Progression Of Hemorrhagic Shock Research Articles

Patterns of Microvascular Response to Refractory Shock and Their Modulation by Vasoactive Resuscitations

Objective: Progressive hemorrhagic shock (HS) causes splanchnic vasoconstriction and hypo-perfusion together with profound depletions of cellular cytosolic energy phosphates (ATP). Cellular energy failure and the splanchnic hypo-perfusion are critical to the pathogenesis of shock decompensation and the subsequent death from cardiocirculatory arrest. We recently demonstrated post-resuscitation survival benefit for cellular cytosolic ATP replenishment but not for vasopressors use in a rat model of refractory HS. The aim of this study was to determine the effects of progressive HS on the splanchnic microvasculature, and to compare the effects of adjuvant resuscitations with either norepinephrine, vasopressin or lipid vesicles encapsulating ATP (ATPv) on this microvasculature. Methods: 40-male Sprague-Dawley rats were randomized into 4 groups of 10 each: HS/conventionalresuscitation (CR), HS/CR+Norepinephrine, HS/CR+Vasopressin, and HS/CR+ATPv. HS=initial removal of 30% of the calculated blood volume plus subsequent transection of the spleen for uncontrolled haemorrhage until a predefined intervention set-point was achieved; CR=shed blood returned+double the shed blood volume as lactated Ringer’s solution. Four-level intestinal microvascular A1 through A4 arterioles (100–8 μm diameter) in the terminalileum were continuously monitored with intravital-microscopy, and their diameters were measured at baseline, during shock, after completion of resuscitation, and during a 2 h post-resuscitation observation period. In addition, we recorded measurements of the mean arterial pressure, shock index, blood-gas profiles, and complete metabolic panels. Results: Progressive HS caused bimodal arteriole responses with progressive vasoconstriction from baseline of first-order A1 and second-order A2 (-22.1 ± 1.9%), a progressive vasodilation of the third-order A3 and fourth-order A4 arterioles (+22.2 ± 2.8%). Resuscitation initially restored A1 and A2 diameters to near baseline. This was followed by post-resuscitation A1 and A2 vasoconstriction in all groups, except the ATPv group (-8.1 ± 3.4%). The hemorrhage-induced vasodilation of the A3 and A4 arterioles was maintained during the post-resuscitation observation period in the CR (+55.3 ± 6.4%) and the ATPv groups (+39.5 ± 5.2%), but remarkably attenuated in the norepinephrine (+9.6 ± 5.8%) and vasopressin (+9.4 ± 8.8) groups. Conclusions: Severe hemorrhagic shock causes specific splanchnic microvascular bimodal response that is dependent on arteriolar level. First-order A1 and second-order A2 arterioles exhibit progressive vasoconstriction, whereas, third-order A3 and fourth-order A4 arterioles show progressive vasodilation. Temporary administration of either norepinephrine or vasopressin along with conventional resuscitation exerted deleterious effects at all splanchnic microvascular levels by virtue of their peripheral vascular actions. The cellular cytosolic ATP replenishment maintained a better microvascular profile when compared with the two vasopressors.

Nitric Oxide Regulates The Lymphatic Reactivity Following Hemorrhagic Shock Through Atp-Sensitive Potassium Channel.

Lymphatic reactivity has been shown to exhibit a biphasic change following hemorrhagic shock, and nitric oxide (NO) is involved in this process. However, the precise mechanism responsible for NO regulation of the lymphatic reactivity along with the progression of hemorrhagic shock is unclear. Therefore, the present study was to investigate how NO participates in regulating the shock-induced biphasic changes in lymphatic reactivity and its underlying mechanisms. First, the expressions or contents of inducible NO synthase, nitrite plus nitrate, and elements of cAMP-PKA-KATP and cGMP-PKG-KATP pathway in thoracic ducts tissue were assessed. The results revealed that levels of nitrite plus nitrate, cAMP, cyclic guanosine monophosphate (cGMP), p-PKA, and p-PKG were increased gradually along with the process of shock. Second, the roles of cAMP-PKA-KATP and cGMP-PKG-KATP in NO regulating lymphatic response to gradient substance P were evaluated with an isolated lymphatic perfusion system. The results showed that the NOS substrate (L-Arg), PKA donor (8-Br-cAMP) decreased the reactivity of shock 0.5 h-lymphatics, and that the PKA inhibitor (H-89) and KATP inhibitor (glibenclamide) restrained the effects of L-Arg while glibenclamide abolished the effects of 8-Br-cAMP. Meanwhile, NOS antagonist (L-NAME), protein kinase G (PKG) inhibitor (KT-5823), and soluble guanylate cyclase inhibitor (ODQ) increased the reactivity of shock 2 h-lymphatics, whereas KATP opener (pinacidil) inhibited these elevated effects induced by either L-NAME, ODQ, or KT-5823. Taken together, these results indicate that NO regulation of lymphatic reactivity during shock involves both cAMP-PKA-KATP and cGMP-PKG-KATP pathways. These findings have potential significance for the treatment of hemorrhagic shock through regulating lymphatic reactivity.

