Vasodilator Therapy In Acute Hemorrhagic Shock

Transcription

1 Vasodilator Therapy In Acute Hemorrhagic Shock By James A. Vick, Capt., MSC, Henry P. Ciuchta, 1/Lh, MSC, Joseph H. Merickel, B.S., and Esten 0. Lindseth, M.D., Ph.D. Irreversible shock associated with acute loss is a serious clinical problem. 1- ' * Attempts have been made to treat this form of shock with a variety of therapeutic agents including vasopressor drugs, steroids, and plasma expanders. Most popular has been the employment of the vasopressor agents, levarterenol (Levophed) 4 and metaraminol (Aramine), r> which support pressure mainly through an increase of peripheral resistance. Opinion is divided, however, as to whether such therapy actually alters the course of hemorrhagic shock. Recent work has indicated that vasopressor substances may be actually detrimental, reducing the already seriously impaired peripheral and renal flow. 0 " 8 This decrease of flow could well account for the death of certain vital tissues even as the pressure is maintained above shock levels by endogenously produced, or by exogenously administered, catecholamines. A completely different concept of treating irreversible shock has recently received much renewed attention. 0 ' 7t ~ 11 This method employs the use of adrenergic blocking agents to facilitate peripheral flow, in preference to the now widely accepted use of vasopressor compounds to increase pressure. Although the use of blocking drugs in the treatment of hemorrhagic shock was first suggested by Wiggers in and again by Remington in 1950, 18 this form of therapy has gone without serious clinical consideration until quite recently. 14 ' 15 Of some concern is the From the Directorate of Medical Research, USA Chemical Research and Development Laboratories, Edgewood Arsenal, Maryland and Veterans Administration Hospital, Minneapolis, Minnesota. Received for publication July 13, fact that most early experimental studies were done by using the sympatholytic agents as pretreatment in shock, rather than as therapy. The purpose of this study, therefore, is to evaluate the effectiveness of one such adrenergic blocking compound, phenoxybenzamine (Dibenzyline), in the "post-treatment" of hemorrhagic shock at a time when the onset of irreversibility appeared imminent. Methods Healthy, adult mongrel dogs, ranging in size from 10 to 15 kg, were anesthetized with pentobarbital sodium, 30 mg/kg. A polyethylene catheter was placed in the right femoral artery and pressure was recorded continuously by means of a Statham strain gauge and a Grass polygraph recorder. The left femoral artery was also catheterized and connected with a Lamson reservoir 10 into which the animal could be bled. Prior to bleeding, the animal was given 5 mg/kg heparin sodium. By adjustment of the hydrostatic level, a mean arterial pressure of 50 mm Hg could be maintained throughout the entire 10- hour observation period. This procedure for producing irreversible hemorrhagic shock has previously been described by both Lamson 50 and Fine. 17 Changes in the animals' volume were recorded hourly as an increase or decrease in the level of the graduated reservoir. Three hours after initial, paired animals were divided at random into either a control or a treated group. The control group of 20 animals received no therapy. The treated group, also 20 dogs, received 0.5 mg/kg phenoxybenzamine as a single intravenous injection. All animals were removed to a recovery cage for determination of survival times. Survivors were those animals still alive 72 hours after. The per cent CO 2 in the expired air was continuously measured using a fine polyethylene catheter with its tip inserted into the endotracheal tube of the dog and with its other end connected to a Beckman gas analyzer. Hourly arterial and venous samples were also drawn for determination of O 2 and CO 2 contents. All samples were heparinized and were collected under oil from 58 CircttUih* Rtstrcb, Vol. XVI, Jtmiury 1963

