Physiologic management of the cancer patient during surgery

PHYSIOLOGIC MANAGEMENT OF THE CANCER PATIENT DURING SURGERY t

WILLIAM S. HOWLAND, M.D. P_AULL. GOLDINER,M:D:

0147-0272/78/0011-0001505.00 9 1978 Year Book Medical Publishers, Inc.

T A B L E OF C O N T E N T S GLOSSARY

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INTRODUCTION

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PREOPERATIVE ANESTHESIA AND PLAN

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FLUID BALANCE

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RENAL DISEASE

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THE BLEEDING PATIENT

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INTRAOPERATIVE PHYSIOLOGIC MONITORING .

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ANTINEOPLASTIC AND CHEMOTHERAPEUTIC AGENTS

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GLOSSARY AaDo2: Alveolar arterial oxygen difference ADH: Antidiuretic hormone Ao: Mean aortic pressure AV: Atrioventricular A-Vo2 diff." Arteriovenous oxygen difference Cao2: Arterial oxygen content CI: Cardiac index COD: Coefficient of oxygen delivery COPD: Chronic obstructive pulmonary disease CPD: Anticoagulant preserved blood C%.,: Mixed venous oxygen content CVP: Central venous pressure DIC: Disseminated intravascular coagulation FDP: Fibrinogen degradation products fdp: Fibrin degradation products FFP: Fresh frozen plasma FIo2: Inspired oxygen concentration GFR: Glomerular filtration rate LA: Left atrium LAP: Left atrial pressure LBBB: Left bundle branch block LV: Left ventricle LVEDP: Left ventricular-end diastolic pressure LVEDV: Left ventricular-end diastolic volume LVSW: Left ventricular stroke work MAP: Mean arterial pressure PA: Pulmonary artery PA: Pulmonary artery mean pressure PADP: Pulmonary artery diastolic pressure Pao2: Oxygen content of arterial blood PAWP: Pulmonary artery wedge pressure PCWP: Pulmonary capillary wedge pressure PEEP: Positive end-expiratory pressure PR: Pulse rate Pvo2: Oxygen content of mixed venous blood PVR: Pulmonary vascular resistance Qs/Qt: Pulmonary shunt fraction RA: Right atrium RA: Mean right atrial pressure RBBB: Right bundle branch block RV: Right ventricle RVEDP: Right ventricular-end diastolic pressure RVESP: Right ventricuhr end systolic pressure "

RVSW: Right ventricular stroke work SAT: Saturation SI: Stroke index TPR: Total peripheral resistance ~'o.,: Oxygen consumption VSD: Ventricular septal defect

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is Chairman of the Department of Anesthesia and Deputy General Director and Vice-President for Clinical Affairs at Memorial Hospital, New York. He received his M.D. from Columbia University College of Physicians and Surgeons and did his postgraduage medical training at Presbyterian Hospital, New York. Dr. Howland's research and clinical interests are in the areas of blood transfusion, coagulation and intensive care.

is Associate Chairman, Department of Anesthesiology, Memorial Sloan-Kettering Cancer Center and Associate Clinical Professor of Anesthesia, Cornell University School of Medicine, New York. He received his D.D.S. from Northwestern University Dental School and his M.D. from New York University School of Medicine. Dr. Goldiner's interests are the chronic and acute problems of the cancer patient: pain, the physiologic derangements of radical surgery and the effects of chemotherapy.

THIS REVIEW is intended primarily to interest oncologists and students who are not anesthesiologists. Emphasis is placed on the patient's physiologic and contributory developments, and not on anesthetic agents and techniques. (Anesthetic agents and techniques m a k e u p only a small proportion, 1 0 - 2 0 % , of the armam e n t a r i u m of the anesthesiologist.) The function of the anesthesiologist in a cancer milieu is to transform the operating room into a critical care unit.

INTRODUCTION The modern use of c h e m o t h e r a p y and of more aggressive surgical procedures has led the Memorial Cancer Center Anesthesia D e p a r t m e n t to care for patients who are such severe operative risks t h a t they would not have been considered for surgical intervention 20 years ago. In the past two decades anesthesiology has emerged as a specialty,~ advances in equipment, monitoring, 5

rapid analysis of biochemical and coagulation parameters and the gradual assumption of professional supervision of respiratory therapy, recovery and intensive care units. In the operating room, the patient has the same support available as in other critical care areas of the hospital. Adequate intraoperative care often requires consultation, principally for cardiac problems. Medical consultants should be members of the team, advising in areas where the anesthesiologist has the knowledge but not the time to assess the patient. W h a t is desired is a regimen and a judgment that the patient is in optim u m condition for the planned procedure. The anesthesiologist should not be forced into an untenable position by an internist advising on a "medical clearance" who suggests the anesthetic technique. Advice to "maintain the blood pressure and avoid hypoxia" (never defined) are of little value to the .anesthesiologist, and, in fact, this advice m a y be faulty. F e w internists have the time or the inclination to visit the operating room, and since there have been so many recent advances in perioperative care, medical consultants should l i m i t themselves to their fields of expertise. In addition to standard blood pressure and respiration, intraoperative monitoring should include at least electrocardiographic monitoring. In this institution, we use a pregelled back plate which is easily attached and is placed outside of most surgical incisions. We have found it necessary to continuously monitor oxygen concentrations with an analyzer because, as will be discussed later, when dealing with patients who have received extensive chemotherapy, too high a concentration of oxygen in the anesthetic mixture may be deleterious. A central venous pressure (CVP) catheter and urinary catheter are necessary if blood loss is anticipated or if the patient's physiologic state makes precise fluid m a n a g e m e n t mandatory. There need be no discussion of postoperative urinary infection, since in these days of massive and varied antibiotic therapy, urinary complications do not occur. A central venous catheter is valuable only in conjunction with hourly urinary output. We have found that an esophageal or rectal thermistor to record core temperature is valuable in preventing hypothermia due to cold blood or, more commonly, cold operating rooms. Anesthetic agents act differently when the patient is hypothermic. Temperature monitoring also enables us to perceive and act on elevations in temperature, whether due to sepsis or malignant hyperpyrexia, both conditions that occur in our hospital. Finally, for cancer surgery, the circulating nurse must cooperate closely so that the surgical sponges can be weighed at frequent intervals and the patient's blood loss recorded. Blood lost by suction should be aspirated into volumetric bottles placed 6

where they can be seen by the anesthesiologist. Additionally, an accurate record of irrigation or other fluids introduced into the operative field should be kept to prevent confusion with blood loss. Because of the number of demands placed on the anesthesiologist during radical cancer surgery, which include monitoring, blood replacement and assessment of alterations in the acid base, electrolyte, coagulation and cardiovascular status, only one anesthesiologist per operating room is not enough. In times of severe and rapid blood loss, a patient may require the attention of many members of the anesthesia team. We meet this need by having circulating members of the department available. Because of this need and because experience in anesthetizing cancer patients is of the utmost importance, we have held the number of our residents in training to no more than two at any time. The most satisfactory arrangement for staffing our department is'to assign one anesthesiologist to cover two operating rooms, while the actual anesthetic agent is administered by nurse anesthetists. This arrangement insures that adequately experienced, knowledgeable and unfatigued personnel are provided to assist at all operative procedures. The choice of anesthetic agent plays a very minor role in the mangement of our patients. About 75% of the Memorial Cancer Center anesthesias are produced with a narcotic technique using Innovar and its components or morphine, with nitrous oxide-oxygen and a muscle relaxant. The other 25% of our patients receive an inhalation agent which at this time is Ethrane (enflurane), a halogenated, nonexplosive anesthetic. We no longer use Penthrane (methoxyflurane) because of its nephrotoxicity. The extensive use of the cautery has rendered explosive agents impractical.

PREOPERATIVE ANESTHESIA AND PLAN The anesthesiologist can no longer wait until arrival in the operating room to initially evaluate the patient. The complexities of today's cancer patient require a careful and often time-consuming preoperative visit that especially should include a history of drug therapy. Particular consideration must be given to which drugs should be continued, modified or stopped. Although cardiac glycosides may increase myocardial sensitivity to potassium changes, which may be marked during transfusion, they should be continued on the day of operation because of the marked cardiac stress that may occur. Antihypertensive drugs and diuretics should be continued to the day of operation. It was never our custom to cease administration of rauwolfia compounds preoperatively even when the practice was universal. We believe that this prevented the wide fluc7

tuations in blood pressure intraoperatively that can occur. We also avoided the hypertensive rebound that occurs with the abrupt cessation of some of these drugs, particularly clonidine and guanethidine. Antiarrhythmic (fl-adrenergic) blocking drugs present aconsiderable problem because of evolving concepts about their discontinuance. The principal fl-blocking agent is propranolol, and the time for discontinuing the drug prior to surgery has dropped from 2 weeks to 8 - 1 2 hours (plasma half-life is 6 - 8 hours) prior to surgery, except where discontinuance leads to severe angina. 1 The anesthesiologist should be aware that the patient is taking propranolol, and should treat hypotension during anesthesia by the usual method of decreasing the depth of general anesthesia and increasing the intravenous fluid administration. Rarely, it may be necessary to administer atropine for bradycardia or isoproterenol, calcium chloride or digitalis to overcome the fl-blockade with its fixed cardiac output. Corticosteroids should be continued through the operation and in the postoperative period, usually in a higher dose than required for maintenance. Coronary artery disease is a concern, and nitroglycerine tablets should accompany the patient to the anesthesia induction area. Previous myocardial infarction may present a serious problem. There is at least a 6% reinfarction rate in these patients, and reinfarctions are associated with a 50% mortality. A 37% reinfarction rate was noted in one series of patients who had suffered myocardial infarctions within 3 months of surgery. 2 Patients with coronary artery disease fall into two groups: those with good and those with poor left ventricular function.3 Although those in the first group may have a history of angina pectoris, there are no signs or symptoms of congestive heart failure and the cardiac output is normal. This group can be anesthetized by the usual methods including halothane and enflurane. In those with poor left ventricular function, there is usually a history of multiple myocardial infarctions associated with the signs and symptoms of congestive failure often associated with a low, fixed cardiac output. The latter group should have a balloon-directed flow catheter inserted preoperatively for careful monitoring of cardiac output and maintenance of an adequate but not excessive plasma volume. The four main factors that increase myocardial oxygen demand must be avoided, i.e., hypertension (increased afterload), increased heart volume (increased preload) tachycardia and increased contractility. In the past, the clinician's concern with maintaining perfusion pressure in the coronary circulation without appreciating the effects of tachycardia, hypertension and vascular load on myocardial oxygen requirements created a detrimental stress on the patient's cardiac performance. In this group 8

of patients, narcotic or neuroleptic anesthesia supplemented by nitrous oxide-oxygen is preferable. The problem of myocardial failure secondary to adriamycin is discussed later. The problem of the patient with bifascicular block4 has not been completely settled. We have seen, but only rarely, patients progress from bifascicular to complete heart block. This complication is rare if the patient has no evidence of transient second or third degree heart block or no history of unexpected syncopal spells. A pacemaker should be inserted if these conditions are not met. The pacemaker is superior to atropine should bradycardia develop due to high grade atrioventricular (AV) block. All patients with potential heart block, right bundle branch block (RBBB) with or without left or right axis deviation or left bundle branch block (LBBB) should be monitored intraoperatively and postoperatively. Patients with severe hypertension who have had poor preoperative control may not be able to be controlled adequately with deep general anesthesia, and a vasodilating agent to reduce the afterload may be necessary. We have used phentolamine, hydralazine hydrochloride and nitroprusside for this condition with about equal results. Tachyarrhythmias during surgery with a falling cardiac output due to myocardial ischemia may be controlled with propranolol in increments of0.25-0.50 mg until the situation is corrected. Most diabetic patients admitted for surgery are aware of their disease. In mild diabetes, managed by diet alone, it is usually possible to avoid insulin during surgery. These patients need no special precautions other than the monitoring of postoperative fractional urine. For patients taking oral hypoglycemic agents, the drugs can be discontinued and moderate elevations of blood sugar accepted, or, if the patient is seriously ill, insulin may be given with careful intraoperative monitoring. For patients requiring insulin, long- or intermediate-acting insulin is not given on the morning of surgery. Instead, 15 units of crystalline insulin in 1,000 ml of 5% dextrose-water is started before anesthesia and administered at a rate of 60-100 ml/hour. Urine and blood sugars are monitored during surgery with reagent strips or, in severe diabetes, with blood gas, electrolyte, glucose and osmolarity measurements. Recently, we have been able to regulate blood glucose levels more accurately if the insulin is given in fresh frozen plasma rather than in dextrose-water. The necessary glucose can be given through a different intravenous line. Despite the fact that some anesthetics have been associated with the production of mild hypoglycemia, the changes in early postoperative blood sugar levels cannot be correlated with the anesthetic agents used during surgery. Currently, therefore, no anesthetic agent is selected on the basis of diabetes alone. The important elements of asafely managed anesthetic course are the 9

