Quantifying the reduction of respiratory motion by mechanical ventilation with MRI for radiotherapy.

BACKGROUND: Due to respiratory motion, accurate radiotherapy delivery to thoracic and abdominal tumors is challenging. We aimed to quantify the ability of mechanical ventilation to reduce respiratory motion, by measuring diaphragm motion magnitudes in the same volunteers during free breathing (FB), mechanically regularized breathing (RB) at 22 breaths per minute (brpm), variation in mean diaphragm position across multiple deep inspiration breath-holds (DIBH) and diaphragm drift during single prolonged breath-holds (PBH) in two MRI sessions. METHODS: In two sessions, MRIs were acquired from fifteen healthy volunteers who were trained to be mechanically ventilated non-invasively We measured diaphragm motion amplitudes during FB and RB, the inter-quartile range (IQR) of the variation in average diaphragm position from one measurement over five consecutive DIBHs, and diaphragm cranial drift velocities during single PBHs from inhalation (PIBH) and exhalation (PEBH) breath-holds. RESULTS: RB significantly reduced the respiratory motion amplitude by 39%, from median (range) 20.9 (10.6-41.9) mm during FB to 12.8 (6.2-23.8) mm. The median IQR for variation in average diaphragm position over multiple DIBHs was 4.2 (1.0-23.6) mm. During single PIBHs with a median duration of 7.1 (2.0-11.1) minutes, the median diaphragm cranial drift velocity was 3.0 (0.4-6.5) mm/minute. For PEBH, the median duration was 5.8 (1.8-10.2) minutes with 4.4 (1.8-15.1) mm/minute diaphragm drift velocity. CONCLUSIONS: Regularized breathing at a frequency of 22 brpm resulted in significantly smaller diaphragm motion amplitudes compared to free breathing. This would enable smaller treatment volumes in radiotherapy. Furthermore, prolonged breath-holding from inhalation and exhalation with median durations of six to seven minutes are feasible. TRIAL REGISTRATION: Medical Ethics Committee protocol NL.64693.018.18.

Safely achieving single prolonged breath-holds of > 5 minutes for radiotherapy in the prone, front crawl position.

OBJECTIVE: Breast cancer radiotherapy is increasingly delivered supine with multiple, short breath-holds. There may be heart and lung sparing advantages for locoregional breast cancer of both prone treatment and in a single breath-hold. We test here whether single prolonged breath-holds are possible in the prone, front crawl position. METHODS: 19 healthy volunteers were trained to deliver supine, single prolonged breath-holds with pre-oxygenation and hypocapnia. We tested whether all could achieve the same durations in the prone, front crawl position. RESULTS: 19 healthy volunteers achieved supine, single prolonged breath-holds for mean of 6.2 ± 0.3 min. All were able to hold safely for the same duration while prone (6.1 ± 0.2 min ns. by paired ANOVA). With prone, the increased weight on the chest did not impede chest inflation, nor the ability to hold air in the chest. Thus, the rate of chest deflation (mean anteroposterior deflation movement of three craniocaudally arranged surface markers on the spinal cord) was the same (1.2 ± 0.2, 2.0 ± 0.4 and 1.2 ± 0.4 mm/min) as found previously during supine prolonged breath-holds. No leakage of carbon dioxide or air was detectable into the facemask. CONCLUSION: Single prolonged (>5 min) breath-holds are equally possible in the prone, front crawl position. ADVANCES IN KNOWLEDGE: Prolonged breath-holds in the front crawl position are possible and have the same durations as in the supine position. Such training would therefore be feasible for some patients with breast cancer requiring loco-regional irradiation. It would have obvious advantages for hypofractionation.

Association between Bone marrow lesions & synovitis and symptoms in symptomatic knee osteoarthritis.

