Prolonged Hemorrhagic Hypotension Research Articles

Extremity trauma exacerbates acute kidney injury following prolonged hemorrhagic hypotension.

The incidence of and mortality due to acute kidney injury is high in patients with traumatic shock. However, it is unclear how hemorrhage and trauma synergistically affect renal function, especially when timely volume resuscitation is not available. We hypothesized that trauma impairs renal tolerance to prolonged hemorrhagic hypotension. Sprague-Dawley rats were randomized into six groups: control, extremity trauma (ET), hemorrhage at 70 mm Hg (70-H), hemorrhage at 55 mm Hg (55-H), ET + 70 mm Hg (70-ETH), and ET + 55 mm Hg (55-ETH). Animals were anesthetized, and ET was induced via soft tissue injury and closed fibula fracture. Hemorrhage was performed via catheters 5 minutes after ET with target mean arterial pressure (MAP) clamped at 70 mm Hg or 55 mm Hg for up to 3 hours. Blood and urine samples were collected to analyze plasma creatinine (Cr), Cr clearance (CCr), renal oxygen delivery (DO2), urinary albumin, and kidney injury molecule-1 (KIM-1). Extremity trauma alone did not alter renal hemodynamics, DO2, or function. In 70-H, CCr was increased following hemorrhage, while Cr, renal vascular resistance (RVR), KIM-1, and albumin levels remained unchanged. Compared with 70-H, ET + 70 mm Hg exhibited increases in Cr and RVR with decreases in CCr and DO2. In addition, ET decreased the blood volume loss required to maintain MAP = 70 mm Hg by approximately 50%. Hemorrhage at 55 mm Hg and ET + 55 mm Hg exhibited a marked and similar decrease in CCr and increases in RVR, Cr, KIM-1, and albumin. However, ET greatly decreased the blood volume loss required to maintain MAP at 55 mm Hg and led to 50% mortality. These results suggest that ET impairs renal and systemic tolerance to prolonged hemorrhagic hypotension. Thus, traumatic injury should be considered as a critical component of experimental studies investigating outcomes and treatment following hemorrhagic shock. This is an original article on basic science and does not require a level of evidence.

Microvascular hemoglobin oxygen saturation (SO 2 ) during prolonged hemorrhagic hypotension (HH)

Since skeletal muscle represents up to 40% of body mass and suffers severe reductions in blood flow during HH, we examined the microcirculatory consequences of prolonged hypotension due to hemorrhage in the rat spinotrapezius muscle. An aortic transducer was implanted for continuous measurement of cardiac output. Systemic hemodynamic and respiratory variables were measured 7 days after the implantation. Functional capillary density, microvascular diameter, arteriolar SO2 and hemoglobin concentration ([Hb]) were measured using intravital microscopy. Measurements were made before and up to 4 h after HH. Additional bleeding or lactated Ringer's infusion were used to maintain mean arterial pressure at 40 mmHg. Controls were subjected to the same procedures except HH. Fifty-three percent of rats survived ≥ 3 h (S); others were considered nonsurvivors (NS). There was a positive correlation (r= 0.83, p ≤ 0.05) between microvascular SO2 and respiratory rate in S. Significant differences between S and NS were obtained for arteriolar SO2 (lower in S, p ≤ 0.05). Microvascular [Hb] was correlated with the systemic [Hb] (r= 0.93, p ≤ 0.001). Small arterioles constricted more in S than in NS, while large arterioles dilated in S. The diameter findings may explain why S showed higher total peripheral resistance levels for a longer period of time during HH. Our findings suggest that respiratory compensations and microvascular changes are essential for survival of prolonged HH. Support: DOD and NIH HL079087.

Continuous peripheral resistance measurement during hemorrhagic hypotension.

We tested the hypotheses that continuous total peripheral resistance (TPR) measurements are superior to intermittent data collection and that variables related to TPR can be used to distinguish between survivors and nonsurvivors (NS), respectively, of prolonged hemorrhagic hypotension (HH). One week after a transit-time ultrasound probe was implanted on their ascending aortas, 21 rats were subjected to 4 h of HH at 40 mmHg. Measurements were made before and up to 4 h after initiation of HH. Additional bleeding or Ringer L-lactate (RL) infusion was used to maintain HH. TPR was continuously measured online using recordings of blood flow and arterial pressure. Approximately 67% of the rats survived > or =3 h; others were considered NS. Data collected at 30-min intervals failed to detect the maximum value of TPR (TPRmax). The times to reach TPRmax were similar for survivors and NS and were strongly correlated with the bleeding end points and with the RL infusion-onset times. However, survivors showed higher TPRmax values than NS (P <0.005) and had a significantly longer period than NS during which TPR was above baseline level (116 +/- 20 vs. 51 +/- 10 min). In conclusion, 1) the transit-time ultrasound technique at high sampling rate allowed continuous and accurate real-time monitoring of TPR, 2) the bleeding end point and RL infusion-onset times may be used as surrogates of the time to TPRmax, 3) TPRmax of survivors and NS could be detected only using a continuous TPR measurement, and 4) differences between survivors and NS could be revealed by the continuous TPR curve.

