Heliox improves pulmonary mechanics in a pediatric porcine model of induced severe bronchospasm and independent lung mechanical ventilation.

BACKGROUND: A helium-oxygen gas mixture (heliox) has low gas density and low turbulence and resistance through narrowed airways. The effects of heliox on pulmonary mechanics following severe methacholine-induced bronchospasm were investigated and compared to those of a nitrogen-oxygen gas mixture (nitrox) in an innovative pediatric porcine, independent lung, mechanical ventilation model. RESULTS: All of the lungs showed evidence of severe bronchospasm after methacholine challenge. Prospective definition of 'heliox response' was a 15% or greater improvement in lung function in the lung receiving heliox compared with the matched lung receiving nitrox. Seven out of 10 pigs responded to heliox therapy with respect to resistance and eight out of 10 pigs responded to heliox therapy with respect to compliance and tidal volume (P < 0.03). After crossover from nitrox to heliox, eight out of eight lungs significantly improved with respect to tidal volume, resistance and compliance (P < 0.001). After crossover from heliox to nitrox all eight lungs showed a significant increase in resistance and a significant decrease in tidal volume (P < 0.001). CONCLUSIONS: In a pediatric porcine model of acute, severe methacholine-induced bronchospasm and independent lung mechanical ventilation, administration of heliox improves pulmonary mechanics, gas flow, and ventilation. Administration of heliox should be considered for support of pediatric patients with acute, severe bronchospasm requiring mechanical ventilation through small artificial airways.

Pain of local anesthetics: rate of administration and buffering.

STUDY OBJECTIVE: To determine the impact of administration rate and buffering on the pain associated with subcutaneous infiltration of lidocaine. METHODS: Forty-two adult volunteers employed at a tertiary care center participated in this prospective, single-blinded study. Each subject received four lidocaine injections prepared and administered as follows: slow, buffered (SB); slow, unbuffered (SU); rapid, buffered (RB); rapid, unbuffered (RU). Buffering was accomplished by mixing 1% lidocaine with 8.4% sodium bicarbonate in a 9:1 ratio. Slow administration was 30 seconds and rapid was 5 seconds. Needle size (27-gauge), injection depth (.25 inch), lidocaine volume (1.0 mL), and temperature (room) were the same for each of the four injections. In all four conditions, the needle remained in the forearm for 30 seconds, to ensure blinding. The main outcome measure was the mean pain score for each condition, as recorded on a 10-cm visual analog scale. RESULTS: The lowest pain scores (mean +/- SE) were recorded for the SU and SB conditions at 1.49 +/- 29 and 1.48 +/- 26, respectively, and they were significantly lower than the scores for RB (2.34 +/- 28; P < .01) or RU (3.11 +/- 33; P < .001). Each of the slow conditions was reported to be the "least painful" of the four significantly more often than either rapid condition. CONCLUSION: This is the largest blinded study to assess administration rate and the pain of a local anesthetic. We found that administration rate had a greater impact on the perceived pain of lidocaine infiltration than did buffering.

Anesthetic regimen effects on a pediatric porcine model of asphyxial arrest.

