Eric Troncy

Inhaled nitric oxide: clinical applications, indications, and toxicology

PurposeAlthough the analogy of nitric oxide (NO) to Endothelium-derived Relaxing Factor remains controversial, medical use of exogenous NO gas by inhalation has grown exponentially. This review presents the mechanisms of action of inhaled NO in pulmonary hypertension, hypoxaemia, inflammation and œdema, as well as its therapeutic and diagnostic indications with emphasis on acute respiratory distress syndrome (ARDS) and toxicology.SourceTwo medical databases (Current Contents, Medline) were searched for citations containing the abovementionned key words to December 1996. Moreover, many presentations in congresses such as 4th International Meeting of Biology of Nitric Oxide, 52nd and 53rd Annual Meeting of Canadian Anæsthetists’ Society or 10th Annual Meeting of European Association of Cardiothoracic Anesthesiologists were used.Principal findingsInhaled NO is now recognized as an invaluable tool in neonatal and paediatric critical care, and for heart/lung surgery. Other clinical applications in adults, such as chronic obstructive pulmonary disease and ARDS, require a cautious approach. The inhaled NO therapy is fairly inexpensive, but it would seem that it is not indicated for everybody with regards to the paradigm of its efficiency and potential toxicity. The recent discovery of its anti-inflammatory and extrapulmonary effects open new honzons for future applications.ConclusionClinical use of inhaled NO was mostly reported in case series, properly designed clinical trials must now be performed to establish its real therapeutic role. These trials would permit adequate selection of the cardiopulmonary disorders, and subsequently the patients that would maximally benefit from inhaled NO therapy,RésuméObjectifMême si la relation entre le monoxyde d’azote (NO) et l’EDRF (endothelium-derived relaxing factor) n’est pas établie de façon absolue, l’utilisation médicale du NO exogène à l’état gazeux a cru de façon exponentielle. Ce survol de la littérature rappelle les mécanismes d’action du NO inhalé dans l’hypertension pulmonaire, l’hypoxémie, l’inflammation et l’oedème et jette un regard sur ses indications diagnostiques et thérapeutiques principalement en rapport avec le syndrome de détresse respiratoire de l’adulte (SDRA) et la toxicologie du NO.SourcesDeux bases de données (Current Contents, Medline) incluant décembre 1996, ont été consuttées en faisant appel aux mots-dés mentionnés plus haut. En outre, on a révisé les travaux présentés à des congrès comme le4th International Meeting of Biology of Nitrous Oxide, les 52e et 53e congrès annuels deLa Sotiété canadienne des anesthésistes et le 10e congrès annuel de l’Assoaationeuropéenne des onesthésiologistes cardiothoraciques.Principales constatationsL’inhalation de NO est maintenant reconnue comme faisant partie de l’arsenal thérapeutique néonatalogique, pédiatrique et chirurgical cardiopulmonaire. Chez les adultes, les autres indications comme la maladie pulmonaire obstructive chronique et le SDRA sont moins évidentes. L’inhalation thérapeutique de NO ne coûte pas cher mais ne constitue pas une panacée, compte tenu de son efficacité et de sa toxicité potentielle. La découverte récente de ses effets anti-inflammatoires et extrapulmonaires ouvre toutefois la porte à de nouvelles applications.ConclusionEn clinique, l’inhalation de NO a surtout fait l’objet d’observations anecdotiques mais des essais cliniques validés doivent être menés pour établir sa valeur thérapeutique réelle. Ces essais devraient permettre d’établir ses indications cardiopulmonaires et ainsi procurer aux patients les avantages maximaux de la thérapie par inhalation au NO.

