T Clim Invest 30: 4381,/9 5! THE COLLAPSE PRODUCED BY VENOUS CONGESTION OF THE EXTREMITIES OR BY VENESECTION FOLLOWING CER- TAIN HYPOTENSIVE AGENTS? By EDWARD D. FREIS, JOSEPH R. STANTON, FRANK A. FINNERTY, JR., HAROLD W. SCHNAPER, ROBERT L. JOHNSON,? CHARLES E. RATH, ann : ROBERT W. WILKINS (Front the Cardiovascular Research Laboratory, Georgetown University Hospital, and Depart- gnent of Medicine, Geargetown University School of Medicine, Washington, D. C.; Veterans Administration Hospital, Washington, D. C.; Evans Memorial, Massa- chusetts Memorial Hospitals, and the Department of Medicine, Boston University School of Medicine, Boston, Mass.) (Submitted for publication December 14, 1950; accepted, February 28, 1951) It ‘is well recognized that interruption of the lower thoracic and lumbar sympathetic nerves, or the administration of certain hypotensive drugs particularly sodium nitrite and the ‘‘sympatholytic” agents may cause hypotension and collapse in the erect position. It has been postulated that this hypotensive reaction is due to pooling of blood in the dependent parts of the body, particularly in the splanchnic vascular bed with consequent failure of venous return and, hence, of cardiac output (1). During studies on the hemodynamic effects of hypotensive drugs in man we have observed sud- den and marked reductions of arterial pressure frequently with collapse occurring in the supine position. This phenomenon was induced by sub- jecting the limbs to brief periods of venous con- gestion, after the administration of certain hypo- tensive agents (2). This paper presents data on the types of agents that cause this phenomenon as well as an analysis of the mechanisms whereby the effect is produced. MATERIALS AND METHODS The subjects were patients both hypertensive and nor- motensive from the hospital wards. Arterial pressure was recorded either by the usual auscultatory method or optically with a Hamilton manometer connected to an 18 gauge needle inserted into the brachial artery. With the patient in the supine position, inflatable cuffs connected to a large air reservoir bottle were applied proximally to both thighs and one arm and were held in place by covering the cuffs and adjacent skin with gauze bandage. In all of the hypertensive patients the limbs 1 Supported in part by research grants from the Na- tional Heart Institute, U. S. Public Health Service, E. R. Squibb and Sons, New York, N. Y., and Irwin, Neisler and Company, Decatur, Tl, 2 Captain, M.C., U.S.A.F. were congested with a pressure of 100 mm. Hg and in the normotensive subjects at pressures of 60 to 80 mm. Hg. Before and after the administration of each of the various drugs tested the extremities were congested for five min- utes unless collapse supervened. After each drug the blood pressure was recorded frequently. The point at which the blood pressure leveled off or began to rise was taken as the point for applying venous congestion. A similar procedure was used in the venesection experiments. The volume of blood trapped in the congested ex- tremities was determined according to the method of Ebert and Stead (3) following a congestion period of five minutes, instead af seven to 10 minutes as used by those investigators.. The shorter congestion period may account for the fact that in the present experiments the volume of blood trapped in the extremities usually was smaller than that observed by Ebert and Stead. Following the congesting period the pressure in the cuffs was raised to 250 mm. Hg after which the dye T-1824 was injected. Samples were drawn at eight and 10 minutes afterwards. The occluding cuffs were then released and further sampling was carried out at 18 and 20 minutes. The latter samples were used to determine total blood volume while the former were used to deter- mine the volume of that portion of the body not removed from the general circulation by the occluding cuffs. It was found that the dye density values of the eight and 10 minute samples agreed closely with each other indi- cating that mixing was essentially complete at the end of eight minutes. Similarly the 18 minute were in good agree- ment with the 20 minute samples. The results of other investigations (4-7) also indicate that in normal sub- jects equilibration of dye is complete’ in less than eight minutes. Hence, it seems probable that this method was sufficiently accurate for