The effects of three anesthetic regimens on an established model of pediatric porcine hypoxic-hypercarbic arrest were examined. Twenty-four preadolescent miniature piglets were paralyzed, mechanically ventilated and anesthetized with one of three regimens: IM + IV pentobarbital (n = 8); IM + IV ketamine (n = 8); or IM ketamine+inhaled isoflurane (n = 8). Asphyxial cardiopulmonary arrest was induced and, after and 8 min cardiac arrest nonintervention interval, a standardized protocol of manual CPR with mechanical ventilation was performed. Outcome variables included incidence of ventricular fibrillation, time to cardiac arrest, endogenous plasma epinephrine levels and arteriovenous epinephrine gradients. IV Ketamine anesthesia produced the highest incidence of ventricular fibrillation (P < 0.01 vs. pentobarbital and isoflurane). Time to asphyxia induced cardiac arrest was greatest for the pentobarbital group (P < 0.05 vs. ketamine and isoflurane). During induction of asphyxial cardiac arrest (low cardiac flow), endogenous venous epinephrine accumulation was highest in the pentobarbital anesthetized group (P < 0.05). After 8 min of untreated cardiac arrest and 1 min of CPR (low flow), arterial epinephrine levels were highest in the ketamine group (P < 0.05). Endogenous epinephrine gradients were venous > arterial in all groups at the end of the 8 min cardiac arrest non-intervention interval (no flow). After 1 min of CPR, the gradients had either equalized or reversed to arterial > venous in all groups except for pentobarbital. As designed and expected, return of spontaneous circulation did not occur in any animal. We conclude that, in developing models of porcine asphyxial cardiopulmonary arrest and resuscitation to simulate pediatric human arrest, variations in anesthetic regimen produce significant differences in parameters that are important to consider: time to asphyxia induced cardiac arrest, fibrillation threshold, plasma epinephrine level and arteriovenous epinephrine gradient. Anesthetic effects need to be carefully considered and clearly explained to facilitate the interpretation of studies of interventions in cardiopulmonary arrest and resuscitation.

Quantitative microfocal radiography detects changes in OA knee joint space width in patients in placebo controlled trial of NSAID therapy.

OBJECTIVE: To assess the usefulness of, and define the time course of changes in the features of osteoarthritic (OA) knees measurable using microfocal radiography, and to determine whether it differs in patients taking a nonsteroidal antiinflammatory drug (NSAID). METHODS: Forty-five patients with knee OA were randomly allocated to receive either diclofenac sodium or placebo for 18 months; 33 (17 NSAID, 16 placebo) completed the study. Clinical and 5 x high definition macroradiographic assessments of both knees in standing semiflexed views were carried out at 6-monthly intervals. Precise measurements were taken of the tibial and femoral subchondral thickness and osteophyte size, and of joint space width (JSW) across the narrowest part of the medial and lateral tibiofemoral compartments. RESULTS: In all knees as a group, there was no statistically significant difference in JSW between treatment groups. However, changes in JSW were significantly different (p < 0.04, multivariate analysis of variance) between treatments in 51 knees with early disease, i.e., those with initially > 50% JSW (22 active, 29 placebo), but not in 15 knees with severe disease, i.e., initially < 50% JSW (10 active, 5 placebo). During the study, osteophyte size in all knees and in those with > 50% JSW increased significantly (p < 0.016; p < 0.008) in the placebo group but remained unchanged in the treatment group. No significant changes were detected in subchondral cortical thickness. CONCLUSION: Using microfocal radiography the time course of changes in JSW and osteophyte size of knees with early, but not late OA, was found to differ in both pattern and magnitude in patients receiving NSAID: In knees with late stage OA the JSW progressively decreased irrespective of treatment. The observations may prove useful for the design of future therapeutic trials.

Joint space width measures cartilage thickness in osteoarthritis of the knee: high resolution plain film and double contrast macroradiographic investigation.

OBJECTIVE: To test reliability of joint space width (JSW) measurements as a predictor of cartilage thickness in knees of patients with osteoarthritis (OA), using high definition microfocal radiography. METHOD: JSW was measured from weight bearing plain film macroradiographs taken in the tunnel view and compared with the sum of femoral and tibial cartilage thicknesses measured from double contrast macroarthrograms of the same regions of the same knees obtained in the non-weight bearing lateral position. RESULTS: All knees had medial compartment OA. Comparison of the JSW with the sum of the tibial and femoral cartilage thicknesses revealed a highly significant correlation (p < 0.0001) between the two measurements in the medial but not the lateral compartment. In the middle region of both compartments, JSW was smaller than the cartilage thickness, indicating that, on standing, the curvature of the femoral condyles compressed the cartilage in this region. CONCLUSIONS: JSW reliably measured cartilage thickness in the medial but not the lateral compartment of knees with medial compartment OA. Depending upon the stage of OA disease, JSW reliably reflects cartilage thinning and compression.

