David O. Brant

Reflex sympathetic activation induces acute insulin resistance in the human forearm.

Inferences about the association between sympathetic overactivity and insulin resistance have been drawn from the infusion of sympathomimetic amines in supraphysiological doses. We used the isolated perfused human forearm to investigate the effect of reflex-induced sympathetic nervous system activation on the peripheral utilization of glucose in the skeletal muscles of 14 healthy men. Local hyperinsulinemia in the forearm (132 +/- 25 microunits/mL for 90 minutes) induced a significant increase in the utilization of glucose from baseline (16.4 +/- 3.1 mg.dL-1.min-1 per 100 mL forearm volume) to a plateau (85.7 +/- 15.1 mg.dL-1.min-1 per 100 mL forearm volume) between 40 and 60 minutes of insulin infusion but did not alter the utilization of oxygen. Reflex sympathetic nervous system activation was elicited by unloading of cardiopulmonary receptors with bilateral thigh cuff inflation to 40 mm Hg between 60 and 90 minutes of insulin infusion. Blood flow in the forearm was significantly decreased with inflation of thigh cuffs (average decrease of 19%, p < 0.0001). As a result of thigh cuff inflation, there was a reduction in the utilization of glucose (a decrease of 23%, p < 0.02), whereas oxygen utilization was unchanged. We find that an increase in sympathetic nervous system activation (within the normal range of physiological responses) can cause acute insulin resistance in the forearm of healthy volunteers. The reflex caused no change in oxygen utilization, but the same stimulus elicited a decrease in the utilization of glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurogenic pressor episodes fail to cause hypertension, but do induce cardiac hypertrophy.

Repeated neurogenic pressor episodes by hindquarter compression were elicited in nine experimental dogs. Conscious dogs underwent 6 hours of compression every day over a period of 9 weeks. The average mean blood pressure increase during the compression periods was 25 mm Hg, but after decompression the blood pressure promptly returned to baseline values. This blood pressure response was constant and did not change over the 9-week period. The blood pressure increase was associated with a significant increase of plasma norepinephrine values. After validity of the model was established, echocardiographic measurements were performed at baseline and after 3, 6, and 9 weeks of compression in six experimental and six time-control dogs. Concentric left ventricular hypertrophy was already detectable at 3 weeks, and at the ninth week, the left ventricular mass was 28% above the baseline value. The left ventricular mass in time-control dogs remained unchanged over the same period of time. The time-left ventricular mass curves in experimental dogs were significantly different (by profile analysis), had different means (p < 0.005), were not parallel (p < 0.0006), and the overall group difference was highly significant (p < 0.00001). Since left ventricular hypertrophy, a poor prognostic sign in clinical situations, can evolve before established hypertension, present therapeutic recommendations based on permanently elevated blood pressure values may not be entirely justified.

The attenuation of platelet and monocyte activation in a rabbit model of extracorporeal circulation by a nitric oxide releasing polymer

Nitric oxide (NO) has been shown to reduce thrombogenicity by decreasing platelet and monocyte activation by the surface glycoprotein, P-selectin and the integrin, CD11b, respectively. In order to prevent platelet and monocyte activation with exposure to an extracorporeal circulation (ECC), a nitric oxide releasing (NORel) polymeric coating composed of plasticized polyvinyl chloride (PVC) blended with a lipophilic N-diazeniumdiolate was evaluated in a 4 h rabbit thrombogenicity model using flow cytometry. The NORel polymer significantly reduced ECC thrombus formation compared to polymer control after 4 h blood exposure (2.8 +/- 0.7 NORel vs 6.7 +/- 0.4 pixels/cm(2) control). Platelet count (3.4 +/- 0.3 NORel vs 2.3 +/- 0.3 x 10(8)/ml control) and function as measured by aggregometry (71 +/- 3 NORel vs 17 +/- 6% control) were preserved after 4 h exposure in NORel versus control ECC. Plasma fibrinogen levels significantly decreased in both NORel and control groups. Platelet P-selectin mean fluorescence intensity (MFI) as measured by flow cytometry was attenuated after 4 h on ECC to ex vivo collagen stimulation (27 +/- 1 NORel vs 40 +/- 2 MFI control). Monocyte CD11b expression was reduced after 4 h on ECC with NORel polymer (87 +/- 14 NORel vs 162 +/- 30 MFI control). These results suggest that the NORel polymer coatings attenuate the increase in both platelet P-selectin and monocytic CD11b integrin expression in blood exposure to ECCs. These NO-mediated platelet and monocytic changes were shown to improve thromboresistance of these NORel-polymer-coated ECCs for biomedical devices.

