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Rev. Bras. Anestesiol. vol.51 no.3 Campinas May/June 2001
Chemotherapy and anesthesia*
Quimioterapia e anestesia
Quimioterapia y anestesia
Márcio Augusto Lacerda, TSA, M.D.
Co-responsável pelo CET/SBA do Hospital de Câncer, Instituto Nacional de Câncer, Rio de Janeiro, RJ
Background and Objectives:
Chemotherapy is one of the main treatment available for cancer patients, but
is still causing important side effects, reversible or not. Knowing such drugs,
complications and interactions is critical for the anesthesiologist during surgeries
in patients under cancer treatment.
CONTENTS: This review presents the different types of chemotherapy agents currently used, their pharmacological classification, organic repercussions, interactions with other drugs and the most adequate anesthetic technique aiming at decreasing perioperative morbidity and mortality.
CONCLUSIONS: The anesthesiologist awareness of types of treatment, pharmacological properties of such substances, their adverse effects, structural lesions and possible drug interactions created by them and exacerbated by several current anesthetic techniques may certainly decrease perioperative morbidity and mortality.
Key Words: DRUGS, Interation: chemotherapic
Justificativa e Objetivos:
A quimioterapia é um dos principais tipos de tratamento oferecido a pacientes
com câncer, mas ainda causam importantes efeitos colaterais, reversíveis
ou não. Para os anestesiologistas, conhecer estas drogas, complicações
e interações medicamentosas, é de importância capital em
cirurgias com pacientes em tratamento de neoplasias.
Conteúdo: Nesta revisão apresentam-se os diferentes tipos de quimioterápicos atualmente utilizados, a classificação farmacológica, repercussões orgânicas, interações com outras substâncias, e a conduta anestésica mais apropriada frente a elas, objetivando reduzir a morbi-mortalidade perioperatória nestes pacientes.
Conclusões: O conhecimento, pelo anestesiologista, das formas de tratamento, das características farmacológicas destas substâncias, seus efeitos adversos, lesões estruturais e possíveis interações medicamentosas por elas geradas e potencializadas pelas várias técnicas anestésicas hoje empregadas, pode certamente reduzir a morbi-mortalidade peri-operatória destes pacientes.
Unitermos: DROGAS, Interação: quimioterápicos
JUSTIFICATIVA Y OBJETIVOS:
La quimioterapia es uno de los principales tipos de tratamiento ofrecido a pacientes
con cáncer, mas aun causan importantes efectos colaterales, reversibles
o no. Para los anestesistas, conocer estas drogas, complicaciones e interacciones
medicamentosas, es de importancia capital en cirugías con pacientes en
tratamiento de neoplasias.
CONTENIDO: En esta revisión se presentan los diferentes tipos de quimioterápicos actualmente utilizados, la clasificación farmacológica, repercusiones orgánicas, interacciones con otras substancias, y la conducta anestésica mas apropiada frente a ellas, objetivando reducirse la morbi-mortalidad perioperatoria en estos pacientes.
CONCLUSIONES: El conocimiento, por el anestesista, de las formas de tratamiento, de las características farmacológicas de estas substancias, sus efectos adversos, lesiones estructurales y posibles interacciones medicamentosas por ellas generadas y potencialidades por varias técnicas anestésicas hoy utilizadas, puede ciertamente reducir la morbi-mortalidad perioperatoria de estos pacientes.
Chemotherapy is one of the main treatment for cancer patients. Its efficacy is proven every day and new substances, protocols and associations are constantly being developed 1,2. In spite of this continuous evolution, such drugs still represent one of the most toxic pharmacological groups. They are blamed of causing structural lesions and of modifying normal human physiology and biochemistry, some of them irreversible, which may even become a limiting treatment factor 3-5. For the anesthesiologist, the awareness of chemotherapeutic drugs, their complications and interactions is critical for surgeries in patients under cancer treatment.
This study aimed at presenting the different types of drugs currently used, their organic repercussions, their interaction with other substances and the most adequate anesthetic technique with them.
CHEMOTHERAPY HISTORY, OBJECTIVES AND STAGES
The first report on the use of a drug for cancer treatment was published in 1940 in a totally accidental way. Researchers were testing new substances for treating tuberculosis when they noticed some cytoreducing effects in patients with solid lymphatic neoplasias. With the results obtained protocols for clinical development, toxicity, performance and tolerance to those agents were developed along time. The results of such evolution may be illustrated by "cure" criteria for some neoplasias and especially by the increase in survival for most patients. But everything has a high cost: increase in reversible or not toxic effects, treatment limitation due to those effects, presence of associated diseases and infections and other complications 3.
The objectives of chemotherapy are:
a) Total destruction of malignant cells through the administration of the highest single or combined CT dose, acting by different mechanisms without superimposed toxic effects. This way, one tries to avoid that the survival of a single malignant cell may generate another progenic strain able to develop a new tumor.
b) Administration of a specific treatment for short periods called "cycles". This principle is based on the observation that healthy cells recover quicker than malignant cells after maximum pulse therapy and that immunosuppression is lower 4.
Major chemotherapeutic drugs are shown in chart I.
Alkylating agents break the purinic ring and, as a consequence, the molecular DNA, generating mitosis blockade. Currently, they are the largest group of cytotoxic drugs. Most below mentioned side effects are shared by all other substances.
Nitrogen mustards cause nausea, vomiting, inadequate ADH secretion syndrome, herpes zoster, thrombophlebitis and bone marrow suppression. Their major limitations are leukopenia and thrombocytopenia.