the present purposes. The segment plethysmograph used to determine changes in calf volume was the same as that described by Wilkins and Ejichna (8) with the exception that proximal and dis- tal blood pressure cuffs were not applied since in the © present experiments the plethysmograph was used to de- termine volume changes rather than blood flow. In the venesection experiments a 15 gauge needle was inserted into an antecubital vein and the blood introduced 435 436 into a vacuum flask containing 130 cc. of acid citrate dex- trose solution (ACD), Immediately following comple- tion of the bleeding period the flask was inverted, and then pressurized by raising it and introducing air into it in order to hasten the return of blood to the circulation. RESULTS Effect of various huypotensive agents in the produc- tion of collapse during venous congestion of the extrenuties In the control period, prior to the administra- tion of any drug only two of the 24 subjects ex- hibited a significant reduction of arterial pres- sure during congestion of the extremities for a five minute period. In these two cases (G. 5. and J. L., Table I) the reductions in average (sores Seer 5 wes arterial pressure were 10 and 12 per cent, respectively. Neither of these patients exhibited signs of collapse. Five patients who received sodium nitrite in doses of 90 to 210 mg. by mouth exhibited changes in average arterial pressure varying from + 1 to — 44 per cent (mean — 25 per cent) during con- FREIS, STANTON, FINNERTY, SCHNAPER, JOHNSON, RATH, AND WILKINS gestion of the extrenuties. Three of these sub- jects developed marked hypotension and symptoms _ of collapse within two to three minutes after the congesting pressures were applied. Five subjects were given 0.5 mg. of dihydro- ergocornine (DHO) intravenously. During con- gestion the changes in average arterial pressure in these patients varied between + 6 and — 48 per cent (mean — 27 per cent). Three of these sub- jects developed signs of collapse prior to the end of the five minute congesting period. In three subjects given tetraethylammonium (250 to 400 mg. intravenously} none developed collapse during congestion of the limbs although all ex- hibited reductions in average arterial pressure varying from — 4 to — 22 per cent (mean — 15 per cent). However, all of the four subjects given the longer acting and more potent ganglionic block- ing agent hexamethonium (C,) developed col- lapse within two to five minutes of venous con- gestion. The reduction of arterial pressure in this group of patients varied between — 16 and — 56 per cent (mean — 37 per cent). TABLE I The effect of various hypotensive agents on the arterial pressure during congestion of the extremities of unsympathectomized patients Control Post-drug period Arterial pressure Arterial pressure Pt. Sex | Age Drug Dose and route Change Change mean*® mean « After five | arterial After five | arterial Collapse Basal min. of Pressure | Basal min, or less | Pressure congestion of congestion num, He mm. Hg percent | mm. Hg mm. He per cent RLM. M 24 Sodium nitrite 180 mg. P.O. 200/120 190/112 - 5 180/106 155/100 ~di 5 A.A. M 48 Sodium nitrite 120 mg. P.O. 226/128 246/146 Ll 170/115 98/66T 4d + E. Cc, F 43 Sodium nitrite 90 mg. P.O. 225/109 210/118 -—2 178/99 $8/70t wn 43 + M.S. M 22 Sodium nitrite 180 mg. P.O. 118/68 114/64 ~4 96/50 68/40 LE + A. P, M 28 Sodium nitrite 210 mg. P.O. 180/110 174/116 — 2 170/106 176/106 +1 a KK. M. F 51 HO 0.5 mg. LV. 218/120 234/128 + 1 184/04 90/56 ~~ 48 + iS. F 45 DHO 0.5 mg. I.V. 194/110 192/102 - 3 174/90 176/99 + 6 Qo E. M, F 29 DHO 0.5 mg. 1.¥. 204/104 191/112 +3 188/104 108/56 43 + J.G. M 28 DHO 0.5 me. LY. 426/84 111/79 - 9 130/82 95/65 25 8 Ss. kK, M 43 DHO 0.5 mg. LV. 120/82 114/78 - 53 114/76 85/62 23 + R.K, M 49 TEAC 300 mg. LV. 197/120 212/133 + 9 160/106 127/89 19 6 ELS. FE 52 TEAC 250 mg. IV. 258/142 252/149 +1 236/146 220/142 om 4 0 J.L. M 28 TEAC 400 mg. I.V, 140/80 118/78 —12 128/80 100/62 22 0 G.S. M 42 Ce 50 mg. LV. 180/110 160/100 ~10 160/100 80/60 ~56 + A.J. F 49 Cs 50 mg. LV 170/120 164/126 0 128/100 90/80 25 + T. B. M 40 Ce 50 mg. LV. 170/110 155/120 —-—2 110/80 5/75 ~16 + L. M. M 37 Ce 50 mg. LV 170/115 160/120 - i 150/110 75/155 ~350 + S.W, M 54 Sodium amytal 0.25 gm. LV. 231/118 220/123 —2 200/110 192/110 ~ 6 Go ALL. M 27 Sodium amytal 0.75 gm. LV. 130/96 122/92 - § 128/106 118/100 —- § 6 ELS. M 