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Background: Anemia has been reported to develop during preoperative chemotherapy with paclitaxel and carboplatin. The use of recombinant human erythropoietin (EPO) has been shown to reduce anemia and subsequent packed red blood cell transfusions. The current study is a report of a Phase III, prospective, randomized trial with or without EPO that confirms the original observations of less anemia and fewer transfusions in those patients randomized to receive EPO concurrently with paclitaxel and carboplatin., Methods: Thirty patients with advanced head and neck or lung carcinoma were treated with 2 courses of paclitaxel, 230 mg/m(2), and carboplatin, 7.5 mg/mL/minute, repeated every 21 days. The treatment group was comprised of 15 patients randomized to receive concurrent EPO, 150 U/kg, 3 times per week; in patients deemed nonresponsive the dose was increased to 300 U/kg and 450 U/kg in subsequent courses. The control group was comprised of 15 patients randomized not to receive EPO., Results: Twenty-seven patients were evaluable. After 2 courses of chemotherapy the mean hemoglobin decrease was 1.2 g/dL in the EPO group versus 2.8 g/dL in the control group (P = 0.037). There was a highly significant decrease in hemoglobin over time in patients who did not receive EPO (P = 0.008). After 4 courses of chemotherapy, fewer patients were transfused in the EPO arm: 2 of 13 (15%) in the EPO treatment group versus 5 of 14 (36%) in the control group., Conclusions: There was significantly less anemia and transfusions were reduced by 50% in patients randomized to receive EPO during chemotherapy with paclitaxel and carboplatin., (Copyright 1999 American Cancer Society.)

The leukemic phase of mantle cell lymphoma (mantle cell leukemia) is defined as an absolute lymphocyte count of greater than 4,000/microliter and characterized by the presence of relatively small, slightly irregular lymphocytes in the peripheral blood. Although a variant of mantle cell lymphoma with blastic morphsology exists and has been previously well described, a blastic morphologic variant of mantle cell leukemia has not been described. We report such a case in a 74-year-old male who presented with splenic rupture and an elevated white blood cell (WBC) count. The diagnosis was based on flow cytometric immunophenotyping and the cytomorphology of the peripheral blood.

Background: Standard therapy for advanced head and neck carcinoma is surgery and radiation, and the subsequent 5-year survival with this treatment has been less than 50%. New combined modality treatment strategies are being tested to improve survival. New chemotherapy combinations are being developed and administered simultaneously with, or sequenced with, radiation and surgery. This article reports the Phase I results of administering paclitaxel and carboplatin preoperatively. The authors' objective was to develop an outpatient chemotherapy that would downstage tumors and allow organ preservation with equal or improved survival as compared with standard therapy., Methods: Thirty-six patients with untreated Stage III/IV head and neck carcinoma were treated and were evaluable for toxicity. All patients had lesions that were measurable in perpendicular planes. A nonrandomized, Phase I design was used, according to which cohorts of patients were treated every 21 days with escalating doses of paclitaxel (150-265 mg/m2) given as a 3-hour infusion immediately preceding carboplatin. Premedication was used to avoid acute hypersensitivity reactions. Carboplatin was administered intravenously over 1 hour at a constant dose calculated with the Calvert formula (area under the curve, 7.5)., Results: The dose-limiting toxicities were neuropathy and thrombocytopenia at a paclitaxel dose of 265 mg/m2. Neutropenic fever was observed in 30% of patients at a paclitaxel dose of 250-265 mg/m2. Other observed adverse effects included pruritus, myalgia, arthralgia, alopecia, nausea, and vomiting., Conclusions: Toxicity was acceptable. The maximum tolerated dose of paclitaxel was 230 mg/m2 without hematopoietic growth factor, or 250 mg/m2 with hematopoietic growth factor, the carboplatin dose held constant, calculated at area under the curve of 7.5. Phase II studies of this combination are warranted in the treatment of these carcinomas.

