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Norepinephrine이 출혈성 Shock에 미치는 영향에 관한 실험적연구

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 Experimental studies on the influence of norepinephrine upon the hemorrhagic shock 
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Since investigators first became interested in hemorrhagic shock, a major problem has been the elucidation of the nature of irreversible shock stated. Although numerous such as fluid loss, toxic humoral agents, acidosis and neurogenic factor etc. have been reported to play an important role in development of hemorrhagic shock, the initiating mechanism of irreversible shock state is still unknown. It is obvious, however, that vasoconstriction is a prominent feature of the early stage o

hemorrhagic shock in experimental animals, Most authorities agree that this is a protective mechanism mediated through the sympathetic nervous system to maintain a blood supply to vital organs. Freeman et al, (1983) pointed out that, although animals with intact sympathetic nervous system were able to compensate more statisfactorily to acute hemorrhagic than were completely sympathectomized animals, the mortality rate was greater in intact than in sympathectomized animals if the hemorrhagic hypotension was prolonged. To explain this finding, he suggested that pronounced hypotension resulting from hemorrhage gives ries to compensatory stimulation of sympathitic nervous system, which causes vasoconstrition whih leads to further reduction in circulating blood volume. Subsquest studies have shown that

adrenergic blocking agents (Wiggers et al, 1950; Levy et al., 1954) and ganglionic blockade (North and Well, 1951 ; Ross and Herczeg, 1956 ; Hershey et al., 1954) could protect from the leihal effects of hemorrhagic hypotension. Those observations appear to indicate that a decrease in sympathetic nervous system

response might be pertinent for a decrease in mortality following hemorrhagic shock. This concept is further supported by Erlanger and Cassel (1919), who produced a shock state by intravenous infusion of epinephrine. In contrast to the above reports, Chien and Hitzig. (1960) determined the amount of blood withdrawal which gave LD^^50 in sympathetic intact and sympathectomized dogs and concluded that the presence of sympathetic nervous system increases the tolerance to hemorrhagic shock. Furthermore, norepinephrine has been found clinically to be beneficial in the treatment of hemorrhagic shock and there are several experimental

studies which indicated that norepinephrine significantly reduced mortality of animals subjected to hemorrhagic shock, (Lansing et al, 1957 ; Fewler at al, 1954 ; Griffin et al, 1958)

In the course of studying the changes of myocardial catecholamines, in was found that the norepinephrine and epinephrine content was markedly reduced in the heart during hemorrhagic hypotension. This role of norepinephrine in hemorrhagic shock and to elucidate the relationship of the myocardial catecholamines depletion to the genesis of irreverrible hemorrhagic shock.


Healthy mongrel male dogs, weighing approximately 15Kg., were anesthetized with pentobarbital sodium(30 mg/kg), given intravenously. A femoral artery was exposed and connected to the blood reservoir which maintains constant pressure of 40 mmHg. The other femoral artery was directly connedted to a mercury manometer for continuous recording of changes in arterial blood pressure on a smoded drum. Femoral veins were also exposed in order to infuse drugs or blood. Endotracheal intubation was employed so that a free air-way was maintained at all times and

heparine (5 mg/Kg) was injected intravenously to prevent blook coagulation. After adequate measurement of heart, respiretion and hematocrit a hypotensie state was produced by permitting blood to flow rapidly into the blood reservoir until arterial blood pressure reached a level of 40mmHg. This hypotension was maintained throughout the experiment until the reinfusion of the witherwan blood.

The content of myocardial catecholamines was determined by the

spectrophotofluorometric procedure described by Shore and Olin(1958). The tissue was homogenized in two volumes of 0.01 N HGI by means of a cornical glass homogenizer. The remainder of the procedure did not differ significantly from that described by the above authors.

L-norepinehrine diluted with distilled water was continuousely infused into the femoral vein for an hour by Bowman's constant infusion pump. The volume of the solution injected was less than 0.2 ml per minute.


1) The catecholamine content was examined in the myocardium of dogs subjected to hemorrhagic hypotension ef 40 mmHg for a duration of 1, 2, 3, 4 and 5 hours respectively. No marked changes were noticed within two hours after production of

hemorrhagic hypotension but a significant reduction was found at the end of 3 hours of hypotension, thus, the mean value of myocardial catecholamine dropped to 1.07±0.10 γ/gm from the control value of 1.42±0.11 γ/gm (p<0.05). By prolonging the hypotensive period more than three hours, the reduction of myocardial catecholamines was progressively pronounced and the mean values at the end of 4 and 5 hours of hypotension were 0.63±0.06 and 0.50±0.04 γ/gm, respectively.