61 Sodium amytal 0.5 gm. LV. 180/104 176/108 0 138/100 124/96 ~ 8 0 B. G. M 38 Veratrone 0,8 cc. LM 210/128 204/124 —3 164/96 162/100 + 0 C.B. F 56 Veratrone 1.0 ce. LM. 272/180 276/182 +1 142/04 146/100 +4 0 J, Me. | M | $2 | Vertavis 40 CRAW V.PO. | 265/160 | 266/165 +i | 185/17 | 145/131 +2 0 E. s. F 52 Vertavis 40 CRAW V.PO, | 255/142 252/149 +1 200/112 196/114 ~ | 0 *"Mean” arterial pressure = systolic + diastolic pressure { Collapse occurred 2} -minutes after application of congesting pressure. } Collapse occurred two minutes after application of congesting pressure, “CONGESTION-COLLAPSE” AFTER CERTAIN HYPOTENSIVE AGENTS 437 TABLE It The amount of blood trapped in the extremities subjected to venous congestion before and after sodium nitrite, dthydroergocornine and hexamethonium Control After drug Subject Vol f Blood Vol f Blood mee blood in Fotal trapped in Drug dose blood in otal trapped in ae - volume congested and route — yolume congested . che cl. Cha ce. ce, ce, J. G.* 4,700 6,350 1,650 DHO 4,860 6,400 1,540 0.35 mg. LV. : Ss. K" 4,150 5,480 1,330 | DHO 4,070 5,460 1,390 0.5 mg. LV. M.S.* 4,040 5,075 ~ 1,025 Sodium nitrite 4,055 5,020 965 . : 210 mg. P.O. , R. M.* 2,990 4,230 1,240 Sodium nitrite 3,010 4,280 1,270 , . 180 mg. P.O. . I. P. 5,540 6,660 1,120 Hexamethonium 5,450 6,540 1,090 . 50 mg. LV. . * Data on the changes in arterial pressure given in Table I. No significant reductions of arterial pressure occurred during congestion of the extremities of three patients given 0.25 to 0.75 gm, of sodium - amytal intravenously, two subjects given 0.8 or . LO cc. of Veratrone (tincture of veratrum viride) intramuscularly and two patients given 40 Craw units of Vertavis (whole powdered root and rhi- zomes of veratrum viride) orally. In all of the latter cases significant reductions of basal arterial pressure had occurred following the administra- - tion of veratrum viride. The signs and symptoms related to the collapse state induced by sodium nitrite and the “sympatho- - lytic” agents during congestion of the extremities ~ Tesembled those observed in other types of acute . hypotension such as carotid sinus and vaso-vagal Syncope, or postural hypotension. The pulse pres- sure became small and bradycardia frequently de- veloped. Pallor, yawning, sweating and vomiting Sometimes occurred. The patients experienced faintness, giddiness and at times nausea. For example, patient E. C. (Table I) who re- ceived 180 mg. of sodium nitrite by mouth 30 Minutes prior to congestion exhibited a marked reduction of arterial pressure from 178/100 to 88/ 70 mm. Hg within three minutes after the venous. tourniquets had been applied. Accompanying the hypotensive response there was profuse sweating, Pallor and bradycardia. The patient complained of faintness and nausea. Release of the congesting pressure at this time and tilting the patient into a five degree head-down position failed to relieve her symptoms, The arterial pressure continued to fall and one minute after releasing the pressure in the cuffs it was 48/33 mm. Hg and the heart rate was 58 per minute. Four minutes after re- leasing the congesting pressure the arterial pres- sure had risen to 110/78 mm. Hg and the heart rate to 72 per minute at which time the patient felt improved. The amount of blood trapped in the congested limbs ‘ In one hypertensive and four normotensive sub- jects the amount of blood trapped in the congested limbs was determined by the dye method of Ebert and Stead (3). In the control period the amount of blood present in both lower extremities and one upper extremity during congestion varied between 1,025 and 1,650 cc. with a mean of 1,273 ce. (Table II, Figure1). There were no significant changes in arterial pressure. Two subjects received sodium nitrite, two were given DHO and one received hex- amethonium. During the congestion period fol- lowing these drugs all of the subjects exhibited sig- nificant reductions of arterial pressure and three developed marked hypotension and symptoms of collapse (Table II). The latter occurred two to 438 CONTROL AFTER HEXAMETHONIUM ARTERIAL PRESSURE MM. HG 00 PALLOR FAINTNESS 80) 690 INCREASE IN VOLUME OF CALF SEGMENT DURING CONGESTION*CG. PER 100 CG. 4 LIMB VOLUME | —@g | BLOOO TRAPPED IN LOWER EXTREMITIES DURING CONGESTION PERIOD ce PRESSURE IN CONGESTING CUFFS MM.HG 0 7 of _ ff 1 ‘ MINUTES fd jd ods a 43 Fic. 1. Cuarr