Survival Following Infusion of Pitressin into the Superior Mesenteric Artery to Control Bleeding Esophageal Varices in Cirrhotic Patients LINDSAY C. GETZEN, M.D., F.A.C.S., ROBERT R. BRINK, M.D., EARL F. WOLFMAN, JR., M.D., F.A.C.S.
Morbidity and mortality data from patients with bleeding esophagogastric varices treated with portosystemic shunts relate to the clinical status of the patient and to control of hemorrhage both in the immediate postoperative period as well as later. To obtain comparable data following selective infusion of pitressin into the superior mesenteric artery (SMA), records of 23 consecutive patients with cirrhosis, diagnosed by endoscopy as bleeding from varices and treated with SMA pitressin infusions, were reviewed. Twenty-four infusions were performed and hemorrhage was controlled in 12. Fourteen of the 23 patients subsequently underwent portosystemic shunts. Pitressin infusion controlled hemorrhage preoperatively in seven of these, and five survived one year or longer. The remaining seven, in whom bleeding was not controlled by pitressin, died postoperatively. One of nine patients not undergoing a portosystemic shunt survived more than eight weeks after pitressin infusion. Vascular complications occurred in seven of 17 who died. These complications and the delay between institution of pitressin and operative therapy to control variceal hemorrhage appears to be a factor in the high mortality rate. Portosystemic shunt remains the best therapy for uncontrolled hemorrhage and to prevent recurrent bleeding from esophageal varices. S ELECTIVE INFUSION OF PITRESSIN
into the superior
mesenteric artery (SMA) has been reported to be an effective method for the control of hemorrhage due to bleeding esophageal varices.2,8,9,14-16 Tachyphylaxis and other side-effects occur less frequently with the intra-arterial route than with intravenous administration and morbidity has been reported to be less than that associated with tamponade therapy.14 However, the infusion of pitressin into the SMA has not affected survival in cirrhotic patients with bleeding varices when compared to other nonoperative therapeutic modalities.9"6 In uncontrolled hemorrhage from bleeding varices, emergent portosystemic shunt remains the best method of management in cirrhotic patients.5"7 This communication presents a retrospective review of 23 consecutive cirrhotic patients with bleeding varices diagnosed by endoscopy and treated with the infusion of pitressin into the SMA. No other selective criSubmitted for publication: June 13, 1977.
From the Department of Surgery, University of California, School of Medicine, Davis, California
teria were utilized to determine this mode of treatment. Hemorrhage was effectively controlled in 12 (52%) of these. Eight of nine patients, 89%, died within eight weeks if a portosystemic shunt was not performed and was due to, or associated with, continued or recurrent bleeding. In addition, vascular complications were a factor in the mortality of these patients whether or not a portosystemic shunt was performed. The high mortality rate and vascular complications relates to the time required to establish whether or not SMA pitressin therapy will control hemorrhage and/or the associated systemic affects of the drug. Clinical Material The esophagogastroscopy records from July 1972 to May 1975 were reviewed at the University of California, Davis - Sacramento Medical Center. Twenty-three cirrhotic patients diagnosed by endoscopy to be bleeding from esophageal varices, and treated with SMA pitressin therapy were identified. Patients with acute upper gastrointestinal hemorrhage from causes other than esophageal varices treated with SMA pitressin were excluded. Those diagnosed to be bleeding from varices who underwent immediate operative therapy or were treated primarily with variceal tamponade were also excluded. Pitressin was infused into the superior mesenteric artery in the manner outlined by Nusbaum'4 and each patient was clinically staged according to Child's classification.6
Definition of Success or Failure of Pitressin Infusion to Control Variceal Hemorrhage A successful infusion was defined as one in which cessation of hemorrhage occurred during the infusion. If the hemorrhage was controlled with the use of
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pitressin but recurred upon cessation or tapering of the dosage and was again controlled by restarting or increasing the dosage, that infusion was also considered to be successful. There was no requirement that hemorrhage remain under permanent control after termination or tapering the infusion.
Adjuvant Use of the Sengstaken-Blakemore Tube If the hemorrhage was brisk during endoscopy, a Sengstaken-Blakemore tube was inserted to gain immediate control of the bleeding prior to arteriography and the institution of pitressin. When such tubes were inserted, they were deflated and left in place during the intra-arterial infusion of pitressin. Portosystemic Shunt after SMA Infusion When a portosystemic shunt was performed, the elapsed time between esophagogastroscopy and the institution of the infusion and the time between the infusion and operative intervention as well as the type of shunt constructed was noted. The type of shunts performed were either those of a portocaval or mesocaval variety. No splenorenal anastomoses were done.
End Results All survivors were followed for a minimum of one year. The cause of death was obtained from postmortem or clinical records of all patients who expired. Results The data obtained on these 23 patients with bleeding esophageal varices verified by endoscopy and treated with SMA pitressin infusion are summarized in Table 1. One was Child's Class A, three Class B, and 19 Class C. Twenty-four SMA pitressin infusions were done on these 23 patients. The success rate for controlling the hemorrhage when related to Child's Classification was one of one Class A infusion, two of four Class B infusions, and nine of 19 (48%) Class C infusions. The adjuvant use ofa Sengstaken-Blakemore tube did not alter the success rate for hemorrhage control. This tube was used in four of 12 (33%) of the successful SMA infusions and seven of 12 (58%) of the failures. From the data of this series when the diagnosis of bleeding varices was made by endoscopy, the success rate for controlling hemorrhage with SMA pitressin infusion was 12 of 24 (50%). Neither the clinical stage of the patient according to Child's classification, nor the adjuvant use of a Sengstaken-Blakemore tube altered the outcome. The mean time from esophagoscopy to control of hemorrhage with pitressin infusion when suc-
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cessful was 5.4 hours plus or minus 2.7 compared to 31.8 hours plus or minus 20.3 when unsuccessful (p < 0.001). Operative Therapy Fourteen of the 23 patients underwent portosystemic decompression. One was a Child's Class A, two were Class B, and 11 were Class C. Six portocaval and eight mesocaval anastomoses were constructed. The delay between esophagoscopy and control of hemorrhage was six hours plus or minus 2.9 with successful pitressin infusions, and 36.1 hours plus or minus 18.2 when infusion therapy failed and operative therapy was used to control the bleeding (p < 0.001).
