Seminars in Surgical Oncology 6:137-140 (1990)
Origin of Oncologic Anesthetic Techniques WILLIAM S. HOWLAND, MD From the Memorial Sloan-KetteringCancer Center and Cornell University Medical College, New York
The patient with cancer poses a challenge to the anesthesiologist for a variety of reasons including the effects of cancer (altered hemostasis, depressed immune response, and compromised airways), the effects of chemotherapy (malfunction of the myocardium, lungs, kidneys, and bone marrow; depression of pseudocholinesterase; and production of the syndrome of inappropriate secretion of antidiuretic hormone), as well as effects of radical cancer surgery (massive blood loss and the need for prolonged anesthesia). Anesthetic techniques to address these problems had their beginnings in the Department of Anesthesiology at Memorial Sloan-Kettering Cancer Center. This paper traces the development of modem oncologic anesthesia and discusses how these advances significantly reduced operative mortality.
KEYWORDS:cancer, chemotherapy, clotting defects, massive blood replacement, hypothermia, citrate intoxication.
INTRODUCTION In order to assess the effectiveness and practicality of radical cancer surgery in the 1950s, it was necessary for the anesthesiologist and the surgeon to differentiate between mortality due to the surgical techniques and that due to failure of supportive measures necessary to maintain the patient’s vital functions. If the patient could be maintained in fluid balance, adequately ventilated, without clotting abnormalities or cardiovascular collapse, then the role of radical surgery for cancer would be established. This was the challenge faced by the Department of Anesthesiology at Memorial Sloan-Kettering Cancer Center at that time. The anesthesiologist must be aware that cancer management is becoming more complex and that the modalities of therapy frequently change. New drugs and combinations of drugs appear and disappear. To a lesser extent, surgical and radiotherapeutic strategies also change. These therapies produce physiologic, metabolic, and electrolytic disturbances which may effect the conduct of anesthesia and the intraoperative management of fluids, blood products, inotropic drugs, ventilator techniques, and sophisticated monitoring. Unique to the practice of adult oncologic anesthesia are 1) the advanced age of the patients compared to the general hospital population; 2) the severity of radical 0 1990 Wiley-Liss, Inc.
cancer operations, and 3) the debilitating effects of concomitant chemotherapy.
BACKGROUND The operating room and recovery room mortality at Memorial Sloan-Kettering Cancer Center over a period of 25 years (1953-1977) was one death for every 1,032 operations (173 deaths in 178,590 operations). Eightytwo percent of all deaths (136 cases) occurred following major operations. The leading cause of death was uncontrolled hemorrhage (52%). Other major causes were septic shock (7%); unexplained cardiac arrest (1 1%); pulmonary edema (5%); acute myocardial infarction (4%); and airway obstruction (5%). All cases of airway obstruction were associated with laryngeal surgery and were due to either bleeding or malposition of a fresh tracheostomy. In 1952, the mortality in operations in which 12 or more units of blood were transfused was 50%. Today, due to a better understanding of the problems of massive transfusion, no mortality is expected in these cases unless uncontrollable venous hemorrhage occurs. The elderly patient with cancer can have many coAddress reprint requests to Dr. William S. Howland, RR3 Box 50A, Brattleboro, VT 05301.
138
Howland
existing diseases. Compared to younger patients, surgery in the aged is associated with a markedly higher morbidity and mortality. In one study of elderly patients, 50% of intraoperative deaths occurred in geriatric patients, who composed only 5% of the surgical population [ 11. Linn [2] studied the relationship among age, immune response, and surgical stress, and found distinct differences in younger patients as compared to those older than 60 years. Although both old and young healthy patients were immunologically similar, some aspects of the immune system were more depressed by surgery in the older patient than in the young patients, and in addition, some immune responses correlated with surgical outcome. In this study involving inguinal herniorraphy in the older patient, it was found that the responses to phytohemagglutinin and concanavalin fell significantly in the first 5 days of the postoperative period. There was also depressed cytoxic, helper, and suppressor T-cell population in this group of patients. In this patient group, the three most important factors leading to pulmonary complications in the postoperative period were age over 70 years, obesity, and the duration of surgery. Another important factor to be considered in elderly patients who undergo prolonged cancer surgery is the occurrence of hypothermia. Much of this drop in temperature is due to air-conditioned operating rooms for the surgeon’s comfort. Also, the basal metabolic rate decreases 1% per year after the age of 30. Thus, all anesthetic agents may be expected to be mobilized and excreted more slowly in elderly patients. Vaughan [3] found that patients over 60 years of age had lower temperatures, both on admission and discharge from the recovery room, and also experienced a longer duration of hypothermia than did young patients. Of the 198 adults studied, 60% had temperatures below 36°C when admitted to the recovery room. This hypothermia can result in shivering with increased oxygen demand, increased minute ventilation, increased cardiac output, and lactic acidosis. Intraoperative cooling can be obviated by using warmed crystalloid solutions, warming blankets and raising the temperature of the operating room. Also, oxygen should be administered during transport of the patient from operating room to recovery room. Patients receiving chemotherapy and requiring surgery may present with a variety of iatrogenic complications. Cardiac failure can result from the anthracyclines. This cardiotoxicity is irreversible and the fibrotic heart responds poorly to digitalis and other inotropic drugs. Pulmonary toxicity can result from bleomycin administration. This condition improves over time, but an F,02 of less than 30 should be administered if bleomycin has been given to the patient. The bone marrow depression that occurs with chemotherapy can be corrected with blood component therapy.