Ethylenamines and methylmelamines, developed as from nitrogen mustards, have fewer side effects although causing bone marrow suppresion.
Triazenes, drugs developed for treating melanomas and Hodgkin Disease, have the lowest bone marrow suppression rates but cause nausea and vomiting in more than 90% of patients.
Alkyl sulfonates cause bone marrow suppression and thrombocytopenia and, in a lesser degree, nausea, vomiting, diarrhea and hyperuricemia.
Nitrous ureas are limited by severe bone marrow suppression. They may also cause renal tubular lesions and a consequent renal failure in 70% of patients.
Antimetabolites are divided in pholic acid, purine and pirimidine analogs. They are structurally similar to those substances and are necessary for cellular metabolism and division. With such characteristics, they inhibit certain enzymes triggering the synthesis of aberrant and non-active compounds which block normal cell cycles. Major target-cells for such drugs are bone marrow and gastrointestinal epithelial cells. As a consequence, they cause inflammations, ulcerations and are potent immunosuppressants.
Their action mechanism is the rupture of microtubules participating on the mitotic cycle. Their fast action generates hyperuricemia and requires a previous treatment with allopurinol. They are potent neurotoxic agents.
Antracyclic antibiotics are cytotoxic and form stable complexes with DNA, inhibiting its synthesis, RNA's or both.
Enzymes act as catalysts of enzymatic reactions which deprive malignant cells of their major metabolic substrates.
This group is composed of several drugs with different action mechanisms, but all with synthetic origin 13,15.
Steroids used in the treatment of pediatric acute leukemia, malignant lymphomas and hemolytic anemia and for leukemia and lymphoma-induced thrombocytopenia.
Progestins used in the treatment of endometrial carcinoma.
Estrogens and Androgens used in the treatment of advanced breast cancer.
Antistrogens used in the palliation of advanced breast cancer in menopausal women.
SYSTEMIC REPERCUSSIONS(Chart II)
The most cardiotoxic drugs are doxorubicin, daunorubicin, cyclophosphamide and cisplatin.
Doxorubicin and daunorubicin-induced cardiomiopathy is present in approximately 3% of patients, it is dose-dependent, affects all ages and is frequently irreversible. The incidence is not significant when total doses are lower than 200 mg.m2 of body surface, but is frequent in doses above 550 mg.m2. Some factors may increase the incidence, including previous mediastinum radiation and the simultaneous use of cyclophosphamide. Histopathologic presentation is myocardial fibrosis. Cardiomiopathies may be acute and severe.
The acute form is present in 10% of cases and is characterized by relatively benign ECG changes, such as nonspecific ST-T segment changes and QRS current decrease, ventricular extrasystole, supraventricular tachycardia, conduction changes and left axis deviation. Such changes may appear during all treatment stages with the most different doses, but are reverted 1 or 2 months after withdrawal. Echocardiography with ejection fraction monitoring is a good follow up method for the evolution of such cardiomiopathy.
The severe form is characterized by the insidious appearance of symptoms 6 to 12 months after chemotherapy withdrawal. It may come with dry cough suggesting "bronchitis", followed by rapidly progressive heart failure in general resistant to inotropics. It occurs in 2% of treated patients and may lead to death in 3 weeks in 60% of cases. There are no specific tests to predict its appearance, but it is believed that diffuse QSR current decrease may indicate its evolution. Specific serum enzymes are only lately increased and have limited values. Other early evaluation methods are echocardiography and systolic time evaluation 12-14.
Myocardial ischemia is rare and is present in less than 1% of patients from 3 hours to one week after treatment with 5-fluorouracil. Its probable etiology is coronary vasospasm. In patients with previous atherosclerotic lesions, the incidence may reach more than 4.5% 15.
Cyclophosphamide and cisplatin may cause other effects such as myocardial instability, that is, increase in dysrhythmias in the presence of cardiostimulating drugs.
Major pulmonary lesions are:
a) Chronic pneumonitis followed by lung fibrosis is the major and more frequent lesion;
b) Hypersensitivity-induced acute lesions with cough, dyspnea and fever for several weeks after the use of the drugs;
c) Non-cardiogenic pulmonary edema;
d) Secondary complications: atelectasis, pleural effusion and infections.
Major agents involved are bleomycin, busulfan, cyclophosphamide, chlorambucil, methotrexate, cytarabine, mitomycin and carmustine.
Bleomycin-induced pulmonary toxicity is present in 25% of treated patients. Those receiving previous radiation therapy, or those with pulmonary diseases, elderly patients and those exposed to cumulative cytotoxic doses above 450 mg.m2 are more predisposed to such complication. Histopathologic pattern is pneumonitis followed by progressive pulmonary fibrosis which may be worsened by smoking and superoxide radicals generated by high oxygen inspired air concentrations. Symptoms appear between the 4th and 8th chemotherapy week and include arterial hypoxemia, non-productive cough and tachypnea. Approximately 20% to 25% of patients develop its mild form and approximately 1% its severe form. Diagnosis and clinical evolution monitoring are preferably performed by carbon monoxide diffusion capacity.
The mild form generates a restrictive syndrome characterized by dyspnea when exercising, cough and low PaO2 at rest. The severe form is characterized by arterial hypoxemia at rest, associated to radiological changes such as interstitial pneumonitis and fibrosis, peri-hilar and basilar infiltrates and changes in the alveolar-capillary barrier with the increase in D[A-a]O2 and decrease in diffusion capacity 16-19.
