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Chapter 17

Chapter 17

Clinical Observations on the Role of Vasoconstrictors In the Treatment of Hypotension Following Injury

(A Study of Battle Casualties)

Captain John M. Howard, MC, USAR

A fundamental principle of resuscitation is that the physician should recognize and correct any injury and any deficiencies in the body's response to the injury. The delineation of the indications for the use of vasoconstrictors should therefore be based on the results of a study of the response of the autonomic nervous system to trauma. Such studies are, to date, incomplete. Meanwhile, clinical experiences have delineated the general areas of usefulness of this therapy as observed in the resuscitation of almost 5,000 battle casualties in Korea. These casualties represent young men (18-30 years) who were in good health prior to injury. Admission to the forward surgical hospital, where these observations were made, occurred on an average of 3.5 hours after injury.

The Preoperative Phase

Resuscitation in the preoperative phase consisted primarily of the control of hemorrhage and the correction of the blood volume deficiency. An occasional problem in the preoperative resuscitation of the very severely injured battle casualty was the development of a hypotension which was somewhat refractory to transfusion. As a result, transfusions of the order of 5,000 to 10,000 ml. of blood (10 to 20 units) were occasionally used during this period. Much of the blood was used after the apparent control of hemorrhage. In spite of transfusion of this degree, the blood pressure was occasionally slow to respond. This was an unusual experience at this early period in resuscitation, and experience with the vasoconstrictors was limited. The following patient is typical of the four such patients studied.

Patient No. 1. This Korean soldier, age 25 years, was wounded at 1040 hours, 26 April, 1953. The injury, inflicted by artillery shell fragments, included incomplete amputations of both legs, avulsive wounds of the thighs (25 cm. diameter), fracture of the left humerus, fracture of the bones of the right elbow, and avulsive wounds of both hands.

On arrival at the hospital, his vital signs were unobtainable. After 2,000 ml. of blood intravenously and 2,000 ml. intra-arterially, his


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blood pressure was 90/70, pulse rate 108 per minute. Tourniquets had been placed around the legs so that external bleeding was not too extensive.

As transfusion was slowed, his pressure dropped to 80/62.

One and one-half hours after admission and after 4,500 ml. of blood, noradrenalin was administered via a drip of blood at the rate of 40 to 56 µg./minute. His pressure rose transiently to 94/70 and then dropped to 70/60 in spite of the continued, slow administration of 1,000 ml. of blood containing 8 mg. of the drug. The drug did not affect the pulse rate which remained at 104 to 108 per minute. Another 1,000 ml. of blood was given rapidly and his pressure again rose to 102/60.

Although his pressure would respond to very rapid transfusion, it could not be stabilized and the vasoconstrictor did not appear to reduce his transfusion requirements. In the hope that débridement might reverse his course, surgery was undertaken. Under minimal anesthesia and employing four surgical teams simultaneously, débridement was undertaken, but he died at the conclusion of the 30-minute procedure.

Experience with the vasoconstrictors during the preanesthetic phase was too limited to permit generalization, but the only preoperative indication for their use which was recognized was in patients with an anatomical wound of the nervous system such as the patient with severe hypotension secondary to an injury of the central nervous system.

The Operative Phase

A fundamental difference between the battle casualty and the non-traumatic civilian patient is that the battle casualty, as he comes to anesthesia, often has a fully developed autonomic response.1 Anesthesia blocks this response. Pentothal, universally used in the Korean Theater, has been described as an autonomic depressant.2 The casualty who was well prepared by transfusion for surgery could tolerate such a blockade; the patient who was inadequately prepared could not. In the latter patient, a sharp drop in blood pressure occurred. This was noted time and time again. To the severely injured men, this drop occasionally proved fatal. Particularly in the presence of abdominal injuries where bleeding was often masked, the patient might begin anesthesia with a decreased blood volume. The blood pressure, being maintained at this time by vasoconstriction, dropped sharply with the induction of anesthesia.

