High-efficiency endovascular gene delivery via therapeutic ultrasound.

OBJECTIVES: We studied enhancement of local gene delivery to the arterial wall by using an endovascular catheter ultrasound (US). BACKGROUND: Ultrasound exposure is standard for enhancement of in vitro gene delivery. We postulate that in vivo endovascular applications can be safely developed. METHODS: We used a rabbit model of arterial mechanical overdilation injury. After arterial overdilation, US catheters were introduced in bilateral rabbit femoral arteries and perfused with plasmidor adenovirus-expressing blue fluorescent protein (BFP) or phosphate buffered saline. One side received endovascular US (2 MHz, 50 W/cm2, 16 min), and the contralateral artery did not. RESULTS: Relative to controls, US exposure enhanced BFP expression measured via fluorescence 12-fold for plasmid (1,502.1+/-927.3 vs. 18,053.9+/-11,612 microm2, p < 0.05) and 19-fold for adenovirus (877.1+/-577.7 vs. 17,213.15+/-3,892 microm2, p < 0.05) while increasing cell death for the adenovirus group only (26+/-5.78% vs. 13+/-2.55%, p < 0.012). CONCLUSIONS: Endovascular US enhanced vascular gene delivery and increased the efficiency of nonviral platforms to levels previously attained only by adenoviral strategies.

Porcine small intestinal submucosa as a dural substitute.

BACKGROUND: The continuing search for the ideal dural substitute is currently directed toward collagen preparations. Xenogeneic porcine small intestinal submucosa (SIS), a naturally occurring extracellular matrix rich in collagen, has been successfully used as a soft tissue graft in several body organ systems, including preliminary studies as a dural substitute in the rat. METHODS: Eight dogs underwent temporoparietal craniotomy and dural resection with replacement by SIS. Five dogs had contralateral procedures without SIS grafting. Three dogs had contralateral SIS grafts placed 2 months after the initial procedure. Histologic assessment was obtained at 7, 30, 60, 90, and 120 days. Cerebrospinal fluid (CSF) cytological examination and routine serum chemistry preceded sacrifice. RESULTS: Histologic evaluation showed initial graft infiltration by mononuclear round cells, spindle-shaped cells within an eosinophilic staining extracellular matrix, and neovascularity. Complete resorption of the graft was evident by 60 days. This pattern is consistent with the previously described incorporation and remodeling of the SIS graft at other sites. CSF cytology and routine serum chemistry at the time of sacrifice were normal. Response to repeat grafting was identical to that of initial exposure. There was no clinical or histologic evidence of sensitization or graft rejection. No evidence of adverse effect on the underlying cerebral cortex was observed. CONCLUSIONS: Porcine small intestinal submucosa demonstrates a favorable biologic response as a dural substitute in the canine model. It is a promising biomaterial for dural replacement.

Post-mortem changes after lead extraction from the ovine coronary sinus and great cardiac vein.

We investigated in sheep, non-thoracotomy extraction of leads which had been chronically implanted in the right atrium (RA), coronary sinus/great cardiac vein (CS/GCV) and right ventricle (RV) for atrial implantable defibrillation. Clinical success of extraction as well as gross and histologic findings in the heart are reported. Six of nine sheep had successful extractions. The major complication was laceration of the wall of the great coronary vein with hemorrhage into the pericardial space and cardiac tamponade. Tissue damage included several reversible changes: intra-tissue hemorrhage, thrombosis in the veins, and some necrosis of fat, vascular wall and myocardium. Myocyte necrosis was estimated as 0.03 to 0.3 grams of tissue. Osseous and cartilaginous metaplasia was more common around the RA lead than the CS/GCV lead. In cases where the lead must be removed, removal from the venous insertion site using lead extraction equipment should only be attempted with surgical back-up for emergency thoracotomy to control hemorrhage in the event of vessel laceration. Safer explantation of these leads from the vein entry site will require the development of new extraction procedures.

Histology after dural grafting with small intestinal submucosa.

