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HISTORY OF THE OFFICE OF MEDICAL HISTORY
Clinical Observations of the Effect of Intravenous Calcium Gluconate on Post-transfusion Hypotension*
First Lieutenant Joseph G. Strawitz, MC, USAR
One of the problems occasionally encountered in the management of seriously injured casualties is post-transfusion, postoperative hypotension. The syndrome occurs within the first 24 hours after transfusion and operation, developing in the seriously injured casualty who has been resuscitated with difficulty. Characteristically the hypotension will respond to additional transfusions although, clinically, the transfusion requirements, being large, may seem out of proportion to blood loss. Less frequently the hypotension will be progressive and refractory to subsequent transfusions and only temporarily responsive to vasoconstrictors. Autopsy of such patients usually revealed an increased weight of the lung.1 This finding suggested the probability of pulmonary edema secondary to cardiac insufficiency.
Following the treatment of hemorrhagic shock with citrated blood in approximately 10 per cent of a series of 70 dogs, post-transfusion hypotension was found to respond to the intravenous injection of calcium lactate.2
Meroney and Herndon,3 while working in the Renal Insufficiency Center in Korea, demonstrated the striking improvement in cardiac function when the hyperkalemic patient was treated intravenously with calcium solutions. Between 12 and 24 hours after injury, a transient state of hyperkalemia was noted in some of the more severely injured casualties who had not developed renal insufficiency.4
Scott and his associates demonstrated the marked alterations in hepatic function of the battle casualty following massive injuries.5 Citrate metabolism was not included in their hepatic studies.
The purpose of this study was the empirical evaluation of intravenous calcium gluconate in the treatment of post-transfusion hypotension. It has been based on the hypothesis that a relative insufficiency in hepatic function following severe injury may result in a slowing of the metabolism of citrate which, as an anticoagulant, is admin-
*Previously published in Archives of Surgery 70: 233, 1955.
istered in large quantities during the course of massive transfusions. This might be associated with a reduction in the concentration of ionized calcium in the serum. A reduction in the ratio of ionized calcium to potassium concentration in the serum would be even more likely, since serum potassium not infrequently rose during the postoperative period. A reduction in cardiac output might result. As the concentration of ionized calcium in the serum cannot be measured chemically, a therapeutic test of calcium appears the most direct method of approach.
Four normotensive controls, eight battle casualties, and one patient with obstructive jaundice were included in this study. Except for the last patient, all were young men in the 20- to 30-year age range who had been healthy previously.
Of the four control subjects, two were normal men and two had received minor injuries. Each was observed for 1 hour following an intravenous injection of 10 cc. of 10 per cent calcium gluconate. One patient noted an increased sense of warmth; but there was no detectable cardiovascular response. The blood pressure and pulse rate were not altered.
Three patients demonstrated a striking response to calcium.
Patient 1. This 21-year-old soldier suffered shell-fragment wounds which resulted in compound, comminuted fractures of the mandible and left humerus, a perforating wound of the left shoulder, and shell-fragment wounds of the left leg and right arm.
He arrived at a forward hospital in moderate shock. Resuscitation was difficult because of a persistently bleeding lingual artery. He was given 4,500 cc. of blood preoperatively and 5,000 cc. during operation. The left lingual artery was ligated and multiple wounds were débrided. Postoperatively the systolic blood pressure remained at 80 mm. Hg and the pulse rate 120 per minute despite infusion of an additional 2,500 cc. of blood.
Five hours postoperatively, 1 gram of calcium gluconate in 10 cc. of distilled water was given intravenously over a period of from 2 to 3 minutes. There was an immediate rise in blood pressure to 120/80 (Fig. 1); and pulse rate was 120 per minute. The pulse volume and heart tones were clinically improved. There was an increase in respiratory rate and excursion.
The blood pressure was maintained at normal levels as 500 cc. of dextran and 1,000 cc. of 5 per cent glucose in water were given over a period of several hours. His subsequent course was uncomplicated.
Patient 2. This Korean soldier suffered shell-fragment wounds of the head, left thigh, right knee, and right forearm.
Postoperative, Post-transfusion Hypotension.
At operation, a bony defect in the right frontoparietal region was explored and wounds of the arms and legs were débrided. The patient received 2,000 cc. of whole blood preoperatively and 2,000 cc. in the operating room.
Postoperatively, his blood pressure remained at levels between 80 and 90 mm. systolic for 3 hours. Further transfusion could not be justified on the basis of a minimal blood loss. One gram of calcium gluconate in 10 cc. of distilled water was given intravenously. Blood pressure immediately rose to 104/70 and was maintained at this level without further transfusion. Clinical improvement of the pulse volume was noted. There was an increase in respiratory rate and excursion.