The use of a laryngotracheal separation procedure in pediatric patients.

The objective of this study was to review experience, outcome, and satisfaction after a laryngotracheal separation (LTS) procedure in pediatric patients. Chart reviews and phone questionnaires were used. Factors reviewed included hospitalizations and infections prior to and after LTS, morbidity, and impact on quality of life. Twenty-one pediatric patients ranging in age from 8 to 172 months underwent LTS. Follow-up time ranged from 1 to 49 months. Complications were minor. Eighty-eight percent of patients had fewer hospitalizations or were discharged for the first time after LTS. Number of pneumonias and suctioning frequency decreased, mobility increased in patients with prior tracheostomies, and care requirements decreased in 95% of patients. Parents reported satisfaction and improved quality of life. LTS is a low-risk, successful procedure which increases quality of life and decreases morbidity in pediatric patients with irreversible upper airway dysfunction.

Quantitative microfocal radiographic assessment of osteoarthritis of the knee from weight bearing tunnel and semiflexed standing views.

OBJECTIVE: Joint space width (JSW) in osteoarthritis (OA) knee radiography is reported to be optimally assessed from semiflexed standing and tunnel views although no detailed assessment of tunnel view radiography of OA knees has been done. The primary objective of our study was to determine the incidence of joint space narrowing (JSN) in semiflexed standing vs weight bearing tunnel views. The data were also analyzed to examined the degree and relationship of JSN and bony features of OA in the 2 views. METHODS: Ninety OA knees had macroradiographs at 5 times magnification taken in weight bearing standing semiflexed and weight bearing tunnel views. JSW and OA related bony features were measured and compared with reference values obtained from the knees of 14 healthy volunteers without arthritis. RESULTS: Comparison of JSW between the 2 radiographic views identified 3 locations of cartilage loss: JSN recorded in the tunnel only (22%), that in standing view only (8%), and that in both the views (30%). Subchondral sclerosis and osteophytes were significantly larger in 40% of OA knees despite a normal JSW. The tunnel view also enabled better visualization and measurement of osteophytes. CONCLUSION: Standing semiflexed view radiography alone failed to detect JSN in 22% of OA knees. Combined standing and tunnel radiographic views detected JSN more frequently than either view alone. Bony changes were radiographically evident without the presence of JSN indicative of cartilage thinning in as many as 40% of the patients with OA studied.

Inspiratory-cycle instillation of endotracheal epinephrine in porcine arrest.

OBJECTIVE: To compare timed inspiratory-cycle endotracheal (ET) instillation of epinephrine (EPI) with instillation during apnea during CPR. METHODS: Prospective randomized laboratory comparison of two ET-EPI instillation techniques in 24 preadolescent anesthetized and paralyzed Yucatan swine (mean weight 10.3 +/- 1.5 kg) with apnea-induced hypoxic and hypercarbic cardiopulmonary arrest. After 8 minutes of cardiopulmonary arrest and 1 minute of CPR, 500 microgram(s) (50 +/- 7 microgram(s)/kg) of radiolabeled ET EPI was either administered timed to a ventilator inpspiratory cycle (IN, n = 15) or injected during apnea (DA, n = 9) using a monitoring lumen built into the sidewall of the ET tube. Injection technique was carefully controlled regarding ET-tube position, dilution, flush, and pressure-limited mechanical ventilations. CPR was resumed and continued for 5 minutes. If resuscitation occurred, monitoring was continued for one hour. Outcome variables included pulmonary EPI distribution pattern (DIST), plasma exogenous and total EPI levels, successful resuscitation, and hemodynamic response. RESULTS: Bilateral DIST occurred in 58% of the pigs, with significantly more bilateral DISTs for IN versus DA pigs (p = 0.01). Plasma radiolabeled exogenous EPI counts were significantly greater for IN versus DA pigs (p = 0.03). Total plasma EPI levels rose significantly above baseline over time within each group, but showed no difference between the IN and DA groups at any time point. Successful resuscitation occurred in 21% of the pigs, with no difference between IN and DA pigs (p = 0.38). CONCLUSION: When other aspects of ET EPI instillation are optimized and controlled during porcine hypoxic-hypercarbic arrest, timed inspiratory-cycle installation of ET EPI (50 microgram(s)/kg) results in an improved bilateral DIST and greater exogenous EPI absorption. However, in this severe pediatric asphyxial arrest model using a 50-microgram(s)/kg dose, inspiratory-cycle instillation does not improve the resuscitation rate or hemodynamic response over currently recommended instillation during apnea.