End Results Nine of the 23 patients, 39%, did not undergo a portosystemic shunt. In four ofthese nine, 44%, hemorrhage was successfully controlled with the infusion of pitressin. These four patients were Class C. Three of the four patients died within eight weeks of control of their initial hemorrhage, a mortality rate of 75%. These deaths were associated with recurrent hemorrhage. The five remaining patients were classified as failures, one Class B and four Class C. These five deaths were associated with either continued or recurrent hemorrhage. Thus, eight of the nine patients died of recurrent or continued hemorrhage, a mortality rate of 89%. Vascular complications were noted at autopsy in two of these eight deaths; one was a splenic infarction associated with a successful pitressin infusion and one a portal vein thrombosis in an unsuccessful infusion. Vascular complications, other than hemorrhage, therefore, contributed to or were the cause of two of the eight deaths, 25%. Variceal hemorrhage was controlled by pitressin infusion in seven of the 14 patients who underwent portosystemic shunts: One Class A, one Class B, and five Class C. Five of these seven (71%) were alive one year or longer after operation; one was classified as Class B and four as Class C. The remaining seven patients whose hemorrhage was not controlled by pitressin infusion, two Class B and five Class C, died postoperatively. Thus, nine of 14 patients undergoing portosystemic shunt with endoscopically detected varices, 64%, expired. Four of these nine deaths, 44% were associated with continued or recurrent hemorrhage compared with 100% noted in eight patients who died without portosystemic shunts. Vascular complications were noted at autopsy in five deaths in this group, 55%; one pulmonary embolus and thrombosed shunt, one infarction of the right colon and terminal ileal with thrombosis of the shunt and ileocolic vein, one diffuse focal necro-
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PITRESSIN INFUSION FOR BLEEDING TABLE 1. Response to Superior Mesenteric Artery Pitressin Infusion
Patient
Child's Classification
SengstakenBlakemore Tube Used
Esophagotomy to SMA Infusion
Infusion Time
Operation after Infusion Started
1
A
Yes
4 hours
90 hours
90 hours
2*
B
Yes
8 hours
42 hours
3
B
No
6 hours
58 hours
4
C
No
2 hours
5
C
No
4 hours
Results
Operation Side-Side Mesocaval
Died 17 days postoperative, autopsy
Recurrent hemorrhage, 26 days, reinfused 58 hours
End-Side Portocaval
Alive 3
years
46 hours
Alive 2
years
71 hours
Died 4 days postinfusion,
autopsy 6
C
No
6 hours
50 hours
-
-
Died 56 days postinfusion,
no
autopsy 7
C
Yes
3 hours
Recurrent hemorrhage, died 4
26 hours
days postinfusion, no autopsy 8
C
No
6 hours
144 hours
144 hours
End-Side Portocaval
Alive I year
9
C
No
12 hours
13 days
34 days
End-Side Portocaval
Alive 2
years
10
C
Yes
6 hours
90 hours
90 hours
H Graft 20 mm Mesocaval
Alive 2
years
11
C
No
5 hours
36 hours
21 days
End-Side Portocaval
Alive I year
12
C
No
3 hours
72 hours
72 hours
H Graft 22 mm Mesocaval
3 G.I. hemorrhages during 21
days. Readmitted during 4th, operated on, died 2 days postoperative. No autopsy Died-exsanguination, autopsy
B
Yes
2 hours
4 hours
B
Yes
2 hours
47 hours
14
C
Yes
4 hours
20 hours
Died, autopsy
15
C
No
27 hours
36 hours
Died-cardiorespiratory arrest,
13 2*
47 hours
End-Side Portocaval
Died 9 days postoperative, autopsy
autopsy
16
C
Yes
5 hours
Died-continued hemorrhage,
25 hours
no
17
C
Yes
3 hours
Died-cardiorespiratory arrest,
2 hours
no
18
C
19
C
No No
7 hours
3 hours
19 hours 44 hours
autopsy
19 hours 44 hours
autopsy
Side-Side Mesocaval
Died 17 days postoperative,
H Graft 16 mm
Died 36 hours postoperative, no autopsy
no
autopsy
Mesocaval
20
C
Yes
1
hour
8 hours
8 hours
H Graft 18 mm
Died 3 days postoperative, autopsy
Mesocaval 21
C
Yes
5 hours
15 hours
15 hours
H Graft 22 mm
Died 2 days postoperative, autopsy
no
Mesocaval 22
C
No
9 hours
51 hours
51 hours
H Graft 19 mm
Died 9 days postoperative, autopsy
Mesocaval 23
C
*
No
Patient 2 infused twice.