The effect of noradrenalin and other vasoconstrictors in preventing or treating the vasodilatation of anesthesia has been so widely expe-


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rienced by anesthesiologists as to need no documentation here. Its effectiveness was repeatedly demonstrated by anesthesiologists in the Korean Theater. The hazard in its continued use was that it sometimes continued to mask a blood volume deficiency. This danger could only be minimized by the alertness of the surgeon and anesthesiologist.

The principle is that the deficiencies in response must be overcome. Pentothal, and other anesthetic agents to a certain extent, apparently block the response of the sympathetic nervous system. As this system is often in full response at this time, its coincident augmentation with vasoconstrictors would often appear advisable.

The Postoperative Phase

Following large transfusions, postoperative hypotension occurred not infrequently. It developed during the first 6 to 18 hours after operation and persisted for a period up to 48 hours, usually ending in recovery, but sometimes in a fatality. Therapy with additional whole blood characteristically led to the restoration of a normal blood pressure. This discussion, however, is based on the occasional casualty who remained refractory to transfusion.

The mechanism of this hypotension is uncertain. That it stems from an absolute, continuing deficit in circulating blood volume has not been disproved,3 but sometimes seemed impossible. In an occasional patient it would appear to be the result of a deficiency in the cardiovascular system.4 Although improbable, it may be that the anesthetic agents are so slowly metabolized or their effects so slowly reversed after severe trauma that the patient's vascular system remains under their influence for many hours.

The vasoconstrictors have been used in two phases of this syndrome. In one, the pressure can be maintained at 80 to 90 mm. systolic by continued transfusion; in the other, the pressure continues to drop in spite of transfusion.

Moderate, Sustained Hypotension

Patient No. 2. This soldier, age 22 years, weight 190 pounds, was wounded by shell fragments at 0200 hours, 7 February 1953. The wounds included multiple perforations of the small bowel and sigmoid; two holes in the urinary bladder; severe, comminuted, compound fractures of the left femur and left tibia; and multiple soft tissue wounds of the buttocks and abdominal wall.

At the collecting station, 0345 hours, he was given 1,000 ml. of blood. At the clearing station his blood pressure was 120/70; he was given another 1,000 ml. of blood. He arrived at the forward surgical


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hospital at 0645 hours. His pressure was normal but he appeared critically injured.

Prior to operation he received an additional 2,000 ml. of blood. His hematocrit at this time was 49 per cent, and his white blood cell count was 4,700.

Operation, lasting 7 hours, was begun at 0800 hours. It consisted of repair of eight holes in the bowel, three bowel resections, colostomy, cystostomy, and débridement of many wounds. His pressure was maintained with difficulty. His operative blood loss, measured by the washed sponge technic, was 1,670 ml. He was given 3,500 ml. of blood during this time. With the onset of pentothal induction (later nitrous oxide, oxygen, ether), his blood pressure fell from 106/84 to 60/40; his pulse rising from 100 to 116. An intravenous drip of 500 ml. of blood containing 4 mg. of noradrenalin resulted in an immediate rise in his pressure to 90/50 and then 100/60. Later in the operation this drug was much less effective.

Peritoneal contamination was massive. A hemoclastic reaction was strongly suggested by the postoperative drop in his white blood cell count to 1,850. His platelet count at this time was 710,000; clot formation was normal.

His hematocrit postoperatively was 55 per cent. His blood pressure ranged 90 to 100 systolic, 50 to 60 diastolic, and his pulse rate ranged around 120 per minute.

One hour after operation his blood volume (T-1824) was 4,720 ml., plasma volume 2,220 ml. One thousand ml. of dextran was then given over a period of 4 hours. No changes in vital signs occurred. His hematocrit was then 42.5 per cent, his plasma volume was 3,070 ml., blood volume 5,200 ml. (Evans Blue).

Throughout the first postoperative night his pressure ranged about 80/50, pulse rate 130, respirations 40. His subcutaneous veins were not prominent. On the first postoperative morning his pressure was 86/56. Blood, 1,500 ml., and dextran, 1,500 ml., were then given over a period of 7 hours. His blood pressure rose to 112/80, pulse rate 104. His plasma volume then measured 3,750 ml.; blood volume 5,980 ml.; hematocrit 41 per cent. He was then given another 500 ml. of blood.

