«DESPITE the employment of a number of remedies that have been suggeMted for the control and prevention of bleeding in patients with obstructive ...»
THE HEMORRHAGIC DIATHESIS OF OBSTRUCTIVE JAUNDICE
AND ITS TREATMENT
BY OWEN H. WANGENSTEEN, M.D.
FROM THE DEPARTMENT OF SURGERY OF THE UNIVERSITT OF MINNESOTA
DESPITE the employment of a number of remedies that have been suggeMted for the control and prevention of bleeding in patients with obstructive
jaundice, hkemorrhage still continues as one of the important causes of postoperative mortality following surgical intervention for the relief of biliary obstruction. It is true, that even after prolonged obstruction in the extrahepatic bile passages, a large number of patients with icterus exhibit no abnormality in the manner in which their blood clots. However, in a rather considerable number who seek surgical relief for biliary obstruction, it is found that the blood when shed does not coagulate in the usual interval.
Following the employment of current methods used to combat the menace of haemorrhage in icteric patients, the prolonged extravascular clotting time of the blood can frequently be brought to a more normal level. The occurrence of dangerous or fatal bleeding after operation in such patients, even when the pre-operative coagulation time is normal, is not unusual. Spontaneous lethal haemorrhages in unoperated patients with obstructive jaundice are not unknown.
Within a year's time, in the Surgical Service at the University Hospital, this haemorrhagic diathesis was observed in four patients with obstructive jaundice. One died of spontaneous haemorrhage while being prepared for operation. Another with a markedly protracted coagulation time which remained refractory to the usual methods of reduction, died in coma after having had numerous spontaneous haemorrhages. A third patient died of parenchymatous bleeding three days after the excision of a benign stricture from the common bile-duct, and another almost lost his life through this dreaded complication.
The first case was in the person of a man of forty-six years, with a normal preoperative clotting time who came to operation with a jaundice of five weeks' standing.
Following preparation with calcium chloride, an obliterating cholangitis was found at operation, and cholecystostomy was done. The first seven post-operative days were uneventful. Then bleeding from the wound occurred, and a haematoma formed. Nitrogen retention occurred. After the administration by vein of calcium chloride and of glucose, and the employment of transfusions of whole blood, the hlemorrhagic tendency was controlled, and recovery followed.
In the second case the patient was a man aged sixty-six years, who presented himself with a painless jaundice of six weeks' duration with marked weight loss. Ascites was present and a diagnosis of carcinoma of the pancreas with metastases was made.
The clotting time was normal when first examined. Ten days later, it was markedly prolonged and remained so despite the employment of transfusions, calcium and
OWEN H. WANGENSTEEN"Fibrogen" in attempts at reduction. During the last few weeks of life, spontaneous haemorrhages were frequent. The patient became lethargic and died in coma a little more than three months after the onset of jaundice, Multiple hxemorrhages were found.
The cause of the biliary obstruction was a small carcinoma below the juncture of the cystic and common bile-ducts. No metastases were present. The ascites was due to biliary cirrhosis.
Case three was a patient whose gall-bladder had been removed previously, developed a stricture of the common bile-duct. Drainage had been omitted at the first operation.
The cystic duct occlusion became insufficient and bile escaped into the peritoneal cavity causing alarming symptoms. Following the evacuation of a large quantity of bile through the operative incision, the patient had an uneventful convalescence.
The sloughing process in the cystic duct probably gradually involved the common bile-duct and biliary obstruction followed. When the patient came for examination with a jaundice of two months' duration the clotting time was prolonged. The patient went home and returned for operation a few days later. Operation (excision of the stricture and the insertion of a T-tube into the common duct) was done despite a prolonged clotting time, after calcium, transfusions, and "Fibrogen" had been ineffective for its reduction. On the third post-operative day severe hTmorrhage into the abdomen occurred and the patient died despite repeated transfusions. A limited necropsy showed the peritoneal cavity to be full of blood.
