Hemorrhage In Conscious Sheep Research Articles

Evaluation of heart rate and blood pressure variability as indicators of physiological compensation to hemorrhage before shock.

Individual responses to hemorrhage vary, with varying periods of compensation before the development of shock. We characterized heart rate and blood pressure variability measures during hemorrhage of 25 mL/kgBody Weight for 15 min in conscious sheep (N = 7, 14 total hemorrhages) as markers of the transition from compensated to decompensated shock using the continuous wavelet transform. Heart rate-low frequency (HR-LF) and systolic blood pressure-low frequency (SBP-LF) indices were developed to represent the change in spectral power during hemorrhage as low-frequency (0.06 - 0.15 Hz) power divided by the sum of high (0.15 - 1.0 Hz)- and very low (0.02 - 0.06 Hz) frequency power. Heart rate rose from 96.3 (22.2) beats/min (mean [SD] across all trials) to a peak of 176.0 (25.4) beats/min occurring at a minimum time of 5.3 min to a maximum of 22.1 min (11.7 [1.6] min), depending on the trial, after the start of hemorrhage. During the HR-compensated response to hemorrhage, there was elevated HR-LF and SBP-LF in five of the seven animals. In these animals, HR-LF and SBP-LF dropped to below baseline levels around the time of the peak HR. The results from this conscious-animal study suggest that HR and SBP low-frequency power rise during the compensation phase of the response to hemorrhage in conscious sheep. Use of variability monitoring could aid in describing an individual's current response to hemorrhage and anticipation of impending decompensation; however, individual differences in the response limit this potential.

Activation of central opioid receptors determines the timing of hypotension during acute hemorrhage-induced hypovolemia in conscious sheep

After an initial compensatory phase, hemorrhage reduces blood pressure due to a widespread reduction of sympathetic nerve activity (decompensatory phase). Here, we investigate the influence of intracerebroventricular naloxone (opioid-receptor antagonist) and morphine (opioid-receptor agonist) on the two phases of hemorrhage, central and peripheral hemodynamics, and release of vasopressin and renin in chronically instrumented conscious sheep. Adult ewes were bled (0.7 ml x kg(-1) x min(-1)) from a jugular vein until mean arterial blood pressure (MAP) reached 50 mmHg. Starting 30 min before and continuing until 60 min after hemorrhage, either artificial cerebrospinal fluid (aCSF), naloxone, or morphine was infused intracerebroventricularly. Naloxone (200 microg/min but not 20 or 2.0 microg/min) significantly increased the hemorrhage volume compared with aCSF (19.5 +/- 3.2 vs. 13.9 +/- 1.1 ml/kg). Naloxone also increased heart rate and cardiac index. Morphine (2.0 microg/min) increased femoral blood flow and decreased hemorrhage volume needed to reduce MAP to 50 mmHg (8.9 +/- 1.5 vs. 13.9 +/- 1.1 ml/kg). The effects of morphine were abolished by naloxone at 20 microg/min. It is concluded that the commencement of the decompensatory phase of hemorrhage in conscious sheep involves endogenous activation of central opioid receptors. The effective dose of morphine most likely activated mu-opioid receptors, but they appear not to have been responsible for initiating decompensation as 1) naloxone only inhibited an endogenous mechanism at a dose much higher than the effective dose of morphine, and 2) the effects of morphine were blocked by a dose of naloxone, which, by itself, did not delay the decompensatory phase.

Central C-type natriuretic peptide augments the hormone response to hemorrhage in conscious sheep.

The effect of intracerebroventricular infusions of C-type natriuretic peptide (CNP-22, 5 micrograms/h for 3 h) or vehicle on the neurohumoral response of conscious sheep (n = 7) to acute moderate hemorrhage (15 ml/kg in 15 min performed 1 h after start of CNP) was studied. CNP alone (prehemorrhage) induced a transient rise (after 30 min) in heart rate (p = 0.0005), plasma aldosterone (p = 0.007), ACTH (p = 0.049), and cortisol (p = 0.049), with values returning to control levels immediately prehemorrhage. Hemorrhage caused arterial pressure to fall (15 mmHg) and heart rate to rise similarly on both study days. Compared with vehicle, posthemorrhage responses of AVP (p = 0.05) and cortisol (p = 0.004) were greater during CNP. Thus, central CNP-22 augmented the hypothalamic-pituitary-adrenal axis at baseline and in response to hemorrhage in conscious sheep.