BACKGROUND: The search for the ideal dural substitute continues, inasmuch as available materials have significant limitations. Xenogeneic porcine small intestinal submucosa (SIS) has been successfully used as a soft tissue graft in several body organ systems, and it was logical to evaluate its use as a dural replacement. METHODS: Twenty rats underwent bihemispheric craniectomy with dural resection. SIS onlay grafting on one side was performed. Histologic assessment was obtained at 7 and 28 days after dural grafting and included descriptive evaluation and quantitative scoring of graft-site thickness, vascularity, and cellular density. The total scores for the respective groups were compared using the Student's t test, significance being accepted for a p value < 0.05. RESULTS: Histologic evaluation showed graft infiltration by spindle-shaped mononuclear cells, deposition of connective tissue, and neovascularity. This pattern is consistent with the previously described incorporation and remodeling of the SIS graft at other sites. A significant difference between the histologic scores of the SIS graft site and control site was found at 7 days (3.4 +/- 0.8 versus 0.1 +/- 0.1) and at 28 days (4.6 +/- 1.1 versus 2.2 +/- 0.5). No evidence of adverse effect on the underlying cortex was observed. CONCLUSIONS: The results of this preliminary study utilizing porcine SIS as a dural substitute are promising and therefore justify further chronic studies.

The pumping and left ventricular unloading capabilities of the ventricular synchronous skeletal-muscle ventricle.

The pumping and left ventricular unloading capabilities of the left ventricular, ventricular synchronous skeletal-muscle ventricle were determined in nine anesthetized dogs ranging in weight from 20.7 to 31.8 kg. The ventricular synchronous skeletal-muscle ventricle consists of the left rectus abdominis muscle wrapped around a 4-mil-thick polyethylene pouch (wrapped volume 80 to 100 ml) connected to the left ventricular apex with no valve and to the aorta via a prosthetic heart valve. The rectus muscle is timed to contract tetanically and relax during left ventricular ejection. This arrangement provides a high precontraction pressure for the rectus muscle and a high muscle capillary blood flow during skeletal muscle relaxation. The timing signal for initiation of the train of stimulating pulses (40/sec) was derived from the ventricular electrogram. The delay for the stimulus train determines the preload for the rectus muscle and along with the stimulus train duration determines ventricular synchronous skeletal-muscle ventricle stroke volume, which was measured by electric impedance. With unconditioned rectus muscles (70 to 120 gm) and with a pumping ratio of 1:3, ventricular synchronous skeletal-muscle ventricle stroke volume average 26.1 ml, which provided an average output of 876 ml/min. The normalized ventricular synchronous skeletal-muscle ventricle output was 35.6 ml/min per kilogram of body weight. In a typical resting dog (and man), the normalized cardiac output is 70 ml/min per kilogram. Therefore the ventricular synchronous skeletal-muscle ventricle is capable of pumping 52% of the cardiac output (with a pumping ratio of 1:3). The optimum train delay from the apex of the ventricular electrogram ranged from 10 to 100 msec. The left ventricular ejection period averaged 309 msec, and this determines the time available for the rectus muscle to contract and relax. Evidence for unloading the left ventricle is shown by the reduced left ventricular diastolic pressure and stroke volume for the postassisted beats.

A selective, non-ischemic, non-pharmacological left ventricular failure animal model.

Selective left ventricular failure was induced in 13 acute anesthetized, closed chest dogs ranging in weight from 18-26 kg. Failure was induced by passing a single, high intensity pulse of current from a defibrillator connected to a left ventricular catheter electrode and a left chest electrode. The intensity of the myocardial damaging shock was related to the predicted current required for transventricular defibrillation, based on heart weight. Thermodilution cardiac output, left ventricular pressure, impedance stroke volume, the cardiac electrogram, and lead II ECG were recorded, along with the pressure impedance (volume) loop, which is a measure of stroke work. It was found that the cardiac output decreased with increasing current intensity. Immediately following the high current shock, cardiac output, and stroke work decreased. In some animals, with a moderate intensity shock, there was a transient increase in cardiac output, followed by a decrease. In the five animals that were monitored continuously for 4 hours, the average percent reduction in cardiac output at this time was 42.5% for an average current overdose ratio of 5.39. The energy setting on the defibrillator to obtain this range of reduction in cardiac output was 175-350 joules. The method described herein is easily applied to the closed chest animal and will allow evaluation of the pumping capabilities of cardiac augmentation techniques, such as dynamic cardio-myoplasty and the skeletal muscle ventricle.

