Muscle metaboreflex-induced coronary vasoconstriction limits ventricular contractility during dynamic exercise in heart failure.

Muscle metaboreflex activation (MMA) during dynamic exercise increases cardiac work and myocardial O2 demand via increases in heart rate, ventricular contractility, and afterload. This increase in cardiac work should lead to metabolic coronary vasodilation; however, no change in coronary vascular conductance occurs. This indicates that the MMA-induced increase in sympathetic activity to the heart, which raises heart rate, ventricular contractility, and cardiac output, also elicits coronary vasoconstriction. In heart failure, cardiac output does not increase with MMA presumably due to impaired ability to improve left ventricular contractility. In this setting actual coronary vasoconstriction is observed. We tested whether this coronary vasoconstriction could explain, in part, the reduced ability to increase cardiac performance during MMA. In conscious, chronically instrumented dogs before and after pacing-induced heart failure, MMA responses during mild exercise were observed before and after α1-adrenergic blockade (prazosin 20-50 µg/kg). During MMA, the increases in coronary vascular conductance, coronary blood flow, maximal rate of left ventricular pressure change, and cardiac output were significantly greater after α1-adrenergic blockade. We conclude that in subjects with heart failure, coronary vasoconstriction during MMA limits the ability to increase left ventricular contractility.

MR imaging of the yucatan pig head and neck vasculature.

PURPOSE: To evaluate the cerebral venous drainage system of the swine as a probable model to test whether extracranial venous abnormalities may play a role in neurodegenerative diseases as reported recently in multiple sclerosis. MATERIALS AND METHODS: Three Yucatan micropigs, 5 to 7 months old, were scanned with a comprehensive MRI protocol at 3 Tesla. The vascular anatomy of the head and neck was imaged using conventional and angiographic MR sequences. Phase-contrast MR images were collected at multiple levels of the neck and intracranial space to monitor flow. RESULTS: Three large cervical veins were observed; the external jugular vein draining the olfactory and gustatory tissues; the internal jugular vein (IJV) draining the cavernous sinus as well as surrounding soft tissues in the neck; and the ventral vertebral venous plexus (VVVP) surrounding the dural sac and paraspinal region. The majority of the cerebral blood flow in the pig appears to drain through the VVVP. Flow through the IJV comprised a nondominant component. Anastamoses were observed connecting the major veins of the neck bilaterally. CONCLUSION: The dominance of outflow from the brain to the VVVP may be analogous to the typical dominance of the IJVs in humans in the supine position.

Dynamic cardiac output regulation at rest, during exercise, and muscle metaboreflex activation: impact of congestive heart failure.

We tested whether mild and moderate dynamic exercise and muscle metaboreflex activation (MMA) affect dynamic baroreflex control of heart rate (HR) and cardiac output (CO), and the influence of stroke volume (SV) fluctuations on CO regulation in normal (N) and pacing-induced heart failure (HF) dogs by employing transfer function analyses of the relationships between spontaneous changes in left ventricular systolic pressure (LVSP) and HR, LVSP and CO, HR and CO, and SV and CO at low and high frequencies (Lo-F, 0.04-0.15 Hz; Hi-F, 0.15-0.6 Hz). In N dogs, both workloads significantly decreased the gains for LVSP-HR and LVSP-CO in Hi-F, whereas only moderate exercise also reduced the LVSP-CO gain in Lo-F. MMA during mild exercise further decreased the gains for LVSP-HR in both frequencies and for LVSP-CO in Lo-F. MMA during moderate exercise further reduced LVSP-HR gain in Lo-F. Coherence for HR-CO in Hi-F was decreased by exercise and MMA, whereas that in Lo-F was sustained at a high level (>0.8) in all settings. HF significantly decreased dynamic HR and CO regulation in all situations. In HF, the coherence for HR-CO in Lo-F decreased significantly in all settings; the coherence for SV-CO in Lo-F was significantly higher. We conclude that dynamic exercise and MMA reduces dynamic baroreflex control of HR and CO, and these are substantially impaired in HF. In N conditions, HR modulation plays a major role in CO regulation. In HF, influence of HR modulation wanes, and fluctuations of SV dominate in CO variations.