Haemodynamic responses to hypotensive haemorrhage in conscious sheep with emphasis on renal and femoral blood flow

Haemodynamic responses to slow (0.7 ml kg-1 min-1) haemorrhage were investigated in eight adult conscious sheep, fitted with permanent ultrasonic flow probes around the renal and femoral artery. The haemorrhage was continued until the mean systemic arterial pressure (MSAP) suddenly dropped to about 50 mmHg. The spontaneous recovery was followed for 60 min and then the blood was retransfused. A distinct fall in MSAP was obtained after 14.5 +/- 0.9 ml blood (kg body weight)-1 (24% of the estimated blood volume) had been removed, but the interindividual differences were rather large (range, 10.2-18.1 ml kg-1). Therefore, the haemodynamic responses during haemorrhage were related to the total bleeding volume and not to time or volume per kilogram body weight. Before 90% of the total haemorrhage volume had been removed, the MSAP decreased gradually, reaching statistical significance at 80% (P < 0.05). At end of bleeding the cardiac output (CO) had fallen from a pre-haemorrhage level of 4.7 +/- 0.2 to 2.9 +/- 0.2 1 min-1. Although the femoral blood flow (FBF) was largely unaffected by the haemorrhage, and thus increased as a fraction of CO, the total systemic vascular resistance was markedly increased during the post-haemorrhage period, indicating a longer lasting elevation of vascular resistance in other vascular beds. In spite of a concomitant marginal decrease in renal blood flow (RBF), the renal vascular resistance (RVR) was unchanged until 90% total haemorrhage had occurred. At the same time as blood pressure fell, RBF decreased markedly, concomitant with a transient increase in RVR, which was followed by a decrease towards basal levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Inefficiency of intracerebroventricular ANP to alter haemodynamic, plasma vasopressin and renin responses to haemorrhage in sheep.

Whether intracerebroventricular (i.c.v.) infusion of atrial natriuretic peptide (human-ANP, 1-28) 25 pmol min-1 influences the tolerance to blood loss and haemorrhage induced cardiovascular, vasopressin and renin responses were studied in five conscious sheep. The i.c.v. infusion was started 60 min prior to a slow (0.7 ml kg-1 min-1) venous haemorrhage, was run concurrently with bleeding, and for 90 min thereafter. Venous blood was removed until the mean systemic arterial pressure suddenly fell to about 50 mmHg. There were no statistically significant differences in either the bleeding volume necessary to induce the sudden decrease in blood pressure, or in cardiovascular parameters measured by venous heart thermodilution catheterization, compared with control experiments with i.c.v. infusion of artificial CSF. The plasma protein and vasopressin concentrations and renin activity were unaffected by the i.c.v. infusion of ANP as were the changes in these parameters occurring during the subsequent haemorrhage. The same negative findings were obtained with a three times higher dose of ANP(1-28) (75 pmol min-1), tested in three of the animals. Thus the i.c.v. infusion of ANP(1-28), in amounts expected to elevate the CSF concentration far above basal levels does apparently not influence normal blood pressure regulation or alter haemodynamic, vasopressin and renin responses to haemorrhage in conscious sheep.