Gastrointestinal complications include the increase in nausea and vomiting, worsened by trophic mucosal changes and autonomic neuropathy which reduces gastric emptying time and may increase the risk for regurgitation. It also includes hydroelectrolytic changes caused by diarrhea followed by hyponatremia and hypopotassemia, nutritional changes generating cachexia by increased catabolism, physical swallowing incapacity or gastrointestinal obstruction; and changes in the acid-base balance. Almost all drugs may cause such adverse effects, but major drugs involved are methotrexate and 5-fluorouracil 21.
Medullar suppression is the most important toxic effect caused by almost all chemotherapeutic drugs, except bleomycin and vincristine. When severe, it may limit clinical use and patient's treatment. There are lymphocytopenia, variable thrombocytopenia degrees, erythropenia and hemophilic anemia.
They may cause liver toxicity and its implications such as metabolism and liver detoxification decrease, enzyme induction and/or inhibition and jaundice. It is exacerbated with methotrexate, cyclophosphamide, doxorubicin, mercaptopurine, asparaginase and nitrous urea, especially in oral chemotherapy regimens in low doses for a long period of time.
Major drugs are methotrexate, mercaptopurine, cisplatin and mitomycin.
Cisplatin produces the most severe renal complications which often limit chemotherapy cycles. In general, symptoms starts 3 to 5 days after cisplatin infusion with glomerular filtration rate decrease followed by acute tubular necrosis, increase in nitrogen waste, proteinuria and hyperuricemia. When this happens, there is a fast development of renal failure with the need for dialysis.
Uric acid-induced nephropathy is caused by the fast destruction of malignant cells increasing purine and pirimidine-derived plasma concentrations, which are deposited in the renal glomerulus causing nephropathy. Adequate fluid replacement, urine alkalinization and administration of purinol before chemotherapy reduce the incidence of such complication 22.
Bone marrow depression caused by most chemotherapeutic drugs triggers an increase in opportunistic infections. In addition, several invasive devices, such as indwelling catheters and the systematic and indiscriminate use of antibiotics also increase this risk. Some drugs have their own antigenic load, such as asparaginase, and cause anaphylactoid reactions in 20% of cases, with a large histamine release 2,5.
Several neurological complications are attributed to chemotherapeutic drugs.
Autonomic and peripheral neuropathies may cause hypovolemia, tachycardia, postural hypotension and changes in intestinal motility with gastric emptying decrease, predisposing to regurgitation. Major drugs implied are vinblastine, vincristine, procarbazine and cisplatin.
Some drugs have a central nervous system depressing effect, such as vincristine, vinblastine and methotrexate. Others have an excitatory effect, such as procarbazide and chloretamine, decrease in seizures threshold and catecholamine depletion, this effect being similar to the monoamine oxidase inhibitors effect.
Spinal methotrexate causes major meningeal irritation in more than 61% of patients, generating symptoms such as headache, neck stiffness, lethargy and paresthesia. Some extrapiramidal reactions may appear after the use of asparaginase 4.
Most important complications are inadequate ADH secretion by cyclophosphamide and vincristine, and the hypercalcemia associated to bone lesions, estrogens and androgens. Vesical irrigation for treating post-chemotherapy hemorrhagic cystitis in a patient with inadequate ADH secretion may cause fluid intoxication-induced relative hyponatremia. In those cases, sodium replacement must be avoided, since it may cause brain edema.
Tumor lysis syndrome occurs after chemotherapy in fast growing tumors, such as Burkitt lymphoma, acute lymphocytic leukemia and non-Hodgkin lymphoma, being rare in solid tumors. It causes hyperuricemia, hypernatremia and hyperphosphatemia with a consequent hypocalcemia, and may trigger acute renal failure 4.
Chart II illustrates major systemic repercussions of chemotherapeutic drugs.
In oncologic patients it is critical to know their clinical history as well as all stages of treatment, including prognosis, drugs, chemotherapy toxic effects, total dose, duration, indication, lab tests, functional tests and morbidity-mortality. Some special care must be taken in addition to history, physical evaluation and supplementary tests.
There should be no limits for performing and/or postponing surgery; each patient must be individually evaluated taking into account physical status, associated diseases, hospital conditions, such as the operating center, monitoring, postoperative period, need for patient's treatment, that is, staging, disease evolution, therapeutic plan and time for the new surgery in case of postponement, as well as survival conditions after the procedure.
Preoperative lab evaluation must be oriented by clinical evaluation, characteristics of the proposed surgery and recent clinical evolution. Lab tests, the results of which may change or even counterindicate perioperative plan should be preferred. In several cancer treatment centers, tests routine always include blood count and coagulogram, since the most common chemotherapeutic complication is medullar depression. Other tests may be requested depending on the case.
Anesthesia should always be planned aiming at long and complex procedures, frequently unpredictable with large volume and tissue loss. Surgeries have their plan modified according to the possibility of tumor resection, the surgical borders of which are determined by pathologic exam.
Frequently, patients recently submitted to chemotherapy are those who were refractory to the initial healing treatment, probably having already received several protocol cycles which vary a lot depending on the institution or the oncology group. A careful patient's record survey, with the identification of drugs, doses, duration, associations, complications and/or limitations, is mandatory in such situations.
Pharynx and upper airways should always be thoroughly evaluated, looking for dental lesions and mucosal changes caused by chemotherapeutic drugs. During local manipulation, such as tracheal intubation, teeth may be lost and hemorrhages and ulcerations may appear.
A systematic and documented neurological exam should be performed before any surgery or procedure, both under general or regional anesthesia, to detect possible chemotherapeutic sequelae. This exam should be repeated and documented after blockade reversion to prevent anesthesia to be blamed of possible lesions.