Effects of different techniques of endotracheal epinephrine administration in pediatric porcine hypoxic-hypercarbic cardiopulmonary arrest.

OBJECTIVE: To compare three endotracheal epinephrine instillation techniques in a pediatric porcine hypoxic-hypercarbic cardiopulmonary arrest model. DESIGN: Prospective, randomized, laboratory comparison of three instillation techniques. SETTING: Large animal research facility at a children's hospital. SUBJECTS: Thirty-six preadolescent anesthetized and paralyzed Yucatan swine (mean weight 10.0 +/- 1.9 kg) with apnea-induced hypoxic and hypercarbic cardiopulmonary arrest. INTERVENTIONS: After 8 mins of cardiopulmonary arrest and 1 min of cardiopulmonary resuscitation (CPR), 500 micrograms (51 +/- 9 micrograms/kg) of radiolabeled endotracheal epinephrine was administered by direct injection (n = 17), injection via feeding catheter (n = 10), or via monitoring lumen built into the sidewall of the endotracheal tube (n = 9). CPR was resumed and continued for 5 mins. If resuscitation occurred, monitoring was continued for 1 hr. Outcome variables included successful resuscitation, pulmonary distribution, heart rate, mean arterial pressure, plasma radiolabeled epinephrine counts, and total plasma epinephrine concentrations. Analysis by Fisher's exact test, one-way analysis of variance and Pearson's phi coefficient was performed. MEASUREMENTS AND MAIN RESULTS: Successful resuscitation occurred in 31% of all pigs with no difference between groups (p = .69). Bilateral distribution occurred in 39% with no difference between groups (p = .25). No correlation was noted between successful resuscitation and distribution (p = .65). HR, mean arterial pressure, plasma radiolabeled epinephrine counts, and total plasma epinephrine concentrations showed significant changes over time within groups, but no difference between groups at any time point. Adherence of the epinephrine dose to the endotracheal tube was < or = 1.5% in all cases. CONCLUSIONS: Instillation of 50 micrograms/kg of endotracheal epinephrine by three different techniques during pediatric porcine asphyxial arrest does not affect resuscitation rate, pulmonary distribution, hemodynamic response, or plasma exogenous and total epinephrine concentrations. No correlation was found between successful resuscitation and bilateral distribution. Therefore, currently recommended cumbersome endotracheal epinephrine instillation techniques may offer no resuscitation advantage over commonly used direct injection in this setting.

Chronic thromboxane synthase inhibition with CGS 12970 in human cyclosporine nephrotoxicity.