prevention of metabolic acidosis, ketosis, hypoglycemia and hyperosmolarity. It is becoming apparent to us that many patients presenting for surgical procedures have unrecognized preoperative infections, and these may become exacerbated during the surgical procedure. An anesthesiologist who fails to appreciate this will often misdiagnose and mistreat the intraoperative symptoms that are due to the underlying infection. Thus, every patient that we anesthetize has continuous esophageal temperatures recorded. Most surveys of postoperative infection rates do not consider anesthetic agents, so the relevance of different anesthetic techniques to postoperative infection cannot be assessed. Almost any infection is more severe after the age of 60 because elderly patients tend to show relatively few of the signs and symptoms of inflammation and their response to infectious agents may be further compromised by preexisting immunosuppressive therapy or disease. The immune mechanisms are additional systems s that deteriorate with age, (e.g., B-lymphocyte function). This is reflected in a variable fall in IgG, IgM and IgD serum levels and a reduced capacity to form a vigorous antibody response to a variety of antigens. T-lymphocyte function also deteriorates after the 4th decade of life, although, as with B-lymphocyte function, the results are most striking after the age of 60. Regardless of the type of tumor, cell-mediated immunity becomes increasingly impaired, in most instances as the cancer metastasizes. Despite the fact that occasional patients suffer immunologically mediated adverse reactions to anesthetic drugs and that all patients may have reduced resistance to infection and malignancy as a result of exposure to anesthesia and surgery, little or no consideration has been given to the effects of anesthetic agents on the spread of metastases and survival after surgery. It has been known for years that diethyl ether produces a leukocytosis occurring maximally 3 - 4 hours after induction of anesthesia; the magnitude of the increase is of the order of 300%, and the levels do not return to normal until the 2d postoperative day. 6 The effects of anesthetic agents themselves may be modified by the effects of hormonal changes caused by the agents administered, the immunologic results of the stress response to exposure to anesthetic agents and surgery, and the immunologic results of other drugs and infection. Corticosteroids and catecholamine levels are altered during the stress reaction. 6 Raised catecholamine levels are associated with increases in both neutrophil and leukocyte counts and with alterations in their distribution and mobilization. The liberation of ACTH is accompanied by neutrophilia, and corticosteroids depress DNA and RNA synthesis and mitosis. In view of the influence of corticosteroids and catecholamines 10

on the immune response, we must consider the effects of anesthetic agents on their levels. Premedication has little effect on urinary catecholamine excretion and no effect on plasma corticosteroids. Morphine blocks ACTH release, but the normal adrenal response to surgery is unaffected. Plasma cortisol levels are elevated with neuroleptic technique (Innovar), diethyl ether and cyclopropane and unchanged with intravenous administration of barbiturates; methoxyflurane and halothane. Catecholamine levels are elevated with diethyl ether and cyclopropane, unchanged with methoxyflurane and reduced with halothane and enflurane. The stress response to surgery is probably more important than that to the anesthetic agents and involves an increase in corticosteroid levels. The degree of postoperative elevation is proportional to the severity of the surgical stress. At this time it is believed that the anesthetic component of surgical procedures has little effect on B-cell depression. Similarly the T-cell depression after surgical operations is due to the hormonal effects of the stress response. The relationship between malignant disease and immune responsiveness is well known. ~ Immune competence is essential in resistance to malignancy, and malignancy may be associated with immune deficiency and immunosuppressive therapy. It is possible, although surprisingly seldom considered, that anesthesia may upset the delicate balance between tumor and host. Clinicians have long observed that patients who survive for years after a primary operation for cancer will often have a rapid spread of metastases following incidental surgery. Additionally, it has been shown in experimental animals that metastases are more widespread with halothane. 8 Thus it is apparent that retrospective and prospective studies of the effects of anesthetic agents on survival after surgery are needed.

ANTINEOPLASTIC AND CHEMOTHERAPEUTIC AGENTS It is a characteristic of most cancer chemotherapeutic agents that they lack tumor specificity and so have a damaging effect on the normal cells of the patient and especially on the rapidly dividing cells within the bone marrow. Therefore, the clinical management of drug-induced secondary anemia, leukopenia and thrombocytopenia is an integral part of the cytotoxic chemotherapy of neoplastic disease. Alternatively, pancytopenia may be caused by other factors, for example, bone marrow invasion by metastatic cancer or secondary hypersplenism. Anemia may occur as a result of gastrointestinal bleeding, hemolysis or ineffective iron utilization in chronic disease. These patients require special con11

siderations during anesthetic management such as sterile, disposable anesthetic rebreathing systems with bacteria filters on both the inspiratory and expiratory limbs of the circuit, ensuring that no cross-contamination between patients occurs, and endotracheal suction performed with strict adherence to sterile technique, including disposal of catheters after a single use. Similarly, disposable endotracheal tubes are used with strict adherence to uncontaminated technique to avoid introductiori of extraoral pathogens. Thrombocytopenia rarely is the cause of intraoperative bleeding that exceeds 50,500 cu mm and is almost never major until the platelet count is reduced to less than 20,000 cu mm. This patient is monitored with serial coagulation profiles, and platelets are available if needed. Platelets should not be given for the thrombocytopenia of hypersplenism until after the spleen has been removed. Associated problems in the management of the cancer patient undergoing anesthesia and surgery arise from the effect of chemotherapeutic agents on the various organ systems of the body. With the continuing increase in the number, range and use of chemotherapeutic agents in patients coming to surgery the clinician must be continually on the lookout for the problems which might arise in those patients. To date, we have identified specific effects of several of these drugs and, with this recognition, have modified our intraoperative management in order to avoid potential complications. It must be appreciated that drug pharmacology'~ may be altered by hepatic or renal insufficiency caused by tumor-related or incidental disease. This promotes prolonged blood level of the drug and subsequent increased marrow exposure. Cyclophosphamide depends on normal liver function for conversion to the active antitumor component. Adriamycin is secreted by the biliary tree and, therefore, may have prolonged activity in jaundiced patients. Methotrexate is excreted in the urine, and its activity may be prolonged by abnormal renal function. Succinylcholine chloride is a muscle relaxant universally used in modern techniques of anesthesia; it possesses the desirable characteristics of rapidity of onset and short duration of action. The return of muscle tone after its administration depends on rapid metabolism by plasma cholinesterase. In 1963, Wang and Ross l~ reported prolonged apnea following succinylcholine administration in two patients receiving a cancer chemotherapeutic drug. In 1966, Robertson H listed radiation therapy among the causes of serum cholinesterase deficiency. These reports suggest that chemotherapy and/or radiation either affect the level of plasma cholinesterase or alter the enzyme qualitatively, depressing its functional capability. Another measure of cholinesterase ac12

tivity, the dibucaine number, reflects structural abnormality which is usually genetically determined. During a 6-month period we studied patients who had recently received chemotherapy or radiation therapy, or both, to determine whether altered plasma cholinesterase activity could be observed, and whether this was caused by a qualitative defect, as determined by dibucaine number, or a quantitative alteration, as determined by its plasma level. In a group of 171 patients, there was a statistically significant difference (P = < 0.001) between the serum cholinesterase levels of the patients who had received radiation therapy and the patients who had received chemotherapy with or without radiation therapy. There was no statistically significant difference between the dibucaine numbers of patients receiving radiation therapy and those receiving chemotherapy, as would be expected (Table 1). Most of the patients undergoing chemotherapy received multiple drugs. Fifty-five patients were treated with a combination of the following drugs: cytosine arabinoside, thioguanine, vincristine, methotrexate, BCNU, hydroxyurea, daunomycin, and 1asparaginase. Four patients were treated with vincristine, BCNU, Cytoxan and Alkeran. Forty-five patients received courses of 5-fluorouracil, bleomycin and/or methotrexate and seven patients were treated with large doses of Cytoxan (200 mg daily). When those patients treated with large doses of Cytoxan were compared to the other chemotherapy patients, a significant decrease in serum cholinesterase level without a difference in dibucaine number was found (Table 2). TABLE 1 . - S E R U M CHOLINESTERASE LEVELS AND DIBUCAINE N U M B E R S OF PATIENTS RECEIVING RADIATION T H E R A P Y OR C H E M O T H E R A P Y OR BOTH TREATMENT Radiation Chemotherapy Radiation and chemotherapy

NO. OF SERUMCHOLINESTERASE DIBUCAINENUMBER PATIENTS (nl*, 1 , 9 0 0 - 3 , 8 0 0 / z U / m l ) (nl, >80% inhibition} 36 104 31

2,067 • 576 1,350 • 711

80.5 72.2

1,322 •

75.02 • 15.9

89

• 7.3 • 15.2

*Normal.

TABLE 2 . - S E R U M CHOLINESTERASE LEVELS AND DIBUCAINE N U M B E R S OF P A T I E N T S RECEIVING LARGE DOSES OF CYTOXAN C O M P A R E D TO PATIENTS RECEIVING OTHER C H E M O T H E R A P Y TREATMENT

Cytoxan Other chemotherapy

S E R U M CHOLINESTERASE

DIBUCAINE NUMBER

664 _+ 376 m U / m l 1,295 --- 069 m U / m l

53.4 _+ 20.0 67.8 • 14.0 13

The use of bleomycin therapy in the treatment of certain cancers before definitive surgery is gaining increasing acceptance. Recent cases, however, have led us to believe that antecedent bleomycin therapy predisposes the patient to the postoperative development of an acute adult respiratory distress syndrome. This report confirms that the problem exists and identifies the tentative cause and solution. During the years 1970-74, 100 patients with a mean age of 26.4 _ 11.3 years had a retroperitoneal node dissection or multiple wedge resection of the lung for dysgenetic neoplasms of the male gonads. None of these patients had been treated with bleomycin prior to operation. Inspired oxygen concentrations (FIo2) during operation and in the postoperative period were in the range of 0.35 to 0.40. Postmortem examination of 7 patients who died within 30 days of operation showed no evidence of pulmonary lesions compatible with the adult respiratory distress syndrome. Five recent patients in a similar age group who had received bleomycin therapy 6 - 1 2 months before operation died within the same period of time after operation. In these 5 patients, postmortem and microscopic findings in every case were characteristic of those attributed to the adult respiratory distress syndrome, raising the question whether the antecedent bleomycin therapy alone or in conjunction with other factors caused this postoperative respiratory complication. Pulmonary lesions that have been associated with bleomycin therapy include intraalveolar exudate, hyaline membranes, interstitial fibrosis, squamous metaplasia type I and later type II pneumonocytes and increased interstitial fluid in the alveolocapillary space. 12 The pulmonary lesions of oxygen toxicity are strikingly similar to those resulting from bleomycin. 13 Because the bleomycintreated patients responded initially to diuretics and fluid restriction, it was felt that two factors might be related to the high postoperative mortality: first, the concentration of inspired oxygen during the long surgical procedures and second, a relative disproportion of crystalloid to colloid replacement, which might have resulted in interstitial pulmonary edema. In order to test the validity of these assumptions relatively low concentrations of inspired oxygen were used in the operative and postoperative period along with careful monitoring of fluid replacement in a group of 12 patients who had been given antecedent bleomycin therapy. These 12 patients had received 1351,108 mg of bleomycin 6 - 1 2 months before retroperitoneal node dissection or multiple wedge resection of the lung. Pulmonary function studies were performed preoperatively on all patients. After induction with thiopental, anesthesia was maintained with nitrous oxide, oxygen, a narcotic and muscle relaxant. Inspired oxygen concentration was kept to a level of0.22-0.25 throughout 14

