【Guidelines Consensus】Expert Consensus on Anesthesia Management after Neoadjuvant Chemotherapy in Chinese Patients with Oncological Heart Disease (2021 Edition)

After neoadjuvant chemotherapy in Chinese patients with oncological heart disease

Expert Consensus on Anesthesia Management (2021 Edition)

Professional Committee of Tumor Anesthesia and Analgesia, Chinese Anti-Cancer Association

Abstract Neoadjuvant chemotherapy is systemic chemotherapy performed to reduce the mass and kill tumor cells as soon as possible before the application of local treatment (surgery or radiotherapy
).
However, neoadjuvant chemotherapy drugs can cause different degrees of damage to the heart, mainly manifested as myocardial ischemia, arrhythmias, arterial hypertension, myocardial dysfunction, and even heart failure, which has become an important risk factor for the perioperative period of subsequent tumor surgery, which may affect the operation and the safety
of the patient's life.
It is particularly important
for anesthesiologists to evaluate, actively prevent and treat patients with oncological heart disease during the perioperative period.
Therefore, the Tumor Anesthesia and Analgesia Professional Committee of the Chinese Anti-Cancer Association organized experts to formulate an expert consensus on the management of neoadjuvant chemotherapy anesthesia in Chinese patients with cancer heart disease (2021 edition), summarized clinical practice experience from the aspects of anesthesia method selection and perioperative cardiac function protection, and hoped to provide work guidelines
for Chinese anesthesia colleagues.

Key words Expert consensus neoadjuvant chemotherapy Patients with oncological heart disease Anesthesia management

doi:10.
12354/j.
issn.
1000-8179.
2022.
20211837 

Neoadjuvant chemotherapy (NAC) is systemic adjuvant chemotherapy for patients with locally advanced tumors, followed by surgery or radiotherapy
.
NAC has the advantages of shrinking tumors, reducing pathological staging of primary and metastatic lymph nodes, and early elimination of small metastases, which is conducive to subsequent surgical treatment and can provide an effective basis for chemotherapy sensitivity [1
].
However, studies have shown that NAC can directly or indirectly cause different degrees of damage to the heart, that is, cardiotoxicity, mainly manifested as myocardial ischemia, arrhythmias, arterial hypertension, myocardial dysfunction, and even heart failure [2-5], the above cardiotoxicity can even continue for several years after treatment [6].

The implementation of precise anesthesia combined with cardiac protection measures during surgery can ensure the smooth progress of the operation and help improve the long-term survival rate
of patients.
Therefore, the Tumor Anesthesia and Analgesia Professional Committee of the Chinese Anti-Cancer Association organized experts to formulate an expert consensus on the management of neoadjuvant chemotherapy in patients with cancer heart disease in China (2021 edition), summarized clinical practice experience from the aspects of anesthesia method selection and perioperative organ function protection, and hoped to provide work guidelines
for Chinese anesthesia colleagues.

NAC tumor therapies commonly used in clinical practice induce cardiotoxicity through a variety of complex mechanisms [7-8] (Table 1), including myocardial dysfunction and heart failure, coronary heart disease (CAD), arrhythmias (especially QT prolonged arrhythmias), arterial hypertension, and pericardial complications [9-10
].

1.
1 Common toxic effects of NAC drugs on the heart

Acute cardiotoxicity triggered by anthracycline antineoplastic drugs (ANT) appears several hours after administration, manifested by transient changes in cardiac electrophysiology and rhythm; Chronic toxicity usually occurs within 1 year of treatment with irreversible congestive heart failure and cardiomyopathy; Delayed toxicity may occur several years
after the end of chemotherapy.
5-fluorouracil (5-fluorouracil, 5-FU) cardiotoxicity is characterized by coronary vasospasm and angina, especially in patients with prolonged continuous intravenous injections can induce myocardial ischemia [11].

Cardiotoxicity caused by cyclophosphamide (CTX) often occurs within three weeks of first dose, with acute onset and dose-dependent [12
].
Taxol (TAX) is widely used in clinical practice, and studies have shown that TAX causes cardiotoxic reactions including asymptomatic bradycardia, arrhythmias, blood pressure fluctuations, acute myocardial infarction, heart failure, chronic cardiomyopathy, etc.
[13].