Effects of reduced CSF Na concentration and osmolality on haemodynamic and humoral responses to hypotensive haemorrhage in conscious sheep

The effects of iso- and hypo-osmotic reduction of the CSF [Na+] on the tolerance to blood loss and concomitant cardiovascular and humoral responses were studied in conscious sheep. Animals only subjected to haemorrhage served as controls. The changes in CSF composition were induced by intracerebroventricular infusions of 0.3 M mannitol, respectively, 0.04 M NaCl. In the former instance the CSF [Na+] was reduced by 18 mM whereas a lowering by 13 mM concomitant with decreased CSF osmolality (mean change 25 mOsm kg-1) was seen in response to the NaCl solution. Apart from a slight lowering of the cardiac output during the infusion of 0.3 M mannitol preceding haemorrhage, the changes in CSF composition did not have any significant haemodynamic effects in the normovolaemic animal, or altered the cardiovascular responses to a subsequent hypotensive haemorrhage. The amount of blood needed to be withdrawn to obtain the predefined degree of hypotension did not differ significantly between treatment groups. The plasma vasopressin and angiotensin II concentrations were consistently increased by the hypotensive haemorrhage, but the magnitude of the vasopressin response was significantly reduced when the CSF [Na+] was lowered. We conclude that lowered CSF [Na+] and/or osmolality, in contrast to increased CSF [Na+], does not influence the tolerance to blood loss or the accompanying haemodynamic changes in sheep, in spite of an attenuated vasopressin response.

Tolerance to haemorrhage during vasopressin antagonism and/or captopril treatment in conscious sheep

The effect of separate and combined blockade of vasopressin (AVP) V1-receptors and angiotensin II formation on resistance to a slow venous haemorrhage (0.7 ml kg-1 min-1) was studied in six conscious adult sheep by bleeding to the point of an abrupt fall in the mean systemic arterial pressure (MSAP). Intravenous administration of the V1-receptor antagonist [d(CH2)5Tyr(Me)AVP] (10 micrograms kg-1) and/or the angiotensin I converting enzyme inhibitor captopril (20 mg + 1 mg h-1) did not cause any significant haemodynamic changes in the normovolaemic animal. The volume of haemorrhage necessary to induce acute hypotension (MSAP < 50 mmHg) was significantly smaller after AVP blockade alone (13.8 +/- 0.7 ml kg-1; P < 0.01) but not after captopril treatment (14.7 +/- 1.6 ml kg-1; n.s.) compared to control animals receiving no drug treatment (16.8 +/- 0.6 ml kg-1). The combined treatment with the AVP antagonist and captopril caused a further decrease in tolerance to haemorrhage (9.4 +/- 1.2 ml kg-1; P < 0.001). Blockade of AVP V1-receptors was associated with an attenuated increase in systemic vascular resistance immediately after the end of haemorrhage, concomitant with an accentuated lowering of the central venous pressure. In contrast, captopril treatment decreased the degree of vasoconstriction mainly during the second half of the posthaemorrhage observation period of 1 hour. It is concluded that both AVP and angiotensin II contribute to the maintenance of the MSAP during haemorrhage in conscious sheep.(ABSTRACT TRUNCATED AT 250 WORDS)

Haemodynamic and humoral responses to repeated hypotensive haemorrhage in conscious sheep

Haemodynamic and humoral responses to two subsequent hypotensive haemorrhages, separated by 3 hours and each followed by retransfusion, were studied in unanaesthetized sheep. Haemorrhage was induced by removal of blood from a jugular vein at a rate of 0.7 ml kg-1 min-1 until the mean systemic arterial pressure suddenly decreased by 35 mmHg or more. In addition to the mean systemic arterial pressure, the cardiac output, the mean pulmonary arterial pressure, the central venous pressure and the pulmonary capillary wedge pressure decreased in response to each haemorrhage. The recovery of the systemic and pulmonary arterial pressure was slower and/or less efficient after the second haemorrhage, due to a less pronounced increase of the vascular resistance. Relative bradycardia, in association with the abrupt fall of the mean systemic arterial pressure, was more apparent during the first haemorrhage. The plasma levels of vasopressin, renin activity and angiotensin II were increased by each blood removal, but the vasopressin response to the second haemorrhage was significantly reduced. The plasma noradrenaline concentration was slightly and transiently elevated only in response to the second haemorrhage. The concentration of neuropeptide Y-like immunoreactivity in plasma was unaffected by both haemorrhages. It is suggested that the reduced and delayed increase in the systemic vascular resistance, accompanied by impaired recovery of the arterial pressure, and the relative absence of 'bleeding bradycardia', during the second haemorrhage, were due to the diminished vasopressin response.