or ArTertat Pressure, INCREASE IN VoLUME or Catr SrGMENT, AmMouNT oF BLoop TRAPPED IN THE EXTREMITIES AND ConcesTING CuFF PRESSURES” BEFORE AND AFTER INTRAVENOUS HEXAMETHONIUM (50 mg.) In Sugyect I.P., Normat Mate, Acep 28 In the control period the arterial pressure was well maintained during venous congestion of the extremities for 544 minutes. Following hexamethonium and 2% min- utes after the venous tourniquets had been applied, hypo- tension and collapse developed. However, the amount of blood trapped in the congested extremities was less and the increase in volume of the calf segment was not as great as in the control period. four minutes after the beginning of congestion. This necessitated application of occluding pressure prior to the end of the five minute congestion pe- tiod. This was done in order to prevent blood from either entering or leaving the limbs while the patient was tilted into a head-down position and allowed to recover during the time that the blood volume determinations were being com- pleted. FREIS, STANTON, FINNERTY, SCHNAPER, JOHNSON, RATH, AND WILKINS The amount of blood present in the congested limbs during the experimental period varied be- tween 965 and 1,540 cc. (mean 1,263 cc.). In two subjects there was a slight increase in the amount of blood trapped in the limbs in the post-drug as compared to the pre-drug congestion period and in three cases a slight decrease. In no case did the pre-and post-drug values vary from each other by more than 12 per cent. Changes in calf volume during venous congestion of the extremities In order to corroborate these observations indi- cating that no more blood is trapped in the limbs during venous congestion after as compared with before the administration of agents which induce “congestion collapse,” the volume changes in the calf were measured using a plethysmograph. Hexamethonium was administered to all of the subjects. In the control period the increase in volume of the calf segment during four and one-half to six and one-half minutes of venous congestion varied between 2.4 to 5.2 ce. per 100 cc. of limb volume (mean 3.8 cc.) (Table II, Figure 1). Hypoten- sion did not occur in any of these subjects. After hexamethonium five of the six subjects developed severe hypotension during periods of congestion of one and one-half to four minutes. The increase in calf volume varied between 2.0 and 3.6 cc. (mean 2.7 cc.). Subject P. G, did not develop severe hypotension during application of venous tourniquets for five and one-half minutes. The rate of increase in calf volume during con- gestion usually was greater after as compared to before hexamethonium (Figure 1). However, in TABLE III ' The increase in volume of the calf segment during application of venous tourniquets before and after the administration of hexamethonium Control After hexamethonium (50 mg. I.V.) Subject : . . . Increase in Duration of Development Increase in Duration of Development volume of venous of hypo- volume of venous of hypo- calf segment congestion tension calf segment congestion tension cc. per 100 cc. ce. per 100 ce. limd volume minutes limb volume minutes A.G. 3.0 53 0 2.8 18 + LP. 4.0 5h 0 3.0 21 + A.H. $.2 64 0 2.3 24 + P.G. 2.8 44 0 5.0 54 0 i: D. 3.0 5 0 3.6 4 + -B. 2.4 6} 0 2.0 1} + “CONGESTION-COLLAPSE” AFTER CERTAIN HYPOTENSIVE AGENTS 439 TABLE IV The effect of dihydroergocornine (DHO), hexamethonium (Cs), and sodium ntirtte on the arterial pressure and heart rate fotlawing venesection and subsequent return of the removed blood to the circulation After drug and During venesection During return of removed blaod Dru Before drug before ose’ venesection Pt. and Blood emnnine Arterial | Heart | Blood | Time from | arterial | Heart route i ea rterial | Hea a vene- re.| rate Te- beginning r seca | Hea | gests | ge | moves | GR | Pere) tea | Ri | ie | per per per per : mm. Hg | min. | mm. He | min. cl. minutes mm, Hg | min. ce. minules mm, Hg | min, L. H. [| Ce 170/100} 82 | 140/80 86 100 2 128/80 92 100 2 130/70 81 50 mg. 200 3 120/75 92 200 8 140/80 80 LV. 300 4 115/75 | 100 300 16 150/85 80 . 400 8 105/70 100 400 21 172/94 80 500 12 98/60 80 500 26 180/96 82 j.B. | C. 220/120} 88 | 140/90 | 84 100 1 120/80 84 | 100 i 90/65 | 84 50 mg. / 200 2 120/85 80 200 2 100/70 80 LV. 300 5 115/75 80 350 4 130/90 80 ‘ 400 6 98/70 8&8 | 450 7 135/95 76 500 8 80/65*| 80 500 9 140/100; 76 M.D.