The Nature of Circulatory Collapse Induced by Sodium Nitrite

THE NATURE OF CIRCULATORY COLLAPSE INDUCED BY SODIUM NITRITE

Soma Weiss, … , Robert W. Wilkins, Florence W. Haynes

J Clin Invest. 1937;16(1):73-84. https://doi.org/10.1172/JCI100840.

Research Article

Find the latest version: https://jci.me/100840/pdf THE NATURE OF CIRCULATORY COLLAPSE INDUCED BY SODIUM NITRITE1 By SOMA WEISS, ROBERT W. WILKINS, AND FLORENCE W. HAYNES (From the Thorndike Memorial Laboratory, Second and Fourth Medical Services (Harvard), Boston City Hospital, and the Department of Medicine, Harvard Medical School, Boston) (Received for publication September 2, 1936) The study to be reported was undertaken with The blood flow through the hands was measured by the purpose of thr.owing light on the mechanism the plethysmographic method of Hewlett and Van Zwalu- wenburg (4) as modified by Freeman (5). The average of vasomotor collapse in man. During a previous of S to 10 determinations was taken for each flow. The investigation (1), it was noted that small doses plethysmographs were arranged on adjustable stands of sodium nitrite, which in normal subjects would which allowed free movement up or down as the subject produce no symptoms and slight if any circulatory was tilted. Usually the blood flow was determined changes in the prone position, would in the up- through one hand at a temperature of 320 C., and through the other at 450 C. At 320 C. the physiological play right position lead to progressive vasomotor col- of the vasomotor reflexes and other local vascular factors lapse, often terminating in syncope. Return to was maintained, whereas at 450 C. practically all the the prone position was followed by immediate vasoconstrictor reflexes were eliminated, and as a result recovery without ill effects. By varying the dose of complete vascular dilatation the maximal or poten- of sodium nitrite and the angle of tilting the body, tial blood flow was registered. The blood flow at 450 C. can thus be considered as an index of the cardiac the duration as well as the degree of the circula- output. In addition, we have determined by the method tory collapse could be regulated. This method, of Van Slyke and Neill (6) the femoral arterial and then, offered an opportunity of recording observa- venous blood gases. The samples were taken and de- tions on vasomotor collapse under well-controlled livered under oil, and duplicate or triplicate determina- experimental conditions. This seemed partic- tions were made on each sample. The femoral arteriovenous oxygen difference under certain conditions is an ularly desirable in view of the fact that the study index of the blood flow through the legs (7). Electro- of vasomotor collapse, as it occurs in various dis- cardiograms were taken using the three standard leads eases, is difficult because it develops unexpectedly and the fifth lead of Wolferth and Wood (8). In some in seriously ill patients and often terminates experiments the respiration was recorded by means of fatally. a Marey pneumograph. When it was not feasible to obtain all the observations METHOD described above in a single experiment, the remaining Our primary aim was to observe simultaneously sev- observations were completed under identical conditions eral aspects of the peripheral circulation before, during on another day. and after recovery from vasomotor collapse. The heart Seven young adult subjects with normal cardiovascular rate was counted by arterial palpation, by auscultation systems were studied systematically. Isolated observa- over the precordium, or from the pulse waves on the tions have been made in an additional larger group on plethysmographic tracings. The arterial blood pressure certain aspects of collapse after nitrite. At least one was determined in the upper arm at heart level by the hour after a meal the subject was placed on a tilting usual auscultatory method, using a mercury manometer. table in a horizontal position, and after all the apparatus The arterial blood pressure and the pulse volume were had been adjusted he was allowed to rest from 45 to registered by sphygmometric oscillometers. 60 minutes. The study of each subject consisted in the The venous pressure was measured in the foot by the following procedures carried out on different days. After indirect method of Krogh, Turner and Landis (2). In first obtaining resting values in the horizontal position, some experiments the pressure in the femoral vein was observations were made upon (1) the effects of eleva- determined by direct venous puncture, after the method tion to an upright position (750) for 45 minutes or of Moritz and von Tabora (3). All measurements are longer, followed by a return to the prone position; (2) given in relation to the right auricle (second costal inter- the effect of oral administration of 0.12 to 0.18 grams space). The skin temperature of the hands and feet was (2 or 3 grains) of sodium nitrite in the horizontal posi- taken by means of a thermocouple. tion for one hour; (3) the effect of the same amount of sodium nitrite followed in 10 to 20 minutes by elevation to the upright position. While in the upright position 1 This investigation was aided in part by a grant from the subjects were urged to remain motionless. At the the Josiah Macy, Jr., Foundation. height of the vasomotor collapse, which was usually 73 74 SOMA WEISS, ROBERT W. WILKINS AND FLORENCE W. HAYNES associated with syncope, the subject was promptly presents the response to the upright position with- brought back to the horizontal position and the observa- out nitrite. The maximal blood flow (at 450 C.) tions were usually continued up to an hour. through the hand remained essentially unaltered. RESULTS The arterial pulse pressure became somewhat The symptoms and clinical signs exhibited, as smaller as a result of the slight fall in the systolic well as the changes observed in the cardiovascular and the rise in the diastolic pressures, which is system, were remarkably uniform in all subjects. the physiological response to standing. The The only essential variation in different persons venous pressure in the foot became elevated and consisted in the amount of nitrite and the subse- later showed a moderate though progressive fall, quent duration of standing required to produce but remained above the hydrostatic level of the complete collapse of the circulation. The suscep- heart. The heart rate increased. The subject tibility to vasomotor collapse did not necessarily remained symptom free. After the return to the depend on the physical state. Some of the robust horizontal position the circulatory measurements and physically trained subjects developed vaso- resumed their previous values. motor collapse and syncope promptly after rela- Figure 2 presents the responses of the same tively small amounts of nitrite. subject, while remaining in the horizontal posi- The series of observations made on D. M., a tion, to 0.18 gram (3 grains) of sodium nitrite. tall, robust subject of 28 years, serve to illustrate There was slight, if any, fall in the potential blood the results obtained on all subjects. Figure 1 flow to the hand, no essential change in the arterial