The effects of hydralazine upon the caudal pressor responses during occlusion of the abdominal aorta and vena cava evoked by: (1) preganglionic electrical stimulation of the lumbar sympathetic chain, (2) neostigmine and (3) McN-A-343 were investigated in the anesthetized dog. Hydralazine (10 microgram/kg, i.v.) produced a small but significant reduction of the pressor response to lumbar electrical stimulation prior and following blockade of nicotinic transmission with chlorisondamine (1.0 mg/kg). However, hydralazine was not effective in blocking the pressor responses elicited by neostigmine and McN-A-343. On the other hand, small doses of atropine (20 microgram/kg) produced a blockade of residual pressor responses evoked by all three stimuli. On the basis of these findings, the site of action of hydralazine appears to be different from that of atropine. It is proposed that hydralazine affects ganglionic transmission by acting at sites other than muscarinic in nature.

Plasma volume loss, cardiac output and hematocrit values have been measured in anesthetized dogs receiving a 15 per cent total body surface area third degree flame burn before and two, four and six hours postburn. One group of dogs received no fluid resuscitation. Five groups of dogs received fluid resuscitation with varying percentages of albumin added to the Ringer's lactate solution. Results of this study show that total fluid loss from the vascular bed increased as the result of fluid resuscitation. The amount of increase in total fluid loss was dependent upon the percentage of albumin in the resuscitation fluid. The higher the percentage of albumin, the lower the amount of total fluid loss. Following fluid resuscitation, cardiac output improved and the hematocrit level decreased toward normal. The amount of change of these variables was also related to the percentage of albumin in the resuscitation fluid. The greatest improvement in these variables was observed in that group of dogs receiving the greatest percentage of albumin in the resuscitation fluid. These results demonstrate that the administration of resuscitation fluid improves cardiovascular function following thermal injury and that the amount of improvement is related to the percentage of albumin present in fluid used for resuscitation.

Thermal trauma to the anaesthetized dog results in an immediate significant decrease in cardiac output, an increase in peripheral resistance and no significant change in mean arterial blood pressure. The infusion of sodium nitroprusside, 5 or 8 micrograms/kg X min, produced a significant increase in cardiac output and a decrease in peripheral resistance. Mean arterial blood pressure fell during the infusion and returned to pre-injection values immediately upon cessation of infusion. Cardiac output and peripheral resistance also returned to pre-infusion values upon cessation of infusion. A comparison between the responses to infusion of sodium nitroprusside and the administration of verapamil showed that infusion of sodium nitroprusside produced a slower onset of increase in cardiac output and a lower maximum increase in cardiac output than observed after verapamil.

Numerous in vitro investigations have reported that prolonged, continuous hyperbaric oxygen (OHP) exposure to certain bacteria and yeast is bacteriostatic. While it is tempting to attribute the lower infection rates reported in OHP-treated patients to this bacteriostatic effect, the duration and intensity of OHP exposure in these experimental studies exceeds that of normal therapeutic use. This study was designed to investigate the effects of human OHP treatment protocols upon the in vitro growth and survival of Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans. Additional studies using antibiotic-containing culture media were conducted to investigate the possible OHP enhancement of antibiotic sensitivity. No differences were observed between the bacterial and yeast growth curves of the control and experimental group. OHP also failed to produce any measurable difference in the bactericidal effectiveness of the selected antibiotics.

The effects of intravenously injected nicotinic acid upon postburn plasma volume loss have been studied in the anesthetized dog. Results of this study have shown that two hours after a third degree flame burn over 40 per cent of the surface area, approximately 12 milliliters per kilogram of plasma are lost to the extravascular spaces. If untreated, this loss will increase to 16 milliliters per kilogram at four hours postburn and 19 milliliters per kilogram at six hours postburn. Treatment of the dogs with nicotinic acid beginning two and one-half hours postburn will reduce the plasma extravasation to 13 milliliters per kilogram four hours postburn and to 11 milliliters per kilogram at six hours postburn. In general, the decrease in cardiac output observed after thermal trauma paralleled the loss of plasma volume. In the untreated dogs, this decrease continued with time postburn, but in the treated dogs, the decrease in cardiac output leveled off during the first two hours after beginning treatment and started what appeared to be a slow return toward control levels in the next two hour period.