TABLE 3.--DATA ON SURGERY PATIENTS WHO RECEIVED BLEOMYCIN THERAPY 6 - 1 2 MONTHS BEFORE OPERATION CHARACTERISTIC Age (yr) Bleomycin dosage (mg) Duration of operation (hr) Fluid replacement (ml/kg/hr) Crystalloid Colloid FIo2 during operation AaDo2 (torr) Preoperative Postoperative

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PATIENTS SURVIVED

27.2 (3.14)* 599 (64) 5.6 • 1.2 3.54 (0.64) 3.13 (0.34) 0.24 (0.004) 31.33 (6.71) 34.67 (5.76)

5 PATIENTS DIED

31.4 (15.9) 426 (181) 5.9 + 0.7

5.86 (1.3.9) 2.38 (2.04) 0.39 (0.01) P < 0.001 39.13 (30.60) 117.82 (57.10) P < 0.01

*Standard error of the mean in parentheses.

the operation. The data are shown in Table 3, along with the data for the 5 patients who died. Three major differences were found between the 2 groups of patients. The first concerned the FIo2 administered during operation and in the immediate postoperative period. Among the survivors, the m e a n FIo2 was 0.24 compared to a m e a n FIo., of 0.39 among patients who died (P < 0.002). Although not statistically significant, there was a difference in the intraoperative crystalloid replacement. The survivors received less crystalloid and more colloid t h a n the patients who died. Calculation of the hourly fluid balance on the basis of crystalloid intake versus hourly urin a r y output revealed a positive intake balance or retention of 320 ml/hour among those who died versus 122 ml/hour among survivors (P = 0.02). Finally, a significant difference existed between the preoperative and postoperative alveolar arterial oxygen difference (AaDo.,) in the 2 groups. Among the 12 survivors, the postoperative AaDo2 (measured on Fio2, 0.21 -0.24) was comparatively unchanged from the preoperative values (34.67 torr versus 31.33 torr). The 5 who died had a postoperative AaDo2 (measured on FIo2, 0.30) of 117.82 torr compared with the preoperative level of 39.13 torr (FIo2, 0.21). Statistical analysis revealed t h a t the difference between preoperative and postoperative AaDo2 correlated closely with the intraoperative FIo2 (P < 0.001) but was not significantly related to the crystalloid and colloid replacement (see Table 3). I~ If oxygen is a factor in the postoperative mortality of these patients, its mode of action is unknown at the present time. The FIo2 used during surgery and during the immediate postoperative period for the patients who died was never higher t h a n 0.45. At the present time there is no evidence that this concentration of oxygen exerts toxic effect~ when used for several weeks. We must 15

assume that antecedent bleomycin therapy in some way sensitizes the lung to levels of oxygen which usually do not produce detrimental lesions. Since we noted in these studies t h a t the generally accepted levels of inspired oxygen of 4 0 - 5 0 % were not necessary to maintain an adequate AaDo2 we have altered our anesthetic techniques to deliver an inspired concentration of 30% or less. We studied an additional 77 patients, including 15 thoracotomy patients, and found it was not necessary to raise the FIo2 above 0.30 to maintain adequate arterial oxygenation in all patients. In 23 patients, lactate levels were measured and all were normal, indicating adequate tissue oxygenation. (An average F~o~ of 0.27 _ 0.014 yielded an average Pao2 of 128 __ 42 torr). Cis-diamminedichloroplatinum (cis-platinum) is a highly effective antitumor agent used in a wide range of diseases, particularly testicular cancer. Although its toxic manifestations are varied (among them are nausea and vomiting, tinnitus, hearing loss and bone marrow depression) during the operative period its nephrotoxicity concerns us.15 Therapy with cis-platinum results in a regular and persistent decrease in glomerular filtration rate (GFR), which appears to be nonreversible. Pathologic changes occur in both the proximal and distal convoluted tubules. In view of this renal damage, patients who have had therapy with cis-platinum are at risk during surgery for further impairment of renal function, and the anesthesiologist must take special precautions to preserve the patient's glomerular filtration. A central venous catheter is placed to monitor central venous pressure and assure an adequate intravascular volume. Mannitol is infused to assure an adequate GFR and diuresis during surgery and the immediate postoperative period. We use a 20% mannitol solution, giving 10 gm (50 cc) intravenously before the induction of anesthesia and then 5 gm (25 cc) per hour. At Memorial Hospital, methoxyflurane, a nephrotoxic anesthetic agent, is no longer used, and would certainly be avoided for patients who have received cis-platinum. Adriamycin, an antitumor antibiotic, is another of the chemotherapeutic agents the toxicity of which m a y affect the intraoperative course of the patient. Cardiomyopathy has been well documented in patients receiving a cumulative dose of more t h a n 550 mg/sq m but has also been reported in patients receiving lower doses, particularly those also receiving concurrent cyclophosphamide and mediastinal radiotherapy. ~6Uncontrolled hypertension also appears to potentiate the development of cardiomyopathy at lower dose levels. In order to minimize the intraoperative and postoperative complications in those patients pretreated with adriamycin, dynamic tests of left ventricular function are recommended. In one group of patients 89%. had a significant prolongation of systolic time 16

intervals after receiving more than 300 mg/sq m of adriamycin. Another study '6a found that the ejection fraction, as measured by echocardiogram, was abnormal in 46% of patients after receiving 400 mg/sq m. Low QRS voltage also indicates cardiotoxic effect of adriamycin, reflecting the diffuse nature of the cardiac injury. Patients coming to surgery with evidence of left ventricular dysfunction due to adriamycin toxicity must be managed carefully to avoid congestive heart failure and pulmonary edema. To avoid this we prefer to give the patient an adequate dose of digitalis preoperatively. Fluid management is monitored by carefully following the central venous pressure and urinary output as well as the blood pressure. In those patients with severe left ventricular dysfunction or in those cases where surgery is expected to be lengthy or blood loss extreme, a Swan-Ganz catheter is placed preoperatively so that a physiologic profile can be determined and, both in the intraoperative and postoperative periods, fluids can be carefully followed by pulmonary artery and wedge pressures and cardiac output. By following this regimen, these patients can be safely managed through major operations. (See section on monitoring.) X-RADIATION THERAPY

All patients treated with radiation therapy alone showed normal serum cholinesterase levels. A depression of serum cholinesterase activity was found in all patients who were treated with chemotherapy but to a varying degree. Several patients who were followed during their course of chemotherapy were found to have continued lowering of their serum cholinesterase as therapy progressed. From these results we concluded that chemotherapy, particularly Cytoxan, had an effect on serum cholinesterase level, and that there was a return to normal pretreatment levels after termination of chemotherapy. Radiation therapy alone or as an adjunct to chemotherapy does not affect serum cholinesterase levels. These findings suggest that succinylcholine should be given with care in cancer patients receiving chemotherapeutic agents, particularly if Cytoxan has been the agent used. 17

PROTECTED-ENVIRONMENT PATIENTS During the past two years, another patient with a special problem has presented for intraoperative management. This is the patient maintained in a sterile state in the Bone Marrow Transplantation Unit because of depressed immunologic defenses. This patient may fall into one of two categories: children with primary genetic disorders and patients with diseases that have been treated by the active irradiation of their bone marrow. Both groups are given bone rharrow transplants. 17

Pulmonary complications necessitating open lung biopsy occur fairly frequently in this group of patients. Although basic anesthetic management (agent, fluids, etc.) does not differ from the ordinary, m a n y problems arise because the patients are mainrained in a bacteria-free environment that must be continued even in the operating room. Two anesthesiologists are necessary, one "sterile" gowned and gloved actually in contact with the patient and another "dirty" anesthesiologist who does 'not contact the patient but circulates, mixing solutions, opening syringes and charting. We use standard anesthesia equipment with bacterial filters on the inspiratory and expiratory sides of the circuit. The anesthesia machine is covered with a sterile drape and the flowmeter knobs are wiped with 70% alcohol immediately prior to use so that the "sterile" anesthesiologist can adjust the anesthesia machine. All anesthesia supplies are sterile, opened for use by the "dirty" anesthesiologist. A bacterial filter is used on the anesthesia ventilator. Whole blood products must be irradiated before transfusion as the patient is unable to produce antibodies and, therefore, the antigens in the whole blood products must be destroyed. Finally, we have the patient recover fully from anesthesia in the operating room so that he can be transported in sterile cloth sheets back to the Bone Marrow Transplantation Unit.

RESPIRATORY FAILURE One of the most disturbing of postoperative complications is adult respiratory distress syndrome. This is especially frustrating because we feel that we have recognized and should be able to avoid the causative factors. We have learned to limit crystalloid administration to no more than 5 ml/kg/hour of surgery; to administer enough colloid to maintain a normal relationship between colloid oncotic pressure and pulmonary artery wedge pressure PAWP; to use micropore filters to prevent pulmonary microembolization of the detritus in bank blood; to carefully monitor the core temperature to detect early sepsis; and, finally, to administer minimal FIo2 to patients who have received bleomycin. And yet, postoperative respiratory insufficiency develops. Adult respiratory failure is characterized by interstitial pulmonary edema, reduced pulmonary compliance, alveolar and small airway closure, decreased functional residual capacity and ventilation-perfusion inequality, resulting in an increasing venoarterial admixture (pulmonary shunt fraction). Most postoperative respiratory distress responds readily to mechanical ventilation, fluid restriction and diuretics, correction of decreased colloid oncotic pressure, optimization of cardiac output and tissue perfusion by proper adjustment of preload and afterload (see section on monitoring) and expansion of collapsed 18

airways and alveoli to restore a high end-expiratory lung volume (functional residual capacity) with positive end-expiratory pressure (PEEP). There is no doubt that the cause of respiratory failure is often obvious and easily treated. However, there now exists a syndrome that is unexplainable and the etiology of which is never determined even though the patient recovers. This syndrome occurs 21- 48 hours postoperatively and is usually heralded by inappropriate hyperventilation with resultant respiratory alkalosis. The oxygen tension is at first within normal limits, but gradually, the patient's condition deteriorates and arterial hypoxemia occurs along with a respiratory and metabolic acidosis. As the hypoxemia occurs, radiographic changes, which initially may be minimal, progress to massive involvement of the lungs, both alveolar and interstitial. It has been proposed that this condition is the result of disseminated intravascular coagulation (DIC), which can occur with septicemia, trauma, hemorrhage, fat embolism and hemolytic diseases including incompatible blood transfusion. DIC may result from: 1. Endothelial damage which activates factor XII (Hageman factor) and initiates the intrinsic clotting system; 2. Tissue injury which activates the extrinsic clotting system; or 3. Red blood cell or platelet damage which releases coagulant phospholipids. Postoperative respiratory insufficiency also has been proposed to be due to the fibrin, platelet and white cell aggregates and fat droplets which can pass through the conventional (170/~) transfusion set filter but may still be large enough to cause pulmonary microembolism. The effects of these aggregates are both mechanical and biochemical. When platelet emboli fragment, they release vasoactive peptides which can cause pulmonary and systemic vasospasm and increased capillary permeability leading to pulmonary hypertension and pulmonary edema. Unfortunately, this attractive hypothesis has not been proved, and even though micropore filters are used routinely, at least by us, during massive transfusion, no definite study of their value has been made. Finally, it has been suggested that, in sepsis, endotoxin increases capillary permeability. Again, there is no definitive demonstration of this occurring in humans in septic shock; we have seen patients in which this did not occur. Pulmonary artery hypertension and elevated pulmonary vascular resistance are observed in all patients undergoing severe respiratory failure even after correction of hypoxemia. Pulmonary vascular resistance is inversely related to pulmonary blood flow. Severe respiratory failure that acutely reduces PEEP to 0 cm of water reduces mean pulmonary pressure little, if at all. 19

Hence, there is no need to disconnect the patient from the ventilator when making pressure measurements. Also, in severe respiratory failure there is a close association between left ventricularend diastolic pressure (LVEDP) and pulmonary capillary wedge pressure (PCWP). The vascular cross-sectional area of the lung is reduced in this condition, and the resultant increased pulmonary vascular resistance may be due to active vasoconstriction, decreased lung volume, increased interstitial pressure, endothelial cell edema, diffuse microembolism or thrombosis and microvascular obliteration by fibrosis or extravascular hemorrhage.

