Acute Dog Model Research Articles

Microstimulators and Intramuscular Hook Electrodes for the Stimulation of Respiratory Muscles

Background/Objectives: We determined the feasibility of stimulating the major muscles of respiration with different types of electrodes. Intramuscular hook electrodes, model microstimulators (M-Micro) developed in our laboratory, and commercial radiofrequency microstimulators (RFM) (Alfred Mann Foundation, Valencia, CA), were employed in this investigation.Methods: In 8 anesthetized dogs, M-Micro were placed bilaterally on the diaphragm and in the abdominal muscles, and hook electrodes were placed in the 3rd and 5th intercostal regions adjacent to the intercostal nerves known to support inspiration. In 3 of the 8 animals, RFMs (Alfred Mann Foundation) in addition to the M-Micros were sutured to each hemidiaphragm at the same optimal site for phrenic nerve stimulation. During a hyperventilation-induced apnea, 2-second stimulations were applied to the diaphragm and with various combinations of diaphragm plus supporting muscles, both thoracic and abdominal.Results: Diaphragm stimulation alone provided tidal volumes adequate for basal alveolar ventilation. However, implantation of the RFM required greater contact with the muscle. Stimulating other respiratory muscles along with the diaphragm further increased tidal volumes. The hook electrodes, M-Micro, and RFM performed equally well.Conclusions: In the acute dog model, M-Micro and hook electrodes can provide an implant system for the maintenance of ventilation. Support of the intercostal and abdominal muscles has the potential to reduce the contraction requirements of the diaphragm with decreased likelihood of diaphragm fatigue and hypoventilation. Whether the electrodes under investigation could provide an implant system for long-term ventilation needs to be determined.

Arterial uptake of biodegradable nanoparticles for intravascular local drug delivery: Results with an acute dog model

Biodegradable nanoparticles (NP) with a spherical diameter ranging from 70 to 160 nm were investigated for potential usefulness for the local intraluminal therapy of restenosis, the disease process responsible for arterial reobstruction following angioplasty. NPs containing a water-insoluble anti-proliferative agent U-86983 (U-86, Pharmacia and Upjohn, Kalamazoo, MI) were formulated from oil–water emulsions using biodegradable polymers such as poly(lactic acid–co-glycolic acid) (PLGA), and specific additives after particle formation, to enhance arterial retention using either heparin, didodecylmethylammonium bromide (DMAB), or fibrinogen, or combinations. Femoral and carotid arteries of male mongrel dogs were isolated in situ, and were then subjected to a balloon angioplasty. A NP suspension of a predetermined concentration was then infused into the artery for various durations. This was followed by a 30 min restoration of blood flow through the vessel. The arterial segments were excised and analyzed for drug levels. From the drug loading of the NP and the drug levels in the artery, the quantity of nanoparticles retained was calculated and expressed as μg per 10 mg dry arteries. In general, repeated short infusions of nanoparticle suspension (15 s×4) were two-fold more effective in terms of higher arterial U-86 levels than a single prolonged infusion (60 s). A single 15 s infusion was not significantly different than a 60 s infusion on NP arterial uptake. NPs modified with either DMAB or fibrinogen had about 2.5-fold higher uptake levels compared to non-modified NPs (39.2±2.5 and 49.1±2.4 vs. 21.5±0.6, μg/10 mg mean±s.e., respectively). A comparably enhanced NP uptake was noted with a combined heparin/DMAB modification. Increasing the concentration of NP in infusate from 5 to 30 mg ml −1 significantly increased arterial NP uptake level (from 22.5±3.5 to 83.7±1.4 μg/10 mg). Thus, the results support the view that modified nanoparticles along with optimized infusion conditions could enhance arterial wall drug concentrations of agents to treat restenosis.

Acute impairment of coronary blood flow by dynamic cardiomyoplasty

The aim of this study was to quantify the effects of three different configurations of cardiomyoplasty on coronary blood flow in an acute dog model. Thirteen dogs had both latissimus dorsi muscles harvested and transposed to the chest. Coronary blood flow was measured using Doppler cuff probes on the left anterior descending and circumflex coronary arteries during each of three cardio-myoplasty configurations: left posterior, right anterior, and double. Multiple beat measures were made of systolic and diastolic flow during a control protocol and a subsequent protocol with the muscle(s) paced. Significant flow reductions during pacing were observed in the left anterior descending coronary artery during left posterior (17%, p = 0.003), right anterior (29%, p < 0.0001), and double (35%, p = 0.0001) myoplasty. Similar reductions occurred in the circumflex artery (14%, p = 0.0009; 20%, p = 0.001; 27%, p = 0.0053). The net flow over an entire pacing cycle also was reduced significantly; left anterior descending artery (11%, p = 0.0035; 23%, p = 0.0001; 23%, p = 0.0047) and circumflex artery (10%, p = 0.0025; 17%, p = 0.0018; 21%, p = 0.0091). Thus, in the acute setting cardiomyoplasty depresses coronary blood flow. A chronic setting will be needed to determine the ultimate significance of these results.