Nonpharmacologic circulatory support in the brain-dead animal.

A nonpharmacologic technique for providing an artificial peripheral resistance enabled the canine heart to pump blood for 12 hours in a brain-dead (spinal) animal model. The artificial peripheral resistance was provided by binding the body with elastic bandage. The only other support provided was artificial respiration. Following the 12-hour preservation period, the hearts were challenged to pump by the intravenous infusion of saline. Aortic pressure, cardiac output (CO), oxygen uptake, body temperature, arterial Na+, K+, pH, and HCO3-, and transchest ECG were monitored in all five animals studied during the control and 12-hour preservation periods. Mean blood pressure fell to 50-60 mmHg following cervical cord transection, rising to above 100 mmHg when the body was bound with elastic bandage that restored the peripheral resistance. During the 12-hour preservation period the average mean blood pressure fell from 118 to 60 mmHg, at which point the average normalized CO was 34 mL/min/kg. Following the saline challenge, the average CO increased to 1.89 times the value at the end of the preservation period, representing an average normalized value of 64.3 mL/min/kg (a typical value for the normal resting dog is 70 mL/min/kg). Body temperature decreased slightly in four animals and increased slightly in one. Na+ was virtually unchanged throughout the control and preservation periods, but K+ increased slightly in all animals, exceeding 5 mEq/L in one animal after 8.5 hours and in another after 10 hours. HCO3- was almost constant in all animals, as was pH. However, the pH was elevated during the preservation period due to slight overventilation to assure a high oxygen saturation.(ABSTRACT TRUNCATED AT 250 WORDS)

Stroke volume with dynamic cardiomyoplasty during ventricular fibrillation in the acute dog.

The objective of this study was to determine the pumping capability of dynamic cardiomyoplasty during induced ventricular fibrillation. In this acute study of 6 dogs, the pumping capability of the unconditioned left latissimus dorsi (LD) muscle (141 to 292 gm), wrapped around both ventricles, was investigated during induced ventricular fibrillation. Left-ventricular and femoral artery pressure, the ECG and aortic root flow velocity were monitored. Prior to inducing ventricular fibrillation, the ability of the unconditioned LD muscle to augment stroke volume (SV), was quantified as the area under the aortic flow-velocity record. The ventricles were then fibrillated and, after 10 sec, rhythmic 250 msec trains (1/sec) of stimuli (40/sec) were delivered to the thoracodorsal nerve to contract the LD muscle tetanically. In no case could dynamic cardiomyoplasty produce the same SV as when the ventricles were beating normally. In one animal, the SV attained two percent of the normal SV by 5 contractions; in another, the SV reached one percent by 25 contractions. In the remaining animals, the SV varied around 20% of the prefibrillation SV. By 90 contractions, the stroke volume was 10% of the prefibrillation value. The progressive decrease in SV was likely a consequence of LD muscle ischemia and fatigue, since the latissimus dorsi muscle provided low blood flow during the period of fibrillation.

The importance of timing muscle contraction in dynamic cardiomyoplasty.

This acute dynamic cardiomyoplasty (CMP) study used ten dogs (weight range 21-32 kg) and was designed to determine the importance of the train of stimuli initiation time when applied to the thoracodorsal nerve, which innervates the latissimus dorsi (LD) muscle that is wrapped around the ventricles. Using the P wave of the cardiac electrogram to trigger a special delay circuit, the stimulus train could be initiated from the apex of the R wave to any time throughout and at the end of the isovolumic period, signaled by opening of the aortic valve. The cardiac electrogram (which contained the R wave), left ventricular pressure (LVP), aortic flow velocity (AFV), beat-by-beat stroke volume (SV), femoral artery pressure, and the envelope of the stimulus train were recorded as the onset of the stimulus train was varied from the R wave to the end of the isovolumic period with a pumping ratio of one LD contraction for every seven ventricular contractions. In four dogs there was a pronounced increase in the augmentation in LVP, AFV, and SV when the stimulus train was initiated later than 40 msec after the first peak of the R wave. In five dogs the augmentation in LVP, AFV, and SV was not as clearly apparent, although all of these dogs exhibited an optimal train delay. Data were not obtained on one dog due to an anomalous LD muscle blood supply. For all of the dogs, the optimum train delay from the R wave averaged 58 msec (range 40-80 msec). The average augmentation in SV was 26% (range 13%-45%). The same muscle-wrap tightness was used in all dogs. In one dog, the muscle-wrap tightness was varied, and by tightening the wrap the SV augmentation increased from 17% to 27%. For all dogs the range of augmentation in SV (13%-45%) perhaps represents variations in muscle-wrap tightness, which may be a major uncontrolled factor in dynamic CMP.