FLUID BALANCE Clinical hypervolemia often occurs after massive fluid and blood replacement for hypovolemic shock. TM This fluid overload syndrome is characterized by weight gain, respiratory failure characterized by hypoxia, elevated central venous, pulmonary artery and wedge pressure, expanded plasma volumes, increased cardiac output and sustained systolic and diastolic hypertension. Renal function is also altered; effective renal plasma and renal blood flow are significantly reduced with a concomitant increase in renal vascular resistance. There is a misconception that the postinjury fluid overload represents overaggressive fluid therapy. It must be appreciated that less aggressive fluid therapy would result in hypovolemia, decreased cardiac output, organ ischemia and renal failure. This apparent fluid overload is really a redistribution of previously administered fluid rather than an overly aggressive exogenous fluid administration. During extensive surgery, extravascular fluid sequestration, "the third space," may lead to hypotension and oliguria. Rapid fluid replacement is mandatory to reestablish vital signs and urinary flow. In the immediate postoperative period, fluid restriction and loop diuretics will help to ameliorate the respiratory insufficiency and hypertension that result from the overexpanded plasma volume. Transfusions of whole blood are necessary when whole blood is being lost. Supplemental fluid therapy with crystalloid or colloid is still controversial. Adherents of crystalloid replacement believe that after hemorrhage, the plasma volume is replaced at the expense of the interstitial fluid. However, after surgical trauma, the interstitial fluid is often increased, even in the face ofhypovolemia. Nevertheless, the "crystalloid school" believes that decreased serum sodium concentrations reflect leakage of salt and water into the cells, and therapy should strive to replace interstitial fluid deficit by replacing both the external sodium losses and sodium lost into the cells. Excessive volumes of saline may increase interstitial fluid to the point where pitting edema occurs with coexistent hypovolemia. The problem of the overreplace20

ment versus underreplacement was a source of considerable confusion in our institution until facilities for m e a s u r e m e n t of the pulmonary capillary pressure became available. Low sodium values in the postoperative period are most often due to dilutional hyponatremia and reflect excess administration of free water, not interstitial fluid deficits. Advocates of colloid administration believe that Starling's hypothesis of the capillary circulation explains the distribution of the volume of water between plasma and interstitial fluid and that increased interstitial water occurs with reduced plasma volume. Thus volume therapy with colloids can restore plasma volume without overexpanding the interstitial space.~9 At Memorial Hospital we have attempted to use both regimens. Lactated Ringer's solution can be tolerated in the patient who is not critically ill quite easily, and crystalloid at a rate of 2 - 4 ml/kg/hour of surgery insures adequate hydration for maintenance of urinary output, compensates for insensible fluid loss and provides water for homeostasis. Colloid therapy, again in the 2 - 4 ml/kg/hour range is necessary to replace the third space losses that occur with surgical t r a u m a or that m a y be present due to peritonitis or sepsis. It must be appreciated, however, that intravascular overload can occur just as readily with injudicious colloid administration as with crystalloid. Despite careful attention to fluid losses and replacement, we are often faced with the dilemma ofunderreplacement versus overreplacement, since both conditions can be accompanied by tachycardia with or without blood pressure changes. Fluid challenge has been designed for use with either the pulmonary artery or central venous catheter to help clarify this problem. When the PAWP is less than 12 torr, 200 ml of fluid is administered over a 10-minute period; when the PCWP is 1 2 - 1 6 torr, 100 ml of fluid is administered; and when the P C W P is greater than 16 torr, 50 ml of fluid is administered. If at any time during the infusions the PCWP increases by 7 torr for 1 minute, the infusion is stopped. If the PCWP returns to within 3 torr of starting value after the period of infusion, the fluid challenge is resumed. At values between 7 and 3 torr, the patient is monitored until the vital signs change. When the CVP is used, the values are: less than 8 cm of water, 8 - 1 4 cm of water and over 14 cm of water. If the CVP rises more than 5 cm of water, the infusion is discontinued; if the CVP returns to within 2 cm of the starting value the fluid challenge is repeated. If the CVP is between 5 and 2 cm of water, the patient is observed for further changes. When the safe limits of fluid challenge are exceeded and perfusion failure persists, a trial of dopamine in concentrations of 5 - 20 ~g/kg is warranted. 21

RENAL DISEASE Acute renal insufficiency continues to be a significant complication after major surgical illness, despite increased understanding ofperioperative fluid dynamics and metabolic derangements. The severity of renal failure can be fairly well correlated with the age of the patient and the basic pathologic process. The very young and the elderly have the highest mortality. Renal failure occurring after major pancreatobiliary and gastrointestinal operation, particularly when associated with sepsis, has a singularly dismal prognosis. Advancing age is associated with a progressive reduction in renal mass. Age-related decreases in cardiac output and reductions in the renal vascular bed also contribute to a progressive reduction in renal plasma flow. The loss of renal mass is primarily cortical, with relative sparing of the renal medulla, and seems to be secondary to the intrarenal vascular changes associated with advancing age. The reduction in daily creatinine clearance with age is attended by a parallel reduction in daily urinary creatinine excretion, reflecting decreased muscle mass. Thus, an elderly patient can have a normal serum creatinine with decreased creatinine clearance. In the perioperative period, drugs that are excreted primarily by the kidney should be adjusted to the 20-30% decrease in GFR which occurs in the elderly.2~ Adaptive mechanisms responsible for maintaining constancy of volume and composition of the extracellular fluid are impaired in the elderly. The aged kidney's response to sodium deficiency is blunted, and the cumulative deficit, before daily renal losses equal intake, is greater in the elderly. The senescent kidney is less able than the younger kidney to excrete an acutely administered salt load and is at risk for expansion of the extracellular fluid volume when presented with a salt load from inappropriate intravenous fluids. Finally, the geriatric patient is at risk for the development ofhyponatremia and water intoxication under anesthesia; narcotics, general anesthetics, stress and positive pressure ventilation all contribute to excess antidiuretic hormone (ADH) secretion. The associated respiratory distress that occurs in acute renal insufficiency is probably due to excess fluid administered in an effort to increase urinary output. It is obvious that prevention of renal ischemia is a prime consideration during surgery. This can be done by preventing shock, replacing adequate volume, treating sepsis, eliminating aminoglycoside antibiotic therapy if possible and using diuretics in patients with compromised renal function as determined by preoperative evaluation. One can often distinguish prerenal oliguria from that due to mechanical ventilation (ADH release) and opiates by giving 22

mannitol, 12.5 gm intravenously over a 3-minute period. If, within 2 hours, the urine output increases to more than 40 ml/minute this is suggestive of prerenal oliguria. If the patient is believed to be volume overloaded, furosemide should be given. Also, occasionally, furosemide will initiate a diuresis when mannitol has failed.

INTRAOPERATIVE PHYSIOLOGIC MONITORING Despite careful mo'nitoring of the patient's blood pressure, pulse, arterial blood gases, urinary output, electrolytes and coagulation parameters, previously we were often in a dilemma during surgical procedures as to the causes of tachycardia, hypotension, hypoxia and oliguria. The advent of the Swan-Ganz catheter and the subsequent development by Del Guercio of the Automated Physiologic Profile21 has enabled us to have a rapid and easily repeatable assessment of the fluid balance, respiratory and hemodynamic status, oxygen transport and tissue oxygen utilization. Figure 1 is a diagram of the pressure and volume relationship between the various circulatory compartments. By measurements obtained with Swan-Ganz catheterization, the inotropic capabilities of the right and left ventricles can be calculated, and the factors that may be operative to alter their function can be assessed. Since more than one factor contributes simultaneously to these functions, alterations in each variable may be assessed individually. This schematic allows the clinician to visualize the various functional components of the central circulation, correFig 1 . - Diagram of the pressure-volume relationship of the various circulatory compartments. See glossary for abbreviations.

PHYSIOLOGICPROFILESYSTEM --

CVP = RVEDP = PADP

C I R C U L A T I O N

--

PCW > LAP > LVEDP,'-~LVEDV

MAP

Peripheral Circulation

23

late them and follow the patient's progress by comparing serial profiles. We have found this to be an excellent teaching device, and, in a short time, physicians and nurses can become expert in assessing the patient's cardiovascular and respiratory status. During operative procedures, a fundamental concern is the pa~ tient's cardiac output. Cardiac output is determined by preload and afterload. Preload is mainly the volume of blood presented to the heart to be pumped. Preload determines left vefitricular-end diastolic volume which is a measure of the heart's ability to pump. For our purposes the PCWP is a valid indicator of left ventricular-end diastolic volume. Preload in the surgical patient is influenced by the left ventricle's intrinsic ability to pump, anesthetic agents, intravascular volume, vena caval obstruction and operative position (venous return). Afterload is the total peripheral resistance of the nonpulmonary vasculature. Afterload is altered by halothane, nitroprusside, temperature and sympathetic nervous system activity. Indications for use of balloon-tipped flow-directed catheter in the perioperative period of cancer surgery are (at Memorial Hospital): 1. A history of recent myocardial infarction or angina; 2. Sepsis with or without shock; 3. Respiratory failure requiring levels of PEEP greater than 15 cm of water; 4. Bleomycin damage to the lung requiring an Fio2 less than O.3O; 5. Anticipated excessive blood loss; 6. Induction of elective, controlled hypotension; 7. Open lung biopsy in immunosuppressed patients with severe respiratory failure; and 8. Liver transplantation when interruption of vena caval return to the heart is anticipated. Swan-Ganz Catheter errors of interpretation: 1. Unexplained deviations in pressure readings are usually due to failure to have the zero point of the tranducer at midchest level in the supine patient. 2. Pressure readings must be done with the patient attached to the ventilator and suitable corrections made for end-expiratory pressure values. Disconnecting the patient from the ventilator to obtain readings is counterproductive and may even by dangerous. 3. "Wedge" pressures should be recorded at the time of end exhalation. 4. The wedge pressure should be slightly lower than the pulmonary artery diastolic pressure (PADP). In many patients there is a constant relationship between the PADP and the wedge pressure. Once this relationship is established, the balloon need not be intermittently inflated, and the PADP 24

can be used to infer ventricular filling pressure. This is particularly valuable during surgical operations when mechanical, positional and technical difficulties make obtaining a true'wedge pressure too time consuming and even disruptive of the operative procedure. The following pages list the measured and derived physiologic parameters used in construction of the automated physiologic profile and include conditions under which these parameterg may be increased or diminished. We have found them to be extremely valuable reference points that often aid us in understanding seemingly conflicting measurements. The measured and calculated physiologic parameters and their significance are explained in the following sections (see glossary for abbreviations). MEASURED PHYSIOLOGIC PARAMETERS

A. Right atrial pressure = CVP = RVEDP Normal, 0 - 8 cm of water J' Right ventricular failure, pulmonary embolism, COPD, cardiac tamponade Hypovolemia B. Pulmonary artery pressure Normal, 15-30 torr. Mean, PA = 13-15 torr 5 - 1 2 torr 1' Pulmonary embolism, pneumonia, atelectasis, chronic lung disease, fluid overload, left ventricular failure, PVR increase, light anesthesia Hypovolemia, nitroprusside PADP = RVEDP = PAW when PVR is normal C. Pulmonary artery wedge pressure PAW = LAP = LVEDP = LV filling pressure Normal, 5 - 1 2 torr 1' LV failure, mitral valve disease, cardiac tamponade, I LV compliance LV hypertrophy, myocardial infarction, fluid overload Hypovolemia, nitroprusside D. Arterial pressure E. Cardiac output thermodilution used to calculate CI Cardiac output. Noncontractile myocardial mass, arrhythmias, mitral insufficiency, VSD, hypovolemia TPR F. Serum lactate Normal, 0.7-1.7 mEq/L G. Base excess Normal, -2.5 to +2.5 mEq/L Oxygen delivery = Cao., • CO 25

