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Cancer is one of the most prevalent disease processes affect- The effects of chemotherapy may be acute and self-limit-
ing people of all ages. Cancer is the second most common ing or chronic and present long after treatment has been com-
cause of death in the United States, exceeded only by heart pleted. Patients who have had chemotherapy often undergo
disease. Cancer survival is dependent on treatment options surgery that may or may not be related to their cancer.
that may include surgery, radiation, and chemotherapy. Chemotherapy administration can have a profound influence
Chemotherapy, or systemic cancer therapy, is designed to on anesthetic management. Safe administration of anesthe-
promote cell death during different phases of cell growth and sia includes knowledge of chemotherapeutic agents and their
division. Unfortunately, chemotherapeutic agents cannot dif- toxic effects. This course discusses the anatomic and physio-
ferentiate between malignant and normal cells. Therefore,
logic effects of cancer chemotherapeutic agents and how they
the toxic effects of chemotherapy are also seen in healthy
specifically affect patients receiving anesthesia.
organs and tissues. In addition, chemotherapeutic agents can
interact with other medications. Key words: Anesthesia, cancer, chemotherapy, toxicity.
* AANA Journal Course No. 27: The American Association of Nurse Anesthetists is accredited as a provider of continuing education in nursing by
the American Nurses Credentialing Center Commission on Accreditation. The AANA Journal course will consist of 6 successive articles, each with
objectives for the reader and sources for additional reading. At the conclusion of the 6-part series, a final examination will be printed in the AANA
Journal. Successful completion will yield the participant 6 CE credits (6 contact hours), code number: 29460, expiration date: June 30, 2008.
Women
1. Breast Doxorubicin, epirubicin, cyclophosphamide, docetaxel, paclitaxel, methotrexate,
tamoxifen, docetaxel, gemcitabine, thiotepa, vincristine, vinblastine, carboplatin,
cisplatin
2. Lung and bronchus Cisplatin, etoposide, carboplatin, docetaxel, gemcitabine, gefitinib, erlotinib, vinblastine,
vinorelbine, cyclophosphamide, doxorubicin, vincristine
3. Colon and rectum Fluorouracil, cetuximab, capecitabine, methotrexate, cisplatin
4. Uterus Progestins, tamoxifen, doxorubicin, cisplatin, fluorouracil
5. Non-Hodgkin lymphoma Doxorubicin, bleomycin, vinblastine, vincristine, etoposide, cyclophosphamide,
methotrexate
6. Melanoma of the skin Cisplatin, paclitaxel, tamoxifen, vincristine
7. Thyroid Doxorubicin, cisplatin, bleomycin, melphalan
8. Ovary Paclitaxel, cisplatin, carboplatin, docetaxel, doxorubicin, cyclophosphamide, etoposide,
liposomal doxorubicin
9. Urinary bladder Methotrexate, vinblastine, doxorubicin, cisplatin, cyclophosphamide, fluorouracil,
gemcitabine
10. Pancreas Fluorouracil, gemcitabine, carmustine, mitomycin, doxorubicin, methotrexate, cisplatin
Table 1 lists the top 10 diagnosed cancers in men and and vinca alkaloids (Table 2). Some drugs are loosely
women along with common chemotherapeutic agents classified as miscellaneous because their mechanism
used to treat them. of action is not fully understood or their action does
not conform to one of the more specific classifica-
Chemotherapy tions.5 Alkylating agents affect DNA, causing cross-
Chemotherapeutic agents act by interfering with the linking and abnormal base pairing and resulting in
cell cycle at different phases of cell replication. Unfor- intracellular imbalance and cell death. Antimetabo-
tunately, because of this mode of action, there is no lites or structural analogs interfere with cell replica-
drug that can destroy cancer cells without also dam- tion by substitution of metabolites necessary for cell
aging normal healthy cells. In contrast with tradi- reproduction. Antitumor antibiotics act by inhibiting
tional cancer therapy, newer treatments are more cell- DNA and RNA synthesis. Vinca alkaloids are known
specific and less globally cytotoxic but are still to interact with the microtubular proteins needed for
associated with the potential for serious side effects.4 cell division.5 Toxic effects are related to the type of
Classifications of cytotoxic drugs are determined by drug, the cumulative dose, and the dosing schedule.6,7
their specificity in the cell cycle. Classes include alky- In preparation for administering anesthesia to a
lating agents, antimetabolites, antitumor antibiotics, patient receiving or who has received chemotherapy, a
comprehensive preoperative history and physical and tachycardia. Prevention of aspiration remains a
examination are paramount. Full knowledge of all primary concern to anesthesia providers, and this
cancer treatment received by the patient, including patient population presents an increased risk. A reli-
surgery and radiation, may reveal potential operative able and valid self-reporting instrument such as the
complications such as exacerbation of surgical bleed- Rhodes Index of Nausea, Vomiting, and Retching may
ing.1 Information obtained by anesthesia providers be a valuable assessment tool. This information will
about cancer treatment received by patients should be provide a view of the patient’s personal symptom
exhaustive and include type of chemotherapeutic experience, allowing the anesthesia provider to plan
agents, number of treatments, date of last treatment, appropriate symptom management.