Cisplatin (DDP) can induce myocardial ischemia by procoagulation and vascular endothelial toxicity, causing arterial thrombosis [14
].
Advanced effects of DDP include left ventricular hypertrophy, ischemic cardiomyopathy, and myocardial infarction
.
vascular endothelial growth factor (VEGF) monoclonal antibodies and VEGF receptor tyrosine kinase inhibitors (VEGFR-TKI) can trigger left ventricular dysfunction (LVD), HF, Reversible cardiotoxicity such as arrhythmias [15-16].

Bevacizumab can cause severe hypertension and irreversible cardiac insufficiency in 1% to 3% of patients and increase the risk of arterial thromboembolic events (ATE) [17].

。 Clinical studies have shown that sunitinib can cause arterial hypertension, decreased left ventricular ejection fraction (LVEF), and heart failure, while reducing cardiomyocyte stress [18-19].

1.
2 Prevention of cardiotoxicity with NAC drugs

1.
2.
1 Control of risk factors At present, there are few effective drugs for the treatment of cardiotoxicity in the clinic, and the most effective way is to control the dose accumulation of chemotherapy drugs under the premise of effective tumor suppression, or reduce the peak concentration of drugs or use drugs
with less cardiotoxicity through multiple small doses 。 1.
2.
2 Application of cardioprotective drugs In clinical studies of breast cancer patients with ANT chemotherapy, angiotensin-converting enzyme inhibitors (ACEI) classes of drugs enalapril and non-selective β receptor blockers carvedilol can significantly improve LVEF decline and exert cardioprotective effects
。 In chemotherapy-induced hypertension, left heart dysfunction, or heart failure, ACE and dihydropyridine calcium channel blockers (amlodipine, felodipine) are recommended as first-line antihypertensive agents [20].

Statins (HMG-CoA reductase inhibitors) not only lower cholesterol, but also have antioxidant, anti-inflammatory effects, and reduce the risk of congestive heart failure [21].

Therefore, prophylactic use of statins may have a protective effect on cardiac function in patients receiving ANT chemotherapy [22].

The American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the diagnosis and treatment of chronic heart failure in adults state that dexproprioxane has a cardioprotective effect
in patients receiving ANT chemotherapy.
It is important to note that dexpropionimide can only prevent ANT cardiac toxicity and not ANT-induced heart failure and cardiomyopathy [23
].

2.
1 Pre-anesthesia evaluation

2.
1.
1 Detailed medical history The preoperative evaluation should focus on the patient's previous heart disease history, chemotherapy history, chemotherapy regimen and chemotherapy cycle, etc.
, which is conducive to the timely detection of potential or existing cardiovascular diseases and the improvement of the pre-intoxication assessment plan
.

2.
1.
2 Assess surgical and anesthesia risks Assess cardiac risk classification (table 2) and surgical risk in patients with non-cardiac surgery (table 2) according to ACC/AHA guidelines [26
].

Major adverse cardiovascular events (MACE) include cardiovascular death, myocardial infarction, and stroke 3 endpoint events
.

2.
1.
3 Physical status grading For patients with high cardiac risk, exercise equivalent testing is recommended (Figure 1
).
If the patient has a good physical status [metabolic equivalent (MET)≥10], exercise tests and cardiac imaging are not required; Patients with a high-risk cardiac risk but moderate to good physical status (MET 4 to 10) do not require further testing; Patients with high cardiac risk and poor physical status (MET<4) should undergo a noninvasive drug stress test and, if necessary, further investigation
.

2.
1.
4 Improve preoperative testing Patients with a high suspicion of cardiotoxic reactions should be actively tested, routinely performed at rest with a 12-lead ECG and, if necessary, echocardiography to evaluate LVEF[27] and local ventricular motomotor of the left ventricle [28], cardiac nucleo, cardiac biomarkers [15], such as natriuretic peptides and troponin I/T [29].

Panel Opinion: Patients with tumors with heart disease or risk factors for heart disease may follow the perioperative cardiac assessment and management protocol for patients with tumors (Figure 2).

2.
2 Preoperative medication management

2.
2.
1 β Receptor blockers Patients with ischemic cardiomyopathy who have taken β receptor blockers before surgery should continue to take conventional doses, including morning and perioperative periods, to reduce tachycardia and ischemia [30].

2.
2.
2 Statins It is recommended that patients who have already taken statins before surgery continue to take them perioperatively
.
Patients who intend to undergo vascular surgery may consider taking statins for more than
2 weeks before surgery.

2.
2.
3 Antiplatelet agents and anticoagulants For patients taking aspirin for cardiovascular disease, bleeding and potential cardiovascular risk need to be weighed, and routine discontinuation for 7 days is not recommended [31].