COD = Coefficient ofoxygen delivery = 02 Cao2

Delivery]V~ = Cao2 - Cvo2 Normal, 3.5-4.5 m]/minute/m] Vo2 COD<3.5 = Pvo,,<35 tort Cao., = Hg x 02 SAT x 1.34 + Pao2 x 0.0031 CALCULATED PHYSIOLOGIC PARAMETERS

cardiac output body surface area Normal, 3.0-3.6 L/minute/sq m ~' Septic shock Hypovolemia, congestive failure, pulmonary embolism, cardiogenic shock, anesthetic agents S I - 1,000 CI PR Normal, 36-48 ml/sq m I' Septic shock, bradycardia, hypovolemia, hypertension, anesthetic agents Cardiogenic and hemorrhagic shock LVSW = (CI • Ao) 13.6 or (1.0136 • Ao • SI) PR Normal, 44-56 gm/m/sq m ~' Some forms of hypertension Hypovolemia, cardiogenic and septic shock TPR = (Ao - RA) 79.9 or (~.o - CVP) 79.9 CI CI Normal, 1,400 - 3,000 d y n e s / s e c o n d / c m S / M 2 T Hypertension, hypovolemia vasoconstrictive states, cardiogenic shock Vasodilation (late septic shock, nitroprusside, fever, adrenal insufficiency, Halothane) RVSW = (CI • PA) 13.6 or (0.136 x PA x SI) heart rate Normal, = 7 - i 0 gm/m/sq m ~' Pulmonary embolus, congestive heart failure, valvular heart disease, fluid overload Hypovolemia, cardiogenic and septic shock PVR = (PA - PAW) 79.9 CI Normal, 80- 240 dyne/sec/cmS/sqm I' Pulmonary embo]us, congestive heart failure, valvular heart disease, interstitial pulmonary fluid, pneumonia, fluid overload Nitroprusside, isoproterenol

A. C I =

B.

C.

D.

E.

F.

26

G. A r t e r i o v e n o u s o x y g e n difference (A - Vo2 diff) = Pao2 - P~r N o r m a l , 3 . 1 - 5 . 0 ml/dl 1' P u l m o n a r y embolism and low cardiac o u t p u t s t a t e s H y p e r d y n a m i c s t a t e s - h i g h cardiac o u t p u t H. O x y g e n c o n s u m p t i o n = CI • A - Vo 2 diff • 10 Normal, 110-160 ml/minute/sq m 1' Exercise, thyrotoxicosis, h y p e r t h e r m i a Hypothermia I. V e n o a r t e r i a l a d m i x t u r e ( p u l m o n a r y s h u n t ) _ (Ca,,- - Car,) = Qs/Qt (Calv -- Oven)

Normal, 4-10% F l u i d overload, p n e u m o n i a (alveolar and interstitial), atelectasis, diffusion a b n o r m a l i t i e s , p u l m o n a r y embolism, p u l m o n a r y fibrosis, cardiogenic shock, septic shock, dopamine, thoracic surgery CLINICAL APPLICATION

P A W and l CI are final c o m m o n p a t h w a y s for p r o d u c t i o n o f v i r t u a l l y all t h e clinical signs a n d s y m p t o m s o f h e a r t failure. 22 T h e clinical applications of t h e m e a s u r e m e n t s listed in t h e previous sections are s h o w n in T a b l e 4 and in t h e two following illust r a t i v e cases: CASE 1 . - A 41-year-old m a n h a d received a d r i a m y c i n a n d Cyt o x a n for r e n a l cell carcinoma. T h e effects of these a g e n t s on vent r i c u l a r function a n d d e v e l o p m e n t o f i n t e r s t i t i a l fibrosis a r e c l e a r l y d e m o n s t r a t e d in F i g u r e 2. T h e left v e n t r i c u l a r insufficiency is r e v e a l e d b y t h e d e c r e a s e d CI a n d LVSW. T h e i n t e r s t i t i a l p u l m o n a r y fibrosis r e s u l t e d in a n e l e v a t e d PVR, a m o d e r a t e l y TABLE 4.-CLINICAL APPLICATIONS OF PHYSIOLOGIC PARAMETERS CI 2.7-4.3 L/minute/sq m = normal 2.2-2.7 = subclinical depression 1.8-2.2 = clinical hypoperfusion <1.8 = cardiogenic shock PADP 1' = pulmonary embolism PAW normal } PADP ~ ) = cardiogenic shock PAW ~ " PAW 18-20 torr-onset pulmonary congestion 20- 25 torr- moderate congestion 25- 30 torr- severe congestion >30 torr-pulmonary edema 27

Memorial Hospital

FORCANCER ANDALLIED DISEASES

Automated

NIFI~ YO4~K. NEW YORK

CI

SI

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TPR

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Fig 2.--Case 1 : Decreased cardiac output is demonstrated by the low cardiac index and low left ventricular stroke work. The interstitial pulmonary fibrosis is revealed by the increased pulmonary vascular resistance and the somewhat elevated pulmonary artery wedge pressure and markedly elevated mean right atrial and mean pulmonary artery pressure.

28

elevated P A W P and a markedly elevated mean right atrial pressure (CVP) and PA. Since we know that it follows that this patient's PVR will be increased. PVR = (PA - PAW) 79.9 CI and in this case PVR = (PA J' - PAW 1' ) 79.9 CI The Sarnoff ventricular function curve demonstrates the poor ventricular function that was suggested by the decreased CI. A previous profile, 24 months before, was essentially the same, indicating that there is no improvement in the inotropic function of the heart or decrease in pulmonary interstitial fibrosis even 2 years after cessation of doxorubicin and cyclophosphamide therapy. CASE 2 . - A 69-year-old 77-kg m a n was scheduled for resection of a carcinoma of the midrectum. Because of severe angina requiring nitroglycerine and a history of repeated myocardial infarction, it was decided to insert a Swan-Ganz catheter preoperatively. Accordingly, the patient was admitted to the Intensive Care Unit (ICU) the day before the scheduled procedure, a Hartman's resection. The initial readings (Fig 3) in the ICU revealed a decreased cardiac output and decreased RVSW. This hypovolemia responded to judicious fluid admihistration, and, at the time of operation the next day, the cardiac output and right ventricular function were normal, b u t the left ventricular function was only partially restored. This malfunction continued throughout the operative and postoperative period, presumably the result of the previous myocardial infarctions. Despite restricted fluid administration, 1 hour after the start of the operation, when the patient had received 350 ml of crystalloid and 600 ml of colloid, with a blood loss of 154 ml, the patient had slightly elevated PA and P A W P and had developed an arteriovenous admixture (shunt fraction) of 32% as manifested by a Pao 2 of 74 torr on an oxygen concentration of 40% (Fig 4). The pulse rate and blood pressure were of little value throughout the m a n a g e m e n t of this patient and did not reflect the circulating overload pressure at this time. As can be seen in Table 5, over the next 2 hours the patient's Qs/Qt increased despite 100% oxygen and the addition of P E E P to increase the patient's functional residual capacity. Fluid administration was difficult to manage because there was a loss of over 3,000 ml of blood at this time which was unfortunately overreplaced (whole blood, 4,500 ml). Approximately 3 hours after the start of the operation (Fig 5) the blood loss and replace29

Memorial Hospital FOR CANCER AND ALLIED DISEASES

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Fig 3.--Case 2: Hypovolemia is indicated by low cardiac index and low right ventricular stroke work.

30

Memorial Hospital FOR CANCER AND ALLIED DISEASES CI

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Fig 4 . - C a s e 2: The inability of the myocardium to compensate for an adequate cardiac index is shown in this figure by the elevated pulmonary artery mean and wedge pressure, marked arteriovenous admixture and low left ventricular stroke work and stroke index.

31

TABLE 5 . - V A R I O U S PHYSIOLOGIC PARAMETERS DURING START OPERATION

ADMITrED

CVP (torr) PA (torr) PCWP (torr) CI (L/sq m) Blood pressure Pulse U r i n e (ml) Blood loss (ml) Blood given (ml) FIo2 Pao2 (torr) Paco2 (torr) P E E P (cm/HzO) 9 Qs/Qt (%) Crystalloid (ml) FFP (ml)

TO ICU

830

900

915

930

945

0 10 4 2.18 116/66 50

0 11 3

3 27 7 2.56 120/80 96 150

3 35 22

3 32 18

3 21 16

0.50

0.40

0.40

0.33 127 36

130180 104

0.50

0.50

1000

1015

3 2 20 36 16 - 22 3.20 130/80 110/80 120/80 112/55 140/90 120 110 104 109 96 180 85 100 154

7

0.40 74 41

1.00

32 350 200

400

600

Note significant changes when blood loss occurs a n d volume is replaced. The effects of therapeutic intervention can also be seen. *Operation, anterior resection of rectum; anesthetic, Innovar, nitrous oxide-oxygen relaxant. TDigoxin, 0.5 mg intravenously; Lasix, 10 mg given.

ment were equal, and with a P E E P of 7.5 cm of water the venoarterial admixture was beginning to be reversed. At this time, the patient received digitalis and furosemide, and by the end of the operative procedure, he had received 9 units of blood, 2 mg/kg/ hour of crystalloid and 4.9 ml/kg/hour of colloid. Despite a urinary output of 1,200 ml, it was believed that there was too much fluid administered to this patient, and the first physiologic profile in the ICU appeared to confirm this because the patient still had a large Qs/Qt and could not be adequately oxygenated on 40% inspired oxygen. This was believed to be left ventricular failure and/or fluid overload as manifested by a pulmonary wedge pressure of 27 torr (Fig 6). This condition responded to dopamine infusion (Fig 7) and the patient's left ventricular function returned to a normal value for the first time. This suggests that the patient was in left ventricular failure throughout the operative procedure and that the fluid administration was correct. During this procedure the necessity for left ventricular support was neglected because of the assumption that his pulmonary difficulties were due to over-zealous fluid administration.

THE BLEEDING PATIENT Nothing is more distressing in the operating room than not knowing whether the patient's bleeding is due to vascular disruption or a coagulfition abnormalityY 3. 24 32

T H E I N T R A O P E R A T I V E PERIOD (CASE 2)*

1030

1045

1100

0 7 2 1.56 120/90 115

0 12 0

0 17 6

7 47 31

100/60 104

95/60 104

1.00

2,500 1.00

110/80 108 290 3,150 4,500 1.00 64 44 2.5

1,000 1,000 1.00 90 36

2.5

800

1,000

. 1130

1145

1200

1215

5 38 24 2.0 130/80 100

4 41 27 2.26 130/80 104 420 4,300

4 33 21 2.25 127/80 103 620

1.00

1.00 209 49 5.0

1.0{) I 126t 46 7.5 18

5.0

1,200

END OPERATION 1315 1445 3 29 21 _ 140/80 84 1,200 5,000 4,500 1.00

650 1,600

2 38 27 2.36 148/80 110 1,700

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In our experience, congenital clotting abnormalities are rare in the cancer patient, and whether there has been previous chemotherapy or radiation therapy can be learned from the chart. The most.important historical fact for the anesthesiologist to know is w h e t h e r pain, headache or arthritis have required the use of aspirin or related drugs. Many proprietary drugs contain aspirin, so the n a m e of the analgesic drug must be obtained and its composition determined. Decreased platelet aggregation due to aspirin is one of the few acquired clotting abnormalities that cannot be readily reversed in the operating room, because the platelets are irreversibly damaged and new ones must be regenerated; therefore, platelet transfusions of some magnitude m a y be required. The understandable lack of an adequate day-and-night coagulation service that can respond in a few minutes forces the anesthesiologist to be more than merely conversant with clotting abnormalities. Although we have developed a sophisticated clotting laboratory to differentiate among lack of hemostasis, platelet abnormalities, coagulation factor abnormalities, hypercoagulability and disseminated intravascular coagulation, hemostatic abnormalities can be approached with the therapies available, which are: 1. Hemostats and ligatures; 2. Fresh frozen plasma; 3. Factor IX complex; 33

