Howard C. Hughes

Effects of chronic parenteral carbohydrate administration on hepatic drug metabolism in the rat

Effects of chronic parenteral carbohydrate administration on hepatic microsomal enzyme activity were studied in the rat. Intraperitoneal injections of either glucose or fructose (2.88 g daily for 7 days) significantly decreased hepatic cytochrome P-450 content and ethylmorphine N-demethylase and aniline hydroxylase activities. By the 5th day, cytochrome P-450 content decreased to 70-76% and ethylmorphine N-demethylase activity to 66-69% of control values. Aniline hydroxylase activity was not significantly altered until the 7th day, by which time it was 77-79% of control values. In vivo assessment of hepatic drug-metabolizing capacity using antipyrine as a test drug confirmed these decreases observed in vitro. Two major conclusions of these experiments are that such variables as time and dose of carbohydrate administration can affect the magnitude of the changes produced and that each parameter measured exhibited a distinctive pattern of change with time. Chronic carbohydrate administration produced hepatic fatty infiltration and glycogen depletion. Since all groups received identical amounts of specific nutrients, fatty infiltration was probably due to increased lipogenesis with decreased hepatic oxidative metabolism of fat. During these experiments neither hypoinsulinemia nor increased levels of cyclic AMP were observed. The molecular mechanisms responsible for hepatic glycogen depletion and decreased MFO activities remain to be established.

Control of Pain in Dogs and Cats

The perception of pain is an extremely complex physiological phenomenon, the reaction possibly involving many systems of the body (14). Just how one particular species may respond to a noxious stimulus can be exhibited in different ways. There can also be a great deal of interspecies and individual variability so that one animal may respond quite differently than another. This variability among animals is decreased in some of the common laboratory animals, such as rats and mice, where generations of breeding for laboratory use have tended to produce animals that respond quite uniformly. Variability, however, is often accentuated in highly outbred populations such as dogs and cats. Some breeds of dogs, such as hounds, are noted for their hardiness and may be less likely to exhibit overt signs of pain to the same stimuli, whereas other breeds, such as poodles or pomeranians, may be more sensitive. Cats may only show visible signs of pain when the stress becomes more pronounced. Apparently, therefore, it is the tolerance to pain that is highly variable, even though pain thresholds are remarkably similar among animal species (12).

Rechargeable silver-modified mercuric oxide-zinc cell for cardiac pacemakers*

Tests were conducted on rechargeable mercury-zinc pacemaker batteries under simulated and actual biologic conditions, using a variety of discharge rates and charging schedules. In tests on 96 cells at a 6.4 milliampere (ma) discharge, recharging once every 15 months of simulated pacing at a 25 microampere (mua) drain, the earliest cell failure occurred after an equivalent of 50 years of pacing. The mean pacing equivalent for all 96 cells was more than 140 years. In 6.4 ma discharge tests on 24 cells, recharging once every 8 days of simulated pacing, only 1 cell in 24 failed after an equivalent of more than 500 years of pacing (actual time 2 years). In tests on 13 cells pacing at a 200 mua drain without recharging, the simulated mean duration of pacing before total discharge was 4.8 years. Seven other cells at a 200 mua drain with periodic recharging continue to function normally after more than 7 years of actual time, simulating 56 years of pacing at a 25 mua drain. Cardiac pacemakers using the rechargeable mercury-zinc cell have been implanted in animals for more than 2 1/2 years and in patients for more than 1 year with all units continuing to function satisfactorily. It has been demonstrated unequivocally that a rechargeable mercury-zinc pacemaker will function continuously for more than 4 years without recharging and that periodic recharging will extend pacing life far beyond that predicted for lithium and nuclear primary power sources.

Effects of intracoronary temperature variation on the coronary circulation

The effects of temperature on coronary pressure-flow relationships were studied in intact dogs using a controlled perfusion technique. Temperature variation did not affect left ventricular performance or total coronary resistance but did significantly alter vasomotor tone in the subepicardial vessels as estimated from the responses of post-occlusive reactive hyperaemia. Vasodilation was noted with heating while vasoconstriction occurred with cooling. Metabolic suppression with practolol did not modify these results.

A New Polyurethane and Process for Pacer Leads

Urethane tubing has largely replaced silicone as the insulation of choice on cardiac pacemaker leads. Although urethane has been shown to be biocompatible, there have been reports of insulation defects. This study was on a segmented polyether polyurethane polymer which is applied and bonded directly to the wire. The SPU adds its strength and flexibility to the lead. SPU is heart settable, enabling special configurations (S-A node and J-Ieads) to be made without significantly affecting the O.D. The modulus of elongation (> 700%), and strength (> 6000 psi) of SPU are superior to silicone < 500% at 1200 psi) and of urethane < 400% at 6000 psi). Implants in rats, rabbits, and dogs have shown SPU to be essentially free of blood and tissue reactions. Long-term transvenous atrial and ventricular leads (up to 30 months) have been implanted in dogs without adverse affects and only a 25% decrease in chronic intrinsic P-wave and 20% in R-wave potentials. Threshold strength-duration curves showed changes similar to those reported for other pacemaker leads. Light and scanning photomicrographs show a freedom from cracks, crazing, and internal/external wear defects after over a cumulative 300 months implant experience. Polarized light has failed to show any stress related defects in the SPU coatings.