Systemic responses to prolonged hemorrhagic hypotension.

Studies are needed to provide a rigorous examination of the relevance of monitored variables during prolonged hemorrhagic hypotension (HH). This study was designed to investigate the parameters that describe biochemical and O2 transport patterns in animals subjected to HH. Systemic parameters that could differentiate survivors from nonsurvivors were identified. An aortic flow probe was implanted in rats (n = 21) for continuous measurement of cardiac output. Experiments were performed 6-9 days after surgery. Rats were bled to a mean arterial pressure of 40 mmHg and kept at that level using Ringer-lactate solution. Arterial and venous blood pressures, gases, acid-base status, glucose, lactate, electrolytes, hemoglobin, O2 saturation, heart and respiratory rates, total peripheral resistance, and O2 delivery and consumption were measured before hemorrhage, soon after 40 mmHg was reached, and 0.5, 1, 2, 3, and 4 h later. Fifty-three percent of rats survived > or =3 h (survivors); others were considered nonsurvivors. Nonsurvivors showed a significantly greater degree of metabolic acidosis than survivors. Arterial PO2, respiratory rate, O2 saturation, O2 content, glucose, and pH were significantly higher in survivors. The rate of Ringer-lactate infusion, arterial K+, and PCO2 were lower in survivors. Arterial K+ and respiratory rate were the only parameters significantly different between survivors and nonsurvivors at all time points during HH. Arterial levels of K+ showed the clearest distinction between survivors and nonsurvivors and may explain the sudden death experienced by animals during HH. The data suggest that early respiratory and metabolic compensations are essential for survival of prolonged HH.

Arginine Vasotocin Gene Expression and Secretion during Osmotic Stimulation and Hemorrhagic Hypotension in Hens

In chickens, hyperosmolality stimulates the secretion of vasotocin (AVT) and up-regulates hypothalamic AVT gene expression. Hemorrhage, on the other hand, has not been considered an effective stimulus for AVT release in this species. The effects of acute osmotic stress and prolonged hemorrhagic hypotension on AVT gene expression and secretion were studied in White Leghorn hens. Conscious hens were osmotically stimulated by administering a single ip injection of 3MNaCl (5 ml/kg). Urethane-anesthetized hens were bled to a mean arterial pressure of 80–90 mm Hg and the pressure was maintained within this range by additional bleeding. A total of about 30% of the estimated blood volume was removed. Both experiments were terminated after 1 hr of stimulation. Plasma AVT levels in the hyperosmotic and hypovolemic hens were 4- and 2-fold higher, respectively, compared to controls. Hypothalamic AVT mRNA levels, detected by Northern blot analysis, were 2.5- and 2-fold higher in the osmotically stimulated and hypotensive groups, respectively, compared to control groups. As determined byin situhybridization, both osmotic stimulation and hypovolemia resulted in an increase in the number of AVT mRNA-containing neurons in the supraoptic and paraventricular nuclei. Our results indicate that, under the conditions used, hypotension and hyperosmolality are equally effective in stimulating AVT gene expression and secretion of AVT.

Changes in tissue blood flow and sympathetic activities to various organs during prolonged hemorrhagic hypotension in monkeys

This experiment was designed to determine whether prolonged hemorrhagic hypotension in anesthetized monkeys produces differential control of tissue blood flow and sympathetic nerve activities to various organs (heart, kidney, liver, spleen, and hind-limb). We performed simultaneous multifiber recording of sympathetic nerve activity to the kidney (RNA), heart (CNA), spleen (SpNA), liver (HNA), and hind-limb (LNA) during sustained hemorrhagic hypotension at a mean blood pressure of 40 mmHg for 2 h. Immediately after bleeding, all of the sympathetic nerve activities increased significantly (Stage I) and then gradually decreased towards the prebleeding levels (Stage II). Thereafter, the secondary sympathetic excitation was observed (Stage III), followed by a gradual decrease in sympathetic activities below the prebleeding levels (Stage IV). The shed blood started to return to the animals at this final stage. Time course of changes in sympathetic nerve activities did not differ among organs innervated. However, tissue blood flow of the renal cortex, liver, skeletal muscle and spleen significantly decreased at Stage I and remained at low levels until the end of the experimental period. In contrast, blood flow of the renal medulla and heart was preserved until Stage III and Stage IV, respectively. These results indicate that although the sympathetic response to prolonged hemorrhagic hypotension of 40 mmHg did not differ among organs, changes in tissue blood flow were variable and blood flow to the heart and renal medulla was maintained at a steady level until a late stage of hemorrhage.