2) Dogs were bled to an arterial blood pressure of 40 mmHg and maintained at this level for 3 hours. The withdrawn blood was then reinfused into a vein and the mortality of these animals was examined within 12 hours. All of the three animals survived, indicating that 3 hours of hypotension under the present experimental conditions was not enough to produce the irreversible shock state. However, when the withdrawn blood was reinfused at the end of 4 hours of hypotension, 3 out of 11

animals survived. showing 28% survival rate.

3) Norepinedphrine was continuously infused at a rate of 5-7 γ/kg/min. for an hour at the end of 3 hours of hypotension and then the withdrawn blood was reinfused. The arterial blood pressure rose to 70-80 mmHg from 40 mmHg at the begining of norepinephrine infusion to almost 40 mmHg. Among 6 animals such treated in this way with norepinedphrine, 2 dogs succumbed during norepinedphrine infusion and 3 animals died within 12 hours after the reinfusion of blood. showing 83% mortality. From this result, it appears that norepinedphrine infusion during the oligemic hypotension may hasten death or increase the mortality of the animals.

4) Norepinedphrine was continuously infused at a rate of 3 γ/kg/min for an hour following reinfusion of the withdrawn blood at the end of 4 hours of hypotension. The blood pressure was markedly elevated by norepinedphrine infusion up to the level or above that prior to bleeding. 10 out of 15 animals so treated with norepinedphrine survived. The Ghi square test on the survival rates of norepinedphrine-treated and control animals revealed that norepinedphrine infusion after blood reinfusion significantly increased the survival rate. (p<0.05)

5) In order to further confirm the beneficial effects of norepinedphrine on hemorrhagic shock, similar experiments were performed on the animals pretreated with adrenergic blocking agents, dibenzyline or dichloroisoproterenol.

Dibenzyline has been Known to block effcetively the vasoconstrictor effect but not the cardiac effects of norepinedphrins. At the end of 4 hours of hypotension, a

dose of 3 mg/kg of dibenzyline was injected with the reinfusion of withdrawn blood and then norepinedphrine was continuously infused at a rate of 3 γ/kg/min for an hour. No elevation of blood pressure by the infusion of norepinedphrine indicated

that dibenzyline completely blocked the vasoconstrictor action. All of the three dogs within 12 hours after the termination of norepinedphrine infusion, indication that vasoconstrictor and pressor activity plays an important role in the beneficial

effects of norepinedphrine on hemorhagic shock.

Numorous investigators (Moran and Perkin, 1958; Lee and Shideman, 1959) have demonstrated that dicholoriosproterenol specifically blocks the cardiac responses but not the pressor response to norepinedphrine. At the end of 3.5 hours of hypotension, dichloroisoproterenol 1mg/kg was slowly injected in travenously while maintaining 40 mmHg of blood pressure. The withdrawn blood was reinfused at 4 hours after the production of hypotension followed by a continuous infusion of norepinedphrine(3γ/kg/min). In spite of the fact that the blood pressure became elevated by the infusion of norepinedphrine like that of the control animal, all 4 dogs so treated with dichloroisoproterenol died, indicating that the cardiostimulant effect of norepinedphrine may also be one of the major benefits in hemorrhagic shock.

6) In an attempt to compare the effects of norepinedphrine with other pressor agent on experimental hemorrhagic shock, pitressin was continuosly injected at a rate of 0.022 μ/kg/min for an hour after the reinfusion of the withdrawn blood at the end of 4 hours of hypotension. Among 5 dogs, 3 animals survided and 2 animals

died. It is difficult to compare statistically this result with that of the control or norepinedphrine-treated animals because of the small number of experimental animals. However, it appears that the survival rate of pitressin-treated dogs may be greater than that of nontreated controls but not as great as that of

norepinedphrine-treated dogs.

7) Myocardial catecholamines were examined in dogs which survived or died follwing continuous infusion of norepinedphrine after the reinfusion of withdrawn blood at the end of 4 hours of hypotension. In the group of 4 dogs which died, the content of catecholamines was determined soon after death and averaged 0.67±0.14 γ/gm. This value is not significantly different from that of dogs subjected to only 4 hours of hypotension. In the group of 5 dogs which survived, the content of catecholamines was determined 12 hours after the termination of norepinedphrine

infusion and averaged 1.10±0.22 γ/gm. This value is near to the average value of normal myocardial catecholamines (1.42±0.11 γ/gm).

From the above results. it may be concluded that norepinedphrine exerts significant beneficial effects on the survival of hemorrhagic shock when it is given after the blood volume has been restored, but a deleterious or abscent effect

when it is given during the olgemic hypotensive state. The effects of norepinedphrine on hemorrhagic shock were discussed on the basis of myocardial catecholamine depletion.
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