2 VASODILATOR THERAPY IN SHOCK 59 catheters placed in either the femoral artery or the femoral vein. Results During the first three hours after, both groups of animals continually lost into the open Lamson reservoir. An average of 10% (range 8 to 12%) of the animals' original volume was bled into the reservoir during this time, in addition to the 36% (range 34 to 42%) required to establish the initial pressure of 50 mm Hg. During the following seven hours, the entire volume of in the reservoir, 46.4% (range 42 to 54%) of the original volume of the dog, was recovered by the control group of animals even as the pressure remained at 50 mm Hg. This is in contrast to an average of 32.9% (range 28 to 36%) recovered during the same period of time by the phenoxybenzamine-treated dogs. Recovery of in the treated group was prompt, 14.1% (range 12 to 18%) occurring within 15 to 30 minutes after the animals received the drug, as compared to 1.8% (range 0.4 to 3.0%) recovery in the untreated animals. At six hours after the amount of recovered from the reservoir in both groups was very similar; 17.4% in the control group and 17.2% in the treated group. From this time, however, recovery of increased in the control group and death occurred between 10 and 14 hours in 80% of the animals. None of the control group were alive at the end of 24 hours. By comparison relatively little change in reservoir level was noted in the treated group after six hours, with 18 of the 20 animals (90%) surviving for 72 hours after. The average data obtained from these two groups of dogs are presented in table 1A. The amount of COo in the expired air decreased rapidly when the animals were bled. Within five minutes after a pressure of 50 mm Hg was reached, the level of CO;, in both groups decreased from a control of % to %. At three hours the level of COn was approximately 2.7%, after which time no significant change occurred in the untreated group. In those dogs treated with phenoxybenzamine, however, the COo in expired air TABLE 1A Blood Volume Changes in Heviorrhagic Shock Without and With Phenoxybenzamine (designated "" and "" respectively) Before After % total volume in reservoir Time 20 min 40 min 60 min Range ( ) ( ) ( ) Hemorrhage to ' 50 mm Hg Initial 1 hr 2 hr 3 hr* 3K hr 4 hr 5 hr 6 hr 7 hr 8 hr 9 hr 10 hr (.34-42) (39-14) (41-50) (42-54) (41-51) (39-47) (32-40) (24-33) (10-20) ( 4-12) ( 0-7 ) ( 0-0 ) % total volume in reservoir Range ( ) ( ) ( ) (34-42) (38-44) (41-50) (42-53)* (28-34) (27-34) (28-33) (27-31) (23-28) (18-22) (13-19) (12-16) % toul volume recovered Range ( ) ( ) ( ) ( ) ( ) ( ) ( 0.4-3) ( 2-6 ) ( 8-14) (11-21) (27-35) (36-40) (.39-45) (42-54) % 1total volume recovered Range ( ) ( ) ( ) ( ) ( ) ( )* (12-18) (12-18) (12-19) (15-20) (18-24) (23-29) (28-32) (28-36) 0/20 survivors at 24 hours. 18/20 survivors at 72 hours. Treatment begun phenoxybenzamine (Dibenzyline) 0.5 mgag- CircuUlion Ruurcb, Vol. XVI, Itnutrj 196)

3 Arterial CO» content vol < % Venous * o < n z o z o m Z TABLE IB Averaged Changes of O s and CO e in Hemorrhagic Shock Without and With Phenoxybenzamine (same dogs as in table 1A) Time % COi! exhaled air Range % CO2 exhaled air Range Arterial O2 content Venous O2 content Arterial Venous h content cc Arterial Venous 15' Before After 20 min 40 min 60 min Hemorrhage to 50 mm Hg Initial 1 hr 2 hr 3 hr* 3K hr 4 hr 5 hr 6 hr 7 hr 8 hr 9 hr 10 hr (3-5) (1-3) (2-2) (4-6) (3-2)* (3-3) (4-5) (4-5) (4-6) vol % vol % * vol % /20 survivors at 24 hours. 18/20 survivors at 72 hours h Treatment begun phenoxybenzamine (Dibenzyline) 0.5 mg/kg. X

