Abstract
An animal model of cardiogenic shock has been developed in the intact unanesthetized dog. 

Investigation was supported by Grants HE-06375 and HTS-5252 from the National Heart Institute, U. S. Public Health Service, and N68-39 and RN-67-65 from the Chicago and the Illinois Heart Associations.

Work was done during Drs. Lluch's and Moguilevsky's tenures of post-doctoral research fellowships from the U. S. Public Health Service (HTS-5252).

Circulation, Volume XXXIX, February 1969 Systemic pressure Probably the most serious obstacle to the proper management of cardiogenic shock is the lack of clear understanding of the performance of the injured left ventricle. Only in very few instances have left ventricular or left atrial pressures been recorded in patients with acute myocardial infarction. [3] [4] [5] Even in those cases, only spot measurements were possible because of the inaccessibility of the left side of the heart for direct puncture and the hazards of cardiac irritability in such gravely ill patients. Instead, recourse has usually been made to remote circulatory measurements (such as central venous pressure) or to indirect respiratory indices (such as the level of arterial oxygenation) to obtain some physiological guides for prognosis and treatment. 205 The present study attempted to develop a suitable model of cardiogenic shock in animals so that hemodynamic events anywhere in the circulation could be systematically and serially examined. Others have also had this interest.-9 But the previous animal models have only provided observations during anesthesia, and generally during thoracotomy. Both of these conditions are far removed from that of the patient with acute myocardial infarction since thoracotomy per se causes serious circulatory derangements, and anesthesia may depress the myocardium by a direct action.10 Also, if anesthesia is prolonged for hours, a changing state of the circulation and respiration ensues which not only complicates the appraisal of the hemodynamic features of cardiogenic shock but also modifies the neurohumoral mechanisms that may determine the pattern of circulatory adjustments to the severe myocardial injury.'1 12 Our observations on cardiogenic shock were made on intact, unanesthetized dogs. To produce cardiogenic shock, the circumflex branch of the left coronary artery was embolized with a single, minute dose of metallic mercury. The clinical syndrome of cardiogenic shock which resulted consisted of acute myocardial infarction, hypotension, tachycardia, depressed sensorium, severe oliguria to anuria, and death within 48 hr after the embolization. In all of these features, the animal model resembled the clinical picture of cardiogenic shock in man.
Methods
The experiments were carried out on 25 healthy mongrel dogs of both sexes, ranging in weight from 17 to 22 kg. The dogs were not trained, but care was taken to select docile animals that were easy to handle. A combination of a shortacting anesthetic and local anesthesia was used to place the catheters and to position them under fluoroscopic control. Thus, sodium thiopental (10 to 15 ml of a 2% solution in sodium chloride) was injected intravenously at the start of the experiment. The right carotid artery and jugular vein were exposed under sterile conditions after the areas around these vessels had been anesthetized by infiltration with lidocaine (Xylocaine, 2% solution). In nine of the dogs the left femoral artery and vein were also exposed under local anesthesia. Periodically, the area around the incision was re-infiltrated with lidocaine. Cournand catheters (no. 7) were guided, under fluoroscopic control, into the pulmonary artery and right ventricle through the jugular and femoral veins, respectively. A Sones catheter (no. 7) was also introduced via the left femoral artery into the left ventricle. A Ducor catheter (no. 8) was introduced into the ascending aorta by way of the right carotid artery; this catheter was used to embolize the circumflex coronary artery and to record the systemic arterial blood pressure. All catheters were connected to Statham pressure transducers (P23AA) and zeroed at the midsternal line. Cardiac output was measured in all the dogs by the indicator-dilution method'3 following the injection of indocyanine green (2.5 mg) into the main pulnonary artery and sampling continuously from the root of the aorta. Blood was drawn through a Gilford 103 densitometer using a Harvard withdrawal-infusion pump.