Platelet coverage for surgical manipulation should be provided for patients with platelet counts of less than 2O,W/mrn3. Packed red blood cells can be utilized as necessary. The place of granulocyte transfusion is not clear because of the possibility of causing pulmonary infiltration and respiratory failure. Patients who have developed renal insufficiency from CIS-platinum therapy must be hydrated to maintain a urine output of 2 ml/kg/hr during the surgical procedure. A loading dose of mannitol of 12.5 g is given followed by infusion of 20% mannitol at S/g/hr. The fluid retention syndrome of inappropriate secretion of antidiuretic hormone (SIADH) that can occur with many of the antineoplastic agents should be managed with fluid restriction and furosemide. The severe ileus of the vinca alkaloids may require a colostomy for correction. These patients should be handled as any other intestinal obstruction. Patients who have received cyclophosphamide and have prolonged apnea after succinylcholine will require prolonged ventilatory support. Malignant disease is associated with a high incidence of hemostatic disorders, including vascular thrombosis, hemorrhage, and disseminated intravascular coagulation. The frequent occurrence of vascular thrombosis in patients with cancer (phlegmasia alba dolens) was first described by Trousseau in 1865. Venous thrombosis was the first symptom of malignancy in more than 50% of patients with cancer of the pancreas, lung, and female reproductive tract [4]. The incidence of deep vein thrombosis in patients undergoing cancer surgery has been reported to be as high as 40% compared to patients without cancer undergoing similar operations, where the incidence was 12% [5]. In contrast to venous thrombosis, which is a sign of early cancer, severe hemorrhage may indicate the presence of widespread metastases. In acute leukemia, hemorrhage may precede other clinical symptoms in up to 50% of patients and may approach 80-90% in acute promyelocytic leukemia. It has been estimated that 10% of patients receiving chemotherapy will suffer from a significant hemorrhagic episode.
BLEEDING AND CLOTTING There are three conditions that exist in cancer patients that alter hemostasis: 1) interactions between cancer cells and procoagulants of the hemostatic system; 2) severe blood loss and massive transfusion; and 3) changes in the hemostatic mechanisms which occur secondary to chemotherapeutic agents, antibiotics, and non-steroidal antiinflamatory drugs. Disseminated intravascular coagulation induced by cancer may be due to platelet activation, monocytes-
Oncologic Anesthetic Techniques
macrophages, tumor neovascularization, penetration of malignant cells into blood vessel walls, liberation of tissue thromboplastin, trypsin from pancreatic cancer, and activation of both the coagulation and fibrinolytic systems by prostatic adenocarcinoma. Thromboplastic activity is produced in greater amounts by malignant tissue and can easily diffuse into its environment, in contrast to normal thromboplastin of which little diffuses unless tissue is damaged. Coagulation disorders other than disseminated intravascular coagulation may be due to the granulocytic proteases released into plasma in acute leukemia, deficient prothrombin complex with liver metastases, factor XI11 deficiency in acute leukemia, dysfibrinogenemia in hepatomas, abnormal fibrin polymerization in microglobulinemia, functional platelet abnormalities, and thrombocytosis in various other oncologic disorders. Bleeding disorders can also occur with antibiotic administration. Thrombocytopenia has been reported with penicillin and cephalosporin derivatives including occasionally with the newer agents [6]. Thrombocytosis occurs in 30% of patients given moxalactam, cefotaxime, and cefoperazone. Recent work indicates that thrombocytosis is an acute phase reaction and parallels the rise of fibrinogen seen in acute illness. Bleeding disorders due to platelet dysfunction can occur with carbenicillin, ticarcillin, piperacillin, and mazlocillin. Depressed platelet aggregation can be due to the binding of penicillin to platelet surface sites. Clinically, bleeding occurs in 1-296 of patients who receive these drugs. Moxalactam inhibits ADP-dependent aggregation and prolongs bleeding time [7]. Cefoperazone and cefamandole can cause hypoprothrombinemia. Malnutrition, total parenteral nutrition, and warfarin therapy can exacerbate hypoprothrombinemia. Patients at risk for antibiotic associated coagulopathy include those with concomitant platelet dysfunction, age over 60 years, or with fresh surgical wounds.