Two groups of dogs anesthetized with sodium pentobarbital were subjected to compression of 60 psig for 60 min and decompressed at the rate of 10 psi/min without staging. Plasma volume was measured in each group by I131-tagged albumin dilution technique prior to compression, 10 min and 60 min after decompression. One group of animals received no other treatment and the other group received 15 mg/kg of body weight of nicotinic acid by intravenous injection immediately prior to compression and an additional 7.5 mg/kg of body weight of nicotinic acid 30 min after decompression. Both the untreated and the nicotinic acid-treated animals lost significant plasma volume at both the 10- and 60-min postdecompression measurements. Nicotinic acid-treated animals lost significantly less plasma.

Thermal trauma to the anaesthetized dog results in an immediate, significant decrease in cardiac output, an increase in peripheral resistance and no significant change in mean arterial blood pressure. The administration of verapamil 1.0 mg/kg by slow intravenous injection produced a rapid increase in cardiac output and a decrease in peripheral resistance. Mean arterial pressure fell and returned to or nearly to pre-injection values within 30 min. The duration of the increase in cardiac output after a single dose of verapamil was approximately 1.5-2.0 h. Administration of a second 0.5 mg/kg dose of verapamil, 1.5 h after the first dose, increased cardiac output and decreased peripheral resistance. After the second dose of verapamil, cardiac output was significantly greater and peripheral resistance was significantly less than in untreated animals for at least 2 h.

The effects of blocking agents upon the depression of transmission of the combined stellate and caudal cervical ganglia produced by the close intra-arterial injection of norepinephrine have been studied in the anesthetized dog. The results of this study showed that combined nicotinic and muscarinic ganglion blockade with chlorisondamine and atropine did not decrease the amount of norepinephrine-produced depression of transmission. This depression of ganglion transmission was converted to a stimulation by the close intra-arterial administration of the alpha adrenergic blocking drug phentolamine. Blockade of all preganglionic impulses by the production of total spinal anesthesia blocked the depression of ganglion transmission produced by norepinephrine and prevented the conversion of this depression to a stimulation by phentolamine. Phentolamine, when administered by close intra-arterial injection, produced a dose-dependent, prolonged stimulation of transmission through the ganglia. The results of this study infer that the norepinephrine depression of ganglion transmission is at some site other than the usual muscarinic and nicotinic ganglion pathways and that spinal pathways are involved.

Previous studies have reported that administration of potent peripheral vasodilating drugs will significantly increase thermal trauma-induced depression of cardiac output. This finding suggests that most of the depression in cardiac output after thermal trauma is due to an increase in peripheral resistance and a decrease in venous return rather than a direct depression of myocardial contractile force. Studies have been carried out using a strain gauge arch sewn on the left ventricle to measure myocardial force of contraction in the mongrel dog anaesthetized with sodium pentobarbital and receiving a 15 per cent total body surface area full skin thickness flame burn. The results of this study showed a significant decrease in cardiac output immediately after burn, which persisted for 7 h. Myocardial force of contraction, measured in grams, fell immediately after burn and returned to pre-burn values by 3 h post-burn. In one series of animals, verapamil, a calcium-channel-blocking substance, was administered. In these animals cardiac output returned to pre-burn levels following the administration of the drug, but myocardial force of contraction remained significantly lower than pre-burn value for the duration of the experiment. Correlation coefficients comparing cardiac output and myocardial force of contraction showed no significant relationship between values in either untreated or verapamil-treated animals.