4 VASODILATOR THERAPY IN SHOCK 61 increased progressively and reached a near control level of 5.13> seven hours after therapy. Average values and their ranges as obtained in the control and treated groups are presented in table IB. Arterial O2 and venous COo contents remained constant or increased slightly during untreated hypotensive shock. In contrast, venous O L. and arterial CO2 fell precipitously resulting in a large increase of the arterialvenous difference in Oo content and an equally sharp rise in the venous-arterial difference of COo. In animals treated with phenoxybenzamine, venous O o and arterial CO 2 increased slowly but progressively and approached control values three to four hours after therapy. Tables IB and 1C present average values for the arterial and venous O o and COo measurements, as well as the averages and ranges of values for the Oo (A-V) and COo (V-A) determinations. The results of a typical control and a typical Dibenzyline-treated animal are shown in figure 1 with comparisons. A comparison of changes in CO 2 (V-A), O L. (A-V), per cent CO 2 in the expired air, per cent total volume in the Lamson reservoir, and pressure prior to and for 10 hours following is presented. Discussion Results of this study show that animals bled until mean arterial pressure was 50 mm Hg, survived approximately three hours without any apparent peripheral pooling or stagnation. During this early period of hypotension, animals appear to undergo intense vasoconstriction and is continually lost into the Lamson reservoir. This loss of is thought to be the result of an outpouring of large amounts of endogenous catecholamines in response to the decrease of pressure. 18 ' i0 Following the initial period of vasoconstriction, generalized pooling occurs and this leads ultimately to a state of irreversibility. This phase of shock has been described fully and is associated with hemoconcentration, acidosis, and renal failure. 20 ' - 1 Phenoxybenzamine corrects or prevents these alterations in cardiovascular hemodynamics TABLE 1C Arteriovenous Differences of O, and CO, in Hemorrhagic Shock Without and With Phenoxybenzamine (same dogs as in tables 1A and IB) Before After Time 20 min 40 min 60 min Hemorrhage to.50 Initial 1 hr 2 hr 3 hr* 3K hr 4 hr 5 hr 6 hr 7 hr 8 hr 9 hr 10 hr (A-V Range vol % 4.8 ( 4-6 ) 5.4 ( 5-6 ) ( 5-6 ) mm Hg ( 8-10) ( 8-11) ( 8-13) ( 8-14) ( 8-13) ( 9-14) (10-15) (10-15) (A- l-v)^ Range vol1 6.5 ( 6-7 ) ( 5-6 ) 5.5 ( 5-6 ) ( 5-7 ) ( 6-10) (10-16)* ( 9-14) ( 5-6 ) ( 3-4 ) ( 3-5 ) ( 3-5 ) ( 4-5 ) ( 4-5 ) 0/20 survivors at 24 hours. 18/20 survivors at 72 hours. 'Treatment begun phenoxybenzamine (Dibenzyline) 0.5 mg/kg. Circmlmtion Resurcb, Vol. XVI, l.nturj 196} (V-A >COo Range vol % ( 9-11) ( 7-10) (14-21) (20-25) (19-28) (22-30) (22-29) (20-26) (22-30) (25-30) (22-29) (V-A) COo Range vol /. 8.3 ( 8-9 ) 8.9 ( 7-10) 9.3 ( 8-10) ( 9-11) (15-22) (24-31)* (20-26) ( 9-15) ( 6-11) ( 8-9 ) ( 6-9 ) ( 7-9 ) ( 7-9 )

5 62 VICK, CIUCHTA, MERICKEL, LINDSETH COMTROL X X Co 1 (V-A) Vol.% n 10 e M It o* (A-V) Vol.% %co* Expired Air s 4 3 O 90 in KBottt* ap to K> too ISO mmnq WO W 00 O I I S 4 3 «7»» I O Cmtrol * Htmorrno g* ' Treotm «nt B egun Hour* Pott HemorrtMQ*» FIGURE 1 Results from a typical control and a typical Dibenzyline-treated animal compared as to: CO, (V-A), O, (A-V), per cent CO, in expired air, per cent total volume in Lamson reservoir (labelled K Bottle) and pressure prior to, and for 10 hours following, to 50 mm Hg. Dibenzyline given three hours after. by blocking the catecholamine-induced vasoconstriction 7 and the histamine-induced venospasm, 22 ' 2S thereby re-establishing the flow of to vital areas of the body. The sharp decrease of the volume of in the reservoir immediately after the administration of phenoxybenzamine indicates the marked vasodilator effect of the drug. Data on alveolar CO o and content of O 2 and CO 2 in the support this observation. The accumulation of metabolic wastes and the lack of oxygen in the inadequately perfused tissues is reversed, relieving the severe detrimental effects of prolonged "stagnant anoxia." Flow increases through the now dilated capillary beds resulting in a re-establishment of tissue metabolism at a nearly normal level. It is to be emphasized that these changes occur even while arterial pressure remains at 50 mm Hg. These findings are consistent with CircmUxion Rtsurcb, Vol. XVI, J,*tur) 196J