Due to bone marrow suppression, there are often patients with intense thrombocytopenia. In these cases, the risk/benefit ratio of invasive devices should be assessed.
All patients with neoplasia and/or under chemotherapy are at high risk for developing deep vein thrombosis. Approximately 20% of those patients may develop it regardless of all recommended prophylactic measures. As a consequence, the use of anticoagulants, such as heparin and warfarin, is frequent. Invasive procedures and/or regional blocks should be evaluated for those cases and, when mandatory, a clinical and lab follow up must be performed until such devices are removed 25.
Patients receiving cardiotoxic drugs shall be specifically evaluated for signs of congestive heart failure, pericardial effusion and changes in dromotropism. In these cases, for those receiving more than 550 mg.m2 of daunorubicin/doxorubicin it is recommended a ventricular function echocardiography evaluation, at rest an especially under stress, which mimics surgical aggression. Care is needed with children, symptomatic patients and those with ejection fraction changes or progressive ventricular function decrease along treatment. In doubt, at rest and at stress cardiac scintigraphy is recommended.
Patients in recent bleomycin use should be submitted to functional respiratory evaluation, especially for the presence of early restrictive pulmonary disease. In doubt, carbon monoxide diffusion capacity is used for being more sensitive, especially if the scheduled surgery may cause any type of postoperative ventilatory restriction.
Patients, mainly children, with a recent history of tumor lysis syndrome, must have their metabolic changes corrected before surgery 3.
In general, special care dedicated to cancer patients is due to organic lesions caused by chemotherapeutic drugs, but there are some important drug interactions (Chart III).
Nitrous oxide for those patients is still arguable. Some authors recommend it only in cases of minimum cell and platelet count decrease and associate its use to postoperative vitamin B12 and pholic acid replacement. Nitrous oxide ionizes vitamin B12 monovalent cobalt to an inactive bivalent state being the possible reason for bone marrow depression associated to multiple and continuous exposure to nitrous oxide. It is known that a single and prolonged exposure for more than 2 to 4 hours may affect the methionine-synthetase enzyme of the DNA and RNA protein synthesis (it participates on the thiamidine synthesis as from deoxyuridine, that is, it is also vitamin B12 dependent). Such protein synthesis blockade does not significantly affects white blood cells in normal patients, but causes bone marrow depression of such strain if the patient is using bone marrow suppressing drugs or antibiotics, is suffering of infection or malnutrition. It is recommended that nitrous oxide be avoided in procedures lasting more than 3 hours, especially when preoperative granulocytes depletion is seen in patients who used chemotherapeutic drugs. There is still synergy between nitrous oxide and methotrexate, which oxidizes vitamin B12 and, as a consequence, irreversibly inhibits 5-methyltetra-hydropholate-homocystein-methyltransferase, active in methotrexate's metabolism, thus increasing its toxic and therapeutic effects especially as to immunosuppression and GI tract ulcerations.
Perioperative hypotension can be observed in patients with autonomic neuropathy caused by vincristine and vinblastine, especially if associated to inhalational agents or vasodilators and can be prevented with increased hydration and vasopressants.
Procarbazide has an effect similar to monoamine oxidase inhibitors (MAOI) type A. Sympathomimetic drugs, tricyclic antidepressants and tiramine-containing food may cause hypertensive reactions. There is no description whether such drug causes chronic catecholamine depletion as it is the case with MAOIs.
Methotrexate, mytotane and procarbazide may lead to a late emergence for prolonging the sedative effect of drugs such as barbiturates, opioids and especially droperidol, frequently used to prevent nausea and vomiting.
In patients using vincristine and vinblastine, drugs which depress CNS functions should be avoided due to synergic interactions.
Neuromuscular Junction Effects
Methochloretamine and cyclophosphamide reduce plasma pseudocholinesterase concentrations which may last for several weeks after infusion, prolonging the effect of succinylcholine. Azathioprine and procarbazide cause post-junctional receptors competitive antagonism, reducing adepolarizing neuromuscular blockers effect. Perioperative neuromuscular monitoring is recommended.
Hypercalcemia generated by estrogens and androgens requires a constant serum calcium monitoring, adequate hydration and renal output control. Neuromuscular block should also be monitored 3-6.
Ester-type local anesthetics metabolism may be decreased in the presence of azathioprine and vinblastine. Vincristine and vinblastine may trigger an exaggerated loss of intracellular potassium. Succinylcholine may cause symptomatic hyperpotassemia in those cases, especially dysrhythmias.
In general, those patients are malnourished, hypovolemic and frequently have associated chronic diseases; they are psychologically affected since they have gone through several distressing and even painful procedures. The surgery is long and mutilating with large volume and tissue loss and may not be curative. In such conditions, special perioperative care must be taken, however without neglecting the best possible preoperative preparation.
The antiseptic standards are essential since immunosuppression makes those patients susceptible to opportunistic infections. It is fundamental that the anesthesiologist be aware of his/hers institution's Nosocomial Infection Committee recommendations, especially with regard to invasive procedures, care with anesthetic material and ventilation system in addition to prophylactic antibiotics.
Some cytotoxic drugs cause major vascular lesions during chemotherapy, such as infusion-induced sclerosis and leakage-induced necrosis, which may difficult the venous access during anesthesia. When arterial, venous or lymphatic circulation in a certain limb are involved it should not be used (as in patients with mastectomy and axillar lifonodes removal). In the presence of indwelling invasive devices, such as deep venous catheters or Hickman and Broviac catheters, the anesthesiologist must be familiar with their manipulation techniques or ask for the help of a qualified professional; without such requirements the device should not be used. Currently, several specialized institutions have a Hospital Catheter Committee, responsible for the maintenance and manipulation of such devices 24.