}|DHO /|130/100]} 84 [130/100} 84 100 2 115/85 80 100 3 110/80 88 0.5 mg. 200 4 110/85 92 200 6 105/80 84 LV, 300 7 108/82 96 300 7 100/85 80 400 12 100/80 96 400 9 110/85 80 500 15 96/72 | 104 500 12 110/90 72 M.C. | DHO | 220/160; 80 | 220/140; 80 100 2 190/120} 80 125 4 160/110; 76 0.5 mg. 200 4 140/105; 76 250 9 180/120] 76 LV. 250 5 120/90*;} 80 E.A. | NaNO, | 122/82 94 | 122/82 96 100 2 108/84 210 mg. 200 5 | 110/82 P.O. 300 9 108/78 » 400 17 105/72 E.R. | NaNO; | 240/140) 60 | 180/120) 84 100 1 180/120) 92 120 2 135/95 80 240 mg. 200 4 150/100; 92 200 3 145/100) 76 P.O. 300 7 150/110} 96 300 7 145/110] 80 400 10 160/100} 104 400 lt 160/120) 72 525 15 125/85 84 525 15 160/120} 72 W.O. | NaNO, } 190/115; 80 | 195/112; 80 150 1 165/110} 84 150 2 160/108| 84 120 mg. 300 2 155/110; 88 400 4 150/110} 80 P.O. 400 4 155/110] 88 500 6 160/110] 82 500 6 155/110} 88 * Yawning, pallor, feels faint. four of the five patients who developed hypoten- sion during the post-drug congestion period marked reduction in arterial pressure occurred before the tofal increase in calf volume was as great as that observed at the end of the pre-drug congestion period. The estimation of the amount of blood trapped in the congested limbs as determined by the ple- thysmographic method agrees approximately with that obtained by the dye method. Previous studies estimate that about 750 cc. of blood are normally Present in the lower extremities (3). The average amount of blood found in the congested extremities was 1,270 cc. Thus, the excess of blood pooled out was approximately 1,270 — 750 or 520 cc. Us- ing the plethysmographic method the average in- crease in calf volume during the control period was approximately 5.6 cc. per 100 cc. of limb volume. Ii the volume of both lower extremities is estimated to be approximately 10 liters the amount of blood pooled out would be 5.6 x 100 or 560 cc. It should be emphasized that this is a crude estimation since the plethysmograph measures the volume change in only one segment of the limb which may repre- sent a selective rather than a representative por- tion of the vascular bed being congested. 440 Effects of certain hypotensive drugs on the arterial pressure during venesection Seven patients, of whom five were hypertensive, were bled rapidly from an antecubital vein with removal of 250 to 525 cc. of blood (Table IV). Two patients received 0.5 mg. of dihydroergocor- nine intravenously, two were given 50 mg. of hexa- methonium by the same route and three received 120 to 240 mg. of sodium nitrite orally. All of these patients exhibited reductions of average ar- terial pressure varying from — 10 to — 42 per cent; in five patients the reduction exceeded — 24 per cent. Two patients developed signs of col- lapse after withdrawal of 250 and 500 cc. of blood, respectively. The arterial pressure did not fall precipitously at any point in the bleeding period. Instead there usually was a stepwise decrease with each 100 cc. of blood removed (Table IV and Figure 2). Simi- larly on returning the blood to the circulation the increase in arterial pressure paralleled the rate at which the blood was reinfused. Thus, there was no evidence of a critical amount of blood loss as in FREIS,. STANTON, FINNERTY, SCHNAPER, JOHNSON, RATH, AND WILKINS untreated subjects beyond which “compensation” fails and the arterial pressure falls suddenly. As a control the arterial pressures of eight blood donors were measured during venesection. No pretreatment with hypotensive agents had been given. The removal of 500 cc. of blood at a similar rate from each of the donors resulted in a decrease of average arterial pressure of — 8 to + 2 per cent (average — 3 per cent). Absence of congestion collapse after hypotensive drugs in partially sympathectomized subjects Eight hypertensive patients who had undergone either a lumbodorsal, or a transthoracic splanch- nicectomy four months to five years previously . were studied. Two patients received sodium ni- trite in doses of 150 to 180 mg. orally, one re- ceived 0.3 mg. of the mixed dihydrogenated alka- loids of ergot (CCK) intravenously and five were given 50 mg. of C, intravenously (Table V). In only two subjects were significant decreases in average arterial pressure observed (— 11 and — 22 per cent, respectively) during the post drug con- RIAL PR RE~-M' . ARTERI L PRESSU M HG 140F * 120} 100 80 60 109 200 