Methods
In nine dogs plasma volume was determined by the injection of 5 ml of a 0.5% solution of Evans blue (T-1824) into the superior vena cava. Samples were then collected from the same site at 10, 20, and 30 min after the injection for extrapolation of dye at zero time as proposed by Erlanger.'4 The plasma T-1824 content was measured with a Beckman Model DU spectrophotometer using a wavelength of 620,u.'5 The hematocrit was read in Wintrobe tubes centrifuged at 3,000 rpm for 30 min. Total blood volume was calculated from the plasma volume and the hematocrit of the blood samples. The oxygen content of blood from the aorta and pulmonary artery was analyzed by the manometric technique of Van Slyke and Neill. 16 The blood drawn through the densitometer for the determinations of cardiac output was reinjected after calibration. The volumes of blood drawn for the determinations of blood volume and oxygen content were immediately replaced after sampling by equal volumes of saline. In seven dogs, the urinary output was determined by collection hr to 100 mm Hg, after which a gradual decline began, terminating in a pressure of 30 mm Hg at 24 hr, that is, 10 min before death. Coinciding xvith the decrease in mean aortic pressure during the 6 hr after embolization, urinary output decreased from 65 to 20 ml/ hr; during the last 10 hr of the experiment no urine could be collected. Cardiac output remained low from the moment of embolization until the end of the experiment. Figure 2 li secj 12 24
Methods
Typical hemodynamic response observed after embolization of circumflex artery with 0. figure 3 . For the first 2 hr after embolization, the average heart rate of the 13 experiments was within normal limits; thereafter the heart rate increased and gradually leveled off at about 25% above control values. The cardiac output decreased to 30% less than the control values; it decreased further to 45% below control during the next 6 hr and subsequently remained at this level. The mean aortic pressure mirrored the changes in cardiac output; on the average, the difference from the control never exceeded 45%. The calculated peripheral resistance exceeded control value by 45% a few hours after embolization, gradually stabilizing at about 20% above control values by 16 hr. Figure 4 shows the same kinds of measurements in the last three dogs of table 1, that is, in which the aortic pressure had stabilized at control levels before death. In these dogs, the cardiac output decreased promptly after embolization but not as much as in the other 17 dogs; in all three dogs, cardiac output had returned to control levels after 8 hr. Also, the changes in heart rate and in calculated peripheral resistance were initially similar to those in the hypotensive group but became normal by 8 hr after embolization. The one dog which survived for more than 1 day (dog 20 in table 1) was also the only one able to walk 4 hr after embolization even though its figure 4 , the cardiac output and mean aortic pressure were similar to the control on these days; the cardiac rhythm was also normal. X-rays taken on the fifth day showed the distribution of the mercury to be unchanged from the original filh. This dog died 11 days after the embolization from cardiac tamponade as a consequence of the rupture of the superficial layers of the myocardium. Figure 5 summarizes the simultaneous end-diastolic pressures in both ventricles (LVEDP and RVEDP, respectively) as well as the mean pulmonary arterial pressure, cardiac output, and pulmonary vascular resistance in seven of the 17 dogs that developed cardiogenic shock. As the cardiac output fell, the left ventricular end-diastolic pressure increased and remained high until death. The end-diastolic pressure in the right ventricle followed the same general pattern, but the changes were less marked and remained within normal limits. Despite the sustained decrease in cardiac output and rise in left ventricular end-diastolic pressure, the pulmonary artery pressure remained relatively stable during the first 4 hr. However, SERIAL The hearts were cut into 12 to 15 blocks; sections were stained with hematoxylin and eosin, Van Gieson-elastin stain for collagen, phosphotungstic acid-hematoxylin for cross striations and periodic-acid-Schiff with diastase for glycogen. The histological changes and their evolution during the first few days following embolization did not differ from the pattern that has been reported for both human and experimental infarcts.17 The earliest available pathological observations were in dog 9 which died 5 hr following embolization. This dog showed free mercury in both extramyocardial and intramyocardial arteries with no evidence of damage of the surrounding vascular wall. During histological preparation the mercury was dislodged, leaving in its place an optically empty space in the distended small arteries. The myocardium revealed small areas of coagulation necrosis and hemorrhages. Periodic acid-Schiff positive material was present only in the subendocardial areas which were not infarcted.
Methods
Seven hours following embolization, the coagulative necrosis and the eosinophilia with loss of cross-striation of the myofibers were more pronounced. The fig. 8) .
Methods
Twelve hours after embolization the small~z, arteries contained fibrin and platelet thrombi; the myocardium showed more pronounced m 4 changes and infiltration with polymorphovi nuclear leukocytes. Eighteen to 24 hr after embolization, the ischemic changes of the myocardium were marlked, manifested by co-*.
Methods
agulation necrosis, eosinophilia, loss of striation, and marked infiltration of neutrophils p (figs. 9 and 10). There were also hemork.
Methods
rhages and edema. The periodic acid-Schiff stain was strongly positive in leukocytes and Twentytl-hour old infrarct characterized by loss of striation, eosinophtilia, and graiular appearance of the myofibers. Tl'here is marked infiltration of neutrophils. I atnd1 E; reduced from X 290.
