Arterial Epinephrine Research Articles

Nitrous Oxide Markedly Increases Cerebral Cortical Metabolic Rate and Blood Flow in the Goat

Studies to date on the influence of N2O on cerebral blood flow (CBF) and metabolism in dogs, rodents, and humans have produced conflicting results. In the present study the authors have employed techniques in the awake, freely breathing nonstressed goat that allowed the authors to 1) serially obtain rapidly frozen cerebral cortical biopsy specimens (for labile metabolite assay) and 2) measure changes in cerebral O2 metabolism (CMRO2) and total and regional CBF (rCBF). Thus, with each animal utilized as its own control, the authors studied N2O effects on the above variables. Two determinations of the effects of 1 h of N2O (70% via a mask) on these variables were performed on each animal. Following introduction of N2O, PaCO2 and arterial blood pressure did not change, but arterial epinephrine levels declined over the 60-min period. Total CBF increased in the first 5 min of N2O exposure, reached a maximum of 165% control at 15 min, and then decreased to 143% control at 60 min. rCBF evaluations showed that much of this CBF increase was confined to cerebral cortical structures (188-246% control at 60 min). Over the same period cortical CMRO2 increased to 170% of control. No appreciable changes in the levels of high-energy phosphates or glycolytic intermediates were found at 60 min of N2O. The authors attribute the described changes solely to the presence of N2O and not to sympathoadrenal influences, altered ventilation, or anything related to the experimental preparation, and they conclude that N2O (at least in goats) is associated with a marked cerebral cortical "activation".

Treatment of hypertension associated with head injury.

Arterial hypertension that occurs after severe head injury is characterized by elevation of systolic blood pressure, tachycardia, increased cardiac output, normal or decreased peripheral vascular resistance, and increased circulating catecholamines. The effects of two drugs used in the management of hypertension, propranolol and hydralazine, on these indices of cardiovascular function were examined in six head-injured patients. Both drugs effectively normalized blood pressure. However, hydralazine increased heart rate by 30%, cardiac index by 49%, left cardiac work by 21%, and pulmonary venous admixture by 53%, and was responsible for an increase in intracranial pressure or decreased compliance in two patients. Hydralazine produced no consistent change in arterial catecholamines. In contrast, propranolol decreased heart rate by 21%, cardiac index by 26%, left cardiac work by 35%, pulmonary venous admixture by 15%, and oxygen consumption by 18%. Propranolol decreased arterial epinephrine levels by 48% and norepinephrine levels by 28%. Propranolol appears to be a useful antihypertensive drug in the hyperdynamic head-injured patient because it normalizes blood pressure and the underlying hemodynamic abnormalities both by its beta-adrenergic blocking action and by decreasing circulating levels of catecholamines.

Alpha-adrenoceptor control of norepinephrine release from acutely ischaemic myocardium: effects of blood flow, arrhythmias, and regional conduction delay.

We studied the effects of yohimbine, and alpha-adrenoceptor blocker with selectivity for the alpha 2-subtype, on myocardial norepinephrine (NE) overflow, regional myocardial blood flow (RMBF), and patterns of epicardial conduction abnormalities during occlusion of the proximal left anterior coronary artery in an open-chest anaesthetised dog model. With a 12-min period of coronary occlusion (n = 9), spontaneous overflow of NE into ischaemic venous effluent was not observed either before or after yohimbine (1 mg/kg i.v.), but the drug significantly potentiated the enhanced NE overflow during supramaximal stimulation of the left stellate ganglion at low (1 Hz) and high (10 Hz) frequency [peak NE 4.3 +/- 0.4 pmol/ml control; 11.8 +/- 5.4 pmol/ml yohimbine (p less than 0.005)] with a delayed return towards prestimulation levels. Myocardial NE overflow on coronary reperfusion was also enhanced. Yohimbine increased arterial epinephrine two- to threefold but did not substantially alter myocardial lactate overflow during coronary occlusion. RMBF was reduced 24 and 36% to ischaemic endocardium and epicardium, respectively (p less than 0.01, compared with control occlusion). This contrasted with a 9 and 6% decrease in flow to the respective nonischaemic areas (p = NS, compared with control occlusion. Spontaneous ventricular fibrillation and the area and magnitude of epicardial conduction abnormalities in the ischaemic myocardium were both increased compared with the control occlusion. Thus, alpha-blockers with selectivity for the alpha 2-adrenoceptor may be detrimental to acutely ischaemic myocardium, presumably through increased local catecholamine release at the nerve terminal.