HORIZONTAL TILTED TO 75O.HORIZONTALI

C.C./MIN. 40 BLOOD 4 S PER 20 FLOW 100 CiC. HAND 0

60 40 CM. H,0 w~- 20 VENOUS PRESSURE 0 M 4-.4

120 SYSTOLIC

MU. HG 100 . 4 . . O. .L...... lf 8o 60 DIASTOLIC 20 100oo BEATS PER 80 HEART RATE MIN. 9 I a I II 0 10 20 30 40 50 00 70 80 90 100 110 120 130 140 150 160 MINUTES FIG. 1. SUBJECT D. M. EFFECT OF TILTING TO 750 ON THE BLOOD FLOW THROUGH THE HAND AT 450 C., ON THE VENOUS PRESSURE IN THE FOOT, THE ARTERIAL BLOOD PRESSURE AND HEART RATE. All measurements of venous pressure are given in relation to the level of the right auricle (second costal interspace). CIRCULATORY COLLAPSE INDUCED BY SODIUM NITRITE. I 75

HORIZON TAL

NAN 02 80 C.C./MIN PER 40 BLOOD FLOWLOWl 100 C.C. 20 I HAND

0 I

110

90 MM. HG 70 HEART RAT E : ~~~~~~~~

50 DIASTOLIC a I

1101

BEATS 90 PER MIN. 70

0 10 20 30 40 50 60 70 80 90 100 110 120 130 MINUTES FIG. 2. SUBJECT D. M. EFFECT OF 0.18 GRAM OF SODIUM NITRITE ON THE BLOOD FLOW THROUGH THE HAND AT 450 C., ON THE ARTERIAL BLOOD PRESSURE AND THE HEART RATE.

