Changes In QL Research Articles

Paraspinal muscles atrophy on both sides and at multiple levels after unilateral lumbar partial discectomy.

To identify the changes in cross-sectional areas (CSAs) and fatty infiltration of both sides of the paravertebral muscles and their associations with prognostic factors in patients who underwent unilateral lumbar discectomy. We retrospectively reviewed 27 patients who underwent magnetic resonance imaging before and after 1- or 2-level lumbar discectomy. The CSAs and functional cross-sectional areas of the paraspinal muscles were bilaterally measured from L1 to L2 to L5 to S1 based on T2-weighted axial images. These parameters were compared pre-and postoperatively. CSAs and functional cross-sectional areas decreased also in non-operative, non-surgical levels, not only in operated levels after discectomy. In the correlation analysis, the CSA of psoas major muscle at L1 to L2 was significantly decreased in patients with lower preoperative lordosis (r = 0.598, P = .040). The postoperative CSA of psoas major muscle at L4 to L5 was lower in those with the higher Pfirrmann grade (r = -0.590, P = .002); however, the CSA of quadratus lumborum muscle at L1 to L2 showed the opposite result (r = 0.526, P = .036). Similar results were also observed in the partial correlation adjusted for age and postoperative duration. Patients who underwent discectomy experienced overall paraspinal muscle atrophy in the lumbar region, including surgical and non-surgical sites. Such atrophic changes emphasized the need for core strengthening and lumbar rehabilitation from the early period after partial discectomy.

The Role of Group III/IV Muscle Afferents in Regulating the Hemodynamic Response to Whole Body Exercise

BACKGROUNDGroup III/IV muscle afferents respond to mechanical and chemical stimuli occurring in skeletal muscle during exercise and contribute, via their feedback to cardiovascular control centers in the brainstem, to the circulatory response to physical activity. In healthy young individuals, feedback from these afferents facilitates leg blood flow during dynamic knee extensor exercise. However, their exact role in determining peripheral hemodynamics during whole body exercise (large active muscle mass), which is characterized by larger sympathetically‐mediated vasoconstriction compared to knee extensor exercise (small active muscle mass), has yet to be investigated.METHODSSeparated by 2 h of rest, 4 healthy males (Age 21 ± 2 yrs) completed 3 bouts of cycling exercise [75 W: ~45% of VO2max, 100 W: ~55% VO2max, and 80% of peak power output (226 ± 12 W): ~95% VO2max] under both control conditions (CTRL) and with lumbar intrathecal fentanyl (FENT) blocking μ‐opioid receptor‐sensitive muscle afferents. To avoid different respiratory muscle metaboreflex and/or chemoreflex effects on leg vascular conductance (LVC) and blood flow, subjects’ breathing during FENT (usually characterized by hypoventilation and asphyxia) was guided to achieve end‐tidal PCO2 (PETCO2) to be similar to that in CTRL. Femoral arterial blood flow (QL; Doppler Ultrasound), heart rate (HR), cardiac output (CO), and leg perfusion pressure (PP; intravascular catheter, arterial – venous blood pressure) were continuously determined, femoral arterial and venous blood samples were collected during the final minute of each workload.RESULTSThere were no hemodynamic differences between conditions at rest. Arterial blood gases, breathing, and PETCO2 were, per design, not different between conditions. During FENT exercise, PP was, compared to CTRL, significantly lower at all intensities (up to 26%). Without affecting HR (P > 0.2), CO was significantly lower during FENT compared to CTRL at 75 W and 100 W (up to 25%), but not at 80% Wpeak. QL was, however, not different between conditions (P = 0.69) as leg vascular conductance was up to 33% higher during FENT compared to CTRL (P < 0.05). Arterial O2 content, leg O2 delivery, and leg VO2 were similar between conditions (P > 0.3).CONCLUSIONThe current findings obtained from humans during leg cycling suggest that group III/IV‐mediated afferent feedback from locomotor muscle facilitates leg perfusion pressure and CO, but restricts leg vascular conductance during whole body exercise. These effects of group III/IV muscle afferents are likely secondary to their role in regulating the autonomic control of the heart and the vasculature. Interestingly, the effect of these sensory neurons on leg vascular conductance differs between exercise characterized by large vs small active muscle mass. While afferent blockade increases leg vascular conductance (with no changes in QL, but decreases in PP) during cycling exercise, it decreases leg vascular conductance (relatively larger fall in QL compared to fall in PP) during knee extensor exercise.Support or Funding InformationNational Heart, Lung, and Blood Institute (HL‐116579)