Effects of prazosin on hemodynamics and sympatho-adrenal activity in hypertensive patients.

We studied peripheral and central hemodynamics and plasma catecholamine levels in 12 previously untreated patients with essential hypertension before and during treatment with the alpha 1-adrenoceptor antagonist prazosin (9.8 +/- 1.1 mg/day for 3-6 weeks following dose titration) as a single drug. Prazosin did not alter intra-arterially recorded blood pressures in the group as a whole, in spite of adequate plasma levels (12.6 +/- 1.2 ng/ml). There were no changes in cardiac output, blood volume, systemic or forearm vascular resistance, or forearm venous tone at rest during treatment. The blood pressure response to prazosin was correlated to pretreatment systemic and forearm vascular resistances. Arterial adrenaline levels were unchanged, but noradrenaline levels increased from 1.30 +/- 0.10 to 1.85 +/- 0.20 nM (p less than 0.05). Both noradrenaline and blood pressure responses to isometric hand-grip exercise were delayed and reduced during treatment. The hemodynamic and plasma catecholamine responses to a cold pressor test and tilting (50% head-up during 10 min) were similar before and during treatment. Our results may be related to development of tolerance to the alpha-adrenoceptor blocking effect of prazosin during long-term treatment. The elevation of arterial noradrenaline levels suggests that increased sympathetic activity also may have opposed the hypotensive response to prazosin.

Increased beta-thromboglobulin in essential hypertension: interactions between arterial plasma adrenaline, platelet function and blood lipids.

Twenty-three 50-year-old men with untreated, essential hypertension had elevated plasma concentrations of the platelet release product beta-thromboglobulin (BTG) compared to 14 age-matched control men (p less than 0.01). BTG correlated with arterial plasma adrenaline concentrations in the hypertensive (r = 0.44, p less than 0.05), normotensive (r = 0.73, p less than 0.01) and combined group (r = 0.51, p less than 0.01). Significant correlations (p less than 0.05) between BTG and cholesterol (LDL + VLDL fraction) were observed both in the hypertensive and the normotensive group. In the hypertensive group arterial adrenaline correlated with cholesterol (LDL + VLDL) (p less than 0.05). These findings are consistent with increased platelet activity in middle-aged men with essential hypertension, and may indicate that plasma adrenaline influence platelet function. The risk factors for coronary artery disease (blood pressure, lipid status, stress as evidenced by catecholamine release and platelet function) were positively related. Measurement of arterial instead of venous adrenaline is essential for the demonstration of the associations presented.

Hemodynamic and Catecholamine Changes after Administration of Naloxone

The hemodynamic and catecholamine response to intravenously administered naloxone, 0.2 mg and 0.4 mg, were determined in one group of surgical patients and one group of volunteers. Naloxone, 0.2 mg, was administered 30 minutes before the 0.4-mg dose. Group I consisted of six normotensive (IA) (aged 18 to 64, mean 35.7 years) and six hypertensive surgical patients (IB) (aged 35 to 67, mean 49.1 years) who were receiving a nitrous oxide, oxygen, and halothane anesthetic. Group II consisted of six normotensive (IIA) (aged 27 to 38, mean 36.1 years) and five hypertensive (IIB) unanesthetized volunteers (aged 41 to 60, mean 51.4 years). Mean arterial pressure, heart rate, plasma norepinephrine, epinephrine, and dopamine levels were compared before and after intravenous naloxone. Changes in mean arterial pressure, heart rate, plasma norepinephrine, epinephrine, and dopamine levels were not statistically significant in any group. This study suggests that intravenous naloxone, per se, alters neither mean arterial pressure, heart rate, or plasma catecholamine levels in normotensive or hypertensive humans.