Hemodynamic effect of a low-resistance artificial lung in series with the native lungs of sheep

BACKGROUND An artificial lung with 1 to 6 month work life could act as a bridge to transplantation. A pumpless artificial lung has been developed. METHODS The artificial lung was placed in series with the native lungs of adult sheep. Hemodynamics were observed, as the right ventricle generated flow through the device. Through a left thoracotomy, two 20-mm grafts were anastomosed in an end-to-side fashion to the pulmonary artery. The grafts were externalized, and directed flow through the chest wall, to the extracorporeal lung. The animals were recovered, weaned from the ventilator, and when standing, flow was diverted through the device. RESULTS Five of 7 animals survived 24 hours with 75% to 100% of the cardiac output diverted through the device. All animals were active, with interest in food and water, and able to stand. CONCLUSIONS The right ventricle perfused the artificial lung with 75% to 100% of the cardiac output for 24 hours. This device demonstrates the feasibility of a pumpless pulmonary assist device relying on the right ventricle for perfusion.

A prototype of a liquid ventilator using a novel hollow-fiber oxygenator in a rabbit model

Objective:A functional total liquid ventilator should be simple in design to minimize operating errors and have a low priming volume to minimize the amount of perfluorocarbon needed. Closed system circuits using a membrane oxygenator have partially met these requirements but have high resistance to perfluorocarbon flow and high priming volume. To further this goal, a single piston prototype ventilator with a low priming volume and a new high-efficiency hollow-fiber oxygenator in a circuit with a check valve flow control system was developed. Design:Prospective, controlled animal laboratory study. Setting:Research facility at a university medical center. Subjects:Seven anesthetized, paralyzed, normal New Zealand rabbits Interventions:The prototype oxygenator, consisting of cross-wound silicone hollow fibers with a surface area of 1.5 m2 with a priming volume of 190 mL, was tested in a bench-top model followed by an in vivo rabbit model. Total liquid ventilation was performed for 3 hrs with 20 mL·kg−1 initial fill volume, 17.5–20 mL·kg−1 tidal volume, respiratory rate of 5 breaths/min, inspiratory/expiratory ratio 1:2, and countercurrent sweep gas of 100% oxygen. Measurements and Main Results:Bench top experiments demonstrated 66–81% elimination of Co2 and 0.64–0.76 mL·min−1 loss of perfluorocarbon across the fibers. No significant changes in Paco2 and Pao2 were observed. Dynamic airway pressures were in a safe range in which ventilator lung injury or airway closure was unlikely (3.6 ± 0.5 and −7.8 ± 0.3 cm H2O, respectively, for mean peak inspiratory pressure and mean end expiratory pressure). No leakage of perfluorocarbon was noted in the new silicone fiber gas exchange device. Estimated in vivo perfluorocarbon loss from the device was 1.2 mL·min−1. Conclusions:These data demonstrate the ability of this novel single-piston, nonporous hollow silicone fiber oxygenator to adequately support gas exchange, allowing successful performance of total liquid ventilation.

Blood pressure elevation during hindquarter compression in dogs is neurogenic

In a previous paper we reported that in pigs and dogs hindlimb compression causes large blood pressure increases which appear to be neurogenic. The present studies explore the utility of this non-invasive pressor model by determining the duration of the blood pressure increase, and by providing definitive evidence that the pressor response is neurogenic. All studies were done in chloralose-anaesthetized mongrel dogs. Prolonged experiments were performed in five experimental and four control dogs. Pressor responses could be elicited over a period of 9 h. The blood pressure increase during the 9th h was +30 +/- (s.e.m.) 6/32 +/- 5 mmHg (P less than 0.001 by paired t-test). The blood pressure in control animals did not change. Short-term hormonal and haemodynamic responses were analysed in 10 dogs. After 20 min hindlimb compression, mean blood pressure was elevated by 41.2 +/- 8.0 mmHg (P less than 0.001), plasma norepinephrine increased by 717 +/- 133 pg/ml (P less than 0.01) and plasma renin rose by 3.4 +/- 1.0 ng/ml/h (P less than 0.05). The pressure elevation was due to a 37% increase in total vascular resistance (P less than 0.01). Spinal anaesthesia at L4-L5 level in nine dogs caused a 70% reduction of blood pressure increase during lower body compression (P less than 0.001) and totally abolished plasma renin and norepinephrine increases. The infrarenal aorta and lower vena cava were occluded in eight dogs. After the ligation, there was a small rise in mean blood pressure (13.1 +/- 3.7 mmHg, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Sustained blood pressure elevation to lower body compression in pigs and dogs.

Inflatable suits were constructed for lower body compression in pigs and dogs. The suit for pigs encompassed hindquarters and part of the abdomen, and the smaller suit for dogs compressed only the hindquarters, leaving free the abdominal cavity. In conscious, diazepam-pretreated pigs, the compression lasted 30 minutes; during that period the blood pressure increased 50/38 mm Hg over the baseline. In chloralose-anesthetized dogs, the compression was extended to 3 hours; the blood pressure increase was 44/53 mm Hg. Blood pressure fell to the baseline immediately after decompression in both animals. In both species the substantial blood pressure increase was due to an increase of vascular resistance; this did not induce the expected baroreceptor-mediated bradycardia. In dogs, the blood pressure increase was accompanied by a large increase of plasma norepinephrine (from 179 to 975/). To test whether the increase of vascular resistance reflected the mechanical compression of the vessels under the suit, animals were pretreated with trimethaphan. In pigs the trimethaphan substantially decreased the vascular resistance and the blood pressure response. This indicated that a portion of the vasoconstriction occurred in areas outside the suit. Lower body compression is a new model to cause prolonged blood pressure elevation by noninvasive and nonpharmacologic means. The mechanism of the blood pressure elevation requires further investigation. (Hypertension 4: 782–788, 1982)

Quinapril, an angiotensin converting enzyme inhibitor, prevents cardiac hypertrophy during episodic hypertension.