300 400 500 BLOOD REMOVED BY VENESECTION AND RETRANSFUSEO-CC, 0 a, MINUTES ~ 20 25 36 Fic, 2. Caart or ARTERIAL PRESSURE AND THE AMoUNT or BLoop REMOVED BY VENESECTION AND RETRANSFUSED IN Patient J. B., FemAve, AGED 48 Hexamethonium (50 mg.) was given intravenously 30 minutes prior to be- . ginning the venesection. Yawning, pallor and a feeling of faintness developed when the blood pressure fell to its lowest point. “CONGESTION-COLLAPSE” AFTER CERTAIN HYPOTENSIVE AGENTS 441 TABLE V The effect of sodium nitrite, Cs and CCK on the arterial pressure during congestion of the extremities of sympathectomized patients Control Post-drug periad Dose Arterial pressure Arterial pressure Pt Sex | Age Drug ~ a Change : Change After five arterial After five artevial Collapse Basal min. of pressure Basal min. of pressure congestion congestion . mm, Hg mm, Hg per cent mm, He mm, He per cent M.C. | Fj 44 | Sodium] 150 mg. P.O. | 164/100 | 159/104 0 156/101 | 160/105 + 3 0 nitrite - PLD. | M | 38 Sodium | 180 mg. P.O. | 170/110 | 168/108 —2 146/94 134/90 —7 0 nitrite H.F. | M [36 |CCK [0.3 mg. LV. | 212/128 | 215/135 +3 225/135 | 220/140 0 0 H.M. |] F | 43 [C, 50'mg. LV. | 210/125 | 200/130 -1i 150/90 160/95 + 6 0 M.D.) F oj 44 ),C. . 50jmg. 1.V. | 190/120} 185/120 —1 140/100 | 130/100 -— 4 0 D.H. | F | 35 iC, 50;mg. LV. | 220/140 | 205/140 —5 140/120 | 140/120 0 0 C.M. | M } 47 1 C, 50img. LV. | 210/140 | 210/138 —i 170/125 | 140/120 —i1 0 PD. | M | 38 | C, 50jmg. L.V. | 164/110 | 160/108 —2 124/95 90/60 —22 0 * “Mean” arterial pressure = 3 gestion period. Neither of these subjects de- veloped signs or symptoms of collapse. Six of the eight had significant reductions of basal arterial pressure following the hypotensive agents and all of these exhibited increased postural hypotension. DISCUSSION The development of collapse during venous con- gestion of the extremities has been observed in normal subjects (3) and in patients who have suffered recent blood loss (9). Our observations . indicated, however, that patients given certain hy- ' potensive agents are unusually susceptible to the development of collapse produced by venous tour- “ niquets and/or hemorrhage. The type of hypo- tensive agents producing this phenomenon were . those which also cause postural hypotension (10, 11), that is, sodium nitrite, hexamethonium, tetra- ethylammonium and the dihydrogenated alkaloids of ergot; whereas hypotensive drugs such as vera- trum viride and sodium amytal which do not ordi- narily cause postural hypotension also did not in- duce congestion collapse. The increased susceptibility. to collapse during venous congestion following sodium nitrite and the sympatholytic agents conceivably might be due ‘to one of several mechanisms. Ebert and Stead have demonstrated that considerable amounts: of blood may be trapped out of the central circula- systolic +4- diastolic pressure tion during venous congestion of the limbs (3). They showed that if venous tourniquets were ap- plied for ten minutes or longer almost 30 per cent of the total blood volume may be present in the congested extremities resulting in collapse even in normal untreated subjects. It should be noted that the period of venous congestion had to be longer than five minutes to produce collapse in these untreated subjects. Since, in the present ex- periments with sodium nitrite and the “sympatho- lytic agents” hypotension appeared early in the congestion period it seemed possible that these agents induced greater pooling of blood in the con- gested extremities. This might have resulted from a reduction of “post-arteriolar tone” in the con- gested limbs produced by these drugs. The in- creased vascular capacity would thus produce criti- cal loss of blood volume from the central circula- tion, However, this possibility was disproven by actual measurement of blood volume trapped in the limbs which demonstrated that despite the ap- pearance of hypotension no more blood was trapped out during the post-drug as compared to the con- trol congestion periods. Plethysmographic measurement of the increase in volume of the calf during congestion also failed to reveal a greater increase in calf volume after as compared with before administration of these agents. In several instances the rate of increase in 442 calf volume was greater following the drug sug- gesting a decrease in arteriolar and/or post-ar- teriolar