Dissociation between Plasma Prostaglandins E and Fα, Renin and Catecholamines in Hypertensive Patients

1. Plasma prostaglandins (PGE and PGFα) and catecholamine concentrations, and plasma renin activity were measured during an uninterrupted graded exercise test on the bicycle ergometer in 11 hypertensive patients. Blood was withdrawn from the brachial and pulmonary artery after 30 min recumbent rest, after 15 min rest sitting and at the final work load of the exercise test, which averaged 143 ± 16.5 W. 2. Exercise did not provoke a significant change in these plasma PGE or PGFα concentrations, but a rise (P < 0.001) in arterial plasma renin activity and (nor)adrenaline concentration was observed. It is thus unlikely that prostaglandins E or Fα are an important determinant of release of plasma renin during exercise.

Plasma prostaglandins, renin, and catecholamines at rest and during exercise in hypertensive humans.

Plasma prostaglandins (PGE and PGF alpha), catecholamine concentration, and plasma renin activity (PRA) were measured during an uninterrupted graded exercise test on the bicycle ergometer in 11 hypertensive patients. Blood was withdrawn from the brachial and pulmonary arteries after 30 min of recumbent rest, after 15 min of rest sitting, and at the final work load of the exercise test, which averaged 143 +/- 16.5 W. Exercise did not provoke a significant change in these plasma PGE or PGF alpha concentrations, whereas a rise (P less than 0.001) in arterial PRA and (nor)epinephrine concentration was observed. It is thus unlikely that PGE or PGF alpha is an important determinant of PRA release during exercise, although circulating levels of PGE and PGF alpha do not necessarily reflect release rate or activity in the kidney.

Plasma renin activity during infusion of epinephrine into the carotid and vertebral arteries of anesthetized dogs.

Previous experiments have demonstrated that increments of epinephrine concentration within the physiological range elevate PRA when epinephrine is infused iv but not when it is infused directly into the renal artery. The present experiments examined whether an elevation of the circulating epinephrine concentration to the head could account for this elevation of PRA by epinephrine. Anesthetized dogs were surgically prepared for blood sampling and blood pressure recording and for the infusion of epinephrine into either a femoral vein (iv) or the carotid and vertebral arteries. After a control period, epinephrine was infused for 45 min at a total rate of 25 ng kg-1 min-1 either iv or into the head vasculature (3.5 ng kg-1 min-1 into each vertebral artery and 9 ng kg-1 min-1 into each carotid artery). PRA (in nanograms per ml h-1) rose from 1.8 +/- 0.5 to 5.9 +/- 1.2 (mean +/- SE) during iv epinephrine infusion. PRA rose similarly (from 1.5 +/- 0.4 to 4.8 +/- 1.8) during epinephrine infusion to the head. The arterial blood epinephrine concentration rose similarly in response to iv and head epinephrine infusions. Furthermore, the changes in hematocrit, heart rate, blood pressure, and plasma potassium concentration were identical regardless of the route of epinephrine infusion. In separate experiments, a smaller infusion of epinephrine infusion. In separate experiments, a smaller infusion of epinephrine directly into the head vasculature at a total rate of 2.5 ng kg-1 min-1 (0.35 ng kg-1 min-1 into each vertebral artery and 0.9 ng kg-1 min-1 into each carotid artery) was without effect on PRA. The data indicate that 1) epinephrine is apparently neither taken up nor degraded by the microcirculation of the head, and 2) the receptors mediating the stimulatory effect of epinephrine on PRA are not located in regions supplied by the carotid and vertebral arteries.

Renal contribution to plasma catecholamines—effect of age

In 18 subjects undergoing diagnostic cardiac catheterization renal venous noradrenaline during rest (296 +/- 26 ng/l, mean +/- SE) was significantly increased over arterial noradrenaline concentrations (250 +/- 20 ng/l, P less than 0.01) while, in contrast, the arterial adrenaline level (79 +/- 9 ng/l) was higher than the renal venous (41 +/- 4 ng/l, P less than 0.001). Age correlated positively with both renal venous noradrenaline (r = 0.56) and the renal venous-arterial difference of noradrenaline (r = 0.56), and negatively with arterial (r = -0.52) and renal venous adrenaline (r = -0.48). According to our data, a net renal venous secretion of noradrenaline and at the same time an uptake of adrenaline from the renal circulation take place at an extent that may influence plasma concentrations of both. With increasing age renal uptake of plasma adrenaline seems to decrease and net release of noradrenaline to increase. The fall in plasma adrenaline may be due to age-dependent involution of the adrenal medulla. In studies of plasma adrenaline concentrations and of the renal handling of plasma catecholamines the influence of age must be taken into account.