Role of central nervous system in renal nerve activity during prolonged hemorrhagic shock in dogs.

The contribution of sympathetic efferent outflow through the central nervous system (CNS) during prolonged hemorrhagic hypotension of 50 mmHg was examined in anesthetized dogs. Mean blood pressure, heart rate, and renal nerve activity (RNA) were recorded simultaneously after arterial bleeding for 2 h. In animals with an intact neuraxis, hemorrhage to approximately 50 mmHg increased RNA to 180 +/- 12% of control level at 5 min after bleeding, but returned close to control level after 10 min. A secondary increase in RNA followed, with its maximum (280 +/- 12%) at 30 min after bleeding. Then RNA gradually decreased so that at end of experiment (120 min after bleeding) RNA was 10 +/- 9% of control. The initial increase in RNA was abolished by denervation of afferents from carotid sinus and cardiopulmonary regions, but secondary RNA response during hemorrhagic hypotension was similar to that in the intact group and occurred when the head region of animals was exposed to a hypotension of 50 mmHg, and perfusion to peripheral regions of the body was maintained near normal range. However, when perfusion to the head was maintained at a steady level and peripheral regions were exposed to hypotension of 50 mmHg, RNA response did not change significantly. These results provide evidence that prolonged hemorrhagic hypotension, which induces severe brain ischemia, causes biphasic sympathetic outflow via the CNS. The increase in sympathetic activity was followed by decrease with time. This decrease may contribute to the pathogenesis of vasomotor paralysis occurring at the irreversible stage of hemorrhagic shock.

Hemodynamics of hemorrhage in the conscious rat and chicken

Hemodynamic responses to hemorrhage in conscious chicks (n = 10, 233 g) and rats (n = 10, 309 g) were compared. The animals were fitted with miniature pulsed Doppler aortic flow probes 2 days (chickens) or 5 days (rats) before catheterization, and the experiment began 1 (chickens) or 2 (rats) days later. Mean arterial pressure (MAP) and cardiac output (CO) were recorded continuously and simultaneously digitized to compute total peripheral resistance (TPR). MAP, CO, and TPR values were graphed on-line by a microcomputer and stored for later analysis. A 4-ml hemorrhage reduced MAP and CO by 25 and 43% in the rat, and 15 and 4% in the chickens, respectively. The fall in CO in the rat was due to reduction of stroke volume (SV) unlike the birds where SV was well maintained. TPR was elevated 65% in the rats and fell 13% in the chickens. The minimal fall in CO and SV in these conscious birds suggests that anesthetic agents used previously (i.e., urethane, paraldehyde, phenobarbital, and pentobarbital sodium) suppressed cardiac function. However, they do not account for the lack of a peripheral vascular response during hemorrhage. The chicken apparently maintains MAP by a volume regulating mechanism operating independently of peripheral vascular tone inasmuch as circulating fluid volume restitution is rapid and occurs without vasoconstriction. The rat maintains MAP through reflex cardiac and peripheral vascular responses which eventually may contribute to transvascular fluid loss and the ultimate collapse after prolonged hemorrhagic hypotension.

The Effect of Indomethacin, 6‐Hydroxydopamine, Saralasin, and Hemorrhage on Renal Hemodynamics

This report describes the response of the renal circulation to prolonged hemorrhagic hypotension and reinfusion of blood, and to the effect of a variety of drugs (saralasin, indomethacin, and 6-hydroxydopamine, 6-OH-DA). Plastic microspheres were used to measure blood flow perfusing the entire kidney and also the outer cortex, inner cortex, and medulla of the kidney. Cardiac output was determined with a Doppler flow probe, and total and regional flows were calculated. Redistribution of blood flow from outer cortex to inner cortex and medulla occurred during hemorrhage and after administration of saralasin and 6-hydroxy-dopamine, while indomethacin did not alter intrarenal flow distribution. Total renal flow increased after reinfusion of blood and saralasin, but decreased after indomethacin. It did not change after 6-hydroxydopamine. The results demonstrate that changes in total and intrarenal flow occur independently and are probably due to different mechanisms.