8 hours
41 hours
41 hours
End-Side Portocaval
Died immediately postoperative, autopsy
TABLE 2. Cause of Death
Patient
Cause of Death
TABLE 2. (Continued)
Child's Classification
Response to Infusion
SMA Pitressin Infusion without Portosysttemic Shunt
5*
Recurrent hemorrhage, increased PTT, decreased platelets. Autopsy revealed splenic
6 7
C
Y(es
Recurrent hemorrhage with progressive liver failure
C
Y es
Recurrent hemorrhage, vomited, aspirated and died in acute cardiorespiratory failure Continued hemorrhage, increased PTT, decreased platelets, and progressive hepatic failure. Autopsy revealed portal vein thrombosis
C
Y(es
B
No
Continued hemorrhage with progressive hepatic failure and encephalopathy Continued hemorrhage, vomited, aspirated and died Continued hemorrhage with increased PTT, decreased platelets and died with progressive liver failure Continued hemorrhage, vomited, aspirated and died with progressive hepatic and cardiopulmonary failure
C
No
C
N0
C
No
C
No
infarction
13*
14
15 16
17
2*
Acute pulmonary failure. Autopsy; pulmonary embolus and thrombosed portocaval shunt
B
No
23*
Continued bleeding postoperatively and died, hypovolemic shock, autopsy revealed thrombosis right external iliac artery
C
No
SMA Pitressin Infusion Followed by a Mes ocaval Shunt A Yes Autopsy; thrombosed shunt and iliocolic vein with iliocolic
12 18 19
20*
infarction Uncontrolled postoperative hypovolemic shock Progressive hepatic and renal failure Recurrent hemorrhage with increased PTT, decreased platelets, vomited, aspirated and died of cardiopulmonary arrest Recurrent hemorrhage, increased PTT, and decreased platelets. Autopsy revealed diffuse focal necrosis of the stomach
Patient
Cause of Death
21
Recurrent bleeding, increased PTT, decreased platelets and cardiopulmonary failure, no autopsy Progressive cardiopulmonary failure. Autopsy; acute myocardial infarction and renal cortical infarction
22*
SMA Pitressin Infusion Followed by a Portlocaval Shunt
1*
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C
Yes
C
No
C
No
C
No
Child's Classification
Response to Infusion
C
No
C
No
* Vascular complications.
sis of the stomach, one acute myocardial infarctitn and renal cortical infarction, and one thrombosed external iliac artery. Four of these five vascular complications, 80%, were in the seven patients regarded as pitressin failures (Table 2). Discussion Attempting to control exsanguinating hemorrhage from bleeding esophageal varices in a cirrhotic patient, Kehne in 1951 administered pitressin intravenously.10 Twenty units of pitressin in 10 ml of normal saline were given over a ten minute period, and the hemorrhage stopped. During the next six months, this patient had nine additional bleeding episodes; four subsided spontaneously and five following pitressin therapy. The patient died during the last hemorrhage in hepatic coma. Kehne based his decision to use intravenously administered pitressin on two reported effects of this drug: experimental studies which revealed an abrupt fall in portal venous pressure following intravenous administration, and clinical success in controlling pulmonary hemorrhage with pitressin. Later that year, he confirmed experimentally in dogs that intravenously administered pitressin did produce an abrupt drop in portal pressure, and he successfully treated a second cirrhotic patient with bleeding esophageal varices. He concluded that pitressin was an adjuvant to, but not a substitute for, tamponade in controlling variceal hemorrhage prior to a portosystemic shunt. In 1968, Nusbaum reported that pitressin infused into the superior mesenteric artery at a rate of 0.2 units per minute in a patient with cirrhosis and bleeding from esophageal varices reduced the portal venous pressure. 13 Subsequently, Millette noted a mean reduction in portal pressure of only 9.6% after the infusion of pitressin into the SMA of patients with cirrhosis and this response was variable.12 Nusbaum and Conn also documented a difference in portal pressure responses to SMA pitressin infusion in cirrhotic patients during hemorrhage when compared to responses noted when these patients were not bleeding.15 The drop in portal pressure was less consistent during hemorrhage. These
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PITRESSIN INFUSION FOR BLEEDING
data have questioned the mechanism of pitressin in reducing portal pressure in patients with variceal hemorrhage. Control of hemorrhage from bleeding varices after SMA infusion therapy in patients with cirrhosis may relate to peripheral vasoconstriction or circular muscle contractions in the intestine with a reduction in arteriolar blood flow rather than in a direct effect upon the portal venous pressure.'2"16'20 In previous reports concerning the effect of SMA pitressin infusion upon the control of variceal hemorrhage, esophagogastroscopy was not performed on all patients.2 4'8'9""'3'6"9 When endoscopy is used to verify the cause of hemorrhage, varices, as well as other, or multiple, bleeding sites can be visualized." 7 By contrast, barium swallow or selective arteriography may confirm the presence of varices but specific bleeding sites are not identified.1'4'7 In this series, active bleeding from a varix was not always seen by the endoscopist; however, varices were visualized, fresh blood was identified in the variceal lined esophagus, and the magnitude of bleeding was established in all cases. Perhaps, the reported low success rates of pitressin to control acute hemnorrhage from esophageal varices relates to the accuracy of diagnosis prior to infusion. Regardless of the mechanism by which pitressin is associated with control of variceal hemorrhage, continued or recurrent bleeding resulting in death occurred in 81% of patients if operative therapy was not subsequently used.'3 This course was observed in eight of the nine patients in this series treated solely with pitressin. By contrast, five of seven patients (71%) who responded to pitressin and subsequently underwent portosystemic shunt survived a minimum of one year. Nusbaum reported an 89% survival rate obtained in 18 similar patients.'5 A postoperative mortality rate of 100% was observed in the seven patients who were classified as pitressin failures and who underwent a portosystemic shunt. In this group the clinical classification was not a determinant factor, but the elapsed time between endoscopy and operation was important. The average time between diagnosis and operative intervention for these patients was 36.1 hours. By contrast, when pitressin was effective and the hemorrhage was controlled within six hours the survival rate was increased. These findings are similar to those of Orloff who reported a 48% survival rate for cirrhotic patients with bleeding esophageal varices who underwent portocaval shunt within eight hours after admission to the hospital.'7 The side-effects of intravenously administered pitressin are peripheral and coronary artery vasoconstriction, decreased cardiac output, cardiac arrhythmias, antidiuresis, nausea, vomiting, abdominal cramps, and tachyphylactic reaction.'4 With SMA pitressin infu-