DEVELOPMENT OF SPECIAL ANESTHETIC TECHNIQUES Recognition of the effects of advanced age, severity of cancer surgery, and the debilitating effects of cancer chemotherapy led to the evolution of anesthesia techniques for cancer surgery as practiced at Memorial SloanKettering Cancer Center. For many years, head and neck surgery was done with local anesthesia. Because of the subsequent difficulty in obtaining adequate anesthesia, the extent of the surgery was often limited. Dr. Olga Schweizer was the first anesthesiologist to utilize pentothal-nitrous-oxide anesthesia in conjunction with topical cocaine ( 5 % ) or dtubocurarine-induced muscular relaxation for endotra-
139
cheal intubation. For head and neck surgery she also introduced the concept of “once a tracheostomy always a tracheostomy” for patients who had more than one operation. At the end of surgery, tracheostomy was routinely performed for 1) patients with bilateral neck dissection; 2) patients who had a radical maxillectomy, and 3) patients with a partial laryngectomy. Bowden and Schweizer [8] also described the syndrome of mediastinal emphysema followed by tension pneumothorax which occurred when surgical dissection was being performed in the lower neck as the middle layer of the deep cervical fascia was opened to room air. The imperfect anesthesia techniques available at that time (pre-halothane) often resulted in bucking and coughing with generation of intrathoracic pressure and the opened mediastrinum caused rupture of the mediastinal pleura with subsequent development of tension pneumothorax. Dr. Paul Boyan of the Memorial Sloan-KetteringCancer Center department was the first to utilize hypotensive anesthesia in the United States. His first report on 12 patients concluded that the operations were greatly facilitated and blood loss reduced as a result of the controlled hypotension [9]. In 1953, Boyan summarized the Memorial SloanKettering Cancer Center experience and concluded that impaired cardiovascular, renal, or respiratory function were definitely contraindications for the hypotensive technique but still believed that hypotensive techniques had a place in selected radical surgical procedures. However, despite the initial optimism, hypotensive anesthesia soon faded from everyday practice [lo]. In 1952, it was difficult to distinguish between the effects of surgery and that of massive blood replacement because of the 50% mortality rate in patients who received 12 or more units of bank blood. At that time, massive blood loss was managed by the administration of citrated bank blood at a temperature of 4°C. With every 2 units of blood administered, the patient was given 1.O g of calcium chloride to prevent “citrate intoxication. ” In our first study of massive transfusion, two major problems were found: the development of hemorrhagic diathesis and/or cardiac malfunction as either asystole or ventricular fibrillation. In addition to the above, we thought that hypocalcemia or hyperkalemia also were operative factors. In 1956 we reported on 9 cases of ventricular fabrillation in 253 patients who had received 5 or more units of bank blood and began to associate the ventricular fibrillation with calcium chloride administration. Our next study involved the administration of acid-citrate-dextrose (ACD) solution without blood to three patients at an analogous rate of 20 units of bank blood per hour. Levels as high as 170 mg % of citrate occurred with a minimal
140
Howland
change in the QT interval in the electrocardiogramin one patient. We concluded that citric acid intoxication did not occur and no longer administered exogenous calcium during massive blood replacement [ 111. In 1957, increasingly sophisticated clotting tests including the thromboelastograph became available to us and we found that massive blood loss during hepatic lobectomy resulted in depressed prothrombin, Factor V , Factor VII, and fibrinogen, with an associated thrombocytopenia and fibrinolytic activity. At that time our only clotting substance replacements were vitamin K, lyophilized plasma (antihemophilic plasma), and freshly drawn bank blood. Having concluded that citrate intoxication did not occur, we compared patients receiving massive blood replacements with and without calcium administration. There were 13 deaths in 114 patients who had received calcium, and 3 deaths in 152 patients