Muscle metaboreflex-induced coronary vasoconstriction functionally limits increases in ventricular contractility.

Muscle metaboreflex activation during dynamic exercise induces a substantial increase in cardiac work and oxygen demand via a significant increase in heart rate, ventricular contractility, and afterload. This increase in cardiac work should cause coronary metabolic vasodilation. However, little if any coronary vasodilation is observed due to concomitant sympathetically induced coronary vasoconstriction. The purpose of the present study is to determine whether the restraint of coronary vasodilation functionally limits increases in left ventricular contractility. Using chronically instrumented, conscious dogs (n = 9), we measured mean arterial pressure, cardiac output, and circumflex blood flow and calculated coronary vascular conductance, maximal derivative of ventricular pressure (dp/dt(max)), and preload recruitable stroke work (PRSW) at rest and during mild exercise (2 mph) before and during activation of the muscle metaboreflex. Experiments were repeated after systemic alpha(1)-adrenergic blockade ( approximately 50 microg/kg prazosin). During prazosin administration, we observed significantly greater increases in coronary vascular conductance (0.64 + or - 0.06 vs. 0.46 + or - 0.03 ml x min(-1) x mmHg(-1); P < 0.05), circumflex blood flow (77.9 + or - 6.6 vs. 63.0 + or - 4.5 ml/min; P < 0.05), cardiac output (7.38 + or - 0.52 vs. 6.02 + or - 0.42 l/min; P < 0.05), dP/dt(max) (5,449 + or - 339 vs. 3,888 + or - 243 mmHg/s; P < 0.05), and PRSW (160.1 + or - 10.3 vs. 183.8 + or - 9.2 erg.10(3)/ml; P < 0.05) with metaboreflex activation vs. those seen in control experiments. We conclude that the sympathetic restraint of coronary vasodilation functionally limits further reflex increases in left ventricular contractility.

Effective aerosol delivery during high-frequency ventilation in neonatal pigs.

BACKGROUND AND OBJECTIVE: Pulmonary delivery of aerosols during high-frequency oscillatory ventilation (HFOV) has not been studied in vivo. This study investigated the pulmonary delivery of aerosolized gadopentetate dimeglumine (Gd-DTPA) in a HFOV circuit in piglets using MRI to visualize contrast excretion in the kidneys. METHODS: Four ventilated piglets (3-7 days old, 1.7-2.4 kg at birth) received aerosolized Gd-DTPA in a HFOV circuit for different durations of time (60, 30, 20 and 10 min). Aerosols were generated using the MiniHeart jet nebulizer. As MR-compatible HFOV was not available, aerosolized Gd-DTPA was administered in the HFOV circuit outside the MR suite followed by MRI 10-20 min later. T1-weighted spin echo sequences were obtained using the Bruker/Siemens 4T MR scanner. RESULTS: Enhancement of the kidneys was observed 10 min after aerosol initiation in piglets who received Gd-DTPA aerosol for 60, 30 and 20 min in the HFOV circuit but not in the piglet who received aerosol for 10 min. Renal concentration of Gd-DTPA, determined from the signal intensity, increased linearly with time until 40 min post Gd-DTPA delivery. CONCLUSIONS: Effective pulmonary aerosol delivery during HFOV was confirmed by contrast visualization in the kidneys within 30 min of aerosol initiation reflecting, alveolar absorption, glomerular filtration and renal concentration.

Progressive muscle metaboreflex activation gradually decreases spontaneous heart rate baroreflex sensitivity during dynamic exercise.