341
sion, Nusbaum noted no side-effects from the drug. However, Millette noted no difference in peripheral and cardiovascular effects of pitressin when given by selective arterial infusion as compared with those reported when given intravenously.'2 Several instances of mesenteric vascular thrombosis have been reported as the cause of death in patients treated by pitressin infusion. Renert et al. reported a case of mesenteric venous thrombosis and infarction of the small intestine after the infusion of pitressin into the superior mesenteric artery.'8 Berardi reported two cases of superior mesenteric artery thrombosis with portal vein thrombosis after SMA pitressin infusion for bleeding esophageal varices.3 A marked reduction in superior mesenteric artery blood flow is usually observed by arteriography during SMA pitressin infusion. 14"18"19 Also, a collapsed portal vein is frequently observed at operation when pitressin is infused. The incidence of vascular complications noted in this series, two of 12 successful (17%) and five of 12 unsuccessful (42%) pitressin infusions, question the ultimate benefit of SMA pitressin infusion in controlling variceal hemorrhage in cirrhotic patients. If prolonged pitressin therapy is used, one should consider using isoproterenol as recommended by Sirenek and Thomford to minimize vascular
complications.21 During the past 20 years, pitressin administered either intravenously or by selective arterial infusion has been used to treat approximately 5,000 patients with upper gastrointestinal hemorrhage.16 Based upon our data we concur with Kehne who stated that "Pitressin is an adjuvant to but not a substitute for Sengstaken-Blakemore tubes in controlling hemorrhage prior to a portosystemic shunt."'0 Therefore, this mode of therapy for control of hemorrhage from esophageal varices should not be used unless selective arteriography can be performed without delay and the effectiveness of treatment can be confirmed by endoscopy within six to eight hours after admission. Furthermore, the infusion of pitressin into the superior mesenteric artery should be used with caution and only to gain immediate control of bleeding varices. Portosystemic shunt remains the treatment of choice for the treatment of uncontrolled hemorrhage and to prevent recurrent bleeding after controlling hemorrhage non-
operatively. References 1. Allen, H. M., Clock, M. A. and Schuman, B. M.: Gastroduodenal Endoscopy Management of Acute Upper Gastrointes-
tinal Hemorrhage. Arch. Surg., 106:450, 1973. 2. Baum, S., Nusbaum, M. and Turmen, H. J.: The Control of Gastrointestinal Hemorrhage by Selective Mesenteric Arterial Infusion of Pitressin. Gastroenterology, 58:926, 1970. 3. Berardi, R. S.: Vascular Complications of Superior Mesenteric
342 4. 5. 6. 7.
8. 9.
10. 11.
12.
GETZEN, BRINK AND WOLFMAN
Artery Infusion with Pitressin in Treatment of Bleeding Esophageal Varices. Ann. Surg., 127:757, 1974. Bolek, B., Rosch, J. and Krippaehne, W. W.: Experience with angiography in diagnosis and treatment of acute gastrointestinal bleeding of varices etiologies. Ann. Surg., 176:419, 1972. Chandler, J. G.: Acute Variceal Bleeding in Patients with Alcoholic Cirrhosis, Va. Med. Monthly, 101:599, 1974. Child, C. G., III: The Liver and Portal Hypertension. Philadelphia, W. B. Saunders, 1964. Conn, H. 0. and Bradoff, M.: Emergency Esophagoscopy in the Diagnosis of Upper Gastrointestinal Hemorrhage: A Critical Evaluation of its Diagnostic Accuracy. Gastroenterology, 47:505, 1964. Conn, H. O., Ramsby, G. R. and Storer, E. H.: Selective Intraarterial Vasopressin in the Treatment of Upper Gastrointestinal Hemorrhage. Gastroenterology, 63:634, 1972. Conn, H. O., Ramsby, G. R., Storer, E. H., et al.: Intra-arterial Vasopressin in the Treatment of Upper Gastrointestinal Hemorrhage: A Prospective Controlled Clinical Trial. Gastroenterology, 68:211, 1975. Kehne, J. H., Hughes, F. A. and Gompertz, M. L.: The Use of Surgical Pituitrin in the Control of Esophageal Varix Bleeding. Surgery, 39:917, 1956. Marubbio, A. T., Lombardo, R. P. and Halt, P. R.: Control of Variceal Bleeding by Superior Mesenteric Artery Pitressin Perfusion: Complications and Indications. Am. J. Dig. Dis., 18:539, 1973. Millett, B., Huet, P. M., Lavoie, P. and Viablet, A.: Portal and Systemic Effects of Selective Infusion of Vasopressin in the
13.
14. 15.
16.
17. 18.
19. 20. 21.
Ann. Surg. * March 1978
Superior Mesenteric Artery in Cirrhotic Patients. Gastroenterology, 69:6, 1975. Murray-Lyon, I. M., Pugh, R. N. H., Nunnerley, H. B., et al.: Treatment of Bleeding Esophageal Varices by Infusion of Vasopressin Into the Superior Mesenteric Artery. Gut, 14:59, 1973. Nusbaum, M., Baum, S., Kuroda, K. and Blakemore, W. S.: Control of Portal Hypertension by Selective Mesenteric Arterial Drug Infusion. Arch. Surg., 97:1005, 1968. Nusbaum, M., Younis, M. T., Baum, S. and Blakemore, W. S.: Control of Portal Hypertension. Arch. Surg., 108:342, 1974. Nusbaum, M., Conn, H. D.: Arterial Vasopressin Infusion: Science or Seance? Gastroenterology, 69:263, 1975. Orloff, M. J., Chandler, J. G., Charters, A. C., III, et al.: Emergency Portocaval Shunt Treatment for Bleeding Esophageal Varices. Arch. Surg., 108:293, 1974. Renert, W. A., Burron, K. F., Field, S. L. and Casarella, W. J.: Mesenteric Venous Thrombosis and Small Bowel Infarction Following Infusion of Vasopressin into the Superior Mesenteric Artery. Radiology, 102:299, 1972. Rosch, J., Dotter, C. T. and Rose, R. W.: Selective Arterial Infusion of Vasoconstrictors in Acute Gastrointestinal Bleeding. Radiology, 99:27, 1971. Shapiro, H. and Britt, L. G.: The Action of Vasopressin on the Gastrointestinal Tract: A Review of the Literature. Am. J. Dig. Dis., 17:649, 1972. Sirenek, K. R. and Thomford, N. R.: Isoproterenol in Offsetting Adverse Effects of Vasopressin in Cirrhotic Patients. Am. J. Surg., 129:130, 1975.