For patients with a high risk of bleeding, such as spine surgery and neurosurgery, or who are difficult to control after bleeding, discontinuation for more than 7 days before surgery [32].

Tigrellor or clopidogrel is discontinued for 5 days, and prasugrel can be performed
after 7 days of discontinuation.
Novel oral anticoagulants are reused
2 to 5 days after surgery.
Bridging therapy
is not recommended except for high-risk patients.

2.
2.
4 ACEI and angiotensin receptor blockers ACEI and angiotensin receptor blockers (ARB) may cause perioperative hypotension, and it is recommended to suspend the use in the
early operation.
If the patient has heart failure and left ventricular insufficiency, it can be continued on the basis of close observation
.
Patients with hemodynamic instability, insufficient blood volume, or acute elevation of creatinine require suspension of ACE and ARB medications
.

2.
2.
5 Other cardiovascular drugs Most long-term medications such as calcium channel blockers, digoxin and diuretics are recommended to continue on a perioperative basis
.

2.
3 Anesthesia management

2.
3.
1 Pre-anesthesia medication to avoid tachycardia and hypertension
caused by preoperative pain or anxiety.
Respiratory depression
should be avoided when midazolam is given 1 to 4 mg, or in the state of supervision, a low-dose opioid such as fentanyl 25 to 50 micrograms is given to relieve preoperative pain.
The elderly should use anticholine drugs and benzodiazepines with caution before surgery to reduce the incidence
of postoperative delirium.

2.
3.
2 Anesthesia method selection Anesthesia method selection should comprehensively consider surgical needs, patient wishes, as well as anesthesia and surgeon preferences, etc.
, and strive to minimize the impact on patients and comfort
.

1) General anesthesia: For surgical patients with poor cardiac function, complicated surgery, large bleeding volume and long time, tracheal intubation general anesthesia should be performed, and hemodynamic monitoring
such as invasive arterial pressure and central venous pressure should be improved.

2) Intraspinal anesthesia or ultrasound-guided regional nerve block complex General anesthesia: Studies have shown that epidural block analgesia or epidural block combined with general anesthesia can reduce the amount of anesthetic drugs and postoperative concurrency, and significantly optimize the immune function of tumor patients by alleviating stress response [33].

With advances in ultrasound technology, single or continuous nerve blocks can provide good analgesia, reduce opioid dosage, reduce the incidence of adverse reactions, and improve immunomodulatory function in patients with tumors [34].

2.
3.
3 Management of intraoperative anesthesia

The overall goal is to maintain myocardial oxygen supply and demand balance, ventilation and anesthesia depth moderate
.
Recommended monitoring items include noninvasive arterial blood pressure, electrocardiogram, oxygen saturation, end-expiratory carbon dioxide, body temperature, etc
.
Critically ill patients are advised to complete invasive arterial blood pressure monitoring prior to anesthesia induction, and if necessary, blood gas analysis, central venous pressure, and transesophageal ultrasound
.
Anesthesia Management for Tumor Surgery in Different Types of Heart Disease Strategies:

1) Hypertension: vascular endothelial damage and sodium retention caused by chemotherapy drugs can increase blood pressure in tumor patients
.
Anesthesia visits should ask about a history of chemoradiotherapy, hypertension (primary or secondary), and treatment options, and take different measures to maintain perioperative circulatory stability
.
Expert opinion: After the patient enters the room systolic blood pressure ≥ 180 mmHg and/or diastolic blood pressure ≥ 110 mmHg, it is recommended to use drugs such as midazolam for sedation, and after the blood pressure drops to a reasonable range, anesthesia
can be considered.

2) Ischemic heart disease:

(1) Stabilize heart rate: coronary blood flow perfusion is mainly in the diastolic period, so appropriately reducing the heart rate can prolong the ventricular diastolic period, improve myocardial oxygen supply, and help cardiac protection
.
When the center rate suddenly increases, the cause should be actively searched for and the heart rate
should be appropriately reduced after excluding factors such as bleeding, carbon dioxide accumulation, and shallow depth of anesthesia, and the use of β blockers (eg, esmolol, metoprolol) should be considered.