Vascular capacitance and fluid shifts in dogs during prolonged hemorrhagic hypotension.

The mean circulatory pressure (Pmc) in dogs anesthetized with chloralose-urethane was estimated from 0.5 to 150 minutes after hemorrhages of 0, 17, or 34 ml/kg, or that volume giving an arterial pressure (Pa) of 40 mm Hg. The Pmc was determined by fibrillating the heart and then rapidly pumping blood from aorta to vena cava until Pa=venous pressure (Pv)=Pmc. Within about 10 seconds, the heart was defibrillated. Vascular compliance was estimated as the ratio of a test blood volume change (0, +/- 8.5, or 17 ml/kg) to the change in Pmc, determined 0.5 minute after the start of the test volume change. Erythrocyte and plasma volumes were measured by 51Cr-erythrocyte and 125I-albumin dilution. In response to prolonged hemorrhage: (1) the total vascular compliance apparently decreased; (2) most of the changes in capacity vessels occurred within 5 minutes, and indeed a large part of the response probably had occurred by the time of the first measurement at 30 seconds; (3) the progressive recovery in Pmc after 5 minutes was primarily from fluid shifting into the vasculature; (4) even after 2 hours of severe hemorrhagic hypotension, the venoconstriction was not lost; but (5) after an hour of severe hemorrhagic hypotension (arterial pressure of 40 mm Hg) there was water loss from the vasculature, because plasma protein and erythrocyte concentrations and plasma oncotic pressure increased.

Pulmonary blood- and extravascular water volumes during prolonged post-hemorrhagic systemic hypotension.

AbstractIn cats prolonged hemorrhagic hypotension had been shown to increase the pulmonary arterial pressure and vascular resistance. Pulmonary extravascular water volume and pulmonary blood volume have been evaluated early and late in such a period of post‐hemorrhagic hypotension. 51Cr‐labelled erythrocytes and 125I‐labelled albumin were injected intravascularly to animals with an opened chest and on positive pressure ventilation. One upper lung lobe was then suddenly clamped, removed and frozen. The lung lobe tissue and a simultaneously taken blood sample from a large vessel were measured for total w‐eight, dry weight and tracer content. The lobe's blood volume and extravascular water volume were then calculated per unit extravascular lung dry weight. A second lung lobe was removed and treated similarly at a later stage. 1 /2 h after the blood loss there was a marked reduction in lung blood volume and at the same time some increase in pulmonary extravascular water volume indicating constriction of postcapillary capacitance vessels. After 3 h of hypotension pulmonary extravascular water volume was found to be the same as before the hemorrhage although the pulmonary arterial pressure increased. This indicated that the increase in vascular resistance must predominantly be due to vasoconstriction at precapillary sites. The reduction in the lungs' blood volume remained at these late stages indicating that capacitance vessels were still constricted. When hyperinflations of the lungs were omitted in the experimental period, there was a tendency towards water accumulation in the lungs.

Influence of aortic constriction on the positive free-water clearance of primate hemorrhagic shock.

SummaryPositive free-water clearance, signifying production of hypotonic urine, is commonly observed in well-hydrated owl monkeys following transfusion of shed blood after prolonged hemorrhagic hypotension. This investigation has examined the nature of this derangement of the urinary concentrating mechanism by experimental reduction of glomerular filtration rate by partial aortic constriction during this phase of experimental shock, and in turn, diminution of solute and water load to the nephron. When the resulting reduced volume was delivered to the final concentrating segment, removal of only a small portion of the residual volume was necessary for the elaboration of a urine of higher solute concentration, approaching that of plasma, so that U/Posm which was well below 1.0 immediately after transfusion was restored close to unity.

Changes in forelimb weight and segmental vascular resistances following severe hemorrhage.

The forelimb was used to study capillary fluid fluxes following hemorrhage in dogs anesthetized with sodium pentobarbital. Arterial hemorrhage (48 ml/kg) and 4 hours of hypovolemia produced decreases in forelimb weight, arterial and venous pressures, and skin and skeletal muscle blood flows. Segmental resistances (large artery, small vessel, large vein) in both skin and skeletal muscle increased markedly, and the increase was either completely or largely maintained throughout the hypovolemic period. The large arteries and large veins constricted proportionately more than the small vessels following hemorrhage. In animals that survived the hypovolemic period, the large arteries and large veins constricted almost proportionately, whereas in the animals that died, the large veins constricted proportionately more than the large arteries. The weight loss exceeded forelimb vascular volume, indicating that net extravascular fluid reabsorption occurred. In fact, the weight loss from 60-240 minutes after hemorrhage began appears to be largely attributable to extravascular fluid reabsorption, since resistance and, inferentially, blood volume were relatively constant in the forelimb capacitance vessels. These data fail to support the hypothesis that fluid filtration is a determinant of irreversibility but rather suggest that the compensatory responses to blood loss in the forelimb, i.e., vasoconstriction and net extravascular fluid reabsorption, persist during severe prolonged hemorrhagic hypotension.