and total amount of agent received.6 Patients and fam- Other central nervous system effects include
ily members are often unable to provide complete and seizures, which may occur with busulfan treatment up
accurate information pertaining to cancer treatment. to 24 hours after the last dose. Numbness and tingling
Anesthesia providers may need to access other of extremities, loss of deep tendon reflexes, and weak-
sources, such as charts from prior admissions, to ness of distal limb musculature are toxic signs of vin-
obtain the necessary information. cristine therapy.9 Other chemotherapeutic agents
associated with neuropathies include cisplatin, tax-
Central nervous system effects anes, and oxaliplatin.10 Vinca alkaloids have been the
Central nervous system toxicity resulting in nausea causative agent in vocal cord paralysis and loss of
and vomiting consistently ranks among the top 3 extraocular muscle function. Central nervous system
reported side effects of chemotherapy. Onset is usually toxic reactions usually disappear after discontinuation
acute, occurring within 12 to 24 hours after treat- or dosage adjustment.9 Agents that may cause central
ment. Delayed nausea and vomiting occurs after 24 nervous system toxicity are listed in Table 3.
hours and may last for 6 to 7 days.8 Cisplatin in high
doses will cause vomiting within 24 hours of admin- Cardiac effects
istration in 90% of patients who are not taking pro- Hemodynamic stability is an important aspect of anes-
phylactic antiemetics.8 Emetogenicity risk factors for thetic management and may be impaired by car-
patients receiving chemotherapy are the same as for diotoxicity. Cytostatic anthracycline antibiotics are
patients who experience postoperative nausea and the chemotherapeutic agents most commonly associ-
vomiting. These factors include young age, female ated with cardiotoxicity.11 Anthracyclines are a subset
gender, and history of motion sickness. of the antibiotic class of chemotherapeutic agents and
Vomiting patients are at risk for electrolyte imbal- include daunorubicin, doxorubicin, epirubicin, and
ances, dehydration, weight loss, and malnutrition. idarubicin. Other agents that also induce this phe-
Patients experiencing nausea alone may have flushing nomenon are listed in Table 4. Because the myocar-
dium consists of cells that have limited regenerative patients), preexisting cardiac disease, obesity, and left
capability, the heart is susceptible to permanent dam- ventricular ejection fraction of less than 50%.14 These
age.12 factors and the type of surgery must be considered
The 3 established forms of anthracycline-induced when evaluating cardiac status before anesthesia. A
cardiotoxicity are separated into acute, chronic, and chest radiograph, a 2-dimensional echocardiogram,
late onset. Acute cardiotoxicity pertains to an onset an electrocardiogram, and the levels of lactate dehy-
immediately after a single dose or course of therapy and drogenase and creatine phosphokinase enzymes can
is usually transient. It may involve abnormal electro- be indicative of altered myocardial function. Anesthe-
cardiographic findings, including ST-T wave changes, sia providers must keep in mind that abnormalities in
QT-interval prolongation, and arrhythmias. Chronic cardiac function can exist even in patients with nor-
toxic effects occur within 1 year of therapy, with rapid mal resting cardiac function.11 Patients who have
onset and progression. Manifestations include tachy- received anthracycline therapy may have an enhanced
cardia, tachypnea, ventricular dilation, exercise intoler- cardiodepressive effect from anesthesia.11 In a com-
ance, pulmonary and venous congestion, poor perfu- promised patient, prolonged sympathetic hyperactiv-
sion, and pleural effusion. This toxicity reflects ity maintains cardiac function and the number of β-
progressive injury and loss of myocytes and will even- adrenergic receptors may be decreased. Therefore,
tually lead to congestive heart failure and decreased left β-adrenergic agonists may be ineffective, and a non-
ventricular ejection fraction. Late-onset toxic effects adrenergic inotropic agent should be considered.