(2) Maintain blood pressure stability: violent fluctuations in circulation will lead to an imbalance in myocardial oxygen supply and demand, and aggravate myocardial ischemia
.
Pump injection of nitroglycerol (0.
1 to 4) micrograms/kg·min
may be considered in patients with hypertension who have persistently elevated intraoperative blood pressure or have manifestations of myocardial ischemia.
Anesthetic drugs and nitroglycerin dilate blood vessels lead to low blood pressure, and it is recommended to use phenylephrine (0.
1 to 2) μg/kg·min
in synergy.
Intraoperative mean arterial pressure (MAP) < 75 mmHg or diastolic blood pressure < 65 mmHg, should reduce the depth of anesthesia, speed up fluid infusion, and actively administer vasoactive drugs, such as phenylephrine (0.
1 to 2) μg / kg · min or ephedrine
。 ACEI and sepsis shock caused by peripheral vascular low resistance, severe and refractory hypotension, vasopressin (1 to 4) U/h and norepinephrine (0.
01 ~ 0.
3) μg / kg · min can effectively treat vascular paralysis
.

(3) Avoid hypoxia and carbon dioxide accumulation: reasonable ventilation management should be carried out according to the patient's situation to ensure adequate oxygen supply and avoid hypoxia and carbon dioxide accumulation
.
Excessive ventilation reduces arterial blood carbon dioxide partial pressure (PaCO2) and causes coronary constriction or spasms
.

(4) Sufficient arterial oxygen content: maintaining hemoglobin oxygen saturation (SpO2), arterial partial oxygen pressure (PaO2), and hemoglobin content (≥80 g/L) can maximize coronary blood oxygen content
within the normal range.

(5) Maintain normal body temperature: hypothermia and chills can increase myocardial oxygen consumption, reasonable control of indoor temperature during perioperative period, appropriate use of warm blankets, take liquid heating and other measures
.
Expert Group Opinion: Maintain reasonable anesthesia depth, maintain blood pressure within the base value ±20%, PaCO2 is maintained at 35 to 45 mmHg, and the patient's core body temperature is not less than 36 °C
.

3) Arrhythmias:

(1) Ventricular premature beats and ventricular tachycardia: patients with frequent ventricular premature beats and ventricular tachycardia should actively identify the causes, and it is recommended to improve the 24-hour kinetic electrocardiogram and echocardiography to correct electrolyte abnormalities, hypotension, myocardial ischemia and other causes
.
Especially for ventricular premature beats> patients with 10 000 beats/24 h should be actively adjusted after treatment adjustment, and then elective surgery
should be performed.

(2) Ventricular fibrillation: immediate cardiopulmonary resuscitation (CPR
).
Repeat defibrillation every 2 min, reasonably increasing energy, during which CPR
is sustained.
After the 2nd defibrillation, epinephrine is given intravenously 1 mg and can be repeated every 3 to 5 min
.
At the same time, the imbalance of water and electrolyte is corrected
.

(3) Atrial fibrillation: thoracic surgery is common, and the precipitating factors, control ventricular rate, control rhythm, and prevent thrombosis should be eliminated during anesthesia
.
Intraoperative atrial fibrillation treatment should be carried out under ECG and blood pressure monitoring, and the commonly used cardioversion drug amiodarone 75 to 150 mg is injected intravenously, followed by 1 mg/min continuous intravenous infusion, and the dosage does not exceed 2.
2 g for 24 hours
.
Rapid atrial fibrillation can be used to control the ventricular rate < 100 beats per minute
using esmolol and diltiazem.
If atrial fibrillation is significantly associated with hypotension, cardiogenic shock, or pulmonary edema, immediate electrical cardioversion is required to quickly restore sinus rhythm
.

(4) Bradycardia: severe bradycardia can lead to insufficient tissue perfusion, such as hypotension, changes in mental status, etc
.
Glycopyrronium bromide, atropine or ephedrine therapy, if necessary, percutaneous pacemaker or epinephrine and other potent positive time-changing drugs
.

(5) Q-T interval prolongation: Tumor treatment drugs that commonly cause Q-T interval prolongation include ondansetron and metoclopramide, which are also used for antiemetic therapy
after anesthesia.
Potential drug interactions should be identified preoperatively, electrolyte abnormalities should be actively corrected, and appropriate sedation should be performed
.
Intraoperative stabilization of blood pressure and heart rate, perioperative β receptor blockers for continued treatment
.
Ketamine, oxycodone, buprenorphine, ondansetron, haloperidol, gastric compound, atropine and other drugs
are contraindicated.