pressure, and only a very slight rise in the heart The subject appeared drowsy. The pupils were rate. There were no subjective symptoms. dilated. At this point the picture corresponded Figure 3 demonstrates his responses after the in every respect to clinical vasomotor collapse. same oral dose of nitrite and subsequent elevation The moderately lowered blood flow, which de- to the upright position. Ten minutes after the veloped right after the tilting, was well main- ingestion of nitrite and while still in the hori- tained until shortly before complete collapse and zontal position, there was again only a slight fall syncope, when it rapidly fell to zero. The blood in the blood flow and moderate rise in the cardiac flow became more and more influenced by the rate. Following elevation, however, marked deep respiration, as well as by the sighing and changes occurred in rapid succession. For about yawning. The arterial pulse pressure became 5 minutes the subject remained symptom free. quite narrow soon after tilting, mainly as a result Thereafter he yawned occasionally, the intervals of a fall in the systolic pressure. The diastolic between yawns becoming progressively shorter to- pressure was well sustained. The pulse at the ward the end of the standing period. The res- wrist became small and thready, while the carotid pirations became deeper and at times assumed the pulsation was still good. Finally, the radial pulse character of sighing. He became restless. Belch- became imperceptible. It was of interest to note ing and increase in peristaltic sounds appeared. that after each yawn or sigh the pulse was in- First warm and later cold perspiration broke out stantly restored, to disappear again after several over the face and extremities, and finally it be- beats. The occurrence of yawning or sighing came beaded and profuse over the entire surface could often be foretold from the preceding disap- of the body. The skin became first slightly cy- pearance of the pulse. The venous pressure anotic and in about 20 minutes it was ashen grey. throughout the standing fell rapidly until it 76 SOMA WEISS, ROBERT W. WILKINS AND FLORENCE W. HAYNES

C.C./ MIN. 60 PER 40 100 C.C. HAND 20

20 CM. Hp 0

-10

130

MM. HG 90

120 BEATS 100 PER MIN. 80

60 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 MINUTES FIG. 3. SUBJECT D. M. EFFECT OF ADMINISTRATION OF 0.18 GRAMI OF SODIUM NITRITE, FOLLOWED BY TILTING TO 750, ON THE BLOOD FLOW THROUGH THE HAND AT 450 C., ON THE VENOUS PRESSURE IN THE FOOT, THE ARTERIAL BLOOD PRESSURE AND THE HEART RATE. After 29 minutes at 750 the subject fainted. All measurements of venous pressure are given in relation to the right auricle.

reached a level which was below the hydrostatic The plethysmographic blood flow andl respira- level of the right auricle. This indicates that the tory tracings of P. C., a 29-year-old subject. are column of blood in the inferior vena cava stood presented on Figure 4. The symptoms and signls at a level below the right auricle. The rate of the of this subject, who received 0.18 gram (3 grains) heart became rapid and remained at about 120 of sodium nitrite and was theni tilted upright, per minute until shortly before the syncope, when were essentially the same as those described above. it slowed markedly to about 80. At this time In the prone position the blood pressure and the the lblood pressure was not ol)tainable. Finally, miaximal blood flow (at 450 C.) through the the vision became dim and manifestations of loss hand showed no change after the administration of muscular power and of unconsciousness ap- of nitrite. After elevation to the upright position peared, whereupon the patient was immediately the pulse pressure became small and the pulse returned to the horizontal position. Within 15 to rapid and thready. The venous pressure fell and 20 seconds he regained consciousness and all reached a negative level before syncope. Two symptoms subsided. minutes before the fainting the blood flow was Coincident with the rapid subjective improve- still about 60 per cent of the original level, in ment after a return to the horizontal position, all spite of a plulse pressure of only 16 mm. Hg and aspects of the circulatioln also promptly returned a cardiac rate of 154 per minute. Thirty seconds to normal. The systolic and diastolic blood pres- before fainting, however, no blood flow or arterial sure, in spite of the normal heart rate, actually pressure was obtainable. The respirations be- became temporarily elevated. came deep and rapid and the cardliac rate slowe(d CIRCULATORY COLLAPSE NDUCE-I)DBY SODIUAI NITRITE. I 7 7

1. HORIZONTAL BEFORE NITRITE 2. HORIZONTAL 10 MIN. AFTER NITRITE FLOW-39.2 R.-I8 B.?-110/70 P-78 FLOW-38.6 R.-21 B.P-112/72 P-90

3. TILTED 750 2 MIN. BEFORE FAINTING 4. TILTED 7501/21MIN. BEFORE FAINTING FLOW-22.7 R-21 B.P-86/70 P-154 FLOW-? R.-32 B.P-? P-66