Morbidity and mortality data from patients with bleeding esophagogastric varices treated with portosystemic shunts relate to the clinical status of the patient and to control of hemorrhage both in the immediate postoperative period as well as later. To obtain comparable data following selective infusion of pitressin into the superior mesenteric artery (SMA), records of 23 consecutive patients with cirrhosis, diagnosed by endoscopy as bleeding from varices and treated with SMA pitressin infusions, were reviewed. Twenty-four infusions were performed and hemorrhage was controlled in 12. Fourteen of the 23 patients subsequently underwent portosystemic shunts. Pitressin infusion controlled hemorrhage preoperatively in seven of these, and five survived one year or longer. The remaining seven, in whom bleeding was not controlled by pitressin, died postoperatively. One of nine patients not undergoing a portosystemic shunt survived more than eight weeks after pitressin infusion. Vascular complications occurred in seven of 17 who died. These complications and the delay between institution of pitressin and operative therapy to control variceal hemorrhage appears to be a factor in the high mortality rate. Portosystemic shunt remains the best therapy for uncontrolled hemorrhage and to prevent recurrent bleeding from esophageal varices. S ELECTIVE INFUSION OF PITRESSIN
into the superior
mesenteric artery (SMA) has been reported to be an effective method for the control of hemorrhage due to bleeding esophageal varices.2,8,9,14-16 Tachyphylaxis and other side-effects occur less frequently with the intra-arterial route than with intravenous administration and morbidity has been reported to be less than that associated with tamponade therapy.14 However, the infusion of pitressin into the SMA has not affected survival in cirrhotic patients with bleeding varices when compared to other nonoperative therapeutic modalities.9"6 In uncontrolled hemorrhage from bleeding varices, emergent portosystemic shunt remains the best method of management in cirrhotic patients.5"7 This communication presents a retrospective review of 23 consecutive cirrhotic patients with bleeding varices diagnosed by endoscopy and treated with the infusion of pitressin into the SMA. No other selective criSubmitted for publication: June 13, 1977.
From the Department of Surgery, University of California, School of Medicine, Davis, California
teria were utilized to determine this mode of treatment. Hemorrhage was effectively controlled in 12 (52%) of these. Eight of nine patients, 89%, died within eight weeks if a portosystemic shunt was not performed and was due to, or associated with, continued or recurrent bleeding. In addition, vascular complications were a factor in the mortality of these patients whether or not a portosystemic shunt was performed. The high mortality rate and vascular complications relates to the time required to establish whether or not SMA pitressin therapy will control hemorrhage and/or the associated systemic affects of the drug. Clinical Material The esophagogastroscopy records from July 1972 to May 1975 were reviewed at the University of California, Davis - Sacramento Medical Center. Twenty-three cirrhotic patients diagnosed by endoscopy to be bleeding from esophageal varices, and treated with SMA pitressin therapy were identified. Patients with acute upper gastrointestinal hemorrhage from causes other than esophageal varices treated with SMA pitressin were excluded. Those diagnosed to be bleeding from varices who underwent immediate operative therapy or were treated primarily with variceal tamponade were also excluded. Pitressin was infused into the superior mesenteric artery in the manner outlined by Nusbaum'4 and each patient was clinically staged according to Child's classification.6
Definition of Success or Failure of Pitressin Infusion to Control Variceal Hemorrhage A successful infusion was defined as one in which cessation of hemorrhage occurred during the infusion. If the hemorrhage was controlled with the use of
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GETZEN, BRINK AND WOLFMAN
pitressin but recurred upon cessation or tapering of the dosage and was again controlled by restarting or increasing the dosage, that infusion was also considered to be successful. There was no requirement that hemorrhage remain under permanent control after termination or tapering the infusion.
Adjuvant Use of the Sengstaken-Blakemore Tube If the hemorrhage was brisk during endoscopy, a Sengstaken-Blakemore tube was inserted to gain immediate control of the bleeding prior to arteriography and the institution of pitressin. When such tubes were inserted, they were deflated and left in place during the intra-arterial infusion of pitressin. Portosystemic Shunt after SMA Infusion When a portosystemic shunt was performed, the elapsed time between esophagogastroscopy and the institution of the infusion and the time between the infusion and operative intervention as well as the type of shunt constructed was noted. The type of shunts performed were either those of a portocaval or mesocaval variety. No splenorenal anastomoses were done.
End Results All survivors were followed for a minimum of one year. The cause of death was obtained from postmortem or clinical records of all patients who expired. Results The data obtained on these 23 patients with bleeding esophageal varices verified by endoscopy and treated with SMA pitressin infusion are summarized in Table 1. One was Child's Class A, three Class B, and 19 Class C. Twenty-four SMA pitressin infusions were done on these 23 patients. The success rate for controlling the hemorrhage when related to Child's Classification was one of one Class A infusion, two of four Class B infusions, and nine of 19 (48%) Class C infusions. The adjuvant use ofa Sengstaken-Blakemore tube did not alter the success rate for hemorrhage control. This tube was used in four of 12 (33%) of the successful SMA infusions and seven of 12 (58%) of the failures. From the data of this series when the diagnosis of bleeding varices was made by endoscopy, the success rate for controlling hemorrhage with SMA pitressin infusion was 12 of 24 (50%). Neither the clinical stage of the patient according to Child's classification, nor the adjuvant use of a Sengstaken-Blakemore tube altered the outcome. The mean time from esophagoscopy to control of hemorrhage with pitressin infusion when suc-
Ann. Surg.
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cessful was 5.4 hours plus or minus 2.7 compared to 31.8 hours plus or minus 20.3 when unsuccessful (p < 0.001). Operative Therapy Fourteen of the 23 patients underwent portosystemic decompression. One was a Child's Class A, two were Class B, and 11 were Class C. Six portocaval and eight mesocaval anastomoses were constructed. The delay between esophagoscopy and control of hemorrhage was six hours plus or minus 2.9 with successful pitressin infusions, and 36.1 hours plus or minus 18.2 when infusion therapy failed and operative therapy was used to control the bleeding (p < 0.001).