Ischemia of active skeletal muscle elicits a pressor response termed the muscle metaboreflex. We tested the hypothesis that in normal dogs during dynamic exercise, graded muscle metaboreflex activation (MMA) would progressively attenuate spontaneous heart rate baroreflex sensitivity (SBRS). The animals were chronically instrumented to measure heart rate (HR), cardiac output (CO), mean and systolic arterial pressure (MAP and SAP), and left ventricular systolic pressures (LVSP) at rest and during mild or moderate treadmill exercise before and during progressive MMA [via graded reductions of hindlimb blood flow (HLBF)]. SBRS [slopes of the linear relationships (LRs) between HR and LVSP or SAP during spontaneous sequences of > or =3 consecutive beats when HR changed inversely vs. pressure] decreased during mild exercise from the resting values (-5.56 +/- 0.86 vs. -2.67 +/- 0.50 beats.min(-1).mmHg(-1), P <0.05), and in addition, these LRs were shifted upward. Progressive MMA gradually and linearly increased MAP, CO, and HR; linearly decreased SBRS; and shifted LRs upward and rightward to higher HR and pressures denoting baroreflex resetting. Moderate exercise caused a substantial reduction in SBRS (-1.57 +/- 0.38 beats.min(-1).mmHg(-1), P <0.05) and both an upward and rightward resetting. Gradual MMA at this higher workload also caused significant progressive increases in MAP, CO, and HR and progressive decreases in SBRS, and the LRs were shifted to higher MAP and HR. Our results demonstrate that gradual MMA during mild and moderate dynamic exercise progressively decreases SBRS. In addition, baroreflex control of HR is progressively reset to higher blood pressure and HR in proportion to the extent of MMA.

Modulation of cardiac output alters the mechanisms of the muscle metaboreflex pressor response.

Muscle metaboreflex activation during submaximal dynamic exercise in normal subjects elicits a pressor response primarily due to increased cardiac output (CO). However, when the ability to increase CO is limited, such as in heart failure or during maximal exercise, the muscle metaboreflex-induced increases in arterial pressure occur via peripheral vasoconstriction. How the mechanisms of this pressor response are altered is unknown. We tested the hypothesis that this change in metaboreflex function is dependent on the level of CO. The muscle metaboreflex was activated in dogs during mild dynamic exercise (3.2 km/h) via a partial reduction of hindlimb blood flow. Muscle metaboreflex activation increased CO and arterial pressure, whereas vascular conductance of all areas other than the hindlimbs did not change. CO was then reduced to the same level observed during exercise before the muscle metaboreflex activation via partial occlusion of the inferior and superior vena cavae. Arterial pressure dropped rapidly with the reduction in CO but, subsequently, nearly completely recovered. With the removal of the muscle metaboreflex-induced rise in CO, substantial peripheral vasoconstriction occurred that maintained arterial pressure at the same levels as before CO reduction. Therefore, the muscle metaboreflex function is nearly instantaneously shifted from increased CO to increased vasoconstriction when the muscle metaboreflex-induced rise in CO is removed. We conclude that whether vasoconstriction occurs with muscle metaboreflex depends on whether CO rises.

Intrauterine administration of endotoxin leads to motor deficits in a rabbit model: a link between prenatal infection and cerebral palsy.

OBJECTIVE: This study was undertaken to determine whether maternal intrauterine endotoxin administration leads to neurobehavioral deficits in newborn rabbits. STUDY DESIGN: Pregnant New Zealand white rabbits were injected with 1 mL saline solution (n = 8) or 20 microg/kg of lipopolysaccharide in saline solution (n = 8) into the uterine wall on day 28/31 of gestation. On postnatal day 1, kits (saline solution [n = 30] and lipolysaccharide in saline solution [n = 18] from 4 consecutive litters) underwent neurobehavioral testing. Neonatal brains were stained for microglial cells and myelin. RESULTS: Kits in the lipopolysaccharide in saline solution group were hypertonic and demonstrated significant impairment in posture, righting reflex, locomotion, and feeding, along with neuroinflammation indicated by activated microglia and hypomyelination in the periventricular regions. A greater mortality was noted in the lipopolysaccharide in saline solution group (16 stillbirths from 3 litters vs 3 from 1 litter). CONCLUSION: Maternal intrauterine endotoxin administration leads to white matter injury and motor deficits in the newborn rabbit, resulting in a phenotype that resembles those found in periventricular leukomalacia and cerebral palsy.