Renal handling of dopa, dopamine, norepinephrine, and epinephrine in the dog.

The uptake and excretion of endogenous dopa, dopamine, norepinephrine, and epinephrine by the kidney were studied. Blood samples were taken from the aorta at the origin of the renal artery and from the renal vein during a timed urine collection in each of six anesthetised greyhound dogs. Arterial plasma dopa (1,043 +/- 129 pg/ml) and epinephrine (218 +/- 96 pg/ml) were consistently higher than venous levels of dopa (591 +/- 80) and epinephrine (54 +/- 16 pg/ml), showing extraction of these by the kidney, whereas arterial plasma norepinephrine (329 +/- 89 pg/ml) and dopamine (64 +/- 9 pg/ml) were lower than the venous levels of norepinephrine (695 +/- 161 pg/ml) and dopamine (239 +/- 45 pg/ml), indicating secretion of these catecholamines into the circulation. The dopa extracted did not appear in the urine. Norepinephrine (7.2 +/- 1.7 ng/min), epinephrine (4.5 +/- 1.7 ng/min), and dopamine (3.2 +/- 0.7 ng/min) were excreted in the urine. These rates of urinary excretion could be accounted for by glomerular filtration and tubular secretion of the three catecholamines. The kidney extracts circulating dopa. It extracts and excretes epinephrine, norepinephrine, and dopamine, and, in addition, secretes both dopamine and norepinephrine into the circulation. These observations emphasize the important relationship between renal function and the peripheral sympathetic nervous system.

Evidence of increased peripheral catecholamine release in patients with long-standing, untreated essential hypertension

In 20 middle-aged men with untreated sustained essential hypertension for more than 5 years, both plasma adrenaline and noradrenaline were positively and significantly correlated with blood pressure. In both hypertensives and 19 normotensive control subjects supine arterial adrenaline concentrations were more than twice the venous concentrations consistent with adrenal production of this catecholamine. Adrenaline a--v(arterial-venous)differences(mean +/- SE) were significantly higher in the hypertensive group (82 +/- 15 pg/ml) than in the controls (50 +/- 5 pg/ml) indicating increased release of adrenaline in the hypertensives (P less than 0.05). Similarly, v-a(venous-arterial) differences of noradrenaline were significantly higher in the hypertensive (44 +/- 20 pg/ml) than in the control group (-10 +/- 16 pg/ml) indicating peripheral noradrenaline release in patients with essential hypertension. The findings are compatible with increased forearm noradrenaline and adrenal adrenaline release in these patients with long-standing untreated essential hypertension.

Effect of Spinal Anesthesia on Adrenergic Tone and the Neuroendocrine Responses to Surgical Stress in Humans

In order to quantitate the effect of spinal anesthesia on adrenergic tone, plasma levels of norepinephrine (NE) and epinephrine (EPI) were measured by radioenzymatic assay in 24 patients were then compared to those of 10 patients receiving inhalation anesthesia (halothane-nitrous oxide). High thoracic dermatome spinal anesthesia caused suppression of both arterial plasma NE and EPI and a fall of mean arterial pressure (MAP); in contrast, no changes of NE, EPI, or MAP were observed in patients receiving low spinal anesthesia. Overall, there was a relationship between the sensory dermatome anesthesia level and changes of both plasma NE (r = 0.71, P less than 0.001) and EPI (r = 0.52,P less than 0.02). In the inhalation anesthesia group, plasma NE increased during the operation and plasma levels of NE, EPI, growth hormone, and cortisol were elevated during the postoperative recovery period. These neuroendocrine responses to surgical stress were not observed in patients receiving either low or high spinal anesthesia. Thus, the effect of spinal anesthesia on adrenergic tone depends on the cord level of anesthesia and can be quantitated by measurement of plasma catecholamines. The neuroendocrine responses to surgical stress were prevented in patients who received low spinal anesthesia and who had no suppression of efferent adrenergic tone. These findings indicate that neural afferents from the site of tissue injury, which were blocked by low spinal anesthesia, mediated both the adrenergic and the hormonal responses to surgical stress in the inhalation anesthesia group.

