine and hyperoxia, and observed a decrease in central arterial stiffness and muscle sympathetic nervous activity in COPD patients, while no change was observed in age- and risk-matched controls. Carotid chemoreceptor inhibition increased vascular conductance, secondary to reduced arterial blood pressure in COPD patients. Findings from the current study suggest that elevated carotid chemoreceptor activity may contribute to the increased arterial stiffness typically observed in COPD patients. ABSTRACT: Chronic obstructive pulmonary disease (COPD) patients have increased central arterial stiffness and muscle sympathetic nervous activity (MSNA), both of which contribute to cardiovascular (CV) dysfunction and increased CV risk. Previous work suggests that COPD patients have elevated carotid chemoreceptor (CC) activity/sensitivity, which may contribute to the elevated MSNA and arterial stiffness. Accordingly, the effect of CC inhibition on central arterial stiffness, MSNA and CV function at rest in COPD patients was examined in a randomized placebo-controlled study. Thirteen mild-moderate COPD patients (forced expired volume in 1 s (FEV1 ) predicted ± SD: 83 ± 18%) and 13 age- and risk-matched controls completed resting CV function measurements with either i.v. saline or i.v. dopamine (2 µg kg-1  min-1 ) while breathing normoxic or hyperoxic air (100% O2 ). On a separate day, a subset of COPD patients and controls completed MSNA measurements while breathing normoxic or hyperoxic air. Arterial stiffness was determined by pulse-wave velocity (PWV) and MSNA was measured by microneurography. Brachial blood flow was determined using Doppler ultrasound, cardiac output was estimated by impedance cardiography, and vascular conductance was calculated as flow/mean arterial pressure (MAP). CC inhibition with dopamine decreased central and peripheral PWV, and MAP (P < 0.05) while increasing vascular conductance in COPD. No change in CV function was observed with dopamine in controls. CC inhibition with hyperoxia decreased peripheral PWV and MSNA (P < 0.05) in COPD, while no change was observed in controls. CC inhibition decreased PWV and MSNA, and improved vascular conductance in COPD, suggesting that tonic CC activity is elevated at rest and contributes to the elevated arterial stiffness in COPD.

Dopamine receptor blockade improves pulmonary gas exchange but decreases exercise performance in healthy humans.

Pulmonary gas exchange, as evaluated by the alveolar-arterial oxygen difference (A-aDO2), is impaired during intense exercise, and has been correlated with recruitment of intrapulmonary arteriovenous anastomoses (IPAVA) as measured by agitated saline contrast echocardiography. Previous work has shown that dopamine (DA) recruits IPAVA and increases venous admixture (Q̇s/Q̇t) at rest. As circulating DA increases during exercise, we hypothesized that A-aDO2 and IPAVA recruitment would be decreased with DA receptor blockade. Twelve healthy males (age: 25 ± 6 years, V̇O2 max : 58.6 ± 6.5 ml kg(-1) min(-1) ) performed two incremental staged cycling exercise sessions after ingestion of either placebo or a DA receptor blocker (metoclopramide 20 mg). Arterial blood gas, cardiorespiratory and IPAVA recruitment (evaluated by agitated saline contrast echocardiography) data were obtained at rest and during exercise up to 85% of V̇O2 max . On different days, participants also completed incremental exercise tests and exercise tolerance (time-to-exhaustion (TTE) at 85% of V̇O2 max ) with or without dopamine blockade. Compared to placebo, DA blockade did not change O2 consumption, CO2 production, or respiratory exchange ratio at any intensity. At 85% V̇O2 max , DA blockade decreased A-aDO2, increased arterial O2 saturation and minute ventilation, but did not reduce IPAVA recruitment, suggesting that positive saline contrast is unrelated to A-aDO2. Compared to placebo, DA blockade decreased maximal cardiac output, V̇O2 max and TTE. Despite improving pulmonary gas exchange, blocking dopamine receptors appears to be detrimental to exercise performance. These findings suggest that endogenous dopamine is important to the normal cardiopulmonary response to exercise and is necessary for optimal high-intensity exercise performance.