Tiludronate treatment improves structural changes and symptoms of osteoarthritis in the canine anterior cruciate ligament model

IntroductionThe aim of this prospective, randomized, controlled, double-blind study was to evaluate the effects of tiludronate (TLN), a bisphosphonate, on structural, biochemical and molecular changes and function in an experimental dog model of osteoarthritis (OA).MethodsBaseline values were established the week preceding surgical transection of the right cranial/anterior cruciate ligament, with eight dogs serving as OA placebo controls and eight others receiving four TLN injections (2 mg/kg subcutaneously) at two-week intervals starting the day of surgery for eight weeks. At baseline, Week 4 and Week 8, the functional outcome was evaluated using kinetic gait analysis, telemetered locomotor actimetry and video-automated behaviour capture. Pain impairment was assessed using a composite numerical rating scale (NRS), a visual analog scale, and electrodermal activity (EDA). At necropsy (Week 8), macroscopic and histomorphological analyses of synovium, cartilage and subchondral bone of the femoral condyles and tibial plateaus were assessed. Immunohistochemistry of cartilage (matrix metalloproteinase (MMP)-1, MMP-13, and a disintegrin and metalloproteinase domain with thrombospondin motifs (ADAMTS5)) and subchondral bone (cathepsin K) was performed. Synovial fluid was analyzed for inflammatory (PGE2 and nitrite/nitrate levels) biomarkers. Statistical analyses (mixed and generalized linear models) were performed with an α-threshold of 0.05.ResultsA better functional outcome was observed in TLN dogs than OA placebo controls. Hence, TLN dogs had lower gait disability (P = 0.04 at Week 8) and NRS score (P = 0.03, group effect), and demonstrated behaviours of painless condition with the video-capture (P < 0.04). Dogs treated with TLN demonstrated a trend toward improved actimetry and less pain according to EDA. Macroscopically, both groups had similar level of morphometric lesions, TLN-treated dogs having less joint effusion (P = 0.01), reduced synovial fluid levels of PGE2 (P = 0.02), nitrites/nitrates (P = 0.01), lower synovitis score (P < 0.01) and a greater subchondral bone surface (P < 0.01). Immunohistochemical staining revealed lower levels in TLN-treated dogs of MMP-13 (P = 0.02), ADAMTS5 (P = 0.02) in cartilage and cathepsin K (P = 0.02) in subchondral bone.ConclusionTiludronate treatment demonstrated a positive effect on gait disability and joint symptoms. This is likely related to the positive influence of the treatment at improving some OA structural changes and reducing the synthesis of catabolic and inflammatory mediators.

Characterization of osteoarthritis in cats and meloxicam efficacy using objective chronic pain evaluation tools

This study aimed to characterize osteoarthritis (OA)-related chronic pain and disability in experimental cats with naturally occurring OA. Peak vertical ground reaction force (PVF), accelerometer-based motor activity (MA) and the von Frey anesthesiometer-induced paw withdrawal threshold were used to define OA and to test the efficacy of meloxicam. A diagnosis of OA was based on radiographic and orthopedic examinations. Cats with OA (n=39) and classified as non-OA (n=6) were used to assess the reliability and sensitivity of the parameters to assess OA over 3weeks while being administered placebo medication. A randomised parallel design study was then used to investigate the effects on OA of daily oral meloxicam treatment for 4weeks at different dose rates (0.025mg/kg, n=10mg/kg; 0.04mg/kg, n=10; 0.05mg/kg, n=9), compared to cats administered a placebo (n=10). The test-retest repeatability for each tool was good (intra-class correlation coefficient ⩾0.6). The PVF and the von Frey anesthesiometer-induced paw withdrawal threshold discriminated OA (P<0.05). Meloxicam did not add to the PVF improvement observed in placebo-treated cats during the treatment period (adj-P⩽0.01). The 0.025 and the 0.05mg/kg meloxicam-treated cats experienced a higher night-time (17:00-06:58h) MA intensity during the treatment period compared to the placebo period (adj-P=0.04, and 0.02, respectively) and this effect was not observed in the placebo group. The high allodynia rate observed in the 0.04mg/kg meloxicam-treated group may explain the lower responsiveness to the drug. The von Frey anesthesiometer-induced paw withdrawal threshold demonstrated no responsiveness to meloxicam. The results from this study indicated that daily oral meloxicam administration for 4weeks provided pain relief according to night-time MA.