OBJECTIVE: Bone marrow lesions (BMLs) on MRI are typically subchondral in location, however, a proportion occur at knee ligament attachments and also include a cyst-like component. Our aim was to determine whether the volume of BML subtypes and synovial tissue volume (STV) was associated with symptoms in symptomatic knee OA. METHOD: Images were acquired in a sub-sample who had taken part in a randomised trial of vitamin D therapy in knee OA (UK-VIDEO). Contrast-enhanced (CE) MRI was performed annually. In those who had ≥1 follow-up and a baseline scan (N = 50), STV and BML volume was assessed. BMLs were categorised by location and by the presence/absence of a cyst-like component. WOMAC was assessed annually. We used fixed-effects panel-regression modelling to examine the association between volume and symptoms. RESULTS: There was no association between knee pain and total subchondral BML volume (b = 0.3 WOMAC units, 95% CI -0.3 to 1.0) or total ligament-based BML volume (b = 1.9, 95% CI -1.6 to 5.3). The volume of subchondral BMLs with a cyst-like component was not associated with pain (b = 0.8, 95% CI -0.5 to 2.1) however, the volume of the cyst-like component itself was associated with pain (b = 51.8, 95% CI 14.2 to 89.3). STV was associated with pain (b = 2.2, 95% CI 0.6 to 3.7). CONCLUSION: The volume of the cyst-like component from subchondral BMLs with a cyst-like component was associated with knee pain. BML location, however, did not influence symptoms. STV was also associated with knee symptoms.

Reappraisal of systemic venous chemoreceptors: might they explain the matching of breathing to metabolic rate in humans?

NEW FINDINGS: What is the topic of this review? One of the major unanswered questions in physiology is that of how breathing matches metabolic rate. Venous chemoreceptors seem to have been dismissed since the 1960s. What advances does it highlight? New evidence shows that their apparent dismissal needs reappraisal. The paper on which this depends has more than one interpretation, and another paper obtained the opposite result. Previous search ignored all locations between skeletal muscle and the right heart. Oxygen sensors other than the arterial chemoreceptors do exist. Heymans and colleagues originally demonstrated some residual breathing response to hypoxia in sino-aortically denervated animals. Similar results occur in humans. One of the major unanswered questions in physiology is that of how breathing matches metabolic rate. The existence in humans of venous chemoreceptors that might control breathing seems to have been dismissed since the 1960s. New evidence has emerged showing that this apparent dismissal needs reappraisal. First, the paper in humans on which this depends has more than one interpretation. Moreover, a previous paper obtained the opposite result and is not cited. Secondly, previous search for venous chemoreceptors failed to examine all venous locations between skeletal muscle and the right heart and lungs. Thirdly, oxygen sensors other than the arterial chemoreceptors do exist. Heymans himself originally demonstrated some residual breathing response to hypoxia in sino-aortically denervated animals. Others confirm a residual breathing response to hypoxia in mammals, including humans. There is now considerable interest in the importance of afferent feedback in controlling the cardiovascular and respiratory systems. Moreover, it is now clear that arterial, aortic and central chemoreceptors have no role in explaining how breathing matches metabolic rate during exercise. These together provide a timely reminder that venous chemoreceptors remain ideal candidates still to be considered as metabolic rate sensors to explain matching in humans. Firstly, this is because venous PO2 and PCO2 values do change appropriately in proportion to metabolic rate, so a metabolic rate signal sufficient to drive breathing might already exist. Secondly, chemoreceptor-like anatomical structures are present in the systemic venous system but remain unexplored. Finally, no extant experimental evidence precludes their existence.

The efficacy of intra-articular steroids in hip osteoarthritis: a systematic review.

OBJECTIVE: International guidelines recommend intra-articular steroid injections (IASIs) in the management of hip osteoarthritis (OA), though these recommendations are extrapolated primarily from studies of knee OA. The aim of this systematic review was to assess the efficacy of IASI on pain in hip OA. METHODS: MEDLINE, EMBASE, AMED, CINAHL Plus, Web of Science and the Cochrane Central Register of Controlled Trials were searched to May 2015. Randomised controlled trials (RCTs) assessing the efficacy of hip IASI on pain were included. Pre-specified data was extracted using a standardised form. Quality was assessed using the Jadad score. RESULTS: Five trials met the inclusion criteria. All had a small number of participants (≤101). All studies reported some reduction in pain at 3-4 weeks post-injection compared to control. Based on data from individual trials the treatment effect size was large at 1 week post-injection but declined thereafter. A significant (moderate effect size) reduction in pain was reported in two trials up to 8 weeks following IASI. Pooled results of two trials (n = 90) showed an increased likelihood of meeting the Outcome measures in Rheumatology Clinical Trials (OMERACT)-Osteoarthritis Research Society International (OARSI) response criteria at 8 weeks post-IASI, odds ratio 7.8 (95% confidence interval (CI): 2.7-22.8). The number needed to treat to achieve one OMERACT-OARSI responder at 8 weeks post-injection was 2.4 (95% CI: 1.7-4.2). Hip IASI appear to be generally well tolerated. CONCLUSIONS: Hip IASI may be efficacious in short-term pain reduction in those with hip OA though the quality of the evidence was relatively poor. Further large, methodologically rigorous trials are required to verify whether intra-articular corticosteroids are beneficial and for how long.