Abstract OT3-1-02: The SNAP trial: Schedules of nab-paclitaxel in metastatic breast cancer, International breast cancer study group (IBCSG 42-12) and breast International group (BIG 2-12)

Abstract Background The SNAP trial aims to improve the tolerability of prolonged chemotherapy administration by studying alternative treatment schedules, while preserving and possibly improving treatment efficacy. Trial Design Randomized phase II study (1:1:1 randomization) evaluates each of 3 treatment arms versus a historical reference to determine whether any of the three are worthy of further investigation. All patients will begin with 3 cycles of nab-Paclitaxel 150 mg/m2 days 1,8,15 every 28 days. Maintenance nab-Paclitaxel will be given every 28 days until disease progression: (A) 150 mg/m2 days 1, 15, (B) 100 mg/m2 days 1, 8, 15, (C) 75 mg/m2 days 1, 8, 15, 22. Major Eligibility Criteria • Histologically or cytologically confirmed HER2-negative metastatic (stage IV) breast cancer • No prior chemotherapy for metastatic breast cancer • Measurable or non-measurable, but radiologically evaluable, disease according to RECIST 1.1 criteria • Either ER-positive or ER-negative disease. Patients with ER-positive disease must be endocrine resistant, defined as having failed at least one prior endocrine therapy for breast cancer, or must be candidates for first-line chemotherapy • Normal hematologic, renal, liver and cardiac functions • No peripheral neuropathy grade 2 or higher Specific Aim To evaluate the efficacy of three different schedules of nab-Paclitaxel for first-line treatment of metastatic breast cancer, measured by progression-free survival (PFS), using the historical reference of PFS for docetaxel. Statistical Methods The primary efficacy endpoint of PFS will be evaluated among each of the three treatment arms separately, in three independent tests, and compared to the historic PFS of first-line docetaxel. Assuming the median PFS of docetaxel is 7 months and the median PFS of a new regimen is 10 months, with 76 patients in each arm, and an accrual rate of 8 patients per month for an accrual period of 30 months plus 12 months additional follow-up, the study will have 88% power to detect an improvement in PFS in a new regimen relative to docetaxel, using a one-sample log-rank test at the one-sided significance level of 0.05. The target number of events per group is 63. The sample size of 80 patients per arm assumes a 5% drop out rate. Accrual Target: 240; Present: 1 (June 1, 2013) Related Research Translational research will investigate the prognostic role of putative markers SPARC and caveolin determined in FFPE tumor tissue from primary surgery and, if available, from metastatic biopsy. Material will be banked centrally. Quality-of-life assessments will be conducted to explore the change in QL over time until treatment discontinuation by LASA scales for physical well-being, mood, coping effort, overall treatment burden, appetite, tiredness, hair loss and feeling sick (nausea/vomiting). Sensory neuropathy will be assessed by the 4-item subscale of the FACT/GOG-Ntx. The SNAP trial is a collaboration through the Breast International Group (BIG). For more information about SNAP contact Dr. Rudolf Maibach, IBCSG Coordinating Center, Bern, Switzerland, rudolf.maibach@ibcsg.org, or the Trial Coordinators at ibcsg42_SNAP@fstrf.org. Pharmaceutical Support Celgene; Sponsor: IBCSG. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-1-02.