tone (or a failure of reflex arteriolar con- striction in the limb). However, marked hypo- tension occurred before the tofal volume increase was as great as that achieved at the end of five minutes of congestion in the control period. Thus, the observed changes in calf volume provided additional confirmatory data that the collapse was not associated with increased amounts of blood trapped in the limbs. The increased rate of blood loss to the extremi- ties following these hypotensive agents may have contributed somewhat to the collapse reaction by producing a rapid decrease in venous return and hence of cardiac output. However, the venesection experiments demonstrated that increased rate of blood loss was not the major cause of the hypo- tensive reaction. Figure 2 shows that the arterial pressure fell despite gradual removal of 500 cc. of blood over a period of eight minutes, whereas a similar rate of removal in the control subjects of these venesection experiments had no significant effect on the arterial pressure. Another possible explanation for the increased susceptibility to congestion collapse was that the hypotension was due to failure of homeostatic vasoconstriction either arteriolar, post-arteriolar or both, in areas other than in the congested limbs (12). The vascular system in essence is com- posed of a pump, an arterial conduit leading to a capillary reservoir and a return or venous conduit. The capillary reservoir which has a huge capacity in comparison to the total blood volume is capable of considerable variation in volume. If the reser- voir were to enlarge to its full capacity blood would be lost from the large conduits, whereas if it be- came smaller an excessive amount of blood would be forced into the central circulation. If this closed system were static, blood loss would produce a fall in pressure throughout and a diminution of venous return. However, since the normal vascular sys- tem is dynamic, the capillary reservoir is capable within certain limits of reducing its capacity in proportion to the degree of blood loss. Thus, the venous conduit remains filled and venous pressure and return are maintained, Certain hypotensive agents by doing away with the ability to reduce the volume of the capillary beds convert the vascula- « FREIS, STANTON, FINNERTY, SCHNAPER, JOHNSON, RATH, AND WILKINS ture into a more static system with the result that during blood loss the pressure falls throughout and venous return fails. If the collapse were due to failure of compensa- tory reactions to minor degrees of blood loss from the central circulation it would be expected that moderate blood loss by any route including vene- section would produce a similar hypotensive reac- tion. After the administration of sodium nitrite, the mixed dihydrogenated alkaloids of ergot or hexamethonium, hypotension and collapse did oc- cur following blood loss by venesection in amounts insufficient to induce significant hypotension in untreated individuals. These venesection experi- ments, therefore, provided direct evidence that the collapse during the post-drug congestion period was due to failure of compensatory vasoconstric- tion in the presence of relatively small amounts of blood loss. The present data are not inconsistent with pre- vious observations that sodium nitrite reduces “ve- nous” (post-arteriolar) tone but does not prevent sympathetic vasoconstrictor reflexes involving the arterioles (10, 11). In the prior studies graded ‘ congesting pressures of 10 to 50 mm. Hg were ap- plied for brief periods of only a few seconds to demonstrate the reduction in post-arteriolar tone (10). However, it must be emphasized that the congesting pressures of 60 to 100 mm. Hg used in the present experiments are far higher than those normally present in the capillaries and ven-— ules (13). When such pressures are applied for as long as five minutes maximum filling of the post- arteriolar vascular bed must occur whether or not sodium nitrite has been given. This accounts for the fact that no more blood was trapped out after as compared to prior to sodium nitrite. Collapse occurs in the post-nitrite congestion period not because of a greater total amount of blood pooled in the limbs but rather from failure of a com- pensatory reduction in the volume of the post-ar- teriolar vascular bed in areas other than in the congested limbs. Although this action of sodium nitrite is not definitely clarified the available data imply that while the drug does not prevent ar- teriolar constriction it must have some paralytic action on the post- arteriolar blood vessels (10). In this respect it differs from the sympatholytic agents which markedly inhibit reflex arteriolar constriction (11).