occur several years or decades after therapy cessation. Anesthetics with negative inotropic effects, such as
These effects include ventricular dysfunction, conduc- halothane, should be avoided. Chronic sympathetic
tion disturbances and arrhythmias, and congestive stimulation maintains cardiac function in compro-
heart failure as a consequence of myocyte damage. mised patients; therefore, ketamine may depress,
Late-onset toxic effects typically occur in patients who rather than enhance, cardiac function.1
received anthracycline therapy as a child or adolescent
and can occur even with low doses. Other clinical signs Pulmonary effects
of cardiotoxicity include mild blood pressure changes, When pulmonary toxic effects occur from cytotoxic
thrombosis, myocarditis, pericarditis, myocardial agents, they involve a combination of direct lung
infarction, and cardiomyopathy.13 damage and indirect inflammatory processes.15 In
Risk factors that can increase the incidence of general, the adverse respiratory effects from cytotoxic
chemotherapy-related cardiotoxicity are history of agents are composed of an early inflammatory inter-
radiation therapy to the mediastinum or left chest stitial pneumonitis, acute noncardiogenic pulmonary
wall, age at treatment (higher incidence in younger edema, bronchospasm, and pleural effusion.11 Some
of the signs and symptoms associated with these Recommendations are to use less than 30% inspired
effects include dyspnea, cough, tachypnea, bibasilar oxygen or the lowest inspiratory oxygen fraction com-
rales, and, occasionally, fever. Pneumonitis occurs patible with adequate tissue oxygenation. Arterial
gradually in the first few months of treatment but can blood gases and pulse oximetry can be used to deter-
occur as long as 6 months after treatment.16 Pneu- mine adequate oxygenation. In surgical procedures in
monitis is accompanied by an increase in fibroblast which inspired oxygen of more than 30% is warranted,
activity. Fibroblast activity is then followed by colla- more invasive monitoring, such as mixed venous
gen synthesis and decreased collagen degradation, oximetry, may allow anesthetists to minimize oxygen
leading to pulmonary fibrosis.17 There is a wide range concentrations safely. Treatment with corticosteroids
of cytotoxic chemotherapy agents that have been before surgery has shown positive results with
implicated in pulmonary fibrosis and are listed in improvements in vital capacity and diffusion capacity
Table 5. Bleomycin is the chemotherapeutic agent and no postoperative respiratory complications.17
most associated with toxicity that can lead to pul- Equally important as the use of low oxygen concentra-
monary fibrosis.11 Fibrosis is accompanied by dysp- tions is the careful management of intravenous fluid
nea, hacking cough, fatigue, chest discomfort, and administration. The restriction of fluids to the mini-
rapid weight loss. Up to 25% of patients with previous mum necessary to maintain hemodynamic stability and
bleomycin therapy may develop postoperative respira- adequate renal output is advised.11 There is a high per-
tory insufficiency, necessitating prolonged postopera- centage of subclinical bleomycin-induced pulmonary
tive intubation.11 Preoperative assessment should damage compromising the ability of the lungs to han-
include questions that focus on accompanying risk dle large volumes of fluids.11 With proper assessment
factors that may increase the likelihood of postopera- and management, the probability of postoperative res-
tive respiratory insufficiency. Risk factors for pul- piratory complications related to prior chemotherapy-
monary toxicity from chemotherapeutic agents induced lung toxicity should be reduced.