Comparison of the Pulmonary Dysfunction Caused by Cardiogenic and Noncardiogenic Pulmonary Edema

We designed a series of experiments to compare the pulmonary dysfunction observed in models of cardiogenic and noncardiogenic pulmonary edema in chronically instrumented awake sheep. Cardiogenic pulmonary edema was induced by inflating the balloon of a Foley catheter surgically positioned in the mitral valve orifice causing increased left atrial pressure (increases PLA). Noncardiogenic pulmonary edema was induced by intravenous infusion of Perilla ketone (PK). Calculated microvascular pressure remained constant during PK infusion but increased from 9.4 +/- 0.7 to 42.8 +/- 2.4 cm H2O during increases PLA. Comparable increases in lung lymph flow (QL) were observed in the two protocols (five to seven times baseline). Pulmonary edema as quantified by chest radiograph scores increased from 0 (normal) to 2.9 +/- 0.5 and 3.4 +/- 0.1 in the PK and increases PLA groups, respectively. Room air alveolar to arterial oxygen pressure difference (P[A-a]O2) increased from 24 +/- 3 to 46 +/- 7 mm Hg in the PK group and from 23 +/- 4 to 56 +/- 6 mm Hg in the increases PLA group. Dynamic compliance of the lungs (Cdyn) expressed as the percentage of the baseline value decreased to 53 +/- 7 and 50 +/- 7% in the PK and increases PLA groups, respectively. Resistance to airflow across the lungs (RL) increased from 2.5 +/- 0.6 to 3.3 +/- 0.8 cm H2O.L-1.sec-1 in the PK group and from 1.4 +/- 0.3 to 4.2 +/- 1.1 in the increases PLA group. Significant correlations were observed between changes in the severity of pulmonary edema observed on chest radiographs, Cdyn, delta P(A-a)O2, and QL in both the increases PLA groups. We conclude that similar degrees of pulmonary edema, regardless of the mechanism, are associated with similar changes in QL, Cdyn, and delta P(A-a)O2. Hydrostatic pulmonary edema appeared to cause greater changes in RL than that resulting from increased microvascular permeability.

Canine hindlimb blood flow and O2 uptake after inhibition of EDRF/NO synthesis.

The nitric oxide synthase (NOS) inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) was used to determine whether the decrease in canine hindlimb blood flow (QL) with NOS inhibition would limit skeletal muscle O2 uptake (VO2). Arterial inflow and venous outflow from the hindlimb were isolated, and the paw was excluded from the circulation. Pump perfusion from the right femoral artery kept the hindlimb perfusion pressure near the auto-perfused level. Six anesthetized dogs received L-NAME (20 mg/kg i.v.), whereas another group of five dogs received the stereospecific enantiomer N omega-nitro-D-arginine methyl ester (D-NAME 20 mg/kg i.v.). Efficacy of NOS inhibition was tested with intra-arterial boluses of acetylcholine. QL was measured continuously, and whole body and hindlimb VO2 were measured 60 and 120 min after L-NAME or D-NAME. Whole body VO2 remained at control levels, but cardiac output decreased from 117 +/- 17 to 57 +/- 7 ml.kg-1.min-1 60 min after L-NAME (P < 0.05) and remained at that level for the duration of the experiment. Cardiac output was significantly higher in the D-NAME group than in the L-NAME group at 60 min. After L-NAME, QL fell 24% but VO2 increased from 5.2 +/- 0.4 to 7.4 +/- 0.6 ml.kg-1.min-1 (P < 0.05). No change in QL or VO2 occurred after D-NAME. NOS inhibition did not limit hindlimb VO2, despite decreases in blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary transvascular fluid flux and cardiovascular function in sheep with chronic sepsis

We studied the mechanisms responsible for the changes in lung lymph flow (QL) in chronic sepsis induced by the continuous infusion of endotoxin [lipopolysaccharide (LPS), 10 ng.kg-1.min-1]. Sheep (n = 11) were studied in the unanesthetized state 7 days after preparation, and cardiopulmonary variables were measured. In the control group (n = 5) given lactated Ringer solution, no significant changes were observed in any measured variables. In the LPS group (n = 6), QL increased from 11.7 +/- 3.8 to 54.0 +/- 15.0 (SE) ml/h 24 h after LPS infusion had begun. This elevation in QL was associated with little or no change (P > 0.05) in reflection coefficient (0.80 +/- 0.03 to 0.87 +/- 0.05) or pulmonary microvascular pressure (14.3 +/- 0.4 to 16.7 +/- 1.2 mmHg). The filtration coefficient, however, was significantly elevated (0.018 +/- 0.006 to 0.083 +/- 0.024 ml.min-1.mmHg-1). In association with changes in QL that occur as a result of LPS administration, there was a significant increase in cardiac index (6.1 +/- 0.5 to 10.2 +/- 0.3 l.min-1.m-2) and a reduction in mean arterial pressure (90.2 +/- 4.4 to 73.7 +/- 7.3 mmHg) and systemic vascular resistance index (1,229 +/- 134 to 583 +/- 62 dyn.s.cm-5.m2), findings similar to those noted in septic humans.