The ventricular-synchronous, skeletal-muscle ventricle: preliminary feasibility studies.

The two requirements for the optimal use of skeletal muscle wrapped around a pouch used to pump blood are:(1) a low pouch diastolic pressure (to assure a high muscle capillary blood flow; and (2) a high pouch precontraction pressure (PCP) (to assure a forceful muscle contraction). Both requirements are satisfied with the pumping method described herein. This new type of skeletal-muscle ventricle (SMV) consists of a rectus abdominis muscle wrapped around a pouch connected to the left ventricular apex (with no valve) and to the aorta via a one-way valve. Consequently, the pressure in the SMV pouch is always equal to left ventricular pressure. The high PCP is obtained by stimulating the rectus muscle to contract at the desired left ventricular pressure. The R (or P) wave of the cardiac electrogram initiates a delayed train of stimuli to cause the rectus muscle to contract tetanically and expel blood from the pouch. We have designated this pumping configuration the ventricular-synchronous SMV (VS-SMV). In this study, eight acute anesthetized dogs were used. The muscles were unconditioned and among the items investigated were the importance of the delay (d) between the R (or P) wave and the onset of the stimulus train, the optimal stimulus frequency and train duration, the VS-SMV output with different ratios of VS-SMV to left ventricular contractions, unloading of the left ventricle, Frank-Starling curves for the VS-SMV, pressure-volume loops for the VS-SMV with and without contraction of the rectus muscle, and washout characteristics of the VS-SMV. It was found that a stimulus frequency of 40/sec, and a train duration of 250 msec is optimal. It was also found that choice of the proper delay from the R or P wave provided maximal augmentation in stroke volume, typically 20 to 40 mL. Pumping with a ratio of 1:2 provided VS-SMV outputs ranging from 20 to 140 mL/min per kg of body weight. With this same pumping ratio, cardiac output increased by 28% and the post-VS-SMV contraction, left ventricular stroke volume was reduced. The Frank-Starling curves showed that PCPs on the order of aortic pressure are needed for the most forceful muscle contraction. With this new pumping configuration, the left ventricle resembles an atrium which delivers blood to the VS-SMV that is stimulated to contract when the desired PCP is reached. Studies were also conducted in which the VS-SMV outlet (valve end) was closed and filling and emptying occurred through the left ventricle.(ABSTRACT TRUNCATED AT 400 WORDS)

Output power and metabolic input power of skeletal muscle contracting linearly to compress a pouch in a mock circulatory system.

Output power and metabolic input power values were determined for unconditioned canine latissimus dorsi (two), gastrocnemius (seven), and triceps (three) muscles contracting linearly to cause compression of a doubly valved pouch in a hydraulic model of the circulation. The motor nerves to the muscles were stimulated tetanically with 450 msec trains of 0.1 msec pulses having a frequency of 50/sec. The muscles were contracted 10, 20, 30, and 40 times per minute and pouch output in milliliters per minute was measured directly for each muscle at each contraction (train) rate. The output power in milliwatts was determined by two methods: (1) by using the pouch output and the pressure rise imparted to the stroke volume (average power) and (2) by using the pressure-volume loop. Metabolic input power in milliwatts was determined from the oxygen consumption in milliliters per minute of the working muscle. It was found that as the pouch output was increased, the pouch output power and the metabolic input power both increased. The average power output was slightly less than that computed from the pressure-volume loop. The mean output power values, when pumping at L liters per minute, were 0.62 L (average) and 0.75 L mW/gm (pressure-volume loop) for the latissimus dorsi muscles; 0.83 L (average) and 1.16 L mW/gm (pressure-volume loop) for the gastrocnemius muscles; and 0.55 L (average) and 0.66 L mW/gm (pressure-volume loop) for the triceps muscles. The percent efficiency of energy conversion ranged from 9.2% to 17.8% for the latissimus dorsi muscles, from 5.1% to 19.5% for the gastrocnemius muscles, and from 10.5% to 27.3% for the triceps muscles. However, it should not be concluded that one muscle type is better than another on the basis of percent efficiency because efficiency does not take endurance into account. An important observation in this study relates to the large output obtained with the three linearly contracting muscle types. All were capable of pumping in excess of 1.5 L/min. A second observation relates to the absence of fatigue, although determination of endurance was not an objective in these studies.