The effects of hydralazine, dihydralazine and 4-propyl-1-hydrazinophthalazine (4-propylhydralazine) were investigated on reflex pressor responses to increased intracranial fluid pressure (IIP) during occlusion of the abdominal aorta and the vena cava (MVO). It has been shown that application of MVO, caudal to the renal arteries, produces two independent vascular zones in the animal (Steinberg and Hilton, 1966a). Increasing intracranial fluid pressure during MVO elicits a reflex pressor response which consists of two components. One component is blocked by the nicotinic ganglionic blocking agent, chlorisondamine, and the other component is blocked by small doses of atropine. It was found that hydralazine and dihydralazine were effective in blocking residual pressor responses following partial blockade of reflex pressor responses to IIP with chlorisondamine. 4-Propylhydralazine, which is chemically similar to hydralazine and dihydralazine, was less active in inhibiting the residual pressor responses. It is suggested that hydralazine may act in part by interfering with muscarinic ganglionic transmission.

Intravenous administration of nicotinic acid to the anesthetized dog prior to thermal trauma reduced plasma loss at 10 minutes after burn from 7 milliliters per kilogram to less than 2 millimeters per kilogram. During the next 50 minutes plasma loss was the same in treated and untreated animals. An additional dose of nicotinic acid 30 minutes after burn prevented this further loss.

Studies have been carried out on dog erythrocytes to determine the effects of heating to 57 degrees C on membrane ATPase and erythrocyte shape. The results of these studies showed that after heating the blood there was approximately a 30 per cent decrease in membrane ATPase and an alteration of erythrocyte shape from biconcave to spherical. Additional studies of the effects of addition of arachidonic acid to erythrocyte-membrane homogenates demonstrated that this substance produced a dose-related inhibition of ATPase. If the additions were made to membranes from blood which had previously been heated, the effects of arachidonic acid and heat were additive. Addition of the hydroxyl-radical scavenger catalase to the blood before heating prevented the observed decrease in ATPase and prevented the change in shape to spherical. These results confirm the previous findings of Bessis that heat will cause a change in the erythrocyte shape from biconcave to spherical and suggest that the mechanism responsible for this change is an alteration in membrane ATPase. The observation that a similar response can be produced by arachidonic acid suggests that metabolism of this substance may generate agents which are capable of inhibiting erythrocyte membrane ATPase. The observation that catalase will prevent the ATPase inhibition and the change in erythrocyte shape suggests that hydroxyl-free radicals play an important part in this thermal trauma-induced response.

The effects of heating blood to 57 degrees C on intraerythrocytic calcium, membrane ATPase activity and cell shape have been studied in canine blood. Intraerythrocytic calcium was determined by use of arsenazo III, membrane ATPase activity was determined by inorganic phosphorous formation and erythrocyte shape was determined by scanning electron microscopy. The results of this study showed that this degree of thermal trauma would cause a 27% increase in intraerythrocytic calcium and a 38% decrease in ATPase activity. During these changes in calcium and ATPase activity the erythrocyte changed form from biconcave to spherical. Addition of catalase (3,200 U/ml) to the blood prior to heating prevented the changes observed in intraerythrocytic calcium, membrane ATPase activity and shape. The addition of the free-radical generating combination of hypoxanthine-xanthine oxidase to blood produced a 20% decrease in membrane ATPase activity and a change in erythrocyte shape, but did not alter intraerythrocytic calcium. These results suggest that free-radicals are responsible for the changes in membrane ATPase activity. The observation that shape change occurs when ATPase activity has been decreased, but calcium has not been increased, suggests that membrane ATPase activity levels are more important in producing changes in erythrocyte shape than are intraerythrocytic calcium levels.

The effects of nicotinic and muscarinic ganglion blockade were studied on the peripheral resistance of the perfused hindlimbs of the dog. Nicotinic ganglion blockade by chlorisondamine (1 mg/kg) significantly reduced reflex vasomotor responses but did not significantly alter hindlimb peripheral resistance. Combined nicotinic ganglion blockade by chlorisondamine (1 mg/kg) and muscarinic ganglion blockade by atropine (50mug/kg) abolished the reflex vasomotor response but did not alter hindlimb peripheral resistance. It was concluded that autoregulatory mechanisms are capable of maintaining a peripheral resistance after block of both muscarinic and nicotinic ganglion transmission.