Effects of hypertonic saline and dextran 70 resuscitation on microvascular permeability after burn.

Administration of hyperosmolar fluids to burn patients has been proposed as a means of decreasing resuscitative fluid volume and, subsequently, wound edema accumulation. To test this hypothesis, canine hindpaw lymph flow (QL) and lymph (CL) and plasma (CP) total protein concentrations were measured, and capillary filtration coefficient (Kf) was calculated before and for 6 h after a 5-s 100 degrees C footpaw scald. Scald was followed 30 min later by bolus infusion (4 ml/kg) of 7% saline or 6% Dextran 70 or the two in combination. Before scald, venous pressure was elevated until a minimal CL/CP was reached. The reflection coefficient (sigma d) was calculated by the formula: 1-minimal CL/CP. Scald increased QL, CL/CP, and Kf, but sigma d was decreased (P less than 0.05). Compared with burn alone, 7% saline exacerbated burn-induced increases in QL and Kf. In contrast, infusion of Dextran 70 did not exacerbate these changes in QL or Kf. Perhaps more importantly, Dextran 70 may have attenuated the increase in CL/CP and reduced edema formation in the burned hindpaw. However, the addition of 7% saline to the dextran eliminated these beneficial effects.

Short-term effect of tidal pleural pressure swings on pulmonary blood flow during rest and exercise

Because pleural pressure (Ppl) has important effects on venous return and left ventricular function, it is possible that the magnitude of respiratory fluctuations in Ppl importantly influences cardiac output (pulmonary blood flow, QL) during exercise. To examine this question, we increased (+15 cmH2O) and decreased (-11 cmH2O) the amplitude of fluctuations in Ppl by elastic loading and unloading, respectively, during steady-state exercise (50 W) and estimated the corresponding changes in QL from measurement of breath-by-breath alveolar O2 consumption [(Vo2)A] by a modification of the technique of Beaver et al. (J. Appl. Physiol. 51: 1662-1675, 1981). Load changes were applied for three breaths. Using oscilloscopic volume feedback, subjects maintained constant breathing pattern and end-expiratory volume during control and experimental breaths. This procedure minimized errors in computing (Vo2)A. Furthermore, because over the brief period of load change (especially the first 1 or 2 breaths) mixed venous and arterial O2 contents were not likely to have changed, changes in (Vo2)A reflected changes in QL according to the Fick principle. In six normal subjects, neither loading nor unloading had any effect on (Vo2)A in the first, second, or third breath (P greater than 0.5). Additional studies at rest produced equally negative results. We conclude that the magnitude of respiratory fluctuations in Ppl has no short-term effect on pulmonary blood flow at rest or during mild exercise.

Cardiopulmonary responses to continuous administration of endotoxin.

The cardiopulmonary response to continuous administration of lipopolysaccharide (LPS) was studied in chronically instrumented sheep. LPS was administered in doses of 0 (sham), 6, 9, 12, and 24 ng.kg-1.h-1 for 24 h. No significant changes in the measured variables occurred in the sham group and in the 6 ng.kg-1.h-1-LPS group. With 9, 12, and 24 ng.kg-1.h-1-LPS, cardiac index rose and peripheral resistance fell to the same extent in all three groups. Lung lymph flow (QL) increased with increasing concentration of LPS. These elevations in QL occurred in the presence of only minor increases in the pulmonary artery pressure, which rose to the same extent in the 9, 12, and 24 ng.kg-1.h-1 groups. Consequently, the changes in QL were attributable to changes in fluid conductance of the pulmonary microvasculature rather than variations in hydrostatic pressure. The increase in QL correlated with a decrease in prekallikrein levels (r = 0.97), indicating that the changes in fluid conductance might have been kinin mediated.

Assessment of fluid balance in isolated sheep lungs.