Use of impedance ratio for the continuous measurement of stroke volume of a valveless pouch used as a cardiac-assist device.

A technique is described for measuring the volume of a valveless compressible plastic pouch and its volume change when used as a cardiac-assist device. The method employs measuring the pouch impedance at high frequency with sleeve electrodes at both ends of the pouch. The use of an adequately high frequency eliminates the electrode impedance and the impedance measured is that of the resistance of the electrolyte in the pouch. By equating the compressible pouch to two truncated cones with their bases adjacent, an equation is derived that relates pouch impedance to volume. It is shown that by plotting the stroke volume ejected (delta V) versus the ratio of systolic (RS) to diastolic (Rd) impedance, the resulting relationship is independent of the resistivity of the fluid in the pouch. Validation tests were made with a 100 mL pouch filled with solutions having resistivities of 60, 102, 145, and 192 omega-cm. The method described herein permits calibration of the volume change of a valveless pouch used as a circulatory-assist device and in use the calibration will not be affected by a change in packed-cell volume which changes resistivity.

The effect of skeletal muscle ventricle pouch pressure on muscle blood flow.

Skeletal muscle powered assist ventricles (SMV) are being investigated in animal studies as a treatment for heart failure. Muscle fatigue is almost always dependent upon muscle capillary blood flow. This study examined the relationship between SMV intrapouch pressure and blood flow to the circumferential muscle in a working SMV with a mock circulation. The unconditioned rectus abdominis muscle was used to create an in situ SMV in five dogs. Muscle blood flow was measured by both the radioactive microsphere and the electromagnetic flow probe method as the pouch pressure was varied between 10 and 70 mmHg and as the SMV was stimulated to contract at a rate of 20 min-1. The correlation coefficient for the two methods was 0.908. At pouch pressures of 10, 40, and 70 mmHg, the respective blood flow values were 22.60 +/- 2.50 (1 SEM), 12.20 +/- 2.10, and 4.40 +/- 0.74 ml min-1 (p less than 0.05). When they were corrected for muscle weight, the mean blood flow values at these same pouch pressures were 0.28 +/- 0.03, 0.15 +/- 0.03, and 0.05 +/- 0.01 ml min-1 g-1, respectively (p less than 0.05). SMV output was measured for each pouch pressure that was tested. Pouch output, expressed as ml min-1, was 458 +/- 20 (1 SEM) at an SMV diastolic pouch pressure of 10 mmHg, 309 +/- 22 at a pouch pressure of 40 mmHg, and 103 +/- 6 at a pouch pressure of 70 mmHg.(ABSTRACT TRUNCATED AT 250 WORDS)

Pumping capabilities of the latissimus dorsi and rectus abdominis muscles wrapped around a valved pouch in a mock circulatory system.

The pumping capabilities of nine unconditioned canine rectus abdominus muscles (93-163 gm) and six latissimus dorsi muscles (99-146 gm) were measured. The muscles were wrapped around a 100 ml ellipsoidal pouch in a mock circulatory system in which the afterload was 100 mmHg. Pouch diastolic pressure was kept low by an electrically controlled inlet valve to maximize muscle capillary blood flow. Immediately before tetanic contraction of the pouch-encircling muscle, the inlet valve opened for 450 msec to increase pouch pressure to 100 mmHg, thereby providing a high preload and ensuring a forceful muscle contraction. The motor nerves to the muscles were stimulated with 450 msec trains of 0.1 msec stimuli, using a frequency of 40/sec. The train rates (muscle contractions/min) were 10-50/min. In this circulatory model it was found that the maximum output for both muscle types occurred between 20 and 40 contractions/min. It was also found that for both muscle types, the maximum output (L/min) was dependent upon muscle weight. The data revealed that an output of 4 ml/min was obtained per gram of muscle. The power (mW/gm) developed was related to the output (L) in L/min. For the rectus muscle W = 0.47L, and for the latissimus muscle W = 0.41L mW/gm. Pumping periods lasted approximately 4 hours, with no evidence of fatigue. When viewed as a potential cardiac assist device, the muscles were able to provide a flow equivalent to approximately 25% of the cardiac output. However, it is important to note that the pumping capability is directly related to muscle weight, indicating that a higher output can be achieved with a larger muscle.