Intracerebroventricular Atrial Natriuretic Peptide Infusion Augments the Adrenocorticotropin and Angiotensin II Responses to Hemorrhage in Sheep

The central actions of atrial natriuretic peptide (ANP) in rats include inhibition of arginine vasopressin (AVP) release, and less consistently, ACTH suppression and hypotension. To explore any such inhibitory actions on basal and stimulated levels of AVP and ACTH, we have studied the effect of intracerebroventricular (ICV) infusion of ANP on the hemodynamic and hormonal response to acute hemorrhage in conscious sheep. Two groups of 5 sheep received rat ANP(101-126) by ICV infusion (0.5 microgram bolus followed by 0.5 microgram/h for 3 h, or 5 micrograms bolus followed by 5 micrograms/h for 3 h) as well as artificial cerebrospinal fluid control infusions in random order. One hour after the start of the ICV infusion, acute hemorrhage (15 ml/kg BW within 10 min) was performed. Basal levels before hemorrhage of mean arterial pressure (MAP), heart rate and plasma hormones were unaltered by either dose of ICV ANP. After hemorrhage, the fall in MAP and rise in heart rate were similar in each group. However, compared to control infusions the response to hemorrhage of ACTH (433 +/- 147 to 2,175 +/- 588 vs. control 541 +/- 103 to 893 +/- 244 ng/l; p less than 0.016) and angiotensin II (AII) (18 +/- 3 to 94 +/- 23 vs. control 18 +/- 4 to 58 +/- 8 pmol/l; p less than 0.001) were significantly greater during high-dose ANP infusion. Although peak AVP levels more than doubled those observed on the control day, the increase did not reach statistical significance (p less than 0.1053). Plasma concentration of cortisol, aldosterone, epinephrine and norepinephrine were not significantly different in control and ANP-treated groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Hormone and hemodynamic responses to atrial natriuretic peptide in conscious sheep and effect of hemorrhage.

The effect of rat atrial natriuretic peptide (ANP) on basal hemodynamic and hormonal function and on the response to acute hemorrhage was studied in eight conscious sheep. ANP infusions (3 micrograms/kg BW bolus, followed by 50 ng/kg.min for 70 min) increased plasma immunoreactive ANP levels from less than 12 pmol/liter to steady state levels of 523 +/- 20 pmol/liter, reduced arterial pressure by 14% (P less than 0.002), increased heart rate by 26% (P less than 0.06), and increased plasma norepinephrine levels (P less than 0.015) compared to control values. These changes were associated with a significant increase in plasma cortisol (P less than 0.05) and smaller increases in plasma ACTH and arginine vasopressin (AVP), but plasma angiotensin II (AII) and aldosterone were unaffected. When hemorrhage (15 ml/kg BW over 10 min) was performed during ANP or control infusions, hypotension was greater (P less than 0.0004) during ANP treatment and the responses of plasma ACTH, AVP, catecholamines, and AII were enhanced compared with those to control hemorrhage. Plasma immunoreactive ANP during ANP infusions was significantly higher after hemorrhage (mean, 833 +/- 46; P less than 0.003), but the disappearance rate after the termination of ANP infusion was the same (3.1 min) with or without hemorrhage. These studies show that ANP infusions, achieving plasma levels observed in pathological states such as congestive heart failure, inhibit the expected responses of plasma AII and aldosterone to mild acute hypotension, but do not inhibit the responses of plasma AVP, ACTH, AII, and aldosterone associated with acute moderate hemorrhage in conscious sheep.

Somatostatin centrally inhibits vasopressin secretion during haemorrhage

Somatostatin is a hypothalamic inhibiting factor which has been reported to be involved in the regulation of the secretion of several anterior pituitary hormones. To determine if somatostatin plays a role in the control of vasopressin secretion from the posterior pituitary, we examined the effects of intracerebroventricular infusion of somatostatin-14 and a super-active analogue, cyclo-(N-Me-Ala-Tyr- d-Trp-Lys-Val-Phe) on the concentration of plasma vasopressin in response to haemorrhage in conscious sheep. Haemorrhage (15 ml/kg over 15 min) elevated plasma vasopressin. Treatment with either somatostatin-14 or the analogue inhibited the elevation of plasma vasopressin induced by haemorrhage. The inhibition may result from an effect of somatostatin on neurotransmitter afferent inputs to the hypothalamus which trigger vasopressin release during haemorrhage. Our study demonstrates for the first time that somatostatin administered centrally inhibits vasopressin secretion during haemorrhage in the conscious animal.