Six control dogs, six dogs treated with 1.5 mg/kg b.i.d. quinapril, and six dogs treated with 8 mg/kg q.d. minoxidil underwent 6 hours daily of hindquarter compression for 9 weeks. Minoxidil significantly decreased baseline blood pressure (−17 mm Hg; p<O.Ol), whereas quinapril decreased baseline blood pressure 11 mm Hg but not significantly (p=0.15). Hindquarter compression elicited blood pressure increases in all three groups (control +18, quinapril +13, minoxidil +19 mm Hg). After 9 weeks, left ventricular mass in control dogs increased 22% (p<0.004); a similar increase was seen in minoxidil-treated dogs (+22%, p<0.0001) but not in the quinapril-treated group (+4%, p<0.15). The increase in left ventricular mass in control dogs was concentric (increased epicardial volume only), whereas in the minoxidil group, the hypertrophy was eccentric (both epicardial and endocardia! volumes increased). The minimal hypertrophy in the quinapril group was concentric (no change in epicardial, but a decrease in endocardia! volume). Quinapril had little hypotensive effect, but prevented the development of left ventricular hypertrophy, whereas minoxidil did not prevent hypertrophy in spite of its hypotensive effect. The mechanism of this differential effect of direct vasodilation versus converting enzyme inhibition on left ventricular hypertrophy is not fully elucidated. The results with quinapril suggest that some antihypertensive agents may positively affect left ventricular hypertrophy in spite of the absence of a large effect on baseline blood pressure or on blood pressure reactivity.

Total liquid ventilation provides superior respiratory support to conventional mechanical ventilation in a large animal model of severe respiratory failure.

Total liquid ventilation (TLV) has the potential to provide respiratory support superior to conventional mechanical ventilation (CMV) in the acute respiratory distress syndrome (ARDS). However, laboratory studies are limited to trials in small animals for no longer than 4 hours. The objective of this study was to compare TLV and CMV in a large animal model of ARDS for 24 hours. Ten sheep weighing 53 ± 4 (SD) kg were anesthetized and ventilated with 100% oxygen. Oleic acid was injected into the pulmonary circulation until PaO2:FiO2 ≤60 mm Hg, followed by transition to a protective CMV protocol (n = 5) or TLV (n = 5) for 24 hours. Pathophysiology was recorded, and the lungs were harvested for histological analysis. Animals treated with CMV became progressively hypoxic and hypercarbic despite maximum ventilatory support. Sheep treated with TLV maintained normal blood gases with statistically greater PO2 (p < 10−9) and lower PCO2 (p < 10−3) than the CMV group. Survival at 24 hours in the TLV and CMV groups were 100% and 40%, respectively (p < 0.05). Thus, TLV provided gas exchange superior to CMV in this laboratory model of severe ARDS.

Assessment of the development of choked flow during total liquid ventilation

ObjectiveThe flow rate of a liquid drainage from the lungs is limited because of the elastic nature of the airways. This study was designed to clarify the relationship between intrapulmonary liquid volume and the development of the flow limitation or choked flow phenomenon as a function of expiratory flow rate during total liquid ventilation with perflubron. DesignProspective animal study. SettingUniversity research laboratory. SubjectsRabbits with a weight of 3.2 ± 0.3 kg. InterventionsAfter the rabbits were killed, the lungs were filled to functional residual capacity with perflubron, followed by administration of an additional volume of 30, 45, or 60 mL of perflubron (initial volume = functional residual capacity + additional volume). Measurements and ResultsIn one set of five animals, the intratracheal pressure at the occurrence of choked flow was established at −20 mm Hg. In another set of six animals, we demonstrated that the volume remaining in the lung at the point of development of choked flow (Vch) was stable for the first 40 mins after the animals were killed. Flow rates of 1.25, 2.5, 3.75, 5.0, 7.5, 10.0, and 12.5 mL/sec were then applied at an additional volume of 30, 45, or 60 mL to 34 animals. Vch approximately doubled as the flow rate increased from 1.25 mL/sec to 12.5 mL/sec (p < .001). At the same flow, Vch was higher for an additional volume of 60 mL than 30 mL when the flow was ≥2.5 mL/sec. ConclusionsFrom these data, we conclude that choked flow occurs at intratracheal pressure of less than −20 mm Hg, that Vch is stable for the first 40 mins after the animals are killed, and that Vch is a function of flow rate and initial volume.