who had not received exogenous calcium ( P < 0.01) [12]. One of the consequences of massive blood replacement is the hypothermic effect of bank blood maintained at a temperature of 4°C. We therefore designed a device to warm the bank blood and maintain the patient’s temperature within the normal range. Results with the blood warmer, summarized in 1963, showed a significant decrease (P < 0.01) in the incidence of cardiac arrest with warmed blood compared with that following transfusion of cold blood [ 131. We next considered the putative “hyperkalemia” of blood transfusion and found essentially normal or low potassium levels during massive blood transfusion, In 1964, we reviewed 872 patients given 50 or more units of warmed bank blood without calcium administration and found that no cases of ventricular fibrillation occurred. At the same time that operative mortality due to cardiovascular irritability was being improved, clotting defects remained a problem. This problem was ameliorated by the use of the thromboelastrograph, which can detect plasma procoagulent defects, platelet deficiencies, fibrinolysis, and over-heparinization. In 1979, Kahn et al. [14] analyzed our experience in 53 patients studied intraoperatively during administration of CPD preserved blood and fresh frozen plasma. Twenty-seven patients received more than 5,000 ml of blood. Blood was administered on the basis of measured losses and fresh frozen plasma was infused to maintain capillary wedge pressure 2-3 mm above baseline levels. All transfused blood was warmed and Dassed through
microfilters . No patients received intraoperative sodium biocarbonate, calcium salts, or inotropic drugs. Baseline concentrations of total calcium, ionized calcium, albumin, and hydrogen ion were measured prior to transfusion, during the transfusion of bank blood, and at the end of transfusion. Intraoperatively the patients’ core temperatures were maintained within 1-1.5”Cof the baseline. Systemic blood pressure, central pulmonary artery catheter pressures, and EKGs were also recorded. Massive transfusion depressed ionized calcium, but this change was transient and ionized calcium levels returned to pre-transfusion levels as the citrate was metabolized. These changes in ionized calcium were without hemodynamic significance.
CONCLUSIONS The patient with cancer offers a challenge to the anesthesiologist because of the alterations in clotting, the effects of massive blood replacement, the overall defects of the immune response, and the protean complications of chemotherapy, as well as the effects of cancer itself. REFERENCES 1. Greenburg AG, Saik RP, Coyle JJ, Peskin GW: Mortality and gastrointestinal surgery. Arch Surg 116:788-791, 1981. 2. Linn BS, Jensen J: Age and immune response to a surgical stress. Arch Surg 118:405-409, 1983. 3. Vaughan MS, Vaughan RW, Cork RC: Postoperative hypothermia in adults: Relationship of age, anesthesia, and shivering to rewarming. Anesth Analg 60:74&751, 1981. 4. Lieberman JS, Borrero J, Uroaneta E, Wright IS: Thrombophlebitis and cancer. JAMA 177542-545, 1961. 5 . Pineo GF, Brain MC, Gallus AS, Hush J, Hatton WMC, Regoeczi E: Tumors, mucus production, and hypercoagulability. Ann NY Acad Sci 230:262-270, 1975. 6. Parry MF: Toxic and adverse reactions encounteres with new beta-lactam antibiotics. Bull NY Acad Med 60:358-368, 1984. 7. Jenkinson SG: Adverse effects of new cephalosporins. Ann Intern Med 98:415-416, 1983. 8. Bowden L, Schweizer 0: Pneumothorax and mediastinal emphysema complicating neck surgery. Surg Gynecol Obstet 91:81-88, 1950. 9. Boyan CP, Brunschwig A: Hypotensive anesthesia in radical pelvic and abdominal surgery. Surgery 31:829-838. 1952. 10. Boyan CP: Hypotensive anesthesia for radical pelvic and abdominal surgery. Arch Surg 67:80>812, 1953. 11. Howland WS, Bellville JW, Zucker MP, Boyan P: Massive blood replacement, V: failure to observe citrate intoxication. Surg Gynecol Obstet 105:52%540, 1957. 12. Howland WS, Schweizer 0, Boyan CP: Massive blood replacement without calcium administration. Surg Gynecol Obstet 118:814818, 1964. 13. Boyan CP, Howland WS: Blood temperature: A critical factor in massive transfusion. Anesthesiology 22:559-563, 1961. 14. Kahn RC, Jascott D, Carlon GC, Schweizer, 0: Massive blood replacement: correlation of ionized calcium, citrate and hydrogen ion concentration. Anesth Anal 58:274-278, 1979.