(6) Conduction block: for patients with complete left bundle branch block, active treatment of primary heart disease is required, and surgery is performed after stabilization; Patients with suspected sinus syndrome, second-degree atrioventricular block with hemodynamic changes, and third-degree AV block may consider isoproterenol or atropine tests after excluding myocardial ischemia and organic heart disease, and if the response is not optimal, a temporary or permanent pacemaker should be placed to pass the perioperative period
.
Use heart rate-lowering anesthetics with caution, such as refentanil, propofol and dexmedetomidine
.

2.
4 Postoperative management of patients with heart disease

2.
4.
1 Close monitoring Perioperative continuous monitoring of patients' vital signs, early detection of myocardial ischemia, arrhythmias, hypotension, prevention of myocardial infarction and other serious complications
。 If necessary, 12-lead electrocardiogram should be recorded continuously, the value of troponin should be measured 1 to 3 days after surgery, and the brain natriuretic peptide (BNP), the amino-terminal brain natriuretic peptide precursor (N-terminal pro-B-type natriuretic peptide, NTpro BNP) and bedside ultrasonography
should be measured in patients aged > 65 years.
Early postoperative recovery of preoperative related cardiovascular drug use
.

2.
4.
2 Pain management Based on the principle of multi-modal analgesia, a multidisciplinary management team such as anesthesia, oncology surgery and nursing is established to individualize the medication according to the specific situation of the patient, so as to achieve the best analgesic effect
.

Expert Group Comments:

Mild pain: peripheral nerve block and (or) local anesthetic incision infiltrates, acetaminophen or NSAIDs
.

Moderate pain: peripheral nerve block and (or) local anesthetic incision infiltration + acetaminophen or NSAIDs
.
Peripheral nerve blocks and (or) local anesthetic incision infiltrates + opioids; Epidural anesthetic compound opioid epidural analgesia (PCEA); Opioids + acetaminophen or nonsteroidal anti-inflammatory drugs
.

Severe pain: epidural local anesthetic complex opioid PCEA; Peripheral nerve blocks and (or) local anesthetic incision infiltrates + opioids; Peripheral nerve block and/or local anesthetic incision infiltration + opioids + acetaminophen or NSAIDs
.

In short, the anesthesia management of neoadjuvant chemotherapy in tumor patients requires the establishment of a multidisciplinary management team to predict and prevent possible cardiovascular complications that may occur in the patient's perioperative period, so as to achieve whole, effective and scientific management and treatment
.

Expert Consensus Committee Expert Group members (in alphabetical order of name)

Cao Hanzhong Nantong Cancer Hospital Cao Minghui Sun Yat-sen Memorial Hospital Sun Yat-sen Memorial Hospital Zeng Wei'an Guangzhou Sun Yat-sen University Cancer Prevention and Control Center Chen Lanren Anhui Provincial Cancer Hospital Fan Zhiyi Peking University Affiliated Cancer Hospital Fang Jun Zhejiang Provincial Cancer Hospital Gu Lianbing Jiangsu Provincial Cancer Hospital Han Fei Harbin Medical University Affiliated Cancer Hospital Huang Zeqing Liaoning Provincial Cancer Hospital Jia Huiqun Hebei Provincial Cancer Hospital Jia Zhen Affiliated Cancer Hospital of Qinghai Medical University Li Jincheng Tianjin Medical University Cancer Hospital Li Tianzuo Beijing Shijitan Hospital Affiliated to Capital Medical University Liu Hongliang Chongqing University Affiliated Cancer Hospital Lu Xihua Henan Provincial Cancer Hospital Miao Changhong Fudan University Affiliated Zhongshan Hospital Pan Linghui Guangxi Medical University Affiliated Cancer Hospital Qi Sihua The Fourth Affiliated Hospital of Harbin Medical University Sun Li Chinese Academy of Medical Sciences Cancer Hospital Shenzhen Hospital Wang Guonian The Fourth Affiliated Hospital of Harbin Medical University Wang Kun Tianjin Medical University Cancer Hospital Wang Zhonghui Yunnan Provincial Cancer Hospital Yang Jinfeng Affiliated Cancer Hospital of Xiangya Medical College of Central South University Zhang Qingong Shanxi Provincial Cancer Hospital Zhao Hongwei Tianjin Medical University Cancer Hospital Zheng Hui Chinese Academy of Medical Sciences Cancer Hospital Secretary Group Wang Liping Harbin Medical University Affiliated Cancer Hospital Chen Hong Harbin Medical University Affiliated Cancer Hospital Wang Yu Harbin Medical University Affiliated Cancer Hospital Chen Meijun Harbin Medical University Affiliated Cancer Hospital