Osteophytosis, subchondral bone sclerosis, joint effusion and soft tissue thickening in canine experimental stifle osteoarthritis: comparison between 1.5 T magnetic resonance imaging and computed radiography.

OBJECTIVE To compare use of 1.5 T magnetic resonance imaging (MRI) and computed radiography (CR) for morphologic and temporal evaluation of osteophytosis, subchondral sclerosis, joint effusion, and synovial thickening in experimentally induced canine stifle osteoarthritis (OA). STUDY DESIGN Prospective study. ANIMALS Dogs (n=8). METHODS CR (mediolateral and caudocranial projections) and MRI (dorsal 3D T1-weighted gradient echo, sagittal 3D SPGR and T2-weighted fast spin echo with fat saturation) were performed at baseline (n=8) and at week 4 (n=5), week 8 (n=8), and week 26 (n=5) after cranial cruciate ligament transection. Osteophytosis, subchondral bone sclerosis, and joint effusion were scored on CR and MRI, and synovial thickening on MRI. RESULTS MRI was more sensitive than CR for detection of osteophytosis and could better discriminate joint effusion from soft tissue thickening, although scores for these variables strongly correlated between modalities (rho=0.94 [osteophytosis] and 0.80 [effusion]; P<.001). Scores for subchondral bone sclerosis also correlated (rho=0.54, P<.004), although this variable may have been over interpreted on CR. Joint effusion and synovial thickening peaked at week 8, before partially regressing at week 26. Conversely, osteophytosis and sclerosis progressed semi-linearly over 26 weeks. CONCLUSION MRI is more sensitive than radiography in assessing onset and progression of osteophytosis in canine experimental stifle OA and provides enhanced discrimination between joint effusion and synovial thickening. CLINICAL RELEVANCE MRI is as a more powerful imaging modality that should be increasingly used in animals to assess the joint related effects of disease-modifying OA drugs.

Magnetic resonance imaging can accurately assess the long-term progression of knee structural changes in experimental dog osteoarthritis

Objectives: Osteoarthritis (OA) structural changes take place over decades in humans. MRI can provide precise and reliable information on the joint structure and changes over time. In this study, we investigated the reliability of quantitative MRI in assessing knee OA structural changes in the experimental anterior cruciate ligament (ACL) dog model of OA. Methods: OA was surgically induced by transection of the ACL of the right knee in five dogs. High resolution three dimensional MRI using a 1.5 T magnet was performed at baseline, 4, 8 and 26 weeks post surgery. Cartilage volume/thickness, cartilage defects, trochlear osteophyte formation and subchondral bone lesion (hypersignal) were assessed on MRI images. Animals were killed 26 weeks post surgery and macroscopic evaluation was performed. Results: There was a progressive and significant increase over time in the loss of knee cartilage volume, the cartilage defect and subchondral bone hypersignal. The trochlear osteophyte size also progressed over time. The greatest cartilage loss at 26 weeks was found on the tibial plateaus and in the medial compartment. There was a highly significant correlation between total knee cartilage volume loss or defect and subchondral bone hypersignal, and also a good correlation between the macroscopic and the MRI findings. Conclusion: This study demonstrated that MRI is a useful technology to provide a non-invasive and reliable assessment of the joint structural changes during the development of OA in the ACL dog model. The combination of this OA model with MRI evaluation provides a promising tool for the evaluation of new disease-modifying osteoarthritis drugs (DMOADs).

Evaluation of osteoarthritis in cats: novel information from a pilot study.