Origin of Oncologic Anesthetic Techniques WILLIAM S. HOWLAND, MD From the Memorial Sloan-KetteringCancer Center and Cornell University Medical College, New York
The patient with cancer poses a challenge to the anesthesiologist for a variety of reasons including the effects of cancer (altered hemostasis, depressed immune response, and compromised airways), the effects of chemotherapy (malfunction of the myocardium, lungs, kidneys, and bone marrow; depression of pseudocholinesterase; and production of the syndrome of inappropriate secretion of antidiuretic hormone), as well as effects of radical cancer surgery (massive blood loss and the need for prolonged anesthesia). Anesthetic techniques to address these problems had their beginnings in the Department of Anesthesiology at Memorial Sloan-Kettering Cancer Center. This paper traces the development of modem oncologic anesthesia and discusses how these advances significantly reduced operative mortality.
KEYWORDS:cancer, chemotherapy, clotting defects, massive blood replacement, hypothermia, citrate intoxication.
INTRODUCTION In order to assess the effectiveness and practicality of radical cancer surgery in the 1950s, it was necessary for the anesthesiologist and the surgeon to differentiate between mortality due to the surgical techniques and that due to failure of supportive measures necessary to maintain the patient’s vital functions. If the patient could be maintained in fluid balance, adequately ventilated, without clotting abnormalities or cardiovascular collapse, then the role of radical surgery for cancer would be established. This was the challenge faced by the Department of Anesthesiology at Memorial Sloan-Kettering Cancer Center at that time. The anesthesiologist must be aware that cancer management is becoming more complex and that the modalities of therapy frequently change. New drugs and combinations of drugs appear and disappear. To a lesser extent, surgical and radiotherapeutic strategies also change. These therapies produce physiologic, metabolic, and electrolytic disturbances which may effect the conduct of anesthesia and the intraoperative management of fluids, blood products, inotropic drugs, ventilator techniques, and sophisticated monitoring. Unique to the practice of adult oncologic anesthesia are 1) the advanced age of the patients compared to the general hospital population; 2) the severity of radical 0 1990 Wiley-Liss, Inc.
cancer operations, and 3) the debilitating effects of concomitant chemotherapy.
BACKGROUND The operating room and recovery room mortality at Memorial Sloan-Kettering Cancer Center over a period of 25 years (1953-1977) was one death for every 1,032 operations (173 deaths in 178,590 operations). Eightytwo percent of all deaths (136 cases) occurred following major operations. The leading cause of death was uncontrolled hemorrhage (52%). Other major causes were septic shock (7%); unexplained cardiac arrest (1 1%); pulmonary edema (5%); acute myocardial infarction (4%); and airway obstruction (5%). All cases of airway obstruction were associated with laryngeal surgery and were due to either bleeding or malposition of a fresh tracheostomy. In 1952, the mortality in operations in which 12 or more units of blood were transfused was 50%. Today, due to a better understanding of the problems of massive transfusion, no mortality is expected in these cases unless uncontrollable venous hemorrhage occurs. The elderly patient with cancer can have many coAddress reprint requests to Dr. William S. Howland, RR3 Box 50A, Brattleboro, VT 05301.
138
Howland
existing diseases. Compared to younger patients, surgery in the aged is associated with a markedly higher morbidity and mortality. In one study of elderly patients, 50% of intraoperative deaths occurred in geriatric patients, who composed only 5% of the surgical population [ 11. Linn [2] studied the relationship among age, immune response, and surgical stress, and found distinct differences in younger patients as compared to those older than 60 years. Although both old and young healthy patients were immunologically similar, some aspects of the immune system were more depressed by surgery in the older patient than in the young patients, and in addition, some immune responses correlated with surgical outcome. In this study involving inguinal herniorraphy in the older patient, it was found that the responses to phytohemagglutinin and concanavalin fell significantly in the first 5 days of the postoperative period. There was also depressed cytoxic, helper, and suppressor T-cell population in this group of patients. In this patient group, the three most important factors leading to pulmonary complications in the postoperative period were age over 70 years, obesity, and the duration of surgery. Another important factor to be considered in elderly patients who undergo prolonged cancer surgery is the occurrence of hypothermia. Much of this drop in temperature is due to air-conditioned operating rooms for the surgeon’s comfort. Also, the basal metabolic rate decreases 1% per year after the age of 30. Thus, all anesthetic agents may be expected to be mobilized and excreted more slowly in elderly patients. Vaughan [3] found that patients over 60 years of age had lower temperatures, both on admission and discharge from the recovery room, and also experienced a longer duration of hypothermia than did young patients. Of the 198 adults studied, 60% had temperatures below 36°C when admitted to the recovery room. This hypothermia can result in shivering with increased oxygen demand, increased minute ventilation, increased cardiac output, and lactic acidosis. Intraoperative cooling can be obviated by using warmed crystalloid solutions, warming blankets and raising the temperature of the operating room. Also, oxygen should be administered during transport of the patient from operating room to recovery room. Patients receiving chemotherapy and requiring surgery may present with a variety of iatrogenic complications. Cardiac failure can result from the anthracyclines. This cardiotoxicity is irreversible and the fibrotic heart responds poorly to digitalis and other inotropic drugs. Pulmonary toxicity can result from bleomycin administration. This condition improves over time, but an F,02 of less than 30 should be administered if bleomycin has been given to the patient. The bone marrow depression that occurs with chemotherapy can be corrected with blood component therapy.