Based upon the prior observation that drugs which reduce sympathetically induced lipolysis also reduce plasma volume loss following thermal trauma, it was postulated that the products of the metabolism of polyunsaturated fatty acids (PUFA) were the substances causing the plasma volume loss. The two major metabolic pathways for PUFA are cyclo-oxygenase transformation to form prostaglandins and lipoxygenase transformation to form fatty acid hydroperoxides. This latter pathway also produces the superoxide anion and metabolism upn plasma volume loss, the effects of indomethacin (a cyclo-oxygenase inhibitor), orgotein (a superoxide dismutase), and catalase (an enzyme which converts hydrogen peroxide to inactive substances) were studied in anesthetized dogs receiving a 15% total body surface area third-degree flame burn. The results of this study showed that indomethacin did nt alter postburn plasma volume loss, orgotein reduced early plasma volume loss but did not reduce continuing loss, and catalase reduced both early and continuing plasma volume loss.

The effects of 3-methyl-5-isoxazole carboxylic acid (MIC) on postburn plasma volume loss have been studied in the anesthetized dog, and the results demonstrated that, when administered before thermal trauma, MIC significantly reduces the plasma volume loss observed at 1 and 2 hours postburn. The reduction of plasma volume loss observed was less than that observed with nicotinic acid administered preburn. A single 0.2-mg dose of MIC/kg body weight given 2 1/2 hours after a 15% body surface area third-degree flame burn significantly reduced the plasma volume loss during the next 4 hours. This effect of MIC was approximately the same as that observed with nicotinic acid under the same conditions. The differences between nicotinic acid and MIC under these conditions were the size of the dose of drug required (0.2 mg/kg of MIC versus 15 mg/kg of nicotinic acid) and the duration of action of the drug (greater than 3 hours for MIC versus 1 hour for nicotinic acid).

The effects of scald injury and scald injury with pretreatment on plasma and water content were studied in the superfused hamster cheek pouch. Catalase (30,000 Units/kg), indomethacin (2.5 mg/kg) and FPL 55712 (2 mg/kg) were administered prior to 10 second scald with 100 degrees C normal saline. Plasma content was measured with 125 I serum albumin and water content was calculated by loss on drying. Significant (P less than 0.05) decreases in plasma content compared to scald alone were observed following pretreatment with catalase (29%) indomethacin (31%) or FPL 55712 (52%). Water content in scalded pouches was significantly reduced by catalase (29%) and FPL 55712 (42%). Pretreatment when combined also resulted in significant reduction of plasma content but not water content. Results suggest that free-radicals, prostaglandins and leukotrienes are involved in vascular response by scald injury.

The effects of H-R, a mixture of beta-hydroxyethyl rutosides, administered post burn, upon thermal-injury-induced plasma volume loss were studied in the anaesthetized dog. All animals received a 15 per cent total body surface area third-degree flame burn and were not fluid resuscitated. Plasma volume, cardiac output and mean arterial blood pressure were measured prior to burn and at 2, 4 and 6 hours post burn. One group of animals received a single 100 mg/kg dose of H-R by intravenous injection at 2.75 hours post burn. One group of animals received two doses of 100 mg/kg of H-R. One dose was administered 2.75 hours post burn and the second dose was administered 4.75 hours post burn. The results of this study showed that H-R administered after burn is capable of reducing the continuing plasma volume loss. The duration of this response is relatively short and a second dose of H-R was necessary to maintain the reduction of continuing plasma volume loss beyond 2 hours. The effects of H-R on thermal-injury-induced changes in cardiac output and mean arterial pressure were less dramatic than the reduction in continuing plasma volume loss. These effects were observed only in the group of animals receiving two doses of H-R.