Effect of modality on cardiopulmonary exercise testing in male and female COPD patients.

The purpose of this study was to examine the physiological responses to treadmill and cycle cardiopulmonary exercise testing (CPET) in male and female COPD patients. Fifty-five patients [28 males (FEV1=58.2±19.5% predicted), and 27 females (FEV1=65.3±16.6% predicted)] completed a treadmill and a cycle CPET in random order on two separate days. Respiratory and cardiovascular data were obtained. Compared to the cycle CPET, the treadmill elicited greater peak power output and peak oxygen uptake, while arterial saturation at peak exercise was lower with the treadmill; however, there were no differences between the responses in men and women. No differences were observed in heart rate, ventilation, tidal volume/breathing frequency, inspiratory capacity, or dyspnea responses between modalities or sex. The physiological responses between treadmill and cycle CPET protocols are largely similar for both men and women with COPD, indicating that either modality can be used in mild/moderate COPD patients.

The effects of dobutamine and dopamine on intrapulmonary shunt and gas exchange in healthy humans.

The development of intrapulmonary shunts with increased cardiac output during exercise in healthy humans has been reported in several recent studies, but mechanisms governing their recruitment remain unclear. Dobutamine and dopamine are inotropes commonly used to augment cardiac output; however, both can increase venous admixture/shunt fraction (Qs/Qt). It is possible that, as with exercise, intrapulmonary shunts are recruited with increased cardiac output during dobutamine and/or dopamine infusion that may contribute to the observed increase in Qs/Qt. The purpose of this study was to examine how dobutamine and dopamine affect intrapulmonary shunt and gas exchange. Nine resting healthy subjects received serial infusions of dobutamine and dopamine at incremental doses under normoxic and hyperoxic (inspired O(2) fraction = 1.0) conditions. At each step, alveolar-to-arterial Po(2) difference (A-aDo(2)) and Qs/Qt were calculated from arterial blood gas samples, intrapulmonary shunt was evaluated using contrast echocardiography, and cardiac output was calculated by Doppler echocardiography. Both dobutamine and dopamine increased cardiac output and Qs/Qt. Intrapulmonary shunt developed in most subjects with both drugs and paralleled the increase in Qs/Qt. A-aDo(2) was unchanged due to a concurrent rise in mixed venous oxygen content. Hyperoxia consistently eliminated intrapulmonary shunt. These findings contribute to our present understanding of the mechanisms governing recruitment of these intrapulmonary shunts as well as their impact on gas exchange. In addition, given the deleterious effect on Qs/Qt and the risk of neurological complications with intrapulmonary shunts, these findings could have important implications for use of dobutamine and dopamine in the clinical setting.

Priming with dendritic cells can generate strong cytotoxic T cell responses to chronic myelogenous leukemia cells in vitro.

Dendritic cells (DC) are antigen-presenting cells that can elicit potent antigen-specific responses. Since the development of techniques to cultivate these cells from peripheral blood, there has been a great deal of interest in their use in immunotherapeutic strategies. Here we show that morphologically, phenotypically, and functionally characteristic DC can be generated in vitro from peripheral blood mononuclear cells (PBMC) isolated from frozen apheresis product (AP) of cancer patients. These DC, when pulsed with whole-tumor lysate, protein, or RNA from a chronic myelogenous leukemia (CML) cell line, can induce anti-CML specific cytotoxicity in vitro by autologous cytotoxic T lymphocytes (CTL). RNA and protein-pulsed DC were more effective than lysate-pulsed DC at inducing cytotoxicity at low effector:target (E:T) ratios. These results were comparable to those obtained when fresh healthy peripheral blood was used as the source of PBMC, indicating that neither the malignant state of the patient nor the storage period detrimentally affected the generation or functionality of DC. CML cells were found to increase their level of MHC class I expression after exposure to CTL and pulsed DC thereby becoming better targets. These investigations lend support for the utilization of DC to generate anti-tumor responses in CML.