Platelet coverage for surgical manipulation should be provided for patients with platelet counts of less than 2O,W/mrn3. Packed red blood cells can be utilized as necessary. The place of granulocyte transfusion is not clear because of the possibility of causing pulmonary infiltration and respiratory failure. Patients who have developed renal insufficiency from CIS-platinum therapy must be hydrated to maintain a urine output of 2 ml/kg/hr during the surgical procedure. A loading dose of mannitol of 12.5 g is given followed by infusion of 20% mannitol at S/g/hr. The fluid retention syndrome of inappropriate secretion of antidiuretic hormone (SIADH) that can occur with many of the antineoplastic agents should be managed with fluid restriction and furosemide. The severe ileus of the vinca alkaloids may require a colostomy for correction. These patients should be handled as any other intestinal obstruction. Patients who have received cyclophosphamide and have prolonged apnea after succinylcholine will require prolonged ventilatory support. Malignant disease is associated with a high incidence of hemostatic disorders, including vascular thrombosis, hemorrhage, and disseminated intravascular coagulation. The frequent occurrence of vascular thrombosis in patients with cancer (phlegmasia alba dolens) was first described by Trousseau in 1865. Venous thrombosis was the first symptom of malignancy in more than 50% of patients with cancer of the pancreas, lung, and female reproductive tract [4]. The incidence of deep vein thrombosis in patients undergoing cancer surgery has been reported to be as high as 40% compared to patients without cancer undergoing similar operations, where the incidence was 12% [5]. In contrast to venous thrombosis, which is a sign of early cancer, severe hemorrhage may indicate the presence of widespread metastases. In acute leukemia, hemorrhage may precede other clinical symptoms in up to 50% of patients and may approach 80-90% in acute promyelocytic leukemia. It has been estimated that 10% of patients receiving chemotherapy will suffer from a significant hemorrhagic episode.
BLEEDING AND CLOTTING There are three conditions that exist in cancer patients that alter hemostasis: 1) interactions between cancer cells and procoagulants of the hemostatic system; 2) severe blood loss and massive transfusion; and 3) changes in the hemostatic mechanisms which occur secondary to chemotherapeutic agents, antibiotics, and non-steroidal antiinflamatory drugs. Disseminated intravascular coagulation induced by cancer may be due to platelet activation, monocytes-
Oncologic Anesthetic Techniques
macrophages, tumor neovascularization, penetration of malignant cells into blood vessel walls, liberation of tissue thromboplastin, trypsin from pancreatic cancer, and activation of both the coagulation and fibrinolytic systems by prostatic adenocarcinoma. Thromboplastic activity is produced in greater amounts by malignant tissue and can easily diffuse into its environment, in contrast to normal thromboplastin of which little diffuses unless tissue is damaged. Coagulation disorders other than disseminated intravascular coagulation may be due to the granulocytic proteases released into plasma in acute leukemia, deficient prothrombin complex with liver metastases, factor XI11 deficiency in acute leukemia, dysfibrinogenemia in hepatomas, abnormal fibrin polymerization in microglobulinemia, functional platelet abnormalities, and thrombocytosis in various other oncologic disorders. Bleeding disorders can also occur with antibiotic administration. Thrombocytopenia has been reported with penicillin and cephalosporin derivatives including occasionally with the newer agents [6]. Thrombocytosis occurs in 30% of patients given moxalactam, cefotaxime, and cefoperazone. Recent work indicates that thrombocytosis is an acute phase reaction and parallels the rise of fibrinogen seen in acute illness. Bleeding disorders due to platelet dysfunction can occur with carbenicillin, ticarcillin, piperacillin, and mazlocillin. Depressed platelet aggregation can be due to the binding of penicillin to platelet surface sites. Clinically, bleeding occurs in 1-296 of patients who receive these drugs. Moxalactam inhibits ADP-dependent aggregation and prolongs bleeding time [7]. Cefoperazone and cefamandole can cause hypoprothrombinemia. Malnutrition, total parenteral nutrition, and warfarin therapy can exacerbate hypoprothrombinemia. Patients at risk for antibiotic associated coagulopathy include those with concomitant platelet dysfunction, age over 60 years, or with fresh surgical wounds.