Arterial-venous differences of plasma catecholamines in man

To investigate the relationship between forearm venous levels of catecholamines and systemic levels, simultaneous arterial and forearm vein blood samples were obtained from 14 subjects undergoing elective dental procedures and assayed with a sensitive and specific radioenzymatic assay. Baseline venous levels of norepinephrine were greater than arterial levels (305 ± 30 pg/ml versus 221 ± 18; ± SEM, p < .005). Conversely, arterial epinephrine levels were higher than venous (132 ± 17 pg/ml versus 80 ± 10; p < .005). There was a significant relationship between arterial and venous levels of both norepinephrine ( r = .77, p < .01) and epinephrine ( r = .67, p < .01). The arterial-venous epinephrine difference increased from the baseline value of 44 ± 14 pg/ml to 108 ± 16 ( p < .005) by 3 min after subcutaneous injection of epinephrine (18 μg), but the arterial-venous difference returned to 65 ± 24 by 5 min after injection ( p = NS versus baseline). These findings indicate that under the conditions of this study, forearm tissues produced more norepinephrine than they removed, but removed more epinephrine than they produced. Baseline venous and arterial levels were related; when epinephrine production was augmented, there was a short time lag for the venous epinephrine increase.

Circulating catecholamines and control of plasma renin activity in conscious dogs

Uninephrectomized dogs were prepared with indwelling catheters in the aorta, inferior vena cava (IVC), and renal artery, and after recovery they were studied in the conscious state. Basal aortic epinephrine and norepinephrine concentrations were 57 +/- 11 and 101 +/- 18 pg/ml, respectively. Elevation of epinephrine concentration to over 2,000 pg/ml by IVC infusion resulted in a sustained 3.5-fold increase in plasma renin activity (PRA), with only a transient decrease in arterial blood pressure. The PRA response to epinephrine was completely blocked by l-propranolol; isoproterenol increased PRA more than did epinephrine. Increasing norepinephrine concentration to 1,600 pg/ml by IVC infusion resulted in only a 1.5-fold increase in PRA. Infusion of epinephrine or norepinephrine directly into the renal artery to achieve similar increments of renal arterial concentration did not increase PRA. Insulin injection or hemorrhage resulted in elevations of arterial epinephrine (but not norepinephrine) concentration greater than the concentrations achieved during IVC infusion in these studies. We conclude that circulating epinephrine in the physiologic range plays a role in the control of PRA by activation of an extrarenal beta-receptor.

CONTROL OF ADRENOCORTICOTROPHIN SECRETION BY CATECHOLAMINES IN THE PREGNANT AND FOETAL SHEEP

The effect of adrenaline on the maternal and foetal plasma ACTH concentration of twelve pregnant sheep with chronically implanted vascular catheters has been studied. Adrenaline infused into the jugular vein of the ewe or foetus produced carotid arterial adrenaline concentrations of 1-9 ng/ml. The foetal plasma ACTH was 253 +/- 73 pg/ml and it showed a fivefold increase during adrenaline infusion; the ACTH concentration achieved was proportional to the plasma adrenaline. In the ewe plasma ACTH was 99 +/- 23 pg/ml. During adrenaline infusion to the ewe this rose by an amount dependent on the adrenaline concentration achieved and there was also a rise in foetal plasma ACTH but no consistent change in foetal plasma adrenaline. There was no reproducible change in plasma corticosteroid concentration during adrenaline infusion into the foetus but a rise in maternal plasma corticosteroid concentration during infusion into the ewes. Because the adrenaline concentrations achieved during the infusions were within the physiological range, the results indicate that circulating catecholamines may directly or indirectly influence the concentration of ACTH in the circulation. Also, physiological rises in plasma catecholamines in pregnant animals may stimulate the release of ACTH from the foetal pituitary.