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4. Platelet transfusion; and 5. Heparin. Since the first therapy listed is the responsibility of the surgeon, we shall confine ourselves to the last four modalities. Fresh frozen plasma (FFP) without cryoprecipitates removed is a valuable and widely used blood component. We cannot emphasize enough the necessity for insuring that cryoprecipitate, which contains about 45% of the original factor VIII and 30-40% of the fibrinogen, has not been removed from the plasma. Fresh frozen plasma may be used for deficiencies of plasma coagulation factors in: 1. Massive transfusion; 2. Liver disease; 3. Reversal ofCoumadin anticoagulation; 4. Deficiencies of antithrombin III which is necessary for the action ofheparin; and 5. Prolongation of the prothrombin time or partial thromboplastin time when emergency surgery is required. Factor IX complex which contains the vitamin K-dependent factors II, VII, IX and X is seldom used in Memorial Hospital but remains an adequate therapy on the few occasions when FFP is not available. Platelet concentrates, although much overused, have a dramatic effect in correcting coagulation defects when indicated. A prime indication for the use of platelets is in thrombocytopenic patients (bone marrow has been replaced by tumor or depressed by chemotherapeutic agents) who must undergo surgery. In these instances, the platelets should be given preoperatively. In thrombocytopenia due to hypersplenism associated with the lymphomas or when idiopathic thrombocytopenic purpura is present, the platelets should be available in the operating room, but they should not be given until the spleen has been removed. Heparin 25is increasingly being used preoperatively and continued into the postoperative period in minidoses (3,000-5,000 units 6 - 8 hours subcutaneously). We have reserved its intravenous use for cases of hypercoagulability during surgery and for fully diagnosed DIC for which we give large doses (5,000 units/ hour) controlled by partial thromboplastin time, since we lack a better test at present. No discussion of clotting would be complete without devoting some space to disseminated intravascular coagulation the catchall diagnosis for bleeding in the perioperative period. This condition which is easy to diagnose on the medical floors of the hospital is fraught with difficulty when associated with anesthesia and surgery. The diagnosis of DIC is classically made when there is a decrease in the platelet and fibrinogen levels, prolongation of the thrombin, prothrombin and partial thromboplastin times, the 37

presence of fibrin degradation products and soluble fibrin monomer. In the perioperative period, the decreased plasma coagulation factors associated with massive transfusion may prolong the prothrombin and partial thromboplastin time, and an elevation of fibrin degradation products may be caused by those present in bank blood. The platelet count may fall as a result of the normal drop that occurs with massive transfusion, and the fibrinogen may fall purely on a basis ofhemodilution. Fibrin degradation products are the result of the proteolytic process that occurs when plasminogen is converted to plasmin. Thrombin is also a proteolytic enzyme, and, thus, one enzyme promotes clotting (thrombin) and the other promotes bleeding (plasmin). The tissue activators of plasminogen are released from blood vessel walls by anoxia or injury, activated by the Hageman factor (factor XII) or by the other proteolytic enzyme involved in clotting, thrombin. Plasmin digests factors V and VIII, fibrinogen, and fibrin and certain components of complement. When plasmin reacts with fibrinogen, a sequential degradation of the fibrinogen molecules takes place. The first degradation produces a large first derivative, Fragment X, which can be clotted by thrombin but at a greatly retarded rate. It, therefore, acts as a competitive inhibitor of thrombin. Fragment X is further cleaved into fragment Y and fragment D. Fragment Y forms soluble complexes with fibrin monomer and, therefore, may persist in serum. Fragment Y is further cleaved into a second fragment D and fragment E. Fragments D and E are powerful inhibitors of polymerization of the fibrin monomer. They not only slow the conversion of fibrin monomer to polymer but produce a fragile clot by being incorporated into the growing fibrin polymer. The Thrombo-Wellco test is used by our coagulation laboratory to detect fibrin degradation products and fibrin monomer in serum and urine. A distinction between the degradation products of fibrinogen (FDP) and fibrin (fdp) cannot be made with this test nor with the two other most commonly used tests, staphylococcol clumping and tanned red blood cell hemoagglutination inhibition immunoassay. Only concentrations of FDP/fdp of 10 tLg/ml will cause agglutination of the latex particles in the Thrombo-Wellco test. Elevated amounts of FDP/fdp may be associated transiently with pulmonary embolism (40 tLg/ml), for 24-48 hours after myocardial infarction (40-160 tLg/ml) and with deep vein thrombosis (10-40 tLg/ml). The presence of FDP/fdp in bank blood probably represents an activation of the enzyme system resulting in formation ofprekallikrein activator (Hageman fragment) or activated factor XII. This activation could also explain the vasodepressor effects of plasma protein fraction prepared from whole blood. Data on 25 patients receiving an average of 7.5 units of blood 38

TABLE 6.-FDP/fdp, PLATELET COUNTS AND FIBRINOGEN LEVELS IN 25 PATIENTS AFTER BLOOD ADMINISTRATION FDP/fdp

Preop

Postop

Units of blood

0 10 2O 4O Fibrinogen Decreased postop Unchanged Platelet count Decreased postop

20 4 1 0

11 9 (Preop 10-20) 4 (Preop 10-10-10) 1

5.27 _ 2.53 8.00 _+ 5.83 12.25_+ 12.69 14.0

22 cases 3 cases 25 cases

are s h o w n in T a b l e 6. T h e fibrinogen d e c r e a s e d in 22 cases a n d p l a t e l e t c o u n t d e c r e a s e d in all cases. Five o f t h e 25 p a t i e n t s h a d FDP]fdp p r e o p e r a t i v e l y a n d all 14 p a t i e n t s h a d positive tests for F D P / f d p after s u r g e r y a n d t r a n s f u s i o n . All 5 of t h e cases w i t h positive p r e t r a n s f u s i o n levels still tested positive in t h e postoperative period. T w e l v e of t h e p a t i e n t s h a d p r o l o n g e d p r o t h r o m b i n time despite the a d m i n i s t r a t i o n of w h a t we believe to be a d e q u a t e F F P (1 u n i t F F P per 5 u n i t s blood). T h e r e was e s s e n t i a l l y no difference in t h e incidence o f F D P / f d p in p a t i e n t s w i t h or w i t h o u t a p r o l o n g e d prot h r o m b i n t i m e (Table 7). T h e p r e s e n c e of F D P / f d p in blood p r o d u c t s is s h o w n in T a b l e 8. T h e c o r r e l a t i o n b e t w e e n u n i t s o f blood t r a n s f u s e d , u n i t s o f F F P t r a n s f u s e d a n d i n c r e a s e in F D P / f d p w a s tested w i t h t h e P e a r s o n ' s p r o d u c t s - m o m e n t formula. A definite c o r r e l a t i o n (P <0.005) existed b e t w e e n t h e increase in F D P a n d t h e a m o u n t of blood adTABLE 7.-THE EFFECT OF WHOLE BLOOD ADMINISTRATION ON PROTHROMBIN TIME PROTHROMBINTIME Prolonged (2.0 seconds or more) FFP (units) Whole blood (units) Partial thromboplastin time prolonged Postop FDP/fdp Negative preop Positive preop Unchanged FFP (units) Whole blood (units) Partial thromboplastin time unchanged Postop FDP/fdp Negative preop Positive preop

NO. OF CASES 12 2.92 - 2.28 9.58 ___8.11 2 7 4 3 13 3.35 • 2.28 6.92 -+ 5.25 13 7 6 1 39

TABLE 8.-THE LEVEL OF FDP/fdp IN COMMON BLOOD PRODUCTS PRODUCT

NO. OF SAI~IPLES

FP 20 gg/ml 10 tLg/ml Negative Packed red cells Negative 10 pg/ml 20 pg/ml CPD bank blood Negative 10 pg/ml 20 pg/ml 80 tag/ml

30 1 1 28 10 4 3 3 50 24 19 5 2

m i n i s t e r e d . T h e r e g r e s s i o n e q u a t i o n i n d i c a t e s t h a t t h e r e will b e a d o u b l i n g of F D P c o n c e n t r a t i o n for e a c h 15 u n i t s of blood a d m i n i s tered. D e s p i t e t h e a b s e n c e of F D P / f d p in F F P , a s i m i l a r c o r r e l a t i o n e x i s t s b e t w e e n t h e i n c r e a s e in F D P / f d p a n d t h e v o l u m e o f F F P a d m i n i s t e r e d . T h i s c a n be e a s i l y e x p l a i n e d b y t h e h i g h corr e l a t i o n e x i s t i n g b e t w e e n v o l u m e o f F F P a n d v o l u m e o f blood a d m i n i s t e r e d . I n fact, a m u l t i p l e c o r r e l a t i o n coefficient i n d i c a t e s t h a t t a k i n g F F P into c o n s i d e r a t i o n will n o t i n c r e a s e t h e signific a n c e of t h e c o r r e l a t i o n b e t w e e n F D P / f d p i n c r e a s e a n d v o l u m e of blood t r a n s f u s e d . I f we consider c a u s a t i o n , r a t h e r t h a n c o r r e l a tion, h o w e v e r , we o b t a i n a d e t e r m i n a t i o n coefficient of 0.26 bet w e e n i n c r e a s e of F D P / f d p a n d v o l u m e of blood t r a n s f u s e d . T h e conclusion is t h a t 74% o f t h e c h a n g e s in F D P / f d p m u s t be exp l a i n e d b y s o m e factor o t h e r t h a n v o l u m e of blood t r a n s f u s e d . T h e difficulties a s s o c i a t e d w i t h d i a g n o s i n g D I C e v e n w i t h ext e n s i v e c l o t t i n g studies a r e s h o w n in T a b l e 9. T h i s p a t i e n t w h o r e c e i v e d 31 u n i t s of w h o l e blood h a d a p o s t o p e r a t i v e t h r o m b o c y t o p e n i a a n d fibrinogen d r o p on a d i l u t i o n a l b a s i s a n d a p r o l o n g e d TABLE 9.-CHANGES IN COAGULATION PARAMETERS AFTER MULTIPLE TRANSFUSIONS DURING HEMICORPORECTOMY IN A 51-YEAR-OLD MAN

Partial thromboplastin time Prothrombin time Thrombin time Platelets 9Fibrinogen FDP/fdp FFP Whole blood 40

PREOP

POSTOP

26.4 12.2 20.4 238.0 460. 0

40.3 sec (normal, 22-36 sec) 14.1 (control, 11.1 sec) 21.3 (control, 19.5 sec) 47.0 (thousand/cu mm) 250 (mg/dl) 20 ~g/ml) 7 units 31 units

partial thromboplastin time because of inadequate administration of FFP, and indeed the prolonged partial thromboplastin time was corrected in the postoperative period by further F F P administration. The presence of FDP/fdp in the face of a normal thrombin time suggests that the FDP]fdp came from the bank blood and were not indicative of DIC. The possibility arises however that the FDP/fdp present did not have anticoagu!ant activity. The patient described in Table 10 was obviously undergoing intravascular coagulation when she arrived in the operating room despite the absence of a positive ethanol gelation, which suggests that the FDP/fdp consisted of fragment X and possibly fragment Y. Again the drop in platelets could be explained on the basis of hemodilution, but the fibrinogen level is below that which would be expected from whole blood (fibrinogen level, 250 mg/dl) alone on a replacement basis. The Reptilase test was significantly prolonged and is a further index of the presence of an abnormal fibrinogen. The putative effects of whole blood preserved in citrate-dextrose-phosphate solution are the result of efforts to prolong the shelf-life of red blood cells. Blood can be anticoagulated by chelation of calcium with citrate alone, but then red cells have a short shelf-life (less than 1 week). The addition of glucose, acidity, phosphate and lowering the temperature to 4 C all result in an increase in in vitro survival of the red cells. As a result of the manipulation of the red cells, the dangers of massive blood transfusion, namely, citrate intoxication, hyperkalemia and hypothermia, have risen, and their significance will be discussed later. A real and universally accepted abnormality with bank blood is the decreasing levels of plasma factors V and VIII and the thrombocytopenia that occurs with storage. A possibly significant hazard of bank blood is the occurrence of TABLE 10.-CHANGES IN COAGULATION PARAMETERS AFTER MULTIPLE TRANSFUSIONS DURING RADICAL NEPHRECTOMY IN A 50-YEAR-OLD WOMAN PREOP