Case four was that of a woman of fifty-two years of age who came with obstructive jaundice of two months' duration. The clotting time was normal. Pre-operative preparation with calcium chloride was commenced. The patient died suddenly without premonitory symptoms or apparent cause. At the postmortem examination, extensive carcinoma of the pancreas and gall-bladder with metastases was found. Hwemorrhagic casts throughout the intestinal tract explained the sudden death.
The Cause of the Hcemorrhagic Diathesis.-When the bile outflow from the liver is interrupted, retention of the biliary constituents in the blood and tissues follows. Attending this stasis, a destruction of liver tissue with marked morphological changes may ensue, together with a diminution in at least some of the functions of this important organ. An attempt will be made to evaluate the etiologic factors concerned in the genesis of the haemorrhagic diathesis of obstructive jaundice.
i. The Relation of Bile Retenttion to the Tenidency to Bleed.-The belief that the retention of bile in the organism is responsible per se for the tendency of icteric patients to bleed is accorded wide credence. King and Stewart64 on finding the blood calcium decreased in dogs with obstruction of the common bile-duct, suggested that calcium combined with the bile pigment in obstructive jaundice to render the pigments less toxic. King, Bigelow and Pearce83 later substantiated this alteration in the blood calcium in dogs with biliary obstruction, but believed that the combination of bile pigment and calcium made the latter less available for the clotting process. The delay in coagulation, and the haemorrhages of jaundice, they suggested, could be accounted for in this manner.
Cantarow, Dodek and Gordon,9 though believing that a functional deficiency of calcium exists in obstructive jaundice due to an increased amount of bile pigments in the blood and tissues, were unable to demonstrate any constant quantitative diminution in the blood calcium. The serum calcium in icteric patients with no delay in coagulation they found to be normal. Snell, Greene and Rowntree118 found that following common
HAEMORRHAGIC DIATHESIS OF OBSTRUCTIVE JAUNDICEbile-duct obstruction in dogs the calcium content of the serum did not vary from the normal. Buchbinder and Kern 8 have recently reported low serum calcium values in three cases of clinical jaundice, and in puppies with obstruction of the common bile-duct.
Zimmerman"47 obtained normal values for calcium in the blood of patients and of dogs with obstructive jaundice, and concluded that the employment of calcium as an aid to coagulation rested on no sound theoretical basis. Kirk and King' have found that, whereas normally, the diffusible portion of the blood calcium is 72.3 per cent. of the blood calcium, this figure may be reduced to 55.2 per cent. in jaundice. Kirk and King observed similar changes in other conditions, however, in which no disturbance of coagulation occurs.
Vines 131, 132 has found that it is the calcium in the combined state rather than the ionized portion that is necessary for the inauguration of normal blood clotting. In accordance with the suggestions of King and Stewart, and of King, Bigelow and Pearce that bile pigments combine with the blood calcium, it would appear that that portion which Vines states is necessary for clotting is increased in obstructive jaundice. The relation of calcium to the bleeding of icterus will be discussed at greater length in a subsequent section of this paper.
It is now generally conceded that, of the components of bile, the bile acids are the most toxic. However, King and Stewart,64 of the more recent investigators dissent from this opinion and believe the bile pigments to be responsible for the toxic symptoms occasionally exhibited by patients with obstructive jaundice. The writer has discussed this question in detail elsewhere.'36 Suffice it here to say, that a constant accompaniment of biliary obstruction is the accumulation of bile pigment in the blood and tissues.
If bile pigments were toxic for the organism in any degree, certainly all patients with prolonged obstructive jaundice should manifest symptoms of toxemia. As is well known, patients with biliary obstruction frequently continue in good health for a long time.