A Miniature Intraventricular Axial Flow Blood Pump That is Introduced Through the Left Ventricular Apex

A new intraventricular axial flow blood pump has been designed and developed as an implantable left ventricular assist device (LVAD). The pump consists of a tube housing (10 cm in length and 14 mm in diameter), a three-vane impeller combined with a guide vane, and a DC motor. This pump is introduced into the LV cavity through the LV apex, and the outlet cannula is passed antegrade across the aortic valve. Blood is withdrawn from the LV through the inlet ports at the pump base, and discharged into the ascending aorta. A pump flow of > 8 L/min was obtained against 90 mmHg differential pressure in the mock circulatory system. In an acute dog model, this pump could produce a sufficient output of 200 ml/kg/min. In addition, the pump flow profile demonstrated a pulsatile pattern, although the rotation speed was fixed. This is mainly due to the changes in flow rate during a cardiac cycle--that is, during systole, the flow rate increases to the maximum, while the differential pressure between the LV and the aorta decreases to the minimum. Thus, this simple and compact axial flow blood pump can be a potential LVAD, with prompt accessibility and need for less invasive surgical procedures.

Inhibition of Factor XIIIa in a Canine Model of Coronary Thrombosis: Effect on Reperfusion and Acute Reocclusion After Recombinant Tissue-Type Plasminogen Activator

The effect of inhibition of factor XIIIa with 2-(l-acetonylthio)-5-methylthiazolo[2,3-b]1,3,4-thiadiazo lium perchlorate (L-722,151) on coronary thrombolysis and reocclusion was studied in an acute dog model of electrically induced coronary thrombosis. L-722,151 (0.1 mg/kg/min intravenously [IV] or placebo was administered 15 minutes before current initiation (150 microA) and for the duration of the experiment (270 minutes). Fifteen minutes after thrombus formation, heparin (300 U/kg, IV) was administered, followed 45 minutes later by recombinant tissue-type plasminogen activator (tPA) (10 micrograms/kg/min, IV for 90 minutes). Placebo-treated animals thrombosed at 48.9 +/- 8.1 minutes (mean +/- SEM) and reperfused in response to tPA at 49.1 +/- 9.3 minutes. L-722,151 pretreated animals thrombosed at 44.4 +/- 9.7 minutes and reperfused in response to tPA at 16.4 +/- 2.8 minutes (P less than .05 v vehicle). Furthermore, residual thrombus mass was reduced by L-722,151 from 6.9 +/- 1.9 mg in placebo-treated animals to 1.7 +/- 0.6 mg (P less than .05 v vehicle). Acute reocclusion occurred in 86% of placebo and in 75% of L-722,151-treated animals. The incidence of tPA-induced reperfusion in L-722,151-treated dogs was 100% (8 of 8), whereas only 70% (7 of 10) of placebo-treated dogs reperfused. These results demonstrate that pretreatment with L-722,151 hastens reperfusion time threefold and reduces residual thrombus mass. These effects occurred with no change in systemic blood pressure in response to L-722,151. When L-722,151 was administered 15 minutes after thrombus formation in a separate group of dogs (n = 5), no beneficial effect on thrombolysis time or thrombus mass was observed. Thus, the specific factor XIIIa catalyzed crosslinking reaction(s), which may determine(s) resistance to plasmin-mediated fibrin degradation, occur(s) rapidly. Inhibition of this crosslinking by pretreatment with L-722,151 promotes tPA-induced thrombolysis.

Inhibition of factor XIIIa in a canine model of coronary thrombosis: effect on reperfusion and acute reocclusion after recombinant tissue- type plasminogen activator