Pharmacologic Control of Hemorrhagic Gastritis: Clinical and Experimental Results

Eight patients with endoscopically proved hemorrhagic gastritis were infused with intra-arterial epinephrine or vasopressin following selective catheterization of the celiac or left gastric artery. Bleeding was controlled by celiac artery epinephrine infusion in 3 patients and by left gastric artery vasopressin infusion in 2. Failure to control bleeding in 3 others was associated with thrombocytopenia. The effects of epinephrine and vasopressin infusions on celiac artery blood flow were documented experimentally. Hemorrhagic gastritis unresponsive to iced saline lavage can be controlled either by celiac artery infusion of epinephrine or left gastric artery infusion of vasopressin.

The diagnosis of traumatic laceration of the spleen by selective arteriography, direct serial magnification angiography, and intra-arterial epinephrine.

ARTERIOGRAPHY in emergency situations I1will often provide definitive diagnoses which expedite and facilitate life-saving treatment (9). Although the literature contains examples of isolated cases of splenic rupture diagnosed by arteriography (1, 2, 7, 8, 10), the problem had not received adequate attention until the recent reports of Love et al. (6) and Berk and Wholey (3). The purpose of this paper is to report the roentgen findings in five proved cases that are presumed to be representative and diagnostic. In addition, the use of intra–arterial aqueous epinephrine and serial magnification angiography as diagnostic adjuncts will be discussed. Material And Methods Ten patients suspected of having a ruptured spleen were examined via the percutaneous transfemoral route using the Seldinger technic. A yellow or red endhole J–shaped Odman-Kifa catheter was used for selective visceral arteriography. Films were obtained with a Schonander 14 × 14 cut–film changer in the frontal projection and were exposed at 3 per second for three seconds followed by one film per second for twelve additional seconds. Approximately 0.5 ml/kg of body weight of Hypaque–M 75 per cent was injected into the celiac artery by means of a ViamonteHobbs injector, with flow rates of 10 ml/ sec. Direct serial magnification angiography was accomplished with an x–ray tube with a 0.3 mm focal spot, positioned 20 inches from the object. Serial films were exposed at one per second for eight seconds using a Sanchez–Perez serialograph positioned 20 inches below the object. The diagnosis of ruptured spleen was made angiographically and confirmed at surgery in 5 patients. In 3 of these, aqueous epinephrine was injected into the celiac artery, and the examination was repeated within thirty seconds, fifteen minutes after the initial study suggested the diagnosis. The celiac arteriograms in 5 additional patients were interpreted as being normal; each of these patients was ultimately discharged and remained in good health. No complications were encountered as a result of any of the examinations. Case Reports CASE I (G. G.): This 12–year–old boy was admitted to Nassau Hospital after tripping and falling on the abdomen in school during gym class. The patient complained of upper abdominal pain, radiating to the left scapula. Physical examination revealed tenderness in the left upper quadrant and left flank. The bowel sounds were normal, and no masses were palpable. Pertinent laboratory findings included a hemoglobin of 13.9 g/100 ml, hematocrit of 40 per cent; white blood count of 1O,000/mm3 with a normal differential. An abdominal tap of the left upper quadrant was performed, and findings were negative.

Intra-arterial epinephrine protection against radiation nephritis. A progress report.

