Page 1289 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

896 PART 7: Hematologic and Oncologic Disorders

In instances of noncardiogenic pulmonary edema, diuretics should be Due to the significant morbidity and mortality associated with
utilized following cardiovascular assessment. cumulative dosing of anthracyclines, agents have been developed in
■ CARDIOTOXICITY attempts to mitigate these dose-limiting cardiotoxic effects. Liposomal
doxorubicin encapsulates the drug within a liposome, thereby limiting
The cardiotoxic effects of cancer therapy range from acute and its exposure to organs with tight capillary junctions such as the heart and
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subacute, including manifestations such as pericarditis, myocardi- GI tract. Mitoxantrone is an anthracycline derivative that was devel-
tis, acute coronary syndrome (ACS), SVTs, and QT prolongation, to oped in attempts to reduce the generation of cardiotoxic ROS associated
chronic, insidious onset of left ventricular dysfunction resulting in car- with the original anthracyclines and early randomized trials did show a
diomyopathy and congestive heart failure (CHF). A critically ill patient significantly lower incidence of CHF or moderate to severe decrease in
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may present acutely with chest pain following recent cancer treatment, LVEF with mitoxantrone compared to doxorubicin. However, as with
or have a remote history of potentially cardiotoxic therapy and is admit- the original anthracyclines, higher cumulative doses (>160 mg/m ) are
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ted after a progressive decline in cardiac status. In either case, knowledge associated with increased risk of developing heart failure. Dexrazoxane
of the common cardiotoxic therapies is essential to the appropriate is an iron chelator which prohibits oxygen-free radical production by
diagnosis and subsequent management of these patients. A summary of anthracyclines but can also interfere with their anticancer effects, so
cardiotoxic effects of chemotherapy is presented in Table 95-4. it is not administered simultaneously with chemotherapy, rather it is
The most well-known cardiotoxic cancer therapy class is the sub- reserved for those patients who have received >300 mg/m and antici-
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group of antibiotics called anthracyclines (doxorubicin, daunorubicin, pate further need for anthracycline-containing regimen. 39
epirubicin, and idarubicin). Via the formation of reactive oxygen species Liposomal doxorubicin was shown to have considerably less risk of
(ROS) and subsequent oxidative stress resulting in apoptosis, anthracy- cardiomyopathy at long-term follow-up of 42 patients who received
2
clines have been reported to cause both symptomatic and asymptomatic ≥500 g/m on posttreatment MUGA scans. Thirty-four of the 42 had
arrhythmias, transient nonspecific ECG changes, rare pericarditis and not been previously treated with doxorubicin and 41 of the 42 were
myocarditis (particularly daunorubicin), and dose-dependent cardio- available for posttreatment MUGA scans at a median of 2.7 years. Only
myopathy. One of the earliest series to describe the dose-related car- 2 patients without a history of prior doxorubicin exposure demonstrated
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diotoxic effects of doxorubicin was published in 1973 by Lefrak et al. a drop of ≥10% in LV EF (5.8%) compared to historical rates of >7%
In his case series of 399 patients treated with doxorubicin, there were with a comparable dose of doxorubicin. A recently published meta-
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11 cases (3%) of acute cardiac decompensations with 8 resultant deaths analysis reviewed 55 randomized controlled trials of anthracyclines in
within 3 weeks. An additional 45 patients (11%) experienced transient a variety of cancers (including metastatic breast, multiple myeloma,
ECG changes. With regard to patients developing refractory heart and ovarian cancer), in patients without preexisting cardiac disease and
failure, a dose cutoff ≥550 mg/m was found to correlate with a much risk for cardiotoxicity. Fifteen of these studies compared an anthra-
2
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higher incidence than doses below 550 mg/m (30% vs 0.27%). Factors cycline with mitoxantrone and showed an anthracycline-containing
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that were found to increase the risks of cardiotoxicity include cumula- regimen increased the risk of clinical cardiotoxicity or CHF (OR 2.88)
tive dose, extremes of age, prior radiation therapy, and combination compared to mitoxantrone. This same analysis also reviewed studies
chemotherapy. An early retrospective study by Von Hoff et al nicely which compared liposomal doxorubicin and epirubicin compared to
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demonstrated an increasing incidence of anthracycline-induced heart conventional doxorubicin and found a decreased risk for clinical car-
failure (3%, 7%, and 18%) with increasing cumulative dosages (400, 550, diotoxicity or CHF (OR 0.18 and 0.39, respectively). Another six studies
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and 700 mg/m , respectively). Early onset heart failure (up to 1 year reviewed compared the use of the cardioprotective agent dexrazoxane
after treatment) has a much more favorable prognosis if identified and versus placebo in combination with an anthracycline and were shown
treated aggressively with traditional CHF regimens (diuretics, β-blocker, to significantly decrease the risk of clinical cardiotoxicity or CHF (OR
ACEIs). Late onset heart failure, typically reported in patients who had 0.21). Studies of other agents and their potential cardioprotective effects
received anthracyclines for malignancy as a child, responds poorly to when combined with anthracyclines showed no significant benefits
treatment and increases what is already a significant mortality of 30% (carvedilol, L-carnitine, amifostine).
to 60%. Given the above findings, the American Society of Clinical The antimetabolite agent fluorouracil (5-FU) is also well known for its
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Oncology recommends frequent cardiac monitoring for patients who cardiotoxic effects. Vasospasm has long been the suspected mechanism
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have received a cumulative doxorubin dose of 400 mg/m and strong of cardiac toxicity. Clinical manifestations reported include ST-segment
consideration for discontinuance of treatment in patients who demon- changes, heart failure, hypertension, hypotension, conduction distur-
strate clinical CHF or decline in LVEF below normal limits. 37 bances, and cardiac arrest. The majority of cardiac events reported
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TABLE 95-4 Cardiotoxicities
Cardiotoxicity Common Agents Treatment Comments
Cardiomyopathy Doxorubicin, daunorubicin, Diuretics, β-blockers, ACE-inhibitors • ∼7% incidence at maximal recommended cumulative dose
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epirubicin, mitoxantrone of 550 mg/m (≥900 mg/m for epirubicin)
2
• Risk decreased with mitoxantrone due to decreased generation of ROS
• Incidence increases with underlying cardiac risk factors and age
• Frequent cardiac monitoring for at-risk patients recommended
• Use of dexrazoxane may decrease incidence
• Prognosis more favorable if identified early and treated aggressively
Myocarditis/pericarditis Cyclophosphamide Supportive • May cause hemorrhagic myocarditis at high doses
Ischemia Fluorouracil (5-FU), taxanes Supportive; discontinue drug and later • Cardiac events reported within the first 72 hours after treatment with 5-FU
dosing schedule • Increased incidence in those with underlying cardiac risk factors
Arrhythmias Paclitaxel, rituximab Supportive; supplement electrolytes • Patients with underlying cardiac risk factors should be monitored during
as needed and after infusion of agent
Hypertension Bevacizumab, cisplatin Supportive; antihypertensive therapy • Systolic blood pressure greater than 220 mm Hg reported

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