During the second postoperative night his pressure again fell to 94/64, pulse rate 140. No bleeding was evident. Dextran, 500 ml., was given at 0330 hours (9 February 1953) with no obvious improvement. He had at this time received 9,000 ml. of blood and 2,000 ml. of dextran.

Noradrenalin, 4 mg./1,000 ml. of 5 per cent glucose in water, was dripped in at a rate of 1.6 µg/minute. The blood pressure gradually


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rose to 120/70, pulse 140 (Fig. 1). He became very flushed and his capillary refilling was rapid. Oxygen, per nasal catheter, changed his appearance from a cyanotic to a reddish flush.

Throughout the second postoperative day, his blood pressure was maintained at 115-125/65-80. His pulse rate gradually fell to 115 per minute. The noradrenalin meanwhile was slowed to 0.6 µg./minute and on the third postoperative day was withdrawn. His pressure was maintained thereafter. A total of only 1.6 mg. of the active base was used during the postoperative period.

At 2115 hours, 10 February, his blood volume measurement was repeated. His plasma volume measured 3,600 ml., blood volume 6,100 ml. Throughout this period when his pressure was above 90 to 100 mm. systolic, he diuresed rapidly. His subsequent course was uneventful.

FIGURE 1. After a prolonged postoperative period of hypotension (90 mm. systolic), his pressure responded to an extremely small dose of noradrenalin (Patient No. 2).


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Patient No. 3. This 26-year-old American soldier was wounded at 0500 hours, 24 February 1953, by mortar shell fragments. The wounds included a scalp laceration, perforation of the liver and kidney, traumatic amputation of the right thigh, and multiple soft tissue injuries.

At 0600 hours, on arrival at the battalion aid station, his blood pressure was unobtainable and he was unconscious. Both pupils were constricted. After 320 ml.of albumin and l,500 ml. of saline, his pressure was 80/40.

On arrival at the hospital, 0740 hours, by helicopter, his pressure and pulse were again unobtainable. Following 6,000 ml. of blood by 1600 hours, his pressure was 140/80, pulse rate 120. Operation was then begun under pentothal, nitrous oxide, and ether anesthesia. His pressure immediately fell to 90/60, pulse rate 124. The pressure was still low, 80/50, 3 hours later, after a total of 9,500 ml. of blood. Meanwhile, re-amputation, débridement and laparotomy had been completed.

Infusion of the 20th unit of blood, containing 4 mg. of noradrenalin, was started just prior to the completion of operation. The response in pressure was immediate (Fig. 2). The drug was gradually withdrawn and was stopped after 5 hours. Two hours later the pressure again dropped to 90/50. Again the pressure responded rapidly to noradrenalin. Three and one-half hours later the drug was again discontinued and his pressure was subsequently maintained at a normal level. Less than 2 mg. of noradrenalin had been used during the entire period of treatment.

He was evacuated on the second day after injury because of post-traumatic renal insufficiency. He had not regained consciousness at that time. Concussion, without evidence of increased intracranial pressure, was the tentative diagnosis. He died of renal insufficiency 19 days post-injury. There was no evidence of intracranial injury. Fat embolism was not excluded.

These two patients represent the rare exceptions where vasoconstrictors appeared to be beneficial in the postoperative period.

Severe, Sustained Hypotension

Patient No. 4. A 24-year-old American soldier was admitted to the forward hospital at 0530 hours, 9 hours after injury by an exploding land mine. His injuries included compound fractures of the humerus and radius, severance of the radial artery, extradural penetration of the frontal bone, perforation of the small bowel, and massive injuries of the lower extremities. His blood pressure was 50/30, his pulse unobtainable. After 4,000 ml. of blood, his pressure had returned to 110/78 and his pulse rate was 110 per minute. With pentothal


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FIGURE 2. As with the preceding patient, the mild postoperative hypotension responded to noradrenalin (Patient No. 3).

induction, his blood pressure became unobtainable. Five milligrams of neosynephrine by rapid intravenous drip resulted in a transient rise in pressure to 100/50 but again his pressure became unobtainable. Intra-arterial transfusion was then begun.