New Interference Sensing Demand Pacemaker Functions

Demand cardiac pacemaker functions are under study that provide new methods to distinguish between cardiac activity and pulsatile electromagnetic interference (PEMI). All known forms of currently marketed ventricular inhibited demand pacemaker (VVI) functions can be inhibited by high level pulsatile electromagnetic interference. The recent introduction of shielded circuitry to protect against disruptive (inhibiting) EMI has reduced pacemaker sensitivity to interference. However, EMI received via the cardiac lead/electrode can still mimic cardiac activity. This mimicing occurs as a consequence of detection by defribrillator protection structures or by amplifier saturation from RF artifacts insufficiently suppressed by input QRS bandpass filters. The new functions under development employ a separate EMI detection receiver for controlling the pacemaker mode to minimize inhibition by PEMI.

Residual effects when chronic propranolol therapy is discontinued within 48 hours of cardiopulmonary bypass

Recommendations regarding the safe waiting period between discontinuing chronic oral propranolol therapy and beginning cardiopulmonary bypass have varied from a few hours to 2 weeks. In the present study, utilizing adult dogs, propranolol was discontinued 8 or 48 hours prior to surgery. A reduction in cardiac output and elevations of left ventricular end-diastolic pressure, peak systolic pressure, and systemic resistance were noted when cardiac function was evaluated following the induction of anesthesia and prior to undertaking cardiopulmonary bypass. The magnitude of these differences was directly related to the degree of volume loading and inversely related to the interval between the last dose of propranol and the determination of cardiac function. Reduction of heart rate was the most evanescent of propranolols hemodynamic effects as the marked bradycardia which persisted throughout the course of propranolol therapy was no longer evident 8 hours after the last oral dose of the drug. Following total cardiopulmonary bypass of 1 hours duration, undertaken 8 hours after the last oral dose of propranolol, cardiac output and left ventricular end-diastolic pressure had returned to normal but peak systolic pressure and systemic resistance remained significantly elevated, When 48 hours had elapsed between discontinuing propranolol and beginning cardiopulmonary bypass, postbypass cardiac function was essentially normal with only slight persistent elevations of peak systolic pressure and systemic resistance detected. When the combined effects of ischemic heart disease and propranolol therapy, the altered metabolic and hemodynamic effects of different routes of drug administration, and the varying durations of cardiopulmonary bypass are taken into consideration, some of the discrepancies between previously reported clinical and experimental findings regarding the duration of persistent propranolol effects can be understood. The clinical course is usually benign in patients who have received propranolol to within a few hours of surgery without specific indication. However, it is often complicated when the drug is continued until just prior to surgery in patients dependant on propranolol for pain or arrhythmia control. In patients demonstrating propranolol dependence, control of symptoms with intra-aortic balloon counterpulsation is recommended followed by the gradual withdrawal of propranolol and elective aortocoronary bypass surgery.

An A-V Data Lead System for Electrogram Detection

Some telemetrically monitored pacemakers are capable of detecting and transmitting either the P- or R-wave, however, none are able to transmit the complete electrogram (EGM) during normal and paced rhythms. A new lead system has been developed that, when used in conjunction with a telemetrypacemaker system, permits the transmissionofthe complete EGM and is not adversely affected by pacemaker outputs or afterpotentials. Detecting electrodes are placed in both right atrium and ventricle in order to optimize EGM detection. Electrically separate from the pacing-sensing electrodes, the A-V Data probes are structurally part of a transvenously placed ventricular lead no larger than a conventional bipolar lead (2.3 mm). The EGM telemetry system is also compatible with telephone monitoring systems. The A-V data lead has consistently demonstrated its ability to accurately detect the EGM during normal sinus rhythms as well as during atrial, ventricular, and A-V sequential pacing. In addition, this system can detect and transmit EGM abnormalities such as ectopic beats and retrograde conduction. Eight A-V data lead, telemetry monitored VVI pacemakers have been implanted in dogs for over two years. This system has provided the means to noninvasively detect and telemetrically record the entire normal and abpormal EGM, even in pacer dependent patients.

The Detection of Unipolar and Bipolar Cardiac Electrograms with a Movable Coaxial Electrode

Abstract To define the effects of endocardial positioning on the sensing electrodes ability to detect the cardiac electrogram, a specially designed coaxial lead system with a movable, large surface area (50 mm 2 ) proximal ring electrode and a small surface area distal tip electrode was placed transvenously in 17 mongrel dogs. When the sensing ring electrode was used in a unipolar mode, there were slight but insignificant decreases in R-wave amplitude while the ring remained in the ventricle. When the electrode was moved out through the valve into the atria there was a marked decrease in R-wave sensing, however, this was accompanied by a significant increase in P-wave amplitude. When the ring electrode was used in conjunction with the tip as a conventional bipolar system, the sensed R wave remained at uniformly high levels except when the two electrodes were very close together at the tip. P-wave amplitudes were not detected in the bipolar mode until the ring entered the atria.