DEVELOPMENT OF SPECIAL ANESTHETIC TECHNIQUES Recognition of the effects of advanced age, severity of cancer surgery, and the debilitating effects of cancer chemotherapy led to the evolution of anesthesia techniques for cancer surgery as practiced at Memorial SloanKettering Cancer Center. For many years, head and neck surgery was done with local anesthesia. Because of the subsequent difficulty in obtaining adequate anesthesia, the extent of the surgery was often limited. Dr. Olga Schweizer was the first anesthesiologist to utilize pentothal-nitrous-oxide anesthesia in conjunction with topical cocaine ( 5 % ) or dtubocurarine-induced muscular relaxation for endotra-
139
cheal intubation. For head and neck surgery she also introduced the concept of “once a tracheostomy always a tracheostomy” for patients who had more than one operation. At the end of surgery, tracheostomy was routinely performed for 1) patients with bilateral neck dissection; 2) patients who had a radical maxillectomy, and 3) patients with a partial laryngectomy. Bowden and Schweizer [8] also described the syndrome of mediastinal emphysema followed by tension pneumothorax which occurred when surgical dissection was being performed in the lower neck as the middle layer of the deep cervical fascia was opened to room air. The imperfect anesthesia techniques available at that time (pre-halothane) often resulted in bucking and coughing with generation of intrathoracic pressure and the opened mediastrinum caused rupture of the mediastinal pleura with subsequent development of tension pneumothorax. Dr. Paul Boyan of the Memorial Sloan-KetteringCancer Center department was the first to utilize hypotensive anesthesia in the United States. His first report on 12 patients concluded that the operations were greatly facilitated and blood loss reduced as a result of the controlled hypotension [9]. In 1953, Boyan summarized the Memorial SloanKettering Cancer Center experience and concluded that impaired cardiovascular, renal, or respiratory function were definitely contraindications for the hypotensive technique but still believed that hypotensive techniques had a place in selected radical surgical procedures. However, despite the initial optimism, hypotensive anesthesia soon faded from everyday practice [lo]. In 1952, it was difficult to distinguish between the effects of surgery and that of massive blood replacement because of the 50% mortality rate in patients who received 12 or more units of bank blood. At that time, massive blood loss was managed by the administration of citrated bank blood at a temperature of 4°C. With every 2 units of blood administered, the patient was given 1.O g of calcium chloride to prevent “citrate intoxication. ” In our first study of massive transfusion, two major problems were found: the development of hemorrhagic diathesis and/or cardiac malfunction as either asystole or ventricular fibrillation. In addition to the above, we thought that hypocalcemia or hyperkalemia also were operative factors. In 1956 we reported on 9 cases of ventricular fabrillation in 253 patients who had received 5 or more units of bank blood and began to associate the ventricular fibrillation with calcium chloride administration. Our next study involved the administration of acid-citrate-dextrose (ACD) solution without blood to three patients at an analogous rate of 20 units of bank blood per hour. Levels as high as 170 mg % of citrate occurred with a minimal
140
Howland
change in the QT interval in the electrocardiogramin one patient. We concluded that citric acid intoxication did not occur and no longer administered exogenous calcium during massive blood replacement [ 111. In 1957, increasingly sophisticated clotting tests including the thromboelastograph became available to us and we found that massive blood loss during hepatic lobectomy resulted in depressed prothrombin, Factor V , Factor VII, and fibrinogen, with an associated thrombocytopenia and fibrinolytic activity. At that time our only clotting substance replacements were vitamin K, lyophilized plasma (antihemophilic plasma), and freshly drawn bank blood. Having concluded that citrate intoxication did not occur, we compared patients receiving massive blood replacements with and without calcium administration. There were 13 deaths in 114 patients who had received calcium, and 3 deaths in 152 patients