Limitations of open-chest cardiac massage after prolonged, untreated cardiac arrest in dogs.

STUDY OBJECTIVES: Open-chest cardiac massage is an effective method of resuscitation if instituted within 15 minutes of normothermic cardiac arrest that has failed to respond to ongoing closed-chest CPR efforts. The usefulness of invasive forms of CPR after various periods of untreated cardiac arrest is less certain. This study was performed to determine the effectiveness of open-chest resuscitation after prolonged periods of untreated cardiac arrest. SETTING AND DESIGN: Prospective, controlled laboratory investigation using an animal model of cardiac arrest. Open-chest cardiac massage initially was compared to standard closed-chest compression CPR. The efficacy of open-chest CPR then was evaluated after ten and 40 minutes of untreated ventricular fibrillation. TYPE OF PARTICIPANTS: Twenty mongrel dogs (24 +/- 1 kg). MEASUREMENTS AND MAIN RESULTS: After 20 minutes of untreated ventricular fibrillation, open-chest resuscitation was significantly better than closed-chest efforts for the production of coronary perfusion pressure (58 +/- 14 vs 2 +/- 1 mm Hg; P less than .05) and initial resuscitation success (five of five vs one of five; P less than .03). Open-chest cardiac massage was equally effective for initial resuscitation if begun after ten or 20 minutes of untreated ventricular fibrillation (five of five vs five of five), but if untreated ventricular fibrillation continued for 40 minutes prior to instituting open-chest massage, no resuscitation benefit was found (none of five; P less than .005). There were marked differences in 24-hour survival depending on the length of time untreated cardiac arrest continued prior to instituting open-chest resuscitation efforts. After 20 minutes of ventricular fibrillation, initial resuscitation was successful with open-chest massage, but long-term survival was poor. CONCLUSION: Open-chest cardiac massage did not produce long-term survival if untreated cardiac arrest persisted for 20 or more minutes prior to invasive resuscitation efforts.

Use of electrical impedance for continuous measurement of stroke volume of a skeletal muscle-powered cardiac assist device.

This study describes the use of electrical impedance Z to continuously measure the stroke volume SV of a skeletal muscle-powered ventricle (SMV). An SMV was constructed surgically in four anaesthetised dogs. The rectus abdominis (two dogs) or latissimus dorsi (two dogs) muscle was wrapped around a compressible pouch, the ends of which were connected to a saline-filled (0.9 per cent) mock circulation. The motor nerves to the muscle were stimulated to produce tetanic contractions at a rate of 10 min-1. Z was measured between brass sleeve electrodes within the end conduits of the pouch. To derive a simple expression relating pouch volume V to Z, the pouch was represented as two truncated cones with their bases joined. For V ranging from 53 to 103 ml, the relationship between Z and 1/square root of V was nearly linear; i.e. Z = m(1/square root of V) + b. Impedance-derived stroke volume SV (delta Z) was calculated using this linear approximation and the impedance measured just before and after muscle contraction. The stroke volume SV (EM) ejected by the pouch during muscle contraction was measured with an electromagnetic flowmeter. The linear regression coefficients ranged from 0.99 to 2.55; the correlation coefficients ranged from 0.90 to 0.98. In general, SV(delta Z) tracked SV(EM) very well, although SV(delta Z) tended to overestimate SV(EM).

Comparison of canine skeletal muscle power from twitches and tetanic contractions in untrained muscle: a preliminary report.

