Battle Casualties in Korea, Studies of the Surgical Research Team, Volume I

Circulatory Homeostasis Following Massive Injury Studies of Vasodepressor and Vaso-excitatory substances in the Circulating Blood*

The liver, kidneys and circulatory system take a major part in the response of the body to massive injury. The hepatic response is indicated by major changes in the metabolism or excretion of carbohydrate, albumin, prothrombin, fibrinogen, bilirubin, urobilinogen, bromsulphalein and other substances.⁵ The kidney responds by vasoconstriction² and by alterations in its excretions of electrolytes. The cardiovascular system responds initially by vasoconstriction⁹ and by changes in cardiac rate and output. The function of the cardiovascular system as a whole may be altered as indicated by a prolonged equilibration time of water (deuterium oxide) following its intravenous administration.¹

These studies of the systemic response to trauma, carried out at a Surgical Hospital on the Eastern Front in Korea, paralleled the clinical problems encountered there. Two of these problems were post-traumatic renal insufficiency and hypotension refractory to transfusion. The latter complication was not infrequently encountered at the forward hospital. Massive transfusions of 5,000, 10,000, and even 15,000 ml. of blood were used. Hypotension sometimes persisted following hemostasis and replacement therapy, and although a normal blood volume could seldom be demonstrated,⁴ surgeons often felt that transfusion requirements exceeded blood lost by hemorrhage. Since transfusions of this magnitude seemed necessary, as indicated by a broad clinical experience, the question arose as to whether the necessity was the result of changes in the peripheral vascular bed. The purpose of this preliminary study, therefore, was to investigate one of 

*Previously published in Annals of Surgery 141: 504, 1955.

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the homeostatic mechanisms in an effort to describe the possible response to injury leading to the two clinical syndromes, refractory hypotension and post-traumatic renal insufficiency.

This homeostatic mechanism centers around two vasoactive substances, one vasodepressor (VDM, ferritin), the other vaso-excitatory (VEM), which are released by the ischemic liver and kidney respectively and exert their effects on the muscular vessels of the capillary bed. The relevance of these principles to the present study derives from their regular participation in the syndromes of experimental hemorrhagic and traumatic shock.^{6, 7}

During the period March 1952-March 1958, 20 patients were selected for study. With a single exception, these patients were healthy, young, adult soldiers prior to combat injury. Casualties were selected with various degrees of injury and at various times after injury. Some were studied on admission or prior to operation (8 to 5 hours after injury); others were studied during various stages of complications or convalescence. Patients were excluded if they had received morphine, anesthetic agents, or any other sedatives within the preceding 19 hours. Blood was drawn under sterile conditions using heparin as an anticoagulant. Maintaining sterile conditions, the blood was centrifuged, separated, the plasma placed in glass containers and frozen within 30 minutes. The frozen plasma was then shipped to the United States and kept frozen until analyses were performed 60 to 90 days later. Plasma from four control subjects was handled in a similar manner and demonstrated no significant amounts of VDM, VEM, or toxic substances when studied simultaneously in two different laboratories.

The analyses were performed by the meso-appendix assay method of Chambers and Zweifach¹⁰ as modified by Shorr and Zweifach.⁸

Analyses for the first 12 patients were carried out in the laboratory of Dr. Ephraim Shorr at the New York Hospital. In these studies the tests were carried out by a fractionation procedure which showed not only the predominant activity of the unaltered plasma but also revealed the oppositely acting factor, when present. The fractionation was based on the observation that hepatic VDM is ferritin and that its vasoactivity can be abolished by incubation with rabbit anti-ferritin serum.⁸ Hence, when the unaltered plasma gives a vasodepressor reaction, a second test after incubation with antiserum will unmask any VEM present. If the unaltered plasma is neutral and gives a VEM reaction after antiserum, experience permits the assump-

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tion that an equivalent amount of hepatic VDM is also present in the unaltered plasma. Should the unaltered plasma exhibit VEM predominance, which was not the case in the samples studied at the New York Hospital, VDM can be unmasked by inactivating VEM through aerobic incubation with kidney slices. It is believed by one of the authors (E. S.) that the VDM titers obtained are a valid though semi-quantitative index of the hepatic VDM in the plasma at the time the specimens were analyzed. Deterioration of VDM while in storage could not, however, be ruled out so that the VDM reported is believed to represent a minimal titer. Since it is not as yet possible to establish by immunochemical means, as in the case of hepatic VDM, that the vaso-excitor activity of plasma is specifically due to renal VEM, if could not be excluded that other vaso-excitor materials might also have contributed to it. This was not suspected but remains a possibility. The instability of VEM, even in the frozen state, suggests that considerable deterioration of activity occurred prior to the analyses. The analysis of the specimens from the last 12 patients was carried out at the Army Medical Service Graduate School by one of the authors (N. L.) who had trained in Dr. Shorr's laboratory. In the latter group, only the predominant activity of the unaltered plasma was determined; the VDM and VEM activity not being fractionated as in the first group.

The results of the assays are summarized in Tables 1, 2, and 3. VDM was often demonstrable and sometimes in relatively large amounts. VEM was seldom demonstrable in significant quantities.

The data demonstrate the single fact: VDM is often present in the plasma in high concentration following major injury. Of the 20 patients, 10 were studied during the first 48 hours after injury; only 2 demonstrating more than a mild VDM reaction. Fifteen patients were studied at some time after the first 48 hours and 12 demonstrated a moderate to strong VDM response. Of the 12 patients studied by the fractionated plasma technic (Fig. 1), 6 were studied after the lapse of at least 48 hours following injury, and all 6 demonstrated a moderate or strong VDM response. The VEM concentration was seldom appreciably increased (Figs. 2 and 3).

It is of interest that in no instance was there any evidence of the presence of VDM of muscle origin, which is uniformly present in the blood following experimental traumatic shock. Muscle VDM, al-

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