Toxicity of prolonged high dose inhaled PGE1 in ventilated neonatal pigs.

OBJECTIVE: To study the toxicity of inhaled PGE1 (IPGE1) in healthy ventilated piglets. METHODS: Mechanically ventilated anesthetized piglets received either high dose IPGE1 (IPGE1 group) or nebulized saline (control group) continuously for 24h. Cardio-respiratory parameters, complete blood counts and serum electrolytes were monitored. Lung histology was evaluated by a masked pathologist for the severity (minimal, moderate, and severe) and extent (focal, multifocal, and diffuse) of histologic injury. RESULTS: Ten neonatal pigs were instrumented. Four received nebulized saline and six received high dose IPGE1. There was no evidence of adverse cardio-respiratory effects, bronchial irritation or hypernatremia related to IPGE1. Diffuse/multifocal alveolar edema and focal polymorphonuclear infiltration was observed in both the control and IPGE1 groups suggesting that alveolar alterations may be secondary to effects of mechanical ventilation. The most distinct histomorphological abnormalities observed in the IPGE1 animals were focal ulceration, flattening of the bronchial epithelium and loss of cilia of moderate to severe degree in the trachea and bronchi. CONCLUSION: In healthy piglets, inhalation of high dose IPGE1 was not associated with adverse cardiorespiratory effects, bronchial irritation, or hypernatremia and produced minimal signs of pulmonary toxicity even after 24h. Prolonged inhalation of high dose PGE1 therefore appears safe in newborn piglets.

The physiologic effects of a conducted electrical weapon in swine.

STUDY OBJECTIVE: By using an animal model, we determine whether repeated exposures to a conducted electrical weapon could have physiologic consequences. METHODS: Exposures to the Stinger S-400 conducted electrical weapon were applied to 10 healthy, anesthetized, Yorkshire-cross, male swine by attaching probes from the cartridge to the sternal notch and anterolateral thorax at a distance of 21.5 cm. The standard pulse generated by the Stinger S-400 during the normal application was applied 20 times during 31 minutes. To evaluate the health effects of the exposures, key physiologic characteristics were evaluated, including arterial pH, PCO2, PO2, blood lactate, cardiac output, ECG, pulse rate, mean arterial pressure, central venous pressure, pulmonary artery pressure and airway pressure, and the cardiac marker troponin I. RESULTS: There were notable changes in pH, PCO2, blood lactate, cardiac output, and mean arterial pressure after 1 or more sets of exposures, all of which normalized during the next few hours. Troponin I, PO2, pulse rate, mean arterial pressure, central venous pressure, pulmonary artery pressure, and airway pressure did not change markedly during or after the shocks. Three premature ventricular contractions occurred in one animal; all other ECG results were normal. CONCLUSION: Repeated exposures to a conducted electrical weapon result in respiratory acidosis, metabolic vasodilation, and an increase in blood lactate level. These effects were transient in this study, with full recovery by 4 hours postexposure. The Stinger S-400 appears to have no serious adverse physiologic effects on healthy, anesthetized swine.

Robotic endoscopic surgery in a porcine model of the infant neck.