The cardiovascular changes induced by 15% total body surface area 3 degrees burn have been studied in dogs anesthetized with sodium pentobarbital. The responses observed were a decrease in plasma volume, a decrease in cardiac output, and a slight but insignificant fall in mean arterial blood pressure. Beta adrenergic blockage with propranolol prior to thermal trauma reduced the plasma volume loss, increased the depression of cardiac output, and caused a rise in mean arterial blood pressure. From these results it has been postulated that beta adrenergic stimulation contributes to the plasma volume loss and the slight fall in mean arterial pressure observed following thermal trauma.

The partial pressures of oxygen and carbon dioxide have been measured in hypertrophic scars in burned patients, using mass spectroscopy. The pO2 in scar tissue was significantly depressed in comparison to the pO2 in normal dermis (a decrease of 13.1 +/- 2.9 mm Hg). The pCO2 was noted to be increased in the scar tissue (2.6 +/- 1.6 mm Hg). The possible significance of these findings is discussed.

Usually, ketoacidosis presents few if any diagnostic or therapeutic problems; in this article, we report a case where ketoacidosis was clinically occult and biochemically obscure. The patient presented with acute pancreatitis associated with a modest antecedent alcohol intake. Metabolic acidosis with a normal anion gap (10 meq/L) was observed together with moderate hyperglycemia and a 2 + (but not 4 +) test for serum ketones. None of the usual causes of metabolic acidosis with a normal anion gap was identified nor was there an obvious explanation for a reduction in unmeasured anion gap (e.g., hypoalbuminemia, dysproteinemia, or the presence of abnormal halides). Despite the initial normal anion gap, ketoacidosis was suspected clinically and this was confirmed by the elevated serum B-hydroxybutyrate of 8 mmol/L. We deduced that the serum unmeasured anions, which should have been increased by at least 8 meq/L, were being underestimated because of the effect of hypertriglyceridemia on the serum chloride determination. When the serum chloride was reestimated by a method not influenced by hyperlipidemia, the value was 102 mmol/L not 112 mmol/L and, when reevaluated, the anion gap was indeed appropriately elevated. In addition, the urine anion gap (Na + K - Cl) was 103 meq/L in the absence of renal disease. This indicated that the expected large quantity of urinary ammonium must have been masked by an even greater quantity of unmeasured anion; in this case proven by direct measurement to be B-hydroxybutyrate. Finally, metabolism of the alcohol ingested, which yields hepatic NADH, could explain, in part, the modest hyperglycemia and the absence of a 4 + test for serum ketones.(ABSTRACT TRUNCATED AT 250 WORDS)

Using the dog anaesthetized with sodium pentobarbital receiving a 15 per cent total body surface full skin thickness flame burn as an experimental model, it was observed that administration of the vasopressin, V-1 receptor, blocking agent d(CH2)5Tyr(Me)AVP (SK&F100273) prior to burn could significantly reduce the increase in peripheral resistance which occurs in untreated burned animals. At 30 min post-burn peripheral resistance was 60.2 +/- 7.8 units in treated animals and 117.1 +/- 16.8 units in untreated animals. At 60 min post-burn these values were 71.3 +/- 7.2 units and 117.0 +/- 13.5 units, respectively. Changes in cardiac output were significantly less in treated than untreated experimental animals. The mean arterial blood pressures were not significantly different. Plasma levels of vasopressin were measured by radio-immunoassay prior to burn and at 30-min intervals for 6 h following burn. At the time of taking blood samples for vasopressin levels, mean arterial blood pressure and cardiac output were measured and peripheral resistance was calculated. The results of this study showed that immediately post-burn vasopressin plasma levels increased from 6.2 +/- 2.2 pg/ml to 27.3 +/- 9.5 pg/ml and peripheral resistance increased from 62.3 +/- 6.3 units to 128.0 +/- 20.3 units. During the remaining 6 h of the experimental study both vasopressin plasma levels and peripheral resistance remained elevated. These results show that following thermal injury there is a significant release of vasopressin and suggest that the increase in peripheral resistance observed could be due in part to the vasoconstrictor action of the released vasopressin.