° “CONGESTION-COLLAPSE” AFTER CERTAIN HYPOTENSIVE AGENTS Perhaps of greater significance was the observa- tion that withdrawal of a relatively small amount of blood by venesection, that is, 100 cc. or 2 to 3 per cent of the total blood volume, resulted in a perceptible decrement in arterial pressure after premedication with a hypotensive drug. This was particularly apparent after hexamethonium, a drug which apparently produces relatively complete sympathetic blockade in man (14). Such obser- vations provide an index of the sensitivity of the homeostatic regulators of the circulation. These data suggest that in the normal, untreated indi- vidual losses of less than 5 per cent of the total blood volume stimulate compensatory decreases in “the capacity of the vascular tree. Following administration of adequate doses of the sympatholytic agents the subsequent level of arterial pressure depended in large measure on the position of the patient. A head down posture usually prevented marked hypotension’ while a slight head up tilt of the body precipitated collapse. In the supine patient following the administration of C, marked reductions in arterial pressure could be induced either by tilting, venous tourniquets or moderate degree of blood loss by venesection. These observations are consistent with the con- cept that the sympathetic vasoconstrictor nerves and associated medullary vasomotor centers are primarily concerned with the rapid reflex adjust- ment of the capacity of the vascular system, toward regulation of arterial pressure under stress, rather than in the primary regulation of the “basal” level of blood pressure. oo The resistance of partially sympathectomized subjects to collapse during venous congestion ap- pears most likely to be related to the mechanisms which result in a gradual restoration of vascular “tone” in denervated areas. This resumption of tone is seen in the disappearance of increased blood flow in the forearm (15), in the hand (16), and in the hepatic-portal circuit (17) after regional sympathectomy as well as the gradual diminution of postural hypotension in patients who have un- dergone extensive splanchnicectomy (18). The mechanism. whereby vascular tone is regained is unknown (19), but apparently, as evidenced by the present experiments, it results in attainment of at least partial homeostasis without dependence on local sympathetic vasoconstrictor reflexes. 443 SUMMARY AND CONCLUSIONS 1. The prior administration of sodium nitrite, the dihydrogenated alkaloids of ergot, hexame- thonium, and to a lesser extent tetraethylam- monium to normotensive or hypertensive patients resulted in a state of increased susceptibility to the development of hypotension and collapse when the limbs were congested with venous tourniquets. 2. Veratrum viride and sodium amytal did not produce this effect. 3. Measurement of the volume of blood trapped in the limbs (dye method) and the increase in vol- ume of the calf (plethysmograph) indicated that the hypotension and collapse were not due to pool- ing of excessive amounts of blood in the con- gested limbs. , 4. The hypotension and collapse were due to failure of compensatory vasoconstriction in other areas than in the congested extremities following moderate blood loss. This was demonstrated by the observation that after the administration of sodium nitrite, the mixed dihydrogenated alkaloids of ergot or hexamethonium hypotension fre- quently with collapse occurred during venesections of only 250 to 525 cc. of blood. 5. After these drugs loss of as little as 2 to 4 per cent of the total blood volume frequently resulted in perceptible decrements of arterial pressure. Such observations illustrate the extreme sensitivity of the homeostatic vasoconstrictor mechanisms in the normal (untreated) individual. 6. Patients who had previously undergone lum- bodorsal or transthoracic sympathectomy were more resistant to hypotension during the post- drug congestion period than were non-sympathec- tomized subjects. 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