CsA nephrotoxicity in rats is associated with an increase in renal thromboxane production. Treatment with selective thromboxane synthase inhibitors or receptor antagonists improves renal function in these animal models. In humans, it is unclear whether intervention aimed at reducing the effects of thromboxane on the kidney will be clinically useful. However, we reported previously that thromboxane metabolite excretion is increased in CsA-treated renal allograft recipients with evidence of CsA toxicity and that 48-hr intravenous infusion of the selective thromboxane synthase inhibitor CGS 13080 improves renal function in such patients. We undertook the present study to determine the effect of more prolonged treatment with an oral thromboxane synthase inhibitor, CGS 12970, in renal transplant recipients taking CsA. We measured glomerular filtration rate and p-aminohippurate clearance before and after 4 weeks of treatment with CGS 12970 in 13 patients with renal allografts who had been treated with CsA for a mean 6.3 months and had mild renal insufficiency. Baseline serum creatinine was 1.8 +/- 0.3. Treatment with CGS 12970 resulted in 83% inhibition of urinary thromboxane B2 (TXB2), 93% inhibition of 2,3-dinor-TXB2, and 89% inhibition of 11-dehydro-TXB2, but no change in the urinary excretion of prostacyclin metabolites. However, suppression of urinary thromboxane metabolites to these levels did not significantly affect renal function. Glomerular filtration rate was 45 +/- 4 ml/min/1.73 m2 at baseline and 43 +/- 4 ml/min/1.73 m2 after 4 weeks of treatment with CGS 12970. Estimated renal plasma flow was 272 +/- 21 ml/min/1.73 m2 at baseline and 251 +/- 38 ml/min/1.73 m2 with thromboxane synthase inhibition. Thus, substantial suppression of thromboxane production with CGS 12970 did not improve renal function in CsA-treated renal allograft recipients.

A two-year, placebo-controlled trial of non-steroidal anti-inflammatory therapy in osteoarthritis of the knee joint.

Eighty-nine patients with established OA of the knee joint, already on regular NSAIDs for joint pain, were randomly allocated to receive 100 mg/day of slow release diclofenac (45 patients) or matching placebo (44), in place of their NSAID, for 2 years. Thirty-eight patients withdrew or dropped out of the study. The major causes for withdrawal were lack of efficacy (three active, 12 placebo, P < 0.01) or side effects (six active, five placebo), and most withdrawals occurred within the first 6 months. Long term follow up of these patients was not possible. Fifty-one patients completed the study (31 active, 20 placebo), 35 of whom reported that they were the same or better at the end of the 2-year period than at the beginning. Most of the recorded clinical parameters showed little or no change over 2 years in these 51 subjects, and in 70% there was no detectable change in the radiographs. We conclude that long term placebo-controlled trials are both feasible and ethical in knee OA, but that conventional clinical and radiographic techniques detect very little change in joint structure or function over a 2-year time period. This may reflect the insensitivity of the methods used to assess progression rather than absence of change. The fact that 20 of 44 patients changed from an NSAID to placebo completed the 2-year study without any symptomatic penalty indicates that not all patients entered needed or responded to NSAIDs.

Variation in MR signal intensity across normal human knee cartilage.

Signal intensity (SI) of individual pixels on sagittal magnetic resonance (MR) images of normal human knee cartilage was quantified to investigate whether it was related to cartilage proteoglycan content. In five subjects, images were acquired with spin-echo sequences with a TR msec/TE msec of 1,000 or 700/20 and a three-dimensional gradient-echo (GRE) sequence (60/15). In a sixth subject, the GRE sequence alone was used with 15 degrees, 30 degrees, and 50 degrees flip angles. In all subjects, SI was maximal in pixel layers of the medial zone and minimal at both cartilage edges, resulting in the presence of a bell-shaped curve of interpixel (zonal) SI variation across the cartilage thickness. The magnitude of SI was dependent on the pulse sequence and flip angle, but the bell shape of the SI variation curve was independent of them. For example, in the medial tibial cartilage, the peak SI was highest with the 1,000/20 spin-echo sequence, intermediate with the 700/20 sequence, and lowest with the GRE sequence. The differences were statistically significant. The bell-shaped SI variation curve resembled the curve for zonal variation in cartilage proteoglycan content but not the curves for collagen or free water content. The physiologic basis for this resemblance and the potential usefulness of the findings for early diagnosis of diseases such as osteoarthritis are discussed.