The therapist sees that the kidneys are shielded to prevent radiation nephritis when cancerocidal doses of irradiation are given for widespread abdominal malignant tumors (2, 4, 6, 7). Unavoidably, he may spare areas of tumor infiltrating or surrounding the kidney. It has recently been shown that, by causing temporary renal hypoxia, it is feasible to protect the normal canine kidney from large single doses of radiation. Before and during kidney irradiation vasoconstrictive doses of epinephrine were delivered selectively into the canine renal artery through a percutaneously placed catheter. Modifications of the infusion technic for clinical application were also described in this report (8). Preliminary results of the clinical application of this method of renal radioprotection to six patients were subsequently reported, along with a review of the experimental data (5). Materials and Methods Since November 1967, five courses of intensive abdominal irradiation and concomitant renal artery epinephrine infusions have been given to four selected patients with inoperable abdominal malignant tumors at the UCLA Clinical Research Center. Preliminary studies in each patient included a complete blood count, urinalysis, blood urea nitrogen, serum creatinine, creatinine clearance, liver battery, chest x-ray and bone survey, intravenous urography, Hippuran renogram, and Hippuran renal camera images.2 At time of placement of a percutaneous catheter in one renal artery, appropriate abdominal angiograms were also obtained to define the tumor more accurately and to visualize the kidney vasculature. Initially all patients had catheter placement into a renal artery by percutaneous axillary artery puncture. This route allowed a moderate amount of mobility, although the patients were confined mostly to bed or a bedside chair while the catheter was in place. A precurved #6 French Teflon catheter (radiopaque) was used, with no side-holes. The most efficient method of maintaining catheter position in the renal artery was to suture the catheter to the skin at the site of puncture. The indwelling catheter remained in place from twelve to twenty-three days. Periodic checks of catheter position were made by portal films and by fluoroscopy, at which time small amounts of Renografin-60 were hand-injected into the catheter. A bedside Sigmamotor pump or a tenfoot gravity drip delivering heparinized normal saline (1,000 /μ/liter) at the rate of one milliliter per minute kept the renal artery catheter open around the clock. One patient temporarily wore a battery-powered, portable pump which permitted him unrestricted mobility on the ward. In one instance (CASE III, below) the axillary artery approach was unsuccessful. A massive retroperitoneal tumor distorted the abdominal aorta, and the catheter tip would not remain within the left renal artery.

Prevention of radiation nephritis with renal artery infusion of vasoconstrictors. Experimental and preliminary clinical studies.

Numerous radiobiologic experiments have documented the validity of the original observations (1, 2) that the state of oxygenation at the time of irradiation markedly influences radiation response. Clinical attempts to exploit this so-called “oxygen effect” have taken a number of forms. These include efforts at increasing tumor oxygenation by respiration of oxygen under hyperbaric (3) as well as ambient conditions (4, 5). A similar objective was approached by the intra-arterial infusion of hydrogen peroxide (6). Conversely, the reduction of normal tissue toxicity by production of ischemia was the design of tourniquet application proximal to the irradiation site for soft-tissue sarcomas and bone neoplasms in the extremities (7, 8). The present study is an attempt to attenuate the radiosensitivity of the normal kidney by creating hypoxia during irradiation with the intra-arterial infusion of a vasoconstrictor agent. Preclinical experiments in dogs, previously reported in part (9), have demonstrated a significant protection against the development of radiation nephritis. A clinical trial has been undertaken, and in this paper our initial experience in patients is reviewed, together with the completed canine investigations. Preclinical Research Physiological studies in dogs on the effect of renal artery infusion with epinephrine are illustrated in Figure 1. Epinephrine infusion was shown to result in a marked decrease in renal blood flow, a fall in renal venous pH and oxygen saturation, and a rise in the lactate/pyruvate ratio in the venous blood. These changes indicate a significant degree of renal ischemia and tissue anoxia which was rapidly reversible with cessation of the epinephrine infusion. Additional canine investigations established that single ischemia-producing infusions of epinephrine of ten to fifteen minutes duration did not cause functional or histologic changes in normal kidneys and confirmed that 1,500 rads delivered in a single treatment resulted in severe damage within three months (10, 11). Arteriographie and radioisotope renogram alterations due to epinephrine infusion in normal dog kidneys are illustrated in Figures 2 and 3. The renograms have been obtained with a gamma scintillation camera as described elsewhere (12, 13). The final series of experiments consisted of evaluating the potential protection afforded irradiated kidneys by renal artery epinephrine infusion. The technic, as previously described (9), involved the percutaneous introduction of an arterial catheter into the renal artery of one kidney via the femoral artery. Epinephrine in normal saline was infused for five minutes at the rate of 1.3 µg per minute to produce ischemia. Without interruption of the infusion, 1,500 rads was then administered simultaneously to both kidneys in a single dose (60Co). At completion of irradiation, the infusion was discontinued and the catheter removed.