Synovial volume vs synovial measurements from dynamic contrast enhanced MRI as measures of response in osteoarthritis.

OBJECTIVE: Synovium is increasingly a target of osteoarthritis (OA) treatment, yet its optimal measurement is unclear. Using dynamic contrast enhanced (DCE) MRI in knee OA patients before and after intraarticular steroid injection, we compared the responsiveness of static synovial volume measures to measures of dynamic changes in synovial enhancement, changes that are strongly related to synovial vascularity. METHODS: Ninety three patients underwent DCE-MRI before and 1-2 weeks after intra-articular injection of 80 mg methylprednisolone. Synovium was segmented and volume, relative enhancement rate (RER), maximum relative enhancement (REmax), late relative enhancement (RElate) and pharmacokinetic parameters (K(trans), ve) were calculated. KOOS (​knee injury and osteoarthritis outcome score) pain score was recorded before and after injection. Standardized change scores were calculated for each parameter. Linear regression and Pearson's correlations were used to investigate the relationship between change in MRI parameters and change in pain. RESULTS: The change in standardized score for the measures of synovial enhancement, RElate and REmax were -0.58 (95% CI -0.79 to -0.37) and -0.62 (95% CI -0.83 to -0.41) respectively, whereas the score for synovial volume was -0.30 (-0.52 to -0.09). Further, change in knee pain correlated more strongly with changes in enhancement (for both REmax and RElate, r = -0.27 (95% CI -0.45 to -0.07)) than with changes in synovial volume -0.15 (-0.35 to 0.05). CONCLUSION: This study suggests DCE-MRI derived measures of synovial enhancement may be more sensitive to the response to treatment and more strongly associated with changes in pain than synovial volume and may be better outcomes for assessment of structural effects of treatment in OA.

Ankle motion influences the external knee adduction moment and may predict who will respond to lateral wedge insoles?: an ancillary analysis from the SILK trial.

OBJECTIVE: Lateral wedge insoles are a potential simple treatment for medial knee osteoarthritis (OA) patients by reducing the external knee adduction moment (EKAM). However in some patients, an increase in their EKAM is seen. Understanding the role of the ankle joint complex in the response to lateral wedge insoles is critical in understanding and potentially identifying why some patients respond differently to lateral wedge insoles. METHOD: Participants with medial tibiofemoral OA underwent gait analysis whilst walking in a control shoe and a lateral wedge insole. We evaluated if dynamic ankle joint complex coronal plane biomechanical measures could explain and identify those participants that increased (biomechanical non-responder) or decreased (biomechanical responder) EKAM under lateral wedge conditions compared to the control shoe. RESULTS: Of the 70 participants studied (43 male), 33% increased their EKAM and 67% decreased their EKAM. Overall, lateral wedge insoles shifted the centre of foot pressure laterally, increased eversion of the ankle/subtalar joint complex (STJ) and the eversion moment compared to the control condition. Ankle angle at peak EKAM and peak eversion ankle/STJ complex angle in the control condition predicted if individuals were likely to decrease EKAM under lateral wedge conditions. CONCLUSIONS: Coronal plane ankle/STJ complex biomechanical measures play a key role in reducing EKAM when wearing lateral wedge insoles. These findings may assist in the identification of those individuals that could benefit more from wearing lateral wedge insoles.

Assessing and ensuring patient safety during breath-holding for radiotherapy.