Immunohistochemical localization of articular cartilage proteoglycan and link protein in situ using monoclonal antibodies and lectin-binding methods.

Lectins have specificity for certain carbohydrate structures in macromolecules. Lectins are, therefore, useful histochemical tools for demonstrating the composition and localization of components of connective tissue matrices, such as articular cartilage. In order to assess the significance of observed lectin-binding patterns, experiments were performed in which monoclonal antibodies against chondroitin sulphate- and keratan sulphate-containing proteoglycans and link proteins were applied to sections of bovine articular cartilage after enzymatic digestion with chondroitinase ABC and keratanase. The following conclusions were made: (1) Binding of peanut agglutinin (PNA) in the interterritorial matrix predominantly indicates the presence of keratan sulphate, but may also detect O-linked oligosaccharides of proteoglycans. (2) In normal cartilage wheat germ agglutinin (WGA) binds nearly exclusively to keratan sulphate. In cartilage degraded with chondroitinase ABC and keratanase this lectin may also detect carbohydrates in link protein due to enhanced accessibility. Binding of WGA to O-linked oligosaccharides may eventually occur. (3) In enzymatically digested cartilage matrix, staining with soybean agglutinin (SBA) may be due to link protein, but not to chondroitin sulphate, because specific breakdown of the glycosaminoglycan chain is required for binding of SBA. (4) Ulex europaeus agglutinin I (UEA I) binding sites are only detectable in digested cartilage matrix.

Chondrocytic monoamine oxidase activity in the development of natural murine osteoarthritis.

Most of the male STR/ORT mice develop osteoarthritis (OA) involving the medial tibial plateau. A peculiarity of two chondroprotective drugs is the presence of a nitrogen atom so that cleavage of the molecule could generate a molecule that might act as an inhibitor of monoamine oxidase (MAO). Direct examination showed abnormal localization of MAO in the potentially osteoarthritic cartilage indicating possible abnormal response to catecholamines. In normal cartilage, the direct effect of excessive concentration of adrenaline caused considerable oedema, as measured by microscopic interferometry. It is therefore suggested that the excess of water found in the matrix of osteoarthritic cartilage may be related to disturbance of the MAO activity.

Changes in the orientation of proteoglycans during the early development of natural murine osteoarthritis.

At least 80% of male STR/ORT mice naturally develop osteoarthritis that predominantly affects the medial tibial cartilage. Overt osteoarthritic changes, as judged by radiological and histological abnormalities, become apparent after 30 weeks of age. Consequently, mice less than 30 weeks of age were used to investigate early changes in the cartilage matrix related to the natural development of osteoarthritis, without the need for experimental intervention to induce this condition. Quantitative Alcian blue staining showed little change in the total amount of proteoglycans in mice of this age. Polarized light microscopy of the birefringence induced by such staining demonstrated a progressive decline in the orientation of the proteoglycans in the medial cartilage of these mice. This decline was not found in CBA mice, which only very rarely develop osteoarthritis of this joint. Such progressive disorganization of the proteoglycans would be likely to permit the increase free water-content characteristic of osteoarthritic cartilage.

Quantitative criteria for evaluating the early development of osteoarthritis and the effect of diclofenac sodium.

In assessing the possible efficacy of drugs for the treatment of osteoarthritis (OA), it may be helpful to have a model, in animals, of the early development of the disease prior to the expression of secondary phenomena. It is also necessary that such effects are quantifiable. To this end, the natural development of OA in the STR/ORT mouse has been investigated. It has been shown that very early events in the development of the disease are disturbances in the activity of chondrocytic glucose 6-phosphate dehydrogenase, the initial step in the pentose-phosphate pathway, and in the orientation of the proteoglycans of the matrix of the articular cartilage. The study has been done by reference to the effect of diclofenac sodium, which previously has been reported to retard the destruction of articular cartilage. The results appear to indicate that these markers may provide quantitative measures for assessing potential therapeutic agents.