Partial thromboplastin time Prothrombin time Thrombin time Reptilase time Platelets Fibrinogen FDP/fdp Ethanol gelation FFP Whole blood

35.1 14.1 25.9 25.9 76.0 214.0 2O negative

POSTOP

43.5 (normal, 22-36 sec) 16.1 (control, 11.3 sec) 23.0 (control, 20 sec) 17.4 (control, 14.1 sec) 45.0 (thousand/cu mm) 114.0 (mg/dl) 10 (~g/ml) negative 5 units 16 units 41

microembolization of the pulmonary circulation by aggregates of white cells, red cells, fibrinogen and platelet ghosts. This has led to the development of blood filters with a pore size of 40/z or less. At the present time, although widely used, there are little or no hard data as to their efficacy. Certainly, the occurrence of pulmonary insufficiency in patients who have received large volumes of blood through micropore filters is still common, probably for the same reasons as for those who have received unfiltered blood. Nonetheless, we have continued their use. Cancer surgery is often associated with rapid and massive blood loss. In the last year in our institution 120 patients received 10 or more blood transfusions in the operating room. Of these, 10 received more than 30 units. Twenty-five years ago in this hospital the mortality in the operating room was 50% after 12 units of blood. Now we expect no immediate mortality except in those cases in which severe and rapid hemorrhage cannot be controlled and blood replacement is inadequate. We believe this improvement in the rate of mortality is due to our improved understanding of the "storage lesion" of bank blood and the methods evolved for control. The therapeutic effectiveness of massive blood replacement depends on the ability of the recipient's circulating environment to reverse the storage lesion of bank blood relative to the speed of transfusion. The life span of preserved red cells is determined primarily by the recipient's intravascular environment. This is especially true in the presence of immunologic, chemical and mechanical factors that may occur in severely impaired or aged patients. The conditions necessary to restore the normal physiologic status of red cells and plasma after transfusion into the recipient include: (1) The outward shift of potassium and repletion of the 2,3-DPG and ATP levels in the red cells must be reversed. (2) The elevated Pco, and buffering of the hydrogen ion load in the plasma must be eliminatedY5 (3) The ionized calcium level of the donor blood, which is nil, must be returned to physiologically active levels. (4) The temperature of the administered blood (4 C ___ 2 degrees) should be returned to nearly normal body temperature before administration. (5) Fresh frozen plasma must be administered to replace factors V and VIII, which are deficient in bank blood. (6) The dilutional thrombocytopenia which occurs with massive transfusion may occasionally require platelet transfusion when inadequate platelet function can be demonstrated. Valeri and Hirsch26 have been able to show that reversibly damaged liquid-stored red cells can be restored in the recipient by demonstrating a rapid decrease in the donor red cell sodium ion level, a slow increase in the donor red cell potassium ion level and a significant increase in 2,3-DPG and ATP levels. 42

PROBLEMS OF HEMOSTASIS

Potassium There are two possible sources of excessive potassium administration during massive blood replacement. The first is the elevated potassium associated with anticoagulant preserved blood (CPD), either whole blood or packed red cell transfusions, and the second is the potassium level of FFP. The latter is becoming the colloid solution of choice in our institution due to doubts about the efficacy of the manufactured plasma proteins. An arithmetical calculation based on the fact that potassium levels are reported in milliequivalents per liter will show the amount of potassium administered during replacement of large volumes of blood is less than indicated by a more superficial assessment. In two different series in our hospital the potassium level in 1-week-old CPD-preserved bank blood was 13.45 _+ 2.72 mEq/L (52 samples tested) and 14.4 _+ 4.26 mEq/L (15 samples tested). In another series the potassium level of F F P separated from the red cells within 6 hours of collection was 3.13 -+ 0.39 mEq/L (55 samples tested). However, these blood products are not administered in liter amounts b u t as units. Each unit of bank blood, assuming a hematocrit of 40 and a volume of 500 _ 25 ml, contains approximately 300 ml of plasma. Therefore, the potassium content in our 2 series was one third of the liter load of 4.48 and 4.8 mEq/unit respectively. Since F F P is available in units of 200 ml, each unit contains one fifth of the potassium load of 3.13 mEq/L or 0.6 mEq/unit of FFP. The same situation exists in the case of packed red blood cells. The number of cells destroyed during storage is the same for whole blood and packed red blood cells. In fact, the potassium concentration in the plasma surrounding the packed red cells is higher than that of whole blood. Since the volume of plasma in 300 ml of packed red blood cells is only about 90 ml, it is not surprising that the potassium level of packed red cells was found to be 1 - 2 mEq of potassium per transfusionY If one assumes a normal potassium level of 5 mEq/L of plasma in the patient receiving blood, on a unit-for-unit replacement, the 500 ml of blood lost will contain approximately 1.5 mEq of potassium. The net gain of potassium on an exchange basis of blood lost to blood administered is approximately 3 mEq/unit. Assuming no urinary loss, the transfusion of 20 units of whole blood would result in the administration of 60 mEq of potassium. If all of the transfused blood is 3 weeks old with a potassium level of 30 mEq/L there would be still only 10 mEq/unit of blood. This does not represent a net gain as blood is being lost and replaced. Alkalosis and Hypokalemia The potassium level of the recipient of massive transfusion is closely associated with the alkalosis resulting from the metabo43

lism of the citrate anticoagulant to bicarbonate. Each unit of CPD blood has a citrate content of 7.6 mM and in turn each millimole of citrate generates 3 mEq of bicarbonate or 22.8 mEq of bicarbonate per u n i t y The hypokalemia occurring with metabolic alkalosis is due to the movement of potassium from extracellular fluid into the cells and the reciprocal movement of hydrogen ions from the cells into the extracellular fluid in an attempt to raise the hydrogen ion concentration and lower the pH of the extracellular fluid. Severe metabolic alkalosis can also occur in patients with impaired renal function. Barcenas et alY 9 reported the case of a patient on chronic hemodialysis who had a total gastrectomy, thus eliminating two of the important sources for production of bicarbonate. This patient developed a severe metabolic alkalosis after 13 units of CPD whole blood and 20 units of FFP. In the postoperative period, his bicarbonate level rose from 36 mEq/L preoperatively (due to gastric drainage) to 52 mEq/L. Since the pH was 7.58, the patient required hemodialysis to reduce the plasma bicarbonate concentration to prevent the complications of severe metabolic alkalosis. There is a progressive fall in the potassium level of patients receiving large amounts of blood with no difference between those receiving blood preserved in acid citrate dextrose and those receiving citrate phosphate dextrose. The resultant hypokalemia depends on the volume of blood administered. In certain cases intraoperative potassium m a y have to be administered to patients receiving massive transfusion when the plasma potassium level falls below 3.0 mEq/L. In summary, hyperkalemia does not occur after massive blood transfusion for four reasons: 1. With adequate renal function, the potassium is eliminated in the urine. 2. In anuric patients, the metabolic alkalosis which is associated with massive transfusion allows the potassium to enter the cell. 3. The potassium load of bank blood is not as great as has been postulated. In patients with adequate urinary output supplemental potassium m a y have to be administered during the surgical procedure. 4. The potassium in donor plasma m a y reenter donor red cells as the recipient's circulating environment accounts for the changes due to hypothermia, acidity, elevated Pco 2 and metabolic acid load of the bank blood. The donor red cell in the recipient acts as a potassium s p o n g e . ~9 Acid Load Bank blood is acid due to a high partial CO 2 pressure (Pco2, 104-130 torr) and a low bicarbonate content ( 8 - 1 2 mEq). The 44

respiratory component is easily handled by the lungs, and, unless hypoventilation occurs, the Paco 2 level is not elevated in patients receiving massive transfusion. We are thus concerned with the metabolic component of the bank blood and the necessity for buffering it. We have reported improvement in the mortality associated with massive ACD blood transfusion and recommended the administration of 50 mEq of bicarbonate for every 5 units of bank blood. 3~ This is probably not necessary today due to the lower hydrogen ion concentration of CPD, but acidosis does occur with rapid transfusion and patients who do not respond to volume alone will often have a satisfactory blood pressure response with bicarbonate administration. Calcium Levels and "Citrate Intoxication" Howland et al2 ~ were unable to demonstrate citrate intoxication, as manifested by depressed myocardial function, in patients receiving large volumes of ACD solution. Since that time we have not administered exogenous calcium salts during massive transfusion irrespective of the volume of blood administered. Even 20 years ago, it was apparent to us that the cessation of calcium administration prevented the occurrence of ventricular fibrillation which had been seen frequently during massive transfusion. Advocates of calcium administration have paid little attention to the specific calcium salt administered and the variation in response that can occur due to varying calcium content. The three most popular calcium salts are chloride, gluconate and gluceptate (glucoheptonate) salts. The total calcium concentration of these three salts are: calcium chloride 10%, 34 mg/ml; calcium gluconate 10%, 13 mg/ml; and calcium gluceptate, 23 mg/ml. In openheart surgical patients, White et al. 32 found no difference in the total calcium levels produced by the three salts when comparable doses were given. However, the ionized calcium increased significantly in those receiving chloride as compared to the others. It has been shown by several authors that the inotropic effect of calcium administration is of short duration. In one exchange transfusion study in babies, it was found that the ionized calcium decreased as transfusion progressed despite the administration of calcium gluconateY, 3~ The deleterious effect of calcium chloride administration in patients with essentially normal ionized calcium has also been reported. 35, 36 Howland et a l Y found a significant decrease in ionized calcium from a pretransfusion level of 1.96 _ 0.27 to a lower level of 1.21 ___0.31 mEq/L (P <0.001) associated with massive transfusion in man. This fall was related primarily to the speed of blood replacement rather than the volume of blood per kilogram of body weight. They also observed a significant prolongation of the corrected Q-T interval (Q-T~) at the time of the lowest ionized cal45

cium level. However, prolongation of the Q-Tc interval was not accompanied by other cardiovascular changes. The blood pressure, cardiac output and pulmonary artery wedge pressure remained stable during operation even in the presence of ionized calcium levels as low as 0.72 mEq/L (normal, 2.00 __ 0.20 mEq/L). From these studies it appears unnecessary to administer exogenous calcium to massively transfused adult patients to improve cardiac function. Warming of bank blood with a thermostatically controlled heating device is probably the most significant factor in reducing the mortality of massive transfusion. There are several interacting factors occurring when the blood is warmed. The first is the maintenance of the patient's temperature and vasodilation. This improves tissue perfusion and also allows the blood pressure to be obtained more easily because of the law of vasoconstriction, a significant and often fatal occurrence with resultant overtransfusion and myocardial failure. A second benefit is the elimination of the risk of ventricular fibrillation in ahypothermic heart, when the diehards who persist in giving calcium salts during massive tranfusion do so. Finally, warmed blood flows more easily than cold blood, and where speed of blood replacement is necessary the advantages are obvious.