OBJECTIVE To describe structural changes associated with osteoarthritis (OA) in cats and to quantify OA-associated disability using functional evaluations. STUDY DESIGN Cross-sectional pilot study with longitudinal data. ANIMALS Normal cats (n = 2) and coxofemoral joint OA cats (n = 4) were evaluated by physical examination, radiography, and magnetic resonance imaging (MRI). METHODS Structural changes related to OA were scored using computed radiographs (CR) and MRI. Functional evaluation consisted of podobarometric gait analyses performed using a pressure-sensitive mattress and motor activity assessments using collar-attached, accelerometer-based activity sensors. RESULTS Structural scores for the coxofemoral joint OA-related lesions were lower in normal cats than OA cats for MRI (P = .07). Use of MRI allowed for whole-organ assessment of the coxofemoral joint. Pelvic limb peak vertical ground reaction force (PVF) was higher in normal cats than OA cats (P = .10). During the night, motor activity was greater in normal cats than OA cats (P = .04). PVF was positively correlated with mean motor activity (Spearman coefficient [Rho] = 0.83, P = .04) and negatively correlated with age and MRI structural score (Rho = -0.93 and -0.79, P < .01 and .06, respectively). CONCLUSIONS This study provides the first description of OA-related lesions in cats using MRI. Gait analysis and accelerometry should be considered as objective tools to characterize OA-associated disability, although these assessments were weakly correlated with structural changes.

Inhaled nitric oxide : Technical aspects of administration and monitoring

OBJECTIVES Clinical applications of inhaled nitric oxide (NO) therapy resulted in the development of delivery systems and monitoring devices applicable to routine clinical care. This article presents the various components necessary for an adequate clinical use of inhaled NO, and discusses the NO gas mixture cylinders, inhaled NO delivery techniques and specifications, monitoring devices, and ending with an exhaustive description of the scavengers of nitrogen oxides (NOx). DATA SOURCES Computerized search (CURRENT CONTENTS, MEDLINE) of published original research and review articles (approximately 200), conference abstracts and compendiums up to May 1997 (approximately 50), personal files, and contact with expert informants. STUDY SELECTION Technical, experimental, and clinical reports were selected from the recent English, French, German, and Spanish literature, if pertinent to the administration or monitoring of inhaled NO. DATA EXTRACTION The authors extracted all applicable data. DATA SYNTHESIS The production of NO gas mixture cylinders must be certified with respect to gas purity, stability, and concentration (limits between 100 and 1000 ppm), guaranteed calibration, and specific color. An ideal inhaled NO delivery device requires a synchronized delivery, a minimal production of nitrogen dioxide (NO2), and should be simple to use (verification, calibration, convenient flushing, cylinder change possible while in use and a simple alarm setting) with full information (high and low alarms and available precision monitoring of NO, NO2, and O2). Emergency and transport systems must be readily available. The choice of the monitoring device (chemiluminescence or electrochemistry) should be made based on the knowledge of their strength and weakness for a particular clinical application. Finally, scavengers of NOx should be used with caution until specific filters are proven safe and effective. CONCLUSIONS The great expectancies generated by inhaled NO action have led researchers to design personal inhaled NO delivery systems, but only with mitigated results. At present, medical companies are finding a financial interest in designing a delivery system which will suit the needs of clinicians and this, along with official governmental approval, will only then permit the use of inhaled NO safely and on a larger scale.

Clinical validity of outcome pain measures in naturally occurring canine osteoarthritis