Special care must be taken with patients positioning and pressure points protection. Demineralization and bone metastasis are frequent and increase the risk for pathological fractures; in addition, some surgical positions may worsen several chemotherapy-induced peripheral neuropathies.
Patients with severe bone marrow depression are in general politransfused; care must be taken to avoid contamination, aloimmunization and especially immunoallergic reactions, such as fever and shock during perioperative replacement of such products, especially platelets.
In addition to the basic recommended monitoring (CFM Resolution 1363), those patients, due to the high incidence of hydroelectrolytic and acid-base problems, pulmonary and cardiovascular diseases and drug interactions, should be followed up with capnography, capnometry and peripheral nerve stimulation. All should be adequately warmed, preferably with a thermal blanket and fluid heaters; and their temperature should be controlled with an esophageal thermometer.
Hourly diuresis control to evaluate tissue perfusion is indicated for long surgeries (more than 2 hours), or for patients with specific indication, such as hypovolemic patients or those to be submitted to large resections. Whenever possible, vesical catheterization should be avoided in the absence of indication due to a higher risk for infections.
Peripheral artery catheterization is often used for large resections. In patients who used cardiotoxic drugs (doxorubicin and daunorubicin), cardiac output monitoring with transesophagic echocardiography is the best for being less invasive. Pulmonary artery catheter is only indicated in patients who are preoperatively symptomatic. For the others, including asymptomatic patients who received less than 550 mg.m2, global cardiovascular function at rest and especially at stress and the decompensation risk of the surgical trauma should be evaluated. Deep vein catheterization for continuous CVP control is once more being used, especially when perioperative volume variations are expected, in patients without symptomatic or early cardiovascular diseases.
To date there is no consensus about the use of new methods, such as bispectral index (BIS), in those patients.
The simplest anesthetic technique causing less perioperative changes should be used. Balanced anesthesia is the best choice in most cases, in association when indicated, with continuous epidural block, using the association local anesthetics and opioids. Spinal methotrexate injection may cause transient neurological changes. Those patients, in general children, anesthetized for the treatment itself, should be carefully observed after anesthesia due to the risk of airway obstruction, late emergence, sedation, meningism, paresthesias and balance alterations.
In patients with cisplatin-induced nephropathy, care must be taken with hydration and the use of diuretics such as furosemide and mannitol, which decrease tubular content and prevent lesion bleeding. Hypomagnesemia should be compensated since it may predispose to dysrhythmias and longer neuromuscular block.
There is a potential risk for regurgitation in patients with autonomic neuropathy-induced late gastric emptying caused by most alkylating agents.
Cyclophosphamide produces a marked and prolonged plasma pseudocholinesterase decrease which may prolong the action of succinylcholine.
Methochloretamine used for vesical irrigation in the treatment of post-chemotherapy hemorrhagic cystitis, when used in patients with inadequate ADH secretion, may cause relative hyponatremia by fluid intoxication. Sodium replacement should be avoided because it may cause brain edema.
In the case of previous liver involvement, halogenates (especially halothane) should be avoided because it may hinder the diagnosis of hepatotoxicity.
Due to the risk of worsening bleomycin-induced pulmonary fibrosis, patients should receive inspired air with oxygen concentration below 28% and should be monitored with pulse oximetry.
In the presence of structural and functional changes, such as previous history of nephropathy by urates, predominantly renal excretion drugs, marked renal blood flow decrease by hypotension or hypovolemia, and halogenated agents with significant fluoride production should be avoided.
There are some problems related to the choice of regional techniques in patients submitted to chemotherapy 3.
Hypotension by autonomic neuropathy or hypovolemia may be severe on those patients. Oxygen, preferably under facial mask with a reservoir and flow above 1.5 L.min-1 and vasopressants are always indicated 1.
The risk of neurological lesions, including the worsening of preexisting ones, is present in all patients submitted to chemotherapy. A preanesthetic neurological evaluation should be performed aiming at documenting preexisting changes and prevent the anesthesiologist to be blamed when using regional techniques, which should be avoided in the presence of preexisting neurological lesions.
As to the simultaneous use of anticoagulants (deep vein thrombosis prophylaxis), hemostatic changes (thrombocytopenia) and infections, blockades and catheters should be limited to precise indications or when postoperative analgesia is an important factor for patients' recovery, such as in thoracotomies.
Care must be taken with the prolonged action of ester-type local anesthetics in patients treated with azathioprine 10,11.
Postoperative analgesia is always desirable since those patients are psychologically less resistant and organically susceptible to pain.
Large resections, especially upper abdominal surgeries, lombotomies and thoracotomies may have their postoperative evolution impaired if an effective analgesia is not planned. Special care must be taken with patients who have recently used bleomycin and other pneumotoxic drugs. Its adequate use may markedly decrease the risk of respiratory failure during this stage of treatment.
Care must be taken with the epidural catheter in patients under anticoagulants, especially because chemotherapy itself may change hemostasis by generating thrombocytopenia. Those drugs, per se, are not a counterindication for such devices since analgesia itself contributes for the prevention of deep vein thrombosis for making easier an early ambulation. It is recommended:
Non-traumatic puncture before anticoagulation;
Methods to avoid physical trauma by catheter movement;
Removal only after the end of anticoagulation and PTTa normalization and, in the case of low molecular weight heparins which do not change such exam, catheter removal is recommended 24 hours after withdrawal;
Continuous evaluation and tracking of spinal compression signs and symptoms 25,26.