5. HORIZONTAL MIN. AFTER FAINTING 6. HORIZONTAL 45 MIN. AFTER FAINTING FLOW-18.4 R.:20 B.P.-104/72 P-60 FLOW-30,3 R-20 B.P-106/72 P-80

1i(;. 4. SUBJECT P. C. PLET.TH)-IYMOGR.\PH1C RECORI)S OF BLOOD FLOWv IN THF HA\N-D AT 450 C. AND RESPIRATORY TIL.\( IN-\.s AFTER 0.18 Giee.\r OF SO- DIUM NITRITE, FOLLO\WED BY TILTIING TO 75 After 16 minlutes at 75° the stullject faiinted. abruptly to 66. \Within 25 milinttes after restumii- bmoth lhandIs. Iigtlre ; rel)resents the response to in-, the horizontal position the blood flow rettlrned tilting without nitrite. Thl e l)1d1)l flow in the to normal. lhand(I at 320 C.. as eNxpcted. w-as slower than inI Because of the slowing of the lheart rate jutst the warm hand ( 450 ,. ) aln(d showed a somewhat lefore syncope, the cquestion arose as to w-hether. g-reater (lecrease x-ith tilting. prestimahly (Itie to the late alnd sudden fall in blood flowv. an(l( helnce vasoconlstrictiI n. Ultimatelv, however, the flow the finial syncopl)e, depended on1 tlis cardiac slow- became alout the samlle in both lhand(Is. As indi- n11 (. The expleriment outlin1e(d on1 Fi-ture 3 w\-as cated in Figure 6. in the (lilltedl hand the maximal therefore reipeated wsith the intramuscular admIinl- flow (lecreasedl after nitrite, while it remained the istr-atioln of 2 momi. of atropine sulphate. This same iln the co(oler halnd( w-itlh no_lrmal vasom1otor eliminatedI the car(liac sloIwin-g itlhotit, however. regulation. Figure 7 shows the responses after alterin,- the manifestations of vasolimotor collapse. 0.12gr1rrains)a (2 (If n'itrite, followed Il) tilt- In the lihllt of tlis fn(linllo it is otir Cointei1tionl Im. Here the blood flow in the (lilate(l hand that cardiac slowino is a mecondaralli festatioIl sow-ed a consi(leral)le (lecrease immee(liatelafter ali(I is dependent oIn Stimulation ot the vaguts cenl- tiltinomS, wx-lile i'n the hand wN'ith Ilorinial vasollotor ters 1w cerebral anoxemia. The (legree oft vagal r-cgullation it became utimisaillv slow, as a resilt of maitifest'atiOlls variedl ill (liftere7lt sUb'jeCts an vasCo strictiml). ()n retuiriivr the sullbject to the in some was nlot l)resent even though faintillr lorlizontal pl)sition. the rise in the coI)lh1band was occurred. partictilarly rapid. reaching the level Otf the m1Cax- Thlie observations miia(le oni S. M.. a 19-y-ear-old imal floNv, indicating anii active vasod(ilatatii. inl sullject. are tVlical of those exl)eriments in which the Co()11 hand. T11tese responIses exemplify th1e the blood flowW -was measured simultaneotlslv in ollservations miia(le in this audi in otlher stti(lies 78 SOMA WEISS, ROBERT W. WILKINS AND FLORENCE W. HAYNES