End Results Nine of the 23 patients, 39%, did not undergo a portosystemic shunt. In four ofthese nine, 44%, hemorrhage was successfully controlled with the infusion of pitressin. These four patients were Class C. Three of the four patients died within eight weeks of control of their initial hemorrhage, a mortality rate of 75%. These deaths were associated with recurrent hemorrhage. The five remaining patients were classified as failures, one Class B and four Class C. These five deaths were associated with either continued or recurrent hemorrhage. Thus, eight of the nine patients died of recurrent or continued hemorrhage, a mortality rate of 89%. Vascular complications were noted at autopsy in two of these eight deaths; one was a splenic infarction associated with a successful pitressin infusion and one a portal vein thrombosis in an unsuccessful infusion. Vascular complications, other than hemorrhage, therefore, contributed to or were the cause of two of the eight deaths, 25%. Variceal hemorrhage was controlled by pitressin infusion in seven of the 14 patients who underwent portosystemic shunts: One Class A, one Class B, and five Class C. Five of these seven (71%) were alive one year or longer after operation; one was classified as Class B and four as Class C. The remaining seven patients whose hemorrhage was not controlled by pitressin infusion, two Class B and five Class C, died postoperatively. Thus, nine of 14 patients undergoing portosystemic shunt with endoscopically detected varices, 64%, expired. Four of these nine deaths, 44% were associated with continued or recurrent hemorrhage compared with 100% noted in eight patients who died without portosystemic shunts. Vascular complications were noted at autopsy in five deaths in this group, 55%; one pulmonary embolus and thrombosed shunt, one infarction of the right colon and terminal ileal with thrombosis of the shunt and ileocolic vein, one diffuse focal necro-
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PITRESSIN INFUSION FOR BLEEDING TABLE 1. Response to Superior Mesenteric Artery Pitressin Infusion
Patient
Child's Classification
SengstakenBlakemore Tube Used
Esophagotomy to SMA Infusion
Infusion Time
Operation after Infusion Started
1
A
Yes
4 hours
90 hours
90 hours
2*
B
Yes
8 hours
42 hours
3
B
No
6 hours
58 hours
4
C
No
2 hours
5
C
No
4 hours
Results
Operation Side-Side Mesocaval
Died 17 days postoperative, autopsy
Recurrent hemorrhage, 26 days, reinfused 58 hours
End-Side Portocaval
Alive 3
years
46 hours
Alive 2
years
71 hours
Died 4 days postinfusion,
autopsy 6
C
No
6 hours
50 hours
-
-
Died 56 days postinfusion,
no
autopsy 7
C
Yes
3 hours
Recurrent hemorrhage, died 4
26 hours
days postinfusion, no autopsy 8
C
No
6 hours
144 hours
144 hours
End-Side Portocaval
Alive I year
9
C
No
12 hours
13 days
34 days
End-Side Portocaval
Alive 2
years
10
C
Yes
6 hours
90 hours
90 hours
H Graft 20 mm Mesocaval
Alive 2
years
11
C
No
5 hours
36 hours
21 days
End-Side Portocaval
Alive I year
12
C
No
3 hours
72 hours
72 hours
H Graft 22 mm Mesocaval
3 G.I. hemorrhages during 21
days. Readmitted during 4th, operated on, died 2 days postoperative. No autopsy Died-exsanguination, autopsy
B
Yes
2 hours
4 hours
B
Yes
2 hours
47 hours
14
C
Yes
4 hours
20 hours
Died, autopsy
15
C
No
27 hours
36 hours
Died-cardiorespiratory arrest,
13 2*
47 hours
End-Side Portocaval
Died 9 days postoperative, autopsy
autopsy
16
C
Yes
5 hours
Died-continued hemorrhage,
25 hours
no
17
C
Yes
3 hours
Died-cardiorespiratory arrest,
2 hours
no
18
C
19
C
No No
7 hours
3 hours
19 hours 44 hours
autopsy
19 hours 44 hours
autopsy
Side-Side Mesocaval
Died 17 days postoperative,
H Graft 16 mm
Died 36 hours postoperative, no autopsy
no
autopsy
Mesocaval
20
C
Yes
1
hour
8 hours
8 hours
H Graft 18 mm
Died 3 days postoperative, autopsy
Mesocaval 21
C
Yes
5 hours
15 hours
15 hours
H Graft 22 mm
Died 2 days postoperative, autopsy
no
Mesocaval 22
C
No
9 hours
51 hours
51 hours
H Graft 19 mm
Died 9 days postoperative, autopsy
Mesocaval 23
C
*
No
Patient 2 infused twice.
8 hours
41 hours
41 hours
End-Side Portocaval
Died immediately postoperative, autopsy
TABLE 2. Cause of Death
Patient
Cause of Death
TABLE 2. (Continued)
Child's Classification
Response to Infusion
SMA Pitressin Infusion without Portosysttemic Shunt
5*
Recurrent hemorrhage, increased PTT, decreased platelets. Autopsy revealed splenic
6 7
C
Y(es
Recurrent hemorrhage with progressive liver failure
C
Y es
Recurrent hemorrhage, vomited, aspirated and died in acute cardiorespiratory failure Continued hemorrhage, increased PTT, decreased platelets, and progressive hepatic failure. Autopsy revealed portal vein thrombosis
C
Y(es
B
No
Continued hemorrhage with progressive hepatic failure and encephalopathy Continued hemorrhage, vomited, aspirated and died Continued hemorrhage with increased PTT, decreased platelets and died with progressive liver failure Continued hemorrhage, vomited, aspirated and died with progressive hepatic and cardiopulmonary failure
C
No
C
N0
C
No
C
No
infarction
13*
14
15 16
17
2*
Acute pulmonary failure. Autopsy; pulmonary embolus and thrombosed portocaval shunt
B
No
23*
Continued bleeding postoperatively and died, hypovolemic shock, autopsy revealed thrombosis right external iliac artery
C
No
SMA Pitressin Infusion Followed by a Mes ocaval Shunt A Yes Autopsy; thrombosed shunt and iliocolic vein with iliocolic
12 18 19
20*
infarction Uncontrolled postoperative hypovolemic shock Progressive hepatic and renal failure Recurrent hemorrhage with increased PTT, decreased platelets, vomited, aspirated and died of cardiopulmonary arrest Recurrent hemorrhage, increased PTT, and decreased platelets. Autopsy revealed diffuse focal necrosis of the stomach
Patient
Cause of Death
21
Recurrent bleeding, increased PTT, decreased platelets and cardiopulmonary failure, no autopsy Progressive cardiopulmonary failure. Autopsy; acute myocardial infarction and renal cortical infarction
22*
SMA Pitressin Infusion Followed by a Portlocaval Shunt
1*
Ann. Surg. a March 1978
GETZEN, BRINK AND WOLFMAN
340
C
Yes
C
No
C
No
C
No
Child's Classification
Response to Infusion
C
No
C
No
* Vascular complications.