Component Therapy Component blood therapy has greatly improved the management of the massively bleeding patient. However, anesthesiologists are distressed by the trend toward complete use of packed red blood cells. Many advantages have been imputed to the use of packed red blood cells because of the other components that can be utilized separately. This is true but not necessarily beneficial to the recipient. Packed red blood cells are cold and viscous and can be administered rapidly only with great difficulty unless reconstituted with FFP. But, because of inadequate help, this may be impossible for a single anesthesiologist to do in the middle of the night with a severely injured patient. However, since the use of packed red cells is in ascendency, a discussion of its advantages and disadvantages is in order. The designation of a whole blood component as "packed red blood cells" is generally assumed to mean red blood cells from which most of the plasma has been removed by sedimentation or centrifugation. However, the term can also include centrifuged cells with the buffy coat largely removed and washed red cells in which plasma and buffy coat have been removed by at least three washings. Thus, four products are available to the clinician, all with different characteristics. Sedimented red blood cells are the most readily available since no mechanical .equipment is needed to prepare them. Sedimented 46

cells contain practically all of the leukocytes, platelets and almost the same (less than I mEq difference) level of potassium as whole blood. The reduction in plasma volume (hematocrit, 6 5 - 7 0 % ) is insufficient to prevent IgA reactions or hepatitis. Centrifuged red blood cells permit the harvesting of more plasma (hematocrit 80%), b u t the same drawbacks are present as with sedimented red blood cells. Centrifuged red blood cells with the buffy coat e s s e n t i a l l y b u t not completely removed contain about 30% of the leukocytes present in the original donor units. The 5 - 1 0 % residual plasma is too high to provide satisfactory protection against the development of hepatitis. Also sufficient leukocytes and platelets are present to cause isosensitization in the previously unsensitized patient. Washed red blood cells offer little over "buffy coat poor" rod blood cells, are more expensive to prepare and increase the risk of contamination. Patients who develop anaphylactoid reactions to IgA must receive rod blood cells almost completely free of plasma, and even the small amount of plasma (less than 1%) that remains in well-washed red blood cells can cause transfusion reactions in some patients. In general, it has been stated that fewer transfusion reactions occur with concentrated rod blood cells, b u t it should be emphasized that this is a reference to "buffy coat poor" rod blood cells or previously frozen, washed cells. These products are not usually available to the clinician and are quite different from the concentratod rod blood cells available in most blood banks. In one report, 59% of transfusion reactions were from concentrated red blood cells when 48% of all rod blood cell products were given as concentratod red blood cells. The only reason for administrating concentrated rod cells is to increase the oxygen-carrying capacity of the blood. Patients with hypoxic symptoms whose anemia is unresponsive to specific treatment, e.g., iron, B12, folic acid, etc., who are not hypovolemic and who do not require plasma clotting factors or protein, will benefit from administration of red cells. Concentrated red blood cells should not be used in cases in which whole blood is indicated for treatment of hypovolemia, unless accompanied by the administration of plasma volume expanders. The hazards of concentrated rod cell transfusions are the same as those which attend whole blood transfusion. The only hazards not associated with whole blood transfusions are possibly those of ammonia accumulation and citrate intoxication. Since potassium from the rod cells equilibrates with the plasma potassium as storage progresses, concentrated red blood cells are only slightly deficient in potassium. Additionally, the deleterious effects of anaphylactic reaction to IgA are not obviated by concentrated rod cells b u t only by "buffy poor" washed rod cells. Also, despite the 47

statement that fewer transfusion reactions are seen with concentrated red blood cells, documentation has generally been in relation to the use of red blood cells markedly depleted of white cells antigen such as "buffy poor" blood or previously frozen washed red blood cells. These products are quite different from the red blood cells available in blood banks. There has been no definitive prospective analysis to substantiate the claim that the incidence of hepatitis with concentrated red blood cells is less than that with whole blood. Concentrated red blood cells should not be reconstituted with lactated Ringer's solution, 5% aqueous dextrose or 5% dextrose in 0.225% saline as clumping, hemolysis or clotting m a y occur. Platelet function does not correlate with the level of circulating platelets, a factor overlooked after massive blood replacement, when there is a thrombocytopenia of some magnitude. This thrombocytopenia persists for some days after transfusion and does not, per se, indicate need for platelet replacement. The thrombocytopenia that occurs with massive blood replacement was studied in 20 patients receiving 2 0 : 7 8 units of whole bank blood. There was no correlation between the degree of thrombocytopenia and the volume of blood administered. There was a significant correlation (r = 0.995) between the extent of the decrease in platelet count and the pretransfusion platelet level. The narrow range (57,000 _ 17,100/cu mm) of the resultant thrombocytopenia suggests that there is an, as yet, unexplained mechanism responsible for the maintenance of the hemostatic level of platelets. The time necessary for return to a platelet count of 100,000/cu mm was 4.62 ___1.50 days. The thrombocytopenia of massive blood replacement is more prolonged than is generally appreciated due to inability of the bone marrow to replenish or restore platelets that have been destroyed or consumed. There is a tendency for the platelets to fall to approximately the same posttransfusion level (57,000 __+17,100 cu mm) despite the number of blood transfusions administered ( 2 0 - 78 units). We regard platelet transfusion as unnecessary during massive blood replacement. In the m a n y patients in whom platelet function has been measured, there has been no evidence of platelet dysfunction by thrombelastogram ( a most reliable indicator of platelet dysfunction) or coagulogram in the coagulation laboratory. We have also found that the administration of as much as 19 units of platelet concentrate failed to raise the platelet count in the presence of continued bleeding. It is our belief that coagulation problems associated with massive blood replacement can be controlled, in the absence of disseminated intravascular coagulation, by the administration of 2 units of F F P for every 10 units of bank blood. Special attention must be paid to the label on the 48

FFP to make sure that factor VIII, which along with factor V, is deficient in bank blood, has not been removed to manufacture cryoprecipitate. REFERENCES 1. Hillis, L. D., and Cohn, P. F.: Noncardiae surgery in patients with coronary artery disease: risks, precautions, and perioperative management, Arch. Intern. Meal. 138:972, 1978. 2. Steen, P. A., Tinker, J. H., and Tarhan, S.: Myocardial reinfarction after anesthesia and surgery, J.A.M.A. 239:2566, 1978. 3. Kaplan, J. A.: Anesthesia for patients with coronary artery disease, Resident StaffPhysician, January 1978, p. 46. 4. Rooney, S. M., Goldiner, P. L., and Muss, E.: Relationship of right bundlebranch block and marked left axis deviation to complete heart block during general anesthesia, Clin. Reports 44:64, 1976. 5. Smith, J. K., Wiener, S. L.: Aging, immunity and antibiotics, Drug Therapy (Hosp), April 1978, p. 19. 6. Walton, B.: Anaesthesia, surgery and immunology, Anaesthesia 33:322, 1978. 7. Wanebo, H. J., Pinsky, C. M., Beattie, E. J., and Oettgen, H. F.: Immunocompetence testing in patients with one of the four common operable cancers-a review, Clin. Bull. 8:15, 1978. 8. Lundy, J., Lovett, E. J., Hamilton, S., and Conran, P.: Halothane, surgery, immunosuppression and artificial pulmonary metastases, Cancer 41:827, 1978. 9. Lokich, J. J.: Managing chemotherapy-induced bone marrow suppression in cancer, Hosp. Pratt. 11:61, 1976. 10. Wang, R. I., and Ross, C. A.: Prolonged apnea following succinylcholine in cancer patients receiving AB-132, Anesthesiology 24:363, 1963. 11. Robertson, G. S.: Serum cholinesterase deficiency. !" Disease and inheritance, Br. J. Anaesth. 38:355, 1966. 12. Luna, M. A., Bedrossian, C. W. M., Lichtiger, B., and Salem, P. A.: Interstitial pneumonitis associated with bleomycin therapy, Am. J. Clin. Pathol. 38:501, 1972. 13. Winter, P. M., and Smith, G.: The toxicity of oxygen, Anesthesiology 37:210, 1972. 14. Goldiner, P. L., Carlon, G. C., Cvitkovic, E., Schweizer, O., and Howland, W. S.: Factors influencing postoperative morbidity and mortality in bleomycin treated patients, Br. Med. J. (in press). 15. Dentino, M., Luft, F. C., Yum, M. N., Williams, S. D., and Einhorn, L. H." Long term effect ofcis-diaminedichloride platinum (CDDP) on renal function and structure in man, Cancer 41:1274, 1978. 16. Minow, R. A., Benjamin, R. S., Lee, E. T., and Gottlieb, J. A.: Adriamycin cardiomyopathy- risk factors, Cancer 39:1397, 1977. 16a. Jones, S. E., Ewy, G. A., and Groves, M. B.: Echocardiographic detection of adriamycin heart disease, Proc. Am. Soc. Clin. Oncol. 16:228, 1975. 17. Gurman, G. hi.: Prolonged apnea after succinylcholine in a case treated with cystostatics for cancer, Anesth. Analg. 51:761, Oct 1972. 18. Lucas, C. E., Ledgerwoed, A. M., Shier, M. R., and Bradley, V. E.: The renal factor in the post-traumatic "Fluid Overload" syndrome, J. Trauma 17:667, 1977. 19. Weaver, D. W., Ledgerwood, A. M., Lucas, C. E., Higgins, R., Bouwman, D. L., and Johnson, S. D.: Pulmonary effects of albumin resuscitation for severe hypovolemic shock, Arch. Surg. 113:387, 1978. 20. Rowe, J. W.: The influence of age on renal function, Resident Staff Physician February 1978, p. 49. 49

21. Cohn, J. D., Engler, P. E., and Del Guercio, L. R. M.: The automated physiologic profile, Crit. Care Med. 3:51, 1975. 22. Forrester, J. S., Diamond, G., Chatterjee, K., and Swan, H. J. C.: Medical therapy of acute myocardial infarction by application of hemodynamic subsets, N. Engl. J. Med. 295:1356, 1976. 23. Collins, G. J., Barber, J. A., Zajtchuk, R., Vanek, D., and Malogne, L. A.: The effects of operative stress on the coagulation profile, Am. J. Surg. 133:612, 1977. 24. Belt, R. J., Leite, C., Haas, C. D., and Stephens, R. L.: Incidence of hemorrhagic complications in patients with cancer, J.A.M.A. 239:2571, 1978. 25. Gurewich, V., Nunn, T., Kuriakose, T. X., and Hume, M.: Hemostatic effects of uniform, low-dose subcutaneous heparin in surgical patients, Arch. Intern. Med. 138:41, 1978. 26. Valeri, R. C., and Hirsch, N. M.: Restoration in vivo of erythrocyte adenosine triphosphate, 2,3-diphospitoglycerate, potassium ion and sodium concentrations following the transfusion of acid-citrate-dextrose-stored human red blood cells, J. Lab. Clin. Med. 73:722, 1969. 27. Valeri, R. C.: Viability and function of preserved red cells, N. Engl. J. Med. 284:81, 1971. 28. Simon, G. E., and Bove, J. R.: The potassium load from blood transfusion, Postgrad. Med. 49:61, 1971. 29. Barcenas, C. G., Fuller, T. J., and Knochel, J. P.: Metabolic alkalosis after massive blood transfusion, correction by hemedialysis, J.A.M.A. 236:953, 1976. 30. Collins, J. A.: Massive Blood Transfusion in Clinics, in Cash, J. D. (ed.): Hematology, Blood Transfusion and Blood Products (Philadelphia: W. B. Saunders Co., 1976), p. 216. 31. Howland, W. S., Schweizer, O., and Boyan, C. P.: The effect of buffering on the mortality of massive blood replacement, Surg. Gynecol. Obstet. 121:777, 1965. 32. Howland, W. S., Bellville, J. W., Zucker, M. B., Boyan, P., and Cliffton, E. E.: Massive blood transfusion V. Failure to demonstrate citrate intoxication, Surg. Gynecol. Obstet. 105:529, 1957. 33. Friedman, Z., Hanley, W. B., and Radde, J. C.: Ionized calcium in exchange transfusion with tham-buffered ACD blood, Can. Med. Assoc. J. 107:742, 1972. 34. White, R. D., Goldsmith, R. S., Rodriquez, R., Moffitt, E., and Pluth, J. R.: Plasma ionic calcium levels following injection of chloride, gluconate and gluceptate salts of calcium, J. Thorac. Cardiovasc. Surg. 71:609, 1976. 35. Drop, L. J., and Laver, M. B.: Low plasma ionized calcium and response to calcium therapy in critically ill man, Anesthesiology 43:300, 1975. 36. Carlon, G. C., Howland, W. S., Goldiner, P. L., Kahn, R. C., Bertoni, G., and Turnbull, A. D.: Adverse effects of calcium administration, Arch. Surg. 113:882, 1978. 37. Howland, W. S., Schweizer, O., Carlon, G. C., and Goldiner, P. L.: The cardiovascular effects of low levels of ionized calcium during massive transfusion, Surg. Gyneeol. Obstet. 145:581, 1977.

UPCOMING MEETINGS

Nov 6-10:

Postgraduate Course: Current Concepts in Surgical Oncology, Memorial Sloan-Kettering Cancer Center, New York

Nov10-11: Diagnostic Laparoscopy (detailed instructions in skills and techniques),Postgraduate Course, Atlanta, Georgia (Contact V. M. Smith, M.D., 301 Saint Paul Place, Baltimore, Md 21202.) 5O