include age older than 70 years, genetic predisposi-
tion, existing pulmonary disease, smoking history, Nephrotoxicity
and thoracic radiation therapy. Pulmonary function Administration of anticancer chemotherapy can cause
tests, such as vital capacity and diffusion capacity for drug-induced nephrotoxicity and can lead to acute or
carbon monoxide, are commonly monitored to detect chronic renal damage.19 Approximately 20% of car-
chemotherapy-induced pulmonary toxicity.15 Meas- diac output perfuses the kidneys, exposing these
urement of diffusion capacity of carbon monoxide organs extensively to systemic chemotherapeutic
(>10%-15% from baseline) has been found to be the agents.20 Mechanisms of renal dysfunction generally
most sensitive indicator of subclinical pulmonary include damage to structures of the kidneys necessi-
damage from chemotherapeutics.15 The 2 main con- tating evaluation of glomerular filtration, proximal
cerns for anesthesia providers are the administration tubular function, and distal tubular function.
of intraoperative oxygen and fluid management. Hemolytic uremic syndrome and prerenal perfusion
High oxygen concentrations have been implicated in deficits are also observed in patients treated with can-
potentiating lung damage in patients who received cer chemotherapy.20 Patients typically experience
bleomycin. Hyperoxia is the delivery of inspired oxy- nonoliguric renal failure.9 Nephrotoxic cancer
gen concentrations equal to or greater than 30%. Previ- chemotherapeutic agents include methotrexate, cis-
ous bleomycin treatment sensitizes the lung to concen- platin, and ifosfamide (Table 6). Chemotherapy
trations of oxygen that are not usually damaging.18 dose–related degrees of nephrotoxicity are experi-
enced with the platinating agents cisplatin and carbo- Hepatic implications
platin. Electrolyte abnormalities subsequent to cis- Hepatic dysfunctions, such as cirrhosis and coagula-
platin administration occur acutely and may persist tion disorders, are frequently reversible effects of can-
for years following cessation of therapy. Hypomagne- cer chemotherapy. Methotrexate may induce the
semia occurs more commonly than hypokalemia, development of hepatic cirrhosis and fibrosis.
other electrolyte abnormalities, or acid-base disor- Although rare, flutamide causes severe hepatotoxicity
ders. Cisplatin administration is also responsible for with associated jaundice and dark urine.9 Other hepa-
acute proximal tubular damage followed by a progres- totoxic chemotherapeutic agents are listed in Table 6.
sive loss of filtration capability. Transient renal dys- Hepatocellular damage may be exacerbated in patients
function occurs frequently and irreversible renal dys- undergoing anesthesia.1 Hepatic metabolism must be
function occurs infrequently following administration considered, and isoflurane is the preferred volatile
of carboplatin.20 Common signs of platinum-induced agent.6 Halothane has been implicated in hepatotoxi-
nephrotoxicity include increased serum creatinine city and should be avoided. Vecuronium and rocuro-
level, uremia, and electrolyte abnormalities. nium should be used judiciously and closely moni-
tored. Liver function tests may be useful in
Estimation of glomerular filtration rate using crea-
monitoring patients who have received a hepatotoxic
tinine clearance is used to assess renal function.20
chemotherapy regimen.
Maintaining fluid and electrolyte balance and ade-
quate renal perfusion are the critical factors in treating Gastrointestinal effects
patients at risk for nephrotoxic effects.1 Nonsteroidal Effects of chemotherapy are manifested in the rapidly
anti-inflammatory drugs should be avoided in dividing cells of the entire gastrointestinal tract, and
patients receiving nephrotoxic chemotherapy because the potential for substantial mucosal tissue injury
they may precipitate acute renal failure.11 Dosages of exists throughout the length of the tract.21 Gastroin-
drugs that undergo renal clearance, such as pancuro- testinal disorders may include oral mucositis or diar-
nium, should be decreased. Isoflurane and desflurane rhea and are limited to patients actively receiving
are the volatile agents of choice due to the association chemotherapy. Chemotherapeutic regimens contain-
of sevoflurane with nephrotoxic compound A. ing fluorouracil and irinotecan have been associated