Shock index: blunt clinical predictions

We appreciate the work of Mutschler and colleagues regarding shock index (SI) in trauma patients [1]; however, we would like to discuss a few points of interest. The SI obtained at the scene differed from the SI obtained in the emergency department (ED). Patients with SI category III had a SI at the scene of 0.7 to 1.5. This indicates that SI can vary with time and vary with changes in medical condition. Patients classified as ‘no shock’ still had a 10.9% mortality rate, a 12.5% risk of multi-organ failure, and a 6.3% risk of sepsis. We do not know when the onset of sepsis occurred in these trauma patients. Thus, a single SI taken within ‘the first hours’ of ED admission might not accurately reflect a patient’s condition, especially if the initial SI is category I or II. Other studies have shown that SI may also lead to an undertriage of those patients most likely to develop early and progressive hemorrhagic shock [2]. In addition, prehospital SI alone was found to have diminished accuracy for patients aged over 60 years [3]. SI may be of limited value in the assessment of systemic oxygen transport [4], which is a more direct measurement of end-organ perfusion and tissue viability than the SI. Finally, the results of this study can best be applied to male patients with blunt trauma injuries who develop hypovolemic shock, but not to every trauma patient on presentation to ED with high risk of other types of shock.

Ethanol consumption impairs the hemodynamic response to hemorrhagic shock in rats

Alcohol intoxication can exacerbate hemodynamic instability following hemorrhagic shock. Impairment of hormonal, neurohumoral, and immune responses can contribute to such instability; however, the relationship between blood alcohol levels and the progression of hemorrhagic shock accompanied with these responses has not been clearly demonstrated. Herein, we examined this relationship in rats treated with various dose of alcohol. After oral administration of alcohol and then hemorrhage, the recovery of mean blood pressure (MBP); increase in plasma level of norepinephrine, epinephrine, and vasopressin; and survival interval decreased in a dose-dependent manner as the blood alcohol level increased. There were no significant differences in the production of proinflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β among the groups. The present results demonstrated alcohol aggravates hemorrhagic shock in a dose-dependent manner not by alerting the immune response, but by suppressing hormonal and neurohumoral responses, thereby inhibiting hemodynamic autoregulation and shortening the survival interval.

A Quantitative Study of p38 Mitogen-Activated Protein Kinase on Renal Dysfunction After Hemorrhagic Shock in Rats

The severity of renal dysfunction correlates with fatal outcome after hemorrhagic shock. However, the precise mechanism for increasing renal dysfunction in response to the degree and the progression of hemorrhagic shock has not been clearly demonstrated. In this study, we examined the role of p38 mitogen-activated protein kinase (MAPK) activation on the progression of renal dysfunction by studying the differential severity of bleeding. Hemorrhagic shock was studied by quantitatively grading four groups of hemorrhaging rats: not hemorrhaged (Sham group); hemorrhaged up to 16.7% of their total body blood volume (16.7% group); hemorrhaged up to 25% (25% group); and hemorrhaged up to 33% (33% group). Mean arterial blood pressure and renal blood flow were recorded up to 5 hours after the bleeding. Kidneys were excised for assays of p38 MAPK and mRNA of the proinflammatory cytokines, such as tumor necrosis factor-α and interleukin-1β, and for histopathological study. The levels the cytokines and creatinine were measured in the renal venous blood. As the amount of bleeding increased, the initial activation of p38 MAPK and the expression of renal cytokines were progressively enhanced. The severity of renal dysfunction, manifested by serum creatinine concentration, histologic damage score, and neutrophil accumulation in the kidney, was well correlated with the degree of initial p38 MAPK activation. The increase of initial p38 MAPK activation after hemorrhagic shock quantitatively enhanced the ensuing renal dysfunction in response to the degree and the progression of hemorrhagic shock.

The utility of an autologous blood salvage system in emergency thoracotomy for a hemothorax after chest trauma

In Japan, little is known about using the Cell Saver in treating blunt or penetrating chest trauma. We therefore report the utility of this autologous blood salvage device. Two patients underwent emergency thoracotomies with the Cell Saver to treat massive hemothorax and made full recoveries. The first was a 29-year-old man who suffered a stab injury to his chest; 5000 ml blood was collected from the thorax, of which about 3000 ml was reinfused. The second was a 51-year-old man involved in a car crash; 1600 ml blood was collected from the thorax, of which about 500 ml was reinfused. When no banked blood is available for an emergency thoracotomy, the Cell Saver is an extremely useful machine. This device is also effective in treating progressive hemorrhagic shock and helpful when the rate of blood loss exceeds the supply available from the blood bank.