The effect of inhibition of factor XIIIa with 2-(l-acetonylthio)-5- methylthiazolo[2,3-b]1,3,4-thiadiazo lium perchlorate (L-722,151) on coronary thrombolysis and reocclusion was studied in an acute dog model of electrically induced coronary thrombosis. L-722,151 (0.1 mg/kg/min intravenously [IV] or placebo was administered 15 minutes before current initiation (150 microA) and for the duration of the experiment (270 minutes). Fifteen minutes after thrombus formation, heparin (300 U/kg, IV) was administered, followed 45 minutes later by recombinant tissue-type plasminogen activator (tPA) (10 micrograms/kg/min, IV for 90 minutes). Placebo-treated animals thrombosed at 48.9 +/- 8.1 minutes (mean +/- SEM) and reperfused in response to tPA at 49.1 +/- 9.3 minutes. L-722,151 pretreated animals thrombosed at 44.4 +/- 9.7 minutes and reperfused in response to tPA at 16.4 +/- 2.8 minutes (P less than .05 v vehicle). Furthermore, residual thrombus mass was reduced by L-722,151 from 6.9 +/- 1.9 mg in placebo-treated animals to 1.7 +/- 0.6 mg (P less than .05 v vehicle). Acute reocclusion occurred in 86% of placebo and in 75% of L-722,151-treated animals. The incidence of tPA-induced reperfusion in L-722,151-treated dogs was 100% (8 of 8), whereas only 70% (7 of 10) of placebo-treated dogs reperfused. These results demonstrate that pretreatment with L-722,151 hastens reperfusion time threefold and reduces residual thrombus mass. These effects occurred with no change in systemic blood pressure in response to L-722,151. When L-722,151 was administered 15 minutes after thrombus formation in a separate group of dogs (n = 5), no beneficial effect on thrombolysis time or thrombus mass was observed. Thus, the specific factor XIIIa catalyzed crosslinking reaction(s), which may determine(s) resistance to plasmin-mediated fibrin degradation, occur(s) rapidly. Inhibition of this crosslinking by pretreatment with L-722,151 promotes tPA-induced thrombolysis.

A new implantable burst generator for skeletal muscle powered aortic counterpulsation.

Skeletal muscle (SM) can be used for long-term circulatory assist. To generate contractions of appropriate duration and strength, SM requires bursts of electrical pulse trains. Presently, the implantable pulse train stimulator for SM assist is unable, at different heart rates, to adjust pulse burst duration or delay time, adversely affecting timing of counterpulsation. A prototype implantable microprocessor based stimulator (Medtronic Prometheus) has been developed to address this issue. The purpose of this study was to test this generator in an acute dog model. A dual chambered counterpulsation device was connected to the aorta in six dogs, using the latissimus dorsi to power the pump. The generator was connected by sensing/stimulating leads to the heart/left thoracodorsal nerve, programmed to give bursts of 2 V, 30 Hz, and pulse widths of 180 microsecs. Burst delay and duration was set as a fixed percent of the R-R interval of the EKG. The baseline aortic pressures ranged from 75/33 to 118/87 mmHg. During counterpulsation, diastolic pressure increased from 17 to 50 mmHg (30-111% increase). With changing heart rates, the pulse generator spontaneously readjusted its burst delay and duration, maintaining optimal diastolic counterpulsation without systolic interference. We conclude that this new pulse generator can stimulate SM for counterpulsation at varying heart rates, and is suitable for implantation in chronic studies.

Continent ileostomy simplified by musculo-serosal window. An experimental study.

Experience with pouch procedures in the quest for continence after total panproctocolectomy has been associated with significant reoperation rates, making these procedures suitable only for highly selected and motivated patients. The purpose of this study was to determine, in an acute dog model, the optimum configuration of a new continence mechanism consisting of a musculo-serosal window formed between the afferent and efferent loops of small bowel. The following geometric measures were varied: single or double window (efferent and afferent loops, respectively); percent circumference of bowel wall used for the window; and distance between pouch apex and window. Intraluminal pressure against volume infused in standard time was recorded. Four hundred seventy experiments in 47 pouches were conducted. The authors suggest that the optimal configuration for this "valve" is bowel circumference used for the window--50 to 60 percent on both the afferent and efferent loops, with a pouch-valve distance of 5 to 6 cm. It is concluded that a biologic valve obviating the need for a nipple may be possible. The geometric configuration has been defined and should be studied in a chronic animal model to determine long-term results.

Origin of the third heart sound: Comparison of ventricular wall dynamics in hyperdynamic and hypodynamic types

To investigate the left ventricular wall dynamics conducive to the third heart sound (S3) in both hyper- and hypodynamic filling conditions, eight dogs were studied in which an S3 was produced by hypoxemia and in eight others by acute mitral regurgitation. Pulse transit sonomicrometry crystals were used to measure external left ventricular dimension dynamics in the two principal axes. A miniature accelerometer was used to detect the epicardial S3 vibration. The development of the S3 was invariably associated with an increased peak velocity of long-axis external dimensional expansion in early diastole. This enhanced long-axis filling activity was not dependent on increased global chamber or short-axis filling dynamics and sometimes occurred when global filling rate was unchanged. In addition, the short-axis filling rate was sometimes reduced as the S3 developed. It is concluded that the common denominator of S3 generation in this acute dog model is exaggerated long-axis diastolic expansion activity which is present in both hyper- and hypodynamic left ventricular filling.