In this study we demonstrate the validity and utility of an isolated lung preparation developed for the study of pulmonary fluid balance. Lungs of 2- to 3-mo-old sheep were perfused in situ with autologous blood treated with indomethacin (20 micrograms/ml). Lung lymph flow (QL), uncontaminated by systemic lymph, was measured from either the efferent duct of the caudomediastinal lymph node or the thoracic duct in the superior mediastinum. Lung weight change (delta W) was measured as the opposite of the change in weight of the extracorporeal blood reservoir. A unique feature of this experimental model is the ability to assess lung fluid balance from simultaneous measurements of delta W and QL. In addition, hemodynamic and blood gas variables can be tightly controlled. Our results show that changes in QL and the lymph-to-plasma oncotic pressure ratio caused by an increase in microvascular pressure were comparable with those seen previously in intact sheep. When microvascular pressure was returned to control levels, QL fell despite a sustained increase in the amount of extravascular lung water, suggesting compartmentalization of the filtrate and/or effects of intravascular volume on lymph-driving pressure or resistance. Lymph flow was directly proportional to respiratory frequency over the range of 0-30 min-1 when the change in frequency was maintained for periods as long as 30 min. This preparation should prove useful in the study of lung fluid balance, particularly when it is desired to use interventions which are precluded or difficult in intact animals.

Effect of outflow pressure on lung lymph flow in unanesthetized sheep.

Studies in anesthetized animals have shown that the flow rate from lung lymphatics (QL) depends on the pressure at the outflow end of the vessels (Po). We tested this in unanesthetized sheep prepared with chronic lung lymph cannula. We measured QL with the lymph cannula held at various heights above the olecranon and calculated Po as the height + QL X cannula resistance. QL decreased with increases in Po (delta QL/delta Po = -8.2 +/- 6.4 microliter X min-1 X cmH2O-1, mean +/- SD). We increased QL by raising left atrial pressure or infusing Ringer solution or Escherichia coli endotoxin and found that QL was even more sensitive to Po (delta QL/delta Po = -32 +/- 22). Cannula resistance caused a 9-70% reduction in QL. Changes in QL caused by increasing Po were not associated with changes in lymph protein concentration for up to 330 min. This indicates that increases in Po shunt lymph away from cannulated vessels but do not substantially effect microvascular filtration rate. The shunted lymph may flow into other vessels or collect in the lung. We conclude that QL does not accurately represent microvascular filtration rate because it depends on the cannula resistance and position at which the investigator chooses to place the cannula.

Effect of lymphatic cannula outflow height on lung microvascular permeability estimations.

Estimates of the pulmonary microvascular membrane reflection coefficient (sigma) and permeability-surface area product (PS) are frequently made with the assumption that a percent change in transmicrovascular fluid flux (Jv) will be represented by an equal percent change in the lymph flow rate (QL) from a single cannulated lung lymph vessel. To test this, we measured QL in seven anesthetized dogs with the outflow end of the lymph cannula set at several heights (H) above and below the lung hilus. The left atrial pressure was then elevated to increase Jv, and QL was again measured at several H's. The percent increase in QL at elevated left atrial pressure depended on H. We used the QL data and lymph and plasma protein concentrations to estimate sigma and PS with a modified form of the Kedem and Katchalsky equations. The calculated values varied considerably with H. Our results indicate that changes in Jv are not represented by equal changes in QL. Therefore, techniques for estimating permeability that depend upon QL as an estimate of Jv may lead to erroneous estimates of sigma and PS.

Effect of aerosol histamine on lung lymph in awake sheep.

This study examined the effect of aerosol histamine on lung lymph in the awake sheep. Eleven sheep were chronically instrumented for measurement of lung lymph, lung mechanics, and vascular pressures. Aerosol histamine was given by use of a Collison nebulizer and delivered via a tracheostomy tube. Five breaths of a 30 mg/ml histamine solution caused lung lymph flow (QL) to increase from a base line of 5.5 +/- 0.5 (SE) ml/h to 14.3 +/- 1.5 (P less than 0.05) and the lymph-to-plasma protein concentration ratio (L/P) to increase from 0.63 +/- 0.02 to 0.72 +/- 0.02 (P less than 0.05). The concentration of aerosol histamine required to change QL by 30% (ED130QL) was determined by giving increasing concentrations of aerosol histamine every 15 min. The mean ED130QL was 22.2 mg/ml. The dose of histamine required to increase QL by 30% did not correlate (r = 0.04, n = 7) with the dose required to decrease dynamic compliance by 35%. The increase in QL lasted 100 +/- 19 min. Hourly exposure to five breaths of 30 mg/ml for 5 h caused a sustained increase in QL in two sheep and a waning effect in two sheep. The combination of aerosol histamine and elevated microvascular pressure (achieved by inflating a Foley catheter situated in the left atrium) caused changes in QL and L/P not totally consistent with the hypothesis that histamine increased pulmonary vascular permeability. Increased vascular permeability in the bronchial circulation was considered a likely explanation of the data.