Heart rate variability during massive hemorrhage and progressive hemorrhagic shock in dogs.

To investigate the sequential changes in heart rate (HR), autonomic nervous activity presented by the spectral analysis of heart rate variability (HRV), hemodynamics and metabolism during massive hemorrhage and progressive hemorrhagic shock in dogs. Twelve dogs were subjected to acute massive hemorrhage until mean arterial pressure (MAP) reached 50 mm Hg. Then bleeding was stopped and they were allowed to reach a plateau phase. They were divided, post hoc, into bradycardic or tachycardic groups according to their HR response to the acute massive hemorrhage. After reaching a plateau phase, the dogs were further bled to keep their MAP around 50 mmHg (progressive hemorrhagic shock). Their heart rate power spectra were quantified into low-frequency (LF) (0.04-0.15 Hz) and high-frequency (HF) (0.15-0.4 Hz) components. In the bradycardic group, both LF and HF increased after massive hemorrhage, but during progressive hemorrhagic shock these components decreased while HR increased. In the tachycardic group, LF increased after massive hemorrhage, but during progressive hemorrhagic shock LF decreased with continuous suppression of HF CONCLUSION: Massive hemorrhage caused two types of HR response: bradycardia and tachycardia. The HRV profile showed differential autonomic characteristics, and could be a valuable tool in assessing various degrees of hemorrhagic shock.

Spinal nitric oxide participates in the control of the blood pressure during graded hemorrhage in the conscious rat.

We sought to evaluate the role of spinal nitric oxide (NO) in the control of blood pressure in the conscious animal and determine its possible participation in the progression of hemorrhagic shock. Adult, male Sprague-Dawley rats were chronically prepared with intrathecal, intravenous, and intra-arterial catheters. We first investigated the role of spinal NO on blood pressure control by intrathecal administration of N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME) at 0.37 micromol, 0.74 micromol. or 1.48 micromol. A dose-related increase in blood pressure was observed. We next pretreated animals with intrathecal or intravenous L-NAME at 0.37 micromol and induced the animal to shock by graded hemorrhage. Animals that received vehicle control or intravenous L-NAME had a decrease in blood pressure after 12% of the total circulatory blood volume (TBV) had been removed and developed severe hypotension after 24% TBV was bled. On the other hand, intrathecal pretreatment of L-NAME significantly attenuated the decrease in blood pressure. The blood pressure was maintained until 40% TBV had been withdrawn. We concluded that inhibition of NO synthase, in the spinal cord, increased blood pressure in a dose-dependent manner, and hemorrhagic shock induced by graded hemorrhage may involve an upregulation mechanism of spinal NO synthase in producing severe hypotension in conscious rats.

Mast Cell Degranulation in Hemorrhagic Shock in Rats and the Effects of Vasoactive Intestinal Peptide, Aprotinin and H<sub>1</sub> and H<sub>2</sub>-Receptor Blockers on Degranulation

Various stressful stimuli cause mast cell degranulation. Hemorrhagic shock is one such stressful stimulus which may cause mast cell degranulation and histamine release. Histamine may be involved in the pathophysiology of hemorrhage. It was reported that there are large amounts of histamine in the anterior and posterior lobes of the pituitary and the adjacent median eminence of the hypothalamus. Most of the histamine in the posterior pituitary is in mast cells. In addition, both vasoactive intestinal peptide (VIP) and histamine-containing neurons are available in the hypothalamus. It therefore seems reasonable to suppose that these three systems (i.e., mast cells, VIP-containing neurons, and histamine-containing neurons) may play an important role in the progression of hemorrhagic shock. 66 albino rats (200-250 g) of either sex were used. The presence of mast cells was examined by light microscopy. Hemorrhage caused mast cell degranulation in a correlation with the amount of blood loss. In all cases, the most intense degranulation was observed in the hypothalamus, especially the nucleus arcuatus, and in the subcutaneous tissue. The intensity of degranulation gradually decreased in the peripheral blood vessel, peritoneum and omentum, in this order. VIP prevented degranulation, but aprotinin and H1 and H2 receptor blockers did not.