sis of the stomach, one acute myocardial infarctitn and renal cortical infarction, and one thrombosed external iliac artery. Four of these five vascular complications, 80%, were in the seven patients regarded as pitressin failures (Table 2). Discussion Attempting to control exsanguinating hemorrhage from bleeding esophageal varices in a cirrhotic patient, Kehne in 1951 administered pitressin intravenously.10 Twenty units of pitressin in 10 ml of normal saline were given over a ten minute period, and the hemorrhage stopped. During the next six months, this patient had nine additional bleeding episodes; four subsided spontaneously and five following pitressin therapy. The patient died during the last hemorrhage in hepatic coma. Kehne based his decision to use intravenously administered pitressin on two reported effects of this drug: experimental studies which revealed an abrupt fall in portal venous pressure following intravenous administration, and clinical success in controlling pulmonary hemorrhage with pitressin. Later that year, he confirmed experimentally in dogs that intravenously administered pitressin did produce an abrupt drop in portal pressure, and he successfully treated a second cirrhotic patient with bleeding esophageal varices. He concluded that pitressin was an adjuvant to, but not a substitute for, tamponade in controlling variceal hemorrhage prior to a portosystemic shunt. In 1968, Nusbaum reported that pitressin infused into the superior mesenteric artery at a rate of 0.2 units per minute in a patient with cirrhosis and bleeding from esophageal varices reduced the portal venous pressure. 13 Subsequently, Millette noted a mean reduction in portal pressure of only 9.6% after the infusion of pitressin into the SMA of patients with cirrhosis and this response was variable.12 Nusbaum and Conn also documented a difference in portal pressure responses to SMA pitressin infusion in cirrhotic patients during hemorrhage when compared to responses noted when these patients were not bleeding.15 The drop in portal pressure was less consistent during hemorrhage. These
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PITRESSIN INFUSION FOR BLEEDING
data have questioned the mechanism of pitressin in reducing portal pressure in patients with variceal hemorrhage. Control of hemorrhage from bleeding varices after SMA infusion therapy in patients with cirrhosis may relate to peripheral vasoconstriction or circular muscle contractions in the intestine with a reduction in arteriolar blood flow rather than in a direct effect upon the portal venous pressure.'2"16'20 In previous reports concerning the effect of SMA pitressin infusion upon the control of variceal hemorrhage, esophagogastroscopy was not performed on all patients.2 4'8'9""'3'6"9 When endoscopy is used to verify the cause of hemorrhage, varices, as well as other, or multiple, bleeding sites can be visualized." 7 By contrast, barium swallow or selective arteriography may confirm the presence of varices but specific bleeding sites are not identified.1'4'7 In this series, active bleeding from a varix was not always seen by the endoscopist; however, varices were visualized, fresh blood was identified in the variceal lined esophagus, and the magnitude of bleeding was established in all cases. Perhaps, the reported low success rates of pitressin to control acute hemnorrhage from esophageal varices relates to the accuracy of diagnosis prior to infusion. Regardless of the mechanism by which pitressin is associated with control of variceal hemorrhage, continued or recurrent bleeding resulting in death occurred in 81% of patients if operative therapy was not subsequently used.'3 This course was observed in eight of the nine patients in this series treated solely with pitressin. By contrast, five of seven patients (71%) who responded to pitressin and subsequently underwent portosystemic shunt survived a minimum of one year. Nusbaum reported an 89% survival rate obtained in 18 similar patients.'5 A postoperative mortality rate of 100% was observed in the seven patients who were classified as pitressin failures and who underwent a portosystemic shunt. In this group the clinical classification was not a determinant factor, but the elapsed time between endoscopy and operation was important. The average time between diagnosis and operative intervention for these patients was 36.1 hours. By contrast, when pitressin was effective and the hemorrhage was controlled within six hours the survival rate was increased. These findings are similar to those of Orloff who reported a 48% survival rate for cirrhotic patients with bleeding esophageal varices who underwent portocaval shunt within eight hours after admission to the hospital.'7 The side-effects of intravenously administered pitressin are peripheral and coronary artery vasoconstriction, decreased cardiac output, cardiac arrhythmias, antidiuresis, nausea, vomiting, abdominal cramps, and tachyphylactic reaction.'4 With SMA pitressin infu-
341