Effects of intracranial and left atrial hypertension on lung fluid balance in sheep.

Elevation of intracranial pressure (ICP; 50-150 Torr) in sheep produces an increase in protein-rich lymph flow (QL) from the lung. This may be attributed to either microvascular permeability changes or increases in filtration surface area through recruitment. To eliminate increases in surface area, we recruited potential filtration beds by increasing left atrial pressure (Pla; 27-35 Torr) prior to elevating ICP in sheep anesthetized with pentobarbital sodium or halothane. Under these conditions, increased pulmonary microvascular permeability would be expected to produce an increased QL, lymphatic protein flux (CL), and plasma clearance of protein (CP). The results of ICP elevation following a period of steady-state Pla hypertension showed no such change in QL, CL or CP (n=8) compared with prior period of increased Pla. ICP elevation alone (n=6) produces a significant increase in CP manifested as an increase in QL (73%), with little change in the lymph-to-plasma ratio of protein concentration. These results suggest that a change in pulmonary microvascular surface area (not permeability) is the primary mechanism underlying increases in protein-rich QL following the elevation of ICP alone.

Effect of histamine and alloxan on canine pulmonary vascular permeability.

We estimated the pulmonary capillary membrane filtration coefficient (Kf) and the maximum capillary pressure (PCcritical) at which the lung could maintain a constant weight in 1) 5 control experiments in anesthetized open-chested dogs, 2) 7 experiments in which the dogs were given 3.6-8.3 microgram . kg-1 . min-1 of histamine phosphate, and 3) in 6 experiments after 75-100 mg/kg of alloxan. In additional experiments, pulmonary lymph flow (QL) and protein concentration (CL) were measured during the infusion of histamine and alloxan. After histamine, Kf averaged 0.045 +/- 0,008 ml . min-1mmHg-1 (SE) and PCcritical was 22.1 +/- 1.1 mmHg. These values were not significantly different from the control Kf and PCcritical (0.036 +/- 0.006 and 22.5 +/- 2.3, respectively). After alloxan, Kf (1.43 +/- 0.69) was larger and PCcritical (12.4 +/- 1.3) was significantly less than control (P less than 0.05). Histamine caused no significant change in QL or CL; however, both were increased after alloxan. These results show that Kf, PCcritical, QL, and CL are all changed by an increase in capillary membrane permeability caused by alloxan. Because none of these factors as significantly affected by histamine, dog lung capillary membrane permeability may not be affected by histamine.

Increased lung lymph transport without heart failure after coronary ligation in sheep.

Pulmonary edema frequently accompanies acute myocardial infarction (MI). We measured pulmonary arterial (PAP), left atrial (LAP), and aortic pressures (AP),lung lymph flow (QL), and clearance of total serum protein and each of eight protein fractions in five anesthetized sheep before and after coronary artery ligation. After a stable base line of 1 h, ligation produced significant increases in LAP, QL, and clearance of total protein and four protein fractions, but no significant changes in PAP, AP, or lymph-to-plasma total protein concentration ratio (CSL/CSP). Variables returned to pre-MI levels within 2 h after occlusion. The ratio of wet to dry lung weight measured 2 h after ligation was within normal limits. Two sheep in which the time course of postligation LAP was duplicated by left atrial balloon inflation showed no change in QL. The QL changes seen cannot be caused by LAP increase alone without substantial decrease in CSL/CSP. Increased QL with high CSL/CSP is typical of increased lung vascular permeability, which is a plausible explanation of our results.