Minimally invasive surgery is rapidly becoming the desired surgical standard, especially for pediatric patients. Infants and children are a particular technical challenge, however, because of the small size of target anatomical structures and the small surgical workspace. Computer-assisted robot-enhanced surgical telemanipulators may overcome these challenges by facilitating surgery in a small workspace. We studied the feasibility of performing robotic endoscopic neck surgery on a porcine model of the human infant neck. The study design was a prospective, feasibility pilot study of a small cohort for proof of concept and for a survival model. Sixteen non-survival piglets weighing 4.5-10 kg were used to develop the surgical approach and operative technique. Eight piglets aged 3-6 weeks old and weighing 4.0-9.1 kg underwent survival thyroidectomy by a cervical endoscopic approach using the Zeus surgical robot, which includes the Aesop endoscope holder and "Microwrist" microdissecting instruments. We succeeded in performing endoscopic robotic neck surgery on a piglet as small as 4 kg, in an operative pocket as small as 2 cm(3). Total incision length for all three ports was ≤23 mm. There were no major complications, no major robotic instrument malfunctions or breakages, and no procedures required conversion to open surgery. These results support the feasibility of robotic endoscopic neck surgery on a neck the size of a human infant's.

Effects of cornual catheterization on uterotubal histology and function.

OBJECTIVE: To assess histologic damage and functional impairment following coaxial tubal catheterization. DESIGN: Prospective randomized controlled study. SETTING: Research laboratory. PATIENT(S): Ninety-two female New Zealand rabbits. INTERVENTION(S): Tubal cannulation and mating. MAIN OUTCOME MEASURE(S): Rabbits randomized for placement of unilateral catheter and guide wire (group 1), unilateral catheter and guide wire plus falloposcope (group 2), and catheterization as in group 1 or 2 but using a cage catheter (groups 3 and 4, respectively). A fifth group consisted of rabbits with tubal perforations. Rabbits were killed at 2 or 4 weeks after catheterization or after mating. The sixth group consisted of only control rabbits. RESULT(S): Only one catheterized tube in groups 1 and 3 showed inflammation, fibrosis, or edema. None of the tubes manifested ciliary loss. Serosal tubal adhesions were identified in two tubes in group 1, in one in group 3, in three tubes in group 5, and one in the control group. The nidation index in control and nonperforated catheterized tubes ranged from 72%-95% (not significant). Nidation index in tubes unintentionally perforated was 81%. CONCLUSION(S): Catheterization of the uterotubal junction and fallopian tube in rabbits does not cause long-term tubal damage or impair tubal function.

Totally minimally invasive robot-assisted unstented pyeloplasty using the Zeus Microwrist Surgical System: an animal study.

BACKGROUND: Minimally invasive pyeloplasty is a difficult procedure even for an expert laparoscopic surgeon. The major difficulty is associated with the limitations of intracorporeal suturing and knot tying. Surgical robots, which hold minimally invasive surgical instruments, have wrists and provide tremor filtration and motion scaling that might be expected to facilitate complex procedures in newborns. METHODS: Seven survival piglets (4.0-7.5 kg) underwent a totally minimally invasive robot-assisted unstented pyeloplasty employing the Zeus Robotic Microwrist System. The ureter was transected at the level of the ureteropelvic junction and 8 mm was resected. The unstented anastomosis was fashioned with running suture and intracorporeal knot tying. The animals were recovered and intravenous urography was performed at 1 month. After sacrifice, the anastomosis and the kidney were evaluated grossly and histologically for leak, caliber, and healing. RESULTS: All animals survived the procedure without postoperative complications. The mean robotic setup time was 19 minutes (range, 10-30 min), mean anastomosis time 51 minutes (range, 39-63 min), and mean total operation time 76 minutes (range, 57-87 min). The urography showed hydronephrosis in the first animal. The other 6 animals had no abnormalities. Histopathology demonstrated severe hydronephrosis in the first pig and moderate hydronephrosis in the sixth and seventh. All other animals had no sign of hydronephrosis. All anastomoses were well healed and intact. CONCLUSIONS: Robot-assisted laparoscopic pyeloplasty is a technically feasible procedure with acceptable morbidity in an animal model. The robotic technology enhances surgical dexterity and precision. Robotic assistance can increase the applicability of minimally invasive surgery to complex procedures in children.