OBJECTIVE: While there is recent interest in using repeated deep inspiratory breath-holds, or prolonged single breath-holds, to improve radiotherapy delivery, breath-holding has risks. There are no published guidelines for monitoring patient safety, and there is little clinical awareness of the pronounced blood pressure rise and the potential for gradual asphyxia that occur during breath-holding. We describe the blood pressure rise during deep inspiratory breath-holding with air and test whether it can be abolished simply by pre-oxygenation and hypocapnia. METHODS: We measured blood pressure, oxygen saturation (SpO2) and heart rate in 12 healthy, untrained subjects performing breath-holds. RESULTS: Even for deep inspiratory breath-holds with air, the blood pressure rose progressively (e.g. mean systolic pressure rose from 133 ± 5 to 175 ± 8 mmHg at breakpoint, p < 0.005, and in two subjects, it reached 200 mmHg). Pre-oxygenation and hypocapnia prolonged breath-hold duration and prevented the development of asphyxia but failed to abolish the pressure rise. The pressure rise was not a function of breath-hold duration and was not signalled by any fall in heart rate (remaining at resting levels of 72 ± 2 beats per minute). CONCLUSION: Colleagues should be aware of the progressive blood pressure rise during deep inspiratory breath-holding that so far is not easily prevented. In breast cancer patients scheduled for breath-holds, we recommend routine screening for heart, cardiovascular, renal and cerebrovascular disease, routine monitoring of patient blood pressure and SpO2 during breath-holding and requesting patients to stop if systolic pressure rises consistently >180 mmHg and or SpO2 falls <94%. ADVANCES IN KNOWLEDGE: There is recent interest in using deep inspiratory breath-holds, or prolonged single breath-holding techniques, to improve radiotherapy delivery. But there appears to be no clinical awareness of the risks to patients from breath-holding. We demonstrate the progressive blood pressure rise during deep inspiratory breath-holds with air, which we show cannot be prevented by the simple expedient of pre-oxygenation and hypocapnia. We propose patient screening and safety guidelines for monitoring both blood pressure and SpO2 during breath-holds and discuss their clinical implications.

Factors associated with arthrogenous muscle inhibition in patellofemoral osteoarthritis.

OBJECTIVES: Arthrogenous muscle inhibition (AMI) is thought to contribute to quadriceps weakness in knee osteoarthritis (OA), but its relationship with structural changes of bone marrow lesions (BMLs), capsular distension and pain is unclear. This study's objective was to investigate the factors associated with AMI in subjects with symptomatic patellofemoral joint OA (PFJOA). DESIGN: 126 Subjects with predominant PFJOA were assessed for pain by the visual analogue scale (VAS) for a nominated aggravating activity. Their more symptomatic knee underwent a magnetic resonance imaging (MRI) scan which was used to assess BMLs and synovitis which were scored using the Whole Organ MRI score (WORMS). Quadriceps AMI was measured by calculating the activation deficit and quadriceps strength assessed by isometric maximum voluntary contraction. Multiple linear regressions were used to assess factors associated with AMI. RESULTS: We studied 124 subjects [mean age 55.5 (SD 7.5); 57.14% female]. In regression analyses, higher levels of AMI were significantly associated with more severe knee pain and with lower BML score. CONCLUSION: Quadriceps AMI in knee OA is associated with severity of knee pain and surprisingly with lower BML scores.

Evaluating the importance of the carotid chemoreceptors in controlling breathing during exercise in man.

Only the carotid chemoreceptors stimulate breathing during hypoxia in Man. They are also ideally located to warn if the brain's oxygen supply falls, or if hypercapnia occurs. Since their discovery ~80 years ago stimulation, ablation, and recording experiments still leave 3 substantial difficulties in establishing how important the carotid chemoreceptors are in controlling breathing during exercise in Man: (i) they are in the wrong location to measure metabolic rate (but are ideally located to measure any mismatch), (ii) they receive no known signal during exercise linking them with metabolic rate and no overt mismatch signals occur and (iii) their denervation in Man fails to prevent breathing matching metabolic rate in exercise. New research is needed to enable recording from carotid chemoreceptors in Man to establish whether there is any factor that rises with metabolic rate and greatly increases carotid chemoreceptor activity during exercise. Available evidence so far in Man indicates that carotid chemoreceptors are either one of two mechanisms that explain breathing matching metabolic rate or have no importance. We still lack key experimental evidence to distinguish between these two possibilities.

Bone marrow lesions in knee osteoarthritis change in 6-12 weeks.