C.C./MIN. _ __ _ _ .__, PER 40 LEFT 45-. 100 C-c- 20 - RIGHT 32. , _ HAND V 0

20 VENOUS PRESSURE CM. HGO L £5-L £-A

0 - . ISO 130 SYSTOLIC

MM.HMG 110 go -LQW II

70 DIASTOLIC 130 BEATS PER 110 MIN. go HEART RATE

70 * . I II I I I 0 10 20 30 40 SO 60 70 80 90 100 110 120 130 140 150 MINUTES FIG. 5. SUBJECT S. M. EFFECT OF TILTING TO 750 ON THE BLOOD FLOW THROUGH THE HANDS, ONE AT 450 C. AND THE OTHER AT 320 C., ON THE VENOUS PRESSURE IN THE FOOT, THE ARTERIAL BLOOD PRESSURE AND THE HEART RATE. All measurements of venous pressure are given in relation to the right auricle. that the cool hand with normal vasomotor regula- TABLE I tion shows greater spontaneous variations in blood Effect of 0.18 gram of sodium nitrite, followed by tilting to 750, on the arteriovenous oxygen difference of the flow than the dilated hand. Spontaneous vaso- femoral blood of Subject P. C. constrictor responses were frequently noted in the Volumes cool hand during tilting. The rest of the cir- per cent culatory changes, as well as the other manifesta- Horizontal-control ...... 5...... s.79 tions of vasomotor collapse, were similar to those At 750, 2 minutes after tilting, 14 minutes after NaNO2 ...... 7.59 described in the first subject. Although, in Sub- At 75°, 19 minutes after tilting, 31 minutes after ject S. M., syncope developed as soon as 12 min- NaNO2 (fainting) ...... 12.26 utes after the in Horizontal, 15 minutes after tilting back to tilting, some subjects the mani- horizontal ...... 7.58 festations of collapse without syncope have been maintained for as long as an hour or more by sults of a typical experiment. As indicated, the varying the dose of nitrite and the degree of oxygen difference, and hence the blood flow, de- tilting. creased slightly soon after the tilting and reached In order to ascertain the effect of nitrite and a level of 12.26 volumes per cent at the time of tilting on the blood flow in the legs, the femoral the fainting. The degree of slowing, however, is arteriovenous oxygen difference was determined not unusual, because similar values have been at different times under the experimental condi- obtained in control observations after standing tions described above. Table I presents the re- only (7). CIRCULATORY COLLAPSE INDUCED BY SODIUM NITRITE. I 79

HORIZONTAL

NA NO2 80

C.C./MIN. 80 LEFT 45' PER BLOOD 40 I 100 C.C. FLOW RIGHT 32I* HAND 20 =* 0

130 SYSTOLIC 110 MM. HG 90

70 DIASTOLIC

-I 100 BEATS 80 HEART RATEI PER _ MIN. 60

0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 MINUTES

FIG. 6. SUBJECT S. M. EFFECT OF 0.12 GRAM OF SODIUM NITRITE ON THE BLOOD FLOW THROUGH THEZ HANDS, ONE AT 450 C. AND THE OTHER AT 320 C., ON THE ARTERIAL BLOOD PRESSURE~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~IAND THE HEART RATE.

The puilse volumnes, as measured with oscillo- whether the electrocardiogramn would reveal any meters, revealed a perceptible increase after the changes indicating anoxemia of the heart. It administration of nitrite, with the subject in the was rather unexpected to find that the changes, prone position, an observation which is in accord even during the height of the collapse, were but with the known effect of nitrite on the larger slight and mainly in the fifth lead, consisting of arteries (1). After tilting, with or without ni- considerably increased amplitude of the T wave, trite, there was a decrease in the arterial pulse vol- slightly out of proportion to the increased rate, umes of both the arm and the leg. This decrease as indicated in Figure 8. This absence of change paralleled the pulse pressure and the character of in the electrocardiographic complexes is in har- the pulse by palpation. mony with lack of symptoms referable to cardiac The changes in the skin temitperature were vari- anoxemia. able, even though care was taken to maintain DISCUSSION constant room temperature, and repeated observations were made. We were unable to correlate In this study, a correlation has been made be- these changes with any of the other measurements tween a group of clinical symptoms and signs and of the circulation. In some of the experimnents, the technical measurements of the cardiovascular a fall in skin temperature was found on standing, system and the circulation. The syndrome pre- but this was not uniformly true. sented by the subjects was identical with that ex- In view of the small brachial pulse pressure, hibited by patients with a pronounced degree of rapid heart rate and markedly decreased flow vasomotor collapse, such as is apt to occur in through the hand toward the end of the vaso- pneumonia and other infectious diseases, in an- motor collapse, it became of interest to ascertain aphylactic shock, abdominal perforation and in 80 SOMA WEISS, ROBERT W. WILKINS AND FLORENCE W. HAYNES