Operation was continued under ether anesthesia, administered endotracheally. Two and one-half hours were required to repair the small bowel and débride the larger wounds, including the extradural wound. His blood pressure was maintained throughout all but the induction phase by the intra-arterial and intravenous administration of 4,000 ml. of blood (8,000 ml. total since admission). His operative loss of blood (washed sponge technic) was estimated at 3,250 ml.

During the night following operation, his blood pressure was maintained in the range of 110/60, pulse 140 by the administration of an additional 4,500 ml. of blood and 300 ml. of albumin. Twenty-four hours after admission and after a total of 12,500 ml. of blood, 300 ml.


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of albumin, and 2,000 ml. of 5 per cent glucose in water, the blood pressure again fell until it could no longer be obtained.

An infusion of noradrenalin was then begun (Fig. 3). (The dosage of noradrenalin is expressed in terms of the active base, 1 mg. of which is equivalent to 2 mg. of the Lephophed bitartrate preparation which was used.) During a steady intravenous infusion of the drug at a rate of 5 µg./minute, the patient responded with an immediate rise in blood pressure which persisted for 1 hour. Thereafter he became refractory to this dosage. The blood pressure could still be titrated by greatly increasing the dose. Three hours after the drug had been started, his pressure was 140/90 and his pulse rate was 156. The rate of infusion was then decreased from 28 µg. to 14 µg./minute. Immediately thereafter his blood pressure and pulse became unobtainable. A transient response followed the subsequent increase in dose. Finally, 4 hours after starting the drug, he became completely refractory to noradrenalin and died a few minutes thereafter. His axillary temperature rose shortly before his death to 106° F. A total

FIGURE 3. The development of refractoriness to noradrenalin (Patient No. 4)


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of 13 mg. of the active base (26 mg. of the commercial preparation) was used.

Patient No. 5. This 20-year-old American soldier was wounded by mortar shell fragments at 1200 hours on 24 October 1952. He sustained injuries to the left brachial artery, a compound fracture of the left humerus, retroperitoneal perforation of the rectum and bladder, and multiple penetrating wounds of the buttocks, thighs and legs. He was given 1,500 ml. of blood at the battalion aid station and arrived at the hospital 3 hours after injury with a blood pressure which was unobtainable. While receiving blood, he was given pentothal and ether and the brachial artery was ligated.

No operative procedure beyond control of hemorrhage was attempted. After 36 units (additional) of blood, 2 units of albumin (200 ml.) and 2 units of dextran (1,000 ml.), his pressure began to fall from its peak of 80 mm. Hg. systolic. Because blood replacement had provided a blood volume which could not conceivably have been deficient, with little bleeding, and because his arterial pressure was falling and he presented no evidence of increased venous pressure, the use of vasoconstrictors was elected. In view of the experiences with the other drugs, pitressin was selected for trial. Figure 4 demonstrates the moderate but transient response to the drug. It was necessary to increase intravenous dosage of the drug gradually, but, after 11 hours, he became completely refractory even to massive doses. The refractoriness was evidently a peripheral effect for there was still no sign of increased venous pressure as might have been anticipated from the vasoconstrictive effect of pitressin on the coronary vessels. A total of 200 units of pitressin was used.

Finally, after his blood pressure had been unobtainable for 6 hours, he was given a slow intravenous drip containing noradrenalin. His pressure responded immediately, but after an hour he developed a complete refractoriness to this drug also and died a few minutes thereafter.

Patient No. 6. This 21-year-old American soldier was wounded at 2000 hours, 6 November 1952, by mortar shell fragments. His wounds included perforation of the spleen, stomach, small intestine, colon, popliteal artery, and multiple wounds of the extremities. He was admitted to the forward surgical hospital 4 hours later. He was profoundly hypotensive at this time. Following transfusion, operation was performed under pentothal, nitrous oxide, oxygen and ether.