sion, Nusbaum noted no side-effects from the drug. However, Millette noted no difference in peripheral and cardiovascular effects of pitressin when given by selective arterial infusion as compared with those reported when given intravenously.'2 Several instances of mesenteric vascular thrombosis have been reported as the cause of death in patients treated by pitressin infusion. Renert et al. reported a case of mesenteric venous thrombosis and infarction of the small intestine after the infusion of pitressin into the superior mesenteric artery.'8 Berardi reported two cases of superior mesenteric artery thrombosis with portal vein thrombosis after SMA pitressin infusion for bleeding esophageal varices.3 A marked reduction in superior mesenteric artery blood flow is usually observed by arteriography during SMA pitressin infusion. 14"18"19 Also, a collapsed portal vein is frequently observed at operation when pitressin is infused. The incidence of vascular complications noted in this series, two of 12 successful (17%) and five of 12 unsuccessful (42%) pitressin infusions, question the ultimate benefit of SMA pitressin infusion in controlling variceal hemorrhage in cirrhotic patients. If prolonged pitressin therapy is used, one should consider using isoproterenol as recommended by Sirenek and Thomford to minimize vascular
complications.21 During the past 20 years, pitressin administered either intravenously or by selective arterial infusion has been used to treat approximately 5,000 patients with upper gastrointestinal hemorrhage.16 Based upon our data we concur with Kehne who stated that "Pitressin is an adjuvant to but not a substitute for Sengstaken-Blakemore tubes in controlling hemorrhage prior to a portosystemic shunt."'0 Therefore, this mode of therapy for control of hemorrhage from esophageal varices should not be used unless selective arteriography can be performed without delay and the effectiveness of treatment can be confirmed by endoscopy within six to eight hours after admission. Furthermore, the infusion of pitressin into the superior mesenteric artery should be used with caution and only to gain immediate control of bleeding varices. Portosystemic shunt remains the treatment of choice for the treatment of uncontrolled hemorrhage and to prevent recurrent bleeding after controlling hemorrhage non-
operatively. References 1. Allen, H. M., Clock, M. A. and Schuman, B. M.: Gastroduodenal Endoscopy Management of Acute Upper Gastrointes-
tinal Hemorrhage. Arch. Surg., 106:450, 1973. 2. Baum, S., Nusbaum, M. and Turmen, H. J.: The Control of Gastrointestinal Hemorrhage by Selective Mesenteric Arterial Infusion of Pitressin. Gastroenterology, 58:926, 1970. 3. Berardi, R. S.: Vascular Complications of Superior Mesenteric
342 4. 5. 6. 7.
8. 9.
10. 11.
12.
GETZEN, BRINK AND WOLFMAN
Artery Infusion with Pitressin in Treatment of Bleeding Esophageal Varices. Ann. Surg., 127:757, 1974. Bolek, B., Rosch, J. and Krippaehne, W. W.: Experience with angiography in diagnosis and treatment of acute gastrointestinal bleeding of varices etiologies. Ann. Surg., 176:419, 1972. Chandler, J. G.: Acute Variceal Bleeding in Patients with Alcoholic Cirrhosis, Va. Med. Monthly, 101:599, 1974. Child, C. G., III: The Liver and Portal Hypertension. Philadelphia, W. B. Saunders, 1964. Conn, H. 0. and Bradoff, M.: Emergency Esophagoscopy in the Diagnosis of Upper Gastrointestinal Hemorrhage: A Critical Evaluation of its Diagnostic Accuracy. Gastroenterology, 47:505, 1964. Conn, H. O., Ramsby, G. R. and Storer, E. H.: Selective Intraarterial Vasopressin in the Treatment of Upper Gastrointestinal Hemorrhage. Gastroenterology, 63:634, 1972. Conn, H. O., Ramsby, G. R., Storer, E. H., et al.: Intra-arterial Vasopressin in the Treatment of Upper Gastrointestinal Hemorrhage: A Prospective Controlled Clinical Trial. Gastroenterology, 68:211, 1975. Kehne, J. H., Hughes, F. A. and Gompertz, M. L.: The Use of Surgical Pituitrin in the Control of Esophageal Varix Bleeding. Surgery, 39:917, 1956. Marubbio, A. T., Lombardo, R. P. and Halt, P. R.: Control of Variceal Bleeding by Superior Mesenteric Artery Pitressin Perfusion: Complications and Indications. Am. J. Dig. Dis., 18:539, 1973. Millett, B., Huet, P. M., Lavoie, P. and Viablet, A.: Portal and Systemic Effects of Selective Infusion of Vasopressin in the
13.
14. 15.
16.
17. 18.
19. 20. 21.
Ann. Surg. * March 1978
Superior Mesenteric Artery in Cirrhotic Patients. Gastroenterology, 69:6, 1975. Murray-Lyon, I. M., Pugh, R. N. H., Nunnerley, H. B., et al.: Treatment of Bleeding Esophageal Varices by Infusion of Vasopressin Into the Superior Mesenteric Artery. Gut, 14:59, 1973. Nusbaum, M., Baum, S., Kuroda, K. and Blakemore, W. S.: Control of Portal Hypertension by Selective Mesenteric Arterial Drug Infusion. Arch. Surg., 97:1005, 1968. Nusbaum, M., Younis, M. T., Baum, S. and Blakemore, W. S.: Control of Portal Hypertension. Arch. Surg., 108:342, 1974. Nusbaum, M., Conn, H. D.: Arterial Vasopressin Infusion: Science or Seance? Gastroenterology, 69:263, 1975. Orloff, M. J., Chandler, J. G., Charters, A. C., III, et al.: Emergency Portocaval Shunt Treatment for Bleeding Esophageal Varices. Arch. Surg., 108:293, 1974. Renert, W. A., Burron, K. F., Field, S. L. and Casarella, W. J.: Mesenteric Venous Thrombosis and Small Bowel Infarction Following Infusion of Vasopressin into the Superior Mesenteric Artery. Radiology, 102:299, 1972. Rosch, J., Dotter, C. T. and Rose, R. W.: Selective Arterial Infusion of Vasoconstrictors in Acute Gastrointestinal Bleeding. Radiology, 99:27, 1971. Shapiro, H. and Britt, L. G.: The Action of Vasopressin on the Gastrointestinal Tract: A Review of the Literature. Am. J. Dig. Dis., 17:649, 1972. Sirenek, K. R. and Thomford, N. R.: Isoproterenol in Offsetting Adverse Effects of Vasopressin in Cirrhotic Patients. Am. J. Surg., 129:130, 1975.