who had not received exogenous calcium ( P < 0.01) [12]. One of the consequences of massive blood replacement is the hypothermic effect of bank blood maintained at a temperature of 4°C. We therefore designed a device to warm the bank blood and maintain the patient’s temperature within the normal range. Results with the blood warmer, summarized in 1963, showed a significant decrease (P < 0.01) in the incidence of cardiac arrest with warmed blood compared with that following transfusion of cold blood [ 131. We next considered the putative “hyperkalemia” of blood transfusion and found essentially normal or low potassium levels during massive blood transfusion, In 1964, we reviewed 872 patients given 50 or more units of warmed bank blood without calcium administration and found that no cases of ventricular fibrillation occurred. At the same time that operative mortality due to cardiovascular irritability was being improved, clotting defects remained a problem. This problem was ameliorated by the use of the thromboelastrograph, which can detect plasma procoagulent defects, platelet deficiencies, fibrinolysis, and over-heparinization. In 1979, Kahn et al. [14] analyzed our experience in 53 patients studied intraoperatively during administration of CPD preserved blood and fresh frozen plasma. Twenty-seven patients received more than 5,000 ml of blood. Blood was administered on the basis of measured losses and fresh frozen plasma was infused to maintain capillary wedge pressure 2-3 mm above baseline levels. All transfused blood was warmed and Dassed through
microfilters . No patients received intraoperative sodium biocarbonate, calcium salts, or inotropic drugs. Baseline concentrations of total calcium, ionized calcium, albumin, and hydrogen ion were measured prior to transfusion, during the transfusion of bank blood, and at the end of transfusion. Intraoperatively the patients’ core temperatures were maintained within 1-1.5”Cof the baseline. Systemic blood pressure, central pulmonary artery catheter pressures, and EKGs were also recorded. Massive transfusion depressed ionized calcium, but this change was transient and ionized calcium levels returned to pre-transfusion levels as the citrate was metabolized. These changes in ionized calcium were without hemodynamic significance.
CONCLUSIONS The patient with cancer offers a challenge to the anesthesiologist because of the alterations in clotting, the effects of massive blood replacement, the overall defects of the immune response, and the protean complications of chemotherapy, as well as the effects of cancer itself. REFERENCES 1. Greenburg AG, Saik RP, Coyle JJ, Peskin GW: Mortality and gastrointestinal surgery. Arch Surg 116:788-791, 1981. 2. Linn BS, Jensen J: Age and immune response to a surgical stress. Arch Surg 118:405-409, 1983. 3. Vaughan MS, Vaughan RW, Cork RC: Postoperative hypothermia in adults: Relationship of age, anesthesia, and shivering to rewarming. Anesth Analg 60:74&751, 1981. 4. Lieberman JS, Borrero J, Uroaneta E, Wright IS: Thrombophlebitis and cancer. JAMA 177542-545, 1961. 5 . Pineo GF, Brain MC, Gallus AS, Hush J, Hatton WMC, Regoeczi E: Tumors, mucus production, and hypercoagulability. Ann NY Acad Sci 230:262-270, 1975. 6. Parry MF: Toxic and adverse reactions encounteres with new beta-lactam antibiotics. Bull NY Acad Med 60:358-368, 1984. 7. Jenkinson SG: Adverse effects of new cephalosporins. Ann Intern Med 98:415-416, 1983. 8. Bowden L, Schweizer 0: Pneumothorax and mediastinal emphysema complicating neck surgery. Surg Gynecol Obstet 91:81-88, 1950. 9. Boyan CP, Brunschwig A: Hypotensive anesthesia in radical pelvic and abdominal surgery. Surgery 31:829-838. 1952. 10. Boyan CP: Hypotensive anesthesia for radical pelvic and abdominal surgery. Arch Surg 67:80>812, 1953. 11. Howland WS, Bellville JW, Zucker MP, Boyan P: Massive blood replacement, V: failure to observe citrate intoxication. Surg Gynecol Obstet 105:52%540, 1957. 12. Howland WS, Schweizer 0, Boyan CP: Massive blood replacement without calcium administration. Surg Gynecol Obstet 118:814818, 1964. 13. Boyan CP, Howland WS: Blood temperature: A critical factor in massive transfusion. Anesthesiology 22:559-563, 1961. 14. Kahn RC, Jascott D, Carlon GC, Schweizer, 0: Massive blood replacement: correlation of ionized calcium, citrate and hydrogen ion concentration. Anesth Anal 58:274-278, 1979.