OBJECTIVES: Knee osteoarthritis (OA) is thought to be a slowly evolving disease with glacial changes in cartilage morphology necessitating trials of potential treatments lasting 1-2 years with evidence that over 6 months change in cartilage is not detectable. In contrast to cartilage, bone has the capacity to adapt rapidly, such as after fracture. We tested whether bone marrow lesions (BMLs) change in volume in 6 and 12 weeks, suggesting they may provide evidence of short term fluctuations of joint damage. METHODS: In 62 patients with patellofemoral knee OA (mean age 55.7 years, 59.7% women, mean BMI 31.0), we obtained baseline, 6 and 12 week knee MRIs with contrast enhancement. Of those with BMLs at baseline, we assessed BML volume on the axial proton density fat saturated (FS) images and postcontrast sagittal T1 weighted FS images. We manually segmented BML volumes, testing repeatability of BML volumes in knees remeasured. Using the standard deviation of the difference between repeated measurements to calculate Bland-Altman Limits of Agreement, we determined how much BML volume change represented a change greater than due to chance. RESULTS: Fifty-two patients had BMLs at baseline. Test-retest reliability for BML volume was high (ICC 0.89, 95% CI 0.80-0.97). All knees showed at least some change in BML volume by 6 and 12 weeks. On the axial view at 6 weeks, 20/49 (40.8%) knees showed BML volume changes greater than the limits of agreement with similar results at 12 weeks. BML changes were evenly divided among knees with enlarging and shrinking BMLs. 63.3% of the knees had more than 50% change in BML volume at either 6 or 12 weeks on the axial view and 48.7% on the sagittal view. CONCLUSIONS: Knee BML volumes change in several weeks in many persons with knee OA. To the extent that they could be regarded as treatment targets, trials testing BML effects could avoid the usual prolonged structure modification trials.

Can baroreflex measurements with spontaneous sequence analysis be improved by also measuring breathing and by standardization of filtering strategies?

Baroreflex sensitivity (BRS) is known to be attenuated by inspiration and all the original BRS methodologies took this into account by measuring only in expiration. Spontaneous sequence analysis (SSA) is a non-invasive clinical tool widely used to estimate BRS in Man but does not take breathing into account. We have therefore modified it to test whether it too can detect inspiratory attenuation. Traditional SSA is also entangled with issues of distinguishing causal from random relationships between blood pressure and heart period and of the optimum choice of data filter settings. We have also tested whether the sequences our modified SSA rejects do behave as random relationships and show the limitations of the absence of filter standardization. SSA was performed on eupneic data from 1 h periods in 20 healthy subjects. Applying SSA traditionally produced a mean BRS of 23 ± 3 ms mmHg(-1). After modification to measure breathing, SSA detected significant inspiratory attenuation (11 ± 1 ms mmHg(-1)), and the mean expiratory BRS was significantly higher (26 ± 5 ms mmHg(-1)). Traditional SSA therefore underestimates BRS by an amount (3 ms mmHg(-1)) as big as the major physiological and clinical factors known to alter BRS. We show that the sequences rejected by SSA do behave like random associations between pressure and period. We also show the minimal effect of the r(2) filter and the biases that some pressure and heart period filters can introduce. We discuss whether SSA might be improved by standardization of filter settings and by also measuring breathing.

Breath-holding and its breakpoint.

This article reviews the basic properties of breath-holding in humans and the possible causes of the breath at breakpoint. The simplest objective measure of breath-holding is its duration, but even this is highly variable. Breath-holding is a voluntary act, but normal subjects appear unable to breath-hold to unconsciousness. A powerful involuntary mechanism normally overrides voluntary breath-holding and causes the breath that defines the breakpoint. The occurrence of the breakpoint breath does not appear to be caused solely by a mechanism involving lung or chest shrinkage, partial pressures of blood gases or the carotid arterial chemoreceptors. This is despite the well-known properties of breath-hold duration being prolonged by large lung inflations, hyperoxia and hypocapnia and being shortened by the converse manoeuvres and by increased metabolic rate. Breath-holding has, however, two much less well-known but important properties. First, the central respiratory rhythm appears to continue throughout breath-holding. Humans cannot therefore stop their central respiratory rhythm voluntarily. Instead, they merely suppress expression of their central respiratory rhythm and voluntarily 'hold' the chest at a chosen volume, possibly assisted by some tonic diaphragm activity. Second, breath-hold duration is prolonged by bilateral paralysis of the phrenic or vagus nerves. Possibly the contribution to the breakpoint from stimulation of diaphragm muscle chemoreceptors is greater than has previously been considered. At present there is no simple explanation for the breakpoint that encompasses all these properties.