C.C./MIN. LEFT 45'.-. < u) 3 o w PER 40 -BLOOD w Z Unua 100 C.C. FLOW RIGHT 32-- '- l ' ' HAND 2 0 VENOUS PRESSURE CM. H20 0 * *

20 SYSTOLIC 120 - 100 MM. HG s0 60 DIASTOLIC D 160 'i 140- SEATS 120r PER MIN. 100 I HEART RATE I

60 0 10 20 30 40 50 60 70 80 90 100 110 120 130 MINUTES FIG. 7. SUBJECT S. M. EFFECT OF 0.12 GRAM OF SODIUM NITRITE FOLLOWED BY TILTING TO 750 ON THE BLOOD FLoW THROUGH THE HANDS, ONE AT 450 C. AND THE OTHER AT 320 C., ON THE VENOUS PRESSURE IN THE FOOT, THE ARTERIAL BLOOD PRESSURE AND THE HEART RATE. All measurements of venous pressure are given in relation to the right auricle.

other conditions. The significance of the study warm, hand. The small pulse pressure was lies in the fact that continuous observations have caused mainly by a fall in the systolic pressure, been made on several aspects of the circulation with fairly well maintained or even elevated dias- in subjects with normal cardiovascular and tolic pressure. Fall in the diastolic pressure was nervous systems, during the induction of col- observed during the advanced state of collapse. lapse by an agent which exerts no primary effect It is of particular significance that in the presence on the heart. Peripheral failure of the circula- of these circulatory changes the maximal blood tion was studied, therefore, in its pure form under flow was but moderately decreased, and the sub- controlled conditions. ject remained free of symptoms. As the above The primary changes in the circulation, which described circulatory changes continued, however, always preceded the symptomatic manifestations symptoms of collapse appeared which were asso- of collapse, consisted in tachycardia, small arterial ciated with a progressive decrease in the maximal pulse pressure with small pulse volume (thready blood flow. When it had decreased to from 20 pulse), fall in the venous pressure and arteriolar to 40 per cent of its normal value, pronounced vasoconstriction, as indicated by moderately de- manifestations of circulatory collapse developed, creased blood flow of the cool, but not of the although consciousness and other vital bodily re- CIRCULATORY COLLAPSE INDUCED BY SODlUM NITRITE. I 81

CONTROL NITRITE 75 FOR Z MIN. 750FOR 13 MIN. HORIZ. HORIZ. B.R 105/66 P85 BRP 102/68 P92 BR 80/60 P125 BR78/60 P 150

75FOR 36MIN. 75' IMMED. HORIZ. IMMED. HORIZ. `16 MIN. BEFORE TILTING AFTER TILTING B.P66/60 P130 B.P 62* P140 IRP 94/64 P120 BP 104/63 P. 84