MYOCARDIAL NOREPINEPHRINE DEPLETION AND ITS RESYNTHESIS FROM DOPA DURING PROLONGED HEMORRHAGIC HYPOTENSION IN DOGS

During hemorrhagic hypotension in dogs, plasma catecholamine level was found to be elevated due to increased secretion of catecholamine from the sympathoadrenal system (1, 2). In rabbits, depletion of norepinephrine and increment of epinephrine in the left ventricle were observed after prolonged hemorrhagic hypotension, and the correlation of myocardial norepinephrine and cardiac performance was suggested (3). On the other hand, metabolic disturbances in shock state were also much discussed (4, 5). Therefore, it seems to be interesting to investigate how elevated plasma catecholamine changes myocardial catecholamine level, and whether prolonged hemorrhagic hypotension induces certain changes to the myocardial norepinephrine synthesis.

Use of levarterenol in treatment of irreversible hemorrhagic shock.

The effectiveness of levarterenol in the treatment of shock resulting from prolonged oligemia was studied in the dog. The survival time of animals receiving levarterenol and whole blood therapy was significantly greater than that of animals receiving a placebo and whole blood. The results of the experiments indicate that levarterenol is an effective adjunct to whole blood therapy in the treatment of shock resulting from prolonged hemorrhagic hypotension.

Dibenzyline protection against shock and preservation of hepatic ferritin systems.

Pretreatment with Dibenzyline, an adrenergic blocking agent, markedly increased the survival rate of normal, arenal or adrenalectomized rats subjected to drum trauma, and of normal rats subjected to prolonged hemorrhagic hypotension. In the latter a larger residual circulating blood volume was not responsible for the increased survival since average maximal blood loss was equal in treated and control rats. Congestion of the liver and gut, regularly seen in the controls, was notably absent in the Dibenzyline-protected rats. Direct microscopic observation of the terminal vascular bed in the mesoappendix, throughout the hemorrhagic procedure, revealed earlier appearance of decompensatory changes and increased vascular fragility in the controls. In livers removed at the end of the hemorrhagic and traumatic procedures, ferritin systems were preserved in treated rats, in contrast to their deterioration in controls. It is suggested that the protection conferred by pretreatment with Dibenzyline may not be due solely to its adrenergic blocking properties, but in part to a direct cellular action in the liver, exemplified by its in vitro protection of the ferritin systems against hypoxic damage.

Right and left atrial pressures in successive stages of oligemic and normovolemic shock.

Summary and Conclusions1. Simultaneous changes in right and left atrial pressures together with aortic pressure pulses were successfully recorded through the experiments in 6 out of 16 dogs which were submitted to standardized procedures of bleeding and reinfusion developed in this laboratory. 2. An analysis of the results supports previous observations from this laboratory that myocardial depression can supervene during the circulatory failure which develops after prolonged hemorrhagic hypotension and subsequent reinfusion of the withdrawn blood. It extends these observations in showing that such myocardial failure may affect either the left or right ventricle dominantly.

Activity of ethyl-1-ethanesulfonyl-4-piperazine hydrochloride on traumatic hemorrhagic shock on the dog.

Researches, in recent years, on traumatic shock therapy, have led us to examine the effects of the following substances on shock induced in the rat by means of the drum technic (Noble and Collip), with polyvinylpyrrolidone (1), some simple aliphatic amides (2), and the protective effect exercised by a new synthetic compound, ethyl-1-ethanesul-fonyl-4-piperazine (3885 R.P.)(3).In previous experiments we tested the effect of ethyl-l-ethanesulfonyl-4-piperazine (3885 R.P.) on shock produced in the mouse, rat and guinea pig, then decided to carry out further experiments on the dog. We used the technic of Wiggers, Ingraham and Dilles(4) which produced an irreversible shock following a prolonged hemorrhagic hypotension period. The animals were treated as described by Wiggers, under morphine or chloralose anesthesia. By extensive bleeding the blood pressure was lowered to 40 mm of kg maintained for a given time by a series of successive hemorrhages and reinjections. A total reinjection of the removed blood immed...