Power output and blood flow were determined in dogs for four muscles (gastrocnemius, latissimus dorsi, rectus abdominis, and triceps) to determine effects of choice of muscle, tetany or twitch rates, force loading of the muscle, and blood flow on muscle power output. Total power for a 20-Kg dog was greatest for triceps at 0.77 watts (W) and least for rectus at 0.22 W; power per gram was greatest for gastrocnemius at 5.77 mW/g. Muscle perfusion of latissimus and rectus is greatly decreased by overstretching of the muscle. Overstretching also produces severe, persistent, power loss in latissimus and rectus muscles. Gastrocnemius and triceps tolerate stretching much better. We conclude that power can be improved without causing muscle fatigue by choice of muscle, choice of electrical stimulation parameters, linear geometry for contraction of the muscle, and matching the force load to each individual muscle.

Depletion of myocardial adenosine triphosphate during prolonged untreated ventricular fibrillation: effect on defibrillation success.

We studied left ventricular endomyocardial adenosine triphosphate levels in 13 large mongrel dogs before and during ventricular fibrillation induced cardiac arrest to assess whether myocardial adenosine triphosphate content could predict successful cardiopulmonary resuscitation. Endomyocardial biopsies were performed during sinus rhythm (control), after 15 min of ventricular fibrillation or 10 min of ventricular fibrillation and 5 min of open chest cardiopulmonary resuscitation, after 20 min of ventricular fibrillation and 10 min of open chest cardiopulmonary resuscitation and after 40 min ventricular fibrillation and 15-20 min open chest cardiopulmonary resuscitation. Myocardial adenosine triphosphate was measured utilizing a bioluminescence method adapted for use with endomyocardial biopsies and normalized to protein content. Left ventricular endomyocardial adenosine triphosphate content fell significantly over time from a control level of 8.88 +/- 0.9 micrograms/mg protein to 5.73 +/- 0.5 micrograms/mg protein at 15 min of cardiac arrest, to 3.4 +/- 0.4 micrograms/mg protein after 30 min of cardiac arrest and to 1.98 +/- 0.3 micrograms/mg protein after 60 min of cardiac arrest (P less than 0.001). Adenosine triphosphate levels were significantly different between animals that received 10 min of ventricular fibrillation and successful open chest cardiopulmonary resuscitation and those that received 40 min of ventricular fibrillation and unsuccessful open chest cardiopulmonary resuscitation (4.35 +/- 0.48 vs. 2.11 +/- 0.43 micrograms/mg protein; P less than 0.025).(ABSTRACT TRUNCATED AT 250 WORDS)

The use of an electrically activated valve to control preload and provide maximal muscle blood flow with a skeletal-muscle ventricle.

A new method for optimally loading a skeletal muscle-wrapped pouch to act as a blood pump is described. The method takes advantage of the fact that the high preload pressure required for a forceful contraction needs to be present for only a short time. By using an electrically controlled valve to delay pouch filling until just before muscle contraction, pouch diastolic pressure can be kept low, which in turn maintains a high muscle capillary blood flow. The intrapouch precontraction pressure can be controlled by selecting the appropriate valve-open time (VOT). The pumping capabilities of untrained rectus abdominis and latissimus dorsi muscles were evaluated using a hydraulic circulatory system in a ten dog study (weight range 20-32.7 kg). The afterload was constant at 100 mmHg, and the pouch precontraction pressure, selected by choice of the VOT, was the test variable. It was found that for maximum pouch output, a precontraction pressure of 60-100 mmHg was required, being attained in this hydraulic model with a VOT of 400-500 msec. Typical pouch outputs were 400-600 mL/min with a muscle contraction rate of 40/min. Muscle capillary blood flow, measured with a periarterial electromagnetic flowmeter, varied inversely with pouch diastolic pressure and was near zero during tetanic muscle contraction. In one animal, a pouch output of 200 mL/min or more was maintained for more than 20 hours of continuous pumping without fatigue. In a related experiment, the method was applied to pump blood in a 32.7 kg dog, in which the muscle-wrapped pouch was connected between the descending thoracic aorta and the abdominal aorta. A pouch output of about 400 mL/min was obtained when the muscle was contracted 30 times/min and the VOT was 400 msec. This flow represented about 20% of the animal's cardiac output. This study demonstrates that by delaying pouch filling until just before the muscle is to be contracted, a low pouch diastolic pressure can be maintained, thereby maximizing muscle capillary blood flow and, in turn, providing the best opportunity for prolonged pumping.