The myocardial contractile responses to electrical stimulation of different segments of the thoracic sympathetic trunk in the pentobarbital-anesthetized dog were studied. Electrical stimulation of the sympathetic trunk between the second and third thoracic ramus and caudal limb of the ansa subclavia elicited myocardial contractile responses which were not completely antagonized by the ganglionic blocking agent chlorisondamine. Atropine in addition to chlone had no effect. When the sympathetic trunk between the third and fourth ramus was electrically stimulated, the response was partially antagonized by atropine as well as by chlorisondamine alone. From these results, it is suggested that impulses travelling via the third thoracic ramus or above it mediate myocardial contractile responses in which the nicotinic type response predominates whereaas impulses travelling via the fourth thoracic ramus or below it mediate myocardial contractile responses in which the muscarinic type predominates. additionally, evidence presented indicates that a major proportion of both nicotinic and muscarinic receptors mediating myocardial contractile changes are located in the caudal cervical ganglion rather than the stellate ganglion of the dog.

We report here a modification of the superfused hamster cheek model for use in vascular permeability studies. Radio-iodine labeled serum albumin (I-125 RISA) is injected prior to the superfusion period. Plasma content is calculated on a microliter/100 mg wet weight basis and compared to the contralateral (non-superfused) cheek pouch. Water content is calculated on a percentage basis and compared in the same manner. Results demonstrate that superfusion causes an increase in permeability of protein and water. Plasma content is reduced by catalase, indomethacin or FPL 55712 pretreatment, suggesting that free-radicals, prostaglandins and leukotrienes are released during superfusion. Water content increase is refractory to pretreatment. The advantages of this system and its application are discussed.

Previous investigators have shown that hypotension will cause an increase in plasma levels of both vasopressin and angiotensin II. Significant increases in peripheral resistance after thermal trauma suggested that a similar increase in plasma vasopressin and angiotensin II levels might occur under this condition. This possibility has been studied in the pentobarbital anesthetized dog. Peripheral resistance was calculated from measured cardiac output and mean arterial blood pressure. Vasopressin and angiotensin II levels were measured by radio-immunoassay. The results of this study showed that vasopressin plasma levels increase 4 to 6 fold 15 minutes after thermal trauma and remained elevated (3 to 4 fold) for at least 6 hours. Angiotensin II increased in a linear manner from 15 minutes to 6 hours post trauma. At 6 hours post trauma angiotensin II plasma levels were 4 times pretrauma levels. For the first 4 hours post trauma there was a positive correlation between the sum of vasopressin and angiotensin II plasma levels and the increase in peripheral resistance. These results suggest that the trauma induced increase in peripheral resistance is due to increases in plasma vasopressin and angiotensin II.

It has been suggested that post-burn myocardial depression may be due to coronary constriction which results in myocardial ischaemia. It has been demonstrated that the levels of vasopressin, a potent natural constrictor of blood vessels, increase four- to six-fold immediately after thermal trauma. Therefore, this substance could be responsible for post-burn coronary constriction and myocardial depression. This was tested using the dog anaesthetized with sodium pentobarbital receiving a 15 per cent total body surface area full thickness flame burn as the experimental model. Cardiac output was measured by the thermal dilution technique. Arterial blood pressure was sensed by a Stathem P-23 transducer. Cardiac force of contraction was measured by a Walton-Brody strain gauge arch sewn on the left ventricle. The results of this study showed a significant decrease in cardiac output, increase in peripheral resistance and decrease in myocardial force of contraction immediately after thermal trauma in untreated animals. The decrease in cardiac output and increase in peripheral resistance remained for the duration of the experimental observations (3 h). The decrease in force of contraction returned to pre-burn levels 1 h post-burn. Pretreatment of the experimental animals with d(CH2)5 Tyr(Me)AVP (SK&F 100273), a vasopressin V-1 receptor blocking agent, prevented the initial decrease in cardiac output, increase in peripheral resistance and decrease in the force of contraction. A correlation plot of peripheral resistance vs. cardiac force of contraction showed a positive correlation between these two variables in the pretreated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of free-radicals generated by either the oxidation of hypoxanthine by xanthine oxidase (HX/XO) or the lipoxidation of arachidonic acid (AA) on the ATPase of the hamster cheek pouch has been studied. Cheek pouches were removed from female golden syrian hamsters and homogenized. ATPase activity was measured by the production of Pi at 37 degrees. HX/XO and AA were added at a final concentration of 9.6 X 10(-5) M HX with 5 X 10(-2) units HX and 5 X 10(-5) M AA with and without 1 X 10(-4) M ouabain. HX/XO produced a 24.7% inhibition alone and 35.0% when combined with ouabain. Ouabain alone produced a 7.1% inhibition. AA produced a 23.6% inhibition alone and 24.3% inhibition when combined with ouabain. Ouabain alone produced a 5.4% inhibition in this series. When AA was added in doses ranging from 1 X 10(-5) to 2 X 10(-3) M, a plot of percent inhibition versus log dose followed a typical sigmoid type curve. The IC50 was 1.5 X 10(-4) M. These results suggest that free-radicals are capable of inhibiting the ATPase found in the hamster cheek pouch tissues. The possible modes of action of the free-radicals in producing this inhibition are discussed.