He was moderately hypotensive throughout the 5-hour reparative operation in spite of the administration of 22 units of blood, 10 of them after the apparent control of hemorrhage. After moving the patient to the ward, his blood pressure was 80/40 but it rapidly became unobtainable. Neosynephrine, 10 mg. in 500 ml. of blood,


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FIGURE 4. Having become refractory to pitressin, the blood pressure responded transiently to noradrenalin
(Patient No. 5).

was given by rapid drip. His pressure rose to 70/50 and remained at that level during the administration of the drug.

He subsequently proved refractory to further transfusion and to neosynephrine and died in shock approximately 20 hours later.

Patient No. 7. The casualty, a 22-year-old American soldier, was wounded at 1900 hours, 23 November 1952, by the explosion of a land mine. The injuries sustained included perforation of the left lateral sinus, penetration of the buttocks, arm and both legs, fracture of the femur, and perforation of the sigmoid colon.

At the collecting station he was given 2,000 ml. of blood after which his blood pressure rose from "shock" level to 100/60.

On admission to the forward surgical hospital, 3.5 hours after injury, his blood pressure was 70/40. He remained in the shock ward until a total of 13 units of blood had been administered. His blood pressure ranged between 95/50 and 0 with a pulse rate of approximately 140 to 150. After 24 units of blood, his pressure was 124/70, pulse 120. A sigmoid colostomy was carried out under pentothal, nitrous oxide, and ether. After the repair of the lateral sinus and


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after the administration of 31 units of blood, his blood volume (radioactive chromium technic) was normal. His pressure, however, fell postoperatively to 44/30. Noradrenalin (32 mg. total) was given intravenously in the next 3 units of blood (17,000 ml. total) over a period of 4 hours. His pressure rose rapidly to 100/40, pulse 124, but he became refractory to the drug and died at the end of the fourth hour.

Patient No. 8. This American soldier, wounded by shell fragments, was admitted to the forward surgical hospital 6.5 hours after injury. His wounds included perforation of the jejunum and transverse colon. He was given 12.5 units of blood and 1 unit of dextran between the time of wounding and the completion of operation. Peritoneal contamination was massive. At the end of operation he experienced a hemoclastic reaction with a fall in blood pressure. Recovery from shock was spontaneous.

Thirty-three hours after injury his pressure fell to 70/40. His blood culture at this time revealed E. coli, beta hemolytic Streptococcus, and nonhemolytic Staphylococcus. Noradrenalin was given in massive doses but there was no persistent response in blood pressure, and he died shortly thereafter.

These patients represent the rather fruitless response to vasoconstrictors in severe postoperative shock. The drugs did not appear to meet the basic deficits of this specific group of patients.

The next two patients are described primarily because one demonstrated the development of refractoriness to one vasoconstrictor while responsive to still another, and the second developed refractoriness to neosynephrine. They are not typical of the problems more frequently encountered.

Patient No. 9. This American soldier was wounded by mine fragments at 1400 hours, 20 May 1952. Injuries included a severe injury to the right eye, laceration of the spleen, left kidney, stomach and diaphragm, and fracture of the left humerus.

He was given 100 ml. of albumin at the battalion aid station and reached the hospital approximately 1 hour after injury. His blood pressure was unobtainable. His hematocrit was 38 percent.

After receiving 3,500 ml. of blood, his pressure rose to 120/80. Reparative surgery, including removal of the spleen and eye, was uneventful. He was supported during the operation with an additional 2,000 ml. of blood.

On the third postoperative day he eviscerated through the laparotomy wound. Operative repair, requiring 1 hour, was associated with a blood pressure of 90 to 100 systolic, 50 diastolic. His pressure postoperatively ranged between 80 and 120 systolic, and between 60 and 80 diastolic. His hematocrit was 46 per cent. The total


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amount of blood administered during his hospital stay was 15 units.

On the sixth day after injury, his pressure, having previously responded to transfusion, fell to 60/40. As blood and fluid had been carried to a degree considered at that time to be optional, vasoconstrictors were used. It should be noted that at this time the patient had been expelling gas per rectum and was not distended. He did not have signs of residual peritonitis.