This patient's subsequent course suggested that his normal pressure was approximately 105 mm. systolic, a pressure often noted among the Korean soldiers.
Patient 3. This 23-year-old American soldier was wounded by mortar-shell fragments sustaining penetrating wounds of the right arm, right lower thorax, right thigh, lower and mid-back. He was admitted to the surgical hospital in severe shock and required 3,500 cc. of blood and 1,000 cc. of dextran for immediate resuscitation.
Surgery revealed a lacerating wound of the right lower lobe of the lung, a large laceration of the right lobe of the liver, and penetrating wounds of the stomach and proximal ileum. Bleeding was controlled, and repair of the bowel was performed. Because of the patient's critical condition, the soft tissue wounds of the extremities were not débrided. He was returned to the ward after having received a total of 7,000 cc. of blood and 1,000 cc. of dextran. His blood pressure and pulse were unobtainable at this time. An additional 2,000 cc. of blood was given; but no clinical improvement was observed.
Two grams of calcium gluconate were then given intravenously over a period of from 3 to 4 minutes. From an imperceptible level to 85 mm. systolic, an immediate rise in blood pressure occurred. The radial pulse became palpable and the heart tones were louder. Another gram of calcium gluconate produced an elevation to 100/50. This was maintained for l½ hours, whereupon a sudden drop in pressure and an increase in pulse rate occurred. He was given alternate blood and dextran infusions and blood pressure and pulse were maintained for 16 hours until the patient died.
Autopsy revealed a retroperitoneal hematoma, large intraperitoneal blood clots, severe laceration of the right lobe of the liver, surgical absence of the right kidney, and marked pulmonary edema. Death may have been due to overtransfusion.
Patient 4. This patient was admitted in moderate shock with penetrating wounds of the left arm, face, and right thigh. He had a skull fracture, and a shell fragment was imbedded in the left parietal region. He also had fractures of the right humerous and left radius. A craniectomy was performed; and skull fragments were elevated and macerated brain tissue was removed. Débridement was performed on wounds of the arm and thigh. The anesthetic course was characterized by moderate hypotension. The patient had received 6,500 cc. of blood by the end of surgery. Despite continued transfusion for 3 hours following the operation, blood pressure remained between 90 and 100 systolic and pulse rate 140 per minute. He was given 10 cc. of a 10 per cent solution of calcium gluconate (1.0 gram) intravenously, causing an immediate rise in blood pressure to 120/80. The pulse rate, however, remained rapid. Subsequently there was a drop in blood pressure to 114/80 which was elevated by an additional infusion of 0.4 gram of calcium gluconate. Thereafter blood pressure was maintained at normal levels.
Patient 5. This 22-year-old Korean soldier was admitted to the surgical hospital in a moribund state, both lower limbs having been traumatically amputated through the upper thighs. In addition, there were large avulsive wounds of the arms. His blood pressure and pulse were unobtainable. Tourniquets were applied to the legs and
an intra-arterial transfusion was started. After infusing a total of 10,500 cc. of blood, both intra-arterially and intravenously, the systolic blood pressure remained below a level of 80 mm./Hg. He was given 10 cc. of a 10 per cent solution of calcium gluconate intravenously over a period of 10 minutes, and his blood pressure rose to 100/70. Pulse and heart tones seemed qualitatively improved. Again, there was evidence of respiratory stimulation. This blood pressure level was maintained for 1 hour after which it dropped to the previous level. Subsequent intravenous injections of calcium gluconate produced transient rises in the blood pressure, but it was not of therapeutic value. The patient died during an extensive operative débridement.
Patient 6. This 41-year-old Korean suffered shell-fragment wounds of the lower right side of the chest and abdomen. On admission to the hospital, neither blood pressure nor peripheral pulse was obtainable.
He was given 1,500 cc. of blood intra-arterially and 2,000 cc. intravenously. After several hours of resuscitation, a thoracotomy was performed, and a rather large shell fragment was removed from the right lung. Laparotomy was then performed and multiple perforations of the duodenum were repaired. Postoperatively, his systolic blood pressure was maintained at 110 mm. for 10 hours, after which it gradually began to drop. Multiple and massive transfusions were given. Thirty hours following completion of the operation and infusion of 14,000 cc. of blood, the patient was given 1.5 grams of calcium gluconate in 15 cc. of distilled water intravenously over a period of 5 minutes. Immediately there was a rise in blood pressure from 80 to 104 systolic; and this pressure was maintained for 1 hour. Subsequently the patient was evacuated to the Renal Insufficiency Center.