IMMEDIATE POSTOPERATIVE PERIOD
All cancer patients' surgeries deserve a more complex postoperative planning, especially as to available resources, monitoring and surveillance methods.
Some drugs deserve special attention. After a recent use of mitomycin and bleomycin, with clinical signs of pulmonary lesion, the possibility of postoperative ventilatory assistance (depending on surgery size and location, simultaneous thoracic radiograph and patient's previous respiratory function) must be always evaluated.
Care must be taken with postoperative fibrinolytic reactions in major surgeries, such as radical prostatectomies where there is a major release of urokinase in the operating field. Chemotherapy-induced thrombocytopenic patients are the most susceptible 27.
Some cases are described, by surgical specialty, where the anesthesiologist must be aware of possible complications caused by chemotherapeutic drugs. In most cases, interactions occur in surgeries in patients with diseases refractory to more than one type of treatment and in metastatic tumors (Chart IV).
Very seldom patients with primary tumors of the infancy arrive to a healing surgery with a previous history of chemotherapy; more often one may see those with disseminated disease, candidates to metastasis resections or patients being treated of non-surgical neoplasias (such as leukemias and lymphomas) where the anesthesiologist is called for radiological exams, radiation therapy or placement of invasive devices (such as deep or indwelling venous catheters). In most cases, patients are using or have recently used those drugs, or present with some complication (especially leukopenia and thrombocitopenia).
Patients with brain metastasis and "mass effect" (adjacent structures compression by the tumor) scheduled for resection, very often have already gone through some cycle of chemotherapy or radiation therapy.
Head and Neck Surgery
Although not being used as a primary protocol, some patients with metastatic tumors may be treated with chemotherapy and return to surgery (cisplatin, bleomycin and 5-fluorouracil in epidermoid carcinomas of salivary glands and larynx, for example).
In testis tumors, patients with masses refractory to first line chemotherapy, such as cisplatin, bleomycin and etoposides, are frequently scheduled for palliation surgeries for mass resection. Care must be taken with oxygen with FiO2 above 0.28% since it is responsible for the highest incidence of bleomycin-induced pulmonary fibrosis and hyperoxia.
Patients with previous chemotherapeutic treatment, in general children are often candidates to chest metastasis resection surgeries. In those cases, postoperative respiratory failure may be expected because there is synergy of pulmonary lesion caused by radiation therapy, chemotherapy and the metastasis itself.
Hyperthermochemotherapy is a technique consisting of the catheterization of the vascular tree by the nutrient and collecting artery of a certain organic segment where the target tumor is located, followed by perfusion for a certain period with a chemotherapeutic solution heated at 40-42 ºC. It is used in some refractory cases of stomach and colon tumors with cisplatin, mitomycin, 5-fluorouracil and folates. It may trigger severe metabolic acidosis, hyperthermia (primary, caused by the technique or secondary, caused by tumor lysis or hemolysis), severe hypotension with marked decrease in hematocrit (by hemolysis and intravascular fluid translocation), and hypercapnia (with the development of dysrhythmias). Blood, plasma, platelets and colloids, patients' cooling devices, such as ice, compresses and chilled solutions, and cardiopulmonary resuscitation material should always be available in the operating room.
Bone and Connective Tissue
Sarcomas are connective tissue neoplasias sensitive to doxorubicin and daunorubicin. Those patients often arrive at the operating room after intensive chemotherapy to decrease tumor volume, hence at a high risk for developing drug-related cardiovascular complications.
Mastectomy, in general, consists on surgical tumor resection followed by chemotherapy and radiation therapy; however, in some cases previous cytoreducing chemotherapy with CMF (cyclophosphamide, methotrexate and 5-fluorouracil) and doxorubicin immediately followed by surgery is recommended. Other patients may be operated after intensive chest radiation therapy which may worsen chemotherapeutic complications.
Patients having used doxorubicin and cisplatin, especially in advanced endometrial tumors may be seen when palliation hysterectomy is indicated.
In general, patients with ovary tumors are scheduled for a second look laparotomy, that is, in cases of already resected tumors where several postoperative chemotherapy cycles are performed (most frequent regimens involve cisplatin, cyclophosphamide and taxol); afterwards the surgeon wants to evaluate the treatment by direct visualization. As a consequence, such patients are submitted to anesthesia soon after chemotherapy.
The presence of the anesthesiologist is needed for such procedures in children and patients with consciousness level changes. There are a wide variety of diseases to be looked for in those cases, but care must be taken especially when the indication of those tests is for chemotherapy efficacy evaluation, that is, patients in recent use of such drugs. Among them, many may have used doxorubicin, which is widely used in lymphomas and solid tumors of the infancy.
For lumbar puncture in children under anesthesia, frequently spinal methotrexate injection is associated to CSF collection. This procedure must be undertaken by the specialist oncologist or hematologist in charge of the patient due to the high incidence of meningeal irritation signs and other transient neurological symptoms. A thorough preanesthetic neurological evaluation must be performed and recorded 28.
During oncologic treatment, it is common to see patients under chemotherapeutic drugs. The anesthesiologist's awareness of types of treatments, pharmacological characteristics of the drugs, their adverse effects, structural lesions and possible drug interactions exacerbated by current anesthetic techniques may certainly decrease perioperative morbidity and mortality.
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03. Robinson PN - Chemotherapy and Anaesthesia, em: Filshie J, Robbie DS - Anaesthesia and Malignant Disease, 1st Ed, London, Edward-Arnold, 1996;19-22.