LEAD 5. FIG. 8. SUBJECT D. M. ELECTROCARDIOGRAPHIC REC- ORDS AFTER THE ADMINISTRATION OF 0.18 GRAM OF SODIUM NITRITE, FOLLOWED BY TILTING TO 75'. Subject remained at 750 for 52 minutes, at the end of which he felt weak and dizzy. sponses were still maintained. Further diminu- with the approach of maximal medullary ischemia tion of the blood flow finally led to fainting, usu- the parasympathetic manifestations became pre- ally associated with rapid fall of the diastolic as dominant. Thus tachycardia, vasoconstriction well as of the systolic pressure. This syncope and dilatation of the pupils were observed simul- exhibited all the characteristics of the vasovagal taneously with sweating, yawning, belching, nau- type (9, 10). sea, cramps (indicating pyloric spasm) and in- The collapse studied furnishes an example of a creased peristalsis. Just before the onset of bodily state in which nervous manifestations arise svncope, bradycardia often appeared. This brad- secondarily to changes in the vascular system. ycardia and some of the other evidences of The marked elevation of the cardiac rate, the parasympathetic overactivity are considered as change in arterial pressure and the vasoconstrictor secondary phenomena to the collapse and syncope, response observed in the hand occurred practically since the latter syndromes occurred in some sub- instantaneously after the tilting and before the jects without these parasympathetic manifesta- appearance of subjective symptoms. The eleva- tions. Furthermore, atropine abolishes the brady- tion of the cardiac rate, which in some cases at- cardia without essentially influencing the course tained a level of 140 to 160 per minute, and the of collapse and syncope. vasoconstrictor response are attributed to the From our data and from what we know of stimulating effect of the lowered systolic pressure experiments on animals it is impossible to state on the carotid sinus and aortic depressor reflex whether this simultaneous overactivity of both mechanisms. Lowering of the arterial pressure in the sympathetic and parasympathetic systems de- these two vascular areas induces a nervous re- pends entirely upon increasing medullary ischemia sponse leading to tachycardia and vasoconstric- stimulating both types of centers directly, or upon tion, as has been shown by Hering (11), Hey- a combination of this effect and the action of the mans (12) and others. The changes observed aortic and carotid sinus depressor reflexes. In subsequently are attributed to a progressively in- response to the drop in systolic pressure, the latter creasing ischemia of the medullary centers. It is reflexes induce overactivity of certain sympathetic of particular interest to note that at this time functions, and at the same time inhibition of para- hyperactivity of both sympathetic and parasympa- sympathetic functions. The simultaneous ad- thetic functions occurred simultaiteously, although vanced ischemia of the medulla acts as a powerful 82 SOMA WEISS, ROBERT W. WILKINS AND FLORENCE W. HAYNES stimulus to the vagal (parasympathetic) centers, about will be discussed in a subsequent report which would partially or completely overcome the (21). inhibitory influence of the carotid sinus and aortic While the vasomotor collapse here described reflexes, resulting in the simultaneous parasympa- depended on the orthostatic position, collapse of thetic overactivity observed. the circulation can also occur in the horizontal The manifestations of increasing cerebral ische- position, provided larger doses of nitrite are ad- mia in man here described correspond to findings ministered or a marked susceptibility exists. The in animals. Kisch and Sakai (13), Anrep and latter was the case in a few individuals with arte- Segall (14), without full appreciation of the r6le rial hypertension in whom transient collapse and of the vascular reflexes, concluded that in animals syncope occurred in the horizontal position (1). cerebral ischemia produces initial tachycardia and Severe vasomotor collapse also follows the admin- vasoconstriction. Subsequently, the vagus center istration of large doses of nitrite to animals in the is reexcited and bradycardia or cardiac arrest fol- horizontal position. The orthostatic position, lows. Heymans (15) concluded that the vagal therefore, merely intensified the type of changes centers of the dog are easily stimulated by acute in the vascular system, which would occur even in cerebral anoxemia. The responses of the medul- the horizontal position after the administration of lary centers of animals of different species, as large doses of nitrite. well as of the same species under different kinds Prolonged orthostatic position alone, particu- of anesthesia, may show differences (16, 17, 18). larly without motion, can produce in certain Our observations on unanesthetized man in this healthy persons changes similar to those here de- and in previous studies (19, 20) are interpreted scribed. As has been discussed in connection with as indicating that under certain physiological postural hypotension (22), under certain physio- stress or pathological conditions partial or general logical conditions the postural adaptation of the overactivity of both sympathetic and parasympa- circulation may gradually become inadequate as thetic nervous systems may occur simultaneously. standing is maintained (23). In most cases the Such overactivity is produced by stimulation of chief cause is not a fault in the postural vascular peripheral reflexes or of the centers, or of both reflexes, which are often operating excessively, together. but a deficient intrinsic vascular tone or poor tone The vasomotor collapse described by us de- in the skeletal musculature. Turner, Newton and pended on the combined effect of nitrite and tilt- Haynes (24) have pointed out that