Serum magnesium increases following severe hemorrhage in dogs blocked by verapamil treatment

The opening of voltage sensitive calcium channels is an important event in the progression of irreversible shock, allowing the entry of toxic amounts of calcium (Ca2+) into the cells. Because intracellular magnesium (Mg2+) can efflux through these same channels, changes in serum Mg2+ may reflect the patency of these channels. In this study, electrolytes and selected serum enzymes were monitored in chronically instrumented conscious dogs to follow the progression of shock following a fixed volume hemorrhage. Plasma enzymes indicative of liver damage were elevated only in the terminal phase of hemorrhagic decompensation. A significant increase in serum Mg2+ was evident 60 min following hemorrhage, even though arterial pressure was still recovering. Serum Mg2+ continued to rise throughout the recovery and decompensating phases of shock. Verapamil treatment, which increased survival time and survival rate, significantly attenuated the changes in serum Mg2+ which normally followed hemorrhage. These results indicate that serum Mg2+ may be a useful indicator of the severity and the progression of hemorrhagic shock.

A continuous hemorrhage model of fatal hemorrhagic shock in swine

We studied the effect of bleed rate on survival time and hemodynamics in a continuous hemorrhage model of fatal hemorrhagic shock in lightly anesthetized swine. Fasted immature swine (12–16 kg) were sedated with intramuscular (i.m.) ketamine, endotracheally intubated, anesthetized with halothane (0.75%), nitrous oxide, and oxygen, and then prepared for experimentation by placement of a pulmonary artery themodilution catheter, femoral arterial and venous catheters, and by splenectomy. After instrumentation, halothane was discontinued and sedation was maintained with nitrous oxide and intravenous lorazepam. Thirty minutes later, the animals were bled continuously at 1.0 ml/kg per min ( n = 8, Group I) or 1.25 ml/kg per min ( n = 8, Group II) by a roller pump connected to the femoral arterial catheter. Hemodynamic parameters were recorded every 15 min until death occurred. Mean survival time was 50.2 ± 3.0 min in Group I and 39.8 ± 3.2 min in Group II ( P < 0.001). There was a stepwise decrease in blood pressure and cardiac index consistent with progressive hemorrhagic shock. This model results in reproducible survival times with small standard deviations. Although the animals are lightly anesthetized and the experiments are performed acutely, the hemodynamic responses and survival times observed are similar to those reported in previous studies of chronically instrumented, unanesthetized swine. This model may be more practical than unanesthetized, chronically instrumented swine models for evaluating the effects of various interventions on survival time and hemodynamics in acute hemorrhagic shock.

Enteric administration of anisodamine in the treatment of hemorrhagic shock.

Anisodamine (654-2) administered intra-enterically for 30-min without reaching the systemic circulation before hemorrhage significantly prevented the accumulation of the lysosomal hydrolase cathepsin D in the plasma during hemorrhagic hypotension and postoligemic period and at the same time significantly attenuated the progression of hemorrhagic shock in cats. Since plasma cathepsin D is derived chiefly from liver and small intestine during hemorrhagic shock, the above results implicate that anisodamine exerts protective effects on intestinal mucosal cells, most probably, through stabilization of its lysosomes from releasing enzymes during splanchnic ischemia.

Platelet aggregation during progressive hemorrhagic shock in pigs: Possible effects on the postperfusion syndrome

Platelet aggregation during progressive hemorrhagic shock in pigs: Possible effects on the postperfusion syndrome

Pathogenesis of experimental shock. II. Absence of endotoxic activity in blood of rabbits subjected to graded hemorrhage.

A series of biological test reactions was used in order to establish the presence of bacterial endotoxins in the blood of rabbits during the progression of hemorrhagic shock. 1. When the shocked animal was used as the test object, it was not possible to induce either the generalized Shwartzman reaction or the dermal Shwartzman phenomenon with exogenous endotoxin (S. enteritidis or E. coli) as one of the two provocative factors. 2. Epinephrine instilled into the skin of rabbits either before, during, or after an episode of hemorrhagic shock did not result in the hemorrhagic skin reaction which occurs in the presence of as little as 1 microg of endotoxin intravenously. 3. Passive transfer from a donor in the irreversible phase of shock of 20 to 25 ml of blood into a primed recipient (B.P. at 40 mm Hg for 1 hour) was uniformly lethal. 4. Similar amounts of blood from such shocked donor failed upon intravenous injection to elicit a protective hemorrhagic reaction in skin sites which were infiltrated with 100 microg of epinephrine. In the same animals 1 microg of endotoxin added to the blood samples caused a positive dermal response. 5. Blood was taken from rabbits which had been pretreated with S. enteritidis endotoxin and then subjected to hemorrhagic shock (35 mm Hg for 2 hours). Such samples upon passive transfer produced positive skin reactions in epinephrine sites but were not lethal to the primed test recipient used in these studies. It is concluded that the contribution of bacterial endotoxemia to the genesis of hemorrhagic shock remains to be determined.