In consequence of the toxic and haemolytic properties of the bile acids and their ability to inhibit the coagulation of blood when present in sufficient concentration in vitro, the origin of the haemorrhagic tendency in jaundice is frequently attributed to them. More than twenty years ago, however, Morawitz and Bierich86 stated that it was unlikely that the bile acids were responsible for abnormalities in the clotting of blood of patients with obstructive jaundice. They founid that the addition of ox-bile to the shed blood of a dog in the dilution of one part of bile to twenty parts of blood had very little influence on coagulation. When the ox-bile was added in dilutions of I :IO to I :I5 the coagulation of the blood was more or less delayed. The addition of one part of bile to five parts of dog's blood completely inhibited coagulation when synthetic bile salts were employed. Very little effect was obtained with dilutions of bile salts of 4 per cent. Definite inhibition of coagulation resulted, however, when the bile salts were present in ½2 to i per cent. dilution.
This concentration, according to Morawitz and Bierich, never occurs in the blood of patients with obstructive jaundice.
Gustav Petren9 in a thorough study of the problem has arrived at the same conclusion. He found that the addition of either taurocholic or glycocholic bile salt in the concentration of o.6i per cent. would delay the extravascular clotting of ox-blood or of
OWEN H. WANGENSTEENthe venous blood of hospital patients. In eighteen patients with obstructive jaundice of long standing the addition of bile salt in the same concentration was necessary to inhibit clotting. In eight other jaundiced patients, however, the delay in coagulation was obtained with an addition of bile salt in lesser concentration.
Wildegans 142 anastomosed the common bile-duct to the vena cava in a number of dogs. All died after a few days, but in no instance could he demonstrate a delay in the coagulation of the blood.
Elsewhere,'", l3 the writer -has pointed out that the excretion of bile acids is diminished following prolonged exclusion of bile from the intestine. This decrease in bile acid formation obtains when bile is lost from the body in the presence of a complete external biliary fistula as well as when the bile escapes into the peritoneal cavity following traumatic severance of the common bile-duct. After prolonged occlusion of the common duct, the synthesis of bile acids also appears to be interfered with.
Hoppe-Seyler 62 used 30 litres of urine from a jaundiced patient to get a qualitative test for bile acids. Malkoff 78 was unable to detect the presence of bile acids in the urine of a number of icteric patients. In--patients with obstruction of the common bile-duct due to malignancy, bile acids were found in the urine early in the course of the jaundice but later could not be demonstrated. Following experimental common bile-duct obstruction in the dog he observed that the bile acids usually disappeared from the urine after a short time.
Brakefield and Schmidt,7 in studying the excretion of bile components in dogs with obstruction of the common bile-duct found that the excretion of bile acids in the urine gradually decreased -to a very small amount. Recently Snell, Greene, and Rowntree"' have reported quantitative determinations of bile acids in the blood of dogs following experimental obstruction of the common bile-duct. A marked increase in the bile acid content of the blood was observed on the second or third day after severance of the common duct, with maximal values during the second week of obstruction. Thereafter the bile acid in the blood-was found to approach the normal level.
(Snell, Greene and Rowntree,"' in accordance with the view of Weintraud,'4' accept the explanation that a decreased synthesis of bile acid by the liver occurs following prolonged biliary obstruction. One should then rather expect values for bile acids below those observed in the normal animal when bile acid synthesis begins to fail).
Rowntree, Greene, and Aldrich 105 also report quantitative bile acid determinations on patients with hepatic disease. Increased values were present early in obstructive jaundice that decreased to the normal level with long continued biliary obstruction.
It would therefore appear unlikely that the explanation of the tendency for patients with obstructive jaundice to bleed is to be found in a bile acid intoxication. The concentration of bile acids in the blood diminishes with continued -biliary obstruction, whereas the tendency toward haemorrhage is most frequently observed in those- patients where the obstruction to the bile flow has been long continued.
'. The Relation of the Lnier to the Hcernorrhagic Tendency.-The important r6le of the liver in maintaining the normal coagulability of the blood has long been known. Pawlow,94 and later Bohr,5 found that when the circulation above the diaphragm was shunted out of the general circulation, that blood drawn from the carotid artery about fifteen minutes later remained incoagulable. Following ligature of the cceliac and mesenteric arteries in a dog, Bohr 5 also observed.that blood shed four hours later remained incoagulable for more than two hours. Some years later the same observation was made by Doyon, Morel and Kareff42 who found that, following the injection