BackgroundThe conceptual validity of kinetic gait analysis and disability outcome assessment methods has guided their use in the assessment of pain caused by osteoarthritis (OA). No consensus on the best clinical methods for pain evaluation in canine OA exists, particularly, when evaluating treatments where a smaller treatment effect is anticipated than with pharmacological pain killers. This study thus aimed at determining the technical validity of some clinical endpoints on OA pain in dogs using the green-lipped mussel (GLM)-enriched diet.Twenty-three adult dogs with clinical OA completed the prospective controlled study. All the dogs were fed a balanced diet over a 30-day control period followed by a GLM-enriched diet over a 60-day period. The kinetic gait analysis parameter (PVFBW, peak vertical force adjusted for body weight change), electrodermal activity (EDA), and a standardized multifactorial pain questionnaire (MFQ) were performed on day (D) 0 (inclusion), D30 (start) and D90 (end). The owners completed a client-specific outcome measures (CSOM) instrument twice a week. Motor activity (MA) was continuously recorded in seven dogs using telemetered accelerometric counts. We hypothesized that these methods would produce convergent results related to diet changes. A Type I error of 0.05 was adjusted to correct for the multiplicity of the primary clinical endpoints.ResultsNeither the EDA nor the MFQ were found reliable or could be validated. Changes in the PVFBW (Padj = 0.0004), the CSOM (Padj = 0.006) and the MA intensity (Padj = 0.02) from D0 to D90 suggested an effect of diet(s). Only the PVFBW clearly increased after the GLM-diet (Padj = 0.003). The CSOM exhibited a negative relationship with the PVFBW (P = 0.02) and MA duration (P = 0.02).ConclusionsThe PVFBW exhibited the best technical validity for the characterization of the beneficial effect of a GLM-enriched diet. The CSOM and MA appeared less responsive following a GLM-diet, but these measures appeared complementary to gait analysis. Apparently, the CSOM provides the capacity to rely on pain OA assessment influenced by both lameness quantification (PVFBW) and physical functioning (MA).

should we treat acute respiratory distress syndrome with inhaled nitric oxide

2(respective survival rate of 80 and 100%), and despite the recommendations of the American-European acute respiratory distress syndrome (ARDS) consensus, 3 no study has been appropriately designed to address the clinical outcome of ARDS patients treated with inhaled nitric oxide (NO). This pilot randomised controlled clinical trial of ARDS patients was implemented to study the efficacy of inhaled NO on lung function; the impact of inhaled NO on morbidity and mortality; and the feasibility of conducting a large multicentre trial. 30 established ARDS (with lung injury score 4

Validation of Orthopedic Postoperative Pain Assessment Methods for Dogs: A Prospective, Blinded, Randomized, Placebo-Controlled Study

In the context of translational research, there is growing interest in studying surgical orthopedic pain management approaches that are common to humans and dogs. The validity of postoperative pain assessment methods is uncertain with regards to responsiveness and the potential interference of analgesia. The hypothesis was that video analysis (as a reference), electrodermal activity, and two subjective pain scales (VAS and 4A-VET) would detect different levels of pain intensity in dogs after a standardized trochleoplasty procedure. In this prospective, blinded, randomized study, postoperative pain was assessed in 25 healthy dogs during a 48-hour time frame (T). Pain was managed with placebo (Group 1, n = 10), preemptive and multimodal analgesia (Group 2, n = 5), or preemptive analgesia consisting in oral tramadol (Group 3, n = 10). Changes over time among groups were analyzed using generalized estimating equations. Multivariate regression tested the significance of relationships between pain scales and video analysis. Video analysis identified that one orthopedic behavior, namely ‘Walking with full weight bearing’ of the operated leg, decreased more in Group 1 at T24 (indicative of pain), whereas three behaviors indicative of sedation decreased in Group 2 at T24 (all p<0.004). Electrodermal activity was higher in Group 1 than in Groups 2 and 3 until T1 (p<0.0003). The VAS was not responsive. 4A-VET showed divergent results as its orthopedic component (4A-VETleg) detected lower pain in Group 2 until T12 (p<0.0009), but its interactive component (4A-VETbeh) was increased in Group 2 from T12 to T48 (p<0.001). Concurrent validity established that 4A-VETleg scores the painful orthopedic condition accurately and that pain assessment through 4A-VETbeh and VAS was severely biased by the sedative side-effect of the analgesics. Finally, the video analysis offered a concise template for assessment in dogs with acute orthopedic pain. However, subjective pain quantification methods and electrodermal activity need further investigation.