Patient 7. This 23-year-old American soldier sustained a penetrating shell-fragment wound of the mid-abdomen. He was admitted to the forward hospital in deep shock; and both blood pressure and pulse were unobtainable.
He was given 4,500 cc. of blood, but remained hypotensive and had a systolic pressure below 90 mm. He was given 1.5 grams of calcium gluconate intravenously over a period of 5 minutes. There was an immediate rise in blood pressure to 118/70, with a marked improvement in pulse volume and heart tones. This blood pressure was maintained for an hour with 500 cc. of blood.
Laparotomy revealed a puncture wound of the right common iliac artery which was bleeding profusely. Upon evacuation of a large retroperitoneal hematoma, the patient's course deteriorated rapidly. He died a few minutes later.
Patient 8. This Korean soldier had a perforation of the colon and mesentery; and 2,000 cc. of blood was infused prior to operation. By the end of surgery, a total of 6,000 cc. of blood had been given to com-
pensate for bleeding from the extensively damaged mesentery; and at this time, systolic blood pressure was 70 mm.
Despite the injection of 1.5 grams of calcium gluconate, he remained hypotensive for several hours. After infusion of an additional 1,500 cc. of blood, his blood pressure reached normotensive levels.
This patient's course again demonstrates that adequate replacement of blood volume is a prerequisite to other therapeutic measures.
Patient 9. This 60-year-old patient had obstructive jaundice, secondary to a carcinoma of the head of the pancreas.
Pancreatectomy was associated with moderate blood loss which did not appear to approach the 4,000 cc. of blood which was infused. Nevertheless, his systolic blood pressure remained from 80 to 85 mm./Hg for the last 45 minutes of the operation. Following a rapid intravenous injection of 2.0 grams of calcium gluconate, his systolic pressure rose immediately to 115 mm. This was the level at which it was subsequently maintained (Fig. 2).
2. Postoperative, Post-transfusion Hypotension.
Although the effect of calcium was transient in several of the patients included in this study, and several of them died as a result of their wounds, occasionally its beneficial effect was very striking. Its effect on the blood pressure was detectable within 1 or 2 minutes following injection. Patient 8 was not the only casualty who failed to respond; he was typical of a dozen such casualties who failed to respond to the injection. Patient 9 was included in this study because the pre-existing hepatic damage and the response to calcium injection were both quite marked.
Beyond the fact that several patients demonstrated a striking response and that fact justifies further study, the results cannot yet be interpreted. The dose of calcium to be injected was selected arbitrarily. One gram of calcium gluconate contains approximately 90 mg. of calcium. If all this is made available to the body as ionized calcium it is equivalent to approximately 60 per cent of the total ionized calcium in the serum. A distinct though transient rise in the ionized calcium concentration of the serum would be expected. Since the casualty may have received the equivalent of a complete exchange transfusion of citrated, calcium-bound blood, such a dose of calcium might well assist in the body's effort in returning calcium rapidly to the ionized state. The presence of an actual deficit in the ionized calcium concentration has not been demonstrated. It may be that only a relative deficit is present.
Ionic calcium is a vital cation which, together with sodium, potassium and magnesium contributes to the function of muscle and nerve cells. The role of the cations in maintaining adequate cardiovascular function is unquestioned. Further study of the cations, as well as the phosphate and citrate content of serum, may explain the mechanism of the cardiovascular response to calcium. Although noted as a response to the injection, respiratory stimulation was transient. By increasing the return of blood to the right side of the heart, it could have been a contributing but minor factor in the response.
Following massive injury and massive transfusion, secondary hypotension occasionally developed in the battle casualty. Under these circumstances hypotension would sometimes respond to the intravenous injection of calcium gluconate. Further study is necessary, but the clinical impression gained was that injection of calcium improved cardiac function. This was indicated by an increased quality in the heart sounds, pulse volume, and blood pressure.
1. Strawitz, J. G., Scully, R. E., and Vickery, A.: A Review of Postmortem Examinations in Combat Casualties. Submitted for publication.
2. Strawitz, J. G.: Unpublished data.
3. Meroney, W. H., and Herndon, R. F.: The Management of Acute Renal Insufficiency. J. A. M. A., 155: 877-883, 1954. (Chapter 4 in Volume IV of this series.)
4. Howard, J. M., Frawley, J. P., and Artz, C. P.: The Electrolyte Pattern of the Serum Following Injury and Resuscitation. A Study of the Korean Battle Casualty. To be published.
5. Scott, Russell, Jr., Howard, J. M., and Olney, J. M.: Hepatic Function of the Battle Casualty: The Systemic Response to Injury. Submitted for publication.