certain indi- ing. The condition was precipitated by the ortho- viduals consistently have a tendency to faint after static position of the body, and was promptly a relatively short standing period. Under certain abolished by a return to the horizontal position. conditions, the upright posture may also lead to The fall in venous pressure and the resultant de- serious consequences (10). It is probable that crease in return of venous blood to the heart in the collapse studied by us could have resulted in the upright position must be due to a pooling of serious sequelae had the subjects not been re- an appreciable amount of blood somewhere en- turned promptly to the horizontal position. That tirely within the vascular bed. Had there been an the position of the body also plays a significant actual loss of a considerable amount of blood or r6le in clinical syncope and collapse is attested by plasma from within the vascular bed, as has been bedside observations. These syndromes are fre- shown to occur in certain types of circulatory fail- quently precipitated in various diseases when the ure, complete recovery within such a short period patient assumes an upright position. Further- of time after returning to the prone position could more, manifestations of collapse, which develop in not have been possible. The essential feature of the horizontal position, may promptly subside if the vasomotor collapse induced by nitrite is, there- the return of blood to the heart and the cerebral fore, a disproportion between the circulating blood ischemia are aided by lowering the head and ele- volume and the volume of the peripheral vascular vating the lower half of the body (" Trendelen- bed (decrease of the " effective blood volume"). burg position"). The exact miechanism by which the pooling of There is an apparent similarity between the col- blood resulting in this disproportion is brought lapse studied by us and the phenomenon described CIRCULATORY COLLAPSE INDUCED BY SODIUM NITRITE. I 83 as " Sportkrankheit " or " gravity shock " which disease, have been correlated with the changes in develops if subjects who have engaged in sudden the circulation. and strenuous exercise are kept immobile in the 3. Tachycardia, fall in the systolic pressure, upright position. This condition, described by small arterial pulse pressure and pulse volume, Jokl (25), Weltzien (26) and Mateeff and Pet- fall in the venous pressure in the foot, arteriolar roff (27), has been studied recently by Mateeff constriction with a moderate or pronounced de- (28), who claims that the condition depends on crease in the " actual " blood flow but with only the pooling of the blood in the dilated capillary a small decrease in the " maximal " blood flow in bed of the legs following exercise. the hands preceded the symptoms of collapse. During the state of collapse the degree of ische- 4. Pronounced manifestations of circulatory mia was not the same in various vascular areas. collapse appeared when the maximal blood flow At a time when the pulse was imperceptible over through the hands reached a level of 20 to 40 per the radial artery it was still felt over the carotid cent of the normal value. Simultaneously, there and femoral arteries. When the maximal flow was a fall in the venous pressure, usually reaching was greatly diminished in the hand, the degree of a level below that of the right auricle. Further ischemia was not always markedly abnormal in decrease in blood flow resulted in vasovagal syn- the leg. The exact cause of this difference is not cope. clear, though the distance of the area from the 5. Even in the presence of markedly decreased heart and the gravity effect must have been fac- blood flow during collapse or syncope the com- tors. It is also of interest that the electrocardio- plexes of the electrocardiogram revealed but grams failed to reveal any appreciable amount of minor changes. myocardial anoxemia. The explanation of the 6. Changes in the autonomic nervous system latter finding may lie in the possibility that the appeared as secondary manifestations to the pri- relative decrease in the coronary circulation was mary action of nitrite on the peripheral vascular less than that in the extremities, and was not out system. It is concluded that the simultaneous of proportion to the decrease in the work of the overactivity of the sympathetic and parasympa- heart, which must have been considerable. This thetic autonomic nervous systems arose first explanation seems to be applicable to similar elec- through peripheral vascular reflexes and subse- trocardiographic findings in the presence of clini- quently through medullary ischemia. cal syncope, collapse and shock (18, 19, 29). The demonstration of severe derangement of This investigation was carried out with the technical the circulation with secondary disturbances of the assistance of Miss Josephine M. Mclntire. functions of several organs in healthy subjects with normal cardiac and vascular reserves offers a BIBLIOGRAPHY rational implication for a similar state of affairs 1. Weiss, Soma, and Ellis, L. B., Influence of sodium in disease, in which there is usually an impaired nitrite on the cardiovascular system and on renal nervous or cardiovascular reserve. The reason activity in health, in arterial hypertension and in renal disease. Arch. Int; Med., 1933, 52, 105. for the progressive downhill course of patients 2. Krogh, A., Turner, A. H., and Landis, E. M., A cel- with collapse, unless the etiological factors are luloid capsule for measuring venous pressures. J. eliminated in time, becomes obvious. Clin. Invest., 1932, 11, 357. 3. Moritz, F., and von Tabora, D., tber eine Methode, SUM MARY beim Menschen den Druck in oberflachlichen Venen exakt zu bestimmen. Deutsches Arch. f. klin. 1. 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