Elizabeth J. Dawe

Reduction of postsurgical adhesion formation in the rabbit uterine horn model with use of hyaluronate/ carboxymethylcellulose gel

OBJECTIVE To assess the efficacy of a bioabsorbable gel for reducing primary postoperative adhesions. DESIGN A randomized, prospective, blinded study. SETTING Academic research environment. ANIMALS Forty-one New Zealand Rabbits. INTERVENTION(S) A chemically modified hyaluronate and carboxymethylcellulose (HA/CMC) gel formulation was applied to a bilateral uterine horn injury. Postoperative adhesions were assessed at a second-look laparoscopy. MAIN OUTCOME MEASURE(S) The uterine horn model was shown to be adhesiogenic, with 29 (70%) of 42 untreated uterine horns found to have adhesions. After gel treatment, 22 (55%) of 40 uterine horns were free of adhesions compared with 12 (30%) of 42 controls. RESULT(S) Animals treated with HA/CMC gel had significantly reduced postsurgical adhesion scores when compared with controls. CONCLUSION(S) Treatment of injured uterine horn with HA/CMC gel resulted in a significant reduction in postoperative surgical adhesions.

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.

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.

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.

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.

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.

Mechanisms of impaired renal function with PEEP

Deterioration in renal function associated with positive end-expiratory pressure (PEEP) has been attributed to renal hypoperfusion from the fall in cardiac output and mean arterial blood pressure. Using a canine in vivo model, renal function was measured during control, zero end-expiratory pressure (ZEEP), and PEEP (5, 10, and 15 cm H2O) ventilatory cycles, while renal blood flow was maintained constant with a pump. High PEEP (15 cm H2O) led to a rise in renal vein pressure (RVP) and a fall in mean arterial pressure (MAP). PEEP resulted in no change in glomerular filtration rate (GFR) or solute exertion; however, free-water clearance (FWC) became less negative in the 15-cm H2O PEEP group. Intrarenal autoregulation maintains GFR during ventilation with PEEP when renal blood flow is constant, supporting the view that altered filtration and solute excretion clinically is secondary to changes in aortic pressure and renal perfusion.

The beneficial role of calcium supplementation during resuscitation from shock.

The role of calcium (Ca) in resuscitation from hemorrhagic shock is controversial and in the present report three regimens were compared: supplementation (Ca-S), avoidance (No-Ca), and Ca channel blockade (Ca-B). This was studied in 40 splenectomized dogs subjected to reservoir shock (MAP 60 torr/90 min, then 40 torr/30 min) and treated with: a) 20 ml/kg balanced electrolyte solution (BES); b) shed blood; c) 30 ml/kg BES; and d) 250 ml autologous bank blood. Three groups of six dogs received Ca-S (0.5 mEq/kg), No-Ca, or Ca-B (verapamil 0.15 mg/kg) in BES. Postoperative therapy of 50 ml/kg/d BES with Ca-S, No-Ca, or Ca-B was given for 3 days. The effects of parathyroidectomy (P) via wide thyroidectomy in 22 dogs treated with calphosan (20 ml/d) and L-thyroxin (0.02 mg/kg) preceding shock was also studied as above: Ca-S/P, No-Ca/P, and Ca-B/P; four sham dogs had anesthesia but no shock (Anes/P). Studies done before, during, and after shock and on day three included systemic pressures (MAP), central pressures (CFP), cardiac output (CO), resistance (SVR), heart work (LVW), and outcome. Post-resuscitation Ca was significantly less in all groups (1.6-3.7 mg%) compared to Ca-S (4.8 mg%). Compared to Ca-S dogs, the post-resuscitation studies in the No-Ca and Ca-B dogs showed lower MAP, CO, and LVW in both intact and hypoparathyroid animals. Post-resuscitation CFP was also lower in the Ca-S and Ca-S/P dogs compared to the other euparathyroid and hypoparathyroid dogs. Death after the initiation of resuscitation occurred in two No-Ca/P and three Ca-B/P dogs. These data suggest that calcium supplementation plus an intact calcium-parathyroid axis enhance the resuscitation effort.

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.

Chronic intracarotid cannulation of pigeons for administration of behaviorally active peptides

Chronic intracarotid cannulation of the common carotid artery was performed in the pigeon. The catheter system of polyethylene tubing consisted of an indwelling component and an injection component. The indwelling component was exteriorized at the occiput so the bird could not reach the catheter with its beak. Following surgery, the pigeons were housed individually and received food and water ad libitum and no special care was necessary. The catheter was flushed daily with heparin in 0·9% NaCl solution to maintain patency. 30 pigeons were continuously or intermittently infused with bioactive peptides for up to 60 days after cannulation.