His response to vasoconstrictors is depicted in Figure 5. Massive doses of neosynephrine and noradrenalin were necessary to maintain his pressure. He developed a refractoriness to one drug while still responsive to the other. When his pressure fell, anuria would occur, but when the pressure was raised by vasoconstrictors, a fairly normal urinary output resulted.

Clinical evidence of a frontal lobe damage was confirmed at autopsy; there was a 2.0 cm. area of necrosis of the frontal lobe adjacent to the injured orbit.

Patient No. 10. This 21-year-old American soldier was accidentally shot with a .45 caliber pistol at 1500 hours on 24 January 1952. The

FIGURE 5. This patient developed a refractoriness first to noradrenalin and then to neosynephrine (Patient No. 9).


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missile perforated his stomach and jejunum and lodged lateral to the vertebral column. He was admitted to the hospital at 1700 hours with blood pressure of 120/60. He was given 1,000 ml. of blood, during which time the bowel perforations were closed.

Twenty-four hours after operation, with a course apparently otherwise smooth, oliguria was noted. His blood pressure at this time was unobtainable, although his cerebral blood flow seemed good as the patient was lying flat, reading a newspaper.

Evidence of a paralysis of the lower portions of the spinal cord was discovered. Paralysis had not been present at the time of admission. During the ensuing 12 hours his pressure could be titrated with a slow drip of neosynephrine. He soon became refractory to the drug and died shortly thereafter. There was no indication by blood culture or temperature of a septicemia. He had received a total of only 2,000 ml. of blood.

Autopsy revealed no evidence of vertebral or spinal injury except the presence of bloody spinal fluid, which had been demonstrated by a spinal tap prior to autopsy.

Summary

In observing the results of resuscitation of almost 5,000 battle casualties over a period of 18 months at a forward hospital in Korea, clinical observations have been recorded on the experiences with vasoconstrictors.

Their usefulness prior to operation was not fully evaluated but appeared limited to an occasional patient with anatomical wounds of the nervous system.

Anesthetic agents depress or block the response of the autonomic nervous system. Since this response appeared activated in most battle casualties by the time of hospitalization, and since it often masked a blood volume deficiency, its depression by anesthesia often resulted in hypotension. Re-augmentation of the response by vasoconstrictors during anesthesia often appeared advantageous.

The usefulness of these drugs in the treatment of refractory, postoperative hypotension in the young, previously healthy battle casualty appeared quite limited. They occasionally seemed beneficial to the patient with a mild hypotension after massive transfusion. After the blood pressure became unobtainable, the drug could be titrated to any desired level, but the patient became refractory and, without exception, died. After developing a complete refractoriness to one vasoconstrictor, the patient sometimes demonstrated a transient sensitivity to another drug.


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Although definitive studies have yet to be performed, these drugs seldom appear to meet any basic deficiency in the response of the young soldier to severe trauma. Their chief usefulness in this age group appears to be as an adjunct to anesthesia.

References

1. Stahl, R. R., Artz, C. P., Howard, J. M., and Simeone, F. A.: Studies of the Response of the Autonomic Nervous System Following Combat Injury. Surg., Gynec. & Obst. 99: 595, 1954. (Chapter 7 in Volume I of this series.)

2. Larrabee, M. G., and Holaday, D. A.: Depression of Transmission through Sympathetic Ganglia during General Anesthesia. J. Pharmacol. and Exper. Therap. 105: 400, 1952.

3. Prentice, T. C., Olney, J. M., Artz, C. P., and Howard, J. M.: Studies of Blood Volume and Transfusion Therapy in the Korean Battle Casualty. Surg., Gynec. & Obst. 99: 542, 1954. (Chapter 9, this Volume.)

4. Howard, J. M.: Shock. Symposium on Recent Advances in Medicine and Surgery Based on the Korean Experience. Army Medical Service Graduate School, Walter Reed Army Medical Center, Washington, D. C., April, 1954.

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