04. Weiss GR - Chemotherapy, em: Weiss GR - Clinical Oncology, 1st Ed, Lange Medical Books, 1995;97-109.
05. DeVita VT - Principles of Chemotherapy in Cancer, em: DeVita VT, Hellman S, Rosemberg SA - Principles and Practices of Oncology, 4rd Ed, Lippincott-Raven, 1995;257-286.
06. Stoelting RK - Chemotherapeutic Drugs, em: Stoelting RK - Pharmacology and Physiology in Anesthetic Practice, 3rd Ed, Philadelphia, Lippincott-Raven, 1998;490-505.
07. Chabner BA, Myers CE - Clinical Pharmacology of Cancer Chemotherapy in Cancer, em DeVita VT, Hellman S, Rosemberg SA - Principles and Practices of Oncology, 4rd Ed, Lippincott-Raven, 1995;287-328.
08. Chabner BA, Allegra CJ, Curt GA et al - Antineoplastic Agents, em: Goodman and Gilman - The Pharmacological Basis of Therapeutics, 9rd Ed, New York, Mc Graw-Hil, 1996;1233-1288.
09. Chabner BA, Donehower RC, Schilsky RL - Clinical pharmacology of methotrexate. Cancer Treat Rep, 1981;65:51-54.
10. Chung F - Cancer, chemotherapy and anaesthesia. Can Anaesth Soc J, 1982;29:364-371.
11. Selvin BF - Cancer chemotherapy: implications for the anesthesiologist. Anesth Analg, 1981;60:425-434.
12. Borgeat A, Chiolero R, Baylon P et al - Perioperative cardiovascular collapse in a patient previouly treated with doxorubicin. Anesth Analg, 1988;67:1189-1191.
13. Doroshow JH - Doxorubicin-induced cardiac toxicity. N Engl J Med, 1991;324:843-845.
14. Gottdiener JS, Appelbaum FR, Ferrans VJ et al - Cardiotoxicity associated with high-dose cyclophosphamide therapy. Arch Intern Med, 1981;141:758-763.
15. Talcott JA, Herman TJ - Acute ischemic vascular events and cisplatin. Ann Intern Med, 1987;107:121-122.
16. Blom-Muilwijk MC, Vriesemdorp R, Veninga TS et al - Pulmonary toxicity after treatment with bleomycin along or in combination with hyperoxia. Studies in the rat. Br J Anaesth, 1988;60:91-97.
17. Goldiner PL, Carlon G, Cvitkovic E et al - Factors influencing postoperative morbidity and mortality in patients treated with bleomicyn. BMJ, 1978;1:1664-1667.
18. Hulbert JC, Grossman JE, Cummings KB - Risk factors of anesthesia and surgery in bleomicyn-treated patients. J Urol, 1983;130:163-164.
19. Mathes DD - Bleomicyn and hyperoxia exposure in the operating roon. Anesth Analg, 1995;81:624-629.
20. Jackson SH, Barker SJ - Methemoglobinemia in a patient receiving flutamide. Anesthesiology, 1995;82:1065-1067.
21. Redding SW - Oral Considerations of Cancer Chemotherapy, em: Rose L, Kaye D - Internal Medicine for Dentistry, 2nd Ed, Mosby Year Book, 1989.
22. Narins RG, Carley M, Bloom EJ et al - The nephrotoxicity of chemotherapeutic agents. Semin Nephrol, 1990;10:556-564.
23. Zsigmond EK, Robins G - The effect of a series of anticancer drugs on plasma cholinesterase activity. Can Anaesth Soc J, 1972;19:75-82.
24. Freitas LC, Raposo LCM, Finoquio RA - Instalação, manutenção e manuseio de cateteres venosos centrais de inserção periférica em pacientes submetidos a tratamento quimioterápico. Rev Bras Cancerol, 1999;45:1.
25. Sociedade Brasileira de Angiologia e Cirurgia Vascular. Consenso sobre tratamento e profilaxia de trombose venosa profunda. Rio de Janeiro, 1998;105-109.
26. American Society of Regional Anesthesia. Recommendations for neuroaxial anesthesia and anticoagulation. 1999 (published on ASRA website www.asra.com).
27. Malkowicz SB, Wein A - Prostate Cancer, em: Kerley et al (editors). Internal Medicine, 3rd Ed, Lippincott-Raven, 1998;1220-1229.
28. Brasil. Ministério da Saúde Secretaria Nacional de Assistência à Saúde. Instituto Nacional de Câncer. Coordenação de Programas de Controle do Câncer. Câncer no Brasil. Protocolos de Tratamento: Quimioterapia 01/2000. Rio de Janeiro, MS/INCA, 2000.