6 VASODILATOR THERAPY IN SHOCK 63 data obtained in experimental endotoxin shock in which increases of both renal flow and survival have been shown to occur with this same form of therapy. 8 ' 24 Summary Results of this study show that 18 of 20 dogs survived prolonged periods of arterial hypotension when phenoxybenzamine was given to maintain adequate flow to the vital tissues of the body. This drug was used in order to block the catecholamine-induced arteriolar vasoconstriction and the histamineinduced venospasm. Reduction of peripheral resistance results in an increased perfusion of the capillary beds and a correction of O 2 and CO 2 tensions at the tissue level. One must emphasize the need for adequate fluid replacement, with this form of therapy; otherwise the marked vasodilation which occurs with phenoxybenzamine might result in an inadequate circulation, even as the resistance to flow in hypoxic tissues is eliminated. References 1. HARDAWAY, R. M., MCKAY, O. G., AND WILLIAMS, J. H.: Lower nephron nephrosis (ischemic nephrosis). Am. J. Surg. 87: 41, FRIESEN, S. R., AND NELSON, R. M.: The occurrence of massive generalized wound bleeding during operation, with reference to the possible role of transfusions in its etiology. Am. Surgeon 17: 609, MUIRHEAD, E. E.: Incompatibility in transfusions with emphasis on acute renal failure. Surg. Cynecol. Obstet. 92: 734, EULEH, U. S. VON: Epinephrine and nor-cpinephrine action and use in man. Clin. Pharmacol. Therap. 1: 65, WEIL, M. H.: Clinical studies on a vasopressor agent: Metaraminol (Aramine). II. Observations on its use in the management of shock. Am. J. Med. Sci. 230: 230, NICKERSON, M.: Conference on shock. Federation Proc. 20: 98, VICK, J. A., LAFAVE, J. W., AND MACLEAN, L. D.: Effect of treatment of endotoxin shock on renal hemodynamics and survival. Surgery 54: 78, NICKERSON, M.: Factors of vasoconstricfion and vasodilatation in shock. J. Michigan State Med. Soc. 54: 45, CircnUtion Rtn.rch, Vol. XVI, Jimntrj 196} 9. WEIL, M. H., SUDRANN, R. B., AND SHUBIN, H.: Treatment of endotoxin shock the dilemma of vasopressor and vasodilator therapy. Calif. Med. 96: 86, NICKERSON, M., AND CARTER, S. A.: Protection against acute trauma and traumatic shock by vasodilators. Can. J. Biochem. Physiol. 37: 1161, IAMPIETRO, P, F., HINSHAW, L. B., AND BRAKE, C. M.: Effect of an adrenergic blocking agent on vascular alterations associated with endotoxin shock. Am. J. Physiol. 204: 611, WIGCERS, H. C, INCRAHAM, R. C, ROEMHILD, F., AND GOLDBERG, H.: Vasoconstriction and the development of irreversible hemorrhagic shock. Am. J. Physiol. 153: 511, REMINGTON, J. W., HAMILTON, W. F., BOYD, G. H., JR., HAMILTON, W. F., JR., AND COD- DELL, H. M.: Role of vasoconstriction in the response of the dog to. Am. J. Physiol. 161: 116, LONCERBEAM, J. K., LlLLEHEI, R. C, ScOTT, W. R., AND ROSENBERG, J. C: Visceral factors in shock. J. Am. Med. Assoc. 181: 878, NICKERSON, M.: Drug therapy of shock. In Shock: Pathogenesis and Therapy, ed. by K. D: Bock. Berlin-Cottingen-Heidelberg, Springer-Verlang, 356: LAMSON, P. D., AND DE TURK, W. E.: Studies on shock induced by ; method for accurate control of pressure. J. Pharmacol. Exptl. Therap. 83: 250, FRANK, H. A., SELJCMAN, A. M., AND FINE, J.: Traumatic shock: XIII. The prevention of irreversibility in hemorrhagic shock by viviperfusion of the liver. J. Clin. Invest. 25: 22, ZWEIFACH, B. W., AND THOMAS, L.: Relationship between the vascular manifestations of shock produced by endotoxins, trauma and. I. Certain similarities between the reactions in normal and endotoxin-tolerant rats. J. Exptl. Med. 106: 385, ROSENBERG, J. C., LILLEHEI, R., LONCERBEAM, J., AND ZIMMERMAN, B.: Studies on hemorrhagic and endotoxin shock in relation to vasomotor changes and endogenous circulating epinephrine, norepinephrine and serotonin. Ann. Surg. 154: 611, LILLEHEI, R. C: The intestinal factor in irreversible hemorrhagic shock. Surgery 42: 1043, HARDAWAY, R. M., BARILA, T. C, BURNS, J. W., AND MOCK, H. P.: Studies on ph changes in endotoxin and hemorrhagic shock. J. Surg. Res. 1: 278, HINSHAW, L. B., VICK, J. A., JORDAN, M. M., AND

7 64 VICK, CIUCHTA, MERICKEL, LINDSETH WITTNEBS, L. E.: Vascular changes associated series of N-naphthylmethyl-2-haloethylamine with the development of irreversible endotoxin derivatives. Brit J. Pharmacol. 8: 54, shock. Am. J. Physiol. 202: 104, VICK, J. A.: Endotoxin shock in the primate: 23. GRAHAM, J. D. P., AND LEWIS, G. P.: The anti- Treatment with phenoxybenzamine. J. Clin. histamine and antiadrenaline properties of a Invest. 43: 279, Circulation Rts rcb, Vol. XVI, Jamurj 196}