Effect of central naloxone on hormone and blood pressure responses to hemorrhage in conscious sheep

The role of the brain opioid system in the control of hypothalamic-pituitary-adrenal activity was studied in 10 conscious sheep with an indwelling cannula in a cerebral lateral ventricle. On separate days, sheep received infusions of artificial CSF (control) and the opiate antagonist, naloxone (100 μg/hr) before and during acute moderate hemorrhage (15 ml/kg over 10 min). Infusion of naloxone before hemorrhage raised plasma ACTH and resulted in a significant increase in cortisol responses to hemorrhage control infusion. In contrast, ACTH and cortisol responses to hemorrhage tended to be blunted by central naloxone infusion. The responses of vasopressin, aldosterone and the catecholamines remained unaffected by naloxone. The fall in blood pressure and the rise in heart rate accompanying hemorrhage were likewise unaltered. These results suggest that brain opioid peptides have an inhibitory effect on basal ACTH secretion but do not play a major role in modulating the hemodynamic or pituitary-adrenal responses to acute moderate hemorrhage in conscious sheep. Numerous studies have established that the brain opioid system is activated by a variety of acute stressors, including hemorrhage (1) and other forms of shock and trauma (2, 3). These same stresses are potent stimuli to ACTH secretion. Several lines of evidence indicate that enkephalins and endorphins may participate directly in the regulation of ACTH secretion. The enkephalin agonist, DAMME, inhibits ACTH in sheep (4) and humans (5), opioid peptides suppress corticotropin-releasing factor (CRF) in vitro (6), and the opiate antagonist naloxone enhances ACTH secretion (7), including the ACTH response to exogenous CRF (8). These findings suggest that the brain opioid system may act to restrain both CRF release and ACTH responsiveness during acute stress. Using conscious sheep with indwelling cannulae in a lateral ventricle, we have examined the effect of central naloxone on the ACTH and neuroendocrine response to acute moderate hemorrhage. Since cardio-depressant effects of brain opioid activation also occur during hemorrhage (2, 9) apparently contributing to the shock syndrome, the hemodynamic response to acute, moderate hemorrhage during central administration of naloxone was also studied.

Intracerebroventricular infusion of a cyclic hexapeptide analogue of somatostatin inhibits hemorrhage-induced ACTH release.

This study examines the effect of intracerebroventricular infusion of the 'superactive' somatostatin (SRIF) analogue cycl--(N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe) on the plasma adrenocorticotrophic hormone (ACTH) response to hemorrhage in conscious sheep. Hemorrhage (15 ml/kg over 15 min) increased plasma ACTH from 55 +/- 20 to 815 +/- 148 pg/ml at 30 min (p less than 0.001). Infusion of the SRIF analogue intracerebroventricularly at 0.08 microgram/min for 10 min prior to and for 60 min after commencement of hemorrhage resulted in a partial inhibition of the plasma ACTH response. Infusion of the analogue at 0.8 microgram/min blocked the increase in plasma ACTH at 30 min. Plasma ACTH was 21 +/- 3 pg/ml as control and 66 +/- 47 pg/ml at 30 min. The SRIF analogue had no effect on plasma ACTH in the same animals in control experiments with no hemorrhage. These studies suggest that SRIF may act as a central inhibitor of ACTH release. The mechanism by which the SRIF analogue inhibits ACTH secretion is unknown but could involve inhibition of corticotropin-releasing factor release and/or an inhibition of ACTH release from the pituitary gland. The route of administration of the SRIF analogue and the finding that the SRIF analogue did not prevent systemic corticotropin-releasing factor stimulation of ACTH suggest an effect of the SRIF analogue in the hypothalamus.