The cardiovascular changes induced by 15% total body surface area third-degree burn have been studied in anesthetized dogs. The responses observed were a decrease in plasma volume, a decrease in cardiac output, and a slight but insignificant fall in mean arterial pressure. Graded doses of reserpine ranging from 0.1 to 1.0 mg/kg were administered preceding thermal trauma, and produced a reduction in plasma volume loss. The most effective dose of reserpine was 0.2 mg/kg. Despite the significant reduction (approximately 50%) of plasma volume loss in this dosage group, there were no significant alterations in either cardiac output or mean arterial pressure. These results demonstrate that reserpine is effective in reducing plasma volume loss but ineffective in altering the other cardiovascular parameters observed. Based upon the size of the maximally effective dose in reducing plasma volume loss and the failure of this dose to alter the other cardiovascular responses, it is postulated that the plasma loss reduction may be due to some action of reserpine other than its release of catecholamines and reduction in catecholamine stores.

The benefits of dopamine resuscitation in neonatal shock are in doubt. To evaluate dopamine's effectiveness on regional perfusion and survival, neonatal pigs were subjected to fecal Escherichia coli peritonitis-induced septic shock and were randomly divided into equal groups. Control animals (Group I) were not resuscitated with dopamine. Dopamine resuscitation, as a continuous infusion of 5 micrograms/kg/min (Group II), 50 micrograms/kg/min (Group III), or 200 micrograms/kg/min (Group IV), began when cardiac output dropped 20% below baseline. Radiolabeled microspheres were used to assess regional perfusion. Survival was defined as no hemodynamic compromise at 24 hr. Increased survival time correlated with sustained increases in cardiac output and blood pressure in Group III, which were not observed in the other groups. Significant changes in multiorgan regional perfusion were also observed in Group III and correlate with the improved survival. These data suggest that higher than usual doses of dopamine may be beneficial in neonates with peritonitis-induced septic shock.

The effects of single and multiple doses of indomethacin and multiple doses of nicotinic acid upon Escherichia coli endotoxin shock were studied in mongrel dogs anesthetized with sodium pentobarbital. Survival, cardiac output, plasma volume loss, and mean arterial pressure were measured. Untreated animals did not survive the procedure; animals treated with either multiple doses of indomethacin or nicotinic acid did survive for 5 hours after endotoxin. Plasma volume losses of indomethacin and nicotinic acid treated animals were substantially less (p less than 0.05) than in untreated animals. Arterialpressures of indomethacin-treated animals were greater than that of either nicotinic acid treated or untreated animals. No differences in cardiac output were noted in surviving animals.

By means of direct arterial perfusion of the adrenal glands in the dog it has been shown that synthetic lysine vasopressin stimulates the secretion of hydrocortisone. This effect is not mediated via the adenohypophysis or any other organ but is rather the result of direct stimulation of the adrenal cortex by vasopressin itself.