Methods
MIicroscopically, the infarcted areas were undergoing repair with young fibroblasts and newly formed capillaries. However, the reparative process appeared delayed, with persistence of large areas of necrosis and infiltration xvith polymorphonuclear leukocytes and macrophages. In addition, numerous intramural arteries were completely necrotic and appeared as empty spaces surrounded by fragments of arteriacl wall.
Methods
In seven dogs, microscopic examination of the lungs showed various degrees of patchy atelectasis, marked congestion of the arteries, capillaries, and veins of the dependent portions of the lungs, and focal pern-arterial and alveolar hemorrhages ( fig. 11 ). These changes appeared more severe the longer the shock had lasted. There was marked congestion of centrolobular veins, sinusoids, and portal veins of the liver in three dogs, with focal necrosis of liver cells throughout the liver lobules.
Methods
MIicroscopic changes in the kidneys generally consisted of moderate congestion of the glomneruli and of the medullary veins. In dog 13 there was extensive necrosis of the tubular epithelium and the interstitial space was infiltrated with neutrophils.
Methods
The adrenals of dog 13 also showed extensive hemorrhages, necrosis, and leukocytic infiltration of the zona reticulosis, and hemorrhages of the medulla. In the remaining organs, the changes consisted of congestion and perivascular hemorrhbage. No dog had necrosis of the intestinal mucosa. Discussion Cardiogenic shock continues to be a troublesome complication of acute myocardial infarction. One of the major problems in its management is the unavailability of a standard therapeutic program based on a full understanding of its pathophvsiology. The present study was undertaken in the attempt to produce a standard experimental model of cardiogenic shock. After many preliminary trials, a standard procedure was developed in which embolization of the circumflex coronary artery by metallic mercury in the intact dog produced a characteristic myocardial infarction (the posterolateral wall of the left ventricle, the posterior papillary muscle, the posterior wall of the right ventricle, and the posterior portion of the septum), regularly followed by a clinical syndrome consisting of hypotension, tachycardia, depressed sensorium, severe oliguria or anuria, and death within 48 hours after embolization. The clinical picture was remarkably conisistent in all 19 dogs and, because of the lack of anesthesia and of thoracotomy, provided the opportunity for examining the hemodynamic changes under near-natural conditions.
Experimental Preparation
The use of metallic mercury in this way to damage the heart is not new. Pisa and Hammer8 produced myocardial infarction by injecting inetallic mercury into the coronary arteries of anesthetized dogs using a technique Sustained arrhythmias following embolization, which themselves could produce a "shocklike" state, did not occur. However, arrhythmias of short duration were present (4 to 15 beats) but did not appear to contribute significantly to the hypotension which developed. The most common of the arrhythmias was ventricular tachycardia with A-V dissociation ( fig. 12) .
Experimental Preparation
Even during ventricular tachycardia, the heart rate was not appreciably different from the sinus rate which obtained during the control period. Similar transient arrhythmias occur in human subjects after acute myocardial 22 infarction28-31 and in dogs with long-standing ligation of a major coronary artery. 32 It seems clear that the present studies have not only provided a model of experimental cardiogenic shock in the dog but also have provided one which has considerable relevance to the syndrome of cardiogenic shock in man. This model may be useful for uncovering some of the pathophysiological features of cardiogenic shock and for developing rational therapeutic approaches to the disorder. 300 Years Ago Paradoxical Pulse The wife of a certain citizen of London, aged 30, healthy and active enough previously, became very dejected and melancholy during the last three years of her life, suffered from breathlessness on the least exertion, had a small and often an intermittent pulse, and complained almost continuously of attacks of pain and of great physical discomfort [p. 1001 in the precordium. . . we discovered a pathological condition of the heart, to which we may rightly attribute the cause of all her troubles. The thorax was opened and the lungs were healthy enough; the pericardium, however, had become closely attached all over to the whole surface of the heart, so that it could only with difficulty be separated from it. Further, this membrane had become thick, opaque, and hard, instead of being thin and transparent, as it should naturally have been. Hence, as there was no space for the free movement of the heart, and no fluid for moistening its surface, it is little wonder that she complained all the time of these ills. Further, as the diaphragm is always attached to the pericardium in man, when the heart itself was also united to [p. 101] the pericardium, the diaphragm must of necessity have carried the heart down with it at every inspiration, and during that time must have held up and suppressed its movement. So the observed intermission of the pulse succeeded regularly at every inspiration. 

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