29. Mihalo RM, Cagle CK, Cronau LH et al - Preanesthetic evaluation of the cancer patient. Cancer Bull, 1995;4:8-12.
Dr. Márcio Augusto Lacerda
Address: Rua Editor José Olympio, 490/402 Botafogo
ZIP: 22251-030 City: Rio de Janeiro, Brazil
Submitted for publication October 6, 2000
Accepted for publication December 14, 2000
* Received from CET/SBA do Hospital de Câncer, Instituto Nacional de Câncer, Rio de Janeiro, RJ
01. Brasil. Ministério da Saúde Secretaria Nacional de Assistência à Saúde. Instituto Nacional de Câncer. Coordenação de Programas de Controle do Câncer. Câncer no Brasil - Dados dos Registros de Câncer de Base Populacional. Volume I. Rio de Janeiro, MS/INCA, 1991. [ Links ]
02. Brasil. Ministério da Saúde Secretaria Nacional de Assistência à Saúde. Instituto Nacional de Câncer. Coordenação de Programas de Controle do Câncer. Câncer no Brasil - Dados dos Registros de Câncer de Base Populacional. Volume II. Rio de Janeiro, MS/INCA, 1995. [ Links ]
03. Robinson PN - Chemotherapy and Anaesthesia, em: Filshie J, Robbie DS - Anaesthesia and Malignant Disease, 1st Ed, London, Edward-Arnold, 1996;19-22. [ Links ]
04. Weiss GR - Chemotherapy, em: Weiss GR - Clinical Oncology, 1st Ed, Lange Medical Books, 1995;97-109. [ Links ]
05. DeVita VT - Principles of Chemotherapy in Cancer, em: DeVita VT, Hellman S, Rosemberg SA - Principles and Practices of Oncology, 4rd Ed, Lippincott-Raven, 1995;257-286. [ Links ]
06. Stoelting RK - Chemotherapeutic Drugs, em: Stoelting RK - Pharmacology and Physiology in Anesthetic Practice, 3rd Ed, Philadelphia, Lippincott-Raven, 1998;490-505. [ Links ]
07. Chabner BA, Myers CE - Clinical Pharmacology of Cancer Chemotherapy in Cancer, em DeVita VT, Hellman S, Rosemberg SA - Principles and Practices of Oncology, 4rd Ed, Lippincott-Raven, 1995;287-328. [ Links ]
08. Chabner BA, Allegra CJ, Curt GA et al - Antineoplastic Agents, em: Goodman and Gilman - The Pharmacological Basis of Therapeutics, 9rd Ed, New York, Mc Graw-Hil, 1996;1233-1288. [ Links ]
09. Chabner BA, Donehower RC, Schilsky RL - Clinical pharmacology of methotrexate. Cancer Treat Rep, 1981;65:51-54. [ Links ]
10. Chung F - Cancer, chemotherapy and anaesthesia. Can Anaesth Soc J, 1982;29:364-371. [ Links ]
11. Selvin BF - Cancer chemotherapy: implications for the anesthesiologist. Anesth Analg, 1981;60:425-434. [ Links ]
12. Borgeat A, Chiolero R, Baylon P et al - Perioperative cardiovascular collapse in a patient previouly treated with doxorubicin. Anesth Analg, 1988;67:1189-1191. [ Links ]
13. Doroshow JH - Doxorubicin-induced cardiac toxicity. N Engl J Med, 1991;324:843-845. [ Links ]
14. Gottdiener JS, Appelbaum FR, Ferrans VJ et al - Cardiotoxicity associated with high-dose cyclophosphamide therapy. Arch Intern Med, 1981;141:758-763. [ Links ]
15. Talcott JA, Herman TJ - Acute ischemic vascular events and cisplatin. Ann Intern Med, 1987;107:121-122. [ Links ]
16. Blom-Muilwijk MC, Vriesemdorp R, Veninga TS et al - Pulmonary toxicity after treatment with bleomycin along or in combination with hyperoxia. Studies in the rat. Br J Anaesth, 1988;60:91-97. [ Links ]
17. Goldiner PL, Carlon G, Cvitkovic E et al - Factors influencing postoperative morbidity and mortality in patients treated with bleomicyn. BMJ, 1978;1:1664-1667. [ Links ]
18. Hulbert JC, Grossman JE, Cummings KB - Risk factors of anesthesia and surgery in bleomicyn-treated patients. J Urol, 1983;130:163-164. [ Links ]
19. Mathes DD - Bleomicyn and hyperoxia exposure in the operating roon. Anesth Analg, 1995;81:624-629. [ Links ]
20. Jackson SH, Barker SJ - Methemoglobinemia in a patient receiving flutamide. Anesthesiology, 1995;82:1065-1067. [ Links ]
21. Redding SW - Oral Considerations of Cancer Chemotherapy, em: Rose L, Kaye D - Internal Medicine for Dentistry, 2nd Ed, Mosby Year Book, 1989. [ Links ]
22. Narins RG, Carley M, Bloom EJ et al - The nephrotoxicity of chemotherapeutic agents. Semin Nephrol, 1990;10:556-564. [ Links ]
23. Zsigmond EK, Robins G - The effect of a series of anticancer drugs on plasma cholinesterase activity. Can Anaesth Soc J, 1972;19:75-82. [ Links ]
24. Freitas LC, Raposo LCM, Finoquio RA - Instalação, manutenção e manuseio de cateteres venosos centrais de inserção periférica em pacientes submetidos a tratamento quimioterápico. Rev Bras Cancerol, 1999;45:1. [ Links ]
25. Sociedade Brasileira de Angiologia e Cirurgia Vascular. Consenso sobre tratamento e profilaxia de trombose venosa profunda. Rio de Janeiro, 1998;105-109. [ Links ]
27. Malkowicz SB, Wein A - Prostate Cancer, em: Kerley et al (editors). Internal Medicine, 3rd Ed, Lippincott-Raven, 1998;1220-1229. [ Links ]
28. Brasil. Ministério da Saúde Secretaria Nacional de Assistência à Saúde. Instituto Nacional de Câncer. Coordenação de Programas de Controle do Câncer. Câncer no Brasil. Protocolos de Tratamento: Quimioterapia 01/2000. Rio de Janeiro, MS/INCA, 2000. [ Links ]
29. Mihalo RM, Cagle CK, Cronau LH et al - Preanesthetic evaluation of the cancer patient. Cancer Bull, 1995;4:8-12. [ Links ]